Potassium Carbonate → HCID 10391639, compound

HRID 1948898Notes

Reaction equation

HRID 1948898 reaction equation
[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][CH3:40]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:37][CH2:38][O:39][CH3:40])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

5

Reactant 3

HCID 11430Potassium Carbonate2×HCID 809722-Bromoethyl methyl ether2×HCID 11742676HCID 11742676, compound

Product 1

HCID 10391639HCID 10391639, compound

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
60 °C

Procedure

4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5 ml). Potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. Further potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added; heating was continued at 60° C. for a further 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the crude product (40 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HCl (1M, 0.5 ml) was added, and the mixture evaporated. Crystallisation from iso-propanol/diethyl ether gave the title product as a hydrochloride salt, a yellow solid (28 mg, 20%); 1H NMR (hydrochloride salt): 1.60-1.75 (m, 2H), 2.00-2.05 (m, 2H), 2.16 (m, 1H), 2.95-3.10 (m, 2H), 3.22 (t, 2H), 3.29 (s, 3H), 3.50-3.57 (m, 2H), 3.70 (t, 2H), 3.99 (s, 3H), 4.12 (d, 2H), 7.34 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H), 7.61 (dd, 1H), 8.46 (s, 1H), 8.78 (s, 1H), 10.08 (br. s, 1H); Mass Spectrum: 475.5, 477

Workup

  1. temperatureheating
  2. waitwas continued at 60° C. for a further 4 hours
  3. customThe solvent was evaporated
  4. customthe residue was partitioned between DCM (20 ml) and water (20 ml)
  5. extractionThe aqueous layer was extracted with DCM (2×10 ml)
  6. extractionthe extractions
  7. filtrationThe combined DCM fractions were filtered through a silicone-
  8. additiontreated
  9. filtrationfilter paper
  10. customevaporated
  11. customThe residue was purified by chromatography
  12. washeluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM
  13. customevaporated
  14. dissolutionthe crude product (40 mg) re-dissolved in 1:1 methanol/DCM (5 ml)
  15. additionEthereal HCl (1M, 0.5 ml) was added
  16. customthe mixture evaporated
  17. customCrystallisation from iso-propanol/diethyl ether

Sources & evidence

ORD record
ord-ec487ef642f644578f1df531b1755e51
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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