For many reasons, this route was assumed suboptimal as a commercial manufacturing for example; it is linear with nine steps, sulphonyl chloride, which is one of the toxic substances produced from this route is in the final bond-forming reaction. Final material required a lot of recrystallizations to reduce the toxic impurities to appropriately low levels in order to produce the high quality of drug required by pharmaceutical company. Due to competing hydrolysis through the increased quenched times on scale-up chlorosulphonation in chemical development; the difficulties of scaling-up reactions are well-known.

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In this route, 2-pentanone and diethyl oxalate are condensed to give the diketoester 1. Then, cyclizating the diketoester by hydrazine produces pyrazole 2 which methylated with selective to give pyrazole3. Hydrolysing the reaction generated the acid 4, then convert acid to the amide by nitration to give nitropyrazole 5, which is common intermediate in all synthetic routes. Reduction of 5 with tin (II) chloride dehydrate to give the amine 6 which is by 2-ethoxybenzoyl chloride was acylated to produce diamide 7. The later was cyclized using aqueous sodium hydroxide and hydrogen peroxide to result in 8 pyrazolo[4,3-d]pyrimidin-7-one. Sildenafil was produced by selective chlorosulfonation and reaction with N-methylpiperazine.(6)
Optimization of the cyclization reaction to make the pyrimidinone was the key finding during the development of the medicinal chemistry route, which impacted on the programme as a whole. Cyclization of compound 4 was done by sodium hydroxide and hydrogen peroxide, which are an aqueous alcoholic solution and lead to moderate yield (30-70%). The hydrolysis of the carboxamide to give the acid either in the presence or absence of the hydrogen peroxide was the main side product from the medicinal reaction. To avoid the hydrolysis side product, cyclization was conducted under anhydrous conditions, KOtBu/ButOH and the reaction continued in 100% product without detected impurities. By considering reordering the steps, the clean cyclization was the final bond-forming reaction. (1)
Modification of the medicinal route:
A lot of modifications were applied into medicinal chemistry route, which was used at the beginning of the project to prepare fifty kilograms and support supply for the four years. (6)
For early scale-up, the tin (II) chloride reduction was removed. Tin is major environmental polluter and a heavy metal. It was replaced with a catalytic hydrogenation. At the early age of the sildenafil production, a tin chloride reduction was employed because the hydrogenation reduction was not in operation. The reason for inefficient of the hydrogenation was a presence of trace levels of sulfur impurities which poison the hydrogenation reaction. Switching to stoichiometric thionyl chloride is one example that controlled sulfur impurities and allows the reliability of the catalytic hydrogenation reaction. Using a hydrogenation, there are options for solvent and catalyst recovery and water is the only by-product. (5)
Hydrogen peroxide was used in cyclization method to convert 7 to 8, but it causes skin burns. Furthermore, in contact with organic materials, it is a fire and transportation hazardous. Then, it was replaced with KOtBu/ButOH. Rather than using oxalyl chloride, thionyl chloride is used to prepare 2-ethoxybenzoyl chloride which eliminates exposure to carbon monoxide emissions by workers. (5)
Through formation of pyrazole 3 which is an exothermic reaction, a solvent was introduced. Moreover, for 5 preparations, toluene was introduced as a solvent which reduces the level of thionyl chloride from 1.6 to 1.8 equivalents. (6)
Sildenafil Citrate
Sildenafil
Commercial Route:
Selection:
The target from Sildenafil citrate was for treatment of angina when entered development. But the clinical results were failed. Pfizer made a trial with 12 patients tolerate from male erectile dysfunction in 1994. The results showed improvements in the problems of 10 patients. As a consequence, sildenafil citrate development became one of the highest priorities in the Pfizer portfolio (6).
There are many advantages of commercial route over the optimized medicinal one, for example;

The synthesis was redesigned to make convergence.
The final bond forming step is the clean cyclisation reaction and at the start of the synthesis, the potentially toxic materials occur.
Large volumes of aqueous acidic waste require an increased level of hydrolysis and neutralization through a larger scale is an example of environmental and scale-up issues associated with chlorosulphonation reaction. In order to reduce these issues, they are placed at the start of the synthesis. Hence, low molecular weight and cheaper materials are used. (5).

DEVELOPMENT:
Sulfonamide preparation:
Through pyrazole 5, many routes of synthesis proceeded.
Using chlorosulfonic acid, 2-ethoxybenzoic acid is Chlorosulfonated by using 1 mol of thionyl chloride to convert the intermediate sulfonic acid to the sulfonyl chloride. Due to low melting point of 2-ethoxybenzoic acid (19-20 C) mp, low molecular volumes of chlorosulfonic acid and thionyl chloride are used and hence no solubilisation. Initially, the sulfonamide 9 was isolated as unusual double salt 10 which is insoluble and difficult to use. Moreover, in order to obtain the double salt to crystallize, the sulphonyl chloride should be dry which lead to a lot of acidic, corrosive fumes in a pilot plant scale. Then, it was discovered that 9 can be isolated as its highly crystalline zwitterions by treatment the double salt with water to dissociate and produce a new form of free crystalline amino acids 8. For efficiency, the sulfonyl chloride was converted to sulfonamide 9 by resuspended in water and reaction with N-methylpiperazine. At the end of the reaction, by the addition of aqueous sodium hydroxide, the pH was adjusted to the isoelectric point and the precipitated compound 8 collected by filtration. As a result, during sulfonamide preparation, no organic solvents are used.
Hydrogenation and coupling reaction:
In medicinal chemistry, the tin (II) chloride reduction was replaced by a palladium catalyzed hydrogenation reaction to convert pyrazole 1 into the amide2. Toluene was introduced as a heat solvent which increased the safety of the process and reduced the levels of thionyl chloride to 1.2-1.6 equivalents. To convert the nytropyrazole (2) to the amine (3) heterogeneous hydrogenation in ethyl acetate was used. A number of reagents, including thionyl chloride, oxalyl chloride and N,N-cabonyldiimidazole (CDI) are used to examine the activation of the carboxylic acid.
CDI costs around 8$/mol and provide such advantages for instances; high quality product, robust and clean chemistry. Furthermore, it provided a combination of the three reactions (hydrogenation, acid activation and acylation) into a single step, employed the ethyl acetate solvent with a simple recovery process and used low energy. In addition, VOC emissions were avoided such as (EtCl) that generated from the interaction of ethyl chloride with thionyl chloride or oxalyl chloride. Moreover, 90% chemical yield over three chemical reactions is produced and optimized to 96%.
Cyclisation Reaction:
The resulting product is heated for several hours and cyclised with 1.2 equivalents of potassium t-BuOH and t-BuOK. In order to minimize the environmental wastes, this process is run at high concentration (2.5-3.75L Kg-1). Water is added to dilute the reaction and the pH was adjusted with 4M HCl to the isoelectric point (7.5). Clinical very high quality yield of 95% sildenafil was obtained by filtration. Using 2-butanone citric acid, sildenafil was converted to sildenafil citrate to give a yield of 99 to 100%.
Sildenafil
History of Sildenafil:
Initially Viagra was developed to treat angina (heart disease). In Morriston hospital, the drug was tried on men in 1991-1992. The clinical observation showed that the drug enhance penile erection more than treating angina. Pharmaceutical company, Pfizer commercialized the drug as a treatment for erectile dysfunction. In 1996, the drug was patented and approved on 27 March 1998 by FDA. It was the first approved drug for penile erection in the United States and the sales exceed 1$ billion in 1999-2001. The Pfizer’s patents on this drug will expire in 2011-2013.
 
Dosage of Viagra:
Viagra could be taken once per day as a dose between 25mg to 100mg between 30 min to 4 hours before sexual intercourse. Three dosages are available in market for this drug (25-50-100) mg with a cost of 10$ per pill for all dosages.
http://www.chemistrydaily.com/chemistry/Sildenafil
Mode of action:
Pharmacodynamics:
Effects on Penile Erection:
Sildenafil citrate is a selective inhibitor of phosphodiesterase-5 (PDE5) and was used for the treatment of the male erectile dysfunction (known as impotence). It is a wide spread condition that effects around 30 million patients in United States. Nitric oxide is released during sexual stimulation and permeates through corpus cavernosum membranes. Then, the enzyme guanylate cyclase is stimulated to enhance levels of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. cGMP has an effects on smooth muscle relaxation and increases blood flow lead to an erection of the penis. Level of PDE5 is high in the corpus cavernosum which hydrolyzes cGMP and leads to inactive GMP. Levels of cGMP in men with impotence are low and as a consequence PDE5 quickly hydrolyses these levels of cGMP. Now, the sildenafil acts by inhibiting the actions of PDE5 and increases the levels of cGMP which cause the erection. (6) figure involved
Erection
Nitric Oxide
Guanylate Cyclase
Sildenafil binds to PDE5 and blocks action
GMP
cGMP
Effects on Visual Function:
In patients taking sildenafil, it has been reported such visual abnormalities for example; increased blurred vision and perception of light. These effects usually happened with dose more that 100mg which is correlated to the weaker inhibition effects of sildenafil on PDE6 that regulates signal transduction pathways in the retinal receptors. (2)
Cardiovascular Effects:
Sidenafil has effects on blood pressures by producing transient reduction in systolic and diastolic at 1 hour after the dose. The clinical tests showed no observed effects on heart rate. Sildenafil effects are not age or dose dependent. (2)
Clinical trials:
The sildenafil was tested in vitro to study the inhibition of PDE5 in human blood platelets. The results showed the potency of sildenafil and it is a selective inhibitor of both c GMP PDEs. Also, a number of trials were carried on rabbit corpus cavernosum to examine the effect on the muscle. From the results, appear that sildenafil was potent in relaxing the corpus cavernosum. Furthermore, to evaluate smooth muscle relaxation, set of experiments were carried in rabbit isolated aortic rings. Sildenafil showed similar values in both denuded and endothelial intact aortic rings. (28)
Side Effects from Clinical studies:
Patients receiving Viagra showed similar adverse effects in all trials. Some studies showed more effects with increased dose. There were some adverse events reported when Viagra is taken in flexible dose for example; headache, rash, dizziness, diarrhea, urinary tract infection, flushing, dyspepsia and nasal congestion.
http://www.rxlist.com/viagra-drug.htm
Pharmacokinetics and Metabolism:
The cytochrome P450 3A4 metabolizes sildenafil which changes to an active N-desmethyl metabolite that has the 50% activity of the drug for inhibiting PDE5. This metabolite has 40% plasma concentrations of sildenafil, therefore it possess 20% of the pharmacological effects of sildenafil. Terminal half-lives of sildenafil and its metabolite are 4 hours each. Sildenafil distributed into the tissues with a volume of 105 L and excreted in the feces as metabolites. In patients aged >65 years, plasma levels increased as well in patients suffered from hepatic impairment and renal impairment. (2)
Viagra Plant:
Pfizer Synthesis Facility, Ringaskiddy, Ireland

Sildenafil citrate which is the active pharmaceutical ingredients for Viagra was manufactured by Pfizer at Ringaskiddy and the total output from Viagra sales was account for 15%. The facility covers 200 acres and composed of four production units with 500 people working there. OSP4 is the main plant at Ringaskiddy that increase production by 40% and started in 2001.
Construction of the new synthetic plant (OSP4), a finished good building (FGB) and all other services were under responsibility of Project Management and Foster Wheeler. Plant started manufacturing in March 2001. Designing facility enable the OSP4 plant to produce primary bulk, batch pharmaceutical products at a reactor of 150,000 liters and six lines are at full scale. To increase service of OSP4, Pfizer was planning to build a third liquid waste incinerator.
At the plant, the manufactured products are either bulk active or drug substances. For the bulk materials, they are sent in order to complete formulation and package for shipping.
Production and plant facility:
http://resources.schoolscience.co.uk/pfizer/viagra/viagch4pg2.html
For all drugs, initially they are produced in small a mounts for the investigation and in vitro analysis. Then, quantities are increased if the carried tests are successful to meet the needs for clinical trials and patients.
For the first time, production of one kg of Viagra requires a series of eleven reactions with 23 kg of reagents and 139 liters of organic wastes. All preparations are carried in a microwave designed especially for organic chemistry.
For scaling up the process, it has to be more efficient and result in fewer wastes. Currently, in Viagra production only 1.5 kg of reagents are used and release just 10 liters of wastes. The company aim to minimize the waste to 6 L per kilogram produced. Now, every year the demand is 45 tones for good quality Viagra in compared to 1998 where the l kg production was enough for people demands in 10 minutes. To scale up reaction, all starting materials were available commercially and used without purification. Using a microwave oven ETHOS 1600, synthesis was performed. In standard Pyrex glassware, all reactions were carried out with a reflux condenser. The reactions were performed by a program which made up of temperature monitoring and holding steps. Purity of the final product was measured using thin-layer chromatography and molecular weight was recorded by electrospray ionization mass spectrometry. sealed vessels are used which controlled and monitored by computers to make the required quantities of pure drug. Pipes are used to add the reagents into the vessel and the products are harvesting later on. Control panels are applied that allow the operator to make any required adjustments and monitoring the process. A microwave-transparent fluoroptic probe that inserted into the solutions was used to monitor the temperature of the stirred reactions mixture. To produce any pharmaceuticals, highest standards of hygiene are necessary and Laboratory should be clean and tidy.
Misuse of Viagra in Asia:
http://www.ergogenics.org/138.html (faked drug)
According to World Health Organization (WHO), one of the most counterfeited drugs in Asia is Viagra which make a big business. Tourists in Thailand use fake Viagra which is bought over numerous pharmacies. Therefore serious health risks affected those tourists. Counterfeited medicines can impose the correct ingredients but fake package, or without active ingredients, wrong ingredients or with insufficient active ingredients. Fake Viagra made up of ingredients that enhance the body’s insulin production which can cause a danger drop in the concentrations of blood glucose. As a result lead to starving the energy of brain which in known as insulin shock syndrome. There is a widespread smuggling of fake and genuine Viagra in Thailand according to A Thai Food and Drug Administration (FDA). Unsurprisingly, Thailand is a centre for fake Viagra. Among young night-clubbers, Viagra is mixing with other party drug to increase the sexual desire.
Viagra competitors:
There were alternative medications prescribed for erectile dysfunction prior to the introduction of Viagra. Most of them are non-oral treatments. For example; the primary alternatives in the United States were vacuum constriction devices, penile injection therapy, penile prostheses, professional counseling and transurethral. Traditional remedies were used in other countries such as yohimbine. (4)
Viagra Sales around the world:
Firstly, after FDA granted approval of Viagra, it was sold in the United States. Nowadays more than fifty countries are selling Viagra in their pharmacies. On the U.S. market, one month after launch, the worth of sales was 400$ million which result from 300,000 Viagra prescriptions. Since then, 7$ per tablet was maintained by Pfizer. The average wholesale price is 8.75$ per pill in compare with other treatments such as; Caverject and Muse which priced at 20-30$ per pill. Furthermore, sales in most European countries began shortly in September 1998 after European Medicines Evaluation Agency (EMEA) granted European countries the registration for Viagra uses. In the United Kingdom, Sweden and republic of Ireland, the government Health System covers the purchases of Viagra for limited uses. Public awareness have been increased and focused on the safety issues in men taking Viagra and lead to limit the use of Viagra after reports over deaths and adverse effects that were sent to the FDA. U.S. and most other countries experienced prescription leveling off after information gained by people used the drug. Most of them were not actually suffer from erectile dysfunction. After drug’s approval in the United States, Latin America launched the drug. Then, Viagra was available in a number of Asian countries, New Zealand, Australia and Canada. In 1999, Japan approved drug’s uses after it accepted from other countries the clinical trials data for the first time. (4)
Environmental Performance:
In the medicinal route, there are a number of organic solvents included in the production of 1000 kg of drug substance and the volume of these solvents equal to 125,000 liters. These solvents are reduced to 13,500 liters in the commercial route. The solvents required in both routes are illustrated in figure 1.
Organic wastes from medicinal route
Organic wastes from commercial route
For environmental assessment, the reduction of some solvents for example; chlorinated solvents and highly volatile solvents such as; methyl chloride, methanol, acetone and diethyl ether. Elimination of these solvents results in elimination of atmospheric emissions. T-butanol that has been used in the commercial route is completely water soluble and is difficult for reuse. In order to improve environmental performance, t-buanol is replaced by another solvent to facilitate recovery. The optimized process was developed in Ringaskiddy and will be used in the production plant which will give 4 l kg-1 of the final optimized solvent usage. (5)
http://en.wikipedia.org/wiki/Atom_economy
Atom economy is the efficiency of conversion all reactants in a chemical process in a way of all atoms involved and no atoms are wasted. All starting materials equal to generated process, this represent an important concept in green chemistry. Reaction mass efficiency is a measure for the effect of yield and an increase of used reagents.
Between 1994 and 1997 where the new commercial route was introduced, there was an improvement in the reaction mass efficiency and chemical yields. In contrast, the atom economy remained constants over time. Comparisons of these parameters between 1994 and 1997 is shown in figure
Fig. Atom economy, chemical yield and RME at 1994, 1997 and the future target in the sildenafil citrate process.
The aqueous and organic wastes are actually measured and from modeling process the atmospheric emissions are estimated. There was a large reduction in the aqueous waste when the commercial route was introduced into the production. Moreover, upon introduction of the commercial route, again there was a noticeable reduction in the organic wastes between 1994 and 1997. Due to the impact of introducing solvent recovery operations and reuse in the manufacturing process, a further large reduction occurred after 1997. These decreasing reflect the importance of eliminating wastes and controlling route selection. For the vapor emissions, there have been smaller diminish in the released amount. In addition, it was found there was 35% decrease in the estimated energy used between 1994 and 1997. There are two reasons behind smaller reduction in the vapor emissions and the used energy; firstly, in order to maximize the yield, there is a significant level of solvents stripping performed in the commercial process. Secondary, the chemistry team actively managed and followed such parameters for instance; organic, aqueous wastes and yield. On the other hand, they calculated retrospectively the emissions and energy. (5) Figure shows the comparisons between these wastes at various times.
The E-factor is the total kilos of wastes per kilogram of product. In commercial route of Viagra production, the E-factor is 6 kg kg-1 which is less than the industry standard of (25-100) (6)
Low volumes of the complicated chemical products and the E-factor of the commercial route for Viagra production generate fewer wastes per year. For all of the environmental awareness taken by Pfizer for the sildenafil citrate process, UK Award was granted to this company in 2003. (2)
Patents:
According to the U.S. Patent and Trademark Office, patent for Viagra by Pfizer will expire on March 27, 2012. Then, a cheap generic version of the blockbuster erectile dysfunction drug will be sold by any drug company. This will allow more competition between Pfizer’s Viagra and the new generic versions and more options with cheaper prices for patients. Pfizer has three options to stay in the Viagra’s market. Firstly, it can market itself as the main company for selling Viagra, taking into account there are over 25 million men used its version and they don’t like to change. Secondary, it can apply for Viagra with FDA for OTC (over-the-counter). Finally, while producing an upgraded version of Viagra which will continue holding value of the patented product, it can license the original recipe to Viagra to other companies.
http://www.accessrx.com/research/viagra-patent-expires.htm
Alternative Routes to Sildenafil:
There are more than 15 different routes have been reported in the chemical and patent literature to sildenafil. Pfizer examined two main alternatives during the development process either by synthesis sildenafil through the aldehyde 11 to produce dihydrosildenafil 12 then oxidize the product or by the halo derivatives for example 13 or 14.
52 % of sildenafil yielded from condensation between aldehyde and aminopyrazole to give dihydrosildenafil by adding an azeotropic distillation to remove the water by product. The yield can be increased to 95% as shown by some workers. (PATENT 22918)
Aldehyde Amine Dihydrosildenafil
Sildenafil
Oxidation of dihydrosildenafil either by using sodium hydrogen sulphite (NaHSO3) or using small quantity of trifluoroacetic acid and Pd/C at high temperature generated a good yield of drug (patent WO 01-98303).
Dihydrosildenafil Sildenafil
Combination between a nucleophilic displacement reaction that uses ethanol as a solvent and a hindered alkoxide (KOBU) or ethoxide (EtOH) as a base and the cyclization reaction which uses a compound like halo derivatives is another potential synthesis for sildenafil. The combination reaction works for both cyclisation compounds, but by using a compound where (x= F) the yield from combination is 100%. The use of the chloro-series compound (x=cl) in the cyclisation reaction is better because of 2-chlorobenzoic acid is cheaper than 2-ethoxybenzoic acid. (Patent number EP 0994 115)
Figure (13, 14, synthesis)
Halo Derivatives
X= Cl
X= Fe, yield= 100%
In the end, all of these alternative routes were put on hold due to the high efficiency of the commercial route and the time pressures of the development program.
(6)
(3)
In the WO Patent (98284), amidine 10 or iminoether 11 can be used in order to build pyrimidine ring (sildenafil). By a Pinner reaction, the iminoether is made from the nitrile.
Amidine is made by reaction of the nitrile with chloromethylaluminium amide which is synthesized from trimethyl aluminium (Me3Al) and ammonium chloride (NH4Cl)
Nitrile
Amidine Iminoether
Sildenafil
Intermediate 14 was prepared from reaction of the acid intermediate 13 with thionyl chloride (SOCl2) to give the lactone which then can be reacted with ammonia (NH3) and (EtOH) to produce the pyrazolopyrimidinone which is away to make sildenafil.
Acid intermediate Lactone
Sildenafil
(Patent EP 1 002 798) sildenafil synthesis from intermediate (6), can be done by chlorosulphonate the intermediate 16 and before cyclisation the intermediate convert to the sulphonamide6.
Sildenafil
There are many patents activities in producing nonconvergent synthesis of sildinafil. Workers at the Torcan Company reduced Carbamate by (LiALH4) to sildenafil in ayield of 61%. ( Patent 2 235 642).
Carbamate Sildenafil
Also, sildenafil was synthesized from pyrazolopyrimidinone and the sulphamoyl chlorid (which is prepared by SO2Cl2 and N-methylpiperazine reaction) using Friedel-Craft reaction which requires ALCl3 by workers at the India Orchid company. (Patent EP 1 077 214)
Pyrazolopyrimidine and sulphamoyl chloride Sildenafil
Furthermore, workers in Cipla Company have synthesized sildenafil by double methylation of this intermediate by using formic acid and formaldehyde (CH2O) and (HCO2H) as the final step. (Patent WO Patent 01/ 19827)
Sildenafil