Example 2: Preparation of Compound of Formula VII
1. Cool a mixture of dichloromethane (90 mL) and trifluoroacetic acid (210 mL) to 2-6 °C and add the compound of Formula IV (100 g, 1 eq.) at 37 °C. Maintain the same temperature.
2. The reaction mixture was heated to 25-30 °C and stirred at this temperature for 2 hours.
3. Add dichloromethane (1.5 L) to the reaction mixture, adjust the pH to 7-8 with 25% sodium carbonate solution at 20-30 °C and stir for 20 min at the same temperature.
4. The organic layer was separated and washed sequentially with water (300 mL) and 10% sodium chloride solution (300 mL).
5. Separate the organic layer and concentrate under vacuum at less than 35°C to obtain a residue.
6. The resulting residue was dissolved in dimethylformamide (500 mL) and cooled to 2-6°C. 7.
7. HOBt (2.9 g, 0.1 eq.), PyBOP (133.5 g, 1.2 eq.), N-Boc-homophenylalanine (59.7 g, 1 eq.) and diisopropylethylamine (110.5 g, 4 eq.) were slowly added to the reaction mixture at 2-6 °C.
8. The reaction mixture was heated to 25-30 °C and stirred at this temperature for 2-3 hours.
9. After completion of the reaction, the reaction mixture was slowly poured into water (5 L) at 25-30 °C and stirred at the same temperature for 2-3 hours.
10. The precipitated solid was filtered, washed with water (500 mL) and dried to afford (αS)-α-[[tert-butoxycarbonyl]amino]phenylbutyryl-L-leucyl-L-phenylalanine benzyl ester.
Yield: 130 g; PXRD: Figure 2; DSC: heat-absorption peak at ca. 150 °C; HPLC chemical purity: 99.97%; HOBt: 0.1%, PyBOP: not detected, tris(pyrrolidinylphosphine) oxide: 0.02% by HPLC, respectively.
