The Discovery and Development of an Environmentally Benign Commercial Route
to Sildenafil Citrate
Dr. Declan DooganSenior Vice-President Global Research and DevelopmentDirector of Sandwich Laboratories and Japan DevelopmentPfizer Global Research and DevelopmentRamsgate RoadSandwichKent CT13 9NJ
Phone: 01304 648667e-mail: [email protected]
Ms. Stella EcclesSandwich site head, ManufacturingPfizer Global ManufacturingPfizer LtdRamsgate RoadSandwichKent CT13 9NJ
Phone: 01304 646213e-mail: [email protected]
Dr. Peter Dunn, DirectorChemical Research & DevelopmentPfizer Global Research and DevelopmentRamsgate RoadSandwich, CT13 9NJUnited Kingdom
Dr. Peter Dunn, PGRD, Sandwich, UKMr. Andy Pearce, PGRD, Sandwich, UKMr. John Holroyde, PGM, Sandwich, UKMs. Stephanie Kealy, PGM, Ringaskiddy, Ireland
The Discovery and Development of an Environmentally Benign
Commercial Route to Sildenafil Citrate
2. Pfizer Ltd affirms that the nominated green chemistry technology has been
demonstrated and implemented in the United Kingdom within the last five years.
ViagraTM was the first oral treatment for Male Erectile Dysfuction, an illness thataffects 130 million men and their partners world wide. More than 20 million menhave received the benefit of treatment with ViagraTM.
Green Chemistry objectives were emphasized in the Discovery and Development ofthe commercial route to sildenafil citrate, the active ingredient in the importantmedicine ViagraTM. The commercial synthesis generates only 9 Kg (10 L) of organicwaste per kilogram sildenafil, compared with the industry norm of 25-100 Kg(Sheldon 1996). The key breakthrough in achieving this exceptional result was thediscovery of a new, convergent, synthetic route, which was designed with a cleancyclisation reaction as the final step hence eliminating purification operations.
Subsequent careful chemical development and diligent solvent recovery optimised theenvironmental performance.
Achievements include a nine-fold yield increase from the pyrazole (1) to sildenafilcitrate. The amount of organic and aqueous waste is reduced 15 and 5 foldeliminating 4000 tonnes and 3900 tonnes of organic and aqueous waste respectively.
In addition, the elimination of highly volatile solvents such as dichloromethane, ether,acetone and methanol also makes a substantial reduction to atmospheric pollution. Atin chloride (toxic heavy metal) reduction was replaced by an environmentally benigncatalytic hydrogenation reaction. Hydrogen peroxide (a worker safety issue and firehazard) was eliminated. Three chemical steps were combined, using a single solventthat was recovered. In eight chemical steps there is no reaction that requires a work-up involving extraction, again leading to low organic waste.
The applicants introduced environmentally friendly chemistry early in thedevelopment and production cycles. This forward planning and upfront investment inGreen Chemistry has greatly minimised the environmental impact and expedited realworld benefits.
Through innovative chemistry, including a new bond forming sequence, wasteelimination, solvent reductions strategies and yield maximisation of the desiredreaction pathways, the applicants have demonstrated significant green chemistryinnovations for an important pharmaceutical agent. The direct pollution preventionbenefits to society are substantial and noteworthy and there are additional benefits inworker safety.
1. The nominated sildenafil citrate chemical technology falls within the scope of the
UK Awards for Green Chemical Technology and demonstrates a substantial
improvement in chemical processes in line with Green Chemistry objectives.
The nominees' accomplishments fall within the selection criteria for the UK Awards for GreenChemical Technology “through research and commercial exploitation of novel chemicaltechnology to achieve a more sustainable, cleaner and healthier environment as well as creatingcompetitive advantage.” The chemistry scheme for the manufacture of sildenafil citrate by themedicinal chemistry route and the commercial route is shown in Scheme 1. In the text below, anannotation highlights which of the 12 Principles of Green Chemistry, published by Paul Anastasand John Warner, was achieved by the particular innovation.
A. Route Selection
The strategic thinking in selecting the commercial route is summarised in Scheme 2. During theinitial scale-up of the medicinal chemistry route, Pfizer discovered that hydrogen peroxide couldbe eliminated from the cyclisation step by using t
-BuOH and t
-BuOK and indeed when thischange was introduced, a 100 % yield of 100% pure product was obtained for the cyclisation togive compound (2) in Scheme 1.
Medicinal Chemistry Route: A linear route. The clean reaction is in the middle of the synthesis
The potentially toxic materials are in the final step.
Commercial Route : A convergent route. Steps have been reordered so that the clean reaction is in the final step
Hence the route was redesigned so that this type of clean cyclisation reaction was repositioned asthe final bond-forming step. This moved potentially toxic materials (such as the sulphonylchloride intermediate) much earlier in the synthesis, avoiding purification operations andeliminating waste (principle 1).
A second advantage of the route change was that the commercial route is convergent. This leadsto more efficient use of key intermediates and again avoids generating waste (principle 1). Thereare no protection/deprotection operations in the sildenafil synthesis (principle 8).
The third advantage of the commercial route was that it placed the chlorosulphonation earlier inthe synthesis. Chlorosulphonation reactions can be difficult to scale-up to full commercial scaledue to the increased levels of hydrolysis back to the sulphonic acid during the aqueous quenchwhich takes longer on a larger scale. In fact during the Pilot Plant runs of the medicinal chemistryroute, some yield drop of the advanced, complex intermediate was already being observed. Byputting the chlorosulphonation early in the synthesis, a simple low molecular weight startingmaterial (2-ethoxybenzoic acid) is chlorosulphonated and the problem is much reduced(chlorosulphonic acid usage reduced 3 fold) (principle 1). By careful control of the quenchconditions and the application of chemical engineering, yields can be maintained at 85-90%.
B. Solvent Usage
The nominees achieved substantial and environmentally beneficial reductions of both the volumeand the number of solvents required (principle 5). The volume and identity of the solvents used inthe manufacture at various stages of the development process are summarised in Figure 1.
The large reduction in solvent usage between the medicinal chemistry synthesis (EP 0 812 845)and its optimized version (1994) would be expected as part of standard process development.
However, the further substantial reduction when the new commercial route was implemented isnoteworthy, confirming the major impact of introducing the commercial route. Of particular note
are the elimination of chlorinated solvents and the elimination of highly volatile solvents (VOCs)(such as dichloromethane, ether, methanol and acetone) reducing atmospheric emissions.
Figure 1 : Solvent Usage at Various Phases of the Sildenafil Citrate Process Development
Two benign solvents, 2-butanone and ethyl acetate, make up 80 % of the solvent usage (principle3). In 1998, the year ViagraTM was launched, solvent recovery for toluene and ethyl acetate wasintroduced. Trials for the recovery of 2-butanone were initiated in 1998. The results weretransferred Ringaskiddy, Ireland and after further technical work, production scale trials for therecovery of 2-butanone have been completed. The final column shows the amount of wasteproduced assuming recovery of ethyl acetate, toluene and 2-butanone.
The commercial route to sildenafil citrate uses toluene, ethyl acetate and 2-butanone as singlesolvents and this substantially reduces energy consumption required for distillation and solventchanges (principle 6). The design of the process to use single solvents also increases thepercentage of solvent which can be recovered.
Despite the achievements already made there is a continued drive for improvement and Pfizerplans to replace the t
-butoxide cyclisation with an ethanol/ethoxide cyclisation. Thisimprovement plus other enhancements will increase the overall yield from 76 to 80 % and furtherreduce solvent usage and organic waste.
C. Development of the Chemical Steps (Commercial Route)
Nitration and Amide Formation (common to both routes) (Preparation of compound 3)
These steps were optimised based on yield, safety and environmental performance. No organicsolvents were used in the nitration step (principle 5). Conversion to the amide (3) was originallycarried out in neat thionyl chloride. Toluene was introduced as a heat sink (worker safety) and the
levels of thionyl chloride reduced to 1.2-1.6 equivalents. The toluene from this reaction isrecovered and reused.
Chlorosulphonation and Sulphonamide Formation (Preparation of compound 5)
Following chlorosulphonation and aqueous quench, the product is isolated as a water wetsulphonyl chloride. The process was then designed for simplicity and efficiency in which thesulphonyl chloride is resuspended in water and reacted with N
-methylpiperazine. At the end ofthe reaction the pH is adjusted and the product (5) collected by filtration. Hence no organicsolvent is used in preparation of the sulphonamide (5) (principle 5) which is prepared in goodyield (80 % over two steps). Both chlorosulphonation and sulphonamide formation are carried outat ambient temperature (principle 6).
Reduction, Activation and Acylation (Conversion of 3 and 5 to compound 4)
The original medicinal chemistry procedure used a tin chloride reduction, as catalytichydrogenation did not initially work for this substrate. Investigation revealed that the reason forthe ineffective hydrogenation was the presence of low levels of sulphur impurities arising fromthe thionyl chloride. Optimising the work up of the previous step removed these catalyst poisonsand allowed the introduction of a catalytic hydrogenation process (principle 9) that proceeds in100% yield and is environmentally friendly. Activation of the acid was examined with a numberof reagents including thionyl chloride, oxalyl chloride and N,N’
-carbonyl diimidazole (CDI).
CDI was selected despite its higher cost because this reagent:
• Provided clean, robust chemistry and high quality product.
• Allowed all three reactions (hydrogenation, activation and acylation) to be combined.
• Enabled a single solvent to be employed, allowing simple solvent recovery with low
• Avoided VOC emissions (EtCl) from the interaction of either thionyl chloride or oxalyl
chloride with ethyl acetate (principle 1).
• Provided a simple process – mix streams, concentrate and filter. This simplicity led to
In 1998 Ringaskiddy production plant introduced solvent recovery for the combined step. TheCDI activation was a key chemistry control point, an undercharge led to poor yield whereas anovercharge led to impurities. An on-line method (using near infrared spectroscopy) wasdeveloped and was used in Ringaskiddy in 1998 to monitor this key quality control point(principle 11).
Cyclisation and Salt Formation (conversion of compound 4 to sildenafil citrate)
This process is run concentrated (2.5-3.75 L/Kg) in order to minimise environmental waste(principle 1). The reaction is not exothermic, so there is no need for a solvent heat sink. At theend of the reaction, water is added and the pH adjusted to the isoelectric point to precipitate puresildenafil which was collected by filtration. There is no need for extractive work-up (principle 1).
Even though the isolation is extremely simple, the material is of very high purity and is suitablefor clinical use directly, for those formulations which employ the free base of sildenafil.
For ViagraTM, the citrate salt is required. The process to convert sildenafil to sildenafil citrate hasto be carefully designed to give a both a high yield and high quality [for example productionmaterial typically contains <0.1 % 2-butanone (principle 4)] using the innocuous solvent, 2-
butanone (principle 5). A 100 % yield for this step is routinely obtained. Production scale trialsfor 2-butanone recovery are complete.
Worker Safety, Transport and Fire Hazards.
The initial synthesis used hydrogen peroxide solution in the reaction to produce thepyrazolopyrimidinone (2). Hydrogen peroxide is a strong oxidant, which causes burns on skincontact. Its strong oxidising behavior can also result in a fire if there is contact with a combustiblematerial. Finally hydrogen peroxide is also extremely destructive to the tissue of mucousmembranes and upper respiratory tract and is an inhalation hazard. The complete removal ofhydrogen peroxide (principle 3) from the synthesis greatly reduced the worker safety, transportand fire hazards (principle 12) of the process.
Tin (II) chloride is corrosive and causes burns. Tin is a toxic heavy metal and a majorenvironmental pollutant. The complete removal of tin (II) chloride (principle 3) from thesynthesis and its replacement with a hydrogenation reaction eliminates heavy metal pollutionissues that would be associated with the tin (II) chloride process. The hydrogenation reactionproceeds in 100% yield and water is the only by-product hence the commercial process hassubstantially improved atom efficiency (principle 2).
Overall Savings for the Environment
In a typical production year Pfizer (worldwide) produces 300 tonnes of organic waste in thepreparation of sildenafil citrate. If the optimised medicinal chemistry process (the 1994 process)were used this figure would be 4300 tonnes. Hence introducing a new route and optimising thatroute saves 4000 tonnes of organic waste per year as well as eliminating 3900 tonnes of aqueouswaste.
2. The technology must have reached a significant milestone during the last 5 years
within the UK and be in development or commercial use.
ViagraTM was approved for use within the European community in September 1998. Commercialproduction in the UK started in May 2001.
3. The nominated sildenafil citrate chemistry technology is generally applicable to a
broad-based segment of chemical manufacturers, users, and society at large and key
features of the technology should be readily transferable
Ultimately, the achievements of the nominees offer society access to the most prescribed medicalagent of its kind at a greatly reduced environmental burden. ViagraTM is used to treat an illness(erectile dysfunction) that affects 130 million men and their partners worldwide. ViagraTM wasthe first oral treatment for erectile dysfunction and has excellent efficacy and safety. Ninety fivepercent of patients who take prescription prefer the oral option that ViagraTM provides and over20 million men worldwide have been prescribed ViagraTM.
The sildenafil citrate process was designed with simplicity, efficiency, quality, cost reduction,safety, and environmental improvements as the key objectives. The substantial accomplishments,illustrate that the highest levels of environmental performance can be achieved in thepharmaceutical industry without compromising quality. The sildenafil citrate process was readilytransferred to three Pfizer manufacturing facilities, demonstrating the feasibility of scaling Green
technologies. The deliberate search for a convergent synthesis is a powerful tool in reducingenvironmental waste and is applicable across pharmaceutical and chemical manufacture.
The applicants have further disseminated these innovations to educational establishments. Forexample, the cyclisation reaction to make compound (2) is used by Universities in the UK forBSc chemistry practical classes. In these classes, students carry out the “clean” reaction andisolate the product using a chemical process designed with Green Chemistry Principles. The ideais to stimulate a new generation of Green Chemists.
Sildenafil citrate is a PDE5 inhibitor and pharmaceutical companies are very active in PDE5research for both erectile dysfunction and other diseases. Much of this research has centered onpyrazolopyrimidines or close heterocyclic analogues. The clean sildenafil cyclisation reaction hasbeen disseminated to the chemistry community and several other pharmaceutical competitors anduniversities have adopted the t
-butoxide cyclisation in their research (see for exampleHeterocycles 2000, 53, 2643 and WO 01/98304). Pfizer has also continued to use the reactionwidely in its own PDE5 research.
4. The nominated sildenafil citrate technology is original and of high scientific merit.
The novelty of the innovative sildenafil citrate route is substantiated by the grant of a EuropeanPatent (EP 0 812 845). The new route resulted from significant and sustained innovation by thenominees. The lead inventor of the patented process, Dr Peter Dunn, led the laboratory team. Thenew process was scaled-up into Pilot Plant equipment by Mr Andy Pearce who also transferredthe process to manufacturing facilities in Groton (USA), Ringaskiddy (Ireland) and Sandwich(UK). Ms Stephanie Kealy and Mr John Holroyde are responsible for sildenafil citrateproduction in Ireland and Sandwich, respectively. All three manufacturing sites includingSandwich, UK have been approved by the EMEA for the commercial manufacture of sildenafilcitrate. The sildenafil citrate process was approved by the EMEA and hence subjected to rigorousreview by experts for the purposes of delivering quality and safety to the public who useViagraTM.
A review of the sildenafil chemical development program was published in Organic ProcessResearch and Development 2000, 4, 17-22, a peer reviewed journal jointly published by theAmerican Chemical Society and Royal Society of Chemistry. This paper also outlines theenvironmental benefits of the new sildenafil route. A further more detailed publication is plannedfor submission in the Green Chemistry Journal. Further dissemination included a presentation atthe Green Chemistry Symposium at the American Chemical Society Meeting in Florida (April2002) and at the IUCT 4th Green Chemistry Conference in Barcelona (11th/12th Nov 2002).
These presentations focused solely on the environmental aspects of chemical development withparticular reference to the sildenafil process.
5. The company should have significant manufacturing and or research facilities in the
Pfizer has significant manufacturing and research facilities in the UK with over 5,000 employeesat the Sandwich site. Sildenafil citrate was discovered and developed at Sandwich and a portionof sildenafil citrate production takes place at Sandwich in the UK.
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