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【结 构 式】 
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【分子编号】22207 【品名】dimethyl 2-[8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinate 【CA登记号】 |
【 分 子 式 】C20H28Cl2O6 【 分 子 量 】435.34412 【元素组成】C 55.18% H 6.48% Cl 16.29% O 22.05% |
合成路线1
该中间体在本合成路线中的序号：(XII)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：(XII)2) In an alternative method, epsilon-caprolactone (XIV) was reduced to lactol (XV) with DIBAL-H and then converted into oxime (XVI). In situ generation of the corresponding nitrile oxide, using NaOCl and Et3N, and subsequent cycloaddition with dimethyl itaconate (IX) afforded the isoxazole (XVII). Swern oxidation of (XVII) generated aldehyde (XVIII), which was condensed with the phosphonium salt (XIX) to give olefin (XX). Hydrogenation of (XX) in the presence of Raney Nickel and boric acid yielded unsaturated ketone (XXI), which by further hydrogenation of using PtO2 gave the previously described hydroxyketone (XI). Reduction of (XI) with sodium triacetoxyborohydride in AcOH gave the same mixture of diastereomeric dihydroxyesters (XII) already described, which was converted into the target compound by hydrolysis, recrystallization and subsequent acid cyclization as already descibed.
| 【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 |
|---|---|---|---|---|---|---|
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 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 | |
| (XIV) | 22209 | 2-oxepanone | 502-44-3 | C6H10O2 | 详情 | 详情 |
| (XV) | 22210 | 2-oxepanol | C6H12O2 | 详情 | 详情 | |
| (XVII) | 22212 | methyl 3-(5-hydroxypentyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C13H21NO6 | 详情 | 详情 | |
| (XVIII) | 22213 | methyl 5-(2-methoxy-2-oxoethyl)-3-(5-oxopentyl)-4,5-dihydro-5-isoxazolecarboxylate | C13H19NO6 | 详情 | 详情 | |
| (XIX) | 22214 | (2,4-dichlorobenzyl)(triphenyl)phosphorane | C25H21Cl2P | 详情 | 详情 | |
| (XX) | 22215 | methyl 3-[(E)-6-(2,4-dichlorophenyl)-5-hexenyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C20H23Cl2NO5 | 详情 | 详情 | |
| (XXI) | 22216 | dimethyl 2-[(E)-8-(2,4-dichlorophenyl)-2-oxo-7-octenyl]-2-hydroxysuccinate | C20H24Cl2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)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 |
合成路线4
该中间体在本合成路线中的序号：(XII)3) In a further method, epsilon-caprolactone (XVIII) was reduced to lactol (XIX) with DIBAL-H and then converted into oxime (XX). In situ generation of the corresponding nitrile oxide, using NaOCl and Et3N, and subsequent cycloaddition with dimethyl itaconate (IX) afforded the isoxazole (XXI). Swern oxidation of (XXI) generated aldehyde (XXII), which was condensed with the phosphonium salt (XXIII) to give olefin (XXIV). Hydrogenation in the presence of Raney Nickel and boric acid acid yielded unsaturated ketone (XXV), which by further hydrogenation of using PtO2 gave the previously described hydroxyketone (XI). Reduction of (XI) with sodium triacetoxyborohydride in AcOH gave the same mixture of diastereomeric dihydroxyesters (XII) already described, which was converted into the target compound by hydrolysis and subsequent, recrystallization as already described.
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 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 | |
| (XVIII) | 22209 | 2-oxepanone | 502-44-3 | C6H10O2 | 详情 | 详情 |
| (XIX) | 22210 | 2-oxepanol | C6H12O2 | 详情 | 详情 | |
| (XX) | 22230 | 6-hydroxyhexanal oxime | C6H13NO2 | 详情 | 详情 | |
| (XXI) | 22212 | methyl 3-(5-hydroxypentyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C13H21NO6 | 详情 | 详情 | |
| (XXII) | 22213 | methyl 5-(2-methoxy-2-oxoethyl)-3-(5-oxopentyl)-4,5-dihydro-5-isoxazolecarboxylate | C13H19NO6 | 详情 | 详情 | |
| (XXIII) | 22214 | (2,4-dichlorobenzyl)(triphenyl)phosphorane | C25H21Cl2P | 详情 | 详情 | |
| (XXIV) | 22215 | methyl 3-[(E)-6-(2,4-dichlorophenyl)-5-hexenyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C20H23Cl2NO5 | 详情 | 详情 | |
| (XXV) | 22216 | dimethyl 2-[(E)-8-(2,4-dichlorophenyl)-2-oxo-7-octenyl]-2-hydroxysuccinate | C20H24Cl2O6 | 详情 | 详情 |