Development of Flow Processes for the Syntheses ofN-Aryl Pyrazoles and Diethyl Cyclopropane-cis-1,2-dicarboxylate

Abstract

Part 1: 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 PhBCl2 to give the final product. Continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable safe scale-up. 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. Part 2: A continuous stirred tank reactor (CSTR) flow process for the preparation of diethyl cyclopropane-cis-1,2-dicarboxylate involved the use of lithium hydride powder is described. Batch reaction kinetics were established and used to design the CSTR. The solid/liquid heterogeneous reaction mixture using lithium hydride with generation of highly flammable hydrogen gas was successfully managed at multi-hundred gram scale in laboratory production. The observed conversion rate was essentially the same as predicted from the design equation for the two equally sized reactors, though the cis/trans ratio was slightly lower than from the batch process. The demonstration of the CSTR flow process made it possible to obtain diethyl cyclopropane-cis-1,2-dicarboxylate on larger scales.