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

HRID 1098061Notes

Reaction equation

HRID 1098061 reaction equation
[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]

Participants

5

Reactant 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

Product 1

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

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-4fbf99b684ce40248b3fda4f6a1a7c3c
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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