The Synthetic Study Of Montelukast’s Intermediates

Asthma is a common chronic respiratory disease. As a main asthma drug, Montelukast has high efficiency and good security, which has a good market prospect in the field of medicine. Recent, the key intermediate, Methyl(E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl] phenyl]-3-oxopropyl]benzoate(EA3), in the procedure of Montelukast, has drawn a lot of attention.The common process in synthesizing EA3 is start from (E)-1-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-1-ol(EA2) via Heck coulping. There are still some shortcomings in reported methods, such as expensive materials, complex catalyst and so on. In order to decrease the cost, this paper used three methods to synthesize EA3 from EA2.Using n-butyl alcohol as solvent, with triethylamine and sodium formate, methyl 2-iodobenzoate and EA2 synthesized EA3 through Heck reaction, the yield was 64.7%, and purity was 94.53% (HPLC). This process used the cheap Pd/C as catalyst, both solvent and catalyst can be recycled. Not only reduced the cost, but satisfied with economic and environmental requirement.Under the protection of N2, with palladium acetate, tri(o-tolyl)phosphine and triethylamine, EA3 was obtained from methyl 2-bromobenzoate and EA2 in n-propyl alcohol, the yield was 51.4%, the purity was 97.14% (HPLC). This method use the cheap methyl 2-bromobenzoate as start material and the simple catalytic components.Intermediates EA3 was prepared from EA2 and arenediazonnium tetrafluoroborate. After optimized the conditions, we found that more undesire byproducts still occurred with EA3. Therefore it not a suitable method in larger scale.