Overview | Sitagliptin, chemical name (2R)-4-oxo-4-[3-trifluoromethyl-5, 6-dihydro [1,2,4] triazole [4,3-a] pyrazin-7 (8h)-Yl]-1-(2,4, 5-trifluorophenyl)-butan-2-amine, which is Merck, USA the first product of the dipeptidyl peptidase-VI (DPP-VI) inhibitor developed by the company. In October 2006, its phosphate monohydrate, as the first dipeptidyl peptidase-VI (DPP-VI) inhibitor, was approved by the US FDA for marketing and clinically used for the treatment of type 2 diabetes. The advantage of the drug is less adverse reactions, low risk of hypoglycemia and does not cause weight gain. In the prior art, sitagliptin impurity 13 is an intermediate compound for the synthesis of sitagliptin. After the further formation of enamine compounds, chiral amine intermediates can be further prepared by asymmetric catalysis, the yield was low. |
preparation | add dichloromethane (ML) and the keto acid compound prepared in Example 8 (10.0g,43.07mmol), stirred to dissolve. Oxalyl chloride (6.56g,51.68mmol) was added dropwise at 10-15 °c, the addition was complete, and the reaction was stirred at 30-35 °c. The reaction was complete, and the reaction was concentrated to a light yellow liquid (10.91g,43.64mmol) at 30~40 °c under reduced pressure, and dichloromethane (5.79 ml) and triethylamine (57.24g, mmol) were added to a 250ml three-necked flask. And the above light yellow liquid (10.0g,52.04mmol) were dissolved with stirring. The temperature was cooled to 0-5 ° C. a solution of the free base of the compound of formula a (13.0g,52.04mmol)/dichloromethane (20ml) was added dropwise, after completion of the dropwise addition, the temperature was raised to 10-15 °c and the reaction was stirred. The reaction was completed and water was added and stirred. The organic phase in the lower layer was taken, and the aqueous phase in the upper layer was discarded. The organic phase was washed with 5% aqueous sodium chloride solution and concentrated to dryness under reduced pressure at 30~40 °c to give sitagliptin impurity 13 (19.24g,47.36mmol), a ketonamide compound, as off-white solid, the molar yield was 91%. |