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【结 构 式】 
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【药物名称】Delafloxacin, ABT-492, WQ-3034 【化学名称】1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 【CA登记号】189279-58-1 【 分 子 式 】C18H12ClF3N4O4 【 分 子 量 】440.76894 |
【开发单位】Wakunaga (Originator), Abbott (Licensee) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones |
合成路线1
Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.
| 【2】 Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient. EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068 . |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 56641 | N-benzyl-3,5,6-trifluoro-2-pyridinamine; N-benzyl-N-(3,5,6-trifluoro-2-pyridinyl)amine | C12H9F3N2 | 详情 | 详情 | |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (V) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VI) | 56643 | N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(4-methoxybenzyl)amine; 3,5-difluoro-N~2~-(4-methoxybenzyl)-2,6-pyridinediamine | C13H13F2N3O | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (VIII) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (IX) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (X) | 56644 | ethyl 8-chloro-1-{3,5-difluoro-6-[(4-methoxybenzyl)amino]-2-pyridinyl}-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C25H18ClF4N3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 |
合成路线2
Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.
| 【2】 Ohshita, Y.; Kuramoto, Y.; Niino, Y.; Yazaki, A.; Structure-activity relationships of fluoroquinolones containing various heteroaromatics at N-1; WQ-3034/ABT-492 and its derivatives. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-544. |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 | |
| (XIII) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (XIV) | 56646 | N~2~-(tert-butyl)-3,5-difluoro-2,6-pyridinediamine; N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(tert-butyl)amine | C9H13F2N3 | 详情 | 详情 | |
| (XV) | 56647 | ethyl (Z)-3-{[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]amino}-2-(3-chloro-2,4,5-trifluorobenzoyl)-2-propenoate | C21H19ClF5N3O3 | 详情 | 详情 | |
| (XVI) | 56648 | ethyl 1-[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C21H18ClF4N3O3 | 详情 | 详情 |