Enzymatic process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid and its conversion into brivaracetam
Inventors
Divi, Satchandra Kiran • Rao, Mysore AswathaNarayana • Nowshuddin, Shaik
Assignees
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Publication Number
US-11400074-B1
Publication Date
2022-08-02
Expiration Date
Abstract
A process for the preparation of Brivaracetam, an anti-convulsion drug, is provided comprising enzymatic conversion of (2RS)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butyric acid methyl ester selectively into (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butyric acid having high chiral purity, using protease from Bacillus licheniformis. Converting the chirally pure acid into amide results in Brivaracetam.
Core Innovation
The described invention relates to an improved industrially scalable synthesis of brivaracetam. The process prepares (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (I) from (2RS)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid methyl ester (II). It first employs enzymatic hydrolysis to obtain the corresponding (2S) chiral acid (III) with high chiral purity.
The invention uses an alcalase protease from Bacillus licheniformis to hydrolyze racemic (2RS) ester (II) to (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid (III). The described approach is contrasted with prior approaches relying on chiral chromatography at industrial scale. It further includes conversion of acid (III) to brivaracetam (I) through mixed anhydride formation using ethyl chloroformate and ammonia.
The document reports example outcomes showing high yields and high chiral purity after the enzymatic and conversion steps. Reported example results include about 80.5% yield and about 99.4% chiral purity for Example 2, and about 88% yield and about 99.8% chiral HPLC purity for Example 6. The described process also includes solvent extraction and acidification steps, and the use of chiral purity measurements such as enantiomeric/chiral purity by HPLC.
Claims Coverage
The independent claim is directed to a four-step process for preparing (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (I) from the racemic methyl ester (II), including enzymatic hydrolysis, sequential extractions with specified solvent sets, acidification to form an acid intermediate with >95% chiral purity, and mixed anhydride conversion to the butanamide using ammonia, ethyl chloroformate, and a base. Dependent claims refine the enzymatic reaction conditions at step (a) by specifying pH control and temperature constraints.
Enzymatic hydrolysis with Bacillus licheniformis alcalase in aqueous solution
Reacting (2RS)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid methyl ester (II) with an alcalase protease from Bacillus licheniformis in an aqueous solution.
First organic extraction to remove unreacted ester and acidify aqueous layer
Extracting the reaction mixture with an organic solvent selected from n-hexanes, n-heptanes, and diisopropyl ether to remove unreacted compound of formula (II), and acidifying the aqueous layer using 5N hydrochloric acid.
Second extraction to obtain chiral acid intermediate with >95% chiral purity
Extracting the acidified layer from the extraction step with an organic solvent selected from dichloromethane, ethyl acetate, and isopropyl acetate to obtain (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid (III) having >95% chiral purity.
Ammonia/ethyl chloroformate mixed-anhydride conversion of acid (III) in dichloromethane
Reacting compound of formula (III) with ammonia in dichloromethane at a temperature of ≥10°C to ≤20°C in the presence of ethyl chloroformate and a base to obtain the butanamide having formula (I).
Across the independent claim, the inventive subject matter centers on enzymatic selective hydrolysis of racemic ester (II) using alcalase protease from Bacillus licheniformis, followed by sequential solvent extractions and aqueous acidification to isolate (2S) acid (III) with >95% chiral purity, and then converting (III) to brivaracetam (I) using ammonia with ethyl chloroformate and a base in dichloromethane.
Stated Advantages
Produces (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butyric acid (III) having >95% chiral purity.
Conversion step obtains (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide (I).
Improved industrially scalable synthesis of brivaracetam as described in the document.
Documented Applications
No documented applications found
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