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【结 构 式】 
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【分子编号】55973 【品名】methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate 【CA登记号】 |
【 分 子 式 】C23H33N3O5 【 分 子 量 】431.53224 【元素组成】C 64.02% H 7.71% N 9.74% O 18.54% |
合成路线1
该中间体在本合成路线中的序号：(V)The intermediate dipeptide ester (V) was prepared as follows. Coupling between D-norleucine tert-butyl ester (I) and N-Boc-D-tryptophan (II) by means of EDC and HOBt provided the protected dipeptide (III). Subsequent acylation of the indole N with methyl chloroformate under phase-transfer conditions yielded the N-(methoxycarbonyl)indole derivative (IV). The N-Boc protecting group was then selectively removed from (IV) by treatment with trifluoroacetic acid at 0 C.
| 【1】 Ishikawa, K.; Fukami, T.; Nagase, T.; Mase, T.; Ihara, M.; Yano, M.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); Endothelin antagonistic substance. EP 0555537; JP 1994107680 . |
| 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) | 55970 | tert-butyl (2R)-2-aminohexanoate | C10H21NO2 | 详情 | 详情 | |
| (II) | 48341 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | C16H20N2O4 | 详情 | 详情 | |
| (III) | 55971 | tert-butyl (2R)-2-{[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino}hexanoate | C26H39N3O5 | 详情 | 详情 | |
| (IV) | 55972 | methyl 3-((2R)-2-[(tert-butoxycarbonyl)amino]-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C28H41N3O7 | 详情 | 详情 | |
| (V) | 55973 | methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C23H33N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Benzyl ester (VII) was prepared by reaction of N-Boc-L-gamma-methylleucine (VI) with benzyl bromide in the presence of Cs2CO3. Subsequent N-Boc group cleavage in (VII) by means of HCl in dioxane furnished gamma-methylleucine benzyl ester (VIII). Amino ester (VIII) was converted into urea (X) by condensation with 2,6-dimethylpiperidine (IX) either in the presence of carbonyl diimidazole or diphosgene. Then, hydrogenolysis of the benzyl ester group of (X) in the presence of Pd/C led to the N-carbamoyl aminoacid (XI). Coupling of amino acid (XI) with dipeptide (V) in the presence of EDC and HOBt gave the tripeptide derivative (XII). The tert-butyl ester group of (XII) was then cleaved under acidic conditions, and the resultant carboxylic acid was finally converted to the corresponding sodium salt by treatment with NaHCO3.
| 【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. |
| 【2】 Ishikawa, K.; Fukami, T.; Nagase, T.; Mase, T.; Ihara, M.; Yano, M.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); Endothelin antagonistic substance. EP 0555537; JP 1994107680 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 55973 | methyl 3-((2R)-2-amino-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C23H33N3O5 | 详情 | 详情 | |
| (VI) | 55974 | (2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (VII) | 55975 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpentanoate | C19H29NO4 | 详情 | 详情 | |
| (VIII) | 55976 | benzyl (2S)-2-amino-4,4-dimethylpentanoate | C14H21NO2 | 详情 | 详情 | |
| (IX) | 32229 | (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine | C7H15N | 详情 | 详情 | |
| (X) | 55977 | benzyl (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoate | C22H34N2O3 | 详情 | 详情 | |
| (XI) | 55978 | (2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoic acid | C15H28N2O3 | 详情 | 详情 | |
| (XII) | 55979 | methyl 3-((2R)-3-{[(1R)-1-(tert-butoxycarbonyl)pentyl]amino}-2-{[(2S)-2-({[(2R,6S)-2,6-dimethylpiperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl]amino}-3-oxopropyl)-1H-indole-1-carboxylate | C38H59N5O7 | 详情 | 详情 |