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AssigneeEmcure Pharmaceuticals Limited
InventorsMukund Keshav Gurjar, Golakchandra Sudarshan Maikap, Shashikant Gangaram Joshi, Sachin Aravind Badhe, Samit Satish Mehta
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Disclosed is process for the preparation of a key Rilpivirine intermediate namely, (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) by a process comprising reaction of the tetrafluoroborate salt of the diazonium ion of 2,6-dimethyl-4-amino-1-carboxybenzyl phenylamine (VI) with acrylonitrile in presence of palladium acetate, followed by treatment with an acid and its subsequent conversion to the hydrochloride salt (II), wherein the undesired Z isomer is less than 0.5% and provides Rilpivirine hydrochloride having Z isomer less than 0.1%.
A process for the preparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) comprising reaction of 2,6-dimethyl-4-amino-1-carboxybenzyl phenyl amine (V) with sodium nitrite in hydrochloric acid, followed by treatment of the diazotized compound with alkali tetrafluoroborate to give the corresponding tetrafluoroborate salt of formula (VI), which on reaction with acrylonitrile in presence of palladium acetate and a solvent gave compound (VII), which after deprotection with an acid followed by treatment with hydrochloric acid gave compound (II) having Z-isomer less than 0.5%.
A process for preparation of Rilpivirine hydrochloride (I) having Z isomer less than 0.1%, comprising reaction of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) with 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile of formula (XI), in acetonitrile as solvent, isolating Rilpivirine free base at alkaline pH, optionally purifying with acetone, dissolving in dimethyl sulphoxide, heating the mixture to 50-55° C., adding hydrochloric acid followed by water and isolating Rilpivirine hydrochloride having Z isomer less than 0.1% at a temperature of 25-30° C.
(E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) having Z isomer less than 0.5%.
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