Montelukast production

Leuko trienes are bronchoconstrictive substances released by the body during the inflammatory process. When leukotriene production is inhibited, bronchodilation is facilitated. Zileuton acts by decreasing tire formation of leukotrienes. Although the result is tire same, montelukast and zafirlukast work in a manner slightly differently from that of zileuton. Montelukast and zafirlukast are considered leukotriene receptor antagonists because they inhibit leukotriene receptor sites in the respiratory tract, preventing airway edema and facilitating bronchodilation. 

Rozzell, D.,Enz3fmatic production of the key montelukast intermediate. Spec. Chem.Mag., 2008, April, 36-38. 

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. 

Several commercial products have been produced via Heck reactions on a scale in excess of one ton year"1 [43]. The sunscreen agent 2-ethylhexyl-p-methoxycinna-mate has been synthesized on a pilot scale by using Pd/C as the catalyst [44]. Albermarle produces Naproxen via a Heck reaction of 2-bromo-6-methoxy-naphthalene with ethylene, followed by carbonylation of the product [45]. A key step in the production of Singulair (montelukast sodium), a leukotriene receptor antagonist for treatment of asthma, is Heck reaction of methyl 2-iodobenzoate with an allylic alcohol to give a ketone [43]. 

Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect. 

SingiJair (Montelukast sodium). Merck Sharp Dohme Ltd UK Summary of product characteristics, November 2006. 

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. 

Formation of this product, in the Heck coupling reaction, is the consequence of the migration of the C=C bond repeatedly observed in this catalytic reaction [21], and transitory formation of the enol form of ketone 15. Reduction of this ketone to the S-enantiomer of benzylic alcohol 16 is the key step on the path to the (R)-enantiomer of montelukast 1. The second Grignard reaction (vi), with subsequent activation of the benzylic OH group (vii) and protection of ferf-OH group (viii) afforded the first key intermediate 18. 

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. 

An inexpensive source of reducing equivalents is a prerequisite for a cost-effective commerdal-scale process that uses a CRED. Typically this is achieved by using an inejqtensive alcohol, for example t50-propanol, as the source of hydride The commercial example of montelukast, described later, used this approach to achieve excellent final yields, together with an insoluble product that precipitated from the reaction mixture. 

The bioreduction step for the production of montelukast key intermediate is shown in Scheme 6.2. The key step is the stereoselective reduction of ketone 8 to the S-configured alcohol 9. The alcohol subsequendy undergoes an S 2 displacement with a thiol to give the J -configured final product. 

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