Water → Tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate

HRID 1867737Notes

Reaction equation

HRID 1867737 reaction equation
C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[C:12]([F:32])=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH2:28]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[NH2:33][C:34]([C:36]1([NH:47][CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)=[O:35].O>CN(C)C=O>[NH2:33][C:34]([C:36]1([N:47]([CH2:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][C:24]=2[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]3[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[C:12]=2[F:32])[CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:37]1)=[O:35]

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 57979822HCID 57979822, compoundHCID 69050638Tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate

Product 1

HCID 69047996Tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

N,N-diisopropylethylamine (0.22 ml, 1.24 mmol) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (160 mg, 0.41 mmol prepared as described in Example 62) in dimethylformamide (1 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (98 mg, 0.43 mmol) was added. After 30 minutes of stirring at 80° C., the reaction mixture was cooled down to room temperature, water was added and the aqueous layer was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate as a yellow solid, (100 mg, 44%); 1H NMR Spectrum: (CDCl3) 1.46 (s, 9H), 2.39 (s, 3H), 3.82 (s, 2H), 3.99 (s, 3H), 4.17 (d, 2H), 4.25 (brd, 2H), 5.47 (brs, 1H), 6.79 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.66 (brs, 1H), 7.83 (s, 1H), 8.49 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 545.

Workup

  1. stirringAfter 30 minutes of stirring at 80° C.
  2. extractionthe aqueous layer was extracted with ethyl acetate (×2)
  3. dry with materialThe combined organics were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residues were purified by column chromatography on silica eluting
  7. temperaturewith increasingly polar mixtures of methanol/dichloromethane (0/100-5/95)

Sources & evidence

ORD record
ord-cb0cd258b0884010bacccbf5fd1d2482
Source dataset
uspto-grants-2009_12
Patent number
US07632840B2

Reaction notes

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