BW-B385C

Chemical Name: N-[1-(S)-Carboxy-5-[4-(2-(S)-hydroxy-3-isopropylaminopropoxy)-1H-indol-2-carboxamido]pentyl]-(S)-alanyl-(S)-proline trihydrate
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:Thermal cyclization of the azidocinnamate (II),obtained from O-benzylsalicylaldehyde (I) by methoxide condensation with ethyl azidoacetate,provides methyl 4-benzyloxyindol-2-carboxylate (III).Debenzylation by catalytic hydrogenolysis and alkylation of the phenol with (2S)-glycidyl tosylate gives the chiral oxirane (IV).Ring opening of (IV) followed by protection of the secondary amine by reaction with di-tert-butyldicarbonate and saponification of the methyl ester gives the key (S)-beta-blocker synthon (V).The required ACE inhibitor svnthon (VIII) is assembled from tert-butyl-N'-benzyloxycarbonyl-(S)-lysinate (VI).Alkylation of the alpha-amino group with the triflate of methyl (R)-lactate and saponification of the methyl ester gives N-[5-benzyloxycarbonylamino-1-(S)-tert-butyloxycarbonylpent-1-yl-(S)-alanine (VII).Condensation of (VII) with tert-butyl-(S)-prolinate.mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole,followed by hydrogenolytic removal of the benzyloxycarbonyl group,provides tert-butyl-N-[5-amino-1-(S)-tert-butyloxycarbonylpent-1-yl]-(S)-alanyl-(S)-prolinate (VIII).Coupling of (V) with (VIII) using dicyclohexylcarbodiimide-1-hydroxybenzotriazole and removal of the tert-butyl protecting groups by acidolysis in trifluoroacetic acid,with ethyl methyl sulfide as a scavenger,gives crude BW-8385C as the bistrifluoroacetate salt.Purification is achieved by ion exchange chromatography on DE52 cellulose,followed by reverse-phase desalting to provide pure BW-B385C as the zwitterionic trihydrate.