| Title of Invention | PROCESS FOR RACEMISATION |
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| Abstract | Disclosed herein is an efficient environment friendly process for racemisation of enantiomerically enriched 3 - carbamoyl methyl - 5 - methylhexanoic acid, an important intermediate used for the preparation of (S) - 3 - (amifiomethyl) - 5 - methylhexanoic acid. |
| Full Text | FORM 2 THE PATENTS ACT 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "PROCESS FOR RACEMISATION" 2. APPLICANT: (a) NAME: INDOCO REMEDIES LIMITED. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the invention and the manner in which it is to be performed. Field of Invention: The present invention provides an efficient environment friendly process for racemisation of enantiomerically enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid, an important intermediate used for the preparation of (S) - 3 - (aminomethyl) - 5 -methylhexanoic acid. Background and Prior Art: 3 - Carbamoylmethyl - 5 - methylhexanoic acid of Formula - I is an important intermediate useful for the preparation of (S) - 3 - (aminomethyl) - 5 - methylhexanoic acid having international nonproprietary name (INN) (S) - Pregabalin. Pregabalin exhibits anti-seizure activity, as discussed first time in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., and is thought to be useful for treating, among other conditions, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including mania and bipolar disorder. (S) - Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures are marketed by Pfizer under the brand name "Lyrica". The synthesis of (S) -Pregabalin was disclosed in US patent no. US6,197,819; wherein, 4 - methyl pentanoic acid ( Formula - II) is converted to 4 - methyl pentanoyl chloride (Formula - III) which is reacted with the chiral auxiliary (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone to get (4R,5S)-3-(4-methylpentanoyl)-4-methyl-5-phenyloxazolidin-2-one (Formula - IV). The compound of Formula - IV is reacted with benzyl - a -bromoacetate in presence of strong base lithium diisopropyl amide to yield benzyl protected (S) - 4-methyl-(2-methylpropyl)-2-dioxo-5-phenyl-3-oxazolidine butanoic acid benzyl ester of Formula - V, which on reaction with hydrogen peroxide in presence of lithium hydroxide on work up and eluting through column chromatography results in the compound (S)-2-(((benzyloxy)carbony])methyl) - 4 - methylpentanoic acid of Formula -VI, reducing the compound of Formula- VI using borane dimethyl sulfide yields alcohol (Formula - VII). The alcohol obtained is reacted further with tosyl chloride followed by reaction with sodium azide to isolate azido compound (S)-benzyl 3-(azidomethyl)-5-methylhexanoate (Formula - VIII) which on hydrogenation yields the compound (S) -Pregabalin (Formula - IX). The reaction sequence is as per the scheme - 1. The drawbacks of the above invention involve hydrogenation and use of hazardous and expensive reagents like lithium diisopropyl amide (LDA), lithium hydroxide, sodium azide, pyridine and borane dimethyl sulfide. Further, the invention uses chromatographic separation for isolation of the chiral intermediate VI and recovery of chiral auxiliary (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone which renders the invention uneconomical and industrially non practicable. Another method disclosed in patent US 5,616,793 involves reaction of isovalaraldehyde (Formula - X) with ethyl - 2 - cyanoacetate (Formula - XI) to get (E) - ethyl 2 - cyano -5 - methylhex — 2 - enoate (Formula - Xll) which on reaction with diethyl malonate followed by hydrolysis results in the formation of 3 - isobutyl -glutaric acid (Formula -XIII). The acid is reacted with acetyl chloride to form 3 - isobutylglutaric anhydride. (Formula - XIV) which on reaction with ammonia yields racemic 3 - carbamoylmethyl -5 - methylhexanoic acid of Formula -1. The racemic compound is reacted with (R) - 1 -phenyl ethylamine to isolate (R) - 3 - carbamoylmethyl - 5 - methylhexanoic acid (Formula XV) which on Hoffmann reaction yields (S) - Pregabalin. The reaction sequence can be represented as below in Scheme - 2. Further, the mother liquor of compound of Formula - XV containing enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid is extracted with aqueous sodium hydroxide solution followed by acidifying the aqueous layer with concentrated hydrochloric acid and heated to reflux for 24 hours. The aqueous layer is extracted further with methyl tert - butyl ether which on concentration gives 3 - isobutylglutaric acid of Formula - XIII. The acid is then converted to corresponding anhydride of Formula - XIV which on further reaction with ammonia results in racemic 3 - carbamoylmethyl - 5 -methylhexanoic acid of Formula - I. Efficient recovery and recycle of (S) - 3 - carbamoylmethyl - 5 - hexanoic acid and (R) -phenyl ethyl amine makes the process most economical. Recovery of (S) - 3 -carbamoylmethyl - 5 - hexanoic acid needs easy and efficient racemisation process. To make the process economically and industrially useful it is important that the (S) isomer of 3 - Carbamoylmethyl - 5 - methylhexanoic acid is recovered, racemised and recycled. The process mentioned for racemisation in the above patent requires longer time for hydrolysis, and involves number of steps to get racemic 3 - carbamoylmethyl - 5 -methylhexanoic acid. The racemisation process as reported in the Journal, Org. Process Res. Dev. 13 (4), 812 -814 (2009); the mother liquor having (R) and (S) enantiomer of 3 - carbamoylmethyl - 5 - methylhexanoic acid was concentrated and decomposed, the residue heated with piperidine in refluxing toluene for 10 hours to form intermediate 3 - isobutyl glutarimide of Formula - XVII. The water formed during cyclisation is removed azeotropically with toluene. The reaction mixture is cooled and charged sodium hydroxide solution at 60°C and maintained for one hour. The aqueous layer is separated and acidified with concentrated hydrochloric acid at 0 - 5°C to isolate racemic 3 - carbamoylmethyl - 5 -methylhexanoic acid. The product is further recrystallised from ethyl acetate. The drawbacks in the above reported process are; • Requires concentration of mother liquor to isolate the salt which is decomposed to obtain free enantoimeric mixture of (R) and (S); • It uses piperidine base and the organic solvent; • It has to remove water formed during the reaction azeotropically; • During hydrolysis there are two phases which hinders completion of the reaction; Yet another racemisation process reported in the Journal Chin. J. Chem., 2009, Vol. 27, No. 5; in which (S) isomer of 3 - carbamoylmethyl - 5 - methylhexanoic acid is taken in xylene and refluxed with simultaneous removal of water through the water separator. The reaction mixture is refluxed till no water is formed. The reaction mixture is cooled and 3 - isobutyl glutarimide of Formula - XVII (cyclic imide) formed is filtered and dried under vacuum. The dried imide is taken in sodium hydroxide solution and heated at 65°C for 10 minutes. The solution was cooled quickly to 5°C and adjusted pH of the solution to 1 with concentrated hydrochloric acid to get racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid. The drawbacks in the reported process are; • Uses high boiling solvent; • Requires simultaneous removal of water through water separator; Therefore there remains a need for an improved process for racemisation of (S) isomer of 3 - carbamoylmethyl - 5 - methylhexanoic acid that eliminates the drawbacks of the process and avoids the use of base and high boiling solvents and employs a more robust process which is convenient and cost efficient. The present inventors have come out with an improved process which ameliorates the drawbacks in the prior art for racemisation of (S) isomer of 3 - carbamoylmethyl - 5 -methylhexanoic acid of Formula -1 by avoiding the use of base and high boiling organic solvents by carrying out the process in environment friendly solvent water, which makes the process robust, operator friendly and techno commercially viable for industrial production. Objective of the invention: The objective of the present invention is to provide a process for the racemisation of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid. Yet another objective of the present invention is to provide an environment friendly and industrial useful process for racemisation of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid. Yet another objective of the present invention is to prepare (S) - pregabalin using the racemised 3 - carbamoylmethyl - 5 - methylhexanoic acid Summary of the invention: In accordance with the objective, the present invention provides a process for the racemisation of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid of Formula-I; which comprises; i. treating the entiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid with dilute hydrochloric acid to form 3- isobutyl glutarimide of Formula - XVII; ii. hydrolyzing 3- isobutyl glutarimide with aqueous sodium hydroxide solution at 20 -45°C to form racemic 3 - Carbamoylmethyl - 5 - methylhexanoic acid of Formula - I; iii. isolating the racemic compound of Formula -I. Description of the Invention: Unless expressly indicated otherwise, in the present description, the term "enantiomeric enriched" used in relation to the process of the invention, refers to the compound 3 -carbamoylmethyl - 5 - methylhexanoic acid having (S) isomer in the range of 80 - 85% and (R) isomer in the range of 15 - 20%. The present invention provides a process for racemisation of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid of Formula -I. The enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid used for the purpose of present invention is obtained by extracting the mother liquor of the reaction between racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid and (R) - (+) -phenylethyl amine with dilute sodium hydroxide solution. In one embodiment of the present invention, the extracted sodium hydroxide solution contains sodium salt of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid. The salt of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid is treated with 2N to I0N dilute hydrochloric acid at a temperature in the range of 45 - 70°C to get cyclic imide 3- isobutyl glutarimide. The preferred concentration of dilute hydrochloric acid used for the reaction is 4N to 8N, wherein the most preferred concentration of dilute hydrochloric acid used is 4N to 5N. The preferred temperature for the reaction is between 50 - 65°C, wherein the most preferred temperature for the reaction is between 55 - 60°C. The time required for complete transformation of enantiomeric enriched 3 - carbamoylmethyl - 5 - methylhexanoic acid into cyclic imide, 3- isobutyl glutarimide is between 6-8 hours. The solid intermediate 3- isobutyl glutarimide thus obtained is isolated by filtration and taken for the preparation of racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid. The intermediate 3- isobutyl glutaritnide formed after the reaction is taken for the treatment with dilute sodium hydroxide solution to get the sodium salt of racemic 3 -carbamoylmethyl - 5 - methylhexanoic acid and the corresponding acid is isolated by adjusting the pH of the reaction solution to 1 - 3 with dilute hydrochloric acid. The isolated solid if required is purified in a solvent mix comprising ethyl acetate and water to isolate pure racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid. The racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid is further resolved by reacting with (R) - (+) - phenylethyl amine to isolate (R) - (-) - 3 - carbamoyl - 5 -methylhexanoic acid R - (+) - phenyl ethylamine salt which on treatment with dilute hydrochloric acid results the compound R - (-) - 3 - (carbamoylmethyl) - 5 -methylhexanoic acid. In yet another embodiment of the present invention the isolated R - (-) - 3 -carbamoylmethyl - 5 - methylhexanoic acid is taken for Hoffmann reaction using the reagent selected from phenyliodine diacetate (PIDA) or benzyltrimethyl ammonium tribromide in presence of base selected from triethyl amine or sodium hydroxide in a suitable solvent to result in the formation of (S) - 3 - (aminomethyl) - 5 -methylhexanoic acid. The preferred combinations of the base with the reagent used are triethylamine with phenyliodine diacetate and sodium hydroxide with benzyltrimethyl ammonium tribromide. The suitable solvent used for the Hoffmann reaction is selected from acetonitrile, N, N - dimethylformamide, N, N - dimethylacetamide and water either single or mixture thereof. The reaction is carried out at preferred temperature of 0 - 30°C wherein the most preferred temperature of the reaction is 0 - 10°C. Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description. Examples: Example - 1: Preparation of (5)-(-)-3-(Carbamoylmethyl)-5-methylliexanoic acid (R)-(+)-Phenylethylamine salt: 3-(Carbamoylmethyl)-5-methy]hexanoic acid (115.0 gm) was charged to the mixture of chloroform (1150 ml) and methanol (11.5 ml) at 25 - 30°C. Raised the reaction temperature to 45 - 50°C and stirred for 15 minutes. (R)-(+)-Phenylethylamine (54.11 gm) and pure (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid, 0.100 gm was then added to the reaction mixture at 45 – 50ºC. Raised the reaction temperature of the reaction mass to 55o-60°C and maintained for one hour. Cooled the reaction to 28°-32°C and stirred. Filtered the solid product at 28°-32°C and washed with Chloroform (207 ml). Dried the product(R)-(-)-3-(CarbamoyImethyl)-5-methyIhexanoic acid (R)-(+)-Phenyl ethylamine salt at 55°-60°C, until constant weight. Weight = 80.5 gm; Yield = 85.0% Example - 2: Preparation of 3-isobutyl glutarimide Charged sodium hydroxide solution (14.83 gm dissolved in 82 ml water) to the mother liquor (1210 ml) containing enantiomeric enriched 3 - (carbamoylmethyl) - 5 -methyl -hexanoic acid obtained from example 1. Cooled the reaction mass to 0 - 5°C and stirred for 30 minutes. Separated the aqueous layer and charged dilute hydrochloric acid (170 ml) to the reaction mass and raised the temperature to 55 - 60°C. Stirred for 8 hours and cooled the reaction mass to 0 - 5°C. Filtered the product, washed with water. Dried the isolated compound 3-isobutyl glutarimide at 55 - 60°C. Weight - 44.7 g, Yield = 74.5% Example - 3: Preparation of racemic 3-(Carbamoylmethyi)-5-methylhexanoic acid Charged 3-Isobutyl glutarimide (40 gm) to water (80 ml). Sodium hydroxide solution (9.93 gm dissolved in 40 ml water) was added to the reaction mass at 10 - 15 °C and stirred for one hour. Raised the temperature to 35 - 40°C for 1 hour. Cooled the reaction mass to 10 - 15°C. Charged dilute hydrochloric acid (27 ml) to adjust pH ~ 1. Cooled the reaction mixture to 0 - 5°C and stirred. Filtered the crude racemic 3 -(Carbamoylmethyl) - 5 - methylhexanoic acid and washed with water. Dried the product at 55 - 60°C. Crude solid product was then purified by ethyl acetate: water (10:1, 2.0 vol.) mixture to obtain pure 3 - (Carbarnoylmethyl) - 5 - methylhexanoic acid. Weight = 39.10 gm; Yield = 88.4% Example - 4: Preparation of (S) - Pregabalin using phenyliodine diacetate (PIDA): (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (2.5 gm) was added to the mixture of acetonitrile (15 ml) and water (2.5 ml) and triethylamine (1.85 ml) at 25 -30°C. Reaction mixture was cooled to 0 - 5°C. Added in small lot phenyliodine diacetate, 5.15 gm at 0 - 5°C. Stirred the reaction mass at 0 - 5°C for 5 hours. Filtered the precipitated product, washed with 5 ml ethyl acetate. Product (S) - pregabalin dried at 55°-60°C. Weight =1.0 gm; Yield = 47.0% Example - 5: Preparation of (S) - Pregabalin using benzyl trimethyl ammonium tribromide (BTMA.Br3) (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic. acid (20 gm) was added to sodium hydroxide solution (22.4 gm dissolved in water 100 ml) at 0°-5°C. Charged in small lot benzyltrimethyl ammonium tribromide (41.36 gm) at 0 - 5°C and stirred for one hour at 0 - 5°C. Raised the temperature of the reaction mass to 65 - 70°C and stirred for 30 minutes. Cooled the reaction mixture to 30 - 35°C, followed by pH adjustment to 7.5 -7.7 using cone, hydrochloric acid. Heated the reaction mass to 45 - 50°C and maintained for three hours at the same temperature and pH.. Cooled the reaction mass to 30 - 35°C and stirred for one hour maintaining the pH at 7.5 -7.7. Cooled the reaction mass to 0°-5°C and stirred for two hours at 0 - 5°C. Filtered the product and washed with cold water, dried the product (S) - pregabalin at 55°-60°C. Weight = 13.3 g, Yield = 78.2% We claim, 1. A process for racemisation of enantiomeric enriched 3 - carbamoylmethyl — 5 — methylhexanoic acid of Formula - 1 comprising the steps of; i. treating the enantiomeric enriched 3 — carbamoylmethyl - 5 - methylhexanoic acid with hydrochloric acid at temperature of 45 - 70°C to form 3- isobutyl glutarimide of Formula - XVII; ii. hydrolyzing the compound 3- isobutyl glutarimide with aqueous sodium hydroxide solution at 20 - 45°C to form racemic 3 - carbamoylmethyl - 5 -methylhexanoic acid of Formula -I; iii. isolating the racemic compound of Formula -= I. 2. The process as claimed in claim 1 (i); wherein the preferred temperature of the reaction is between 55 - 60°C. 3. The process as claimed in claim 1; wherein hydrochloric acid is used in diluted form having a strength of 2N to 10N. 4. The process as claimed in claim 1, further comprising a step of converting the racemic compound of formula -I into (S) - 3 - (aminomethyl) - 5 -methylhexanoic acid of Formula - IX. 5. The process as claimed in claim 4, wherein said process comprises: i. treating the enantiomeric enriched 3 - carbamoylmethyl - 5 -methylhexanoic acid with hydrochloric acid at temperature of 45 - 70ºC to form 3- isobutyl glutarimide of Formula - XVII; ii. hydrolyzing the compound 3- isobutyl glutarimide with aqueous sodium hydroxide solution at 20 - 45°C to form racemic 3 - carbamoylmethyl - 5 - methylhexanoic acid of Formula -I; iii. isolating the racemic compound of Formula -I. iv. reacting the racemic compound of Formula - I with (R) - (+) - phenylethyl amine to form (R) - (-) - 3 - carbamoyl - methyl - 5 -methylhexanoic acid (R)-(+)-phenylethyl amine salt of Formula - XV; v. reacting the compound of Formula - XV with hydrochloric acid to get (R) -(-) - 3 - carbamoylmethyl - 5 - methylhexanoic acid of Formula - XVI; vi. reacting the compound of Formula XVI with reagents selected from phenyliodine diacetate and benzyitrimethyl ammonium tribromide in presence of base and solvent at temperature of 0 - 30°C to get (S) - 3 - (aminomethyl) - 5 - merhylhexanoic acid of Formula - IX; Formula - IX 6. The process as claimed in claim 5 (iv); wherein the preferred temperature of the reaction is 0-10°C. 7. The process as claimed in claim 5 (vi); wherein the solvent used for the reaction is selected from acetonitrile, N,N - dimethylformamide, N,N - dimethylacetamide and water or combinations thereof. |
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| Patent Number | 272002 | |||||||||||||||
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| Indian Patent Application Number | 2804/MUM/2009 | |||||||||||||||
| PG Journal Number | 12/2016 | |||||||||||||||
| Publication Date | 18-Mar-2016 | |||||||||||||||
| Grant Date | 14-Mar-2016 | |||||||||||||||
| Date of Filing | 03-Dec-2009 | |||||||||||||||
| Name of Patentee | INDOCO REMEDIES LIMITED | |||||||||||||||
| Applicant Address | INDOCO HOUSE, 166 C.S.T.ROAD, SANTACRUZ(EAST), MUMBAI-400 098, MAHARASHTRA, INDIA. | |||||||||||||||
Inventors:
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| PCT International Classification Number | C07C233/05, C07C231/16 | |||||||||||||||
| PCT International Application Number | N/A | |||||||||||||||
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