Improved Synthesis Of Important Intermediate Of Aminomethylbenzoic Acid And Preliminary Exploration Of Innovative Synthesis Process Of Aminomethylbenzoic Acid

Aminomethylbenzoic acid is a hemostatic drug,which can act with lysine in fibrin to stop bleeding.Because of its low toxicity,safety and good effect,it is widely used in the treatment of different parts of bleeding caused by a variety of reasons.In this thesis,based on the previous work of our laboratory,the synthesis process of ethyl p-chloromethyl benzoate(intermediate 1),an important intermediate of aminotoluene acid,was further improved.It is found that the reaction can be carried out by mixing p-chloromethyl benzoic acid with ethanol without any additional reagent or catalyst,and the results are good.After the optimum reaction conditions were determined,the substrate applicability of the reaction was studied.Methyl p-chloromethyl benzoate,propyl p-chloromethyl benzoate,n-butyl p-chloromethyl benzoate and butyl p-chloromethyl benzoate were prepared with satisfactory results.This method has higher atomic efficiency,more green environmental protection,easier operation,no special requirements for equipment and plant,and is more suitable for industrial production.This discovery not only provides a new method for the preparation of p-chloromethyl benzoates,but also provides a new thinking direction for the mature esterification research,and makes a useful attempt.On this basis,the more economical ethyl p-chloromethyl benzoate was selected as an important intermediate for the synthesis of aminotoluene acid,and the step-by-step scale-up reaction(2.5 times,5 times,10 times,25 times,50 times,100 times)was preliminarily studied.The results show that satisfactory results can also be obtained in the 100 fold amplification experiment.This study laid an experimental foundation for the further industrialization of the intermediate.Because of the shortcomings of the traditional nitrogen source for the synthesis of aminotoluene acid,acetamide,which is cheap and easy to obtain,was used as a new nitrogen source for the synthesis of aminotoluene acid in this thesis.In this thesis,we found that in dioxane,acetamide reacted with sodium hydride first,and then condensed with intermediate 1 under the catalysis of sodium bromide to obtain intermediate 2;the crude product of intermediate 2 can be directly used for the synthesis of aminotoluene acid,which can be hydrolyzed under the action of acid,neutralized by alkali to obtain crude aminotoluene acid,and purified to obtain pure aminotoluene acid.This method has no special requirements for plant and equipment,high production safety,all raw materials and reagents are commercially available,cheap and easy to obtain,less pollution to the environment,high yield and good purity.It is suitable for industrial production,and overcomes many shortcomings of traditional nitrogen source in the synthesis of aminotoluene acid.