Acetoxyacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]methoxy}quinazoline

HRID 1948952Notes

Reaction equation

HRID 1948952 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:34](=[O:33])[CH2:35][OH:36])[CH:15]=2)[N:10]=[CH:9][N:8]=1

Participants

5

Reactant 2

HCID 26297Acetoxyacetyl chlorideHCID 685223024-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride

Product 1

HCID 600366794-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]methoxy}quinazolineYield 38.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 81531DiisopropylethylamineSolvent

Conditions

Temperature
4 °C

Procedure

4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as described in Example 31-starting materials) was dissolved in a mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) 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 methanol (5 ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight the solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine). The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a white solid (0.1 g, 38%); 1H NMR Spectrum: (CDCl3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m, 2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H); 7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48 (s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H)+ 461.

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 methanol (5 ml)
  8. additioncontaining anhydrous powdered potassium carbonate (0.2 g)
  9. stirringAfter stirring overnight the solvent
  10. customwas evaporated
  11. customthe residue purified by column chromatography
  12. washeluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine)
  13. additionThe fractions containing the expected product
  14. customwere evaporated
  15. customthe residue was triturated with diethylether

Sources & evidence

ORD record
ord-aa5c150054e24c6f96fadb9c8f699cfe
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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