Diisopropylethylamine → 4-(3-Chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazoline

HRID 1948966Notes

Reaction equation

HRID 1948966 reaction equation
Cl.[CH2:2]1[O:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[O:3]1.[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33]Cl)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:10][C:11]1[C:12]([F:41])=[C:13]([CH:38]=[CH:39][CH:40]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:36][CH3:37])=[C:22]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:35])[CH2:33][N:6]3[CH2:5][CH:4]4[O:3][CH2:2][O:9][CH:8]4[CH2:7]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 66763181Tetrahydro-4H-1,3-dioxolo[4,5-C]pyrrole hydrochlorideHCID 685201434-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline

Product 1

HCID 100992814-(3-Chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazolineYield 70%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

3,4-methylenedioxypyrrolidine hydrochloride (87 mg) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.25 g; prepared as described in Example 43) and diisopropylethylamine (0.2 ml) in acetonitrile (10 ml) and the mixture heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/isopropanol/triethylamine (97/2/1) to (95/4/1). The fractions containing the expected product were evaporated under vacuum to give the title product as a yellow solid (0.203 g; 70%); 1H NMR Spectrum: (CDCl3) 1.92-222 (m, 4H), 2.54-2.61 (m, 2H), 3.05-3.15 (m, 2H), 3.26-3.38 (q, 2H), 3.42-3.47 (m, 1H), 3.58-3.65 (m, 1H), 4.00-4.10 (m, 4H), 4.47-4.55 (m, 3H), 4.65-4.72 (m, 1H), 4.84 (s, 1H), 5.02 (s, 1H), 7.11-7.22 (m, 2H), 7.24 (s, 1H), 7.96-8.02 (m, 1H), 8.38 (s, 1H), 8.61 (s, 1H), 8.63 (s, 1H); Mass Spectrum: (M+H)+ 558.

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux for 2 hours
  3. customThe reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3
  4. washThe organic layer was washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified by column chromatography
  9. washeluting
  10. temperaturewith increasingly polar mixtures of methylene chloride/isopropanol/triethylamine (97/2/1) to (95/4/1)
  11. additionThe fractions containing the expected product
  12. customwere evaporated under vacuum

Sources & evidence

ORD record
ord-8ad2e01a14534d208bc319e38c2bac16
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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