Improved Process for the Preparation of Montelukast: Development of an Efficient Synthesis, Identification of Critical Impurities and Degradants

Abstract

An improved and scalable process for the production of montelukast (Singulair, drug for asthma) based on a new and advantageous method of carrying out the key substitution reaction has been developed. The present procedure is distinguished from the previous solutions in the use of linear or cyclic polyethers, which ensures higher selectivity of the key step. The improved process for the preparation of montelukast is able to minimize a content of impurities and allows the effective production of montelukast and its scale-up.

Copper‐Catalyzed C−S Coupling of Quaternary Ammonium Salts and Dialkylcarbamodithioic Acid Salts

“…Optically active benzyl sulfides exhibit excellent biological activities and are important in medicines including montelukast, cardizem (diltiazem), eflucimibe, and mPEES‐1 inhibitors . These chiral benzylic dithiocarbamates were hydrolyzed using an aqueous KOH solution to give benzylic thiol salts, which were reacted with diverse aryl bromides via aromatic nucleophilic substitution to produce various aryl sulfides with extremely high ee values (95%–99% ee) (Scheme ) …”

Development of an enantioselective capillary electrophoretic method for the simultaneous determination of montelukast enantiomeric and diastereoisomeric forms and its main degradation product

“…MK blocks CysLT 1 , in lungs and bronchial tubes, reducing bronchoconstriction. It was the first leukotriene antagonist receptor granted for its use in children by FDA and it has been widely employed in the last years .…”

“…MK production has been described by several synthetic processes involving a stereoselective synthesis . Thus, MK has a chiral center in the carbon next to the thio side chain, and a double bound, which define both optical and geometric isomers, giving place to four stereoisomeric forms.…”

“…(S)‐trans isomer (Fig. B), an enantiomeric form of MK, is a by‐product of the stereoselective synthesis, therefore the importance of the determination of MK enantiomeric purity .…”

“…MK is also prone to chemical degradation as broadly described but many research groups such as Halama et al. who clearly describe the functional groups and the type of degradation associate to them (Fig. ).…”