beta-amino acids to piperidinones by petasis methylenation and acid-induced cyclization

[GRAPHICS] Ester-imine derivatives of beta-amino acids were methylenated with dimethyltitanocene under microwave irradiation and the resulting enol ethers cyclized with Bronsted acid or triisopropylaluminium to give 2,6-syn-disubstituted piperidinones in good yield and diastereoselectivity. The method is analogous to the Petasis-Ferrier rearrangement of 1,3dioxan-4-ones to give tetrahydropyranones

Development of Scalable Processes for the Preparation of <i>N</i>‑Methyl-3-Bromo-5-Methyl Pyrazole

The development and optimization of two scalable routes to <i>N-</i>methyl-3-bromo-5-methyl pyrazole is described. The initial Sandmeyer route entailed a three-step sequence from crotonitrile and methyl hydrazine, proceeding through the 3-amino pyrazole intermediate. Due to the GTI liability of the 3-amino pyrazole intermediate, a tedious steam-distillation, and <30% overall yield, we developed a second-generation Sandmeyer-free approach from methyl crotonate and methyl hydrazine which leveraged a condensation, bromination, and oxidation sequence. Process development led to the improved preparation of <i>N-</i>methyl-3-bromo-5-methyl pyrazole with increased efficiency and overall yield. The isolation, handling, and storage of the final product was greatly improved through the generation of the triflic acid salt, and salt form studies are also discussed