Telescoped Flow Process for the Syntheses of N-Aryl Pyrazoles

Abstract

N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl 2 to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N-aryl pyrazole.

Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen

“…[151] Chemiker bei Pfizer verçffentlichten eine vierstufige Synthese eines N-Arylpyrazols. [152] N-Arylpyrazol-oder N-Alkylpyrazol-Einheiten liegen in mehreren Blockbuster-Wirkstoffen vor,zudenen Celecoxib,Rimonabant, Sildenafil und der vor kurzem zugelassene Wirkstoff Crizotinib zur Behandlung von Lungenkrebs gehçren. Die Synthese bei Pfizer begann mit der Diazotierung des Anilins 84 durch Zusammenführung eines Anilin/BF 3 ·THF-Gemischs mit tert-Butylnitrit (Schema 39 c).…”

Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides

“…Ir-catalyzed asymmetric allylations of these nucleophiles (Figure 1) would be valuable because the reaction creates a stereocenter β to the carbonyl group, and the vinylogous ester or amide moiety in the resulting products can undergo a variety of subsequent transformations. 5,6 …”

Two-stage continuous flow synthesis of epoxidized fatty acid methyl esters in a micro-flow system

“…4 N-arylpyrazoles were synthesized continuously in a micro-flow system which was composed of separation units based on gravity and microreactor. 16 <Scheme 1>…”