3-(Trifluoromethyl)aniline → 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-(3-(trifluoromethyl)phenyl)benzamide

HRID 1051992Notes

Reaction equation

HRID 1051992 reaction equation
[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:62])([F:61])[C:54]1[CH:55]=[C:56]([CH:58]=[CH:59][CH:60]=1)[NH2:57]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[C:54]([C:53]([F:52])([F:61])[F:62])[CH:55]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1

Participants

6

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 866958153-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid

Product 1

HCID 717353603-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N-(3-(trifluoromethyl)phenyl)benzamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), triethylamine (0.335 mL, 2.4 mmol), and HBTU (250 mg, 0.66 mmol) in 4.0 mL DMF was briefly warmed to approx. 40° C. to dissolve solids. After 3 minutes 3-(trifluoromethyl)aniline (0.149 mL, 1.2 mmol) was added and the reaction stirred at 50° C. for 3 hours, at rt for 16 hours, then an additional 1 hour at 50° C. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oily solid was chromatographed eluting with CHCl3, warm EtOAc, CHCl3:EtOAc (1:1), then 5% MeOH in CHCl3:EtOAc (1:1) giving a pale yellow solid. This solid was recrystallized from EtOAc giving a white solid (100 mg, 40%). 1H NMR (DMSO-d6) δ: 10.46 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.34-7.48 (m, 3H), 7.22-7.27 (m, 1H), 6.41 (s, 2H), 4.30 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).

Workup

  1. dissolutionto dissolve solids
  2. customan additional 1 hour
  3. customat 50° C
  4. customThe reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution
  5. washthe EtOAc layer washed with brine
  6. dry with materialdried with anhydrous Na2SO4 and rotary evaporated
  7. customThe resulting oily solid was chromatographed
  8. washeluting with CHCl3
  9. temperaturewarm EtOAc, CHCl3:EtOAc (1:1)
  10. custom5% MeOH in CHCl3:EtOAc (1:1) giving a pale yellow solid
  11. customThis solid was recrystallized from EtOAc giving a white solid (100 mg, 40%)

Sources & evidence

ORD record
ord-a807f8be9a7b451e835adcb219917e84
Source dataset
uspto-grants-2016_07
Patent number
US09388176B2

Reaction notes

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