1,1,2-Trimethoxyethane → 4-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline

HRID 634736Notes

Reaction equation

HRID 634736 reaction equation
[CH3:1][O:2][CH:3](OC)[CH2:4]OC.C(=O)([O-])O.[Na+].Cl.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])[C:30]([CH3:38])=[CH:29][C:28]=3[F:39])=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>O.Cl.C(O)C.C(O)(=O)C>[F:39][C:28]1[CH:29]=[C:30]([CH3:38])[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([NH:15][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1

Participants

9

Reactant 4

HCID 475201,1,2-TrimethoxyethaneHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 226250847-Amino4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride

Product 1

HCID 212602754-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-methoxyethylamino)quinazolineYield 77%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolvent2×HCID 313Hydrochloric AcidSolventHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A solution of methoxyacetaldehyde dimethyl acetal (1.27 g, 10 mol) in water (7 ml) and 2M hydrochloric acid (76 μl) was heated at 50-60° C. for 2 hours. The mixture was allowed to cool and adjusted to pH7.5 with saturated aqueous sodium hydrogen carbonate solution. This solution was added to a suspension of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (400 mg, 1 mmol), (prepared as described for the starting material in Example 30), in ethanol (32 ml) and acetic acid (95 μl, 1.5 mmol). The mixture was then stirred for 5 minutes, sodium cyanoborohydride (133 mg, 2 mmol) added and the solution adjusted to pH5.5 with glacial acetic acid. The mixture was stirred for 18 hours and the organic solvents removed by evaporation and the resulting aqueous mixture partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4 followed by 12/8) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline (308 mg, 77%) as a yellow foam.

Workup

  1. temperatureto cool
  2. custom(prepared
  3. stirringThe mixture was stirred for 18 hours
  4. customthe organic solvents removed by evaporation
  5. customthe resulting aqueous mixture partitioned between ethyl acetate and water
  6. customThe organic layer was separated
  7. washwashed with brine
  8. dry with materialdried (MgSO4)
  9. customthe solvent removed by evaporation
  10. customThe residue was purified by column chromatography
  11. washeluting with methylene chloride/methanol (96/4 followed by 12/8)

Sources & evidence

ORD record
ord-094fb5e7fdd84e748005f65c0a3f51ff
Source dataset
uspto-grants-2001_02
Patent number
US06184225B2

Reaction notes

Loading…