benzene is next displaced with the alkoxide from the morpholylpropyl
alcohol ( 151 ) to afford the ether 152. Catalytic hydrogenation serves
to reduce the nitro group to the corresponding amine ( 153 ). Acylation of
the newly formed amine with acryloyl chloride completes the synthesis
of 154.^23
The preparation of yet another variant on the theme starts with quina-
zolone ( 155 ). Treatmment with methanesulfonic acid selectively cleaves
the ether at the more electron-rich position to give the phenol ( 156 ).
This functional group is then acylated by means of acetic anhydride
( 157 ). The ring carbonyl group is next converted to the enol chloride
( 158 ), in this case by means of thionyl chloride. Condensation with the
same aniline used in the previous example leads to the secondary amine
( 159 ). The product is then saponified so as to remove the acetyl group
( 160 ). Alkylation of the enolate from treatment of the phenol with base
with the chloropropyl morpholine ( 161 ) then affordsgefitinib( 162 ).^24
NCH 3 O NHCH 3 OO155NHO NHCH 3 OO
CH 3 SO 3 H Ac 2 O
NCH 3 CO (^2) NH
CH 3 O
O
SO 2 Cl
156 157
N
CH 3 CO (^2) N
CH 3 O
Cl
158
H 2 N
F Cl
N
RO N
CH 3 O
HN
F
Cl
149
159 ; R = CH 3 CO
160 ;R = H
N
O
ON Cl
N
O N
CH 3 O
HN
F
Cl
162
161
A somewhat different strategy is used to preparevandetanib( 171 ). The
starting material in this case is analogous to 155 above with the ether and
free phenol ring oxygen atoms reversed. The ring nitrogen in this molecule
is protected as its pivaloyloxymethyl (POM) derivative, a group that is
stable to most conditions, but can be selectively cleaved by ammonia.
Mitsonobu coupling of the free phenol 163 with the alcohol oxygen on
hydroxymethyl piperidine ( 164 ) leads to the ether ( 165 ). Thet-BOC pro-
tecting group on piperidine nitrogen is then removed with mild base 166.
Reductive alkylation of the newly revealed amine with formaldehyde and
borohydride then affords the N-methylated derivative ( 167 ). The POM pro-
tecting group is then cleaved with ammonia ( 168 ). The quinazolone carbo-
nyl is next converted to the enol chloride with thionyl chloride ( 169 ).
- COMPOUNDS WITH TWO HETEROATOMS 181