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药物详细合成路线

Name Sorafenib;BAY-43-9006
Chemical Name 4-[4-[3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido]phenoxy]-N-methylpyridine-2-carboxamide
CAS 284461-73-0
Related CAS
Formula C21H16ClF3N4O3
Structure
Formula Weight 464.83487
Stage 上市-2005
Company Bayer (Originator), Onyx (Codevelopment)
Activity/Mechanism Colorectal Cancer Therapy, Leukemia Therapy, Liver Cancer Therapy, Melanoma Therapy, Myelodysplastic Syndrome Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Renal Cancer Therapy, Solid Tumors Therapy, Inhibitors of Signal Transduction Pathways, Raf Kinase Inhibitors, Vascular Endothelial Growth Factor (VEGF) Inhibitors
Syn. Route 1
Route 1
reaction of picolinic acid (i) with hot thionyl chloride in dmf gives 4-chloropyridine-2-carbonyl chloride (ii), which is treated with methanol to give ester (iii). subsequent displacement of the methyl ester function withmethylamine provides amide (iv). alternatively, acid chloride (ii) is directly converted into amide (iv) by reaction with a cold solution of methylamine. in a different synthetic procedure, amide (iv) can be obtained from 4-chloropyridine (v) via the menisci reaction using n-methylformamide and hydrogen peroxide in the presence of feso4 and h2so4. coupling of the amide (iv) with potassium 4-aminophenolate (vi) -obtained by treatment of 4-aminophenol (vii) with potassium tert-butoxide- in hot dmf yields the pyridyloxyaniline (viii). aniline (viii) isfinally condensed with either 4-chloro-3-(trifluoromethyl)phenyl isocyanate (ix) in ch2cl2 or 4-chloro-3-(trifluoromethyl)aniline (x) by means of cdi in ch2cl2.
List of intermediates No.
dimethyl 2,2-dichloro-1-hydroxyvinylphosphonate (vii)
(2s)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-(diethoxymethyl)-4-penten-2-ol (i)
(1s,4r)-4-(2-amino-6-chloro-9h-purin-9-yl)-2-cyclopenten-1-ol (v)
(ix)
methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate; methyl 6-[4-(methyloxy)-3-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl]-2-naphthalenecarboxylate (ii)
methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate; methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate (iii)
methyl 6-[4-(methyloxy)-3-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl]-2-naphthalenecarboxylate; methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (iv)
1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid (vi)
(1s,2s,3r,5s)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-pinanediol (viii)
diphenylmethyl 3-({[(dimethylamino)carbonyl]oxy}methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (x)
Reference 1:
    sorbera, l.a.; castaner, j.; bozzo, j.; leeson, p.a.; bay-43-9006. drugs fut 2002, 27, 12, 1141.
Reference 2:
    monahan, m.-k.; sibley, r.; natero, r.; dumas, j.; bankston, d.; riedl, b.; a scaleable synthesis of bay 43-9006: a potent raf kinase inhibitor for the treatment of cancer. org process res dev 2002, 6, 6, 777.
Reference 3:
    smith, r.a.; monahan, m.-k.; riedl, b.; scott, w.j.; khire, u.; lowinger, t.b.; natero, r.; sibley, r.n.; wood, j.e.; renick, j.; dumas, j. (bayer corp.); omega-carboxy aryl substd. diphenyl ureas as p38 kinase inhibitors. wo 0041698 .
Reference 4:
    lowinger, t.b.; monahan, m.-k.; dumas, j.; scott, w.j.; khire, u.; wood, j.e.; renick, j.; riedl, b.; smith, r.a.; natero, r.; sibley, r.n. (bayer corp.); omega-carboxyaryl substd. diphenyl ureas as raf kinase inhibitors. ep 1140840; wo 0042012 .

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索拉非尼;英文名Sorafenib;BAY-43-9006;CAS[284461-73-0]

 
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