(E)-7-(2,4-dichlorophenyl)-6-heptenoic acid -Drug Synthesis Database

【结构式】

【分子编号】22198

【品名】(E)-7-(2,4-dichlorophenyl)-6-heptenoic acid

【CA登记号】

【分子式】C₁₃H₁₄Cl₂O₂

【分子量】273.15836

【元素组成】C 57.16% H 5.17% Cl 25.96% O 11.71%

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：(III)

1) Wittig reaction of 2,4-dichlorobenzaldehyde (I) with phosphonium bromide (II) using NaH in DMSO provided 7-(2,4-dichlorophenyl)-6-heptenoic acid (III) as a mixture of E and Z isomers. Esterification of (III) with MeOH in the presence of H2SO4 afforded ester (IV), which was reduced with DIBAL-H to afford alcohol (V). Subsequent hydrogenation of (V) over Pd/C gave 7-(2,4-dichlorophenyl)-1-heptanol (VI) and further Swern oxidation yielded the corresponding aldehyde (VII). Oxime (VIII) was then prepared by reaction of (VII) with hydroxylamine. Treatment of (VIII) with NaOCl and Et3N generated an intermediate nitrile oxide which, in the presence of dimethyl itaconate (IX), experienced a [3+2] cycloaddition to afford the isoxazole (X). Reductive opening of this heterocycle by hydrogenation in the presence of Raney Nickel and boric acid produced hydroxyketone (XI), and further reduction of (XI) using NaBH4 and CeCl3 in MeOH yielded the dihydroxyester (XII) as a mixture of diastereoisomers. Saponification of (XII) with NaOH, followed by recrystallization of the resulting disodium salt, then furnished the racemic (3R*,5S*)-diasteroisomer (XIII), which was finally cyclized with HCl in aqueous THF to the target lactone.

参考文献中间体

合成目标

【1】 Gribble, A.D.; Ife, R.J.; Shaw, A.; McNair, D.; Novelli, C.E.; Bakewell, S.; Shah, V.P.; Dolle, R.E.; Groot, P.H.; Pearce, N.; Yates, J.; Tew, D.; Boyd, H.; Ashman, S.; Eggleston, D.S.; Haltiwanger, R.C.; Okafo, G.; ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3,5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo. J Med Chem 1998, 41, 19, 3582.
【2】 Gribble, A.D.; Groot, P.H.E.; Shaw, A.N.; Dolle, R.E. (SmithKline Beecham plc); Phenylderivate as inhibitors of ATP citrate lyase. EP 0639187; WO 9322304 .

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)	22196	2,4-dichlorobenzaldehyde	874-42-0	C₇H₄Cl₂O	详情	详情
(II)	21416	dimethyl 2-methylenesuccinate	617-52-7	C₇H₁₀O₄	详情	详情
(III)	22198	(E)-7-(2,4-dichlorophenyl)-6-heptenoic acid		C₁₃H₁₄Cl₂O₂	详情	详情
(IV)	22199	methyl (E)-7-(2,4-dichlorophenyl)-6-heptenoate		C₁₄H₁₆Cl₂O₂	详情	详情
(V)	22200	(E)-7-(2,4-dichlorophenyl)-6-hepten-1-ol		C₁₃H₁₆Cl₂O	详情	详情
(VI)	22201	7-(2,4-dichlorophenyl)-1-heptanol		C₁₃H₁₈Cl₂O	详情	详情
(VII)	22202	7-(2,4-dichlorophenyl)heptanal		C₁₃H₁₆Cl₂O	详情	详情
(VIII)	22203	7-(2,4-dichlorophenyl)heptanal oxime		C₁₃H₁₇Cl₂NO	详情	详情
(X)	22205	methyl 3-[6-(2,4-dichlorophenyl)hexyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate		C₂₀H₂₅Cl₂NO₅	详情	详情
(XI)	22206	dimethyl 2-[8-(2,4-dichlorophenyl)-2-oxooctyl]-2-hydroxysuccinate		C₂₀H₂₆Cl₂O₆	详情	详情
(XII)	22207	dimethyl 2-[8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinate		C₂₀H₂₈Cl₂O₆	详情	详情
(XIII)	22208	2-[8-(2,4-Dichlorophenyl)-2(R)-hydroxyoctyl]-2-hydroxysuccinic acid disodium salt		C₂₀H₂₈Cl₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

1) The Wittig reaction of 2,4-dichlorobenzaldehyde (I) with phosphonium bromide (II) using NaH in DMSO provided 7-(2,4-dichlorophenyl)-6-heptenoic acid (III) as a mixture of E and Z isomers. Esterification of (III) with MeOH in the presence of H2SO4 afforded (IV), which was reduced with DIBAL-H to afford alcohol (V). Subsequent hydrogenation of (V) over Pd/C gave 7-(2,4-dichlorophenyl)-1-heptanol (VI) and further Swern oxidation yielded the corresponding aldehyde (VII). Oxime (VIII) was then prepared by reaction of (VII) with hydroxylamine. Treatment with NaOCl and Et3N generated an intermediate nitrile oxide which, in the presence of dimethyl itaconate (IX), experienced a [3+2] cycloaddition to afford the isoxazole (X). Reductive opening of this heterocycle by hydrogenation in the presence of Raney Nickel and boric acid produced hydroxyketone (XI), and further reduction of (XI) using NaBH4 and CeCl3 in MeOH yielded the dihydroxy ester (XII) as a mixture of diastereoisomers. Saponification of (XII) with NaOH, followed by recrystallization of the resulting disodium salt, then furnished the racemic (3R*,5S*)-diasteroisomer (XIII).

参考文献中间体

合成目标

【1】 Gribble, A.D.; Ife, R.J.; Shaw, A.; McNair, D.; Novelli, C.E.; Bakewell, S.; Shah, V.P.; Dolle, R.E.; Groot, P.H.; Pearce, N.; Yates, J.; Tew, D.; Boyd, H.; Ashman, S.; Eggleston, D.S.; Haltiwanger, R.C.; Okafo, G.; ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3,5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo. J Med Chem 1998, 41, 19, 3582.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(rac-XIII)	22208	2-[8-(2,4-Dichlorophenyl)-2(R)-hydroxyoctyl]-2-hydroxysuccinic acid disodium salt		C₂₀H₂₈Cl₂O₄	详情	详情
(I)	22196	2,4-dichlorobenzaldehyde	874-42-0	C₇H₄Cl₂O	详情	详情
(II)	18264	(5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide	50889-29-7	C₂₄H₂₆BrO₂P	详情	详情
(III)	22198	(E)-7-(2,4-dichlorophenyl)-6-heptenoic acid		C₁₃H₁₄Cl₂O₂	详情	详情
(IV)	22199	methyl (E)-7-(2,4-dichlorophenyl)-6-heptenoate		C₁₄H₁₆Cl₂O₂	详情	详情
(V)	22200	(E)-7-(2,4-dichlorophenyl)-6-hepten-1-ol		C₁₃H₁₆Cl₂O	详情	详情
(VI)	22201	7-(2,4-dichlorophenyl)-1-heptanol		C₁₃H₁₈Cl₂O	详情	详情
(VII)	22202	7-(2,4-dichlorophenyl)heptanal		C₁₃H₁₆Cl₂O	详情	详情
(VIII)	22203	7-(2,4-dichlorophenyl)heptanal oxime		C₁₃H₁₇Cl₂NO	详情	详情
(IX)	21416	dimethyl 2-methylenesuccinate	617-52-7	C₇H₁₀O₄	详情	详情
(X)	22205	methyl 3-[6-(2,4-dichlorophenyl)hexyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate		C₂₀H₂₅Cl₂NO₅	详情	详情
(XI)	22206	dimethyl 2-[8-(2,4-dichlorophenyl)-2-oxooctyl]-2-hydroxysuccinate		C₂₀H₂₆Cl₂O₆	详情	详情
(XII)	22207	dimethyl 2-[8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinate		C₂₀H₂₈Cl₂O₆	详情	详情

Extended Information