Trifluoroacetic acid → 4-(2-(2-Methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812118Notes

Reaction equation

HRID 1812118 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>FC(F)(F)S(O)(=O)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[CH:18][N:17]=2)=[CH:38][N:37]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 59548317N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 595483164-(2-(2-Methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 32.4%

Reagents, catalysts & solvents 1

HCID 62406Trifluoromethanesulfonic acidCatalyst

Conditions

Temperature
80 °C

Procedure

A mixture of N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (301 mg, 0.414 mmol) in trifluoroacetic acid (638 nL, 8.28 mmol) was treated with a couple of drops of trifluoromethanesulfonic acid and the mixture was heated at 80° C. overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% (2 M NH3 in MeOH)/DCM (5 mL) and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM→3% MeOH in DCM). The isolated yellow solid was dissolved in DMSO and was subjected to a reversed phase preparative HPLC purification (10% MeCN in H2O to 100% MeCN w/0.1% (v/v) TFA). The product fraction was basified with saturated NaHCO3(aq), extracted with dichloromethane (3×20 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (65 mg, 0.134 mmol, 32.3% yield) as a bright yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 9.03 (s, 2H); 8.73 (d, J=1.56 Hz, 1H); 8.23 (d, J=1.76 Hz, 1H); 7.91 (br. s., 1H); 7.75 (br. s., 1H); 3.91 (s, 3H); 3.50 (s, 2H); 3.11 (br. s., 4H); 2.86 (s, 3H); 2.46-2.49 (m, 4H); 2.44 (s, 3H). m/z (ESI, +ve ion) 486.8 (M+H)+.

Workup

  1. temperatureAfter cooling
  2. concentrationthe mixture was concentrated
  3. dissolutionthe residue was dissolved in 5% (2 M NH3 in MeOH)/DCM (5 mL)
  4. customchromatographed through a Redi-Sep pre-packed silica gel column (pure DCM→3% MeOH in DCM)
  5. dissolutionThe isolated yellow solid was dissolved in DMSO
  6. customwas subjected to a reversed phase preparative HPLC purification (10% MeCN in H2O to 100% MeCN w/0.1% (v/v) TFA)
  7. extractionextracted with dichloromethane (3×20 mL)
  8. dry with materialthe combined organic layers were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-2444094fb7af49fea44f19ac77f9c71b
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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