DMF (320.2 kg) was charged, and the resulting mixture was concentrated under vacuum to give (R)-2,2,2-trifluoro-N-(1-(5-fluoro-2- hydroxyphenyl)ethyl)acetamide (12) as a solution in DMF. DMF (1808.0 kg) and Cs2CO3 (328 kg, 1006.7 mol, 1.2 equiv) were charged sequentially to a 5000 L reactor, and the (R)-2,2,2-trifluoro-N-(1-(5-fluoro-2-hydroxyphenyl)ethyl)- acetamide (12) DMF solution was charged to the reactor at 25 °C. (R)-tert-Butyl 5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (13) (214.4 kg, 903.6 mol, 1.08 equiv) was charged. The mixture was heated up to 40 °C, stirred for 30 min, further heated to 55 °C, and stirred for 4 h. After reaction completion (<5% RAP), the reaction mixture was cooled to 0− 5 °C. HCl (141.0 kg, 3863.0 mol) solution in H2O (1500.0 kg) was charged at ≤10 °C. The mixture was agitated at 10−15 °C for 90 min before MTBE (640.0 kg) was charged. The mixture was agitated for 25 min, and phases were separated; the aqueous layer was extracted with MTBE (384.0 kg). The organic layers were combined and was washed sequentially with NaHCO3 (30.4 kg) solution in H2O (400.0 kg) and brine solution (100.8 kg NaCl in 320.0 kg H2O). The resulting organic layer was concentrated under vacuum to 950−1100 L. n-Heptane (616.0 kg) was charged, and the mixture was heated to 65−70 °C and then cooled to 0−5 °C for 4−5 h. Solids were collected by a centrifuge, and the cake was washed with nheptane (80.0 kg) and dried under vacuum at 40−50 °C to give tert-butyl ( (S)-2-(4-fluoro-2-((R)-1-(2,2,2- trifluoroacetamido)ethyl)phenoxy)propyl)carbamate (14). The procedure was performed with 160 kg input six times and afforded an average output of 315.7 kg in 92.5% yield. https://doi.org/10.1021/acs.oprd.4c00061
