The chemical name of sildenafil is 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1- methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and its formula is C22H30N6O4S. The melting point of sildenafil is 189-190oC. Its solubility is 3.5 mg/mL in water.
The 1H NMR data of sildenafil is given below. The abbreviations used are s for singlet, d for doublet, t for triplet and q for quartet. The chemical shifts are given in ppm (parts per million) and are followed by the number of Hydrogens the peaks account for:
Sildenafil, sold as Viagra and other trade names, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. Its effectiveness for treating sexual dysfunction in women has not been demonstrated.
Common side effects include headaches and heart burn, as well as flushed skin. Caution is advised in those who have cardiovascular disease. Rare but serious side effects include prolonged erections, which can lead to damage to the penis, and sudden-onset hearing loss. Sildenafil should not be taken by people who take nitrates such as nitroglycerin, as this may result in a severe and potentially fatal drop in blood pressure.
It was originally discovered by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett. Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (Cialis) and vardenafil (Levitra).
The preparation steps for synthesis of sildenafil are:
- Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
- Hydrolysis with aqueous NaOH to free acid
- Nitration with oleum/fuming nitric acid
- Carboxamide formation with refluxing thionyl chloride/NH4OH
- Reduction of nitro group to amino
- Acylation with 2-ethoxybenzoyl chloride
- Sulfonation to the chlorosulfonyl derivative
- Condensation with 1-methylpiperazine.
The synthesis of sildenafil citrate was first reported in the Bioorganic & Medicinal Chemistry Letters, Vol 6, pp. 1819, 1824, 1996. The reaction scheme is reproduced below. Sildenafil was reported in this journal as “a potent and selective inhibitor of type 5 PDE with utility for the treatment of male erectile dysfunction”.
|he first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product.
This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5′-position of the phenyl ring. This can then couple with an amine to give sildenafil (7).
The yield of each step is given on the reaction scheme.
This is the original synthesis which was reported in the literature when the molecule was first synthesised. A variant of the synthesis was published but the changes it involved only consisted in the change of a few reactants, and no major changes were reported. This synthesis appeared in the January 1999 issue of Chemistry in Britain. This journal only reported the original discovery synthesis and said that the synthesis used commercially had not been published.
The drug is commercially manufactured by an alternative route. The reaction scheme is described in the patent which was published on 17 decembre 1997. However, the synthesis used in the commercial manufacture could be different to this. The patent was filed by the Pfizer Research and Development Company. The scheme is reproduced below.
The synthesis was described in a lot of detail, including the solvents that were the best to use, however, these details have not been reproduced here. These and further details about the synthesis can be found on the original patent document.
The reaction pathway is explained in more detail below.
The reagents employed in the reactions can vary, but the following are among the ones recommended by the submitters of the patent:
Pfizer’s patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013. A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.
In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases. This patent was published in 1993 and expired in 2012. In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.
The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013. No legal barrier exists to doctors prescribing this form of sildenafil “off label” for erectile dysfunction, although the dosage typically required for treating ED requires patients to take multiple pills.
On November 8, 2012, the Supreme Court of Canada ruled that Pfizer’s patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information “to enable any person skilled in the art or science to which it pertains” to produce it. It added further: “As a matter of policy and sound statutory interpretation, patentees cannot be allowed to ‘game’ the system in this way. This, in my view, is the key issue in this appeal.”
Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision. To remain competitive, Pfizer then reduced the price of Viagra in Canada. However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada, on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent. Finally, on April 22, 2013, the Supreme Court of Canada invalidated Pfizer’s patent altogether.
Manufacture and sale of sildenafil citrate drugs known as “generic viagra” is common in India, where Pfizer’s patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), and Zenegra (Alkem Laboratories).
Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer’s patent claim is not widely enforced.
Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer’s price.
Pfizer’s patent on sildenafil citrate expired in Brazil in 2010.
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Official Viagra Website
- Official Viagra UK Website
- Official Revatio Website
- prescribing information for Viagra and prescribing information for Revatio from Pfizer
- FDA Information
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|Systematic (IUPAC) name|
|Trade names||Viagra, Revatio, others|
|Licence data||EMA: , US FDA:|
|Metabolism||Hepatic (mostly CYP3A4, also CYP2C9)|
|Biological half-life||3 to 4 hours|
|Excretion||Fecal (80%) and renal (around 13%)|
|CAS Registry Number|
|PDB ligand ID||VIA (, )|
|Molecular mass||base: 474.6 g/mol|