【结 构 式】 |
【分子编号】21882 【品名】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 【CA登记号】 |
【 分 子 式 】C42H67N5O10 【 分 子 量 】802.02168 【元素组成】C 62.9% H 8.42% N 8.73% O 19.95% |
合成路线1
该中间体在本合成路线中的序号:(IX)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 |