Process for preparing Brivaracetam
Inventors
Divi, Murali Krishna Prasad • Rao, Mysore Aswatha Narayana • Nowshuddin, Shaik
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10781170-B1
Publication Date
2020-09-22
Expiration Date
Abstract
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.
Core Innovation
The invention describes a process for preparing brivaracetam by forming the key intermediate (R)-4-propyl-pyrrolidin-2-one (I) through conversion of the (S)-acid (II). The process begins by reacting (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) with a chlorinating agent in a selected solvent to produce (S)-3-(2-(chloroamino)-2-oxoethyl) hexanoic acid (III).
The intermediate (III) is then reacted with sodium hydroxide in water under staged temperature conditions to produce (R)-4-propyl-pyrrolidin-2-one (I). Optionally, (III) is converted under the initial sodium hydroxide/water conditions into (R)-3-(aminomethyl) hexanoic acid (IV), followed by cyclizing (IV) to form (R)-4-propyl-pyrrolidin-2-one (I).
The disclosure further relates to preparing (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) from 4-propyl piperidine-2,6-dione (V) via hydrolysis to a racemate and resolution using (S)-(-)-1-phenylethylamine. The remaining unwanted isomer is addressed by dehydration to regenerate symmetrical (V), and the document reports conversions and purities for isolating intermediates and for cyclization, including recovery of cyanuric acid byproduct.
Claims Coverage
The independent claim is directed to an overall process for preparing brivaracetam with four inventive features centered on the conversion of (S)-acid (II) to brivaracetam through intermediates (III), (IV), and (I).
Chlorinating (S)-3-(2-amino-2-oxoethyl) hexanoic acid to (S)-chloroamino acid (III)
Reacting (S)-3-(2-amino-2-oxoethyl) hexanoic acid having the structure (II) with a chlorinating agent selected from trichloroisocyanuric acid, sodium dichloroisocyanurate, and N-chlorosuccinimide in a solvent selected from methanol, ethanol, acetonitrile, and dimethylformamide to produce (S)-3-(2-(chloroamino)-2-oxoethyl) hexanoic acid having the structure (III).
Staged sodium hydroxide/water conversion of (III) to (R)-4-propyl-pyrrolidin-2-one (I)
Reacting (III) with sodium hydroxide in water under staged temperatures to produce (R)-4-propyl-pyrrolidin-2-one having the structure (I).
Optional formation and cyclization via (R)-3-(aminomethyl) hexanoic acid (IV)
Optionally reacting (III) with sodium hydroxide to obtain (R)-3-(aminomethyl) hexanoic acid having the structure (IV), followed by cyclizing (IV) to form (R)-4-propyl-pyrrolidin-2-one (I).
Conversion of (R)-4-propyl-pyrrolidin-2-one-forming product to brivaracetam
Converting the reaction product of step (b) or (c) into brivaracetam.
Across the independent claim, the coverage centers on chlorination of (S)-acid (II) to (III), sodium hydroxide/water treatment to form (R)-4-propyl-pyrrolidin-2-one (I), an optional (R)-aminomethyl intermediate (IV) pathway, and final conversion into brivaracetam.
Stated Advantages
Avoiding hazardous or explosive nitromethane.
Reducing the need for industrially unsuitable chiral chromatography.
Avoiding expensive nickel/chiral-ligand and specialized transaminase enzymes.
Recycling the unwanted isomer.
Documented Applications
Preparation of brivaracetam by converting (S)-3-(2-amino-2-oxoethyl) hexanoic acid into the intermediate (R)-4-propyl-pyrrolidin-2-one and then converting to brivaracetam.
Preparation of (S)-3-(2-amino-2-oxoethyl) hexanoic acid (II) from 4-propyl piperidine-2,6-dione (V) via hydrolysis to a racemate and resolution using (S)-(-)-1-phenylethylamine, with recycling of the unwanted isomer by dehydration to regenerate symmetrical (V).
Interested in licensing this patent?