Potassium Carbonate → Linagliptin

HRID 2172568Notes

Reaction equation

HRID 2172568 reaction equation
[CH3:1][N:2]1[C:10]2[N:9]=[C:8](Br)[NH:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].C(N(C(C)C)CC)(C)C.Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:45]=[C:44]([CH3:46])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=1.Cl.Cl.[NH:49]1[CH2:54][CH2:53][CH2:52][C@@H:51]([NH2:55])[CH2:50]1>CN(C)C=O>[CH3:24][C:25]#[C:26][CH2:27][N:7]1[C:8]([N:49]2[CH2:50][C@H:51]([NH2:55])[CH2:52][CH2:53][CH2:54]2)=[N:9][C:10]2[N:2]([CH3:1])[C:3]([N:4]([CH2:35][C:36]3[N:45]=[C:44]([CH3:46])[C:43]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N:37]=3)[C:5](=[O:12])[C:6]1=2)=[O:13]

Participants

8

Reactant 6

HCID 11430Potassium Carbonate2×HCID 81531DiisopropylethylamineHCID 2415182-(Chloromethyl)-4-methylquinazolineHCID 15487978-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-dioneHCID 27568621-Bromo-2-butyneHCID 16211333(3R)-Piperidin-3-amine--hydrogen chloride (1/2)

Product 1

HCID 10096344LinagliptinYield 12.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
85 °C

Procedure

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.

Workup

  1. customequipped with a mechanical stirrer
  2. temperaturemaintained at this temperature for 4 hours
  3. temperatureThe reaction mixture is cooled to 30° C.
  4. temperatureThe reaction mixture was heated to 85° C.
  5. temperaturemaintained at this temperature for 4 hours
  6. temperatureThe reaction mixture was cooled to 30° C.
  7. temperatureThe reaction mixture was heated to 80° C.
  8. temperaturemaintained at this temperature for 8 hours
  9. temperatureThe reaction mixture was cooled to 30° C.
  10. customDMF was evaporated under vacuum
  11. additionDichloromethane (DCM, 30 mL) was added
  12. filtrationThe reaction mixture was filtered
  13. customto separate out the undissolved material
  14. washthe undissolved material was washed with dichloromethane (30 mL)
  15. customThe dichloromethane was evaporated under vacuum and 10% acetic acid (100 mL)
  16. additionwas added
  17. stirringThe resulted solution was stirred for 30 minutes
  18. washwashed with dichloromethane (25 mL×3)
  19. extractionThe aqueous layer was extracted with dichloromethane (25 mL×2)
  20. customthe dichloromethane was evaporated under vacuum

Sources & evidence

ORD record
ord-8dce820fc8d74c428c84d34662c97454
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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