【结 构 式】 |
【药物名称】SB-201076 【化学名称】2(R*)-[8-(2,4-dichlorophenyl)-2(S*)-hydroxyoctyl]-2-hydroxybutanedioic acid 【CA登记号】154566-05-9 【 分 子 式 】C18H24Cl2O6 【 分 子 量 】407.29438 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ATP Citrate Lyase Inhibitors |
合成路线1
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2
2) Alternatively, aldehyde (VII) was condensed with the dianion of methyl acetoacetate (XIV) to give hydroxyketone (XV), which was converted to the cyanohydrin (XVI) using KCN and KH2PO4. Basic hydrolysis of (XV) then provided a mixture of the (3R*,5S*)- (XIII) and (3R*,5R*)- (XVII) diastereoisomers.
【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 | |
(rac-XVII) | 22227 | (2S)-2-[(2R)-8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxybutanedioic acid | C18H24Cl2O6 | 详情 | 详情 | |
(VII) | 22202 | 7-(2,4-dichlorophenyl)heptanal | C13H16Cl2O | 详情 | 详情 | |
(XIV) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
(XV) | 22225 | methyl 11-(2,4-dichlorophenyl)-5-hydroxy-3-oxoundecanoate | C18H24Cl2O4 | 详情 | 详情 | |
(XVI) | 22226 | methyl 3-cyano-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoate | C19H25Cl2NO4 | 详情 | 详情 |
合成路线3
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 |