Drug synthesis convergent routes

The development phase invokes many instances where reactions must be optimised quickly because of changes in the route to or specification of the drug substance. The final challenge is to converge upon the most appropriate and environmentally acceptable methods for manufacture. In identifying optimal synthesis conditions, real-time tuning of a mi-... 

A few drug discovery synthesis routes were used to diversify the thiohydantoin structures. The first route exploited a convergent concept where a three-component Strecker reaction of an amine, a ketone and trimethylsilyl cyanide was used to generate (he cyanoamine analog 24 (Scheme 1). Isothiocyanate prepared from the amine with thiophosgene was added to the cyanoamine to give thiohydantoin -imine 25 which was hydrolyzed to afford the desired thiohydantoins 26. 

Inspection of the synthetic methods described in Sections 21-5 through 21-8 may give you further ideas about how to tackle the synthesis of Prozac, but they are all variations on the schemes formulated so far. However, consideration of the Mannich reaction (Section 21-9) provides a more fundamental alternative, attractive because of its more highly convergent nature to a derivative of compound B with the intact amino function in place. Indeed, this is the commercial route used by Eli Lilly to the final drug. 

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