Formaldehyde → HCID 10070557, compound

HRID 1948897Notes

Reaction equation

HRID 1948897 reaction equation
[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3CCNC[CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:5]([CH3:6])[CH2:4][CH2:3]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

4

Reactant 2

HCID 712FormaldehydeHCID 11742676HCID 11742676, compound

Product 1

HCID 10070557HCID 10070557, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Conditions

Temperature
90 °C

Procedure

6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (Reference Example 3; 300 mg, 0.66 mmol) was dissolved in formic acid (10 ml). Aqueous formaldehyde solution (40%, 1 ml) was added, and the mixture heated to 90° C. for 3 hours. The mixture was evaporated, and the residue dissolved in water (30 ml). The solution was adjusted to pH 8-9 by the addition of sodium hydroxide solution (1M), causing precipitation of a white solid; this was collected by filtration and washed with water (20 ml). The crude product was purified by chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. Evaporation of the appropriate fractions followed by crystallisation of the residue from acetonitrile gave the product as a white crystalline solid (55 mg, 20%); 1H NMR: 1.66-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.14-2.22 (m, 2H), 2.18 (s, 3H), 2.65-2.70 (m, 2H), 3.92 (s, 3H), 4.51 (m, 1H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.78 (s, 1H), 8.34 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 417.2, 419.3

Workup

  1. customThe mixture was evaporated
  2. dissolutionthe residue dissolved in water (30 ml)
  3. additionThe solution was adjusted to pH 8-9 by the addition of sodium hydroxide solution (1M)
  4. customprecipitation of a white solid
  5. filtrationthis was collected by filtration
  6. washwashed with water (20 ml)
  7. customThe crude product was purified by chromatography
  8. washeluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM
  9. customEvaporation of the appropriate fractions
  10. customfollowed by crystallisation of the residue from acetonitrile

Sources & evidence

ORD record
ord-eb1eb2bb297748fbbb3992e454274958
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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