Sildenafil VIAGRA Pfizer

The chemical development of the commercial route to sildenafil also serves as an excellent example of the different issues that need to be considered when moving from drug discovery to commercial quantities. This problem is therefore based on the commercial synthesis of sildenafil as published by the Pfizer research group around P. J. Dunn  

Pyrazoles are very common parts of commercially available pharmaceuticals, agrochemicals and dyestuffs. The reaction of fi-diketones with hydrazines is the most widely used method to synthesize pyrazoles. The reaction proceeds via the formation of hydrazone 13 which on subsequent cyclization and dehydration produces the corresponding pyrazole 2. This method usually has the disadvantage that with unsymmetrical diketones generally a mixture of isomeric pyrazoles is formed. Here the authors report no other isomer probably because of the great electronic differences of the two ketones being substituted with an ester vs. an alkyl group. 

Me2S04 is used under basic conditions as source of a methyl nucleophile. It can thus transform alcohols into methyl ethers or transform amines into the methylamine. Usually a phase transfer catalyst such as tetrabutylammonium iodide is added to the aqueous basic solution.4 Other reagents to create methyl ethers include iodomethane or trimethoxonium tetrafluoroborate (Meerwein s reagent).5 

Ester hydrolysis can proceed under acidic or basic (saponification) conditions to the carboxylic acid. In this case aqueous NaOH is used. The order of reaction, methylation before saponification, both under basic conditions, is presumably important since the free acid would be again methylated by Me2S04 

This reaction is the most dangerous in the commercial synthesis since it requires at least 50 °C to start, and once the reaction starts it is very exothermic. This would increase the heat under adiabatic conditions still further until at 120 °C the carboxylic acid would decarboxylate in another exothermic reaction creating C02 gas thus increasing the pressure in the reactor. The research group at Pfizer designed the 

Pyrazoles are very common parts of commercially available 

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Very often, drugs are discovered through persistent work and continual optimization and many tests and trials. This is exemplified by the history behind the discovery of sildenafil (Viagra, Pfizer), a drug for the treatment of erectile dysfunction, and the AIDS drug zidovidine (Retrovir, GlaxoSmithKline) (Exhibits 3.18 and 3.19). 

The pyrazolopyrimidinone derivative sildenafil (Viagra /Pfizer), the indolopyrazinone... 

Sildenafil (Viagra , Pfizer), the first drug effective in male erectile dysfunction (MED), has a very interesting history. More than 30 years ago, the company May Baker started research on antiallergic xanthine derivatives [19]. Their first leads 27... 

Exhibit 4.8). Botulinum toxin (Botox) is being injected as an anti-wrinkle treatment (Exhibit 11.11), and a vitamin A derivative (Retin-A gel, Tretinoin) is prescribed for the treatment of facial wrinkles. Drugs such as tacrine and donepezil, which work by attacking enzymes that breakdown acetylcholine, have been approved for boosting memory. Sildenafil (Viagra, Pfizer) is used to treat sexual dysfunction (Exhibit 3.15). 

The pharmaceutical businesses produce drugs and medicinal products of many kinds. One of the great revolutions of modern life has been the expectation that humans will survive diseases because of a treatment designed to deal specifically with that disease. The most successful drug ever is ranitidine (Zantac), the Glaxo-Wellcome ulcer treatment, and one of the fastest-growing is Pfizer s sildenafil (Viagra). Success refers both to human health and to profit ... 

Pfizer s Sildenafil (Viagra ) has attracted world-wide attention as a drug for the treatment of male erectile dysfunction."-12 Our synthesis of this important molecule (Scheme 9) demonstrates the principles of using supported reagents in both a sequential and convergent fashion.13 We believe that these concepts could be easily extended to encompass the synthesis of many other chemical substances in target directed synthesis or in a multi-parallel mode. 

Sildenafil citrate Viagra Pfizer Oral tablet 25, 50,100 mg... 

Sildenafil Citrate Viagra Pfizer OBS Erectile dysfunction... 

Sildenafil citrate (VIAGRA, Pfizer Inc.) is an oral therapy for erectile... 

Viagra (Sildenafil cittate). Pfizer Ltd. UK Summaiy of product characteristics, June 2006. 

Viagra (Sildenafil citrate). Pfizer Inc. US Prescribii information, October 2006. 

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