Water → 1-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol

HRID 1621567Notes

Reaction equation

HRID 1621567 reaction equation
[CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=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)=[CH:5][CH:4]=1.[CH3:45][Mg]Br.[Cl-].[NH4+].O>C1COCC1.CCOC(C)=O>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[CH3:45])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)[N:10]=2)=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 962WaterHCID 25517Ammonium ChlorideHCID 715003625-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehydeHCID 178418573HCID 178418573, compound

Product 1

HCID 666112271-(5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanolYield 82.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.0538 g, 1.769 mmol) was suspended in THF (16 mL) and the reaction flask was cooled in an ice water bath. Then, methylmagnesium bromide (3.0 M in diethyl ether, 1.80 mL, 5.40 mmol) was added via syringe, and the reaction was stirred at 0° C. for 25 min. Then, the reaction was treated with saturated ammonium chloride (3 mL, dropwise at first as gas evolution is observed) and water (20 mL). The reaction was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH (to elute non-polar impurities) to 40:1 (to elute product)) to give 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (893.8 mg). 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 8.83 (d, J=2.35 Hz, 1H), 8.32 (d, J=2.35 Hz, 1H), 8.01 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.96 (d, J=2.35 Hz, 1H), 7.21 (dd, J=10.76 Hz, 8.61 Hz, 4H), 6.87 (dd, J=12.13 Hz, 8.80 Hz, 4H), 4.94-4.81 (m, 5H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.59 (s, 3H), 1.73 (d, J=3.72 Hz, 1H), 1.53 (d, J=6.46 Hz, 3H). m/z (ESI, pos. ion) 612 (M+H)+.

Workup

  1. temperaturethe reaction flask was cooled in an ice water bath
  2. customthe layers were separated
  3. extractionThe aqueous phase was extracted with EtOAc
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified on a silica gel
  8. filtrationfilter
  9. wash(150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH (to elute non-polar impurities) to 40:1 (to elute product))

Sources & evidence

ORD record
ord-c3614b9122b6463a87f4220e39e19ad6
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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