Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide

HRID 1098243노트

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HRID 1098243 반응식
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:48]([CH3:55])=[C:49]([CH:52]=[CH:53][CH:54]=3)[C:50]#[N:51])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[C:48]=3[CH3:55])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

참가 물질

8

반응물 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57504665(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamideHCID 575046943-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile

생성물 1

HCID 57504556(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide수율 42.3%

시약·촉매·용매 3

HCID 962Water용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

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온도
0 °C

실험 절차

Sodium hydride (60% in oil) (92 mg, 2.30 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (500 mg, 1.04 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (282 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane. No separation was achieved. The column was repeated with a 0-10% MeOH/DCM gradient. Still no separation! Mixed fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (313 mg, 42.1%). m/z (ES+) (M+H)+=712.63; HPLC tR=3.85 min.

후처리

  1. temperatureto warm to room temperature
  2. stirringstirred for 4 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with EtOAc
  5. washThe combined organics were washed with saturated brine
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe crude product was purified by flash silica chromatography
  9. washeluting with 0 to 50% EtOAc in isohexane
  10. customNo separation
  11. customStill no separation
  12. customMixed fractions were evaporated to dryness

출처 및 근거

ORD 기록
ord-9254d9bec9994735a3b777d4607b1080
출처 데이터셋
uspto-grants-2012_03
특허 번호
US08143263B2

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