Sitagliptin phosphate monohydrate

486460-32-6

654671-77-9

The general procedure for the synthesis of (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one as a raw material and its phosphate hydrate was carried out in the following manner: 8.14 g of (R)-3-amino-1-( 3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one, 16.3 mL of isopropanol, and 7.3 mL of water, followed by the slow dropwise addition of 1.73 mL of 85% (v/v) phosphoric acid aqueous solution. The temperature of the reaction system was raised to 80 °C until complete dissolution to form a clear solution. The solution was then cooled to 70 °C and the reaction was continuously stirred at this temperature for 2 hours. Upon completion of the reaction, the mixture was cooled to 54 °C at a rate of 8 °C/h and then continued to cool to 22 °C at a rate of 16 °C/h, at which point a large amount of white solid precipitated. 57 mL of isopropanol was added slowly over a period of 40 minutes and stirring was continued for 15 minutes after addition. The white solid was collected by diafiltration and washed twice with 40.7 mL of mixed isopropanol-water solvent (V/V=11:1). Finally, the product was dried under vacuum at 25 °C and -0.08 MPa for 5.5 h to give 10.22 g of white crystalline solid. The purity was 99.91% by HPLC, the moisture content was 3.54% and the molar yield was 97.7%.