US 8,476,437 B2Granted

Process for preparation of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine and new impurities in preparation thereof

AssigneeCadila Healthcare Limited

InventorsHimanshu Madhusudan Kothari, Mayank Ghanshyambhai Dave, Bipin Pandey, Bhavin Shriprasad Shukla

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Abstract

The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4-[3-Ctrifluoromethyl)-5,6-dihydrol[1,2,4]triazolo[4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).

Claims8

Dependent claims

A process for the preparation of compound of formula (I) or its salts comprising,

a) reacting trifluorophenylacetic acid (II) or its acid chloride with Meldrum's acid and 3-trifluoromethyl 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine.HCl of formula (III) in presence of a suitable base and suitable acid, which is further converted to the compound of a formula (IV) by reacting with suitable alkali and alkali earth metals in suitable solvent
b) reacting the compound of formula (IV) with suitable ammonia source or with a suitable organic amine in a suitable solvent and optionally in the presence of a suitable acid to obtain the compound of formula (V)
(c) reducing the compound of formula (V) by using suitable borane containing reducing agent optionally in the presence of an acid in a suitable solvents to obtain racemic compound of formula (VI)
d) resolution of the compound formula (VI) by suitable chiral resolving agents in suitable solvents to obtain the diastereomeric salt of compound of formula (I)
e) optionally, deprotecting the compound of formula (VI) (Wherein R≠H) prior to resolution;
f) converting the diastereomeric salt of compound of formula (I), with suitable base in presence of suitable solvents to obtain compound of formula (I);
g) optionally preparing a salt of formula (I), as formula (Ib), having at least 70% chiral purity, by reacting the compound of formula (I) with a suitable acid(s) in a suitable solvent(s), with the salt further converted to the compound of formula (Ia), having at least 90% chiral purity, by suitable chiral enrichment

4 more elements

Dependencies are inferred from the claim text.