阅读说明：本技术 大环内酯的制备 (Preparation of macrolides ) 是由 P·N·戴维 于 2017-03-08 设计创作，主要内容包括：制备包含14-17个环碳原子的大环内酯的方法,该方法包括以下步骤：i)将包含通过复分解反应形成的含烯烃的无规聚酯的反应混合物进行环-解聚反应,形成大环内酯,和ii)同时从反应混合物中除去所述大环内酯。(A process for the preparation of a macrolide containing 14-17 ring carbon atoms, which process comprises the steps of: i) subjecting a reaction mixture comprising an olefin-containing random polyester formed by a metathesis reaction to a ring-depolymerization reaction to form a macrolide, and ii) simultaneously removing the macrolide from the reaction mixture.)

1. A process for the preparation and isolation of a macrolide by ring-depolymerization of an olefin-containing random polyester contained in a reaction mixture, the process comprising the steps of:

i) depolymerizing the olefin-containing random polyester in the reaction mixture to form fragments capable of intramolecular cyclization;

ii) intramolecular cyclisation of the fragment to form the desired macrolide; and

iii) simultaneously isolating the macrolide from the reaction mixture,

wherein the polyester is prepared by acyclic diene metathesis polymerization of a diene-ester, wherein the diene-ester contains one terminal olefinic group and one internal olefinic group.

2. The process of claim 1 wherein the olefin-containing polyester contains at least one unit of the formula

Wherein

A is a divalent radical-CHR-, wherein R is hydrogen or C_1-4An alkyl group;

b is a divalent radical-CHR '-, in which R' is hydrogen or C_1-4An alkyl group;

the sum of n and m is an integer selected from 11,12,13 or 14; and

wherein the divalent groups A and B in the unit may be the same or different.

3. The process of claim 2 wherein the olefin-containing polyester contains at least one of each of the following units

4. The process of claim 1 wherein the polyester contains at least 5 to 50 units.

5. The process according to claim 1, wherein the ring-depolymerization reaction is carried out by metathesis, and wherein the metathesis reaction is catalyzed with a tungsten or molybdenum metathesis catalyst.

6. The process of claim 5 wherein the metathesis reaction is catalyzed by a catalyst selected from the group consisting of

Wherein

M ═ Mo or W;

x is O, or N-R¹Wherein R is¹Is aryl, heteroaryl, alkyl or heteroalkyl, optionally substituted;

R²and R³May be the same or different and is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, or alkoxy, optionally substituted;

R⁵is alkyl, alkoxy, heteroalkyl, aryl, aryloxy, heteroaryl, silylalkyl, silyloxy, optionally substituted; and

R⁴is a residue R⁶-X '-, wherein X' - ═ O and R⁶Is aryl or heteroaryl, which is optionally substituted; or X' is S and R⁶Is aryl or heteroaryl, optionally substituted; or X' is O and R⁶Is (R)⁷,R⁸,R⁹) Si; wherein R is⁷，R⁸，R⁹Is alkyl or phenyl, whichOptionally substituted; or X' is O and R⁶Is (R)¹⁰,R¹¹,R¹²) C, wherein R¹⁰，R¹¹，R¹²Independently selected from phenyl, alkyl; which is optionally substituted;

or R⁴And R⁵Are linked together and are bound to M by oxygen, respectively.

7. A process according to claim 1 wherein the simultaneous isolation of the macrolide from the reaction mixture is carried out by distillation.

8. The method according to claim 1, wherein the macrocyclic lactone is selected from the group consisting of E/Z-7-abelmosclactone; E/Z-9-abelmoschus manihot lactone; E/Z-norvalactone (Nirvanolide); and E/Z-cyclopentadecanolide.

9. The method according to claim 8, wherein the macrolide is hydrogenated to form a compound corresponding to E/Z-7-abelmosclactone; E/Z-9-abelmoschus manihot lactone; E/Z-norvalactone; or a hydrogenated macrolide of E/Z-cyclopentadecanolide.

10. The process according to claim 1, wherein the diene-ester has the formula

Wherein the content of the first and second substances,

the sum of A, B and m and n is as defined in claim 1; and

R₁，R₂，R₃and R₄Is represented by H or C_1-10Residue of an alkyl group, with the proviso that R₁，R₂，R₃And R₄Only one of the residues may be C_1-10Alkyl, the remaining residues are all H.

11. The process according to claim 10, wherein the diene-ester is selected from the group consisting of:

12. a diene-ester selected from the compounds (a), (c), (d), (e), (f) and (g):

Technical Field

The present invention relates to the synthesis of macrolides by ring-depolymerisation of olefin-containing polyesters, and to monomers and polymers useful for preparing said macrolides.

Background

Macrolides are important structural motifs (motifs) in perfume ingredient chemistry. In particular, macrocyclic lactones are gaining attention for their desirable musk odor in fine and technical perfumery to provide in various forms of consumer products.

The smell of musk is probably the most commonly appreciated olfactory signal in perfumes. Synthetic musks can be divided into three main classes: aromatic nitro musks, polycyclic musks and macrocyclic musks. However, the detection of nitro-and polycyclic chemical groups in human and environmental samples has led to open debates on the use of these compounds; and some studies have shown that these musk compounds do not decompose in the environment and accumulate in the human body. Thus, in recent years, macrocyclic musks have become increasingly important to perfumers.

Common macrocyclic musks include AMBRETTOLIDE^TM(including 9-ambrettolide and 7-ambrettolide), NIRVANOLIDE^TM，HABANOLIDE^TM，COSMONE^TM，MUSCENONE^TM，VELVIONE^TM，CIVETONE^TMAnd GLOBANONE^TM。

7-abelmosclactone is naturally present in muskiness malva seed oil (m.kerschbaum, chember.1927, 60B, 902) and is a valuable fragrance base due to its pleasant odor. 9-Abelmoschus manihot lactone is also a component of a favorable perfume; it is currently synthesized industrially from laccaic acid, which comes from natural sources.

Of course, the availability and quality of natural raw materials depends on climatic conditions as well as socioeconomic factors. Furthermore, since the starting materials can be extracted from natural sources, sometimes in moderate yields, their price is likely to make their use uneconomical on an industrial scale increasing. Thus, if one continues to obtain macrocyclic musks (e.g., AMBRETTOLIDE) at a reasonable cost^TM) The commercial industrial supply of (a) requires more cost-effective, industrially scalable processes for their production, isolation and purification.

Summary of The Invention

In a first aspect, the present invention relates to a process for the preparation and isolation of a macrolide by ring-depolymerization of an olefin-containing random polyester contained in a reaction mixture, which process comprises the steps of:

i) depolymerizing the olefin-containing random polyester in the reaction mixture to form fragments capable of intramolecular cyclization;

ii) intramolecular cyclisation of the fragment to form the desired macrolide; and

iii) simultaneously isolating the macrolide from the reaction mixture.

In another aspect, the invention relates to olefin-containing random polyesters useful for preparing macrolides.

In another aspect, the invention relates to a precursor monomer of said olefin-containing random polyester.

In another aspect, the invention relates to the use of an olefin-containing random polyester in the formation of a macrolide.

Detailed Description

The term "random" when used in relation to a polyester refers to the arrangement of monomer units within the polyester, and more specifically to arrangements in which the monomer units are arranged in a non-predetermined pattern along the polymer chain.

In one embodiment of the invention, the olefin-containing random polyester contains at least one unit of the formula

Wherein

A is a divalent radical-CHR-, wherein R is hydrogen or C_1-4An alkyl group;

b is a divalent radical-CHR '-, in which R' is hydrogen or C_1-4An alkyl group;

the sum of n and m is an integer selected from 11,12,13 or 14; and

wherein the divalent groups A and B contained in the unit may be the same or different.

In a more particular embodiment of the invention, the olefin-containing random polyester contains at least one of each of the following units (at least one of the following units)

Wherein A, B, m and n are as defined above.

The olefin-containing random polyesters of the invention may be acyclic or cyclic. The polymer chain may contain any number of monomer units. In particular, the olefin-containing random polyester may consist of a mixture of polymers having a distribution of from 2 to 100, more particularly from 10 to 50, and more particularly from 10 to 25 monomer units.

Olefin-containing random polyesters can be prepared by polymerizing diene ester monomers using diene metathesis. Suitable monomers are esters containing a first reactive olefinic group (the alcohol olefin) on the alcohol side of the ester and a second reactive olefinic group (the carboxylic acid olefin) on the carboxylic acid side of the ester. It will be apparent to those skilled in the art that metathesis reactions can occur between two alcohol olefins, between two carboxylic acid olefins, or between an alcohol olefin and a carboxylic acid olefin. Thus, the monomer units will be arranged in a random manner along the polyester chain. Thus, the polyester is referred to as a random polyester.

In a preferred embodiment of the present invention, the diene-ester monomers used to prepare the olefin-containing random polyester contain at least one terminal olefinic group.

In a preferred embodiment of the invention, the diene-ester monomer contains one terminal olefinic group and one internal olefinic group.

In a preferred embodiment of the invention, the diene-ester contains two terminal olefinic groups.

Specific diene ester monomers useful in the practice of the present invention can be represented by the formula

Wherein the content of the first and second substances,

a, B and the sum of m and n are as defined above and the sum of n and m is an integer selected from 11,12,13 or 14; and

R₁，R₂，R₃and R₄Independently represent H or C_1-10Residue of an alkyl group, with the proviso that R₁，R₂，R₃And R₄Only one of the residues may be C_1-10Alkyl, the remaining residues are all H.

In one embodiment, R₁And R₂At least one of (1) or R₃And R₄At least one of them represents C_1-10An alkyl group.

Specific diene ester monomers include, but are not limited to, compounds having the following formulas (a) to (g):

the diene ester monomers of the formulae a), c), d), e), f) and g) are regarded as novel compounds. Thus, each of these compounds, their use in the preparation of olefin-containing random polyesters, and the random polyesters formed from the monomers form independent aspects of the invention.

The dienyl esters may be prepared by techniques well known in the art using commercially available starting materials. For example, octenyl decenoate (compound (a) above) can be prepared by transesterification of oct-7-en-1-ol with an alkyl dec-9-enoate in the presence of an acid, e.g., a strong acid, such as sulfuric acid. The reaction conditions are well known to those skilled in the art and it is not necessary to discuss them in further detail here.

The polymerization of the dienyl esters to form the olefin-containing random polyesters may be carried out by a diene metathesis reaction using a suitable metathesis catalyst.

The metathesis reaction conditions required to combine the two olefin functionalities of the reacting monomers are generally well known in the art. The reaction can be carried out at room temperature, elevated temperature or lower temperature. Typically, the reaction may be carried out at a temperature in the range of from 0 to 120 ℃, more particularly from 0 to 60 ℃, still more particularly about 50 ℃. Preferably, the reaction is carried out at a temperature such that the polymerization reaction proceeds rapidly and substantially without concomitant decomposition reactions, and the viscosity of the reaction mixture is such that typical commercial operations, such as mixing, pumping and stirring, should be easy to perform. In view of these factors, it is within the scope of the skilled artisan to select an appropriate reaction temperature.

Metathesis polymerization (metathesis polymerization) reactions can be carried out neat or in a solvent. If a solvent is to be used, it should be unreactive with the catalyst. Suitable solvents may include those chlorinated or aromatic solvents such as toluene, which are acceptable for use in industrial processes. Suitable solvents include, but are not limited to, behenyl and tetraglyme. Alternatively, other solvents having a boiling point near or above the boiling point of the desired macrocyclic product may additionally be added to maintain the fluidity of the mixture during the reaction, for example paraffins, long chain esters such as phthalates, for example dialkyl phthalates, ethers, and the like.

Due to the reactivity of the metathesis catalyst (metathesis catalyst), the reaction should preferably be carried out in an inert atmosphere free of moisture and oxygen, or at least in an inert atmosphere substantially free of moisture and oxygen.

In addition, any material that is contacted with the metathesis catalyst should be purified. Thus, in the process according to the invention, it is desirable to purify the diene ester as well as any solvent or other reagent used in the metathesis reaction prior to introducing the catalyst. Purification requires removal of contaminants that otherwise negatively impact the reactivity of the metathesis catalyst. These impurities include water, alcohols, aldehydes, peroxides, hydroperoxides, protic materials, polar materials, lewis base catalyst poisons, or any mixture thereof. Methods of purifying metathesis catalysts are described, for example, in US2014/0275595 and WO2015/136093, which are incorporated herein by reference.

Catalysts for effecting metathesis reactions are well known in the art. Typically, the olefin metathesis catalyst is an organometallic catalyst with a transition metal atom such as vanadium, rhenium, titanium, tantalum, ruthenium, molybdenum or tungsten. Although there are large variations in the ligands bonded to the metal atom, all effective catalyst systems have a basic metal alkylene or alkylidene (alkylidyne) ligand structure. A review of metathesis catalysts useful in the present invention is described in Michrowska et al, Pure appl. chem., vol 80, No.1, pp 31-432008; schrock et al, chem.rev.2009, 109, 3211-; and Grubbs et al, J.am.chem.Soc.2011, 133, 7490-. Suitable catalysts are also described in the patent literature, for example US2013/0281706 and US6,306,988.

The diversity of substituents or ligands that can be used in the catalyst means that a wide variety of catalysts are now available. The ligands or substituents may be selected to affect catalyst stability (with respect to contaminants or temperature) or selectivity (chemo-, regio-and enantio-selectivity), as well as the turnover number (TON) and turnover frequency (TOF). As is well known in the art, TON describes the degree of activity of a catalyst, i.e., the average number of substrate molecules converted by each molecule of catalyst, while TOF represents the catalyst efficiency (in units of h)^-1)。

Particularly useful catalysts in the metathesis reaction of this invention are those metal alkylidene catalysts in which the metal atom is a ruthenium, molybdenum or tungsten atom. Most preferred are the catalysts wherein the metal atom is molybdenum or tungsten.

Preferred molybdenum or tungsten catalysts are represented by the following general formula

Wherein

M ═ Mo or W;

x is O, or N-R¹(ii) a Wherein R is¹Is aryl, heteroaryl, alkyl or heteroalkyl, optionally substituted;

R²and R³May be the same or different and is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, or alkoxy, optionally substituted;

R⁵is alkyl, alkoxy, heteroalkyl, aryl, aryloxy, heteroaryl, silylalkyl, silyloxy, optionally substituted;

and R⁴Is a residue R⁶-X '-, wherein X' - ═ O and R⁶Is aryl or heteroaryl, which is optionally substituted; or X' is S and R⁶Is aryl or heteroaryl, optionally substituted; or X' is O and R⁶Is (R)⁷，R⁸，R⁹) Si; wherein R is⁷，R⁸，R⁹Is alkyl or phenyl, which is optionally substitutedIs substituted; or X' is O and R⁶Is (R)¹⁰，R¹¹，R¹²) C, wherein R¹⁰，R¹¹，R¹²Independently selected from phenyl, alkyl; which is optionally substituted;

or R⁴And R⁵Are linked together and are bound to M by oxygen, respectively.

Particularly preferred catalysts are [2, 6-bis (1-methylethyl) phenylamino (2-) ] (6 '-bromo-4', 5 '-diphenyl [1,1':2',1 "-terphenyl ] -3' -hydroxy- κ O) (2, 5-dimethyl-1H-pyrrol-1-yl) (2-methyl-2-phenylpropylene) -molybdenum; and (6 '-bromo-4', 5 '-diphenyl [1,1':2',1 "-terphenyl ] -3' -hydroxy) [2, 6-dichlorophenylamino (2-) - κ N ] (2, 5-dimethyl-1H-pyrrol-1-yl) (2-methyl-2-phenylpropylene) -tungsten.

In general, ring-depolymerization using metathesis can be carried out using homogeneous or heterogeneous catalysts. For example, suitable homogeneous catalysts are disclosed in EP2703081, WO2014/139679 and US 2012/0302710. Suitable heterogeneous catalysts are disclosed, for example, in WO2015/003815, WO2015/003814 and WO 2015/049047. The disclosures of these publications in this regard are incorporated herein by reference.

Particularly preferred catalysts include, but are not limited to:

-a molybdenum catalyst a of formula:

molybdenum catalyst B of formula (CAS: 1445990-85-1):

ruthenium catalyst C (CAS: 934538-04-2) of the formula:

among them, catalyst A is particularly preferable because it has very high thermal stability.

The level of catalyst used in the polymerization reaction described hereinabove may be from 10 to 1000ppm, and more particularly from 50 to 200ppm, and still more particularly from 100 to 200ppm, on a molar basis.

The catalyst may be provided on a solid support. Suitable solid catalyst supports are well known in the art and include silica or alumina, or polymers, which are optionally blocked to reduce the number of free hydroxyl groups. The capping may be performed by heat treatment, and optionally using a capping agent such as a silylating agent. The catalyst loading on the support may vary depending on the particular synthetic conversion being carried out, but the catalyst may be present on the solid support in an amount of from 1 to 10 wt%, based on the total weight of the catalyst and support.

Olefin-containing random polyesters formed according to the process described above are converted by a ring-depolymerization process to macrolides of the general formula

Wherein A, B, m and n are as defined above.

As used herein, the term "ring-depolymerisation" refers to a process in which a polyester is depolymerised by bond cleavage of its ester or alkene functionality, and then the intramolecular cyclization of the fragment formed by the bond cleavage forms the desired macrolide.

During ring-depolymerization, the olefin-containing random polyester is cleaved by breaking the olefin or ester functionality, depending on the particular depolymerization chemistry used. Bond scission is random and will form a complex equilibrium mixture of cyclic and/or linear oligomers or polymers of varying chain length. When the adjacent ester functionality or the adjacent alkene functionality reacts, the smallest (and lowest boiling) fragment obtained during ring-depolymerization is produced, and this cleaved fragment can undergo intramolecular cyclization to form the desired macrolide, which is subsequently removed from the reaction mixture by a suitable separation technique such as distillation or filtration, e.g. membrane filtration, e.g. zeolite membrane filtration.

If the macrolide is to be removed from the reaction mixture by distillation, the pressure and temperature conditions are such that once the macrolide is formed, it boils and separates from the reaction mixture. Removal of the macrolide in this manner will rebalance the reaction mixture and promote the formation of more macrolide. The skilled person will appreciate that removal of the macrolide by other means (e.g. membrane filtration) will also re-equilibrate the reaction mixture and promote the formation of the macrolide.

In one embodiment of the invention, the ring-depolymerization is carried out by cleavage of the ester function during the transesterification reaction.

Transesterification chemistry is well known in the art. Typical reaction conditions are described by Collaud et al in US2,234,551. Ring-depolymerization by transesterification can be carried out by heating an olefin-containing random polyester in the presence of a transesterification catalyst. Suitable catalysts include, but are not limited to, lewis acids and bronsted acids and bases. Titanium tetraalkoxide catalysts are particularly preferred.

If the method of removing the macrolide is distillation, the reaction should be carried out at a temperature and pressure sufficient to distill off the macrolide once it has formed. Once the macrolide formed in this way is removed from the reaction vessel, any remaining homo-dimer residue may be recycled if desired.

The suitable temperature at which the reaction is carried out depends on the pressure in the reaction vessel. The reaction can be carried out under reduced pressure, which can be achieved economically on an industrial scale, for example in the range from 0.1 to 100 mbar. The temperature at which the reaction is carried out may be in the range of about 50 to 250 c, more particularly in the range of 100 to 200 c.

In another preferred embodiment of the present invention, the ring-depolymerization is carried out by olefin metathesis cleavage of the olefin functionality as previously described.

Depending on the functionality of the cracked olefin, oligomeric or polymeric segments of all forms may be formed. However, when adjacent olefin functional groups react, the fragments formed may cyclize to form the desired macrolide. Removal of this macrolide from the reaction mixture by distillation or by other methods as described above will drive the reaction to more macrocyclic musks which in principle may result in substantially 100% conversion of the polyester to the desired macrolide.

The skilled artisan can select reaction conditions (e.g., temperature and pressure) based on a number of considerations, including the activity of the particular catalyst used; the need to promote ring-depolymerization and reduce unwanted reactions such as double bond isomerization; and desirably the reaction mixture is a low viscosity liquid. Furthermore, when it is desired to effect the separation of the macrolide by distillation, the temperature and pressure should be selected such that the lactone can be distilled, preferably without co-distillate.

Typically, the reaction may be carried out at atmospheric or reduced pressure, for example in the range 1bar to 1mbar, more particularly 10 to 100mbar, and still more particularly 10 to 30 mbar. Typical temperatures may be between ambient and 250 ℃, more particularly 100 and 250 ℃, and still more particularly 150 to 200 ℃.

Any of the metathesis catalysts mentioned above may be used in the ring-depolymerization reaction. However, tungsten and molybdenum metathesis catalysts may be particularly useful if it is desired to reduce any side reactions that may occur, such as double bond isomerization reactions.

Whereas isolation of the macrolide from the reaction mixture is necessary to re-equilibrate the mixture and facilitate further macrolide formation, it may be necessary to heat the mixture to distill off the lactone. If the reaction mixture is heated, it is desirable to use a metathesis catalyst that is thermally stable at the distillation temperature. Of course, if the macrolide is isolated by membrane filtration rather than by distillation, then such precautions may not be necessary.

Regardless of the thermal stability of any given catalyst, the ring-depolymerization reaction can be carried out under conditions in which the catalyst is physically separated from the reaction mixture heated to the distillation temperature of the macrolide.

For example, the catalyst may be contained in the first part of the reactor at a first temperature below the distillation temperature of the macrolide and at which the catalyst is stable, or substantially stable. The first portion of the reactor is in fluid communication with a second portion of the reactor at a second temperature that is equal to or greater than the temperature at which the macrolide is distilled. The reactor is equipped with means for distilling the macrolide so that the macrolide is separated from the reaction mixture by distillation as the reaction mixture flows from the first portion of the reactor to the second portion of the reactor. The apparatus for distilling the macrolide may consist of a conventional distillation vessel and column, or it may consist of an apparatus for molecular distillation (e.g. a wiped film distillation apparatus). The reaction mixture may be continuously circulated between the first and second sections of the reactor and then heated and cooled as it passes between the second and first sections of the reactor.

The methods described above can be used to prepare all forms of macrolides. Preferred macrolides are those useful in perfumery. Particularly preferred macrolides are those containing from 14 to 17 carbon atoms in the ring.

Examples of preferred macrolides include, but are not limited to, AMBRETTOLIDE^TM(two types, having a double bond at the 9-or 7-position), NIRVANOLIDE^TM，HABANOLIDE^TMOr globalitide^TM. These macrocyclic musk compounds contain unsaturation in the ring and may therefore exist in the E/Z form. The invention relates to a method for producing said macrocyclic musks in pure E or pure Z form or in E/Z mixtures in any desired ratio.

In addition to these musks, their saturated counterparts can also be prepared in a manner known per se by hydrogenation of the carbon-carbon double bond. These hydrogenated derivatives include, but are not limited to, hexadecanolide and cyclopentadecanolide.

Although musks are referred to by their trade name, the skilled person will appreciate that this is for ease of reference only and the applicant expects that the teachings of the present invention are applicable to the preparation of general musk molecules. For each musk named in the above commercial names, the skilled person is either familiar with the more conventional chemical nomenclature used to name the musk or realizes that the correspondence between the trivial and chemical nomenclature can be found in standard perfume references such as the Leffingwell or the theodscent company.

The invention is further illustrated by the following non-limiting examples:

example 1: preparation of octenyl decenoate

To a 2L sulfonation flask equipped with a thermometer, distillation head, condenser and receiver and connected to a house vacuum through a cold trap was added methyl 9-decenoate (500g, 2.70mol), 7-octenol (350g, 2.70mol, 1.01eq) and concentrated sulfuric acid (10g, 2%) with stirring.

Vacuum was applied and maintained at 28 mbar. The mixture was then heated to 100 ℃. The distillation started at about 75 ℃.

Recording the reaction:

distillate + cold trap 91.75g

After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate solution (50ml) was added and stirred for 15 minutes. The mixture was poured into a separatory funnel to allow the layers to settle. The aqueous layer was separated, the organic layer was washed with water (2X 200ml), dried over magnesium sulfate and filtered.

737.7g of crude product were obtained.

Tocopherol (0.2g) was added to the mixture, which was then purified by distillation through a 0.5m Sulzer packed column.

Preparation of octenyl decenoate was confirmed by GLC analysis on HP6890 using a 25m HP5(0.33m) column programmed at 15 deg.C/min at 70 deg.C to 220 deg.C.

Example 2: preparation of octenyl polydecenoate

A1L glass jacketed autoclave (Buchi) was equipped with an anchor stirrer, baffle, temperature probe, argon inlet, vacuum line and liquid addition line. The latter is a simple ball valve fitted with a diaphragm inlet. When liquids were added, they were added to the reactor under positive argon pressure through a stainless steel cannula. Before the cannula is pulled out, the cannula is pulled out of the valve and the valve is closed. Before use, the reactor glass was heated to 130 ℃ for 3 hours and cooled under vacuum overnight.

Stock solutions and feeds were prepared in a glove box under dry nitrogen (five 0s grade). They were placed in a sealed Schlenk tube and removed from the glove box.

The reaction and mass transfer were carried out under argon, but it is expected that five 0s grade dry nitrogen could be easily substituted.

The reactor was rated at 12bar but was equipped with a 6bar rupture disc, the vent tube leading to the rear of the fume hood.

Stock solution:

for ease of handling on a small laboratory scale, stock solutions of triethylaluminum (25% in toluene as received) and [2, 6-bis (1-methylethyl) phenylamino (2-) ] (6 '-bromo-4', 5 '-diphenyl [1,1':2',1 "-terphenyl ] -3' -hydroxy- κ O) (2, 5-dimethyl-1H-pyrrol-1-yl) (2-methyl-2-phenylpropylene) -molybdenum metathesis catalyst (molybdenum catalyst B; 0.021M in d 6-benzene for ease of NMR analysis) were used.

Feed pretreatment:

dec-9-enoic acid oct-7-enyl ester (H) through cannula₂O53 ppm, peroxide value PV 1.6meq/kg) was charged to an argon filled reactor. Addition and purging through the funnel was poor (only-50% conversion was observed).

Triethylaluminum (1 mol%) was added as a stock solution in toluene at room temperature (about 25 ℃) to oct-7-enyl dec-9-enoate under a slight positive pressure of nitrogen (1.3bar) in the order of five 0 s. The cannula was rinsed with dry toluene (2ml) before removal, since triethylaluminum is pyrophoric at > 10% concentration. The mixture was stirred at room temperature for 3 hours. It appears that heating the mixture to 50 ℃ or higher at this stage is detrimental to the conversion. The reactor was cycled three times by vacuum (7 mbar)/argon (1.3bar) purge to remove any impurity build-up.

Polymerization:

to the pretreated oct-7-enyl dec-9-enoate was added a solution of 200ppm of molybdenum catalyst B. After about 15 minutes, the viscosity increased and the reactor was heated to 50 ℃ to keep the reaction liquid. This took approximately 15 minutes. The reaction was not exothermic. Note that if the molybdenum catalyst B was added from 50 ℃, the reaction effect was poor.

The raw material pretreatment was carried out as described above:

the reaction mixture was cooled overnight and solidified. This was melted (jacketed at 50 ℃) and sampled for NMR and GPC (see below) to give 238 g. Additional material was washed from the reactor and the overhead was washed with toluene and removed under vacuum to give an additional 37 g. In total: 275 g. The theoretical maximum for 100% conversion of pure material is 270 g. The crude polymer contains residual catalyst and aluminate.

The formation of the polymer was confirmed using Gel Permeation Chromatography (GPC) analysis. The analysis was performed on a self-established GPC. Two columns were used in series with a guard column (Phenogel 5 mm)Then the mixture is subjected to the Phenogel of 5mm,all from Phenomenex), eluted with THF and a refractive index detector was used.

Example 3: preparation of okra lactone by ring-depolymerization using transesterification reaction

A round bottom flask equipped with a Kirschner distillation head, magnetic stirrer and thermometer was attached to a peristaltic pump to allow addition of polyethylene glycol (PEG200) during the reaction.

The flask was charged with polymer (100g, which could be handled as a liquid at 50 ℃). PEG200(130g) was added along with titanium tetraisopropoxide (5g, 17 mmol). Initially, the mixture is immiscible. The vacuum was set to 10mbar and the stirred mixture was heated. Degassing is observed when the mixture reaches about 40-50 ℃. The vacuum was temporarily reduced to 30-50mbar and then slowly increased. When the mixture reaches 110-120 deg.C, degassing occurs, the mixture becomes viscous and the polymer begins to dissolve in the PEG. At 160 ℃, the mixture became less viscous and was easily stirred again. Heating is continued to a reaction temperature of 190 ℃ and 200 ℃.

When the distillation head temperature was about 170 ℃ at 10mbar, material began to distill off, PEG was pumped into the flask to maintain a standard liquid level (total addition: 885 g).

The total distillation time was about 40 hours, using 5 working days. The fractional analysis of E-and Z-abelmonolide was performed by relative peak area GLC. Fractions were combined and then worked up:

to the combined fractions (707g) was added water (700ml), which was extracted with hexane (700 ml). Three phases were observed. The middle one was treated with the aqueous phase and extracted with hexane (2X 200 ml). The combined organics were washed twice with water (2X 200 ml). The organic layers were combined, dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator to give crude okra lactone (43.0g, 171 mmol). GLC showed 87% purity by rpa. This represents a chemical yield of 75%.

Example 4: preparation of okra lactone by ring-depolymerization using metathesis and distillation

The reaction is carried out in a glove box containing a dry low oxygen atmosphere (nitrogen or argon) to facilitate handling.

Octenyl polydecenoate (prepared as described above; 0.25g) was placed in a Kugellof continuous distillation bulb (Kugelrohr bulb). Molybdenum catalyst a (see above) was added as a solution in toluene (250mol.ppm) and the system was placed under vacuum (0.2 mbar). After removal of the toluene, the Kugelloff ball tube furnace (Kugelrohr oven) was heated to 130 ℃ and 150 ℃ and the okra lactone was distilled off. When the rate of okra lactone distillation slowed, an additional aliquot of catalyst was added and distillation continued. Repeating this technique can yield over 60% pelargonilide from the polymer.

Example 5: preparation of okra lactone by ring-depolymerization using metathesis and distillation

The reaction is carried out in a glove box containing a dry low oxygen atmosphere (nitrogen or argon) to facilitate handling.

Octenyl polydecenoate (prepared as described above; 0.25g) was dissolved in docosane (2.5ml) and placed in a Cogelif continuous distillation bulb. Molybdenum catalyst A (see above) (400mol.ppm) was added and the system was placed under vacuum (0.5 mbar). The Couguer bulb furnace was heated to 130 ℃ and 150 ℃ and the mixture of pelargonide and docosane was distilled off. Periodically, fresh aliquots of catalyst and solvent were added and distillation continued to obtain more okra lactone.

Example 6: preparation of okra lactone by ring-depolymerization using metathesis

The reaction is carried out in a glove box containing a dry low oxygen atmosphere (nitrogen or argon) to facilitate handling.

Octenyl polydecene (prepared as described above; 0.25g) was dissolved in tetraglyme. Molybdenum catalyst A (see above; 400ppm) was added and the mixture was heated to 160 ℃ for 6 h. Internal standard glc analysis showed 13.8% formation of pelargonidin.

Example 7: preparation of okra lactone by ring-depolymerization using metathesis and filtration

Octenyl polydecenoate (prepared as described above; 50g) was added to ethyl acetate (700ml) and dissolved at 60 ℃. TiO modified by 1nm C8₂The flux measurements of the membranes were performed at a transmembrane pressure of 5 bar. Ruthenium catalyst C (see above; 0.6 mol%) was added. The cell was placed under pressure (5 bar). With acetic acidThe ethyl ester was subjected to constant volume diafiltration for about 2 hours. The permeate and retentate were analyzed and shown to contain okra lactone (total yield 20%). The reaction can be continued to produce and isolate more okra lactone.