Diisopropylethylamine → 4-[(3-Chloro-4-fluorophenyl)amino]-6-[(3-ethoxycarbonyl-1-oxo-2-propen-1-yl)-amino]-7-cyclopropylmethoxy-quinazoline

HRID 488412Notes

Reaction equation

HRID 488412 reaction equation
Cl[C:2]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[N:18]=[CH:17][N:16]=[C:15]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([NH:27][C:15]2[C:14]3[C:19](=[CH:20][C:21]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)=[C:12]([NH:11][C:2](=[O:3])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:33]=[CH:32][C:31]=1[F:34]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 155418526-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazolineHCID 53401111Ethyl 4-chloro-4-oxobut-2-enoate

Product 1

HCID 698057484-[(3-Chloro-4-fluorophenyl)amino]-6-[(3-ethoxycarbonyl-1-oxo-2-propen-1-yl)-amino]-7-cyclopropylmethoxy-quinazoline

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 3.00 g of ethyl 3-chlorocarbonyl-acrylate in 50 ml of tetrahydrofuran is added dropwise to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-quinazoline and 3.5 ml of diisopropylethylamine in 150 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture is stirred for a further hour while cooling with an ice bath and then stirred overnight at ambient temperature. Next, the solvent is largely distilled off in the rotary evaporator and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The brown, oily crude product is stirred with diethylether, the precipitate formed is suction filtered and washed with a little diethylether. Yield: 3.20 g (47% of theory), Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z=485, 487 [M+]*

Workup

  1. temperaturewhile cooling with an ice bath
  2. temperaturewhile cooling with an ice bath
  3. stirringstirred overnight at ambient temperature
  4. distillationNext, the solvent is largely distilled off in the rotary evaporator
  5. customthe residue is partitioned between water and ethyl acetate
  6. washThe organic phase is washed with saturated sodium chloride solution
  7. dry with materialdried over magnesium sulphate
  8. concentrationconcentrated by evaporation
  9. stirringThe brown, oily crude product is stirred with diethylether
  10. customthe precipitate formed
  11. filtrationfiltered
  12. washwashed with a little diethylether

Sources & evidence

ORD record
ord-2094a098413749ab821f75dcef6da8f8
Source dataset
uspto-grants-2005_12
Patent number
US06972288B1

Reaction notes

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