Water → Linagliptin

HRID 2172575Notes

Reaction equation

HRID 2172575 reaction equation
[CH3:1][C:2]#[C:3][CH2:4][N:5]1[C:9]([N:10]2[CH2:15][C@H:14]([NH2:16])[CH2:13][CH2:12][CH2:11]2)=[N:8][C:7]2[N:17]([CH3:35])[C:18]([N:20]([CH2:23][C:24]3[N:25]=[C:26]([CH3:34])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[N:33]=3)[C:21](=[O:22])[C:6]1=2)=[O:19].C([C@H]([C@@H](C([O-])=O)O)O)([O-])=O.O.[OH-].[Na+]>ClCCl>[CH3:1][C:2]#[C:3][CH2:4][N:5]1[C:9]([N:10]2[CH2:15][C@H:14]([NH2:16])[CH2:13][CH2:12][CH2:11]2)=[N:8][C:7]2[N:17]([CH3:35])[C:18]([N:20]([CH2:23][C:24]3[N:25]=[C:26]([CH3:34])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[N:33]=3)[C:21](=[O:22])[C:6]1=2)=[O:19]

Participants

5

Reactant 3

HCID 962WaterHCID 14798Sodium HydroxideHCID 131732960HCID 131732960, compound

Product 1

HCID 10096344LinagliptinYield 98.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
26 °C

Procedure

Linagliptin-(D)-tartrate (8 gm) and water (100 mL) were charged into 1000 mL round bottomed flask and stirred for 30 minutes at 26° C. Dichloromethane (80 mL) was added to the solution and cooled to 5° C. Aqueous sodium hydroxide solution (0.6 gm of NaOH is added to 20 mL of water) was added to the mixture at 5° C. and maintained for 1 hour. Layers were separated and aqueous layer was extracted with dichloromethane (20 mL). Combined both organic layers and dried over sodium sulphate and distilled off the organic layer under vacuum at 45° C. Hexane (20 mL) was added to the crude and stirred for 1 hour at 26° C. The precipitate was filtered and washed with 4 mL of hexane and dried the compound at 60° C. under vacuum to give 6 gm of pure Linagliptin. PXRD pattern: FIG. 2, Chemical Purity: 99.67%, Chiral purity: 99.85%, (S)-isomer content: 0.15%, Regio impurity: 0.09%, Bromo impurity: 0.07%.

Workup

  1. temperaturecooled to 5° C
  2. temperaturemaintained for 1 hour
  3. customLayers were separated
  4. extractionaqueous layer was extracted with dichloromethane (20 mL)
  5. dry with materialdried over sodium sulphate
  6. distillationdistilled off the organic layer under vacuum at 45° C
  7. additionHexane (20 mL) was added to the crude
  8. stirringstirred for 1 hour at 26° C
  9. filtrationThe precipitate was filtered
  10. washwashed with 4 mL of hexane
  11. customdried the compound at 60° C. under vacuum

Sources & evidence

ORD record
ord-703fa294abfb4e82855f01a065ea800d
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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