Fundamentals of Medicinal Chemistry

ozonolysis, which is very expensive and needs specialized equipment, and

sodium ethanethiolate, which would need special containment since it is a

volatile liquid with a vile odour.

The initial manufacturing scale route (Figure 11.5) used the formation of a

suitably substituted 1,4-butrolactone by a Perkin reactions any phenolic

hydroxyl groups were protected by forming their methyl ethers. The investi-

gators found that the 3,4-substituents of these lactone ring should betransto

each other in order to produce a final product in which these substituents had

the requiredcisorientation in the dioxan ring. The reduction of the lactone to

the lactol enabled the team to use a Wittig reaction to introduce thecisalkenoic

acid side chain into the structure. Although this reaction produces a mixture of

isomers, it was relatively easy to isolate a relatively purecisproduct. The use of

the Wittig reaction also avoids the use of ozonolysis and the expense of special-

ized plant. Cyclization of the product from the Wittig reaction, achieved by a

variety of routes, depending on the nature and stability of the final product, was

HO

F 3 C

H

O

O

COOH

+

Perkin reaction

ZnCl 2 /EtN 3

A mixture of cis and trans isomers is produced.

Thecis isomer in this mixture is converted by treatment

with acid into the trans isomer.

H+

OCH 3

O

O

COOC 2 H 5

COOH

O

O

OCH 3

COOH

O

O

OCH 3

O

O

OCH 3

COOH

O

OH

OCH 3

CH 2 OH

A mixture of enantiomers

is produced. This mixture

is used for the next stage.

This reduction reduces

both the lactone and

the ester side chain at

the same time but

must be carried out

under an inert

atmosphere on a large

scale because of the

pyrophoric nature of

DIBAL.

Bui 2 AlH 4 /5
(DIBAL)

OCH 3

HO

CH 2 OH

COOH

Ph 3 P+(CH 2 ) 4 COOHBr−

KOBut

in a nitrogen

atmosphere

Wittig reaction

Dioxan ring formation.
Various routes were used,
depending on the stability and
nature of the final product.
The substituents at position 2
in the dioxan ring are
introduced in this stage.

Demethylation using ICI 185282

freshly prepared lithium

diphenylphosphide Ph 2 PLi

C

O

C

O

O

+

CHO

CH 3 O

H

O

O

COOH

H 3 CO

F 3 C

Figure 11.5 An outline of the manufacturing route developed for the production of ICI 185282

and its analogues. Both succinic anhydride and the appropriate aromatic aldehydes are readily

available

230 DRUG DEVELOPMENT AND PRODUCTION