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Scheme 7 Continuous flow synthesis of pharmaceutical intermediate 21.
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quickly generate large amounts of product. Compound 21
serves as a precursor to acid 24: a recently reported D-amino
acid oxidase (DAAO) inhibitor that can be used for the
treatment of schizophrenia.28,29 To study the cyclisation of
17d in continuous flow and demonstrate the scalability of the
reaction, the system was reconfigured to pump a solution of
17d directly from a reservoir into the reactor. However, during
reaction of a 1.0 M solution (reduced to 0.5 M by mixing) of
17d, an exotherm was observed, resulting in reactor fouling. A
two-fold dilution of the substrate solution alleviated this
problem and an 8.5 g batch of 21 was prepared within
21 min in excellent purity and yield, corresponding to a
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2008, 1441 and references therein.
sz-To
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13 (a) H. Hemetsberger and D. Knittel, Monatsh. Chem., 1972, 103,
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throughput of 2.5 mmol minÀ1
.
In summary, we have demonstrated a practical procedure
for the thermolysis of azidoacrylates in continuous flow,
applicable to the synthesis of indoles and related heterocycles.
Importantly, the scalability of this process has been shown in
the synthesis of pharmaceutical intermediate 21 (Scheme 7).
We thank the Max Planck Society, AstraZeneca R&D,
Macclesfield, UK and Fonds de Recherche sur la Nature et
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2690 Chem. Commun., 2011, 47, 2688–2690
This journal is The Royal Society of Chemistry 2011