【结 构 式】 |
【药物名称】A-62824 【化学名称】9-Cyclopropyl-6-fluoro-7-(1-piperazinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione 【CA登记号】111279-87-9 【 分 子 式 】C17H17FN4O2S 【 分 子 量 】360.41304 |
【开发单位】Abbott (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones |
合成路线1
The cyclization of 2-(2,4-dichloro-5-fluorobenzoyl)acetic acid ethyl ester (I) with S-phenyl(cyclopropylimino)chlorothioformate (II) by means of NaH in DMF gives 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III), which is oxidized with MCPBA in dichloromethane, yielding the sulfinyl derivative (IV). The cyclization of (IV) with NaSH and hydroxylamine-O-sulfonic acid in THF affords the isothiazoloquinoline (V), which is finally condensed with piperazine in pyridine to furnish the target compound.
【1】 Mohamadi, F.; Spees, M.M.; Grindey, G.B.; Antineoplastic bicyclic sulfonylureas. Bioorg Med Chem Lett 1992, 3, 987-992. |
【2】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101. |
【3】 Ehlhardt, W.J.; Woodland, J.M.; Worzalla, J.F.; Bewley, J.R.; Grindey, G.B.; Todd, G.C.; Toth, J.E.; Howbert, J.J.; Comparison of metabolism and toxicity to the structure of the anticancer agent sulofenur and related sulfonylureas. Chem Res Toxicol 1992, 5, 5, 667. |
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) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
(II) | 43201 | 1-[[chloro(cyclopropylimino)methyl]sulfanyl]benzene | C10H10ClNS | 详情 | 详情 | |
(III) | 43208 | ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydro-3-quinolinecarboxylate | C21H17ClFNO3S | 详情 | 详情 | |
(IV) | 43209 | ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfinyl)-1,4-dihydro-3-quinolinecarboxylate | C21H17ClFNO4S | 详情 | 详情 | |
(V) | 43210 | 7-chloro-9-cyclopropyl-6-fluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione | C13H8ClFN2O2S | 详情 | 详情 | |
(VI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线2
The condensation of 2-(2,4,5-trifluorobenzoyl)acetic acid ethyl ester (I) with cyclopropyl isothiocyanate (II) by means of NaH in DMF gives the sodium salt (IIIa-b), which is methylated with methyl iodide to afford the methylsulfanyl derivative (IVa-b). The cyclization of (IVa-b) by means of NaH in THF provides the methylsulfanyl quinolone (V), which is oxidized with MCPBA to the corresponding methylsulfinyl compound (VI). The reaction of (VI) with NaSH in THF furnishes 1-cyclopropyl-6,7-difluoro-4-oxo-2-sulfanyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (VII), which is cyclized with hydroxylamine-O-sulfonic acid and NaHCO3 through the intermediate (VIII), affording the isothiazoloquinoline (IX). Finally, this compound is condensed with piperazine (X) in pyridine to give the target compound.
【1】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101. |
【2】 Aquilar-Bryan, L.; Bryan, J.; Boyd, A.E. III; et al.; Sulfonylurea signal transduction. Recent Prog Horm Res 1991, 47, 299-317. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IIIa) | 43212 | sodium (Z)-1-(cyclopropylamino)-3-ethoxy-3-oxo-2-(2,4,5-trifluorobenzoyl)-1-propene-1-thiolate | C15H13F3NNaO3S | 详情 | 详情 | |
(IIIb) | 43213 | sodium (E)-1-(cyclopropylamino)-3-ethoxy-3-oxo-2-(2,4,5-trifluorobenzoyl)-1-propene-1-thiolate | C15H13F3NNaO3S | 详情 | 详情 | |
(IVa) | 43214 | ethyl (Z)-3-(cyclopropylamino)-3-(methylsulfanyl)-2-(2,4,5-trifluorobenzoyl)-2-propenoate | C16H16F3NO3S | 详情 | 详情 | |
(IVb) | 43215 | ethyl (E)-3-(cyclopropylamino)-3-(methylsulfanyl)-2-(2,4,5-trifluorobenzoyl)-2-propenoate | C16H16F3NO3S | 详情 | 详情 | |
(I) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
(II) | 43211 | 1-isothiocyanatocyclopropane; cyclopropyl isothiocyanate | 56601-42-4 | C4H5NS | 详情 | 详情 |
(V) | 43216 | ethyl 1-cyclopropyl-6,7-difluoro-2-(methylsulfanyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H15F2NO3S | 详情 | 详情 | |
(VI) | 43217 | ethyl 1-cyclopropyl-6,7-difluoro-2-(methylsulfinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H15F2NO4S | 详情 | 详情 | |
(VII) | 43218 | ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-2-sulfanyl-1,4-dihydro-3-quinolinecarboxylate | C15H13F2NO3S | 详情 | 详情 | |
(VIII) | 43219 | ethyl 2-(aminosulfanyl)-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H14F2N2O3S | 详情 | 详情 | |
(IX) | 43220 | 9-cyclopropyl-6,7-difluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione | C13H8F2N2O2S | 详情 | 详情 | |
(X) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |