
The safe use of diazo reagents for the preparation of a key structure in the synthesis of milnacipran analogues is described herein. Using continuous flow technology, the diazo reagent is synthesized, purified, dried, and subsequently used in semi-batch mode for an intramolecular cyclopropanation. Side products formed in the reaction are isolated and rationalized to optimize the process. Different separation techniques in flow are compared with regard to their ability to produce pure and dry diazo reagents. The studies yield a scalable process to a key intermediate in the syntheses of milnacipran and its possible substituted analogues.
Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry
† School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, U.K.
‡ Institut de Recherche Pierre Fabre, 81603 Gaillac, France
§ Pierre Fabre Médicament, Parc Industriel de la Chartreuse, 81106 Castres, France
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00308
Publication Date (Web): October 29, 2015
Copyright © 2015 American Chemical Society
*E-mail: wirth@cf.ac.uk.
http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00308
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