Potassium Carbonate → Linagliptin

HRID 2172567Notes

Reaction equation

HRID 2172567 reaction equation
[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH2:44])[CH2:39]1>CN(C)C=O>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:38]2[CH2:39][C@H:40]([NH2:44])[CH2:41][CH2:42][CH2:43]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 16211333(3R)-Piperidin-3-amine--hydrogen chloride (1/2)HCID 247500498-Bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione

Product 1

HCID 10096344LinagliptinYield 76.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (5 gm) and N,N-dimethylformamide (DMF, 50 mL) were charged into a 500 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (4.57 gm) and (R)-piperidine-3-amine dihydrochloride (2.86 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and DMF was evaporated under vacuum, then dichloromethane (DCM, 50 mL) was added, and stirred for 15 minutes. The reaction mixture was filtered to separate out the non-dissolved material and the non-dissolved material was washed with 15 mL of dichloromethane. The dichloromethane was evaporated under vacuum to give 4 gm of crude Linagliptin.

Workup

  1. customequipped with a mechanical stirrer
  2. temperaturemaintained at that temperature for 8 hours
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customDMF was evaporated under vacuum
  5. additiondichloromethane (DCM, 50 mL) was added
  6. filtrationThe reaction mixture was filtered
  7. customto separate out the non-dissolved material
  8. washthe non-dissolved material was washed with 15 mL of dichloromethane
  9. customThe dichloromethane was evaporated under vacuum

Sources & evidence

ORD record
ord-1824b45b1b934ec2b8410b9caf3ee749
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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