FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
Title: "An in-situ process for the preparation of intermediates used for the synthesis of GAB A derivative"
Name: PAB Organics Pvt. Ltd.
Address: 65, Suryakiran Complex,
Opp. Bankers Heart Institute
Old Padra Road, Vadodara
Gujarat, India Nationality: Indian
The following specification particularly describes the invention and the manner in which it is to be performed.

Title of the invention
An in-situ process for the preparation of intermediates used for the synthesis of GABA derivative
Field of the invention
The present invention relates to an in-situ process for the preparation of compound of Formula II i.e. 3-(carbamoylmethyl)-5-methylhexanoic acid and 3-isobutylglutaric acid of Formula IV. The compound of Formula II and IV are key intermediates for the synthesis of GABA derivative (S)-(+)-(aminomethyl)-5-methylhexanoic acid of Formula I commonly known as Pregabalin.

Background of the invention
It has been well established that the level of Gamma-aminobutyric acid (GABA) in the brain plays a vital role in controlling the convulsions. This led to the development of GABA derivatives like Gabapentin and Pregabalin. These compounds are known to activate L-glutamic acid decarboxylase (GAD) concentrations resulting in increased GABA levels. Pregabalin is an anticonvulsant having mechanism of action similar to Gabapentin but having higher activity and increased duration of action compared to Gabapentin (Yuen, P.; et al, Bioorg. Med. Chem. Lett., 1994, 6, 823). Pregabalin is a (S)-stereoisomer of isobutyl-GABA.

The compound of Formula II i.e. 3-(carbamoylmethyl)-5-rnethylhexanoic acid is a key intermediate for the synthesis of Pregabalin and 3-isobutylglutaric acid of Formula IV is a key intermediate for synthesis of 3-(carbamoylmethyl)-5-methylhexanoic acid. The process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid and its use for the preparation of Pregabalin was first disclosed in EP-B-828704. The process involves condensation of isovaleraldehye with an alkyl cyanoacetate to obtain an intermediate which was reacted with dialkylmalonate to obtain cyano-ester intermediate. The intermediate on hydrolysis give 3-isobutylglutaric acid of Formula IV, which was converted to its anhydride. The anhydride intermediate on treatment with ammonia gives compound of Formula II.
The compound of Formula II may be converted to Pregabalin either by first carrying out the resolution followed by Hoffman degradation or vice-versa.
An another process for the conversion of compound of formula II to Pregabalin as disclosed in WO2006136087 involves treatment of 3-isobutylglutaric acid with nitrogenous compounds like ammonium hydroxide, ammonium salts, urea or thiocarbamide to give imide intermediate which on hydrolysis produces compound of Formula II.
Various synthetic approaches for the preparation of Pregabalin and its intermediates were disclosed and discussed in Org. Process Res. & Dev., 1997, 1, 26-38 (Hoeskstra, M. S. et al). The paper discusses alternate route (Scheme-7) for synthesis of 3-isobutylglutaric acid which involves condensation of cyanoacetamide with isovaleraldehydein the presence of organic base to obtain dicyano-diamide intermediate of Formula V which is isolated.


The compound of Formula V on hydrolysis in the presence of hydrochloric acid results in 3-isobutylglutaric acid. However, the paper does not disclose or elaborate the reaction parameters explored by the scientists for the synthesis of 3-isobutylglutaric acid. Conversely, the scientist found this route unfavourable for the synthesis of 3-isobutylglutaric acid due to practical problems associated with isolation of compound of Formula V and several other drawbacks associated with low solubility and emulsifying tendencies of the intermediate of Formula V. This in turn requires large volumes of solvent to keep the reaction mixture in fluid form. Therefore, the cyanoacetamide route is largely left unexplored for commercial application.
In spite of different synthetic routes known in the state of art there is a need to develop a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II and its key intermediate 3-isobutylglutaric acid of Formula IV which is advantageous over the existing prior art.
The inventors of present invention have directed the efforts towards development of a process for the preparation of the compound of Formula II i.e. 3-(carbamoylmethyl)-5-methylhexanoic acid and compound of Formula IV i.e. 3-isobutylglutaric acid which is simple, economically advantageous, eco-friendly and easily scalable. The efforts have resulted in a process wherein the cyanoacetamide route for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid and 3-isobutylglutaric acid becomes adaptable for large scale production. The said process involves shorter

reaction time, improvements in yield, use of small volumes of solvent, easy handling on commercial scale and non-hazardous reaction conditions which makes the process commercially adaptable and economically acceptable.
Summary of the invention
The object of the present invention is to provide an in-situ process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II and 3-isobutylglutaric acid of Formula IV and its conversion to Pregabalin of Formula I.
In accordance with the object an aspect of the present invention provides an in-situ process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II comprising steps of:
(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V,
(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV,
(c) extracting the reaction mass obtained in step-(b) with a suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV,
(d) concentrating the organic layer to obtain residue,
(e) treating the residue obtained in step-(c) with urea to obtain imide intermediate of Formula III, and
(f) carrying out the hydrolysis of imide intermediate to obtain 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II.
Another aspect of the present invention provides an in-situ process for the preparation of 3-isobutylglutaric acid of Formula IV comprising steps of:

(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V,
(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV,
(c) extracting the reaction mass obtained in step-(b) with a suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV, and
(d') isolating 3-isobutylglutaric acid of Formula IV.
The present invention also provides a process wherein compound of Formula II and Formula IV prepared by the process of present invention is converted to Pregabalin of Formula I.
Detailed description of the invention
The term "3-(carbamoylmethyl)-5-methylhexanoic acid" as used herein the specification means racemic i.e. (±)-3-(carbamoylmethyl)-5-methylhexanoic acid unless otherwise specified.
The term "in-situ" as used herein the specification indicates a process wherein the intermediate obtained after carrying out any step is not isolated and also includes a process wherein the intermediate obtained after any step is used in the next step without further drying or purification.
The present invention may be described by schematic representation depicted in Figure-1.


The process described in Figure-1 generally comprises of:
Step-(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V;
Step-(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV;

Step-(c) extracting the reaction mass obtained in step-(b) with a suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV;
Step-(d) concentrating the organic layer to obtain residue;
Step-(e) treating the residue obtained in step-(c) with urea to obtain imide intermediate of Formula III; and
Step-(f) carrying out the hydrolysis of imide intermediate to obtain 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II.
In step-(a) isovaleraldehye and cyanoacetamide are condensed to form dicyano-diamide intermediate of Formula V. The reaction is generally carried out in the presence of catalytic amount of inorganic base. The reaction may be carried out in the presence of water or mixture of water and alcoholic solvents like ethanol, methanol and the like preferably water only. The reaction is generally carried in the temperature range of about 5°C to about 25°C, preferably at the temperature of about 0°C to 5°C.
The reaction is proceeded in the presence of catalytic amount of inorganic base such alkali metal hydroxides, carbonates and bi-carbonates for example sodium or potassium hydroxide, carbonate or bicarbonate.
The available prior art have not disclosed the use inorganic base as catalyst for condensation of isovaleraldehye and cyanoacetamide. The greatest advantage of using inorganic base is that the commercial quantities are easy to handle, they are cheaper in cost, easily available, can be stored comfortably and is non-hazardous in comparison to organic base. The use of inorganic base also results in shorter reaction time, milder reaction conditions and better yield.
In step-(b) the reaction mass of step-(a) is treated with mineral acid to obtain 3-isobutylglutaric acid of Formula IV. The mineral acid used for the step of hydrolysis

and decarboxylation may be selected from aqueous solution of hydrochloric acid, sulphuric acid or hydrobromic acid and the like. The intermediate of Formula V is not isolated from the reaction mass of step-(a).
The state of art teaches isolation of the dicyano-diamide intermediate. However, the isolation of the intermediate is cumbersome and tricky for scale-up production. This fact is acknowledged by researchers on page 30 of Org. Process Res. & Dev., 1997, 1, (Hoeskstra, M. S. et al). Further, they state that isolation of solid intermediate is unavoidable. The reaction conditions of present invention do not lead to such circumstances i.e. isolation of intermediate of Formula V can be avoided and addition of mineral acid can be proceeded in-situ. Therefore, the present invention has a definite niche over the prior art.
Step-(c) comprises of extracting the reaction mass of step-(b) containing 3-isobutylglutaric with a suitable solvent which includes but is not limited to toluene. The aqueous layer is discarded and the organic layer is concentrated in step-(d) to obtain residue containing 3-isobutylglutaric.
In step-(e) the residue is treated with urea to obtain imide intermediate of Formula III. The reaction is preferably carried out in absence of solvent at temperature of about 130°C to about 150°C. The imide intermediate thus formed is not purified but leached with water and centrifuged to obtain a wet cake. Thus, the step of drying and purification is avoided and the crude intermediate is used in the next step.
In step-(f) the wet cake of step-(e) is hydrolyzed in the presence of aqueous base to give 3-(carbamoylmethyI)-5-methylhexanoic acid of Formula II. The step of hydrolysis is carried out in the presence of base such as alkali metal hydroxides, carbonates or bicarbonates for e.g. sodium or potassium hydroxide, carbonates or bicarbonates and the like. The reaction may be carried out at ambient temperature or at elevated temperature of about 80°C. The product thus formed is(±)-3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II which is isolated and dried.

If desired it may be subject to further purification techniques like crystallization and the like known perse.
(±)-3-(carbamoylmethyl)-5-methylhexanoic acid may be subject to resolution followed by Hoffmann degradation to give Pregabalin or may be subjected of Hoffmann degradation first followed by resolution to give Pregabalinof Formula (I) by methods known in the art.
Another embodiment of the present invention provides an in-situ process for the preparation of 3-isobutylglutaric acid of Formula IV comprising steps of:
(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V,
(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV,
(c) extracting the reaction mass obtained in step-(b) with an suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV, and
(d') isolating 3-isobutylglutaric acid of Formula IV.
Step (a) to (c) are carried out in accordance with process described hereinabove. In step-(d') organic layer containing 3-isobutylglutaric acid of Formula IV is concentrated to obtain a residue with is further subject to complete removal of solvent i.e. evaporating solvent to dryness in order to obtain solid 3-isobutylglutaric acid.
If desired 3-isobutylglutaric acid may be converted to (±)-3-(carbamoylmethyl)-5-methylhexanoic acid by process disclosed in steps (e) and (f) or by other methods known in prior art. (±)-3-(carbamoylmethyl)-5-methylhexanoic acid thus obtained may be converted to Pregabalin of Formula (I) by method known perse.

Technical advancement of the present invention
Having described the invention in detail the technical advancement of the present invention in the light of prior art can be summarized as follows:
1) Use of inorganic base in catalytic quantities.
2) Avoiding isolation and purification of the intermediates by carrying out in-situ process.
3) Minimum use of solvent.
4) Easily scalable process with shorter reaction time and improved yield.
Economic significance of the present invention
The present invention is economically significant due to following reasons:
1) The reagent/catalyst used for the reaction i.e. inorganic base is cheap, easily available, non-hazardous and easy to use in scale-up process.
2) The use of inorganic base provides a reaction condition in which the intermediate need not be isolated, therefore cumbersome operations like drying and purification may be avoided which in turn saves time, cost and overheads associated with commercial production.
3) Avoiding the use of solvent for reaction results in environmental friendly process and additional costs involved with recovering the solvent.
4) Since the overall reaction time is reduced and the yields are improved the cost of production is dropped significantly making process desirable for commercial manufacturing.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining with the spirit and scope of the invention. The examples are provided by way of illustration only and should not be construed as to limit the scope of the invention in any manner.

Examples
Example 1: Preparation of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid
In a clean reactor was charged 1600 liters of D.M. water and 253 kg. of 2-cyanoacetamide. The reaction mixture was stirred at ambient temperature till clear solution is obtained. 120 kg. of isovaleraldehyde is added at about 15°C to 18°C. Cool the reaction mixture to 5° to 8°C followed by slowly addition of 3.5 kg. aqueous sodium hydroxide solution (50 % cone). The reaction mass is stirred for about 8 hours. 1520 kg of aqueous HC1 is added and the reaction mass is stirred for about 25-30 hours at approximately 110°C. The reaction mass is cooled to about 70°C. 450 liters of Toluene is added to the reaction mass and layers are separated. The aqueous layer is discarded and the organic layer is concentrated to obtain a residue. 140 kg. of urea is added to the residue and the reaction mass is stirred for about 6 hours at about HOT. The reaction mass is cooled and 1800 litters of D.M. water is added to it. The reaction mass is centrifuged and the wet cake is transferred back to the reactor. Charge 2000 liters of D.M. water and adjust the pH to 11.5 to 12.5 using caustic lye. Heat the reaction mass to 50° to 55°C for about 3 hours. Charge activated carbon and stir for few minutes. Filter the reaction mass and transfer back to the reactor. Add concentrated HC1 at about 30°C till pH is between 1 to 2. Centrifuge the reaction mass and dry the product at about 65° C in tray dryers under vacuum. The dry product is (±)-3-(carbamoylmethyl)-5-methylhexanoic acid, 160 kg. to 170 kg., yield: 63 to 67 % (w/w), purity: above 99.0 % (by HPLC method)
Example 2: Preparation of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid
In a clean reactor was charged 1600 liters of D.M. water and 253 kg. of 2-cyanoacetamide. The reaction mixture was stirred at ambient temperature till clear solution is obtained. 120 kg. of isovaleraldehyde is added at about 15°C to 18°C. The

reaction mixture is cooled to about 5° to 8°C followed by slowly addition of 5.0 kg. aqueous Potassium carbonate solution (30 % cone). The reaction mass is stirred for about 8 hours. 1000 kg of aqueous Sulphuric acid is added and the reaction mass is stirred for about 20 hours at approximately 115°C. The reaction mass is cooled to about 70°C. 450 liters of Toluene is added to the reaction mass and layers are separated. The aqueous layer is discarded and the organic layer is concentrated to obtain a residue. 140 kg. of urea is added to the residue and the reaction mass is stirred for about 6 hours at about 140°C. The reaction mass is cooled and 1800 litters of D.M. water is added to it. The reaction mass is centrifuged and the wet cake is transferred back to the reactor. Charge 2000 liters of D.M. water and adjust the pH to 11.5 to 12.5 using caustic lye. Heat the reaction mass to 50° to 55°C for about 3 hours. Charge activated carbon and stir for few minutes. Filter the reaction mass and transfer back to the reactor. Add concentrated HC1 at about 30°C till pH is between 1 to 2. Centrifuge the reaction mass and dry the product at about 65° C in tray dryers under vacuum. The dry product is (±)-3-(carbamoylmethyl)-5-methylhexanoic acid, 150 to 160 kg., yield: 50 to 55 % (w/w), purity: above 99.0 % (by HPLC method)
Example 3: Preparation of 3-isobutylglutaric acid
In a clean reactor was charged 760 liters of D.M. water and 126 kg. of 2-cyanoacetamide. The reaction mixture was stirred at ambient temperature till clear solution is obtained. 60 kg. of isovaleraldehyde is added at about 15°C to 18°C. The reaction mixture is then cooled to about 5° to 8°C followed by slowly addition of 3.5 kg. aqueous Potassium carbonate solution (30 % cone). The reaction mass is stirred for about 8 hours. 500 kg of aqueous HC1 is added and the reaction mass is stirred for about 30 hours at approximately 110°C. The reaction mass is cooled to about 70°C. 225 liters of Toluene is added to the reaction mass and layers are separated. The aqueous layer is discarded and the organic layer is concentrated to obtain a residue.

The solvent was evaporated to dryness to obtain 130 to 140 kg. of 3-isobutylglutaric acid. Yield: 65 to 70%.
Example 4: Preparation of (R)-3-(carbamoylmethyI)-5-methylhexanoic acid
In a clean reactor is charged 1500 liters chloroform and 20 liters ethanol followed by 100 kg. of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid prepared in Example 1. The reaction mass is heated to 50°-55°C. 47 kg. (R)-(+)-alphaphenylethylamine is added to it and stirred for 10-15 minutes. The reaction mass is seeded with 30 grams crystals of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid and cooled to 20°C. The solid is centrifuged and dried to obtain (R)-(+)-alphaphenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid. Yield: 62 kg.
(R)-(+)-alphaphenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid 50 kg. is charged in reactor. 400 liters of D.M. water is added to it, followed by 40 liters of concentrated HC1 at ambient temperature. The reaction mass is cooled to 10°C and the solid is centrifuged to give (R)-3-(carbamoylmethyl)-5-methylhexanoic acid. The solid is dried to give 29 kg. of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid.
Example 5: Preparation of Pregabalin
In a clean reactor is charged 50 liters of D.M. water and 14 kg. of sodium hydroxide. Stir the reaction mass till complete dissolution. Cool the solution to about 5°C. Charge 20 kg. of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid and 70 kg. sodium hypochlorite solution (10-14%). Stir the reaction mass for about 1 hour at about 15°C. Raise the temperature to about 45°C and stir for another hour. Cool the reaction mass to about ambient temperature and add concentrated HC1 till pH is between 5.5 and 6.5. Stir the reaction mass for 1 hour at ambient temperature and centrifuge the solid. The dry solid is Pregabalin. Yield: 12 kg.

Claims
1. An in-situ process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II comprising steps of:

(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V,

(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV,


(c) extracting the reaction mass obtained in step-(b) with an suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV,
(d) concentrating the organic layer to obtain residue,
(e) treating the residue obtained in step-(c) with urea to obtain imide intermediate of Formula III, and

(f) carrying out the hydrolysis of imide intermediate to obtain 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II.
2. The process claimed in claim 1, wherein inorganic base is alkali metal hyroxides, carbonates and bicarbonates, comprising of sodium and potassium hydroxide, carbonate and bicarbonate.
3. The process claimed in claim 1, wherein mineral acid in step-(b) is hydrochloric acid, sulphuric acid or hydrobromic acid.
4. The process claimed in claim 1, wherein suitable solvent in step-(c) is toluene.
5. The process claimed in claim 1, wherein hydrolysis in step-(f) is carried out using aqueous base comprising of sodium and potassium hydroxide, carbonate and bicarbonate.
6. An in-situ process for the preparation of 3-isobutylglutaric acid of Formula IV comprising steps of:

(a) reacting isovaleraldehye and cyanoacetamide in the presence of catalytic amount of inorganic base to obtain a reaction mass containing intermediate of Formula V,
(b) treating the reaction mass obtained in step-(a) with mineral acid to obtain 3-isobutylglutaric acid of Formula IV,
(c) extracting the reaction mass obtained in step-(b) with an suitable solvent to obtain an organic layer containing 3-isobutylglutaric acid of Formula IV, and
(d') isolating 3-isobutylglutaric acid of Formula IV.
7. The process claimed in claim 6, wherein steps (a) to (c) are in accordance with claims 2 to 4.
8. The process claimed in claim 6, wherein step (d') comprises on concentrating the organic layer obtained in step-(c) and evaporating the solvent to dryness.
9. The process for the preparation of Pregabalin of Formula 1 using 3-(carbamoylmethyl)-5-methylhexanoic acid of Formula II or 3-isobutylglutaric acid of Formula IV prepared in accordance with process claimed in any of the preceding claims.