WO2000001660A1 - Process for the preparation of gabapentin - Google Patents

Process for the preparation of gabapentin Download PDF

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Publication number
WO2000001660A1
WO2000001660A1 PCT/EP1999/004289 EP9904289W WO0001660A1 WO 2000001660 A1 WO2000001660 A1 WO 2000001660A1 EP 9904289 W EP9904289 W EP 9904289W WO 0001660 A1 WO0001660 A1 WO 0001660A1
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WO
WIPO (PCT)
Prior art keywords
gabapentin
process according
weight
methoxyethanol
amount
Prior art date
Application number
PCT/EP1999/004289
Other languages
French (fr)
Inventor
Maurizio Paiocchi
Katiuscia Arrighi
Laura Russo
Marco Villa
Original Assignee
Zambon Group S.P.A.
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 Zambon Group S.P.A. filed Critical Zambon Group S.P.A.
Priority to EP99931121A priority Critical patent/EP1095010A1/en
Publication of WO2000001660A1 publication Critical patent/WO2000001660A1/en

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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
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • 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 the preparation of gabapentin and, more particularly, it relates to a process for the preparation of gabapentin in _ anhydrous form by treating an aqueous suspension of gabapentin with 2- methoxyethanol or 2-ethoxyethanol and crystallising with an alcoholic solvent.
  • Gabapentin, 1-(aminomethyl)cyclohexanacetic acid (The Merck Index, XII ed., page 733, no. 4343), is a known drug with anti-epileptic activity described for the first time by Warner-Lambert Co. in the US patent 4,024,175.
  • monohydrate gabapentin is particularly troublesome because it foresees, after the usual treatment of an aqueous solution of a gabapentin salt through a weak basic ionic exchange resin, the partial evaporation of water from the aqueous gabapentin solution eluted from the resin, the addition of an alcoholic solvent and the crystallisation.
  • the resultant pure monohydrate gabapentin is then dissolved in warm methanol, diluted with isopropanol and crystallised obtaining anhydrous gabapentin with a content of methanol and of isopropanol equal to 100 ppm respectively.
  • object of the present invention is a process for the preparation of pure gabapentin in anhydrous form comprising (a) the addition of 2-methoxyethanol or of 2-ethoxyethanol to an aqueous gabapentin suspension, (b) the removal of water by azeotropic distillation up to obtain a suspension still containing 20-30% by weight of water with respect to gabapentin, (c) the dilution with an alcoholic solvent and the cooling to a temperature from -10°C to +10°C and (d) the filtration and the drying of the crystallised of gabapentin
  • the anhydrous gabapentin obtained with the process object of the present invention is characterised by a high purity degree and by a total content of residual solvents lower than 100 ppm
  • 2-methoxyethanol is used
  • the amount of 2-methoxyethanol or of 2-ethoxyethanol that is added is not a critical parameter but it will obviously depend on the amount of water present in the aqueous gabapentin suspension to be treated Generally the aqueous suspension which 2-methoxyethanol or 2-ethoxyethanol is added has a gabapentin concentration from 30% to 40% (w/w)
  • the amount of 2-methoxyethanol or of 2- ethoxyethanol must allow the removal of water by azeotropic distillation up to a residual amount equal to 20%-30% by weight with respect to gabapentin according to what foreseen in step (b) of the process
  • step (b) the gabapentin suspension is heated under reduced pressure by distilling the water/2-methoxyethanol or 2-ethoxyethanol mixture Preferably a temperature from 40°C to 50°C and a pressure from 50 to 80 mmHg are used
  • step (c) the suspension is diluted with an alcoholic solvent
  • the amount of alcoholic solvent is generally from 4 to 10 times by weight with respect to gabapentin, preferably from 4 to 6 times by weight
  • alcoholic solvents are linear or branched C C 4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert- butanol and mixtures thereof Isopropanol is preferably used After optional heating to a temperature from 50°C to 70°C, the mixture is cooled to a temperature from -10°C to +10°C, preferably from -5°C to 0°C
  • the subsequent step (d) foresees the filtration and the drying of the crystallised according to conventional techniques so allowing to obtain gabapentin in pure _ anhydrous form (HPLC t ⁇ tre>99 5%) and with a content of residual solvents (alcoholic solvent + 2-methoxyethanol or 2-ethoxyethanol) lower than 100 ppm
  • the aqueous gabapentin suspension used as starting product in the process object of the present invention is generally an aqueous suspension obtained after elution from a weak basic ionic exchange resin, according to one of the methods described in the literature, and concentration
  • a further object of the present invention is a process for the preparation of pure gabapentin in anhydrous form comprising the preparation of an aqueous gabapentin solution by eluting a gabapentin salt solution through a Relite EXA10 resin, the concentration up to obtain an aqueous gabapentin suspension at 30%- 40% by weight and the subsequent treatment according to what foreseen in the already reported steps (a), (b), (c) and (d)
  • Gabapentin hydrochlonde can be prepared according to one of the methods described in the literature
  • the process object of the present invention has the advantage to avoid the complete removal of water and to be reproducible at industrial level because during the concentration phase, the mass can be aiways easily stirred
  • the used amount of solvent is reduced (high productivity) and the product is obtained in anhydrous form with yields higher than 90%, even in the presence of amounts of water higher than 30% w/w with respect to gabapentin
  • the content of residual solvents is extremely low, generally lower than 100 ppm, notwithstanding gabapentin monohydrate is not used
  • Example 1 Water (130 g), gabapentin hydrochlonde (40 g, HPLC titre 94%), prepared according to the process described in US 4,024,175, and charcoal L4S (1 0 g) were charged into a 250 ml reactor at room temperature After keeping under stirring for 15 minutes, the mixture was filtered through a cehte.
  • Example 2 2-Methoxyethanol (200 ml) and gabapentin hydrochlonde (100 g, HPLC titre 92%) were charged into a 0 5 I reactor, equipped with mechanic stirring, condenser and thermometer, kept under inert atmosphere

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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)
  • Pyridine Compounds (AREA)

Abstract

A process for the preparation of pure gabapentin in anhydrous form by treating an aqueous suspension of gabapentin with 2-methoxyethanol or 2-ethoxyethanol and crystallising with an alcoholic solvent is described.

Description

"Process for the preparation of gabapentin"
*********************************
The present invention relates to a process for the preparation of gabapentin and, more particularly, it relates to a process for the preparation of gabapentin in _ anhydrous form by treating an aqueous suspension of gabapentin with 2- methoxyethanol or 2-ethoxyethanol and crystallising with an alcoholic solvent. Gabapentin, 1-(aminomethyl)cyclohexanacetic acid (The Merck Index, XII ed., page 733, no. 4343), is a known drug with anti-epileptic activity described for the first time by Warner-Lambert Co. in the US patent 4,024,175.
In the literature several processes for the preparation of gabapentin in anhydrous form are reported (see for example the patents US 4,024,175, US 5,068,413 and US 5,091,567). Substantially all these methods foresee a final step for the purification of gabapentin which consists in the treatment of an aqueous solution of a gabapentin salt (generally hydrochloride) through a weak basic ionic exchange resin, the complete evaporation of water from the aqueous gabapentin solution eluted from the resin and the crystallisation from an alcoholic solvent, generally methanol or methanol/isopropanol mixtures. The complete evaporation of water, described in the above-cited patents, is an expensive and difficult operation with little reproducibility at industrial level, because the product precipitates on the reactor walls and therefore the mixture cannot be stirred. Furthermore, the yield of the subsequent crystallisation depends on the amount of water remained in the product. In the US patent 4,894,476 is underlined that a further problem related to the known methods for the preparation of gabapentin is the amount of residual solvent contained in the product (column 1 , lines 56-59). The same patent describes, as a solution of the problem of the residual solvents, a process for the preparation of anhydrous gabapentin on a large scale that uses monohydrate gabapentin as starting material. However, the preparation of monohydrate gabapentin is particularly troublesome because it foresees, after the usual treatment of an aqueous solution of a gabapentin salt through a weak basic ionic exchange resin, the partial evaporation of water from the aqueous gabapentin solution eluted from the resin, the addition of an alcoholic solvent and the crystallisation. The resultant pure monohydrate gabapentin is then dissolved in warm methanol, diluted with isopropanol and crystallised obtaining anhydrous gabapentin with a content of methanol and of isopropanol equal to 100 ppm respectively. We have now found a method for the preparation of anhydrous gabapentin that allows to obtain the product with a high purity degree and with a low content of residual solvents without using monohydrate gabapentin Therefore, object of the present invention is a process for the preparation of pure gabapentin in anhydrous form comprising (a) the addition of 2-methoxyethanol or of 2-ethoxyethanol to an aqueous gabapentin suspension, (b) the removal of water by azeotropic distillation up to obtain a suspension still containing 20-30% by weight of water with respect to gabapentin, (c) the dilution with an alcoholic solvent and the cooling to a temperature from -10°C to +10°C and (d) the filtration and the drying of the crystallised of gabapentin
The anhydrous gabapentin obtained with the process object of the present invention is characterised by a high purity degree and by a total content of residual solvents lower than 100 ppm Preferably in step (a) of the process 2-methoxyethanol is used
The amount of 2-methoxyethanol or of 2-ethoxyethanol that is added is not a critical parameter but it will obviously depend on the amount of water present in the aqueous gabapentin suspension to be treated Generally the aqueous suspension which 2-methoxyethanol or 2-ethoxyethanol is added has a gabapentin concentration from 30% to 40% (w/w) The amount of 2-methoxyethanol or of 2- ethoxyethanol must allow the removal of water by azeotropic distillation up to a residual amount equal to 20%-30% by weight with respect to gabapentin according to what foreseen in step (b) of the process Preferably an amount of 2-mehoxyethanol or 2-ethoxyethanol corresponding to 2-5 times the amount by weight of gabapentin, still more preferably corresponding to 2-3 times by weight, is used
In step (b) the gabapentin suspension is heated under reduced pressure by distilling the water/2-methoxyethanol or 2-ethoxyethanol mixture Preferably a temperature from 40°C to 50°C and a pressure from 50 to 80 mmHg are used In the subsequent step (c), the suspension is diluted with an alcoholic solvent
The amount of alcoholic solvent is generally from 4 to 10 times by weight with respect to gabapentin, preferably from 4 to 6 times by weight Examples of alcoholic solvents are linear or branched C C4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert- butanol and mixtures thereof Isopropanol is preferably used After optional heating to a temperature from 50°C to 70°C, the mixture is cooled to a temperature from -10°C to +10°C, preferably from -5°C to 0°C
The subsequent step (d) foresees the filtration and the drying of the crystallised according to conventional techniques so allowing to obtain gabapentin in pure _ anhydrous form (HPLC tιtre>99 5%) and with a content of residual solvents (alcoholic solvent + 2-methoxyethanol or 2-ethoxyethanol) lower than 100 ppm The aqueous gabapentin suspension used as starting product in the process object of the present invention is generally an aqueous suspension obtained after elution from a weak basic ionic exchange resin, according to one of the methods described in the literature, and concentration
Preferably the aqueous gabapentin suspension used as starting product comes from the elution of a gabapentin hydrochlonde solution through a Relite EXA10 resin The aqueous solution obtained after crossing through this resin results to be much more concentrated with respect to those obtained after crossing through the resins described in the literature, giving a significant industrial advantage Therefore a further object of the present invention is a process for the preparation of pure gabapentin in anhydrous form comprising the preparation of an aqueous gabapentin solution by eluting a gabapentin salt solution through a Relite EXA10 resin, the concentration up to obtain an aqueous gabapentin suspension at 30%- 40% by weight and the subsequent treatment according to what foreseen in the already reported steps (a), (b), (c) and (d)
Gabapentin hydrochlonde can be prepared according to one of the methods described in the literature The process object of the present invention has the advantage to avoid the complete removal of water and to be reproducible at industrial level because during the concentration phase, the mass can be aiways easily stirred The used amount of solvent is reduced (high productivity) and the product is obtained in anhydrous form with yields higher than 90%, even in the presence of amounts of water higher than 30% w/w with respect to gabapentin
The content of residual solvents is extremely low, generally lower than 100 ppm, notwithstanding gabapentin monohydrate is not used
In order to better illustrate the present invention the following examples are now given Example 1 Water (130 g), gabapentin hydrochlonde (40 g, HPLC titre 94%), prepared according to the process described in US 4,024,175, and charcoal L4S (1 0 g) were charged into a 250 ml reactor at room temperature After keeping under stirring for 15 minutes, the mixture was filtered through a cehte. panel and the panel was washed with water (5 g) The solution was pumped with a flux of 15 ml/minute in a column containing Relite EXA10 resin (115 ml) At the end of the addition of the solution, the elution of water in the column went on and the solution was collected following the BRIX index The resultant aqueous gabapentin solution (300 g, HPLC titre 10 06%) was concentrated under vacuum (25 mmHg/50°C) up to obtain a stirrable mixture (still containing 46 g of water)
2-Methoxyethanol (80 ml) was added and a water/2-methoxyethanol mixture (50 50 w/w 76 g) was distilled under vacuum (40-45°C/60 mmHg) Isopropanol (180 ml) was added to the suspension and the mixture was heated at
60°C for 30 minutes
After cooling at 20°C in about 2 hours, the mixture was kept 2 hours at -5°C/-10°C
The precipitate was filtered and washed with isopropanol (2x10 ml)
After drying under vacuum at 50°C up to constant weight pure gabapentin (28 3 g) was obtained
HPLC tιtre=99 8%, K F =0 05%
Isopropanol < 30 ppm
2-methoxyethanoi < 70 ppm
Example 2 2-Methoxyethanol (200 ml) and gabapentin hydrochlonde (100 g, HPLC titre 92%) were charged into a 0 5 I reactor, equipped with mechanic stirring, condenser and thermometer, kept under inert atmosphere
The suspension was heated at internal 50-55°C for 30 minutes The insoluble (about
4 g) was filtered and the solution was concentrated under vacuum (external 50°C, 30 mmHg) distilling about 115 g of 2-methoxyethanol Water (250 ml) was added to the residue, kept warm
The mixture was kept under stirring up to obtain a solution
The solution, cooled and kept at room temperature, was pumped with a flux of 15 ml/minute into a column containing Relite EXA10 resin (300 ml) At the end of the addition of the solution, the elution of water in the column went on and the solution was collected following the BRIX index The resultant aqueous gabapentin solution (580 g, HPLC titre 12 7%) was heated at 45°C and then charcoal L4S (5 g) was added
The mixture was kept under stirring for 30 minutes and filtered through a celite panel that was washed with water (15 ml)
The aqueous solution was concentrated under vacuum (25 mmHg/50-55°C) up to obtain a stirrable mixture (weight of the distilled about 380 g) 2-Methoxyethanol (180 ml) was added and the mixture was concentrated at an internal temperature of 40°C at 60 mmHg (distilled about 180 ml of water/2-methoxyethanol=1/1) Isopropanol (400 ml) was added to the suspension and, after heating at 60°C, the mixture was kept at that temperature for 30-60 minutes and then was cooled in about 2 hours at 20°C and then at -5°C
After 2 hours at -5°C, the precipitate was filtered, washed with isopropanol (2x25 ml) and dried under vacuum at 50°C up to constant weight obtaining pure gabapentin (68 g) HPLC tιtre=100%, K F =0 05% residual solvent (isopropanol + 2-methoxyethanol) < 100 ppm

Claims

Claims 1) A process for the preparation of pure gabapentin in anhydrous form comprising (a) the addition of 2-methoxyethanol or of 2-ethoxyethanol to an aqueous gabapentin suspension, (b) the removal of water by azeotropic distillation up to - obtain a suspension still containing 20-30% by weight of water with respect to gabapentin, (c) the dilution with an alcoholic solvent and the cooling to a temperature from -10°C to +10°C and (d) the filtration and the drying of the crystallised of gabapentin 2) A process according to claim 1 wherein 2-methoxyethanol is used
3) A process according to claim 1 wherein an amount of 2-methoxyethanol or 2- ethoxyethanol corresponding to 2-5 times the amount by weight of gabapentin is used
4) A process according to claim 3 wherein the amount corresponds to 2-3 times by weight
5) A process according to claim 1 wherein step (b) is carried out at a temperature from 40°C to 50°C and at a pressure from 50 to 80 mmHg
6) A process according to claim 1 wherein the alcoholic solvent is a linear or branched C1-C4 alcohol selected among methanol, ethanol n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, terf-butanol and mixtures thereof
7) A process according to claim 1 wherein the amount of alcoholic solvent is from 4 to 10 times by weight with respect to gabapentin
8) A process according to claim 7 wherein the amount is from 4 to 6 times by weight
9) A process according to claim 6 wherein the solvent is isopropanol
10) A process according to claim 1 wherein, in step (c), the mixture is cooled at a temperature from -5°c to 0°C
11) A process according to claim 1 further comprising the preparation of an aqueous gabapentin solution by elution of a gabapentin salt solution through a Relite
EXA10 resin, the concentration up to obtain an aqueous gabapentin suspension at 30%-40% by weight
PCT/EP1999/004289 1998-07-03 1999-06-21 Process for the preparation of gabapentin WO2000001660A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP99931121A EP1095010A1 (en) 1998-07-03 1999-06-21 Process for the preparation of gabapentin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT98MI001535A ITMI981535A1 (en) 1998-07-03 1998-07-03 PROCESS FOR THE PREPARATION OF GABAPENTINA
ITMI98A001535 1998-07-03

Publications (1)

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WO2000001660A1 true WO2000001660A1 (en) 2000-01-13

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IT (1) ITMI981535A1 (en)
WO (1) WO2000001660A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064857A1 (en) * 1999-04-26 2000-11-02 Medichem S.A. Process for producing gabapentine of pharmaceutical grade
WO2003089403A1 (en) * 2002-04-16 2003-10-30 Taro Pharmaceutical Industries Ltd. Process for preparing gabapentin
WO2004113269A1 (en) * 2003-06-20 2004-12-29 Zambon Group Spa Process for the purification of gabapentin
US7098362B2 (en) 2004-07-20 2006-08-29 Sandoz Ag Processes for the preparation of gabapentin
US7439387B2 (en) 2003-04-21 2008-10-21 Matrix Laboratories Ltd. Process for the preparation of Gabapentin form-II
CN102363598A (en) * 2011-11-25 2012-02-29 浙江精进药业有限公司 Method for preparing high-purity gabapentin

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024175A (en) * 1974-12-21 1977-05-17 Warner-Lambert Company Cyclic amino acids
US4894476A (en) * 1988-05-02 1990-01-16 Warner-Lambert Company Gabapentin monohydrate and a process for producing the same
US5068413A (en) * 1989-08-25 1991-11-26 Godecke Aktiengesellschaft Process for the preparation of cyclic amino acids and intermediates useful in the process

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024175A (en) * 1974-12-21 1977-05-17 Warner-Lambert Company Cyclic amino acids
US4894476A (en) * 1988-05-02 1990-01-16 Warner-Lambert Company Gabapentin monohydrate and a process for producing the same
US5068413A (en) * 1989-08-25 1991-11-26 Godecke Aktiengesellschaft Process for the preparation of cyclic amino acids and intermediates useful in the process

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064857A1 (en) * 1999-04-26 2000-11-02 Medichem S.A. Process for producing gabapentine of pharmaceutical grade
WO2003089403A1 (en) * 2002-04-16 2003-10-30 Taro Pharmaceutical Industries Ltd. Process for preparing gabapentin
US7439387B2 (en) 2003-04-21 2008-10-21 Matrix Laboratories Ltd. Process for the preparation of Gabapentin form-II
WO2004113269A1 (en) * 2003-06-20 2004-12-29 Zambon Group Spa Process for the purification of gabapentin
US7393975B2 (en) 2003-06-20 2008-07-01 Zach System S.P.A. Process for the purification of gabapentin
US7098362B2 (en) 2004-07-20 2006-08-29 Sandoz Ag Processes for the preparation of gabapentin
CN102363598A (en) * 2011-11-25 2012-02-29 浙江精进药业有限公司 Method for preparing high-purity gabapentin

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Publication number Publication date
EP1095010A1 (en) 2001-05-02
ITMI981535A1 (en) 2000-01-03

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