Organic Chemistry of Drug Synthesis. Volume 7

to afford the dichloro derivative ( 136 ). Treatment with ammonia results in
the displacement of the more labile halogen to give the monoamine ( 137 ).
Reaction of this last intermediate with the future side-chain amine 134
under more forcing conditions, leads to displacement of the remaining
ring halogen. Thus thea-2 blocker 139 is obtained.^21

NH

NH

CH 3 O

CH 3 O

O

O

131

POCl 3

N

CH 3 O N

CH 3 O

Cl

Cl

132

NH 3

N

CH 3 O N

CH 3 O

NH 2

Cl

133

NC NH

CH 3

C 2 H 5 OCO O

O

NC

CH 3

O

O

N

H 2

CH 3

O

O

+ H 2 N N

134

(^135136137)
N
CH 3 O N
CH 3 O
NH 2
CH 3
O
O
NH N
139
The particularly good activity against protein kinases ofa-aminoquin-
azoline derivatives is borne out by their activity against bothin vitroand
in vivo models of human tumor. The seven compounds that follow
reflect the large amount of research that has recently been devoted to
this structural class.
In the first example, nitration of the benzoate ( 140 ) with nitric acid
affords the nitro derivative. Hydrogenation converts this to the anthranilate
( 141 ). In one of the standard conditions for forming quinazolones, that
intermediate is then treated with ammonium formate to yield the hetero-
cycle ( 142 ). Reaction of 142 with phosphorus oxychloride leads to the cor-
responding enol chloride ( 143 ). Condensation of 143 withm-iodoaniline
( 144 ) leads to displacement of chlorine and consequent formation of the
aminoquinazoline ( 145 ). Reaction with the trimethylsilyl derivative of
acetylene in the presence of tetrakis-triphenylphosphine palladium leads
to replacement of iodine by the acetylide. Tributylammonium fluoride
then removes the silyl protecting group to afford the kinase inhibitor
erlotinib( 146 ).^22

2. COMPOUNDS WITH TWO HETEROATOMS 179