Study On The Synthetic Process Of Ketoprofen And Its Chiral Resolution

As a kind of nonsteroidal anti-inflammatory drugs,ketoprofen bears several advantages,such as less dose,better curative effect and less side effects and so on.At present,the problems of high preparation cost and serious pollution caused by the backward production technique of ketoprofen have attracted great concerns and attentions.With the development of organic chemical industry,refinement of the present technological line and exploring a novel environmentally friendly procedure with simple process under mild conditions will lead to great economic value and has certain academical significance.This thesis optimized and improved the primary technological line based on the previous literatures and a number of related experiments.This route used the unexpensive isophthalic acid as starting material for the synthesis of ketoprofen;and diethyl 2-(3-(methoxycarbonyl)benzoyl)malonate was synthesized via chlorination,monoesterification and condensation in a one-pot countinuous reaction;followed by hydrolysis and decarboxylation,3-acetylbenzoic acid was obtained in the yield of 68.3%;1-(3-benzoylphenyl)ethan-1-one was generated from 3-acetylbenzoic acid and benzene by AlCl3 catalyzed via Friedel-Crafts reaction in the yield of 80.5%;1-(3-benzoylphenyl)ethan-1-one was then treated with sodium isopropoxide and ethyl chloroacetate via Darzens reaction to give birth to 2-(3-benzoylphenyl)propanal in the yield of 64.3%;ketoprofen was finally obtained by oxidation of 2-(3-benzoylphenyl)propanal with H2O2-NaClO2 in the yield of 82.4%.The total yield of the route is 29.1%.The operations were smoother and all the reaction conditions were milder compared with the former one.Meanwhile,this thesis also developed a new technological line.With p-aminopropiophenone as starting material,1-(4-nitrophenyl)propan-1-one was prepared via oxidation reaction in the yield of 85.4%;1-(4-amino-3-benzoylcy-clohexa-1,5-die-1-yl)propan-1-one was synthesized by annulation of glycol protected 1-(4-nitrophenyl)propan-1-one and benzyl cyanide,and then the reductive ringopening reaction with Fe and hydrochloric acid in the yield of 76.4%;1-(4-benzoylphenyl)propan-1-one was delivered via deamination in the yield of 81.3%;bromination of 1-(4-benzoylphenyl)propan-1-one produced 1-(3-benzoylcyclohexa-1,5-dien-1-yl)-2-bromopropan-1-one in yield of 90.2%,which was converted to(3-(2-(1-bromoethyl)-5,5-dimethyl-1,3-dioxan-2-yl)cyclohexa-2,4-dien-1-yl)(phenyl)methanone by ketalation of neopentyl glycol in the yield of 75.2%;ketoprofen was finally obtained via rearrangement mediated by KOAc and hydrolysis reaction in the yield of 77.6%.The total yield of this new technological line was 27.9% in the optimized process,and the posttreatment is simple.The thesis also preliminarily studied the resolution process of racemic ketoprofen by deoxy-1-D-glucitol and S-?-phenethylamine.The resulting spectrums of the key intermediates and target products are related to the structural characteristics of the compounds.