Process for the preparation of (R)-4-propyl pyrrolidine-2-one, a key intermediate for synthesis of brivaracetam
Inventors
Divi, Murali Krishna Prasad • Bolneni, Nageswara Rao • BANDARUPALLI, Leela Maheswara Rao
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11884623-B2
Publication Date
2024-01-30
Expiration Date
Abstract
A process for the preparation of (R)-4-propyl-pyrrolidine-2-one, is provided which includes enzymatic conversion of dimethyl 3-propyl pentanedioate selectively into (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid using Novozyme's Promea® enzyme, amidation of (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid, followed by ester hydrolysis to obtain (S)-3-(2-amino-2-oxoethyl) hexanoic acid having high chiral purity >99% and converting the amide to amine by Hofmann rearrangement and cyclization resulting in (R)-4-propyl-pyrrolidine-2-one. It is further converted to Brivaracetam by N-alkylation with 2-bromobutyric acid, esterification followed by enzymatic resolution.
Core Innovation
The invention relates to an improved industrial process for the preparation of (R)-4-propyl-pyrrolidin-2-one and for the preparation of (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (brivaracetam). The process includes stereoselective transformations that convert dimethyl 3-propylpentanedioate into intermediates and ultimately to brivaracetam.
A key step is stereoselective hydrolysis of dimethyl 3-propylpentanedioate using Novozyme’s Promea®, a lipase liquid enzyme having EC 3.1.1.3, in the presence of a buffer solution at a pH from 7.0 to 9.0 and a temperature from 15° C. to 30° C. to obtain (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid with high chiral purity.
The obtained (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid is then converted through reacting with ammonia to obtain methyl (S)-3-(2-amino-2-oxoethyl) hexanoate, followed by conversion to (S)-3-(2-amino-2-oxoethyl) hexanoic acid and Hofmann rearrangement/cyclization to obtain (R)-4-propyl-pyrrolidin-2-one with high enantiomeric excess, after which (R)-4-propyl-pyrrolidin-2-one is converted into brivaracetam.
Claims Coverage
The document contains one independent claim that covers a stereoselective multi-step synthesis sequence from dimethyl 3-propylpentanedioate to brivaracetam, including a Promea®-based stereoselective hydrolysis step and subsequent conversions to the (R)-4-propyl-pyrrolidin-2-one intermediate and final amide formation. The claim includes multiple inventive features spanning enzyme-based resolution and structured conversion steps constrained by specified reagents, and pH/temperature ranges.
Promea® EC 3.1.1.3 stereoselective hydrolysis in buffered pH 7.0–9.0 at 15–30° C.
Stereoselective hydrolysis of dimethyl 3-propylpentanedioate using Novozyme’s Promea®, a lipase liquid enzyme having EC 3.1.1.3, in the presence of a buffer solution at pH 7.0 to 9.0 and at a temperature from 15° C. to 30° C. to obtain (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid.
Methyl chloroformate/amine amidation to methyl (S)-3-(2-amino-2-oxoethyl) hexanoate at -20–0° C.
Reacting the compound of formula (IV) with ammonia in dichloromethane, in the presence of methyl chloroformate and base N-methylmorpholine or triethylamine at a temperature from -20° C. to 0° C. to obtain methyl (S)-3-(2-amino-2-oxoethyl) hexanoate of formula V.
Hydrochloric acid conversion to (S)-3-(2-amino-2-oxoethyl) hexanoic acid at 20–40° C.
Reacting the compound of formula (V) with hydrochloric acid at 1.0M to 4.0M solution at a temperature from 20° C. to 40° C. to obtain (S)-3-(2-amino-2-oxoethyl) hexanoic acid of formula VI.
Hofmann rearrangement/cyclization using tricholoroisocyanuric acid and sodium hydroxide in water with staged temperatures
Converting the compound of formula (VI) by Hofmann rearrangement using tricholoroisocyanuric acid and sodium hydroxide in water at a temperature from 15° C. to 30° C., and later at a temperature from 85° C. and 100° C. to obtain (R)-4-propyl-pyrrolidin-2-one (I).
Conversion of (R)-4-propyl-pyrrolidin-2-one to brivaracetam
Converting the compound of formula (I) into (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (brivaracetam).
Across the independent claim, the inventive coverage centers on using Promea® (EC 3.1.1.3) to stereoselectively hydrolyze dimethyl 3-propylpentanedioate to the (S)-methoxy-oxoethyl hexanoic acid intermediate, followed by constrained conversion steps to the (S)-amino acid intermediate and Hofmann rearrangement/cyclization to the (R)-4-propyl-pyrrolidin-2-one intermediate, with final conversion to brivaracetam.
Stated Advantages
High chiral purity for the (S)-3-(2-methoxy-2-oxoethyl) hexanoic acid obtained by stereoselective hydrolysis using Promea®.
High enantiomeric excess for the (R)-4-propyl-pyrrolidin-2-one obtained by Hofmann rearrangement/cyclization (reported as >99% ee in the provided content).
Avoidance of prior hazardous/toxic or expensive catalysts/reagents, as described in the provided content.
Documented Applications
Preparation of the key intermediate (R)-4-propyl-pyrrolidin-2-one for brivaracetam production.
Preparation of (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (brivaracetam) from dimethyl 3-propylpentanedioate using the described stereoselective sequence.
Interested in licensing this patent?