Formaldehyde → HCID 10454614, compound

HRID 1948973Notes

Reaction equation

HRID 1948973 reaction equation
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.[CH2:30]=O>C(O)=O>[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[CH3:30])[CH:15]=2)[N:10]=[CH:9][N:8]=1

Participants

4

Reactant 2

HCID 712FormaldehydeHCID 68521248HCID 68521248, compound

Product 1

HCID 10454614HCID 10454614, compound

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (250 mg) (Prepared as described in Example 32), formic acid (5 ml) and formaldehyde (37% w/v in water) (2.5 ml) was heated to 85° C. for one hour. The reaction mixture was then evaporated under vacuum, azeotroped with toluene and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residues were then purified by flash chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (98/2-94/6). The fractions containing the desired product were combined and evaporated to give a colourless gum, which was triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.15 g); 1H NMR Spectrum: (DMSO d6) 1.55-1.83 (m, 3H); 1.95-2.10 (m, 1H); 2.20-2.35 (m, 1H); 2.45 (s, 3H); 2.68-2.85 (m, 1H); 2.93-3.10 (m, 1H); 3.92 (s, 3H); 1924.15 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (m, 1H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M+H)+ 417.

Workup

  1. customThe reaction mixture was then evaporated under vacuum
  2. customazeotroped with toluene
  3. custompartitioned 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 residues were then purified by flash chromatography
  9. washeluting
  10. temperaturewith increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (98/2-94/6)
  11. additionThe fractions containing the desired product
  12. customevaporated
  13. customto give a colourless gum, which
  14. customwas triturated with diethylether
  15. filtrationfiltered
  16. customdried under vacuum

Sources & evidence

ORD record
ord-bbd844301759403da120f4079728078a
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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