Study On The Synthesis Of Ramosetron Hydrochloride And Enzymatic Resolution

Along with the development of spit medicine market, ramosetron hydrochloridebecome the new generation of5-HT3receptor antagonist, its market share has continued toincreasing trend. The advantage of ramosetron hydrochloride is its long half-life, andrequires one dose everyday, besides, it has no obvious side effects. Compared with5-HT3receptor antagonist of ondansetron and granisetron, ramosetron hydrochloride has a verydistinct advantage.In addition, the product is growing every year in our demand, and part need to beimported, so developing high purity and low cost of ramosetron hydrochloride has veryimportant practical significance and market value.Ramosetron hydrochloride is a new type of serotonin (5-HT3) receptor antagonists. Dueto its high efficiency, light adverse reactions and high safety, it becomes the spit compoundof wide prospect function. The chemical structure has one chiral carbon atom, so it has twoconfigurations of R-isomers and S-isomers. Literatures reported that effect intensity ofS-isomers is much lower than the R-isomers, so R-isomer is the main component oframosetron hydrochloride.In the process of preparing ramosetron hydrochloride, we reviewed the reaction of afew steps, and discussed synthetic route through the literatures, ultimately part of theprocess of synthesis conditions are optimized.In the synthesis of benzimidazole-5-carboxylic acid, we emphasized the influence ofreaction time to the reaction, and found that shorten the reaction time to3h can reduce sideeffects and extend the reaction time can not increase the conversion rate.In the process of synthesizing N-[(4,5,6,7-4H-benzoglioxaline-5-base)] pyrrole, weused thionyl chloride directly as solvent and reactant in the preparation of acyl chloride.when reacting with tetrahydro-1H-benzoimidazole-5-carboxylic acid sulpHate, we avoidusing toxic reaction solvent of acetonitrile solvent, thus convenient post-processing andimprove the production rate.Meanwhile, after the process of synthesizing N-[(4,5,6,7-tetrahydro-benzoglioxaline-5-base)] pyrrole, we didn’t let it become hydrochloride according to theliterature from home and abroad. In contrast, we directly let it react with N-methyl indole and phosphoryl chloride. After the reaction, we put the post-processing into the ice water,and used saturated sodium hydroxide solution to adjust PH to9~10, then filtered afterprecipitation has separated out. The above steps can simplify the synthetic process.At present, the first step of the synthesis of ramosetron hydrochloride is to getracemization of ramosetron hydrochloride, then chemically split, and then get the (R)-ramosetron hydrochloride. This clearly appears that a few steps in the synthesis increasedthe use of raw material, increasing the pollution of the environment and operation costs.Therefore, it’s very important to synthesize (R)-ramosetron hydrochloride from split oforiginal optical isomers. Enzyme, as biological catalyst, compared with chemical method,has more advantage. For example, it has substrate specificity, good stereo selectivity, mildreaction conditions, besides, its products can easily separated. So using enzymes to organicsynthesize and design with high selectivity and high-efficient receives great value fromorganic chemist and drug chemist. Now it has become the most hot spot of synthesischemistry.As ramosetron is a kind of chiral drug, we try to use the method of enzymic resolution,after the literature review, we select Nov435to split intermediates oftetrahydro-1H-benzoimidazole-5-carboxylate sulfate, for the enzyme activity can beinfluenced by solvent, buffer and other various effects, our separation test mainlyinvestigate the influences of temperature, reaction time, enzyme quantity and pH. We havemany advantages of using enzymatic separation technology, such as mild reaction conditionsand fewer side effects. It creates conditions to the further study of spliting ramosetron.