A Synthesis of Sildenafil

A synthesis of sildenafilFor umteen reasons, this r breake was assumed suboptimal as a commercial manufacturing for deterrent congresswoman it is linear with nine steps, sulphonyl chloride, which is one of the toxic substances realized from this dispatch is in the final bond-forming answer. final examination material postulate a lot of recryst anyizations to expurgate the toxic impurities to befittingly low levels in enact to cook the high quality of medicine required by pharmaceutical caller. Due to competing hydrolysis through the increase fill times on scale leaf-up chlorosulphonation in chemical outgrowth the difficulties of scaling-up responses argon salubrious-known.In this highroad, 2-pentanone and di ethyl group oxalate ar condensed to repay the diketoester 1. Then, cyclizating the diketoester by hydrazine produces pyrazole 2 which methylated with discriminating to r abolisher pyrazole3. Hydrolysing the chemical reaction generated the social diseas e 4, then permute panelling to the amide by nitration to constitute nitropyrazole 5, which is common intermediate in all synthetic routes. Reduction of 5 with tin (II) chloride dehydrate to feature the amine 6 which is by 2-ethoxybenzoyl chloride was acylated to produce diamide 7. The later was cyclized victimisation aqueous sodium hydroxide and hydrogen bleach to import in 8 pyrazolo4,3-dpyrimidin-7-one. sildenafil citrate 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 medicative chemistry route, which impacted on the programme as a whole. Cyclization of flux 4 was done by sodium hydroxide and hydrogen peroxide, which argon an aqueous alcoholic solution and troika to moderate pay up (30-70%). The hydrolysis of the carboxamide to give the dosage each in the presence or absence of the hydrogen peroxide was the main f ount final payment 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 fair cyclization was the final bond-forming reaction. (1)Modification of the medicinal routeA lot of modifications were applied into medicinal chemistry route, which was utilize at the beginning of the project to prep atomic number 18 fifty kilograms and support emerge for the four grades. (6)For proterozoic scale-up, the tin (II) chloride drop-off 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 ware, 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 report levels of atomic number 16 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. employ a hydrogenation, in that respect are options for dissolvent and catalyst recovery and water is the only by-product. (5)Hydrogen peroxide was utilize in cyclization method to veer 7 to 8, nevertheless(prenominal) it causes skin burns. Further more(prenominal) than, in contact with entire materials, it is a fire and transportation hazardous. Then, it was replaced with KOtBu/ButOH. Rather than using oxalyl chloride, thionyl chloride is utilise to prepare 2-ethoxybenzoyl chloride which eliminates exposure to carbon monoxide emissions by workers. (5)Through composition of pyrazole 3 which is an exformer(a)mic 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 equival ents. (6)Sildenafil CitrateSildenafilcommercial RouteSelectionThe target from Sildenafil citrate was for treatment of angina pectoris when entered development. But the clinical results were failed. Pfizer made a trial with 12 patients substantiate from male erectile dysfunction in 1994. The results showed improvements in the problems of 10 patients. As a government issue, sildenafil citrate development became one of the highest introductoryities in the Pfizer portfolio (6). in that respect are many advantages of commercial route over the optimized medicinal one, for exampleThe synthetic thinking 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 loony toonsic waste require an change magnitude level of hydrolysis and neutralization through a wide-rangingr scale is an example of environmental and scale-up issues associated with chlorosu lphonation reaction. In order to reduce these issues, they are placed at the start of the synthesis. Hence, low molecular angle and cheaper materials are used. (5).DEVELOPMENTSulfonamide preparationThrough 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 signalise 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 sulfa medicine 9 was isolated as unusual look-a handle season 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, acerb fumes in a pilot typeset scale. Then, it was discovered that 9 so-and-so be isolated as its exceedingly crystalline zwitterions by treat ment 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 sulfa do medicines 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 reactionIn 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 make for 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 come across the activation of the carboxylic acid.CDI costs around 8$/mol and go out such advantages for instances high quality product, robust and clean chemistry. Furthermore, it provided a faction of the one-third reactions (hydrogenation, acid activation and acylation) into a single step, employed the ethyl acetate solvent with a simple recovery process and used low energy. In addition, VOC emissions were avoided such as (EtCl) that generated from the interaction of ethyl chloride with thionyl chloride or oxalyl chloride. Moreover, 90% chemical yield over three chemical reactions is produced and optimized to 96%.Cyclisation ReactionThe resulting product is heated for several hours and cyclised with 1.2 equivalents of potassium t-BuOH and t-BuOK. In order to minimize the environmental wastes, this process is run at high tightness (2.5-3.75L Kg-1). Water is added to dilute the reaction and the pH was adjusted with 4M HCl t o the isoelectric point (7.5). clinical very high quality yield of 95% sildenafil was obtained by filtration. Using 2-butanone citric acid, sildenafil was converted to sildenafil citrate to give a yield of 99 to 100%.SildenafilHistory of SildenafilInitially sildenafil citrate was developed to treat angina (heart disease). In Morriston hospital, the drug was tried on men in 1991-1992. The clinical observation showed that the drug enhance penile erection more than treating angina. Pharmaceutical connection, Pfizer commercialized the drug as a treatment for erectile dysfunction. In 1996, the drug was patent and approve on 27 March 1998 by FDA. It was the first approved drug for penile erection in the united States and the sales go past 1$ billion in 1999-2001. The Pfizers patents on this drug bequeath asphyxiate in 2011-2013.Dosage of sildenafilsildenafil could be taken in one case per day as a dose between 25mg to 100mg between 30 min to 4 hours before internal intercourse. T hree dosages are for sale in market for this drug (25-50-100) mg with a cost of 10$ per pill for all dosages.http//www.chemistrydaily.com/chemistry/SildenafilMode of actionPharmacodynamics make on Penile erectingSildenafil 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 pitch around 30 million patients in United States. Nitric oxide is released during sexual stimulation and permeates through head teacher cavernosum membranes. Then, the enzyme guanylate cyclase is stimulated to enhance levels of cyclic guanosine monophosphate (cGMP) in the star 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 in busy GMP. Levels of cGMP in men with impotence are low and as a consequence PDE5 quickly hydrolyses th ese levels of cGMP. Now, the sildenafil acts by inhibiting the actions of PDE5 and increases the levels of cGMP which cause the erection. (6) ensure involvedErectionNitric OxideGuanylate CyclaseSildenafil binds to PDE5 and blocks actionGMPcGMP make on Visual bitIn patients taking sildenafil, it has been inform 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 suppression effects of sildenafil on PDE6 that regulates signal transduction pathways in the retinal receptors. (2)Cardiovascular EffectsSidenafil has effects on blood pressures by producing transient reduction in systolic and diastolic at 1 hour afterward(prenominal) the dose. The clinical tests showed no observed effects on heart rate. Sildenafil effects are not age or dose dependent. (2)Clinical trialsThe 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 twain 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 some(prenominal) denuded and endothelial intact aortic rings. (28)Side Effects from Clinical studiesPatients receiving sildenafil showed similar inauspicious effects in all trials. Some studies showed more effects with increased dose. in that location 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.htmPharmacokinetics and MetabolismThe cytochrome P450 3A4 metabolizes sildenafil which changes to an nimble N-desmethyl metabolite that has the 50% activity of the drug for inhibiting PDE5. This metabolite has 40% plasma concentrations of sildenafil, thitherfore it ingest 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 faecal matter as metabolites. In patients aged 65 years, plasma levels increased as well in patients suffered from hepatic impairment and renal impairment. (2)Viagra PlantPfizer Synthesis Facility, Ringaskiddy, IrelandSildenafil 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 cholecalciferol people working there. OSP4 is the main arrange 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 work were under responsibility of Project Management and Foster Wheeler. Plant started manufacturing in March 2001. Designing facility enable the OSP4 plant to produce primary coil 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 send in order to complete formulation and package for shipping.Production and plant facilityhttp//resources.schoolscience.co.uk/pfizer/viagra/viagch4pg2.htmlFor all drugs, initially they are produced in slight a mounts for the investigation and in vitro analysis. Then, quantities are increased if the carried tests are undefeated to meet the needs for clinical trials and patients.For the first time, produc tion 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 fuck off 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 continueing steps. Purity of the final p roduct was mensural using thin-layer chromatography and molecular weight was recorded by electrospray ionization mass spectrometry. squiffy 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. defend 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 Asiahttp//www.ergogenics.org/138.html (faked drug)According to World Health makeup (WHO), one of the most counterfeited drugs in Asia is Viagra which make a whacking business. Tourists in Siameseland use fake Viagra which is bought over numerous pharmacies. wh erefore 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 bodys 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. at that place is a widespread export 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 two-year-old night-clubbers, Viagra is mixing with other party drug to increase the sexual desire.Viagra competitorsThere were alternative medications prescribed for erectile dysfunction prior to the entryway of Viagra. Most of them are non-oral treatments. For example the primary alternatives in the United States were vacuum constriction d evices, penile injection therapy, penile prostheses, professional advocate and transurethral. Traditional remedies were used in other countries such as yohimbine. (4)Viagra Sales around the worldFirstly, after FDA granted approval of Viagra, it was change in the United States. Nowadays more than fifty countries are marketing Viagra in their pharmacies. On the U.S. market, one month after launch, the cost of sales was 400$ million which result from 300,000 Viagra prescriptions. Since then, 7$ per tab key 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 find oute d uses. Public ken cast 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 displace 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 drugs approval in the United States, Latin America launched the drug. Then, Viagra was available in a number of Asiatic countries, New Zealand, Australia and Canada. In 1999, Japan approved drugs uses after it accepted from other countries the clinical trials data for the first time. (4)Environmental PerformanceIn 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 pertain to 125,000 liters. These solvents are reduced to 13,500 liters in the commercial route. The solvents required in both route s are illustrated in figure 1. constitutive(a) wastes from medicinal routeOrganic wastes from commercial routeFor 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 totally 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_ providenceAtom 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 figureFig. 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 trading operations and reuse in the manufacturing p rocess, 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 squad actively managed and followed such parameters for instance organic, aqueous wastes and yield. On the other hand, they compute 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 stand ard 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)PatentsAccording 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 Pfizers Viagra and the new generic versions and more options with cheaper prices for patients. Pfizer has three options to stay in the Viagras 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 dont 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 manifest the original recipe to Viagra to other companies.http//www.accessrx.com/research/viagra-patent-expires.htmAlternative Routes to SildenafilThere 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 annulus derivatives for example 13 or 14.52 % of sildenafil yielded from abridgement 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 DihydrosildenafilSildenafilOxidation 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 SildenafilCombination 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 junto 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 DerivativesX= ClX= 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 t o 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 ion chloride (NH4Cl)NitrileAmidine IminoetherSildenafilIntermediate 14 was prepared from reaction of the acid intermediate 13 with thionyl chloride (SOCl2) to give the lactone which then can be reacted with ammonium hydroxide (NH3) and (EtOH) to produce the pyrazolopyrimidinone which is away to make sildenafil.Acid intermediate LactoneSildenafil(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.SildenafilThere are many patents activities in producing nonconvergent synthesis of sildinafil. Workers at the Torcan union reduced Carbamate by (LiALH4) to sildenafil in ayield of 61%. ( Patent 2 235 642).Carbamate S ildenafilAlso, 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 SildenafilFurthermore, 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