Synthesis Of 1-(Mercaptomethyl) Cyclopropaneacetic Acid As The Intermediate Of Montelukast

Bronchial asthma is one of the most common disease in chronic respiratory diseases. Montelukast is one of the main drugs for the treatment of asthma. Because of its high efficiency, low toxicity and good security, Montelukast gains more and more sharings in the global asthma medicine market. The synthesis of Montelukast is relatively complicated so that the demand of its intermediate increases quickly. Thus, there should be good market prospects for the research of Montelukast intermediates.1-(mercaptomethyl)cyclopropaneacetic acid is one of the most important intermediate of Montelukast. And the synthesis of it has become hotspot in recent years. However, by refering to related literatures, it is not difficult to find that there are common shortcomings in these studies:the price of raw material is relatively expensive so that it leads to the high cost.In this paper, research is carried on the existing synthesis technology of 1-(mercaptometh-yl)cyclopropaneacetic acid. It is synthesized from relatively cheap raw material.Cyclosulfurous ester is obtained from 1,3-dibromo-2,2-bis(hydroxymethyl) propane via sulfonation, zinc reduction, hydrolysis, and substitution reaction. But the reduction generates a large number of by-products instead of target compound.Cyclosulfurous ester is obtained from 1,3-dibromo-2,2-bis(hydroxymethyl) propane via four steps reactions of esterification, zinc reduction, hydrolysis and substitution reaction in overall yield of 34.8%. But the route is long and it is not suitable for industrial production.1-(mercaptomethyl)cyclopropaneacetic acid is obtained from 1,3-dibromo-2,2-bis-(hydroxymethyl) propane via six steps reactions of substitution, zinc reduction, nucleophilic substitution, bromination, salt-forming reaction and hydrolysis in overall yield of 25.5%. Even though the overall yield is not high, it uses the cheap raw material and short synthetic steps so that it has low cost.By a large number of experiments, it is determined the synthesis route which is obtained from 1,3-dibromo-2,2-bis-(hydroxymethyl) propane. The product and related intermediates are confirmed by mp, IR,1H NMR, MS. The whole synthesis step which is short, low cost, and mild reaction condition, is expected to realize industrialization production.