WO2009004643A2 - An improved process for preparation of (s)-pregabalin and intermediates thereof - Google Patents

An improved process for preparation of (s)-pregabalin and intermediates thereof Download PDF

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WO2009004643A2
WO2009004643A2 PCT/IN2008/000287 IN2008000287W WO2009004643A2 WO 2009004643 A2 WO2009004643 A2 WO 2009004643A2 IN 2008000287 W IN2008000287 W IN 2008000287W WO 2009004643 A2 WO2009004643 A2 WO 2009004643A2
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acid
process according
carbamoylmethyl
methylhexanoic acid
pregabalin
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PCT/IN2008/000287
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French (fr)
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WO2009004643A3 (en
Inventor
Thirupathi Rao Tippanu
Shriprakash Dhar Dwivedi
Ketan Ambalal Doshi
Rakesh Brijnandan Sahay
Rushikesh Udaykumar Roy
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis

Definitions

  • the present invention relates to the process for the preparation of (S)-Pregabalin of formula (I) and its intermediates thereof. Particularly, the present invention relates to the process for the preparation (S)-Pregabalin having chiral purity not less than 99.0% by area percentage of HPLC. Further, the present invention relates to the process for the preparation of (S)-Pregabalin having low level of impurities, determined by area percentage of HPLC.
  • (S)-Pregabalin which is chemically, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid and represented by below mentioned formula (I).
  • (S)-Pregabalin is a gamma-amino butyric acid or (S)-3-isobutyl (GABA) analogue.
  • GABA GABA
  • (S)-Pregabalin has been found to activate GAD (L- glutamic acid decarboxylase).
  • (S)-Pregabalin has a dose dependent protective effect on- seizure, and is a CNS-active compound.
  • (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses.
  • (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
  • (S)-Pregabalin is marketed under the name LYRICA.RTM. by Pfizer, Inc., in tablets of 25, 50, 75, 150, 200, and 300 mg doses.
  • the preparation of (S)-Pregabalin from 3- isbutylglutaric acid is disclosed in DRUGS OF THE FURTURE, 24 (8), 862-870 (1999), and in U.S. Pat. No. 5,616,793, and is described by the following Scheme-1:
  • WO 2006/122259 Al discloses the optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid via Ephedrine salt and Norephedrine salt.
  • WO 2007/035890 Al discloses an asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
  • the 3-isobutylglutaric acid may be prepared by the condensation of isovaleraldehyde and ethylcyanoacetate, followed by a Michael addition, and hydrolysis. See Day and Thorpe, J Chem. Soc, 117:1465 (1920); J. Casson, et. Al., "Brached-Chain Fatty Acids. XXVII. Further study of the Dependence of Rate of Amide Hydrolysis on Substitution near the Amide Group. Relative Rates of Hydrolysis of Nitrile to Amide and Amide to Acid, "Prochiral Recognition in the Reaction of 3 -Substituted Glutaric Anhydrides with Chiral Secondary Alcohols,"J. Org.
  • Scheme-7 US 2006/0276543 Al discloses crystalline Pregabalin racemate in hemihydrate form.
  • WO 2008/040935 A2 discloses four polymorphic forms viz. Form-I, Form-II, Form-Ill and Form-FV of Pregabalin characterized by XRPD peaks and unit cell dimensions.
  • US 20080014280 Al discloses amorphous form of Pregabalin by lyopholization or spray drying in an alcoholic solvent, aromatic hydrocarbon solvent, non-aromatic hydrocarbon solvents and mixtures thereof having D 50 particle size less than about 10 microns and D90 particle size less than 150 microns.
  • the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent.
  • the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
  • the product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture.
  • certain stages during processing of an API such as (S)-Pregabalin, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
  • the API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent
  • impurities side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate.
  • a peak position such as that in a chromatogram, or a spot on a TLC plate.
  • the impurity can be identified, e.g., by 1 its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector.
  • the relative position in the chromatogram is known as the "retention time.”
  • Pregabalin that yields highly pure (S)-Pregabalin with every single individual impurities less than 0.1 % by area percentage of HPLC.
  • Yet another object of the present invention is to provide (S)-Pregabalin having overall purity more than 99.94%.
  • Further object of the present invention is to provide a novel process for preparing (S)-Pregabalin, which is cost effective, eco-fiiendly, non-hazardous and applicable for large-scale productions.
  • the invention encompasses tetraethyl 2-isobutyl propane- 1,1, 3, 3- tetracarboxylate (P-02)
  • the present invention encompasses (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid in crystalline form, which is characterized by XRD and IR.
  • Yet another aspect of the present invention is to provide a process for preparation of isobutylglutaric anhydride by cyclization of isobutylglutaric acid with thionyl chloride.
  • the invention provides a process for preparing (S)-Pregabalin, which provides highly pure (S)-Pregabalin with single every single individual impurities less than 0.1 % by area percentage of HPLC.
  • FIG.l X-ray diffraction of (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5- methylhexanoic acid
  • FIG.2 FTIR of (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid
  • FIG.3 Chiral HPLC chromatogram of (S)-Pregabalin.
  • FIG.4 GC chromatogram of 2-carboxyethyl-5-methylhex-2-enoic acid (P-01 )
  • FIG.5 GC chromatogram of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester
  • FIG.6 GC chromatogram of isobutylglutaric acid (P-03) DETAILED DESCRD7TTON OF THE INVENTION
  • the term "Substantially pure (S)-(+)-3-aminomethyl-5-methylhexanoic acid" as used herein before or after means (S)-(+)-3-aminomethyl-5-methylhexanoic acid having purity greater than or equal to about 99.5% with every single individual impurities less than 0.1% and total impurities less than or equal to about 0.50% by area percentage of HPLC.
  • Substantially pure (R)-(+)- ⁇ - ⁇ henylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid as used herein before or after means that crystalline (R)- (+)- ⁇ -phenylethylamine salt of (RK-)-3-(Carbamoylmethyl)-5-methylhexanoic acid is having purity greater than or equal to about 99%, preferably greater than or equal to about 99.5%.
  • Substantially pure crystalline (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid is substantially pure having purity greater than or equal to about 99%, preferably greater than or equal to about 99.5% is also the scope of the present inventioa According to the first embodiment of the present invention, there is provided a process for preparation of substantially pure (S)-( + )-Pregabalin of formula (I)
  • the alkali hydroxide for the preparation of alkali hypobromide solution can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide.
  • the temperature for the preparation of sodium hypobromide solution-A is preferably from about O 0 C to about 25°C, most preferably at about
  • the solution-B as in step (c) can be prepared by reacting (R)-(-)-3-(carbamoylmethyl)-
  • 5-methylhexanoic acid P-06 with alkali hydroxide and water at about O 0 C to about 25°C.
  • Preferable alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide.
  • the temperature for the preparation of solution-B as in step (c) is preferably from about O 0 C to about 25 0 C, most preferably at about O 0 C to 1O 0 C.
  • the addition of solution-B into the solution-A as in step (d) can be carried out at a temperature of about 0 0 C to about 25 0 C, preferably at about O 0 C to about 1O 0 C.
  • the reaction mixture is heated as in step (e) at about 40 0 C to about 80 0 C, preferably at about 50 0 C to about 7O 0 C, more preferably at about 60 0 C to about 65°C for sufficient amount of time with stirring.
  • the reaction mixture is cooled to 45 0 C and treated with strong mineral acid selected from H 2 SO 4 , HCl, HBr and H 3 PO 4 , preferably HCl as in step (f) to adjust the pH below 4.0.
  • the reaction mixture is treated with cone. HCl to adjust the pH 1.0 and allowed to cool to room temperature of about 20 0 C to about 35 0 C, preferably 25 0 C to about 30 0 C.
  • the reaction mixture obtained upon cooling is extracted with non-polar organic solvent selected from toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene dichloride, ethyl acetate and the like, preferably methyl tert-butyl ether to remove the unreacted starting material (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-06), any degradants or byproducts whereby the organic layer will contain the impurities and' the aqueous layer will contain the desired product.
  • non-polar organic solvent selected from toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene dichloride, ethyl acetate and the like, preferably methyl tert-butyl ether to remove the unreacted starting material (R)-(-
  • the separated aqueous layer is neutralized with suitable base selected from inorganic base or organic base, like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropyl ethyl amine, pyridine etc., preferably sodium hydroxide to adjust the pH of about 4.0 to about 5.0, preferably of about 4.5 to about 5.0. to precipitate substantially pure (S)-(+)- Pregabalin.
  • suitable base selected from inorganic base or organic base, like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropyl ethyl amine, pyridine etc., preferably sodium hydroxide to adjust the pH of about 4.0 to about 5.0, preferably of about 4.5 to about 5.0. to precipitate substantially pure (S)-(+)- Pregabalin
  • the invention encompasses tetraethyl 2-isobutyl propane- i 1,1,3,3-tetracarboxylate (P-02) which is treated with cone.
  • HCl to obtain carboxylic acid derivative which on subsequent decarboxylation will be converted to 3-isobutylglutaric acid (P-03).
  • the reaction of P-02 intermediate with cone. HCl is carried out at reflux temperature of about 7O 0 C to about 150 0 C, preferably at about 100 0 C to about 105 0 C for -70 to 80 hours followed by cooling to 85°C to 9O 0 C.
  • reaction mixture was extracted with toluene at 70 0 C to 80 0 C whereby toluene is distilled under vacuum at 60 0 C to 70 0 C to isolate 3-isobutyl glutaric acid (P-03).
  • (S)-(+)-Pregablin substantially free from impurites, it is necessary that the intermediates should be highly pure.
  • ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) intermediate can be prepared with substantially purity from 3-isobutylglutaric acid (P- 03) by reacting with thionyl chloride for in-situ preparation of 3-isobutylglutaric anhydride.
  • This method is more advantageous over the prior art method for cyclization whereby uses of acetic anhydride or acetyl chloride is reported.
  • 3-isobutylglutaric acid (P-03) is refluxed in thionyl chloride for 30 min followed by distillation to remove excess of thionyl chloride.
  • the residue 3-isobutylglutaric anhydride is dissolved in methyl tert-butyl ether and treated with aqueous ammonia (28% ammonium hydroxide) to separate the organic and aqueous layer.
  • the aqueous layer is distilled and treated with cone.
  • HCl to adjust the pH below 4.0, preferably of about 1.5 to obtain ( ⁇ )-3-(Carbamoylmethyl)-5-methylhexanoic acid.
  • P-01 P-01-a (b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane- 1,1,3 ,3 -tetracarboxy late (P-02);
  • the condensed product 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) as obtained in step (a) is further reacted with diethyl malonate in absence of organic solvent in presence of organic base selected from morpholine, piperidine, pyridine, triethylamine, di-n- propylamine, diisopropylethyl amine etc., preferably piperidine at a temperature of about 40 0 C to about 60 0 C, preferably of about 50 0 C to about 52°C.
  • the reaction mixture was cooled to room temperature to isolate tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02).
  • the isolated compound tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) can be hydrolyzed to obtain 3-isobutylglutaric acid (P-03) as described herein above as in step
  • Pregabalin is a chiral compound having (R) and (S) isomers.
  • Pregabalin can be obtained from ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04).
  • the resolution of ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with chiral amines like (R)-(+)- ⁇ .-phenylethyl- amine can be conveniently carried out in mixture of chloroform and ethanol to obtain substantially pure (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3-
  • the (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid (P-05) can be acidified with cone. HCl followed by cooling at O 0 C to about 5°C to precipitate (R)-(-)-3-(carbamoylrnethyl)-5-methylhexanoic acid (P-06). The precipitated product is filtered and washed with IM HCl. The isolated product (R)-(-)-3-
  • (carbamoylmethyl)-5-methylhexanoic acid (P-06) readily undergoes Hoffman Bromide degradation reaction as described herein above to obtain substantially pure (S)-(+)-Pregabalin of formula (I).
  • (S)-(+)-3-aminomethyl-5-methylhexanoic acid in the solid state contains less than or of about 0.50% total impurities as measured by area percentage HPLC is also the scope of present invention.
  • the present invention further provides a crystalline (R)-(+)- ⁇ -phenylethylamine salt of
  • the crystalline (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid is further characterized by X-ray powder diffraction pattern having peaks at 20 5.9, 6.3, 7.7, 8.8. 9.2, 10.2, 12.62, 13.8, 14.5, 15.8, 17.1, 18.4, 20.5, 22.4, 23.3,
  • Crystalline (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid is further characterized by characterized by X-ray powder diffraction pattern of as depicted in FIG.1
  • FIG.4 A sample Chromatogram is shown in FIG.4
  • Example-2 Preparation of 1,1,3.3-PropanetetracarboxyIic acid. 2-isobutyl, tetraethyl ester of formula P-02
  • Purity of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl., tetraethyl ester (P-02) can be determined by using the following gas chromatography apparatus and procedures:
  • FIG.5 A sample Chromatogram is shown in FIG.5
  • Purity of Isobutylglutaric acid (P-03) can be determined by using the following gas chromatography apparatus and procedures:
  • Carrier gas Nitrogen
  • FIG.6 A sample Chromatogram is shown in FIG.6
  • 3-Isobutylglutaric acid (68.8 kg) and thionyl chloride (445 kg) are combined and placed under reflux for 0.5 hours.
  • the mixture is placed under atmospheric distillation followed by vacuum distillation to remove thionyl chloride.
  • the un-distilled 3- isobutylglutaric acid anhydride is dissolved in methyl tert-butyl ether (63 kg) and added to a solution of aqueous ammonia (49 kg of 28% ammonium hydroxide) and water (92 kg) at a temperature of 25°C or less.
  • the mixture is stirred for 35 minutes and the layers are separated.
  • the aqueous layer is placed under vacuum distillation to remove any remaining volatile nonaqueous solvent.
  • Concentrated hydrochloric acid (51 kg) is added to the aqueous mixture to obtain a pH of 1.5.
  • the mixture is cooled to O 0 C-IO 0 C. and filtered.
  • the solid is washed with water (50 L) and dried under reduced pressure.
  • the solid is then dissolved in hot (70 0 C) ethyl acetate (237 kg) and filtered.
  • the solution is cooled to 0°C-5°C and the product is collected by filtration.
  • reaction mixture is cooled to room temperature and extracted with methyl tert-butyl ether (600 ml).
  • the separated aqueous layer is treated with 15% NaOH solution (15 g of NaOH dissolved in 15 ml of water).
  • the pH of the reaction mixture is adjusted to 4.5 to 5.0.
  • the mixture is heated to 6O 0 C. and then cooled to 0 0 C to 5 0 C.
  • the mixture is filtered and the solid is washed with water (30 mL). The solid is dried under reduced pressure to give 55 grams of (S)-(+)-3-aminomethyl-5- methylhexanoic acid.
  • the solid (16.3 g) is recrysatllized from a mixture of isopropanol (54 g) and water (54 g) to give 14.7 g of recrysatllized (S)-(+)-3-aminomethyl-5-methylhexanoic acid having a melting point in the range of about 184°C to about 186°C-decomposes.
  • Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
  • HPLC shows purity > 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.1% and total impurity NMT 0.50%.
  • the present invention provides a very cost-effective, eco-friendly, non-hazardous and large scale applicable method
  • the present invention provides a method for preparation of (S)-(+)-3-aminomethyl-5- methylhexanoic acid which encompasses through a new intermediate P-02.
  • the present invention provides crystalline (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid which is well characterized by XRD and IR
  • the present invention provides (S)-(+)-3-aminomethyl-5-methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
  • the present invention provides crystalline (R)-(+)- ⁇ -phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5 -methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
  • the present invention provides an improved process for the preparation of (S)-(+)-3- aminomethyl-5 -methylhexanoic Acid by Hoffman-degradation reaction of (R)-(-)-3-
  • the present invention provides an improved process for the preparation of substantially pure (S)-(+)-Pregabalin which is cost effective, environment friendly and easily applicable to large scale production.

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Abstract

The present invention relates to an improved process for the preparation of (S)- Pregabalin of formula (I) and its intermediates thereof. Particularly, the present invention relates to the process for the preparation (S)-Pregabalin having chiral purity not less than 99.0% by area percentage of HPLC. Further, the present invention relates to the process for the preparation of (S)-Pregabalin having low level of impurities, determined by area percentage of HPLC.

Description

AN IMPROVED PROCESS FOR PREPARATION OF (S)-PREGABALIN
AND INTERMEDIATES THEREOF
FIELD OF INVENTION
The present invention relates to the process for the preparation of (S)-Pregabalin of formula (I) and its intermediates thereof. Particularly, the present invention relates to the process for the preparation (S)-Pregabalin having chiral purity not less than 99.0% by area percentage of HPLC. Further, the present invention relates to the process for the preparation of (S)-Pregabalin having low level of impurities, determined by area percentage of HPLC.
Figure imgf000002_0001
BACKGROUND AND PRIOR ART OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
(S)-Pregabalin, which is chemically, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid and represented by below mentioned formula (I). (S)-Pregabalin is a gamma-amino butyric acid or (S)-3-isobutyl (GABA) analogue. (S)-Pregabalin has been found to activate GAD (L- glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on- seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity. (S)-Pregabalin is marketed under the name LYRICA.RTM. by Pfizer, Inc., in tablets of 25, 50, 75, 150, 200, and 300 mg doses. The preparation of (S)-Pregabalin from 3- isbutylglutaric acid is disclosed in DRUGS OF THE FURTURE, 24 (8), 862-870 (1999), and in U.S. Pat. No. 5,616,793, and is described by the following Scheme-1:
Figure imgf000003_0001
P-06 (S)-Pregabalin Scheme- 1 j : 1) Dialkyl malonate, 2) HCl, H2O k : Ac2O 1 : 1) NH3 (aq), MTBE, 2) HCl m: EtOH/CHCla n : HC1/H2O o : 1) NaOH, Br2, 2) HCl Accordingly, 3-isobutylglutaric acid (P-03) is converted into the corresponding anhydride, compound (P-04), by treatment with acetic anhydride. The reaction of the anhydride with NH4OH , produces the glutaric acid mono-amide (P-04), which is resolved with (R)-(+)-α-phenylethylamine, yielding the (R)-phenylethylamine salt of (R>3-(carbamoyhnethyl)-5|-methylhexanoic acid (P-05). Combining the salt with an acid liberates the R-enantiomer (P-06). Finally, Hoffinann degradation with Br2ZNaOH results in precipitation of (S)-Pregabalin, after treatment with Cone. HCl.
A very similar process is disclosed in U.S. Patent No. 5,616,7,93, wherein (S)-Pregabalin is also obtained by Hoffinan degradation, followed by precipitation of (S)-Pregabalin, after addition of HCl. The product is further purified by crystallization from a mixture of isopropanol and water.
Various patent applications US 2007/0073085 Al, U1S 2007/0066846 Al, US 2006/0281816 Al, US 2006/0276544 Al etc. discloses various process for the preparation of (S)- Pregabalin via the above discussed isobutyl glutaric acid intermediate followed by Hoffinan degradation at the end. The process disclosed in US '085 Al, US '846 Al and US '816 Al or US '544 Al involves in-situ generation of sodium hypobromite by mixing CHM i.e. P-06 herein above with aqueous alkaline solution and addition of bromine in the reaction mixture. The resulting Hoffman degraded product is treated with strong mineral acid followed by extraction with alcohols and treatment with base to obtain (S)-Pregabalin. The crude product thus obtained was purified in isobutanol and water mixture.
WO 2006/122259 Al discloses the optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid via Ephedrine salt and Norephedrine salt. WO 2007/035890 Al discloses an asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
US 2007/0293694A1 discloses a process for the preparation of (S)-Pregabalin by asymmetric ring opening of 3-isobutylglutaric anhydride as depicted in scheme-2 and scheme-3 below.
I
Figure imgf000004_0001
Scheme-2
Figure imgf000004_0002
R-CMH or salt thereof
Scheme-3 The 3-isobutylglutaric acid may be prepared by the condensation of isovaleraldehyde and ethylcyanoacetate, followed by a Michael addition, and hydrolysis. See Day and Thorpe, J Chem. Soc, 117:1465 (1920); J. Casson, et. Al., "Brached-Chain Fatty Acids. XXVII. Further study of the Dependence of Rate of Amide Hydrolysis on Substitution near the Amide Group. Relative Rates of Hydrolysis of Nitrile to Amide and Amide to Acid, "Prochiral Recognition in the Reaction of 3 -Substituted Glutaric Anhydrides with Chiral Secondary Alcohols,"J. Org. Chem., 58(1):142-146 (1993); M. S. Hoekstra, et al., "Chemical Development of CI- 1008, an Enantiomerically Pure Anticonvulsant, "Organic Process Research & Development, 1(1): 26-38 (1997) as shown in scheme-4 below:
Figure imgf000005_0001
Hydrolysis
Figure imgf000005_0002
3-isobutylglutaric acid
Scheme-4
US 2007/0259917 Al discloses the processes for the preparation of 3-isobutylglutaric acid as depicted in Scheme-5 as below.
a
Figure imgf000005_0003
The process disclosed above involves combining isovaleraldehyde with diester of formula
(A) as shown above in a non-polar organic solvent in presence of an organic acid and an organic base to obtain compound of formula (B) and reacting further with diester of formula (A) results in general compound of formula (C) which upon subsequent hydrolysis results in 3-isobutylglutaric acid. The entire reaction disclosed herein above is one-pot process. 3-isobutylglutaric acid being a key starting material for the preparation of (S)-Pregabalin should have minimum degree of purity in terms of individual impurity. The process disclosed in US '917 Al claims one-pot process for the preparation of 3-isobutylglutaric acid results in impure material.
The key stage in the synthesis of 3-isobutylglutaric acid via tetraester derivative of formula (C) is synthesis of pure compound (B). The condensation of isovaleraldehyde with diethyl malonate compound of formula (A) results in 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester as a major isomer and 10-13% by GC is believed to be 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester. Hence, in-situ process will carry forward 13% isomeric impurity. US Patent No. 5,637,767 discloses in column- 11, Line-11 to Line-20 that both the isomers are converted to same product on reaction with potassium cyanide type reagent. But, as per scheme-5 the product (B) having 13% approximately the olefin isomer may not be converted to same desired product. The mixture of isomers on treatment with diethyl malonate in presence of base will lead to further undesired impurity of formula (C) as shown below in scheme-6 and scheme-7. Hence, isolation and purification of (B) is necessary.
Figure imgf000006_0001
Scheme-6
Figure imgf000006_0002
Scheme-7 US 2006/0276543 Al discloses crystalline Pregabalin racemate in hemihydrate form. WO 2008/040935 A2 discloses four polymorphic forms viz. Form-I, Form-II, Form-Ill and Form-FV of Pregabalin characterized by XRPD peaks and unit cell dimensions.
US 20080014280 Al discloses amorphous form of Pregabalin by lyopholization or spray drying in an alcoholic solvent, aromatic hydrocarbon solvent, non-aromatic hydrocarbon solvents and mixtures thereof having D50 particle size less than about 10 microns and D90 particle size less than 150 microns.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At . certain stages during processing of an API, such as (S)-Pregabalin, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent
Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach; 3rd ed. (Wiley & Sons: New • York 1989)). Thereafter, the impurity can be identified, e.g., by1 its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Thus, there is a need in the art for Pregabalin and (S)-Pregabalin having a low level of impurities through a pure intermediate and for a process for preparation thereof.
Therefore, there is a need to have simple process, that allow for preparation of highly pure Pregabalin and (S)-Pregabalin in a facile manner on an industrial scale, which yields Pregabalin and (S)-Pregabalin by resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid and in high purity.
The inventors of the present invention have found that the use of this new intermediate for preparation of Pregabalin enables to prepare isobutyl glutaric acid in a highly pure form. OBJECTS OF THE BSfVENTION
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.
It is another object of the present invention to provide process for the preparation of intermediate, tetraethyl 2-isobutylpropane-l,l,3,3-tetracarboxylate (P-02) for preparing (S)- Pregabalin.
It is yet another object of the present invention to provide process for the preparation of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid (P-04) via tetraethyl 2-isobutylpropane- 1,1,3,3-tetracarboxylate (P-02) and isobutylglutaric acid (P-03) in highly pure form having olefinic impurity not more than 2% by GC.
It is still another object of the present invention to provide crystalline form of crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid. It is another object of the present invention to provide a process for preparing (S)-
Pregabalin that yields highly pure (S)-Pregabalin with every single individual impurities less than 0.1 % by area percentage of HPLC.
Yet another object of the present invention is to provide (S)-Pregabalin having overall purity more than 99.94%. < Further object of the present invention is to provide a novel process for preparing (S)-Pregabalin, which is cost effective, eco-fiiendly, non-hazardous and applicable for large-scale productions. SUMMARY OF THE INVENTION
According to the first aspect of the present invention, there is provided an improved process for the preparation of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid of formula (P- 04), an important intermediate for the (S)-Pregabalin,
Figure imgf000009_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2- carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a);
Figure imgf000009_0002
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane- 1,1, 3 ,3-tetracarboxylate (P-02);
Figure imgf000009_0003
(c) hydrolyzing tetraethyl 2-isobutyl propane- 1,1, 3, 3 -tetracarboxy late (P-02) to obtain 3- isobutyl- glutaric acid (P-03); and
Figure imgf000009_0004
P-03 (d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3-(carbamoylmethyl)- 5-methylhexanoic acid (P-04).
According to the another aspect of the present invention, there is provided an improved process for preparing substantially pure (S)-(+)-pregabalin of formula (I),
Figure imgf000010_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2- carboxyethyl-S-methylhex-S-enoic acid, ethyl ester of formula (P-01 -a);
Figure imgf000010_0002
P-01 P-01-a
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane- 1,1,3 ,3 -tetracarboxylate (P-02);
Figure imgf000010_0003
(c) hydrolyzing tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03);
Figure imgf000010_0004
P-03 (d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3-(carbamoylmethyl)- 5-methylhexanoic acid (P-04);
Figure imgf000011_0001
(e) reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with (R)-(+)-α.- phenylethylamine to obtain the substantially pure (R)-(+)-α-phenylethylamine salt of (R)- (-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-05);
R-(+)-alpha phenylethyl amne
Figure imgf000011_0003
Figure imgf000011_0002
(f) dissolving the salt (P-05) in water to form a solution and acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoylmethyl)-5-methylhexanoic acid (P-06);
Figure imgf000011_0004
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
Figure imgf000011_0005
(h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin) According to yet another aspect of the present invention, there is provided a process for preparation of substantially pure (S)-(+)-Pregabalin of formula (I)
Figure imgf000012_0001
comprising: (a) combining alkali hydroxide and water;
(b) adding bromine at a temperature of about 0°C to about 25°C to obtain alkali hypobromide solution-A;
(c) reacting (R)-(:)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-06) with alkali hydroxide and water at about O0C to about 250C to obtain solution-B; (d) adding above solution-A into the solution-B at about O0C to about 250C;
(e) heating;
(f) reacting with strong mineral acid to adjust the pH below 4.0;
(g) cooling;
(h) extracting with suitable non-polar organic solvent; (i) neutralizing aqueous layer with suitable base to precipitate (S)-(+)-3-aminomethyl-5- methylhexanoic acid; and
Q) isolating substantially pure (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)- Pregabalin).
It is also an important aspect of the present invention, to provide process to prepare (±)-3-(carbamoylrnethyl)-5-methylhexanoic acid (P-04), comprising: a) reacting tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) with a concentrated hydrochloric acid followed by decarboxylation to give isobutylglutaric acid (P-03); b) reacting 3 -isobutylglutaric acid (P-03) with thionyl chloride followed by reaction with ammonia to obtain (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04); and c) isolating (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04).
In one of the aspect, the invention encompasses tetraethyl 2-isobutyl propane- 1,1, 3, 3- tetracarboxylate (P-02)
Figure imgf000012_0002
In another important aspect, the present invention encompasses (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid in crystalline form, which is characterized by XRD and IR.
Yet another aspect of the present invention is to provide a process for preparation of isobutylglutaric anhydride by cyclization of isobutylglutaric acid with thionyl chloride.
It another aspect, the invention provides a process for preparing (S)-Pregabalin, which provides highly pure (S)-Pregabalin with single every single individual impurities less than 0.1 % by area percentage of HPLC. BRIEF DESCRIPTION OF THE DRAWINGS FIG.l: X-ray diffraction of (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5- methylhexanoic acid FIG.2: FTIR of (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid
FIG.3: Chiral HPLC chromatogram of (S)-Pregabalin. FIG.4: GC chromatogram of 2-carboxyethyl-5-methylhex-2-enoic acid (P-01 )
FIG.5: GC chromatogram of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester
(P-02)
FIG.6: GC chromatogram of isobutylglutaric acid (P-03) DETAILED DESCRD7TTON OF THE INVENTION The term "Substantially pure (S)-(+)-3-aminomethyl-5-methylhexanoic acid" as used herein before or after means (S)-(+)-3-aminomethyl-5-methylhexanoic acid having purity greater than or equal to about 99.5% with every single individual impurities less than 0.1% and total impurities less than or equal to about 0.50% by area percentage of HPLC.
The term "Substantially pure (R)-(+)-α-ρhenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid" as used herein before or after means that crystalline (R)- (+)-α-phenylethylamine salt of (RK-)-3-(Carbamoylmethyl)-5-methylhexanoic acid is having purity greater than or equal to about 99%, preferably greater than or equal to about 99.5%.
Substantially pure crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid is substantially pure having purity greater than or equal to about 99%, preferably greater than or equal to about 99.5% is also the scope of the present inventioa According to the first embodiment of the present invention, there is provided a process for preparation of substantially pure (S)-(+)-Pregabalin of formula (I)
Figure imgf000014_0001
comprising:
(a) combining alkali hydroxide and water; (b) adding bromine at a temperature of about 00C to about 25°C to obtain alkali hypobromide solution-A;
(c) reacting (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-06) with alkali hydroxide and water at about 00C to about 250C to obtain solution-B;
(d) adding above solution-A into the solution-B at about 00C to about 250C; (e) heating;
(f) reacting with strong mineral acid to adjust the pH below 4.0;
(g) cooling;
(h) extracting with suitable non-polar organic solvent;
(i) neutralizing aqueous layer with suitable base to precipitate (S)-(+)-3-aminomethyl-5- methylhexanoic acid; and
Q) isolating substantially pure (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)- Pregabalin).
The alkali hydroxide for the preparation of alkali hypobromide solution can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide. The temperature for the preparation of sodium hypobromide solution-A is preferably from about O0C to about 25°C, most preferably at about
O0C tO lO0C.
The solution-B as in step (c) can be prepared by reacting (R)-(-)-3-(carbamoylmethyl)-
5-methylhexanoic acid (P-06) with alkali hydroxide and water at about O0C to about 25°C. Preferable alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide. The temperature for the preparation of solution-B as in step (c) is preferably from about O0C to about 250C, most preferably at about O0C to 1O0C. The addition of solution-B into the solution-A as in step (d) can be carried out at a temperature of about 00C to about 250C, preferably at about O0C to about 1O0C. After the addition is completed, the reaction mixture is heated as in step (e) at about 400C to about 800C, preferably at about 500C to about 7O0C, more preferably at about 600C to about 65°C for sufficient amount of time with stirring. The reaction mixture is cooled to 450C and treated with strong mineral acid selected from H2SO4, HCl, HBr and H3PO4, preferably HCl as in step (f) to adjust the pH below 4.0. The reaction mixture is treated with cone. HCl to adjust the pH 1.0 and allowed to cool to room temperature of about 200C to about 350C, preferably 250C to about 300C. The reaction mixture obtained upon cooling is extracted with non-polar organic solvent selected from toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene dichloride, ethyl acetate and the like, preferably methyl tert-butyl ether to remove the unreacted starting material (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-06), any degradants or byproducts whereby the organic layer will contain the impurities and' the aqueous layer will contain the desired product.
The separated aqueous layer is neutralized with suitable base selected from inorganic base or organic base, like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropyl ethyl amine, pyridine etc., preferably sodium hydroxide to adjust the pH of about 4.0 to about 5.0, preferably of about 4.5 to about 5.0. to precipitate substantially pure (S)-(+)- Pregabalin.
According to another embodiment of the present invention, there is provided a process for preparation of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04), comprising:
(a) reacting tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) with a concentrated hydrochloric acid followed by decarboxylation to give isobutylglutaric acid (P-03);
(b) reacting 3-isobutylglutaric acid (P-03) with thionyl chloride followed by reaction with ammonia to obtain (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04); and
(c) isolating (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04)
According to the most preferred embodiment, it is important to obtain isobutylglutaric acid (P-03) in pure form. Thus, the invention encompasses tetraethyl 2-isobutyl propane- i 1,1,3,3-tetracarboxylate (P-02) which is treated with cone. HCl to obtain carboxylic acid derivative which on subsequent decarboxylation will be converted to 3-isobutylglutaric acid (P-03). The reaction of P-02 intermediate with cone. HCl is carried out at reflux temperature of about 7O0C to about 1500C, preferably at about 1000C to about 1050C for -70 to 80 hours followed by cooling to 85°C to 9O0C. After the completion of the reaction, the reaction mixture was extracted with toluene at 700C to 800C whereby toluene is distilled under vacuum at 600C to 700C to isolate 3-isobutyl glutaric acid (P-03).
To obtain (S)-(+)-Pregablin substantially free from impurites, it is necessary that the intermediates should be highly pure. Thus, (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) intermediate can be prepared with substantially purity from 3-isobutylglutaric acid (P- 03) by reacting with thionyl chloride for in-situ preparation of 3-isobutylglutaric anhydride. This method is more advantageous over the prior art method for cyclization whereby uses of acetic anhydride or acetyl chloride is reported. 3-isobutylglutaric acid (P-03) is refluxed in thionyl chloride for 30 min followed by distillation to remove excess of thionyl chloride. The residue 3-isobutylglutaric anhydride is dissolved in methyl tert-butyl ether and treated with aqueous ammonia (28% ammonium hydroxide) to separate the organic and aqueous layer. The aqueous layer is distilled and treated with cone. HCl to adjust the pH below 4.0, preferably of about 1.5 to obtain (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
According to another preferred embodiment of the present invention, there is provided an improved process for the preparation of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid of formula (P-04), an important intermediate for the (S)-Pregabalin,
Figure imgf000016_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2- carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a);
cAΛΛA)Cc2H5
Figure imgf000016_0003
Figure imgf000016_0002
P-01 P-01-a (b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane- 1,1,3 ,3 -tetracarboxy late (P-02);
Figure imgf000017_0001
P-02
(c) hydrolyzing tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03); and
Figure imgf000017_0002
P-03
(d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3-(carbamoylmethyl)- 5-methylhexanoic acid (P-04). The condensation of isovaleraldehyde with diethyl malonate is well reported in the prior art. However, the reported process in the prior at as provided in U.S. Patent No.
5,637,767 discloses that the said condensation also results in the formation of 10%-13% olefin isomer 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a).
Figure imgf000017_0003
P-01-a Further, very recently published application US 20070259917 Al also reports the condensation of isovaleraldehyde and diethyl malonate in presence of base like di-n- propylamine and acetic acid in cyclohexane. However, the condensed product is not isolated. Thus, the advantage of the present process over the prior art is to obtain said condensed product 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a).
The condensed product 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) as obtained in step (a) is further reacted with diethyl malonate in absence of organic solvent in presence of organic base selected from morpholine, piperidine, pyridine, triethylamine, di-n- propylamine, diisopropylethyl amine etc., preferably piperidine at a temperature of about 400C to about 600C, preferably of about 500C to about 52°C. The reaction mixture was cooled to room temperature to isolate tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02).
The isolated compound tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) can be hydrolyzed to obtain 3-isobutylglutaric acid (P-03) as described herein above as in step
(c) which is then converted to (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) by treatment with thionyl chloride via in-situ generation of 3-isobutylglutaric anhydride as described herein above.
According to preferred embodiment of the present invention , there is provided an improved process for preparing substantially pure (S)-(+)-Pregabalin of formula (I),
Figure imgf000018_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol);
Figure imgf000018_0002
P-01
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02);
Figure imgf000018_0003
(c) hydrolyzing tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03);
Figure imgf000019_0001
P-03
(d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3-(carbamoylmethyl)-
5-methylhexanoic acid (P-04);
Figure imgf000019_0002
(e) reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with (R)-(+)-α.- phenylethylamine to obtain the substantially pure (R)-(+)-α-phenylethylamine salt of (R)-
(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-05);
P M αlnho phenylethyl amine
Figure imgf000019_0004
Figure imgf000019_0003
(f) dissolving the salt (P-05) in water to form a solution and acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoyhτiethyl)-5-methylhexanoic acid (P-06);
Figure imgf000019_0005
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
Figure imgf000020_0001
(S)-Pregabalin (h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin).
According to most preferred embodiment of the present invention , there is provided an improved process for preparing substantially pure (S)-(+)-Pregabalin of formula (I),
Figure imgf000020_0002
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2- carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a);
Figure imgf000020_0003
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02);
Figure imgf000020_0004
P-02
(c) hydrolyzing tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03);
Figure imgf000020_0005
P-03 (d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3-(carbamoylmethyl)- 5-methylhexanoic acid (P-04);
Figure imgf000021_0001
(e) reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with (R)-(+)-α.- phenylethylamine to obtain the substantially pure (R)-(+)-α-phenylethylamine salt of (R)- (-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-05);
R-(+)-alpha phenylethyl amine
Figure imgf000021_0003
Figure imgf000021_0002
(f) dissolving the salt (P-05) in water to form a solution and acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoylmethyl)-5-methylhexanoic acid (P-06);
Figure imgf000021_0004
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
Figure imgf000021_0005
P-06 (S)-PregabaDn (h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin)
Pregabalin is a chiral compound having (R) and (S) isomers. The desired (S)-isomer of
Pregabalin can be obtained from (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04). The resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with chiral amines like (R)-(+)-α.-phenylethyl- amine can be conveniently carried out in mixture of chloroform and ethanol to obtain substantially pure (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid (P-05)
The (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid (P-05) can be acidified with cone. HCl followed by cooling at O0C to about 5°C to precipitate (R)-(-)-3-(carbamoylrnethyl)-5-methylhexanoic acid (P-06). The precipitated product is filtered and washed with IM HCl. The isolated product (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid (P-06) readily undergoes Hoffman Bromide degradation reaction as described herein above to obtain substantially pure (S)-(+)-Pregabalin of formula (I). According to further embodiments, (S)-(+)-3-aminomethyl-5-methylhexanoic acid in the solid state contains less than or of about 0.50% total impurities as measured by area percentage HPLC is also the scope of present invention.
The present invention further provides a crystalline (R)-(+)-α-phenylethylamine salt of
(R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid, which is X-ray powder diffraction pattern having peaks at 20 5.9, 7.7, 12.6, 17.1, 23.3 (±0.2).
The crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid is further characterized by X-ray powder diffraction pattern having peaks at 20 5.9, 6.3, 7.7, 8.8. 9.2, 10.2, 12.62, 13.8, 14.5, 15.8, 17.1, 18.4, 20.5, 22.4, 23.3,
24.0, 25.0, 25.7, 28.7, 29.6 and 30.3, (±0.2) Crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid is further characterized by characterized by X-ray powder diffraction pattern of as depicted in FIG.1
It is also the preferred embodiment to provide the crystalline (R)-(+)-α- phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid is characterized by IR spectrum as depicted in FIG.2. According to the most preferred embodiment of present invention, the process for the preparation of substantially pure (S)-(+)-Pregabalin of formula (I) can be illustrated by below mentioned schemes, which should not be considered as limiting the scope of the invention.
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
P-05 P-06 (S)-Pregabalin
Scheme-8
The invention is described with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any1 way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention can be embodied in many other forms. Example-1: Preparation of P-Ol
Figure imgf000024_0001
P-01 To a solution of 100 g of Isovaleraldehyde in 450 ml methylene dichloride was added
18O g of diethyl malonate in round bottom flask fitted with a dean-stark. 11.8 g of morpholine and 8.3 gm of acetic acid were added twice. The reaction mixture was heated at reflux temperature 45°C-50°C for 4-5 hours till azeotropic removal of water and was cooled to 250C- 300C. 225 ml of water was added to the reaction mixture, stirred & settled for 15 minutes. Separated organic layer was treated with 150 ml of 10% HCl Solution. The aqueous layer and organic layer are separated. The separated organic layer is then treated with 100 ml of 2% NaHCθ3 solution and with 225 ml of water, stirred and settled. Finally separated organic layer is filtered through hyflow bed, washed with methylene dichloride. The excess of methylene dichloride is distilled under vacuum by hot water below 40°C-50°C. [% Yield = 87%; G.C purity = 84-86%, isomer = 1-2%].
IR (Nujol-mull, v cm'1) : sp3 C-H stretch : 2980, 2960, 2935; CO : 1724; C=C stretch : 1649 1H NMR (CDCl3, 300 MHz): δ 0.90-1.01 (m, 6H), 1.24-1.35 (m, 6H), 1.77-1.84 (m, IH), 2.16-2.22 (m, 2H), 4.17-4.34 (m, 4H), 6.99-7.04 (t, IH, J = 7.9 Hz) MS: m/z = 228.28 (M+l).
Purity of 2-carbethoxv-5-methvl hex-2-enoic acid ethyl ester (P-Ol) can be determined by using the following gas chromatography apparatus and procedures:
Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer or equivalent
Length: 30 m
Diamter : 0.53 mm
Film thickness : 5 μm
Injector Temperature : 21O0C
Detector Temperature : 23O0C Oven temperature Time (min) Temperature
Initial 0 1000C Final 44 2200C Temp Programme rate: 20°C/minute
Equilibrium time : 1.0 minute Injection Volume : 0.5 μl Carrier gas : Nitrogen Split Flow : 60 ml/min. Detector : FID
A sample Chromatogram is shown in FIG.4
Example-2: Preparation of 1,1,3.3-PropanetetracarboxyIic acid. 2-isobutyl, tetraethyl ester of formula P-02
Figure imgf000025_0001
98.23 g of diethyl malonate, 22.38 g of piperidine were taken in a round bottom flask. The above prepared intermediate P-Ol, 100 g was added dropwise at room temperature. After the addition was completed the reaction mixture was heated to 5O0C to 52°C and maintained. The reaction mixture was cooled to room temperature and the product P-02, was isolated (215 g).
Purity of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl., tetraethyl ester (P-02) can be determined by using the following gas chromatography apparatus and procedures:
Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer or equivalent
Length : 30 m
Diamter : 0.53 mm
Film thickness : 5 μm
Injector Temperature : 2100C
Detector Temperature : 23O0C Oven temperature Time (min) Temperature
Initial 0 1000C
Final 44 22O0C
Temp Programme rate: 20°C/minute
Equilibrium time : 1.0 minute Injection Volume : 0.5 μl Carrier gas : Nitrogen Split Flow : 60 ml/min. Detector : FID
A sample Chromatogram is shown in FIG.5
Example-3: Preparation of Isobutylglutaric acid (P-03)
Figure imgf000026_0001
100 g of P-02 intermediate as prepared above was taken in a round bottom flask and
300 ml cone. HCl was added. The reaction mixture was heated to reflux at 1000C to 1050C slowly for 72 hours. The reaction mixture was cooled to 85-900C. The reaction mixture was extracted with toluene at 7O0C to 800C and stirred for 30 min. The product was filtered through hyflow bed and washed with toluene. The excess toluene was distilled under vacuum at 6O0C to 700C to isolate P-03, 35 g.
Purity of Isobutylglutaric acid (P-03) can be determined by using the following gas chromatography apparatus and procedures:
Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer or equivalent Length : 30 m Diamter : 0.53 mm Film thickness : 5 μm
Injector Temperature : 21O0C
Detector Temperature : 23O0C Oven temperature Time Crnin) Temperature
Initial 0 1000C
Final 44 2200C Temp Programme rate: 20°C/minute
Equilibrium time : 1.0 minute
Injection Volume : 0.5 μl
Carrier gas : Nitrogen
Split Flow : 60 ml/min.
Detector : FID
A sample Chromatogram is shown in FIG.6
ExampIe-4: Preparation of (±)-3-(Carbamoylmethyl)-5-Methylhexanoic Acid (P-04) (Without Isolation and Purification 3-Isobutylglutaric Acid Anhydride)
Figure imgf000027_0001
3-Isobutylglutaric acid (68.8 kg) and thionyl chloride (445 kg) are combined and placed under reflux for 0.5 hours. The mixture is placed under atmospheric distillation followed by vacuum distillation to remove thionyl chloride. The un-distilled 3- isobutylglutaric acid anhydride is dissolved in methyl tert-butyl ether (63 kg) and added to a solution of aqueous ammonia (49 kg of 28% ammonium hydroxide) and water (92 kg) at a temperature of 25°C or less. The mixture is stirred for 35 minutes and the layers are separated. The aqueous layer is placed under vacuum distillation to remove any remaining volatile nonaqueous solvent. Concentrated hydrochloric acid (51 kg) is added to the aqueous mixture to obtain a pH of 1.5. The mixture is cooled to O0C-IO0C. and filtered. The solid is washed with water (50 L) and dried under reduced pressure. The solid is then dissolved in hot (700C) ethyl acetate (237 kg) and filtered. The solution is cooled to 0°C-5°C and the product is collected by filtration. The solid is washed with cold ethyl acetate (45 kg) and dried under reduced pressure to give 47.5 kg of (±)-3-(Carbamoylmethyl)-5τmethylhexanoic acid as an off-white solid having a melting point in the range of 1060C to about 1080C. Example-5: Preparation of (RH-)-3-(CarbamoylmethvI)-5-Methyl Hexanoic Acid, (RH+)- .alpha.-phenylethylamine Salt (P-05)
R-(+)-alpha phenylethyl amine
Figure imgf000028_0002
Figure imgf000028_0001
(±)-3-(Carbamoylmethyl)-5-methylhexanoic acid (17.0 g) is placed in chloroform (292 g) and ethanol (3.2 g) is added. The mixture is heated to 550C and (R)-(+)-α- phenylethylamine (6.0 g) is added. After a solution forms additional (R)-(+)-α- phenylethylamine (2.0 g) and (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid seed crystals (50 mg) are added. The mixture is cooled to 320C and filtered. The solid is washed with chloroform (30 ml). The solid is dried under reduced pressure to give 10.5 g of the (R)- (+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid as a white solid having a melting point in the range of about 123° C to about 1260C (Chiralpak AD-H (250 mm X 4.6 mm, 5μ) n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1) enantiomeric purity >99% (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
Example-6: Preparation of (RH-)-3-(CarbamoylmethvD-5-Methylhexanoic Acid (P-06)
Figure imgf000028_0003
The (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid (10.9 g) is placed in water (35 ml). The mixture is acidified to pH 1.7 at 310C with concentrated hydrochloric acid. The mixture is cooled to 40C and filtered. The solid is washed with cold (4°C) IM hydrochloric acid (10 ml) and dried under reduced pressure to give 6.2 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid as a white solid having a melting point in the range of about 1300C to about 133°C (Chiralpak AD-H (250 mm X 4.6 mm, 5μ) n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1) enantiomeric purity >99% (R)-(- )-3 -(Carbamoylmethyl)-5 -methylhexanoic acid. Example-7: Preparation of (SH+)-3-AminomethyI-5-Methylhexanoic Acid
Figure imgf000029_0001
P-06 (S)-Pregabalin
(R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (100 g) is dissolved in water
(114.5 g) and 50% sodium hydroxide solution (21 g) and cooled to 5°C. In a separate flask water (372 g), 50% sodium hydroxide solution (88.40 g), and bromine (102 g) are combined while maintaining a temperature of less than 1O0C. The bromine solution is added to the solution of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and warmed until a temperature of 600C is reached. The solution is cooled to 45°C and quenched into 37% hydrochloric acid solution (225 mL) whereby adjust the pH to 1.0. The reaction mixture is cooled to room temperature and extracted with methyl tert-butyl ether (600 ml). The separated aqueous layer is treated with 15% NaOH solution (15 g of NaOH dissolved in 15 ml of water). The pH of the reaction mixture is adjusted to 4.5 to 5.0. The mixture is heated to 6O0C. and then cooled to 00C to 50C. The mixture is filtered and the solid is washed with water (30 mL). The solid is dried under reduced pressure to give 55 grams of (S)-(+)-3-aminomethyl-5- methylhexanoic acid. The solid (16.3 g) is recrysatllized from a mixture of isopropanol (54 g) and water (54 g) to give 14.7 g of recrysatllized (S)-(+)-3-aminomethyl-5-methylhexanoic acid having a melting point in the range of about 184°C to about 186°C-decomposes.
Enantiomeric purity can be established bv the following chiral HPLC method:
(High-performance liquid chromatography was performed using a Shimadzu LC201 OC HPLC system) \
Column Chiralpak AD-H (250 mm X 4.6 mm, 5μ) or equivalent
Mobile Phase n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1 Flow Rate l.O ml/min. ' Column oven temp 250C
Run Time 30 mintues Detector dual wavelength UV-VIS Wavelength 264 run Injection Volume 10 /d Diluent n-Hexane/Isopropyl alcohol-50/50. Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
HPLC shows purity > 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.1% and total impurity NMT 0.50%.
ADVANTAGES OF THE PRESENT INVENTION:
1. The present invention provides a very cost-effective, eco-friendly, non-hazardous and large scale applicable method
2. The present invention provides a method for preparation of (S)-(+)-3-aminomethyl-5- methylhexanoic acid which encompasses through a new intermediate P-02.
3. The present invention provides crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5-methylhexanoic acid which is well characterized by XRD and IR
4. The present invention provides (S)-(+)-3-aminomethyl-5-methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
5. The present invention provides crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3- (Carbamoylmethyl)-5 -methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
6. The present invention provides an improved process for the preparation of (S)-(+)-3- aminomethyl-5 -methylhexanoic Acid by Hoffman-degradation reaction of (R)-(-)-3-
(carbamoylmethyl)-5 -methylhexanoic acid (P-06).
7. The present invention provides an improved process for the preparation of substantially pure (S)-(+)-Pregabalin which is cost effective, environment friendly and easily applicable to large scale production.

Claims

We claim:
1. An improved process for preparation of substantially pure (S)-(+)-Pregabalin of formula (I)
Figure imgf000031_0001
comprising:
(a) combining alkali hydroxide and water;
(b) adding bromine at a temperature of about O0C to about 250C to obtain alkali hypobromide solution-A;
(c) reacting (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-06) with alkali hydroxide and water at about 00C to about 250C to obtain solution-B;
(d) adding above solution-A into the solution-B at about O0C to about 250C;
(e) heating;
(f) reacting with strong mineral acid to adjust the pH below 4.0;
(g) cooling; (h) extracting with suitable non-polar organic solvent;
(i) neutralizing aqueous layer with suitable base to precipitate (S)-(+)-3-aminomethyl-
5-methylhexanoic acid; and (j) isolating substantially pure (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-
Pregabalin). 2. An improved process according to claim 1, wherein the alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide. 3. An improved process according to claim 1, wherein addition of bromine is carried out at about O0C to about 250C, most preferably at about O0C to 1O0C. 4. An improved process according to claim 1 , wherein alkali hydroxide used in step (c) can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide.
5. An improved process according to claiml , wherein addition of solution-A into the solution- B is carried out at about 00C to about 25°C, most preferably at about 00C to 1O0C.
6. An improved process according to claim 1, wherein heating as in step (e) can be done at about 4O0C to about 8O0C, preferably at about 5O0C to about 700C, more preferably at about 600C to about 65°C for sufficient amount of time with stirring.
7. An improved process according to claim 1 , wherein strong mineral acid can be selected from H2SO4, HCl, HBr and H3PO4, preferably HCl to adjust the pH below 4.0, preferably pH of about 1.0.
8. An improved process according to claim 1, wherein cooling is done to room temperature of about 200C to about 350C, preferably 250C to about 300C.
9. An improved process according to claim 1, wherein suitable non-polar organic solvent for extraction can be selected from toluene, xylene, diethyl ether, diisopropyl ether, methyl tert- butyl ether, methylene dichloride, ethyl acetate and the like, preferably methyl tert-butyl ether.
10. An improved process according to claim 1, wherein suitable base for neutralizing aqueous layer can be selected from inorganic base or organic base, like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropyl ethyl amine, pyridine etc., preferably sodium hydroxide.
11. An improved process according to claim 1, wherein substantially pure (S)-(+)-3- aminomethyl-5-methylhexanoic acid ((S)-Pregabalin) can be isolated by adjusting the pH of about 4.0 to about 5.0, preferably of about 4.5 to about 5.0. 12. An improved process for the preparation of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04),
Figure imgf000032_0001
comprising:
(a) reacting tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) with a concentrated hydrochloric acid followed by decarboxylation to give 3- isobutylglutaric acid (P-03);
(b) reacting 3-isobutylglutaric acid (P-03) with thionyl chloride followed by reaction with ammonia to obtain (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04); and (c) isolating (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04).
13. An improved process according to claim 12, wherein tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) is reacted with cone. HCl at reflux temperature.
14. An improved process according to claim 13, wherein reflux temperature is of about 7O0C to about 15O0C, preferably at about 1000C to about 1050C.
15. An improved process according to claim 13, wherein reaction mixture is cooled at an ambient temperature after the reaction of tetraethyl 2-isobutyl propane- 1,1, 3,3- tetracarboxylate (P-02) is reacted with cone. HCl at reflux temperature.
16. An improved process according to claim 15, wherein ambient temperature is of about 850C to about 900C.
17. An improved process according to claim 12, wherein in step (a) the reaction mixture is extracted with toluene followed by distillation of solvent to obtain 3-isobutylglutaric acid of formula (P-03).
18. An improved process according to claim 12, wherein in step (b) 3-isobutylglutaric acid (P-03) is reacted with thionyl chloride under reflux conditions for 30 min.
19. An improved process according to claim 12, wherein in step (b) in-situ generated 3- isobutylglutaric anhydride is treated with 28% ammonium hydroxide solution.
20. An improved process according to claim 19, wherein treatment with 28% ammonium hydroxide solution results in separation of aqueous layer containing (±)-3- (carbamoylme&yl)-5-methylhexanoic acid (P-04).
21. An improved process according to claim 20, wherein aqueous layer containing (±)-3- (Carbamoylmethyl)-5-methylhexanoic acid (P-04) is treated with cone. HCl to adjust the pH below 4.0, preferably of about 1.5 to isolate containing (±)-3-(carbamoylmethyl)-5- methylhexanoic acid (P-04). 22. A process for the preparation of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid of formula (P-04),
Figure imgf000033_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a);
Figure imgf000034_0001
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane- 1,1,3 ,3 -tetracarboxylate (P-02);
Figure imgf000034_0002
(c) hydrolyzing tetraethyl 2-isobutyl propane- 1,1,3 ,3 -tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03); and
Figure imgf000034_0003
(d) reacting 3-isobutylglutaric acid with tlύonyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3- (carbamoylmethyl)-5-methylhexanoic acid (P-04). 23. A process according to claim 22, wherein in steps (a) and (b) dialkyl malonate is diethyl malonate.
24. A process according to claim 22, wherein in step (a) condensation of isovaleradehyde with diethyl malonate obtains 2-carboxyethyl-5-methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a) 25. A process according to claim 22, wherein in step (b) 2-carboxyethyl-5-methylhex-2- enoic acid, ethyl ester (P-Ol) is reacted with diethyl malonate in absence of solvent. 26. A process according to claim 22, wherein in step (b) suitable organic base can be selected from selected from morpholine, piperidine, pyridine, triethylamine, di-n- propylamine, diisopropylethyl amine etc., preferably piperidine.
27. A process according to claim 22, wherein in step (c) hydrolysis of tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) can be carried out with mineral acid like H2SO4, HCl, HBr and H3PO4, preferably HCl.
28. A process according to claim 22, wherein in step (d) 3-isobutylglutaric acid (P-03) is reacted with thionyl chloride under reflux conditions for 30 min.
29. A process according to claim 22, wherein in step (d) in-situ generated 3- isobutylglutaric anhydride is treated with 28% ammonium hydroxide solution. 30. A process according to claim 28, wherein treatment with 28% ammonium hydroxide solution results in separation of aqueous layer containing (±)-3-(carbamoylmethyl)-5- methylhexanoic acid (P-04).
31. A process according to claim 29, wherein aqueous layer containing (±)-3- (Carbamoylmethyl)-5-methylhexanoic acid (P-04) is treated with cone. HCl to adjust the pH below 4.0, preferably of about 1.5 to isolate containing (±)-3-
(carbamoylmethyl)-5-methylhexanoic acid (P-04).
32. A process for the preparation of substantially pure (S)-(+)-Pregabalin of formula (I),
Figure imgf000035_0001
comprising:
(a) condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5- methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer
2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-Ol -a);
Figure imgf000035_0002
(b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02);
EKXNXP Qx^OEt
EIYγV0Et
-CH3 CH3 P-02
(c) hydrolyzing tetraethyl 2-isobutyl propane- 1,1,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03);
Figure imgf000036_0001
(d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3- (carbamoylmethyl)-5-methylhexanoic acid (P-04);
Figure imgf000036_0002
(e) reacting (±)-3-(carbamoylmethyl)-5-methyihexanoic acid (P-04) with (R)-(+)-α.- phenylethylamine to obtain the substantially pure (R)-(+)[-α-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-05);
Figure imgf000036_0003
(f) dissolving the salt (P-05) in water to form a solution and acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoylmethyl)-5-methylhexanoic acid (P-06);
Figure imgf000037_0001
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
Figure imgf000037_0002
(h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin).
33. A process according to claim 32, wherein in steps (a) and (b) dialkyl malonate is diethyl malonate.
34. (S)-(+)-Pregabalin prepared according to any preceding claims, wherein (S)-(+)-3- aminomethyl-5-methylhexanoic acid i.e. (S)-(+)-Pregabalin is in the solid state contains less than or of about 0.50% total impurities as measured by area percentage HPLC. 35. A crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid, which is X-ray powder diffraction1 pattern having peaks at 2Θ
5.9, 7.7, 12.6, 17.1, 23.3 (±0.2). 36. A crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid according to claim-35, further characterized by X-ray powder diffraction pattern having peaks at 2Θ 5.9, 6.3, 7.7, 8.8. 9.2, 10.2, 12.62, 13.8, 14.5,
15.8, 17.1, 18.4, 20.5, 22.4, 23.3, 24.0, 25.0, 25.7, 28.7, 29.6 and 30.3 (±0.2). (f) dissolving the salt (P-05) in water to form a solution and acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoylmethyl)-5-methylhexanoic acid (P-06);
Figure imgf000038_0001
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
Figure imgf000038_0002
P-06 (S)-Pregabalin
(h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin).
33. A process as claimed in claim 31, wherein in steps (a) and (b), wherein dialkyl malonate is diethyl malonate.
34. (S)-(+)-Pregabalin prepared as claimed in any preceding claims, wherein (S)-(+)-3- aminomethyl-5-methylhexanoic acid i.e. (S)-(+)-Pregabalin is in the solid state contains less than or of about 0.50% total impurities as measured by area percentage HPLC.
35. A crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid, which is X-ray powder diffraction pattern having peaks at 20 5.9, 7.7, 12.6, 17.1, 23.3 (±0.2).
36. A crystalline (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5- methylhexanoic acid as claimed in claim-35, further characterized by X-ray powder diffraction pattern having peaks at 2Θ 5.9, 6.3, 7.7, 8.8. 9.2, 10.2, 12.62, 13.8, 14.5, 15.8, 17.1, 18.4, 20.5, 22.4, 23.3, 24.0, 25.0, 25.7, 28.7, 29.6 and 30.3 (±0.2). (b) reacting 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-Ol) with a dialkyl malonate in absence of organic solvent, and in presence of organic base to obtain tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02);
Figure imgf000039_0001
(c) hydrolyzing tetraethyl 2-isobutyl propane-l,l,3,3-tetracarboxylate (P-02) to obtain 3- isobutyl- glutaric acid (P-03);
Figure imgf000039_0002
P-03
(d) reacting 3-isobutylglutaric acid with thionyl chloride to obtain 3-isobutylglutaric anhydride in-situ followed by treatment with ammonia to obtain (±)-3- (carbamoyknethyl)-5-methylhexanoic acid (P-04);
Figure imgf000039_0003
(e) reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (P-04) with (R)-(+)-α.- phenylethylamine to obtain the substantially pure (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(carbamoyhnethyl)-5-methylhexanoic acid (P-05);
(f) dissolving the salt (P-05) in water to form a solution and! acidifying the solution with hydrochloric acid to obtain solid (R)-(-)-(3)-(carbamoylmethyl)-5-methylhexanoic acid (P-06); '
(g) reacting the (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-06) with sodium hydroxide and bromine to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid; and
(h) isolating (S)-(+)-3-aminomethyl-5-methylhexanoic acid ((S)-Pregabalin)
44. A process according to claim 43, wherein in steps (a) and (b) dialkyl malonate is diethyl malonate.
45. A process according to claim 43, wherein in step (a) condensation of isovaleradehyde with diethyl malonate obtains 2-carboxyethyl-5-methylhexe-2-enoic acid, ethyl ester (P-Ol) having not more than 2% olefin isomer 2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester of formula (P-01 -a)
46. A process according to claim 43, wherein in step (b) 2-carboxyethyl-5-methylhex-2- enoic acid, ethyl ester (P-Ol) is reacted with diethyl malonate in absence of solvent.
47. A process according to claim 43, wherein in step (b) suitable organic base can be selected from selected from morpholine, piperidine, pyridine, triethylamine, di-n- propylamine, diisopropylethyl amine etc., preferably piperidine.
48. A process according to claim 43, wherein in step (c) hydrolysis of tetraethyl 2- isobutyl propane-l,l,3,3-tetracarboxylate (P-02) can be carried out with mineral acid like H2SO4, HCl, HBr and H3PO4, preferably HCl. ' 49. A process according to claim 43, wherein in step (d) 3-isobutylglutaric acid (P-03) is reacted with thionyl chloride under reflux conditions for 30 min.
50. A process according to claim 43, wherein in step (d) in-situ generated 3- isobutylglutaric anhydride is treated with 28% ammonium hydroxide solution.
51. A process according to claim 50, wherein treatment with 28% ammonium hydroxide solution results in separation of aqueous layer containing (±)-3-(carbamoylmethyl)-
5-methylhexanoic acid (P-04).
52. A process according to claim 51, wherein aqueous layer containing (±)-3- (CarbamoyImethyl)-5-methylhexanoic acid (P-04) is treated with cone. HCl to adjust the pH below 4.0, preferably of about 1.5 to isolate containing (±)-3- (carbamoylmethyl)-5-methylhexanoic acid (P-04).
53. A process for preparing Pregabalin or any of its intermediates such as here in described in accordance with the accompanying text, description, drawings and examples.
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CN102115439B (en) * 2009-12-31 2015-09-16 浙江华海药业股份有限公司 A kind of preparation method of pregabalin intermediate 3-isobutylglutaric acid
WO2012093411A3 (en) * 2011-01-07 2012-09-07 Dr Braja Sundar Pradhan Process for the preparation of r-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid and the intermediates
AU2012245073B2 (en) * 2011-04-21 2016-02-11 Garvan Institute Of Medical Research Modified variable domain molecules and methods for producing and using them b
CN102964263A (en) * 2012-11-29 2013-03-13 太仓市茜泾化工有限公司 Process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid
CN103980144A (en) * 2014-05-16 2014-08-13 浙江华海药业股份有限公司 Nesting method for pregabalin intermediate mother liquor
CN103980144B (en) * 2014-05-16 2018-08-17 浙江华海药业股份有限公司 A kind of using method of pregabalin intermediate mother liquor
CN105175276A (en) * 2015-07-25 2015-12-23 安徽东凯生物科技有限公司 Synthetic method for optically pure(R)-3-carbamyl methyl-5-methyl caproic acid
CN105348123A (en) * 2015-11-26 2016-02-24 太仓运通生物化工有限公司 Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate
CN108912004A (en) * 2018-08-01 2018-11-30 宏冠生物药业有限公司 A kind of synthetic method of pregabalin intermediate
CN108912004B (en) * 2018-08-01 2021-05-07 宏冠生物药业有限公司 Synthetic method of pregabalin intermediate
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