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药物详细合成路线

Name Fulvestrant;ZD-9238;ZM-182780;ZD-182780;ICI-182780;Faslodex
Chemical Name 7alpha-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol
CAS 129453-61-8
Related CAS
Formula C32H47F5O3S
Structure
Formula Weight 606.78559
Stage 上市-2002
Company AstraZeneca (Originator)
Activity/Mechanism Breast Cancer Therapy, Oncolytic Drugs, Antiestrogens
Syn. Route 2
Route 1
protection of 9-bromononan-1-ol (i) with tert-butyldimethylsilyl chloride and imidazole in thf gives the silyl ether (ii), which reacts with mg in the same solvent to yield the grignard reagent (iii). reaction of compound (iii) with cui affords the corresponding organocuprate that condenses with 6,7-didehydro-19-nortestosterone (iv) to provide the adduct (v). cleavage of the silyl ether group of (v) with hoac/water in thf gives alcohol (vi), which is esterified with ac2o and pyridine, yielding the corresponding diacetate (vii). aromatization of enone (vii) with cubr2 and libr in refluxing acetonitrile affords phenol (viii), which is selectively hydrolyzed with naoh in methanol to provide the primary alcohol (ix). the selective esterification of the phenolic oh group of (ix) with benzoyl chloride and naoh in acetone/water furnishes the aryl benzoate (x).
List of intermediates No.
(e)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid (i)
2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)acetyl chloride (ii)
ethyl 4-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-3-oxobutanoate (iii)
diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)acetyl]succinate (iv)
ethyl 2-bromoacetate (v)
diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)acetyl]succinate (vi)
2,2-dimethyl-1,3-dioxane-4,6-dione (vii)
ethyl 4-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-3-oxobutanoate (viii)
diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)acetyl]succinate (ix)
methyl phenyl sulfone; methyl(dioxo)phenyl-lambda~6~-sulfane (x)
Reference 1:
    castaner, j.; dsouza, n.; levin, m.; fulvestrant. drugs fut 2001, 26, 9, 841.
Reference 2:
    bowler, j.; tait, b.s. (astrazeneca plc); steroid derivs.. ep 0138504; jp 1985097995; us 4659516 .

Route 2
by reaction of primary oh group of (x) with mesyl chloride and tea in dichloromethane gives the mesylate (xi). compound (xi) is condensed with 4,4,5,5,5-pentafluoropentanethiol (xii) by means of nah in thf to yield the thioether (xiii), which is submitted to basic hydrolysis of the ester groups by means of naoh in meoh/water to afford the corresponding dihydroxy compound (xiv). finally, this compound is oxidized with sodium metaperiodate to provide fulvestrant.
List of intermediates No.
methyl phenyl sulfone; methyl(dioxo)phenyl-lambda~6~-sulfane (x)
ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}acetate (xi)
1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone (xii)
ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate (xiii)
ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate (xiv)
Reference 1:
    castaner, j.; dsouza, n.; levin, m.; fulvestrant. drugs fut 2001, 26, 9, 841.
Reference 2:
    bowler, j.; tait, b.s. (astrazeneca plc); steroid derivs.. ep 0138504; jp 1985097995; us 4659516 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名氟维司群;英文名Fulvestrant;ZD-9238;ZM-182780;ZD-182780;ICI-182780;Faslodex;CAS[129453-61-8]

 
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