Synthesis Technology Of Dexlansoprazole

Delansoprazole delayed-release capsules (trade name DEXILANT), with a Dual DelayedRelease formulation,is the first proton pump inhibitor for the treatment of heartburn,Erosiveesophagitis with good effect. Dexlansoprazole, the R-enantiomer of lansoprazole, is the activeingredient. In this article, Dexlansoprazole has been synthesized and at the same time a simpleroute with high yield, good quality up to the requirements of industrial production has beendeveloped and the synthetic route is suitable for industrial production well.In this article, we analysed the four reported process, on the basis of the four process, westudied the synthetic technology by4-chrolo-2,3-dimethyl-pyridine-N-oxide as the startingmaterial. Finally we designed to get the product by4-nitro-2,3-dimethyl-pyridine-N-oxide asthe starting material.In this process,compound24was obtained by substitution, rearrangement,halogenation and hydrolysis to4-nitro-2,3-dimethyl-pyridine-N-oxide, then compound25wasgot by substitution reaction with2-mercaptobenzimidazole under phase transfer catalyticconditions.In the last,dexlansoprazole was efficiently synthesized via an asymmetric oxidationcatalyzed by titanium tetraisopropoxide,diethyl tartrate, with total yields of37.5%, in purity99.9%, and99.8%in enantiomeric excess (ee). After the experiment was done in small dose,experiment suitable for pilot scale was researched.The innovation points of the essay as follows:(1) in order to improve the purity of theproduct, hydrongen in the forth place of Pyridine ring was replaced by was a substitutionreaction of compound21with trifluoro-ethanol;(2) thionyl chloride was substituted bybenzenesulfonyl chloride in order to improve the yield of the experiment and avoid theproduce of genotoxic impurities;(3)In the process of asymmetric oxidation, the properquantity of the catalyst and temperature conditions was determined according to themechanism, by which the peroxide impurity sulfone was controlled at a very low level, thesulfide compound was completely transformed to sulfone and high purity and ee values wasobtained by recrystallization only.