Sodium hydride → (2S)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanamide

HRID 1098061ノート

反応式

HRID 1098061 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]=[C:32]([Cl:36])[C:31]=3[Cl:37])[N:28]=[CH:29][C:22]=12>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[N:26]=[CH:25][N:24]=[C:23]3[N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[Cl:37])[N:28]=[CH:29][C:22]=23)[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4]

参加物

5

反応物 3

HCID 24758Sodium hydrideHCID 574386164-chloro-1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504495(S)-N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide

生成物 1

HCID 57504442(2S)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanamide収率 125%

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

Sodium hydride (60% in oil) (80 mg, 2.00 mmol) was added to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (314 mg, 1.34 mmol) in THF (10 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 minutes. 4-chloro-1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AR4) (400 mg, 1.34 mmol) in THF (2 mL) was then added dropwise and stirred at 0° C. for a further 10 mins. The reaction was then allowed to warm to r.t. and stirred for 3½ hours. The reaction mixture was quenched with 1M citric acid, extracted with EtOAc and washed with water ×2. The organic layer was dried (MgSO4), filtered and evaporated to afford yellow gum (835 mg). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (285 mg, 42.8%, 96% ee). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 3.58-3.74 (2H, m), 4.04-4.17 (2H, m), 6.04 (1H, t), 7.37-7.48 (2H, m), 7.64-7.69 (1H, m), 7.93-7.99 (1H, m), 8.36-8.41 (1H, m), 8.43 (1H, s), 8.56-8.58 (1H, m), 8.58 (1H, s), 9.02 (1H, s); m/z (ES−) (M−H)−=496.33; HPLC tR=2.70 min.

後処理

  1. stirringstirred at 0° C. for a further 10 mins
  2. temperatureto warm to r.t.
  3. stirringstirred for 3½ hours
  4. customThe reaction mixture was quenched with 1M citric acid
  5. extractionextracted with EtOAc
  6. washwashed with water ×2
  7. dry with materialThe organic layer was dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated

出典と根拠

ORDレコード
ord-4fbf99b684ce40248b3fda4f6a1a7c3c
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…