ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate -Drug Synthesis Database

【结构式】

【分子编号】22098

【品名】ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate

【CA登记号】

【分子式】C₁₄H₁₃Cl₂FO₄

【分子量】335.1586232

【元素组成】C 50.17% H 3.91% Cl 21.16% F 5.67% O 19.09%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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：(IV)

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.

参考文献中间体

合成目标

【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：(VI)

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.

参考文献中间体

合成目标

【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

Extended Information