In some chemical processes, extractive workup is used to remove
the solvent of reaction in an aqueous layer and to isolate the
product in the organic layer. Most of the time some reaction
solvent is co-extracted in the organic layer, along with some
water. This has a non-negligible impact on subsequent operations (washing, crystallization), and we have thus determined
those levels for ten reaction solvents and five extraction solvents
in order to help the process chemist in the development of
efficient isolation procedures.
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.
We report herein a short and efficient synthesis of (R,R)-2-methylcyclopropanecarboxylic acid via a Horner−Wadsworth−Emmons reaction involving commercially available (S)-propylene oxide and triethylphosphonoacetate (TEPA). The TEPA/base/propylene oxide stoichiometry was found critical to achieve
high yields. We therefore studied the TEPA anion formation
and stability using in situ IR spectroscopy. The reaction yield
is strongly influenced by the counterion and solvent, whereas
high diastereoselectivities are always obtained. Under the best
experimental conditions (HexLi/MeTHF/150 °C), crude (R,R)-2-methylcyclopropanecarboxylic acid is obtained in 85−90%
yield with >98% trans selectivity.
A general strategy for the synthesis of 4-mono-and -disubstituted tetrahydroazepines of type (VI) starts with optically active lactones (I) and uses Grubbs' ring-closing metathesis as the key step. Due to their instability at room temperature, products (VI) are transformed to the hexahydro analogues (VII). -(DELHAYE, L.; MERSCHAERT*, A.; DIKER, K.; HOUPIS, I. N.; Synthesis 2006, 9, 1437-1442; Lilly Res. Lab., Chem. Proc. R&D, Lilly Dev. Cent. S. A., B-1348 Mont St. Guibert, Belg.; Eng.) -Mais 36-160
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