WO2009044409A2 - Nouveau procédé de résolution pour la prégabaline - Google Patents

Nouveau procédé de résolution pour la prégabaline Download PDF

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Publication number
WO2009044409A2
WO2009044409A2 PCT/IN2008/000621 IN2008000621W WO2009044409A2 WO 2009044409 A2 WO2009044409 A2 WO 2009044409A2 IN 2008000621 W IN2008000621 W IN 2008000621W WO 2009044409 A2 WO2009044409 A2 WO 2009044409A2
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WO
WIPO (PCT)
Prior art keywords
formula
salt
solvents
pregabalin
mixture
Prior art date
Application number
PCT/IN2008/000621
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English (en)
Other versions
WO2009044409A3 (fr
Inventor
Durga Prasad Konakanchi
Ramakrishna Pilli
Subba Rao Pula
Buchappa Gongalla
Kotayya Babu Sikha
Nannapaneni Venkaiah Chowdary
Original Assignee
Natco Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Limited filed Critical Natco Pharma Limited
Publication of WO2009044409A2 publication Critical patent/WO2009044409A2/fr
Publication of WO2009044409A3 publication Critical patent/WO2009044409A3/fr

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Classifications

    • 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
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C07C69/70—Tartaric acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Present invention relates to a novel and improved process for the resolution of racemic pregabalin of formula-I into (S)-(+)-pregabalin [(S)-(+)-3-aminomethyl-5- methylhexanoic acid] of formula-Ill via the novel acid addition salt [(S)-(+) 3- aminomethyl-5-methylhexanoic acid, (-)-O,O'-di-p-toluoyl-L-tartaric acid salt] of formula-II.
  • (S)-(+)-pregabalin of formula-Ill has analgesic, anticonvulsant and anxiolytic properties and hence is of great therapeutic significance.
  • the main drawbacks in this process are: 1) The resolving agent (S- (+)-Mandelic acid) is expensive. 2) The resolving agent is used in large excess.
  • Scheme- V illustrates a method for making pregabalin, which comprises: 1) heating racemic Pregabalin [( ⁇ )-3- (Amino methyl)-5-methylhexanoic acid] of formula-I with (O, O')- di-toluoyl-L-tartaric acid of formula-IV in a suitable solvent mixture to form a novel salt, S-(+)-3-aminomethyl-5-methylhexanoic acid, di-(O,O')-toluyl-L-tartaric acid salt of formula-II; 2) heating the novel salt of formula-II in aqueous tetrahydrofuran to give S- (+)-pregabalin of formula-Ill.
  • the present invention provides a novel resolution process for the preparation of chirally pure S-(+)-pregabalin of formula-Ill,
  • Formula-IV in the presence of a solvent medium comprising solvents such as methylene chloride, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, isopropyl alcohol, toluene, hexanes including cyclohexane, n-heptane as separately or with a mixture of these solvents and with or with out water at temp ranging 0 - 90 0 C to get the novel salt of formula-II,
  • solvent medium comprising solvents such as methylene chloride, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, isopropyl alcohol, toluene, hexanes including cyclohexane, n-heptane as separately or with a mixture of these solvents and with or with out water at temp ranging 0 - 90 0 C to get the novel salt of formula-
  • the crude salt of formula-II is leached/recrystallized from solvent mixtures aqueous isopropyl alcohol, aqueous acetone, aqueous ethyl alcohol aqueous methanol etc., to improve the chiral purity of the salt.
  • the salt is treated with aq THF to liberate pregabalin from the salt.
  • the liberated solid pregabalin is filtered and recrystallized from a solvent to get pharmaceutically acceptable grade S- (+)-pregabalin of formula-Ill.
  • Chiral purity of S-(+)-pregabalin prepared according to the present process is >99.90 % with ⁇ 0.10% of (R)-pregabalin content.
  • Solvent used in salt formation step (i) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents.
  • Temperature of reaction during salt formation stage can be in the range of 20°C to boiling point of the solvent used in the process.
  • Solvent used in recrystallization step (ii) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents
  • Isolation temperature of recrystallized salt is preferably 0 - 50 0 C
  • Solvent used in pregabalin liberation step (iii) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform,
  • Solvent employed in recrystallization step (iv) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents
  • Isolation temperature of recrystallized pregabalin is preferably -10 0 C to 70 0 C.
  • the temperatures for formation of the salt range from 20 0 C to 140 0 C and the temperatures for the preferential crystallisation of the desired salt ranges from -10 0 C to 70 0 C
  • Chiral resolving agent of formula-IV used in the process is recovered from the mother liquor of resolution step (i) by distilling off the solvent form the mother liquors and recrystallised from acetone, methyl ethyl ketone etc,.
  • the resultant crystallized chiral reagent is isolated by filtration to get pure compound of formula-IV.
  • the invention also provides a novel resolution process for the synthesis of other isomer of Pregabalin whose chemical name is (R)-(-)-3-aminomethyl-5-methyl- hexanoic acid of formula-V,
  • novel compounds of formulae-IV (((S)-(+) 3-aminomethyl-5-methyl-hexanoic acid, (-)-(O,O'-di-p-toluoyl-L-tartaric acid salt) and VII ((R)-(-) 3-aminomethyl-5-methyl- hexanoic acid, (+)-O,O'-di-p-toluoyl-L-tartaric acid salt) are well characterized by 1 H, 13 C NMR, IR, and Mass spectral analysis.
  • the resolving agent can be easily recycled making the process economically feasible.
  • step c) material is leached twice as per the step c) procedure to obtain chiral purity of the (+) isomer salt - 99.5%
  • IR Spectra 3437.9,2960, 2926, 1727, 1610 cnT 1
  • Weight of the dried material (pharma grade): 22.5 g.
  • the product obtained by recycling the solvent, salt rich in the desired isomer and the resolving agent matches with pharma specifications, making the process economically and commercially feasible.
  • leached salt (140.Og) of the above (-) isomer was taken into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition funnel.
  • a mixture of 350.0 ml of Acetone and 350.0ml of methanol were charged while under stirring. Raised the temperature of the mass to 55- 60°C. Maintained the mass at reflux temperature for 60-90min. Then slowly cooled the reaction mass to 32.5 ⁇ 2.5°C over a period of 90-120min period. Maintained the reaction mass for 60-90 min at 32.5 ⁇ 2.5°C. Filtered the reaction mass on Buchner and washed with 30.0ml of Acetone (lot-II). Suck dried thoroughly.
  • step c) material was leached twice as per the step c) procedure to obtain chiral purity of the (-) isomer salt - 99.5%
  • Recrystallisation procedure The above technical grade material (25.0 g) was dissolved mixture of Isopropyl alcohol (125.0 ml), demineralised water (125.0 ml) at 70 -75 0 C. Activated carbon (1.25 g) was added and maintained for 10-15 min at 70 -75 0 C. Filtered the hot solution on hyflow bed and transferred to a particle free 1.0 L three necked RB flask equipped with a condenser and a thermometer socket. Cooled the solution to temperature 30 ⁇ 5.0°C.
  • Acetone (375.0 ml) was charged in single lot at temperature 3O ⁇ 5.O°C, held at the same temperature for 60- 90 min, and then cooled to 0.0 ⁇ 2.5°C and further held at that temperature for 4-5 hrs.
  • the crystallized product was filtered and washed with 20.0 ml of chilled isopropyl alcohol. Suck dried thoroughly. Dried the wet material in a oven at temperature 60 ⁇ 5.0°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur un procédé nouveau et perfectionné pour la résolution de la prégabaline racémique de formule (I) en (S)-(+)-prégabaline [acide (S)-(+)-3-aminométhyl-5-méthylhexanoïque] de formule (III) par l'intermédiaire du nouveau sel d'addition avec un acide [sel d'acide (-)-O,O'-di-p-toluoyl-L-tartrique, de l'acide (S)-(+)-3-aminométhyl-5-méthylhexanoïque] de formule (II). La (S)-(+)-prégabaline de formule III a des propriétés analgésiques, anti-convulsivantes et anxiolytiques et, de ce fait, est de grande importance thérapeutique.
PCT/IN2008/000621 2007-10-01 2008-09-26 Nouveau procédé de résolution pour la prégabaline WO2009044409A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2208CH2007 2007-10-01
IN2208/CHE/2007 2007-10-01

Publications (2)

Publication Number Publication Date
WO2009044409A2 true WO2009044409A2 (fr) 2009-04-09
WO2009044409A3 WO2009044409A3 (fr) 2009-05-22

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122215A1 (fr) * 2008-04-04 2009-10-08 Generics [Uk] Limited Nouveau procédé
WO2009087674A3 (fr) * 2007-12-18 2010-03-04 Watson Pharma Private Limited Procédé perfectionné pour la préparation de (s)-prégabaline
EP2527319A1 (fr) * 2011-05-24 2012-11-28 Laboratorios Del. Dr. Esteve, S.A. Formes cristallines de prégabaline et co-formateurs pour le traitement de la douleur
WO2014072785A2 (fr) 2012-11-07 2014-05-15 Hikal Limited Procédé de préparation de prégabaline
CN114034760A (zh) * 2020-07-21 2022-02-11 中国计量科学研究院 一种用于3-氨甲基-5-甲基己酸分子手性结构分析的试剂和方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840956A (en) * 1995-06-07 1998-11-24 Warner-Lambert Company Method of making (S)-3-(Aminomethyl)-5-Methylhexanoic acid
WO2008117305A2 (fr) * 2007-03-28 2008-10-02 Glenmark Pharmaceuticals Limited Nouveau procédé pour préparer de la prégabaline et ses sels d'addition avec les acides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840956A (en) * 1995-06-07 1998-11-24 Warner-Lambert Company Method of making (S)-3-(Aminomethyl)-5-Methylhexanoic acid
WO2008117305A2 (fr) * 2007-03-28 2008-10-02 Glenmark Pharmaceuticals Limited Nouveau procédé pour préparer de la prégabaline et ses sels d'addition avec les acides

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087674A3 (fr) * 2007-12-18 2010-03-04 Watson Pharma Private Limited Procédé perfectionné pour la préparation de (s)-prégabaline
WO2009122215A1 (fr) * 2008-04-04 2009-10-08 Generics [Uk] Limited Nouveau procédé
CN102089273A (zh) * 2008-04-04 2011-06-08 基因里克斯(英国)有限公司 新方法
EP2527319A1 (fr) * 2011-05-24 2012-11-28 Laboratorios Del. Dr. Esteve, S.A. Formes cristallines de prégabaline et co-formateurs pour le traitement de la douleur
ES2396663A1 (es) * 2011-05-24 2013-02-25 Laboratorios Del Dr. Esteve S.A. Forma cristalina de pregabalina y co-formadores en el tratamiento del dolor
WO2014072785A2 (fr) 2012-11-07 2014-05-15 Hikal Limited Procédé de préparation de prégabaline
CN114034760A (zh) * 2020-07-21 2022-02-11 中国计量科学研究院 一种用于3-氨甲基-5-甲基己酸分子手性结构分析的试剂和方法

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