Potassium Carbonate → Linagliptin

Participants

Reaction Conditions

Reaction Steps

3-Methyl-8-bromo-xanthine (5 gm) and N,N-dimethylformamide (DMF, 28.5 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 2.6 gm) and 1-bromo-2-butyne (2.7 gm) were added at 30° C. The reaction mixture was heated to 85° C. and maintained at this temperature for 4 hours. The reaction mixture is cooled to 30° C. and N,N-dimethylformamide (DMF, 100 mL) was added. Potassium carbonate (4.4 gm) and 2-(chloromethyl)-4-methylquinazoline (4.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 85° C. and maintained at this temperature for 4 hours. The reaction mixture was cooled to 30° C. and N,N-dimethylformamide (DMF, 90 mL) was added. Potassium carbonate (8.3 gm) and (R)-piperidine-3-amine dihydrochloride (5.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80° C. and maintained at this temperature for 8 hours. The reaction mixture was cooled to 30° C. and DMF was evaporated under vacuum. Dichloromethane (DCM, 30 mL) was added and stirred for 15 minutes. The reaction mixture was filtered to separate out the undissolved material and the undissolved material was washed with dichloromethane (30 mL). The dichloromethane was evaporated under vacuum and 10% acetic acid (100 mL) was added. The resulted solution was stirred for 30 minutes and washed with dichloromethane (25 mL×3). The pH of the aqueous layer was adjusted to 8.5 with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (25 mL×2) and the dichloromethane was evaporated under vacuum to get 1.2 gm of Linagliptin.

Provenance & Evidence