Hydrochloric Acid → 5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

HRID 1811979Notes

Reaction equation

HRID 1811979 reaction equation
[O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=2)[C:9](F)=[N:10][CH:11]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1.O.C(Cl)Cl.CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:15]2[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]3[C:9]([NH:48][C:42]4[CH:43]=[N:44][C:45]([O:46][CH3:47])=[C:40]([F:39])[CH:41]=4)=[N:10][CH:11]=[C:6]([CH:7]=3)[CH:2]=[O:1])[N:14]=2)=[CH:27][CH:26]=1

Participants

9

Reactant 4

HCID 313Hydrochloric Acid2×HCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 601549954-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 715003625-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehydeYield 56.5%

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.688 g, 3.262 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.477 g, 3.36 mmol) were dissolved in THF (28 mL) and the reaction flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 9.5 mL, 9.5 mmol) was added, and the reaction was stirred under nitrogen for 35 min. Then, aqueous HCl (5.0 M, 4.5 mL, 22.50 mmol) and MeOH (5.8 mL) were added, and the reaction was warmed to room temperature and stirred. After 10 min, the reaction was treated with water (20 mL) and extracted with DCM. 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; DCM to 100:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum. LCMS showed mostly product, but some unhydrolyzed acetonide was also present. The material was dissolved in THF (20 mL) and MeOH (4.0 mL) and aqueous HCl (5.0 M, 2.0 mL, 10 mmol) was added, and the solution was stirred at room temperature. After 25 min, the reaction was diluted with water (20 mL) and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum overnight to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.098 g). 1H NMR (CDCl3, 400 MHz) δ 12.58 (s, 1H), 9.92 (s, 1H), 9.25 (d, J=2.35 Hz, 1H), 8.75 (d, J=2.15 Hz, 1H), 8.03-7.97 (m, 2H), 7.21 (dd, J=15.06 Hz, 8.41 Hz, 4H), 6.87 (dd, J=11.15 Hz, 8.61 Hz, 4H), 4.89 (s, 2H), 4.85 (s, 2H), 4.04 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H). m/z (ESI, pos. ion) 596 (M+H)+.

Workup

  1. temperaturethe reaction flask was cooled in an ice water bath under nitrogen
  2. stirringstirred
  3. waitAfter 10 min
  4. extractionextracted with DCM
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified on a silica gel
  9. filtrationfilter (150 mL fritted filter with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH)
  10. customThe fractions with product were collected
  11. concentrationconcentrated
  12. customdried under high vacuum
  13. dissolutionThe material was dissolved in THF (20 mL)
  14. stirringthe solution was stirred at room temperature
  15. waitAfter 25 min
  16. customThe layers were separated
  17. extractionthe aqueous phase was extracted with DCM
  18. dry with materialdried over sodium sulfate
  19. filtrationfiltered
  20. concentrationconcentrated
  21. customdried under high vacuum overnight

Sources & evidence

ORD record
ord-8315f68419234169a1cc76d273b2ee3f
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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