Synthesis Of The Proton Pump Inhibitor Lansoprazole And Preparation Of Lansoprazole Enteric-coated Pellets Capsules

We developed a improved method of the four-step synthesis of lansoprazole,using 2,3-dimethyl-4-nitropyridine-N-oxide as raw material,through two "one-pot" on the basis of the synthesis method of lansoprazole in the literature.Improved synthetic route shortened the synthesis process and improved the product yield in a relatively mild reaction conditions.The total yield of the synthesis of lansoprazole is 39.2%,much higher than the 18.8%reported in the literature,suitable for industrial production.(1)A simple way to introduce 4-bit on the trifluoroethoxy is a key step in the synthesis.This group also is the key of the difference between lansoprazole and onmeprazole.The method reported in the literature was using the reagents of potassium tert-butanol and trifluoroacetic ethanol.But potassium tert-butanol is very expensive.The reaction conditions is also high.These reagents were not suited to mass production requirements.In this paper,We used sodium hydride instead of potassium tert-butanol,in a relatively mild reaction conditions to introduce of trifluoroethoxy.(2)The lansoprazole sulfide precursor 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole is synthsized by on pot of 2-(hydroxymethyl)-3-methyl-4-(2,2,2)-trifluoroethoxy-pyridyl.we also replaced hydroxide with methanol sodium as a condensing agent,in the solvent methanol.The yield of product 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole was up to 98%.(3)The oxidation was using hydrogen peroxide as an cheap oxidant,sodium molybdate as a catalyst to replace the traditional oxidant.The prescription and process of lansoprazole Enteric-coated pellets capsules were studied on the base of the optimization of the synthesis of lansoprazole.We get the optimal process conditions.Then we made the amplification test and we made the heat,humidity,light and other factors test of the samples.We found that the pellets capsule was developed and stable quality.the production of commercially available enteric-coated pellets capsules and enteric-coated pellets capsules,the results show that the lansoprazole Enteric-coated pellets capsules made by us is better than the original plant(Japan Takeda)by comparison.