Trifluoroacetic acid → HCID 178519563, compound

HRID 2177598Notes

Reaction equation

HRID 2177598 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](I)=[N:21][N:22](C3CCCCO3)[C:16]=2[CH2:15]1)=[O:13].[F:30][C:31]1[CH:32]=[CH:33][C:34](B2OC(C)(C)C(C)(C)O2)=[N:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].[Cu](Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=3)[NH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]

Participants

12

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 12052TriethylsilaneHCID 177504665-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 90409420HCID 90409420, compound

Product 1

HCID 178519563HCID 178519563, compoundYield 6%

Reagents, catalysts & solvents 6

HCID 24014Cupric ChlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (a mixture of regioisomers) (81 mg, 0.15 mmol) in DMF (1 mL) was added 5-fluoropyridine-2-boronic acid pinacol ester (84 mg, 0.38 mmol), cesium carbonate (198 mg, 0.600 mmol), copper chloride (15 mg, 0.15 mmol), palladium acetate (2 mg, 0.008 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (8 mg, 0.150 mmol). The reaction was stirred at 85° C. overnight under an atmosphere of N2. The reaction was diluted with water and aqueous sodium carbonate (5%) and extracted with EtOAc three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by HPLC (Agilent prep system, Waters XBridge, C18, 5 μm, 30×100 mm column, 5-99% MeOH/20 nM NH4OH over 18 min at 30 mL/min). The product fractions were concentrated in vacuo and then dissolved in CH2Cl2 (1 mL). (THP deprotection) To the solution, triethylsilane (0.011 mL, 0.0737 mmol) and TFA (0.236 mL, 0.059 mmol) were added. The reaction was stirred at rt for 1 h then concentrated in vacuo. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a colorless oil (4 mg, 6%). MS (ESI) mass calcd. C19H13ClF4N4O, 424.1. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.50-8.47 (m, 1H), 7.81-7.74 (m, 1H), 7.56-7.42 (m, 4H), 5.13 (d, J=16.5 Hz, 0.5H), 4.93 (d, J=16.5 Hz, 0.5H), 4.51 (d, J=15.8 Hz, 0.5H), 4.40 (d, J=15.9 Hz, 0.5H), 4.34-4.25 (m, 0.5H), 4.07-3.98 (m, 0.5H), 3.61-3.49 (m, 1H), 3.08-3.03 (m, 1H), 3.01-2.94 (m, 0.5H), 2.88-2.78 (m, 0.5H).

Workup

  1. extractionextracted with EtOAc three times
  2. dry with materialdried over anhydrous MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by HPLC (Agilent prep system, Waters XBridge, C18, 5 μm, 30×100 mm column, 5-99% MeOH/20 nM NH4OH over 18 min at 30 mL/min)
  6. concentrationThe product fractions were concentrated in vacuo
  7. dissolutiondissolved in CH2Cl2 (1 mL)
  8. stirringThe reaction was stirred at rt for 1 h
  9. concentrationthen concentrated in vacuo

Sources & evidence

ORD record
ord-fadf1f83ca3f4f8b8a0ae45a3ceccb52
Source dataset
uspto-grants-2015_06
Patent number
US09066946B2

Reaction notes

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