Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-5-yl)nicotinamide

HRID 73791Notes

Reaction equation

HRID 73791 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCCCC1[N:15]1[C:19](B(O)O)=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[N:16]1.Br[C:28]1[C:29]([N:48]2[CH2:52][CH2:51][C@@H:50]([OH:53])[CH2:49]2)=[N:30][CH:31]=[C:32]([CH:47]=1)[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([Cl:46])([F:45])[F:44])=[CH:38][CH:37]=1)=[O:34].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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:46][C:43]([F:44])([F:45])[O:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33](=[O:34])[C:32]2[CH:47]=[C:28]([C:19]3[NH:15][N:16]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=3)[C:29]([N:48]3[CH2:52][CH2:51][C@@H:50]([OH:53])[CH2:49]3)=[N:30][CH:31]=2)=[CH:37][CH:38]=1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 53216481(1-(Tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acidHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 178522234(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

K3PO4 (135 mg, 0.635 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid (112 mg, 0.424 mmol) and Pd(PPh3)4 (12.24 mg, 10.59 mmol) were added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 100 mg, 0.212 mmol) in toluene (2 mL) and the RM was stirred at 110° C. for 2 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with water and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.462 mL, 5.99 mmol) and stirred for 1 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 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, 4 g, DCM/EtOH from 99:1 to 9:1). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated in DCM/n-hexane, filtered and dried to give the title product as a white solid. HPLC (Condition 5) tR=6.545 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=518.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.95 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.24 (m, 2H) 3.44 (m, 1H) 4.17-4.32 (m, 1H) 4.91 (br. s, 1H) 6.88 (s, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.86 (d, J=9.38 Hz, 2H) 8.12 (s, 1H) 8.81 (s, 1H) 10.17 (s, 1H) 13.94 (s, 1H).

Workup

  1. filtrationThe RM was filtered through Hyflo®
  2. washwashed with water
  3. customthe solvent was evaporated off under reduced pressure
  4. customto give the crude product which
  5. customwas purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6)
  6. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
  7. stirringstirred for 1 h at RT
  8. extractionextracted with EtOAc
  9. washThe combined extracts were washed with brine (20 mL)
  10. dry with materialdried over Na2SO4
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a crude product which
  13. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1)
  14. additionFractions containing pure product
  15. customthe solvent was evaporated off under reduced pressure
  16. customto give a residue which
  17. customwas triturated in DCM/n-hexane
  18. filtrationfiltered
  19. customdried

Sources & evidence

ORD record
ord-c546f5afe71148f88fbf600b38e2a0bd
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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