1025925-41-0Relevant academic research and scientific papers
Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine
Hirokawa, Yoshimi,Horikawa, Tamaki,Noguchi, Hideto,Yamamoto, Katsuhisa,Kato, Shiro
, p. 28 - 35 (2002)
The optically active (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine (1) is the amine moiety of a novel and potent dopamine (D2 and D3) and 5-HT3 receptors antagonist AS-8112, which is a clinical candidate expected to be abroad antiemetic agent. Process development of an effective synthetic route to the optically active amine 1 from N-Cbz- and N-Ts-L-serine methyl esters was undertaken. In two potential scale-up processes, the route from N-Ts-L-serine methyl ester (21) was chosen because of its better overall yield (>30% yield for seven steps) and handling. The optically active amine 1 with high purity (>99.5% ee)was prepared via the reaction of the key intermediate N-Ts-aziridine 23 with EtNH2 and successive LiAlH4 reduction without racemization. Moderate scale-up synthesis of the amine 1 and AS-8112 by condensation of 1 and 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid is described.
Efficient synthesis of (R)-6-benzyloxycarbonylamino-1-methyl-4-(3- methylbenzyl)hexahydro-1,4-diazepine. I
Harada, Hiroshi,Morie, Toshiya,Kato, Shiro
, p. 1160 - 1164 (2007/10/03)
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.
