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

HRID 1867684노트

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HRID 1867684 반응식
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

참가 물질

5

반응물 3

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

생성물 1

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

시약·촉매·용매 1

HCID 31347Sulfolane용매

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온도
90 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-a5608a37629b4385b3fa13359ccdaa27
출처 데이터셋
uspto-grants-2009_12
특허 번호
US07632840B2

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