Med chem route

A med chem route is very rarely amenable to scale-up. This statement is not a condemnation of the chemistry skills of the medicinal chemistry group. Medicinal chemists make molecules for testing and optimization. How the molecules are made is less important than the fact that they are made and made quickly. Only when a compound shows sufficient promise as a candidate is time invested to significantly improve the efficiency of its synthesis. 

The original med chem route is shown in Scheme 13.10.21 Note that the med chem route produces a close analogue of fluvastatin. Structural differences between fluvastatin and... 

The process or commercial route addressed problems in the med chem route by completely redesigning the indole synthesis (Scheme 13.11).21 Indole 13.63 is prepared in just two steps. In two more steps, all the carbons in the molecule of the drug are present. Ketone 13.65 can be reduced with almost complete stereoselectivity for the syn diol shown as 13.66. The anti diol, which is not pictured, has the new OH group in the back configuration. Improvement in this reductive step was a significant... 

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 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... 

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