The present invention relates to improved, safe and industrially applicable process for preparing 3-Isobutylpyrrolidine-2,5-dione.
BACKGROUND OF THE INVENTION:
Pregabali'n of formula-1 is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. Pregabalin is marketed by pfizer under the trade name lyrica. Pregabalin has been developed for use in the treatment of epilepsy, Pain, anxiety and Physiological conditions associated with Psychomotor stimulants, inflammation, gastrointestinal damages, alcoholism, insomnia, convulsions, attention deficit hypersensitivity disorder (ADHD) and various psychiatric disorders, including depression, mania, bipolar disorder.
Pregabalin first synthesis has been disclosed in US 5563175 and EP 641330. US 5,616,793 discloses methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid starting from isovaleraldehyde with an alkyl cyanoacetate mainly ethyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester further reacting it with diethyl malonate, in the presence of a base such as di-n-propylamine in an inert solvent such as hexane, heptane, toluene and then adding a hydrochloric acid solution to form 3-isobutylglutaric acid. The anhydride is formed by reacting the 3-isobutylglutaric acid with acetic anhydride or acetyl chloride with a Hofmann reagent to obtain (S)-(+)-3-aminomethyl 5-methylhexanoic acid (VIII).
The present invention provides preparation of 3-Isobutylpyrrolidine-2,5-dione which is an impurity for Pregabalin.
The present invention relates to develop an eco-friendly, cost-effective process for 3-Isobutylpyrrolidine^^-dione.

SUMMARY OF THE INVENTION:
The present invention relates to robust, eco-friendly and industrially feasible process for the preparation of 3-lsobutylpyrrolidine-2,5-dione of formula-2
Formula-2
One embodiment of the present invention provides process for preparing 3-Isobutylpyrrolidine-2,5-dione of formula-2 comprises;
(a) reacting 2-isobutylsuccinic acid with aq. Ammonia solution
(b) extracting and isolating 3-Isobutylpyrrolidine-2,5-dione
(c) purifying 3-Isobutylpyrrolidine-2,5-dione in presence of solvent BRIEF DESCRIPTION OF DRAWINGS:

1. 'H NMR(CDC13) spectrum of 3-Isobutylpyrrolidine-2,5-dione
2. I3C NMR (CDC13) spectrum of 3-Lsobutylpyrrolidine-2,5-dione
3. Mass spectrum of 3-Isobutylpyrrolidine-2,5-dione
4. H.PLC of 3-Isobutylpyrrolidine-2,5-dione
5. IR spectrum of 3-Isobutylpyrro!idine-2,5-dione OBJECT OF THE INVENTION:

(1) The main object of the present invention is that the process establishes new impurity of pregabalin.
(2) The another object of the present invention is that the process is suitable for identification of unknown impurity (non-pharmacopeia) of pregabalin.
(3) One another object of the present invention is that the process gives good yield with good purity.

DETAIL DESCRIPTION OF THE INVENTION:
rhe present invention relates to improved, safe, economical and industrially applicable process for the preparation of 3-Isobutylpyrrolidine-2,5-dione of formula-2
One aspect of the present invention provides process for preparing 3-lsobutylpyrrolidine-2,5-dione of formu!a-2 comprises;
Formula-2
(a) reacting 2-isobutylsuccinic acid with aq. Ammonia solution
(b) extracting and isolating 3-lsoburylpyrrolidine-2,5-dione
(c) purifying 3-lsobutylpyrrolidine-2,5-dione in presence of solvent
The aq. Ammonia solution used in step (a) is 20-25%.
The solvent used for extraction in step (b) is selected from the group consisting of Cyclohexane, Hexane, Dichloromethane, Toluene, methyl tert butyl ether mixture thereof. The temperature for step (a) is about 30-150°C.
The solvent used for purification in step (c) is selected from the group consisting of Cyclohexane, Hexane, Dichloromethane, Toluene, methyl tert butyl ether mixture thereof.
The process for preparation of 3-Isobutylpyrrolidine-2,5-dione impurity of formula-2 given in the below reaction scheme-1

The 3-Isobutylpyrrolidine-2,5-dione impurity is characterized by 'H NMR(CDC13) 0.92-0.98 *(6H, m,-2CH3), 1.37-1.44 (1H, m, 7-CH), 1.68-1.75 (1H, m, 6-CH2), 1.79-1.86 (1H, m, 6-CH2), 2.38-2.46 (1H, m, 3-CH), 2.85-2.92 (2H, m, 4-CH2), 8.10 (1H, s, -NH). 'H NMR spectrum is depicted in Fig.l.
The 3-IsobutylpyrroIidine-2,5-dione impurity is characterized by l3C NMR (CDCb): 181.72, 177.93, 40.34, 39.75, 36.04, 26.15, 23.09, 21.45. l3C NMR spectrum is depicted in Fig.2.
The 2-isobutylsuccinic acid'impurity is characterized by IR having peak at 3177.19 for CONH and 1711.57 for C=0. IR spectrum is depicted in Fig. 5.
The 3-Isobutylpyrrolidine-2,5-dione impurity is characterized by Mass having peak at 156.63 (M+H)+. Mass spectrum is depicted in Fig.3
The 3-Isobutylpyrrolidine-2,5-dione impurity is having melting range about 111.9°C to 112.9°C.

The following examples explain various other embodiments without limiting the scope of the present invention.
Example-!: Preparation of 3-Isobutylpyrrolidine-2,5-dione
To a solid of Diacid, aq. Ammonia solution was slowly added at 10-20 °C with continuous stirring for 30 min. After completion of addition, the reaction mixture was slowly distilled out with the rotary evaporator under temperature control 20 °C to 70°C. After distillation of complete ammonia, crude mass was refluxed at the 110°C to 150°C until the completion of reaction. Reaction mixture cooled to RT. Added Dichloromethane and sodium bicarbonate solution and stirred for 30 min. Separated the organic layer. Organic layer washed with water and distilled out solvent completely under reduced pressure. Solid was purified with hexane to afford the desired compound as a white solid.
HPLC Purity: 100% . . . .