阅读说明：本技术 由二氧化碳生产缩醛的方法 (Process for producing acetals from carbon dioxide ) 是由 T·绍布 I·杰夫托维科伊 A·S·K·哈什米 关根浩平 于 2020-02-05 设计创作，主要内容包括：本发明涉及一种由二氧化碳制备缩醛的方法。本发明还涉及包含至少一种多齿配体和至少一种单齿配体的含磷配体的混合物。此外,本发明还涉及包含至少一种多齿配体和至少一种单齿配体的混合物在用于制备缩醛的过渡金属络合物中的用途。(The present invention relates to a process for the preparation of acetals from carbon dioxide. The invention also relates to a mixture of phosphorus-containing ligands comprising at least one polydentate ligand and at least one monodentate ligand. Furthermore, the present invention relates to the use of a mixture comprising at least one polydentate ligand and at least one monodentate ligand for the preparation of transition metal complexes for acetals.)

1. A process for the production of a compound of formula (I)

Wherein

Each R¹Are independently selected from

C₁-C₄₀Alkyl, unsubstituted or substituted by 1,2,3, 4 or 5 groups selected from OH, halogen, C₁-C₆Alkoxy or C₆-C₂₀Aryl substituent substitution;

or two R¹Together form a linear chain selected from C₂-C₉Divalent bridging radicals R of alkanediyl radicals²Wherein said alkanediyl is unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₆Alkyl or C₁-C₆Substituent substitution of alkoxy;

the process comprises at least one reaction step in which carbon dioxide and hydrogen are reacted with at least one compound of the general formula (II.a) or (II.b)

R¹-OH (II.a),

HO-R²-OH (II.b),

Wherein

R¹As defined above;

R²is selected from straight chain C₂-C₉A divalent radical of an alkanediyl, wherein said alkanediyl is unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₆Alkyl or C₁-C₆Substituent substitution of alkoxy;

the reaction is carried out in the presence of

-at least one transition metal catalyst complex comprising at least one polydentate ligand containing at least three phosphorus atoms capable of coordinating to a transition metal, wherein the transition metal is selected from metals of groups 7, 8, 9 and 10 of the periodic table of the elements according to IUPAC;

-at least one monodentate ligand containing one phosphorus atom;

-at least one lewis acid.

2. The process according to claim 1, wherein the molar ratio of transition metal catalyst complex to the at least one monodentate ligand is in the range of 1:5.0 to 1: 1.1.

3. The process according to claim 1 or 2, wherein the metal of the transition metal catalyst complex is selected from ruthenium, iron, osmium, cobalt, rhodium, rhenium, iridium, nickel, platinum and palladium, preferably ruthenium and cobalt.

4. A process according to claim 1,2 or 3, wherein the multidentate ligand is selected from the group consisting of organic phosphines, organic phosphites, organic phosphonites, organic phosphinites and organic phosphoramidites, and the transition metal catalyst complex preferably comprises at least one multidentate ligand selected from the group consisting of compounds of formula (III)

Wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another, is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl can carry 1,2,3, 4 or 5 substituents selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxyl, mercapto, polyalkylene oxide, polyalkylene imine, carboxyl, P (aryl)₂、SO₃H. Sulfonic acid group, NE¹E²、NE¹E²E³⁺X^-Halogen, nitro, formyl, acyl and cyano, wherein E¹、E²And E³Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an anionic equivalent and in which the radicals cycloalkyl, heterocycloalkyl, aryl and heteroaryl R^A、R^B、R^C、R^D、R^EAnd R^FIt may carry 1,2,3, 4 or 5 substituents selected from alkyl and the above para-alkyl radicals R^A、R^B、R^C、R^D、R^EAnd R^FThe mentioned substituents, or

R^AAnd R^BAnd/or R^CAnd R^DAnd/or R^EAnd R^FWith P atoms and, if present, groups X bonded to them¹、X²、X⁵、X⁶、X⁸And X⁹Together form a 5-to 8-membered heterocycle which is optionally fused with one, two or three groups selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where the heterocycle and, if present, the groups fused on may each, independently of one another, carry 1,2,3 or 4 groups selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, alkoxy, halogen, carboxy, SO₃H. Sulfonic acid group, NE⁴E⁵、NE⁴E⁵E⁶⁺X^-Nitro, alkoxycarbonyl, formyl, acyl and cyano, in which E⁴、E⁵And E⁶Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

X¹、X²、X⁵、X⁶、X⁸and X⁹Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, X³、X⁴And X⁷Independently of one another are C₁-C₁₀Alkanediyl, O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Y is chosen from C₁-C₁₀An alkanetriyl group, a bridging group of N or P,

a. b, c, d, e, f, g, h and i are independently of one another 0 or 1.

5. The process according to any one of claims 1 to 4, wherein the transition metal catalyst complex comprises at least one ligand selected from compounds of formula (III), wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another, are alkyl, aryl or heteroaryl, where alkyl, aryl or heteroaryl can carry 1,2,3, 4 or 5 substituents selected from alkoxy, NE¹E²、NE¹E²E³⁺X^-Wherein E is¹、E²And E³Identical or different and selected from hydrogen or alkyl, and X^-Is an equivalent to the anion of an anion,

X¹、X²、X⁵、X⁶、X⁸and X⁹As defined in claim 4, wherein the first and second groups are,

X³、X⁴and X⁷Are methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene,

y is selected from C₁-C₆-an alkanetriyl or N bridging group,

a. b, e, f, h and i are each independently of the others 0 or 1, preferably 0,

c. d and g are 0 or 1, preferably 1.

6. The process according to any one of the preceding claims, wherein the transition metal catalyst complex comprises at least one additional ligand selected from the group consisting of hydrides, halides, amides, carboxylates, acetylacetonates, aryl-or alkylsulfonates, CO, alkenes, dienes, cycloalkenes, nitriles, arenes and heteroarenes.

7. The process according to any one of the preceding claims, wherein the transition metal catalyst complex is selected from the group consisting of

Ru (tris (diphenylphosphinomethyl) ethane) (2-methylallyl) ], a salt thereof,

[ Ru (tris (diphenylphosphinomethyl) ethane) (H)₂]、

[ Ru (tris (diphenylphosphinomethyl) amine) (2-methylallyl) ], a salt thereof, and a metal salt thereof,

[ Ru (tris (diphenylphosphinomethyl) amine) (H)₂]、

[ Ru (tris (diphenylphosphinoethyl) amine) (2-methylallyl) ] or

[ Ru (tris (diphenylphosphinoethyl) amine) (H)₂]。

8. The process according to any of the preceding claims, wherein a transition metal catalyst complex is used in an amount of up to 50 mol%, preferably up to 20 mol%, in particular from 0.001 mol% to 20 mol%, calculated as transition metal and based on the amount of compound (II).

9. The process according to any one of the preceding claims, wherein said at least one monodentate ligand is selected from the group consisting of organophosphines, organophosphites, organophosphonites, organophosphinites and organophosphonites, preferably wherein said at least one monodentate ligand comprises at least one ligand selected from the group consisting of compounds of formula (IV)

Wherein

R^M、R^NAnd R^OIndependently of one another, is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl can carry 1,2,3, 4 or 5 substituents selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, carboxy, SO, polyalkylene imine, and optionally alkylene imine₃H. Sulfonic acid group, NE¹E²、NE¹E²E³⁺X^-Halogen, nitro, formyl, acyl and cyano, wherein E¹、E²And E³Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

and wherein the radicals cycloalkyl, heterocycloalkyl, aryl and heteroaryl R^M、R^NAnd R^OIt may carry 1,2,3, 4 or 5 substituents selected from alkyl and the above para-alkyl radicals R^G、R^HAnd R^IThe mentioned substituents, or

R^MAnd R^NOr R^NAnd R^OWith P atoms and, if present, groups X bonded to them¹⁰、X¹¹And X¹²Together form a 5-to 8-membered heterocycle which is optionally fused with one, two or three groups selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where the heterocycle and, if present, the groups fused on may each, independently of one another, carry 1,2,3 or 4 groups selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, alkoxy, halogen, carboxy, SO₃H. Sulfonic acid group, NE⁴E⁵、NE⁴E⁵E⁶⁺X^-Nitro, alkoxycarbonyl, formyl, acyl and cyano, in which E⁴、E⁵And E⁶Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

X¹⁰、X¹¹and X¹²Are independent of each otherGround is O, S, CR^xR^y、SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and p, q and r independently of one another are 0 or 1.

10. The process according to any one of the preceding claims, wherein the at least one monodentate ligand is selected from the group consisting of triphenylphosphine, tri (p-tolyl) phosphine, tri (4-methoxyphenyl) phosphine, tri (4-trifluoromethylphenyl) phosphine, tri (o-tolyl) phosphine, triphenyl phosphite and trimethyl phosphite.

11. The process according to any one of the preceding claims, wherein the molar ratio of the transition metal catalyst complex to the at least one monodentate ligand is in the range of 1:3.0 to 1:1.2, in particular in the range of 1:2.5 to 1: 1.3.

12. The process according to any of the preceding claims, wherein the at least one Lewis acid is selected from the group consisting of Al (OTf)₃、Sc(OTf)₃、Fe(OTf)₃、Yb(OTf)₃、Eu(OTf)₃、B(C₆F₅)₃、B(2,4-(CF₃)₂C₆H₃)₃、BF₃、BF₃*Et₂O、BF₃*THF、Ag(OTf)、Pr(OTf)₃And Zn (OTf)₃。

13. A process according to any preceding claim wherein the polydentate ligand is tris (diphenylphosphinomethyl) methane and the monodentate ligand is triphenyl phosphite.

14. The method according to any one of the preceding claims, wherein each R in formula (I)¹Is selected from C₁-C₂₀Alkyl, unsubstituted or substituted by 1,2,3, 4 or 5 groups selected from OH, halogen, C₁-C₆Alkoxy and C₆-C₁₀Aryl group.

15. The method according to any one of the preceding claims, wherein each R in formula (I)¹Is selected from C₁-C₆Alkyl, unsubstituted or substituted by 1,2,3 or 4 radicals selected from OH, halogen and C₁-C₄Substituent of alkoxy.

16. The method according to any one of the preceding claims, wherein each R in formula (I)¹Is selected from C₁-C₄Alkyl, which is unsubstituted or substituted with 1 or 2 substituents selected from OH and halogen.

17. The method according to any one of the preceding claims, wherein each R in formula (I)¹Selected from unsubstituted C₁-C₄Alkyl, especially C₁-C₂An alkyl group.

18. A mixture comprising at least one polydentate ligand and at least one monodentate ligand as defined in any one of claims 1 to 13, wherein the molar ratio of polydentate ligand to the at least one monodentate ligand is in the range of 1:5.0 to 1: 1.1.

19. Use of a mixture as claimed in claim 18 in the preparation of a transition metal complex of compound (I) as claimed in any one of claims 1 to 17.

Technical Field

The present invention relates to a process for the preparation of acetals from carbon dioxide. The invention also relates to a mixture of phosphorus-containing ligands comprising at least one polydentate ligand and at least one monodentate ligand. Furthermore, the present invention relates to the use of a mixture comprising at least one polydentate ligand and at least one monodentate ligand for the preparation of transition metal complexes for acetals.

Background

Dialkoxymethane or acetals of formaldehyde, especially dimethoxymethane, are of particular commercial interest. Because they can increase octane number and reduce carbon smoke and NO_xThey are attractive candidates for use as gasoline additives. In addition, acetals are also valuable compounds for the pharmaceutical or cosmetic industry. Acetals of formaldehyde are particularly useful as solvents for the preparation of pharmaceutical or cosmetic compounds. Therefore, there is an urgent need for a novel and simple process for producing the acetal. To minimize production costs, the process should be particularly highly reactive and very selective for the formation of the desired acetal.

Acetals of formaldehyde are generally prepared by oxidation of alcohols or reaction of formaldehyde with the corresponding alcohols. Formaldehyde itself is produced by the oxidation of methanol.

Another method for producing acetals of formaldehyde is the direct reduction of carbon dioxide with hydrogen in the presence of the corresponding alcohol using a transition metal catalyst and a lewis acidic co-catalyst.

Angewandte Chemie International Edition,2016, DOI:10.1002/anie.201606427 and Angewandte Chemie International Edition,2017, DOI:10.1002/anie.201702905 describe the use of a Lewis acid promoter such as Al (OTf)₃Or HNTf₂(Tf: trifluoromethanesulfonic acid) in combination with a catalyst [ Ru (triphosphos) (tmm)]Or [ Co (triphos) ]](triphos: 1,1, 1-tris (diphenylphosphinomethyl) ethane, tmm: trimethyleneMethyl methane) from carbon dioxide, hydrogen and methanol. Dimethoxymethane (DMM) has been formed with a Turn Over Number (TON) of 71. It was investigated that higher loading of catalyst resulted in lower TON of DMM. However, the lower loading of catalyst resulted in an increase in the TON of the DMM. The turnover number of the by-product Methyl Formate (MF) is likewise increased.

Journal of the American Chemical Society,2018, DOI:10.1021/jacs.8b10233 discloses a catalyst for use in combination with Al (OTf) as a cocatalyst₃Bound ruthenium catalysts with tridentate phosphine ligand tris (diphenylphosphinomethylene) amine₂、H₂And methanol to the acetal dimethoxymethane, whereby high turnover numbers can be achieved. However, the selectivity is still low, since methyl formate is formed as a by-product with a high TON. Higher selectivity to dimethoxymethane can only be achieved at significantly lower catalyst activity.

Currently, high catalyst activity is only obtained at low selectivity to the desired product. The prior art processes are therefore uneconomical, since unwanted methyl formate has to be separated from the product and methanol is lost due to the formation of by-products. Therefore, high activity of the catalyst system and selectivity of the reaction to acetal are required to minimize production costs.

It is therefore an object of the present invention to overcome these disadvantages. In particular, it is an object of the present invention to provide an optimized catalyst system to obtain the desired acetals with high activity but with only small amounts of by-products, such as formates.

The underlying problem of the present invention is solved by a process wherein carbon dioxide and hydrogen are reacted with at least one alcohol compound in the presence of a transition metal catalyst complex comprising at least one polydentate ligand, at least one monodentate ligand and a lewis acid.

Summary of The Invention

The invention relates to a method for producing compounds of formula (I)

Wherein

Each R¹Are independently selected from

C₁-C₄₀Alkyl, unsubstituted or substituted by 1,2,3, 4 or 5 groups selected from OH, halogen, C₁-C₆Alkoxy or C₆-C₂₀Aryl substituent substitution;

or two R¹Together form a linear chain selected from C₂-C₉Divalent bridging radicals R of alkanediyl radicals²Wherein said alkanediyl is unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₆Alkyl or C₁-C₆Substituent substitution of alkoxy;

the process comprises at least one reaction step in which carbon dioxide and hydrogen are reacted with at least one compound of the general formula (II.a) or (II.b)

R¹-OH (II.a),

HO-R²-OH (II.b),

Wherein

R¹As defined above;

R²is selected from straight chain C₂-C₉A divalent radical of an alkanediyl, wherein said alkanediyl is unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₆Alkyl or C₁-C₆Substituent substitution of alkoxy; the reaction is carried out in the presence of

-at least one transition metal catalyst complex comprising at least one polydentate ligand containing at least three phosphorus atoms capable of coordinating to a transition metal, wherein the transition metal is selected from metals of groups 7, 8, 9 and 10 of the periodic table of the elements according to IUPAC;

-at least one monodentate ligand containing one phosphorus atom;

-at least one lewis acid.

The invention also relates to mixtures comprising at least one polydentate ligand and at least one monodentate ligand.

The invention also relates to the use of a mixture comprising at least one polydentate ligand and at least one monodentate ligand for preparing transition metal complexes of acetals.

Detailed Description

In the sense of the present invention, the term "monodentate ligand" is a compound having only one donor (donor) atom or donor group.

In the sense of the present invention, the term "multidentate ligand" is a compound which can simultaneously form coordinate bonds to a transition metal atom via at least three donor atoms or donor atom groups.

In the sense of the present invention, the term "turnover number (TON)" is the number of moles of substrate which can be converted in 1 mole of catalyst before deactivation.

The terms "reaction mixture" and "reaction medium" are used synonymously. In the sense of the present invention, these terms refer to mixtures comprising the compounds (ii.a) or (ii.b), a lewis acid, at least one transition metal catalyst complex and at least one monodentate ligand.

In the sense of the present invention, the term "alkyl" refers to both straight-chain and branched alkyl groups. Preference is given to straight-chain or branched C₁-C₂₀-alkyl, more preferably C₁-C₁₂-alkyl, even more preferably C₁-C₈Alkyl, especially C₁-C₆-an alkyl group. Examples of alkyl are, in particular, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1, 2-dimethylpropyl, 1-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3-dimethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethylbutyl, tert-butyl, 2-pentyl, 2-methylpentyl, 4-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 1, 2-trimethylpropyl, 1-ethylbutyl, tert-butyl, 1, 2-dimethylpropyl, 2-pentyl, 4-methylpentyl, 1, 2-dimethylpropyl, 2-butyl, 2-dimethylpropyl, 2-one, 2-dimethylpropyl, 2-one, 2-dimethylpropyl, 2-one, 2-butyl, 2-dimethylpropyl, 2-one, 2-dimethylpropyl, 2-one, 2-one, and one, or more, one, or more, one, or more, each, one, or more, one, or more, one, each, one, 2-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl, 2-propylheptyl, nonyl anda decyl group.

The term "alkyl" also encompasses substituted alkyl which can carry 1,2,3, 4 or 5 substituents, preferably 1,2 or 3 substituents, particularly preferably 1 substituent, and is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, P (aryl)₂Halogen, nitro, formyl, acyl and cyano, NE¹E²、NE¹E²E³⁺X^-COOH, carboxylic acid (carboxylate), SO₃H and a sulfonic acid group (sulfonate), wherein E¹、E²And E³And X^-As defined hereinafter.

The term "haloalkyl" refers to a straight or branched alkyl group as defined above in which some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. The preferred fluorinated alkyl group is trifluoromethyl. The term "alkyl" also encompasses alkyl groups, preferably alkoxyalkyl groups, interrupted by one or more non-adjacent oxygen atoms.

The term "alkylene" in the sense of the present invention represents a straight-chain or branched alkanediyl group having preferably 1 to 6 carbon atoms. These are methylene (-CH)₂-) ethylene (-CH₂-CH₂-), n-propylidene (trimethylene) (-CH)₂-CH₂-CH₂-) isopropylidene (-CH₂-CH(CH₃) -) tetramethylene group (-CH₂-CH₂-CH₂-CH₂-) pentamethylene (-CH₂-CH₂-CH₂-CH₂-CH₂-) and hexamethylene (-CH)₂-CH₂-CH₂-CH₂-CH₂-CH₂-) and the like.

The term "alkanetriyl" in the sense of the present invention represents a straight-chain or branched alkanetriyl group having preferably from 1 to 10 carbon atoms. These are C- (CH)₂)_nH、C-(CH₂)_n-CH₃Wherein n is 0 to 8.

The term "cycloalkyl" in the sense of the present invention comprises both unsubstituted and substituted cycloalkyl, preferablyC selection₅-C₇Cycloalkyl, such as cyclopentyl, cyclohexyl or cycloheptyl, which, if substituted, may carry 1,2,3, 4 or 5 substituents, preferably 1,2 or 3 substituents, particularly preferably 1 substituent, selected from the group consisting of alkyl, alkoxy, halogen, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, P (aryl)₂Nitro, formyl, acyl and cyano, NE¹E²、NE¹E²E³⁺X^-COOH, carboxylic acid group, SO₃H and a sulfonic acid group, wherein E¹、E²、E³And X^-As defined hereinafter.

The term "heterocycloalkyl" in the sense of the present invention comprises a saturated or partially unsaturated cycloaliphatic radical having preferably 3 to 7, more preferably 4 to 7, in particular 5 or 6 ring atoms, wherein 1,2,3 or 4 ring atoms may be replaced by heteroatoms preferably selected from the elements oxygen, nitrogen and sulfur and which is optionally substituted. If substituted, these heterocycloaliphatic groups carry preferably 1,2 or 3 substituents, more preferably 1 or 2 substituents, in particular 1 substituent. These substituents are preferably selected from alkyl, cycloalkyl, aryl, COOR (R ═ H, alkyl, cycloalkyl, aryl), COO^-M⁺And NE¹E²More preferably an alkyl group. Examples of such heterocycloaliphatic groups are pyrrolidinyl, piperidinyl, 2,6, 6-tetramethylpiperidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, morpholinonyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, piperazinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl and dioxanyl.

In the present invention, the term "aryl" includes monocyclic or polycyclic aromatic hydrocarbon groups typically having 6 to 10 carbon atoms. Examples of aryl radicals are, in particular, phenyl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl and naphthacenyl (naphthacenyl), preferably phenyl and naphthyl.

Substituted aryl groups may have one or more substituents (e.g., 1,2,3, 4, or 5) depending on the number and size of their ring systems. Each of these is preferably independently selected fromAlkyl, alkoxy, carboxyl, carboxylic acid group, trifluoromethyl, -SO₃H. Sulfonic acid group, NE¹E²alkylene-NE¹E²Nitro, cyano and halogen. Examples of substituted aryl groups are tolyl, xylyl, mesityl. The preferred fluorinated aryl group is pentafluorophenyl.

The term "heteroaryl" is also referred to as "heteroryl", which is used synonymously and in the sense of the present invention comprises unsubstituted or substituted heterocyclic aromatic groups, preferably pyridyl, quinolyl, acridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, indazolyl, pyrazolyl, indolyl, purinyl, indazolyl, benzotriazolyl, 1,2, 3-triazolyl, 1,3, 4-triazolyl and carbazolyl; in the case where these heterocyclic aromatic groups are substituted, they may carry preferably 1,2 or 3 groups selected from alkyl, alkoxy, carboxyl, carboxylic acid groups, -SO₃H. Sulfonic acid group, NE¹E²alkylene-NE¹E²Trifluoromethyl and halogen. A preferred substituted indolyl group is 3-methylindolyl.

In the sense of the present invention, the terms "carboxylic acid group" and "sulfonic acid group" preferably represent a carboxylic acid function or a sulfonic acid function derivative, in particular a metal carboxylate or metal sulfonate, a carboxylic acid ester or sulfonic acid ester or a carboxylic acid amide or sulfonic acid amide. Particularly preferred is a compound of formula (I) and (II)₁-C₄Esters of alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol. Also preferred are primary amides and their N-alkyl and N, N-dialkyl derivatives.

In the sense of the present invention, the term "alkoxy" is an alkyl group as defined above attached via an oxygen atom. C₁-C₂-alkoxy is methoxy or ethoxy. C₁-C₄Alkoxy is, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1, 1-dimethylethoxy (tert-butoxy). C₁-C₆The alkoxy radical comprises para C₁-C₄Alkoxy and also includes, for example, pentyloxy,1-methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2, 2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy. The "alkoxy" may carry 1,2,3, 4 or 5 substituents, preferably 1,2 or 3 substituents, particularly preferably 1 substituent, selected from halogen.

The term "haloalkoxy" is a haloalkyl group as defined above attached via an oxygen atom.

The term "cycloalkoxy" refers to a cycloalkyl group as defined above attached via an oxygen atom.

The term "aryloxy" refers to an aryl group as defined above attached via an oxygen atom.

The term "heterocycloalkoxy" refers to a heterocycloalkyl group as defined above attached via an oxygen atom.

The term "heteroaryloxy" refers to a heteroaryl group as defined above attached via an oxygen atom.

The term "cyclic olefin" refers to cycloalkanes (cycloalkanes), which are defined as monocyclic hydrocarbon groups having at least one C-C double bond in the ring, but the ring is not aromatic. Preferably, the hydrocarbyl group has 3 to 8 carbon atoms (C)₃-C₈-cycloalkenes).

The term "alkene" refers to an alkeneene, which is a straight-chain or branched ethylenically monounsaturated hydrocarbon radical having 2 to 20, for example 2 to 10 or 2 to 6, carbon atoms and a C ═ C-double bond at any position.

The term "diene" refers to an olefin containing two double bonds.

In the sense of the present invention, the term "acyl" denotes alkanoyl or aroyl groups having preferably 2 to 11, more preferably 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, 2-ethylhexanoyl, 2-propylheptanoyl, benzoyl and naphthoyl.

Radical NE¹E²、NE⁴E⁵Preferably selected from the group consisting of N, N-dimethylamino, N-diethylamino, N-dipropylamino, N-diisopropylamino, N-di-N-butylamino, N-di-tert-butylamino, N-dicyclohexylamino and N, N-diphenylamino.

Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

M⁺Represents a cation equivalent (equivalent), which refers to a monovalent cation or a moiety representing a polyvalent cation of positive single charge. Cation M⁺Only neutralising negatively charged substituents, e.g. COO^-Or sulfonic acid groups and substantially optionally counterions. Preference is given to alkali metal ions, in particular Na⁺、K⁺And Li⁺Ions, or onium ions, such as ammonium ions, mono-, di-, tri-, tetra-alkylammonium ions, phosphonium ions, tetraalkylphosphonium ions and tetraarylphosphonium ions.

The same applies to the anion equivalent X^-Which is simply a counterion to the positively charged substituent, such as an ammonium group, and can be selected essentially arbitrarily from monovalent anions and moieties corresponding to singly negatively charged polyvalent anions. Preferred are halide ions X^-Especially chlorine and bromine. Also preferred are sulfate and sulfonate, especially SO₄ ^2-Tosylate, triflate and methylsulfonate.

Fused ring systems are aromatic, heteroaromatic or cyclic compounds having fused rings obtained by end-ring closure (annulation). Fused ring systems consist of two, three or more than three rings. Adjacent-annulation and forced-annulation (ortho-annulation) are distinguished according to the type of ligation. In the case of ortho-ring-cyclization, each ring has two atoms in common with each adjacent ring. In the case of peri-ring cyclization, the carbon atoms belong to more than two rings. Among the condensed ring systems, ortho-condensed ring systems are preferred.

Raw materials and reaction conditions

To obtain the compound of formula (I), at least one alcohol compound of formula (II.a) or (II.b) is used as starting material

R¹-OH (II.a),

HO-R²-OH (II.b),

Wherein R is¹And R²Have the meaning as defined above.

Preferably, R¹Selected from unsubstituted or substituted by 1,2,3, 4 or 5 substituents selected from OH, halogen, C₁-C₆Alkoxy or C₆-C₁₀Aryl substituted by substituents C₁-C₂₀Alkyl, more preferably unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₄C substituted by substituents of alkoxy₁-C₆Alkyl, especially C, unsubstituted or substituted by 1 or 2 substituents selected from OH or halogen₁-C₄Alkyl, especially unsubstituted C₁-C₄Alkyl, especially C₁-C₂An alkyl group.

In one embodiment, R¹Is methyl.

Preferably, R²Selected from straight chain C₂-C₆Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1,2 or 3 substituents selected from OH, halogen, C₁-C₄Alkyl or C₁-C₄Substituent of alkoxy, more preferably C₂-C₅Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1 or 2 groups selected from C₁-C₂Substituent substitution of alkyl, especially C₂-C₅Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1 atom selected from C₁-C₂Alkyl substituents.

In one embodiment, R²is-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH(CH₃)-、-CH₂-CH(CH₃)-CH₂-or-CH₂-CH(CH₃)-。

Hydrogen (H) gas for the reduction reaction₂) It can be used in pure form or, if desired, also in a mixture with at least one other gas, preferably an inert gas, such as nitrogen or argon. Preference is given to using H in undiluted form₂。

The reaction is generally carried out at from 0.1 to 400 bar, preferably from 5 to 200 bar, more preferably from 10 to 180 bar of H₂Under pressure.

Carbon dioxide (CO) for the reaction₂) It can be used in pure form or, if desired, also in a mixture with at least one other gas, preferably an inert gas, such as nitrogen or argon. Preference is given to using CO in undiluted form₂。CO₂It can be used in its gaseous form, liquefied or in a supercritical state.

The reaction is generally carried out at from 0.1 to 400 bar, preferably from 5 to 200 bar, more preferably from 10 to 70 bar of CO₂Under pressure.

Can change H₂And CO₂And preferably in the range of 1:100 to 100:1, more preferably 1:30 to 30:1, most preferably 1:10 to 10: 1.

The reaction may be carried out substantially continuously, semi-continuously or discontinuously. A continuous process is preferred.

The reaction can be carried out in essentially all reactors known to those skilled in the art for catalytic gas-liquid reactions, and the reactor will therefore be selected accordingly. For example in Ullmannsder technischen Chemie, vol.1, 3 rd edition, 1951, p 743 et seq or in UllmannsSuitable reactors are described in der technischen Chemie, vol.1, 3 rd edition, 1951, page 769 and beyond. Preferably, an autoclave is used for the reaction, which may have an internal stirrer and a liner.

The process according to the invention can be carried out over a wide temperature range. Preferably, the reaction is carried out at a temperature of from 20 ℃ to 200 ℃, more preferably from 50 ℃ to 180 ℃, in particular from 60 ℃ to 170 ℃.

The process according to the invention can be carried out over a wide pressure range. Preferably, the reaction is carried out at a pressure of from 1 to 400 bar, more preferably from 10 to 300 bar, in particular from 40 to 200 bar.

In addition to the alcohol compounds of the formula (II.a) or (II.b), the reaction can also be carried out in combination with inert solvents. Suitable solvents are selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers, and mixtures thereof.

The process of the invention can be carried out without or with additional solvents. In a preferred embodiment, the reaction is carried out in the presence of an additional solvent. In another preferred embodiment, the reaction is carried out in the absence of additional solvent.

Suitable solvents are selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, amides, esters, ethers, and mixtures thereof. Preferably, the solvent is

Aliphatic hydrocarbons, such as pentane, hexane, heptane, octane or cyclohexane;

-aromatic hydrocarbons, such as benzene, toluene, xylene, ethylbenzene, mesitylene or trifluorotoluene;

esters, such as methyl acetate, ethyl acetate, tert-butyl acetate;

ethers, such as dioxane, tetrahydrofuran, diethyl ether, dibutyl ether, methyl tert-butyl ether, diisopropyl ether or diethylene glycol dimethyl ether.

Mixtures of two or more of the above solvents may also be used if desired.

Preferably, aliphatic hydrocarbons, aromatic hydrocarbons and mixtures thereof are used as solvents.

The molar ratio of the compound of the formula (II.a) or (II.b) to the additional solvent used is preferably in the range from 50:1 to 1:50, more preferably from 2:1 to 1:30, in particular from 2:1 to 1: 10.

Lewis acids are chemical species containing an empty orbital capable of accepting an electron pair from a lewis base to form a lewis acid-base adduct.

A suitable Lewis acid is AlCl₃、ZnCl₂、PF₅、AsCl₃、SnCl₄、TiCl₄、SbCl₅、Al(OTf)₃、Sc(OTf)₃、Fe(OTf)₃、Yb(OTf)₃、Eu(OTf)₃、B(C₆F₅)₃、B(2,4-(CF₃)₂C₆H₃)₃、BF₃、BF₃*Et₂O、BF₃*THF、Ag(OTf)、Pr(OTf)₃、Zn(OTf)₃And mixtures thereof, in particular Al (OTf)₃、Sc(OTf)₃、Fe(OTf)₃、Yb(OTf)₃、Eu(OTf)₃、B(C₆F₅)₃、B(2,4-(CF₃)₂C₆H₃)₃、BF₃、BF₃*Et₂O、BF₃*THF、Ag(OTf)、Pr(OTf)₃、Zn(OTf)₃And mixtures thereof.

In a preferred embodiment, Al (OTf)₃As a lewis acid.

The amount of Lewis acid is preferably from 1 to 1000 mol%, in particular from 50 to 500 mol%, based on the transition metal catalyst used.

Catalyst and process for preparing same

In the process of the present invention, the production of compound (I) is carried out in a liquid reaction medium in the presence of a transition metal catalyst complex. According to the invention, homogeneous transition metal catalyst complexes are used. This means that the transition metal catalyst complex is dissolved in the liquid reaction medium under the reaction conditions. In other words, the transition metal catalyst complex is in the same phase as the reactants.

The transition metal of the transition metal catalyst complex is selected from metals of groups 7, 8, 9 and 10 of the periodic table of the elements according to IUPAC. In a preferred embodiment, the metal of the transition metal catalyst complex is selected from ruthenium, iron, osmium, cobalt, rhodium, rhenium, iridium, nickel, platinum and palladium, in particular ruthenium and nickel, especially ruthenium and cobalt.

In a preferred embodiment, the ligand is selected from the group consisting of organic phosphines (organo-phosphines), organic phosphites (organo-phosphines), organic phosphonites (organo-phosphonites), organic phosphinites (organo-phosphonites) and organic phosphoramidites (organo-phosphonamides).

Organophosphines are derived from phosphines (also known as phosphanes) in which one or more hydrogens are replaced by an organic substituent.

The organophosphite is of the general structure P (OR)₃Phosphonic acid (phosphonic acid) P (OH)₃Wherein R is an organic substituent.

The organic phosphonites are of the general structure P (OR)₂Phosphonous acid HP (OH) of R')₂Wherein R and R' are the same or different organic substituents.

The organic phosphinate is of the general structure (P (OR) R'₂) Phosphinic acid (phosphinius acid) H of (1)₂Esters of P (OH), wherein R and R' are the same or different organic substituents.

The organophosphorous amides are formally derived from organophosphites in which at least one OR group substituent is replaced by an amid group NR₂Alternatively, wherein R is hydrogen or an organic substituent.

In a preferred embodiment of the present invention, the at least one polydentate ligand is chosen from compounds of formula (III)

Wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another, is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl can carry 1,2,3, 4 or 5 substituents selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, carboxy, SO, polyalkylene imine, and optionally alkylene imine₃H. P (aryl)₂Sulfonic acid group, NE¹E²、NE¹E²E³⁺X^-Halogen, nitro, formyl, acyl and cyano, wherein E¹、E²And E³Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an anionic equivalent, and whichMiddle group cycloalkyl, heterocycloalkyl, aryl and heteroaryl R^A、R^B、R^C、R^D、R^EAnd R^FIt may carry 1,2,3, 4 or 5 substituents selected from alkyl and the above para-alkyl radicals R^A、R^B、R^C、R^D、R^EAnd R^FThe mentioned substituents, or

R^AAnd R^BAnd/or R^CAnd R^DAnd/or R^EAnd R^FWith P atoms and, if present, groups X bonded to them¹、X²、X⁵、X⁶、X⁸And X⁹Together form a 5-to 8-membered heterocycle which is optionally fused with one, two or three groups selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where the heterocycle and, if present, the groups fused on may each, independently of one another, carry 1,2,3 or 4 groups selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, alkoxy, halogen, carboxy, SO₃H. Sulfonic acid group, NE⁴E⁵、NE⁴E⁵E⁶⁺X^-Nitro, alkoxycarbonyl, formyl, acyl and cyano, in which E⁴、E⁵And E⁶Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

X¹、X²、X⁵、X⁶、X⁸and X⁹Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

X³、X⁴and X⁷Independently of one another are C₁-C₁₀Alkanediyl, O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Y is chosen from C₁-C₁₀An alkanetriyl group, a bridging group of N or P,

a. b, c, d, e, f, g, h and i are independently of one another 0 or 1.

In another preferred embodiment of the present invention, the transition metal catalyst complex comprises at least one polydentate ligand selected from compounds of the formula (III), wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another are C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₆-C₁₀An aryl, heterocycloalkyl or heteroaryl group,

wherein C is₁-C₁₀The alkyl radical being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from F, Cl, Br, OH, CN, NH₂、C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution;

wherein C is₃-C₁₀Cycloalkyl is unsubstituted or carries 1,2,3, 4 or 5 substituents selected from halogen, OH, CN, NH₂、C₁-C₁₀Alkyl radical, C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by 1,2,3, 4 or 5C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution; wherein C is₆-C₁₀Aryl being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from OH, C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀-alkoxy, C₁-C₁₀Haloalkoxy or C unsubstituted or substituted by OH₆-C₁₀An aryl group;

wherein heterocycloalkyl is a 3-, 4-, 5-, 6-, 7-or 8-membered saturated or partially saturated heteromonocyclic ring containing one, two or three heteroatoms selected from O, S or N as ring members or a 7-, 8-, 9-, 10-, 11-or 12-membered saturated or partially saturated heterobicyclic ring containing one, two, three or four heteroatoms selected from O, S or N as ring members; wherein the hetero-monocyclic ring and the hetero-bicyclic ring may carry 1,2,3, 4 or 5 ring members selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group;

wherein heteroaryl is a 5-or 6-membered monocyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members, and a 9-or 10-membered bicyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members, wherein the monocyclic or bicyclic heteroaryl ring may carry 1,2,3, 4 or 5 heteroatoms selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group; or R^AAnd R^BAnd/or R^CAnd R^DAnd/or R^EAnd R^FWith P atoms and, if present, groups X bonded to them¹、X²、X⁵And X⁶、X⁸And X⁹Together form a 5-to 8-membered heterocyclic ring, optionally with C₅-C₁₀Cycloalkyl radical, C₆-C₁₀One, two or three radicals of aryl, 5-or 6-membered monocyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members or 9-or 10-membered bicyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members, heteroaryl are fused, where the heterocycles and, if present, the fused radicals can each, independently of one another, carry 1,2,3 or 4 radicals from the group consisting of C₁-C₁₀-a substituent of an alkyl group,

X¹、X²、X⁵、X⁶、X⁸and X⁹Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another are hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, heterocycloalkyl, C₆-C₁₀An aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof,

X³、X⁴and X⁷Independently of one another are C₁-C₁₀Alkanediyl, O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another are hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl or C₆-C₁₀An aryl group; y is selected from C₁-C₁₀An alkanetriyl group, a bridging group of N or P,

a. b, c, d, e, f, g, h, i are independently 0 or 1.

In another preferred embodiment of the present invention, the at least one transition metal catalyst comprises at least one polydentate ligand selected from compounds of the formula (III), wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another, are alkyl, aryl or heteroaryl, where alkyl, aryl or heteroaryl can carry 1,2,3, 4 or 5 substituents selected from alkoxy, NE¹E²、NE¹E²E³⁺X^-Wherein E is¹、E²And E³Identical or different and selected from hydrogen or alkyl, and X^-Is an equivalent to the anion of an anion,

X¹、X²、X⁵、X⁶、X⁸and X⁹Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Y is chosen from C₁-C₆-an alkanetriyl or N bridging group,

X³、X⁴、X⁷are methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene;

a. b, e, f, h and i are independently of one another 0 or 1, preferably 0, c, d and g are 0 or 1, preferably 1.

In another preferred embodiment of the present invention, the transition metal catalyst complex comprises at least one polydentate ligand selected from compounds of the formula (III), wherein

R^A、R^B、R^C、R^D、R^EAnd R^FIndependently of one another are C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₆-C₁₀An aryl, heterocycloalkyl or heteroaryl group,

wherein C is₁-C₁₀The alkyl radical being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from F, Cl, Br, OH, CN, NH₂、C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution;

wherein C is₃-C₁₀Cycloalkyl is unsubstituted or carries 1,2,3, 4 or 5 substituents selected from halogen, OH, CN, NH₂、C₁-C₁₀Alkyl radical, C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by 1,2,3, 4 or 5C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution; wherein C is₆-C₁₀Aryl being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from OH, C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀-alkoxy, C₁-C₁₀Haloalkoxy or C unsubstituted or substituted by OH₆-C₁₀An aryl group;

wherein heterocycloalkyl is a 3-, 4-, 5-, 6-, 7-or 8-membered saturated or partially saturated heteromonocyclic ring containing one, two or three heteroatoms selected from O, S or N as ring members or a heterocyclic ring containing one, two,A 7-, 8-, 9-, 10-, 11-, or 12-membered saturated or partially saturated heterobicyclic ring having three or four heteroatoms selected from O, S or N as ring members; wherein the hetero-monocyclic ring and the hetero-bicyclic ring may carry 1,2,3, 4 or 5 ring members selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group;

wherein heteroaryl is a 5-or 6-membered monocyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members and a 9-or 10-membered bicyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members, wherein the monocyclic or bicyclic heteroaryl ring may carry 1,2,3, 4 or 5 heteroatoms selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group; or R^AAnd R^BAnd/or R^CAnd R^DAnd/or R^EAnd R^FWith P atoms and, if present, groups X bonded to them¹、X²、X⁵And X⁶、X⁸And X⁹Together form a 5-to 8-membered heterocyclic ring, optionally with C₅-C₁₀Cycloalkyl radical, C₆-C₁₀One, two or three radicals of aryl, 5-or 6-membered monocyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members or 9-or 10-membered bicyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members, heteroaryl are fused, where the heterocycles and, if present, the fused radicals can each, independently of one another, carry 1,2,3 or 4 radicals from the group consisting of C₁-C₁₀-a substituent of an alkyl group,

X¹、X²、X⁵、X⁶、X⁸and X⁹Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another are hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, heterocycloalkyl, C₆-C₁₀An aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof,

X³、X⁴and X⁷Independently of one another are C₁-C₁₀Alkanedioic acidRadical O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another are hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl or C₆-C₁₀An aryl group; y is selected from C₁-C₁₀An alkanetriyl group, a bridging group of N or P,

a. b, c, d, e, f, g, h, i are independently 0 or 1.

Preferably, Y, wherever it appears, is selected from C₁-C₁₀Alkanetriyl, N or P, more preferably C₁-C₆Alkanetriyl or N, especially C₁-C₂An alkanetriyl group or a bridging group of N.

Preferably, X³、X⁴And X⁷Wherever they appear, they are preferably, independently of one another, C₁-C₁₀Alkanediyl, O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, more preferably C₁-C₁₀Alkanediyl, in particular methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene.

A particularly preferred group of embodiments relates to polydentate ligands of formula (III.a),

wherein

R^A、R^B、R^C、R^D、R^EAnd R^FHave one of the meanings as defined above. In particular, R^A、R^B、R^C、R^D、R^EAnd R^FIndependently selected from C₆-C₁₀Aryl which is unsubstituted or carries 1,2,3 or 4 radicals selected from OH, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆-alkoxy or C₁-C₆HaloalkoxyA substituent of the group. R^A、R^B、R^C、R^D、R^EAnd R^FEspecially phenyl.

a. b, e, f, h and i are independently 0 or 1. a. b, e, f, h and i are preferably 0. c. d and g are 0 or 1. c. d and g are preferably 1.

X³、X⁴And X⁷Independently of one another, are selected from C₁-C₁₀An alkanediyl group. X³、X⁴And X⁷In particular from methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. X³、X⁴And X⁷In particular from methylene, ethylene.

R^VSelected from hydrogen or C₁-C₆An alkyl group. R^VIn particular from methyl, ethyl, propyl, isopropyl. R^VIn particular methyl.

A further particularly preferred group of embodiments relates to polydentate ligands of the formula (III.b),

wherein

R^A、R^B、R^C、R^D、R^EAnd R^FHave one of the meanings as defined above. In particular, R^A、R^B、R^C、R^D、R^EAnd R^FIndependently selected from C₆-C₁₀Aryl which is unsubstituted or carries 1,2,3 or 4 radicals selected from OH, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆-alkoxy or C₁-C₆A substituent of a haloalkoxy group. R^A、R^B、R^C、R^D、R^EAnd R^FEspecially phenyl.

a. b, e, f, h and i are independently 0 or 1. a. b, e, f, h and i are preferably 0. c. d and g are 0 or 1. c. d and g are preferably 1.

X³、X⁴And X⁷Independently of one another, are selected from C₁-C₁₀An alkanediyl group. X³、X⁴And X⁷In particular from methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. X³、X⁴And X⁷In particular from methylene, ethylene.

A further particularly preferred group of embodiments relates to polydentate ligands of the formula (III.c),

wherein

R^A、R^B、R^C、R^D、R^EAnd R^FHave one of the meanings as defined above. In particular, R^A、R^B、R^C、R^D、R^EAnd R^FIndependently selected from C₆-C₁₀Aryl which is unsubstituted or carries 1,2,3 or 4 radicals selected from OH, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆-alkoxy or C₁-C₆A substituent of a haloalkoxy group. R^A、R^B、R^C、R^D、R^EAnd R^FEspecially phenyl.

a. b, e, f, h and i are independently 0 or 1. a. b, e, f, h and i are preferably 0. c. d and g are 0 or 1. c. d and g are preferably 1.

X³、X⁴And X⁷Independently of one another, are selected from C₁-C₁₀An alkanediyl group. X³、X⁴And X⁷In particular from methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. X³、X⁴And X⁷In particular from methylene, ethylene.

Furthermore, the liquid reaction medium may comprise at least one additional ligand different from the polydentate ligand and the monodentate ligand. In this embodiment, the transition metal catalyst complex of the process of the present invention comprises at least one additional ligand selected from the group consisting of hydrides (hydrido), halides, amides, carboxylates, acetylacetonates, aryl-or alkylsulfonates, CO, alkenes, dienes, cycloalkenes, nitriles, arenes, and heteroarenes.

In a preferred embodiment, the transition metal catalyst complex is selected from the group consisting of Ru (tris (diphenylphosphinomethyl) ethane) (2-methylallyl)][ Ru (tris (diphenylphosphinomethyl) ethane) (H)₂][ Ru (tris (diphenylphosphinomethyl) amine) (2-methylallyl)][ Ru (tris (diphenylphosphinomethyl) amine) (H)₂][ Ru (tris (diphenylphosphinoethyl) amine) (2-methylallyl)]Or [ Ru (tris (diphenylphosphinoethyl) amine) (H)₂]。

The transition metal catalysts according to the invention can be used in the form of preformed metal complexes comprising a metal compound and one or more ligands. Alternatively, the transition metal catalyst is formed in situ in the reaction medium by combining a metal compound, also referred to herein as a pre-catalyst (pre-catalyst), with one or more suitable ligands to form a catalytically active metal complex in the reaction medium. It is also possible to form the transition metal catalyst in situ in the presence of the ancillary ligand by combining a metal compound (also referred to herein as a precatalyst) with one or more ancillary ligands to form a catalytically active metal complex in the reaction medium.

Suitable precatalysts are selected from the group consisting of neutral metal complexes, oxides and salts of metals of groups 7, 8, 9 and 10 of the periodic Table of the elements. Preferred precatalysts are selected from metal complexes, oxides and salts of ruthenium, rhenium, iridium, nickel, platinum or palladium.

Ruthenium compounds which can be used as precatalyst are, for example, [ Ru (methallyl)₂COD][ Ru (p-cymene) Cl₂]₂And [ Ru (benzene) Cl₂]_n、[Ru(CO)₂Cl₂]_n、[Ru(CO)₃Cl₂]₂[ Ru (COD) (+) (allyl)]、[RuCl₃·H₂O][ Ru (acetylacetone)₃]、[Ru(DMSO)₄Cl₂]、[Ru(PPh₃)₃(CO)(H)Cl]、[Ru(PPh₃)₃(CO)Cl₂]、[Ru(PPh₃)₃(CO)(H)₂]、[Ru(PPh₃)₃Cl₂]、[Ru(Cp)(PPh₃)₂Cl]、[Ru(Cp)(CO)₂Cl]、[Ru(Cp)(CO)₂H]、[Ru(Cp)(CO)₂]₂、[Ru(Cp*)(CO)₂Cl]、[Ru(Cp*)(CO)₂H]、[Ru(Cp*)(CO)₂]2. [ Ru (indenyl) (CO)₂Cl][ Ru (indenyl) (CO)₂H][ Ru (indenyl) (CO)₂]₂、ruthenocen、[Ru(binap)(Cl)₂][ Ru (2,2' -bipyridine)₂(Cl)₂·H₂O]、[Ru(COD)(Cl)₂H]₂、[Ru(Cp*)(COD)Cl]、[Ru₃(CO)₁₂][ Ru (tetraphenylcyclopentadienyl) (CO)₂H]、[Ru(PMe₃)₄(H)₂]、[Ru(PEt₃)₄(H)₂]、[Ru(Pn-Pr₃)₄(H)₂]、[Ru(Pn-Bu₃)₄(H)₂]、[Ru(Pn-octyl₃)₄(H)₂]Wherein [ Ru (methallyl)₂COD]、Ru(COD)Cl₂]₂、[Ru(Pn-Bu₃)₄(H)₂][ Ru (Pn-octyl)₃)₄(H)₂]、[Ru(PPh₃)₃(CO)(H)Cl]And [ Ru (PPh)₃)₃(CO)(H)₂]Is preferred, in particular [ Ru (methallyl)₂COD]。

Iridium compounds which can be used as precatalysts are, for example, [ IrCl ]₃·H₂O]、KIrCl₄、K₃IrCl₆、[Ir(COD)Cl]₂, [ Ir (cyclooctene)₂Cl]₂, [ Ir (ethylene)₂Cl]₂、[Ir(Cp)Cl₂]₂、[Ir(Cp*)Cl₂]₂、[Ir(Cp)(CO)₂]、[Ir(Cp*)(CO)₂]、[Ir(PPh₃)₂(CO)Cl]And [ Ir (PPh)₃)₃Cl]In which [ Ir (COD) Cl]₂, [ Ir (cyclooctene)₂Cl]₂And [ Ir (Cp) Cl₂]₂Is preferred.

Nickel compounds which can be used as precatalysts are, for example, [ Ni (COD) ]₂]、Ni(CO)₄、NiCl₂、NiBr₂、NiI₂、Ni(OAc)₂[Ni(AcAc)₂]、[Ni(Cl)₂(TMEDA)]、[Ni(Cl)₂(DME)]、[Ni(Br)₂(DME)]、[Ni(Cl)₂(PPh₃)₂]、[Ni(CO)₂(PPh₃)][ Ni (Cl) (methallyl group)]2、[Ni(CO₃)]Nickel (II) dimethylglyoxime, nickel (II) 2-ethylhexanoate, nickel (II) hexafluoroacetylacetonate, nickel (II) bis (N, N' -di-tert-butylacetamidoato), nickel (II) oxalate and Ni (NO)₃)₂Nickel (II) stearate, Ni (SO)₄) Nickel (II) tetrafluoroborate hexahydrate, dehydrated nickel trifluoroacetylacetonate (II) and nickel (II) trifluoromethanesulfonate.

Rhenium compounds which can be used as precatalyst are, for example, ammonium perrhenate, chlorotrimethylcarbonyl (2,2 '-bipyridine) rhenium (I), chlorotrimethylcarbonyl (4,4' -di-tert-butyl-2, 2 '-bipyridine) rhenium (I), cyclopentadienyl rhenium tricarbonyl, iododioxobis (triphenylphosphine) rhenium (V), methyltrioxorhenium (VII), pentamethylcyclopentadienyl rhenium tricarbonyl, rhenium carbonyl, rhenium (V) chloride, rhenium pentacarbonyl bromide, trifluoromethylsulfonato tricarbonyl (2,2' -bipyridine) rhenium (I).

Platinum compounds which can be used as precatalyst are, for example, ammonium tetrachloroplatinum (II), bis (tri-tert-butylphosphino) platinum (0), bis (ethylenediamine) platinum (II) chloride, dibromo (1, 5-cyclooctadiene) platinum (II), dichlorobis (benzonitrile) platinum (II), cis-dichlorobis (diethylsulfur) platinum (II), cis-dichlorobis (pyridine) platinum (II), cis-dichlorobis (triethylphosphine) platinum (II), dichloro (1, 5-cyclooctadiene) platinum (II), cis-dichlorodiammineplatinum (II), di-mu-chloro-dichlorobis (ethylene) diplatinum (II), dichloro (dicyclopentadienyl) platinum (II), di-mu-iodobis (ethylenediamine) diplatinum (II) nitrate, diiodo (1, 5-cyclooctadiene) platinum (II), dimethyl (1, 5-cyclooctadiene) platinum (II), acetylacetonatoplatinum (II), platinum (II) bromide, platinum (II) chloride, platinum (II) iodide, potassium bis (oxalato) platinum (II) dihydrate, tetrakis (triphenylphosphine) platinum (0), and tris (dibenzylideneacetone) diplatinum (0).

Palladium compounds which can be used as precatalyst are, for example, allyl (cyclopentadienyl) palladium (II), bis [ (trimethylsilyl) methyl ] (1, 5-cyclooctadiene) palladium (II), allyl palladium chloride dimer, ammonium tetrachloropalladium (II), bis [1, 2-bis (diphenylphosphino) ethane ] palladium (0), bis (dibenzylideneacetone) palladium (0), trans-bis (dicyclohexylamine) bis (acetato) palladium (II), bis (2-methylallyl) palladium chloride dimer, bis (tri-tert-butylphosphino) palladium (0), bis (tricyclohexylphosphine) palladium (0), bis (tri-o-tolylphosphine) palladium (0), chloromethyl (1, 5-cyclooctadiene) palladium (II), diacetyl [1, 3-bis (diphenylphosphino) propane ] palladium (II), diacetyl bis (triphenylphosphine) palladium (II), Diacetyl (1, 10-phenanthroline) palladium (II), di-mu-bromobis (tri-tert-butylphosphino) dipalladium (I), trans-dibromobis (triphenylphosphine) palladium (II), dibromo (1, 5-cyclooctadiene) palladium (II), dichlorobis (benzonitrile) palladium (II), dichlorobis (di-tert-butylphenyl-phosphino) palladium (II), di-mu-chlorobis {2- [ (dimethylamino) methyl ] phenyl } dipalladium, trans-dichlorobis (tricyclohexylphosphine) palladium (II), trans-dichlorobis (triphenylphosphine) palladium (II), dichloro (1, 5-cyclooctadiene) palladium (II), dichloro (norbornadiene) palladium (II), cis-dichloro (N, N, N ', N' -tetramethylethylenediamine) palladium (II), cis-dimethyl (N), n, N' -tetramethylethylenediamine) palladium (II), (1-methallyl) palladium chloride dimer, palladium (II) acetate, palladium (II) acetylacetonate, palladium (II) benzoate, palladium (II) bromide, palladium (II) chloride, palladium (II) hexafluoroacetylacetonate, palladium (II) iodide, palladium (II) sulfate, palladium (II) trifluoroacetate, palladium (II) trimethylacetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0).

In the compounds mentioned above, the name "COD" refers to 1, 5-cyclooctadiene; "Cp" means a cyclopentadienyl group; "Cp" means pentamethylcyclopentadienyl; and "bin" refers to 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl.

In the process of the invention, a substoichiometric amount of catalyst is generally used, where the amount of catalyst, based on the amount of compound (II), is generally not more than 50 mol%, generally not more than 20 mol%, in particular not more than 10 mol% or not more than 5 mol%. The catalyst is generally used in the process of the invention in an amount of from 0.001 to 50 mol%, usually from 0.001 to 20 mol%, in particular from 0.005 to 5 mol%, based on the amount of compound (II). Preference is given to using the catalyst in an amount of from 0.01 to 2 mol%, particularly preferably from 0.01 to 1 mol%. All amounts of the catalysts indicated are calculated as transition metals and are based on the amount of compound (II).

Monodentate ligands

In the process of the present invention, the production of compound (I) is carried out in a liquid reaction medium in the presence of a transition metal catalyst complex and at least one monodentate ligand containing one phosphorus atom.

In a preferred embodiment, the monodentate ligand is selected from the group consisting of organophosphines, organophosphites, organophosphonites, organophosphinites, and organophosphinites. These P-containing compounds are defined above.

In a preferred embodiment of the present invention, the at least one monodentate ligand is selected from compounds of formula (IV)

R^M、R^NAnd R^OIndependently of one another, is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl can carry 1,2,3, 4 or 5 substituents selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, carboxy, SO, polyalkylene imine, and optionally alkylene imine₃H. Sulfonic acid group, NE¹E²、NE¹E²E³⁺X^-Halogen, nitro, formyl, acyl and cyano, wherein E¹、E²And E³Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

and wherein the radicals cycloalkyl, heterocycloalkyl, aryl and heteroaryl R^M、R^NAnd R^OIt may carry 1,2,3, 4 or 5 substituents selected from alkyl and the above para-alkyl radicals R^G、R^HAnd R^IThe mentioned substituents, or

R^MAnd R^NOr R^NAnd R^OWith the P atom and, if present, a bondRadicals X bound to them¹⁰、X¹¹And X¹²Together form a 5-to 8-membered heterocycle which is optionally fused with one, two or three groups selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where the heterocycle and, if present, the groups fused on may each, independently of one another, carry 1,2,3 or 4 groups selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, mercapto, polyalkylene oxide, polyalkylene imine, alkoxy, halogen, carboxy, SO₃H. Sulfonic acid group, NE⁴E⁵、NE⁴E⁵E⁶⁺X^-Nitro, alkoxycarbonyl, formyl, acyl and cyano, in which E⁴、E⁵And E⁶Identical or different and selected from hydrogen, alkyl, cycloalkyl and aryl, and X^-Is an equivalent to the anion of an anion,

X¹⁰、X¹¹and X¹²Independently of one another is O, S, CR^xR^y、SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and p, q and r independently of one another are 0 or 1.

In another preferred embodiment of the present invention, the at least one monodentate ligand is selected from compounds of formula (IV), wherein

R^M、R^NAnd R^OIndependently of one another are C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₆-C₁₀An aryl, heterocycloalkyl or heteroaryl group,

wherein C is₁-C₁₀The alkyl radical being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from F, Cl, Br, OH, CN, NH₂、C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution;

wherein C is₃-C₁₀Cycloalkyl is unsubstituted or carries 1,2,3, 4 or 5 substituents selected from halogen, OH, CN, NH₂、C₁-C₁₀Alkyl radical, C₆-C₁₀Aryl or P (aryl)₂Wherein the last two mentioned radicals are aryl and P (aryl)₂Is unsubstituted or substituted by 1,2,3, 4 or 5C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀Alkoxy or C₁-C₁₀Haloalkoxy substitution; wherein C is₆-C₁₀Aryl being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from OH, C₁-C₁₀Alkyl radical, C₁-C₁₀Haloalkyl, C₁-C₁₀-alkoxy, C₁-C₁₀Haloalkoxy or C unsubstituted or substituted by OH₆-C₁₀An aryl group;

wherein heterocycloalkyl is a 3-, 4-, 5-, 6-, 7-or 8-membered saturated or partially saturated heteromonocyclic ring containing one, two or three heteroatoms selected from O, S or N as ring members or a 7-, 8-, 9-, 10-, 11-or 12-membered saturated or partially saturated heterobicyclic ring containing one, two, three or four heteroatoms selected from O, S or N as ring members; wherein the hetero-monocyclic ring and the hetero-bicyclic ring may carry 1,2,3, 4 or 5 ring members selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group;

wherein heteroaryl is a 5-or 6-membered monocyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members, and a 9-or 10-membered bicyclic heteroaryl ring containing 1,2,3 or 4 heteroatoms selected from N, O and S as ring members, wherein the monocyclic or bicyclic heteroaryl ring may carry 1,2,3, 4 or 5 heteroatoms selected from halogen, OH, CN, NH₂Or C₁-C₁₀A substituent of an alkyl group;

or

R^MAnd R^NOr R^NAnd R^OWith P atoms and, if present, groups X bonded to them¹⁰、X¹¹Or a group X¹¹And X¹²Together form a 5-to 8-membered heterocyclic ring, optionally with C₅-C₁₀Cycloalkyl radical, C₆-C₁₀One, two or three radicals of aryl, 5-or 6-membered monocyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members or 9-or 10-membered bicyclic heteroaromatic ring having 1,2,3 or 4 heteroatoms from the group consisting of N, O and S as ring members, heteroaryl are fused, where the heterocycles and, if present, the fused radicals can each, independently of one another, carry 1,2,3 or 4 radicals from the group consisting of C₁-C₁₀-a substituent of an alkyl group,

X¹⁰、X¹¹and X¹²Independently of one another is O, S, SiR^xR^yOr NR^zWherein R is^x、R^yAnd R^zIndependently of one another are hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl or C₆-C₁₀Aryl, p, q and r are independently of each other 0 or 1.

In a particularly preferred embodiment of the present invention, the at least one monodentate ligand is selected from compounds of formula (IV), wherein

R^M、R^NAnd R^OIndependently of one another are C₁-C₆Alkyl or C₆-C₁₀Aryl radicals, especially C₁-C₆Alkyl or C₆-C₁₀In particular C₁-C₄An alkyl group, a phenyl group,

wherein C is₁-C₆The alkyl radical being unsubstituted or carrying 1,2,3, 4 or 5 substituents selected from F, Cl, Br, OH, CN, NH₂A substituent of (1);

wherein C is₆-C₁₀Aryl being unsubstituted or carrying 1,2,3, 4 or 5 members selected from OH, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄-alkoxy, C₁-C₄Haloalkoxy, especially methyl, ethyl, CF₃Methoxy, ethoxy substituents;

X¹⁰、X¹¹and X¹²Independently of each other is O, S, and,

p, q and r are independently of one another 0 or 1.

In a particular embodiment, the at least one monodentate ligand is selected from the group consisting of triphenylphosphine, tri (p-tolyl) phosphine, tri (4-methoxyphenyl) phosphine, tri (4-trifluoromethylphenyl) phosphine, tri (o-tolyl) phosphine, triphenyl phosphite, and trimethyl phosphite.

In the process of the present invention, the at least one monodentate ligand is generally used in excess based on the amount of transition metal catalyst complex.

Preferably, the molar ratio of the transition metal catalyst complex to the at least one monodentate ligand is in the range of 1:5.0 to 1:1.1, more preferably in the range of 1:3.0 to 1:1.2, especially in the range of 1:2.5 to 1: 1.3.

In a preferred embodiment, the at least one polydentate ligand is selected from tris (diphenylphosphinomethyl) methane or tris (diphenylphosphinomethyl) amine and the at least one monodentate ligand is selected from triphenyl phosphite.

According to the process of the present invention, Compound (I) is obtained

Wherein R is¹Have one of the meanings as defined above.

Preferably, R¹Selected from unsubstituted or substituted by 1,2,3, 4 or 5 substituents selected from OH, halogen, C₁-C₆Alkoxy or C₆-C₁₀Aryl substituted by substituents C₁-C₂₀Alkyl, more preferably unsubstituted or substituted by 1,2,3 or 4 substituents selected from OH, halogen, C₁-C₄C substituted by substituents of alkoxy₁-C₆Alkyl, especially C, unsubstituted or substituted by 1 or 2 substituents selected from OH or halogen₁-C₄Alkyl, especially unsubstituted C₁-C₄Alkyl, especially C₁-C₂An alkyl group.

In one embodiment, bothR is¹Have the same meaning.

In one embodiment, R¹Is methyl.

In another preferred embodiment, the two R' s¹Together form a divalent bridging radical R²(ii) a It is preferably selected from straight chain C₂-C₆Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1,2 or 3 substituents selected from OH, halogen, C₁-C₄Alkyl or C₁-C₄Substituent of alkoxy, more preferably C₂-C₅Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1 or 2 groups selected from C₁-C₂Substituent substitution of alkyl, especially C₂-C₅Alkanediyl, wherein alkanediyl is unsubstituted or substituted by 1 atom selected from C₁-C₂Alkyl substituents.

In one embodiment, R²is-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH(CH₃)-、-CH₂-CH(CH₃)-CH₂-or-CH₂-CH(CH₃)-。

Typically, a composition is obtained comprising the compound of formula (I), a catalyst, a monodentate ligand, water, a lewis acid, and unreacted alcohol of formula (ii.a) or (ii.b). The work-up of the reaction mixture and the isolation of the acetals of the process of the invention are carried out in a conventional manner, for example by filtration, extractive work-up or by distillation, for example under reduced pressure. By applying these measures or a combination thereof, the compound of formula (I) can be obtained in sufficient purity to avoid additional purification steps. Alternatively, further purification may be achieved by methods commonly used in the art, such as chromatography.

In one embodiment of the present invention, the process of the invention is characterized in that the compound of formula (I) is separated from the transition metal catalyst by distillation.

The distillation residue usually still contains the transition metal catalyst, the Lewis acid and the monodentate ligand in active form, which can be reused in a new reaction in a new process cycle to prepare the compound of formula (I). The transition metal catalyst remains active as long as the distillation conditions, in particular the temperature treatment, are less severe.

In one embodiment of the present invention, the process of the present invention is characterized in that the compound of formula (I) and other volatile compounds of the reaction mixture are removed by distillation to recycle the homogeneous transition metal catalyst.

Another aspect of the present invention relates to a mixture comprising at least one polydentate ligand and at least one monodentate ligand as defined above.

In a preferred embodiment, the mixture comprises at least one polydentate ligand selected from tris (diphenylphosphinomethyl) ethane or tris (diphenylphosphinomethyl) amine and at least one monodentate ligand selected from triphenylphosphine, tris (p-tolyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (4-trifluoromethylphenyl) phosphine, tris (o-tolyl) phosphine, triphenyl phosphite and trimethyl phosphite.

In another preferred embodiment, the mixture comprises at least one polydentate ligand and at least one monodentate ligand as defined above, wherein the molar ratio of transition metal catalyst complex to the at least one monodentate ligand is in the range of 1:5.0 to 1:1.1, more preferably in the range of 1:3.0 to 1:1.2, in particular in the range of 1:2.5 to 1: 1.3.

Another aspect of the present invention relates to the use of a mixture comprising at least one polydentate ligand and at least one monodentate ligand in a transition metal complex as defined above for the preparation of compound (I).

The present invention is described in more detail in the following examples.

Examples

All chemicals and solvents were purchased from Sigma-Aldrich, Merck or ABCR and used without further purification.

The following abbreviations are used:

MF: formic acid methyl ester

DMM: dimethoxymethane

Triphos: 1,1, 1-tris (diphenylphosphinomethyl) ethane

COD: 1, 5-cyclooctadiene

Ph: phenyl radical

Tol: tolyl radical

To summarize:

chemicals were purchased from commercial suppliers and used as received. 1,1, 1-tris (diphenylphosphinomethyl) ethane (triphos), Ru (PPh)₃)₄H₂And bis (2-methallyl) (1, 5-cyclooctadiene) ruthenium (II) from Merck. Ru (triphos) was synthesized according to the previous report ((ChemCatchem 2013,5,439-441) (tmpm) anhydrous solvent was dispensed by the solvent purification system MB SPS-800. reactions requiring inert conditions were carried out under nitrogen atmosphere in flame-dried glassware using standard Schlenk techniques, if not otherwise mentioned, NMR spectra were recorded at room temperature on a spectrometer Bruker Avance-III-300, Bruker Avance DRX-500 and Bruker Avance-III-500 Hz chemical shifts are given in ppm and coupling constants are given in ppm.

With respect to deuterated solvents, i.e. CDCl₃(7.26 ppm; 77.16ppm) calibration¹H and¹³and (4) C spectrum.

Example 1:

in an argon-filled glove box, the ruthenium precursor (12.5. mu. mol), the triphos ligand (12.5. mu. mol), Al (OTf)₃(25. mu. mol), additives (25. mu. mol) and MeOH (2mL) were added to the vial equipped with a magnetic stir bar and sealed. The vial was placed in a high pressure Paar reactor steel autoclave (internal volume 300 mL). The autoclave was closed and CO was used₂Purging was performed twice. Open the reactor, two microwave vial seals perforated with a large bore needle to allow gas transfer, seal the autoclave and use CO₂Purging, finally with CO₂(10 bar) and H₂(30 bar) to a pressure of 40 bar (total pressure). The autoclave was brought to the desired temperature (100 ℃) using a heating coil and stirred at 600rpm for 16 h. The autoclave was cooled to room temperature with an ice bath and then vented. Mesitylene was added as an internal standard to the vial and the resulting solution was then addedIn CDCl₃Is transferred to an NMR tube and passed¹H NMR analysis. The experimental data are shown in table 1.

TABLE 1

Experiment of	Monodentate ligand (additive)	TON of MF	TON of DMM
				1 (comparison)	Is free of	18	4
2	Ph3P	21	32
				3	p-Tol3P	21	32
4	(4-MeOC6H4)3P	21	29
				5	(PhO)3P	18	46
6a	(PhO)3P	24	46

a) Using [ Ru (triphosphos) (tmm)](12.5. mu. mol) instead of [ Ru (2-methylallyl)₂(COD)](12.5. mu. mol) and triphos (12.5. mu. mol)

The positive effect of the different phosphines on activity and DMM selectivity is clearly shown at a pressure of 40 bar. The data demonstrate that examples according to the present invention exhibit significantly higher TON to DMM than comparative experiment 1.

Example 2:

in an argon-filled glove box, the ruthenium precursor (12.5. mu. mol), the triphos ligand (12.5. mu. mol) (if necessary), Al (OTf)₃(Y, 25. mu. mol), additive (Z, 25. mu. mol) and MeOH (2mL) were added to the vial equipped with a magnetic stir bar and sealed. The vial was placed in a high pressure Paar reactor steel autoclave (internal volume 300 mL). The autoclave was closed and CO was used₂Purging was performed twice. Open the reactor, two microwave vial seals perforated with a large bore needle to allow gas transfer, seal the autoclave and use CO₂Purging, finally with CO₂(20 bar) and H₂(60 bar) to a pressure of 80 bar (total pressure). The autoclave was brought to the desired temperature (100 ℃) using a heating coil and stirred at 600rpm for 16 h. The autoclave was cooled to room temperature with an ice bath and then vented. Mesitylene was added as an internal standard to the vial, and the resulting solution was then placed in CDCl₃Is transferred to an NMR tube and passed¹H NMR analysis. Number of experimentsThis is shown in Table 2.

TABLE 2

Experiment of	Catalyst and process for preparing samea	X	Y	Z	TON of MF	TON of DMM
							7 (comparison)	A	12.5	25	0	48	83
8	A	12.5	25	25	44	95
							9	B	12.5	25	25	49	92
10	A	6.0	12	12	71	148
							11	B	6.0	12	12	54	114
12	C	6.0	12	0	70	160

A：[Ru(triphos)(tmm)]

B: [ Ru (2-methylallyl)₂(COD)]And triphos

C：Ru(PPh₃)₄H₂And triphos

At a pressure of 80 bar, in P (Ph)₃The activity in the presence of monodentate ligands (see exp.12) can be further increased to 160 TON_DMM(compare ex.2, Table 1).In comparative experiment 7, a TON of 83 was achieved_DMMIs significantly lower.

Example 3:

screening experiments were performed in 8 parallel steel autoclave reactors (internal volume 300 mL). The general experimental procedure for each screening experiment was as follows: in a first step, the reaction mixture is prepared by mixing 79.2 g (100mL) of solvent (MeOH), 90 mg (125. mu. mol) of Ru-catalyst (Ru (triphosphats) (tmm)), 237.095 mg (500. mu. mol) of Al (OTf)₃And 155.14 (500. mu. mol) monodentate ligand P (OPh)₃A steel autoclave reactor (internal volume 300mL) was charged to prepare the starting reaction mixture. In a second step, the filled steel autoclave reactor was tightly sealed and charged with 100 bar H₂And 20 bar CO₂The steel autoclave reactor was heated to a temperature of 100 ℃ while being pressurized (total pressure of 120 bar) and stirred at 2000 rpm. After the corresponding reaction temperature was reached, the reaction temperature was maintained for the given reaction time while continuing to stir the reaction mixture in the heated and pressurized steel autoclave reactor. Subsequently, the steel autoclave reactor was allowed to cool to room temperature (about 22 ℃), the pressure was released and the steel autoclave reactor was opened. For further analysis, 1 ml of the resulting reaction mixture was subjected to GC analysis to quantify the reaction products.

GC method: column: varian CP7475 CP-Sil 5 CB; 60m 320 μm 8 μm, injection volume: 1 μ L, inlet: at 250 ℃, splitting: 20:1, flow rate: constant flow 5 mL/min, oven: the starting temperature was 40 ℃ for 3 minutes, 20 ℃/min to 225 ℃ for 8.25 minutes. The experimental data are shown in table 3.

TABLE 3

Experiment of	Time [ h ]]	TON of MF	TON of DMM
				13	8	191	857
14	10	170	890
				15	12	166	930
16	14	171	962
				17	16	160	913
18	36	141	780

By combining Ru (triphosphos) (tmm) and P (OPh) Using a Steel autoclave₃(125. mu. mol of Ru catalyst in 100ml of MeOH) and high-pressure CO₂(20 bar) and H₂(100 bar) to achieve a further increase in activity and selectivity. Reaction timeThe cross-screen showed that the highest TON was achieved after 14 hours_DMM962) (see example 16). No P (OPh)₃Ru (triphos) (tmm) gave a number of revolutions of up to 700 cycles under the same conditions. Increased TON_DMMThe significant reduction in the rate (. about.40%) and MF formation indicates the monodentate ligand P (OPh)₃The positive effect of the composition.

Example 4:

the mixture obtained in experiment 16 was applied to a rotary evaporator until all solvent and liquid product were evaporated under air. The remaining solids were transferred to a glove box and added to a steel autoclave reactor (internal volume 300mL) with 79.2 grams (100mL) of solvent (MeOH). In a second step, the filled steel autoclave reactor was tightly sealed and charged with 100 bar H₂And 20 bar CO₂The steel autoclave reactor was heated to a temperature of 100 ℃ while being pressurized (total pressure of 120 bar) and stirred at 2000 rpm. After the corresponding reaction temperature was reached, the reaction temperature was maintained for 12 hours while continuing to stir the reaction mixture in the heated and pressurized steel autoclave reactor. Subsequently, the steel autoclave reactor was allowed to cool to room temperature (about 22 ℃), the pressure was released and the steel autoclave reactor was opened. For further analysis, 1 ml of the resulting reaction mixture was subjected to GC analysis to quantify the reaction products.

GC method: column: varian CP7475 CP-Sil 5 CB; 60m 320 μm 8 μm, injection volume: 1 μ L, inlet: at 250 ℃, splitting: 20:1, flow rate: constant flow 5 mL/min, oven: the starting temperature was 40 ℃ for 3 minutes, 20 ℃/min to 225 ℃ for 8.25 minutes. The experimental data are shown in table 4.

TABLE 4

Experiment 19	TON of MF	TON of DMM
			For the first time	171	962
For the second time	161	709

The reuse of the Ru catalyst was also verified using the following method, which means a 74% recovery of catalyst activity according to experiment 19.