Potassium Carbonate → Linagliptin

Participants

Reaction Conditions

Reaction Steps

1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (4 gm) and methyl isobutyl ketone (MIBK 100 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (3.7 gm) and (R)-piperidine-3-amine dibenzoyl-D-tartrate (6.1 gm) were added to the reaction mixture at 26° C. The reaction mixture was heated to 100° C. and maintained at that temperature for 6 hours. The reaction mixture was cooled to 30° C. and filtered, and the salt was washed with MIBK (8 mL). The filtrate was charged into another flask and added slowly 10% aqueous acetic acid solution (40 mL) and stirred for one hour at 26° C. The aqueous layer was separated and washed with 12 mL of dichloromethane. The aqueous layer was charged into another flask and 40 mL of dichloromethane and 20 mL of 16% aqueous sodium hydroxide solution was added drop-wise at 26° C. The mixture was stirred for one hour at 26° C. and the organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Isopropyl alcohol (8 mL) was added to the residue and evaporated under vacuum at below 45° C. Isopropyl alcohol (16 mL) was added to the residue and stirred for 2 hours at 26° C. Filtered the compound and washed with isopropyl alcohol (4 mL) and dried the compound at 60° C. under vacuum to give 3.2 gm of Linagliptin. PXRD pattern: FIG. 2, Chemical Purity: 98.68%, Chiral Purity: 99.82%, S-isomer content: 0.12%, Regio impurity: 0.57%, Bromo impurity: 0.28%

Provenance & Evidence