Montelukast , synthesis

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

Montelukast sodium (3) has the (R) absolute configuration and its synthesis was first descnbed by Labelle et The synthesis of the side-chain commenced with... 

Synthesis of fluticasone propionate 14.3 Synthesis of salmeterol xinafoate 14.4 Synthesis of montelukast sodium 14.5 References... 

Leukotriene inhibitors, one leukotriene inhibitor blocks leukotriene synthesis by inhibiting the action of 5-lipooxygenase (Zileuton Zyflo). Another blocks leukotriene receptors on the surface of smooth-muscle cells and eosinophils (Montelukast Singulair). 

Two clinically distinct cysteinyl leukotriene receptor antagonists (zafirlukast and montelukast) and one inhihitor of leukotriene synthesis (zUeuton) have been available in the United States since 1996 for both children and adults with persistent asthma. In challenge studies, they reduce allergen-, exercise-, cold-air hyperventilation-, irritant-, and aspirin-induced asthma. Chnical use of zileuton is limited owing to the need for four-times-daily dosing, the potential for elevated liver enzymes (especially in the first 3 months of therapy), and the potential inhibition of drugs metabolized by the CYP3A4 isoenzymes. ... 

The reduction shown below is particularly important because it generates a late intermediate in the industrial synthesis of the anti-asthma drug montelukast (Singulair). Several methods have been used, but in 2008 chemists at the Croatian pharmaceutical company Pliva patented a method using the ruthenium catalyst with a derivative of TsDPEN as a ligand to gives the product in 83% yield and 99.8% ee on a scale of several kilograms. 

The Cilag resolution of the pyridyl amino acid is described in Org. Process Res. Dev. 2001, 5, 23. For an informative comparison of different auxiliary and catalytic methods for the synthesis of a simple chiral carboxylic acid, see Org. Process Res. Dev. 2003, 7, 370. For a leading reference to the use of enzymes to reduce ketones, see the account of the Codexis work on montelukast in Org. Process Res. Dev. 2010, 14, 193. The spectacular synthesis of discodermolide by Novartis using a series of aldol reactions is described in Org. Process Res. Dev. 2004, 8, 92, 101 and 107. 

Scheme 11.1 Initial steps en route to montelukast sodium synthesis of intermediate (S)-18...

Scheme 11.9 Synthesis of the cyclopropane-derived building block 26 on the path to montelukast...

With thiol 26 available, the process was improved using free acid 28 as a thiolating agent, and non-THP protected (5)-27 (Scheme 11.10). Formation of the C-S bond in (S)-27, with inversion of the configuration, is the last cracial step in the synthesis of montelukast. It was soon observed that the original conditions for steps i and ii in Scheme 11.10 needed improvement, since the yield of montelukast in the product mixture was regularly low and large quantities of the side-products 29 and 30, up to 60%, were observed [36]. 

Alcohol 17 is a key intermediate in the synthesis of Montelukast, a broadly used drug in the therapy of asthma. The biological aclivily of (/ )-enantiomer is much higher than that of (5)-enanliomer therefore, the direction of enantioselectivity and optical purity of the product are cmcial for the technological feasibility of this synthetic step. For dmgs used in human therapy in the optically pure form, an optical purity of 98-100 % e.e. is required. 

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