No abstract

Two routes for the synthesis of cis-N-protected-3-methylamino-4-methylpiperidine (3) were examined:  a route hinging on the electrochemical oxidation of carbamate 1 to install a ketone at the 3 position of the piperidine followed by reductive amination (disconnection A), and a route involving the hydrogenation of an appropriately functionalized pyridine (disconnection B). While both routes to the desired compound were ultimately successful, the pyridine hydrogenation approach proved to be more amenable to kilogram-scale preparations due to the crystallinity and purity of intermediates in that route.

The regioselectivity of the addition of 2,4,6-trimethylphenol to 2,4dichloro-3,6-dimethylpyridine can be controlled by the proper choice of catalyst and solvent. The use of catalytic copper(I) salts and pyridine as solvent results in exclusive addition at C-2. In their absence, a mixture of regioisomers is obtained in which addition at C-4 is dominant.

Propylphosphonic anhydride, or T3P, is a commonly used reagent for amidation reactions with numerous examples of application on scale. One process-friendly aspect of the reagent is the ease of workup, in which quench and extraction or crystallization from aqueous systems should remove any residual T3P or related byproducts. This communication discusses the isolation and characterization of a T3P degradation byproduct and removal of the water-soluble byproduct by washing or further degradation at low pH. A second example demonstrates the degradation of a T3P-related phosphonic ester at low pH.

To address challenges in the preparation of a key building block containing a difluorocyclopropane moiety, we have developed a new protocol for difluorocarbene generation that relies on a Krapcho-type dealkylation of ethyl bromodifluoroacetate (EBDFA), an inexpensive and readily available fluorinated feedstock. Application of DoE and kinetic modeling was used to understand key reaction parameters and identify an optimal process. We report two variants of this procedure that offer different processing advantages and that have both been scaled successfully multiple times to deliver hundreds of kilograms of the resulting difluorocyclopropane. To access a single enantiomer of the target compound, we have also developed a classical resolution strategy and recycling protocol for the undesired enantiomer to replace previous chromatographic methods for separation.