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

• Published in: Chemical & pharmaceutical bulletin Vol. 46; no. 7; pp. 1160 - 1164
• Main Authors: HARADA, Hiroshi, MORIE, Toshiya, KATO, Shiro
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1998; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: (R)-6-aminohexahydro-1, 4-diazepine; (S)-2, 3-diaminopropyl-aminoacetate; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; DAT-582; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; intramolecular reductive cyclization; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Preparations and properties; Science & Technology; Serotoninergic system; intramolecular reductive cyclization; GR38032F; (S)-2,3-diaminopropyl-aminoacetate; (R)-6-aminohexahydro-1,4-diazepine; PREVENTION; 5-HT3 RECEPTOR ANTAGONIST; EMESIS; DAT-582; Reaction intermediate; Intramolecular reaction; Chemical reduction; α-Aminoacid; Cyclization; Enantioselectivity; Nitrogen heterocycle; 5-HT3 Serotonine receptor; Antagonist; Chemical synthesis; R configuration; Seven membered ring
• ISSN: 0009-2363; 1347-5223
• 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.