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 384

FIGURE 11.5 Automated flow synthesis equipment used to prepare casein kinase I

inhibitors [49].

11.5.2. A Quinolone 5HT 1B Antagonist
The quinolone derivative , which is a potent 5HT 1B antagonist developed by

AstraZeneca, was prepared by a seven-step batch synthesis with an overall yield of 7%
in 2007 [50], thus setting a benchmark for improvement by flow chemistry [51].
The flow synthesis was achieved by combining streams of nitroanisole

151

146

and
piperizine 147 at 135 C. The exiting reaction products were scavenged with benzy-
lamine to remove the hydrofluoric acid by-product before subsequent transmission to
continuous flow hydrogenation. The outflow was scavenged with thiourea to remove
any leached palladium to give aniline (Scheme 11.45).

After a solvent switch from ethanol to toluene, flow streams containing

148

148 and

were combined and heated to 130 C (Scheme 11.46). This was
followed by inline scavenging for residual dicarboxylate and use of anhydrous
potassium carbonate to remove traces of water. The stream was then subjected to a
high-temperature cyclocondensation reaction in a stainless steel flow coil at 250 C.
Since this wasmuch higher than the boiling point of the toluene, an inline back pressure
regulator (BPR) operating at 250 psi was fitted to the system. The output stream from
the stainless steel reactor was rapidly cooled to ambient temperature prior to being
mixed with a third input of THF/H 2 O. The combined stream was then progressed
through a column containing immobilized trimethylamine with a hydroxide

dicarboxylate 149

MeO

NO 2

S

MeO

F

H-Cube
10% Pd/C, 70°C

20 min, 135°C

H NH 2

146

NH 2

NH 2

EtOH

N

100 psi bpr

N H

N

147

148

(98%)

SCHEME 11.45 Flow synthesis of aniline intermediate 148 .