of the quinazoline involves first alkylation of the nitrophenol ( 172 ) with the
benzyl bromide ( 173 ) to afford the ether ( 174 ). The nitro group is next
reduced to the corresponding aniline. In a convergent sequence the quina-
zolone ( 177 ) is then converted to its enol chloride ( 176 ). Reaction of the
aniline ( 175 ) with the enol chloride leads to displacement of halogen
and formation of 178. Suzuki coupling of this product with the furan
boric acid ( 179 ) in the presence of the usual palladium catalyst attaches
the furyl aldehyde group to the fused benzene ring ( 180 ).
The aldehyde group on the newly attached furan ring is then used to
further elaborate the side chain. Thus reductive amination of the carbonyl
group with ammonia leads to primary amine 181. This newly introduced
function is next alkylated with 2-methylsulfonylethyl chloride. There is
thus obtained the kinase inhibitor 182.^26
NNHNCl O FO = HC O
180NNHNCl O FO181NH (^3) H 2 N
CH 3 SO 2 CH 2 CH 2 Cl
NaB(OAc) 3 H
N
N
HN
Cl O F
O
182
OS
2
H HN
3 C
The preceding compounds all featured a more or less complex aromatic
amine attached to the heterocyclic part of the quinazoline. Aliphatic nitro-
gen by way of contrast occupies that position in the inhibitortandutinib
( 189 ). Alkylation of the phenolic function in 183 with 3-chloropropyl
tosylate affords the ether ( 184 ) from displacement of the tosyl group.
Reaction with nitric acid gives the ortho nitro derivative ( 185 ). Catalytic
hydrogenation then reduces this to the corresponding amine. Treatment
of this intermediate with formamide then adds the requisite atoms for
forming the quinazoline ring. The carbonyl group is then converted to
the enol chloride ( 187 ) by means of thionyl chloride. The sequence
departs from previous schemes by the use of an alycyclic amine in the
next step. Thus, the reactive enol halogen atom is displaced by the free
amine in the monoacylated piperazine to afford 188. Reaction of the
- COMPOUNDS WITH TWO HETEROATOMS 183