agents. Solid tumors are highly dependent on the growth of new blood
vessels, a process termed neoangiogenisis, which provide oxygen and
nutrients to new tissue masses. The tyrosine kinase inhibitorsemaxanib
( 86 ) has shown promising early activity against solid tumors; this com-
pound inhibits neoangiogenisis and also shows antimetastatic activity.
Villsmeyer-type reaction of 3,5-dimethylpyrrole ( 83 ) affords the corre-
sponding carboxaldehyde ( 84 ). Condensation of 84 with indolone proper
( 85 ) in the presence of base affords 86.^12
NONH NHOO=HC NH(^8384)
NH
85
86
DMF
POCl 3
The synthesis of a structurally somewhat more complex indolone tyro-
sine kinase inhibitor starts with the construction of the pyrrole ring.
Reaction oftert-butyl acetoacetate ( 87 ) with nitrous acid leads to nitrosa-
tion on the activated methylene carbon. This reaction introduces the nitro-
gen atom that will appear in the target pyrrole. Condensation of 88 with
O
NH NH
O
t-BuO
O
O
87
NaNO 2
AcOH t-BuO
O
O
88
NOH
O
O
OC 2 H 5
CO 2 C 2 H5
89 tBuO 2 C
90
NH NH
NH
H 3 O+
CO 2 C 2 H 5
91
HC(OCH 3 ) 3
TFA
CO 2 C 2 H 5
O=HC
92
85
93 ; R = C 2 H 5
94 ; R = H
CO 2 R
O
NH
N NH
H
NH
O
95
H 2 N N(C^2 H^5 )^2
N(C 2 H 5 ) 2
ethyl acetoacetate ( 89 ) completes formation of the pyrrole ring ( 90 ). The
strategy depends on the presence of carboxyl groups at the 2 and 4 pos-
itions bearing esters with different reactivity. Thus, treatment of the
diester ( 90 ) with aqueous acid leads to hydrolytic decarboxylation of the
carboxyl adjacent to the ring nitrogen ( 91 ). Reaction of this intermediate
- COMPOUNDS WITH ONE HETEROATOM 149