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【结 构 式】 
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【分子编号】27719 【品名】benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate 【CA登记号】 |
【 分 子 式 】C23H26N2O4 【 分 子 量 】394.47052 【元素组成】C 70.03% H 6.64% N 7.1% O 16.22% |
合成路线1
该中间体在本合成路线中的序号：(XIII)In a related synthetic method, N-Boc-tryptophan (II) was coupled with benzyl alcohol using EDC and HOBt to produce the corresponding benzyl ester (XIII). Incorporation of the methoxycarbonyl group into the indole N (XIV) was accomplished by treatment of (XIII) with dimethyl carbonate in the presence of DMAP. The Boc protecting group of (XIV) was then removed under acidic conditions to afford amino ester (XV). The dipeptide derivative (XVI) was prepared by coupling of amino ester (XV) with the N-carbamoyl aminoacid (XI). After hydrogenolysis of the benzyl ester group of (XVI), acid (XVII) was coupled with norleucine benzyl ester (XVIII) yielding tripeptide (XIX). Further benzyl ester hydrogenolysis in (XIX) gave the corresponding carboxylic acid, which was finally converted into the title sodium salt.
| 【1】 He, J.X.; et al.; An efficient preparation of the pseudopeptide endothelin-B receptor selective antagonist BQ-788. J Org Chem 1995, 60, 25, 8262. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 48341 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | C16H20N2O4 | 详情 | 详情 | |
| (XI) | 55978 | (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoic acid | C15H28N2O3 | 详情 | 详情 | |
| (XIII) | 27719 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate | C23H26N2O4 | 详情 | 详情 | |
| (XIV) | 55980 | methyl 3-{(2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-1H-indole-1-carboxylate | C25H28N2O6 | 详情 | 详情 | |
| (XV) | 55981 | methyl 3-[(2R)-2-amino-3-(benzyloxy)-3-oxopropyl]-1H-indole-1-carboxylate | C20H20N2O4 | 详情 | 详情 | |
| (XVI) | 55982 | methyl 3-((2R)-3-(benzyloxy)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C35H46N4O6 | 详情 | 详情 | |
| (XVII) | 55983 | (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-[1-(methoxycarbonyl)-1H-indol-3-yl]propanoic acid | C28H40N4O6 | 详情 | 详情 | |
| (XVIII) | 55984 | benzyl (2R)-2-aminohexanoate | C13H19NO2 | 详情 | 详情 | |
| (XIX) | 55985 | methyl 3-((2R)-3-({(1R)-1-[(benzyloxy)carbonyl]pentyl}amino)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C41H57N5O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Alternatively, N-Boc-D-tryptophan (IX) was esterified with benzyl alcohol in the presence of EDC and DMAP to give benzyl ester (XIII). Deprotection of the Boc group of (XIII) with TFA, followed by coupling of the resulting amino ester (XIV) with N-Boc-2-aminoisobutyric acid (XI) provided protected dipeptide (XV). Hydrogenolytic removal of the benzyl ester of (XV) gave carboxylic acid (XVI), which was coupled to the (S)-nipecotate (VIII) to afford the precursor (XII). Finally, removal of the Boc protecting group by treatment with HCl in EtOAc yielded the title compound.
| 【1】 Cheng, K.; Yang, L.; Morriello, G.; Smith, R.; Patchett, A.A.; Scheim, k.D.; Jacks, T.; Leung, K.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogue L-165,666. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 074. |
| 【2】 Morriello, G.J.; Patchett, A.A.; Yang, L.; Chen, M.H.; Nargund, R. (Merck & Co., Inc.); Piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone. EP 0739204; US 5492916; US 5492920; US 5494919; WO 9513069 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (IX) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 详情 | 详情 | |
| (XIII) | 27719 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate | C23H26N2O4 | 详情 | 详情 | |
| (XIV) | 25797 | benzyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate | C18H18N2O2 | 详情 | 详情 | |
| (XV) | 27720 | benzyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoate | C27H33N3O5 | 详情 | 详情 | |
| (XVI) | 27721 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propionic acid | C20H27N3O5 | 详情 | 详情 |