EP2516384A1 - Nouveau procédé pour la préparation de la (s)-prégabaline - Google Patents

Nouveau procédé pour la préparation de la (s)-prégabaline

Info

Publication number
EP2516384A1
EP2516384A1 EP10801165A EP10801165A EP2516384A1 EP 2516384 A1 EP2516384 A1 EP 2516384A1 EP 10801165 A EP10801165 A EP 10801165A EP 10801165 A EP10801165 A EP 10801165A EP 2516384 A1 EP2516384 A1 EP 2516384A1
Authority
EP
European Patent Office
Prior art keywords
pregabalin
salt
mandelic acid
iii
acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10801165A
Other languages
German (de)
English (en)
Inventor
Carles SÁNCHEZ CASALS
Alicia DOBARRO RODRÍGUEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Moehs Iberica SL
Original Assignee
Moehs Iberica SL
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 Moehs Iberica SL filed Critical Moehs Iberica SL
Publication of EP2516384A1 publication Critical patent/EP2516384A1/fr
Withdrawn legal-status Critical Current

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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
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton

Definitions

  • the present invention relates to a novel method for the preparation of (S) -pregabalin .
  • (S) -pregabalin or (S) - (+) -3- (aminomethyl) -5- methylhexanoic acid is an analogue of gamma-aminobutyric acid (GABA) which is known and used as anticonvulsive agent and whose chemical structure is represented by:
  • Patent application W093/23383 Al discloses (S)- pregabalin (called S- (+) -4-amino-3- (2-methylpropyl) butanoic acid) and its salts for the first time.
  • S- (+) -4-amino-3- (2-methylpropyl) butanoic acid and its salts for the first time.
  • the same document discloses synthesis routes for this compound that involve a large number of steps.
  • Patent application WO 96/38405 Al discloses a method of synthesis of (S) -pregabalin wherein it makes use of racemic ( ⁇ ) -3- (carbamoylmethyl) -5-methylhexanoic acid. From this racemic acid two forms are disclosed of resolving the R isomer of said acid by the use of a-phenylethylamine enantiomers. The enantiomer (R) of 3- (carbamoylmethyl ) -5- methylhexanoic acid is finally subjected to a Hofmann reaction to obtain (S) -pregabalin .
  • Patent application WO 96/40617 Al discloses an alternative method of synthesis of the racemic mixture of ( ⁇ ) -3- (aminomethyl) -5-methylhexanoic acid that does not start from racemic ( ⁇ ) -3- (carbamoylmethyl) -5-methylhexanoic acid.
  • the racemic mixture obtained is isolated and then resolved to (S) -pregabalin by the use of (S) - or (R) - mandelic acid.
  • the same article also discloses the obtaining of a diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (S) -(+) -mandelic acid with a diastereomeric ratio of 99:1 by the addition of (S)-(+)- mandelic acid to a racemic pregabalin solution in a mixture of water/isopropanol, the purification, in the same solvent mixture and with an additional quantity of ( S )-(+) -mandelic acid, of the diastereoisomeric salt obtained, the release thereof in a water/THF mixture to isolate (S ) -pregabalin, which is finally recrystallized in water/isopropanol.
  • the overall yield of the four steps is 27.7%. It does not indicate the partial yield of the resolution with the chiral agent.
  • Application WO2008/062460 A2 discloses the resolution of racemic pregabalin in identical conditions as in the Organic Process Research & Development article.
  • the salt obtained is purified also making use of an additional quantity of mandelic acid.
  • the yield of the obtaining step of the diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (L) -(+) -mandelic acid and later purification thereof is 26.5% (example 5).
  • the diastereoisomeric salt is released in a mixture of THF/water with a yield of 83% to obtain ( S ) -pregabalin which is later recrystallized in water/isopropanol with a yield of 90%.
  • Patent application US2006/0270871 Al discloses polymorfic form I of pregabalin and a process for its preparation which includes the resolution of racemic pregabalin with mandelic acid to obtain (S) -pregabalin which is later crystallized.
  • An object of the present invention is to provide an improved method for the synthesis of the (S) -stereoisomer of pregabalin starting from ( ⁇ ) -3- (carbamoylmethyl) -5- methylhexanoic acid that makes it possible to increase the yield in relation to that obtained following the methods described in the state of the art which makes it possible to decrease process costs.
  • a method for the preparation of a salt (III) of pregabalin and (S) -mandelic acid with a (S,S) diastereomer content greater than 80% which comprises the following steps:
  • step (c) optionally, purification of the salt obtained in step (b) ;
  • step (b) is performed without isolating the product obtained in step (a) .
  • a method for the obtaining of (S) -pregabalin (IV) which comprises the obtaining of a salt of pregabalin and (S) -mandelic (III) acid with a (S,S) diastereomer content greater than 80% as previously described, followed by the following steps :
  • the inventors have developed a method of synthesis wherein a "one-pot" reaction is carried out in 2 steps which consists of a) the Hofmann reaction of racemic 3- (carbamoylmethyl) -5-methylhexanoic acid and b) the subsequent obtaining of a diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (S)-( + )- mandelic acid, without isolating the racemic pregabalin obtained in step a) .
  • the method according to the invention has a yield greater than that obtained following the methods described in the state of the art.
  • the present invention provides a method for the preparation of a salt (III) of pregabalin and (S)- mandelic acid with a (S,S) diastereomer content greater than 80% which comprises the following steps:
  • step (c) optionally, purification of the salt obtained in step (b) ;
  • step (b) is performed without isolating the product obtained in step (a) .
  • the salt (III) of pregabalin and (S) -mandelic acid obtained after step (b) has a (S,S) diastereomer content greater than 85%, preferably greater than 90%, more preferably between 90% and 98% and even more preferably between 94.5% and 95.5%.
  • the preparation of a salt (III) of pregabalin and (S) -mandelic acid with a (S,S) diastereomer content greater than 80% comprises step (c) of purification.
  • step a racemic 3- ( carbamoylmethyl ) -5-methylhexanoic acid (I) is subjected to a Hofmann reaction to give racemic pregabalin (II), reaction intermediate which is not isolated, since then (+) - (S) -mandelic acid is added in aqueous medium (step b) in a same reaction to obtain the salt of pregabalin and (S) -mandelic acid (III) with a yield of 49.4% and with a (S,S) diastereomer content greater than 80%.
  • Hofmann reaction or reordering is understood as the reaction of a primary amide (R-CONH 2 ) to give an amine (R- NH 2 ) with one carbon atom less.
  • the conditions of the Hofmann reaction are well known by persons skilled in the art.
  • a suitable Hofmann agent is a hypohalite of alkaline metal, which may be prepared combining a base such as sodium hydroxide with a halogen, such as bromine. Other alkaline metals or alkaline earth metal bases or other halogens can also be used.
  • Hofmann agents that can be used include, but are not limited to: bis ( trifluoroacetoxy) -iodobenzene , iodobenzene with formic acid, [hydroxy (tosyloxy) iodo] benzene, bis (acetoxy) iodobenzene, lead tetraacetate, benzyltrimethylammonium tribromide, N-bromosuccinimide in basic medium (such as a potassium hydroxide solution) , and N-bromosuccinimide in the presence of mercury II acetate or silver acetate.
  • the Hofmann reaction of step (a) is performed with sodium hypobromite, preferably in aqueous medium which can also be prepared by the addition of bromine to a sodium hydroxide solution.
  • Racemic 3- (aminomethyl ) -5-methylhexanoic acid or racemic pregabalin (II) formed in step (a) can be resolved by selective crystallization with (S) -mandelic acid.
  • the S,S salt precipitates from the solution.
  • step (b) of the reaction (S) -(+ ) -mandelic acid is added to the racemic pregabalin (II) formed in step (a) to obtain the diastereoisomeric salt of pregabalin and (S)- mandelic acid (III) which is enriched with the (S,S) diastereomer .
  • the salt enriched with (S,S) diastereomer can be preferably purified (step c) .
  • Said purification is performed without the need to add an additional quantity of mandelic acid, and preferably in aqueous medium. More preferably, step (c) is performed in water containing NaCl.
  • the purification methods that can be used are well known by persons skilled in the art and include, but are not limited to, recrystallization, filtration, etc.
  • step (c) is carried out by recrystallization of the salt of pregabalin and -(S)- mandelic acid.
  • step c) is carried out by recrystallization of the salt of pregabalin and -(S)- mandelic acid.
  • step (c) is performed in water, more preferably in water containing NaCl. In yet another embodiment of the invention, step (c) is performed without the addition of
  • step (c) (S) - (+ ) -mandelic acid.
  • the yield obtained by the inventors in step (c) is 64.9%.
  • steps (a) and (b) of the reaction are performed in the absence of organic solvents. In another embodiment of the invention, steps (a) and (b) of the reaction are carried out in aqueous medium.
  • a method for the obtaining of (S) -pregabalin (IV) which comprises the obtaining of a salt of pregabalin and (S)- mandelic acid (III) with a (S,S) diastereomer content greater than 80% as previously described, followed by the following steps:
  • the first steps of this method consist, as previously described, of the reaction of ( ⁇ ) -3- (carbamoylmethyl) -5- methylhexanoic acid (I) to obtain racemic pregabalin which is not isolated (step a), and whereto (S) -(+) -mandelic acid is added to obtain the salt of pregabalin and (S) -mandelic acid (III) (step b) .
  • Step (d) of the reaction consists of the conversion of the salt of pregabalin and (S) -mandelic acid (III) in (S)- pregabalin (IV) .
  • the release of (S) -pregabalin is performed by a hot extraction with water/isopropyl acetate or more preferably by using water/acetone.
  • a base in aqueous medium can be used. Examples of bases include, but are not limited to, ammonium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate. In all cases the yield of the reaction to release the salt is 85.3% or more.
  • step (d) is performed in water/isopropyl acetate. In another preferred embodiment of the invention, said step is performed in aqueous sodium hydroxide. In a more preferred embodiment of the invention, step (d) is performed in water/acetone .
  • the ( S ) -pregabalin obtained in the previous step can be purified (step e) .
  • the purification methods that can be used are well known by persons skilled in the art and include, but are not limited to, recrystallization, filtration, etc.
  • step (e) is performed by a recrystallization in a mixture of isopropanol/water, obtaining a yield of 91.5%.
  • this purification can be performed by recrystallization only with water.
  • steps (a) and (b) of the present invention simplifies the aforementioned method as the intermediate (II) is not isolated.
  • the method of the present invention provides a greater yield in comparison with those disclosed in the documents of the state of the art.
  • the yield of steps (a), (b) and (c) is 32.1%, compared with 21.0% resulting from combining the yields previously described from documents WO2006/122258 Al and WO2008 /062460 A2.
  • the overall yield for the preparation of (S) -pregabalin from a compound of formula (I) is of 25.0%, and therefore greater than those obtained from combining the yields from the different documents previously described, and which range between 15.7% and 22.0%.
  • the compounds obtained in the examples described below are identified by their x-ray powder diffraction (XRPD) standards and differential scanning calorimetry (DSC) .
  • XRPD analyses were performed in an x-ray powder diffractometer , model Siemens D-500, equipped with a copper anode. Scanning parameters: 4-50 degrees 2 ⁇ , continuous scanning, ratio: 1.2 degrees/minute.
  • EXAMPLE 1 "One pot" synthesis of a salt of pregabalin and (S) -mandelic acid (steps a and b)
  • EXAMPLE 3a Release of pregabalin to obtain crude (S) - pregabalin (step d)
  • the aqueous phase was loaded in a flask together with
  • pregabalin was performed by loading 20.0 g of the salt of pregabalin and (S)- mandelic acid (III), 40 ml of water (2 volumes) and 8.6 g of 30% caustic soda (1 equivalent) in a 250 ml flask. It was heated to 70 °C obtaining a suspension and it was stirred for 2 minutes. It was then gradually cooled to 20°C. It was then cooled to 0-5°C in an ice bath. It was then stirred at 0°C for a minimum of 2 hours. It was plate filtered and the flask was washed. The solid was compacted and drained. It was finally washed four times with 30 ml of acetone. The solid obtained was dried in an air oven at 55°C and 8.7 g of crude (S ) -pregabalin (IV) was obtained in the form of white crystalline solid.
  • pregabalin was performed by loading 50.0 g of the salt of pregabalin and (S) -mandelic acid (III), 100 ml of water and 1250 ml of acetone in a 2 L flask. The reaction mixture was heated to 56-57°C and stirred for 25 minutes at said temperature. The suspension obtained was cooled slowly to 20-22°C during 1 hour and it was kept at said temperature for approximately one more hour. The solid obtained was filtered and washed with acetone. After drying it 22.0 g of crude (S ) -pregabalin (IV) were obtained in the form of white crystalline solid ( ⁇ 0.2% isomer R, 0% ash, 99.1% HPLC, crystalline form I). EXAMPLE 4 : Recovery of mandelic acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention a pour objet un procédé pour la préparation d'un sel (III) de prégabaline et d'acide (S)-mandélique contenant une teneur en diastéréoisomère (S, S) supérieure à 80 % qui comprend les étapes suivantes : (a) la réaction de Hofmann de l'acide (±)-3-(carbamoylméthyle)-5-méthylhexanoïque (I) pour obtenir de la prégabaline racémique (II), (b) l'ajout d'acide (S)-(+)-mandélique pour obtenir le sel diastéréoisomère correspondant (III) contenant une teneur en diastéréoisomère (S, S) supérieure à 80 %, (c) facultativement, la purification du sel obtenu dans l'étape (b); caractérisé en ce que l'étape (b) est réalisée sans isolement du produit obtenu dans l'étape (a).
EP10801165A 2009-12-24 2010-12-23 Nouveau procédé pour la préparation de la (s)-prégabaline Withdrawn EP2516384A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200931267A ES2362913B1 (es) 2009-12-24 2009-12-24 Nuevo método para la preparación de (s)-pregabalina.
PCT/EP2010/070634 WO2011076915A1 (fr) 2009-12-24 2010-12-23 Nouveau procédé pour la préparation de la (s)-prégabaline

Publications (1)

Publication Number Publication Date
EP2516384A1 true EP2516384A1 (fr) 2012-10-31

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP10801165A Withdrawn EP2516384A1 (fr) 2009-12-24 2010-12-23 Nouveau procédé pour la préparation de la (s)-prégabaline

Country Status (3)

Country Link
EP (1) EP2516384A1 (fr)
ES (1) ES2362913B1 (fr)
WO (1) WO2011076915A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014016776A1 (fr) * 2012-07-27 2014-01-30 Piramal Enterprises Limited Procédé perfectionné pour la racémisation d'acide (s)-3-(carbamoylméthyl)-5-méthylhexanoïque
CN109867609A (zh) * 2019-03-21 2019-06-11 常州工程职业技术学院 一种制备普瑞巴林消旋体的方法

Family Cites Families (8)

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Publication number Priority date Publication date Assignee Title
JP3856816B2 (ja) 1992-05-20 2006-12-13 ノースウェスターン ユニヴァーシティ 抗発作治療用のｇａｂａ及びｌ−グルタミン酸類縁体
US5616793A (en) 1995-06-02 1997-04-01 Warner-Lambert Company Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid
US5637767A (en) 1995-06-07 1997-06-10 Warner-Lambert Company Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid
CA2604602A1 (fr) * 2005-05-10 2006-11-16 Teva Pharmaceutical Industries Ltd. Procede pour preparer de la pregabaline et des sels de celle-ci
US20060270871A1 (en) 2005-05-30 2006-11-30 Khanduri Chandra H Polymorphic form i of pregabalin and processes for its preparation
WO2008062460A2 (fr) * 2006-10-06 2008-05-29 Cadila Healthcare Limited Formes cristallines de la prégabaline
WO2009001372A2 (fr) * 2007-06-25 2008-12-31 Manne Satyanarayana Reddy Nouveau procédé pour la préparation de la prégabaline
WO2009147528A1 (fr) * 2008-06-02 2009-12-10 Actavis Group Ptc Ehf Procédé perfectionné de préparation de prégabaline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011076915A1 *

Also Published As

Publication number Publication date
ES2362913B1 (es) 2012-05-24
ES2362913A1 (es) 2011-07-15
WO2011076915A1 (fr) 2011-06-30
WO2011076915A8 (fr) 2011-11-03

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