Efficient synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepine from methyl (2R)- and (2S)-1-benzyloxycarbonylaziridine-2-carboxylates

Abstract

An efficient and practical method for the synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepine 2, which serves as the amine part of DAT-582, a potent and selective 5-HT₃ receptor antagonist, is described. The key intermediates, the chiral 2,3-diaminopropionic esters 20 and 26, are prepared by treatment of the optically active aziridines (R)-13 and (S)-13, obtained from D- and L-serine methyl ester hydrochlorides (R)-9 and (S)-9, with the ethylenediamine 19 and its protected derivative 18, respectively. Intramolecular reductive cyclization of 20 gives the chiral 6-benzyloxycarbonylaminohexahydro-1H-1,4-diazepine 22 with high optical purity via the corresponding iminium salt. Deprotection of 22 affords the desired chiral amine 2. As an alternative method, intramolecular amidation of the 2,3-diaminopropionic acids 23 and 28, which are prepared from 20 and 26, gives the 6-benzyloxycarbonylaminohexahydro-1H-1,4-diazepin-5-one 24 and the 7-oxo analogue 29. After removal of the benzyloxycarbonyl group, the resultant compounds 25 and 30 are reduced with diisobutylaluminium hydride to produce the optically active amine 2.

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