Formaldehyde → HCID 10408841, compound

HRID 1948941Notes

Reaction equation

HRID 1948941 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH2:29]=O>C(O)=O>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([CH3:29])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1

Participants

4

Reactant 2

HCID 712FormaldehydeHCID 68522948HCID 68522948, compound

Product 1

HCID 10408841HCID 10408841, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Conditions

Temperature
85 °C

Procedure

4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.24 g, 0.56 mmole; prepared as described in Example 29-preparation of starting materials) was dissolved in formic acid (4 ml) and formaldehyde (37% w/v in water) (2 ml) was added. The mixture was heated to 85° C. for one hour and then evaporated under vacuum and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated aqueous NaFfCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (94/6). The fractions containing the expected product were combined, evaporated and the residue triturated with isohexane/diethylether, filtered and dried under vacuum to give the title product as a white solid (0.13 g; 59%); 1H NMR Spectrum: (DMSO d6) 1.70-1.9 (m, 1H); 2.27 (s, 3H); 2.30-2.50 (m, 2H); 2.55-2.75 (na, 2H); 2.91-3.00 (m, 1H); 3.91 (s, 3H); 4.90-5.10 (m, 1H); 7.18 (s, 1H); 7.20-7.35 (m, 1H); 7.40-7.58 (m, 2H); 7.64 (s, 1H); 8.35 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M−H)− 401.

Workup

  1. customevaporated under vacuum
  2. customazeotroped with toluene
  3. customThe residue was partitioned between ethyl acetate and saturated aqueous NaFfCO3
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by column chromatography
  10. washeluting with methylene chloride/methanol (saturated with ammonia) (94/6)
  11. additionThe fractions containing the expected product
  12. customevaporated
  13. customthe residue triturated with isohexane/diethylether
  14. filtrationfiltered
  15. customdried under vacuum

Sources & evidence

ORD record
ord-1669f83e7b8344debe28a7b02831f51d
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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