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【结 构 式】

【药物名称】BW-B385C

【化学名称】N-[1-(S)-Carboxy-5-[4-(2-(S)-hydroxy-3-isopropylaminopropoxy)-1H-indol-2-carboxamido]pentyl]-(S)-alanyl-(S)-proline trihydrate

【CA登记号】

【 分 子 式 】C29H49N5O11

【 分 子 量 】643.74078

【开发单位】GlaxoSmithKline (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors, beta-Adrenoceptor Antagonists

合成路线1

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.

1 Allan, G.; Hardy, G.W.; BW-B385C. Drugs Fut 1988, 13, 3, 203.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16242 (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 113826-06-5 C10H12O4S 详情 详情
19832 tert-butyl (2S)-2-pyrrolidinecarboxylate C9H17NO2 详情 详情
23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
32916 ethyl 2-azidoacetate 637-81-0 C4H7N3O2 详情 详情
63428 3-methyl-1H-indole C9H9N 详情 详情
(I) 21874 2-(benzyloxy)benzaldehyde 5896-17-3 C14H12O2 详情 详情
(II) 21875 methyl (Z)-2-azido-3-[2-(benzyloxy)phenyl]-2-propenoate C17H15N3O3 详情 详情
(III) 21876 methyl 4-(benzyloxy)-1H-indole-2-carboxylate C17H15NO3 详情 详情
(IV) 21877 methyl 4-[(2R)oxiranylmethoxy]-1H-indole-2-carboxylate C13H13NO4 详情 详情
(V) 21878 4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indole-2-carboxylic acid C20H28N2O6 详情 详情
(VI) 21879 tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate C18H28N2O4 详情 详情
(VII) 21880 (2S)-2-[[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(tert-butoxycarbonyl)pentyl]amino]propionic acid C21H32N2O6 详情 详情
(VIII) 21881 tert-butyl (2S)-1-((2S)-2-[[(1S)-5-amino-1-(tert-butoxycarbonyl)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate C22H41N3O5 详情 详情
(IX) 21882 tert-butyl (2S)-1-((2S)-2-[[(1S)-1-(tert-butoxycarbonyl)-5-([[4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indol-2-yl]carbonyl]amino)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate C42H67N5O10 详情 详情
Extended Information