【结 构 式】 |
【分子编号】46624 【品名】methyl 3-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate 【CA登记号】 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号:(X)The selective monoesterification of 2,2-dimethylsuccinic acid (VIII) with methanol and sulfuric acid gives 2,2-dimethylsuccinic acid 4-methyl ester (IX), which is submitted to degradation with diphenylphosphoryl azide, TEA and benzyl alcohol in refluxing benzene, yielding 3-(benzyloxycarbonylamino)-3-methylbutyric acid methyl ester (X). The hydrolysis of (X) with NaOH in methanol affords the corresponding butyric acid (XI). The hydrogenation of 3-azido-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (XII) with H2 over Pt/C in methanol gives the racemic 3-amino derivative (XIII), which is submitted to optical resolution by crystallization of the L-tartrate salt, yielding the 3(R)-amino derivative (XIV). The condensation of amine (XIV) with acid (XI) by means of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BTPF) and DIEA in dichloromethane affords the corresponding amide (XV), which is condensed with the tetrazole derivative (VII) by means of NaH in DMF to provide the protected adduct (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol and a treatment with TFA.
【1】 Watthey, J.W.; et al.; Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme. J Med Chem 1985, 28, 10, 1511. |
【2】 Fisher, M.H.; Wyvratt, M.J.; Schoen, W.R.; DeVita, R.J. (Merck & Co., Inc.); Benzo-fused lactams promote release of growth hormone. EP 0513974; JP 1994172316; US 5206235; WO 9216524 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
(VIII) | 46622 | 2,2-dimethylsuccinic acid | C6H10O4 | 详情 | 详情 | |
(IX) | 46623 | 4-methoxy-2,2-dimethyl-4-oxobutyric acid | C7H12O4 | 详情 | 详情 | |
(X) | 46624 | methyl 3-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C14H19NO4 | 详情 | 详情 | |
(XI) | 46625 | 3-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
(XII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
(XIII) | 46628 | 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H12N2O | 详情 | 详情 | |
(XIV) | 15929 | (3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H12N2O | 详情 | 详情 | |
(XV) | 46626 | benzyl 1,1-dimethyl-3-oxo-3-[[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]propylcarbamate | C23H27N3O4 | 详情 | 详情 | |
(XVI) | 46627 | benzyl 1,1-dimethyl-3-oxo-3-[((3R)-2-oxo-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino]propylcarbamate | C56H51N7O4 | 详情 | 详情 |