Sildenafil medicinal route

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. 

The synthesis of sildenafil serves as an excellent example of the demands of commercial chemistry. The route described contains all of the desired attributes required in chemical development, namely a safe, robust route, a convergent synthesis and a high yielding process. The authors managed to improve the yield from 7.5 % in the medicinal chemistry to 75.8 % overall from pyrazole 3. The synthesis also has an exceptionally low environmental impact. Only toluene and ethyl acetate are organic waste while the other solvents (ethanol and tert-butanol) can be treated in the water plants. The synthesis has been... 

The medicinal chemistry route was completely linear and produced sildenafil citrate in 3.8% overall yield from 2-pentanone. Although these facts made it suboptimal for commercialization, the route was fully suitable for early project supply. Of course all steps were modified to make them suitable for scale-up. Some of the most important modifications were the following ... 

SCHEME 16.1 The medicinal chemistry route to sildenafil citrate. 

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