2-(3,4-dichlorophenyl)-4-pentenoic acid -Drug Synthesis Database

【结构式】

【分子编号】50421

【品名】2-(3,4-dichlorophenyl)-4-pentenoic acid

【CA登记号】

【分子式】C₁₁H₁₀Cl₂O₂

【分子量】245.1046

【元素组成】C 53.9% H 4.11% Cl 28.93% O 13.06%

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：(XXI)

In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound

参考文献中间体

合成目标

【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319.
【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	59283	N-(4-phenyl-4-piperidinyl)acetamide		C₁₃H₁₈N₂O	详情	详情
(XIV)	30414	2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid	5807-30-7	C₈H₆Cl₂O₂	详情	详情
(XV)	58942			C₁₀H₁₀LiNO₂	详情	详情
(XVI)	62381	(4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one		C₁₈H₁₅Cl₂NO₃	详情	详情
(XVII)	32112	3-iodo-1-propene;3-iodo-propen;allyl iodide	556-56-9	C₃H₅I	详情	详情
(XVIII)	62382	(4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one		C₂₁H₁₉Cl₂NO₃	详情	详情
(XIX)	62383	(2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid		C₁₁H₁₀Cl₂O₂	详情	详情
(XX)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XXI)	50421	2-(3,4-dichlorophenyl)-4-pentenoic acid		C₁₁H₁₀Cl₂O₂	详情	详情
(XXII)	62384	(2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide		C₁₂H₁₃Cl₂NO	详情	详情
(XXIII)	62385	(2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine		C₁₂H₁₅Cl₂N	详情	详情
(XXIV)	62386	N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide		C₁₉H₁₉Cl₂NO	详情	详情
(XXV)	62387	N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide		C₁₉H₂₁Cl₂NO₃	详情	详情
(XXVI)	26943	N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide		C₁₈H₁₇Cl₂NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The esterification of 3,4-dichlorophenylacetic acid (I) with methanol and ClH gives the methyl ester (II), which is alkylated with allyl bromide and LDA in THF to yield 2-(3,4-dichlorophenyl)-4-pentenoic acid methyl ester (IV). The hydrolysis of (IV) with LiOH in MeOH/water affords the corresponding free acid (V), which is epoxidated with MCPBA in refluxing chloroform to provide epoxide (VI), which, without isolation, is treated in acid medium, giving the tetrahydrofuranone (VII). The silylation of the OH group of (VII) with Tbdms-Cl and imidazole in DMF yields the protected silyl ether (VIII), which is treated with LDA in THF to afford the lithium enolate (IX). The reaction of (IX) with phenylselenyl chloride in THF provides the phenylselenyl derivative (X), which is oxidized with MCPBA to the corresponding selenoxide. This nonisolated compound undergoes spontaneous syn elimination to give, after hydrolysis of the silyl ether with AcOH, 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)furan-2(5H)-one (XI). Finally, this compound is esterified with pivaloyl chloride and pyridine in dichloromethane to afford the target ester.

参考文献中间体

合成目标

【1】 Pour, M.; et al.; 3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: Synthesis and biological activity of a novel group of potential antifungal drugs. J Med Chem 2001, 44, 17, 2701.

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)	30414	2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid	5807-30-7	C₈H₆Cl₂O₂	详情	详情
(II)	47947	methyl 2-(3,4-dichlorophenyl)acetate		C₉H₈Cl₂O₂	详情	详情
(III)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(IV)	50420	methyl 2-(3,4-dichlorophenyl)-4-pentenoate		C₁₂H₁₂Cl₂O₂	详情	详情
(V)	50421	2-(3,4-dichlorophenyl)-4-pentenoic acid		C₁₁H₁₀Cl₂O₂	详情	详情
(VI)	50422	2-(3,4-dichlorophenyl)-3-(2-oxiranyl)propionic acid		C₁₁H₁₀Cl₂O₃	详情	详情
(VII)	50423	3-(3,4-dichlorophenyl)-5-(hydroxymethyl)dihydro-2(3H)-furanone		C₁₁H₁₀Cl₂O₃	详情	详情
(VIII)	50424	5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)dihydro-2(3H)-furanone		C₁₇H₂₄Cl₂O₃Si	详情	详情
(IX)	50425			C₁₇H₂₃Cl₂LiO₃Si	详情	详情
(X)	50426	5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)-3-(phenylselanyl)dihydro-2(3H)-furanone		C₂₃H₂₈Cl₂O₃SeSi	详情	详情
(XI)	50427	3-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2(5H)-furanone		C₁₁H₈Cl₂O₃	详情	详情
(XII)	44281	pivalic acid	75-98-9	C₅H₁₀O₂	详情	详情

Extended Information