Potassium Carbonate → HCID 72550059, compound

HRID 879229Notes

Reaction equation

HRID 879229 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH3:14])[C@H:11]([N:15]2[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[N:16]2)[C@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:9]1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=1[C:59]1[N:64]=[C:63]([C:65](O)=[O:66])[CH:62]=[CH:61][C:60]=1[F:68].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C.CN(C=O)C.CCOC(C)=O.CCO.C(Cl)Cl>[NH2:22][C@H:10]1[C@@H:11]([N:15]2[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[N:16]2)[C@@H:12]([CH3:14])[CH2:13][N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][C:65](=[O:66])[C:63]2[CH:62]=[CH:61][C:60]([F:68])=[C:59]([C:53]3[C:52]([F:51])=[CH:57][CH:56]=[CH:55][C:54]=3[F:58])[N:64]=2)[CH2:9]1

Participants

11

Reactant 5

HCID 11430Potassium CarbonateHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 181649HOAtHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 86705284HCID 86705284, compound

Product 1

HCID 72550059HCID 72550059, compoundYield 69%

Reagents, catalysts & solvents 5

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 21891449acetonitrile N,N-dimethylformamideSolvent

Procedure

To a round-bottomed flask was added tert-butyl (3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.) and BSA (2.5 equiv.) in Acetonitrile/DMF (4/1, 0.05 M) to give a orange suspension. The mixture was stirred at room temperature for 1 hr at which time all of the solids had dissolved into solution. The mixture was taken to dryness. The crude in DMF (0.10 M) was added EDCI (2.4 equiv.), HOAT (2.4 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (2.4 equiv.). The mixture was stirred at rt for 16 hrs. The reaction was taken to dryness and dissolved in EtOAc and cooled to 0° C. to precipitate the urea byproduct. The mixture was filtered and the organics were washed with H2O, dried over MgSO4, filtered and concentrated. To a solution of the residue in EtOH (0.01 M) was added potassium carbonate (10.0 equiv.). The mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM and quenched with NaHCO3(aq.). The organics were separated and the aqueous solution was extracted with DCM. The combined organics were dried over MgSO4, filtered, and concentrated. The crude alcohol was then dissolved in 25% TFA/DCM. The solution was stirred at room temp for 1 hr. The volatiles were removed on the rotovap. The crude product was taken up in DMSO, filtered, purified via prep-HPLC to yield N-(4-((3R,4S,5S)-3-amino-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 69% yield. LC/MS (m/z)=539.3 (MH+), Rt=0.57 min.

Workup

  1. customto give a orange suspension
  2. dissolutionhad dissolved into solution
  3. stirringThe mixture was stirred at rt for 16 hrs
  4. temperaturecooled to 0° C.
  5. customto precipitate the urea byproduct
  6. filtrationThe mixture was filtered
  7. washthe organics were washed with H2O
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. stirringThe mixture was stirred at room temperature for 2 hrs
  12. customquenched with NaHCO3(aq.)
  13. customThe organics were separated
  14. extractionthe aqueous solution was extracted with DCM
  15. dry with materialThe combined organics were dried over MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated
  18. dissolutionThe crude alcohol was then dissolved in 25% TFA/DCM
  19. stirringThe solution was stirred at room temp for 1 hr
  20. customThe volatiles were removed on the rotovap
  21. filtrationfiltered
  22. custompurified via prep-HPLC

Sources & evidence

ORD record
ord-4108bd5976ce4979ac132905b861ce6d
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Reaction notes

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