The Design And Synthesis Of Montelukast's Intermediates

Bronchial asthma is a kind of chronic inflammatory airway diseases as many kinds of cells and cellular components involved in. There are about 160 million patients all over the world. National prevalence rate are different in different countries. The study of international childhood asthma and allergic disease showed that the prevalence rate of 13 to 14 years-old children with asthma is about 0~30% , the studies about the treatment with the similar age children of the five large cities of China showed that the incidence of asthma for children is about 3% ~ 5%. Prevalence rate of children is higher than its of young adults, its rate of older age groups has the trendency to increase. The prevalence rate of adult men and women are basically the same, it's higher in the developed country than its'in the developping country, it's higher in the city than its'in the countryside. The pathogenesis of asthma is associate with various of the cytokines from cell secretion and the inflammatory mediators, of which leukotriene is a major inflammatory cytokines that causes the airway contraction. Leukotriene receptor antagonists can effectively block or inhibit the synthesis of leukotrienes ,it can be used for the treatment of asthma. At present the first-line clinical using drug for asthma is inhaled corticosteroids, but the treatment of some special types of patients (such as children and the one who are allergic to aspirin) with the inhaled corticosteroids were ineffective, and the long-term use of the drugs of corticosteroids will induce adverse effects such as osteoporosis. Clinical trial results showed that the leukotriene receptor antagonists (eg. Montelukast. already launched) and glucocorticoid used in combination, not only can enhance the therapeutic effect on asthma, but also control the asthma that glucocorticoid hormones can not effectively treat alone. In addition, leukotriene receptor antagonist is also effective for asthma caused by aspirin is or exercise. Therefore, to find a suitable leukotriene receptor antagonist has a significance meaning for the treatment and relieve asthma.By the study of the structure-activity relationship of the leukotrienes, we found that the molecule which has a structure that similar to the chain of the leukotrienes will play the similar role as leukotrienes, after appropriate structural modification, this molecule can be expected to be used as a bronchial asthma drug for asthma treatment. Following the result of the study, Merck has designed a new molecule refer to the leukotriene receptor antagonist which was already launched in different countries as the brand name of Singular. The experiment results both in vivo and in vitro all indicated that Montalukast can inhibit the inflammatory affect of LTD4,histamine and 5– HT, thus inhibit the bronchoconstriction to treat the asthma. CompoundⅠis a significant intermediate for the synthesis, its chemical name is 2-(3-(2-(7-Cl-2-quinolyl)- vinyl) phenyl)-(3-carbonyl) propyl) methyl benzoate, this intermediate could be made to get the Montelukast via 2 or 3 synthesis process steps, so the synthesis of this intermediate is important for the whole process of industrialaization and the enlarge of the production , by the way this intermediate can be sold as a commodity or be used directly, so the synthesis of intermediates for the synthesis of montelukast in the whole process of industrialization or even to enlarge the future production is important, and that the intermediates can be directly used as a commodity for sale and therefore has the intermediate process of economic significance,so the study of this intermediate has the meaning for the economic.In this paper, we describe the design and the process of the synthesis of the compoundⅠ. In accordance with the published reference and improvement, we design and modify the synthetic route. According to the synthetic methods reported in the literature, we designed three synthetic routes. The final products of each step was test by NMR, IR, MS and other test devices, and the results confirmed the structures are correct. In addition, our study has optimizated the first step of the whole process,we considerated the solvent, temperature, reaction time and the condition of the purification.Finally, the reaction condition we established has raised the yield and the content of the final product.In this paper we choose the best synthetic route in order to decrease the reaction steps and the time, the raw materials are easy to buy, and after the optimization of the reaction, the cost of the reaction has been greatly cutted down, the yield has been improved, all of above are positive to the industrial production and the economy.