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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
ノート
印刷プレビュー

反応式

HRID 1098019 の反応式
[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]
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

6

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-48f084abac0f486ea20306543652b97b
出典データセット
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08143263B2

反応ノート

読み込み中…

このページの内容参加物反応条件実験手順後処理出典と根拠反応ノート