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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:

1H NMR data:
peak (ppm) integration multiplicity
0.94 3H t
1.32 3H t
2.15 3H s
2.35 4H broad s
2.76 2H t
2.88 4H broad s
4.14 3H s
4.18 2H q
7.36 1H d
7.80 2H multiplet
12.16 1H broad s

Sildenafil, sold as Viagra and other trade names, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.[1] Its effectiveness for treating sexual dysfunction in women has not been demonstrated.[1]

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.[1]

It acts by inhibiting cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis.

It was originally discovered by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett.[2][3] Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (Cialis) and vardenafil (Levitra).


Chemical synthesis

Dunn PJ (2005). “Synthesis of Commercial Phosphodiesterase(V) Inhibitors”. Org Process Res Dev 2005 (1): 88–97. doi:10.1021/op040019c.

The preparation steps for synthesis of sildenafil are:[40]

  1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
  2. Hydrolysis with aqueous NaOH to free acid
  3. Nitration with oleum/fuming nitric acid
  4. Carboxamide formation with refluxing thionyl chloride/NH4OH
  5. Reduction of nitro group to amino
  6. Acylation with 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonation to the chlorosulfonyl derivative
  9. 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.
Compound 2 can be prepared by the chlorosulphonation of 2-ethoxybenzoic acid (1). The conversion of compound 2 to compound 4 is achieved by N-sulphonation of 1-methylpiperazine and may be conducted in a one or two step procedure. Coupling of compound 4 with compound 6 can be achieved by any of the known amide bond-forming reactions. The aminopyrazole (6) is obtainable by the conventional reduction of the corresponding nitropyrazole (5). The resulting solution of compound 6 may be used directly after filtration in the coupling reaction with compound 4.
The cyclisation of compound 7 to give sildenafil has been achieved in yields up to 95%. Thus the overall yield of sildenafil based on compound 1 as a starting material, depending on whether the one or two step sulphonylation procedure is used can be as high as 51.7% or 47.8% respectively. This compares favourably with the first synthesis in which the overall yield is 27.6%.
The cyclisation of compound 7 to sildenafil can be conducted under neutral or acidic conditions. Under neutral conditions, compound 7 is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or mechanical water removal system. Under acidic conditions, the reaction is carried out with a prolic acid or Lewis acid optionally in the presence of a solvent.

The reagents employed in the reactions can vary, but the following are among the ones recommended by the submitters of the patent:
The first step is the chlorosulphonylation of 2-ethoxybenzoic acid. This can be achieved by reacting 1 equivalent mole of thionyl chloride with 4 equivalent mole of chlorosulphonic acid. Addition of 1-methylpiperazine to an aqueous suspension of compound 2 is a suitable reaction to obtain compound 4 in one step. The carboxylic function of compound 4 can be activated using a 5% excess of N,N’-carbonyldiimidazole in ethyl acetate. This intermediate can then be reacted with imidazolide and compound 6. Compound 6 is obtainable by reduction of the corresponding nitropyrazole 5 for example by using palladium catalysed hydrogenation in ethyl acetate. Compound 7 is then cyclised to complete the reaction scheme and give sildenafil.
Information about the synthesis used to manufatcure Viagra was not available, and the two presented above are only the ones which were published. It is not surprising that the commercial manufacture of the drug is by a pathway that is not published.



Figure imgf000007_0001

Example 1
Preparation of 2- hydroxy-5-(4 methyl)-l-piperazinyl sulphonyl) benzoic acid Step-1: Preparation of 5-Chlorosulfonyl-2-hydroxy benzoic acid
To the chilled chlorosulfonic acid (1012 g), salicylic acid (200 g) was added at 0-50C over a period of 1 hour 40 min. The temperature of the reaction mixture was maintained at 20-250C for 2 hrs. Then thionyl chloride (172.4 g) was added over a period of 15 min and maintained for 12 hrs. The product formed was poured onto ice and maintained for lhr. The product was filtered and washed with DM water to get 5-Chlorosulfonyl-2- hydroxy benzoic acid.
Step-2: Preparation of 2-hydroxy-5-(4-methyI)-l-piperazinylsulphonyl)benzoic acid
5-Chlorosulfonyl-2-hydroxy benzoic acid (40Og) obtained in step 1 was dissolved in acetone (1200 ml) and cooled to 5-100C. To this clear solution N-methyl piperazine (254 g) was added and maintained for 2 hrs. The product formed was filtered, washed with water and purified in methanol to get 308 g of the titled compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 2.78 (3H, s), 3.17 (8H, brs), 6.85(1H, d, J = 8.7),
7.52 – 7.56 (IH, dd, J=8.7, 2.7), 7.95 (IH, d, J = 2.7)
13C-NMR (75 MHz in DMSO-d6): δ 41.98, 43.36, 51.60, 117.58, 118.33, 119.46,
130.28, 132.01, 167.63, 170.35.
Melting point: 268-2720C
Purity by HPLC: 99.4% Example 2
Preparation of 4-[2-hydroxy-5-(4-methyI-l-piperazinyIsulphonyl)benzamido]-l- methyl-3-n-propyl-lH-pyrazole-5-carboxamide
2-Hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid (10Og) was dissolved in dichloromethane (500 ml) and triethylamine (50 ml) followed by distillation to get residual mass. The residual mass was dissolved in dichloromethane (1500ml) followed by the addition of 1,3-dicyclohexylcarbodiimide (75.6 g) and 1-hydroxybenzotriazole (45g). The reaction mixture was stirred at 27-280C and then 4-amino-l-methyl-3-n-propyl- pyrazole-5-carboxamide (60.6 g) was added. The reaction mixture was heated to reflux temperature and maintained for 3 hours. Filtered the undissolved material at hot and washed the cake with dichloromethane (200ml). The filtrate was distilled out completely to get residue. Dissloved the residue in methanol (300ml) at 4O0C and then cooled the mass to 27-280C and stirred overnight. Further, cooled the mass to 5-70C and stirred for lhr. Filtered the product and washed the cake with chilled methanol (100ml) and dried to get 130 g of title compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.87 (3H, t, J = 7.5), 1.53-1.60 (2H, m), 2.39- 2.46(5H, m), 2.72 (4H, brs), 2.96 (4H, brs), 3.17 (3H, s), 3.91 (3H, s), 6.93 (H, d, J = 8.7), 7.57-7.61 (H, dd, J=8.7 & 2.1), NH2-(2H, brs, J =7.69 & 7.72), 8.15 (IH, d, J=2.1) 11.5 (OH, br).
13C-NMR (75 MHz in DMSO-(I6): 613.80, 21.37, 27.45, 44.05, 44.75, 48.60, 52.87, 116.37, 118.06, 119.67, 120.03, 130.64, 132.17, 132.38, 146.16, 160.83, 166.33, 166.89.
Purity by HPLC: 97.5%
Example 3
Preparation of 5-[2-hydroxy-5-(4-methylpiperazinyl-l-yl-sulphonyl)phenyl]-l- methyl -3-n- propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one Sodium hydroxide (34 g) was added into diethylene glycol (780ml) and then heated to 110-1150C. 4-[2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzamido)-l-methyl-3-n- propyl-lH-pyrazole-5-carboxamide (130 g) obtained from example 2 was added to the above reaction mixture. The reaction mixture was maintained at 125-13O0C for 4-6 hrs. The reaction mixture was cooled to room temperature and then DM water (1300ml) was added slowly over 20min at 250C and maintained at this temperature for 1 hour. Filtered the mass and filtrate pH was adjusted to 6.5-7.5 with dilute hydrochloric acid at room temperature and stirred at room temperature for 2-3hrs. Product was filtered and slurried the cake with excess DM Water followed by purification in methanol to get 91 g of titled compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.96 (3H, t, J=7.2), 1.71-1.83 (2H, m), 2.41 (3H, s), 2.78-2.83 (6H, m), 2.99 (4H, brs), 4.15 (3H3 s), 6.93 (IH, d, J=8.7), 7.54-7.57 (IH, dd, J=8.7, 2.1), 8.47 (lH, d, J=2.1).
13C-NMR (75MHz in DMSO-d6): 513.84, 21.52, 27.20, 37.80, 43.94, 44.72,- 52.80, 115.97, 119.82, 120.19, 124.48, 128.71, 131.13, 136.46, 143.82, 151.26, 154.05, 167.24.
Purity by HPLC: 97.8%
Example 4
Preparation of 5-[2-ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyI)phenyl]- l-methyI-3n-propyI-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one
5-[2-hydroxy-5-(4-methylpiperazinyl-l -yl-sulphonyl)phenyl]- 1 -methyl-3 -n- propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (90 g) obtained from example 3 was dissolved in dichloromethane (360 ml) and added triethyl amine (41 ml) at room temperature and stirred for 10 min. The reaction mixture was cooled to 0-50C and followed by the addition of ethyl chloro formate (24ml) over 30 min under nitrogen atmosphere. The temperature of the reaction was raised slowly to 28-3O0C and maintained for 24 hrs. The reaction mixture was cooled to 0-50C and kept it for 1 hr. The product formed was filtered, washed with dichloromethane, dried and purified from methanol (270ml) to obtain 81 g of the title compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.92 (3H, t, J=7.2), 1.17 (3H, t, J=7.2), 1.68-1.75 (2H, m), 2.16 (3H, s), 3.99 (4H, br), 2.73 (2H, t, J=7.0), 4.12-4.19 (2H, t, J=6.9), 4.15 (3H, s), 7.71 (IH, d, J = 8.7), 7.93-7.97 (IH, dd, J=8.7 & 2.1), 8.01 (IH, d, J=2.0)
13C-NMR (75 MHz in DMSO-d6): 513.47, 13.80, 21.57, 27.03, 37.90, 45.72, 53.49, 65.12, 124.51, 127.65, 130.14, 130.61, 132.82, 137.30, 144.96, 146.51, 151.38, 151.66, 154.36.
Purity by HPLC: 98.6%
Example 5
Preparation of 5-[2-ethoxy-5-(4-methyl piperazine-l-ylsulfonyl)phenyl]-l-methyl-3- n-propyl-1 ,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (Sildenafil base)
5-[2-Ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyl)phenyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (50g) was dissolved in ethanol (750ml) in an autoclave and then added dicyclohexylcarbodimide (29.8g). The reaction temperature was raised to HO0C with internal pressure of 1.8-4.0 kg/cm and maintained for 6 hours followed by cooling to room temperature. The solvent was distilled off to get the crude Sildenafil base. The base thus obtained was dissolved in dichloromethane (380ml), filtered and filtrate was distilled out completely to get solid material, which is again dissolved in a mixture dichloromethane and isopropyl ether. The crude obtained was recrystallized from ethanol (260ml) to obtain 17.4gm of pure Sildenafil base.
Purity by HPLC: 99.77% Example 6
Preparation of 5-[2-Ethoxy-5-(4-methylpiperazine-l-yI-sulfonyl)phenyl]-l-methyl- 3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil Citrate)
Sildenafil base (50 g) was dissolved in acetone (850 ml) at 550C and then slowly added citric acid solution (20 g in 100 ml acetone) over 45 min and maintain the reaction mixture for about 30 min. The reaction mixture was cooled, filtered and dried to get 65 g of Sildenafil citrate.
Purity by HPLC: 99.85%

Chemical synthesis









European Union

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.[53][54][55] 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.[56][57]

United States

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[58] 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.[59] 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.[60]

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.[61] 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.


In Canada, Pfizer’s patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.[62][63]

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.”[64]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[65][66][67] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[68] However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[69] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[70] Finally, on April 22, 2013, the Supreme Court of Canada invalidated Pfizer’s patent altogether.[71]


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.

Other countries

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.[72]

Pfizer’s patent on sildenafil citrate expired in Brazil in 2010.[73]


External link

Official Viagra Website

Systematic (IUPAC) name
Clinical data
Trade names Viagra, Revatio, others
AHFS/ monograph
MedlinePlus a699015
Licence data EMA:Link, US FDA:link
  • US: B (No risk in non-human studies)
Legal status
Routes of
Oral, IV
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic (mostly CYP3A4, also CYP2C9)
Biological half-life 3 to 4 hours
Excretion Fecal (80%) and renal (around 13%)
CAS Registry Number 139755-83-2 Yes
ATC code G04BE03
PubChem CID: 5281023
DrugBank DB00203 Yes
ChemSpider 56586 Yes
KEGG D08514 Yes
ChEBI CHEBI:58987 Yes
Chemical data
Formula C22H30N6O4S
Molecular mass base: 474.6 g/mol


1 Comment

  1. Thanks for the information. it will help me.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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