n-(4-Amino-2-fluorophenyl)acetamide → N-(4-(3-(4-Amino-6-methyl-1,3,5-triazin-2-YL)-5-chloropyridin-2-ylamino)-2-fluorophenyl)acetamide

HRID 1621789Notes

Reaction equation

HRID 1621789 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[N:32]=2)[C:27](F)=[N:28][CH:29]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:26]2[C:27]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=3)=[N:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)[N:32]=1

Participants

5

Reactant 3

HCID 255648n-(4-Amino-2-fluorophenyl)acetamideHCID 2733832Lithium HexamethyldisilazideHCID 666118184-(5-Chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 59548450N-(4-(3-(4-Amino-6-methyl-1,3,5-triazin-2-YL)-5-chloropyridin-2-ylamino)-2-fluorophenyl)acetamideYield 24.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A mixture of N-(4-amino-2-fluorophenyl)acetamide (0.084 g, 0.501 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.487 mL, 2.504 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.417 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min and then removed from the ice bath and stirred for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by prep HPLC. Fractions containing the product were combined and the solvent was removed in vacuo. The residue was basified using sat. NaHCO3 (10 mL). The aqueous layer was extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated to give the product as a brown solid (40 mg). m/z (ESI, +ve ion) 388.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H); 9.63 (s, 1H); 8.75 (d, J=2.74 Hz, 1H); 8.43 (d, J=2.74 Hz, 1H); 7.93-8.06 (m, 2H); 7.88 (br. s., 1H); 7.71 (t, J=8.80 Hz, 1H); 7.45 (dd, J=8.80, 1.76 Hz, 1H); 2.45 (s, 3H); 2.06 (s, 3H).

Workup

  1. additionwas added
  2. customremoved from the ice bath
  3. stirringstirred for 2 h
  4. customThe reaction was quenched with sat. NH4Cl
  5. customThe resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3
  6. extractionThe aqueous layer was extracted with CHCl3 (2×15 mL)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. concentrationconcentrated
  9. customThe crude product was purified by prep HPLC
  10. additionFractions containing the product
  11. customthe solvent was removed in vacuo
  12. extractionThe aqueous layer was extracted with CHCl3 (3×15 mL)
  13. dry with materialThe combined organic layers were dried over MgSO4
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-8a9195e13e1a445cbb178657a88104ac
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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