Research Of Vonoprazan Fumarate Synthesis Process And Quality Specification

Vonoprazan fumarate is a novel potassium-competitive acid blocker which was approved in Japan in December 2014 for the treatment and prevention of acid-related diseases.This dissertation presents the process optimization of vonoprazan fumarate,the synthesis of related impurities and the design and synthesis of a new synthetic route,as well as establishing quality standards.The research would lay a solid foundation for industrialized production and CFDA application.Study on the synthesis and process of vonoprazan fumarate:In this part,vonoprazan fumarate was successfully synthesized started from 2-fluoroacetophenone(6),6 was brominated with bromine in ethyl acetate to get 7,followed by nucleophilic substitution of malononitrile(12)and cyclization under acid condition to give 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile(14),then 14 was converted to 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(3)via dechlorination and hydrogenation,after substitution with pyridine-3-sulfonyl chloride(4),5-(2-fluorophenyl)-1-(pyrdin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(25)was obtained.Finally,vonoprazan fumarate(1)was prepared through reductive amination with methylamine hydrochloride and salification with fumaric acid with an overall yield of 22.2%(Ref.26.1%).The raw material is cheap and the operation is suitable for scale up,having the potential to enlarge production of industrialization.Specific innovations are listed as follows:(1)Based on the investigation of reaction mechanism and conditions of ?-substitution with malononitrile,the production of impurity A was under control,the yield was increased and the purity of product was improved.(2)Through the analysis of the mechanism of pyrrole ring formation and mass and 1H NMR spectrum,the structure of impurity C was speculated and the compound was synthesized directionally.(3)Based on the research of reductive amination,the production of impurity B was under control,the purity of product was improved and the yield was increased by optimizing the reaction conditions.(4)Eight impurities(A~H)were synthesized,which would lay a foundation to the quality research of vonoprazan fumarate.Study on the design of a new synthetic route for vonoprazan fumarate:This study designed a new route to avoid the problems existed in the original route: 2-bromo-1-(2-fluorophenyl)ethan-1-one(7)was synthesized from 6 by substitution with bromine,followed by substitution of ethyl 2-cyanoacetate(8)to give ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate(9).9 cyclized under acid condition and catalytic hydrogenated to get ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate(11).Methylamine and compound E,the hydrolysate of 11,were coupled first to furnish 5-(2-fluorophenyl)-N-methyl-1H-pyrrole-3-carboxamide(26)in the presence of trimethylamine and EDCI.Then compound 26 was converted to amide 31 by the treatment with 4.Finally,vonoprazan fumarate(1)was obtained through the reduction of 31 and the salt formation with fumarate.(1)Intermediates 26,31 were the first reported intermediates;(2)The new synthesis route got rid of using expensive and explosive reagents such as Raney nickel;(3)The formation of impurity B was avoided in reduction amination and the purity of the final crude product was great improved.Study on the quality standards research of vonoprazan fumarate:The quality standards of vonoprazan fumarate API have not yet been included in China pharmacopoeia.In this paper,we research the quality standard of API in order to provide a reference for quality control in production process.Specific innovations are listed as follows:(1)In moisture check project,Fischer's method was used to detect water content;(2)According to Chinese pharmacopoeia,the solubility of API in water,ethyl acetate,methanol,ethanol,isopropanol,acetonitrile,THF,DMF,DMSO were investigated;(3)Gas chromatography determination method was established.The separation degree and peak shape of the five kinds of solvent meet the requirements;(4)In related substances examination project,a method which can separate the relevant material and the degradation impurities in acid,alkali,strong oxidation,high temperature and illumination damage experiment was established;(5)In the content determination project,HPLC method was used for the content determination of active ingredients in the sample;In conclusion,this dissertation accomplished the process optimization of vonoprazan fumarate,the synthesis of related impurities,the design and synthesis of new synthetic route,and quality standards study.The research would lay a solid foundation for its industrialized production and CFDA application.