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药物详细合成路线

Name Desogestrel;Org-2969;Cerazette
Chemical Name 13-Ethyl-11-methylene-18,19-dinorpregn-4-en-20-yn-17alpha-ol
CAS 54024-22-5
Related CAS
Formula C22H30O
Structure
Formula Weight 310.4838
Stage 上市-1999
Company Organon (Originator)
Activity/Mechanism Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Female Contraceptives, Oral Contraceptives, Progestogens
Syn. Route 2
Route 1
the silylation of the hydroxyketone (i) with tbdms-cl and imidazole in hot dmf gives the silyl ether (ii), which is reduced with dibal to the silylated perhydroindanone (iii). the carboxylation of (iii) with dimethyl carbonate and nah in thf affords the methyl ester (iv), which is condensed with 2-(3-methoxyphenyl)ethyl iodide (v) by means of nah and n-buli in thf yielding the addition compound (vi). the cyclization of (vi) by means of tfa and k2co3 in dichloromethane gives the gonatetraene derivative (vii), which is silylated with tbdms-cl and imidazole yielding the silyl ether (viii). the reduction of the ester group of (viii) with lah in thf affords the hydroxymethyl derivative (ix), which is treated with dead and o-nitrobenzensulfonylhydrazide in thf to provide the methylene derivative (x). the reaction of (x) with li in liquid ammonia, followed by hydrolysis with hcl gives 13-beta-ethyl-17-beta-hydroxy-11-methylenegona-4-en-3-one (xi), which is treated with ethanedithiol and bf3/et2o yielding the ethylenedithioketal (xii). the reduction of (xii) with li in liquid ammonia affords 13-beta-ethyl-11-methylenegona-4-en-17-beta-ol (xiii), which is oxidized with dess martin periodinane (dmp) to the corresponding ketone (xiv). finally, this compound is condensed with the cerium acetylide (xv) in thf.
List of intermediates No.
ethyl 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoate
8-methoxy-8-oxo-1-octanaminium chloride (i)
methyl 8-[[2-(acetoxy)benzoyl]amino]octanoate (ii)
1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone (iii)
1-[2-hydroxy-4-(tetrahydro-2h-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2h-pyran-2-yloxy)phenyl]-1-ethanone (iv)
2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-7-(tetrahydro-2h-pyran-2-yloxy)-3-[4-(tetrahydro-2h-pyran-2-yloxy)phenyl]-2,3-dihydro-4h-chromen-4-one (v)
3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2h-chromen-7-ol (vi)
(2s)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2h-chromen-7-ol (vii)
4-chloro-6-quinazolinylamine; 4-chloro-6-quinazolinamine (viii)
4-chloro-6-[(e)-3-methyl-1-triazenyl]quinazoline (ix)
2,4-dimethylpyrrole (x)
3,5-dimethyl-1h-pyrrole-2-carbaldehyde (xi)
benzyl 2-allyl-3-oxo-1-piperidinecarboxylate (xii)
benzyl (2r)-2-allyl-3-oxo-1-piperidinecarboxylate (xiii)
benzyl (2s,3s)-2-allyl-3-hydroxy-1-piperidinecarboxylate (xiv)
benzyl (3as,7as)-2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2h)-carboxylate (xv)
Reference 1:
    huang, a.x.; corey, e.j.; a short enantioselective total synthesis of the third-generation oral contraceptive desogestrel. j am chem soc 1999, 121, 4, 710.

Route 2
the ketalization of 11-methylene-18-methyl-delta4-oestrene-3,17-dione (i) with ethanedithiol (a) and bf3 etherate in methanol gives the 3,3-ethylenediothioketal (ii), which is reduced to hydryl derivative (iii) with nabh4 in ethanol. this compound is reduced with na in liquid ammonia yielding 11-methylene-18-methyl-delta4-oestrene-17-ol (iv), which is then oxydized with cro3 in acetone affording 11-methylene-18-methyl-delta4-oestren-17-one (v). finally (v) is treated with potassium acetylyde in thf.
List of intermediates No.
ethyl 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoate (a)
(1s,2r)-1-[(benzyloxy)methyl]-2-hydroxy-2,6-dimethyl-5-heptenyl acetate (i)
benzyl (2s,3s)-2-allyl-3-hydroxy-1-piperidinecarboxylate (v)
methyl (1r,2r,3s,5s)-3-(benzoyloxy)-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (ii)
(1r,2r,3s,5s)-3-hydroxy-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (iii)
methyl (1r,5s)-8-(2-propynyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (iv)
Reference 1:
    de 2361120; fr 2209577; nl 7216767 .
Reference 2:
    vanden broek, a.j.; et al.; 11-alkylidene steroids in the 19-nor series. recl trav chim pays-bas 1975, 94, 2, 35.
Reference 3:
    casta?er, j.; hillier, k.; org-2969. drugs fut 1977, 2, 9, 616.

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去氧孕烯;英文名Desogestrel;Org-2969;Cerazette;CAS[54024-22-5]

 
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