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【结 构 式】 
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【分子编号】25797 【品名】benzyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate 【CA登记号】 |
【 分 子 式 】C18H18N2O2 【 分 子 量 】294.3532 【元素组成】C 73.45% H 6.16% N 9.52% O 10.87% |
合成路线1
该中间体在本合成路线中的序号：(VI)The compound can be prepared by two related ways. Coupling of N-Boc-L-tryptophan (I) with benzyl methyl amine (II) employing EDC and HOBt afforded amide (III). The Boc of (III) group was removed by treatment with trifluoroacetic acid and anisole to give amine (IV). Then, sequential reaction of (IV) with 1,1'-carbonyldiimidazole and with piperidine (V) yielded the target urea. In a related procedure, urea formation between L-tryptophan benzyl ester (VI) and piperidine (V) gave (VII). Subsequent catalytic hydrogenolysis of the benzyl ester of (VII) provided acid (VIII). This was finally coupled to benzyl methyl amine (II) to produce the title compound.
| 【1】 Qi, S.; Shah, S.K.; Cascieri, M.A.; Sadowski, S.J.; MaCcoss, M.; L-tryptophan urea amides as NK1/NK2 dual antagonists. Bioorg Med Chem Lett 1998, 8, 16, 2259. |
| 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) | 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 |
| (III) | 25794 | tert-butyl (1S)-2-[benzyl(methyl)amino]-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamate | C24H29N3O3 | 详情 | 详情 | |
| (IV) | 25795 | (2S)-2-amino-N-benzyl-3-(1H-indol-3-yl)-N-methylpropanamide | C19H21N3O | 详情 | 详情 | |
| (V) | 25833 | Spiro[indane-1,4'-piperidine] | C13H17N | 详情 | 详情 | |
| (VI) | 25797 | benzyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate | C18H18N2O2 | 详情 | 详情 | |
| (VII) | 25834 | N-[Spiro[indane-1,4'-piperidin]-1'-ylcarbonyl]-L-tryptophan benzyl ester | C32H33N3O3 | 详情 | 详情 | |
| (VIII) | 25835 | N-[Spiro[indane-1,4'-piperidin]-1'-ylcarbonyl]-L-tryptophan | C25H27N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The compound can be prepared by two related ways. Coupling of N-Boc-L-tryptophan (I) with benzyl methyl amine (II) employing EDC and HOBt afforded amide (III). The Boc group of (III) was removed by treatment with trifluoroacetic acid and anisole to give amine (IV). Then, sequential reaction of (IV) with 1,1'-carbonyldiimidazole and with piperidine (V) yielded the target urea. In a related procedure, urea formation between L-tryptophan benzyl ester (VI) and piperidine (V) gave (VII). Subsequent catalytic hydrogenolysis of the benzyl ester of (VII) provided acid (VIII). This was finally coupled to benzyl methyl amine (II) to produce the title compound.
| 【1】 Qi, S.; Shah, S.K.; Cascieri, M.A.; Sadowski, S.J.; MaCcoss, M.; L-tryptophan urea amides as NK1/NK2 dual antagonists. Bioorg Med Chem Lett 1998, 8, 16, 2259. |
| 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) | 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 |
| (III) | 25794 | tert-butyl (1S)-2-[benzyl(methyl)amino]-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamate | C24H29N3O3 | 详情 | 详情 | |
| (IV) | 25795 | (2S)-2-amino-N-benzyl-3-(1H-indol-3-yl)-N-methylpropanamide | C19H21N3O | 详情 | 详情 | |
| (V) | 25796 | 1-(Methylsulfonyl)spiro[indoline-3,4'-piperidine] | C13H18N2O2S | 详情 | 详情 | |
| (VI) | 25797 | benzyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate | C18H18N2O2 | 详情 | 详情 | |
| (VII) | 25798 | N-[1-(Methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-ylcarbonyl]-L-tryptophan benzyl ester | C32H34N4O5S | 详情 | 详情 | |
| (VIII) | 25799 | N-[1-(Methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-ylcarbonyl]-L-tryptophan | C25H28N4O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)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 |