• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】43719

【品名】(1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol

【CA登记号】

【 分 子 式 】C8H12O3

【 分 子 量 】156.18148

【元素组成】C 61.52% H 7.74% O 30.73%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VIa)

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:(VIa)

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:(VIa)

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
Extended Information