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.

The continuous flow protocol overcomes problems associated with the spontaneous decomposition of ethyl lithiodiazoacetate.

Chemistry. -(MUELLER, S. T. R.; SMITH, D.; HELLIER, P.; WIRTH*, T.; Synlett 25 (2014) 6, 871-875, http://dx.doi.org/10.1055/s-0033-1340835 ; Sch. Chem., Cardiff Univ., Cardiff CF10 3AT, UK; Eng.) -M. Tismer 40-052

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