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【结 构 式】 
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【分子编号】22096 【品名】ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate 【CA登记号】 |
【 分 子 式 】C11H9Cl2FO3 【 分 子 量 】279.0944632 【元素组成】C 47.34% H 3.25% Cl 25.41% F 6.81% O 17.2% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 2,4-dichloro-5-fluorobenzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid water yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (VIII). The cyclization of (VIII) with NaH in refluxing dioxane yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IX), which is finally condensed with piperazine (X) in hot DMSO.
| 【1】 Reddy, P.G.; Baskaran, S.; Microwave assisted amination of quinolone carboxylic acids: An expeditious synthesis of fluoroquinolone antibacterials. Tetrahedron Lett 2001, 42, 38, 6775. |
| 【2】 Grohe, K.; Zeiler, H. J.; Metzger, K.G. (Bayer AG); 1-Cyclopropyl-6-fluoro-1,4-dihidro-4-oxo-7-piperazino-quinoline-3-carboxilic acids, process for their preparation and antibacterial agents containing them. EP 0078362; JP 4253963; JP 58074667 . |
| 【3】 Serradell, M.N.; Castaner, J.; Ciprofloxacin. Drugs Fut 1984, 9, 3, 179. |
| 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) | 22093 | 2,4-dichloro-5-fluorobenzoyl chloride | 86393-34-2 | C7H2Cl3FO | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 22095 | diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate | C14H13Cl2FO5 | 详情 | 详情 | |
| (IV) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (V) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (VI) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (VII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (VIII) | 22100 | ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate | C15H14Cl2FNO3 | 详情 | 详情 | |
| (IX) | 30340 | ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | 86483-54-7 | C15H13ClFNO3 | 详情 | 详情 |
| (X) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Condensation of 2,4-dichoro-5-fluoroacetophenone (I) with diethyicarbonate (II) in the presence of sodium hydride gives ethyl 2,4-dichloro-5-fluorobenzoylacetate (III). The condensation of (III) with triethylorthoformate in reftuxing acetic anhydride yields ethyl 2-(2,4-dichloro-5-fluornbenzoyl)-3-ethoxyacrylate (IV), which is treated with p-fluoroaniline in methylene chloride to yield ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(p-fluoroanilino)acrylate (V). Cyclization of (V) with sodium hydride in tetrahydrofuran followed by hydrolysis yields 7-chloro-1-(p-fluorophenyl)-8 fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (VI). Condensation of (VI) with N-methylpiperazine in 1-methyl-2-pyrrolidinone followed by treatment with hydrochloric acid yields A-56619.
| 【1】 Clairbone, A.K.; Pihuleac, E.; Nordeen, C.; Fernandes, P.B.; Pernet, A.; Chu, D.T.W.; O'Donell, T.J.; A-56619 and A-56620: Synthesis and antibacterial activities of the novel aryl-fluoro-quinolones and their analogs. 24th Intersci Conf Antimicrob Agents Chemother (Oct 8-10, Washington, D.C) 1984, Abs 72. |
| 【2】 Granneman, G.R.; Chu, D.T.W.; Fernandes, P.B.; Abbott-56619. Drugs Fut 1985, 10, 7, 543. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 | |
| 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 | |
| (I) | 24574 | 1-(2,4-dichloro-5-fluorophenyl)-1-ethanone | 704-10-9 | C8H5Cl2FO | 详情 | 详情 |
| (II) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (III) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (IV) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (V) | 24578 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-(4-fluoroanilino)-2-propenoate | C18H13Cl2F2NO3 | 详情 | 详情 | |
| (VI) | 24579 | 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H8ClF2NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)1) The condensation of 2,4-dichloro-5-fluoro-benzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially decarboxylated with p-toluenesulfonic acid yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) by means of refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol giving ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(cyclopropylamino)acrylate (VII). The cyclization of (VII) by means of NaH in refluxing dioxane yields 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX), which is finally condensed with N-ethylpiperazine (X) by heating at 140 C in DMSO.
| 【1】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 . |
| 【2】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 . |
| 【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305. |
| 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) | 22093 | 2,4-dichloro-5-fluorobenzoyl chloride | 86393-34-2 | C7H2Cl3FO | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 22095 | diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate | C14H13Cl2FO5 | 详情 | 详情 | |
| (IV) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (V) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (VI) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (VII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (VIII) | 22100 | ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate | C15H14Cl2FNO3 | 详情 | 详情 | |
| (IX) | 22101 | 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 86393-33-1 | C13H9ClFNO3 | 详情 | 详情 |
| (X) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(I)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 |