THE SYNTHESIS OF A DRUG

  Synthetic organic chemistry is one of the corner stones of medicinal chemistry. There are a number of criteria by which a synthesis may be evaluated in a medicinal chemistry context. A convergent synthesis rather than a linear synthesis (Scheme 3) has significant advantages. Not only are there benefits in terms of yield but there is increased flexibility. Structural variation is possible in one arm of the synthesis while keeping the other constant and vice versa. This enables structure: activity studies to be made more easily. Metabolic studies require the preparation of labelled material. It is necessary to explore not only what happens to the intact drug in the body but also to trace metabolic fragments. A convergent synthesis makes labelling different parts of the molecule easier. If a chiral centre is created in the drug then the synthesis should not only be stereospecific but also enantiospecific. The targets for most drugs are chiral. Although the required biological activity may reside in one enantiomer, the other enantiomer may have different, potentially toxic properties. A racemic mixture has to be avoided. Biotransformations involving a chiral enzymatic step have an increasingly important role to play in the preparation of a single enantiomer. While retrosynthetic analysis must play an important role in the design of a synthetic scheme, economic considerations in terms of the availability of starting materials play an equal part. The art of synthesis in a medicinal chemistry context lies in the combination of retrosynthetic analysis with the identification of readily available basic building blocks in the target structure. The dissection of a structure into its basic building blocks can also be a useful way of remembering the structure of drugs.

Scheme 1 Stages in the development of a drug

Scheme 2 The effect of an 80% yield at each step on a convergent and a linear synthesis​

In recent years high throughput enzyme and receptor screens have been developed which require large numbers of small samples for testing. This has placed considerable demands on synthetic chemists who have responded by introducing automated combinatorial methods Scheme 2 The effect of an 80% yield at each step on a convergent and a linear synthesis Scheme 1 Stages in the development of a drug synthesis. The object of a combinatorial synthesis is to maximize the number of compounds that might be produced by simple combinations of starting materials and reagents to generate a library of related structures. The reactions are usually carried out by attaching the starting materials to a solid phase such as a resin by a linker. In a simple example there might be two starting materials, A and B, which are attached to separate sets of resins. These are mixed and split into two and each is then reacted with either C or D to give four compounds. If these are mixed and split again to be combined with E and F, there are eight possible combinations (2 X 2 X 2). Although this is a small library, larger libraries (e.g. 5 X 5 X 5 =125) can be developed quite rapidly. Once a drug reaches the stages of toxicity and clinical trials, relatively large quantities will be required. A number of additional chemical features have to be considered. Steps involving low yields and difficult separations must be eliminated. The large-scale use of hazardous reagents or those, which produce toxic residues have to be avoided. A laboratory synthesis may need to be redesigned to overcome these problems.