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

HRID 1948952Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1948952
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

Komponenten

5

Edukt 2

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

Produkt 1

HCID 600366794-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]methoxy}quinazolineAusbeute 38,1 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 81531DiisopropylethylamineLösungsmittel

Reaktionsbedingungen

Temperatur
4 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-aa5c150054e24c6f96fadb9c8f699cfe
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08399667B2

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