2-Bromoethanol → 4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-(2-hydroxyethyl)piperidine-4-carboxamide

HRID 1867684Notes

Reaction equation

HRID 1867684 reaction equation
Br[CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>S1(=O)(=O)CCCC1>[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1

Participants

5

Reactant 3

HCID 108982-BromoethanolHCID 11430Potassium CarbonateHCID 57979867HCID 57979867, compound

Product 1

HCID 579798824-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-(2-hydroxyethyl)piperidine-4-carboxamideYield 16%

Reagents, catalysts & solvents 1

HCID 31347SulfolaneSolvent

Conditions

Temperature
90 °C

Procedure

2-Bromoethanol (47 μl, 0.66 mmol) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (250 mg, 0.53 mmol) (Example 16) and anhydrous potassium carbonate (150 mg, 1.08 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane) (5 ml). The mixture was heated at 90° C. for 3 hours and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was washed with brine and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated to a foam. This was triturated with diethyl ether to give the title product as a white solid (43 mg, 16%); 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.13-2.21 (m, 2H), 2.25 (s, 3H), 2.26-2.33 (m, 2H), 3.13-3.17 (t, 2H), 3.17-3.25 (m, 2H), 3.42-3.49 (m, 2H), 3.71-3.77 (m, 4H), 3.94 (s, 3H), 7.18-7.22 (m, 1H), 7.23 (s, 1H), 7.33-7.38 (m, 1H), 7.58-7.63 (m, 1H), 8.28 (s, 1H), 8.39 (s, 1H); Mass Spectrum: (M+H)+ 517.

Workup

  1. custompartitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate
  2. washThe organic phase was washed with brine
  3. customevaporated
  4. customThe residues were purified by column chromatography on silica
  5. washeluting with 7M ammonia in methanol/methylene chloride (16/84)
  6. additionFractions containing the desired product
  7. customevaporated to a foam
  8. customThis was triturated with diethyl ether

Sources & evidence

ORD record
ord-a5608a37629b4385b3fa13359ccdaa27
Source dataset
uspto-grants-2009_12
Patent number
US07632840B2

Reaction notes

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