Fundamentals of Medicinal Chemistry

necessary to devise appropriate chemical quantitative and qualitative protocols

for all of the compounds involved in the pilot and manufacturing routes.

Physical methods, such as HPLC and GC, are often used for these purposes.

It is also necessary to be able to identify impurities and any closely related

structures or stereoisomers as this will be required by the licencing authority.

Consequently, some thought should be given to how all these analyses may be

made when designing the production route.

In some synthetic routes, an intermediate product may be used in the next

stage of the synthesis without it being isolated and purified. This procedure is

known astelescoping. It has the advantage of avoiding handling very toxic

intermediates. It also makes it easier to deal with non-crystalline and oily

products. In order for telescoping to be effective, the initial reaction has to

produce a relatively pure product. Consequently, when this technique is used an

analytical procedure must be available to ensure that the purity of the product is

high enough for the next reaction to be carried out in an efficent manner.

11.2.4 A case study

Adapted from S. Lee and G. Robinson,Process Development, Fine Chemicals

from Grams to Kilograms, Oxford University Press, 1995.

COOH

OH

O

O

1

5

6

4

3

2

(b)

O
H 3 C O

H 3 C

COOH

HO

H 3 C

H 3 C

O

O

COOH

ICI 180080

HO

F 3 C

H

O

O

COOH

ICI 159651 ICI 185282

(a)

Figure 11.3 (a) Thromboxane A 2 (TXA 2 ).Note:The locants given are those of the dioxan ring

only and not those for the complete molecule. They are used for reference purposes only (see text).

(b) Examples of some of the thromboxane antagonists developed by ICI

The release of thromboxane A 2 (Figure 11.3(a) ) in the body can cause a

number of toxic reactions including bronchoconstriction, blood vessel constric-

tion and platelet aggregation. This activity led ICI to develop a number of

228 DRUG DEVELOPMENT AND PRODUCTION