Chloroacetyl chloride → HCID 68519517, compound

HRID 1948908Notes

Reaction equation

HRID 1948908 reaction equation
[Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1

Participants

5

Reactant 3

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 574768654-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)quinazoline dihydrochloride

Product 1

HCID 68519517HCID 68519517, compoundYield 65.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Chloroacetyl chloride (135 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-4-yloxy)-7-methoxyquinazoline di-hydrochloride (500 mg) (Starting material for Example 16) and diisopropylethylamine (368 mg) in methylene chloride (15 ml) that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and were re-purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 96/4). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline as a crystalline solid (0.33 g); 1H NMR Spectrum: (DMSO d6) 1.60-1.83 (m, 2H), 1.94-2.10 (m, 2H), 3.36-3.46 (m, 2H), 3.67-3.86 (m, 2H), 3.94 (s, 3H), 4.40 (s, 2H), 4.77 (m, 1H), 7.22 (s, 1H), 7.27 (t, 1H), 7.46-7.55 (m, 2H), 7.89 (s, 1H), 8.38 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 479.

Workup

  1. temperatureto warm to room temperature
  2. customthe residue purified by column chromatography on silica eluting
  3. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6)
  4. additionThe fractions containing the expected product
  5. customwere re-purified by column chromatography on silica eluting
  6. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0 to 96/4)
  7. additionThe fractions containing the expected product
  8. customevaporated under vacuum

Sources & evidence

ORD record
ord-7f2793ded02743dab5cc82215fc200c5
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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