Chloroacetonitrile → HCID 10411719, compound

HRID 1948901Notes

Reaction equation

HRID 1948901 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+].Cl[CH2:37][C:38]#[N:39]>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][C:38]#[N:39])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

5

Reactant 3

HCID 7856ChloroacetonitrileHCID 11430Potassium Carbonate2×HCID 11742676HCID 11742676, compound

Product 1

HCID 10411719HCID 10411719, compoundYield 9%

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 chloroacetonitrile (17 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 chloroacetortitrile (17 μl, 0.25 mmol) were added, and 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% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated. The residue was further purified using reverse phase HPLC, eluting with 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid. The appropriate fractions were combined; the acetonitrile was evaporated from the solution, and the resulting aqueous solution was adjusted to pH 8 using concentrated aqueous ammonia. The resulting suspension was extracted twice with DCM, and the extractions combined, filtered through a silicone-treated filter paper, and evaporated. The residue was triturated with diethyl ether to give the product as a white solid (10 mg, 9%); 1H NMR: 132-1.46 (m, 2H), 1.75-1.92 (m, 3H), 220 (m, 2H), 2.84 (m, 2H), 3.72 (s, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 7.20 (s, 1H), 7.26 (dd, 1H), 7.47 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.36 (s, 1H), 9.59 (s, 1H); Mass Spectrum; 456.4, 458.4

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% (7:1 MeOH/concentrated aqueous NH4OH) in DCM
  13. customevaporated
  14. customThe residue was further purified
  15. washeluting with 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid
  16. customthe acetonitrile was evaporated from the solution
  17. extractionThe resulting suspension was extracted twice with DCM
  18. extractionthe extractions
  19. filtrationfiltered through a silicone-
  20. additiontreated
  21. filtrationfilter paper
  22. customevaporated
  23. customThe residue was triturated with diethyl ether

Sources & evidence

ORD record
ord-8b7309e679814a5b89eb499a90c8228b
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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