Abstract: " A Process for Preparing Brivaracetam" A process for the preparation of Brivaracetam, an anti-convulsion drug, is provided comprising Hofmann rearrangement of (S)-3-(2-(chloroamino)-2-oxoethyl) hexanoic acid, followed by cyclization resulting in (R)-4-propyl-pyrrolidin-2-one which on condensation with bromo butyric acid or ester followed by reaction with ammonia results in Brivaracetam.
1. A process for the preparation of brivaracetam having the structure:
Di Lvamuemm comprising :
a) reacting (S)-3-(2-amino-2-oxoethyl) hcxanoic acid having the staicture (II):
with a chlorinating agent selected from the group consisting of trichloroisocyanuric acid, sodium dichloroisocyanurate and N-chtorosuccinimide, in a solvent selected from the group consisting of methanol, ethanol, acetonitrile, and dimethyl formamide at a temperature between 20° C and 40°C to produce (S)-3-(2-(chloroamino)-2-oxoethyl) hexanoic acid having the structure (III):
b) reacting (III) with sodium hydroxide in water, initially at a temperature between 15° C and 30°C, and later at a temperature between 85° C and 95° C to produce (R)-4-propyl-pyrrolidin-2-one having the structure (1)
(I) or optionally, the compound (III) is reacted with sodium hydroxide at a temperature between 15° C and 30°C to obtain (R)-3-(aminomethyl) hexanoic acid having the structure (IV)
followed by cyclizing the compound (IV) at a temperature between 85° C and 95° C to form (R)-4-propyl-pyrrolidin-2-one (I)
c) converting the reaction product of step (b) or (c) into brivaracetam.
2. A compound (S)-3-(2-(chloroamino)-2-oxoethyl) hexanoic acid having the structure (III)
3. The process as claimed in claim la, wherein the (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) is prepared by:
a) reacting 4-propyl piperidine-2,6-dione having the structure (V)
with an aqueous solution of sodium hydroxide at a temperature between 40° C and 60° C to obtain a racemic mixture of 3-(2-amino-2-oxoethyl) hexanoic acid having the structure (VI):
b) reacting racemic (VI) with (S)-(-)-l-PhenyIethylamine in chloroform containing (
2 to 5 % ethanol at a temperature between 40° C and 55° C followed by cooling to
obtain (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) as a salt of (S)-(-)-l-Phenylethylamine; and
c) hydrolyzing the precipitated salt to obtain (S)-3-(2-amino-2-oxoethyl) hexanoic
acid (II).
4. A process as claimed in claim 1, wherein the isomer, (R)-3-(2-amino-2-oxoethyl) hexanoic acid having the structure (Ha), remaining after obtaining (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) from the racemic mixture as per the reaction of claim 5 stage (b),
is heated in toluene in the presence of a catalyst selected from the group consisting of boron trioxide, para-toluenesulfonic acid and sulfuric acid at a temperature between 100°C and 110° C to obtain4-propyl piperidine-2,6-dione (V).
| # | Name | Date |
|---|---|---|
| 1 | Form2 Title Page_Complete_21-10-2019.pdf | 2019-10-21 |
| 2 | Form 1_As Filed_21-10-2019.pdf | 2019-10-21 |
| 3 | Description Complete_As Filed_21-10-2019.pdf | 2019-10-21 |
| 4 | Correspondence by Applicant _As Filed_21-10-2019.pdf | 2019-10-21 |
| 5 | Claims_As Filed_21-10-2019.pdf | 2019-10-21 |
| 6 | Abstract_As Filed_21-10-2019.pdf | 2019-10-21 |
| 7 | Form9_Earlier Publication_28-10-2019.pdf | 2019-10-28 |
| 8 | Form18_Normal Request_28-10-2019.pdf | 2019-10-28 |
| 9 | Form 5_After Provisional_28-10-2019.pdf | 2019-10-28 |
| 10 | Correspondence by Applicant _Form 9_28-10-2019.pdf | 2019-10-28 |
| 11 | Correspondence by Applicant _Form 18_28-10-2019.pdf | 2019-10-28 |
| 12 | Form3_As Filed_21-11-2019.pdf | 2019-11-21 |
| 13 | Correspondence by Applicant_Form-3_21-11-2019.pdf | 2019-11-21 |
| 14 | 201941042636-Marked Copy-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 15 | 201941042636-Form 3-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 16 | 201941042636-Form 2 Title Page_Complete-04-11-2020.pdf | 2020-11-04 |
| 17 | 201941042636-Form 1-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 18 | 201941042636-Correspondence-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 19 | 201941042636-Claims-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 20 | 201941042636-Amended Pages Of Specification-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 21 | 201941042636-Abstract-FER Reply-04-11-2020.pdf | 2020-11-04 |
| 22 | 201941042636-PatentCertificate28-12-2020.pdf | 2020-12-28 |
| 23 | 201941042636-IntimationOfGrant28-12-2020.pdf | 2020-12-28 |
| 24 | 201941042636-Renewal Fee_26-07-2021.pdf | 2021-07-26 |
| 25 | 201941042636-FER.pdf | 2021-10-17 |
| 26 | 201941042636-Correspondence_Renewal Fee_08-08-2022.pdf | 2022-08-08 |
| 27 | 201941042636-Renewal 7 th Year .pdf | 2025-07-18 |
| 1 | 2020_0029_TranscriptC_29-09-2020.pdf |
| 2 | 201941042636searchreportE_24-07-2020.pdf |