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

HRID 525700Notes

Reaction equation

HRID 525700 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCCCC1[N:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[N:16]1.[Cl:29][C:30]1[C:49](I)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)=[O:35])=[CH:32][N:31]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.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>[Cl:29][C:30]1[C:49]([C:19]2[NH:15][N:16]=[CH:17][CH:18]=2)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=2)=[O:35])=[CH:32][N:31]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acid2×HCID 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

K3PO4 (5.70 g, 26.8 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) and Pd(PPh3)4 (0.517 g, 0.447 mmol) were added to a solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.2, 4.0 g, 8.95 mmol) in toluene (45 mL) added under an argon atmosphere and the RM was stirred at 80° C. for 5 h. The RM was filtered through Hyflo®, which was washed with EtOAc. The filtrate and washings were combined and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) and triturated under n-hexane, filtered and dried to afford a solid, a portion of which (1.5 g, 3.02 mmol) was treated with TFA (1.163 mL, 15.10 mmol) in DCM (20 mL) and stirred at RT for 4 h. TFA (1.16 mL) was added and the mixture was allowed to stand for 3 days at RT. The solvent was evaporated off under reduced pressure and the residue was diluted with EtOAc, treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1) to afford the title product as beige crystals. UPLC-MS (Condition 3) tR=1.02 min, m/z=383.1 [M+H]+.

Workup

  1. additionadded under an argon atmosphere
  2. filtrationThe RM was filtered through Hyflo®, which
  3. washwas washed with EtOAc
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a residue which
  6. customwas purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1)
  7. customtriturated under n-hexane
  8. filtrationfiltered
  9. customdried
  10. customto afford a solid
  11. stirringstirred at RT for 4 h
  12. waitto stand for 3 days at RT
  13. customThe solvent was evaporated off under reduced pressure
  14. additionthe residue was diluted with EtOAc
  15. additiontreated with sat. aq. Na2CO3
  16. extractionextracted with EtOAc
  17. washThe combined organic layers were washed with brine (50 mL)
  18. dry with materialdried over Na2SO4
  19. customthe solvent was evaporated off under reduced pressure
  20. customto give a crude product which
  21. customwas purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1)

Sources & evidence

ORD record
ord-b0c0ef4ff13e419eb41319a62dfc18a8
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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