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WO2004110981A1 - Procede permettant la preparation de gabapentine de forme ii - Google Patents

Procede permettant la preparation de gabapentine de forme ii Download PDF

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Publication number
WO2004110981A1
WO2004110981A1 PCT/IN2004/000103 IN2004000103W WO2004110981A1 WO 2004110981 A1 WO2004110981 A1 WO 2004110981A1 IN 2004000103 W IN2004000103 W IN 2004000103W WO 2004110981 A1 WO2004110981 A1 WO 2004110981A1
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WO
WIPO (PCT)
Prior art keywords
gabapentin
ill
followed
temperature
ethanol
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.)
Ceased
Application number
PCT/IN2004/000103
Other languages
English (en)
Inventor
Chava Satyanarayana
Gorantla Seeta Ramanjaneyulu
Indukuri Venkata Sunil Kumar
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.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2004110981A1 publication Critical patent/WO2004110981A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07C229/28—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 saturated and containing rings
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a process for preparing Gabapentin Form-Ill and its use for the preparation of Gabapentin Form-II.
  • Gabapentin i.e. 1-aminomethyl-l-cyclohexaneacetic acid
  • Gabapentin mainly used for the treatment of convulsive type cerebral disorders, such as epilepsy, hypokinesia including fainting and other brain trauma and in general, it is deemed to produce an improvement in the cerebral functions.
  • Commercially available Gabapentin is crystalline and exhibits various polymorphic Forms such as monohydrate; Form-II and Form-Ill characterized by their typical IR and X-ray diffraction patterns.
  • Patent Nos. US 4,087,544 and US 4,024,175 discloses some preparation methods starting from cyclohexane-1, 1-diacetic acid. They also discloses an acid salt Gabapentin hydrochloride hydrate in a stoichometric ratio of 4:4:1 and a sodium salt of Gabapentin hydrate in a stoichometric ratio of 2: 1.
  • US 4,960,931 discloses a method for converting the hydrochloride salt into a crystalline monohydrate by eluting the aqueous solution through a basic ion-exchange resin, producing a slurry from the elute, adding an alcohol to the slurry and isolating the final product by centrifuging followed by drying.
  • Our co-pending Indian Patent Application No 330/M AS/2003 discloses a method for the conversion of Gabapentin acid addition salts into Gabapentin Form-II directly by neutralization with base in a solvent at specified temperatures.
  • PCT Publication WO 98 / 28,255 discloses a method for the preparation of
  • Gabapentin Form-Ill from Gabapentin hydrochloride.
  • the process involves the dissolution of Gabapentin hydrochloride salt in an organic solvent (Iso-propyl alcohol) by mixing at 25 0 C for 30 min. followed by the addition of carbon, subjected to mixing for 2 hrs, followed by removal of inorganics by filtration.
  • the solvent is then removed from the filtrate to obtain the solid so obtained is dried in vacuum at temperature not to exceed 35 0 C.
  • the dried residue is then treated with a second solvent and a base, rnixed for 2hrs at 25 0 C followed by filtration and drying yielding Gabapentin Form-Ill.
  • Form-Ill is converted to Form-II either by suspending Form-Ill in methanol at 25 0 C for about 14 hrs followed by filtration and drying under vacuum at 35 0 C or by suspending the humid cake of Form-Ill in methanol, refluxing followed by cooling to 34 0 C 5 '
  • Crystallization is induced by seeding with pure Form-II for 60 min. followed by cooled to
  • Another object of the invention is to provide an elegant process for the preparation of Gabapentin Form-II from the Gabapentin hydrochloride via Gabapentin Form-Ill.
  • Yet another object of the invention is to provide an elegant process for the preparation of Gabapentin Form-II from the Gabapentin hemisulphate hemihydrate via Gabapentin Form-Ill.
  • 1,1-Cyclohexane diacetic acid monoamide is reacted with alkali hypo halite followed by acidification with acids in presence of an organic solvent to extract the liberated acid salts into that solvent followed by the addition of an ante solvent to crystallize the Gabapentin acid salts.
  • the separated salts is then suspending in organic solvent(s) and pH is adjusted with base(s) in a specified temperature range, cooled to ambient temperature, followed by separation of Gabapentin Form-Ill which is further converted into Gabapentin Form-II by slurrying in ethanol at specified temperature.
  • the process according to the present invention comprise steps:
  • XRD and IR is used to characterize the products of the process.
  • 1,1-cyclohexane diacetic acid mono amide used as starting material is prepared as per the literature (US Patent No. US 4,024,175).
  • the reaction mass is allowed to settle and the organic layer is separated.
  • the aqueous layer is extracted few times with the organic solvent.
  • the combined extracts is dried over dehydrating agents and the dried organic layer is diluted with ante solvent(s) selected from hydrocarbons, aromatic hydrocarbons, alkyl ketones, alkyl ethers, etc.
  • the preferred solvent is hexane, toluene, acetone, di isopropyl ether or their mixtures.
  • the reaction mass is cooled to precipitate the acid addition salt(s).
  • the precipitated Gabapentin acid addition salt(s) is separated and dried to constant weight.
  • Gabapentin acid addition salt(s) is dissolved in short chain alcohols, preferred alcohol being ethanol, n-propanol, iso propanol, and n-butanol at 20 0 C to 50 0 C.
  • the solution is stirred to get a clear solution. Insolubles if any are filtered off and pH adjustment of the filtrate is done with base(s).
  • the preferred bases are triethyl amine, di isopropyl ethylamine, etc.
  • the precipitated Gabapentin Form-Ill is separated wash the solvent of the reaction medium, dried in a preferred temperature range of 45 0 C - 50 0 C.
  • the Gabapentin Form-Ill is further converted into Form-II by suspending Form- III in alcohol, raising the temperature to 60 0 C - 75 0 C, maintaining the system at this temperature for 1 to 6 hrs, followed by gradual cooling and stirring for 1 - 2 hrs at temperature 20 0 C - 25 0 C.
  • the product is separated and dried to obtain Gabapentin Form-II of pharmaceutically acceptable quality.
  • Sodium hydroxide (51 g) is dissolved in sodium hypochlorite solution (6.25%, 625 G) and cooled to 10 0 C. The solution is stirred for 10 - 15 min, and further cooled to -5 0 C.
  • 1,1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15 0 C - 20 0 C. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5 0 C to -3 0 C. The solution is then maintained at about O 0 C for 2 hrs.
  • the temperature is gradually raised over 3 hrs to 20 0 C - 25 0 C and then maintained at this temperature for 4 hrs.
  • Sodium meta bisulphite solution (5 g in 10 ml water) is then added to the solution.
  • the reaction mass is filtered remove any un-dissolved material. pH of the filtrate is adjusted to around 9.0 by the addition of hydrochloric acid at temperature 20 0 C - 25 0 C.
  • n-Butanol (200 ml) is added arid the pH is further adjusted to 1.5 with hydrochloric acid and stirred for 10 - 15 min.
  • the reaction mass is allowed to settle with separation of the layers.
  • the aq. Layer is extracted with n- Butanol (200 ml).
  • the dry wt of the hydrochloride salt is 80.0 g (Yield: 75.0%)
  • the Gabapentin hydrochloride salt (100 g) prepared in stage- 1 is suspended in n-propanol (1000 ml) and stirred for 20 min at room temp. Filtered the mass to remove insolubles if any. The filtrate is slowly heated to 35 0 C - 40 0 C and pH is adjusted to 7.2 by slow addition of di isopropyl ethylamine solution (180 ml in 180 ml of n-propanol) at 35 - 40 0 C over 40 min. The reaction mass is gradually cooled to 20 0 C - 25 0 C over 30 min. The product is filtered, washed with n-propanol (50 ml) and dried at 45 0 C - 50 0 C to constant weight.
  • Stage -3 Preparation of Gabapentin Form-II from Gabapentin Form-Ill.
  • Gabapentin Form-Ill (40 g) prepared in stage - 2, is suspended in ethanol (280 ml) and the temperature is raised to 70 0 C and maintained for 90 min. at 70 0 C - 75 0 C. The reaction mass is gradually cooled to room temperature and stirred for 30min. The product is filtered, washed with ethanol (20 ml) and dried at 50 0 C - 55 0 C to constant weight.
  • Sodium hypochlorite solution (6.25%, 625 g) is cooled to 10 0 C and sodium hydroxide flakes (51 g) is dissolved in it by stirring for 10 - 15 min. at 10 0 C - 15 0 C. The mass is further cooled to -5 0 C.
  • 1-cyclohexane diacetic acid monoamide (10Og) is dissolved in 4N sodium hydroxide solution (150 ml) at 15 0 C - 20 0 C. The amide solution is slowly added to sodium hypochlorite solution at temperature -5 0 C to -3 0 C over 3hrs and then maintained at about O 0 C for 2 hrs.
  • the temperature is slowly raised to 20 0 C - 25 0 C over 3 hrs and maintained for 4 hrs at 20 0 C - 25 0 C.
  • Sodium metabisulphite solution (5 g in 10 ml water) is then added.
  • the reaction mass is filtered to remove any undissolved material. pH of the filtrate is adjusted to 9.0 by the addition of 1:1 dilute sulphuric acid at temperature 20 0 C - 25 0 C.
  • n-Butanol (200 ml) is added and the pH id further adjusted to 1.5 with dilute sulphuric acid.
  • the reaction mass is stirred for 10 - 15 min. and then allowed to settle. The layers are separated. The aqueous layer is extracted with n-Butanol (200 ml).
  • the combined extract is dried over anhydrous sodium sulphate (15 g ).
  • Di isopropyl ether (1200 ml) is slowly added at room temperature over 30 - 45 min to the dried extracted layer.
  • the reaction mass is stirred for 1 hr and then cooled to 5 0 C and stirred for 1 hr at about O 0 C - 5 0 C.
  • the product is filtered, washed with di isopropyl ether (50 ml) and dried at 45 0 C - 50 0 C to constant weight.
  • the Gabapentin hemisulphate hemihydrate salt (100 g ) in stage- 1 is suspended in ethanol (700 ml) and stirred for 30 min. at room temperature.
  • the insolubles is filtered and washed with ethanol (50 ml).
  • the filtrate is heated to 40 0 C - 45 0 C and the pH of the filtrate is adjusted to 7.3 by slow addition of di isopropyl ethylamine solution (135 ml in 145 ml ethanol) at 40 0 C - 45 0 C over 20 min.
  • the reaction mass is then immediately cooled to 20 0 C . - 25 0 C over 30 min.
  • the filtered product is washed with ethanol (50 ml) and dried at 45 0 C - 50 0 C to constant weight.
  • Stage -3 Preparation of Gabapentin Form-II from Gabapentin Form-Ill.
  • the Gabapentin Form-Ill (40 g) prepared is suspended in ethanol (240 ml) and the temperature is raised to 65 0 C and maintained for 60 min. between 65 0 C - 70 0 C. The mass is cooled to room temperature and stirred for 30min. at room temperature. The filtered product is washed with ethanol (25 ml) and dried at 50 0 C - 55 0 C to constant weight.
  • the dry weight of the Gabapentin Form-II is 35 g corresponding to 87.5% yield.

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

Abstract

L'invention concerne un nouveau procédé applicable à l'échelle industrielle permettant la préparation de Gabapentine forme III, qui consiste à faire réagir une monoamine 1,1-cyclohexane acide diacétique avec un hypohalite d'alcali, puis à procéder à une acidification par des acides en présence d'un solvant organique, à extraire le sel d'acide libéré dans ce solvant, puis à ajouter un second solvant pour cristalliser les sels d'acide de Gabapentine. Le sel séparé est ensuite mis en suspension dans le(s) solvant(s) organique(s) et son pH est ajusté au moyen d'une ou de plusieurs bases dans une plage de température déterminée, après quoi il est refroidi à température ambiante, cette étape étant suivie d'une séparation de la Gabapentine de forme III, laquelle subit ensuite une nouvelle conversion en Gabapentine de forme II par mise en suspension dans de l'éthanol à une température déterminée.
PCT/IN2004/000103 2003-06-12 2004-04-16 Procede permettant la preparation de gabapentine de forme ii Ceased WO2004110981A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN481/MAS/2003 2003-06-12
IN481MA2003 2003-06-12

Publications (1)

Publication Number Publication Date
WO2004110981A1 true WO2004110981A1 (fr) 2004-12-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092837A3 (fr) * 2004-03-25 2005-12-22 Zambon Spa Procede de preparation de la gabapentine
WO2006002972A1 (fr) * 2004-07-05 2006-01-12 Sandoz Ag Methode servant a preparer gabapentine
CN112321442A (zh) * 2020-11-06 2021-02-05 中国药科大学 加巴喷丁与2，6-吡啶二羧酸的盐及其制备方法与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028255A1 (fr) * 1996-12-24 1998-07-02 Teva Pharmaceutical Industries Ltd. Preparation de gabapentine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028255A1 (fr) * 1996-12-24 1998-07-02 Teva Pharmaceutical Industries Ltd. Preparation de gabapentine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092837A3 (fr) * 2004-03-25 2005-12-22 Zambon Spa Procede de preparation de la gabapentine
US7417166B2 (en) 2004-03-25 2008-08-26 Zach System S.P.A. Process for the preparation of gabapentin
WO2006002972A1 (fr) * 2004-07-05 2006-01-12 Sandoz Ag Methode servant a preparer gabapentine
CN112321442A (zh) * 2020-11-06 2021-02-05 中国药科大学 加巴喷丁与2，6-吡啶二羧酸的盐及其制备方法与应用

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