Sulfuric Acid → 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

HRID 555543Notes

Reaction equation

HRID 555543 reaction equation
NC1C=C(OC)C=C(OC)C=1C(N)=O.OCCC1C=C(C=CC=1OCOC)C=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:46][CH2:47][CH2:48][C:49]1[CH:50]=[C:51]([C:59]2[NH:68][C:67](=[O:69])[C:66]3[C:61](=[CH:62][C:63]([O:72][CH3:73])=[CH:64][C:65]=3[O:70][CH3:71])[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55]COC.S(=O)(=O)(O)O>CN(C)C(=O)C.O.C(O)(=O)C>[OH:55][C:54]1[CH:53]=[CH:52][C:51]([C:59]2[NH:68][C:67](=[O:69])[C:66]3[C:61](=[CH:62][C:63]([O:72][CH3:73])=[CH:64][C:65]=3[O:70][CH3:71])[N:60]=2)=[CH:50][C:49]=1[CH2:48][CH2:47][OH:46]

Participants

10

Reactant 6

HCID 1118Sulfuric AcidHCID 6101p-Toluenesulfonic acidHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 859581153-(2-Hydroxy-ethyl)-4-methoxymethoxy-benzaldehydeHCID 1363988462-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one

Product 1

HCID 1360380072-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneYield 21.9%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1.4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customthe solvent evaporated under reduced pressure
  3. additionWater (70 mL) was added
  4. customto obtain a solid
  5. filtrationThe yellow solid was filtered off
  6. washwashed with water
  7. customdried under vacuum
  8. customto provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which
  9. temperatureAfter cooling to room temperature the reaction mixture
  10. customto obtain a solid
  11. filtrationThe solid was filtered off
  12. washwashed with water
  13. customdried under high vacuum
  14. customto provide crude solid (0.135 g, 85%)
  15. customThe crude was purified by flash column chromatography

Sources & evidence

ORD record
ord-3013e27f51964fc0a89c73e409a8948b
Source dataset
uspto-grants-2011_11
Patent number
US08053440B2

Reaction notes

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