THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 385

MeO

NH 2

N

10 min, 130°C 13 min, 250°C

N

NH 2 NMe 3 OH

K 2 CO 3

Toluene

waste

148

250 psi bpr

(product trapped
on resin)

stainless steel
coil

O

OMe

MeO

THF/H 2 O

149

O

SCHEME 11.46 Flow synthesis of quinoline carboxylic acid intermediate trapped on resin.

O

MeO

-

O

H

N

N O

150

N

O

(product caught
on resin)

MeO

HOBt and TBTU

50 min, rt

H
N

SO 3 H

H

DMF

NH 2 N O

N

40 psi bpr

151

O

N

N

O

NH 3 , MeOH

waste

SCHEME 11.47

Flow synthesis of a 5HT 1B antagonist 151 .

counterion. The presence of the third streamwas necessary to promote efficient ester
hydrolysis within the column. The resulting carboxylic acid was immediately

deprotonated and retained within the basic resin column (Scheme 11.45).
The final step involved an amide coupling reaction and a catch-and-release
purification. This arose by use of a solution of O -(benzotriazol-1-yl)- N,N,N 0 ,N 0 -
tetramethyluronium tetrafluoroborate (TBTU) and HOBt in DMF, being flowed
through the column containing immobilized intermediate

150

that activated and
released the carboxylic acid. The output stream from this step containing the
newly generated activated ester was then coupled directly with a second stream of
4-morpholinoaniline in DMF. The flow stream was maintained at ambient temperature
for 50min and then passed through a sulfonic acid column that trapped the product
that could be released by washing with methanolic ammonia, thus completing the
catch-and-release purification. The final solution was concentrated and the crude
inhibitor

150

was recrystallized to obtain an 18% overall yield of product and
thereby nearly trebling the yield of the batch process (Scheme 11.47).

151

11.5.3. Imatinib Mesylate
The synthesis of the tyrosine kinase inhibitor imatinib mesylate (Gleevec )

158

,
which is used to treat chronic myeloid leukemia and gastrointestinal stromal tumors,
is a significant test of the flow chemistry methods since the batch method had been
optimized to provide very insoluble intermediates. Nevertheless, a flow synthesis