Benzylamine → 4-(4-Amino-2-fluorophenoxy)-N-benzylpyridin-2-amine

HRID 2373972Notes

Reaction equation

HRID 2373972 reaction equation
[CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:10]1[N:15]=[CH:14]N=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:19][C:18]=2[F:37])[CH:11]=1.[C:38]([O-])([O-])=O.[K+].[K+]>[Cu]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:12]2[CH:11]=[CH:10][N:15]=[C:14]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:38]=2)=[C:18]([F:37])[CH:19]=1

Participants

5

Reactant 3

HCID 7504BenzylamineHCID 11430Potassium CarbonateHCID 115389121-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea2×

Product 1

HCID 598529014-(4-Amino-2-fluorophenoxy)-N-benzylpyridin-2-amineYield 52.1%

Reagents, catalysts & solvents 1

HCID 23978CopperCatalyst

Conditions

Temperature
160 °C

Procedure

Benzylamine (9.1 mL, 83.8 mmol, 20 eq) was added to 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound B of Example 20, 1.0 g, 4.19 mmol, 1.0 eq), copper powder (0.266 g, 4.19 mmol, 1.0 eq) and K2CO3 (0.578 g, 4.19 mmol, 1.0 eq) in a sealed tube and the reaction mixture was heated to 160° C. for 12 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaCl solution. The solution was extracted with ethyl acetate (3×100 mL), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (YMC C-18 ODS-A S10 50×500 mm, eluting 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.675 g, 52%) as a solid. 1H NMR (CD3OD) δ 7.78-7.80 (m, 1H), 7.28-7.30 (m, 5H), 6.80-6.90 (m, 1H), 6.52-6.55 (m, 2H), 6.18-6.20 (m, 1H), 5.87-5.88 (m, 1H), 4.40 (s, 2H); MS(ESI+) m/z 310 (M+H)+; HRMS(ESI+) calcd.: 310.1356, found: 310.1360.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customquenched with saturated aqueous NaCl solution
  3. extractionThe solution was extracted with ethyl acetate (3×100 mL)
  4. dry with materialthe combined organic extracts dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by preparative reverse phase HPLC (YMC C-18 ODS-A S10 50×500 mm, eluting 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient)
  8. concentrationthe appropriate fractions were concentrated in vacuo
  9. extractionextracted with CH2Cl2 (3×100 mL)
  10. dry with materialThe combined organic extracts were dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f50212e5c4c841538e413b9114b455ab
Source dataset
uspto-grants-2008_12
Patent number
US07459562B2

Reaction notes

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