Preparation Of (S)-2-amino-3-(chlorobenzene) Propionic Acid By Enzymatic Dynamic Kinetic Resolution And Synthetic Process Optimization Of (S)-indoline-2-carboxylic Acid

Hypertension is the most common risk factor for cardiovascular disease and the main reason for the high mortality of cardiovascular disease.Perindopril as a first-line treatment for hypertension,in the past three years,has been sold up to 500-600 million US dollars per year in the world.And(S)-indoline-2-carboxylic acid is an important intermediate in the synthesis of perindopril.Therefore,the research and development of efficient and green synthesis of(S)-indoline-2-carboxylic acid is of great significance.In the thesis,we have designed a new route to synthesize(S)-indoline-2-carboxylic acid.Firstly,we use cheap and easily available 2-chlorobenzyl chloride and diethyl acetamidomalonate as starting materials to undergo nucleophilic substitution reaction under alkaline conditions to produce 2-acetylamino-2-(2-chlorobenzyl)diethyl malonate(compound3).Then,compound 3 reacts with propionic anhydride under DMAP catalyst to form2-amino-3-(2-chlorophenyl)propionate hydrochloride(compound 4).Next,compound 4 is esterified with propionyl chloride to give ethyl 2-amino-3-(2-chlorophenyl)propionate hydrochloride(compound 5b);compound 5b is stereoselectively catalyzed by the enzyme HEC-8 to provide a chiral(S)-2-amino-3-(2-chlorophenyl)propionic acid(compound 6).Finally,compound 6 undergoes an intramolecular nucleophilic substitution reaction under Cu Cl catalyst to obtain the targeted product(S)-indoline-2-carboxylic acid(compound 7).The synthesis of compound 6 and compound 7 is the key step in the whole synthesis process.Therefore,this thesis optimizes the process of these two steps.(1)The key intermediate(S)-2-amino-3-(2-chlorophenyl)propionic acid(compound 6)was synthesized by enzymatic dynamic kinetic resolution method.We have screened the process conditions,and obtained the optimized process conditions as follows: substrate concentration is 100 g/L,enzyme is HEC-8,the concentration of HEC-8 is 2 wt%,the bufferconcentration is 0.2 mol/L,the p H regulator is 10% sodium hydroxide solution,the system p H is 7.5,the reaction temperature is 45 ? ± 5 ?,the racemic agent is 5-nitrosalicylic aldehyde and the amount of 5-nitrosalicylic aldehyde is 0.03 eq.The yield of this step was89%,and the ee value of the obtained product product is 99.74%.(2)We optimized the synthesis process conditions of(S)-indoline-2-carboxylic acid(compound 7),and obtained the optimized process conditions as follows: the potassium carbonate dosage was 1.60 eq,and the water mass ratio was 5 g/g?6 g /g,the amount of cuprous chloride is 0.005 eq,and the reaction temperature is 65 ??85 ?.The yield of this step is 85%,the purity of the obtained product(compound 7)is 98.46%,and the ee value is96.52%.The synthetic route in this thesis has the advantages of mild reaction conditions,low cost,high yield,high optical purity,and environmental friendly.It can promote the industrial production of(S)-indoline-2-carboxylic acid.