Syntheses Of A Key Intermediate Of Montelukast And A Natural Product Pseudorubrenoic Acid A

This paper were focused on the syntheses of Methyl-(E)-2-[3-[3-[2-(7-Chloro-2-quinolinyl) ethenyl]phenyl]-3-oxopropyl]benzoate which is an important intermediate of Motelukast. and Pseudorubrenoic acid A which was a natural product probably with the activity of bronchiectasis.Motelukast was invented by Merck in recent years, it is a highly selective cysteinyl leukotriene (Cys-LT) receptor antagonist, that can restraint the binding of leukotriene D4 and Cys-LT1 receptor.Montelukast not only can improve the lung function of the patients with asthma, but also can play an important role in anti-inflammatory and immune.Motelukast was first launched to market in Finland and Mexico in February of 1998. The target compound was synthesized from 3-bromobenzaldehyde by a seven-step procedure with an overall yield of 50%. Firstly, the aldehyde group of 3-bromobenzaldehyde was protected by glycol, and then the production was prepared to Grignard reagent which reacted with acetic anhydride to afford 1-(3-(1,3-dioxolan-2-yl) phenyl)ethanone. Afterwards, with the help of NaH, the intermediate was condensated with dimethyl carbonate to generate Methyl 3-(3-(1,3-dioxolan-2-yl)phenyl)-3-oxopropanoate. Next, the compound reacted with methyl 2-(bromomethyl)benzoate to get Methyl 2-(2-(3-(1,3-dioxolan-2-yl) benzoyl)-3-methoxy-3-oxopropyl)benzoate. After deprotected with hydrochloric acid the intermediate was decarboxylated following the method of Krapcho decarboxylation to give Methyl 2-(3-(3-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl)-3-oxopropyl)benzoate. Finally, the anticipated product Methyl (E)-2-(3-(3-(2-(7-Chloro-2-quinolinyl) ethenyl)phenyl)-3-oxopropyl) benzoate was obtained through the condensation with 7-chloroquinaldine. The structure of all the intermediates and final product were identified by spectral data 1H-NMR,13C-NMR and MS.Natural products had served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today were derived from natural products. Especially the antibiotics, had become the cornerstone of the modern pharmaceutical industry. Pseudorubrenoic acid A is an antimicrobial carboxylic acid isolated from the soil bacterium Pseudomonas fluorescens. Meanwhile, it probablely has the bronchodilator activity. Due to a wide variety of physiological properties, extensive efforts have been made to synthesize ortho-dialkyl-substituted benzenoid(e.g., Pseudorubrenoic acid A) for the further research. In our study, Pseudorubrenoic acid A was synthesized through two different routes respectively from the raw materials 2-cyanobenzylbromide and 3,4-dihydropyran. In route one, Pseudorubrenoic acid A was synthesized by a nine-step procedure via Wittig reaction, reduction of cyano, Homer-Wittig reaction, Jones' oxidation, etc. with an overall yield of 27%. The key reaction is Homer-Wittig reaction, by which cis-butenyl was obtained. In the second route, cis-butenyl was obtained through the hydrogenation of the alkyne with the catalysis of Lindlar catalyst. The alkyne was converted from cyano by three reactions. The total yield of this ten-step route is 28%. The structure of all the intermediates and final product were identified by spectral data 1H-NMR,13C-NMR and HRMS.