Sulfamides (R 1 R 2 N-SO 2 -NR 3 R 4 ) are traditionally prepared by using strong electrophilic and hazardous reagents such as N-sulfamoyl chloride, sulfonyl chloride, phosphorus oxychloride, or phosphorus pentachloride. We report here a safer and more convenient synthetic methodology for large-scale preparation of sulfamides using the N-substituted oxazolidin-2-one derivatives 5 as synthetic equivalent of the corrosive and hazardous N-sulfamoyl chloride. The scope of the use of N-sulfamoyloxazolidinones to prepare nonsymmetrical sulfamides is explored.
Several novel approaches have been investigated for the
synthesis of the LTD4/E4 antagonist LY290154. Significant
improvements to the discovery route were first made by using
an indoline nucleophile instead of an indolyl anion in the key
substitution step. An alternative approach, introducing the
7-chloroquinoline moiety in the latest stages of the synthesis
was then demonstrated. Interestingly, the pivotal intermediate
of this latter route was also obtained in a one-pot process
following a Katritzky methodology. Finally, an asymmetric
synthesis offering significant advantages over the enantioselective route reported by McKillop was demonstrated.
A scalable process has been developed for the synthesis of trans-2-methylcyclopropanecarboxylic acid via the stereoselective cyclopropanation of ethyl crotonate with dimethylsulfoxonium methylide (Corey's ylide). This well-known reaction is generally low yielding and very challenging to scale up as it involves highly reactive reagents. A design of experiment (DoE) allowed us to quickly define the optimal ranges for the reaction parameters. A very significant increase of the yield was obtained by adding the ylide to ethyl crotonate in DMSO at 80 °C in anhydrous conditions. In view of a scale-up at a multikilogram scale, several experiments were then performed combining Process Analytical Technologies (PAT) and Calorimetry (Dynamic DSC, Adiabatic Reaction Calorimetry and Vent Sizing Package). For safety reasons at high temperatures on large scale the reaction was also evaluated in a continuous flow reactor. Thanks to these studies, we were able to develop an efficient process avoiding the hazardous accumulation of the thermally unstable dimethylsulfoxonium methylide.
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