Synthesis And Optimization Of Fudosteine

Fudosteine is a low molecular weight cysteine derivative expectorant,which has the advantages of strong efficacy,little side effects,wide indications,and large market potential,etc.Moreover,it is a kind of expectorant with relatively few side effects because it does not cause drug accumulation when given in large quantities,has no effect on local mucin,and has little gastrointestinal reaction.It is suitable for expectoration of cough,chronic bronchitis,bronchiectasis,pneumoconiosis,emphysema,and non-stereotypical antacid bacteria.In recent years,Fudosteine has been widely used as a combination medicine for expectorant and anti-inflammatory treatment of chronic obstructive pulmonary disease,sleep apnea syndrome,and various diseases.It is reported that there are three main processes for synthesizing Fudosteine API:(1)the synthesis of Fudosteine by L-cysteine and propylene alcohol;(2)the synthesis of Fudosteine from L-cysteine and 3-halogenated propanol;(3)the synthesis of Fudosteine through L-cysteine and oxacyclobutane;(4)the synthesis of Fudosteine through L-cysteine and acrolein.The common problems of these processes are that the difficult accessible raw materials,the long reaction time,the inconvenient operation,the high cost,the below-standard purity of Fudosteine API,or high content of the single impurity content.Therefore,it is of great significance to develop a new process for the preparation of Fudosteine.This paper carried out a lot of experimental research on the basis of literature,and finally developed a new process route for the synthesis of Fudosteine API.In the new process,L-cysteine and propyl haloacetate were used to synthesize Fudosteine API,and the crude product obtained by the reaction could be easily purified to obtain Fudosteine API.In thestudy of new processes,the effects of the purity of each raw material on the reaction,the influence of the reaction temperature and reaction time on the reaction,the influence of the reaction base on the reaction,and the influence of the reaction solvent on the reaction were explored.In the purification process,we mainly explored the effects of various organic reagent extraction on impurity removal,activated carbon adsorption,and the effects of recrystallization using various poor solvents for purification.Regarding the control of the content of single impurities in the product,the thesis not only controlled the reaction process,but also studied the influence of the purity of the raw materials on the single impurities.It was found that the purity of L-cysteine had almost no effect on the single impurity,but the purity of propyl haloacetate had a greater impact on the single impurity.Therefore,it is necessary to use high-purity propyl haloacetate to participate in the reaction.The reaction is investigat edfrom the small-scale laboratory synthesis to the process scale-up to 50 g,500 g,1 kg,and 20 kg.The total yield is over 98.2%,the purity is over 99%,and the content of single impurity is no more than 0.1%.The process of amplification technology is explored,and then the amplification synthesis process for Fudosteine is finally identified.Compared with the reported synthesis process of Fudosteine,this process is characterized by easy acquisition of raw materials,mild reaction conditions,high yield(calculated by the amount of L-cysteine),low hybrid content,environmentally friendly,which can be easier to industrialize production,and make the Fudosteine stronger competitive advantage in market.