Acetoxyacetyl chloride → HCID 10478764, compound

HRID 1948967Notes

Reaction equation

HRID 1948967 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:33](=[O:32])[CH2:34][OH:35])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1

Participants

5

Reactant 2

HCID 26297Acetoxyacetyl chlorideHCID 68522948HCID 68522948, compound

Product 1

HCID 10478764HCID 10478764, compoundYield 61%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 81531DiisopropylethylamineSolvent

Conditions

Temperature
4 °C

Procedure

4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.25 g; prepared as described in Example 29) was dissolved in a mixture of methylene chloride (10 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.069 ml) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 7M methanolic ammonia (10 ml) and the resulting solution stirred overnight. The solvent was evaporated and the residue purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) 98/2 to 92/8 The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a pale yellow solid (0.161 g, 61%); 3H NMR Spectrum: (DMSO-d6 @ 393K, 500 MHz) 2.10-2.40 (m, 2H), 3.50-3.70 (m, 3H), 3.70-3.85 (m, 1H), 3.95 (s, 3H), 4.05 (s, 2H), 5.15 (s, 1H), 7.15-730 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.70 (m, 1H), 7.85 (s, 1H), 8.40 (s, 1H), 9.20 (bs, 1H); Mass Spectrum: (M+H)+ 447.

Workup

  1. custompartitioned between methylene chloride and saturated aqueous NaHCO3
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. dissolutionThe residue was dissolved in 7M methanolic ammonia (10 ml)
  8. stirringthe resulting solution stirred overnight
  9. customThe solvent was evaporated
  10. customthe residue purified by column chromatography
  11. washeluting
  12. temperaturewith increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) 98/2 to 92/8 The fractions
  13. additioncontaining the expected product
  14. customwere evaporated
  15. customthe residue was triturated with diethylether

Sources & evidence

ORD record
ord-31495ac03d664431baa8e99ae89bd79e
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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