Process for the preparation of gabapentin

Abstract

The present invention relates to an improved process for the preparation of Gabapentin. The process also relates to a new process for the preparation of 1, 1-cyclohexane diaceitic acid monoamide (CDMA), which is a key intermediate for the preparation of Gabapentin.

Claims

1. A process for the preparation of gabapentin comprising the steps of: a) reacting spiro[cyclohexane-1,9-(3,7-diazabicyclo-[3.3.1]nonane)]-2,4,6,8-tetraone of the formula VI: ##STR00007## with an alkali to obtain 1,1-cyclohexane diacetic acid monoamide of the formula IV and ##STR00008## b) converting the compound IV obtained in step-a to gabapentin I by Hofmann reaction using alkali hypo halite.

2. The process as claimed in claim 1, wherein at step-a, the alkali used is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide and potassium tert-butoxide.

3. The process as claimed in claim 2, wherein the alkali is sodium hydroxide.

4. The process as claimed in claim 3, wherein the concentration of the alkali is in the range of 5% to 50% (w/v).

5. The process as claimed in claim 3, wherein the concentration of the alkali is in the range of 15% to 25% (w/v).

6. The process as claimed in claim 1, wherein at step-a, the reaction is carried out at reflux temperature for a time period of 6 to 24 hours.

7. The process as claimed in claim 6, wherein at step-a, the reaction is carried out for a time period of 15 hours to 20 hours.

8. The process as claimed in claim 1, wherein the compound of the formula VI used in step-a is prepared by reacting 2,4-dioxo-3-aza-spiro[5.5]undecane-1,5-dicarbonitrile of the formula V ##STR00009## with 50% to 70% solution of sulfuric acid at 90 C. to 110 C.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention provides a novel process for the preparation of gabapentin (I), comprising the steps of: (a) reacting diimide VI with an alkali to produce CDMA (IV) and (b) converting CDMA (IV) to gabapentin (I).

(2) The starting material, diimide VI, can be prepared by the method described in J. Med. Chem. 1998, 41, pg. 318-331 and U.S. Pat. No. 4,742,172. It involves treating the dinitrile V with 60% sulphuric acid at a temperature of 120 to 140 C. for 10 to 15 minutes to obtain the diimide VI in 40% yields. The same method is described in U.S. Pat. No. 4,742,172, but does not mention the yields. Earlier, Thorpe and Wood (J. Chem. Soc. 1913, 1586-1600) had mentioned that the dinitrile V on reacting with concentrated sulphuric acid results in the diimide VI. They had not mentioned any details of the reaction conditions.

(3) Since the reported yield (40%) is not satisfactory, the reaction was reinvestigated and studied in detail.

(4) The study showed that the optimum concentration of sulphuric acid is between 50% to 70%. Below this concentration, the reaction is incomplete and at higher concentration, significant amount of diamide VII is formed as impurity. At >95% concentration, diamide VII is the major product.

(5) The temperature also plays an important role. At the reported temperature of 120 to 140 C., a mixture of diimide VI and CDA (II) is obtained. The optimum temperature for the reaction is in the range of about 90 C. to 110 C. Below about 80 C., the reaction is incomplete. Thus, under the optimum conditions, diimide VI is obtained in about 80% yield, which is double the yield compared to prior art report.

(6) The diimide VI undergoes base catalyzed decarboxylation and hydrolysis to give CDMA (IV) in about 80% yield having purity of >99%.

(7) The reaction can be carried out by heating the diimide VI with an aqueous solution of an alkali base. The alkali solution can have strength of 5% to 50%, preferably 15% to 25% (w/v). Although most experiments were conducted using sodium hydroxide as the base, other alkali bases such as potassium hydroxide, lithium hydroxide, sodium tert-butoxide and potassium tert-butoxide also gave similar results. Heating can be conveniently carried out at reflux temperature (100-105 C.). At lower temperatures of about 70 C. to 80 C., conversion is slow and the reaction is incomplete.

(8) Duration of the reaction plays a significant role on the yields and purity of the product CDMA(IV). When the reaction is carried out using 20% solution of sodium hydroxide at reflux temperature for about 20 hours, CDMA (IV) is obtained in about 80% yields having a purity of >99% (HPLC). At shorter duration, the product gets contaminated with monoimide IX as the major impurity. At about 5 hours, monoimide IX is obtained as the major product, while CDMA (IV) is the minor product. At about 24 hours, slight amount (1-2%) of CDA(II) formation is observed.

(9) After the reaction, the reaction mixture is cooled, diluted with water and pH adjusted to about 4 by addition of acid. During the adjustment of pH, some amount of carbon dioxide gas liberation is observed. But this does not result in the frothing of the reaction medium and can be easily regulated by adjusting rate of addition of acid. Filtering the solids and washing with little cold water gives pure CDMA (IV).

(10) The CDMA (IV) can then be converted into Gabapentin by several processes, including the process developed earlier by the present assignee as described in U.S. Pat. No. 8,431,739.

(11) Thus, the present process is simple and does not use any organic solvents. It eliminates the use of highly concentrated sulphuric acid. Another advantage of the present process is that, carbon dioxide is liberated only during the neutralization of the alkaline reaction mixture at room temperature. This does not result in foaming and frothing unlike in the Warner-Lambert process (U.S. Pat. No. 4,024,175) where heavy frothing occurs when carbon dioxide is liberated during heating of the reaction mixture containing sulphuric acid at 170 C.

(12) The present process is also more economical as the more advanced intermediate, CDMA (IV), is obtained directly from the dinitrile V without going through the steps of CDA (II) and its anhydride intermediate III.

(13) The embodiments of the present invention are illustrated in the following examples, which are not intended in any way to limit the scope of the invention. One skilled in the art can modify the details to suit the inputs and desired outcomes without affecting the present invention.

EXAMPLES

(14) Chemical purity was determined using HPLC under the following conditions:

(15) Column: X-Terra RP C18, 1504.6 mm, 5 m

(16) Mobile phase: Buffer: Acetonitrile (760:240); flow rate: 1.0 ml/min

(17) Buffer preparation: 0.58 g of monobasic ammonium phosphate and 1.83 g of sodium perchlorate in 1.0 lit of water adjust with perchloric acid to a pH 1.8.

(18) Column Temperature: 40 C., Detection: 215 nm

Example 1: Preparation of Spiro [cyclohexane-1, 9-(3, 7-diazabicyclo-[3.3.1] nonane)]-2, 4, 6,8-tetraone (VI)

(19) 120 mL of 60% solution of sulphuric acid was heated to 70-75 C. and to this solution was added 2, 4-dioxo-3-aza-spiro [5.5] undecane-1, 5-dicarbonitrile (V) (30.0 g, 0.129 moles) slowly. After the addition, the reaction mixture was heated to 100 C.-105 C. and maintained at this temperature for 22 hours. The reaction mixture was cooled, diluted with 180 mL water and stirred for 1 hour. The solids were filtered, washed with water and dried at 60 C. for 5 hours to obtain spiro[cyclohexane-1, 9-(3, 7-diazabicycle-[3.3.1] nonane)]-2, 4, 6, 8-tetraone (VI), 27 g (Yield: 83.3%). Melting Range (DSC): 406.88-410.96 C. (Lit: 400-405 C.; J. Chem. Soc., 1911, 99, 422-448). IR(KBr): 3209, 3097 (NH stretch), 2948, 2850 (CH Stretch, 1708 (CO), 1425& 1363 cm.sup.1. .sup.1H NMR (300 MHz, DMSO): 11.67 (s, 2H, NH), 3.75 (s, 2H) & 1.39-1.48 (m, 10H, cyclohexyl group). .sup.13C NMR (75 MHz, DMSO): 166.60 (4CO), 57.19 (2CH), 37.69 (CR.sub.4), 20.74, 25.33 & 31.84 (cyclohexyl group). MS: m/z: 249.22 (M-1). Purity by HPLC: 98.23%.

Example 2: Preparation of Spiro [cyclohexane-1, 9-(3, 7-diazabicyclo-[3.3.1] nonane)]-2, 4, 6, 8-tetraone (VI)

(20) Experiment was conducted as described in Example 1, but instead of using 60% solution of sulphuric acid, 70% solution of sulphuric acid was used. Yield: 78.7%, HPLC: 96.8%.

Example 3: Preparation of Spiro [cyclohexane-1, 9-(3, 7-diazabicyclo-[3.3.1] nonane)]-2, 4, 6, 8-tetraone (VI)

(21) Experiment was conducted as described in Example 1, but instead of carrying out the reaction at 100 to 105 C., the reaction was carried out at 90 to 95 C. Yield: 77.1%, HPLC: 98.27%.

Example 4: Preparation of 1, 1-cyclohexane Diacetic Acid Monoamide (CDMA, IV)

(22) To 36 mL of solution of 20% sodium hydroxide was added di-imide VI, (15.0 g, 0.0599 moles) and refluxed (100-105 C.) for 18 hours. The reaction mixture was cooled, diluted with 400 mL water, further chilled to 5-10 C., the pH of the solution was adjusted to about 4.0 with concentrated hydrochloric acid and stirred for 30 minutes. The solids were filtered, washed with water and dried at 55 C. for 1 hour to obtain 1,1-cyclohexane diacetic acid monoamide IV, 9.65 g (Yield: 80.8%). Melting Range: 145.6-146.8 C. (Lit.: 141-146 C., https://www.sigmaaldrich.com/catalog). IR (KBr): 3400, 2932, 1717 (CO), 1653 &1591 cm.sup.1. .sup.1H NMR (300 MHz, DMSO): 12.45 (s, 1H, COOH), 7.02-7.44 (s, 2H, CONH.sub.2), 2.40 (s, 2H), 2.23 (s, 2H) & 1.36-1.41 (m, 10H, cyclohexyl group). .sup.13C NMR (75 MHz, DMSO): 174.28, 173.41 (2CO), 42.55, 42.26 (2-CH.sub.2), 35.28 (CR.sub.4), 35.08, 26.02 &21.48 (cyclohexyl group). MS: m/z: 200.08 (M+1). Purity by HPLC: 99.68%. (Monoimide IX: 0.21%; CDA (II): 0.06%).

Example 5: Preparation of 1, 1-cyclohexane Diacetic Acid Monoamide (CDMA, IV)

(23) Experiment was conducted as described in Example 4, but instead of using 20% solution (w/v) of sodium hydroxide, 40% solution was used. Yield: 81.7%, HPLC: 99.01%.

Example 6: Preparation of 1, 1-cyclohexane Diacetic Acid Monoamide (CDMA, IV)

(24) Experiment was conducted as described in Example 4, but using 20% solution of potassium hydroxide in place of 20% solution of sodium hydroxide. Yield: 77.7%, HPLC: 96.5%.

Example 7: Preparation of 1, 1-cyclohexane Diacetic Acid Monoamide (CDMA, IV)

(25) Experiment was conducted as described in Example 4, but instead of refluxing the reaction for 18 hours, the reaction was refluxed for 15 hours. Yield: 80.4%, HPLC: 96.3%; 1.5% monoimide IX.

Example 8: Reference Example: Preparation of Gabapentin (I)

(26) CDMA (IV) was treated with a solution of sodium hypochlorite in an alkaline medium and converted into gabapentin as described in the U.S. Pat. No. 8,431,739.