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【结 构 式】 
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【药物名称】FR-161282 【化学名称】4'-Methyl-N-[4-[5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-ylcarbonyl]phenyl]biphenyl-2-carboxamide 【CA登记号】168046-41-1, 168046-43-3 (monomesylate salt), 168046-42-2 (sulfate salt(2:1)) 【 分 子 式 】C37H37N5O4 【 分 子 量 】615.73854 |
【开发单位】Fujisawa (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Diuretics, Hypertension, Treatment of, RENAL-UROLOGIC DRUGS, Vasopressin V2 Antagonists |
合成路线1
2-Methoxybenzoic acid (I) was protected as the oxazoline (II). Further coupling with tolylmagnesium bromide, followed by acid hydrolysis of the oxazoline provided the intermediate biphenyl carboxylic acid (III).
| 【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 | |
| (I) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
| (II) | 13927 | 2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether | 57598-33-1 | C12H15NO2 | 详情 | 详情 |
| (III) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
合成路线2
Condensation of benzodiazepinone (IV) with 4-nitrobenzoyl chloride (V) afforded amide (VI), which was alkylated with ethyl bromoacetate in the presence of NaH to give (VII). The nitro group of (VII) was reduced to aniline (VIII) using Fe and AcOH. Subsequent coupling of (VIII) with the acid chloride generated from biphenyl carboxylic acid (III) and oxalyl chloride produced the corresponding amide (IX). The ester group of (IX) was then hydrolyzed with NaOH, and the resulting carboxylic acid (X) was finally condensed with N-methylpiperazine (XI) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as the coupling reagents.
| 【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| (III) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
| (IV) | 18498 | 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C9H10N2O | 详情 | 详情 | |
| (V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VI) | 27975 | 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C16H13N3O4 | 详情 | 详情 | |
| (VII) | 27976 | ethyl 2-[5-(4-nitrobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C20H19N3O6 | 详情 | 详情 | |
| (VIII) | 27977 | ethyl 2-[5-(4-aminobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C20H21N3O4 | 详情 | 详情 | |
| (IX) | 27978 | ethyl 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate | C34H31N3O5 | 详情 | 详情 | |
| (X) | 27979 | 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetic acid | C32H27N3O5 | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |