Drug design synthetic routes

There are two approaches to producing drugs as a single enantiomer. If a synthetic route produces a racemic mixture, then it is possible to separate the two enantiomers by a process known as resolution (see Section 3.4.8). This is often a tedious process and, of course, half of the product is then not required. The alternative approach, and the one now favoured, is to design a synthesis that produces only the required enantiomer, i.e. a chiral synthesis. 

A large number of drugs feature a heterocyclic component. Thus, the design, synthesis, and evaluation of heterocyclic libraries have rapidly become a major field of organic chemistry. Over the past decade, we have developed synthetic routes to a wide range of different heterocycles starting from resin-bound amino acids, short peptides, and polyamines. 

Once the structure of a lead has been decided it is necessary to design a synthetic pathway to produce that lead. These pathways may be broadly classified as either partial or full synthetic routes. However, partial synthetic routes tend to be more concerned with the large scale production of proven drugs rather than the synthesis of lead compounds. This chapter is intended to introduce some of the strategies used, and the challenges associated with the design of these synthetic routes. 

Our interest in expanding the acylative pyrrole annulation approach to additional heterocyclic systems has led to an efficient synthesis of pyrrolo[3,2-c]pyridin-2-ones and pyrido[3,4-6]pyrrolizidin-l-ones starting from 4-chloro-N-benzyl-2(l//)-pyridinone and amino acid salts.811 Over the years pyrrolo[3,2-c]pyridines (5-azaindoles)41 have been of interest for applications as elements in new drug design, nucleotide analogues,42 and biochemical tools. However, available synthetic routes to multifunctionalized members from this class of heterocyclic structures are limited.41 43... 

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

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