Organic Chemistry of Drug Synthesis. Volume 7

O

O

R CO^2 C^2 H^5

R

140

1. HNO 3
   2. H 2

R = CH 3 OCH 2 CH 2 –

O

O

R CO^2 C^2 H^5

R

141

NH 2

HCO 2 – NH 4 +

O

O

R

R

142

N

NH

O

O

O

R

R N

N

Cl

[POCl] 3

143

Si(CH 3 ) 3

Pd(Ph 3 P) 4

O

O

R

R N

N

HN

O

O N

N

146

HN

H 3 CO 144

H 3 CO

H 2 N I

144

I

145

1.

2. Bu 3 N+F–

O

O

The nucleophile-accepting acrylamide group in the kinase inhibitor
canertinib( 154 ) may lead to covalent binding of that group to sites on the
enzyme and thus irreversible inhibition. The starting quinazolone ( 147 )is
available by some scheme such as that above. The carbonyl group is first
converted to its enol chloride ( 148 ) by means of phosphorus oxychloride.

N

F NH

O 2 N

O

POCl 3

147

N

F N

O 2 N

Cl

148

F

Cl

H 2 N

ClF

149

N

F N

O 2 N

HN

150

N OH

O

N

O

151

F

Cl

N

O N

R 2 N

HN

152 ; R = O

153 ; R = H

N

O

F

Cl

N

OO N

HN

COCl

NH

154

Displacement of this halogen by the amino group of the substituted aniline
( 149 ) then affords intermediate 150. The labile fluoride on the quinazoline

180 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING