Efficient Synthesis of (R)-6 Benzyloxycarbonylamino-1-methyl-4(3-methylbenzyl)hexahydro-1,4-diazepine. I.

Abstract

An efficient and practical method for large scale synthesis of (R)-6-benzyloxycarbonylamino-1-methyl-4-(3-methylbenzyl)hexahydro-1, 4-diazepine (R-3), which is a key intermediate in the synthesis of DAT-582, a potent and selective serotonin-3 receptor antagonist, is described. The precursor of R-3, the (S)-2, 3-diaminopropylaminoacetate S-5, was obtained from the chiral triaminopropane derivative R-19. Nucleophilic reaction of the chiral mesylate R-11 with 3-methylbenzylamine gave the racemic 2, 3-diaminopropylaminoacetate (±)-5 via the achiral azetidinium cation 12, while the reaction of the N-protected mesylate R-14 produced the desired triamine S-15 but in poor yield.However, reaction of the N-protected mesylate S-18 with a large excess of methylamine proceeded smoothly to afford R-19 in good yield. S-5 was converted into R-3 with >99% enantiomeric excess using an intramolecular reductive cyclization method.