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【结 构 式】 
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【药物名称】FR-193517 【化学名称】3-(6-Acetamidopyridin-3-yl)-N-[1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrol-2-ylmethyl]-2(E)-propenamide dihydrochloride 【CA登记号】189266-51-1 (free base) 【 分 子 式 】C32H29Cl4N5O3 【 分 子 量 】673.43163 |
【开发单位】Fujisawa (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Bradykinin B2 Antagonists |
合成路线1
Benzyl alcohol (I) was treated with mesyl chloride and triethylamine in CH2Cl2 at 0 C, and the resulting mesylate (II) was subsequently coupled with 2-methyl-8-hydroxyquinoline (III) in the presence of NaH to afford ether (IV). Reduction of the nitro group of (IV) with hydrazine in the presence of FeCl3 and carbon gave aniline (V). Pyrrole (VII) was then obtained by heating (V) with 2,5-dimethoxy tetrahydrofuran (VI) in AcOH. Further reaction of (VII) with chlorosulfonylisocyanate (VIII) at low temperature provided the 2-cyanopyrrole (IX). The cyano group of (IX) was reduced with LiAlH4 to give amine (X). This was finally condensed with pyridinylacrylic acid (XI) using EDC and HOBt to yield the target amide, which was isolated as the dihydrochloride salt.
| 【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation. J Med Chem 1998, 41, 23, 4587. |
| 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) | 18590 | (2,6-dichloro-3-nitrophenyl)methanol | C7H5Cl2NO3 | 详情 | 详情 | |
| (II) | 19295 | 2,6-dichloro-3-nitrobenzyl methanesulfonate | C8H7Cl2NO5S | 详情 | 详情 | |
| (III) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (IV) | 18926 | (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid | C11H11NO3 | 详情 | 详情 | |
| (V) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (VI) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (VII) | 19300 | 2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl 2-methyl-8-quinolinyl ether; 8-[[2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl]oxy]-2-methylquinoline | C21H16Cl2N2O | 详情 | 详情 | |
| (VIII) | 14010 | ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H20ClN5O2S | 详情 | 详情 | |
| (IX) | 19302 | 1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrole-2-carbonitrile | C22H15Cl2N3O | 详情 | 详情 | |
| (X) | 19303 | [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methanamine; [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methylamine | C22H19Cl2N3O | 详情 | 详情 | |
| (XI) | 19304 | (E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid | C10H10N2O3 | 详情 | 详情 |