| This paper is divided into two parts,the solubility of enalapril maleate and its intermediates and the synthesis and process optimization of the intermediates of chlorpromazine were studied.First part:ACE inhibitors are a kind of polypeptides which have important significance in the control of heart failure.They have very high therapeutic value for cardiovascular diseases,Enalapril,as the second generation of ACE inhibitors,can exert a strong inhibitory effect on the invertase,relax the blood vessels,and the effect of blood pressure reduction is lasting.At present,enalapril is widely used in the medical treatment.However,their poor solubility limited their application in clinical medicine.In order to improve their universality,it is often to prepare the form of maleate compounds to improve the solubility.Enalapril is mainly prepared from enalapril hydrides and amino acids,then acidified with diethyl maleate to prepare enalapril maleate,and finally crystallized and purified.The solubility data and thermodynamic properties of enalapril maleate and its intermediate,enalapril hydride,were studied.In this paper,the solubility behavior of enalapril maleate and its intermediates in water and seven organic single solvents was studied by isothermal saturation method in the temperature range of 273.15k-318.15k at atmospheric pressure.The solubility of enalapril maleate in benzoic acid was determined.The reliability of the method was verified by comparing the experimental value with the theoretical value.Apelblat,λh and Wilson equations were used to correlate the solubility data measured in the experiment.The error range of RAD was 0.08%-4.63%,and RMSD was 0.015×10-4-2.85×10-4.In general,Apelblat equation was more suitable for calculation and simulation.At the same time,Wilson equation was used to calculate and analyze the thermodynamic properties of dissolution.The results show thatΔmixG<0,ΔmixH>0,indicating that the dissolution of the two compound is spontaneous and exothermic.Second part:With the increasing demand of pesticides for Disease Control in agriculture,the research and development of nitrogen-containing heterocyclic compounds,especially those containing pyrazoles and pyridines,is one of the hot spots in this field.Many of them have been widely used because of their high efficiency and low toxicity of insecticidal and herbicidal activities.In order to further understand the synthesis and response of pesticides containing halopyrazoles heterocyclic structure.In this part,the synthesis process of ethyl-3-bromo-1-（3-chloro-2-pyridyl）-pyrazol-5-carboxylic acid（acid intermediate）of chlorobenzamide and its by-products were studied.Using diethyl maleate and pyridine chlorhydrazine as raw materials,acid intermediates were synthesized by four steps of cyclization,bromination,oxidation and hydrolysis with a total yield of51.38%.In view of the low yield of cyclization,two new methods were explored.First,the intermediate product was directly brominated without separation.The total yield of the acid intermediate was increased to 62.68%.Secondly,a new route of 3-bromo-1-（3-chloro-2-pyridyl）-4,5-dihydropyrazol-5-carboxylic acid methyl ester was explored by using hydrazine hydrate and dimethyl maleate as raw materials to produce 3-hydroxy-4,5-dihydropyrazol-5-carboxylic acid methyl ester,which was then brominated and substituted.This reaction can produce cyclized product,but the yield is low.Four by-products,1-（3-chloro-2-pyridyl）-5-hydroxy-4,5-dihydropyrazol-3-carboxylic acid ethyl ester,N,1-bis（3-chloro-2-pyridyl）-3-hydroxy-4,5-dihydropyrazol-5-carbohydrazide,1,2-bis（dimethyl succinate）hydrazine and 3-bromo-1-（5-bromo-3-chloro-2-pyridyl）-pyrazol-5-carboxylic acid ethyl ester were identified,the formation reason and the effect on the yield were discussed,which provided a reference for the optimization of the subsequent process. |
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