945667-22-1

709031-43-6

945667-22-1

The synthesis of (1S,3S,5S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester was carried out using (1S,3S,5S)-2-((2S)-2-amino-2- (3-hydroxyadamantan-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate was carried out in the following general steps: 300 g (0.723 mol, 90.6% purity) of Boc-protected saxagliptin IA was added to a 12L three-necked flask equipped with a mechanical stirrer, a temperature probe and a nitrogen inlet. Dichloromethane (3L) and methanol (288 ml, 7.23 mol) and 36% hydrochloric acid (288 ml, 3.5 mol, 4.8 equiv) were added. The reaction mixture was stirred for 18 h until the reaction was complete (Boc-protected saxagliptin concentration in dichloromethane < 1 mg/ml as monitored by HPLC). After the reaction the mixture was divided into two phases, the upper aqueous phase was separated and collected (the lower dichloromethane phase was discarded). To the recovered aqueous phase, dichloromethane (6 L) and water (720 ml) were added, and then the pH was adjusted to 9.0-10.5 by slow dropwise addition of 5N NaOH solution (~600 ml). solid sodium chloride (120 g) was added and stirring was continued for 20 min. After phase separation, the lower dichloromethane phase was collected (the upper aqueous phase was discarded). The dichloromethane phase was washed with 1% aqueous ammonium chloride solution (450 ml), and after separation again, the lower dichloromethane phase was collected (the upper aqueous phase was discarded, pH=7.8). Dichloromethane was removed by adding about 4 L of ethyl acetate while distilling under reduced pressure at 25 °C and 50 mmHg until the final volume was reduced to 2.5 L when distillation was stopped. The remaining liquid was polished and filtered to remove solid sodium chloride. Concentration was continued until about 1 Kg (about 170 g of saxagliptin free base) was dissolved in 1 L of ethyl acetate. Water (17 ml) was added slowly and stirring was maintained for 10 minutes after crystallization was observed. Another 17 ml of water was added and stirring of the slurry was continued for 30 minutes. The solid was collected by filtration and the filter cake was washed with ethyl acetate (150 ml). The washed filter cake was dried under vacuum at room temperature to give 186 g of saxagliptin free base monohydrate (crystalline form H-1) in 81% yield.