【结 构 式】 |
【药物名称】 【化学名称】3-Benzyl-1-(3-guanidinobenzyl)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one 【CA登记号】 【 分 子 式 】C30H27N5O 【 分 子 量 】473.58259 |
【开发单位】Bristol-Myers Squibb (Originator), Novartis (Originator) 【药理作用】Bradykinin B2 Antagonists |
合成路线1
N-Boc-Phenylalanine (I) was treated with isobutyl chloroformate and N-methylmorpholine, and the resulting mixed anhydride (II) was coupled to 2-aminobenzophenone (III) to yield the corresponding amide (IV). After Boc deprotection of (IV) with HCl in EtOAc, the intermediate aminoketone was cyclized with NaOH to the benzodiazepine (V). Alkylation of (V) with 3-nitrobenzyl bromide (VI) in the presence of t-BuOK in THF gave the (nitrobenzyl)benzodiazepine (VII). The nitro group of (VV) was subsequently reduced with SnCl2 in boiling EtOAc to affford (VIII). Then, the resulting amine (VIII) was treated with N,N'-di-Boc-thiourea (IX) in the presence of HgCl2 to provide the diprotected guanidine (X), which was finally deprotected with trifluoroacetic acid in CH2Cl2.
【1】 Dziadulewicz, E.K.; et al.; The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold. Bioorg Med Chem Lett 1999, 9, 3, 463. |
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) | 21835 | N-(tert-butoxycarbonyl)phenylalanine | 4530-18-1 | C14H19NO4 | 详情 | 详情 |
(II) | 21836 | N-(Tert-butoxycarbonyl)-DL-phenylalanine isobutoxycarbonyl anhydride | C19H27NO6 | 详情 | 详情 | |
(IV) | 21838 | tert-butyl 2-(2-benzoylanilino)-1-benzyl-2-oxoethylcarbamate | C27H28N2O4 | 详情 | 详情 | |
(V) | 21839 | 3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C22H18N2O | 详情 | 详情 | |
(VI) | 19636 | 1-(bromomethyl)-3-nitrobenzene | 3958-57-4 | C7H6BrNO2 | 详情 | 详情 |
(VII) | 21841 | 3-benzyl-1-(3-nitrobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C29H23N3O3 | 详情 | 详情 | |
(VIII) | 21842 | 1-(3-aminobenzyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C29H25N3O | 详情 | 详情 | |
(IX) | 21843 | tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate | 145013-05-4 | C11H20N2O4S | 详情 | 详情 |
(X) | 21844 | tert-butyl (Z)-[3-[(3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl]anilino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C40H43N5O5 | 详情 | 详情 |