The Development of a New Manufacturing Route to the Novel Anticonvulsant, SB-406725A

The development of an efficient manufacturing route to 3-acetyl- N -(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methylethoxy)-benzamide hydrochloride SB-406725A ( 1 ) is described. The synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane. Nitroisoquinoline ( 12 ) was hydrogenated under pressure using Pt/C. The resultant tetrahydroisoquinoline ( 13 ) was selectively coupled with benzoate side chain ( 15 ) under base-promoted conditions using sodium hexamethyldisilazane to yield the parent molecule SB-406725 ( 16 ). SB-406725 was then converted to the HCl salt SB-406725A ( 1 ). This process has been successfully demonstrated on a pilot-plant scale to prepare ∼30 kg of SB-406725A ( 1 ).