INTRODUCTION
The present application concerns an improved process for the preparation of 3-lsobutyl glutaric acid, which is a useful intermediate in the preparation of pharmaceutical^ active agents and in particular the compound S-(+)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin).
Pregabalin, has been found to activate GAD (L-20 glutamic acid decarboxylase), has dose dependent protective effect on-seizure and is a CNS-active compound. . Pregabalin is useful in anticonvulsant therapy due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitor neurotransmitters, which is released at 30% of the brain's synapses. Pregabalin has analgesic, anticonvulsant and anxiolytic activity and marketed under the name LYRICA® by Pfizer,Inc., in tablets of 25, 50 75, 200 and 300 mg doses.

Several processes were reported in the literature for the synthesis of 3-isobutyl glutaric acid. The process disclosed in US5616793 comprises that isovaleraldehyde is condensed with ethyl cyanoacetate in the presence of di n-propylamine in hexane (knoevenagel condensation). Michael addition reaction was done using diethyl malonate in the 'presence of di n-propylamine to obtain intermediate 3 which was refluxed with 6N HCI to get the target compoundof formula 1.
The process disclosed in WO2009004643A2 comprises that isovaleraldehyde

condensed with diethyl malonate in the presence of di n-propylamine in cyclohexane (knoevenagel condensation). Michael addition reaction was done using diethyl malonate in the presence of potassium carbonate to obtain intermediate 5 which was refluxed with 6N HCI to get the target compound of formula 1.
The process disclosed in US20070259917A1 comprises that isovaleraldehyde condensed with meldrum's acid in the presence of di n-propylamine in cyclohexane (knoevenagel condensation). Michael addition reaction was done again with meldrum's acid in the presence of potassium carbonate to obtain intermediate 7 which was refluxed with 6N HCI to get the target compoundof formula 1.
Although several processes have been reported in the prior art for the preparation of 3-isobutyl glutaric acid, they suffer from one or more drawbacks such as low yields, long reaction durations with laborious-work up procedures and uses expensive organic solvents and organic bases. Hence, there is still a need for simple, cost effective and industrially viable process for the production of 3-isobutyl glutaric acid.
Objective of present invention:
The objective .of the present invention is to provide a simple and cost effective process for the preparation of 3-isobutyl glutaric acid.

Summary of the present invention:
In an aspect, the present application provides a process for the preparation of 3-isobutyl glutan'c acid comprising:
Reacting isovaleraldehyde with cyanoacetic acid in the presence of an inorganic base in water to form compound of formula 8, which was then converted into desired compound of formula 1 in-situ using a mineral acid. Both Knoevenagel condensation . and Michael addition reactions were carried out concurrently in one stage to obtain intermediate 8.
Detailed description of the present invention:
Aspects of the present application relate to process for preparing 3-isobutyl glutaric acid.
Inventors of the present application have developed a robust one pot process for preparing 3-isobutyl glutaric acid using a commercially available cyanoacetic acid having purity of 50-100% (by chemical assay).The other major impurities in the commercial cyanoacetic acid are water and sodium chloride. The process of the present application is favorable for large scale production, avoids time-consuming steps, avoids cost involved in isolation of intermediates and also saves time and resources by'avoiding purifications between individual steps as desired, minimizes the transfer of material between vessels and thus renders the process more suitable for a commercial scale up,
3-lsobutyl glutaric acid prepared using the process of the present application
may be used directly in the manufacture of pregabalin without further purification. i
Pregabalin may be manufactured according to any of the processes reported in the literature by using the 3-lsobutyl glutaric acid of the present application.
In an aspect the present invention provides a process for the preparation of 3-Isobutyl glutaric acid comprising:
Reacting isovaleraldehyde with cyanoacetic acid in the presence of an inorganic base and water as reaction medium to give a compound of the formula 8,

which is hydrolysed and de-carboxylation in-situ with a mineral acid to give a compound of formula 1.
Compound of formula 1 can be isolated from the reaction mixture using appropriate techniques known to a person skilled in the art.
In embodiments of step a) the cyanbacetic acid used is having purity of 50-100% (by chemical assay). The other major components of cyanoacetic acid are water and sodium chloride which do not have any impact on the reaction time, purity or yield of the reaction.
In embodiments of step a) the inorganic base used comprises an alkali or
alkaline earth metal hydroxide, carbonate or bicarbonate. The useful inorganic bases

carbonate, sodium bicarbonate, potassium bicarbonate. Preferably the inorganic
base used is sodium hydroxide.

Suitable solvents for use in step a) include, but are not limited to: water, alcohols, such as, for example, methanol, ethanol, isopropanol, n-propanol, and the like; hydrocarbons, such as, for example, toluene, xylene, n-hexnane, n-heptane, cyclohexane, and the like; mixtures thereof; and combinations thereof with water in various proportions.

Step a) may be accomplished at temperatures about 0-60°C, such as, for example, about 0-40°C.

In embodiments of step a) the reaction is maintained at 0-25°C for 2-8 hours, preferably for 3-5 hours. The reaction may be maintained till completion of the reaction as long as there is no impact on quality and yield of the product.

In embodiments of step b) the compound of formula 8 formed in step a) is hydrolysed and de-carboxylated with a suitable mineral acid or a base. The mineral acid useful for hydrolysis are HCI, H2SO4

In embodiments of step b) the hydrolysis and decarboxylation may be carried out from 50-150°C, preferably at 80-120°C more preferably at 100-120°C.

In embodiments of step b) the hydrolysis reaction may be carried out for any desireditime periods to'achieve the desired product yield and purity. The hydrolysis, decarboxylation reaction generally takes 8-36 hours for completion.

After completion of the reaction, the compound of formula 1 can be isolated directly from the reaction mixture by cooling the same to below room temperature. The mixture may be optionally seeded with compound of formula 1, stirred for solid formationat temperatures such as, for example, below about 0°C to about 25°C, for periods of time as required for complete solid formation. The exact temperatures and time required for complete solid formation can be readily determined by a person skilled in the art.

Optionally the compound of formula 1 may be extracted with a suitable organic solvents followed by evaporation and crystallization using appropriate solvents. Suitable solvents that can be used for extraction of the compound include, but are not limited to: C3-C6 ketones, such as, for example, ethyl methyl ketone and diethyl ketone; halogenated solvents, such as, for example, dichloromethane, ethylene dichloride, chloroform, and carbon tetrachloride; esters, such as, for example, ethyl acetate, isopropyl acetate, t-butyl acetate and aromatic or aliphatic hydrocarbons such as hexane, heptane, toluene, xylene.

The suitable crystallization techniques include but are not limited to: concentrating, cooling, stirring, shaking, a solution containing the compound or by adding anti-solvent, adding seed crystals, evaporation, flash evaporation and the like. Anti-solvent as used herein refers to a solvent in which compound of formula 1 is less soluble or poorly soluble.

The wet cake obtained may optionally be further dried. Drying can be suitably carried out in a tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying can be carried out for any desired times until the desired product purity is achieved.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are ' provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES
Example-1: Preparation of 3-isobutyl glutaric acid using LR grade cyanoacetic acid: 103g of cyanoacetic acid (LR grade, 98% purity by chemical assay) charged into a clean round bottom flask along with 200 mL water and cooled to 0-5°C. An aqueous sodium hydroxide solution (60 g of NaOH dissolved in 100mL water) was added drop wise over a period of 20 min. The reaction mixture was stirred at the same temperature for another 30 min. Isovaleraldehyde (50 g) was added dropwise over a period of 20 min to the above reaction mixture at 0-5°C. The reaction mixture was stirred for another 30 min at the same temperature. The reaction mixture was slowly warmed up to 25-35°C and stirring was continued for another 3 hours. The reaction mixture was re-cooled to 0-5°C and added 500ml_ of concentrated HCI over a period of 30 min. The reaction mixture was slowly heated to reflux temperature at 110°C. The reaction mixture was maintained under reflux condition for 24 h. The reaction was monitored for completion of the reaction using TLC. The reaction mixture was cooled to 90°C and extracted with toluene (2x400mL). The toluene extracts were combined and concentrated under vacuum (recovered toluene was re-used) to yield a yellow viscous oily mass (100-106 g). The viscous oily mass was triturated with n-hexane (100 mL) and the separated solid was filtered and dried under vacuum for 5-6 h. 90 g of off white free flowing 3-isobutyl glutaric acid was obtained (yield: 82%).
Example-2: Preparation of 3-isobutyl glutaric acid using LR grade cyanoacetic acid: 103g of Cyanoacetic acid (LR grade, 98% purity by chemical assay) charged into a clean round bottom flask along with 200 mL water and cooled to 0-5°C. An aqueous sodium hydroxide solution (60 g of NaOH dissolved in 100mL water) was added drop wise over a period of 20 min. The reaction mixture was stirred at the-same temperature for another 30 min. Isovaleraldehyde (50 g) was added dropwise over a period of 20 min to the above reaction mixture at 0-5°C. The reaction mixture was
stirred for another 30 min at the same temperature. The reaction mixture was slowly warmed to 25-35°C and maintained at the same temperature for another 3h.The reaction mixture was re-cooled to 0-5°C and added 600mL of 12N H2SO4 over a period of 30 min. The reaction mixture was slowly heated to reflux temperature at 110°C. The reaction mixture was maintained under reflux condition for 24 h. The
'reaction was monitored for completion of the reaction using TLC. The reaction :
extracts were combined and concentrated under vacuum (recovered toluene was re-used) to yield a yellow viscous oily mass (70 g). The viscous oily mass was triturated with n-hexane (100 ml_)and the separated solid was filtered and dried under vacuum for 5-6 h. 60 g of off white free flowing 3-isobutyl glutaric acid was obtained (yield: 55%).
Example-3: Preparation of 3-lsobutyl glutaric acid using commercial cyanoacetic acid:
445 g of cyanoacetic acid (70% pure by HPLC/assay by chemical titration) charged into a clean and dry round bottom flask and cooled to 0-5°C. An aqueous sodium hydroxide solution (181 g of NaOH dissolved in 300ml_ water) was added dropwise over a period of 30 min. The reaction mixture was stirred at the same temperature for another 30 min. Isovaleraldehyde (150 g) was added drop wise over a period of 30 min to the above reaction mixture at 0-5°C. The reaction mixture was stirred for another 30 min at the same temperature. The reaction mixture was slowly warmed to 25-35°C and the stirring was continued at the same temperature for another 3 hours. 1500ml_of concentrated HCI was added slowly at room temperature (using water bath) over a period of 30 min. The reaction mixture was slowly heated to reflux temperature (~110°C). The reaction mixture was maintained under reflux condition for 24 h. The reaction was monitored for completion of the reaction using TLC. The reaction mixture was cooled to 90°C and extracted with toluene (2x1000mL). The toluene extracts were combined and concentrated under vacuum (recovered toluene was re-used) to yield a yellow viscousoily mass (300g). The viscous oily masswas triturated with n-hexane (750 ml_) and the separated solid was filtered and driedunder vacuum for 5-6 h.290 g of off white free flowing 3-isobutyl glutaric acid was obtained (88.5%). Purity by GC: 96%
Preparation of pregabalin using 3-isobutyl glutaric acid prepared by the process of the present application:
Synthesis of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid: 450 g of Isobutyl glutaricacid and 183.5 g of urea were charged in a RB flask, heated to 125° C-130°C for 4 hours. The reaction was monitored for completion by TLC. The reaction mixture was cooled to 60° C and 108 ml_ of water was added. An aqueous solution of NaOH ;
reaction mass at 40° C (temperature should be below 40° C). The reaction mixture was stirred at 40° C for 4 hours. The reaction was monitored for completion by TLC (checked absence of imide). The reaction mixture was washed with 100 mL of toluene in a separating funnel. Aqueous layer was taken in a RB flask and cooled to 5°C. The reaction mixture pH was adjusted to 2 using con. HCI. Separated solid collected by filtration, washed with cold water and dried in a vacuum oven at 50°C to get the title compound as white crystalline solid (350 gms).
Preparation of (R)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid: 300 g of 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid was charged in a clean RB flask and charged chloroform (2 Its). The reaction mixture was heated 40°C, (R)-1-Phenyl ethylamine (157.5 g) was added at the same temperature. The reaction mixture was heated to 60°C and stirred for 1 hour. The reaction mixture was cooled to 25-30°C, the separated solid was filtered and washed with pre-cooled chloroform. The material was dried (231 g), the same was charged in a 1 It RB flask and added 500 mL of water. An aqueous solution of NaOH prepared by dissolving 42 g of NaOH in 105 mL of water was added to the reaction mixture at 15°C. The reaction mixture was stirred until a clear solution was obtained. The reaction mixture was washed with 175 mL of chloroform and the organic layer concentrated to recover the (R)-1-Phenyl ethylamine. The aqueous layer was cooled to 5°C, pH was adjusted to 2 using con. HCI. Separated solid collected by filtration, washed with cold water and dried in a vacuum oven at 50°C to get the title compound as white crystalline (120 gms)
Preparation of Pregabalin:
50 gms of (R)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid was added to an aqueous solution of NaOH prepared by dissolving 12 g of NaOH in 80 mL of water at 25°C. The reaction mixture was stirred until a clear solution was obtained. The reaction mixture was cooled to 5°C and 195 gms. of 10% sodium hypochlorite solution was added. An aqueous solution of NaOH prepared by dissolving 36.25 g of NaOH in 40 mL of water was added to the above reaction mass at 5°C. The reaction mixture was stirred at 15°C for 8hrs. The reaction mixture was acidified with Con. HCI to pH~2.5, the reaction mixture was heated to 50°C and stirred for 30min. The : jfor^actjjpiF mixtu/g wgsfpgc*l,ef|
NaOH solution to pH~7.5. The reaction mixture cooled to 5°C and stirred for 1 hour. Separated solid collected by filtration and washed with cold water and dried in a vacuum oven at 50°C to get colourless solid (30 gms). Advantages with the present invention:
a) Both Knoevenagel condensation and Michael addition reactions were carried out concurrently in one stage.
b) Reaction time for these two steps greatly reduced, compared to reported procedures. - . -
c) Hydrolysis and de-carboxylation reaction time also significantly reduced, compared to reported procedures.
d) Environment friendly reaction medium and base (organic solvent and organic base were completely avoidedin the reaction)
e) This process is viable with various grades of cyanoacetic acid, i.e. 50% to 98% purity.
f) 3-lsobutyl glutaric acid obtained according to the present invention is a white to off-white crystalline powder.

We Claim:
1. A process for the preparation of 3-lsobutyl glutaric acid comprising:
a. reacting isovaleraldehyde with cyanoacetic acid in the presence of an
inorganic base and water to give a compound of the formula 8,
b. reacting the compound of fornula 8 in-situ with a mineral acid to give a
compound of formula 1.
2. The process according to claim 1, wherein the cyanoacetic acid used is an aqueous solution having purity of 50-100% (by chemical assay).
3 The process according to claim 1, wherein the inorganic base used comprises sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.
4 The process according to claim 3, the inorganic base is sodium hydroxide.
5 The process according to claim 1, wherein Step a) is accomplished at
6 temperatures about 0-60°C for 2-8 hours.
7 The process according to claim 5, wherein step a) is accomplished at 0-25°C for 3-5 hours.

8The process according to claim 1, wherein in step b) the compound of formula 8 formed in step a) is hydrolysed and de-carboxylated with a suitable mineral acid or a base.

The process according to claim 7, wherein the mineral acid is selected from
hci H2SO4
The process according to claim 1, wherein step b) is accomplished at 50-
150°C for 8-36 hours.

The process according to claim 9, wherein step b) is accomplished at 100-120°C for 12-24 hours.'