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【结 构 式】 
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【药物名称】Y-26611 【化学名称】7-[2-(Aminomethyl)-4-morpholinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 【CA登记号】122894-02-4, 122894-15-9 (HCl) 【 分 子 式 】C18H19F2N3O4 【 分 子 量 】379.36663 |
【开发单位】Japan Tobacco (Originator), Mitsubishi Pharma (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones |
合成路线1
The condensation of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (I) with 2-(formylamino-methyl)- morpholine (II) by means of 1,8-diazabicyclo[5.4.0]-7-undecene (DABU) in refluxing acetonitrile gives the formamido derivative (III), which is then hydrolyzed with concentrated HCl in refluxing methanol.
| 【1】 Araki, K.; Kuroda, T.; Uemori, S.; Moriguchi, A.; Ikeda, Y. (Welfide Corporation); Quinolonecarboxylic acid cpds. and pharmaceutical use thereof. EP 0311948; US 4889857 . |
| 【2】 Castaner, J.; Prous, J.; Y-26611. Drugs Fut 1992, 17, 2, 114. |
| 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) | 13393 | 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C13H8F3NO3 | 详情 | 详情 | |
| (II) | 13394 | 2-Morpholinylmethylformamide | C6H12N2O2 | 详情 | 详情 | |
| (III) | 13395 | 1-Cyclopropyl-6,8-difluoro-7-[2-[(formylamino)methyl]-4-morpholinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C19H19F2N3O5 | 详情 | 详情 |
合成路线2
A new synthesis for Y-26611 has been reported: The reaction of 4-benzyl-2-(chloromethyl)morpholine (I) with potassium phthalimide (II) in refluxing DMF gives 4-benzyl-2-(phthalimidomethyl)morpholine (III), which is treated with hydrazine hydrate in refluxing ethanol yielding 2-(aminomethyl)-4-benzylmorpholine (IV). The acetylation of (IV) with acetic anhydride in cool toluene affords 2-(acetamidomethyl)-4-benzylmorpholine (V), which is debenzylated by hydrogenation with hydrazine hydrate over Pd/C in isopropanol to give 2-(acetamidomethyl)morpholine (VI). The condensation of (VI) with 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of triethylamine in refluxing acetonitrile yields 7-[2-(acetamidomethyl)morpholin-4-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VIII), which is finally deacetylated with refluxing aqueous HCl.
| 【1】 Hirayama, F.; Yokoyama, Y.; Moriguchi, A.; Ikeda, Y.; Araki, K.; Iwao, E.; Uemori, S.; Yakushiji, T.; Kuroda, T.; Quinolone antimicrobial agents substituted with morpholines at the 7-position. Syntheses and structure-activity relationships. J Med Chem 1993, 36, 10, 1356. |
| 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) | 13396 | 4-Benzyl-2-(chloromethyl)morpholine | C12H16ClNO | 详情 | 详情 | |
| (II) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (III) | 13398 | 2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione | C20H20N2O3 | 详情 | 详情 | |
| (IV) | 13399 | (4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine | C12H18N2O | 详情 | 详情 | |
| (V) | 13400 | N-[(4-Benzyl-2-morpholinyl)methyl]acetamide | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 13401 | N-(2-Morpholinylmethyl)acetamide | C7H14N2O2 | 详情 | 详情 | |
| (VII) | 13393 | 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C13H8F3NO3 | 详情 | 详情 | |
| (VIII) | 13403 | 7-[2-[(Acetamido)methyl]-4-morpholinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C20H21F2N3O5 | 详情 | 详情 |