Process 91AV / Route Selection are important activities in the path of a drug from mind to market. The medicinal chemistry routes for synthesis although amenable to analogue design are usually low yielding and are fraught with a plethora of intractable problems such as such as commercially unavailable reagents and intermediates, capricious and cryogenic reactions that preclude efficient scale up, tedious chromatography unfavorable atom economy and problems in waste disposal and management. Considerable research efforts have to be expended in developing novel, cost efficacious and scalable processes and seamlessly transferring these technologies to manufacturing operations. These principles will be demonstrated by our process development efforts on an anti-epileptic and an anti-asthma drug that have resulted in amelioration of many of these problems and removal of significant bottlenecks in the progress of a drug from conception to commercialization.
Several problems are currently associated with the use of biological systems in studying drug metabolism.
• In vitro studies produce very small quantities of the product. Primary metabolites are often hydrophilic and difficult to isolate.
• Animals studies necessitate the sacrifice of animals and are extremely expensive to conduct. Liver slice preparations are of variable potency; it is difficult to quantitate the precise stoichiometry of the oxidant.
• Many of the metabolites are not amenable to organic synthesis by conventional routes.
We present rare examples of porphyrin-mediated oxidations of sophisticated pharmaceutical entities. The reactions (mimics of cytochrome P-450) are generally applicable and have been used in our laboratories to achieve hydroxylation and N-demethylation on numerous other substrates. This approach affords and efficient method for the systematic preparation and identification of the entire spectrum of metabolites from a chosen drug.
Several problems are currently associated with the use of biological systems in studying drug metabolism.
• In vitro studies produce very small quantities of the product. Primary metabolites are often hydrophilic and difficult to isolate.
• Animals studies necessitate the sacrifice of animals and are extremely expensive to conduct. Liver slice preparations are of variable potency; it is difficult to quantitate the precise stoichiometry of the oxidant.
• Many of the metabolites are not amenable to organic synthesis by conventional routes.
We present rare examples of porphyrin-mediated oxidations of sophisticated pharmaceutical entities. The reactions (mimics of cytochrome P-450) are generally applicable and have been used in our laboratories to achieve hydroxylation and N-demethylation on numerous other substrates. This approach affords and efficient method for the systematic preparation and identification of the entire spectrum of metabolites from a chosen drug.
