阅读说明：本技术 醌化合物及其获得方法 (Quinone compound and method for obtaining same ) 是由 K·沙因-阿尔布雷希特 W·西格尔 于 2019-02-12 设计创作，主要内容包括：公开一种用于氧化至少一种色满化合物(C1)的方法,在包含至少两种溶剂的溶剂混合物中或在含C溶剂中,在铜催化剂存在下,用包含氧、基本上由氧组成或由氧组成的气态化合物氧化所述至少一种色满化合物,所述铜催化剂表现出氧化态(+1)或(+2)。本公开的再一个部分是一种组合物,其包含至少一种色满化合物(C1)和/或至少一种醌(C30),包含至少两种溶剂的溶剂混合物或含C溶剂,铜催化剂,包含氧、基本上由氧组成或由氧组成的气态化合物,所述铜催化剂表现出氧化态(+1)或(+2)。醌制剂及其制备方法也是本发明的一个部分。(Disclosed is a process for the oxidation of at least one chroman compound (C1) by oxidizing the at least one chroman compound with a gaseous compound containing, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C. Yet another part of the present disclosure is a composition comprising at least one chroman compound (C1) and/or at least one quinone (C30), a solvent mixture comprising at least two solvents or a C-containing solvent, a copper catalyst, a gaseous compound comprising, consisting essentially of, or consisting of oxygen, said copper catalyst exhibiting an oxidation state (+1) or (+ 2). Quinone formulations and methods of preparation are also part of the invention.)

1. A process for the oxidation of at least one chroman compound (C1),

wherein R1, R3, R4 and R5 are H or CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, and R6 is alkyl, alkenyl,

oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst, the copper catalyst exhibiting an oxidation state (+1) or (+ 2).

2. The method of claim 1, wherein the gaseous compound comprising, consisting essentially of, or consisting of oxygen is actively moved through the solvent mixture comprising at least two solvents or through the C-containing solvent.

3. The process according to claim 1 or 2, wherein the copper catalyst is used in the following amounts: an amount of 0.001 to 10 molar equivalents, preferably a stoichiometric or almost stoichiometric amount, even more preferably a substoichiometric amount, further preferably an amount of 0.01 to 0.75 molar equivalents, still further preferably an amount of 0.1 to 0.5 molar equivalents, further preferably an amount of 0.1 to 0.35 molar equivalents, and most preferably an amount of 0.11 to 0.25 molar equivalents, relative to the molar amount of the chroman compound (C1) used.

4. A process according to any one of claims 1 to 3, wherein the copper catalyst is a copper halide, preferably copper chloride, and most preferably CuCl₂。

5. The process according to any one of claims 1 to 4, wherein the copper catalyst is combined with at least one metal compound selected from the group consisting of: na, Li, K, Cs, Mg, Ca, Sr, Ba, Fe, Cr, Mn, Co, Ni, Zn, La, Ce, Pr, Nd compounds, preferably in combination with one metal halide of the aforementioned group, more preferably in combination with at least one metal chloride of said group, and most preferably with LiCl and/or MgCl ₂And (4) combining.

6. The method according to any one of claims 1 to 5, wherein the chroman compound (C1) is at least one of the group consisting of: alpha-tocopherol of formula (C3), (C4), (C5) and alpha-tocotrienol of formula (C12), (C13), (C14).

7. The method of any one of claims 1 to 6, wherein the solvent mixture comprising at least two solvents or the C-containing solvent does not contain any detergent.

8. The method according to any one of claims 1 to 7, wherein the at least two solvents in the solvent mixture comprise water and an organic solvent, preferably an organic solvent that is not miscible with water.

9. The method of claim 8, wherein the at least two solvents in the solvent mixture comprise as organic solvents:

at least one primary alcohol or

At least one secondary alcohol or

-a mixture of at least one primary alcohol and at least one secondary alcohol,

wherein the secondary alcohol is preferably an alcohol having at least six carbon atoms and more preferably having at least seven carbon atoms.

10. The method of claim 8 or 9, wherein the weight ratio of organic solvent to water is in the range of: 0.01:1 to 499:1, preferably 0.1:1 to 450:1, further preferably 0.4:1 to 350:1, still further preferably 1:1 to 300:1, in yet a further embodiment 1.1:1 to 200:1, in yet a further preferred variant 2.9:1 to 175:1, in another preferred embodiment 3.1:1 to 150:1, more preferably 4.3:1 to 100:1, still more preferably 5:1 to 70:1, still further preferably 6:1 to 31.4:1, more preferably 7:1 to 29:1, in yet a further improved embodiment 7.5:1 to 21.3:1, and in yet a further embodiment 7.9:1 to 19.6:1, still further preferably 10:1 to 17.4:1, further preferably 11.6:1 to 10.13: 1, and most preferably 10:1 to 13: 1.

11. A composition, comprising:

a) at least one chroman compound (C1),

wherein R1, R3, R4 and R5 are H or CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, and R6 is alkyl, alkenyl,

and/or at least one quinone (C30),

wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl;

b) a solvent mixture comprising at least two solvents or a solvent containing C;

c) a copper catalyst exhibiting an oxidation state (+1) or (+ 2);

d) a gaseous compound comprising, consisting essentially of, or consisting of oxygen;

the composition is preferably obtained by the method according to any one of claims 1 to 10.

12. The composition of claim 11, wherein the gaseous compound in the composition is in the form of gas bubbles in an amount of

Higher than the amount obtained when a) to c) are combined and stored in ambient air,

preferably higher than the amount obtained when combining a) to c) and stirring in ambient air.

13. A method for obtaining a quinone preparation, said method comprising the steps of:

i) removing a solvent from the solvent mixture comprising at least two solvents of the composition of claim 11 or 12, or removing the C-containing solvent of the composition of claim 11 or 12;

Optionally adding hydrochloric acid before or during the following operations

-removing a solvent from said solvent mixture or

-removing the C-containing solvent;

iia) distilling off the remaining solvent or solvents

iib) degassing the composition or

iic) distilling off the remaining solvent or solvents and degassing the composition;

iii) applying the composition of step iia), step iib), or step iic) to a separation device having a surface with a diameter greater than the height of the separation device;

iv) optionally subjecting the residue of step iii) to further distillation,

or

i) Removing a solvent from the solvent mixture comprising at least two solvents of the composition according to claims 11 to 12, or removing the C-containing solvent of the composition according to claims 11 or 12,

optionally adding hydrochloric acid before or during the following operations

-removing a solvent from said solvent mixture or

-removing the C-containing solvent;

iia) distilling off the remaining solvent or solvents

iib) degassing the composition or

iic) distilling off the remaining solvent or solvents and degassing the composition;

iii) subjecting the composition of step iia), step iib) or step iic) to a further distillation step;

iv) optionally subjecting the residue of step iii) to further distillation,

or

i) Removing a solvent from the solvent mixture comprising at least two solvents of the composition according to claims 11 to 12, or removing the C-containing solvent of the composition according to claims 11 or 12,

optionally adding hydrochloric acid before or during the following operations

-removing a solvent from said solvent mixture or

-removing the C-containing solvent;

iia) distilling off the remaining solvent or solvents

iib) degassing the composition; or

iic) distilling off the remaining solvent or solvents and degassing the composition;

iii) applying the composition of step iia), step iib) or step iic) to a separation column;

iv) optionally subjecting the residue of step iii) to further distillation.

14. The method of claim 13, wherein after step i), the method comprises:

ia) reducing the volume of a solvent removed from the composition according to claim 11 or 12 and/or;

ib) adding hydrochloric acid to said removed one solvent;

ic) storing or reinjecting the mixture obtained in step ia) or ib) for further use in the process according to at least one of claims 1 to 10,

Or

id) adding hydrochloric acid and/or to a solvent removed from the composition according to claim 11 or 12;

ie) reducing the volume of the mixture obtained in step id);

if) storing or re-injecting the mixture obtained in step id) or ie) for further use in the method according to at least one of claims 1 to 10.

15. The method of any one of claims 13 or 14, wherein the separation device or the separation column comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica.

16. The process according to claim 15, wherein the solid support, preferably silica, has:

-a particle size of 5 μm to 1000 μm, preferably 10 μm to 150 μm, more preferably 30 μm to 100 μm and most preferably 40 μm to 63 μm; and

-an average pore diameter of 1 to 100 nm.

17. The method of claim 15 or 16, wherein

-suspending the solid carrier in a suspending solvent or a mixture of suspending solvents selected from the group consisting of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulfoxide, formamide, dimethylformamide and water, preferably suspended in aliphatic hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane;

-applying the slurry thus obtained to the separation device or the separation column.

18. The method according to any one of claims 13 to 17, wherein the composition is applied after step iia), step iib) or step iic)

-dissolved or suspended in a diluting solvent or mixture of diluting solvents selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons, and most preferably in n-hexane, n-heptane or cyclohexane, and

-subjecting the diluted composition thus obtained to step iii).

19. The method of any one of claims 13 to 18, wherein

iii) after applying the composition of step iia), step iib) or step iic) to the separation device, the diameter of the surface of the separation device is greater than the height of the separation device, or

After applying the composition of step iia), step iib) or step iic) onto the separation column;

iiia) eluting impurities and by-products with a mixture of non-polar solvent and polar solvent in a volume ratio of 90:10 to 99:1, preferably 92:8 to 98:2 and most preferably 94:6 to 97: 3;

iiib) eluting the product with a mixture of non-polar solvent and polar solvent in a volume ratio of 60:40 to 85:15, preferably 70:30 to 82:18 and most preferably 75:25 to 80: 20;

iv) optionally subjecting the residue of step iiib) to further distillation,

or

iii) after applying the composition of step iia), step iib) or step iic) to the separation device, the diameter of the surface of the separation device is greater than the height of the separation device, or

After applying the composition of step iia), step iib) or step iic) onto the separation column;

iiia) eluting the product with a mixture of non-polar solvent and polar solvent in a volume ratio of 60:40 to 85:15, preferably 70:30 to 82:18 and most preferably 75:25 to 80: 20;

iiib) eluting impurities and by-products with a mixture of non-polar solvent and polar solvent in a volume ratio of 90:10 to 99:1, preferably 92:8 to 98:2 and most preferably 94:6 to 97: 3;

iv) optionally subjecting the residue of step iiia) to further distillation.

20. The method of claim 19, wherein

-the non-polar solvent is at least one of heptane or cyclohexane,

-the polar solvent is at least one of isopropyl acetate or ethyl acetate, and

-the mixture of non-polar solvent and polar solvent comprises at least one polar solvent and at least one non-polar solvent.

21. A quinone preparation preferably obtained by the method according to any one of claims 13 to 20, comprising:

A)90 to 100 wt.% quinone (C30), preferably 94 to 100 wt.% quinone (C30), more preferably 96 to 100 wt.%, even more preferably >96 to 100 wt.%, still further preferably 98 to 100 wt.% and most preferably 100 wt.% minus the amount of components B) to D) defined below;

wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl;

B)0.0001 to 9999/1000ppm of Cu, preferably 0.0001 to 2999/1000ppm of Cu;

C)0.0001 to 100ppm of organic chlorine, preferably 4 to 78 ppm;

D) the trace components are mixed and stirred to prepare the micro-emulsion,

wherein the minor components are all chemical entities other than those mentioned under A), B) and C), in amounts of up to 10% by weight minus the amounts of components B) and C),

preferably, the minor components are all chemical entities other than those mentioned under A), B) and C), in amounts of up to 6% by weight minus the amounts of components B) and C),

further preferably, the minor components are all chemical entities other than those mentioned under A), B) and C), in amounts of up to 4% by weight minus the amounts of components B) and C),

still further preferably, the minor components are all chemical entities other than those mentioned under A), B) and C), in amounts up to a value of less than 4% by weight minus the amounts of components B) and C),

still further preferably, the minor components are all chemical entities other than those mentioned under A), B) and C), in amounts of up to 2% by weight minus the amounts of components B) and C), and

most preferably, the minor components are all chemical entities other than those mentioned under A), B) and C),

In a first embodiment, in an amount of at most 300ppm,

in a second embodiment, in an amount of at most 200ppm,

in a third embodiment, in an amount of up to 100ppm,

and the sum of A) to D) adding up is 100% by weight.

22. Use of the quinone preparation preferably as claimed in claim 21 in animal nutrition or as a dietary supplement or as a beverage additive.

The quinone compounds of the prior art are obtained either by reduction of the corresponding carboxylic acid, ester or amide or by oxidation of an alcohol or ether. However, the main disadvantage of these reactions is that the formation of by-products cannot be avoided or inhibited to a large extent, thus making the synthesis on an industrial scale expensive and laborious. Some reactions of the prior art require and consume catalyst, requiring constant make-up of catalyst. At the same time, the spent catalyst will be disposed of luxuriously. Furthermore, simple molecules exhibit different behavior upon oxidation or reduction compared to more complex entities, i.e. the reaction conditions used with these simple compounds cannot be transferred directly to reactions starting from more complex compounds.

Attempts have been made to convert alpha-tocopherol to the corresponding alpha-tocopherolquinone. However, these attempts have several drawbacks and are not suitable for use on an industrial scale.

Nagata et al (Chem. pharm. Bull.), 48(1)71-76(2000)) attempted to react α -tocopherol (0.1mmol) with gaseous oxygen in the presence of 1 to 5 micromoles of a metal salt selected from the group consisting of CuSO and CuSO in distilled water containing a solubilizing agent₄(NH₄)₂SO₄、Cu(ClO₄)₂、Fe(ClO₄)₃、Ni(ClO₄)₂、Co(ClO₄)₂And Mn (ClO)₄)₂(see procedure). The solubilizer is selected from the following detergents: sodium Deoxycholate (DOC), sodium Cholate (CO), Sodium Dodecyl Sulfate (SDS), dodecyl trimethyl ammonium bromide (C12-TBr), tetradecyl trimethyl ammonium bromide (C14-TBr), hexadecyl trimethyl ammonium bromide (C16-TBr), chenodeoxycholic acid sodium (ChenoDOC), ursodeoxycholic acid sodium (UDOC), taurodeoxycholic acid sodium (TDOC), taurochenodeoxycholate sodium (TchenoDCO), taurocholic acid sodium (TCO), tauroursodeoxycholic acid sodium (TUDOC), stearyl trimethyl ammonium bromide (C18-TBr).

Under these conditions, "Cu" was found²⁺The ion isThe most effective catalyst for the formation of 5-formyl-7, 8-dimethyltocopherol (5-FDT), but not α -tocopherolquinone ". moreover, it was found that all the metal ions used above accelerate the formation of 5-FDT to a greater or lesser extent, while the yield of α -tocopherolquinone (α -TQ) remains low (see page 71, results) ²⁺、Mn²⁺、Fe³⁺、Ni²⁺Or in the absence of any metal catalyst, in Cu²⁺In the presence of (A), the consumption of α -tocopherol is very low, and when Co is used with²⁺Or Fe³⁺The formation of α -tocopherolquinone is moderate in relation to the reaction effected as a metal ion (see fig. 1)²⁺Cannot be considered as a good catalyst for the selective oxidation of α -tocopherol to α -tocopherolquinone.

Furthermore, the amount of unreacted α -tocopherol is rather high without the use of solubilizers (i.e., detergents), i.e., the solubilizers are mandatory, thus complicating the reaction conditions²⁺To promote the formation of α -tocopherolquinone in preference to the formation of 5-FDT (see figure 1, page 73, left column, figure 2, next row, right), thus making the reaction conditions very specific it was also observed that the reaction rate is hindered at high concentrations of solubilising agent (see page 72, left column), which requires precise dosing regimes and would make the industrial process time consuming, more complex and therefore expensive.

In any oxidation reaction effected by Nagata et al, at least two products are formed, of which 5-FDT is in most cases the predominant one. More products are likely to be observed, that is, copper mediated oxidation of tocopherols, as disclosed by Nagata et al, does not allow one skilled in the art to achieve clean or reasonably clean tocopherolquinone in high yields and short reaction times, which are a prerequisite for industrial production processes.

Another attempt to oxidize α -tocopherol to α -tocopherol quinone is disclosed in WO2011139897 a2, which will oxidize 0.1 on a shaker at ambient temperatureg (0.23mmol) of pure α -tocopherol and 0.1g of CuCl₂(0.74mmol) were incubated in 10ml of methanol for 24 hours (see page 9, line 12) or ten times the amount of α -tocopherol and CuCl were incubated on a shaker at room temperature₂Incubate for 12 hours in 10ml methanol (see page 12, line 15, page 15, line 4).

Likewise, the process disclosed in the' 897 publication also suffers from the disadvantage that α -tocopherolquinone cannot be provided in high yield and purity (see page 12, line 23 "chromatogram (b) showing the formation of oxidation products, including the major compounds identified by HPLC (high performance liquid chromatography) as TQ, by comparing their retention time with that of commercial α -TQ obtained under the same conditions" and page 15, line 14 "chromatogram (b) in FIG. 8 shows CuCl ₂Complete oxidation of TOH to TQ and other unidentified products "). however, in curve b of fig. 3, the peak corresponding to α -tocopherolquinone is far from the dominant one, instead, substantial peaks can be observed between 3 and 4 minutes, in addition to other earlier elution peaks, as is the case for curve b in fig. 8, if it is considered that the product sample before HPLC analysis has been subjected to a first purification step (i.e. filtration on a 0.2 μm nylon filter), these results seem to be even more disadvantageous (see page 9, line 15, page 12, line 19), even obtaining so many by-products after the first and second chromatographic steps (i.e. after two successive purification steps) that a series of complementary purification steps is required to achieve α -tocopherolquinone of high purity, thus making the synthesis of said α -tocopherolquinone according to the method of the' 897 publication laborious and expensive.

It seems to be difficult to properly and selectively oxidize chroman compounds (chroman) to the corresponding quinones and especially α -tocopherol to α -tocopherolquinone, which can also be seen in Ito et al publication (tetrahedron lett, 24(47), 5249-5252(1983)) it was observed that high yields can only be obtained by oxidation of the small entity 2,3, 6-trimethylphenol 1 to the corresponding quinones by hydrogen peroxide in the presence of ruthenium chloride as catalyst Is then that high and can only use RuCl₃x3H₂O as a catalyst (similarly, model compounds of vitamin E)4Can be easily converted into the corresponding quinone in a yield of 80%5First, one skilled in the art cannot transfer the teachings of oxidizing small molecules with a catalyst to larger entities exhibiting very different solubility patterns, second, with molecules that mimic the starting material α -tocopherol, even with RuCl₃x3H₂The yield of O as a catalyst does not exceed 80%. For industrial processes, this remains to be improved. Furthermore, RuCl₃x3H₂O is a fairly expensive catalyst that would make the production of chroman compounds by oxidation costly and unacceptable as an industry standard.

It is therefore an object of the present invention to overcome the disadvantages of the prior art and to devise a process for the selective oxidation of chroman compounds to the corresponding quinone compounds. The process should avoid the production of by-products as far as possible. The quinone compound formed should contain only small amounts, if any, of the reagents of the process of the invention or components thereof. The method should be fast, cost effective and easy to implement. The process should be such that it can be carried out industrially and scaled up accordingly. Cleaning, separation or purification steps should be minimized and preferably avoided altogether.

It is another object of the present invention to provide a composition containing at least one chroman compound adapted to be converted or to be converted into a composition containing the corresponding quinone or quinones. The object therefore also comprises a composition containing at least one quinone obtained from a composition containing chroman compounds by the process for the selective oxidation of chroman compounds according to the invention.

A further object of the invention is a method for obtaining quinone preparations. The method should be easy to implement and therefore cost-effective. It should be applicable to any type of composition containing at least one quinone obtained from the process for the selective oxidation of chroman compounds. The method for obtaining the quinone preparation should enable the skilled person to influence the concentration of the different components in the composition containing at least one quinone simultaneously. In other words, the method of obtaining the quinone preparation should be designed to enable the skilled person to tailor the amount of trace components (e.g., the inventive method reagents or components thereof) in the quinone preparation. In one embodiment, the method of obtaining the quinone preparation should be developed to recover or recycle the components or trace components in a purity sufficient to allow their reuse in a process for selective oxidation of chroman compounds.

It is another object of the present invention to provide a quinone preparation. The quinone preparation should be adapted to meet the purity and trace spectrum requirements required by the feed, dietary supplement or pharmaceutical industry. The requirements for purity and reduced amounts of trace compounds should also take into account traces of the reagents or metabolites thereof of the process of the invention.

All these objects can be solved by a process for the oxidation of at least one chroman compound C1,

wherein R1, R3, R4 and R5 are H or CH₃R2 is OH, OAc, OCO-C₁-C₁₈-an alkyl group and R6 is an alkyl group, an alkenyl group, the at least one chroman compound is oxidized with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C.

As can be seen from the examples below, high yields of quinone C30 can be obtained by this method, while reducing or completely suppressing the amount of by-products. No significant peaks were observed as observed in figures 3 and 8 of the' 897 paper, thus making the process simple, straightforward and cost-effective. No solubilizers (detergents) as required by Nagata et al in the aqueous reaction solution are required anymore. This makes the process of the present invention less complex and prevents the formation of by-products such as 5-FDT (as disclosed by Nagata et al). Due to its simplicity, the process of the present invention can be easily scaled up and used on an industrial scale.

In the present disclosure, chroman compound C1 (also referred to as 2, 3-dihydro-4H-benzopyran or 3, 4-dihydro-2H-1-benzopyran) is understood to be at least one molecule of formula C1,

wherein R1, R3, R4 and R5 are H or CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, and R6 is alkyl, alkenyl.

Alkyl is C₁₀-C₂₀-alkyl, preferably C₁₄-C₁₈-alkyl and most preferably C₁₆Alkyl, i.e. an entity comprising a given number of carbon atoms.

In one embodiment, alkyl groups with respect to R6 are understood to have the structure of formula C2,

wherein the stereogenic centers in positions 4, 8 have a 4R, 8R-configuration, a 4R, 8S-configuration, a 4S, 8R-configuration or a 4S, 8S-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopherol of formula C3,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopherol of formula C4,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl and the stereocentre at C2 of the cyclic moiety and the stereocentres at positions 4, 8 of the side chains have the R-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopherol of formula C5,

wherein R1, R3, R4 and R5 are CH₃R2 is OH and has the R-configuration at the stereocenter at C2 of the ring moiety and the stereocenters at positions 4, 8 of the side chain.

In one embodiment, the chroman compound C1 is a beta-tocopherol of formula C6,

wherein R1, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, R3 is H, the stereocenter at position 4, 8 of the side chain has 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration, and the stereocenter at C2 of the ring moiety has R or S configuration.

In one embodiment, the chroman compound C1 is a gamma-tocopherol of formula C7,

wherein R1 is H, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a-tocopherol of formula C8,

wherein R1 and R3 are H, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

Alkenyl means C₁₀-C₂₀-alkenyl, preferably C₁₄-C₁₈-alkenyl and most preferably C₁₆Alkenyl, i.e. an entity comprising a given number of carbon atoms and having at least one double bond.

In one embodiment, alkenyl is understood to have the structure of formula C9,

wherein the methyl groups in positions 4, 8 have:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, alkenyl is understood to have the structure of formula C10,

wherein the stereogenic centers in positions 4, 8 have a 4R, 8R-configuration, a 4R, 8S-configuration, a 4S, 8R-configuration or a 4S, 8S-configuration.

In one embodiment, alkenyl is understood to have the structure of formula C11,

wherein the stereogenic centers in positions 4, 8 have a 4R, 8R-configuration, a 4R, 8S-configuration, a 4S, 8R-configuration or a 4S, 8S-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocotrienol of formula C12,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-an alkyl group having R or S configuration at the stereocentre at C2 of the ring moiety and the methyl group at the exocyclic position 4, 8 having:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocotrienol of formula C13,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-an alkyl group and the stereocentre at C2 of the ring moiety has the R configuration and the methyl group at the exocyclic position 4, 8 has:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocotrienol of formula C14,

wherein R1, R3, R4 and R5 are CH₃R2 is OH and has the R-configuration at the stereocenter at C2 of the ring moiety and the methyl group at the exocyclic position 4, 8 has:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is a beta-tocotrienol of formula C15,

wherein R1, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, R3 is H, the stereocentre at C2 of the ring moiety has R or S configuration, and the methyl group at the exocyclic position 4, 8 has:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is a gamma-tocotrienol of formula C16,

wherein R1 is H, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-an alkyl group having R or S configuration at the stereocentre at C2 of the ring moiety and the methyl group at the exocyclic position 4, 8 having:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

The 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is a-tocotrienol of formula C17,

wherein R1 and R3 are H, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-an alkyl group having R or S configuration at the stereocentre at C2 of the ring moiety, andthe methyl groups in the exocyclic positions 4, 8 have:

4 cis-form and 8 cis-form-configuration,

4 cis-form, 8 trans-form-configuration,

4 trans, 8 cis-configuration, or

4 trans-form and 8 trans-form configuration,

and the double bonds in the exocyclic positions 3 and 7 have:

the 3E, 7E-configuration,

the 3E, 7Z-configuration,

3Z, 7E-configuration, or

3Z, 7Z-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopheryl monoalkenol of formula C18,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopheryl monoalkenol of formula C19,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl and the stereocentre at C2 of the cyclic moiety and the stereocentres at positions 4, 8 of the side chains have the R-configuration.

In one embodiment, the chroman compound C1 is an alpha-tocopheryl monoalkenol of formula C20,

wherein R1, R3, R4 and R5 are CH₃R2 is OH and has the R-configuration at the stereocenter at C2 of the ring moiety and the stereocenters at positions 4, 8 of the side chain.

In one embodiment, the chroman compound C1 is a beta-tocopheryl monoalkenol of formula C21,

wherein R1, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, R3 is H, the stereocenter at position 4, 8 of the side chain has 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration, and the stereocenter at C2 of the ring moiety has R or S configuration.

In one embodiment, the chroman compound C1 is a gamma-tocopheryl monoalkenol of formula C22,

wherein R1 is H, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a-tocopheryl monoalkenol of formula C23,

wherein R1 and R3 are H, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a marine-derived alpha-tocopherol (alpha-MDT) of formula C24,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a marine-derived alpha-tocopherol (alpha-MDT) of formula C25,

wherein R1, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl and the stereocentre at C2 of the cyclic moiety and the stereocentres at positions 4, 8 of the side chains have the R-configuration.

In one embodiment, the chroman compound C1 is a marine-derived alpha-tocopherol (alpha-MDT) of formula C26,

wherein R1, R3, R4 and R5 are CH₃R2 is OH and has the R-configuration at the stereocenter at C2 of the ring moiety and the stereocenters at positions 4, 8 of the side chain.

In one embodiment, the chroman compound C1 is a marine source of beta-tocopherol (beta-MDT) of formula C27,

wherein R1, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, R3 is H, the stereocenter at position 4, 8 of the side chain has 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration, and the stereocenter at C2 of the ring moiety has R or S configuration.

In one embodiment, the chroman compound C1 is a marine-derived gamma-tocopherol (gamma-MDT) of formula C28,

wherein R1 is H, R3, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a marine source of formula C29-tocopherol (-MDT),

wherein R1 and R3 are H, R4 and R5 are CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkyl, the stereocenter at position 4, 8 of the side chain having 4R,8R-, 4R,8S-, 4S, 8R-or 4S, 8S-configuration and the stereocenter at C2 of the ring moiety having R or S configuration.

In one embodiment, the chroman compound C1 is a mixture of at least two of embodiments C3, C4, C5, C6, C7, C8, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29.

In one embodiment, the solvent mixture of the present invention comprising at least two solvents is a solvent mixture made from a polar solvent and a non-polar solvent.

In a preferred embodiment, the solvent mixture comprising at least two solvents is a mixture of water and another solvent. The further solvent is selected from the group: alcohols, glycols, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, glycol ethers, polyethers, polyethylene glycols, ketones, esters, amides, nitriles, halogenated solvents, carbonates, dimethyl sulfoxide and sulfolane.

In a further refinement, the further solvent is hardly mixed with water, preferably not mixed with water at all.

The term alcohol in the present invention includes at least one primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms.

The at least one preferably saturated primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, tert-butanol, all isomeric forms of pentanols, for example 1-pentanol or n-pentanol, 3-methylbutan-1-ol or isopentanol, 2-methyl-1-butanol, 2-dimethylpropan-1-ol, 2-pentanol, 3-methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, all isomeric forms of hexanols, for example 1-hexanol or n-hexanol, cyclohexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 4-methyl-1-pentanol, 2-dimethyl-1-butanol, butanol, 1, 3-dimethyl-1-butanol, 2, 3-dimethyl-1-butanol, 3-dimethyl-1-butanol, 2-ethylbutan-1-ol, 2-hexanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 3-dimethyl-2-butanol, 2-methyl-2-pentanol, 3-methylpentan-3-ol, 2, 3-dimethyl-2-butanol, methylcyclopentanol, all isomeric forms of heptanol, such as 1-heptanol, 2-heptanol, 3-ethyl-3-pentanol, all isomeric forms of octanol, such as 1-octanol, 2-dimethyl-1-butanol, 3-pentanol, 3-dimethyl-2-pentanol, 3-dimethyl-2-pentanol, 4-methyl-2-pentanol, 2-octanol, 2-ethylhexanol, 1-nonanol, 1-decanol, 2-ethyl-1-hexanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol.

Higher primary, secondary or tertiary alcohols show less sensitivity to ignition, which is preferred for the process of the invention working with or at gaseous compounds comprising or consisting of oxygen. In addition, it is hardly mixed with water or not mixed with water at all, so that it can be easily separated from the aqueous solution portion.

Thus, in a preferred embodiment of the present invention, an alcohol is understood to be at least one primary, secondary or tertiary alcohol having from 5 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 5 to 18 carbon atoms.

In another preferred embodiment of the invention, the alcohol is understood to be at least one primary, secondary or tertiary alcohol having from 6 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 6 to 18 carbon atoms.

For ease of availability, the alcohol is at least one primary, secondary or tertiary alcohol having from 5 to 8 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 5 to 8 carbon atoms.

Availability reveals that the alcohol is at least one, preferably saturated, primary, secondary or tertiary alcohol selected from the group consisting of: 1-pentanol, 1-hexanol or hexanol, 2-ethylhexanol, 3-heptanol, 2-octanol, 3-ethyl-3-pentanol, 1, 3-dimethylbutanol or pentylmethanol, diacetone alcohol, methyl isobutyl methanol or 4-methyl-2-pentanol, tert-hexanol, cyclohexanol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol or 2, 3-dimethyl-2, 3-butanediol, 1,2, 5-hexanetriol, 1,2, 6-hexanetriol, trimethylolpropane.

Another aspect of the present process focuses on the small amounts of the inventive process reagents or components thereof associated with the quinones formed. This can be facilitated or achieved by using a particular type of alcohol. Thus, in a preferred embodiment of the present invention, an alcohol is understood to be at least one secondary or tertiary alcohol having from 5 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having from 5 to 18 carbon atoms.

A valuable embodiment of the present invention is therefore a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein the solvent mixture comprising at least two solvents is a mixture of water and at least one primary, secondary or tertiary alcohol having from 5 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having from 5 to 18 carbon atoms.

Thus, a further elaborated and valuable embodiment of the invention is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein the solvent mixture comprising at least two solvents is a mixture of water and at least one secondary or tertiary alcohol having 5 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having 5 to 18 carbon atoms.

The diols in the present disclosure are understood to be at least one compound selected from the following group: 1, 2-ethanediol or ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 2, 3-butanediol, 1, 3-butanediol, 2-methyl-1, 2-propanediol, 1, 4-butanediol, 1, 2-pentanediol, 1, 3-pentanediol, 1, 4-pentanediol, 1, 5-pentanediol, 2-dimethyl-3-propanediol, 3-methyl-2, 4-pentanediol, 4-hydroxy-4-methyl-2-pentanol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol, and mixtures thereof, 2, 3-dimethyl-2, 3-butanediol, diethylene glycol, triethylene glycol, glycerol, 1, 2-butanediol, 1,2, 3-butanetriol, 1,2, 4-butanetriol and 2-methyl-2, 3-butanediol.

Aliphatic hydrocarbons in the present disclosure are understood to be selected from the group consisting of: n-pentane, isopentane, neopentane, n-hexane, all isomeric forms of hexane, n-heptane, all isomeric forms of heptane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, all isomeric forms of octane, all isomeric forms of nonane, all isomeric forms of decane, all isomeric forms of undecane, all isomeric forms of dodecane, polyethylene, and nitromethane.

Aromatic hydrocarbons within the context of the present disclosure are understood to be selected from the group consisting of: benzene, toluene, all isomeric forms of xylene (e.g., ortho-, meta-, or para-xylene), ethylbenzene, 1,3, 5-trimethylbenzene, cumene, all isomeric forms of diisopropylbenzene, 2-isopropyltoluene, 3-isopropyltoluene, 4-isopropyltoluene, and nitrobenzene.

Ethers within the context of the present disclosure are understood to be selected from the group: dimethyl ether, diethyl ether, di-n-propyl ether, diisopropyl ether, methyl ethyl ether, dibutyl ether, diamyl ether, diisoamyl ether, n-butyl methyl ether, sec-butyl methyl ether, tert-butyl ethyl ether, methyl isobutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 3-methyl tetrahydrofuran, 2, 5-dimethyl tetrahydrofuran, 1, 3-dioxolane, tetrahydropyran, 1, 4-dioxane, 1,3, 5-trioxane, benzyl ethyl ether, cyclopentyl methyl ether, and anisole.

Glycol ethers or polyethers within the context of the present disclosure are understood to be selected from the following group: dimethoxymethane, diethoxymethane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoisopropyl ether, dipropylene glycol, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol diacetate, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, tetramethylene glycol dimethyl ether, polyethylene glycol, 2-methoxy-1-propanol.

Ketones within the context of the present disclosure are understood to be selected from the group: acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, diisopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone, methyl tert-butyl ketone, 2-pentanone, cyclopentanone, 2-hexanone, cyclohexanone, 2-heptanone, 4-heptanone.

Esters within the context of the present disclosure are understood to be selected from the group consisting of: methyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, hexyl acetate, methyl propionate, gamma-butyrolactone, ethyl benzoate, ethylene glycol diacetate, and diethylene glycol diacetate.

Within the context of the present disclosure, an amide is understood to be selected from the group consisting of: n-methylformamide, N-dimethylformamide, N-methylacetamide, N-dimethylacetamide, N-diethylacetamide, N-dimethylpropionamide, N-dibutylformamide and N-methylpyrrolidone.

Nitriles within the context of the present disclosure are understood to be selected from the group: acetonitrile, propionitrile, benzonitrile and trimethylacetonitrile.

Halogenated solvents within the context of the present disclosure are understood to be selected from the group consisting of: dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethylene, 1, 2-dichloroethane, 1,1,1, -trichloroethane, 1,1,1, 2-tetrachloroethane, 1,1,2, 2-tetrachloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, 1,2, 3-trichlorobenzene, 1,2, 4-trichlorobenzene, 4-chlorotoluene, trichloroacetonitrile, 2-chloroethanol, 2,2, 2-trichloroethanol, 1-chloro-2-propanol, 2, 3-dichloropropanol, all isomeric forms of 2-chloro-1-propanol, trichlorotoluene, fluorobenzene, all isomeric forms of difluorobenzene, 2,4, 6-trifluorotoluene, 2-fluorobutanol, trifluorotoluene.

Carbonates within the context of the present disclosure are understood to be selected from the following group: ethylene carbonate, propylene carbonate, dimethyl carbonate or diethyl carbonate.

The C-containing solvent of the process of the invention is any solvent which is adapted to dissolve to a large extent or completely all of the reagent chroman compound C1, the gaseous compound comprising, consisting essentially of or consisting of oxygen, and the copper catalyst. Such C-containing solvents should be both hydrophilic and lipophilic.

Such a C-containing solvent is at least one selected from the group consisting of: low aliphatic alcohols, i.e. at least one C1-C8-alcohol selected from the group comprising C1-C8 diols and C1-C8 triols, N-dimethylformamide, N-diethylformamide, N-methylpyrrolidone, ethylene carbonate, propylene carbonate, glycol ethers.

C1-C8 alcohols are selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, 1-pentanol, isopentanol, 2-methyl-1-butanol, neopentyl alcohol, 2-pentanol, 3-methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, n-hexanol (1-hexanol), 2-methyl-1-pentanol, 3-methyl-1-pentanol, 4-methyl-1-pentanol, 2-dimethyl-1-butanol, 2, 3-dimethyl-1-butanol, 3-dimethyl-1-butanol, 2-ethylbutan-1-ol, 2-hexanol, 3-hexanol, 3-methyl-2-pentanol, all isomeric forms of 4-methyl-2-pentanol, 3-dimethyl-2-butanol, 2-methyl-2-pentanol, 3-methylpentan-3-ol, 2, 3-dimethyl-2-butanol, cyclohexanol, methylcyclopentanol, 1, 3-dimethylbutanol, pentylmethanol, methylisobutylmethanol, 4-methyl-2-pentanol, tert-hexanol, n-heptanol, 2-heptanol, 3-ethyl-3-pentanol, n-octanol or 1-octanol, 2-ethylhexanol, 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 2-methyl-1, 2-propanediol, 1, 4-butanediol, 1, 2-pentanediol, 1, 3-pentanediol, 1, 4-pentanediol, 1, 5-pentanediol, 2, 4-pentanediol, 2-dimethyl-1, 3-propanediol, 3-methyl-2, 4-pentanediol, 4-hydroxy-4-methyl-2-pentanol, 1,2, 4-trihydroxybutane, 1,2, 3-trihydroxybutane, triethylene glycol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol, 2, 3-dimethyl-2, 3-butanediol, 1,2, 5-hexanetriol, 1,2, 6-hexanetriol, 2-methyl-2, 3-butanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, 2-ethoxyethanol, ethylene glycol monobutyl ether, 2-isopropoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol diacetate, propylene glycol, 1, 2-butanediol, triethylene glycol, glycerol, ethylene glycol diacetate and diethylene glycol diacetate, 2-methoxy-1-propanol.

Glycol ethers are, for example, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dipropylene glycol, 1, 3-propanediol dimethyl ether, 1, 3-propanediol diethyl ether, triethylene glycol dimethyl ether.

The gaseous compound in the present invention is any compound that meets the requirement of being gaseous at the reaction temperature of the process of the present invention and containing at least one oxygen atom. In one embodiment, the gaseous compound is selected from the group consisting of: singlet or triplet oxygen, ozone, air, lean gas, gaseous superoxide, gaseous peroxides, mixtures of inert gases and oxygen (the amount of oxygen is from 1% to 100% by volume, including mixtures of oxygen and nitrogen), which are preferably selected from air, lean gas and triplet oxygen, and most preferably from air and lean gas.

The copper catalyst exhibiting the oxidation state (+1) or (+2) is any sulfur-type or halogen-type copper compound. The copper catalyst of the present invention is selected from the group consisting of: CuCl₂x2H₂O (CAS No.:10125-13-0)；CuCl₂(CAS number 7447-39-4); CuCl (CAS number: 7758-89-6); CuCl₂x2H₂O in combination with LiCl (CAS number: 7447-39-4) or with LiClx2H₂O (CAS number: 10125-13-0) combination; CuCl₂x2H₂O and MgCl₂(CAS number: 7786-30-3) or with MgCl ₂x6H₂O (7791-18-6) combination; CuSO₄x5H₂O (CAS number: 10257-54-2); cu (II) trifluoromethanesulfonate (CAS number: 34946-82-2); CuBr (CAS number: 7787-70-4); CuBr₂(CAS number: 7789-45-9); CuI (CAS number: 7681-65-4); CuI₂(CAS number: 13767-71-0); cu (NO)₃)₂(CAS number: 3251-23-8); cu (NO)₃)₂x3H₂O (CAS number: 10031-43-3); cu (NO)₃)₂x6H₂O (CAS number: 13478-38-1); cu (NO)₃)₂x2.5H₂O (CAS number: 19004-19-4); cu (OH)₂(CAS number: 20427-59-2); cu (ClO)₄)₂x6H₂O (CAS number: 10294-46-9); cu (NH)₃)₄SO₄xH₂O (CAS number: 10380-29-7); cu (II) (OAc)₂(CAS number: 142-71-2); cu (II) (OAc)₂,xH₂O (CAS number: 6046-93-1); m_l(Cu(II)_mX_n)_pWherein M is an alkali metal comprising one of Li, K, Rb, Cs or ammonium, cu (ii) is divalent copper, X is a halogen atom selected from chlorine, bromine or iodine, l is an integer from 1 to 3, M is 1 or 2, n is an integer from 3 to 8, p is 1 or 2, and l +2mp ═ np.

In yet another embodiment, said copper catalyst exhibiting an oxidation state (+1) or (+2) is understood to be at least one of the following compounds: CuCl₂x2H₂O (CAS number: 10125-13-0); CuCl₂(CAS number: 7447-39-4); CuCl (CAS number: 7758-89-6); CuCl₂x2H₂O in combination with LiCl (CAS number: 7447-39-4) or with LiClx2H₂O (CAS number: 10125-13-0) combination; CuCl₂x2H₂O and MgCl₂(CAS number: 7786-30-3) or with MgCl ₂x6H₂O (7791-18-6) combination; CuSO₄x5H₂O (CAS number: 10257-54-2); cu (II) trifluoromethanesulfonate (CAS number: 34946-82-2);CuBr (CAS number: 7787-70-4); CuBr₂(CAS number: 7789-45-9); CuI (CAS number: 7681-65-4); CuI₂(CAS number: 13767-71-0); cu (NO)₃)₂(CAS number: 3251-23-8); cu (NO)₃)₂x3H₂O (CAS number: 10031-43-3); cu (NO)₃)₂x6H₂O (CAS number: 13478-38-1); cu (NO)₃)₂x2.5H₂O (CAS number: 19004-19-4); cu (OH)₂(CAS number: 20427-59-2); cu (ClO)₄)₂x6H₂O (CAS number: 10294-46-9); cu (NH)₃)₄SO₄xH₂O (CAS number: 10380-29-7); cu (II) (OAc)₂(CAS number: 142-71-2); cu (II) (OAc)₂xH₂O (CAS number: 6046-93-1); m_l(Cu(II)_mX_n)_pWherein M is an alkali metal comprising one of Li, K, Rb, Cs or ammonium, cu (ii) is divalent copper, X is a halogen atom selected from chlorine, bromine or iodine, l is an integer from 1 to 3, M is 1 or 2, n is an integer from 3 to 8, p is 1 or 2, and l +2mp ═ np, associated with at least one alkali metal halide or alkaline earth metal halide.

In yet another embodiment, said copper catalyst exhibiting an oxidation state (+1) or (+2) is understood to be at least one of the following compounds: CuCl₂x2H₂O (CAS number: 10125-13-0); CuCl₂(CAS number: 7447-39-4); cu (CAS number: 7758-89-6); CuCl₂x2H₂O in combination with LiCl (CAS number: 7447-39-4) or with LiClx2H ₂O (CAS number: 10125-13-0) combination; CuCl₂x2H₂O and MgCl₂(CAS number: 7786-30-3) or with MgCl₂x6H₂O (7791-18-6) combination; CuSO₄x5H₂O (CAS number: 10257-54-2); cu (II) trifluoromethanesulfonate (CAS number: 34946-82-2); CuBr (CAS number: 7787-70-4); CuBr₂(CAS number: 7789-45-9); CuI (CAS number: 7681-65-4); CuI₂(CAS number: 13767-71-0); cu (NO)₃)₂(CAS number: 3251-23-8); cu (NO)₃)₂x3H₂O (CAS number: 10031-43-3); cu (NO)₃)₂x6H₂O (CAS number: 13478-38-1); cu (NO)₃)₂x2.5H₂O (CAS number: 19004-19-4); cu (OH)₂(CAS number: 20427-59-2); cu (ClO)₄)₂x6H₂O (CAS number: 10294-46-9); cu (NH)₃)₄SO₄xH₂O (CAS number: 10380-29-7); cu (II) (OAc)₂(CAS number: 142-71-2); cu (II) (OAc)₂xH₂O (CAS number: 6046-93-1); m_l(Cu(II)_mX_n)_pWherein M is an alkali metal comprising one of Li, K, Rb, Cs or ammonium, cu (ii) is divalent copper, X is a halogen atom selected from chlorine, bromine or iodine, l is an integer from 1 to 3, M is 1 or 2, n is an integer from 3 to 8, p is 1 or 2, and l +2mp ═ np, is associated with at least one alkali or alkaline earth metal halide and copper hydroxide.

The at least one alkali metal halide of the first two embodiments is selected from the group consisting of: NaCl, LiCl, KCl, CsCl, LiBr, NaBr, NH₄Br、KBr、CsBr、NaI、LiI、KI、CsI。

The at least one alkaline earth metal halide is selected from the group consisting of: CaCl ₂、CaBr₂、MgCl₂、MgBr₂。

In yet another embodiment, said copper catalyst exhibiting an oxidation state (+1) or (+2) is understood to be at least one compound of: CuCl₂x2H₂O (CAS number: 10125-13-0); CuCl₂(CAS number: 7447-39-4); CuCl (CAS number: 7758-89-6); CuCl₂x2H₂O in combination with LiCl (CAS number: 7447-39-4) or with LiClx2H₂O (CAS number: 10125-13-0) combination; CuCl₂x2H₂O and MgCl₂(CAS number: 7786-30-3) or with MgCl₂x6H₂O (7791-18-6) combination; CuSO₄x5H₂O (CAS number: 10257-54-2); cu (II) trifluoromethanesulfonate (CAS number: 34946-82-2); CuBr (CAS number: 7787-70-4); CuBr₂(CAS number: 7789-45-9); CuI (CAS number: 7681-65-4); CuI₂(CAS number: 13767-71-0); cu (NO)₃)₂(CAS number: 3251-23-8); cu (NO)₃)₂x3H₂O (CAS number: 10031-43-3); cu (NO)₃)₂x6H₂O (CAS number: 13478-38-1); cu (NO)₃)₂x2.5H₂O (CAS number: 19004-19-4); cu (OH)₂(CAS number: 20427-59-2); cu (ClO)₄)₂x6H₂O (CAS number: 10294-46-9); cu (NH)₃)₄SO₄xH₂O (CAS number: 10380-29-7); cu (II) (OAc)₂(CAS number: 142-71-2); cu (II) (OAc)₂xH₂O (CAS number: 6046-93-1); m_l(Cu(II)_mX_n)_pWherein M is an alkali metal comprising one of Li, K, Rb, Cs or ammonium, cu (ii) is divalent copper, X is a halogen atom selected from chlorine, bromine or iodine, l is an integer from 1 to 3, M is 1 or 2, n is an integer from 3 to 8, p is 1 or 2, and l +2mp ═ np, is associated with at least one compound of transition metals.

The at least one compound of a transition metal is selected from the group consisting of: fe. The halide of Cr, Mn, Co, Ni, Zn, a rare earth metal such as Ce, is preferably selected from the halides of Fe, Cr, Mn, Co, Ni, Zn, a rare earth metal such as Ce, and is further preferably selected from the chlorides of Fe, Cr, Mn, Co, Ni, Zn, a rare earth metal such as Ce.

M indicated in the last seven sections respectively_l(Cu(II)_mX_n)_pTypical representatives of (A) are Li [ CuCl ]₃]x2H₂O、NH₄[CuCl₃]x2H₂O、(NH₄)₂[CuCl₄]x2H₂O)、K[CuCl₃]、K₂[CuCl₄]x2H₂O、Cs[CuCl₃]x2H₂O、Cs₂[CuCl₄]x2H₂O、Cs₃[Cu₂Cl₇]x2H₂O、Li₂[CuBr₄]x6H₂O、K[CuBr₃]、(NH₄)₂[CuBr₄]x2H₂O、Cs₂[CuBr₄]And Cs [ CuBr ]₃]。

Experiments have shown that the copper catalyst as defined in at least one of the preceding eight paragraphs can be reused without losing its catalytic activity. Accordingly, one cost-effective embodiment of the present invention discloses a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst, the copper catalyst exhibiting an oxidation state (+1) or (+2) and the same copper catalyst being employed repeatedly or continuously, in a solvent mixture comprising at least two solvents or in a solvent comprising C.

The process of the present invention aims to obtain the corresponding quinone C30 in high yield and purity from the chroman compound C1. Thus, a further detailed process of the present invention is the oxidation of at least one chroman compound C1 to quinone C30 by oxidizing said at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C.

Quinone C30 is represented by the following formula,

wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl, and R9 is preferably alkyl of formula C31.

Alkyl radicals in respect of R9 mean C₁₀-C₂₀-alkyl, preferably C₁₄-C₁₈-alkyl and most preferably C₁₆Alkyl, i.e. an entity comprising a given number of carbon atoms.

In one embodiment, alkyl with respect to R9 is understood to have the structure of formula C31,

wherein the stereogenic center in position 7,11 has a 7R, 11R-configuration, a 7R, 11S-configuration, a 7S, 11R-configuration or a 7S, 11S-configuration.

In one embodiment, the quinone C30 is an alpha-tocopheryl quinone of formula C32,

wherein R7, R8 and R10 are CH₃The stereocenter at position 3,7,11 of the side chain has a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration or a 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, the quinone C30 is an alpha-tocopheryl quinone of formula C33,

wherein R7, R8 and R10 are CH₃The stereogenic centers at positions 3,7,11 of the side chain have the 3R,7R, 11R-configuration, and the OH group at position 3 of the side chain has the 3R configuration.

The preferred molecules are also known as 2- [ (3R,7R,11R) -3-hydroxy-3, 7,11, 15-tetramethylhexadecyl ] -3,5, 6-trimethyl-2, 5-cyclohexadiene-1, 4-dione, or 2- ((7R,11R) -3-hydroxy-3, 7,11, 15-tetramethylhexadecyl) -3,5, 6-trimethylcyclohexanone-2, 5-diene-1, 4-dione, or (3R,7R,11R) -2- (3-hydroxy-3, 7,11, 15-tetramethylhexadecane-1-yl) -3,5, 6-trimethyl-1, 4-benzoquinone or 2- (3-hydroxy-3, 7,11, 15-tetramethylhexadecyl) -3,5, 6-trimethyl- [1,4] benzoquinone, or (R, R, R) -alpha-tocopherolquinone, or p-alpha-tocopherolquinone, or d-alpha-tocopherolquinone.

In one embodiment, the quinone C30 is a beta-tocopheryl quinone of formula C34,

wherein R8 and R10 are CH₃(ii) a R7 is H; the stereogenic centers at positions 3, 7, 11 of the side chains have a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, or a 3S,7S,11S configurationAnd the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, the quinone C30 is a gamma-tocopheryl quinone of formula C35,

wherein R7 and R8 are CH₃(ii) a R10 is H; the stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, or a 3S,7S,11S configuration, and the OH group at position 3 of the side chain has either the 3R or 3S configuration.

In one embodiment, the quinone C30 is a-tocopheryl quinone of formula C36,

wherein R8 is CH₃(ii) a R7, R10 are H; the stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, or a 3S,7S,11S configuration, and the OH group at position 3 of the side chain has either the 3R or 3S configuration.

The alkenyl radicals for R9 mean C₁₀-C₂₀-alkenyl, preferably C₁₄-C₁₈-alkenyl and most preferably C₁₆Alkenyl, i.e. an entity comprising a given number of carbon atoms and having at least one double bond.

In one embodiment, alkenyl groups with respect to R9 are understood to have the structure of formula C37,

wherein the methyl groups in positions 7, 11 have:

the 7 cis, 11 cis-configuration,

the 7 cis, 11 trans-configuration,

7 trans, 11 cis-configuration, or

The 7 trans, 11 trans-configuration,

and the double bonds in positions 6 and 10 have:

the 6E, 10E-configuration,

the 6E, 10Z-configuration,

6Z, 10E-configuration, or

6Z, 10Z-configuration.

In one embodiment, alkenyl groups referred to as R9 are understood to have the structure of formula C38,

wherein the stereogenic center in position 7, 11 has a 7R, 11R-configuration, a 7R, 11S-configuration, a 7S, 11R-configuration or a 7S, 11S-configuration and a double bond in position 14.

In one embodiment, alkenyl groups referred to as R9 are understood to have the structure of formula C39,

wherein the stereogenic center in position 7, 11 has a 7R, 11R-configuration, a 7R, 11S-configuration, a 7S, 11R-configuration or a 7S, 11S-configuration.

In one embodiment, the quinone C30 is an alpha-tocotrienol quinone of formula C40,

wherein R7, R8 and R10 are CH₃，

Wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

The methyl groups in positions 7, 11 have a cis configuration, and

the double bond in the 6-and 10-positions has an E-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bond in the 6-and 10-positions has a Z-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in the 6-and 10-positions has an E-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a cis configuration,

The methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R7, R8 and R10 are CH₃，

Wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bonds in positions 6, 10 have the Z-configuration.

In one embodiment, the quinone C30 is an alpha-tocotrienol quinone of formula C41,

wherein R7, R8 and R10 are CH₃，

Wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have a cis configuration,

the double bond in positions 6, 10 has the E-configuration, and

the OH group at position 3 of the side chain has the 3R configuration.

In one embodiment, the quinone C30 is a beta-tocotrienol quinone of formula C42,

wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

The double bonds in positions 6, 10 have the E configuration,

wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

The double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bond in the 6-and 10-positions has a Z-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in the 6-and 10-positions has an E-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a cis configuration,

The methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R8 and R10 are CH₃R7 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bonds in positions 6, 10 have the Z-configuration.

In one embodiment, the quinone C30 is a gamma-tocotrienol quinone of formula C43,

wherein R7 and R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in position 6, 10 having the E-configuration, wherein R7, R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 having the Z-configuration, wherein R7, R8 are CH ₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 having the E-configuration, wherein R7, R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bond in position 6, 10 having the Z-configuration, wherein R7, R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in position 6, 10 having the E-configuration, wherein R7, R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 having the Z-configuration, wherein R7, R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

The double bond in position 10 has the E-configuration,

Wherein R7 and R8 are CH₃R10 is a hydrogen atom or a hydrogen atom,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bonds in positions 6, 10 have the Z-configuration.

In one embodiment, the quinone C30 is a-tocotrienol quinone of formula C44,

wherein R8 is CH₃R7 and R10 are H,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in the 6-and 10-positions has an E-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereogenic center at position 3 of the side chain has the 3R configuration,

The methyl groups in positions 7, 11 have the trans configuration, and

the double bond in the 6-and 10-positions has a Z-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have a cis configuration, and

the double bond in the 6-and 10-positions has an E-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a cis configuration,

the methyl group in position 11 has a trans configuration,

the double bond in position 6 has the E-configuration, and

the double bond in position 10 has a Z-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl group in position 7 has a trans configuration,

the methyl group in position 11 has a cis configuration,

the double bond in position 6 has the Z-configuration, and

the double bond in position 10 has the E-configuration,

Wherein R8 is CH₃R7 and R10 are H,

wherein the stereocenter at position 3 of the side chain has a 3S configuration,

the methyl groups in positions 7, 11 have the trans configuration, and

the double bonds in positions 6, 10 have the Z-configuration.

In one embodiment, the quinone C30 is an alpha-tocopheryl monoalkenol quinone of formula C45,

Wherein R7, R8 and R10 are CH₃The stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, 3R,7R,11S configuration, 3R,7S,11R configuration, 3S,7R,11R configuration, 3R,7S,11S configuration, 3S,7R,11S configuration, 3S,7S,11R configuration, or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, the quinone C30 is an alpha-tocopheryl monoalkenol quinone of formula C46,

wherein R7, R8 and R10 are CH₃The stereogenic centers at positions 3, 7, 11 of the side chain have the 3R,7R, 11R-configuration, and the OH group at position 3 of the side chain has the 3R configuration.

In one embodiment, the quinone C30 is a beta-tocopheryl monoalkenol quinone of the formula C47,

wherein R7 is H, R8 and R10 are CH₃The stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, 3R,7R,11S configuration, 3R,7S,11R configuration, 3S,7R,11R configuration, 3R,7S,11S configuration, 3S,7R,11S configuration, 3S,7S,11R configuration, or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, the quinone C30 is a gamma-tocopheryl monoalkenol quinone of formula C48,

wherein R7 and R8 are CH₃R10 is H, the stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, or a 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, the quinone C30 is a tocopheryl monoalkenol quinone of formula C49,

wherein R7 and R10 are H, and R8 is CH₃The stereogenic centers at positions 3, 7 and 11 of the side chain have a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, a,Or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has 3R or 3S configuration.

In one embodiment, quinone C30 is a quinone of marine origin alpha-tocopherol (alpha-MDT) of formula C50,

wherein R7, R8 and R10 are CH₃The stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, 3R,7R,11S configuration, 3R,7S,11R configuration, 3S,7R,11R configuration, 3R,7S,11S configuration, 3S,7R,11S configuration, 3S,7S,11R configuration, or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, quinone C30 is a quinone of marine origin alpha-tocopherol (alpha-MDT) of formula C51,

wherein R7, R8 and R10 are CH₃The stereogenic centers at positions 3, 7, 11 of the side chain have the 3R,7R, 11R-configuration, and the OH group at position 3 of the side chain has the 3R configuration.

In one embodiment, quinone C30 is a quinone of marine-derived beta-tocopherol (beta-MDT) of formula C52,

Wherein R7 is H, R8 and R10 are CH₃The stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, 3R,7R,11S configuration, 3R,7S,11R configuration, 3S,7R,11R configuration, 3R,7S,11S configuration, 3S,7R,11S configuration, 3S,7S,11R configuration, or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, quinone C30 is a quinone of marine origin gamma-tocopherol (gamma-MDT) of formula C53,

wherein R7 and R8 are CH₃R10 is H, the stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, a 3R,7R,11S configuration, a 3R,7S,11R configuration, a 3S,7R,11R configuration, a 3R,7S,11S configuration, a 3S,7R,11S configuration, a 3S,7S,11R configuration, or a 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, quinone C30 is a quinone of tocopherol (-MDT) of marine origin of formula C54,

wherein R7 and R10 are H, and R8 is CH₃The stereocenter at position 3, 7, 11 of the side chain has a 3R,7R, 11R-configuration, 3R,7R,11S configuration, 3R,7S,11R configuration, 3S,7R,11R configuration, 3R,7S,11S configuration, 3S,7R,11S configuration, 3S,7S,11R configuration, or 3S,7S,11S configuration, and the OH group at position 3 of the side chain has a 3R or 3S configuration.

In one embodiment, quinone C30 is a mixture of at least two of examples C32, C33, C34, C35, C36, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54.

As can be seen from the examples and comparative examples, it is advantageous to obtain a high yield of quinone C30 of the present invention within a reasonable reaction time if the gaseous compound is not only in contact with the surface of the reaction mixture, but also in contact with the whole part of said reaction mixture. This can be achieved by shaking the reaction mixture under a gaseous atmosphere comprising oxygen. However, significant results are achieved if the gaseous compound travels through the reaction mixture. Accordingly, embodiments of the present invention seek to protect gaseous compounds comprising, consisting essentially of, or consisting of oxygen that actively move through the solvent mixture comprising at least two solvents or through the C-containing solvent. Actively moving means applying a gas or gaseous compound to the reaction mixture by pressure means at a pressure above ambient pressure. This movement ensures that the gas or gaseous compound continuously enters the reaction mixture in excess and its unreacted part subsequently leaves the reaction vessel. Actively moving also means applying a gas or a gaseous compound to the reaction mixture by means of pressure at a pressure above ambient pressure, which application causes the gas to be released under the surface of the solvent mixture comprising at least two solvents or to pass through the C-containing solvent.

One embodiment of the invention uses the so-called off-gas or off-gas mode, which means that the gaseous compounds continuously travelling through the reaction mixture are not used any further. This mode is advantageously used with less expensive gaseous compounds (e.g., air), thereby allowing for a reduction in the complexity and cost of the synthesis apparatus or equipment. This embodiment is defined by the following method: a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst, the copper catalyst exhibiting an oxidation state (+1) or (+2) wherein the gaseous compound actively moves through the solvent mixture comprising at least two solvents or through the solvent comprising C in an off-gas mode.

Various embodiments of the present invention use a so-called recycle gas mode, which is defined as follows: injecting said gaseous compound into the reaction apparatus, collecting excess gaseous compound at different points of the reaction apparatus, replenishing fresh oxygen or oxygen-containing compound with the collected excess gaseous compound depleted in oxygen or oxygen-containing compound, and reintroducing the gaseous compound thus recycled into the reaction apparatus. This embodiment is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a C-containing solvent in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein the gaseous compound actively moves through or through the solvent mixture comprising at least two solvents in a circulating gas mode.

The key subject of the present invention is the use of a suitable amount of catalyst, especially copper catalyst. This is to increase the yield, to reduce the reaction costs and to try to minimize the amount of by-products or traces of starting materials with respect to the corresponding catalyst employed. Therefore, an important feature of the present invention is to determine that the copper catalyst is used in the following amounts relative to the molar amount of chroman compound C1 used: an amount of 0.001 to 10 molar equivalents, preferably a stoichiometric or almost stoichiometric amount, even more preferably a sub-stoichiometric amount, further preferably an amount of 0.01 to 0.95 molar equivalents, still further preferably an amount of 0.01 to 0.75 molar equivalents, still further preferably an amount of 0.1 to 0.5 molar equivalents, further preferably an amount of 0.1 to 0.35 molar equivalents, and most preferably an amount of 0.11 to 0.25 molar equivalents. For example, examples 968(CN10), 952(CN11), 985(CN12), 988(CN13), 905(CN14), 1052(CN15), 1086(CN16), 977(CN17) and 979(CN18) disclose stoichiometric and sub-stoichiometric amounts of at least one catalyst under claimed conditions for obtaining higher yields of quinone C30 (see comparative examples 1004(CN7), 903(CN8) related thereto, see WO2011139897a2 which does not use oxygen or actively introduce gaseous compounds).

After comparing the different types of copper catalysts, it was found that copper halide gave high yield in shorter reaction time (see examples 977(CN19), 1052(CN20), 1021(CN21), 1060(CN22), 946(CN23), 1054(CN24), 1032(CN25), 877(CN26), 905(CN27), 935(CN28), 942(CN29), 952(CN11), 976(CN 31)). Reaction time in this disclosure refers to the total reaction time, i.e., the time to add chroman compound C1 plus the time to add gaseous compound (if any) plus further agitation. Thus, one embodiment of the present invention identifies the copper catalyst as a copper halide, preferably copper chloride, and most preferably CuCl₂。

This is also reflected in an important embodiment of the present invention, which discloses a process for the oxidation of at least one chroman compound C1, said at least one chroman compound being oxidized with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst, said copper catalyst being a copper halide which exhibits an oxidation state (+1) or (+2), and said process being carried out in the following time periods: 2 to 23 hours, preferably 2.6 to 15 hours, preferably 3 to 10 hours, further preferably 3 to 9 hours, still further preferably 3 to 7 hours, further preferably 3 to 6.3 hours, still further preferably 3.6 to 6 hours, and most preferably 4 to 5 hours, including 4.75 and 4.8 hours.

When the copper catalyst used is CuCl₂The most relevant results with respect to reaction time and yield were obtained (see example 1021(CN21), 1032(CN25), 1060(CN22), 877(CN26), 905(CN 27)). Accordingly, the foregoing embodiments are further improved such that it discloses a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst selected from the group consisting of: CuCl₂x2H₂O (CAS number: 10125-13-0); CuCl₂(CAS number: 7447-39-4); and the method is implemented in the following time: 2 to 23 hours, preferably 2.6 to 15 hours, more preferably 3 to 10 hours, further preferably 3 to 9 hours, still further preferably 3 to 7 hours, further preferably 3 to 6.3 hours, still more preferably 3.6 to 6 hours, and most preferably 4 to 5 hours, including 4.75 and 4.8 hours.

When the copper catalyst was used together with other metal compounds, satisfactory results were also obtained in terms of yield, reaction time and reaction temperature (see examples 941(CN32), 946(CN 33)). Accordingly, a further embodiment of the present invention is a process wherein the copper catalyst is combined with at least one metal compound selected from the group consisting of: na, Li, K, Cs, Mg, Ca, Sr, Ba Fe, Cr, Mn, Co, Ni, Zn, La, Ce, Pr, Nd compounds, preferably in combination with one metal halide of the aforementioned group, more preferably in combination with at least one metal chloride of said group, and most preferably with LiCl and/or MgCl₂And (4) combining.

For embodiments of the invention that use at least one metal compound in addition to the copper catalyst, the amount of metal compound used relative to the chroman compound C1 has an effect on the formation of quinone C30. High yields of quinone C30 (see examples 941(CN32), 946(CN35), 390(CN34), 952(CN30)) are obtained when the following process defines a molar ratio between the at least one metal compound and the at least one chroman compound C1 of 0.1 to 10, preferably 0.2 to 5 and most preferably 0.4 to 1, including 0.5: the process is for oxidizing at least one chroman compound C1, the at least one chroman compound being oxidized with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) and being combined with at least one metal compound selected from the group consisting of: na, Li, K, Cs, Mg, Ca, Sr, Ba, Fe, Cr, Mn, Co, Ni, Zn, La, Ce, Pr, Nd compounds.

This observation applies in particular to the following embodiments: the process is for oxidizing at least one chroman compound C1 with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) and in combination with at least one metal halide selected from the group consisting of: na, Li, K, Cs, Mg, Ca, Sr, Ba, Fe, Cr, Mn, Co, Ni, Zn, La, Ce, Pr, Nd compounds, the method defining a molar ratio between the at least one metal compound and the at least one chroman compound C1 of from 0.1 to 10, preferably from 0.2 to 5 and most preferably from 0.4 to 1 (including 0.5).

An even more convincing yield was obtained with the following method: the methodFor oxidizing at least one chroman compound C1, said at least one chroman compound being oxidized with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) and being combined with at least one metal compound selected from the group consisting of: LiCl and/or MgCl ₂The process defines a molar ratio between the at least one metal compound and the at least one chroman compound C1 of from 0.1 to 10, preferably from 0.2 to 5 and most preferably from 0.4 to 1 (including 0.5).

In one embodiment of the invention, the way of obtaining the reaction mixture (comprising chroman compound C1, solvent mixture or C-containing solvent, gaseous compound, copper catalyst and other metal compound) is straightforward, since it does not require any additional effort to obtain the copper catalyst and optionally the other metal compound dissolved or finely dispersed in the reaction mixture. This embodiment is any of the claimed or disclosed embodiments wherein the copper catalyst and optionally at least one metal compound are added to the solvent mixture or the C-containing solvent in the form of an aqueous solution. Thus, particular preference is given to a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, wherein an aqueous solution of the copper catalyst and optionally an aqueous solution of at least one metal compound are added to the solvent mixture or to the solvent comprising C.

Another feature makes the process of the invention fast and therefore cost-effective, provided that the solvent mixture comprising at least two solvents comprises a hydrophilic solvent, preferably water. For each of the claimed or disclosed embodiments of the invention, this feature defines that the copper catalyst and the optional presence of the at least one metal compound are soluble in the aqueous phase of the solvent mixture comprising at least two solvents. This feature is particularly advantageous if the following inventive process determines that the copper catalyst and optionally the at least one metal compound are soluble in the aqueous phase of the solvent mixture comprising at least two solvents: the process of the present invention is used for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+ 2).

Both of the aforementioned embodiments serve to rapidly dissolve the required reagents and to omit the cumbersome synthesis of complex catalysts.

According to the experiments carried out, it was found to be beneficial to have a concentration of copper catalyst in one of at least two solvents of a solvent mixture (see examples 960(CN37), 974(CN38), 958(CN39), 952(CN40), 971(CN 41)). Both below and above the above concentrations of copper catalyst, the yield of quinone C30 was smaller and/or the reaction time was longer. However, given that for each of the claimed or disclosed embodiments, the concentration of the copper catalyst is in the range of 5 to 70% by weight, based on one solvent in the solvent mixture comprising at least two solvents or based on the C-containing solvent, a rather high yield of quinone C30 is obtained within a reasonable reaction time, especially when the copper catalyst is selected from CuCl₂x2H₂O (CAS number: 10125-13-0) or CuCl₂(CAS number: 7447-39-4). This applies in particular to a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting the oxidation state (+1) or (+2) and in a concentration of from 5 to 70% by weight, based on one solvent in the solvent mixture comprising the at least two solvents or on the solvent comprising C, in particular when the copper catalyst is selected from CuCl ₂x2H₂O (CAS number: 10125-13-0) Or CuCl₂(CAS number: 7447-39-4). Even higher yields can be obtained if the concentration of the copper catalyst is from 10 to 50 wt.%, based on one solvent of the solvent mixture comprising at least two solvents or on the C-containing solvent.

As already mentioned above, some embodiments of the present invention use a copper catalyst in combination with at least one metal compound. High yields of quinone C30 are obtained within reasonable reaction times if the concentration of the at least one metal compound in one of the solvent mixtures comprising at least two solvents or in the C-containing solvent is from 5 to 80 wt.% for each of the at least one metal compound containing the claimed or disclosed embodiments. Accordingly, a further embodiment of the present invention seeks to protect a process for the oxidation of at least one chroman compound C1 by oxidizing said at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) and being combined with at least one metal compound selected from the group consisting of: na, Li, K, Cs, Mg, Ca, Sr, Ba, Fe, Cr, Mn, Co, Ni, Zn, La, Ce, Pr, Nd compounds, preferably in combination with one metal halide of the aforementioned group, more preferably in combination with at least one metal chloride of said group, and most preferably with LiCl and/or MgCl ₂A combination wherein the concentration of at least one metal compound in one solvent of the solvent mixture comprising at least two solvents or in the C-containing solvent is from 5 to 80 wt.%.

The process of the invention has been shown to be applicable to a variety of chroman compounds. It can be successfully achieved not only with tocopherol compounds but also with tocotrienol compounds, in particular alpha-tocopherol or alpha-tocotrienol. Thus, a further important embodiment of the present invention discloses the process according to the invention, wherein the chroman compound C1 is an alpha-tocopherol of formula C3, C4, C5 or an alpha-tocotrienol of formula C12, C13, C14. That is, chroman compound C1 used in the method of the present invention is at least one of the following group: alpha-tocopherols of the formulae C3, C4, C5 and alpha-tocotrienols of the formulae C12, C13, C14.

Further experiments were conducted in order to determine the appropriate amount of chroman compound C1 in the reaction mixture of the process of the present invention. The results show that for each of the claimed or disclosed embodiments, 5 to 80 wt. -%, preferably 20 to 50 wt. -%, based on one solvent of the solvent mixture comprising at least two solvents or based on the C-containing solvent, of chroman compound C1 leads to higher yields in shorter reaction times (see examples 872(CN42), 1052(CN1) compared to 875(CN 44)). This is reflected in particular by a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein the chroman compound C1 is used in an amount of from 5 to 80% by weight, preferably from 20 to 50% by weight, based on one solvent in the solvent mixture comprising at least two solvents or based on the solvent comprising C.

The process of the invention is suitably carried out batchwise or semibatchwise, by batch it being meant that the chroman compound C1, the gaseous compound and the copper catalyst are reacted in the solvent mixture or in the C-containing solvent, the reaction mixture obtained being subjected to work-up and the process of the invention being started again with a new set of starting compounds. Semi-batchwise is understood to be the execution of the process of the invention such that some of the reagents (e.g. gaseous compounds) are added continuously to the reaction mixture, while some of the other reagents (e.g. chroman compounds C1) are added, the reaction is carried out, the reaction products are removed, and new reagents C1 are added again. Also, semi-batchwise is understood to mean carrying out the process of the invention so that the catalyst and the solvent mixture or the solvent containing C are charged into a reactor, the chroman compound C1 optionally dissolved in one of the solvents is added to the catalyst or solvent mixture over a period of time and then stirred until complete conversion, while the gaseous compound is added continuously over a period of time starting from the addition of the chroman compound C1 and until complete conversion, the reaction mixture obtained undergoes a work-up and the process of the invention is started again with a new set of starting compounds.

Yet another embodiment defines a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound containing, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out batchwise.

Yet another embodiment defines a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out semi-batchwise.

Yet another aspect of the invention is the simplification of the process. This can be achieved with the starting chroman compound C1, the gaseous compound and the copper catalyst together in the solvent mixture or in the C-containing solvent. No auxiliary agents at all are required, such as detergents, emulsifiers, wetting agents, phase transfer agents, etc. This makes any purification step at the end of the process of the invention straightforward and time-saving. Therefore, it is disclosed that the embodiment of the solvent mixture comprising at least two solvents or the C-containing solvent not containing any detergent is very important for the present invention.

Chroman compound C1 is readily soluble in lipophilic solvents, whereas copper catalysts can be readily soluble in water. This is advantageous because in many cases the lipophilic solvent and water will separate without mixing, and thus separate out the respective dissolved reagents. In other words, the process of the invention carried out in a mixture of lipophilic solvent and water will be stopped immediately after the interruption of the stirring device. This offers the skilled person the possibility of easily controlling the progress and reaction time of the reaction. Furthermore, the copper catalyst or the copper catalyst and the at least one metal compound on the one hand and the chroman compounds C1 and/or quinone C30 on the other hand are separated immediately without any additional steps or procedural burden.

This advantageous feature is reflected by the following two embodiments, namely:

a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, wherein the solvent mixture comprising at least two solvents is vigorously stirred. Within the present disclosure, intense stirring means 600 to 1500 revolutions per minute (rpm), preferably 700 to 1200 revolutions per minute (rpm) and most preferably 1000 to 1200 revolutions per minute (rpm).

A process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein at least two solvents in the solvent mixture comprise water and an organic solvent, preferably a water-immiscible organic solvent.

The solvent or organic solvent of the solvent mixture comprising at least two solvents is selected from the group consisting of: alcohols, glycols, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, glycol ethers, polyethers, polyethylene glycols, ketones, esters, amides, nitriles, halogenated solvents, carbonates, dimethyl sulfoxide and sulfolane.

In one embodiment, the one solvent or organic solvent is hardly mixed with water, preferably not mixed with water at all.

The term alcohol in the present invention comprises at least one primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms.

The at least one, preferably saturated, primary, secondary or tertiary alcohol having from 1 to 18 carbon atoms is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, tert-butanol, all isomeric forms of pentanols, for example 1-pentanol or n-pentanol, 3-methylbutan-1-ol or isopentanol, 2-methyl-1-butanol, 2-dimethylpropan-1-ol, 2-pentanol, 3-methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, all isomeric forms of hexanols, for example 1-hexanol or n-hexanol, cyclohexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 4-methyl-1-pentanol, 2, 2-dimethyl-1-butanol, 1, 3-dimethyl-1-butanol, 2, 3-dimethyl-1-butanol, 3-dimethyl-1-butanol, 2-ethylbutan-1-ol, 2-hexanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 3-dimethyl-2-butanol, 2-methyl-2-pentanol, 3-methylpentan-3-ol, 2, 3-dimethyl-2-butanol, methylcyclopentanol, all isomeric forms of heptanol, for example 1-heptanol, 2-heptanol, 3-ethyl-3-pentanol, all isomeric forms of octanol, for example 1-octanol, 2-ethylhexanol, 1-nonanol, 1-decanol, 2-ethyl-1-hexanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol.

Higher primary, secondary or tertiary alcohols show less sensitivity to ignition, which is preferred for the process of the invention working with or at gaseous compounds comprising or consisting of oxygen. Furthermore, it is hardly mixed with water or not mixed with water at all, so that it can be easily separated from the water-containing part.

Thus, in a preferred embodiment of the present invention, an alcohol is understood to be at least one primary, secondary or tertiary alcohol having from 5 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 5 to 18 carbon atoms.

In another preferred embodiment of the invention, the alcohol is understood to be at least one primary, secondary or tertiary alcohol having from 6 to 18 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 6 to 18 carbon atoms.

For ease of availability, the alcohol is at least one primary, secondary or tertiary alcohol having from 5 to 8 carbon atoms, preferably at least one saturated primary, secondary or tertiary alcohol having from 5 to 8 carbon atoms.

Availability reveals that the alcohol is at least one, preferably saturated, primary, secondary or tertiary alcohol selected from the group consisting of: 1-pentanol, 1-hexanol or hexanol, 2-ethylhexanol, 3-heptanol, 2-octanol, 3-ethyl-3-pentanol, 1, 3-dimethylbutanol or pentylmethanol, diacetone alcohol, methyl isobutyl methanol or 4-methyl-2-pentanol, tert-hexanol, cyclohexanol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol or 2, 3-dimethyl-2, 3-butanediol, 1,2, 5-hexanetriol, 1,2, 6-hexanetriol, trimethylolpropane.

Another aspect of the present process focuses on the small amounts of the inventive process reagents or components thereof associated with the quinones formed. This can be facilitated or achieved by using a particular type of alcohol. Thus, in a preferred embodiment of the present invention, an alcohol is understood to be at least one secondary or tertiary alcohol having from 5 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having from 5 to 18 carbon atoms.

A valuable embodiment of the present invention is therefore a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) wherein the solvent mixture comprising at least two solvents is a mixture of water and at least one primary, secondary or tertiary alcohol having 6 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having 6 to 18 carbon atoms, as organic solvent.

Thus, a further elaborately valuable embodiment of the invention is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), wherein the solvent mixture comprising at least two solvents is a mixture of water and at least one secondary or tertiary alcohol having 5 to 18 carbon atoms, preferably at least one saturated secondary or tertiary alcohol having 5 to 18 carbon atoms.

The diols of the present disclosure are understood to be at least one compound selected from the following group: 1, 2-ethanediol or ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 2, 3-butanediol, 1, 3-butanediol, 2-methyl-1, 2-propanediol, 1, 4-butanediol, 1, 2-pentanediol, 1, 3-pentanediol, 1, 4-pentanediol, 1, 5-pentanediol, 2-dimethyl-3-propanediol, 3-methyl-2, 4-pentanediol, 4-hydroxy-4-methyl-2-pentanol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol, and mixtures thereof, 2, 3-dimethyl-2, 3-butanediol, diethylene glycol, triethylene glycol, glycerol, 1, 2-butanediol, 1,2, 3-butanetriol, 1,2, 4-butanetriol and 2-methyl-2, 3-butanediol.

Aliphatic hydrocarbons of the present disclosure are understood to be selected from the group consisting of: n-pentane, isopentane, neopentane, n-hexane, all isomeric forms of hexane, n-heptane, all isomeric forms of heptane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, all isomeric forms of octane, all isomeric forms of nonane, all isomeric forms of decane, all isomeric forms of undecane, all isomeric forms of dodecane, polyethylene, and nitromethane.

Aromatic hydrocarbons within the context of the present disclosure are understood to be selected from the group consisting of: benzene, toluene, all isomeric forms of xylene, for example o-, m-or p-xylene, ethylbenzene, 1,3, 5-trimethylbenzene, cumene, all isomeric forms of diisopropylbenzene, 2-isopropyltoluene, 3-isopropyltoluene, 4-isopropyltoluene and nitrobenzene.

Ethers within the context of the present disclosure are understood to be selected from the group: dimethyl ether, diethyl ether, di-n-propyl ether, diisopropyl ether, methyl ethyl ether, dibutyl ether, diamyl ether, diisoamyl ether, n-butyl methyl ether, sec-butyl methyl ether, tert-butyl ethyl ether, methyl isobutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 3-methyl tetrahydrofuran, 2, 5-dimethyl tetrahydrofuran, 1, 3-dioxolane, tetrahydropyran, 1, 4-dioxane, 1,3, 5-trioxane, benzyl ethyl ether, cyclopentyl methyl ether, and anisole.

Glycol ethers or polyethers within the context of the present disclosure are understood to be selected from the following group: dimethoxymethane, diethoxymethane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoisopropyl ether, dipropylene glycol, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol diacetate, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, 1, 4-butanediol dimethyl ether, polyethylene glycol, 2-methoxy-1-propanol.

Ketones within the context of the present disclosure are understood to be selected from the group: acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, diisopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone, methyl tert-butyl ketone, 2-pentanone, cyclopentanone, 2-hexanone, cyclohexanone, 2-heptanone, 4-heptanone.

Esters within the context of the present disclosure are understood to be selected from the group consisting of: methyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, hexyl acetate, methyl propionate, gamma-butyrolactone, ethyl benzoate, ethylene glycol diacetate, and diethylene glycol diacetate.

Within the context of the present disclosure, an amide is understood to be selected from the group consisting of: n-methylformamide, N-dimethylformamide, N-methylacetamide, N-dimethylacetamide, N-diethylacetamide, N-dimethylpropionamide, N-dibutylformamide and N-methylpyrrolidone.

Nitriles within the context of the present disclosure are understood to be selected from the group: acetonitrile, propionitrile, benzonitrile and trimethylacetonitrile.

Halogenated solvents within the context of the present disclosure are understood to be selected from the group consisting of: dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethylene, 1, 2-dichloroethane, 1,1,1, -trichloroethane, 1,1,1, 2-tetrachloroethane, 1,1,2, 2-tetrachloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, 1,2, 3-trichlorobenzene, 1,2, 4-trichlorobenzene, 4-chlorotoluene, trichloroacetonitrile, 2-chloroethanol, 2,2, 2-trichloroethanol, 1-chloro-2-propanol, 2, 3-dichloropropanol, all isomeric forms of 2-chloro-1-propanol, trichlorotoluene, fluorobenzene, all isomeric forms of difluorobenzene, 2,4, 6-trifluorotoluene, 2-fluorobutanol, trifluorotoluene.

Carbonates within the context of the present disclosure are understood to be selected from the following group: ethylene carbonate, propylene carbonate, dimethyl carbonate or diethyl carbonate.

The C-containing solvent of the process of the invention is any solvent which is adapted to dissolve to a large extent or completely all of the reagent chroman compound C1, the gaseous compound comprising, consisting essentially of or consisting of oxygen, and the copper catalyst. Such C-containing solvents should be both hydrophilic and lipophilic.

Such C-containing solvents are selected from at least one of the group consisting of low aliphatic alcohols, i.e. at least one C1-C8-alcohol selected from the group comprising C1-C8 diols and C1-C8-triols, N-dimethylformamide, N-diethylformamide, N-methylpyrrolidone, ethylene carbonate, propylene carbonate, glycol ethers.

C1-C5 alcohols are selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, 1-pentanol, isopentanol, 2-methyl-1-butanol, neopentyl alcohol, 2-pentanol, 3-methyl-2-butanol, 2-methyl-2-butanol, cyclopentanol, n-hexanol (1-hexanol), 2-methyl-1-pentanol, 3-methyl-1-pentanol, 4-methyl-1-pentanol, 2-dimethyl-1-butanol, 2, 3-dimethyl-1-butanol, 3-dimethyl-1-butanol, 2-ethylbutan-1-ol, 2-hexanol, 3-hexanol, 3-methyl-2-pentanol, all isomeric forms of 4-methyl-2-pentanol, 3-dimethyl-2-butanol, 2-methyl-2-pentanol, 3-methylpentan-3-ol, 2, 3-dimethyl-2-butanol, cyclohexanol, methylcyclopentanol, 1, 3-dimethylbutanol, pentylmethanol, methylisobutylmethanol, 4-methyl-2-pentanol, tert-hexanol, n-heptanol, 2-heptanol, 3-ethyl-3-pentanol, n-octanol or 1-octanol, 2-ethylhexanol, 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 2-methyl-1, 2-propanediol, 1, 4-butanediol, 1, 2-pentanediol, 1, 3-pentanediol, 1, 4-pentanediol, 1, 5-pentanediol, 2, 4-pentanediol, 2-dimethyl-1, 3-propanediol, 3-methyl-2, 4-pentanediol, 4-hydroxy-4-methyl-2-pentanol, 1,2, 4-trihydroxybutane, 1,2, 3-trihydroxybutane, triethylene glycol, 1, 6-hexanediol, 1, 5-hexanediol, 1, 4-hexanediol, 1, 3-hexanediol, 2-methyl-2, 4-pentanediol, pinacol, 2, 3-dimethyl-2, 3-butanediol, 1,2, 5-hexanetriol, 1,2, 6-hexanetriol, 2-methyl-2, 3-butanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, 2-ethoxyethanol, ethylene glycol monobutyl ether, 2-isopropoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol diacetate, propylene glycol, 1, 2-butanediol, triethylene glycol, glycerol, ethylene glycol diacetate and diethylene glycol diacetate, 2-methoxy-1-propanol.

Glycol ethers are, for example, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dipropylene glycol, 1, 3-propanediol dimethyl ether, 1, 3-propanediol diethyl ether, triethylene glycol dimethyl ether.

In yet another embodiment, a solvent mixture comprising water, an alcohol comprising 1 to 8 carbon atoms (preferably an alcohol comprising 1 to 6 carbon atoms), and a hydrocarbon is disclosed to increase the rate and/or yield of the process of the present invention. The reason for this is not fully understood. May be related to the following facts: the alcohol in the water increases the ability of the mixture to dissolve small amounts of hydrocarbons in the alcohol/water phase. Thus, a further improved embodiment of the present invention is a process for the oxidation of at least one chroman compound C1, said at least one chroman compound being oxidized with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C, in the presence of a copper catalyst, said copper catalyst exhibiting an oxidation state (+1) or (+2), and said solvent mixture comprising water, alcohols and hydrocarbons comprising from 1 to 8 carbon atoms, preferably water, alcohols and hydrocarbons comprising from 1 to 6 carbon atoms, more preferably said solvent mixture comprising water, alcohols and aromatic hydrocarbons comprising from 1 to 8 carbon atoms, and most preferably said solvent mixture comprising water, alcohols and aromatic hydrocarbons comprising from 1 to 6 carbon atoms.

The essential aim of the process according to the invention is not only to avoid by-products as far as possible, but also to reduce or completely avoid traces of reagents or reagent fractions, such as copper ions, chloride ions, organochlorine compounds, etc. This was found to be achieved by means of the use of an alcohol, preferably a secondary alcohol and even more preferably a secondary alcohol having at least six carbon atoms, in the solvent mixture. This finding is reflected in embodiments wherein at least two solvents of the solvent mixture comprise as organic solvent at least one primary alcohol or at least one secondary alcohol or a mixture of at least one primary alcohol and at least one secondary alcohol, wherein the secondary alcohol is preferably an alcohol having at least six carbon atoms and more preferably having at least seven carbon atoms.

In yet another embodiment of the present invention, the weight ratio of the organic solvent to water is in the range of: 0.01:1 to 499:1, preferably 0.1:1 to 450:1, further preferably 0.4:1 to 350:1, still further preferably 1:1 to 300:1, in yet another embodiment 1.1:1 to 200:1, in yet a further preferred variant 2.9:1 to 175:1, in another preferred embodiment 3.1:1 to 150:1, more preferably 4.3:1 to 100:1, still more preferably 5:1 to 70:1, still further preferably 6:1 to 31.4:1, more preferably 7:1 to 29:1, in yet a further improved embodiment 7.5:1 to 21.3:1, and in yet another embodiment 7.9:1 to 19.6:1, still further preferably 10:1 to 17.4:1, further preferably 11.6:1 to 19.6:1, still further preferably 10:1 to 17.4:1, further preferably 11.1 to 14:1, and most preferably 1 to 13.73: 1.

Many of the previously disclosed embodiments emphasize shorter reaction times from 2 hours to 8 hours, preferably from 2 hours to 7 hours, and even more preferably from 2 hours to 6 hours (see examples 905(CN58), 1032(CN59), 879(CN60), 1021(CN61), 1074(CN62), 941(CN63), 877(CN64), 1054(CN65), 1052(CN66), 1086(CN 67)). Accordingly, one embodiment of the present invention defines a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst, the copper catalyst exhibiting an oxidation state (+1) or (+2), and the oxidation process is effected in less than 48 hours, preferably in a time of from 2 hours to 8 hours, more preferably in a time of from 2 hours to 7 hours, even more preferably in a time of from 4 hours to 6 hours, and most preferably in a time of from 4.75 hours to 6 hours, including 4.8 hours and 5 hours.

Another advantageous feature of the process of the invention is that high yields and short reaction times can be achieved even at moderate temperatures (see examples 1024(CN68), 877(CN69), 883(CN70), 941(CN71), 942(CN72), 1060(CN73), 905(CN74), 988(CN75), 894(CN76), 1054(CN77), 879(CN78), 994(CN79), 1032(CN 80)). This is less energy consuming and therefore cost effective. The embodiments define a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out at a temperature of from 2 ℃ to 170 ℃, preferably from 10 ℃ to 60 ℃, more preferably from 15 ℃ to 55 ℃, even more preferably from 20 ℃ to 50 ℃ and most preferably from 25 ℃ to 40 ℃ (including 23 ℃).

The embodiment defines a further process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), the process being carried out at a temperature of from 2 ℃ to 170 ℃, preferably from 10 ℃ to 60 ℃, more preferably from 10 ℃ to 55 ℃, even more preferably from 15 ℃ to 40 ℃ and most preferably from 15 ℃ to 25 ℃ (including 23 ℃).

Both temperature and reaction time influence the amount of quinone C30 formed. However, the results show that not only does the amount of quinone C30 change with changes in reaction time and reaction temperature, but also the amount of trace amounts of products or reagents (e.g., copper ions, organic chlorides or chlorides) changes with changes in reaction time and reaction temperature:

from the semibatch reaction of R, R- α -tocopherol C5, quinone preparations with the composition shown in table 1a and table 1b can be obtained after distillation or after extraction and solvent removal:

TABLE 1a

The examples of table 1b are used as a comparison in terms of trace formation depending on temperature and reaction time. However, when trace formation depending on temperature and reaction time is not emphasized, it is still an inventive example of the present invention.

TABLE 1b

From the batch reaction of R, R- α -tocopherol C5, quinone preparations with the composition as shown in table 2a and table 2b can be obtained after distillation or after extraction and solvent removal:

TABLE 2a

The examples of table 2b are used as a comparison in terms of trace formation depending on temperature and reaction time. However, when trace formation depending on temperature and reaction time is not emphasized, it is still an inventive example of the present invention.

TABLE 2b

From these tables it is observed that small amounts of organic chloride, chloride and copper ions can be obtained as long as suitable reaction times and reaction temperatures are observed. One embodiment that is suitable for small amounts of organic chlorine, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), the process being carried out at a temperature of from 10 ℃ to 50 ℃ and over a time of from 2 hours to 7 hours.

Another embodiment that is suitable for small amounts of organic chloride, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), the process being carried out at a temperature of from 10 ℃ to 25 ℃ and over a time of from 2 hours to 7 hours.

Yet another embodiment adapted to small amounts of organic chlorine, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out at a temperature of from 20 ℃ to 50 ℃ and over a time of from 2 hours to 7 hours.

Yet another refinement of the previous embodiment is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out at a temperature of 20 ℃ to 40 ℃ and over a time 15 of 2 hours to 7 hours, including 6 hours.

An additional embodiment adapted to small amounts of organic chlorine, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in a solvent mixture comprising at least two solvents or in a solvent comprising C in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2), the process being carried out at a temperature of from 10 ℃ to 50 ℃ and over a time of from 2 hours to 8 hours.

Yet another embodiment adapted to small amounts of organic chlorine, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing the at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, the process being carried out at a temperature of from 10 ℃ to 50 ℃ and over a time of from 5 hours to 8 hours.

Finally, a highly preferred embodiment adapted to small amounts of organic chlorine, chloride and copper ions is a process for the oxidation of at least one chroman compound C1 by oxidizing said at least one chroman compound with a gaseous compound comprising, consisting essentially of, or consisting of oxygen in the presence of a copper catalyst exhibiting an oxidation state (+1) or (+2) in a solvent mixture comprising at least two solvents or in a solvent comprising C, said process being carried out at a temperature of from 10 ℃ to 25 ℃ and over a period of from 5 hours to 8 hours.

As can be seen from tables 1a and 2a, this last embodiment results in the lowest amount of organic chloride, chloride and copper ions compared to tables 1b and 2 b.

The essential part of the invention is a composition comprising: a) at least one chroman compound C1,

wherein R1, R3, R4 and R5 are H or CH₃R2 is OH, OAc, OCO-C₁-C₁₈-alkanesAnd R6 is alkyl, alkenyl, and/or at least one quinone C30,

wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl; b) a solvent mixture comprising at least two solvents or a solvent containing C; c) a copper catalyst exhibiting an oxidation state (+1) or (+ 2); d) a gaseous compound comprising, consisting essentially of, or consisting of oxygen; the composition is preferably obtained by a method as disclosed in any one of the previously mentioned embodiments. It has been shown that only this composition contains a large amount of the chroman compound C1 and is the starting point for selectively obtaining quinone C30 in high yield and short reaction time. It has been shown that the same composition consists mainly of a high amount of quinone C30, without by-products. For clarity, the compositions of the present invention are understood to contain the components as indicated. However, the amount of chroman compound C1 varies with time depending on the time of sampling from the composition. If this sample is taken before starting the process of the invention, the amount of chroman compound C1 is the highest and the amount of quinone C30 is zero. At the end of the process of the invention, the amount of chroman compound C1 in the composition is zero or only trace amounts thereof remain, while the amount of quinone C30 is the highest possible. In a preferred embodiment, it ranges from 85% to 100% of the molar amount of chroman compound C1 originally present in the composition. During the method of the present invention, the compositions contained varying amounts of chroman compound C1 and quinone C30, depending on the time at which samples of the compositions were sampled and analyzed in the method of the present invention. Since for several embodiments of the invention the process of the invention can be stopped at any time by simply turning off the stirring device, thus revealing any molar ratio of chroman compound C1 to quinone C30 (i.e. the range of chroman compound C1: quinone C30 equals 0 mol%: 100 mol% to 0 mol%), any composition comprising one of the aforementioned chroman compound C1/quinone C30 ratios and components b) to d) is understood to be a composition of the invention.

Another embodiment of the invention further features a composition of the invention. It is a composition as mentioned before, i.e. a composition comprising: a) at least one chroman compound C1 and/or at least one quinone C30; b) a solvent mixture comprising at least two solvents or a solvent containing C; c) a copper catalyst exhibiting an oxidation state (+1) or (+ 2); d) a gaseous compound comprising, consisting essentially of, or consisting of oxygen; the composition is preferably obtained by a method according to any one of the previously mentioned embodiments. The embodiments are further defined as such that the gaseous compound in the composition is in the form of bubbles in an amount higher than that obtained when combining and storing a) to c) in ambient air, preferably higher than that obtained when combining a) to c) and stirring in ambient air. It can be seen that this embodiment necessarily requires the inclusion of a certain amount of bubbles. Said bubbling of gaseous compound helps to obtain an embodiment of the composition of the invention that exhibits or is capable of forming a large amount of quinone C30, while avoiding the amount of by-products formed from chroman compound C1.

Another aspect of the invention relates to a method of converting the composition of the invention into a quinone preparation. For certain food and pharmaceutical applications, the composition of the invention itself, and in particular quinone C30, must meet certain specifications required by national and/or multinational regulatory agencies. The specifications require that the combined amount of by-product or reagent traces be limited to a predetermined range.

In an advantageous embodiment, this need is solved by a method for obtaining a quinone preparation, comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; iv) optionally subjecting the residue of step iii) to further distillation. By subjecting the composition of the invention to the process as described above, a quinone preparation of the invention can be obtained having the following characteristics:

from the semibatchwise reaction of R, R- α -tocopherol C5, it is possible to obtain, after applying it to the separation device, a preparation containing traces of quinone as given in table 3:

TABLE 3

From the batch reaction of R, R- α -tocopherol C5, a preparation containing traces of quinone as given in table 4 was obtained after applying it to the separation device:

TABLE 4

From the batch reaction of racemic (rac) - α -tocopherol C3 (wherein R2 is OH), it was possible to obtain after applying it to a separation device a quinone preparation containing traces as given in table 5:

TABLE 5

As can be seen from tables 3 to 5, the separation apparatus greatly reduced the amount of organic chloride, chloride and copper ions, resulting in the quinone formulation of the present invention.

In another embodiment of the invention, this need to meet regulatory agency specifications is addressed by a method for obtaining a quinone preparation, comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a further distillation step; iv) optionally subjecting the residue of step iii) to further distillation. Proceeding in this way, quinone preparations of the invention can be obtained with the following characteristics:

From the semibatchwise reaction of R, R- α -tocopherol C5, it is possible to obtain, after distillation thereof, a quinone preparation according to the invention containing traces as given in table 6:

TABLE 6

From the batch reaction of R, R- α -tocopherol C5, it is possible to obtain after (further) distillation thereof a quinone preparation according to the invention containing traces as given in table 7.

TABLE 7

From the semi-batch reaction of rac-alpha-tocopherol C3, it was possible to obtain after distillation a quinone preparation according to the invention containing traces as given in table 8:

TABLE 8

As can be seen from tables 6 to 8, distillation reduced the amount of organic chloride, chloride and copper ions, resulting in the quinone formulation of the present invention. However, its performance is not as pronounced as with the separation device.

In yet another embodiment, this need to meet regulatory agency specifications is addressed by a method for obtaining a quinone preparation, comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column; iv) optionally subjecting the residue of step iii) to further distillation. By subjecting the composition of the invention to the process as described above, a quinone preparation of the invention can be obtained having the following characteristics:

From the semibatch reaction of R, R- α -tocopherol C5, a preparation containing traces of quinone as given in table 9 was obtained after applying it to the separation column:

TABLE 9

As can be seen from the above table, an embodiment using a further distillation step in step iii) is most suitable if the amount of residual copper ions is not required to be very low. On the other hand, with the same low copper ion concentration and low chlorine concentration, the separation column can meet this requirement. The resin or solid support of the separation column is more expensive than distillation. Reducing the amount of resin or solid support used can reduce process costs. This is achieved by the separating means having a surface with a diameter larger than its height. From the above table it can be seen that even if the amount of resin or solid carrier used in the separation device is reduced, similar or even better results are obtained for the residual amounts of organic chloride, chloride and copper ions, which is surprising.

During the process of the present invention for oxidizing chroman compound C1 in the presence of a copper catalyst and in the process for obtaining a quinone formulation, in some, but not all embodiments, depletion of the copper catalyst is observed over time. If the same catalyst sample is used repeatedly, the depletion is cumulative whether it is used in batch or semi-batch. However, when a certain threshold is exceeded, the reduced amount of copper catalyst also reduces the reaction rate and increases the reaction cost, since the reaction mixture is replenished with additional fresh copper catalyst. To avoid this, several measures are suitable and are reflected by the following three embodiments.

When the chroman compound C1 used in the oxidation process of the present invention and the quinone C30 used in the process for obtaining a quinone preparation can be subjected to acidic conditions, the process for obtaining a quinone preparation by means of a separation device comprises the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; adding hydrochloric acid before or during removal of one solvent from the solvent mixture or before or during removal of the solvent containing C; iia) distilling off the remaining solvent or solvents; or iib) degassing the composition; or iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; iv) optionally subjecting the residue of step iii) to further distillation.

When the chroman compound C1 used in the oxidation process of the present invention and the quinone C30 used in the process for obtaining a quinone preparation can be subjected to acidic conditions, said process for obtaining a quinone preparation by means of a distillation step comprises the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; adding hydrochloric acid before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents; or iib) degassing the composition; or iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a further distillation step; iv) optionally subjecting the residue of step iii) to further distillation.

When the chroman compound C1 used in the oxidation process of the present invention and the quinone C30 used in the process for obtaining a quinone preparation can be subjected to acidic conditions, the process for obtaining a quinone preparation by means of a separation column comprises the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; adding hydrochloric acid before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents; or iib) degassing the composition; or iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column; iv) optionally subjecting the residue of step iii) to further distillation.

By each of these three embodiments, i.e., by the addition of hydrochloric acid, the degraded or used copper catalyst can be regenerated or recycled for reuse.

Not every chroman compound C1 and every quinone C30 readily supports acidic conditions without some degradation. The three previously mentioned embodiments are less advantageous for such acid labile chroman compounds C1 and/or acid labile quinone C30. This disadvantage can be solved by the following embodiments. It also has the advantage of recovering or recycling components such as solvents in sufficient purity to make them reusable in the process. Likewise, it is suitable for reconverting trace components (for example copper oxychloride) into a reagent (for example CuCl) of the process of the invention for the selective oxidation of at least one chroman compound C1 or in the process for obtaining a quinone preparation ₂). The following embodiments include separation devices.

One embodiment adapted for acid-labile chroman compounds C1, quinone C30 in a solvent mixture comprising at least two solvents discloses a method for obtaining a quinone preparation, the method comprising the steps of: i) removing a solvent from a solvent mixture comprising at least two solvents of the composition of the present invention; ia) reducing the volume of a solvent removed and/or; ib) adding hydrochloric acid to said removed one solvent; ic) storing or reinjecting the mixture obtained in step ia) or ib) for further use in the process of the invention for the oxidation of at least one chroman compound C1, or instead of steps ia) to ic); id) adding hydrochloric acid and/or to said removed one solvent; ie) reducing the volume of the mixture obtained in step id); if) storing or reinjecting the mixture obtained in step id) or ie) for further use in the process of the invention for the oxidation of at least one chroman compound C1; iia) distilling off the remaining solvent not removed in step i), or iib) degassing the composition, or iic) distilling off the remaining solvent not removed in step i) and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; iv) optionally subjecting the residue of step iii) to further distillation.

The previous embodiment may have another distillation step or separation column in step iii) instead of the separation device. This provides two further embodiments which differ from the preceding examples only in step iii). In one of these two embodiments, step iii) is as follows: "applying the composition of step iia), step iib) or step iic) to a further distillation step; ", in another embodiment thereof, step iii) is as follows: "applying the composition of step iia), step iib) or step iic) to a separation column; ". Both embodiments are also part of the invention, in addition to the one mentioned earlier.

By "separation device, the surface of which has a diameter greater than the height of the separation device" is understood a container, the surface of which has a diameter greater than the height and contains or is supplemented by a solid support synonymous with resin. The term "separation device, the diameter of the surface of which is larger than the height of the separation device" also encompasses embodiments made from a vessel comprising or supplemented with a solid support, wherein only the surface given by the solid support has a diameter larger than the height of the solid support. Also, the term "separation device, the diameter of the surface of which is larger than the height of the separation device" includes embodiments wherein the diameter of the surface of the vessel of the separation device is larger than the height of the vessel and the diameter of the surface given by the solid support is larger than the height of the solid support. Whether the "surface" belongs to a container or to a solid support, it refers to a region perpendicular to the respective height.

The characteristic feature of the separation device is its size. The diameter of the surface of the separating means is greater than the height of the separating means. Thus, less solid support or resin may be placed in the container and used for the separation task than the amount of solid support or resin used, for example, in the separation column. Due to the smaller amount of solid support or resin used in the separation device, one would estimate that the separation results are not as good as in e.g. a separation column. However, unexpectedly, the opposite was observed as described above.

When a chemical entity in a solvent or solvent mixture is applied to a solid support, the solid support of the separation device is any support suitable for separating the chemical entity (e.g. molecule, ion) according to at least one of polarity, size, charge, chirality. In one embodiment, the solid support is selected from at least one of: silica, silica-based materials also known as modified silica (i.e., coated with inorganic or organic molecules), zeolites, alumina, aluminum silicate, carbon-based materials, carbohydrates (including carbohydrate softgels, carbohydrates crosslinked with agarose or acrylamide), polymeric organic materials (including crosslinked organic polymers such as polymeric resins or ion exchange materials), methacrylic resins, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid, or nitrilotriacetic acid (NTA), preferably silica.

A "separation column" is understood to be a tube, pipe or tube containing or supplemented with a solid support synonymous with resin, the surface of which has a diameter less than or equal to its height. A "separation column" is also understood to be a tube, pipe containing or supplemented with a solid support synonymous with resin, wherein the diameter of the surface given by the solid support is less than or equal to the height of said solid support in the tube, pipe or pipe. Likewise, a "separation column" is understood to be a tube, pipe or pipe containing or supplemented with a solid support synonymous with resin, wherein the diameter of the surface of the tube, pipe or pipe is less than or equal to its height and the diameter of the surface of the solid support is less than or equal to its height. Whether the "surface" belongs to a container or to a solid support, it refers to a region perpendicular to the respective height.

When a chemical entity in a solvent or solvent mixture is applied to a solid support, the solid support of a separation column is any support suitable for separating the chemical entity (e.g. molecule, ion) according to at least one of polarity, size, charge, chirality. In one embodiment, the solid support is selected from at least one of: silica, silica-based materials also known as modified silica (i.e., coated with inorganic or organic molecules), zeolites, alumina, aluminum silicate, carbon-based materials, carbohydrates (including carbohydrate softgels, carbohydrates crosslinked with agarose or acrylamide), polymeric organic materials (including crosslinked organic polymers such as polymeric resins or ion exchange materials), methacrylic resins, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid, or nitrilotriacetic acid (NTA), preferably silica.

It was found that the separation ability of quinone C30 from trace amounts of by-products and/or reagents was also affected by the particle size of the solid support employed in the separation device and/or in the separation column. Convincing results were obtained when the particle size of the solid support, preferably silica, was from 5 μm to 1000 μm, preferably from 10 μm to 150 μm, more preferably from 30 μm to 100 μm and most preferably from 40 μm to 63 μm and the average pore size was from 1 to 100 nm. Particle size and pore size should be done according to the instructions of the supplier of the solid support.

In one embodiment, the separation device or separation column is operated in batch mode. Batch mode refers to applying a sample to a separation device or separation column, effecting separation, optionally regenerating the separation device and applying a subsequent sample.

In one embodiment, the separation device or separation column is operated at ambient pressure.

In another embodiment, the separation device or separation column, respectively, is operated under pressure (at low pressure or at high pressure) instead of at ambient pressure. For operation under pressure, the particle size determination required for the solid support is slightly different from that required when working at ambient pressure, or in other words, a different particle size determination will result in a different pressure being formed during separation.

As understood within this specification, the pressure other than ambient pressure is from 1.1x10⁵Pascal to 150x10⁵Any pressure in pascal. Ambient pressure is any pressure measured at atmospheric conditions without the application of any pressure means, i.e. from 0.9x10⁵Pascal to 1.1x10⁵Pascal pressure, depending on the actual weather conditions. Within this specification, low pressure means 1.1x10⁵Pascal to 10x10⁵Pascal. Within this specification, high pressure is understood to be 10x10⁵Pascal to 150x10⁵Any value of pascal.

Yet another embodiment of the present invention seeks to protect a method for obtaining a quinone preparation, the method comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; the separation device comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica, and the solid support has a particle size of from 50 μm up to 1000 μm, preferably from 200 μm up to 500 μm, particularly preferably from 250 μm up to 350 μm, and a pore size of from 1nm to 100 nm; iv) optionally subjecting the residue of step iii) to a further distillation, preferably at least one further distillation. The process using the separation device is particularly suitable for low-pressure operation and gives good purification results both in terms of chlorine traces and copper traces.

Yet another embodiment of the present invention seeks to protect a method for obtaining a quinone preparation, the method comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; the separation device comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica, and the solid support has a particle size of 5 to 50 μm and a pore size of 1 to 100 nm; iv) optionally subjecting the residue of step iii) to further distillation. This embodiment of the process of the invention using a separation device provides the opportunity to satisfactorily separate traces of chlorine or copper ions at high pressure using a separation device.

Given that in the process for oxidizing at least one chroman compound C1 or in the composition comprising at least one chroman compound C1 and/or at least one quinone C30, other reagents or compounds are required for any other reason, the separation device may not be effective in removing substantially all traces or by-products and the like of the process or the composition of the invention. This need is addressed by two additional embodiments, one of which is:

for use at ambient or low pressure, a method for obtaining a quinone formulation, the method comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column; the separation column comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica, and the solid support has a particle size of from 50 μm up to 1000 μm, preferably from 200 μm to 500 μm, particularly preferably from 250 μm to 350 μm and a pore size of from 1nm to 100 nm; iv) optionally subjecting the residue of step iii) to further distillation. This embodiment of the process of the invention is suitable for removing a greater variety of traces or by-products at low pressure.

Another embodiment adapted for use at high pressure is a process for obtaining a quinone preparation, the process comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents; or iib) degassing the composition; or iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column; the separation column comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica, and the solid support has a particle size of from 5 μm to 50 μm and a pore size of from 2nm to 50 nm; iv) optionally subjecting the residue of step iii) to further distillation. This embodiment of the process of the invention provides a route to remove a greater variety of trace compounds or by-products at high pressure.

With the implementation of the experiment, it was found that the solvent in which the solid support is suspended or immersed has an effect on the manner of separation of the solid support. Good separation conditions can be achieved when the solid support is suspended in a suspending solvent or a mixture of suspending solvents selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane, and the slurry thus obtained is applied to a separation apparatus or a separation column.

Aliphatic hydrocarbons, aromatic hydrocarbons, alcohols are as defined above for one solvent of a solvent mixture comprising at least two solvents or for a C-containing solvent.

The halogenated hydrocarbon is selected from the group consisting of: dichloromethane, chloroform, perchloroethylene, chlorobenzene, dichlorobenzene, all isomeric forms of difluorobenzene, trifluorotoluene, fluorinated lower alkanes.

The carboxylic acid is intended to be selected from the group: formic acid, acetic acid, propionic acid.

As understood within this disclosure, esters are selected from the following group: methanol, ethanol, propanol, isopropanol, the formates, acetates or propionates of butanol, for example methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, methyl propionate.

The ethers meant within the present description are selected from the following group: dimethyl ether, diethyl ether, methyl ethyl ether, di-n-propyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, anisole, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoisopropyl ether, dipropylene glycol, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol diacetate, 2-methoxy-1-propanol.

As understood within the present invention, the ketone is selected from the group of: acetone, butanone, methyl ethyl ketone, diethyl ketone, diisopropyl ketone, isopropyl methyl ketone, isobutyl methyl ketone, methyl tert-butyl ketone, 2-pentanone, cyclopentanone, 2-hexanone, cyclohexanone, 2-heptanone, 4-heptanone.

The acetal is selected from the group consisting of: formaldehyde dimethyl acetal, formaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acetaldehyde diethyl acetal, propionaldehyde dimethyl acetal, propionaldehyde diethyl acetal.

The ketals of the present disclosure are intended to be selected from the group consisting of: 2, 2-dimethoxypropane, 2-diethoxypropane.

The nitriles of the present specification are selected from the following group: acetonitrile, propionitrile, butyronitrile, benzonitrile.

The experiments carried out reveal in further defined embodiments that the solvent in which the solid support is suspended or immersed has an effect on the manner in which the solid support is isolated. Good separation conditions can be achieved when the solid support of the preceding embodiment, which has a particle size of below 50 to 100 μm and an average pore diameter of 1 to 100nm, is suspended in a suspending solvent or a mixture of suspending solvents selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane, and the slurry thus obtained is applied to a separation apparatus or a separation column.

However, for particle sizes greater than 50 μm to 100 μm, another precision of the penultimate embodiment was found to be more appropriate. Good separation conditions can be achieved when the solid support of the penultimate embodiment, which has a particle size of above 50 to 100 μm and an average pore diameter of 1 to 100nm, is applied in dry form to a separation device or separation column and then a suspension solvent or a mixture of suspension solvents, which is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably in a hydrocarbon and most preferably in n-hexane or n-heptane, is applied to the separation device or separation column.

It should be noted that for particles having a particle size of 50 to 100 μm and an average pore diameter of 1 to 100nm, all of the foregoing three embodiments are suitable for use.

A further embodiment for obtaining quinone formulations is the process of the present invention, wherein the composition is dissolved or suspended in a dilution solvent or a mixture of dilution solvents after step iia), step iib) or step iic), the dilution solvent being selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane, and subjecting the diluted composition thus obtained to step iii).

The different types of dilution solvents indicated above have the same meaning as given above for the suspension solvent.

When the suspending solvent and the diluting solvent used for the solid carrier are different, a quinone preparation having a small amount of trace compounds (e.g., organic chlorine, chloride, and copper ions) is obtained.

This is reflected by a method for obtaining a quinone preparation, comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface with a diameter greater than the height of the separation device; the separation device comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica; the particle size of the solid support (preferably silica) is from 5 μm to 1000 μm, preferably from 10 μm to 150 μm, more preferably from 30 μm to 100 μm and most preferably from 40 μm to 63 μm; and having an average pore diameter of 1 to 100 nm; suspending the solid support in a suspending solvent or a mixture of suspending solvents (the suspending solvent being selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in aliphatic hydrocarbons and most preferably suspended in n-hexane, n-heptane or cyclohexane) and applying the slurry thus obtained to a separation device; the composition is then dissolved or suspended in a dilution solvent or solvent mixture after step iia), step iib) or step iic) (the dilution solvent being selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane), and applying the so obtained diluted composition to a separation device (step iii), wherein the suspending solvent or mixture of suspending solvents is different from the diluting solvent or mixture of diluting solvents; iv) optionally subjecting the residue of step iii) to further distillation.

However, good results are also obtained when the suspending solvent and the diluting solvent have the same properties.

This is taken into account by a process for obtaining a quinone preparation, comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation device having a surface diameter greater than the height of the separation device; the separation device comprises a solid support selected from at least one of: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica; the particle size of the solid support (preferably silica) is from 5 μm to 1000 μm, preferably from 10 μm to 150 μm, more preferably from 30 μm to 100 μm and most preferably from 40 μm to 63 μm; and having an average pore diameter of 1 to 100 nm; suspending the solid support in a suspending solvent or a mixture of suspending solvents (the suspending solvent being selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in aliphatic hydrocarbons and most preferably suspended in n-hexane, n-heptane or cyclohexane) and applying the slurry thus obtained to a separation device; the composition is then dissolved or suspended in a dilution solvent or solvent mixture after step iia), step iib) or step iic) (the dilution solvent being selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons and most preferably in n-hexane, n-heptane or cyclohexane), and applying the so obtained diluted composition to a separation device (step iii), wherein the suspending solvent or mixture of suspending solvents is the same as or different from the diluting solvent or mixture of diluting solvents; iv) optionally subjecting the residue of step iii) to further distillation.

Another embodiment involving a separation column rather than a separation device is defined as follows:

a method for obtaining a quinone preparation, the method comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column comprising a solid support selected from at least one of the following: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica; the particle size of the solid support (preferably silica) is from 5 μm to 1000 μm, preferably 10 μm to 150 μm, more preferably 30 μm to 100 μm and most preferably 40 μm to 63 μm; and having an average pore diameter of 1 to 100 nm; suspending the solid support in a suspending solvent or a mixture of suspending solvents (the suspending solvent being selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in aliphatic hydrocarbons and most preferably suspended in n-hexane, n-heptane or cyclohexane) and applying the slurry thus obtained to a separation column; the composition is then dissolved or suspended in a dilution solvent or solvent mixture after step iia), step iib) or step iic) (the dilution solvent being selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons and most preferably in n-hexane or n-heptane), and applying the so obtained diluted composition onto a separation column (step iii), wherein the suspending solvent or mixture of suspending solvents is different from the diluting solvent or mixture of diluting solvents; iv) optionally subjecting the residue of step iii) to further distillation.

However, good results are also obtained when the suspending solvent and the diluting solvent have the same properties.

A method for obtaining a quinone preparation, the method comprising the steps of: i) removing one solvent, or removing the C-containing solvent of the composition of the invention, from a solvent mixture comprising at least two solvents of the composition of the invention; wherein hydrochloric acid is optionally added before or during removal of one solvent from the solvent mixture or before or during removal of the C-containing solvent; iia) distilling off the remaining solvent or solvents or, iib) degassing the composition or, iic) distilling off the remaining solvent or solvents and degassing the composition; iii) applying the composition of step iia), step iib) or step iic) to a separation column comprising a solid support selected from at least one of the following: silica, silica-based materials also known as modified silica, zeolites, alumina, aluminium silicates, carbon-based materials, carbohydrates, polymeric organic materials, acrylic polymers, ascorbic acid, tetrasodium iminodisuccinate, citric acid, dicarboxymethylglutamic acid, ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), methylenephosphonic acid, malic acid or nitrilotriacetic acid (NTA), preferably silica; the particle size of the solid support (preferably silica) is from 5 μm to 1000 μm, preferably from 10 μm to 150 μm, more preferably from 30 μm to 100 μm and most preferably from 40 μm to 63 μm; and having an average pore diameter of 1 to 100 nm; suspending the solid support in a suspending solvent or a mixture of suspending solvents (the suspending solvent being selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably suspended in aliphatic hydrocarbons and most preferably suspended in n-hexane, n-heptane or cyclohexane) and applying the slurry thus obtained to a separation column; the composition is then dissolved or suspended in a dilution solvent or solvent mixture after step iia), step iib) or step iic) (the dilution solvent being selected from the group of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, carboxylic acids, esters, alcohols, ethers, ketones, acetals, ketals, nitriles, dimethyl sulphoxide, formamide, dimethylformamide and water, preferably dissolved or suspended in aliphatic hydrocarbons and most preferably in n-hexane or n-heptane), and applying the so obtained diluted composition onto a separation column (step iii), wherein the suspending solvent or mixture of suspending solvents is the same as the diluting solvent or mixture of diluting solvents; iv) optionally subjecting the residue of step iii) to further distillation.

Another key feature for obtaining the quinone preparation of the present invention is a process wherein iii) after applying the composition of step iia), step iib) or step iic) onto a separation device, the surface of said separation device has a diameter larger than the height of said separation device, or after applying the composition of step iia), step iib) or step iic) onto a separation column; iiia) eluting impurities and by-products with a mixture of non-polar solvent and polar solvent in a volume ratio of 90:10 to 99:1, preferably 92:8 to 98:2 and most preferably 94:6 to 97: 3; iiib) eluting the product with a mixture of non-polar solvent and polar solvent in a volume ratio of 60:40 to 85:15, preferably 70:30 to 82:18 and most preferably 75:25 to 80: 20; iv) optionally subjecting the remainder of step iiib) to further distillation, preferably to at least one further distillation, or iii) after applying the composition of step iia), step iiib) or step iic) to a separation device, the surface of which has a diameter larger than the height of the separation device, or after applying the composition of step iia), step iiib) or step iic) to a separation column; iiia) eluting the product with a mixture of non-polar solvent and polar solvent in a volume ratio of 60:40 to 85:15, preferably 70:30 to 82:18 and most preferably 75:25 to 80: 20; iiib) eluting impurities and by-products with a mixture of non-polar solvent and polar solvent in a volume ratio of 90:10 to 99:1, preferably 92:8 to 98:2 and most preferably 94:6 to 97: 3; iv) optionally subjecting the residue of step iiia) to further distillation, preferably to at least one further distillation.

As understood within the present disclosure, a non-polar solvent is a solvent selected from the group consisting of: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers. The meaning of each of these solvent groups is as indicated above.

As defined in the present specification, a polar solvent is a solvent selected from the group consisting of: alcohols, carboxylic acids, esters, ketones, acetals, ketals, nitriles and water. Each solvent group has the meaning as defined above.

The method of obtaining the quinone formulation of the present invention is further detailed by the following solvents: the non-polar solvent is at least one of heptane or cyclohexane, the polar solvent is at least one of isopropyl acetate or ethyl acetate, and a mixture of the non-polar solvent and the polar solvent (comprising at least one polar solvent and at least one non-polar solvent). As can be seen from the following examples 1019(CN101), 1027(CN98), 1052(CN1) and 1053(CN2), 1056(CN3), 1057(CN107), by using these solvents, quinone formulations with low traces of chloride, organic chloride and copper ions are obtained.

Yet another essential embodiment of the disclosed invention is a quinone preparation, preferably obtained by one of the previously disclosed method embodiments. Preferably the quinone preparation obtained by the method of the invention comprises: A)90 to 100 wt.% of quinone C30, preferably 94 to 100 wt.% of quinone C30, more preferably 96 to 100 wt.%, even more preferably >96 to 100 wt.% and most preferably 98 to 100 wt.%,

Wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl; B)0.0001 to 9999/1000ppm of Cu, preferably 0.0001 to 2999/1000ppm of Cu; C)0.0001 to 100ppm of organic chlorine, preferably 4 to 78 ppm; D) minor components, wherein the sum of A) to D) adds up to 100% by weight.

Another essential embodiment of the invention is a quinone preparation, preferably obtained by the method of the invention as disclosed in at least one of the preceding embodiments, comprising: A)90 to 100 wt.% of quinone (C30), preferably 94 to 100 wt.% of quinone C30, more preferably 96 to 100 wt.%, even more preferably >96 to 100 wt.%, still further preferably 98 to 100 wt.%, and most preferably 100 wt.% minus the amount of components B) to D) as defined below,

wherein R7, R8 and R10 are H or CH₃(ii) a R9 is alkyl, alkenyl; B)0.0001 to 9999/1000ppm of Cu, preferably 0.0001 to 2999/1000ppm Cu; C)0.0001 to 100ppm of organic chlorine, preferably 4 to 78 ppm; D) a minor component, wherein the minor component is all chemical entities other than those mentioned under A), B) and C) in an amount of up to 10% by weight minus the amount of components B) and C), preferably the minor component is all chemical entities other than those mentioned under A), B) and C) in an amount of up to 6% by weight minus the amount of components B) and C), further preferably the minor component is all chemical entities other than those mentioned under A), B) and C) in an amount of up to 4% by weight minus the amount of components B) and C), still further preferably the minor component is all chemical entities other than those mentioned under A), B) and C) in an amount of up to less than 4% by weight minus the amount of components B) and C), still further preferably, the minor component is all chemical entities other than those mentioned under A), B) and C) in an amount of up to 2% by weight minus the amount of components B) and C), and most preferably, the minor component is all chemical entities other than those mentioned under A), B) and C), in a first embodiment in an amount of up to 300ppm, in a second embodiment in an amount of up to 200ppm, in a third embodiment in an amount of up to 100ppm,

And the sum of A) to D) adding up is 100% by weight.

The quinone formulation is adapted to meet purity and trace spectrum requirements required by the feed, dietary supplement or pharmaceutical industry. Thus, the formulation can be delivered directly to the customer.

Yet another embodiment is the use of the quinone preparation of the present invention in animal nutrition or as a dietary supplement or as a beverage additive.

The invention will now be further elaborated by explaining the analytical methods employed, by describing one embodiment of the oxidation of the chroman compound C1 and one embodiment of the method of obtaining the quinone C30 formulation. Then, the embodiments as indicated above will be explained in detail.

Method for determining the amount of quinone C30 in or from a reaction mixture by means of HPLC

In a process from

Was measured on a Zorbax Eclipse PAH HPLC column (particle size 1.8mm, 50mmx4.6 mm) incorporated into an Agilent series 1100 HPLC. The elution system consists of a solvent A and a solvent B, wherein the solvent A consists of 0.1 volume percent of orthophosphoric acid aqueous solution, and the solvent B consists of acetonitrile. The elution profile is as follows:

TABLE 11

The injection volume was 5 μ l and elution occurred at 60 ℃.

Use byCalibration was achieved by external calibration of five indicated substances, each at respective concentrations:

Substance 1: 0.04g/L

Substance 2: 0.08g/L

Substance 3: 0.12g/L

Substance 4: 0.16g/L

Substance 5: 0.20g/L

And when the concentration is plotted against elution time, a calibration line is given.

As indicated in the examples below, the samples were weighed in 100ml volumetric flasks and dissolved or diluted in a predetermined amount of acetonitrile or tetrahydrofuran. An aliquot of 5. mu.l of the solution was injected onto an HPLC column.

As given in the examples below,% values are area percent values based on the total peak area obtained in the respective chromatograms. It can be converted to a wt% value according to the following equation:

weight% (Peak area x response factor of analyte)/weight of sample

Response factor ═ weight of analyte/area of analyte

Method for determining the amount of copper ions

Sample preparation

Samples 300 to 400mg were weighed to the nearest 0.1mg and digested as follows:

lysis of the samples with concentrated sulfuric acid (8ml) at 320 ℃

Complete digestion of the organic residue at 160 ℃ with 7ml of an acid mixture of nitric acid, perchloric acid and sulfuric acid, all concentrated in a volume ratio of 2:1:1

-evaporating excess acid

Adding 50% (v/v) hydrochloric acid to the residue and heating to boiling

After digestion is complete, the exact volume of solution obtained is determined by weighing and corrected for the appropriate density.

The analysis was performed in duplicate. Blanks were run in a similar manner.

Determining

The obtained solution was used as it was to determine copper by inductively coupled plasma emission spectrometry (ICP-OES) using an ICP-OES Agilent5100 apparatus. The detection wavelengths used were: cu 324.754nm and internal standard Sc361.383nm were used via an internal loop. Calibration is achieved with an external standard.

Method for determining the amount (ppm) of chloride (i.e. chloride ions)

Sample preparation:

an aliquot of 200mg of the sample was weighed into a centrifuge tube and supplemented with 10ml of toluene and 10ml of ultrapure water. After separation of the organic phase, the remaining aqueous phase was used for ion chromatography. The analysis was performed in duplicate.

Blanks were run in a similar manner.

Measurement:

chloride was determined by ion chromatography; detection is performed by means of a conductivity detector (after suppression of the basic conductivity):

measuring parameters:

equipment: 850 professional IC (spectral peak thinking series ion chromatograph) (Metrohm)

Front column: metrose Paspp 4/5S-Guard

A chromatographic column: metrose PaSupp5250x4.0 mm

Eluent: 3.2mmol of Na₂CO₃1.0mmol of NaHCO ₃

Eluent flow rate: 0.7 ml/min

A suppressor: MSM (Metrohm)

Injection volume: 25 μ l

Column temperature: 45 deg.C

Detector temperature: 40 deg.C

Calibration range: beta (Cl-) -10. mu.g/l-200. mu.g/l

Method for determining total chlorine (ppm)

The total chlorine is produced by using equipment by microcoulomb method(Elemental Combustion Analyzer from Trace Elemental Instruments).

Specifically, an aliquot of 10 to 20mg of the sample to be analyzed is burned in an oxygen/argon atmosphere (furnace temperature: 1050 ℃ C.). The resulting hydrochloric acid sample, which is free of combustion by-products (e.g., sulfur, nitrogen oxides, and water), is then transferred to a coulometric titration cell. In the cell, auto-titration of chloride ions occurs with automatically generated silver ions according to the following equation:

A g→A g⁺+e^-(Electrolysis)

A g⁺+Cl^-→A gCl

Each assay was performed in duplicate.

Method for determining the amount of organochlorines

The amount of organic chloride is determined as follows:

organo-chlorine [ ppm ] ═ total chlorine [ ppm ] -chloride [ ppm ]

Each having its own embodiment number. Each embodiment is also assigned a consecutive number CN for ease of retrieval.

CN1, example 1052

Batch Synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS No.: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed in α reactor 144.20g (312.51mmol) of α -tocopherol of the formula C5 was dissolved in 386.38g (3.8mol) of 3-hexanol and added to the reactor the reaction mixture was maintained at 25 ℃ while 40l/h of air was bubbled through the reaction mixture for α period of 4.75 hours (overall being an example of α composition of the invention.) the aqueous phase was removed the organic phase was washed three times with water at 48 ℃ and at least one solvent of the organic phase or solvent containing C was removed under reduced pressure 150.9g of crude α -tocopherolquinone of the formula C33 (MW 446.71g/mol), corresponding to α yield of 94.1%.

CN2, example 1053

Purification of samples from CN1 by degassing

148.6g of crude α -tocopheryl quinone of formula C33 at 2.3X10²Pa under reduced pressure and at a temperature of 110 ℃ for 155 minutes, after which 132.8g of an- α -tocopherolquinone of the formula C33 were obtained, the amount of organic chloride being 73ppm, the amount of chloride 47ppm and the amount of copper ions being 70 ppm.

CN3, example 1056

The sample from CN2 was further purified by application to a short plug (short-plu g) as a separation device

A G3 glass suction filter (volume 1L, inner diameter 12.5cm) was packed with a slurry of silica (particle size 40 to 63 μm) in n-heptane to a packing height of 6.7cm, giving a volume of 822 ml. 35.5g of alpha-tocopherolquinone of formula C33 from CN2 (example 1053) were dissolved in 14.2g of n-heptane and applied to wet silica. Under suction, a further 1000ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.428g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.428g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 34.0g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 18ppm, the amount of chloride < 3ppm, and the amount of Cu < 3 ppm.

CN4, COMPARATIVE EXAMPLE 384

Reaction of chroman compound C1 without catalyst

25g (58.04mmol) of the alpha-tocopherol of the formula C5 are dissolved in 225g of dimethylformamide and the reaction mixture is supplemented with 30l/h of air at room temperature for 6 hours. Then, 0.8g (5.8mmol) of potassium hydrogencarbonate was added with stirring and 30l/h of air were added over a further 24 hours. The potassium bicarbonate was filtered off and a sample was taken for HPLC analysis. Quinone C30 could not be detected.

CN5, comparative example 389

Reaction of chroman compound C1 without catalyst

32g (74.29mmol) of alpha-tocopherol of the formula C5 were dissolved in 92.27g of n-hexanol and the reaction mixture was supplemented with 30l/h of air at room temperature for 6 hours. Samples were taken for HPLC analysis. Quinone C30 could not be detected.

CN6, comparative example 1023

Reaction of chroman compound C1 without actively moving gaseous compound containing oxygen through the reactor

55.0g (120mmol) of α -tocopherol of the formula C3 or C5 are dissolved in 550ml of a solvent, 5.12g (30.0mmol) of CuCl are added₂x2H₂O (CAS number: 10125-13-0). The mixture was allowed to stand under air for 8 hours. Then, 200ml of cyclohexane and 100ml of water were added in the case of using methanol as a solvent, and 200ml of water was added in the case of using n-hexanol as a solvent. The phases were separated. The organic phase was washed with water and the corresponding yield was determined from the organic phase by HPLC-wt% as described in table 12.

TABLE 12

CN7, comparative example 1004

Reaction of chroman compound C1 without actively moving gaseous compound containing oxygen through the reactor

1.0g (2.32mmol) of formula C3 or C5 in 10ml of solvent, and placing each mixture in a different 100ml conical flask, 1.0g (37.2mmol) of CuCl was added to each mixture₂(CAS number: 7447-39-4). Each flask was placed on a shaker set at 40rpm at room temperature and shaken for 8 hours or 16 hours, respectively. After 8 or 16 hours, the reaction mixture was filtered over 1.5 g of silica to remove CuCl₂. The silica is washed with the solvent used for the reaction. Table 13 describes the yields determined by HPLC-wt% in the solutions after filtration.

Watch 13

CN8, comparative example 903

Reaction of chroman compound C1 without actively moving gaseous compound containing oxygen through the reactor

5.0g (11.00mmol) of α -tocopherol of the formula C5 are dissolved in 39.5g of methanol and 5.0g (37.19mmol) of CuCl are added₂(CAS number: 7447-39-4). The whole was stirred at room temperature for 48 hours. 20ml of cyclohexane and 25ml of double distilled water were added. The organic phase is washed twice with 25ml of double distilled water and the solvent of the organic phase is removed under reduced pressure. 5.8g of crude product are obtained, which contains 4.59% by weight of quinone of formula C33. This corresponds to a yield of 5.4%, as determined by HPLC.

CN9, comparative example 1015

Reaction of chroman compound C1 without actively moving gaseous compound containing oxygen through the reactor

55.0g (94.0%, 120mmol) of rac- α -tocopherol of the formula C3 are dissolved in 550ml of the corresponding solvent, 5.12g (30.0mmol) of CuCl are added each₂x2H₂O (CAS number: 10125-13-0). Each mixture was stirred at 100 rpm. After 8 hours, 200ml of cyclohexane and 100ml of water were added to each mixture in the case of methanol as solvent and 200ml of water in the case of n-hexanol as solvent. The phases were separated. Washing with water from each mixtureThe organic phases were obtained, and the yield of each organic phase was determined by HPLC-wt% as shown in table 14.

TABLE 14

CN10, example 968

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

1.69g (9.91mmol) of CuCl₂x2H₂O (CAS No.: 10125-13-0) was dissolved in 15g (0.83mol) of water and placed into a reactor together with 83g of n-hexanol a solution of 44.90g (98.93mmol) of α -tocopherol of formula C3 in 39.9g of n-hexanol was added dropwise over 4 hours at 25 ℃ the mixture was stirred for a further 8 hours during the entire reaction air was bubbled through the reaction mixture at a rate of 12 to 14l/h while stirring at 1200rpm, after termination of the reaction 54ml of double distilled water was added to the mixture and the phases were separated, the organic phase was washed twice with 54ml of double distilled water, a sample of the organic phase was taken and the yield of α -tocopherolquinone of formula C32 was revealed to be 92.8% as determined by HPLC.

CN11, example 952

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

4.22g (24.75mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) and 4.19g (98.85mmol) LiCl (CAS number: 7447-41-8) were dissolved in 35.7g of double distilled water, 33g of n-hexanol were added and placed in the reactor, a solution of 90g of n-hexanol (containing 42.15g (98.83mmol) of α -tocopherol of formula C3) was added dropwise to the reactor at room temperature over a time span of 2 hours, while air was injected into the reaction mixture at a rate of 12 to 14l/h, the reaction mixture was stirred at 1000rpm for a further 6 hours while air was bubbled through the mixture, the organic phase was separated and washed three times with 30ml of double distilled water (35 ℃ C.) A sample of this purified organic phase was determined by HPLC-wt.%, showing a yield of 92.7% of quinone of formula C32.

CN12, example 985

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g of water and placed in a reactor A solution of 134.6g (312.51mmol) of α -tocopherol of the formula C3 in 388.3g of n-hexanol is added dropwise over 2 hours at 25 ℃ the mixture is stirred for a further 5 hours.

CN13, example 988

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g of water and placed into the reactor together with 87.46g of n-hexanol A solution of 134.60g (312.51mmol) of α -tocopherol of the formula C3 in 298.86g of n-hexanol is added dropwise over 2 hours at 25 ℃ and the mixture is stirred for a further 4.5 hours throughout the process air is bubbled through the reaction mixture at a rate of 40l/h and simultaneously stirred at a rate of 1000rpm, after the reaction has ended the aqueous phase is separated, a sample of the upper organic phase is taken and the yield of α -tocopherolquinone of the formula C32 is revealed to be 97% as determined by HPLC.

CN14, example 905

Semi-batch synthesis of alpha-tocopherolquinone of formula C33 using appropriate amounts of catalyst

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 143.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (3.8mol) of n-hexanol and added to the reactor, the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the mixture for 6 hours, the aqueous phase is separated and the organic phase is taken up at 25 ℃ washed three times with 170ml of water at 100 ℃/8 × 10²Pa to remove the solvent, then at 100 deg.C/2 × 10²The product was further degassed at Pa to give 100% quinone C33 as determined by HPLC-wt%. By the above method, the amount of organic chloride was determined to be 77ppm, the amount of chloride was determined to be 21ppm, and the amount of copper ion was determined to be 13 ppm.

CN15, example 1052, see CN1

Batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

CN16, example 1086

Semi-batch synthesis of alpha-tocopherolquinone of formula C33 using appropriate amounts of catalyst

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.38g (3.78mol) of n-hexanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 80l/h of air are bubbled through the reaction mixture for a period of 4 hours the aqueous phase is removed the organic phase is washed three times with 170ml of water at 40 ℃ and a sample is taken from the washed organic phase, as determined by HPLC-wt%, revealing a yield of quinone C33 of 95%.

CN17, example 977

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

40.07g (235.04mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was placed in the reactor and dissolved in 84.6g of water A solution of 101.23g (235.03mmol) of α -tocopherol of the formula C3 in 291.9g of n-hexanol was added dropwise to the reactor at 25 ℃ over a time span of 2 hours, while stirring at 1200rpm and injecting air at a rate of 30l/h into the reaction mixture, stirring and air injection continued for a further hour, after which a sample of the upper, organic phase was taken for HPLC analysis, which indicated a yield of 100% of the quinone of the formula C32.

CN18, example 979

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 using appropriate amounts of catalyst

16.87g (99.0mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 36.0g (2.0mol) of water and placed in the reactor.83.0 g of n-hexanol were added to the reactor.42.6 g (98.9mmol) of rac- α -tocopherol C3 was dissolved in 39.9g of n-hexanol and added to the reactor over 4 hours, followed by stirring for 1 hour (1200 rpm). in the entire process, the reaction mixture was maintained at 25 ℃ while 12-14l/h of air was bubbled through the reaction mixture.the aqueous phase was removed and the organic phase was washed three times with 54ml of water, the yield of quinone C32 in the organic phase was determined by HPLC-weight% to be 95.5%.

CN19, example 977, see CN17

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN20, example 1052, see CN1

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

CN21, example 1021

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed into a reactor 134.60g (312.51mmol) of α -tocopherol of formula C5 was dissolved in 386.42g (3.78mol) of n-hexanol and added to the reactor the reaction mixture was maintained at 25 ℃ with stirring at 1000rpm while 40l/h of air was bubbled through the reaction mixture for a period of 4.75 hours A sample of the organic phase was taken and the yield of α -tocopherolquinone of formula C33 was revealed to be 99% as determined by HPLC-weight%.

CN22, example 1060

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed in the reactor. 134.60g (312) 51mmol) of α -tocopherol of the formula C5 was dissolved in 386.36g (3.78mol) of n-hexanol and added to the reactor the reaction mixture was maintained at 25 ℃ with stirring at 1000rpm while 40l/h of air were bubbled through the reaction mixture for a period of 4.75 hours, the aqueous phase was removed, the organic phase was washed three times with water at 48 ℃ and 2X10 at 90 ℃²a sample of the residue was taken and the yield of α -tocopherolquinone of formula C33 was revealed to be 100% as determined by HPLC-wt%.

CN23, example 946

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

4.22g (24.6mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) and 10.06g (49.48mmol) MgCl₂x6H₂O was dissolved in 35.7g of water and placed in a reactor, a solution of 42.6g (98.93mmol) of α -tocopherol of the formula C3 in 122.9g of n-hexanol was also placed in the reactor, then air was bubbled through the mixture at a rate of 12 to 14l/h while the mixture was stirred with an air charge at 23 ℃ for 5 hours after the reaction was terminated, the phases were separated and the organic phase was washed 3 times with 30ml of water at 35 ℃.

CN24, example 1054

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.38g (3.33mol) of 3-heptanol and added to the reactor the reaction mixture is maintained at 25 ℃ with stirring at 1000rpm while 40l/h of air are bubbled through the reaction mixture for a period of up to 5 hours the aqueous phase is removed, the organic phase is washed three times with 170ml of water at 46 ℃ and the at least one solvent or C-containing solvent of the organic phase is removed at 90 ℃ within 90 minutes under reduced pressure, samples are taken and the organic phase is freed of at least one solvent or C-containing solvent, e.g. by HPLCdetermined in weight% revealing a yield of α -tocopherolquinone of formula C33 of 95.2% the amount of organic chloride analyzed by the above method was 60ppm, the amount of chloride was 26ppm and the amount of Cu was 12 ppm.

CN25, example 1032

Short reaction time and high yield, and semi-batch synthesis of the alpha-tocopherol quinone of the formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed in a reactor, which was then supplemented with 87.5g (856.42mmol) of n-hexanol, the reaction mixture was maintained at 40 ℃ with stirring at 1000rpm, while 40l/h of air was bubbled through the reaction mixture, 134.60g (312.51mmol) of the α -tocopherol of the formula C5 was dissolved in 298.87g (2.93mol) of n-hexanol and added dropwise to the reactor over 4 hours while stirring and bubbling, after one hour of further reaction, the aqueous phase was removed, the organic phase was washed three times with water and at 90 ℃ and 2x10 ℃ ²Pa the solvent was removed a sample of the residue was taken and the yield of α -tocopherolquinone of formula C33 was 99% as determined by HPLC-wt. -%. by the above method the amount of organic chloride was determined to be 149ppm, the amount of chloride 21ppm and the amount of copper ions 31 ppm.

CN26, example 877

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 143.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (3.8mol) of n-hexanol and added to the reactor, the reaction mixture is stirred at 1000rpm at 15 ℃ while 40l/h of air are bubbled through the mixture for 6 hours, the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 45-50 ℃, 100 ℃/10 × 10-0²Pa to remove the solvent, then at 100 deg.C/1 × 10²The product was further degassed at Pa to give 99.1% quinone C33 as determined by HPLC-wt%. The amount of organic chlorine was determined to be 27ppm, chlorine, by the above method The amount of the compound was determined to be 9ppm, and the amount of copper ions was determined to be 5 ppm.

CN27, example 905, see CN14

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

CN28, example 935

Short reaction time and high yield, and semi-batch synthesis of the alpha-tocopherol quinone of the formula C32

5.8g (25.9mmol) of CuBr₂(CAS number: 7789-45-9) was dissolved in 9.4g of water and placed into a reactor together with 38.8g of 2-ethyl-1-hexanol A solution of 42.61g (98.99mmol) of α -tocopherol of the formula C3 in 90.6g of 2-ethyl-1-hexanol was added dropwise over 2 hours at 50 ℃ the mixture was stirred for a further 5 hours at 50 ℃ during the entire reaction air was bubbled through the reaction mixture at a rate of 12 to 14l/h while stirring at 1000rpm, after the reaction was terminated, the phases were separated and the organic phase was washed 3 times with 30ml of redistilled water, a sample of the organic phase was taken and the yield of alpha-tocopherolquinone of the formula C32 was revealed to be 34% as determined by HPLC-wt%.

CN29, example 942

Short reaction time and high yield, and semi-batch synthesis of the alpha-tocopherol quinone of the formula C32

4.22g (24.6mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) and 10.06g (49.48mmol) MgCl₂x6H₂O is dissolved in 35.7g of water and placed into the reactor together with 34.6g of n-hexanol a solution of 42.6g (98.93mmol) of α -tocopherol of the formula C3 in 88.3g of n-hexanol is added dropwise over 2 hours at 23 ℃ and then stirred for a further 5 hours during the entire reaction air is bubbled through the reaction mixture at a rate of 12 to 14l/h while stirring at a rate of 1000rpm after the reaction has ended, the phases are separated and the organic phase is washed 3 times (35 ℃) with 30ml of double distilled water, a sample of the organic phase is taken and the yield of α -tocopherolquinone of the formula C32 is revealed to be 97.5% as determined by HPLC-wt%.

CN30, example 952, see CN11

Short reaction time and high yield, and semi-batch synthesis of the alpha-tocopherol quinone of the formula C32

CN31, example 976

Short reaction time and high yield, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

1.69g (9.91mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 15g of water and placed in a reactor, a solution of 42.6g (98.93mmol) of an α -tocopherol of the formula C3 in 122.3g of n-hexanol is likewise placed in the reactor, the reactor is warmed to 25 ℃ and air is bubbled through the reaction mixture at a rate of 12 to 14l/h for 10 hours, while stirring at 1200rpm, 54ml of redistilled water is added, followed by stirring and phase separation, the organic phase is washed twice with 54ml of redistilled water, a sample of the organic phase is taken and the yield of α -tocopherolquinone of the formula C32, as determined by HPLC-wt%, is revealed to be 92.5%.

CN32, example 941

Removing CuCl₂in addition to the metal compound, α -tocopherolquinone of the formula C32 was synthesized in batches

4.2g (24.64mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) and 4.19g (98.85mmol) LiCl (CAS number: 7447-41-8) were dissolved in 35.65g (1.98mol) of water and placed in a reactor 42.6g (98.93mmol) of α -tocopherol of the formula C3 were dissolved in 122.92g (1.20mol) of n-hexanol and added to the reactor the reaction mixture was maintained at 25 ℃ with stirring at 1000rpm while 12-14l/h of air was bubbled through the reaction mixture over 5 hours the aqueous phase was removed, the organic phase was washed three times with 30ml of water, a sample of the organic phase was taken and the yield of alpha-tocopherolquinone of the formula C32 was revealed to be 94.6% as determined by HPLC.

CN33, example 946, see CN23

Removing CuCl₂in addition to the metal compound, α -tocopherolquinone of the formula C32 was synthesized in batches

CN34, example 390

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 relative to the amount of metal compound used in chroman compound C3

4.02g (23.58mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) and 3.99g (94.13mmol) LiCl (CAS number: 7447-41-8) were dissolved in 84.65g (4.69mol) of water and placed in a reactor 101.23g (235.03mmol) of α -tocopherol of the formula C3 were dissolved in 291.9g (2.86mol) of n-hexanol and added to the reactor over 2 hours and 15 minutes and then stirred for 10.3 hours, the reaction mixture was maintained at 22 to 25 ℃ during the entire reaction and stirred at 1000rpm while bubbling 30l/h of air through the reaction mixture, after addition of water and phase separation, a sample of the organic phase revealed a yield of α -tocopherolquinone of the formula C32 of 87.2%, as determined by HPLC-wt%.

CN35, example 946, see CN23

The alpha-tocopherolquinone of formula C32 was synthesized in batches with respect to the amount of the metal compound used for the chroman compound C3

CN36, example 952, see CN11

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 relative to the amount of metal compound used in chroman compound C3

CN37, example 960

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of copper catalyst in one of at least two solvents in a solvent mixture

4.22g (24.8mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 6.3g (350.0mmol) of water and placed in the reactor, 27.9g (273.0mmol) of α -hexanol are added to the reactor, 44.9g (98.9mmol) of an alpha-tocopherol of the formula C3 are dissolved in 95.1g (0.9mol) of α -hexanol and added dropwise to the reactor over a period of 4 hours, and then stirred further for 10 hours, during the entire process the reaction mixture is stirred at 1000rpm at 25 ℃ and 12-14l/h of air are bubbled through the mixture, 54ml of water are added to the reactor and the aqueous phase is separated, the organic phase is washed twice with 54ml of water, yielding 87.2% of quinone C32 as determined by HPLC-weight% in the organic phase.

CN38, example 974

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of copper catalyst in one of at least two solvents in a solvent mixture

3.37g (19.8mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 33.0g (1.8mol) of water and placed in the reactor.83.0 g (0.8mol) of n-hexanol are added to the reactor.44.9 g (98.9mmol) of α -tocopherol of the formula C3 are dissolved in 39.9g (0.4mol) of n-hexanol and added dropwise to the reactor over a period of 4 hours and then stirred for a further 5 hours.during the entire process the reaction mixture is stirred at 1200rpm at 25 ℃ and 12-14l/h of air is bubbled through the mixture, the aqueous phase is separated and the organic phase is washed three times with 54ml of water to give 89.5% of quinone C32 as determined by HPLC-weight% in the organic phase.

CN39, example 958

Batch synthesis of alpha-tocopherolquinone of formula C32 at a copper catalyst concentration in one of at least two solvents in a solvent mixture

4.22g (24.8mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 6.3g (350.0mmol) of water and placed in a reactor, 44.9g (98.9mmol) of α -tocopherol of the formula C3 are dissolved in 123.0g (1.2mol) of n-hexanol and added to the reactor, the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while bubbling 12-14l/h of air through the mixture for 18 hours, 54ml of water are added and the aqueous phase is separated, the organic phase is washed twice with 54ml of water, so that 91.8% of quinone C32 are obtained as determined by HPLC-wt.%.

CN40, example 952, see CN11

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of copper catalyst in one of at least two solvents in a solvent mixture

CN41, example 971

Semi-batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of copper catalyst in one of at least two solvents in a solvent mixture

3.37g (19.8mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 8.0g (444.4mmol) of water and placed in the reactor. 83g (0.81mol) of n-hexanol were added to the reactor. 44.9g (98) 9mmol) of α -tocopherol of the formula C3 is dissolved in 39.9g (0.4mol) of n-hexanol and added dropwise to the reactor over a period of 4 hours and then stirred for a further 12 hours, the reaction mixture is stirred at 25 ℃ at 1200rpm and 12-14l/h of air are bubbled through the mixture throughout the process 54ml of water are added to the reactor and the aqueous phase is separated, the organic phase is washed twice with 54ml of water to give 93.5% of quinone C32 as determined by HPLC-wt%.

CN42, example 872

Batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of chroman compound C1 in one of at least two solvents in a solvent mixture

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor, 142.6g (312.5mmol) of α -tocopherol of the formula C3 are dissolved in 285.2g (2.8mol) of n-hexanol and added to the reactor, the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the mixture for 5 hours, the mixture is washed three times with 170ml of water at 45 ℃ to give 97.5% of quinone C32 as determined by HPLC-weight% in the organic phase.

CN43, example 1052, see CN1

Batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of chroman compound C1 in one of at least two solvents in a solvent mixture

CN44, example 875

Batch synthesis of alpha-tocopherolquinone of formula C32 at a concentration of chroman compound C1 in one of at least two solvents in a solvent mixture

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 142.6g (312.5mmol) of α -tocopherol of the formula C3 are dissolved in 142.6g (1.4mol) of n-hexanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the mixture for 5.5 hours, the mixture is washed three times with 170ml of water at 45 ℃ in order to re-weigh, e.g. by HPLCThe% amounts were determined in the organic phase to give 91.1% quinone C32.

CN45, example 403

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

22.76g (133.7mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 47.9g (2.7mol) of water and placed in a reactor 57.2g (89.5mmol) of R, R, R- α -tocopherol C5 are dissolved in 165.0g of n-hexanol and added to the reactor, the reaction mixture is maintained at 25 ℃ with stirring (750rpm) while 30l/h of air are bubbled through the reaction mixture for 7 hours, the individual phases are separated and the aqueous phase is removed, the organic phase is washed three times with 100ml of water and washed at 85 ℃/3.5x10 ²the solvent was removed Pa a sample of the residue was taken and the yield of α -tocopherolquinone of formula C33 was revealed to be 97.9% as determined by HPLC.

CN46, example 872, see CN42

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN47, example 405

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

11.93g (70.0mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 25.1g (1.4mol) of water and placed in a reactor 30.0g (46.5mmol) of α -tocopherol of the formula C5 are dissolved in 173.0g (1.7mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 850rpm at 35-40 ℃ while bubbling 30l/h of air through the mixture for 6 hours the aqueous phase is separated, the organic phase is washed three times with 100ml of water and the solvent is removed under reduced pressure at 85 ℃ to yield 96.2% of quinone C33 as determined by HPLC-wt%.

CN48, example 941, see CN32

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN49, example 1052, see CN1

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C33 is synthesized in batches

CN50, example 971, see CN41

The weight ratio of the organic solvent to the water is used for synthesizing the alpha-tocopherol quinone with the formula C32 in a semi-batch mode

CN51, example 968, see CN10

The weight ratio of the organic solvent to the water is used for synthesizing the alpha-tocopherol quinone with the formula C32 in a semi-batch mode

CN52, example 952, see CN11

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN53, example 958, see 39

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN54, example 875, see CN44

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN55, example 974, see CN38

The weight ratio of the organic solvent to the water is used for synthesizing the alpha-tocopherol quinone with the formula C32 in a semi-batch mode

CN56, example 390, see CN34

The weight ratio of the organic solvent to the water, and the alpha-tocopherol quinone of the formula C32 is synthesized in batches

CN57, example 960, see CN37

The weight ratio of the organic solvent to the water is used for synthesizing the alpha-tocopherol quinone with the formula C32 in a semi-batch mode

CN58, example 905, see CN14

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN59, example 1032, see CN25

Short reaction time, and semi-batch synthesis of alpha-tocopherol quinone of formula C33

CN60, example 879

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed in a reactor134.6g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.38g (3.0mol) of 2-octanol and added to the reactor the reaction mixture is stirred at 1000rpm at 25 ℃ while 80l/h of air are bubbled through the mixture for up to 6 hours, the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 45 ℃, 130 ℃/10 × 10²Pa to remove the solvent, then 130 ℃/1.3 × 10²The product was further degassed at Pa to give 98.8% quinone C33 as determined by HPLC-wt%. By the above method, the amount of organic chloride was determined to be 61ppm, the amount of chloride was determined to be 9ppm, and the amount of copper ion was determined to be 11 ppm.

CN61, example 1021, see CN21

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN62, example 1074

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.38g (3.33mol) of n-hexanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the reaction mixture for a period of up to 6 hours the aqueous phase is removed the organic phase is washed three times with 170g of redistilled water at 44-49 ℃ and a sample is taken from the washed and slightly concentrated organic phase, as determined by HPLC-weight%, revealing a yield of 98% of quinone C33.

CN63, example 941, see CN32

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C32

CN64, example 877, see CN26

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN65, example 1054, see CN24

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN66, example 1052, see CN1

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN67, example 1086, see CN16

Short reaction time, and batch synthesis of alpha-tocopherol quinone of formula C33

CN68, example 1024

Intermediate temperature, batch synthesis of alpha-tocopherolquinone of formula C33

9.99g (58.60mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 21.11g (1.17mol) of water and placed in a reactor 100.95g (234.38mmol) of α -tocopherol of the formula C5 are dissolved in 289.77g (2.84mol) of n-hexanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 10 ℃ while bubbling 30l/h of air through the reaction mixture for a period of up to 9 hours the aqueous phase is removed the organic phase is washed three times with 128ml of water at 40-45 ℃ and a sample is taken from the washed organic phase, as determined by HPLC-wt%, revealing a yield of quinone C33 of 93.6%, the organic phase containing mainly n-hexanol is removed in 45 minutes at 90 ℃ of at least one solvent or C-containing solvent, the amount of organic chlorine is determined as 100ppm by the above method, the amount of chloride is determined as 100ppm and the amount of copper ions is determined as 105 ppm.

CN69, example 877, see CN26

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN70, example 883

Intermediate temperature, batch synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.38g (4.4mol) of n-pentanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 15 ℃ while 40l/h of air are bubbled through the reaction mixture for a period of 7 hours the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 20-41 ℃, 100 ℃ C/10×10²Pa to remove the solvent, then at 100 deg.C/2.4 × 10²The product was further degassed at Pa to give 93.4% quinone C33 as determined by HPLC-wt%. By the above method, the amount of organic chloride was determined to be 30ppm, the amount of chloride was determined to be 480ppm, and the amount of copper ion was determined to be 630 ppm.

CN71, example 941, see CN32

Intermediate temperature, batch synthesis of alpha-tocopherolquinone of formula C32

CN72, example 942, see CN29

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C32

CN73, example 1060, see CN22

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN74, example 905, see CN14

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN75, example 988, see CN13

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C32

CN76, example 894

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 143.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (4.4mol) of n-pentanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the mixture for 8 hours, the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 25 ℃, 100 ℃/10 × 10-0²Pa to remove the solvent, then at 100 deg.C/2 × 10²The product was further degassed at Pa to give 94.0% quinone C33 as determined by HPLC-wt%.

CN77, example 1054, see CN24

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN78, example 879, see CN60

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN79, example 994

Intermediate temperature, batch synthesis of alpha-tocopherolquinone of formula C32

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C3 are dissolved in 386.32g (3.78mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 25 ℃ at a speed of 1000rpm while 40l/h of air are bubbled through the reaction mixture for a period of up to 7 hours the aqueous phase is separated and the organic phase is washed three times with water the at least one solvent or C-containing solvent of the organic phase is removed at 80 ℃ under reduced pressure to yield 145.3g, corresponding to a yield of 92.1% as determined by HPLC-weight%, at 110 ℃ and 2.3 × 10²The product was degassed at Pa and the amount of organic chloride was determined to be 126ppm, the amount of chloride 14ppm and the amount of Cu 49 ppm.

CN80, example 1032, see CN25

Intermediate temperature, semi-batch synthesis of alpha-tocopherolquinone of formula C33

CN81, example 1042

Influence of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, semi-batch synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor, which is then supplemented with 87.5g (856.42mmol) of n-hexanol, the reaction mixture is maintained at 25 ℃ with stirring at 1000rpm, while 40l/h of air are bubbled through the reaction mixture, 134.60g (312.51mmol) of the α -tocopherol of the formula C5 are dissolved in 298.87g (2.93mol) of n-hexanol and added dropwise to the reactor within 4 hours while stirring and bubbling, after a further reaction for two hours, the aqueous phase is removed, the organic phase is washed three times with 170ml of water at 40-47 ℃, the solvent is removed from the organic phase,α -tocopherolquinone of formula C33 gave 98.6% as determined by HPLC-wt. -%. by the above method, the amount of organic chloride was determined to be 88ppm, the amount of chloride was determined to be 12ppm, and the amount of copper ions was determined to be 8 ppm.

CN82, example 1032, see CN25

Influence of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, semi-batch synthesis of alpha-tocopherolquinone of formula C33

This example is itself an inventive example, however, it is used as a comparison with respect to reaction temperature and reaction time on the aforementioned trace formation.

CN83, example 1036

Influence of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, semi-batch synthesis of alpha-tocopherolquinone of formula C33

This example is itself an inventive example, however, it is used as a comparison with respect to reaction temperature and reaction time on the aforementioned trace formation.

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) was dissolved in 28.15g (1.56mol) of water and placed into a reactor, which was then supplemented with 87.5g (671.89mmol) of 2-ethylhexanol, the reaction mixture was maintained at 55 ℃ while stirring at 1000rpm, 40l/h of air was bubbled through the reaction mixture, 134.60g (312.51mmol) of α -tocopherol of formula C5 was dissolved in 298.72g (2.29mol) of 2-ethylhexanol and added dropwise to the reactor within 4 hours while stirring and bubbling, after one hour of further reaction, the aqueous phase was removed, the organic phase was washed three times with 170ml of water at 48 ℃.

CN84, example 886

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 143.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (3.8mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 1000rpm at 10 ℃ while bubbling 40l/h of air through the mixture for 8 hours, the mixture is washed three times with 170ml of water at 45-50 ℃ and then washed with 100 ℃/10x10²Removing solvent under Pa at 100 deg.C/1 × 10²The product was further degassed at Pa as determined by HPLC-wt% to give α -tocopherolquinone c33 at 95.6% by the above method the amount of organic chloride was determined to be 70ppm, the amount of chloride was determined to be 80ppm and the amount of copper ions was determined to be 95 ppm.

CN85, example 877, see CN26

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

CN86, example 883, see CN70

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

CN87, example 1080

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 144.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (3.8mol) of n-hexanol and added to the reactor the reaction mixture is stirred at a speed of 1000rpm at 25 ℃ while 40l/h of air are bubbled through the mixture for 4.75 hours, the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 47-49 ℃, 100 ℃/10 × 10-0²Pa to remove the solvent, then at 100 deg.C/1 × 10²The product was further degassed at Pa, as determined by HPLC-wt%To obtain 94.5% of quinone C33. By the above method, the amount of organic chloride was determined to be 44ppm, the amount of chloride was determined to be 32ppm, and the amount of copper ion was determined to be 30 ppm.

CN88, example 905, see CN14

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

CN89, example 1054, see CN24

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

CN90, example 879, see CN60

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

CN91, example 1024, see CN68

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

This example is itself an inventive example, however, it is used as a comparison with respect to reaction temperature and reaction time on the aforementioned trace formation.

CN92, example 1040

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

This example is itself an inventive example, however, it is used as a comparison with respect to reaction temperature and reaction time on the aforementioned trace formation.

13.32g (78.13mmol) of CuCl ₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.42g (3.78mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 25 ℃ at 1000rpm while 40l/h of air are bubbled through the reaction mixture for a period of up to 23 hours the aqueous phase is removedThree times and the organic phase is freed from at least one solvent or solvent containing C at 90 ℃ under reduced pressure within 45 minutes. Sampling was performed and the yield of quinone C33 was revealed to be 96% as determined by HPLC-wt%. By the above method, the amount of organic chloride was determined to be 293ppm, the amount of chloride was determined to be 27ppm, and the amount of copper ions was determined to be 23 ppm.

CN93, example 1010

Effect of reaction temperature and reaction time on the formation of traces of reagents and traces of by-products, the batch Synthesis of alpha-tocopherolquinone of formula C33

This example is itself an inventive example, however, it is used as a comparison with respect to reaction temperature and reaction time on the aforementioned trace formation.

13.32g (78.1mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.2g (1.6mol) of water and placed in a reactor 144.2g (312.5mmol) of α -tocopherol of the formula C5 are dissolved in 386.4g (3.8mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 1000rpm at 40 ℃ while 40l/h of air are bubbled through the mixture for 5 hours, the aqueous phase is separated and the organic phase is washed three times with 170ml of water at 40 ℃, 90 ℃/2 × 10 ²Removal of the solvent under Pa, as determined by HPLC-wt%, gives 148.9g, 88.8 t% of α -tocopheryl quinone of formula C33. by the above method, the amount of organic chloride is determined to be 250ppm, the amount of chloride is determined to be 70ppm, and the amount of copper ions is determined to be 100 ppm.

CN94, example 1044, sample from example 1042

Effect of the separation apparatus on the formation of reagent traces and by-product traces, semi-batch Synthesis of alpha-tocopherolquinone of formula C33

A G3 glass suction filter (volume: 1L, inner diameter: 12.5cm) was charged with 355G of a slurry of silica (particle size: 40 to 63 μm) in n-heptane to a fill height of 6.7cm, giving a volume of 822 ml. 35.5g of alpha-tocopherolquinone of formula C33 from example 1042 (cf. CN81) were dissolved in 35.5g of n-heptane and applied to wet silica. Under suction, a further 1000ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.428g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.428g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 34.1g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 16ppm, the amount of chloride < 3ppm, and the amount of Cu < 3 ppm.

CN95, example 1033, sample from example 1032

Effect of the separation apparatus on the formation of reagent traces and by-product traces, semi-batch Synthesis of alpha-tocopherolquinone of formula C33

A G3 glass suction filter (volume: 1L, inner diameter: 12.5cm) was charged with 355G of a slurry of silica (particle size: 40 to 63 μm) in n-heptane to a fill height of 6.7cm, giving a volume of 822 ml. 35.5g of alpha-tocopherolquinone of formula C33 from example 1032 (cf. CN25) were dissolved in 35.5g of n-heptane and applied to wet silica. Under suction, a further 1000ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.428g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.428g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 34.1g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 76ppm, the amount of chloride was < 3ppm, and the amount of Cu was < 3 ppm.

CN96, example 1038, sample from example 1036

Effect of the separation apparatus on the formation of reagent traces and by-product traces, semi-batch Synthesis of alpha-tocopherolquinone of formula C33

A G3 glass suction filter (volume: 1L, inner diameter: 12.5cm) was charged with 355G of a slurry of silica (particle size: 40 to 63 μm) in n-heptane to a fill height of 6.7cm, giving a volume of 822 ml. 35.5g of alpha-tocopherolquinone of formula C33 from example 1036 (see CN83) were dissolved in 35.5g of n-heptane and applied to wet silica. Under suction, a further 1000ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.428g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.428g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 30.0g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 210ppm, the amount of chloride < 3ppm, and the amount of Cu < 3 ppm.

CN97, example 895, sample from example 886

Effect of the separation apparatus on the formation of traces of reagents and traces of by-products for the batchwise synthesis of alpha-tocopherolquinone of formula C33

A G3 glass suction filter (volume 1L, inner diameter 12.5cm) was filled with 300G of a slurry of silica (particle size 40 to 63 μm) in n-heptane to a fill height of 6.5 cm. 30.0g of alpha-tocopherolquinone of formula C33 from example 886 (see CN84) were dissolved in 13g of n-heptane and applied to wet silica. Under suction, a further 500ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.403g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.403g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 25.9g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 12ppm, the amount of chloride < 1ppm, and the amount of Cu < 3 ppm.

CN98, example 1027, sample from example 1024

Effect of the separation apparatus on the formation of traces of reagents and traces of by-products for the batchwise synthesis of alpha-tocopherolquinone of formula C33

A G3 glass suction filter (volume: 1L, inner diameter: 12.5cm) was charged with 355G of a slurry of silica (particle size: 40 to 63 μm) in n-heptane to a fill height of 6.7cm, giving a volume of 822 ml. 35.5g of alpha-tocopherolquinone of formula C33 from example 1024 (cf. CN68) were dissolved in 14.2g of n-heptane and applied to wet silica. Under suction, a further 1500ml of n-heptane were added. Thereafter, the fractions 1 and 2 were obtained by eluting twice with 2.428g of an n-heptane solution containing 3% by weight of isopropyl acetate, and then fraction 3 was obtained by eluting once with 2.428g of an n-heptane solution containing 20% by weight of isopropyl acetate. The fraction 3 was separated from the solvent and dried to obtain 33.8g of alpha-tocopherolquinone of formula C33 (quinone preparation of the present invention). The amount of organic chloride in the quinone formulation was 20ppm, the amount of chloride < 3ppm, and the amount of Cu < 3 ppm.

CN99, example 1092, sample from example 1091

Effect of the separation apparatus on the formation of traces of reagents and traces of by-products for the batchwise synthesis of alpha-tocopherolquinone of formula C33

Example 1091

13.32g (78.13mmol) of CuCl₂x2H₂O (CAS number: 10125-13-0) is dissolved in 28.15g (1.56mol) of water and placed in a reactor 134.60g (312.51mmol) of α -tocopherol of the formula C5 are dissolved in 386.42g (3.78mol) of n-hexanol and added to the reactor the reaction mixture is stirred at 1000rpm at 15 ℃ while 40l/h of air are bubbled through the reaction mixture for a period of 4.75 hours the aqueous phase is removed the organic phase is washed three times with 170ml of water at 40 ℃ 100 ℃/10 × 10²Pa the organic phase is freed of solvent and then dried at 100 ℃ at 1 × 10²The product was further degassed at Pa as determined by HPLC-wt% to give 87.4% quinone C33. By the above method, the amount of organic chloride was determined to be 10ppm, the amount of chloride was determined to be 140ppm, and the amount of copper ion was determined to be 160 ppm.