Acetone → HCID 58801813, compound

Participants

Reaction Steps

Three 22 L 3-neck RBFs equipped with heating mantles, mechanical stirrers, thermowells, condensers, and nitrogen bubblers were purged under nitrogen for at least ten minutes. The flasks were charged with 0.454 kg (10 wt %) Pd/C, and 13.62 L (3 vol) methanol. A solution of 4.54 kg (˜16.1 mol) of a mixture of 1-[(R)-3-(3-fluoro-5-nitro-phenoxy) -piperidin-1-yl]-ethanone and 1-[(R)-3-(3,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone in 4.54 L (1 vol) methanol was then charged to the flasks, and an additional 4.54 L (1 vol) methanol was added to the flasks. The solutions were warmed to a gentle reflux, and a solution of 5.07 kg (80.4 mol) ammonium formate in 3.63 L water was then added drop-wise for 10 hours. The reactions were deemed complete by TLC (1:1 hexanes:acetone/PMA stain) and HPLC, and were filtered through celite and concentrated. The concentrate was transferred to two 50 L extractors, and was partitioned between 47.2 L MTBE and 17.7 L 3N HCl. The layers were separated, and the organics were extracted with 6 L (2×) 3N HCl. The aqueous layers were neutralized with 3.54 kg NaOH to pH ˜7, then 9.6 L saturated sodium bicarbonate was added. The aqueous layers were then extracted with 6 L (3×) DCM. The combined organics were washed with 18 L brine, dried over sodium sulfate, filtered and concentrated to yield 3.06 kg of 1-[(R)-3-(3-amino-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone in 75% yield as a thick brown oil (theoretical yield=4.06 kg, purity=90.7% and 95.4% ee).

Provenance & Evidence