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

HRID 1867684Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1867684
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

Komponenten

5

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 31347SulfolaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-a5608a37629b4385b3fa13359ccdaa27
Quelldatensatz
uspto-grants-2009_12
Patentnummer
US07632840B2

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