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【结 构 式】 
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【分子编号】25649 【品名】(methoxymethyl)(triphenyl)phosphonium bromide 【CA登记号】 |
【 分 子 式 】C20H20BrOP 【 分 子 量 】387.255962 【元素组成】C 62.03% H 5.21% Br 20.63% O 4.13% P 8% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(VIII)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：(VIII)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：(XIII)The enantioselective condensation of 2-bromovanillin (I) with cyclohexenecarboxylate (II) by means of the chiral phosphine ligand (III) gives the chiral aryl ether (IV), which is reduced with DIBAL to yield the diol (V). The protection of (V) with Tbdms-OTf affords the bis silyl ether (VI), which is cyclized by means of Pd(OAc)2 to furnish the tetrahydrodibenzofuran (VII). The deprotection of (VII) with TBAF gives the diol (VIII), which is chemoselectively oxidized with MnO2 to yield the hydroxyaldehyde (IX). The reductocondensation of (IX) with methylamine and NaBH3CN affords the secondary amine (X), which is protected with Boc2O, providing the carbamate (XI). The oxidation of (XI) with DMP gives the aldehyde (XII), which is condensed with the phosphonium bromide (XIII) and NaHMDS, yielding the vinyl ether (XIV). The deprotection and cyclization of (XIV) by means of TFA affords the seven-member ring hemiaminal (XV), which is reduced with NaBH3CN to provide deoxygalanthamine (XVI). The epoxidation of (XVI) with dimethyldioxirane (DMDO) and TsOH furnishes the epoxide (XVII), which is regioselectively opened with diphenyl diselenide and NaBH4 to give the alpha-hydroxy selenide (XVIII). Elimination of the selenide group of (XVIII) by oxidation with NaIO4 at 80 C yielded isogalanthamine (XIX), which is finally isomerized to the target compound by treatment with Osborn's rhenium catalyst (Ph3SiO-ReO3).
| 【1】 Trost, B.M.; Toste, F.D.; Enantioselective total synthesis of (-)-galanthamine. J Am Chem Soc 2000, 122, 45, 11262. |
| 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) | 26230 | 2-bromo-3-hydroxy-4-methoxybenzaldehyde | C8H7BrO3 | 详情 | 详情 | |
| (II) | 43984 | methyl 6-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-1-cyclohexene-1-carboxylate | C11H13Cl3O5 | 详情 | 详情 | |
| (III) | 43985 | 2-(diphenylphosphino)-N-((1S,2S)-2-[[2-(diphenylphosphino)benzoyl]amino]-1,2-diphenylethyl)benzamide | C52H42N2O2P2 | 详情 | 详情 | |
| (IV) | 43986 | methyl (6S)-6-(2-bromo-3-formyl-6-methoxyphenoxy)-1-cyclohexene-1-carboxylate | C16H17BrO5 | 详情 | 详情 | |
| (V) | 43987 | [(6S)-6-[2-bromo-3-(hydroxymethyl)-6-methoxyphenoxy]-1-cyclohexen-1-yl]methanol | C15H19BrO4 | 详情 | 详情 | |
| (VI) | 43988 | 3-bromo-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-[[(1S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclohexen-1-yl]oxy]phenyl methyl ether; ([(6S)-6-[2-bromo-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6-methoxyphenoxy]-1-cyclohexen-1-yl]methoxy)(tert-butyl)dimethylsilane | C27H47BrO4Si2 | 详情 | 详情 | |
| (VII) | 43989 | [(5aS,9aS)-9a-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl tert-butyl(dimethyl)silyl ether; [[(5aS,9aS)-9a-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methoxy](tert-butyl)dimethylsilane | C27H46O4Si2 | 详情 | 详情 | |
| (VIII) | 43990 | [(5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methanol | C15H18O4 | 详情 | 详情 | |
| (IX) | 43991 | (5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-carbaldehyde | C15H16O4 | 详情 | 详情 | |
| (X) | 43992 | [(4aS)-6-methoxy-9-[(methylamino)methyl]-4,4a-dihydrodibenzo[b,d]furan-9(3H)-yl]methanol | C16H21NO3 | 详情 | 详情 | |
| (XI) | 43993 | tert-butyl [(5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C21H29NO5 | 详情 | 详情 | |
| (XII) | 43994 | tert-butyl [(5aS,9aR)-9a-formyl-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C21H27NO5 | 详情 | 详情 | |
| (XIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (XIV) | 43995 | tert-butyl [(5aS,9aR)-4-methoxy-9a-[(Z)-2-methoxyethenyl]-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C23H31NO5 | 详情 | 详情 | |
| (XV) | 43996 | (4aS,8aR)-11-methyl-5,6,11,12-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl methyl ether; (4aS,8aR)-3-methoxy-11-methyl-5,6,11,12-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine | C17H19NO2 | 详情 | 详情 | |
| (XVI) | 43997 | (4aS,8aS)-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine; (4aS,8aS)-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl methyl ether | C17H21NO2 | 详情 | 详情 | |
| (XVII) | 43998 | (1aS,3aR,4aS,4bR)-11-methoxy-7-methyl-2,3,3a,4a,5,6,7,8-octahydro-1aH-oxireno[2',3':4,5][1]benzofuro[3a,3,2-ef][2]benzazepine; (1aS,3aR,4aS,4bR)-7-methyl-2,3,3a,4a,5,6,7,8-octahydro-1aH-oxireno[2',3':4,5][1]benzofuro[3a,3,2-ef][2]benzazepin-11-yl methyl ether | C17H21NO3 | 详情 | 详情 | |
| (XVIII) | 43999 | (4aS,7S,8S,8aR)-3-methoxy-11-methyl-7-(phenylselanyl)-5,6,7,8,9,10,11,12-octahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-8-ol | C23H27NO3Se | 详情 | 详情 | |
| (XIX) | 44000 | (4aS,8R,8aR)-3-methoxy-11-methyl-5,8,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-8-ol | C17H21NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Alkylation of N-Boc-piperazine (I) with bromoacetal (II) provided piperazine acetal (III). This was submitted to Fisher cyclization with 4-(1,2,4-triazol-4-yl)phenyl hydrazine (IV) in aqueous H2SO4 to afford the deprotected indole (V). Wittig reaction of 3-fluorobenzaldehyde (VII) with phosphorane prepared from (methoxymethyl)phosphonium salt (VI) and PhLi furnished the methoxyvinyl compound (VIII) as an E:Z mixture. Subsequent acid hydrolysis of the enol ether function of (VIII) yielded aldehyde (IX). The target compound was then obtained by reductive alkylation of piperazine (V) with aldehyde (IX) in the presence of NaBH3CN.
| 【1】 Chambers, M.S.; Goodacre, S.; Street, L.J.; et al.; 3-(Piperazinylpropyl)indoles: Selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents. J Med Chem 1999, 42, 4, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 25650 | 1-fluoro-3-[(E)-2-methoxyethenyl]benzene; (E)-2-(3-fluorophenyl)ethenyl methyl ether | C9H9FO | 详情 | 详情 | |
| (VIIIb) | 53875 | (Z)-2-(3-fluorophenyl)ethenyl methyl ether; 1-fluoro-3-[(Z)-2-methoxyethenyl]benzene | n/a | C9H9FO | 详情 | 详情 |
| (I) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 25645 | 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane | C7H15BrO2 | 详情 | 详情 | |
| (III) | 25646 | tert-butyl 4-(5,5-dimethoxypentyl)-1-piperazinecarboxylate | C16H32N2O4 | 详情 | 详情 | |
| (IV) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (V) | 25648 | 3-[3-(1-piperazinyl)propyl]-5-(4H-1,2,4-triazol-4-yl)-1H-indole | C17H22N6 | 详情 | 详情 | |
| (VI) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (VII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (IX) | 25651 | 3-(3-fluorophenyl)propanal | C9H9FO | 详情 | 详情 |