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药物详细合成路线

Name SB-203580
Chemical Name 4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole
CAS 152121-47-6
Related CAS
Formula C21H16FN3OS
Structure
Formula Weight 377.44357
Stage 临床前
Company GlaxoSmithKline (Originator)
Activity/Mechanism Antiarthritic Drugs, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Calcium Channel Activators, p38 Protein Kinase Inhibitors, Stress-Activated Protein (SAP/Jun) Kinase Inhibitors
Syn. Route 2
Route 1
4-[(tert-butyldimethylsilyloxy)methyl]pyridine (ii) was prepared by silylation of 4-hydroxymethylpyridine (i) with tert-butyldimethylsilyl chloride and imidazole. deprotonation of (ii) by means of lda in cold thf, followed by condensation with 4-fluorobenzaldehyde (iii), furnished the protected diol adduct (iv), which was further desilylated upon treatment with tetrabutylammonium fluoride in thf. oxidation of the resultant diol (v) under swern conditions provided diketone (vi). the triaryl imidazole (viii) was then obtained by condensation of diketone (vi) with 4-(methylsulfanyl)benzaldehyde (vii) in the presence of ammonium acetate in refluxing hoac. finally, oxidation of the thioether function of (viii) with k-2s2o8 furnished the title sulfoxide.
List of intermediates No.
methyl (1r,2s,3r)-3-acetyl-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate (iii)
5-([1,1-biphenyl]-4-ylmethoxy)-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one (vii)
1-[2-(2-thienyl)ethyl]-4-piperidinone (ii)
(1r,5r)-10,10-dimethyl-4-[(2s)piperidinylcarbonyl]-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione (i)
methyl 2-(3,4-dichlorophenyl)-4-pentenoate (vi)
Reference 1:
    adams, j.l.; gallagher, t.f.; lee, j.c.; white, j.r. (glaxosmithkline plc); imidazole derivs. and their use as cytokine inhibitors. ep 0623126; ep 0943616; jp 1995503017; us 5686455; wo 9314081 .

Route 2
in a related procedure, 4-fluorobenzoyl chloride (ix) was converted to the corresponding weinreb amide (x) upon treatment with n,o-dimethylhydroxylamine. condensation of (x) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (ii) furnished the silylated hydroxy ketone (xi). this was then condensed with 4-(methylthio)benzaldehyde (vii) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (viii), which was finally oxidized as above.
List of intermediates No.
1-(1h-imidazol-1-ylsulfinyl)-1h-imidazole (ix)
5-([1,1-biphenyl]-4-ylmethoxy)-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one (vii)
1-[2-(2-thienyl)ethyl]-4-piperidinone (ii)
[4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol (xi)
4-[[(3r,4s)-1,3-dimethylpiperidinyl]anilino]benzoic acid (x)
Reference 1:
    gallagher, t.f.; et al.; regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of csbp kinase. bioorg med chem 1997, 5, 1, 49.
Reference 2:
    gallagher, t.f.; et al.; 2,4,5-triarylimidazole inhibitors of il-1 biosynthesis. bioorg med chem lett 1995, 5, 11, 1171.
Reference 3:
    adams, j.l.; gallagher, t.f.; lee, j.c.; white, j.r. (glaxosmithkline plc); imidazole derivs. and their use as cytokine inhibitors. ep 0623126; ep 0943616; jp 1995503017; us 5686455; wo 9314081 .
Reference 4:
    adams, j.l.; gallagher, t.f.; lee, j.c.; white, j.r. (glaxosmithkline plc); imidazoles for treating cytokine mediated disease. wo 9503297 .

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SB 203580;英文名SB-203580;CAS[152121-47-6]

 
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