Potassium Carbonate → Linagliptin

Temperature

100 °C

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%

1. customequipped with a mechanical stirrer
2. temperaturemaintained at that temperature for 6 hours
3. temperatureThe reaction mixture was cooled to 30° C.
4. filtrationfiltered
5. washthe salt was washed with MIBK (8 mL)
6. additionThe filtrate was charged into another flask
7. additionadded slowly 10% aqueous acetic acid solution (40 mL)
8. customThe aqueous layer was separated
9. washwashed with 12 mL of dichloromethane
10. additionThe aqueous layer was charged into another flask
11. addition40 mL of dichloromethane and 20 mL of 16% aqueous sodium hydroxide solution was added drop-wise at 26° C
12. stirringThe mixture was stirred for one hour at 26° C.
13. customthe organic layer was separated
14. extractionthe aqueous layer was extracted with 20 ml of dichloromethane
15. customevaporated under vacuum at below 45° C
16. additionIsopropyl alcohol (8 mL) was added to the residue
17. customevaporated under vacuum at below 45° C
18. additionIsopropyl alcohol (16 mL) was added to the residue
19. stirringstirred for 2 hours at 26° C
20. filtrationFiltered the compound
21. washwashed with isopropyl alcohol (4 mL)
22. customdried the compound at 60° C. under vacuum

ORD record

ord-463ca29998474626b63904e271cad7e5

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09056112B2