Citric Acid → (2S)-N-(5-cyanopyridin-2-yl)-3-ethoxy-2-[1-[2-(trifluoromethyl)phenyl]pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide

HRID 1098001ノート

反応式

HRID 1098001 の反応式
[H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([O:18][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:38])([F:39])[F:37])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4]

参加物

6

反応物 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 114834004-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504495(S)-N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide

生成物 1

HCID 57504368(2S)-N-(5-cyanopyridin-2-yl)-3-ethoxy-2-[1-[2-(trifluoromethyl)phenyl]pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide収率 86.4%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
0 °C

実験手順

60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (235 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (4 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 100% ethyl acetate in isohexane to give the product (430 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.62-3.70 (2H, m), 4.08-4.14 (2H, m), 6.04 (1H, t), 7.53-7.55 (1H, m), 7.68-7.77 (2H, m), 7.91 (1H, dd), 7.97 (1H, dd), 8.39 (1H, dd), 8.41 (1H, s), 8.56 (1H, s), 8.57-8.59 (1H, m), 9.02 (1H, s); m/z (ESI−) (M−H)−=496; HPLC tR=2.55 min.

後処理

  1. stirringThe mixture was stirred at 0° C. for 15 mins
  2. temperatureto warm slowly to ambient temperature
  3. stirringstirred for 2 hours
  4. extractionthe mixture extracted with ethyl acetate (2×25 mL)
  5. washThe combined organic extracts were washed with water (25 mL) and brine (25 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe crude product was purified by flash silica chromatography
  9. washeluting with 20 to 100% ethyl acetate in isohexane

出典と根拠

ORDレコード
ord-92e85405f13f4a9b96e93e525daa3d28
出典データセット
uspto-grants-2012_03
特許番号
US08143263B2

反応ノート

読み込み中…