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【结 构 式】 
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【分子编号】52482 【品名】methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate 【CA登记号】 |
【 分 子 式 】C25H30N6O4 【 分 子 量 】478.55124 【元素组成】C 62.75% H 6.32% N 17.56% O 13.37% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of tert-butyl 4-fluoro-3-(bromomethyl)benzoate (I) with N-Boc-1,3-propanediamine (II) afforded the aminomethyl benzoate derivative (III). This was coupled with N-Cbz-L-aspartic acid beta-methyl ester (IV), yielding amide (V). After hydrogenolysis of the carbobenzoxy protecting group of (V), the resultant fluoro amine (VI) was cyclized to the benzodiazepinone (VII) upon treatment with 2,6-di-tert-butylpyridine in hot NMP. Acidic cleavage of both the tert-butyl ester and the N-Boc groups of (VII), followed by reprotection of the amine with Boc2O, furnished the N-Boc acid (VIII). This was then coupled to 2-(methylaminomethyl)benzimidazole (IX) to afford, after acidic Boc group cleavage, the amino amide (X).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77. |
| 【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 . |
| 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) | 52473 | 1,1-dimethylethyl 3-(bromomethyl)-4-fluorobenzoate | C12H14BrFO2 | 详情 | 详情 | |
| (II) | 52474 | 1,1-dimethylethyl 3-aminopropylcarbamate | C8H18N2O2 | 详情 | 详情 | |
| (III) | 52475 | 1,1-dimethylethyl 3-({[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}methyl)-4-fluorobenzoate | C20H31FN2O4 | 详情 | 详情 | |
| (IV) | 52476 | O-methyl-4-oxo-N-{[(phenylmethyl)oxy]carbonyl}homoserine | C13H15NO6 | 详情 | 详情 | |
| (V) | 52477 | 1,1-dimethylethyl 3-({[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl][4-(methyloxy)-4-oxo-2-({[(phenylmethyl)oxy]carbonyl}amino)butanoyl]amino}methyl)-4-fluorobenzoate | C33H44FN3O9 | 详情 | 详情 | |
| (VI) | 52478 | 1,1-dimethylethyl 3-({[2-amino-4-(methyloxy)-4-oxobutanoyl][3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}methyl)-4-fluorobenzoate | C25H38FN3O7 | 详情 | 详情 | |
| (VII) | 52479 | 1,1-dimethylethyl 4-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-2-[2-(methyloxy)-2-oxoethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate | C25H37N3O7 | 详情 | 详情 | |
| (VIII) | 52480 | 4-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-2-[2-(methyloxy)-2-oxoethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid | C21H29N3O7 | 详情 | 详情 | |
| (IX) | 52481 | 1H-benzimidazol-2-yl-N-methylmethanamine; N-(1H-benzimidazol-2-ylmethyl)-N-methylamine | C9H11N3 | 详情 | 详情 | |
| (X) | 52482 | methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate | C25H30N6O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Coupling between gamma-tert-butoxy glutamic acid (XI) and gamma-tert-butoxy-N-Cbz-glutamic acid succinimidyl ester (XII) produced the protected dipeptide (XIII). This was further coupled to the intermediate amine (X) to furnish the corresponding amide (XIV). After hydrogenolysis of the N-Cbz protecting group of (XIV), the resultant amine (XV) was acylated with tetraazacyclododecanetetraacetic acid tri-tert-butyl ester (XVI), yielding the amide adduct (XVII).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77. |
| 【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 52482 | methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate | C25H30N6O4 | 详情 | 详情 | |
| (XI) | 51009 | (2S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid | C9H17NO4 | 详情 | 详情 | |
| (XII) | 51010 | tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate | C21H26N2O8 | 详情 | 详情 | |
| (XIII) | 51011 | (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid | C26H38N2O9 | 详情 | 详情 | |
| (XIV) | 52486 | C51H66N8O12 | 详情 | 详情 | ||
| (XV) | 51014 | 2-[4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C28H52N4O8 | 详情 | 详情 | |
| (XVI) | 52483 | C43H60N8O10 | 详情 | 详情 | ||
| (XVII) | 52484 | C71H110N12O17 | 详情 | 详情 |