dimethyl 2-[(E)-8-(2,4-dichlorophenyl)-2-oxo-7-octenyl]-2-hydroxysuccinate -Drug Synthesis Database

【结构式】

【分子编号】22216

【品名】dimethyl 2-[(E)-8-(2,4-dichlorophenyl)-2-oxo-7-octenyl]-2-hydroxysuccinate

【CA登记号】

【分子式】C₂₀H₂₄Cl₂O₆

【分子量】431.31236

【元素组成】C 55.7% H 5.61% Cl 16.44% O 22.26%

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：(XXI)

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.

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
(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：(XXV)

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.

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
(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