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【结 构 式】 
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【分子编号】22372 【品名】Furan 【CA登记号】110-00-9 |
【 分 子 式 】C4H4O 【 分 子 量 】68.07516 【元素组成】C 70.57% H 5.92% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(II)The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The oxidation of the primary alcohol group of (XI) with pyridinium chlorochromate (PCC) in dichloromethane affords the aldehyde (XII), which is finally reductocondensed with 4-phenylsemicarbazide (XIII) by means of NaBH3CN and hydrolyzed with LiOH to furnish the target semicarbazide.
| 【1】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【2】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 【3】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【4】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43729 | methyl (Z)-7-[(1R,2R,3S,4S)-3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H22O4 | 详情 | 详情 | |
| (XIII) | 43730 | N-phenyl-1-hydrazinecarboxamide | 537-47-3 | C7H9N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The oxidation of the primary alcohol group of (XI) with pyridinium chlorochromate (PCC) in dichloromethane affords the aldehyde (XII), which is condensed with dimethyl 2-oxobutylphosphonate (XIII) and NaH, providing the pentenone (XIV). Finally, the ketonic group of (XIV) is reduced with NaBH4/CeCl3, and the resulting ester hydrolyzed with LiOH to furnish the target hydroxyacid as a diastereomeric mixture that is separated by conventional methods.
| 【1】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 【2】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【3】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【4】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43729 | methyl (Z)-7-[(1R,2R,3S,4S)-3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H22O4 | 详情 | 详情 | |
| (XIII) | 43731 | dimethyl 2-oxobutylphosphonate | C6H13O4P | 详情 | 详情 | |
| (XIV) | 43732 | (Z)-7-[(1R,2R,3S,4S)-3-[(E)-3-oxo-1-pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C18H26O4 | 详情 | 详情 | |
| (XV) | 43733 | (Z)-7-[(1R,2R,3S,4S)-3-[(E,3R)-3-hydroxy-1-pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C18H28O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The sulfonation of the primary alcohol group of (XI) with TsOH affords the tosylate (XII), which is condensed with potassium phthalimide (XII) to provide the phthalimido derivative (XIV). The treatment of (XIV) with hydrazine gives the aminomethyl compound (XV), which is finally condensed with N-(heptanoyl)glycine (XVI) by means of CDI and hydrolyzed with LiOH to afford the target glycinamide compound.
| 【1】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【2】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【3】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 【4】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43724 | methyl (Z)-7-[(1R,2R,3R,4S)-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C22H30O6S | 详情 | 详情 | |
| (XIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XIV) | 43725 | methyl (Z)-7-[(1R,2R,3R,4S)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C23H27NO5 | 详情 | 详情 | |
| (XV) | 43726 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(aminomethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H25NO3 | 详情 | 详情 | |
| (XVI) | 43727 | 2-(heptanoylamino)acetic acid | C9H17NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of furan (I) with BuLi and Bu3Sn-Cl gives the bis tributyltin derivative (II), which is condensed with 4-bromobenzonitrile (III) by means of Pd(PPh3)4 in dioxane to yield 4,4'-(furan-2,5-diyl)-bis(benzonitrile) (IV). The reaction of (IV) with HCl and ethanol affords 4,4'-(furan-2,5-diyl)bis(ethyl benzimidate) (V), which is finally treated with O-methylhydroxylamine in ethanol to provide the target bis-O-methyl benzamidoxime.
| 【1】 McChesney-Harris, L.; et al.; Synthesis, characterization, and formulation of DB289, a novel dication prodrug for the treatment of African sleeping sickness and Pneumocystis carinii pneumonia (PCP). 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-2162. |
| 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) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (II) | 51325 | 2-[3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl methanesulfonate | C25H31Cl2NO5S | 详情 | 详情 | |
| (III) | 45833 | 4-Bromobenzonitrile | 623-00-7 | C7H4BrN | 详情 | 详情 |
| (IV) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (V) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The oxidation of 5-(trimethylsilyl)-4-pentyn-1-ol (I) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (II),which is condensed with furan (III) by means of BuLi in THF, yielding 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol (IV). The optical resolution of (IV) by means of diisopropyl-L-tartrate affords the (R)-isomer (V), which is treated with NBS and sodium acetate in THF to provide the dihydropyranone derivative (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of PPTS gives the 1-ethoxyethyl ether as a diastereomeric mixture that is separated by column chromatography affording the desired isomer (VIII). The reduction of the carbonyl group of (VIII) by means of LAH in ethyl ether provides alcohol (IX) along with minor amounts of its diastereomer that is separated by column chromatography. The dihydroxylation of (IX) by means of OsO4 in ethyl ether proceeded diastereoselectively giving triol (X), which is treated with 2,2-dimethoxypropane (XI) and PPTS in acetone to yield the acetonide (XII). The reaction of (XII) with thiocarbonyl diimidazole (TCDI) in dichloroethane affords intermediate (XIII), which is submitted to a radical cyclization by means of Bu3SnH and AIBN in benzene to provide the exomethylene derivative (XIV). The oxidation of the vinylsilane (XIV) by means of NaIO4 and OsO4 in t-butanol/pyridine gives the ketone (XV), which is submitted to a Birch reduction with Na in liquid ammonia to yield alcohol (XVI) along with some of its diastereomer that is separated by chromatography. The reaction (XVI) with benzyl bromide and NaH in THF affords the benzyl ether (XVII), which is treated with HCl in THF to provide the lactol (XVIII). The reduction of (XVIII) with NaBH4 in methanol/dichloromethane gives the diol (XIX), which is selectively monosilylated with Tbdms-Cl, yielding the primary silyl ether (XX). The oxidation of the secondary OH group of (XX) by means of TPAP in dichloromethane affords the cyclopentanone (XXI), which is treated with hydroxylamine and pyridine in methanol to provide the corresponding oxime (XXII). The oxime (XXII) was subjected to a Beckmann rearrangement by means of SOCl2 to give the lactam (XXIII), which is finally desilylated by means of TBAF in THF to yield the primary alcohol (XXIV).
| 【1】 Honda, T.; et al.; Enantioselective synthesis of indolizidine alkaloids: Formal synthesis of (-)-swainsonine and of (+)-pumiliotoxin 251D. J Chem Soc - Perkins Trans I 1994, 15, 2091. |
| 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) | 62628 | 5-(trimethylsilyl)-4-pentyn-1-ol | C8H16OSi | 详情 | 详情 | |
| (II) | 62115 | 5-(trimethylsilyl)-4-pentynal | C8H14OSi | 详情 | 详情 | |
| (III) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (IV) | 62629 | 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (V) | 62630 | (1R)-1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (VI) | 62631 | (2R)-6-hydroxy-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C12H18O3Si | 详情 | 详情 | |
| (VII) | 62632 | 1-propoxyethylene; propyl vinyl ether | C5H10O | 详情 | 详情 | |
| (VIII) | 62633 | (2R,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C17H28O4Si | 详情 | 详情 | |
| (IX) | 62634 | (2R,3S,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-3,6-dihydro-2H-pyran-3-ol | C17H30O4Si | 详情 | 详情 | |
| (X) | 62635 | (2R,3S,4S,5S,6R)-2-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-2H-pyran-3,4,5-triol | C17H32O6Si | 详情 | 详情 | |
| (XI) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XII) | 62636 | (3aS,4R,6R,7R,7aS)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C20H36O6Si | 详情 | 详情 | |
| (XIII) | 62637 | O-{(3aS,4R,6R,7R,7aR)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl} 1H-imidazole-1-carbothioate | C24H38N2O6SSi | 详情 | 详情 | |
| (XIV) | 62638 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-8-[(E)-(trimethylsilyl)methylidene]hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4(4H)-yl 1-propoxyethyl ether; {[(3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-ylidene]methyl}(trimethyl)silane | C20H36O5Si | 详情 | 详情 | |
| (XV) | 62639 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-one | C16H26O6 | 详情 | 详情 | |
| (XVI) | 62640 | (3aS,4R,5aR,8R,8aS,8bS)-2-ethyl-2-methyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8-ol | C17H30O6 | 详情 | 详情 | |
| (XVII) | 62641 | (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-yl 1-propoxyethyl ether; (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran | C23H34O6 | 详情 | 详情 | |
| (XVIII) | 62642 | (3aS,4S,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-ol | C18H24O5 | 详情 | 详情 | |
| (XIX) | 62643 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C18H26O5 | 详情 | 详情 | |
| (XX) | 62644 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C24H40O5Si | 详情 | 详情 | |
| (XXI) | 62645 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone | C24H38O5Si | 详情 | 详情 | |
| (XXII) | 62646 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone oxime | C24H39NO5Si | 详情 | 详情 | |
| (XXIII) | 62647 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C24H39NO5Si | 详情 | 详情 | |
| (XXIV) | 62648 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C18H25NO5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Artemisinin (I) was reduced to the dihydro analogue (II), and subsequently the 10-hydroxyl group was substituted for a fluorine atom using diethylaminosulfur trifluoride. The desired 10-beta-isomer (III) was then separated by column chromatography. Finally, boron trifluoride-promoted Friedel Crafts condensation with furan (IV) at low temperature provided the target furyl compound, the major 10-beta isomer being isolated by chromatography on Florisil.
| 【1】 Posner, G.H.; Parker, M.H.; Northrop, J.; Elias, J.S.; Ploypradith, P.; Xie, S.; Shapiro, T.A.; Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family. J Med Chem 1999, 42, 2, 300. |
| 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) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 22371 | (1R,4S,5R,8S,9R,10R,12S,13R)-10-fluoro-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane | C15H23FO4 | 详情 | 详情 | |
| (IV) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)Hexachloroplatinic acid (I) was reduced to potassium tetrachloroplatinate (II) using hydrazine. Treatment of (II) with KI produced the tetraiodoplatinate (III), which was converted to the diamino compound (IV) by reaction with isopropylamine. Conversion to the dinitrate (V) was then effected by iodide ion exchange with silver nitrate. Diels-Alder condensation of maleic anhydride (VI) with furan (VII) furnished adduct (VIII), which was further hydrogenated to (IX) using Pd/C. Then, basic hydrolysis of the cyclic anhydride in the presence of the platinum complex (V) afforded the title compound.
| 【1】 Lin, G.; To, K.K.W.; Wang, X.; Han, X.; Au-Yeung, S.C.F.; Ho, Y.-P.; Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety. J Med Chem 2001, 44, 13, 2065. |
| 【2】 Ho, Y.P.; Au-Yeung, S.C.F.; Jiang, T.; Han, X.; Wang, X.; Lin, G.; Lu, S. (Chinese University of Hong Kong); Synthesis of platinum complexes and uses thereof. WO 9849174 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (VIII) | 49887 | exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride; exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride; 7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride | 6118-51-0 | C8H6O4 | 详情 | 详情 |
| (IX) | 49888 | 4,10-Dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 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 Diels-Alder cycloaddition between maleic anhydride (I) and furan (II) produced adduct (III). Subsequent double-bond hydrogenation in the presence of Pd/C furnished the saturated anhydride (IV).
| 【1】 Lin, G.; To, K.K.W.; Wang, X.; Han, X.; Au-Yeung, S.C.F.; Ho, Y.-P.; Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety. J Med Chem 2001, 44, 13, 2065. |
| 【2】 Ho, Y.P.; Au-Yeung, S.C.F.; Jiang, T.; Han, X.; Wang, X.; Lin, G.; Lu, S. (Chinese University of Hong Kong); Synthesis of platinum complexes and uses thereof. WO 9849174 . |
| 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) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 49887 | exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride; exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride; 7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride | 6118-51-0 | C8H6O4 | 详情 | 详情 |
| (IV) | 49888 | 4,10-Dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 |