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

Article abstract of DOI:10.1248/cpb.46.1160

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.

Full text of DOI:10.1248/cpb.46.1160

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NII-Electronic Library Service

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NII-Electronic Library Service

NII-Electronic Library Service