Potassium Carbonate → HCID 66838599, compound

HRID 1752335Notes

Reaction equation

HRID 1752335 reaction equation
[Cl:1][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.FC(F)(F)C(O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([OH:39])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:22]([Cl:40])[C:21]=1[Cl:41].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[ClH:1].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:2][C@H:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][CH2:10][CH2:11][N:5]5[CH2:4]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:22]([Cl:40])[C:21]=1[Cl:41]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 53630913HCID 53630913, compoundHCID 136335140HCID 136335140, compound

Product 1

HCID 66838599HCID 66838599, compoundYield 34%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (115 mg, 0.655 mmol) and 4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetic acid salt (347 mg, 0.655 mmol) were dissolved in dimethylacetamide (0.8 mL) and potassium carbonate (452 mg, 3.28 mmol) was added. The mixture was stirred at 130° C. for 36 h. The mixture was cooled to room temperature and the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and the combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (ethyl acetate-ethanol 1:1). The purified material was dissolved in ethanol and treated with 4M solution of HCl in 1,4-dioxane (0.25 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water and lyophilized to afford N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a brown solid (131 mg, 0.222 mmol, 34% yield). 1H NMR (400 MHz, d6-DMSO): 11.9-11.5 (m, 2H), 8.79 (s, 1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.54 (d, 1H), 7.41 (s, 1H), 4.47-4.25 (m, 4H), 4.03 (s, 3H) 3.96-3.00 (m, 6H), 2.18-1.88 (m, 3H), 1.73-1.57 (m, 1H); MS (EI) for C23H23N4O3Cl2Br: 553 (MH+).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. customthe mixture was partitioned between ethyl acetate and water
  3. extractionThe aqueous portion was extracted with ethyl acetate
  4. washthe combined organic portion was washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford a brown oil which
  9. customwas purified by column chromatography (ethyl acetate-ethanol 1:1)
  10. dissolutionThe purified material was dissolved in ethanol
  11. additiontreated with 4M solution of HCl in 1,4-dioxane (0.25 mL)
  12. concentrationthe mixture was concentrated in vacuo
  13. dissolutionThe residue was dissolved in water

Sources & evidence

ORD record
ord-55ce2b95697d4b439ed07c38301b3311
Source dataset
uspto-grants-2015_10
Patent number
US09163006B2

Reaction notes

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