WO2003070683A1 - Preparation de nouveaux sels mineraux d'addition acides de gabapentine - Google Patents

Preparation de nouveaux sels mineraux d'addition acides de gabapentine Download PDF

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Publication number
WO2003070683A1
WO2003070683A1 PCT/IN2002/000029 IN0200029W WO03070683A1 WO 2003070683 A1 WO2003070683 A1 WO 2003070683A1 IN 0200029 W IN0200029 W IN 0200029W WO 03070683 A1 WO03070683 A1 WO 03070683A1
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WO
WIPO (PCT)
Prior art keywords
gabapentin
alcohol
solvent
acid addition
mineral acid
Prior art date
Application number
PCT/IN2002/000029
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English (en)
Inventor
Tangirala Venkata Subramanya Krishna Vittal
Shabbir Ali Taj
Armugam Kodimuthali
Kasturaiah Maddali
Original Assignee
Shasun Chemicals And Drugs 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 Shasun Chemicals And Drugs Limited filed Critical Shasun Chemicals And Drugs Limited
Priority to AU2002246303A priority Critical patent/AU2002246303A1/en
Priority to PCT/IN2002/000029 priority patent/WO2003070683A1/fr
Publication of WO2003070683A1 publication Critical patent/WO2003070683A1/fr

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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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a process for preparing mineral acid addition salts of Gabapentin.
  • This invention also relates to a process for converting mineral acid addition salts of Gabapentin to anhydrous Gabapentin form II directly.
  • Gabapentin is l -(amino methyl)- 1 -cyclohexane acetic acid having the chemical structure is a known drug which was described first time by Warner- Lambert Co. in US patent no. 4,024,175 in 1977 (The Merck Index. 12 lh edition, 1996 )
  • Gabapentin is used in the treatment of cerebral diseases such as epilepsy, hypokinesia, cranial trachmas and the like.
  • Gabapentin (Neurontin.RTM.) is a structural analogue of .gamma.-aminobutyric acid (GABA), the major inhibitory neurotransmitter in mammalian brain.
  • GABA .gamma.-aminobutyric acid
  • GABA .gamma.-aminobutyric acid
  • U.S. Patent No. 4,024,175 described at least three methods of preparing Gabapentin from Cyclohexane diacetic acid mono amide through, Hoffmann, Curtius and the Lossen rearrangements.
  • the product that is isolated in these methods is Gabapentin HCl salt, which on treatment with base ion exchanger liberates the free Gabapentin.
  • U.S. Patent No. 4,894,476 specially discloses an improved method of converting Gabapentin HCl to the Gabapentin.
  • This method involves the treatment of aqueous solution of Gabapentin HCl with base ion exchange resin to afford Gabapentin monohydrate. which on further treatment with methanol and isopropyl alcohol mixture affords the anhydrous Gabapentin.
  • U.S. Patent No. 6,255,526 Bl discloses the preparation of Gabapentin HCl whicK is substantially free from the inorganic salts and the treatment of the pure Gabapentin HCl with bases like triethyl amine, tributyl amine in a solvent in which the hydrochloride of the corresponding bases are soluble but the Gabapentin is insoluble. This process liberates the crystalline polymorph of Gabapentin form III and the conversion of Gabapentin form HI to form II is accomplished by the literature methods known in the art.
  • the object of the present invention to provide a process for the preparation of new mineral acid addition salts of Gabapentin starting from cyclohexane diacetic acid monoamide, which are substantially free from the Gabapentin lactam.
  • novel mineral acid addition salt of Gabapentin are useful intermediates for the synthesis of anhydrous Gabapentin form II
  • the present invention relates a novel mineral acid addition salt of Gabapentin of general formula
  • the novel mineral acid addition salt of Gabapentin is Gabapentin hydrogen sulphate of formula I and Gabapentin dihydrogen phosphate of formula II.
  • This invention also relates to a process for preparing mineral acid addition salts of Gabapentin comprising: -
  • step (a) cyclohexane diacetic acid monoamide is reacted with sodium hypobromite at a temperature between about -10 ° C to 0 ° C, warmed to 60 0 C and thereafter cooled to ambient temperature immediately.
  • the reaction mass is cooled to 15- 20 °C.
  • the mineral acid includes concentrated sulfuric acid, phosphoric acid and nitric acid.
  • the said aliphatic hydrocarbon solvent containing carbonyl group is preferably a keto group having a specific gravity less than that of water and includes acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone preferably methyl ethyl ketone.
  • Step (d) comprises evaporating the said solvent under reduced pressure at temperature between about 30°-60°C, preferably between 40°-50°C, most preferably 40°C.
  • the said alcohol solvent includes primary, secondary and tertiary alcohol and is selected from methanol, ethanol, n-propanol, n-butanol, isopropyl alcohol, secondary butyl alcohol, tertiary butyl alcohol, preferably from methanol, isopropyl alcohol or ethanol, and most preferably from isopropyl alcohol.
  • the said non-polar organic solvent is selected from low boiling aromatic hydrocarbon, halogenated solvents and lower alkyl esters of acetic acid.
  • the said low boiling aromatic hydrocarbon includes benzene and toluene preferably toluene.
  • the said halogenated solvents includes dichloromethane, chloroform, ethylene dichloride, trichloro ethylene.
  • the said lower alkyl ester includes methyl acetate or ethyl acetate.
  • the said mineral acid addition salt of Gabapentin is converted to anhydrous Gabapentin form II by neutralization reaction.
  • Said neutralization reaction comprises: (a) dissolving said acid addition salt of Gabapentin in alcohol solvent and
  • the neutralization reaction is carried out at a temperature between 10 °C - 60 °C for about 6- 48 hours preferably 25 -30 °C for 12-24 hours.
  • Said alcohol solvent are polar protic solvents such as primary, secondary or tertiary alcohol or mixtures thereof.
  • Said alcohol solvent includes methanol, ethanol, isopropanol, n-proponal, n-butanol and t-butanol or mixtures thereof, preferably a mixture of isopropanol and methanol.
  • the ratio in which isopropanol is diluted with methanol is 1 : 1 to 4: 1 by volume preferably 1 : 1 to 2:1.
  • the said organic base is an amine.
  • Said amines include tr ⁇ nemylamine, friemylamine, tributylamine, fripropylamine, frmexylamine, preferably triethyl amine.
  • Cyclohexane diacetic acid monoamide is treated with sodium hypobromite solution at -10°C to 0°C and is allowed to warm to 60°C.
  • the reaction mass is cooled immediately without further maintenance to ambient temperature preferably at 15-20°C. hi this way the Gabapentin lactam formation is suppressed quantitatively.
  • the reaction mass is acidified with mineral acids to pH 2.
  • the mineral acids include the concentrated Sulphuric acid; Phosphoric acid, HN0 3 , H 2 P0 3 etc.,
  • the acid addition salt that is present in the aqueous layer is extracted with aliphatic hydrocarbon solvents containing the carbonyl group preferably the keto group wherein the specific gravity of the solvents is less than water.
  • the solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone etc.,
  • the solvent after the extraction from the aqueous layer is evaporated under reduced pressure at temperatures in the range of 30°C-60°C preferably at 40°C -50°C to complete dryness.
  • the crude product thus obtained was redissolved in an alcohol solvent wherein the mineral acid addition salts are highly soluble, for example the primary, secondary, tertiary alcohols that includes methanol, ethanol, n-propanol, n-butanol, isopropyl alcohol, secondary butyl alcohol, tertiary butyl alcohol etc.;
  • the preferred solvents include methanol, ethanol or isopropyl alcohol.
  • the solution is maintained at -5°C to 40°C preferably at 10°C-20°C and the undissolved material is filtered completely.
  • the alcohol mother liquor that is obtained after the filtration is evaporated under reduced pressure to dryness at temperatures from 30°C to 70°C preferably at 35°C-40°C to afford a syrupy residue.
  • the residue is slurried to get the product in non polar organic solvents preferably the low boiling aromatic hydrocarbon, halogenated solvents and the lower alkyl esters of acetic acid.
  • the low boiling aromatic hydrocarbons include benzene, toluene etc.
  • the halogenated solvents include dichloromethane, chloroform, ethylene dichloride, trichloro ethylene etc.
  • the lower alkyl esters of acetic acid includes methyl acetate, ethyl acetate etc:,
  • the acid addition salt that is obtained is substantially free from all the inorganic salts and can be taken up for the neutralisation to liberate the anhydrous Gabapentin Form II.
  • the neutralisation of acid addition salt of Gabapentin can be accomplished by neutralising the salt with organic bases particularly the amines.
  • the amines include frime ylamine, triemylamine, tributylamine, tripropylamine, trihexylamine etc.
  • the preferred solvents for neutralisation are polar protic solvents preferably the alcohol solvents for example the primary, secondary, tertiary alcohol wherein the mineral acid addition salts of the Gabapentin are freely soluble at ambient temperatures.
  • the neutralisation is accomplished with mixture of alcohol solvents wherein the Gabapentin Form II is liberated directly from the reaction.
  • the mixture of alcohol solvents that are used for neutralisation in which the acid addition salts are freely soluble includes methanol, ethanol, isopropanol, n-proponal, n-butanol and t-butanol etc.,
  • the acid addition salt of Gabapentin is dissolved in an alcohol solvent, for example in isopropanol, n-proponal, n-butanol, isobutanol, t- butanol etc., Preferably in isopropanol and is diluted with methanol.
  • the dilution ratio of isopropanol to methanol that used for the reaction varies from 1:1 to 4:1 by volume preferably in the range of 1:1 to 2:1 and the temperature of the reaction varies from 10°C-60°C. Preferably in the range of 25°C-30°C.
  • the time that is required for the complete conversion of Gabapentin acid addition salt to Gabapentin form II is around 6-48 hours preferably the time required is 12-24 hours.
  • the product that is precipitated from the reaction mass is filtered, dried and the dried product is pure enough which does not require any further purification.
  • the product meets all the specification of Anhydrous Gabapentin Form II.
  • the reaction mass is acidified with Phosphoric acid (300 ml) to pH 2 and the reaction mass is diluted with methyl ethyl ketone (600 ml).
  • the organic layer is separated and the aqueous layer is again extracted with methyl ethyl ketone (2x300 ml).
  • the combined organic layers are concentrated under reduced pressure at 40°C to the complete dryness.
  • the thick syrupy residue obtained is diluted with isopropyl alcohol (11) and the solution is cooled to 10°C under stirring.
  • the undissolved material is filtered over celite and concentrated under reduced pressure at below 30°C.
  • the syrupy residue is slurried in toluene, filtered, and dried to afford Gabapentin dihydrogen phosphate in 90% yield.
  • Gabapentin Hydrogen Sulphate 250 g was dissolved in 1 litre of Isopropyl alcohol in 3 litre flask and is diluted with methanol (500ml) at room temperature Tri ethyl amine (135.4 ml) was added very slowly at room temperature and the reaction mixture was maintained at room temperature for 24 hours. The precipitated product is filtered, dried to afford Gabapentin form ⁇ in 80% yield.
  • Gabapentin dihydrogen phosphate 250 g was dissolved in 1 litre of Isopropyl alcohol in 3 litre flask and is diluted with methanol (500ml) at room temperature Tri ethyl amine (135.4 ml) was added very slowly at room temperature and the reaction mixture was maintained at room temperature for 24 hours. The precipitated product is filtered, dried to afford Gabapentin form II in 60% yield.

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

Abstract

L'invention porte sur un procédé de préparation de nouveaux sels minéraux d'addition acides de Gabapentine, et sur un nouveau procédé de conversion directe des sels minéraux d'addition acides de Gabapentine en Gabapentine de forme II.
PCT/IN2002/000029 2002-02-22 2002-02-22 Preparation de nouveaux sels mineraux d'addition acides de gabapentine WO2003070683A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002246303A AU2002246303A1 (en) 2002-02-22 2002-02-22 Preparation of new mineral acid addition salts of gabapentin
PCT/IN2002/000029 WO2003070683A1 (fr) 2002-02-22 2002-02-22 Preparation de nouveaux sels mineraux d'addition acides de gabapentine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2002/000029 WO2003070683A1 (fr) 2002-02-22 2002-02-22 Preparation de nouveaux sels mineraux d'addition acides de gabapentine

Publications (1)

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WO2003070683A1 true WO2003070683A1 (fr) 2003-08-28

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WO (1) WO2003070683A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006002972A1 (fr) * 2004-07-05 2006-01-12 Sandoz Ag Methode servant a preparer gabapentine
US7071356B1 (en) 2005-12-01 2006-07-04 Isp Investments Inc. Process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid
US7098362B2 (en) 2004-07-20 2006-08-29 Sandoz Ag Processes for the preparation of gabapentin
WO2006090208A1 (fr) * 2005-02-28 2006-08-31 Medichem S.A. Procede et methodes de preparation de gabapentine et de produits intermediaires du gabapentine
JP2007530504A (ja) * 2004-03-25 2007-11-01 ザンボン　グループ　エス．ピー．エー． ガバペンチンの調製方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5319135A (en) * 1989-08-25 1994-06-07 Warner-Lambert Company Process for cyclic amino acid anticonvulsant compounds
US6255526B1 (en) * 1996-12-24 2001-07-03 Teva Pharmaceutical Industries Ltd. Preparation of gabapentin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5319135A (en) * 1989-08-25 1994-06-07 Warner-Lambert Company Process for cyclic amino acid anticonvulsant compounds
US6255526B1 (en) * 1996-12-24 2001-07-03 Teva Pharmaceutical Industries Ltd. Preparation of gabapentin

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007530504A (ja) * 2004-03-25 2007-11-01 ザンボン　グループ　エス．ピー．エー． ガバペンチンの調製方法
US7417166B2 (en) 2004-03-25 2008-08-26 Zach System S.P.A. Process for the preparation of gabapentin
JP4801043B2 (ja) * 2004-03-25 2011-10-26 ザンボン グループ エス．ピー．エー． ガバペンチンの調製方法
WO2006002972A1 (fr) * 2004-07-05 2006-01-12 Sandoz Ag Methode servant a preparer gabapentine
US7098362B2 (en) 2004-07-20 2006-08-29 Sandoz Ag Processes for the preparation of gabapentin
WO2006090208A1 (fr) * 2005-02-28 2006-08-31 Medichem S.A. Procede et methodes de preparation de gabapentine et de produits intermediaires du gabapentine
US7071356B1 (en) 2005-12-01 2006-07-04 Isp Investments Inc. Process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid

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Publication number Publication date
AU2002246303A1 (en) 2003-09-09

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