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【结 构 式】 
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【分子编号】21416 【品名】dimethyl 2-methylenesuccinate 【CA登记号】617-52-7 |
【 分 子 式 】C7H10O4 【 分 子 量 】158.154 【元素组成】C 53.16% H 6.37% O 40.47% |
合成路线1
该中间体在本合成路线中的序号：(II)The precursor (R)-9-[4-hydroxy-2-(hydroxymethyl)]guanine (VI) was prepared by conjugate addition of dimethyl itaconate (II) to 2-amino-6-chloropurine (I), followed by reduction of the resultant diester (III) with LiBH4 to yield (IV). Subsequent displacement of the 6-chloro group of (IV) with ammonia under pressure furnished the racemic 2,6-diaminopurine (V). Then, enantioselective deamination of (V) in the presence of adenosine deaminase provided the target (R)-guanine derivative (VI). Esterification of the 4-hydroxy group of (VI) with N-Boc-L-valine (VII) by means of DCC gave the valine ester (VIII). The remaining free hydroxyl group of (VIII) was further esterified with stearoyl chloride (IX) in pyridine, yielding stearate (X). Finally, acid-promoted N-Boc group cleavage in (IX) furnished the title compound.
| 【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 . |
| 【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 . |
| 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) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (III) | 52956 | dimethyl 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]succinate | C12H14ClN5O4 | 详情 | 详情 | |
| (IV) | 52957 | 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,4-butanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (V) | 52958 | 2-[(2,6-diamino-9H-purin-9-yl)methyl]-1,4-butanediol | C10H16N6O2 | 详情 | 详情 | |
| (VI) | 52959 | 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C10H15N5O3 | 详情 | 详情 | |
| (VII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 52960 | (3R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-(hydroxymethyl)butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate | C20H32N6O6 | 详情 | 详情 | |
| (IX) | 52961 | n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride | 112-76-5 | C18H35ClO | 详情 | 详情 |
| (X) | 52962 | (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}oxy)butyl stearate | C38H66N6O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Bromination of 4-bromo-3-methyl anisole derivative (I) by means of NBS and light in CH2Cl2 and (BzO)2 affords derivative (II), which is then treated with protected trifluoroethane derivative (III) in DMF to give (IV). Alternatively, (II) can be converted into (IV) by first treating with 2,2,2-trifluoroethylamine (V) in DMSO followed by N-protection by means of Boc2O in CH2Cl2. Treatment of (IV) with dimethyl itaconate (VII) in the presence of Pd(OAc)2, P(o-tol)3, DIEA and propionitrile yields intermediate (VIII), which is then reduced by hydrogenolysis over Pd/C in EtOAc to afford butanoate (IX). Removal of the Boc protecting group of (IX) by treatment with TFA and anisole provides derivative (X), which is then cyclized by means of tripropylamine in refluxing xylenes to afford benzazepine derivative (XI) in its racemic form. Separation of the two enantiomers of (XI) by chiral HPLC affords (S)-(XII), which is demethylated with BBr3 in CH2Cl2 to yield (XIII). Treatment of N-oxide derivative (XIV) with 3-amino-1-propanol (XV) in tert-amyl alcohol in the presence of NaHCO3 yields derivative (XVI), which is then reacted with phenol derivative (XIII) in a Mitsunobu reaction with PPh3 and DEAD in THF/DMF to give ether derivative (XVII). Reduction of (XVII) with cyclohexene in isopropanol in the presence of Pd/C affords methyl acetate (XVIII), which is finally hydrolyzed by means of aqueous NaOH in dioxane.
| 【1】 Miller, W.H.; Bhatnager, P.K.; Alberts, D.P.; et al.; Discovery of orally active nonpeptide vitronectin receptor antagonists based on a 2-benzazepine gly-asp mimetic. J Med Chem 2000, 43, 1, 22. |
| 【2】 Callahan, J.F.; Cousins, R.D.; Keenan, R.M.; Kwon, C.; Miller, W.H.; Uzinkas, I.N. (SmithKline Beecham plc); Vitronectin receptor antagonists. EP 0957917; WO 9814192 . |
| 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) | 42539 | 4-bromo-3-methylphenyl methyl ether; 1-bromo-4-methoxy-2-methylbenzene | 27060-75-9 | C8H9BrO | 详情 | 详情 |
| (II) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (III) | 42540 | C7H11F3NNaO2 | 详情 | 详情 | ||
| (IV) | 42541 | tert-butyl 2-bromo-5-methoxybenzyl(2,2,2-trifluoroethyl)carbamate | C15H19BrF3NO3 | 详情 | 详情 | |
| (V) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (VI) | 42543 | N-(2-bromo-5-methoxybenzyl)-2,2,2-trifluoro-1-ethanamine; N-(2-bromo-5-methoxybenzyl)-N-(2,2,2-trifluoroethyl)amine | C10H11BrF3NO | 详情 | 详情 | |
| (VII) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (VIII) | 42544 | dimethyl 2-[(E)-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxyphenyl)methylidene]succinate | C22H28F3NO7 | 详情 | 详情 | |
| (IX) | 42545 | dimethyl 2-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxybenzyl)succinate | C22H30F3NO7 | 详情 | 详情 | |
| (X) | 42546 | dimethyl 2-(4-methoxy-2-[[(2,2,2-trifluoroethyl)amino]methyl]benzyl)succinate | C17H22F3NO5 | 详情 | 详情 | |
| (XI) | 42547 | methyl 2-[8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XII) | 42548 | methyl 2-[(4S)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XIII) | 42549 | methyl 2-[(4S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C15H16F3NO4 | 详情 | 详情 | |
| (XIV) | 34524 | 2-chloro-1-pyridiniumolate | 2402-95-1 | C5H4ClNO | 详情 | 详情 |
| (XV) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVI) | 34525 | 2-[(3-hydroxypropyl)amino]-1-pyridiniumolate | C8H12N2O2 | 详情 | 详情 | |
| (XVII) | 42550 | 2-[(3-[[(4S)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]oxy]propyl)amino]-1-pyridiniumolate | C23H26F3N3O5 | 详情 | 详情 | |
| (XVIII) | 42551 | methyl 2-[(4S)-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C23H26F3N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(II)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5
该中间体在本合成路线中的序号：(II)The Grignard reagent (II), prepared from 6-(benzyloxy)hexyl bromide (I), was condensed with 3-chlorofluoren-9-one (III) to give the carbinol (IV). Hydrogenolysis of (IV) over Pd/C gave fluorenylhexanol (V), which was oxidized to the corresponding aldehyde (VI) under Swern conditions using oxalyl chloride and DMSO. Oxime (VII) was then prepared by reaction of (VI) with hydroxylamine. Treatment of (VII) with NaOCl and Et3N generated an intermediate nitrile oxide which, in the presence of dimethyl itaconate (VIII), experienced a [3+2] cycloaddition to afford the isoxazole (IX). Reductive opening of this heterocycle by hydrogenation in the presence of Raney Nickel and boric acid produced the hydroxyketone (X), and further reduction of (X) using NaHB(OAc)3 in AcOH yielded dihydroxyester (XI) as a mixture of diastereoisomers. Saponification with NaOH, followed by recrystallization of the resulting disodium salt, then furnished the racemic mixture of (3R*,5S*,9R*)- and (3R*,5S*,9S*)-diastereoisomers (XII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 22173 | 1-[[(6-bromohexyl)oxy]methyl]benzene; benzyl 6-bromohexyl ether | C13H19BrO | 详情 | 详情 | |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (II) | 22174 | [6-(benzyloxy)hexyl](bromo)magnesium | C13H19BrMgO | 详情 | 详情 | |
| (III) | 22175 | 3-chloro-9H-fluoren-9-one | C13H7ClO | 详情 | 详情 | |
| (IV) | 22176 | 9-[6-(benzyloxy)hexyl]-3-chloro-9H-fluoren-9-ol | C26H27ClO2 | 详情 | 详情 | |
| (V) | 22177 | 6-(3-chloro-9H-fluoren-9-yl)-1-hexanol | C19H21ClO | 详情 | 详情 | |
| (VI) | 22178 | 6-(3-chloro-9H-fluoren-9-yl)hexanal | C19H19ClO | 详情 | 详情 | |
| (VII) | 22179 | 6-(3-chloro-9H-fluoren-9-yl)hexanal oxime | C19H20ClNO | 详情 | 详情 | |
| (IX) | 22181 | methyl 3-[5-(3-chloro-9H-fluoren-9-yl)pentyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate | C26H28ClNO5 | 详情 | 详情 | |
| (X) | 22182 | dimethyl 2-[7-(3-chloro-9H-fluoren-9-yl)-2-oxoheptyl]-2-hydroxysuccinate | C26H29ClO6 | 详情 | 详情 | |
| (XI) | 22183 | dimethyl 2-[7-(3-chloro-9H-fluoren-9-yl)-2-hydroxyheptyl]-2-hydroxysuccinate | C26H31ClO6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)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7
该中间体在本合成路线中的序号：(IX)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 |
合成路线8
该中间体在本合成路线中的序号：(II)The condensation between cyclohexanone (I) and dimethyl itaconate (II) in the presence of NaOMe in cold Et2O afforded the spirobutenolide (III) together with some hydrolyzed product (IV). A further hydrolytic treatment with aqueous NaOH provided acid (IV), which was then converted to acid chloride (V) by treatment with PCl5 in refluxing cyclohexane. Reaction of this acid chloride with N-(2-methoxyphenyl)piperazine in CH2Cl2 at 0 C produced the title amide.
| 【1】 Bador, P.; et al.; Synthesis of acetylenic spirobutenolide derivatives and evaluation of their growth inhibitory effect on cells in culture. Arzneim-Forsch Drug Res 1990, 40(II), 10, 1135-1139. |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (II) | 21417 | methyl 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylate | C12H16O4 | 详情 | 详情 | |
| (IV) | 21418 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylic acid | C11H14O4 | 详情 | 详情 | |
| (V) | 21419 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carbonyl chloride | C11H13ClO3 | 详情 | 详情 | |
| (VI) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The condensation between cyclohexanone (I) and dimethyl itaconate (II) in the presence of NaOMe in cold Et2O afforded the spirobutenolide (III) together with some hydrolyzed product (IV). A further hydrolytic treatment with aqueous NaOH provided acid (IV), which was then converted to acid chloride (V) by treatment with PCl5 in refluxing cyclohexane. Reaction of this acid chloride with N-(4-fluorophenyl)piperazine in CH2Cl2 at 0 C produced the title amide.
| 【1】 Bois, F.; et al.; Spirobutenolides substituted by arylpiperazinyl-carbonyl moieties. Synthesis and antinociceptive properties. Arzneim-Forsch Drug Res 1998, 48, 12, 1156. |
| 【2】 Bador, P.; et al.; Synthesis of acetylenic spirobutenolide derivatives and evaluation of their growth inhibitory effect on cells in culture. Arzneim-Forsch Drug Res 1990, 40(II), 10, 1135-1139. |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (III) | 21417 | methyl 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylate | C12H16O4 | 详情 | 详情 | |
| (IV) | 21418 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carboxylic acid | C11H14O4 | 详情 | 详情 | |
| (V) | 21419 | 3-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-4-carbonyl chloride | C11H13ClO3 | 详情 | 详情 | |
| (VI) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |