Study On The Synthesis Of The Reversible Proton Pump Inhibitor Revaprazan Hydrochloride

Peptic ulcer is one of the most familiar diseases, the total incidence of peptic ulcer is about 10%～20%. As the development of China's society, changes of environment, changes of population structure and the changes of lifestyle, the incidence of peptic ulcer mainly increased. As a common and frequently-occurring disease, peptic ulcer makes people afflicted. Thus, the treatment of peptic ulcer receives increasing attention, the development and production of safe and effective anti-ulcer drugs have been concerned, and become the focus of drug research, and be one of the popular areas.Revaprazan hydrochloride(YH-1885), its chemical name is 5,6-Dimethyl-2- (4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydro- chloride, a new reversible proton pump inhibition developed by South Korea Yuhan company, it was listed with FDA in 2007 in the treatment of duodenal ulcer and gastritis. Indication for the treatment of gastric ulcer patients have completed PhaseⅢclinical research and treatment of gastroesophageal reflux disease, functional dyspepsia, as well as the indication for eradication of Helicobacter pylori has also been research into the clinical stageⅡ. Glaxo Smith Kline Company has revaprazan hydrochloride's global license to develop, and not yet listed in domestic. This paper mainly studies on the synthesis of revaprazan hydrochloride.In the light of the relevant literature and on the basis of repeated experiments, this paper prepared revaprazan hydrochloride and made some attempt of chemical resolution to 1-methyl-1,2,3,4-tetrahydroisoquinoline, in order to prepare optically pure revaprazan hydrochloride: 1. In accordance with the method reported in the literature and the other method to synthesis N-(4 - fluorophenyl) guanidine carbonate.2. The method was different from the literature synthesis of 4 - hydroxy -2 - (4 - fluoro aniline) -5,6 - dimethyl-pyrimidine, and the yield was significantly higher than that reported in the literature.3. Reaction with phosphorus oxychloride and phosphorus pentoxide as catalyst and dehydrating agent in the reaction of preparation of 1 - methyl -3,4 - dihydroisoquinoline, to replace the method of poly-phosphate used in the literature, in the post-processing it was easy to deal, and phosphorus oxychloride can also be re-used.4. With D (-) - tartaric acid to 1 - methyl -1,2,3,4 - tetrahydroisoquinoline to split. This paper studies on the synthesis of revaprazan hydrochloride, which structures were confirmed by 1H-NMR, MS and elemental analysis. The total yield was 64.7% based on 4-fluorophyenylamine, higher than that reported in the literature. Its raw materials is cheap and easy to get, operating technology is simple, so this paper can provide a reference for the industrial production.