Organic Process Research and Development p. 1062 - 1067 (2015)
Update date:2022-08-10
Topics:
Gutmann, Bernhard
Elsner, Petteri
O'Kearney-Mcmullan, Anne
Goundry, William
Roberge, Dominique M.
Kappe, C. Oliver
The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key step in the preparation of certain ATR kinase inhibitors. Reactions with NaN3 or TMSN3 and concentrated sulfuric acid under literature conditions provided low conversions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10-15 min at 50 °C. The imidation reaction using TMSN3 as reagent was successfully performed in a flow reactor utilizing CH2Cl2/H2SO4 biphasic conditions. The mixture was subsequently quenched in-line with H2O. Phase separation, neutralization, and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.
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