Ethanol → 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile

HRID 578827Notes

Reaction equation

HRID 578827 reaction equation
Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)[C:6]([O:9][CH2:10][CH3:11])=[N:7][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=2)O1.CCO.C(=O)(O)[O-].[Na+]>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.C1C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:5]2[N:4]=[C:3]([CH2:2][C:30]3[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=3)[CH:8]=[N:7][C:6]=2[O:9][CH2:10][CH3:11])[CH:17]=[CH:16][CH:15]=1

Participants

7

Reactant 4

HCID 702EthanolHCID 516892Sodium BicarbonateHCID 164142762-Cyanopyrimidine-5-boronic acid pinacol esterHCID 904148165-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine2×

Product 1

HCID 816897195-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrileYield 53.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 241BenzeneSolvent

Conditions

Temperature
125 °C

Procedure

Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), and sodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125° C. under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49 (q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=384.15.

Workup

  1. customThe vial was sealed
  2. custompurged with nitrogen
  3. customWater was removed from the reaction with a pipette
  4. customthe crude reaction mixture
  5. filtrationwas filtered thru CELITE®
  6. washwashed with EtOAc (3×5 mL)
  7. dry with materialThe combined organic layers were dried (Na2SO4)
  8. customthe solvent was removed under reduced pressure
  9. customPurification (FCC, SiO2, 0-30%, EtOAc/hexanes)

Sources & evidence

ORD record
ord-383030cab651434a8369723b5f8345fc
Source dataset
uspto-grants-2015_05
Patent number
US09040692B2

Reaction notes

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