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Synthesis Of Ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-1, 3-thiazole-5-carboxylate

Posted on:2006-03-26Degree:MasterType:Thesis
Country:ChinaCandidate:G Q ZhouFull Text:PDF
GTID:2121360152471824Subject:Applied Chemistry
Abstract/Summary:Order a copy of this thesis
Ethyl 4-methyl-2- [4-(trifluoromethyl)phenyl]-1,3- thiazole-5-carboxylate is an important intermediate of certain novel medicines which activate human peroxisome proliferator receptors("hPPARs"), the research of the chemical synthesis technology for the intermediate has few been reported. In this paper, p-chlorobenzotrifluoride was chosen as starting material to synthesize p-trifluoromethylbenzonitrile catalyzed by a special tris(triphenylphosphine)nickle(0) , the catalyst was prepared from anhydrous MCl2 and triphenylphosphine in the presence of zinc. Then p-trifluoromethylbenzonitrile reacted with hydrogen sulfide to give 4-(trifluoromethyl)thiobenzamide. Ethyl 2-chloroacetoacetate was prepared by chlorination of ethyl acetoacetate with sulfonyl chloride as the regent, which was in turn reacted with 4-(trifluoromethyl)thiobenzamide to give the object product. By the way, several other thiobenzamide derivates from the corresponding cyanobenzenes reacting with hydrogen sulfide, were also studied.Firstly, p-chlorobenzotrifluoride reacted with potassium cyanide to get p-trifluoromethylbenzonitrile which catalyzed by tris(triphenylphosphine)nickle(0). According to yields, the influence of various factors were studied experimentally. Thus we got the optimum conditions of the reaction: the reaction temperature was about 40 ℃ and 4 hours were needed, while the amount of catalyst of triphenylphosphine was 25mmol with respect to 0.68mmol p-chlorobenzotrifluoride, 0.68mmol potassium cyanide, 10mmol NiCl2 and 60mmol zinc. The conversion for p-chlorobenzotrifluoride was 85%, the yield was 83%. Additionally the composition and structure of product was analysed by GC/MS and IR, which helped to confirm the corresponding character.Secondly, the addition reaction of p-trifluoromethylbenzonitrile and hydrogen sulfide was studied, the optimum conditions for synthesis of 4-(trifiuoromethyl) thiobenzamide was got as following: with methonal as the reaction solvent and sodium ethoxide as the catalyst, at the reaction temperature about 20 ℃ and thereaction time of 12, the yield of 90% from p-trifluoromethylbenzonitrile to 4-(trifluoromethyl) thiobenzamide was obtained. The purity of the product was 99.7% analysed by HPLC, the product was also identified by GC-MS. Several other thiobenzamide derivates were aslo synthesized with the similar chemical technology, and the yields of 70%, 90% and 88% were obtained for thiobenzamide, 4-hydroxy thiobenzamide and 4-methyl thiobenzamide respectively..By chlorinating with sulphuryl chloride instead of chlorine, better results for ethyl 2-chloroacetoactate from ethyl acetoactate was archived. The reaction of ethyl acetoactate with sulphuryl chloride was studied and the optimized condition of reaction as following: the molar ratio of ethyl acetoactate to sulphuryl chloride was 1:1, benzoyl peroxide was needed as initiator, the reaction temperature was at 0-5 ℃, when dropped sulphuryl chloride into ethyl acetoactate,. The yield of 90% for ethyl 2-chloroacetoactate with the purity of 97% was obtained. The product was identified by GC-MS. While chlorination by chlorine, the yield and selectivity for object matter were only 58% and 64.3% based on ethyl acetoactate.The above synthesized 4-(trifluoromethyl)thiobenzamide reacted with ethyl 2-chloroacetoacetate to give Ethyl 4-methyl-2- [4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate, and we got the optimum condition of reaction: the molar ratio of ethyl 2-chloroacetoacetate to 4-(trifluoromethyl)thiobenzamide was 1.2:1 and at the same time the molar ratio of kalium carbonate to 4-(trifluoromethyl)thiobenzamide was 1.3:1, while toluene was selected as suitable solvent and 6 hours were needed. The purity of product was 90%, the yield was 86.8%. The composition and structure of product were ananlysed by GC-MS, which helped to confirm the corresponding character.
Keywords/Search Tags:Ethyl 4-methyl-2- [4-(trifluoromethyl)phenyl]-1,3- thiazole-5-carboxylate p-chlorobenzotrifluoride, triphenylphosphine, catalyst, p-trifluoromethylbenzonitrile, 4-(trifluoromethyl)thiobenzamide, thiobenzamide derivates, sulfonyl chloride, chlorine
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