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【结 构 式】

【分子编号】13616

【品名】(4-Carboxybutyl)triphenylphosphonium bromide

【CA登记号】17814-85-6

【 分 子 式 】C23H24BrO2P

【 分 子 量 】443.320122

【元素组成】C 62.31% H 5.46% Br 18.02% O 7.22% P 6.99%
与该中间体有关的原料药合成路线共 20 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20

合成路线1

该中间体在本合成路线中的序号：(X)

The esterification of 4alpha-carboxymethyl-5beta-benzyloxymethyl-cyclopent-2-en-1alpha-ol (I) with methyl iodide and K2CO3 in acetone gives the corresponding methyl ester (II), which by reaction with triethyl - orthoacetate (III) at 145 C is converted into 3-ethoxycarbonylmethyl-4-methoxycarbonylmethyl-5-benzyloxymethyl-1-cyclopentene (IV). The cyclization of (IV) with potassium tert-butoxide in benzene yields 6-benzyloxymethyl-cis-bicyclo[3.3.0]oct-7-ene-3-one (V), which by reaction with N-bromosuccinimide in DMSO - water affords 6-benzyloxymethyl-7-hydroxy-8-bromo-cis-bicyclo[3.3.0]octan-3-one (VI). Debromination of (VI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light gives 6-benzyloxymethyl-7-hydroxy-cis-bicyclo[3.3.0]octan-3-one (VII), which is treated with dihydropyran and p-toluenesulfonic acid in methylene chloride yielding the corresponding protected compound (VIII). Elimination of the benzyl group of (VIII) with H2 over Pd/C in acetic acid affords 6-hydroxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (IX), which is submitted to a Wittig condensation with (4-carboxybutyl) triphenylphosphonium bromide (X) and the sodium salt of DMSO in this solvent, followed by a methylation with diazomethane, affording 3-(4-methoxycarbonylbutylidene)-6-hydroxymethyl-7-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XI). Oxidation of (XI) with CrO3 in methylene chloride gives the corresponding 6-formyl derivative (XII), which is submitted to a new Wittig condensation with dimethyl 2-oxo-2-cyclopentylethylphosphonate (XIII) and NaH in THF yielding methyl 6,9-methano-11-(tetrahydropyranyloxy)-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-3,5-dienoate (XIV). Deprotection of (XIV) with acetic acid in THF - water gives the corresponding 11-hydroxy compound (XVI), which is reduced with NaBH4 in methanol affording the 11,15-dihydroxy ester (XVI). Finally, this compound is hydrolyzed with NaOH in methanol - water.

参考文献 中间体
合成目标
【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 .
【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833.
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) 34221 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetic acid C15H18O4 详情 详情
(II) 34222 methyl 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetate C16H20O4 详情 详情
(III) 12940 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate 78-39-7 C8H18O3 详情 详情
(IV) 34223 methyl 2-[(1S,2R,5S)-2-[(benzyloxy)methyl]-5-(2-ethoxy-2-oxoethyl)-3-cyclopenten-1-yl]acetate C20H26O5 详情 详情
(V) 34224 (3aS,4R,6aS)-4-[(benzyloxy)methyl]-3,3a,4,6a-tetrahydro-2(1H)-pentalenone C16H18O2 详情 详情
(VI) 34225 (3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone C16H19BrO3 详情 详情
(VII) 34226 (3aS,4S,5R,6aR)-4-[(benzyloxy)methyl]-5-hydroxyhexahydro-2(1H)-pentalenone C16H20O3 详情 详情
(VIII) 34227 (3aS,4R,5R,6aR)-4-[(benzyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone C22H30O4 详情 详情
(IX) 34228 (3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone C15H24O4 详情 详情
(X) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XI) 34229 methyl 5-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate C21H34O5 详情 详情
(XII) 34230 methyl 5-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate C21H32O5 详情 详情
(XIII) 34231 dimethyl 2-cyclopentyl-2-oxoethylphosphonate C9H17O4P 详情 详情
(XIV) 34232 methyl 5-[(3aS,4S,5R,6aR)-4-[(E)-3-cyclopentyl-3-oxo-1-propenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate C28H42O5 详情 详情
(XV) 32433 (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Si2 详情 详情
(XVI) 34234 methyl 5-[(3aS,4S,5R,6aS)-4-[(E,3S)-3-cyclopentyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]pentanoate C22H34O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Intermediate (XII) is converted in four steps through the «Corey synthesis» to Dimoxaprost.

参考文献 中间体
合成目标
【1】 Peel, R.; Sutherland, J.K.; Beeley, N.R.A.; Tetrahedron 1981, 37, 411.
【2】 Jahne, G.; Wess, G.; Bartmann, W.; Beck, G.; Lerch, U.; Liebigs Ann Chem 1987, 321-326.
【3】 Beck, G.; Dimoxaprost. Drugs Fut 1987, 12, 12, 1101.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 28194 (3aR,4R,5R,6aS)-4-[(E,3R)-5-ethoxy-4,4-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H42O7 详情 详情
(XIII) 28195 (3aR,4R,5R,6aS)-4-[(E,3R)-5-ethoxy-4,4-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C26H44O7 详情 详情
(XIV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XV) 28196 (Z)-7-[(1R,2R,3R,5S)-2-[(E,3R)-5-ethoxy-4,4-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C31H52O8 详情 详情
(XVI) 28197 (Z)-7-[(1R,2R,3R)-2-[(E,3R)-5-ethoxy-4,4-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C31H50O8 详情 详情

合成路线3

该中间体在本合成路线中的序号：(X)

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.

参考文献 中间体
合成目标
【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4

该中间体在本合成路线中的序号：(X)

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.

参考文献 中间体
合成目标
【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5

该中间体在本合成路线中的序号：(X)

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.

参考文献 中间体
合成目标
【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6

该中间体在本合成路线中的序号：(X)

The condensation of dimethyl methylphosphonate (I) with ethyl octanoate (II) by means of butyllithium in THF gives dimethyl 2-oxononylphosphonate (III), which is condensed with the protected aldehyde (IV) by means of NaH in THF, yielding the unsaturated ketone (V). The hydrogenation of (V) with H2 over Pd/C in ethyl acetate affords the corresponding saturated ketone (VI), which is treated with ethylene glycol and p-toluenesulfonic acid to give the cyclic ketal (VII). The mild hydrolysis of (VII) with K2CO3 and acetic acid gives the alcohol derivative (VIII); the reduction of the lactone group of (VIII) with dibutylaluminum hydride in toluene affords the lactol (IX), which is condensed with (4-carboxybutyl)triphenylphosphonium bromide (X) by means of NaH in DMSO yielding the protected prostaglandin (XI). Esterification of (XI) with isopropyl iodide and DBU in acetonitrile gives the precursor (XII), which is finally deprotected with acetic acid in THF - water.

参考文献 中间体
合成目标
【1】 Ueno, R.; Ueno, R.; Oda, T. (Ueno Fine Chemicals Industry, Ltd.); Prostaglandins of the F series. EP 0289349; JP 1989151552; US 5001153; US 5106869 .
【2】 Ueno, R.; Ueno, R.; Oda, T. (Ueno Fine Chemicals Industry, Ltd.); 13,14-Dihydro-15-keto-PGFs. GB 2225573 .
【3】 Ueno, R.; Ueno, R.; Oda, T. (Ueno Fine Chemicals Industry, Ltd.); Ocular hypotensive agents. EP 0308135; JP 1994080571; US 5151444; US 5166178; US 5212200 .
【4】 Prous, J.; Castaner, J.; UF-021. Drugs Fut 1992, 17, 3, 193.
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) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(II) 13608 ethyl octanoate; ethyl caprylate 106-32-1 C10H20O2 详情 详情
(III) 13609 dimethyl 2-oxononylphosphonate C11H23O4P 详情 详情
(IV) 13610 (3aR,4R,5R,6aS)-2-oxo-4-(2-oxoethyl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C22H20O5 详情 详情
(V) 13611 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-1-decenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H34O5 详情 详情
(VI) 13612 (3aR,4R,5R,6aS)-2-oxo-4-(3-oxodecyl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H36O5 详情 详情
(VII) 13613 (3aR,4R,5R,6aS)-4-[2-(2-heptyl-1,3-dioxolan-2-yl)ethyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C32H40O6 详情 详情
(VIII) 13614 (3aR,4R,5R,6aS)-4-[2-(2-Heptyl-1,3-dioxolan-2-yl)ethyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one C19H32O5 详情 详情
(IX) 13615 (3aR,4R,5R,6aS)-4-[2-(2-Heptyl-1,3-dioxolan-2-yl)ethyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol C19H34O5 详情 详情
(X) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XI) 13617 (Z)-7-[(1R,2R,3R,5S)-2-[2-(2-Heptyl-1,3-dioxolan-2-yl)ethyl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid C24H42O6 详情 详情
(XII) 13618 isopropyl (Z)-7-[(1R,2R,3R,5S)-2-[2-(2-heptyl-1,3-dioxolan-2-yl)ethyl]-3,5-dihydroxycyclopentyl]-5-heptenoate C27H48O6 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XV)

Wittig condensation of lactol (XIII) with (carboxybutyl)triphenylphosphonium bromide (XV) in the presence of potassium tert-butoxide produced the Z-olefin (XVI). Conversion of carboxylic acid (XVI) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of DBU.

参考文献 中间体
合成目标
【1】 Kovács, G.; Hermecz, I.; Szabó, T.; Ivanics, J.; Ivanics, J.; Dalmadi, G.; Bahram, R. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); Chemical process. WO 9300329 .
【2】 Resul, B.; et al.; Phenyl-substituted prostaglandins: Potent and selective antiglaucoma agents. J Med Chem 1993, 36, 2, 243.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 59563 (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol C18H26O4 详情 详情
(XV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XVI) 59565 (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}-5-heptenoic acid C23H34O5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XV)

A closely related strategy using tetrahydropyranyl protection has been reported. Protection of the allylic alcohol (X) with dihydropyran in the presence of p-toluenesulfonic acid yielded the tetrahydropyranyl ether (XVII). Catalytic hydrogenation of (XVII) gave rise to (XVIII), which was further reduced to lactol (XIX) employing DIBAL in cold toluene. After methanolysis of the phenylbenzoyl group of (XIX), the resultant lactol (XX) was subjected to Wittig condensation with the phosphonium reagent (XV), yielding olefin (XXI). After conversion of acid (XXI) to the corresponding isopropyl ester(XXII), the tetrahydropyranyl group was removed by means of pyridinium tosylate in MeOH.

参考文献 中间体
合成目标
【1】 Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Judovich, L.; Pertsikov, B.; A new process for the preparation of latanoprost. WO 0155101 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 43182 (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C31H30O5 详情 详情
(XV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XVII) 59566 (3aR,4R,5R,6aS)-2-oxo-4-[(E,3S)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C36H38O6 详情 详情
(XVIII) 59567 (3aR,4R,5R,6aS)-2-oxo-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C36H40O6 详情 详情
(XIX) 59568 (3aR,4R,5R,6aS)-2-hydroxy-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C36H42O6 详情 详情
(XX) 59569 (3aR,4R,5R,6aS)-4-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol C23H34O5 详情 详情
(XXI) 59570 (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]cyclopentyl}-5-heptenoic acid C28H42O6 详情 详情
(XXII) 59571 isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl]cyclopentyl}-5-heptenoate C31H48O6 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XV)

In an alternative method, the aldehyde lactone (XXIII) was subjected to Wadsworth-Emmons reaction with phosphonate (IV) to afford enone (XXIV). Stereoselective ketone reduction, followed by catalytic hydrogenation of the resultant allylic alcohol (XXV), provided (XXVI). Both the benzoate ester and the lactone groups of (XXIV) were hydrolyzed by KOH, yielding trihydroxy acid (XXVII), which was further cyclized to lactone (XIV) in boiling toluene. The hydroxyl groups of (XIV) were then protected with ethyl vinyl ether in the presence of trichloroacetic acid to produce the bis-acetal (XXVIII). Reduction of the lactone function of (XXVIII) to the corresponding lactol (XXIX), followed by Wittig reaction with the phosphorane generated from phosphonium salt (XV) and potassium t-butoxide, furnished olefin (XXX). After acidic hydrolysis of the acetal protecting groups of (XXX), the carboxylate function was converted to the corresponding isopropyl ester by treatment with 2-iodopropane and cesium carbonate.

参考文献 中间体
合成目标
【1】 Henegar, K.E. (Pharmacia Corp.); Process and intermediates to prepare latanoprost. WO 0187816 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 59558 dimethyl 2-oxo-4-phenylbutylphosphonate C12H17O4P 详情 详情
(XIV) 59562 (3aR,4R,5R,6aS)-5-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one C18H24O4 详情 详情
(XV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XXIII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(XXIV) 59578 (1S,2S,3aR,6aS)-5-methylene-1-[(1E)-3-phenethyl-1,3-butadienyl]-2-(2-phenyl-2-propenyl)octahydropentalene C30H34 详情 详情
(XXV) 59572 (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H26O5 详情 详情
(XXVI) 59573 (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H28O5 详情 详情
(XXVII) 59574 2-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}acetic acid C18H26O5 详情 详情
(XXVIII) 59575 (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one C26H40O6 详情 详情
(XXIX) 59576 (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol C26H42O6 详情 详情
(XXX) 59577 (Z)-7-{(1R,2R,3R,5S)-3-(1-ethoxyethoxy)-2-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]-5-hydroxycyclopentyl}-5-heptenoic acid C31H50O7 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XI)

1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224.
【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 .
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) 15780 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate C11H19NO5 详情 详情
(II) 15781 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate C12H21NO7S 详情 详情
(III) 15782 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate C18H23NO6 详情 详情
(IV) 15783 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate C11H19NO5 详情 详情
(V) 15784 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate C12H21NO7S 详情 详情
(VI) 15785 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H18N4O4 详情 详情
(VII) 15786 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H20N2O4 详情 详情
(VIII) 15787 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 98-60-2 C6H4Cl2O2S 详情 详情
(IX) 15788 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate C17H23ClN2O6S 详情 详情
(X) 15789 tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate C16H21ClN2O5S 详情 详情
(XI) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XII) 15791 (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid C21H29ClN2O6S 详情 详情
(XIII) 15792 methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate C17H23ClN2O4S 详情 详情
(XIV) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(XV) 15794 methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate C23H28ClN3O4S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VII)

The title compound was synthesized starting from the described intermediate (I). Hydrogenation of the olefinic double bond in the presence of PtO2 afforded (II). After protection of the free hydroxyl group of (II) as the corresponding silyl ether (III) with tert-butyldimethylsilyl chloride and imidazole, hydrolysis of the acetate ester of (III) by means of K2CO3 in MeOH furnished alcohol (IV). Further protection of (IV) employing dihydropyran and camphorsulfonic acid gave tetrahydropyranyl ether (V). Reduction of the lactone function of (V) with DIBAL in toluene at -78 C produced lactol (VI), which was submitted to a Wittig reaction with the ylide resulting from phosphonium salt (VII) and t-BuOK to yield the cis olefin (VIII). Esterification of (VIII) with isopropanol in the presence of 2-chloro-1-methylpyridinium iodide gave isopropyl ester (IX). Inversion of the configuration of the 9beta-hydroxyl group of (IX) was then achieved by Mitsunobu coupling with formic acid to give the 9beta-formate ester (X). Subsequent hydrolysis of the formate ester of (X) with K2CO3 in hot isopropanol, followed by acid deprotection of the tetrahydropyranyl and silyl groups yielded the title compound.

参考文献 中间体
合成目标
【1】 Miyazaki, T.; Kawakura, M.; Shirasawa, E. (Ono Pharmaceutical Co., Ltd.); 13,14-Dihydro-PGF2BETA and its isopropyl ester. CA 2125804; EP 0628545; JP 1995061965 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 34696 2-chloro-1-methylpyridinium iodide 14338-32-0 C6H7ClIN 详情 详情
(I) 34689 (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-1-octenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate C17H26O5 详情 详情
(II) 34690 (3aR,4R,5R,6aS)-4-[(3S)-3-hydroxyoctyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate C17H28O5 详情 详情
(III) 34691 (3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate C23H42O5Si 详情 详情
(IV) 34692 (3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one C21H40O4Si 详情 详情
(V) 34693 (3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C26H48O5Si 详情 详情
(VI) 34694 (3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C26H50O5Si 详情 详情
(VII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(VIII) 34695 (Z)-7-[(1R,2R,3R,5S)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C31H58O6Si 详情 详情
(IX) 34697 isopropyl (Z)-7-[(1R,2R,3R,5S)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C34H64O6Si 详情 详情
(X) 34698 isopropyl (Z)-7-[(1R,2R,3R,5R)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-formyl-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C35H64O6Si 详情 详情

合成路线12

该中间体在本合成路线中的序号：(X)

The condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (I) with methylphosphonic acid dimethyl ester (II) by means of BuLi in THF gives 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester (III), which is condensed with the known bicyclic aldehyde (IV) by means of BuLi in dimethoxyethane, yielding the unsaturated ketone (V). The reduction of (V) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (VI), which is treated with K2CO3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (VII). The protection of (VII) with dihydropyran and TsOH in dichloromethane provides the bis(tetrahydropyranyl) ether (VIII), which by reduction of the lactone ring with diisobutylaluminum hydride in THF gives the lactol (IX). The condensation of (IX) with the phosphonium bromide (X) by means of NaH in DMSO yields the prostenoic acid (XI), which is esterified with isopropyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to afford the corresponding isopropyl ester (XII). Finally, this compound is deprotected with acetic acid in hot THF/water.

参考文献 中间体
合成目标
【1】 Klimko, P.G.; Bishop, J.A.; DeSantis, L. Jr.; Sallee, V.L. (Alcon Laboratories, Inc.); Use of cloprostenol, fluprostenol and their analogues for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension. EP 0639563; JP 1995165703; JP 1998182465; US 5665773 .
【2】 Castañer, J.; Sorbera, L.A.; Travoprost. Drugs Fut 2000, 25, 1, 41.
【3】 Bowler, J.; Crossley, N.S. (AstraZeneca plc); Method of inducing luteolysis using 16-aryloxy-17,18,19,20-tetranor-prostanoic acid derivs. US 4321275 .
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) 32120 2-[3-(trifluoromethyl)phenoxy]acetyl chloride C9H6ClF3O2 详情 详情
(II) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(III) 32121 dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate C12H14F3O5P 详情 详情
(IV) 32042 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C21H18O5 详情 详情
(V) 32122 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C31H25F3O6 详情 详情
(VI) 32123 (3aR,4R,5R,6aS)-4-[(E)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C31H27F3O6 详情 详情
(VII) 32124 (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one C18H19F3O5 详情 详情
(VIII) 32125 (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one C28H35F3O7 详情 详情
(IX) 32126 (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-ol C28H37F3O7 详情 详情
(X) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XI) 32128 (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoic acid C33H45F3O8 详情 详情
(XII) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(XIII) 32129 isopropyl (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoate C36H51F3O8 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XII)

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer predominantly with the desired stereochemistry (VIII).The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is eliminated by hydrogenation with hydrogen over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173.
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) 52922 2-iodo-5-(trifluoromethyl)phenol C7H4F3IO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 52923 ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate n/a C11H10F3IO3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 52924 dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate C12H13F3IO5P 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 52925 (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H20F3IO6 详情 详情
(VIII) 52926 (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H22F3IO6 详情 详情
(IX) 52927 (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one C18H18F3IO5 详情 详情
(X) 52928 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C28H34F3IO7 详情 详情
(XI) 52929 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C28H36F3IO7 详情 详情
(XII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XIII) 52930 (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C33H44F3IO8 详情 详情
(XIV) 52931 isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C36H50F3IO8 详情 详情
(XV) 52932 isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate C26H34F3IO6 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XII)

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer (VIII) predominantly with the desired stereochemistry. The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is substituted with tritium by hydrogenation with tritium gas over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173.
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) 52922 2-iodo-5-(trifluoromethyl)phenol C7H4F3IO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 52923 ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate n/a C11H10F3IO3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 52924 dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate C12H13F3IO5P 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 52925 (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H20F3IO6 详情 详情
(VIII) 52926 (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H22F3IO6 详情 详情
(IX) 52927 (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one C18H18F3IO5 详情 详情
(X) 52928 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C28H34F3IO7 详情 详情
(XI) 52929 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C28H36F3IO7 详情 详情
(XII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XIII) 52930 (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C33H44F3IO8 详情 详情
(XIV) 52931 isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C36H50F3IO8 详情 详情
(XV) 52932 isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate C26H34F3IO6 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XXII)

Synthesis of the alkenyl cuprate (XVII): Enzymatic acylation of the racemic acetylenic alcohol (VII) with vinyl butyrate (VIII) by means of Chirazyme L9 gives a mixture of the ester (R)-(IX) and the alcohol (S)-(X). Reaction of this mixture with Ms-Cl and TEA yields a mixture of ester (R)-(IX) and the mesylate (S)-(XI). Treatment of this mixture with butyric acid and TEA results in the acylation of mesylate (S)-(XI) with optical inversion, providing pure ester (R)-(IX). Enzymatic hydrolysis of (R)-(IX) with Chirazyme L2 affords the enantiomerically pure alcohol (R)-(XIII). Silylation of alcohol (XIII) with TBDMS-Cl and imidazole gives the silyl ether (XIV), which is iodinated with Cp2ZrCl2 and I2 to yield the iodovinyl derivative (XV). Finally, the reaction of compound (XV) with the lithium cuprate (XVI) ­prepared by lithiation of thiophene with BuLi followed by treatment with copper (I) cyanide­ affords the alkenyl cuprate (XVII). Condensation of the alkenyl cuprate (XVII) with the tricyclic ketone (VI) in toluene provides the bicyclic ketone (XVIII), which is submitted to a Baeyer-Villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (XIX) and (XX). The minor and unwanted regioisomer (XIX) is selectively hydrolyzed by treatment with aqueous Na2CO3 and separated by crystallization. Reduction of lactone (XX) with DIBAL in toluene gives lactol (XXI), which is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-BuOK in THF, followed by esterification with isopropyl iodide and DBU, yielding a mixture of the monosilylated compounds (XXIII) and (XXIV) due to migration of the silyl group on the cyclopentane ring. Finally, this mixture is deprotected with HCl in isopropanol.

参考文献 中间体
合成目标
【1】 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138.
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) 53260 (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one n/a C13H22O2Si 详情 详情
(VII) 53262 1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol 88462-65-1 C11H9F3O2 详情 详情
(VIII) 53263 n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate 123-20-6 C6H10O2 详情 详情
(IX) 53264 (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl butyrate n/a C15H15F3O3 详情 详情
(X) 53265 (2S)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol n/a C11H9F3O2 详情 详情
(XI) 53266 (1S)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl methanesulfonate n/a C12H11F3O4S 详情 详情
(XII) 53267 Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid 107-92-6 C4H8O2 详情 详情
(XIII) 53278 (2R)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol n/a C11H9F3O2 详情 详情
(XIV) 53268 tert-butyl(dimethyl)[((1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl)oxy]silane; tert-butyl(dimethyl)silyl (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl ether n/a C17H23F3O2Si 详情 详情
(XV) 53269 tert-butyl(dimethyl)silyl (1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl ether; tert-butyl[((1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl)oxy]dimethylsilane n/a C17H24F3IO2Si 详情 详情
(XVI) 53270 lithium cyano(2-thienyl)cuprate(1-) n/a C5H3CuLiNS 详情 详情
(XVII) 53271 　 n/a C22H27CuF3Li2NO2SSi 详情 详情
(XVIII) 53272 (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}bicyclo[2.2.1]heptan-2-one n/a C30H47F3O4Si2 详情 详情
(XIX) 53273 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-oxabicyclo[3.2.1]octan-2-one n/a C30H47F3O5Si2 详情 详情
(XX) 53274 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-one n/a C30H47F3O5Si2 详情 详情
(XXI) 53275 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-ol n/a C30H49F3O5Si2 详情 详情
(XXII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XXIII) 53276 isopropyl (Z)-7-((1R,2R,3R,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-hydroxycyclopentyl)-5-heptenoate n/a C38H63F3O6Si2 详情 详情
(XXIV) 53277 isopropyl (Z)-7-((1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-5-hydroxycyclopentyl)-5-heptenoate n/a C38H63F3O6Si2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XIV)

Wittig reaction of lactol (XIII) with the ylide generated from phosphonium salt (XIV) and potassium tert-butoxide afforded acid (XV), which was subsequently esterified with isopropyl iodide and DBU to give the isopropyl ester (XVI). Cleavage of the tetrahydropyranyl ethers of (XVI) under mildly acidic conditions followed by HPLC separation using a chiral column provided the desired alcohol diastereoisomer (XVII). Finally, hydrolysis of ester (XVII) under basic conditions provided the corresponding free acid.

参考文献 中间体
合成目标
【1】 Feng, Z.; et al.; Design and synthesis of 13-oxa prostaglandin analogs as antiglaucoma agents. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 236.
【2】 Feng, Z.; Hellberg, M.R. (Alcon Laboratories, Inc.); 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension. US 6232344; WO 9932441 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 50705 (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-ol C28H39F3O7 详情 详情
(XIV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XV) 50706 (Z)-7-((1S,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl)-5-heptenoic acid C33H47F3O8 详情 详情
(XVI) 50707 isopropyl (Z)-7-((1S,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl)-5-heptenoate C36H53F3O8 详情 详情
(XVII) 50708 isopropyl (Z)-7-[(1S,2R,3R,5S)-3,5-dihydroxy-2-([(2S)-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl]oxy)cyclopentyl]-5-heptenoate C26H37F3O6 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IX)

Commercially available aldehyde (I) was reduced to alcohol (II) with NaBH4. After protection of the hydroxyl group of (II) as the tert-butyldiphenylsilyl ether (III), hydrolysis of the benzoate ester of (III) using K2CO3 in MeOH afforded the 11R alcohol (IV). Displacement of the hydroxyl group of (IV), with inversion of the configuration, by means of (diethylamino)sulfur trifluoride generated the 11S fluoride (V), along with minor amounts of olefin (VI). Separation was achieved by dihydroxylation of the olefin (VI) with N-methylmorpholine-N-oxide and OsO4, followed by column chromatography. Reduction of the lactone group of (V) with diisobutylaluminum hydride at -78 C yielded lactol (VIII). Wittig condensation with the phosphorane resulting from phosphonium salt (IX) and t-BuOK furnished the Z-olefin (X). The carboxylate group was then converted to isopropyl ester (XI) by treatment with isopropyl iodide and DBU.

参考文献 中间体
合成目标
【1】 Klimko, P.; Sharif, N.A.; Griffin, B.W.; Crider, J.Y.; AL-8810: A novel prostaglandin F2alpha analog with selective antagonist effects at the prostaglandin F2alpha (FP) receptor. J Pharmacol Exp Ther 1999, 290, 3, 1278.
【2】 Sallee, V.L.; Hellberg, M.R.; Klimko, P.G.; Zinke, P.W. (Alcon Laboratories, Inc.); 11-Halo prostaglandins for the treatment of glaucoma or ocular hypertension. WO 9820880 .
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) 35585 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate 39746-01-5 C15H14O5 详情 详情
(II) 35586 (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C15H16O5 详情 详情
(III) 35587 (3aR,4S,5R,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C31H34O5Si 详情 详情
(IV) 35588 (3aR,4S,5R,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one C24H30O4Si 详情 详情
(V) 35589 (3aR,4S,5S,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-one C24H29FO3Si 详情 详情
(VI) 35590 (3aR,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C24H28O3Si 详情 详情
(VII) 35591 (3aS,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4,5-dihydroxyhexahydro-2H-cyclopenta[b]furan-2-one C24H30O5Si 详情 详情
(VIII) 35592 (3aR,4S,5S,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-ol C24H31FO3Si 详情 详情
(IX) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(X) 35593 (Z)-7-[(1R,2S,3S,5S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluoro-5-hydroxycyclopentyl]-5-heptenoic acid C29H39FO4Si 详情 详情
(XI) 35594 isopropyl (Z)-7-[(1R,2S,3S,5S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluoro-5-hydroxycyclopentyl]-5-heptenoate C32H45FO4Si 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IX)

Oxidative cleavage of 4,6-O-ethylidene glucose (I) with sodium periodate afforded 5-hydroxy-2-methyl-1,3-dioxan-4-carbaldehyde (II), which was reduced to alcohol (III) using sodium borohydride (1). Protection of the primary hydroxyl of (III) with tert-butyldimethylsilyl chloride, followed by Moffatt oxidation of the secondary hydroxyl group provided ketone (V). Subsequent Wittig reaction of (V) with ethyl (triphenylphosphoranylidene)acetate gave a mixture of E,Z unsaturated esters (VIa-b). Catalytic hydrogenation of the double bond of (VIa-b) produced the saturated ester (VIIa-b) as a diastereomeric mixture that was separated by column chromatography. Diisobutylaluminum hydride reduction of the desired ester furnished aldehyde (VIII), which was subjected to a Wittig reaction with the sodium salt of (4-carboxybutyl)triphenylphosphonium bromide (IX) yielding acid (X). Conversion of (X) to the methyl ester (XI) by methylation with iodomethane and K2CO3, followed by desilylation with Bu4NF afforded hydroxy ester (XII). Oxidation of the alcohol group of (XII) with Collins' reagent gave aldehyde (XIII). This was converted to the thiosemicarbazone (XV) upon condensation with phenyl thiosemicarbazide (XIV). Finally, the methyl ester group of (XV) was hydrolyzed, and the carboxylic acid was converted to the corresponding sodium salt.

参考文献 中间体
合成目标
【1】 Setoi, H.; Kuroda, A.; Tanaka, H.; Hirai, H.; Marusawa, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Oxygen-containing heterocyclic cpd., processes for their preparation and pharmaceutical compsns. comprising them. EP 0346511 .
【2】 Kuroda, A.; setoi, H.; Motoyama, Y.; Sawada, A.; Seki, J.; Marusawa, H.; Tanaka, H.; Synthesis and biological activity of 4-methyl-3,5-dioxane derivatives as thromboxane A2 receptor antagonists. Bioorg Med Chem 1999, 7, 11, 2635.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(VIa) 37365 ethyl 2-[(2R,4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ylidene]acetate C16H30O5Si 详情 详情
(VIb) 37366 ethyl 2-[(2R,4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ylidene]acetate C16H30O5Si 详情 详情
(VIIa) 37367 ethyl 2-[(2R,4R,5R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetate C16H32O5Si 详情 详情
(VIIb) 37368 ethyl 2-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetate C16H32O5Si 详情 详情
(I) 37360 (2R,4aR,7R,8R,8aS)-2-methylhexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triol 13224-99-2 C8H14O6 详情 详情
(II) 37361 (2R,4R,5R)-5-hydroxy-2-methyl-1,3-dioxane-4-carbaldehyde C6H10O4 详情 详情
(III) 37362 (2R,4S,5R)-4-(hydroxymethyl)-2-methyl-1,3-dioxan-5-ol C6H12O4 详情 详情
(IV) 37363 (2R,4S,5R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ol C12H26O4Si 详情 详情
(V) 37364 (2R,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-one C12H24O4Si 详情 详情
(VIII) 37369 2-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetaldehyde C14H28O4Si 详情 详情
(IX) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(X) 37370 (Z)-7-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoic acid C19H36O5Si 详情 详情
(XI) 37371 methyl (Z)-7-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoate C20H38O5Si 详情 详情
(XII) 37372 methyl (Z)-7-[(2R,4R,5S)-4-(hydroxymethyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoate C14H24O5 详情 详情
(XIII) 37373 methyl (Z)-7-[(2R,4R,5S)-4-formyl-2-methyl-1,3-dioxan-5-yl]-5-heptenoate C14H22O5 详情 详情
(XIV) 37374 N-phenyl-1-hydrazinecarbothioamide 5351-69-9 C7H9N3S 详情 详情
(XV) 37375 methyl (Z)-7-((2R,4R,5S)-4-[[(E)-2-(anilinocarbothioyl)hydrazono]methyl]-2-methyl-1,3-dioxan-5-yl)-5-heptenoate C21H29N3O4S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

The hydrogenation of ethyl 3-(2-furyl)acrylate (I) with H2 over Raney-Ni in ethanol gives ethyl 3-(2-furyl)propionate (II), which oxidative methoxylation with Br2 in methanol affords ethyl 3-(2,5-dimethoxy-2,5-dihydro-2-furyl)propionate (III). The partial reduction of (III) with diisobutylaluminum hydride in toluene yields the substituted propionaldehyde (IV), which by a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide by means of NaH in DMSO gives 8-(2,5-dimethoxy-2,5-dihydro-2-furyl)-5-octenoic acid (VI). The hydrolytic ring opening of (VI), followed by an aldol cyclization in refluxing dioxane - water by means of sodium acetate - NaH2PO4 - hydroquinone affords 7-(2-oxo-5-hydroxycyclopent-3-en-1-yl)-5-heptenoic acid (VII), which is isomerized by treatment with H2SO4 yielding 7-(5-oxo-3-hydroxycyclopenten-1-yl)-5-heptenoic acid (VIII). Methylation and esterification of (VIII) with H2SO4/refluxing methanol gives the methoxy methyl ester (IX), which by reaction with 2-mercaptoethanol (A) and sodium methoxide in methanol is converted into methyl 7-[5-oxo-3-(2-hydroxyethylthio)cyclopenten-1-yl]-5-heptenoate (X). The methylation of acid (VI) with NaH and methyl iodide gives the corresponding methyl ester (XIV), which is submitted to a hydrolytic ring opening and aldol cyclization as before to afford methyl 7-(2-oxo-5-hydroxycyclopent-3-en-1-yl)-5-heptenoate (XV). The silylation of (XV) with trimethylchlorosilane and hexamethyldisilazane as usual yields the corresponding trimethylsilyloxy derivative (XVI), which is treated with 2-mercaptoethanol (A) and sodium methoxide to give the isomerized compound (X).

参考文献 中间体
合成目标
【1】 Floyd, M.B.; Prostaglandins and congeners. 18. Synthesis of cyclopentenolone precursors to prostaglandins from 2,5-dihydro-2,5-dimethoxyfurans. J Org Chem 1978, 43, 9, 1641-43.
【2】 Floyd, M.; et al.; Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators. J Med Chem 1980, 23, 8, 903-913.
【3】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castañer, J.; DHET-PGE2. Drugs Fut 1982, 7, 4, 241.
【4】 Weiss, M.J.; Siuta, G.J. (American Cyanamid Co.); 11-(2-Hydroxyethylthio)prostenoic acid E{HD 2 {B series derivatives. US 4085272 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 36375 2-Sulfanyl-1-ethanol; 2-Mercaptoethanol 60-24-2 C2H6OS 详情 详情
(I) 36362 ethyl (E)-3-(2-furyl)-2-propenoate 623-20-1 C9H10O3 详情 详情
(II) 36363 ethyl 3-(2-furyl)propanoate 10031-90-0 C9H12O3 详情 详情
(III) 36364 ethyl 3-(2,5-dimethoxy-2,5-dihydro-2-furanyl)propanoate C11H18O5 详情 详情
(IV) 36365 3-(2,5-dimethoxy-2,5-dihydro-2-furanyl)propanal C9H14O4 详情 详情
(V) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(VI) 36367 (Z)-8-(2,5-dimethoxy-2,5-dihydro-2-furanyl)-5-octenoic acid C14H22O5 详情 详情
(VII) 36368 (Z)-7-(2-hydroxy-5-oxo-3-cyclopenten-1-yl)-5-heptenoic acid C12H16O4 详情 详情
(VIII) 36369 (Z)-7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-5-heptenoic acid C12H16O4 详情 详情
(IX) 36370 methyl (Z)-7-(3-methoxy-5-oxo-1-cyclopenten-1-yl)-5-heptenoate C14H20O4 详情 详情
(X) 36371 methyl (Z)-7-[3-[(2-hydroxyethyl)sulfanyl]-5-oxo-1-cyclopenten-1-yl]-5-heptenoate C15H22O4S 详情 详情
(XIV) 36372 methyl (Z)-8-(2,5-dimethoxy-2,5-dihydro-2-furanyl)-5-octenoate C15H24O5 详情 详情
(XV) 36373 methyl (Z)-7-(2-hydroxy-5-oxo-3-cyclopenten-1-yl)-5-heptenoate C13H18O4 详情 详情
(XVI) 36374 methyl (Z)-7-[2-oxo-5-[(trimethylsilyl)oxy]-3-cyclopenten-1-yl]-5-heptenoate C16H26O4Si 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IX)

Desilylation of commercial Corey's lactone (I) with TBAF in THF gives carbinol (II), which is oxidized by means of (COCl)2 and DMSO in dichloromethane to yield the carbaldehyde (III). Condensation of compound (III) with phosphonate (IV) by means of thallium ethoxide in dichloromethane affords the unsaturated difluoroketone (V), which is reduced with H2 over Pd/C in ethyl acetate to afford the saturated ketone (VI). Reduction of ketone (VI) with NaBH4 in methanol provides the secondary alcohol (VII), which is further reduced with diisobutylaluminum hydride in toluene to give the lactol (VIII). Condensation of lactol (VIII) with 4-carboxybutyl triphenylphosphonium bromide (IX) by means of t-BuOK in THF yields the prostaglandin F2a derivative (X), which is esterified by means of benzyl bromide and DBU in dichloromethane to afford the benzyl ester (XI). Oxidation of ester (XI) with CrO3 and pyridine in dichloromethane provides the THP-protected prostaglandin E2 derivative (XII), which is treated with AcOH in THF/water to give the prostaglandin E2 benzyl ester derivative (XIII). Finally, this compound is submitted to simultaneous benzyl ester group cleavage and double bond reduction by means of H2 over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Ueno, R. (R-Tech Ueno, Ltd.); Promotion of wound-healing with 15-keto-prostaglandin cpds.. EP 0503887; US 5252605 .
【2】 Ueno, R. (R-Tech Ueno, Ltd.); Endothelin antagonist. EP 0978284; US 6197821; WO 9927934 .
【3】 Sorbera, L.A., Castaner, J., Mealy, N.E.; Lubiprostone. Drugs Fut 2004, 29 (4): 336.
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) 65188 (3aR,4S,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-{[(trimethylsilyl)oxy]methyl}hexahydro-2H-cyclopenta[b]furan-2-one C16H28O5Si 详情 详情
(II) 56988 (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C13H20O5 详情 详情
(III) 56989 (3aR,4R,5R,6aS)-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde C13H18O5 详情 详情
(IV) 65189 dimethyl 3,3-difluoro-2-oxoheptylphosphonate C9H17F2O4P 详情 详情
(V) 65190 (3aR,4R,5R,6aS)-4-[(E)-4,4-difluoro-3-oxo-1-octenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C20H28F2O5 详情 详情
(VI) 65191 (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxooctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C20H30F2O5 详情 详情
(VII) 65192 (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C20H32F2O5 详情 详情
(VIII) 65193 (3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxyoctyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C20H34F2O5 详情 详情
(IX) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(X) 65194 (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C25H42F2O6 详情 详情
(XI) 65195 benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C32H48F2O6 详情 详情
(XII) 65196 benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C32H44F2O6 详情 详情
(XIII) 65197 benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-3-hydroxy-5-oxocyclopentyl]-5-heptenoate C27H36F2O5 详情 详情
Extended Information