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【结 构 式】 
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【分子编号】55792 【品名】(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide 【CA登记号】 |
【 分 子 式 】C22H32N4O4 【 分 子 量 】416.52064 【元素组成】C 63.44% H 7.74% N 13.45% O 15.36% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reaction of pyrimidine-2,4(1H,3H)-dione (I) with benzyl 2-bromoacetate (II) by means of K2CO3 in DMF gives the pyrimidine-1-acetic acid benzyl ester (III), which is condensed with tert-butyl 2-bromoacetate (IV) by means of NaH in DMF to yield the pyrimidine bis acetate (V). Selective deprotection of the benzyl ester of (V) by means of H2 over Pd(OH)2 in ethyl acetate affords the mono acetic acid derivative (VI), which is condensed with the free amino group of the tripeptide analogue (VII) by means of EDC in pyridine to provide the acylated tripeptide analogue (VIII). The oxidation of the secondary OH group of (VIII) by means of DMP in dichloromethane furnishes the acylated 2-(L-valyl-L-prolyl-L-valyl)benzoxazole derivative (IX), which is finally deprotected with TFA in dichloromethane to give the target tripeptide analogue.
| 【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 . |
| 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) | 30912 | (2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide | C19H21NO4S | 详情 | 详情 | |
| (II) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (III) | 55789 | benzyl 2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetate | C13H12N2O4 | 详情 | 详情 | |
| (IV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (V) | 55790 | tert-butyl 2-[3-[2-(benzyloxy)-2-oxoethyl]-2,6-dioxo-1(2H,6H)-pyrimidinyl]acetate | C19H22N2O6 | 详情 | 详情 | |
| (VI) | 55791 | 2-[3-[2-(tert-butoxy)-2-oxoethyl]-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetic acid | C12H16N2O6 | 详情 | 详情 | |
| (VII) | 55792 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide | C22H32N4O4 | 详情 | 详情 | |
| (VIII) | 55793 | tert-butyl 2-[3-(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate | C34H46N6O9 | 详情 | 详情 | |
| (IX) | 55794 | tert-butyl 2-[3-{2-[((1S)-1-{[(2S)-2-({[(1S)-1-(1,3-benzoxazol-2-ylcarbonyl)-2-methylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-2-oxoethyl}-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate | C34H44N6O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)N-Cbz-L-Valinal cyanohydrin (I) is converted into imidate (II) and then condensed with 2-aminophenol (III) to afford benzoxazole (IV). Removal of the N-Cbz group of (IV) with H2 and Pd/C provides amine (V), which is then coupled to N-Cbz-valyl proline (VI), yielding the dipeptide amide (VII). After hydrogenolysis of the N-Cbz protecting group of (VII), the free amine (VIII) is coupled to the acid fragment (IX) by means of EDC/pyridine to furnish (X).
| 【1】 Sato, F.; Inoue, Y.; Omodani, T.; Imano, K.; Okazaki, H.; Takemura, T.; Komiya, M.; Design and synthesis of peptide-based carboxylic acid-containing transition-state inhibitors of human neutrophil elastase. Bioorg Med Chem Lett 2002, 12, 4, 551. |
| 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) | 62768 | benzyl (1S)-1-[cyano(hydroxy)methyl]-2-methylpropylcarbamate | C14H18N2O3 | 详情 | 详情 | |
| (II) | 62769 | ethyl (3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-methylpentanimidoate | C16H24N2O4 | 详情 | 详情 | |
| (III) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (IV) | 62770 | benzyl (1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropylcarbamate | C20H22N2O4 | 详情 | 详情 | |
| (V) | 62771 | (2S)-2-amino-1-(1,3-benzoxazol-2-yl)-3-methyl-1-butanol | C12H16N2O2 | 详情 | 详情 | |
| (VI) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (VII) | 62772 | benzyl (1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropylcarbamate | C30H38N4O6 | 详情 | 详情 | |
| (VIII) | 55792 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide | C22H32N4O4 | 详情 | 详情 | |
| (IX) | 62773 | 2-({4-[2-(tert-butoxy)-2-oxoethoxy]benzoyl}amino)acetic acid | C15H19NO6 | 详情 | 详情 | |
| (X) | 62774 | tert-butyl 2-(4-{[(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)amino]carbonyl}phenoxy)acetate | C37H49N5O9 | 详情 | 详情 |