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Sodium hydride → (2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide

HRID 655731
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HRID 655731 반응식
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2=[N:44][CH:45]=[N:46][C:47](Cl)=[C:42]2[CH:41]=[N:40]1>C1COCC1.CCOC(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2[N:44]=[CH:45][N:46]=[C:47]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])[C:42]=2[CH:41]=[N:40]1
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6

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HCID 24758Sodium hydrideHCID 574386801-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidineHCID 57504703(S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide

생성물 1

HCID 57504702(2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide수율 93.5%

시약·촉매·용매

2
HCID 8028Tetrahydrofuran용매2회HCID 8857Ethyl Acetate용매

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온도
0 °C

실험 절차

Sodium hydride (0.875 g, 21.87 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (3.0 g, 7.29 mmol) in anhydrous THF (35 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 1-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BO2) (2.507 g, 7.29 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to ambient temperature for 6 hours. It was then cooled to ˜0° C., the mixture poured into ice cold 1M citric acid and diluted with EtOAc (50 mL). It was stirred vigorously for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (4.90 g, 93%).

후처리

  1. stirringThe mixture was stirred at 0° C. for 10 minutes
  2. temperatureto warm to ambient temperature for 6 hours
  3. temperatureIt was then cooled to ˜0° C.
  4. stirringIt was stirred vigorously for 10 minutes
  5. customThe organic phase was separated
  6. washwashed with water and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

출처 및 근거

ORD 기록
ord-f5979439b3d94ca2b4a47b03e14199f9
출처 데이터셋
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08071608B2

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