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【结 构 式】 
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【分子编号】17971 【品名】2-(2-phenylhydrazono)malonoyl dichloride 【CA登记号】 |
【 分 子 式 】C9H6Cl2N2O2 【 分 子 量 】245.06432 【元素组成】C 44.11% H 2.47% Cl 28.93% N 11.43% O 13.06% |
合成路线1
该中间体在本合成路线中的序号：(IV)N-Phenyl-1,2-phenylenediamine (I) was alkylated with bromoacetanilide (II) in the presence of potassium carbonate in DMF, and the resulting alkylated phenylenediamine (III) was condensed with diacid chloride (IV) in THF to afford dioxobenzodiazepine (V). Reduction of the hydrazone function with zinc-acetic acid provided amine (VI) (1). Urea (VIII) was then prepared by treatment of amine (VI) with isocyanate (VII) in dichloromethane, and finally, ethyl ester was hydrolyzed on treatment with K2CO3 in a refluxing mixture of methanol and THF.
| 【1】 Hirst, G.C.; et al.; Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent. J Med Chem 1996, 39, 26, 5236. |
| 【2】 Finch, H.; Shah, P.; Carr, R.A.E. (Glaxo Wellcome plc); 1,5-Benzodiazepine derivs. having CCK and/or gastrin antagonistic activity. US 5585376; US 5646140; WO 9424149; WO 9424151 . |
| 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) | 18990 | N-(2-aminophenyl)-N-phenylamine; N(1)-phenyl-1,2-benzenediamine | 534-85-0 | C12H12N2 | 详情 | 详情 |
| (II) | 18991 | 2-bromo-N-isopropyl-N-phenylacetamide | C11H14BrNO | 详情 | 详情 | |
| (III) | 18992 | 2-(2-anilinoanilino)-N-isopropyl-N-phenylacetamide | C23H25N3O | 详情 | 详情 | |
| (IV) | 17971 | 2-(2-phenylhydrazono)malonoyl dichloride | C9H6Cl2N2O2 | 详情 | 详情 | |
| (V) | 18994 | 2-[2,4-dioxo-5-phenyl-3-[(Z)-2-phenylhydrazono]-4,5-dihydro-1H-1,5-benzodiazepin-1(2H)-yl]-N-isopropyl-N-phenylacetamide | C32H29N5O3 | 详情 | 详情 | |
| (VI) | 18995 | 2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)-N-isopropyl-N-phenylacetamide | C26H26N4O3 | 详情 | 详情 | |
| (VII) | 18996 | ethyl 3-isocyanatobenzoate | 67531-68-4 | C10H9NO3 | 详情 | 详情 |
| (VIII) | 18997 | ethyl 3-[[([1-[2-(isopropylanilino)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]amino)carbonyl]amino]benzoate | C36H35N5O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)2-nitroaniline (III) was prepared by reaction of an excess of cyclohexylamine (II) with either 2-chloronitrobenzene (Ia) in the presence of CuI and K2CO3 at 150 C or 2-fluoronitrobenzene (Ib) in chloroform. Catalytic hydrogenation gave phenylenediamine (IV), which was selectively alkylated on the primary N atom with bromoacetylpyrrolidine (V) in the presence of K2CO3 in DMF. Condensation of the resulting (VI) with the malonic acid dichloride (VII) yielded benzodiazepine (VIII). Hydrazone function was then reduced with zinc dust in acetic acid to provide amine (IX). Separation of the racemic mixture was performed by treatment with the chiral carbonic acid derivative (X), followed by chromatographic separation to give the desired (S)-isomer (XI). Cleavage of the carbamate group of (XI) was effected by hydrogenolysis to afford chiral amine (XII). The target urea was then prepared by reaction of (XII) with 4-fluorophenylisocyanate (XIII) in dichloromethane.
| 【1】 Bailey, N.; et al.; Novel 1,5-benzodiazepindione gastrin/CCKB antagonists. Bioorg Med Chem Lett 1997, 7, 3, 281. |
| 【2】 Finch, H.; Shah, P.; Carr, R.A.E. (Glaxo Wellcome plc); 1,5-Benzodiazepine derivs. having CCK and/or gastrin antagonistic activity. US 5585376; US 5646140; WO 9424149; WO 9424151 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 17964 | (2-chlorophenyl)(oxo)-lambda(5)-azanolate | C6H5ClNO2 | 详情 | 详情 | |
| (Ib) | 17965 | (2-fluorophenyl)(oxo)-lambda(5)-azanolate | C6H5FNO2 | 详情 | 详情 | |
| (II) | 17966 | cyclohexanamine; cyclohexyl amine; cyclohexylamine | 108-91-8 | C6H13N | 详情 | 详情 |
| (III) | 17967 | [2-(cyclohexylamino)phenyl](oxo)-lambda(5)-azanolate | C12H17N2O2 | 详情 | 详情 | |
| (IV) | 17968 | N-(2-aminophenyl)-N-cyclohexylamine; N(1)-cyclohexyl-1,2-benzenediamine | C12H18N2 | 详情 | 详情 | |
| (V) | 17969 | 2-bromo-1-(1-pyrrolidinyl)-1-ethanone | C6H10BrNO | 详情 | 详情 | |
| (VI) | 17970 | 2-[2-(cyclohexylamino)anilino]-1-(1-pyrrolidinyl)-1-ethanone | C18H27N3O | 详情 | 详情 | |
| (VII) | 17971 | 2-(2-phenylhydrazono)malonoyl dichloride | C9H6Cl2N2O2 | 详情 | 详情 | |
| (VIII) | 17972 | 1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,3,4(5H)-trione 3-(N-phenylhydrazone) | C27H31N5O3 | 详情 | 详情 | |
| (IX) | 17973 | 3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione | C21H28N4O3 | 详情 | 详情 | |
| (X) | 17974 | 4-nitrophenyl (1S)-1-phenylethyl carbonate | C15H13NO5 | 详情 | 详情 | |
| (XI) | 17975 | (1S)-1-phenylethyl (3R)-1-cyclohexyl-2,4-dioxo-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate | C30H36N4O5 | 详情 | 详情 | |
| (XII) | 17976 | (3R)-3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione | C21H28N4O3 | 详情 | 详情 | |
| (XIII) | 17977 | 1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate | 1195-45-5 | C7H4FNO | 详情 | 详情 |