ethyl (E)-3-(4-fluorophenyl)-2-propenoate -Drug Synthesis Database

【结构式】

【分子编号】56459

【品名】ethyl (E)-3-(4-fluorophenyl)-2-propenoate

【CA登记号】

【分子式】C₁₁H₁₁FO₂

【分子量】194.2055432

【元素组成】C 68.03% H 5.71% F 9.78% O 16.48%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of 4-fluorocinnamic acid ethyl ester (I) with cyanacetic acid ethyl ester (II) by means of NaOEt in ethanol gives 2-cyano-3-(4-fluorophenyl)glutaric acid diethyl ester (III). Alternatively, glutarate (III) can also be obtained by condensation of 4-fluorobenzaldehyde (V) with cyanacetic ester (II) and acetic acid ethyl ester (VI). The reduction of the cyano group of (III) with H2 over PtO2 in ethanol, followed by cyclization in refluxing toluene, yields 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) as a mixture of the cis- and trans-isomers. The reaction of the mixture (IV) with EtONa in refluxing toluene causes isomerization of the cis-isomer, affording (rac)-trans-4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (VII), which is reduced with LiAlH4 or borane (NaBH4/BF3) to provide the (rac)-(trans)-hydroxymethylpiperidine (VIII). Finally, this compound is reductively methylated by treatment with formaldehyde and H2 over Pd/C in ethanol to furnish (rac)-(trans)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IX), the desired intermediate. Alternatively, the cis/trans mixture 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) can be methylated first with formaldehyde as before to give 4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (X), also as a cis/trans mixture. This mixture is treated with EtONa in refluxing toluene to yield (rac)-(trans)-4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (XI). Finally, this compound is reduced with LiAlH4 in THF/toluene to afford the previously described target intermediate (IX).

参考文献中间体

合成目标

【1】 Bosch Rovira, A.; Dalmases Barjoan, P.; Herbera Espinal, M.R.; Carulla Oliver, J.M.; Marquillas Olóndriz, F. (Laboratorios Vita, SA); Process for obtaining (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. ES 2121685 .
【2】 Bosch Rovira, A.; Dalmases Barjoan, P.; Herbera Espinal, M.R.; Carulla Oliver, J.M.; Marquillas Olóndriz, F. (Laboratorios Vita, SA); Process for obtaining ethyl (±)-cis/(±)-trans-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylate. ES 2121684 .
【3】 Bosch Rovira, A.; Dalmases Barjoan, P.; Marquilla Olondriz, F.; Herbera Espinal, M.R.; Carulla Oliver, J.M. (Laboratorios Vita, SA); Ethyl 4-(4-fluorophenyl)-2-piperidinone-5-carboxylate and process for obtaining it. ES 2121682 .

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)	56459	ethyl (E)-3-(4-fluorophenyl)-2-propenoate		C₁₁H₁₁FO₂	详情	详情
(II)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(III)	56460	diethyl 2-cyano-3-(4-fluorophenyl)pentanedioate		C₁₆H₁₈FNO₄	详情	详情
(IV)	56461	ethyl 4-(4-fluorophenyl)-6-oxo-3-piperidinecarboxylate		C₁₄H₁₆FNO₃	详情	详情
(V)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(VI)	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
(VII)	56462	ethyl (3S,4R)-4-(4-fluorophenyl)-6-oxo-3-piperidinecarboxylate		C₁₄H₁₆FNO₃	详情	详情
(VIII)	56463	(rac)-[(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol		C₁₂H₁₆FNO	详情	详情
(IX)	43487	[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol	105812-81-5	C₁₃H₁₈FNO	详情	详情
(X)	56464	ethyl 4-(4-fluorophenyl)-1-methyl-6-oxo-3-piperidinecarboxylate		C₁₅H₁₈FNO₃	详情	详情
(XI)	56465	ethyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-6-oxo-3-piperidinecarboxylate		C₁₅H₁₈FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The cyclization of 4-fluorocinnamic acid ethyl ester (I) with malonic acid diethyl ester (II) by means of NaOMe or t-Bu-OK in THF or ethyl acetate gives (rac)-(trans)-4-(4-fluorophenyl)2,6-dioxopiperidine-3-carboxylic acid ethyl ester (III), which is reduced with LiAlH4 in THF to yield the piperidine methanol (rac)-(trans)-(IV). The protection of the NH group of (IV) with benzyl chloroformate and Na2CO3 in dichloromethane affords the benzyl carbamate (rac)-(trans)-(V), which is acylated with Ac2O and pyridine to provide the acetoxy compound (rac)-(trans)-(VI). The biological optical resolution of (rac)-(trans)-(VI) by means of Lipase CAL-A in hexane gives an easily separable mixture of the unreacted ester (3R,4S)-(trans)-(VI) and the hydrolyzed carbinol (3S,4R)-(VII). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol to yield the target intermediate, the (3S,4R)-(trans)-4-(4-fluorophenyl)piperidine-3-methanol (3S,4R)-(trans)-(VIII).

参考文献中间体

合成目标

【1】 Ali, F.E.; Thomas, M.R. (Beecham Group PLC); Process for the preparation of aryl-piperidine carbinols. EP 0223334 .
【2】 De Gonzalo, G.; et al.; Enzymatic resolution of trans-4-(4'-fluorophenyl)-3-hydroxymethylpiperidines, key intermediates in the synthesis of (-)-paroxetine. J Org Chem 2001, 66, 26, 8947.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(rac)-(VI)	56489	(rac)-benzyl (3S,4R)-3-[(acetyloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate	C₂₂H₂₄FNO₄	详情	详情
(3R,4S)-(VI)	56490	benzyl (3R,4S)-3-[(acetyloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate	C₂₂H₂₄FNO₄	详情	详情
(I)	56459	ethyl (E)-3-(4-fluorophenyl)-2-propenoate	C₁₁H₁₁FO₂	详情	详情
(II)	56486	ethyl 3-amino-3-oxopropanoate	C₅H₉NO₃	详情	详情
(III)	56487	ethyl (3S,4R)-4-(4-fluorophenyl)-2,6-dioxo-3-piperidinecarboxylate	C₁₄H₁₄FNO₄	详情	详情
(IV)	56463	(rac)-[(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol	C₁₂H₁₆FNO	详情	详情
(V)	56488	(rac)-benzyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate	C₂₀H₂₂FNO₃	详情	详情
(VII)	56491	benzyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate	C₂₀H₂₂FNO₃	详情	详情
(VIII)	56492	[(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol	C₁₂H₁₆FNO	详情	详情

Extended Information