Citric Acid → (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

HRID 1098204노트

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HRID 1098204 반응식
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[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:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[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:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

참가 물질

6

반응물 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 574386624-chloro-1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 59279512(S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate

생성물 1

HCID 59279498(2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate수율 53.3%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
0 °C

실험 절차

60% Sodium hydride (156 mg, 3.89 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1119 mg, 2.78 mmol) in anhydrous THF (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AK3) (730 mg, 2.78 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The residue was diluted with water (20 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica (120 g) chromatography, elution gradient 0 to 20% EtOAc in isohexane to afford the product (932 mg, 53.3%). 1H NMR (400 MHz, DMSO) δ 0.94 (9H, s), 2.03 (3H, s), 3.80-3.65 (7H, m), 4.16-4.03 (2H, m), 5.89 (1H, dd), 7.46-7.33 (8H, m), 7.54-7.48 (1H, m), 7.65-7.61 (4H, m), 8.48 (1H, s), 8.59 (1H, s); m/z (ES+) (M+H)+=629; HPLC tR=3.41 min.

후처리

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe residue was diluted with water (20 mL) and EtOAc (100 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with EtOAc (100 mL)
  7. washThe combined organics were washed with saturated brine (75 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica (120 g) chromatography, elution gradient 0 to 20% EtOAc in isohexane

출처 및 근거

ORD 기록
ord-e8bd294d99524ae78d09a0a9b3fa4c27
출처 데이터셋
uspto-grants-2012_03
특허 번호
US08143263B2

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