Phosphoric Acid → HCID 56640795, compound

Participants

Reaction Conditions

Reaction Steps

Benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylate in the form of a tosylate salt (8.1 kg, 12.68 mol) was slurried in dichloromethane (108 kg), after which 5 wt % NaHCO3 (42 kg, 25.36 mol) was added and the resulting biphasic mixture was stirred vigorously for 30 minutes. The phases were separated, and the organic phase was washed with water (40.5 kg). The organic phase was then distilled at atmospheric pressure to ˜20 L, followed by the addition of DCM (108 kg). DIPEA (5.25 kg, 40.58 mol) was then added and the batch cooled to 0-5° C. Triphosgene (3.01 kg, 10.14 mol) was added in four portions, while keeping the temperature at <10° C. After 30 minutes, a dilute phosphoric acid solution (4.97 kg 85 wt % phosphoric acid in 32 kg water) was added, and the batch aged at 20° C. overnight. The phases were separated and the organic phase was washed with 5 wt % NaHCO3 (26 kg) and water (25 kg). The organic phase was then distilled at atmospheric pressure to 30 L. Ethanol (77 kg) was then added, followed by the addition of seed (10 g). (Note: Crystallization will occur without the use of seed, but the use of seed is preferred as it typically provides a more consistent product and a better yield.) The slurry was distilled in vacuo to a volume of 33 L, then heptane (55 kg) was added dropwise. The slurry was then cooled to 0° C., filtered, washed with 3:1 heptane:ethanol (30 L), and dried on the filter under nitrogen stream to give the title product (5.90 kg, 94%). 1H NMR (CDCl3) 7.35 (10H, m), 6.57 (1H, d), 5.14 (2H, s), 5.07 (1H, d), 4.92 (1H, d), 4.13 (2H, m), 3.95 (1H, m), 3.89 (1H, d), 3.31 (1H, s), 2.99 (3H, m), 2.65 (1H, d), 2.38 (1H, m), 1.94 (4H, m), 1.62 (2H, m) and 1.34 (2H, m).

Provenance & Evidence