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

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Abstract

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).

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