Sodium hydride → 5-((2,6-Difluoro-4-hydroxyphenethyl)(4H-1,2,4-triazol-4-yl)amino)biphenyl-2-carbonitrile

HRID 82789Notes

Reaction equation

HRID 82789 reaction equation
[H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]#[N:22])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:24][CH2:25][C:26]1[C:42]([F:43])=[CH:41][C:29]([O:30][Si](C(C)C)(C(C)C)C(C)C)=[CH:28][C:27]=1[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.CC(O)=O>[F:43][C:42]1[CH:41]=[C:29]([OH:30])[CH:28]=[C:27]([F:44])[C:26]=1[CH2:25][CH2:24][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]#[N:22])=[CH:11][CH:10]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 2724141Tetrabutylammonium FluorideHCID 68004578(4-(2-Bromoethyl)-3,5-difluorophenoxy)triisopropylsilaneHCID 682279925-(4H-1,2,4-triazol-4-ylamino)biphenyl-2-carbonitrile

Product 1

HCID 682285555-((2,6-Difluoro-4-hydroxyphenethyl)(4H-1,2,4-triazol-4-yl)amino)biphenyl-2-carbonitrileYield 50%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent2×

Procedure

NaH (60% dispersion in mineral oil, 0.039 g, 0.98 mmol) was added to a solution of 5-(4H-1,2,4-triazol-4-ylamino)biphenyl-2-carbonitrile (CAB06022) (0.23 g, 0.88 mmol) in DMF (5 mL). After stirring for 30 minutes a solution of PMW04158 (0.38 g, 0.97 mmol) in DMF (3 mL) was added and stirring was continued for 48 h. TBAF (1M in THF, 1.35 mL) was added and after 30 minutes the reaction mixture was poured onto H2O (15 mL) and acidified with 3M aq. AcOH. The product was extracted with EtOAc (0.3×25 ml) and the combined organics were washed with H2O (4×50 ml) and brine (50 mL) then dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (CHCl3/Acetone) to give the title compound (0.18 g, 50%) as a white solid; 1H NMR (270 MHz, DMSO-d6) 2.81 (2H, t, J=7.5, CH2), 4.01 (2H, t, J=7.5, CH2), 6.41-6.51 m, ArH), 6.61 (1H, d, J=2.2, ArH), 7.45-7.56 (5H, m, ArH), 7.83 (1H, d, J=8.8, ArH), 8.93 (2H, s, NCHN), 10.40 (1H, s, OH); HRMS (ESS) calcd. for C13H18F2N5O1 (M++1) 418.1474. found 418.1466; LC/MS (ES+) tr=1.39 min, m/z 418.0 (M++1, 100%).

Workup

  1. additionwas added
  2. additionwas poured onto H2O (15 mL)
  3. extractionThe product was extracted with EtOAc (0.3×25 ml)
  4. washthe combined organics were washed with H2O (4×50 ml) and brine (50 mL)
  5. dry with materialthen dried (MgSO4)
  6. customthe solvent was removed in vacuo
  7. customThe crude product was purified

Sources & evidence

ORD record
ord-c5adf8a4d2d445f8b733557795e1a79d
Source dataset
uspto-grants-2014_09
Patent number
US08846737B2

Reaction notes

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