Study On Production Process Of Antidepressant Escitalopram

Chiral drugs generally comes from natural product extraction,racemic compound resolution and asymmetric synthesis.Due to its single structure of high optical purity,it is usually characterized with higher selectivity,less side effect and obvious curative effect,and it is an important direction of new drug research.Depression,also known as Major Depressive Disorder(MDD),is a kind of mental disorder caused by monoamine function disorder of the neurotransmitter system.Depression has already been the world's fourth largest disease with a high morbidity,but because of high price of various antidepressants and expensive treatment cost,only about 10% of the patients with depression received drug treatment at present.Escitalopram is a selective serotonin reuptake inhibitors as a kind of new antidepressant drug,joinly developed by Forest Laboratories in the US and Lundbeck in Denmark.Due to its high chiral purity and the advantages of high selectivity,fast effect,mild adverse reactions etc,its market demand is increasing.However,influenced by low yield of the current production process,high cost and environmental pressure,the market price of Escitalopram is very expensive.Through consulting the domestic and foreign literatures,this paper has screened out a production process preparing Escitalopram by chiral source synthesis method and has successfully optimized the process conditions of each step after repeated experimental study.Using racemic citalopram intermediate: 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile(racemic diol)as the starting material,we receive S-diol by resolution;obtain Escitalopram by acylation and cyclization synthesis of S-diol;on the other hand,reveive racemic diol and R-diol by recycling and seperating the residual diol in the resolution mother liquid;cyclicutilization and repeated resolution of the recycled racemic diol;get citalopram products rich in S-configuration by cyclization and configuration inversion with sulfuric acid by R-diol,then,with heptane as the crystalline solvent,we separated racemic citalopram and Escitalopram in the products completely,thus receiving another part of Escitalopram;Escitalopram Oxalate,as the major product with an overall yield increasing from 10.3% in the literatures to 42.4% was prepared from the two parts of Escitalopram combined,salification and recrystallization.At the same time,we have also got some secondary products,Citalopram Hydrobromide,with the yield of 9.1%,and got racemic diol by recylcing,with the yield of 36%.As a result,the optimized process with a material loss rate of only 12.5%,so we has greatly improving the utilization rate of materials.This paper has conducted industrialized pre-production verificaiton with the scale of 100 kg to the optimized process,completed the recycling and reuse of racemic diol,resolution agent and the main solvents and ensured stability and reliability of the process.We have also evaluated the process.The result is that production cost of the materials is less than 1000 yuan per kilogram,the major product,Escitalopram,and the secondary product,Citalopram Hydrobromide,can all reach the quality requirements of EP 8.0.The process is economic,rational and reliable and has practical guiding significance on the implementation of industrialization.