Trifluoroacetic acid → 5-(4-Amino-6-methyl-1,3,5-triazin-2-YL)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

HRID 1812078Notes

Reaction equation

HRID 1812078 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)=[N:18][CH:19]=[C:20]([CH:23]=2)[CH:21]=[O:22])[N:10]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 62406Trifluoromethanesulfonic acid2×HCID 715003625-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

Product 1

HCID 595484735-(4-Amino-6-methyl-1,3,5-triazin-2-YL)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (380 mg, 0.638 mmol) in DCM (5 mL) was treated with TFA (6.0 mL, 78 mmol) and then TfOH (0.050 mL, 0.563 mmol). The solution was heated at 80° C. under a condenser. After 2.5 h, more TfOH (0.050 mL, 0.563 mmol) was added. After 24 h, the mixture was concentrated. The residue was azeotroped with toluene (10 mL) once. The mixture was suspended in 1:1 DMSO-water (5 mL each) and filtered. The resulting solid was then suspended in saturated NaHCO3 for several hours and filtered. The mother liquor was discarded. The resulting sludge was dissolved in hot DMSO and filtered. The filtrate was diluted with MeOH (2× v/v) and allowed to settle. The resulting suspension was filtered. The resulting solid was again dissolved in hot DMSO and diluted with MeOH. After 3 repetitions, the solid was about 95% pure product (50 mg). LCMS (ES, pos.): calcd for C16H14FN7O2: 355.1; found: 356.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.47 (br. s., 1H); 9.92 (s, 1H); 9.17 (br. s., 1H); 8.81 (br. s., 1H); 8.42 (br. s., 1H); 8.32 (d, J=13.11 Hz, 1H); 8.01 (br. s., 1H); 7.85 (d, J=0.78 Hz, 1H); 3.96 (s, 3H); 2.46 (br. s., 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.31 (d, J=11.44 Hz, 1 F).

Workup

  1. waitAfter 24 h
  2. concentrationthe mixture was concentrated
  3. customThe residue was azeotroped with toluene (10 mL) once
  4. filtrationfiltered
  5. waitThe resulting solid was then suspended in saturated NaHCO3 for several hours
  6. filtrationfiltered
  7. dissolutionThe resulting sludge was dissolved in hot DMSO
  8. filtrationfiltered
  9. additionThe filtrate was diluted with MeOH (2× v/v)
  10. filtrationThe resulting suspension was filtered
  11. dissolutionThe resulting solid was again dissolved in hot DMSO
  12. additiondiluted with MeOH

Sources & evidence

ORD record
ord-311275ffa09c4f4da2a89fbdacf4195d
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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