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Andrews, Ian P; Atkins, Richard J; Breen, Gary F; Carey, John S; Forth, Michael A; Morgan, David O; Shamji, Amin; Share, Andrew C; Smith, Stephen A. C; Walsgrove, Timothy C; Wells, Andrew S
Organic process research & development, 09/2003, Letnik: 7, Številka: 5Journal Article
The development of an efficient manufacturing route to 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester SB-235349, a key intermediate in the synthesis of lotrafiban is described. The synthesis starts with 2-nitrobenzyl alcohol which is mesylated, reacted with methylamine and then dimethylacetylene dicarboxylate followed by reduction of the nitro group. Treatment of the resultant aniline with acid gives an intermediate quinazoline which rearranges on treatment with base to give a 1,4-benzodiazapine. Reduction of the exocyclic double bond affords SB-235349. The process can be run without isolation of any of the intermediates and has been used to prepare several tons of SB-235349.
