WO2004093779A2

WO2004093779A2 - Process for the preparation of gabapentin form-ii

Info

Publication number: WO2004093779A2
Application number: PCT/IN2004/000101
Authority: WO
Inventors: Satyanarayana Chava; Seeta Ramanjaneyulu Gorantla; Venkata Sunil Kumar Indukuri; Srinivas Simhadri
Original assignee: Matrix Laboratories Ltd
Priority date: 2003-04-21
Filing date: 2004-04-16
Publication date: 2004-11-04
Also published as: WO2004093779A3

Abstract

The present invention relates to a new industrial feasible process for the preparation of Gabapentin Form-II by converting the Gabapentin hydrochloride salt directly into Form-II without the formation of Form-III by neutralizing the Gabapentin hydrochloride solution with a base at higher temperatures followed by cooling to yield Gabapentin Form-II with chloride ions less than 100 ppm with respect to Gabapentin.

Description

Process for the preparation of Gabapentin Form-II

The present invention relates to a new industrial feasible process for the preparation of

Gabapentin Form-II via the Gabapentin hydrochloride

Gabapentin, namely 1-aminomethyl-l-cyclohexaneacetic acid, is the active ingredient used

Gabapentin for the treatment of various cerebral diseases like epilepsy, hypokinesia including fainting and other brain trauma and in general, it is deemed to produce an improvement in the cerebral functions.

Gabapentin and several processes for its preparation as the Hydrochloride salt, sodium salts are disclosed in US Patent No's. US 4,024,175 and US 4,087,544.

All processes described in the prior art e.g. in US Patent Application No. US 2003/ 0009055, US 6,465,689, US 5,091,567, PCT publications WO 02/ 44,123, WO 02/ 34,709., WO 00/ 01,660, WO 99 / 14,184 and European patent EP 1,174,418, yields Gabapentin hydrochloride which is converted to the corresponding free amino acid by neutralization with a basic ion-exchanger followed by crystallization. US 4,894,476 specifically 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 by centrifuging followed by drying. Alternate methods disclosed in US Patents US 5,132,451, US 5,095,148, US 5,091,567 and US 5,068,413 involve hydrogenation of the cyano intermediate to liberate the free amino acid.

PCT publication No. WO 98/28255 discloses a method for the conversion of hydrochloride salt into Gabapentin Form-II via Gabapentin Form-III by elaborate multistep procedure of dissolution into a solvent, filtration of inorganics, distillation of solvent under vacuum in a heating bath at temperature below 35°C, then adding a second solvent, and neutralizing with a base at 25°C to yield Form-III. Form-III is then converted to Form-II by slurrying in methanol at 25°C for 14 hrs or recrystallizing it from methanol.

These processes are not industrially appropriate as large volumes of ion exchange columns and distillation of water are involved thereby leading to the formation of undesired lactam impurity. The method of conversion of hydrochloride into Form-II disclosed in PCT publication No WO 98/ 28255 involves the distillation of first solvent under vacuum at temperatures below 35°C, then addition of a second solvent for crystallization of Form-III and finally an extra step for the conversion of Form-III to required Form-II by slurring in methanol thereby lowering the yields, and producing a product with unacceptable levels of chloride ions and enhancing the cost of the final product.

There is therefore an unfulfilled need to provide cost effective industrially feasible process for the preparation of Gabapentin Form-II directly from Gabapentin hydrochloride without the multistep conversions described in the prior art.

Gabapentin by converting the hydrochloride salt directly into Form-II without the formation of Form-III. The present invention avoids the disadvantages associated with prior art methods, by simply neutralizing the Gabapentin hydrocliloride solution with a base at higher temperatures followed by cooling. Accordingly, the present invention relates to a method for the preparation of Gabapentin hydrochloride from the 1,1-Cyclohexane diacetic acid mono amide and the conversion of hydrochloride salt to Gabapentin Form-II as follows (Scheme-I):

A

Schemt^l

The essential features of the present invention comprises steps:

- Reaction of 1,1-Cyclohexane diacetic acid mono amide with alkali hypo halite solution, acidification with hydrochloric acid in presence of a solvent

- Extraction of the formed hydrocliloride salt into organic layer

- Separation of the organic layer, drying over dehydrating agents - Addition of an ante solvent, cooling to precipitate the hydrochloride salt and isolation

- Dissolution of the obtained hydrochloride salt in a short chain alcohol,

- Separation of the insolubles if any

- Neutralization of the filterate with a base at temperature to liberate the free amino acid

- Isolation of the liberated free amino acid by cooling, leaving the formed byproduct base-salt in the mother liquor / solvent,

- Separation of the formed Gabapentin Form-II

- Purification of the product by slurring in ethanol at temperature - Recovery of the product by filtering and drying

Both the precipitated Gabapentin and the purified Gabapentin are identified and confirmed as polymorph Form-II with XRD and IR data. Further objectives and advantages of the present invention will be apparent from the detailed description of the disclosed invention to those skilled in the art.

Brief description of the drawings

Fig. 1 is the X-ray diffraction pattern of the Gabapentin Form-II Fig. 2 is the FTIR spectrum of the Gabapentin Form -II Fig. 3 is the X-ray diffraction pattern of the Gabapentin Form-III Fig. 4 is the FTIR spectrum of the Gabapentin Form-III

The 1,1-cyclohexane diacetic acid mono amide used as starting material is prepared as per the literature (US patent No. 4,024,175).

1,1-cyclohexane diacetic acid mono amide is reacted in alkali medium with alkali hypo halite solution at temperature -10°C to 5°C, preferred temperature range being -5°C to 5°C. The preferred alkali hypo halite reagent is sodium hypochlorite. Acidification of the reaction mass to pH is below 2.0 preferably 1.0 to 1.5 is earned out with hydrochloric acid in presence of an organic solvent in a temp range 15°C -25°C. The preferred organic solvent is n-Butanol.

The reaction mass is allowed to settle and the organic layer is separated, The aqueous layer is extracted with a solvent and the combined organic layer is dried over dehydrating agents such as anhydrous sodium sulphate, anliydrous^' magnesium sulphate and anhydrous calcium sulphate. The preferable ones being anhydrous sodium sulphate and magnesium sulphate.

An ante solvent is added to the dried organic layer, cooled if required to precipitate the hydrochloride salt. The ante solvent is selected from the hydrocarbons, aromatic hydrocarbons, all yl ketones, alkyl ethers, the preferred solvent being hexane, toluene, acetone, di-isopropyl ether or a mixture of the above solvents. The precipitated hydrochloride salt is isolated by conventional methods such as filtration, centrifugation and dried to constant weight.

The Gabapentin hydrocliloride salt is dissolved in a short chain alcohol, preferably ethanol at 20 C - 25 C_s filtered to remove any insolubles, and the temperature of the filtrate is raised above 70 C. Slow neutralization is then carried out using an organic base. The preferred bases are the tri ethylamine, di isopropyl ethylamine. Temperature of the reaction mass is maintained at 70°C - 75°C for 1 - 2 hrs, followed by gradual cooling to 10°C-25°C, preferably between 20°C - 25°C and maintained with stirring for 1 - 2hrs. The precipitated free amino acid is isolated by conventional methods such as filtration, centrifugation, washed with solvent, ethanol and dried at 45°C- 50°C.

The free amino acid is further purified by suspending in ethanol, raising the temperature to about 60°C - 65°C, maintained for about one hour, followed by gradual cooling and stirring for about 1 -2 hrs at temperature 20°C - 25°C. The product is isolated and dried yielding pharmaceutically acceptable quality Gabapentin with chloride ions in the range of about 20 - 100 ppm, and lactam impurity below 0.1%.

The present invention relates to a new industrial feasible process for the preparation of Gabapentin by converting the hydrochloride salt directly into Form-II without the formation of Form-III. The present invention avoids the disadvantages associated with prior art methods, by simply neutralizing the Gabapentin hydrochloride solution with a base at higher temperatures followed by cooling

The invention can be further illustrated by the below non-limiting examples.

EXAMPLE - 1

Stage - 1: Preparation of Gabapentin hydrochloride Sodium hydroxide (51 g) is dissolved in sodium hypochlorite solution (6.25%, 625 g) cooled to 10°C. The solution is stirred for 10 - 15 min and further cooled to -5°C. In a separate flask, 1,1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15°C - 20°C. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5°C to -3°C over 3 hrs. The solution is then maintained at about 0°C for 2 hrs. The temperature is gradually raised over 3 hrs to 20°C - 25°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 to remove any undissolved material. pH of the filtrate is adjusted to around 9.0 by the addition of hydrochloric acid at temperature 20 - 25°C. n-Butanol (200 ml) is added and 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 organic layer is dried over anhydrous sodium sulphate ( 15 g). Di isopropyl ether (1200 ml) is slowly added to the dried organic layer at RT over 30 - 45 min and maintained for about 1 hr under stirring. The system is cooled to 5°C and stirred for 1 hr at 0°C - 5°C.

The product is filtered, washed with Di iso propyl ether (50 ml) and dried at 45°C - 50°C to constant weight and finally crystalised from tert.butanol - di-isopropyl ether to get the pure hydrochloride.

The dry wt of the hydrochloride salt is 80.0 g (Yield: 75.0%)

Stage - 2: Conversion of Gabapentin hydrochloride to Gabapentin Form-II

The Gabapentin hydrochloride salt (lOOg) prepared as above in stage- 1 is suspended in ethanol (950 ml) and stin-ed for 30 min. at room temp. The insolubles are filtered and washed with ethanol (50 ml). The filtrate is heated to 70°C - 75°C and the pH is adjusted to 7.1 to 7.2 by slow addition of di isopropyl ethylamine solution (170 ml in 170 ml of ethanol) at 70 C - 75°C over 60 min. The reaction mass is maintained at 70°C - 75°C for 2 hrs, gradually cooled and maintained at 20°C - 25°C for about 1 hr. The product is filtered, washed with ethanol (50 ml) and dried at 45°C - 50°C to constant weight.

Dry wt of the product is 52.8 g (Yield: 66%). Stage -3: Purification of Gabapentin Form-II

Gabapentin (50 g) prepared as above is suspended in ethanol (350 ml) and the temperature is raised to 65 C and maintained for 30 min. at 65°C - 68°C. The reaction mass is cooled to room temp and stirred for 30min. The product is filtered, washed with ethanol (25 ml) and dried at 50°C - 55°C to constant weight.

The dry weight of the Gabapentin Form-II is 45 g (Yield: 90%)

EXAMPLE - II

Stage - 1: Preparation of Gabapentin hydrochloride.

Sodium hydroxide (51 g) is dissolved in sodium hypochlorite solution ,(6.25%, 625 g) cooled to 10°C. The solution is stirred for 10 - 15 min. And further cooled to -5°C. In a separate flask, 1,1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15°C-20°C. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5°C to -3°C over 3hrs. The solution is then maintained at about 0°C for 2 hrs. The temperature is gradually raised over 3 hrs to 20°C - 25°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 to remove any undissolved material. pH of the filtrate is adjusted to 9.0 by the addition of hydrochloric acid at temperature 20-- 25°C. n-Butanol (200 ml) is- added and 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 organic layer is dried over anhydrous sodium sulphate (15 g). Di isopropyl ether (1200 ml) is slowly added to the dried organic layer at room temp over 30 - 45 min and maintained for about 1 hr under stirring. The system is cooled to 5°C and stirred for 1 hr at 0°C - 5°C. The product is filtered, washed with acetone (50 ml) and dried at 45°C-50°C to constant weight and finally crystallized from tert.butanol and di-isopropyl ether to get the pure Gabapentin hydrochloride. The dry wt of the hydrochloride salt is 76 g (Yield: 70.0%) Stage - 2: Conversion of Gabapentin hydrochloride to Gabapentin Form-II

The Gabapentin hydrocliloride salt (lOOg) prepared as above in stage- 1 is suspended in ethanol (950 ml) and stirred for 30 min. at room temp. The insolubles are filtered and washed with ethanol (50 ml). The filtrate is heated to 70°C - 75°C and the pH is adjusted to 7.1 to 7.2 by slow addition of tri ethylamine solution (130 ml in 130 ml ethanol) at 70°C - 75°C over 60 min. The reaction mass is maintained at 70°C-75°C for 2 hrs, gradually cooled and maintained at 20°C-25°C for about 1 hr. The product is filtered, washed with ethanol (50 ml) and dried at 45°C - 50°C to constant weight. Diy wt of the product is 53.0 g (Yield: 66%).

Which was converted to Gabapentin Form-II in the overall Yield of 60% by following the similar procedure as mentioned in example - 1, stage-3.

Claims

Claims;

1. A process for the preparation of Gabapentin Form-II comprising steps: - Reaction of the 1.1-cyclohexane di acetic acid mono amide λvith alkali hypohalite solution at temperature of -10 to 5°C, followed by acidification with hydrochloric acid in presence of an organic solvent-1,

- Extraction of the formed hydrochloride salt with organic solvent-2,

- Separation of the organic layer and drying over dehydrating agents, - Precipitation of hydrocliloride salt by addition of an ante solvent followed by isolation of the salt,

- Dissolution of hydrochloride salt in ethanol,

- Separation of insolubles (if any),

- Neutralization of the filterate with base at temperature about 70°C to liberate the corresponding free amino acid,

Isolation of the liberated free amino acid by cooling, leaving the by-products in the mother liquor / solvent,

- Separation of the formed Gabapentin Form-II,

- Purification ofthe product by slurrying in ethanol at 60°C -70°C, - Isolation ofthe final product by filtration followed by drying.

to yield Gabapentin Form-II with chloride ions less than lOOppm with respect to Gabapentin

2. A process as claimed in claim 1, wherein the acidification to pH 1.0 to 1.5 is carried out with hydrochloric acid

3. A process as claimed in claim 1, wherein the organic solvent-1 is selected from n-Butanol, MIBK, methyl ethyl ketone and TFTF, the preferred solvent being n-Butanol

4. A process as claimed in claim 1, wherein the extraction of hydrochloride salt with is carried out using n-Butanol

5. A process as claimed in claim 1, where drying of organic layer is done using dehydrating agents such as anhydrous sodium sulphate, anhydrous magnesium sulphate and anhydrous calcium sulphate, the preferred ones being anhydrous sodium sulphate and anliydrous magnesium sulphate

6. A process as claimed in claim 1, wherein the ante solvent is selected from acetone, toluene, n-Hexane and di isopropyl ether

7. A process as claimed in claim 1 , wherein the base used is di isopropyl ethylamine or tri ethylamine.

8. A process as claimed in claim 1, wherein the neutralization temperature is between about 70°C to about 75°C

9. A process as claimed in claim 1, wherein purification of Gabapentin is done by slurrying Gabapentin in ethanol at temperature between about 60°C to about 70°C