【结 构 式】 |
【分子编号】46282 【品名】propyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C17H14F2N2O3 【 分 子 量 】332.3066464 【元素组成】C 61.45% H 4.25% F 11.43% N 8.43% O 14.44% |
合成路线1
该中间体在本合成路线中的序号:(XI)The condensation of 3,4-difluoroaniline (I) with 3-chloropropionyl chloride (II) and pyridine in hot acetone give the anilide (III), which is cyclized by means of AlCl3 at 110?C, yielding 6,7-difluoro-1,2,3,4-tetrahydroquinolin-2-one (IV). The reaction of (IV) with POCl3 and dimethylformamide affords the carbaldehyde (V), which is oxidized and aromatized by means of KMnO4 and KOH in water, providing 2-chloro-6,7-difluoroquinoline-3-carboxylic acid (VI). The reaction of (VI) with SOCl2 in chloroform gives the corresponding acyl chloride (VII), which is condensed with the magnesium salt of the malonic acid monoethyl ester (VIII) in THF to yield the 3-oxopropanoate (IX). The reaction of (IX) with dimethylformamide dimethylacetal (DMF) in hot ethyl acetate affords the 3-(dimethylamino)acrylate (X), which is cyclized by means of methylamine in ethanol to provide 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[g][1,8]naphthyridine-3-carboxylic acid ethyl ester (XI). The hydrolysis of (XI) with HCl in hot HOAc gives the corresponding carboxylic acid (XII) (1), which is condensed with 1-(4-fluorophenyl)piperazine (XIII) by heating at 90?C to yield the adduct (XIV). Finally, this compound is treated with choline hydroxide (XV) in methanol to afford the target choline salt.
【1】 Tabart, M.; et al.; Synthesis and biological evaluation of benzo[b]naphthyridones, a series of new topical antibacterial agents. Bioorg Med Chem Lett 2001, 11, 7, 919. |
【2】 Tabart, M.; et al.; Synthesis and biological evaluation of RP60556A, a new topical antibacterial agent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1512. |
【3】 Wentzler, S.; Desconclois, J.-F.; Girard, P.; Picaut, G.; Tabart, M. (Aventis Pharma SA); 1,8-Benzonaphthyridine derivs.. FR 2787452; WO 0037467 . |
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) | 13451 | 3,4-Difluoroaniline; 3,4-Difluorophenylamine | 3863-11-4 | C6H5F2N | 详情 | 详情 |
(II) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
(III) | 46274 | 3-chloro-N-(3,4-difluorophenyl)propanamide | C9H8ClF2NO | 详情 | 详情 | |
(IV) | 46275 | 6,7-difluoro-3,4-dihydro-2(1H)-quinolinone | C9H7F2NO | 详情 | 详情 | |
(V) | 46276 | 2-chloro-6,7-difluoro-1,4-dihydro-3-quinolinecarbaldehyde | C10H6ClF2NO | 详情 | 详情 | |
(VI) | 46277 | 2-chloro-6,7-difluoro-3-quinolinecarboxylic acid | C10H4ClF2NO2 | 详情 | 详情 | |
(VII) | 46278 | 2-chloro-6,7-difluoro-3-quinolinecarbonyl chloride | C10H3Cl2F2NO | 详情 | 详情 | |
(VIII) | 46279 | C6H9MgO4 | 详情 | 详情 | ||
(IX) | 46280 | propyl 3-(2-chloro-6,7-difluoro-3-quinolinyl)-3-oxopropanoate | C15H12ClF2NO3 | 详情 | 详情 | |
(X) | 46281 | propyl (Z)-2-[(2-chloro-6,7-difluoro-3-quinolinyl)carbonyl]-3-(dimethylamino)-2-propenoate | C18H17ClF2N2O3 | 详情 | 详情 | |
(XI) | 46282 | propyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate | C17H14F2N2O3 | 详情 | 详情 | |
(XII) | 46283 | 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid | C14H8F2N2O3 | 详情 | 详情 | |
(XIII) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
(XIV) | 46284 | 7-fluoro-8-[4-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid | C24H20F2N4O3 | 详情 | 详情 | |
(XV) | 46285 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium hydroxide | C5H15NO2 | 详情 | 详情 |