Dimethylformamide → HCID 178493889, compound

HRID 339775Notes

Reaction equation

HRID 339775 reaction equation
[OH:1][C:2]([C:4](F)(F)F)=O.O[C:9](C(F)(F)F)=O.[OH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:21]([CH2:37][CH2:38][N:39]=3)[C:22]([NH:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=3)=[N:23][C:24]=2[C:25]=1[O:26][CH3:27].[C:40]([O-:43])([O-])=O.[Cs+].[Cs+].[CH3:46][N:47]([CH:49]=O)[CH3:48]>>[OH:1][C@@H:2]([CH2:49][N:47]1[CH2:46][CH2:40][O:43][CH2:9][CH2:48]1)[CH2:4][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:21]([CH2:37][CH2:38][N:39]=3)[C:22]([NH:28][C:29]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:36])=[N:23][C:24]=2[C:25]=1[O:26][CH3:27]

Participants

4

Reactant 3

HCID 6228DimethylformamideHCID 10796Cesium carbonate2×HCID 178493832HCID 178493832, compound2×

Product 1

HCID 178493889HCID 178493889, compoundYield 82%

Procedure

To a solution of N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide bis-TFA salt (Intermediate I, Step 2, 0.210 g, 0.37 mmol) in DMF (12 mL) was added Cs2CO3 (0.61 g, 1.86 mmol, 5.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of cyclic sulfite ester (0.092 g, 0.45 mmol, 1.2 equiv). This mixture was stirred at 60° C. for 12 hr, cooled to room temperature, treated with additional caesium carbonate (0.86 g, 2.6 mmol, 2.0 equiv.) and cyclic sulfite ester (0.076 g, 0.37 mmol, 1.0 equiv.) and stirred at 60° C. for an additional 3.5 days. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a 4:1 CH2Cl2/isopropanol solution (50 mL), then was washed with a saturated NaHCO3 (25 mL) and a saturated NaCl solution (25 mL), dried (anh. Na2SO4), and concentrated under reduced pressure. Trituration with MeOH afforded crystals that were washed with water, then MeOH, and dried at 50° C. under reduced pressure. The resulting solids (0.077 g) were purified by preparative HPLC to give N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.52 g, 82%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.35; HPLC (condition A) ret. time 4.29 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 3.09-3.41 (m, 4H), 3.48 (br d, J=11.7 Hz, 2H), 3.62-3.85 (m, 2H), 3.88-4.01 (m, 2H), 4.03 (s, 3H), 4.20-4.31 (m, 4H), 4.41 (br s, 1H), 4.52-4.62 (m, 2H), 7.50 (d, J=9.4 Hz, 1H), 7.95 (dd, J=5.3, 7.9 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.92 (br d, J=8.1 Hz, 1H), 8.98 (dd, J=1.1, 5.3 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H).

Workup

  1. stirringThis mixture was stirred at 60° C. for 12 hr
  2. temperaturecooled to room temperature
  3. stirringstirred at 60° C. for an additional 3.5 days
  4. concentrationThe resulting mixture was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in a 4:1 CH2Cl2/isopropanol solution (50 mL)
  6. washwas washed with a saturated NaHCO3 (25 mL)
  7. dry with materiala saturated NaCl solution (25 mL), dried (anh. Na2SO4)
  8. concentrationconcentrated under reduced pressure
  9. washTrituration with MeOH afforded crystals that were washed with water
  10. dry with materialMeOH, and dried at 50° C. under reduced pressure
  11. customThe resulting solids (0.077 g) were purified by preparative HPLC

Sources & evidence

ORD record
ord-8296f9ed57ab4b3ab6dbe30c4cefc7df
Source dataset
uspto-grants-2014_11
Patent number
US08895549B2

Reaction notes

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