Dimethylformamide → HCID 178493890, compound

HRID 339772Notes

Reaction equation

HRID 339772 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 178493890HCID 178493890, 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, 0.750 g, 1.3 mmol) in DMF (50 mL) was added caesium carbonate (1.30 g, 3.9 mmol, 3.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of cyclic sulfite ester (0.275 g, 1.3 mmol, 1.0 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 (0.275 g, 1.3 mmol, 1.0 equiv.) and stirred at 60° C. for an additional 12 hr. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a 4:1 CH2Cl2/isopropanol solution (100 mL), then was washed with a saturated sodium bicarbonate solution (50 mL) and a saturated sodium chloride solution (50 mL), dried (anh. sodium sulfate), and concentrated under reduced pressure. The residue (1.77 g) was purified by preparative HPLC to give N-(8-{[(2R)-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; Preparative HPLC (condition A) ret. time 3.70 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 3.10-3.40 (m, 4H), 3.47 (br d, J=11.9 Hz, 2H), 3.63-3.84 (m, 2H), 3.88-4.01 (m, 2H), 4.03 (s, 3H), 4.20-4.30 (m, 4H), 4.42 (br s, 1H), 4.57 (app t, J=10.3 Hz, 2H), 7.50 (d, J=9.2 Hz, 1H), 7.96 (dd, J=5.0, 7.5 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.94 (br d, J=7.7 Hz, 1H), 8.99 (D, J=5.2 Hz, 1H), 9.50 (d, J=1.1 Hz, 1H); mass spectrum m/z 481 ((M+1)+, 11%).

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 12 hr
  4. concentrationThe resulting mixture was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in a 4:1 CH2Cl2/isopropanol solution (100 mL)
  6. washwas washed with a saturated sodium bicarbonate solution (50 mL)
  7. dry with materiala saturated sodium chloride solution (50 mL), dried (anh. sodium sulfate)
  8. concentrationconcentrated under reduced pressure
  9. customThe residue (1.77 g) was purified by preparative HPLC

Sources & evidence

ORD record
ord-dfb87c46d04444b7a7dcc682352eee59
Source dataset
uspto-grants-2014_11
Patent number
US08895549B2

Reaction notes

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