DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201841047956 filed on December 18, 2018; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of Brivaracetam and the intermediates useful for the preparation of Brivaracetam.

BACKGROUND OF THE INVENTION

Brivaracetam is chemical analog of levitracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients sixteen years of age and older with epilepsy.

Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrole-1-yl] butanamide and is represented by formula I as mentioned below.

Brivaracetam is first disclosed in the US Patent No. 6784197 assigned to UCB. This Patent discloses the below mentioned schemes for the preparation of Brivaracetam.

The formation of undesired isomer in during these processes, decreases the yield of Brivaracetam.
Similar reactions are also exemplified in this patent as mentioned below in Scheme-4.

The Scheme-1, Scheme-2, Scheme-3 and Scheme-4 are also disclosed in the US Patent No. 8034958 assigned to UCB and the publication Journal of Medicinal Chemistry 2004, 47, 530-549.

The US Patent No. 8796262 filed on July 8, 2011 and published on August 5, 2011 discloses the preparation of the 4-chloro-3-methyl-butyric acid methyl ester as mentioned below.

The Publication Organic Process Research Development entitled “A bio-catalytic route to the novel anti-epileptic drug Brivaracetam” published on August 24, 2016 discloses the process for the Brivaracetam as disclosed below.

Here, the unreacted lactones in the ethyl estered hexanoate intermediate is more and thereby decreases yield.

The PCT publication WO 2016191435 assigned to Wang, Peng disclosed the process for the preparation of Brivaracetam given in the following Scheme-7 & Scheme-8.

The PCT publication WO 2018042393 assigned to Microlabs Limited exemplified the process for preparing Brivaracetam given in the following Scheme-9.

Besides the existence of various processes for the preparation of Brivaracetam, there remains a need for improved processes for the preparation of Brivaracetam producing high yields and purity, and being well-suited for use on an industrial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Brivaracetam.

Another objective of the present invention is to provide an improved process for preparing the compound of formula II, which is an intermediate useful for the preparation of Brivaracetam.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for preparing Brivaracetam.

In one of theaspect of the present invention, there is provided a process for preparing the compound of formula II, an intermediate useful in the preparation of Brivaracetam

said process comprising the steps of:
(a) providing the compound of formula III in a suitable solvent;

(b) adding thionyl chloride at temperatures above 40°C to step (a);
(c) maintaining the reaction mixture at temperatures above 40°C obtained in step (b) till the completion of the reaction;
(d) optionally concentrating the reaction mixture obtained in step (c);
(e) cooling the reaction mixture obtained in step (c) or step (d); and
(f) isolating the compound of formula II from the reaction mixture obtained in step (e).

In some embodiment, step (a) of the described process for the preparation of formula II is carried out in suitable solvent selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

In some embodiment, step (b) of the above described process for the preparation of formula II is carried out at temperatures above 40°C, preferably at 45°C. In some embodiment, step (c) of the above described process for the preparation of formula II is carried out at temperatures above 40° C, preferably at 45°C.

In some embodiment, step (d) of the above described process for preparing the formula II is carried out by distillation or conventional techniques. In some embodiment, step (e) of the above described process for the preparation of formula II is carried out at temperature below 20°C, preferably at 15?.

In some embodiment, the compound of formula II prepared by the above described process is isolated by adding water and water immiscible solvent to the reaction mixture obtained in the step (e) followed by separating of organic layer and concentrating. In some embodiment, the water immiscible solvent is ethyl acetate.

Another aspect of the present invention is to provide a process for the preparation of Brivaracetam of formula I,

said process comprising the steps of:
(a) reacting compound of formula III with thionyl chloride to obtain a compound of formula II;

(b) reacting the compound of formula II with 2-(S)-aminobutanamide hydrochloride to obtain the compound of formula I.
In some embodiment, step (a) of the above described process for the preparation of Brivaracetam is carried out in suitable solvent selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

In some embodiment, step (a) of the above described process for the preparation of Brivaracetam is carried out at temperatures above 40°C, preferably at 45?.

In some embodiment, the step (b) of the above described process for the preparation of Brivaracetam is carried out in the presence of sodium carbonate and tetrabutyl ammonium iodide.

In some embodiment, the step (b) of the above described process for the preparation of Brivaracetam is carried out in presence of n-butyl acetate as solvent.

In some embodiment, the reaction mixture obtained in step (b) of the above described process for the preparation of Brivaracetam is heated at 105? for 20 hours.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for preparation of Brivaracetam and intermediates thereof.

The present invention provides a process for the preparation of a compound of formula II, an intermediate useful in the preparation of Brivaracetam.

One of the aspect of the present invention is to provide a process for the preparation of compound of formula II

said process comprising the steps of:
(a) providing the compound of formula III in a suitable solvent;

(b) adding thionyl chloride at temperatures above 40°C to step (a);
(c) maintaining the reaction mixture at temperatures above 40° C obtained in step (b) till the completion of the reaction;
(d) optionally concentrating the reaction mixture obtained in step (c);
(e) cooling the reaction mixture obtained in step (c) or step (d); and
(f) isolating the compound of formula II obtained in step (e).

In some embodiment, step (a) of the described process for the preparation of formula II is carried out in suitable solvent is selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

In some embodiment, step (b) of the above described process for the preparation of formula II is carried out at temperatures above 40°C, preferably at 45?.

In some embodiment, step (c) of the above described process for the preparation of formula II is carried out at temperatures above 40°C, preferably at 45?.

In some embodiment, step (d) of the above described process for preparing the formula II is carried out by distillation or conventional techniques.
In some embodiment, step (e) of the above described process for the preparation of formula II is carried out below 20°C, preferably at 15?.

In some embodiment, the compound of formula II prepared by the above described process is isolated by adding water and water immiscible solvent to the reaction mixture obtained in the step (e), followed by separating of organic layer and concentrating. In some embodiment, the water immiscible solvent is ethyl acetate.

Present inventors tried the chlorination reaction for the preparation of compound of formula II by different reagents in different conditions. Surprisingly, the present inventors found that the chlorination reaction by thionyl chloride achieves better conversion, is simple and easy to work up.

In general, chlorination reactions by thionyl chloride are performed at less than room temperature due to acid fume generation during the addition as well as during the reaction. The present inventors observed the sudden acid fumes during the chlorination reaction after addition of thionyl chloride at low temperature. This sudden generation of acid fumes builds an internal pressure that is not desirable on large scale preparation. Unexpectedly, the present inventors found the thionyl chloride addition at temperature above 40° C reduces the sudden generation of acid fumes during the reaction, and also avoids the risk of internal pressure release of acid fumes.

In some embodiment of the invention, the compound of formula III is converted to compound of formula II by treating compound of formula III with thionyl chloride at temperature of 45?.

Another aspect of the present invention is to provide a process for the preparation of Brivaracetam of formula I,

said process comprising the steps of:
(a) reacting compound of formula III with thionyl chloride to obtain a compound of formula II;

(b) reacting the compound of formula II with 2-(S)-aminobutanamide hydrochloride to obtain the compound of formula I.

In some embodiment, step (a) of the described process for the preparation of of Brivaracetam is carried out in suitable solvent selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

In some embodiment, step (a) of the above described process for the preparation of Brivaracetamis carried out at temperatures above 40°C, preferably 45?.

In some embodiment, the step (b) of the above described process for the preparation of Brivaracetam is carried out in the presence of sodium carbonate and tetrabutyl ammonium iodide.

In some embodiment, the step (b) of the above described process for the preparation of Brivaracetam is carried out in presence of n-butyl acetate as solvent.

In some embodiment, the reaction mixture obtained in step (b) of the above described process for the preparation of Brivaracetam is heated at 105? for 20 hours.

In some embodiment of the invention, there is provided a process for preparation of Brivaracetam from compound of formula II.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example -1: Preparation of compound of formula II
To a solution of (R)-dihydro-4-propylfuran-2(3H)-one (350 g) of formula III in methanol (1750 ml), thionyl chloride (1136.4 g) was added slowly at 45°C and the reaction mixture was maintained at 60°C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under reduced pressure at 40°C then cooled to 20°C. The obtained cooled mass was mixed with water (1750 ml) followed by ethyl acetate (1750 ml) to form a biphasic mixture then separated the ethyl acetate layer. The obtained ethyl acetate layer was washed with water and concentrated under reduced pressure to obtain the compound of formula II. Yield: 483 g.

Example -2: Preparation of compound of formula I
To a solution of methyl (R)-3-(chloromethyl) hexanoate (400 g) of formula II in n-butyl acetate (2800 ml), 2-S-aminobutanamide hydrochloride (465.5 g), sodium carbonate (593.3 g) and tetrabutylammonium iodide (248.1 g) were added and the reaction mixture was heated to 105°C and maintained for 20 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was cooled to 20°C and maintained the temperature for about 30 minutes. The obtained cooled reaction mass was filtered. Then the filtrate was heated to 65°C followed by the addition of acetic acid (100 ml) and maintained the temperature for one hour. Then, the reaction mass was cooled to 20°C and maintained the same temperature for 30 minutes. The obtained cooled mass was filtered by hyflo bed and the filtrate was washed with aqueous sodium bicarbonate (400 ml) followed by water (400 ml). The obtained organic layer was concentrated under reduced pressure at 55°C then cooled to 20°C followed by the addition of methyl tert-butyl ether. The cooled reaction mass was maintained at 20°C for 2 hours. The resulted reaction mass was filtered through hyflo bed and then the filtrate was concentrated under reduced pressure followed by the addition of isopropyl acetate (400 ml). The reaction mixture was cooled to 10°C and maintained at the same temperature for 2 hours. The resulted mass was filtered and washed with di-isopropyl ether (200 ml) and dried to obtain the compound of formula I. Yield: 120 g.
,CLAIMS:1. A process for preparation of a compound of formula II

said process comprising the steps of:
(a) providing the compound of formula III in a suitable solvent;

(b) adding thionyl chloride at temperatures above 40°C to step (a);
(c) maintaining the reaction mixture at temperatures above 40°C obtained in step (b) till the completion of the reaction;
(d) optionally concentrating the reaction mixture obtained in step (c);
(e) cooling the reaction mixture obtained in step (c) or step (d); and
(f) isolating the compound of formula II from the reaction mixture obtained in step (e).

2. The process as claimed in claim 1, wherein the step (a) is carried out in suitable solvent selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

3. The process as claimed in claim 1, wherein the step (b) is carried out at temperatures above 40°C, preferably at 45°C.

4. The process as claimed in claim 1, wherein the (c) is carried out at temperatures above 40°C, preferably at 45°C.

5. The process as claimed in claim 1, wherein the step (d) is carried out by distillation technique.
6. The process as claimed in claim 1, wherein the step (e) is carried out at temperature below 20°C, preferably at 15°C.
7. The process as claimed in claim 1, wherein the compound of formula II is isolated by adding water and water immiscible solvent to the reaction mixture obtained in the step (e) followed by separating of organic layer and concentrating.

8. The process as claimed in claim 7, wherein the water immiscible solvent is ethyl acetate.

9. A process for the preparation of Brivaracetam of formula I,

said process comprising the steps of:
(a) reacting compound of formula III with thionyl chloride to obtain a compound of formula II;

(b) reacting the compound of formula II with 2-(S)-aminobutanamide hydrochloride to obtain the Brivaracetam of formula I.

10. The process as claimed in claim 9, wherein the step (a) is carried out in suitable solvent selected from the group comprising ethanol, methanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, toluene, benzene, xylene or mixture thereof, preferably methanol.

11. The process as claimed in claim 9, wherein the step (a) is carried out at temperatures above 40°C, preferably at 45°C.

12. The process as claimed in claim 9, wherein the step (b) is carried out in the presence of sodium carbonate and tetrabutyl ammonium iodide.

13. The process as claimed in claim 9, wherein the step (b) is carried out in presence of n-butyl acetate as solvent.

14. The process as claimed in claim 9, wherein the reaction mixture obtained in step (b) is heated at 105? for 20 hours to obtain Brivaracetam of formula (I).