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Citric Acid → (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

HRID 1098019
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HRID 1098019 반응식
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].O([C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])[N:34]=[CH:35][C:28]=12)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])[N:34]=[CH:35][C:28]=12)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
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참가 물질

6

반응물 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57504492HCID 57504492, 화합물2회HCID 575045144-phenoxy-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine

생성물 1

HCID 57504386(2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide수율 54.5%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
0 °C

실험 절차

Sodium hydride (10.78 mg, 0.27 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (53.5 mg, 0.22 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-phenoxy-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate Z1) (80 mg, 0.22 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 reaction mixture was 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), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane. The residue was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents to afford the product (60.0 mg, 53.4%). 1H NMR (400 MHz, CDCl3) δ 1.17-1.20 (6H, m), 2.30 (3H, s), 3.69-3.75 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.52-7.56 (2H, m), 7.69 (1H, t), 7.76 (1H, t), 7.91 (1H, d), 8.10-8.15 (2H, m), 8.42 (1H, s), 8.56 (1H, s), 8.72 (1H, s); m/z (ES+) (M+H)+=501; HPLC tR=2.70 min.

후처리

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with ethyl acetate (2×100 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 chromatography
  11. washeluting with 50 to 100% ethyl acetate in isohexane
  12. customThe residue was purified by preparative HPLC

출처 및 근거

ORD 기록
ord-48f084abac0f486ea20306543652b97b
출처 데이터셋
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08143263B2

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