875444-08-9

Trifluoroacetic acid (TFA, 9 L) was added to a 100 L Buchi reactor under inert atmosphere and cooled to -5 °C. Benzyl {(1S)-2-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-2-oxoethyl}carbamate (5.50 kg, 13.1 mol) was added to the reactor, followed by rinsing the reactor walls with TFA (2 L). The reaction mixture was cooled to -5 °C and stirred continuously until all solids were completely dissolved. Phenyldimethylsilane (2.18 kg, 15.7 mol in two additions) was added slowly over about 1 hour while the reaction temperature was controlled below 0 °C. The reaction mixture was aged at -2 to -6 °C for 15-20 h until LC analysis showed ketone residue below 2%. Preparation of 50% w/w KOH solution: 13.6 kg of KOH pellets were slowly added to 10 L of water, controlling the exothermic reaction during the dissolution process and keeping the temperature below 30 °C. The prepared KOH solution was stored in a refrigerator for backup. The reaction was quenched with about 2 L of 50% w/w KOH solution under vigorous stirring and cooling conditions, controlling the temperature at about 20 °C. Subsequently, pre-cooled THF (16.5 L) was added, followed by slow addition of the remaining KOH solution (~13.7 L) and rinsing of the reactor walls with 2 L of water while maintaining the temperature below 20 °C. After complete addition of KOH, the reaction mixture was aged for 3 h at room temperature. The reaction mixture was quenched with 27.5 L of isopropyl alcohol acetate (IPAC) and 20 L of 20% w/v NaCl aqueous solution to separate the aqueous and organic layers. The organic layer was washed sequentially with 26 L 20% w/v NaCl aqueous solution, 36 L water, 31 L 0.5 N HCl and 32 L water. After concentrating the organic layer to about 10 L volume, heptane (20 L) was added to induce crystallization. The step of concentrating the organic layer to about 10 L and adding heptane (20 L) was repeated once, and finally heptane (22 L) was added and the slurry was aged at room temperature. The solid product was collected by filtration and washed with 24 L of heptane. The solid product obtained was 98.8% pure with an ee value greater than 99.95% (by LC analysis). The solid product was redissolved in 12.5 L of methanol (heat absorption process). Crystallization was initiated by the addition of 3 L of water at room temperature. This was followed by slow addition of water (9.5 L) over about 60 minutes. After aging for 60 minutes, the slurry was filtered and the solids were washed sequentially with 5 L of methanol/water (1/1.5), 5 L of methanol/water (1/4) and 4 L of water. The solid product was dried under vacuum at 50 °C to give a final product with a purity of 99.9% and an ee value greater than 99.95% (analyzed by LC). The product yield (Ry) was 0.38 (50% EtOAc/hexane).LCMS calculated value was 314.06; measured value was 314.1 (M+1)+.1H NMR (CDCl3, 600 MHz) δ 7.90 (br s, 1H), 7.79 (br s, 2H), 5.83 (d, J = 8.0 Hz, 1H), 5.34 (br s, 1H), 4.31 (br pentet, J = 7.0 Hz, 1H), 0.84 (d, J = 6.6 Hz, 1H). HPLC analytical method (Step C): an Ace-C8 column (250 × 4.6 mm) was used; mobile phase A was acetonitrile (MeCN) and mobile phase B was an aqueous solution containing 0.1% H3PO4; the gradient elution program was: initial conditions 5% A:95% B, 0 min to 95% A:5% B, 9 min; maintain 95% A:5% B until 13 min; return to 5% A: 95% B, 13-15 min. Operating conditions: 35°C, flow rate 1.5 mL/min, detection wavelength 210 nm.

[1] Patent: WO2007/81569, 2007, A2. Location in patent: Page/Page column 34-35
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3851 - 3865
[3] Patent: WO2007/92642, 2007, A2. Location in patent: Page/Page column 23-24
[4] Patent: WO2014/157994, 2014, A1
[5] Patent: WO2008/82567, 2008, A1. Location in patent: Page/Page column 12-13