A Study On The Synthesis Technology Of Cetilistat

Based on the current research and development with market trend of the weight-loss drug market,combined with recent research results,it can be found that there is a huge business opportunity in the lipase inhibitor Cetilistat.As a new type of pancreatic lipase inhibitor,Cetilistat was approved to be marketed in Japan in September 2013 for the treatment of obesity.The advantages of Cetilistat are that it does not act on the nervous system,does not affect other enzyme activities in the gastrointestinal tract,does not absorbed end enter the blood,does not suppress appetite,does not need to restrict diet.There is not a corresponding product in the market of China,and its standards is not included in pharmacopoeia at home and abroad.Therefore,it will be of great significance to study on Cetilistat.A new route to synthesize Cetilistat was designed in this thesis.In this new route,2-amino-5-methyl benzoic acid was synthesized by catalytic hydrogenation which is environmental friendly and effective.Also,in the process of catalytic hydrogenation,pollution generated in traditional chemical oxidation-reduction method could be avoided.The effects of kinds of catalysts,catalyst dosages and reaction temperatures on the reaction were investigated during the experiments.At last,palladium carbon was chosen as the best catalyst for the reaction.The optimized reaction condition was that the catalyst dosage was 10%,the hydrogen pressure was 0.3-0.4 MPa and the reaction temperature was 45°C.The yield is 93.2% when reaction was carried out on the above conditions.In the condensation reaction,2-hexadecyloxycarbonylamino-5-methylbenzoic acid was synthesized with dichloromethane as solvent and pyridine as the acid binding agent.At the same time,pyridine played a role of catalyst in the reaction.Kinds of acid binding agents and solvents were investigated in the reaction.Pyridine,triethylamine,and diisopropylethylamine were used as the acid binding agents and the experiment results were compared.The mechanism of pyridine accelerates the reaction was explained.Due to the special structure of pyridine,the lone pair of electrons of the nitrogen atom in pyridine was not involved in the electron delocalization,thus the nitrogen atom had a strong ability of electron donating.In this case,active intermediate generated during the reaction of pyridine and cetyl chloroformate.The reactivity of the intermediate was much higher than that of cetyl chloroformate,thus the reaction could be accelerated obviously.In the condensation reaction,different solvents were investigated,such as dichloromethane,tetrahydrofuran and acetone.It was found that the product shown a dark color when acetone was used as the solvent.This mechanism was clear.Due to the electron withdrawing effect of the carbonyl group,hydrogen atoms on the acetone methyl group had some activities.In the presence of acid and alkali,acetone was easily enolized and the enolized product was prone to polymerization,resulting in a darker color of the product.In the cyclation reaction,catalytic effects of different catalysts such as methyl chloroformate,methanesulfonyl chloride,pivaloyl chloride,phosphorus oxychloride were investigated.After comparing the results,phosphorus oxychloride was chosen as the final catalyst.The amount of phosphorus oxychloride and the content of water in the solvent were investigated in the reaction.The conclusion was that when the reaction was carried out in anhydrous dichloromethane,and the amount of phosphorus oxychloride was 2.5 molar equivalents,the yield was 91.1%.The use of phosphorus oxychloride as the catalyst avoided the use of highly toxic methyl chloroformate,methanesulfonyl chloride reported in the literatures.The synthetic route designed in this thesis was safe,simple,environmental friendly and inexpensive,which was safe and beneficial to industrial production.