Chemical and Pharmaceutical Bulletin p. 1160 - 1164 (1998)
Update date:2022-08-04
Topics:
Harada, Hiroshi
Morie, Toshiya
Kato, Shiro
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.
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