(4-Cyano-3-fluorophenyl)boronic acid → HCID 58504808, compound

HRID 2367324Notes

Reaction equation

HRID 2367324 reaction equation
[NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[CH2:4]1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19]>O1CCOCC1.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>[NH2:17][C:12]1[N:13]=[C:14]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[CH:15]=[C:10]([N:5]2[C@H:6]([CH3:9])[CH2:7][O:8][C@H:3]([CH2:2][NH2:1])[CH2:4]2)[N:11]=1

Participants

6

Reactant 2

HCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 58504523HCID 58504523, compound

Product 1

HCID 58504808HCID 58504808, compoundYield 59.7%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 4-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-6-chloro-2-pyrimidinamine (0.809 g, 3.14 mmol) and (4-cyano-3-fluorophenyl)boronic acid (1.038 g, 6.29 mmol) in 1,4-dioxane (30 mL) and saturated aqueous NaHCO3 (10 mL) was degassed with nitrogen for 10 minutes. Pd(PPh3)4 (0.185 g, 0.16 mmol) was then added and the mixture was stirred at reflux under nitrogen for 16 hours. The mixture was then cooled and slowly quenched with 1 M HCl (75 mL), then washed with EtOAc (2×75 mL). The aqueous phase was then neutralized with saturated aqueous NaHCO3, brought to about pH 10 with saturated aqueous Na2CO3, and then extracted with 90/10 CH2Cl2/IPA (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient). The product fractions were concentrated and azeotroped a few times with CH3CN to give the title compound (642 mg) as a yellow solid. LC-MS (ES) m/z=343 [M+H]+.

Workup

  1. customwas degassed with nitrogen for 10 minutes
  2. temperatureat reflux under nitrogen for 16 hours
  3. temperatureThe mixture was then cooled
  4. customslowly quenched with 1 M HCl (75 mL)
  5. washwashed with EtOAc (2×75 mL)
  6. extractionextracted with 90/10 CH2Cl2/IPA (3×100 mL)
  7. dry with materialThe extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by flash chromatography (40 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient)
  11. concentrationThe product fractions were concentrated
  12. customazeotroped a few times with CH3CN

Sources & evidence

ORD record
ord-040838fb77c840f69e166f726c912331
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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