Organic Chemistry of Drug Synthesis. Volume 7

HN

O

46

2. (t-BuOCO) 2 O
   
   
   1. CH 3 OH
   
   
   
   

t-BOCNH CO 2 CH 3

47

NO 2

t-BOCNH CO 2 CH 3

NO

N OH

48

49

1. H 2


2. Ac 2 O
   tBOCNH CO 2 CH 3

NHAcOH

50

H+

H 2 N CO 2 CH 3

NHAcOH

51

NH CO 2 CH 3

NHAcOH

53

NH

H 2 N

N N

H 2 N NH

52

C 6 H 5 N=C=O

C. Miscellaneous Monocyclic Compounds

The venerable drug theophylline has been used to treat asthmatic attacks
for many years. Research on the mechanism of action of this purine led
to the discovery that it acted by blocking the action of the enzyme phos-
phodiesterase (PDE). The clinical utility of this compound pointed to the
potential of PDE inhibitors as a source for new drugs. Modern method-
ology has led to the subdivision of PDE receptors into a number of sub-
types, each of which seems to be involved in the regulation of a discrete
organ system. It is of interest that a newly developed PDE inhibitor, in
this case specific for PDE 4, has shown clinical activity in alleviating
the symptoms of chronic obstructive pulmonary disease. This finding of
course involves the same organ that led to the discovery of the field
many decades ago. The first sequence in the synthesis of this new PDE
inhibitor comprises homologation of the benzaldehyde ( 54 ) to phenyl-
acetonitrile ( 56 ). Reduction of the aldehyde in the presence of lithium
bromide gives the corresponding benzyl bromide; displacement of
halogen by reaction with potassium cyanide gives the substituted aceto-
nitrile ( 56 ). Condensation of that intermediate with ethyl acrylate in the
presence of base leads to Michael addition of two molecules of the acrylate
and formation of the diester ( 57 ). Treatment of this last intermediate with
strong base leads to internal Claisen condensation with consequent for-
mation of the carberthoxycyclohexanone derivative 58. Heating the keto-
ester with acid initially leads to hydrolysis of the ester to an acid. This
decarboxylates under reaction conditions to give the cyclohexanone ( 59 ).
Condensation of the ring carbonyl group in this intermediate with the
anion from 1,3-dithiane leads to 60 , in what in effect comprises addition

1. MONOCYCLIC COMPOUNDS 29