Organic Chemistry of Drug Synthesis. Volume 7

includes a substituted naphthyl moiety, has shown preliminaryin vivo
activity. The convergent synthesis starts with construction of a heterocyclic
fragment. Condensation of the keto-nitrile ( 35 ) withp-tolylhydrazine ( 36 )
proceeds to give the pyrazole ( 37 ). The overall transform can be rational-
ized by initial formation of a hydrazone; addition of the remaining hydra-
zine nitrogen to the nitrile would then form the pyrazole ring. Reaction of
this intermediate with phosgene then converts the primary amine to an iso-
cyanate ( 38 ). The other branch of the scheme first involves alkylation of the
t-BOC protected naphthylamine ( 39 ) in the presence of base with chloro-
ethyl morpholine ( 40 ). Exposure to acid then cleaves thet-BOC group to
afford the free amine ( 41 ). Addition of the amino group in this intermediate
to the reactive iscocyanate in 38 connects the two halves via a newly
formed urea function. Thus, the p38 kinase inhibitordoramapimod( 42 )
is obtained.^7

O

(CH 3 ) 3 C

CN

35

+

H 2 N NH

NN

(CH 3 ) 3 C

NH 2

CH 3

(^36) CH 3
OH
tBuOCHN
39

• N
  O
  40
  H 2 N
  N
  O
  Cl
  O

1. Base
   2. H+

COCl 2

N

N O

H

O O

NN

(CH 3 ) 3 C

NH

CH 3 42

NN

(CH 3 ) 3 C

N=C=O

CH 3

37 38

41

3. TETRAHYDRONAPHTHALENES

Drug therapy for treating Parkinson’s disease involves supplementing the
deficient levels of dopamine in the brain that characterize the disease. The
blood–brain barrier virtually dictates that the agents need to be lipophillic;

74 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING