Trifluoroacetic acid → 6-Chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 629125Notes

Reaction equation

HRID 629125 reaction equation
[Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O1CCCCC1[N:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[N:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:21]([C:31]2[NH:30][N:29]=[CH:33][CH:32]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 867025996-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 899072816-Chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 56.1, 4.0 g, 8.95 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 13.42 mmol), Pd(PPh3)4 (0.517 g, 0.447 mmol), K3PO4 (5.70 g, 26.8 mmol) and toluene (45 mL) was stirred at 80° C. for 5 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with EtOAc (100 mL) and the combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) to give the protected intermediate, of which 1.5 g (3.02 mmol) was dissolved in DCM (20 mL), treated with TFA (2.32 mL, 30.2 mmol) and stirred for at RT for 76 h. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. Na2CO3 (80 mL) and extracted with EtOAc. The combined extracts were washed with brine (50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1) to give the title compound as beige crystals. UPLC-MS (Condition 2) tR=1.02 min, m/z=382.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.91 (s, 1H) 7.38 (d, J=8.99 Hz, 2H) 7.80-8.00 (m, 3H) 8.73 (d, J=2.35 Hz, 1H) 8.88 (d, J=2.74 Hz, 1H) 10.73 (s, 1H) 13.29-13.42 (m, 1H).

Workup

  1. filtrationThe RM was filtered through Hyflo®
  2. washwashed with EtOAc (100 mL)
  3. customthe combined filtrates were evaporated to dryness under reduced pressure
  4. customThe residue was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1)
  5. customto give the protected intermediate
  6. stirringstirred for at RT for 76 h
  7. customThe solvent was evaporated off under reduced pressure
  8. additionthe residue was treated with sat. aq. Na2CO3 (80 mL)
  9. extractionextracted with EtOAc
  10. washThe combined extracts were washed with brine (50 mL)
  11. dry with materialdried over Na2SO4
  12. customthe solvent was evaporated off under reduced pressure
  13. customto give the crude product which
  14. customwas purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1)

Sources & evidence

ORD record
ord-2c3d330121e24f788482c7c3b88d86c5
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

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