Synthesis Of A Significant Intermediate Of Montelukast And The Structural Modification Of Milbemycins

This thesis were focused on the syntheses of Methyl-(E)-2-[3-[3-[2-(7-Chloro-2-quinolinyl) ethenyl]phenyl]-3-oxopropyl]benzoate, the key intermediate of Motelukast sodium. and the exploratory structure modification of milbemycins which were natural products.Motelukast was one of LTRAs which were received widely attention, it developed by Merck and marketed in the Mexico、USA and other countries unded the trade name Singulair. Montelukast, as a cysteinyl leukotriene receptor antagonist, is one of the first-line drugs of asthma treatment, is generally considered to have a niche application in the therapy of exercise and aspirin induced asthma. As a key intermediate, Methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl) ethenyl)ph-enyl)-3-oxopropyl)benzoate paly a important role in synthesis of Motelukast. In this paper a more efficient strategy was presented to synthesis of the intermediate from isophthalaldehyde with a four-step prodecure and the overall yield was61%. All of intermediates can be purified by simple recrystallization that makes it more suitable for industrial production. In our synthetic strategy, the1,3-di(1,3-dithian-2-yl)benzene was prepared by the reaction of isophthalaldehyde with1,3-propanedithiol-catalyzed by a Lewis acid. Then the dipole reversal of1,3-di(1,3-dithian-2-yl)benzene was achieved by the aid of BuLi and and then reaction with methyl2-(2-bromoethyl)benzoate to give methyl2-(2-(2-(3-(1,3-dithian-2-yl)phenyl)-1,3-dithian-2-yl) ethyl)-benzoate. Afterwards with the help of NBS, the1,3-dithian was removed. Finnally, the condensation of methyl2-(3-(3-formylphenyl)-3-oxopropyl)benzoate with7-chloroquinaldine was carried out to give the final product Methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)--3-o-xopropyl)benzoate-ate.The structure of final product was identified by MS, HRMS,1H NMR,13CNMR and2D NMR.Natural products was the cradle of medical innovation and many drugs derived from natural products.Chemical modification to the active ingredients of nature products was an important measure of drud discovery. The milbemycins are a family of16-membered ring macrocyclic lactones isolated from Streptomyces hydroscopicus by Sankyo in1975, Which are known to possess high anthelmintic and insecticidal activity. many modified derivatives of milbemycins have high bioactivities and have been used in the practical production. In this paper the milbemycinA4was used as a starting material and with the help of activated MnO2it becomed a5-oxomilbemycinA4. Then the product was take off a molecule of water given the5-hydroxy aromatic milbemycinA4. At last the5-hydroxy aromatic milbemycinA4reacted with DDQ to give a novel milbemycins derivative and have a good antibacterial activity but a weak cytotoxic activity. On this basis further research of C-13substituent was made to obtain new chemical compound which may have more better bioactivity. The structure of final product was identified by MS, HRMS,1H NMR,13C NMR and2D NMR. The sutdy not only enrich the types of milbemycins derivatives but also was expected to make the milbemycins as a antibiotics for human use, and have great innovation significance and some practical application value.