Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【药物名称】Froxiprost, Ono-995

【化学名称】16-(3-Trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-DELTA2-PGF2alpha methyl ester
　　　　　　Methyl 9alpha,11alpha,15alpha-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-2-trans-5-cis-13-trans-trienoate
　　　　　　7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-2,5-heptadienoic acid methyl ester
　　　　　　Methyl (2E,5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3R)-3-hydroxy-4-[(alpha,alpha,alpha-trifluoro-m-tolyl)oxy]-1-butenyl]cyclopentyl]-2,5-heptadienoate

【CA登记号】62559-74-4

【 分 子 式 】C24H29F3O6

【 分 子 量 】470.49033

【开发单位】Ono (Originator), Pfizer (Originator)

【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy

合成路线1合成路线2合成路线3

合成路线1

The Wittig reaction of 1alpha-acetoxy-2alpha-(6-methoxycarbonyl-hex-2-cis-enyl)-3beta-formyl-4alpha-(2-tetrahydropyranyloxy)cyclopentane (I) and dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propylphosphonate (II) by means of NaH in hot THF gives 9alpha-acetoxy-11alpha-(2-tetrahydropyranyloxy)-15-oxo-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranorprosta-5-cis-13-trans-dienoate (III), which is reduced with NaBH4 in methanol yielding the protected trihydroxy compound (IV). The partial hydrolysis of (IV) with K2CO3 in methanol affords the dihydroxytetrahydropyranyloxy compound (V), which by reaction with diphenyldiselenide (A) by means of 17-butyllithium and diisopropylamine in THF is converted into the mixed selenide (VI). The treatment of (VI) with H2O2 in THF-ethyl acetate gives methyl 9alpha,15alpha-dihydroxy-11alpha-(2-tetra)-17,18,19,20-tetranorprosta-2-trans-5-cis-13-trans-trienoate (VII), which is finally treated with HCl in THF-water to eliminate the tetrahydropyranyl group.

参考文献 中间体
【1】 Hayashi, M.; et al.; US 4065632 .
【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499.
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) 39170 1,2-diphenyldiselane 1666-13-3 C12H10Se2 详情 详情
(I) 20983 methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-formyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C22H34O7 详情 详情
(II) 32121 dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate C12H14F3O5P 详情 详情
(III) 39167 methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C32H41F3O8 详情 详情
(IV) 39168 methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C32H43F3O8 详情 详情
(V) 39169 methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C30H41F3O7 详情 详情
(VI) 39171 methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-(phenylselanyl)-5-heptenoate C36H45F3O7Se 详情 详情
(VII) 39172 methyl (2E,5Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2,5-heptadienoate C30H39F3O7 详情 详情

合成路线2

The hydrolysis of 2-oxa-3-oxo-6-syn-hydroxymethyl-7-anti-acetoxy-cis-bicyclo[3.3.0]octane (VIII) (2) with KOH in methanol gives the dihydroxy compound (IX), which is acetylated with acetic anhydride in pyridine to give the acetoxymethyl compound (X). The treatment of (X) with dihydropyran and p-toluenesulfonic acid in methylene chloride affords the tetrahydropyranyl derivative (XI), which is reduced with diisobutylaluminum hydride in toluene to yield 2-oxa-3-hydroxy-6-syn-hydroxymethyl-7-anti-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XII). The Wittig reaction of (XII) with 4-carboxybutyltriphenylphosphonium bromide (B) by means of NaH in DMSO gives 2alpha-(6-carboxyhex-2-cis-enyl)-3beta-hydroxymethyl-4alpha-(2-tetrahydropyranyloxy)cyclopentan-1alpha-ol (XIII), which is esterified with CH2N2 to the corresponding methyl ester (XIV). The reaction of (XIV) with trimethylchlorosilane in pyridine - methylene chloride gives the monotrimethylsilyl derivative (XV), which is acetylated with acetyl chloride affording the fully protected compound (XVI). The partial hydrolysis of (XVI) with oxalic acid in water-ethyl acetate yields the compound (XVII) with a free hydroxymethyl group, which is finally oxidized with CrO3 in methylene chloride pyridine to give the starting 1alpha-acetoxy-2alpha-(6-methoxycarbonylhex-2-cis-enyl)-3beta-formyl-4alpha-(2-tetrahydropyranyloxy)cyclopentane (I).

参考文献 中间体
【1】 Hayashi, M.; et al.; US 4065632 .
【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIIa) 39177 (2R,3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C14H24O5 详情 详情
(XIIb) 39178 (2S,3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C14H24O5 详情 详情
(B) 39179 butyl(triphenyl)phosphonium bromide 1779-51-7 C22H24BrP 详情 详情
(I) 39185 ethyl 2-[3-(trifluoromethyl)phenoxy]acetate C11H11F3O3 详情 详情
(VIII) 39173 (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate C10H14O5 详情 详情
(IX) 39174 (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one 32233-40-2 C8H12O4 详情 详情
(X) 39175 [(3aR,4S,5R,6aS)-5-hydroxy-2-oxohexahydro-2H-cyclopenta[b]furan-4-yl]methyl acetate C10H14O5 详情 详情
(XI) 39176 [(3aR,4S,5R,6aS)-2-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-4-yl]methyl acetate C16H24O6 详情 详情
(XIII) 39180 (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoic acid C19H32O6 详情 详情
(XIV) 39181 methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C20H34O6 详情 详情
(XV) 39182 methyl (Z)-7-((1R,2S,3R,5S)-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[[(trimethylsilyl)oxy]methyl]cyclopentyl)-5-heptenoate C23H42O6Si 详情 详情
(XVI) 39183 methyl (Z)-7-((1R,2S,3R,5S)-5-(acetoxy)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[[(trimethylsilyl)oxy]methyl]cyclopentyl)-5-heptenoate C25H44O7Si 详情 详情
(XVII) 39184 methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate C22H36O7 详情 详情

合成路线3

The reaction of 3-trifluoromethylphenol (XVIII) with ethyl chloroacetate (XIX) by means of NaI and K2CO3 in acetone gives ethyl-(3-trifluoromethylphenoxy)acetate (XX), which is then condensed with dimethyl methylphosphonate (C) by means of butyllithium in THF to afford dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propylphosphonate (II).

参考文献 中间体
【1】 Hayashi, M.; et al.; US 4065632 .
【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 32121 dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate C12H14F3O5P 详情 详情
(XVIII) 33504 3-(trifluoromethyl)phenol 98-17-9 C7H5F3O 详情 详情
(XIX) 16601 ethyl chloroacetate; ethyl 2-chloroacetate 105-39-5 C4H7ClO2 详情 详情
(XX) 39185 ethyl 2-[3-(trifluoromethyl)phenoxy]acetate C11H11F3O3 详情 详情
(C) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
Extended Information