Application of the Coumarin and Chromones Ring, Chemistry tutorial

Introduction:

While coumarin consists of no anticoagulant activity, it is converted to the natural anticoagulant dicoumarol via a number of species of fungi. This takes place as the result of the production of 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) to the actual anticoagulant dicoumarol, a fermentation product and mycotoxin. This substance was responsible for the bleeding disease acknowledged historically as 'sweet clover disease' in cattle eating moldy sweet clover silage.

The Coumarin is employed in the pharmaceutical industry as a precursor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals alike to dicoumarol, notably warfarin (Coumadin) and some even more potent Rodenticides which work by the similar anticoagulant procedure.

The drugs, cromolyn sodium (or cromolyn) and nedocromil are generally grouped altogether as Chromones (as well termed as cromoglycates). Strictly speaking, cromolyn is a Chromone, while nedocromil belongs to the structural class of pyranoquinolines. Both agents encompass a Chromone ring configuration (that is, one ring in nedocromil, two in cromolyn) and they share numerous clinical features.

Cromolyn was first introduced in Great Britain in the early year of 1970 for severe allergic asthma. Since then, recommendations for its utilization have shifted to milder asthma, where the agent gained greater acceptance. The Chromones are presently listed as alternate initial controller therapies for mild asthma in the national and international guidelines, however inhaled glucocorticoids (as well termed as inhaled corticosteroids or ICS) are the preferred agents. The low incidence of side effects compared to ICS is the leading reason some patients prefer Chromones over ICS.

Warfarin:

The Warfarin is a white crystalline compound, C19H16O4, utilized as a Rodenticide and as an anticoagulant. (As well acknowledged under the brand names Coumadin,  Marevan,  Jantoven, Lawarin, Waran and Warfant) is an anticoagulant. This is most likely to be the drug popularly termed to as a 'blood thinner', yet this is a misnomer, since it doesn't influence the thickness or viscosity of the blood. Rather, it acts on the liver to reduce the quantity of some key proteins in blood which allow blood to clot.

This was initially marketed as a pesticide against rats and mice and is still popular for this purpose; however more potent poisons like brodifacoum have since been developed. Some years after its introduction, warfarin was found to be efficient and comparatively safe for preventing thrombosis and embolism (that is, abnormal formation and migration of the blood clots) in numerous disorders. This was approved for the use as a medication in the early 1950s and has remained popular ever since; warfarin is the most broadly prescribed anticoagulant drug in North America.

In spite of its effectiveness, treatment by warfarin has some inadequacies. Many generally employed medications interact by warfarin, as do some foods (specifically fresh plant-based foods containing vitamin K), and its activity has to be monitored through blood testing for the international normalized ratio (INR) to make sure an enough yet safe dose is taken.

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Fig: Structure of Warfarin

Warfarin is mainly employed to reduce the tendency for thrombosis or as secondary prophylaxis (that is, prevention of further episodes) in such individuals that have already made up a blood clot (thrombus). Warfarin treatment can help prevent formation of future blood clots and help decrease the risk of embolism (that is, migration of a thrombus to a spot where it blocks blood supply to the vital organ).

=> Racemic synthesis:

A classic manner of synthesizing racemic warfarin is via the base (or acid) catalyzed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone either in the water or piperidine.

2197_Synthesis of Racemic Warfarin.jpg

Fig: Synthesis of Racemic Warfarin

The method for this reaction is as shown below:

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Fig: Mechanism for racemic warfarin

The result for this synthesis whenever carried out in water (4-8 h reflux) is usually 40 %. Higher results can be obtained via carrying out the reaction in methanol (20 h reflux), isolating the product made up and hydrolyzing with acid. Typical results are 93%.

There has been increasing interest in the pharmaceutical industry to substitute existing racemic drugs via their pure enantiomeric form because of the fact that one enantiomer often consists of a pharmacological profile superior to the race mate. In this case, S-warfarin is found to be 5 times more potent as the anticoagulant as compare to R-warfarin. The preparation of enantiomerically pure warfarin can be made up by the classical resolution of the race mate employing quinidine/quinine salts or chromatographic separation. Though, such methods are limited to the small scale preparations.

1) Asymmetric hydrogenation:

In the year 1996, researchers at the Dupont Merck pharmaceutical company build up a practical asymmetric synthesis of R- and S- warfarin starting from the racemate and employing DuPHOS-Rh(I) catalyzed hydrogenation (figure given below).

By using this process, S-warfarin was obtained in 83% enantiomeric excess (e.e), and R-warfarin in 86% e.e

2430_Asymmetric Synthesis of R- and S-Warfarin.jpg

Fig: Asymmetric Synthesis of R- and S-Warfarin

2) Hetero-Diels-Alder cycloaddition

The prior synthesis utilized racemic warfarin as its starting material. A novel approach to asymmetric synthesis of warfarin by employing simpler starting materials was developed in the year 2001. It carries on by a hetero-Diels-Alder cycloaddition (figure shown below).

2407_Asymmetric Synthesis of Warfarin by Hetero-Diels-Alder Cycloaddition.jpg

Fig: Asymmetric Synthesis of Warfarin by Hetero-Diels-Alder Cycloaddition

In the above reaction, S-warfarin was obtained in 95 % e.e

Sodium Cromoglycate:

Cromolyn, a synthetic compound, slows downs antigen-induced bronchospasms and, therefore, is employed to treat asthma and allergic rhinitis. Cromolyn is employed as an ophthalmic solution to treat conjunctivitis and is taken orally to treat the systemic mastocytosis and ulcerative colitis.

Cromolynn (USAN) (as well termed to as cromglicic acid (INN), cromoglycate (former BAN), or cromoglicate) is traditionally illustrated as a mast cell stabilizer, and is generally marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the discharge of inflammatory chemicals like histamine from the mast cells.

Due to their convenience (and apparent safety), leukotriene receptor antagonists have mainly substituted it as the non-corticosteroid treatment of choice in the treatment of asthma. Cromoglicic acid needs administration four times daily, and doesn't give additive benefit in combination by inhaled corticosteroids.

187_Sodium Cromoglycate.jpg

Fig: Sodium Cromoglycate (5,5′-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxylic acid)

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