Citric Acid → (3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one

HRID 1098146노트

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HRID 1098146 반응식
[H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[N:18]=[CH:19][C:12]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:26][C:25]1[C:20]([N:17]2[C:13]3=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]4[CH2:8][CH2:7][O:6][C:5]4=[O:9])=[C:12]3[CH:19]=[N:18]2)=[N:21][CH:22]=[CH:23][CH:24]=1

참가 물질

6

반응물 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 3578532-Hydroxy-gamma-butyrolactone, (2S)-HCID 575044824-Chloro-1-(3-chloropyridin-2-YL)-1H-pyrazolo[3,4-D]pyrimidine

생성물 1

HCID 57504502(3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one수율 61%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
0 °C

실험 절차

60% Sodium hydride in mineral oil (0.470 g, 11.75 mmol) was added to (S)-3-hydroxydihydrofuran-2(3H)-one (0.764 mL, 9.80 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (CAS no. 52079-23-9) (2.87 g, 10.77 mmol) was added portionwise maintaining the temperature below 5° C. 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 reaction mixture diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), water (75 mL) dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (1.970 g, 61%). 1H NMR (400 MHz, CDCl3) 2.52-2.62 (1H, m), 2.92-3.00 (1H, m), 4.41-4.47 (1H, m), 4.59-4.64 (1H, m), 6.11-6.16 (1H, m), 7.46-7.49 (1H, m), 8.00-8.02 (1H, m), 8.37 (1H, s), 8.61-8.63 (1H, m), 8.64 (1H, s); m/z (ESI+) (M+H)+=332; HPLC tR=1.51 min.

후처리

  1. addition52079-23-9) (2.87 g, 10.77 mmol) was added portionwise
  2. temperaturemaintaining the temperature below 5° C
  3. temperatureto warm to room temperature
  4. stirringstirred for 1 hour
  5. customthe majority of the THF removed in vacuo
  6. additionThe reaction mixture diluted with water (20 mL) and ethyl acetate (50 mL)
  7. customThe organic layer was separated
  8. extractionthe aqueous layer re-extracted with ethyl acetate (2×100 mL)
  9. washThe combined organics were washed with saturated brine (75 mL), water (75 mL)
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. customevaporated
  13. customThe residue was purified by flash silica chromatography
  14. washeluting with 50 to 100% ethyl acetate in isohexane

출처 및 근거

ORD 기록
ord-1b855cdf8d4b434d8959b82caf8bf480
출처 데이터셋
uspto-grants-2012_03
특허 번호
US08143263B2

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