935888-69-0

1148157-29-2

1010136-49-8

935888-69-0

Synthesis of N-((S)-3-methoxy-1-((S)-3-methoxy-1-((S)-1-((R)-2-methoxy-2-yl)-1-oxo-3-phenylpropan-2- yl)amino)-1-oxopropan-2-yl) from compound (CAS:1148157-29-2) and compound (CAS:1010136-49-8) (Amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide was prepared in the general steps as follows: in an inert atmosphere, Compound H (1.2 eq.), Compound G (1.0 eq.), H1311J (1.2 eq.), HOST (1.2 eq.), and N-methylpyrrolidinone (8 L/kg of Compound G) were added to a dry flask at 23°C and stirred until completely dissolved. Subsequently, the reaction mixture was cooled to -5 to 0 °C and diisopropylethylamine (2.1 eq.) was slowly added over 15 min while the internal reaction temperature was controlled below 0 °C. The reaction mixture continued to be stirred at 0 °C. The reaction mixture was poured into 8% sodium bicarbonate solution (40 L/kg of compound G) to precipitate crude compound 1 and the suspension was stirred at 20 to 25 °C for 12 hours. Afterwards, it was stirred at 0 to 5°C for 1 h. The white solid was obtained by filtration and washed with water (5 L/kg compound G). The white solid was then slurried in water (15 L/kg) at 20 to 25°C for 3 h. The white solid was filtered and washed with water (5 L/kg Compound G) and isopropyl acetate (2 x 2 L/kg Compound G). The white solid was dried under vacuum at 45 °C to constant weight to give crude compound 1 in 65% yield and 97.2% HPLC purity. Crude compound 1 was completely dissolved in isopropyl acetate (20 L/kg crude compound 1) by heating to 85 °C, and a clarified solution was obtained by thermal filtration to remove particulate matter before heating to 85 °C. The clarified solution was cooled to 65°C at a rate of 10°C/hour and crystalline species were added. When significant crystallization was observed, cooling was continued to 20°C at a rate of 10°C/hour and the suspension was stirred at 20°C for 6 hours, followed by stirring at 0 to 5°C for at least 2 hours. Filtration and rinsing with isopropyl acetate (1 L/kg crude compound 1) was performed and the purified compound 1 was dried under vacuum at 45 °C for at least 24 h to constant weight in a final yield of 87% and HPLC purity of 97.2%.