Formaldehyde → HCID 11754635, compound

HRID 1948924Notes

Reaction equation

HRID 1948924 reaction equation
[Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:34][CH3:35])=[C:13]([O:16][C@@H:17]3[CH2:21][N:20]([C:22](OC(C)(C)C)=O)[C@H:19]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:34][CH3:35])=[C:13]([O:16][C@@H:17]3[CH2:21][N:20]([CH3:22])[C@H:19]([C:29](=[O:33])[N:30]([CH3:31])[CH3:32])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

4

Reactant 2

HCID 712FormaldehydeHCID 60036687HCID 60036687, compound

Product 1

HCID 11754635HCID 11754635, compoundYield 72.2%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (prepared as described in Example 24; 0.18 g), formic acid (0.31 ml) and formaldehyde (0.51 ml) were heated at 85° C. for 6 hours. The reaction mixture was cooled and evaporated under vacuum. The resulting residue was partitioned between methylene chloride/n-propanol and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to yield a white crystalline solid. The solid was washed with water, dissolved in methylene chloride and dried over magnesium sulfate. The solvent was removed under vacuum to give the title product (0.11 g); 1H NMR Spectrum: (DMSO d6) 1.87 (t, 1H), 2.24 (s, 3H), 2.61-2.68 (m, 1H), 2.83 (s, 3H), 2.85-2.94 (m, 1H), 3.10 (s, 3H), 3.22-3.31 (m, 2H), 3.92 (s, 3H), 5.04 (m, 1H), 7.22 (s, 1H), 7.29 (t, 1H), 7.45-7.56 (m, 2H), 7.64 (s, 1H), 8.35 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H)+ 474.

Workup

  1. temperatureThe reaction mixture was cooled
  2. customevaporated under vacuum
  3. customThe resulting residue was partitioned between methylene chloride/n-propanol and saturated sodium bicarbonate
  4. dry with materialThe organic layer was dried over magnesium sulfate
  5. custompurified by column chromatography
  6. washeluting
  7. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10)
  8. additionThe fractions containing the desired product
  9. customevaporated under vacuum
  10. customto yield a white crystalline solid
  11. washThe solid was washed with water
  12. dissolutiondissolved in methylene chloride
  13. dry with materialdried over magnesium sulfate
  14. customThe solvent was removed under vacuum

Sources & evidence

ORD record
ord-7a67e93edd1b4bef9599437824878059
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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