Method for synthesizing dexlansoprazol by titanium catalyst ligand

Abstract

The invention discloses a method for synthesizing dexlansoprazol by a titanium catalyst ligand. The chemical name of the titanium catalyst ligand is (1R,2S)-N-p-methylbenzene sulfonic acid-1,2-diphenyl ethylenediamine. The method comprises the following steps: mixing the ligand with tetraisopropyl titanate, N,N-diisopropylethylamine and purified water according to a certain ratio, and catalyzing 2-[[[3-methyl-4-(2,2,2 trifluoroethyoxyl)-2-pyridine]methyl]thioxo]-1H-benzimidazole by heating to synthesize dexlansoprazol. According to dexlansoprazol, the enantiomer excess is not less than 99.2% and the yield is not less than 80%. The process is good in stability and high in enantioselectivity, and can be better applied to industrialization production.

Description

technical field [0001] The invention belongs to the application field of chemical synthesis, and in particular relates to a titanium catalyst ligand used in the synthesis of D-lansoprazole. Background technique [0002] The new proton pump inhibitor dexlansoprazole is an anti-ulcer drug that inhibits gastric acid secretion, chemical name: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2 -Pyridyl]methyl]sulfinyl]-1Hbenzimidazole, which was rated as one of the top ten best-selling drugs in the world by the American "Forbes" magazine in 2006, is clinically used for duodenal ulcer and gastric ulcer , anastomotic ulcer, reflux esophagitis and Zhuoi syndrome (also known as gastrinoma) and other diseases [Mao Yu et al., Chinese Journal of New Drugs, 2006，15 (1):17-20 ]. R-lansoprazole in the mixture has more significant proton pump inhibitory effect than S-lansoprazole, and the action time is longer. Its enteric-coated sustained-release capsules have been approved by the US FDA in 2009....

AI Technical Summary

Problems solved by technology

Patent DE403545 describes the preparation of dexlansoprazole by chemical resolution, which uses stereoselective nitrogen derivatization to resolve lansoprazole. The disadvantage of this method is that the racemic lansoprazole Azole needs two steps to produce optically pure lansoprazole, the reaction yield is only 40-50%, the process is complicated, and it is not suitable for industrial production

[0011] titanium( ) catalyst, Ti( i -PrO) 4 In coordination with the ligand L-diethyl tartrate, the Ti-O bond is extremely unstable, resulting in titanium ( ) The catalyst complex is unstable during the production process and is prone to failure, resulting in low yield and uncertain ee value of the product