Synthesis sildenafil

TABLE 13.5 E-Factors of different stages of sildenafil synthesis... 

In 2005 we reported the synthesis of some sildenafil (3) analogues and their tyrosinase inhibitory potential [43]. The compoimds were synthesized using microwave irradiation in key steps, such as the SNAr reaction on important precursor bromopyrazole [44]. Their molecular structures are shown in Fig. 3. 

Khan KM et al. (2005) A facile and improved synthesis of sildenafil (Viagra) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies. Mol Divers 9(l-3) 15-26... 

Baxendale IR, Ley SV (2000) Polymer-supported reagents for multi-step organic synthesis application to the synthesis of sildenafil. Bioorg Med Chem Lett 10 1983-1986... 

The literature on these ring systems in the last 10 years is vast. An Internet search alone provides 3500 citations for sildenafil (60a, Viagra). Not only Viagra is of medical interest allopurinol (ALP) 61, the classical treatment of gout arthritis, is still of interest, and pyrazolopyridazines and thiazolopyridazines have also been shown to be of biological importance. These activities extend beyond an interest in the synthesis and chemistry of these compounds indicated by the large number of patented potential applications. 

The development of an environmentally benign synthesis of sildenafil citrate (Viagra ) and its assessment by green chemistry metrics. Green Chem. 6 (1) 43-48. 

Scheme 1. Pfizer medicinal chemistry synthesis of sildenafil (1).

Discovery and synthesis of sildenafil 13.3 Synthesis of vardenafil 13.4 Synthesis of tadalafil 13.5 References... 

The initial medicinal chemistry route for the early syntheses of sildenafil required -1540 kg solvent/kg API. After four years of development, a modified chemical route and process led to a 93.9% reduction in the total amount of solvent used. The continued optimization of the sildenafil process as it went into commercial production further reduced the amount of solvent used from 94 to 19 kg solvent/kg API. Several highly hazardous solvents were also eliminated from the production scheme including DCM, methanol, and diethyl ether. Upon implementation of solvent recovery, the total amount of solvent required was only 5 kg solvent/kg API produced [17, 20]. The final commercial route used only 0.32% of the total solvent used for the initial synthesis. 

Sildenafil (Viagra,13.73) is the prototype of a drug class that treats erectile dysfunction. The original med chem route for sildenafil is shown in Scheme 13.12. From pyrazole 13.67, the synthesis occurs in 7.5% yield. Sulfonyl chloride 13.72 was identified as the major problem in the sequence. Compound 13.72 reacts slowly with water, and loss of product to hydrolysis is unavoidable during isolation. Also, sulfonyl chloride 13.72 is toxic. In the conversion of 13.72 to 13.73, unreacted 13.72 contaminates the final product. Complete removal of 13.72 from sildenafil requires multiple recrystallizations, which further decrease the overall yield. 

The E-factors of different types of chemical processes are shown in Table 13.4.32 In general, processes performed on a larger scale tend to involve fewer operations and form simpler products. Both facets help lead to lower E-factor values. Remarkably, oil refining generates approximately 10-fold more product than waste. In contrast, pharmaceutical processes can be less than 1% efficient based on waste production. The commercial process of sildenafil (13.73), highlighted in the Case Study below, has been optimized more extensively than the typical pharmaceutical synthesis. 

The various improvements in synthesis of sildenafil (13.73) in a previous section of this chapter have been analyzed by their E-factors (Table 13.5). Note that in this analysis, E-factors are reported in L waste per kg product. Most waste consists of solvents and aqueous solutions, so measuring waste in volume is convenient. Like most med chem routes, the original synthesis of sildenafil was inefficient and intended only for quick synthesis. Within four years, the med chem route had been optimized in terms of its E-factor by over an order of magnitude. Further improvements dropped the E-factor down to 22 L/kg. Implementation of recovering solvents from the waste stream reduced the E-factor to just 7 L/kg. Such a low E-factor is more typical of a bulk or... 

The timeline of sildenafil is interesting by itself. Most successful drugs do not require seven years to progress from the med chem synthesis to commercialization. Sildenafil, however, started as a candidate for treating angina. 

Its impact on erectile dysfunction was discovered as a side effect in the clinical trials for angina efficacy. Because sildenafil s target was unknown, Pfizer spent additional time researching the biological processes behind sildenafil s erectile dysfunction activity. This research explains the gap between the original synthesis of sildenafil and its advancement to a commercial process. 

Dunn, P. J., Galvin, S., Hettenbach, K. The Development of an Environmentally Benign Synthesis of Sildenafil Citrate (Viagra) and Its Assessment by Green Chemistry Metrics. Green Chem. 2004, 6, 43 18. 

The chemical development of the commercial route to sildenafil also serves as an excellent example of the different issues that need to be considered when moving from drug discovery to commercial quantities. This problem is therefore based on the commercial synthesis of sildenafil as published by the Pfizer research group around P. J. Dunn ... 

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