Sodium Bicarbonate → 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide

HRID 526546Notes

Reaction equation

HRID 526546 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[CH3:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:8][O:7][C:6]1[N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=1

Participants

7

Reactant 3

HCID 516892Sodium Bicarbonate2×HCID 41926642-Methylpyridine-4-boronic acid2×HCID 1176002516-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide

Product 1

HCID 1176010586-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamideYield 100.5%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 962WaterSolvent3×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
110 °C

Procedure

Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25 mg, 0.063 mmol), (2-methylpyridin-4-yl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), and PdCl2(dppf)-CH2Cl2 adduct (2.58 mg, 3.16 μmol) in dioxane (0.2 mL) and water (0.05 mL) and purged with nitrogen. The mixture was heated in a microwave reactor on high absorbance for 1 hour at 110° C. Additional portions of (2-methylpyridin-4-yl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), PdCl2(dppf)-CH2Cl2 Adduct (2.58 mg, 3.16 μmol), dioxane (0.1 mL), and water (0.025 mL) were added and the reaction mixture was heated again in a microwave reactor on high absorbance for 1 hour at 110° C., then cooled to 23° C. and diluted with water (1 mL) to give a residue which was extracted with EtOAc (2×1 mL), the organic layers were combined, washed with brine (0.5 mL), dried over Na2SO4, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with EtOAc, and dried in vacuo to provide crude 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25.8 mg, 100% yield) as a brown oil. MS m/z [M+H]+ 408.5.

Workup

  1. temperaturethe reaction mixture was heated again in a microwave reactor on high absorbance for 1 hour at 110° C.
  2. temperaturecooled to 23° C.
  3. customto give a residue which
  4. extractionwas extracted with EtOAc (2×1 mL)
  5. washwashed with brine (0.5 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered through a Hydrophilic PTFE 0.45 um
  8. filtrationfilter (Millipore Millex™-LCR)
  9. washrinsed with EtOAc
  10. customdried in vacuo

Sources & evidence

ORD record
ord-5d68ec246ecb4bf1b034f651b9597006
Source dataset
uspto-grants-2016_05
Patent number
US09345713B2

Reaction notes

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