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【结 构 式】

【分子编号】22213

【品名】methyl 5-(2-methoxy-2-oxoethyl)-3-(5-oxopentyl)-4,5-dihydro-5-isoxazolecarboxylate

【CA登记号】

【 分 子 式 】C13H19NO6

【 分 子 量 】285.297

【元素组成】C 54.73% H 6.71% N 4.91% O 33.65%

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:(XVIII)

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2

该中间体在本合成路线中的序号:(XXII)

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
Extended Information