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【结 构 式】 
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【分子编号】21879 【品名】tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate 【CA登记号】 |
【 分 子 式 】C18H28N2O4 【 分 子 量 】336.4314 【元素组成】C 64.26% H 8.39% N 8.33% O 19.02% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(II)Coupling of N-Boc-beta-methyltryptophan (I) with N-Cbz-lysine tert-butyl ester (II) using EDC and HOBt afforded dipeptide (III). Selective deprotection of the Boc group of (III) with methanesulfonic acid gave amine (IV). This was converted to urea (VI) upon treatment with benzimidazolylpiperidine (V) and N,N'-disuccinimidyl carbonate in the presence of diisopropyl ethylamine. The N-carbobenzoxy group of (VI) was finally deprotected by hydrogenolysis over Pd/C.
| 【1】 Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2. Proc Natl Acad Sci USA 1998, 95, 18, 10836. |
| 【2】 Berk, S.; Yang, L.; Chen, M.H.; Johnston, D.; Pasternak, A.; Chapman, K.; Guo, L.; Nargund, R.; Tata, J.R.; Patchett, A.A. (Merck & Co., Inc.); Somatostatin agonists. EP 0984779; US 6063796; WO 9844922 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28255 | (2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)butyric acid | C17H22N2O4 | 详情 | 详情 | |
| (II) | 21879 | tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C18H28N2O4 | 详情 | 详情 | |
| (III) | 28256 | tert-butyl (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[[(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)butanoyl]amino]hexanoate | C35H48N4O7 | 详情 | 详情 | |
| (IV) | 28257 | tert-butyl (2S)-2-[[(2R,3S)-2-amino-3-(1H-indol-3-yl)butanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate | C30H40N4O5 | 详情 | 详情 | |
| (V) | 12138 | 1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine | 20662-53-7 | C12H15N3O | 详情 | 详情 |
| (VI) | 28258 | tert-butyl (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[[(2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butanoyl]amino]hexanoate | C43H53N7O7 | 详情 | 详情 |