DESC:FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of Brivaracetam.

BACKGROUND OF THE INVENTION
Brivaracetam is a chemical analog of levetiracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.

Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide and is represented by following general Formula I,

Formula I
Brivaracetam as well as their processes and uses as pharmaceuticals are described in US patents having publication numbers US6784197 B2 & US6911461 B2. The synthetic scheme exemplified in above patents is given in Scheme 1.

Scheme 1
The reported process utilizes preparative HPLC for chiral resolution of isomers. This process used for chiral resolution involving preparatory chromatographic technique makes it difficult for bulk manufacturing as well as it affects the overall yield making the process uneconomical.

Patent publications such as US6713635 B2, US7122682 B2, US7563912 B2, US7629474 B2, US8076493 B2, US8338621 B2, US8957226 B2, WO2016191435 A1, WO2017076738 A1, WO2018152949 A1, WO2018152950 A1, US10781170 B1, IN201711038420 A, IN201741028352 A, IN201811006881 A, IN201811006882 A, IN201821032919 A, IN201821041984 A, IN201841007514 A, IN201841013148 A, IN201841047956 A, IN201941004232 A and IN201941042636 A also describe processes for preparing Brivaracetam.

The processes for the preparation of Brivaracetam described in the above-mentioned patents suffer from many disadvantages which includes difficulty in achieving desired chiral purity, tedious and cumbersome work up procedures, high temperature and longer time reaction, multiple crystallizations or isolation steps, use of excess reagents and solvents, column chromatographic separations & purifications etc. All these disadvantages affect the overall yield as well as the quality of the final product.

Further CN106748950 B and WO2020125536 describes process for preparation of Brivaracetam wherein Brivaracetam Intermediate (V) is subjected to resolution in presence of phenylethylamine and 1S,2S-diphenylethylenediamine respectively. Present inventors tried to repeat the CN’950 process using phenylethylamine and was unsuccessful. Further use of 1S,2S-diphenylethylenediamine was uneconomical on commercial level. Hence these processes described in these publications is not reproducible or uneconomical.

Brivaracetam is highly soluble in most of the organic solvents and the absence of suitable functionality that can form diastereomeric salts with chiral reagents, the removal of diastereomer impurity from the process is difficult and making the process not feasible or uneconomical due to multiple purifications or use of chromatographic techniques.

Based on the above discussed facts there is a need for an improved process for the preparation of Brivaracetam with high purity and yield which overcome the drawback of prior publications. The present inventors have found an efficient process for the preparation of Brivaracetam which offers the following advantages over the prior publications such as simple scalable procedures suitable for large scale production, high yields, less effluent, highly economical and pure Brivaracetam.

The present disclosure provides a cost effective and efficient process for the preparation of Brivaracetam which offers economical, industrially viable, highly pure Brivaracetam in high yields and avoiding chiral resolutions by chromatography.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of Brivaracetam using a novel intermediate.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Brivaracetam comprising conversion of compound of Formula V a novel intermediate to Brivaracetam.

According to first aspect of the present invention, provides an improved process for preparing Brivaracetam of Formula (I) comprising:
1) treating a compound of formula IV with reducing agent followed by chiral base to give compound of formula V;
2) converting compound of formula V to Brivaracetam.

In accordance with yet another aspect of the present invention, improved process for the preparation of Brivaracetam overcomes the above discussed disadvantages associated with the process disclosed in the cited prior arts.

DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide an improved process for the preparation of Brivaracetam using novel intermediate a compound of formula V.

In an embodiment of the present invention provides an improved process for preparing Brivaracetam of Formula (I)

(I)
comprising; treating a compound of formula IV with reducing agent followed by chiral base to give compound of formula V, which is further converted to Brivaracetam of Formula (I).

In accordance with the present invention, an improved process for preparing Brivaracetam of Formula (I) as per the Scheme 2 given below:

Scheme 2
In accordance with the present invention, the reaction intermediates of scheme 2 are further reacted either in isolated form or in-situ for next steps.

In yet another embodiment of the present invention provides novel intermediate of Formula V.

In an embodiment of the present invention, a process for the preparation of novel intermediate of Formula V comprises treating compound of formula IV with reducing agent followed by chiral base to give compound of formula V

In an embodiment of the present invention, compound of formula IV is subjected to undergo diastereoselective reduction using a reducing agent and hydrogen source.

According to the specific embodiment of the present invention, reducing agent for above diastereoselective reduction is selected from the group consisting of but not limited to Pd/C, Pd(OH)2, Pt/C, Palladium (II) acetate, Raney Ni, Pd/Alumina or Rh/C and more preferably Pd/C.

According to the present invention, diastereoselective reduction of compound of Formula IV is performed in the presence of organic solvents.

According to the present invention the reduced compound, i.e., after the completion of reaction of compound of formula IV, is then treated with chiral base to obtain compound of Formula V.

The chiral bases used for the above reaction is selected from the group consisting of but not limited to cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine, ephedrine, or mixtures thereof and more preferably is cinchonidine.

The above resolution stage using chiral base is carried out optionally in the presence of aliphatic and aromatic, cyclic and acyclic tertiary amines such as triethylamine, diethylamine, diisopropylethylamine etc.

According to the present invention compound of formula V is further undergo nonepimerizable amidation to get the Brivaracetam with high purity.

The amidation reaction of the present invention is carried out in presence of ammonia source, which is selected from the group consisting of but not limited to ammonium hydroxide, gaseous ammonia, (NH4)2CO3, (NH4)HCO3, H2NCOONH4 or NH4Cl.

In the present invention, wherein the amidation is further carried out in presence of condensing agent such as EDC, HOBT or mixtures thereof or optionally in presence of metal salts such as copper salts.

The solvent used in the present invention is selected from the group consisting of but not limited to organic solvent such as "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and like; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and like; "polar solvents" such as water; and mixtures thereof.

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.

Examples:
Example 1: Preparation of Compound of Formula V (Chiral base is Cinchonidine)
Methanol (180 mL) was charged into autoclave at room temperature followed by the addition of compound of Formula IV (20 g). 10% Pd/C (1.0 g) was charged and the reaction mass was cooled to below 15°C. Hydrogen gas was applied into reaction mass and stirred for 8-12 hours. After completion of the reaction, reaction mass was filtered and washed with methanol (20 mL). The filtrate was distilled out completely under vacuum and the residue was treated with mixture of ethyl acetate: water (3:2) at room temperature. The organic layer was separated and treated with (-)-Cinchonidine (24.85 g) at 55-60°C followed by stirring for 2-3 hours. After completion of the reaction the reaction mass was cooled to room temperature and solid was filtered and washed. The obtained solid recrystallized with ethyl acetate (570 mL) and dried at 50°C-55°C for 6-8 hours to obtain the titled compound.
Yield: 60 %
Example 2: Preparation of Brivaracetam
The compound of Formula V (100 g) was charged into the RBF having mixture of dichloromethane (300 mL) and water (200 mL) mixture at room temperature followed by the addition of conc. HCl (120 g) and stirred. After the completion of reaction, the organic layer was separated. The organic layer was distilled under vacuum to get the residue. The obtained residue was charged with mixture of water (200 mL) and acetonitrile (300 mL) at room temperature followed by the addition of HOBT.H2O (24.1 g) and ammonium chloride (31.6 g) and stirred. Triethyl amine (27.9 g) was added followed by the addition of EDC.HCl (45.3 g) in lot wise and stirred. After the completion reaction mass was distilled out under vacuum followed by the addition of water (800 mL) and the pH was adjusted to 2-3. The reaction mass was cooled and stirred. The obtained solid was filtered and aqueous layer was treated with Dichloromethane (500 mL) twice and stirred; settled the reaction mass and the desired dichloromethane layer was separated. The organic layers were combined and treated with 2N Hydrochloric acid (200 mL), the reaction mass was allowed to settle, and the organic layer was separated. The obtained organic layer was further treated with aqueous NaHCO3 (200 mL) under stirring and settled the reaction mass. The organic layer was separated, distilled under vacuum to obtain the residue. The residue was treated with Diisopropyl ether (500 mL) at reflux for an hour and cooled to 0°C-5°C. The solid obtained was filtered and dried at 30°C-35°C for 6-8 hours. Yield: 80%
,CLAIMS:1. A process for preparing Brivaracetam of Formula (I) comprising:

converting compound of formula V to Brivaracetam.

wherein the chiral base is selected from cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine or ephedrine.
2. The process according to claim 1, wherein the compound of Formula V is converted by treating with an amidation agent.
3. The process according to claim 2, wherein the amidation agent is ammonia source such as ammonium hydroxide, gaseous ammonia, (NH4)2CO3, (NH4)HCO3, H2NCOONH4 or NH4Cl mixture thereof and condensing agent.
4. A compound of Formula V

wherein the chiral base is selected from cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine, ephedrine.

5. A process for the preparation of compound of Formula V which comprises
treating compound of formula IV

with reducing agent followed by chiral base selected from cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine or ephedrine.
6. The process according to claim 5, wherein the reducing agent is selected from Pd/C, Pd(OH)2, Pt/C, Palladium(II) acetate, Raney Ni, Pd/Alumina or Rh/C.
7. The process according to claim 5 further comprises compound of formula V undergo nonepimerisable amidation.
8. The process according to claim 7, wherein the amidation is carried out in presence of ammonia source and condensing agent.
9. The process according to claim 8, wherein the ammonia source include ammonium hydroxide, gaseous ammonia, (NH4)2CO3, (NH4)HCO3, H2NCOONH4 or NH4Cl.
10. The process according to claim 7, wherein the amidation is carried out in the presence of condensing agent such as EDC, HOBT or mixtures thereof optionally in presence of metal salts such as copper salts.