Fundamentals of Medicinal Chemistry

compounds that can act as antagonists for thromboxane (Figure 11.3(b) ). It was

found that significant antagonist activity is obtained when:

1. at position 2 there is a substituentcisto the other substituents of the dioxan

ring,

2. the phenolic and alkenoic acid side chains at positions 5 and 6 have acis

orientation and

3. the C¼C of the alkenoic acid side chain has acisconfiguration.

These active analogues were initially synthesized in gram quantities by routes

that allowed numerous analogues to be produced for the preliminary biological

evaluation (Figure 11.4).

O

O

H 3 C

H 3 C

O

O

H 3 C

H 3 C

H 3 CO

The product is a

mixture of

Ozonolysis stereoisomers (B).

O

O

O

H 3 C

H 3 C

H 3 CO

O

O

H 3 C

H 3 C

H 3 CO

COOH

H 3 C

H 3 C

O

O

COOH

HO

ICI 180080

NaSEt

Separation of

the stereoisomers

of mixture B by

chromatography.

Wittig

reaction

Ph 3 P(CH 2 ) 4 COOH

Br−

+

Diethyl

allylmalonate

Treatment of the magnesium enolate

of diethyl malonate with an aroyl

halide, followed by decarboxylation

EtOOC

O

H 3 CO

Various

reducing agents

HO

HO

H 3 CO

The product is a

mixture of

stereoisomers (A).

OCH 3

Dimethoxypropane,

the acetal of acetone

This reaction was carried

out on the mixture A

produced in the previous

stage.

COOEt

EtOOC

H 3 CO

COCl

Aroyl chlorides

Variations in the phenyl

substituents were introduced

at this stage.

H 3 CO

H 3 CO

Figure 11.4 An outline of the initial research route for the synthesis of ICI 180080 and other

analogues. The intermediates and products were produced as racemates. Geometric stereoisomers

were synthesized as shown in the reaction scheme.

The potential manufacturing route for the active thromboxane antagonists

synthesized by the small scale route outlined in Figure 11.4 must include a way

of controlling the stereochemistry of the product that will also give a single

enantiomer. In addition, it must also include alternatives to the chromato-

graphic separation, since this technique is not practical on a large scale, the

CHEMICAL DEVELOPMENT 229