Process for the preparation of febuxostat
An improved and efficient process for the preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (febuxostat) that is substantially free from amide by-product is provided.
1. A process for the preparation of febuxostat of Formula I
comprising the steps of:
(i) reacting 4-hydroxy thiobenzamide of Formula II
with a compound of Formula III (wherein X is halogen and R is alkyl or arylalkyl)
to give a compound of Formula IV;
(ii) formulation of the compound of Formula IV with hexamethylene tetramine in presence of an acid to give a compound of Formula V;
(iii) reaction of the compound of Formula V with hydroxylamine hydrochloride to give a compound of Formula VI;
(iv) alkylation of the compound of Formula VI with isobutyl halide of Formula VII (wherein X is halogen)
to give a compound Formula VIII; and
(v) hydrolysis of the compound of Formula VIII in the presence of barium oxide.
2. A process for the preparation of febuxostat of Formula I
comprising the steps of:
(i) reacting 4-hydroxy thiobenzamide of Formula II
with a compound of Formula III (wherein X is halogen and R is alkyl or arylalkyl)
to give a compound of Formula IV;
(ii) formulation of the compound of Formula IV with hexamethylene tetramine in presence of an acid to give a compound of Formula V;
(iii) reaction of the compound of Formula V with hydroxylamine hydrochloride to give a compound of Formula VI;
(iv) alkylation of the compound of Formula VI with isobutyl halide of Formula VII (wherein X is halogen)
to give a compound Formula VIII; and
(v) hydrolysis of the compound of Formula VIII in the presence of barium hydroxide octahydrate.
3. A process for the preparation of febuxostat of Formula I
comprising hydrolysis of the compound of the following formula
with barium hydroxide octahydrate.
4. The process according to claim 3 , wherein febuxostat of Formula I is substantially free of amide by-product.
5. The process according to claim 3 , wherein febuxostat of Formula I contains 0.07% amide by-product.
6. The process according to claim 3 , wherein in febuxostat of Formula I contains less than 0.07% amide by-product.