Potassium Phosphate, Tribasic → 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73731Notes

Reaction equation

HRID 73731 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>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>[OH:55][C@@H:52]1[CH2:53][CH2:54][N:50]([C:31]2[C:30]([C:11]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 867025946-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (59.9 g, 214.4 mmol), K3PO4 (105.7 g, 498.1 mmol) and Pd(PPh3)4 (9.6 g, 8.30 mmol) were added to a suspension of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 74 g, 165.8 mmol) in toluene (740 mL) and stirred at 110° C. for 2.5 h under argon. The mixture was then diluted with EtOAc (2 L), washed with water (2×1 L) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5). The resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL) and was treated with Si-Thiol (Biotage, 15 g, 19.5 mmol) at RT for 17 h. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from MeOH to give the title compound as a white crystalline solid. HPLC (Condition 5) tR=5.99 min, UPLC-MS (Condition 6) m/z=518.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br. s, 3H) 1.63-1.98 (m, 4H) 2.20-2.37 (m, 1H) 2.71-2.94 (m, 1H) 3.21 (d, J=6.65 Hz, 3H) 3.32-3.51 (m, 1H) 3.69-3.92 (m, 1H) 4.08-4.24 (m, 1H) 4.75-4.88 (m, 1H) 4.89-5.17 (m, 1H) 6.29-6.49 (m, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.59 (s, 1H) 7.78-8.10 (m, 3H) 8.80 (t, J=2.54 Hz, 1H) 10.05-10.28 (m, 1H).

Workup

  1. washwashed with water (2×1 L)
  2. dry with materialdried over Na2SO4
  3. customThe solvent was evaporated off under reduced pressure
  4. customthe crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5)
  5. dissolutionThe resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL)
  6. filtrationThe mixture was filtered
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a residue which
  9. customwas crystallized from MeOH

Sources & evidence

ORD record
ord-fe8bf8f28e014121988cc5f661b947ed
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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