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【结 构 式】

【分子编号】22200

【品名】(E)-7-(2,4-dichlorophenyl)-6-hepten-1-ol

【CA登记号】

【 分 子 式 】C13H16Cl2O

【 分 子 量 】259.17484

【元素组成】C 60.25% H 6.22% Cl 27.36% O 6.17%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

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.

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:(V)

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).

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