SB-204990, -Drug Synthesis Database

【结构式】

【药物名称】SB-204990

【化学名称】(±)-(3R*,5S*)-5-[6-(2,4-Dichlorophenyl)hexyl]-3-hydroxy-2-oxo-2,3,4,5-tetrahydrofuran-3-acetic acid

【CA登记号】154566-12-8, 154566-58-2 ((-)-trans-isomer)

【分子式】C₁₈H₂₂Cl₂O₅

【分子量】389.27904

【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 合成路线2

合成路线1

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.

参考文献中间体

【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

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

【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

Extended Information

Drug NewChemical Entity Original Patent(1)