CN113179630A - Improved process for the preparation of pregabalin - Google Patents

Improved process for the preparation of pregabalin Download PDF

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CN113179630A
CN113179630A CN201980006968.6A CN201980006968A CN113179630A CN 113179630 A CN113179630 A CN 113179630A CN 201980006968 A CN201980006968 A CN 201980006968A CN 113179630 A CN113179630 A CN 113179630A
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lipase
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苏迪尔·南比亚尔
戈弗德汗·吉拉
桑托什·克拉斯塔
希瓦吉·古盖尔
拉文德拉·兰德奇
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Abstract

The present invention relates to an improved process for the preparation of pregabalin (i), which is simple, economical, efficient and environmentally friendly, commercially viable, having a chemical and chiral purity of at least 99.95%.

Description

Improved process for the preparation of pregabalin
Technical Field
The present invention relates to a commercially viable, more green process for the manufacture of pregabalin in high yield and purity.
Background
Pregabalin, chemically known as 3- (S) - (aminomethyl) -5-methylhexanoic acid having the structure of formula (i), is known to treat several central nervous system disorders including epilepsy, neuropathic pain, anxiety and social phobia.
It has been found that (S) -pregabalin activates GAD (L-glutamate decarboxylase) in a dose-dependent manner and promotes the production of GABA (gamma-aminobutyric acid), one of the main inhibitory neurotransmitters of the brain. The discovery of antiepileptic activity was first disclosed in U.S. Pat. No. 5,563,175. Pregabalin has been prepared in various ways; the most common route involves the synthesis of racemic pregabalin, usually a 50:50 mixture of the R and S isomers, followed by resolution by diastereomeric salt formation. This approach is disclosed in patent publications such as WO2009122215, WO2009087674, WO2009044409, WO2008138874, WO2009125427 and WO 2009001372. The major difficulties associated with this route involve the loss of the R-isomer and the inability to efficiently recover the desired S-isomer, resulting in increased overall costs. The WO2009087674 patent discloses the use of chloroform for chemical resolution, which is not the preferred solvent for the preparation of drugs on a commercial scale.
PCT publication No. WO9638405 describes the synthesis of S-pregabalin (scheme 1). The synthetic procedure involves Knoevenagel condensation followed by Micheal addition and acidic hydrolysis to provide the diacid. The diacid is converted to the monoamide, which is resolved by (R) -phenylethylamine. The prepared R-monoamide is further converted into (S) -pregabalin by Hoffmann degradation (Hoffmann degradation). The disadvantage of this process is that the overall yield is low (12%) and can only be obtained after 8 steps.
Scheme 1:
Figure BDA0002559231380000021
PCT publication No. WO2008062460 and patent No. US6,046,353 describe condensation of diethyl malonate with isovaleraldehyde followed by cyanation. The product is selectively hydrolyzed and decarboxylated to a cyanoester, which upon hydrolysis yields the cyanoacid. The cyanoacid is hydrogenated to racemic pregabalin and resolved by (S) - (+) mandelic acid (scheme 2). The disadvantages of this process are the use of expensive reagents, the low overall yield (15.5%) and the availability after 6 steps.
Scheme 2:
Figure BDA0002559231380000022
patent No. US8,304,252 describes the preparation of pregabalin by an enzymatic route (scheme 3). The process involves the condensation of isovaleraldehyde with ethyl cyanoacetate followed by cyanation to provide the racemic dicyano compound. Nitrilases are used to obtain (S) -cyano acids and to racemize the undesired dinitriles in toluene in the presence of DBU. Hydrogenation of (S) -cyanoacid salt after 4 steps gives (S) -pregabalin in low overall yield (7.7%). The main drawbacks of this process are the low yield and the use of corrosive reagents, which makes the process economically and environmentally impracticable.
Scheme 3:
Figure BDA0002559231380000031
therefore, in order to overcome the drawbacks of the above prior art processes, it is necessary to develop an improved process for the preparation of the desired (S) -pregabalin of formula (i) in higher yields and with high chemical and chiral purity, which is easy to apply on an industrial scale. Therefore, in view of the above disadvantages and needs, the present inventors have motivated the development of an improved and simple process for the preparation of "substantially pure" of (S) -pregabalin of formula (i) from undesired isomers in higher yield, higher chemical purity and chiral purity. The process is made more industrially suitable by using a genetically modified nitrilase and a lipase in a cost-effective and environmentally friendly manner for the recovery and reuse of the undesired isomers formed in the reaction.
Disclosure of Invention
In one aspect, the present invention provides a process for the preparation of pregabalin of formula (i), comprising the steps of:
Figure BDA0002559231380000032
a) reacting a compound of formula (ii) with a compound of formula (iii) in the presence of a cyanide source in water, optionally in the presence of a phase transfer catalyst, to obtain a compound of formula (iv);
Figure BDA0002559231380000041
wherein R is1Is straight-chain or branched C1-C4An alkyl group;
b) reacting a compound of formula (iv) with a minimum loading of nitrilase to obtain a compound of formula (v) or a salt thereof, optionally isolating the compound of formula (v) or a salt thereof;
Figure BDA0002559231380000042
wherein R is2Is a cationic counterion selected from the group consisting of: hydrogen, alkali metals, alkaline earth metals, ammonium, alkylammonium and organic amines;
c) esterifying the compound of formula (v) or a salt thereof to obtain a racemic compound of formula (vi) free of impurities;
Figure BDA0002559231380000043
whereinR3Selected from the group consisting of: straight or branched C1-C4Alkyl radical, C6-C10Aryl and alkylaryl groups;
d) the racemic compound of formula (VI) is separated into the (S) -isomer of formula (VII) and the (R) -isomer of formula (VIII) or their salts by enantioselective hydrolysis in a minimum volume of buffer solution or solvent or their mixture;
Figure BDA0002559231380000044
e) optionally converting the compound of formula (VIII) to a racemic compound of formula (VI) by racemisation after esterification;
f) the compound of formula (VII) is converted to pregabalin of formula (I) by hydrolysis of the ester group with a base followed by hydrogenation in a solvent with a minimum loading of hydrogenation catalyst.
In one embodiment, the present invention provides a process for the preparation of a compound of formula (I) with a shortened cycle time (four steps), 22% overall yield and reduced formation of impurities.
In another embodiment, the present invention provides a process for preparing compounds of formula (I) using environmentally friendly solvents (e.g., water) and low cost phase transfer catalysts to promote a greener route and reduce the loading of wastewater.
The following general synthetic scheme illustrates the above process:
Figure BDA0002559231380000051
wherein
R1Is straight-chain or branched C1-C4An alkyl group;
R2is a cationic counterion selected from the group consisting of: hydrogen, alkali metals, alkaline earth metals, ammonium, alkylammonium and organic amines;
R3is selected from the group consisting ofGroup (c): straight or branched C1-C4Alkyl radical, C6-C10Aryl, and alkylaryl.
Detailed Description
The present invention will now be described more fully hereinafter. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The term "substantially pure" (S) enantiomer means that the (S) enantiomer and the (R) enantiomer are in a preferred ratio of 85:15 to 100: 0; more preferably in a ratio of 95:5 to 100: 0; most preferably in a ratio of 99:1 to 100: 0.
In one embodiment of the present invention, the present invention provides an improved process for the preparation of compounds of formula (i) with high chemical and chiral purity via an enantioselective enzymatic route.
In one embodiment of the present invention, wherein the cyanide source in step (a) is preferably selected from lithium cyanide, sodium cyanide, potassium cyanide, trimethylsilylcyanide and the like; more preferably sodium cyanide or potassium cyanide.
In another embodiment of the present invention, wherein the phase transfer catalyst in step (a) is selected from ammonium salts, such as acetylcholine chloride, Aliquat 336, benzalkonium chloride (BZK), cetyltrimethylammonium chloride (CTAC), decyltrimethylammonium bromide, cetyltrimethylammonium bromide (CTAB), tetrabutylammonium acetate (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium difluorotriphenylstannate; or from heterocyclic ammonium salts such as N- (allyloxycarbonyloxy) succinimide, 1-butyl-2, 3-dimethylimidazolium chloride, cetylpyridinium bromide, methyl viologen dichloride hydrate, etc.; or from phosphonium salts such as bis [ tetrakis (hydroxymethyl) phosphonium ] sulphate, tetrabutylphosphonium bromide, tetrabutylphosphonium methanesulfonate and the like, preferably tetrabutylammonium bromide.
In another embodiment of the present invention, wherein the water used in any reaction of the process is process water, mineral water, demineralized water, or the like.
In another embodiment of the present invention, wherein said reacting of step (a) is at 10 ℃ to 120 ℃; preferably 60 ℃ to 120 ℃.
In another embodiment of the invention, wherein step (a) involves the formation of by-products, the by-products are removed by simple distillation techniques to reduce the cost of incineration.
In another embodiment of the present invention, wherein said nitrilase in step (b) is a genetically modified nitrilase, such as Nit 9N __56_ 2.
In another embodiment of the present invention, wherein the nitrilase loading in step (b) is 50% to 300%; more preferably from 65% to 125%.
In another embodiment of the present invention, wherein in step (b) the compound of formula (V) or a salt thereof is obtained by: maintaining the initial pH of the reaction mixture between 7.5 ± 1.0, preferably between 7.5 ± 0.5, using a base, preferably selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide, ammonia, methylammonium chloride, triethylamine, etc., more preferably sodium bicarbonate; and further maintaining the later pH of the organic solution between 1.0 and 2.0 using an acid selected from acetic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, and the like, more preferably concentrated hydrochloric acid or concentrated sulfuric acid.
In another embodiment of the invention, wherein the compound of formula (V) or a salt thereof is optionally isolated and used as such in a subsequent step without purification.
In another embodiment of the present invention, wherein said esterification reaction in step (c) is in the presence of an alcohol (R)3OH) or alkyl halides (R)3X) in the presence of an acid or base catalyst and a solvent.
In another embodiment of the present invention, wherein said alcohol (R)3OH) is preferably selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, n-butanol, benzyl alcohol, cyclopentanol, cyclohexanol, etc.; more preferably methanol or ethanol.
In another embodiment of the present invention, wherein the alkyl halide (R)3X) is selected from the group consisting of: methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl bromide, isopropyl chloride and isopropyl bromide.
In another embodiment of the present invention, wherein the acid catalyst used for the esterification in step (c) and step (e) is preferably selected from the group consisting of: hydrochloric acid, sulfuric acid, thionyl chloride, trimethylchlorosilane, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, lewis acid, or strongly acidic sulfonated resin, or the like; more preferably hydrochloric acid or sulfuric acid.
In another embodiment of the present invention, wherein the base catalyst used for the esterification in step (c) and the racemization in step (e) is selected from organic or inorganic bases, alkoxides, and is added in solid or solution state to minimize the formation of impurities such as succinimide and amide ester impurities.
In another embodiment of the present invention, wherein the organic base in step (c) and step (e) is selected from the group consisting of monoalkylamines, dialkylamines and trialkylamines, such as triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, imidazole, 4-dimethylaminopyridine, morpholine, N-methylmorpholine; inorganic bases such as potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal hydroxides or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide); preferably sodium bicarbonate and alkoxides such as sodium or potassium methoxide, sodium ethoxide, etc.; more preferably sodium bicarbonate in step (c) and sodium methoxide in step (e).
In one embodiment of the present invention, wherein the solvent in step (c) and step (e) is selected from the group consisting of: water, ethanol, methanol, isopropanol, n-butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl tert-butyl ether, cyclohexane, toluene, o-xylene, and the like.
In one embodiment of the present invention, wherein the reaction of step (b) and step (c) is preferably carried out at ambient to reflux temperature.
In one embodiment of the present invention, wherein the compounds of step (a) and step (c) can be purified by using a thin film evaporator, this reduces time and reduces degradation of the compounds compared to conventional high vacuum distillation techniques.
In another embodiment of the present invention, wherein the racemic compound of formula (vi) free of impurities of step (c) is isolated by: quench with base, filter and distill off solvent to give a residue. The residue is diluted with water, extracted with one or more hydrocarbon solvents or one or more ester solvents, and the one or more solvents are removed.
In another embodiment of the present invention, wherein the racemic compound of formula (vi) of step (c) is free of succinimide impurities (less than 0.1%) and amide ester impurities (less than 0.1% by GC).
In one embodiment of the invention, wherein the filtration, distillation or concentration in the description is performed by known techniques well known in the art.
In one embodiment of the present invention, the one or more hydrocarbon solvents referred to in the specification herein are selected from cycloheptane, cyclohexane, cyclopentane, heptane, hexane, toluene, xylene, pentane, and the like; more preferably toluene, and the one or more ester solvents are selected from ethyl acetate, isopropyl acetate, and the like.
In one embodiment of the present invention, wherein the esterification step (c) is carried out at 7.0 ± 1.0; more preferably at a pH in the range of 6.8 to 7.2.
In another embodiment of the present invention, wherein said enantioselective hydrolysis in step (d) is performed by using an enzyme.
In another embodiment of the present invention, wherein the enzyme of step (d) is selected from the group of: esterases, Lipolases (Lipolases), Lipases (Lipases), and the like.
In another embodiment of the present invention, wherein the esterase, libo lipase, lipase of step (d) is selected from the group consisting of: candida Antarctica (Candida Antarctica) Lipase A, Candida Antarctica Lipase B1, Candida Antarctica Lipase BY2, Novoxin 435 Lipase, Rhizomucor miehei (Rhizomucor meihei), Thermomyces lanuginosa (Thermomyces lanhirosa), Pseudomonas cepacia (Pseudomonas cepacia), resinase HT, Lipex 100L, Bacillus subtilis (Bascillus subtillis), Lipase 3.101, Lipase 3.102, Lipase 3.104, Lipase 3.105, Lipase 3.106, Lipase 3.107, Lipase 3.108, Lipase 3.109, Lipase 3.111, Lipase 3.115, Lipase 3.113, Lipase 3.117, Lipase 3.136, AYS Amino, AS Amano, preferably Novozyme B, Novosyl Amerino, Candida Antarctica Lipase B, Novosa, Candida Antarctica B, Novosa, Candida Antarctica No. 3.3, Lipase D, Lipase 3, Lipase 3.107, Lipase 3, Lipase D, Lipase 3, Lipase D, Lipase D, or Candida antarcase D, Lipase D, commercially available from Candida antarcase D, Candida Antarctica; more preferably a novacin 435 lipase.
In another embodiment of the present invention, wherein the enantioselective hydrolase in step (d) is in the range of > 0.1% w/w to < 5% w/w compared to the substrate; more preferably in the range of 1.0% w/w to 2.0% w/w loading compared to the substrate.
In one embodiment of the present invention, wherein the buffer in step (d) is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium hydroxide, magnesium oxide; more preferably sodium bicarbonate.
In one embodiment of the present invention, wherein the volume of the buffer solution in step (d) is in the range of 2 to 10 times the volume; more preferably 5.0 volumes.
In one embodiment of the present invention, wherein the solvent in step (d) is selected from the group consisting of: water, methanol, ethanol, isopropanol, tert-butanol, isobutanol, acetone, methyl isobutyl ketone, acetonitrile; methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dimethyl sulfoxide, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl tert-butyl ether, cyclohexane, toluene, o-xylene, and the like; more preferably, the solvent is water, toluene, 1, 4-dioxane, dimethyl sulfoxide.
In one embodiment of the present invention, wherein the preferred enzyme in step (d) may be recovered and reused several times until almost all of the enzyme activity is retained; whereas during enzyme recovery, if the activity is lower, an additional amount of fresh enzyme may be added, and the additional amount may be in the range of 0.5% w/w to 2.0% w/w relative to the initial enzyme load.
In another embodiment of the invention, wherein the preparation of the compounds of formula (vii) and formula (viii) in step (d) is obtained at a pH of 7.5 ± 1.0, preferably 7.7 ± 0.7, using a suitable reagent selected from the group consisting of: acetic acid, citric acid, boric acid, ethylenediamine acetic acid, hydrochloric acid, sulfuric acid, triethylamine, diisopropylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium hydroxide, magnesium oxide, or a suitable combination thereof. The amount of the suitable reagent may be selected in such a way that the final pH after completion of the reaction does not exceed 8.5.
In one embodiment of the present invention, wherein the esterification in step (e) is performed in the presence of one or more solvents in combination with an alcohol and a hydrocarbon solvent.
In another embodiment of the present invention, wherein the base used for hydrolysis in step (f) is selected from alkali metal hydroxide or alkaline earth metal hydroxide selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C1-C5Quaternary ammonium bases and the like; more preferably potassium hydroxide.
In one embodiment of the present invention, wherein the base in step (f) is present in an amount of 0.75 to 2.5 equivalents; more preferably 1.5 equivalents.
In one embodiment of the present invention, wherein the solvent in step (f) is preferably selected from the group consisting of: water, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, cyclohexanol, toluene, monochlorobenzene, dichlorobenzene, tetrahydrofuran, dioxane, dimethylformamide, or a combination thereof; preferably methanol.
In one embodiment of the present invention, wherein the hydrogenation catalyst in step (f) is preferably selected from the group consisting of: nickel, palladium, ruthenium, rhodium, and their different chemical forms and grades, with or without a support, optionally fresh catalyst, or recycled catalyst, or a mixture of fresh and recycled catalyst, more preferably nickel.
In one embodiment of the present invention, wherein the loading of the hydrogenation catalyst in step (f) is preferably 5-30% w/w loading, and more preferably 10% w/w.
In one embodiment of the present invention, wherein step (f) is preferably between 10 ℃ and 100 ℃; more preferably between 25 ℃ and 65 ℃.
In one embodiment of the present invention, wherein the hydrogenation in step (f) is preferably at 0.5kg/cm2To 25kg/cm2Hydrogen pressure in the range or equivalent units; more preferably, the pressure is 7kg/cm2To 15kg/cm2。
In one embodiment of the present invention, wherein the hydrogenation step (f) for isolating compound (I) optionally requires a carbonization step.
In one embodiment of the present invention, wherein in the hydrogenation in step (f) (S) -pregabalin of formula (I) is at a pH of 6.9 to 7.8; more preferably at a pH of 7.0 to 7.5; maintaining the pH using inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, formic acid, trifluoroacetic acid, and the like; preferred acids are hydrochloric acid or acetic acid.
In one embodiment of the invention, wherein the compound of formula (I) of step (f) is prepared by reacting water, C1-C5Alcohol or their mixture to obtain 99.95% chemical purity and more than 99.9% chiral purity.
In the present invention for the preparation of formula (I)In another embodiment of pregabalin of (a), the process further comprises recovering the pregabalin of formula (I) from the mother liquor, preferably after concentration and filtration. After filtration, the solid is separated from water, C1-C5Purifying the alcohol or the mixture thereof.
In another embodiment of the present invention for the preparation of (S) -pregabalin of formula (I), each compound may be used as such, or purified by known purification techniques and used in subsequent steps.
Examples
The invention is further illustrated by the following examples which should not be construed as in any way limiting the scope of the invention.
Example 1: preparation of 2-isobutyl succinonitrile
To a reaction mixture containing methyl cyanoacetate (500g, 1.0 equiv.) and isovaleraldehyde (273g, 1.0 equiv.) and TBAB (10g) was slowly added a solution of sodium cyanide (250g, 1.0 equiv.) in water (950ml, 1.9V) at 10 ℃ to 50 ℃. The reaction mixture was heated to 70 ℃ to 80 ℃ and held for 2-3 hours (h). After the reaction was completed, the solvent was removed and further maintained to 90 ℃ to 100 ℃ for 5 hours. The reaction mixture was cooled to room temperature, and extracted with toluene (1000 ml). The solvent was removed under reduced pressure to obtain a crude compound, and the crude compound was subjected to high vacuum distillation or thin film evaporation to provide 2-isobutylsuccinonitrile having a GC purity of 98% and a yield of 79%.
Example 2: preparation of 3-cyano-5-methyl-hexanoic acid.
To the compound 2-isobutylsuccinonitrile (350g, 1.0 eq) was added water (4550ml, 13V) at room temperature. The pH of the reaction mixture was maintained using sodium bicarbonate solution and heated to 30 ℃ to 40 ℃. Nitrilase (30.24g) was added to the reaction mixture and stirred for 20 to 24 hours. After completion of the reaction, the reaction mixture was filtered, cooled to 0 ℃ to 5 ℃, and further acidified with concentrated sulfuric acid. The precipitated compound was filtered to obtain a racemic 3-cyano-5-methyl-hexanoic acid compound (378 g).
Example 3: preparation of methyl 3-cyano-5-methyl-hexanoate.
To a racemic 3-cyano-5-methyl-hexanoic acid compound (400g, 1.0 eq) was added methanol (1500mL, 5.0V) and concentrated sulfuric acid (60mL, 0.2V) at room temperature. The reaction mixture was heated to reflux temperature and held for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate. The reaction mass was concentrated in vacuo and water (1500ml) was added and stirred for 15 minutes. The aqueous layer was extracted with toluene (600ml), and the organic layer was concentrated under reduced pressure to obtain a residue. The residual material was subjected to high vacuum distillation to obtain a racemic compound methyl 3-cyano-5-methyl-hexanoate compound (294.1g) having a GC purity of 99.83%, a yield of 78.90% and a succinimide impurity of 0.01%.
Example 4: preparation of (S) -3-cyano-5-methyl-hexanoic acid methyl ester.
To a racemic methyl 3-cyano-5-methyl-hexanoate compound (600g, 1.0 eq) was added sodium bicarbonate solution (3000ml, 5V) and novacin 435 lipase (Novozyme 435). The pH of the reaction mixture was maintained between 7.5 and 8.1 and further stirred at room temperature for 3 hours. After completion, the reaction mixture was filtered, washed with 600ml of toluene, and the aqueous layer was extracted with toluene (1200 ml). The solvent was removed under reduced pressure, and methanol (120ml) was added to the residue. The reaction solution was stirred, and methanol was removed under vacuum to obtain a methyl (S) -3-cyano-5-methyl-hexanoate compound (256.8g) having a chiral purity of 99.39% by GC; the undesired R-isomer was 0.61% and the GC chemical purity was 99.40%, and the yield was 42.8%.
Example 5: preparation of (S) -pregabalin (I).
To a methyl (S) -3-cyano-5-methyl-hexanoate compound (90g, 1.0 eq) was added methanol (225ml, 2.5V) at room temperature. The reaction mixture was cooled to 5 ℃ to 10 ℃ and potassium hydroxide solution (52.5g) was slowly added. The reaction mixture was stirred, warmed to room temperature and held for 1-2 hours. The reaction mixture was hydrogenated in the presence of raney nickel (9g), methanol (25ml, 2.5V) for 6 to 8 hours. After completion, the reaction mixture was filtered with activated carbon and neutralized. The solvent was removed until the minimum stirrable volume to obtain crude (S) -pregabalin (71.9g), which was further purified in the presence of water, IPA, to provide pure (S) -pregabalin with a chiral purity of 99.91% and a yield of 80% by HPLC.
Example 6: racemic methyl 3-cyano-5-methyl-hexanoate was prepared from (R) -3-cyano-5-methyl-hexanoate.
To compound (R) -3-cyano-5-methyl-hexanoic acid (298) were added toluene (894ml, 1.0V), methanol (298ml, 1V). The solution was stirred and concentrated sulfuric acid (23.8g, 8%) was added slowly at 25 ℃ to 45 ℃ for 10 minutes. The reaction mixture was heated at 60 ℃ to 70 ℃ and held for 1 h. The reaction mixture was quenched with sodium bicarbonate and filtered. The solvent was removed to the minimum stirrable volume. To the solution was added sodium methoxide (0.1 eq) and the reaction mixture was refluxed for 1 h. The reaction mass was cooled to 0 ℃ to 5 ℃ and the pH of the reaction mass was adjusted to neutral pH using 10% hydrochloric acid. The organic layer was concentrated to obtain a crude compound, which was further purified by distillation using high vacuum to obtain pure racemic methyl 3-cyano-5-methyl-hexanoate (252.8g) having a GC purity of 99.76% and a yield of 77%.

Claims (18)

1. An improved process for the preparation of pregabalin of formula (I),
Figure FDA0002559231370000011
the method comprises the following steps:
a) reacting a compound of formula (ii) with a compound of formula (iii) in the presence of a cyanide source in water, optionally in the presence of a phase transfer catalyst, to obtain a compound of formula (iv);
Figure FDA0002559231370000012
wherein R is1Is straight-chain or branched C1-C4An alkyl group;
b) reacting a compound of formula (iv) with a nitrilase having a loading of 60-200% and optionally isolating a compound of formula (v) or a salt thereof;
Figure FDA0002559231370000013
wherein R is2Is a cationic counterion selected from the group consisting of: hydrogen, alkali metals, alkaline earth metals, ammonium, alkylammonium and organic amines;
c) using an alcohol (R) in the presence or absence of an acid or base catalyst and a solvent or solvent mixture thereof3OH) or alkyl halides (R)3X) esterifying the compound of formula (V) or a salt thereof to obtain a racemic compound of formula (VI) substantially free of impurities;
Figure FDA0002559231370000014
wherein R is3Selected from the group consisting of: straight or branched C1-C4Alkyl radical, C6-C10Aryl and alkylaryl radicals
d) -separation of the racemic compound of formula (vi) into the (S) -isomer of formula (vii) and the (R) -isomer of formula (viii) or their salts by enantioselective hydrolysis in 2-10 volumes of buffer solution or solvent (S) or mixture thereof;
Figure FDA0002559231370000021
wherein the enantioselective hydrolysis is performed using an enzyme selected from the group consisting of: candida antarctica lipase a, candida antarctica lipase B1, candida antarctica lipase BY2, novacin 435 lipase, lipase 3.101, lipase 3.102, lipase 3.104, lipase 3.105, lipase 3.106, lipase 3.107, lipase 3.108, lipase 3.109, lipase 3.111, lipase 3.115, lipase 3.113, lipase 3.117 and lipase 3.136;
e) optionally, by using an alcohol (R) in the presence or absence of an acid or base catalyst and one or more solvents3OH) or alkyl halides (R)3X) esterification and racemization in the presence of a base, a solvent to obtain an improved yield of racemic compound of formula (VI);
f) the compound of formula (vii) is converted to pregabalin of formula (i) by hydrolysis of the ester with a base followed by hydrogenation with 5-30% catalyst loading in the presence of one or more solvents.
2. The method of claim 1, wherein the cyanide source in step (a) is selected from the group consisting of: lithium cyanide, sodium cyanide, potassium cyanide and trimethylsilyl cyanide.
3. The process of claim 1, wherein the phase transfer catalyst in step (a) is selected from ammonium salts such as acetylcholine chloride, Aliquat 336, benzalkonium chloride, cetyltrimethylammonium chloride, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutyl difluorotriphenylammonium stannate, or from heterocyclic ammonium salts such as N- (allyloxycarbonyloxy) succinimide, 1-butyl-2, 3-dimethylimidazolium chloride, cetylpyridinium bromide, methyl viologen dichloride hydrate, and the like, or from phosphonium salts such as bis [ tetrakis (hydroxymethyl) phosphonium ] sulfate solution, tetrabutylphosphonium bromide, tetrabutylphosphonium methanesulfonate.
4. The method of claim 1, wherein step (a) is carried out at a temperature of 10 ℃ to 120 ℃; and steps (b) and (c) are carried out at ambient to reflux temperatures.
5. The process according to claim 1, wherein the nitrilase is supported at 60 to 80%.
6. The method of claim 1, wherein the steps (b), (c), (d) are performed at a pH of 1.0 to 8.5.
7. The method of claim 1, wherein the solvent in step (c), step (d), step (e) and step (f) is selected from the group consisting of: water, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, cyclohexanol, toluene, monochlorobenzene, dichlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dimethylformamide, dimethylamine, dimethyl sulfoxide, sulfolane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl t-butyl ether, cyclohexane.
8. The process of claim 1, wherein the alcohol (R) in step (c) and step (e)3OH) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, cyclopentanol and cyclohexanol.
9. The process of claim 1, wherein the alkyl halide (R) in step (c) and step (e)3X) is selected from the group consisting of methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl bromide, isopropyl chloride and isopropyl bromide.
10. The process of claim 1, wherein the acid catalyst of step (c) and step (e) is selected from hydrochloric acid, sulfuric acid, thionyl chloride, trimethylchlorosilane, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, a lewis acid, or an acidic sulfonated resin.
11. The process according to claim 1, wherein the base catalyst in step (c) and step (e) is selected from the group consisting of monoalkylamines, dialkylamines and trialkylamines, such as triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, 1, 5-diazabicyclo [4.3.0]Non-5-ene, 1, 5-diazabicyclo [4.3.0]Non-5-ene, imidazole, 4-dimethylaminopyridine, pyridine, morpholineQuinoline, N-methylmorpholine; inorganic bases, e.g. potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, alkali or alkaline earth metals C1-C6An alkoxide.
12. The process of claim 1, wherein the impurities of step (c) are succinimide and amide ester impurities.
13. The process of claim 1 wherein racemic compound of formula (vi) in step (c) is substantially free of succinimide impurities and amide esters with less than 0.1% impurities as measured by GC.
14. The process according to claim 1, wherein the enantioselective hydrolysis in step (d) is performed using the enzyme novacin 435 lipase; and the volume of the buffer solution was 5.0V.
15. The process of claim 1, wherein the base in step (f) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, and C1-C5A quaternary ammonium base; and has 0.75 to 2.5 equivalents; more preferably 1.5 equivalents.
16. The process of claim 1, wherein the hydrogenation catalyst in step (f) is selected from the group consisting of: nickel, palladium, ruthenium, rhodium and any chemical forms and grades thereof with or without a support, said hydrogenation catalyst having a loading of 10% w/w; and at a temperature of 25 ℃ to 65 ℃ and 7kg/cm2To 15kg/cm2The hydrogenation is carried out under hydrogen pressure.
17. The process according to claim 1, wherein the hydrogenated product of step (f) optionally comprises carbonized and isolated pregabalin obtained by a pH maintenance and crystallization process, said pregabalin having a desired chemical purity of more than 99.95% and a chiral purity of more than 99.9%.
18. The method according to claim 17, wherein the pH is maintained in the range of 7.0 to 7.5 using inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, formic acid, trifluoroacetic acid; and the crystallization is performed in the presence of water, methanol, ethanol, n-propanol, isopropanol.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123134A1 (en) * 2010-11-01 2012-05-17 Drug Process Licensing Associates LLC Manufacturing process for (S)-Pregabalin
US20150344919A1 (en) * 2012-11-07 2015-12-03 Hikal Limited Process for the preparation of pregabalin
CN109232311A (en) * 2018-10-08 2019-01-18 浙江新和成股份有限公司 A kind of Pregabalin synthetic method of green high-efficient

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123134A1 (en) * 2010-11-01 2012-05-17 Drug Process Licensing Associates LLC Manufacturing process for (S)-Pregabalin
US20150344919A1 (en) * 2012-11-07 2015-12-03 Hikal Limited Process for the preparation of pregabalin
CN109232311A (en) * 2018-10-08 2019-01-18 浙江新和成股份有限公司 A kind of Pregabalin synthetic method of green high-efficient

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