Study On The Synthesis Of Sulindac

Sulindac is an efficient Non-steroidal Anti-inflammatory Drug(NSAIDs),which is used to treat Rheumatoid Arthritis,Ankylosing Spondylitis,Osteoarthritis,Acute Gout,Frozen Shoulder and so on.In the last few years,study found that Sulindac had shown effectiveness in treating arthritis inhibiting and eliminating colonic polyps.An improved synthetic process of Sulindac was proposed:It was started from 4-fluorobenzyl chloride,via condensation with di-Et methylmalonate,hydrolysis in the presence of KOH,decarboxylation,reaction with SOCl₂,intermolecular Friedel-Crafts reaction,condensation with cyanacetic acid,hydrolysis,condensation with p-methylthiobenzaldehyde,and oxidization to yield Sulindac,the overall yield was about 41.9%.The effects of temperature,amount of catalysts,and ratio of reactants on the reactions were investigated,and the suitable reaction conditions were obtained as follows.In decarboxylation reaction,the temperature was controlled within 130-140℃;in Friedel-Crafts reaction,the mass ratio of anhydrous AlCl₃ and 2-(4-fluorobenzyl)-2-methymaleic acid was 0.6:1;in the condensation between 6-fluoro-2-methyl-2,3-dihydro-1H-inden-1-one and cyanacetic acid,the mass ratio of catalyst ammonium acetic acid and 6-fluoro-2-methyl-2,3-dihydro-1H-inden-1-one was 0.1:1;in the condensation reaction between 2-(5-fluoro-2-methyl-1H-inden-3-yl) acetic acid and p-methylthiobenzaldehyde,the molar ratio of 2-(5-fluoro-2-methyl-1H -inden-3-yl)acetic acid,p-methylthiobenzaldehyde and sodium methoxide was 1:1:2.5～4.0;in the oxidization,the mass ratio of(Z)-2-(5-fluoro-2-methyl-1-(4-(met hylthio)benzylidene)-1H-inden-3-yl)acetic acid and H₂O₂ was 1:0.15.This proposed synthetic process is much of industrial value because of the high yield,cheap and easily gained materials,the moderate reaction condition and the convenient operation.The purities and structures of products for each reaction were examined by GC,GC-MS,IR and ¹H NMR.