Organic Chemistry of Drug Synthesis. Volume 7

the carbonyl group in 2 with hypochlorite followed by reaction with
thionyl chloride leads to the acid chloride ( 3 ). Condensation of the
last intermediate ( 3 ) with the substituted aminopyridine ( 4 ) affords the
benzamideroflumilast( 5 ).^1

HO

O CH=O

1

F 2 CHCl

F 2 CHO

O CH=O

2

1. NaClO 2
   2. SO 2 Cl F 2 CHO

O CO 2 Cl

3

Cl N

F Cl

2 CHO

O N

H

O

5

Cl N

Cl

H 2 N

4

The discovery of the “statin” mevalonic acid synthesis inhibitors
focused new attention on control of blood lipid levels as a measure to
stave off heart disease. A number of compounds have been found that
treat elevated lipid levels by other diverse mechanisms. The phosphonic
acid derivativeibrolipim( 9 ) is believed to lower those levels by accelerat-
ing fatty acid oxidation. The phosphorus-containing starting material 7 can
in principle be obtained by the Arbuzov reaction of a protected from of
p-bromomethylbenzoic acid ( 6 ) with triethyl phosphate. Removal of the
protecting group and conversion of the acid to an acyl chloride then
affords 7. Condensation of this intermediate with substituted aniline 8
leads to the hypolipidemic agent ( 9 ).^2

P(OC 2 H 5 ) 3

ClOC

P

O

O O

C 2 H 5 C^2 H^5

7

PO 2 C

Br

6

NH 2

CN

Br

8

P

O

O O

C 2 H 5 C^2 H^5

CN

Br

+

HN

O

9

44 MONOCYCLIC AROMATIC COMPOUNDS