DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF BRIVARACETAM

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Brivaracetam and its intermediates.

BACKGROUND OF THE INVENTION

Brivaracetam is chemically known as (2S)-2-((4R) -2- oxo-4-n-propyl-1-pyrrolidinyl) butanamide as shown below a Compound of Formula (I). It is developed by UCB and marketed under the brand name of Briviact®. Brivaracetam is an antiepileptic agent and available in injection, oral solution and tablets. It is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

Formula (I)

(2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide was first disclosed in US 6,911,461 (herein after referred as US ‘461). US ‘461 also generically discloses the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide and it’s intermediate. US ‘461 discloses the purification of the compound of formula-I by using column chromatography.

The synthetic scheme described in above reference is schematically represented below (Scheme I):

The said process provides the racemic mixture of Brivaracetam, which was separated by preparative column chromatography which is not friendly process at plant scale due to expensive preparative column, extensive usage of solvent to separate the mixture. Moreover, it is not an environmental friendly process due to solvent evaporation on larger scale.

Journal of Medicinal Chemistry 2004, 47, 530-549, by Kenda et al., disclosed a process for the preparation of Brivaracetam as shown below (Scheme II)

The said process for the preparation of Brivaracetam involves chiral HPLC which is tedious, time consuming with low yield and less purity and thus making the process commercially non-viable.

In view of the above drawbacks, there is still an unmet need to develop an improved, economical, and feasible process for the preparation of Brivaracetam.

The present inventors have developed an efficient process for the preparation of Brivaracetam with good yield and purity without the use of preparative column chromatography.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to develop an improved process for the preparation of Brivaracetam and its intermediates with high purity and good yield on viable scale.

Yet another objective of the present invention is to provide a process for pure Brivaracetam using kinetic resolution of racemic Brivaracetam using a chiral reagent.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for preparation of Brivaracetam with good yield and high purity.

In another aspect, the present invention relates to a process for the preparation of Brivaracetam intermediate.

In another aspect, the present invention relates to a process for kinetic resolution of racemic mixture of Brivaracetam.

In another aspect, the present invention relates to the preparation of a co-crystal of Brivaracetam with chiral reagent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: PXRD pattern of Brivaracetam- D-tartaric acid co-crystal.

Figure 2: DSC pattern of Brivaracetam-D-tartaric acid co-crystal.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, the present invention provides an improved process for the preparation of Brivaracetam comprising the steps of:

a) reduction of [(S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl) butanamide (Compound 1) using Raney Nickel in the presence of hydrogen and an organic acid to give a diastereomeric mixture of [(2S)-2-((4R)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A- desired isomer) and [(2S)-2-((4S)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B- undesired isomer);

b) resolution of mixture of isomers i.e. [(2S)-2-((4R)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A) and [(2S)-2-((4S)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B) using chiral reagent to give corresponding salt with [(2S)-2-((4R)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide (Compound 3);

c) de-salification of Brivaracetam salt obtained in step (b) using a suitable base to give Brivaracetam.

The present invention provides a process for the preparation of Brivaracetam as depicted in Scheme III below.

The catalyst employed in step (a) comprises Pd/C, Pt/C or Raney Nickel.

The organic acid employed in step (a) comprises formic acid, acetic acid, malonic acid, citric acid, tartaric acid, mandelic acid or succinic acid.

The chiral reagent used in step (b) comprises R-Mandelic acid, D-Tartaric acid or D-Malic acid, more preferably D-tartaric acid.

The solvent(s) used in the said step comprises of water, methanol, ethanol, isopropanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, iso propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, toluene, methyl tertiary butyl ether, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or mixtures thereof.

The base employed in step (c) comprises of hydroxides, carbonates and bicarbonates of alkali & alkaline earth metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate or the like; ammonium hydroxide, ammonium bicarbonate or mixture thereof.

Another aspect of the present invention provides a process for the resolution of racemic mixture of Brivaracetam using D-tartaric acid as chiral reagent and forming a co-crystal with Brivaracetam.

The process for resolution of a diastereomeric mixture of Brivaracetam (Compound 2) comprises the steps of
i) dissolving the diastereomeric mixture of Brivaracetam in a solvent;
ii) adding D-tartaric acid to the solution obtained in step (i) and heating the reaction mixture to a temperature ranging between 40-100°C;
iii) cooling the reaction mixture to 10-25°C and filter the precipitated compound and wash with suitable solvent;
iv) drying the obtained solid until a constant weight is achieved.

The present invention provides a process for the resolution of diastereomeric mixture of Brivaracetam as depicted in Scheme IV below.

In another aspect the present invention provides Brivaracetam- D-tartaric acid co-crystal having Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another aspect the present invention provides Brivaracetam- D-tartaric acid co-crystal characterized by DSC thermogram shown in Figure -2.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of (2S)-2-((4R)-2-Oxo-4-n-propyl-1-pyrrolidinyl) butanamide (2A) with 1:1 ratio of Raney Nickel in presence of citric Acid.

Purified water (1000 mL) was charged into autoclave at room temperature followed by the addition of compound-1 [(S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl) butanamide; 100 g, 0.476 mol] and citric acid (91g, 0.47 mol). After dissolution, Raney Nickel (100 mL) was charged at room temperature. The reaction mixture was degassed and hydrogen gas was introduced into reaction mass and stirred for 4-6 hours at room temperature. After completion of the reaction, reaction mass was filtered and washed with water (100 mL). From the filtrate, product was extracted with methylene dichloride (2*500 mL) by adjusting pH 6.5 to 7.5 with aqueous sodium carbonate solution. The organic layer was evaporated under vacuum at 40 °C to dryness leading to solid. This solid was dissolved in MTBE (200 mL) and crystalized from n-heptane (400 mL). Isolated solid was dried under vacuum (10 mbar) at 40° C for 10 h to give the mixture of the two stereoisomers i.e. [(2S)-2-((4R)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A) and [(2S)-2-((4S)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B), (86 g, 86% yield, 61.4% d.e.).
EXAMPLE 2: Preparation of (2S)-2-((4R)-2-Oxo-4-n-propyl-1-pyrrolidinyl) butanamide (2A) with 1:1 ratio of Raney Nickel in presence of tartaric acid.

Purified water (150 mL) was charged into autoclave at room temperature followed by the addition of compound-1 [(S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl) butanamide; 10 g, 0.0476 mol] and tartaric acid (7.14 g, 0.0476 mol). After dissolution, Raney Nickel (10 mL) was charged at the room temperature. The reaction mixture was degassed and hydrogen gas was introduced into reaction mass and stirred for 4-6 hours at room temperature. After completion of the reaction, reaction mass was filtered and washed with water (40 mL). From the filtrate, the product was extracted with methylene dichloride (2*50 mL) by adjusting pH 6.5 to 7.5 with aqueous sodium carbonate solution. The organic layer was evaporated under vacuum at 40° C to dryness leading to solid which was dissolved in MTBE (20 mL) and crystalized with n-heptane (40 mL). The solid was isolated and dried under vacuum (10 mbar) at 40° C for 10 h to give the mixture of two stereoisomers i.e., (2S)-2-((4R)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide (Compound 2A) and (2S)-2-((4S)-2-Oxo-4-N-propyl-1-pyrrolidinyl) butanamide (Compound 2B), (8.5 g, 85 % yield, 50% d.e.).

EXAMPLE 3: Preparation of Brivaracetam D-tartaric acid Co-Crystal

Ethyl acetate (300 mL) and mixture of Compounds 2A & 2B (30 g, 0.14 mol) obtained from example-1 were charged into the reactor and stirred until a clear solution. D-tartaric acid (21.2g, 0.14 mol) was charged and heated to 45-50°C, stirring was continued until solid was precipitated. The reaction mass was cooled to room temperature, precipitate was filtered and washed with ethyl acetate to obtain white solid.

The obtained solid was added to ethyl acetate (200 mL) followed by D-tartaric acid (4.2g) and heated to 60-70°C and stirred for 60 minutes. The reaction mass was cooled to 20-25°C. The precipitate was filtered and washed with ethyl acetate to obtain white solid.

The obtained solid was charged again in ethyl acetate (200 mL) followed by addition of D-tartaric acid (4.2g) and heated to 60-70°C and stirred for an hour. The reaction mass was cooled to 20-25°C and the precipitate was filtered, washed with ethyl acetate to obtain white solid. The obtained solid was dried at 50-60 ? under vacuum. (38 g, 75% yield, 99.9 % de).

EXAMPLE 4: Preparation of Brivaracetam D-tartaric acid Co-Crystal

Acetonitrile (300 mL) and mixture of Compounds 2A & 2B (30 g, 0.14 mol) obtained from example-1 were charged into the reactor and stirred until a clear solution. D-tartaric acid (21.2g, 0.14 mol) was charged and heated to 45-50°C, stirring was continued until solid was precipitated. The reaction mass was cooled to room temperature, precipitate was filtered and washed with acetonitrile to obtain white solid.

The obtained solid was charged into acetonitrile (200 mL) followed by addition of D-tartaric acid (4.2g), heated up to 50-60°C and stirred for an hour. The reaction mass was cooled to 20-25°C. The precipitate was filtered and washed with acetonitrile to obtain white solid.

The obtained solid was charged into acetonitrile (200 mL) and followed by addition of D-tartaric acid (4.2g) and the total mass was heated to 50-60°C. Stirring was continued for an hour. The reaction mass was cooled to 20-25°C. The precipitate was filtered and washed with acetonitrile to obtain white solid which was then dried at 50-60 ? under vacuum. (30 g, 59% yield, 99.8 % de).

EXAMPLE 5: Preparation of Brivaracetam
Water (76mL), methylene chloride (228 mL) and 38g (0.18mol) of Compound 3 were charged into a reactor at room temperature followed by addition of an aqueous solution of sodium carbonate (100 ml of water and 30g) in dropwise manner at 20-30 ? and the pH was adjusted between 6.5-7.5. The organic layer was separated and aqueous layer was extracted with methylene chloride (228 mL). The organic layers were combined and washed with brine solution, concentrated and residue obtained was dissolved in MTBE at 50°C followed by addition of n-heptane. The reaction mass was cooled to room temperature, the precipitate was filtered and washed with MTBE and n-heptane mixture to obtain white solid. (21 g, 94% yield, HPLC purity is 99.9%). ,CLAIMS:WE CLAIM:

1. A process for the preparation of Brivaracetam (I),

(I)

which comprises:

a) reduction of [(S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl) butanamide (Compound 1) using a catalyst in the presence of hydrogen and an organic acid to give a diastereomeric mixture of [(2S)-2-((4R)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A) and [(2S)-2-((4S)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B);

b) resolution of mixture of isomers i.e. [(2S)-2-((4R)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A) and [(2S)-2-((4S)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B) using a chiral reagent to give Brivaracetam chiral salt (Compound 3);

c) de-salification of Brivaracetam chiral salt obtained in step (b) using a suitable base to give Brivaracetam.

2. The process as claimed in claim-1, wherein the catalyst comprises Pt/C, Pd/C, or Raney Nickel.

3. The process as claimed in claim-1,wherein the organic acid comprises formic acid, acetic acid, malonic acid, citric acid, tartaric acid, mandelic acid or succinic acid.

4. The process as claimed in claim-1, wherein the chiral catalyst comprises R-mandelic acid, D-tartaric acid or D-malic acid.

5. The process as claimed in claim-1, wherein D-tartaric acid is used as chiral reagent to prepare Brivaracetam – D-tartaric acid co-crystal.

6. A process for the resolution of mixture of Brivaracetam isomers i.e. [(2S)-2-((4R)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2A) and [(2S)-2-((4S)-2-oxo-4-N-propyl-1-pyrrolidinyl) butanamide] (Compound 2B) using a chiral reagent comprising of R-mandelic acid, D-tartaric acid or D-malic acid.

7. The process as claimed in claim-5, wherein D-tartaric acid is used as the chiral reagent to produce Brivaracetam-D-tartaric acid co-crystal.

8. The process as claimed in claim-5 and claim-6 wherein the obtained chiral acid salt is further converted to Brivaracetam.