Study On The Procass For Preparation Of Dexlansoprazole

Dexlansoprazole,trade name Dexilant,is developed by Takeda and appeared on the market in the United States for the first time in 2009.As one of the PPIs with high efficiency in the treatment of peptic ulcer disease and gastricesophagitis reflux disease,dexlansoprazole has become the most promising drugand wide marketing prospect.The synthetic routes of Dexlansoprazole reported in the literature and patents are summarized and analyzed in the dessertation.The appropriate route was selected,which used2,3-dimethylpyridine as starting material to prepare the important intermediate 2-chloromethyl-3-methyl-4-?2,2,2-trifluoroethoxy?pyridine hydrochloride?6?,through N-oxidation,nitrification,substitution,rearrangement,hydrolyzation,chlorination.Futher2-[[[3-Methyl-4-?2,2,2-trifluoroethoxy?-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole?7?was synthesized via condensation reaction of the intermediate 6 with 2-mercaptobenzimidazole.Then Dexlansoprazole was synthesized through asymmetric oxidation from the L-?+?-diethyl tatarate as the chiral ligand and titanium?IV?isopropoxide as the catalytic agent and cumene hydroperoxide as the oxidizing agent.The synthesis process was optimized and the mechanisms of key steps were discussed.After the process optimization,the N-oxidation reaction yield is96%,the nitrification reaction yield is 94%,the substitution reaction yield is 94%,the rearrangement reaction yield is 85%,the hydrolyzation reaction yield is 93%,the chlorination reaction yield is 93%,the condensation reaction yield is 96%?The asymmetric oxidation were investigated in detail.Experiments were carried out to study the effect of components ratio,the formation of the catalyst system,types of solvent,organic bases,reaction temperature and time.The optimal reaction condition of the asymmetric oxidation was obtained as follows:the molar ratio of Ti?O-iPr?₄,?R,R?-DET,H₂O,DIPEA,Cumene hydroperoxide and the intermediate 7 was 0.15:0.3:0.15:0.15:1.5:1;the reaction temperature was3-5°C and the reaction time was 6 hours.The asymmetric oxidation yield is 80%.The crude Dexlansoprazole was recrystallized with 95%ethanol to obtain the purified product in the yield of 50%with a chemical purity of 98%and optical purity of 99.5%.According to the optimum parameters and the demand of the market,the process of 10 t/y of Dexlansoprazole was designed.The process flow chartand was also determined.The technological and economic feasibility was evaluated.