Ethyl cyanoformate → Ethyl 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-carboxylate

HRID 1054802Notes

Reaction equation

HRID 1054802 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1.[Li]CCCC.[C:33](C#N)(=[O:37])[O:34][CH2:35][CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[C:13]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1

Participants

5

Reactant 3

HCID 69336Ethyl cyanoformateHCID 86698793HCID 86698793, compoundHCID 178418339Butyllithium

Product 1

HCID 86698794Ethyl 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-carboxylateYield 58.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (650 mg, 1.68 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.74 mL, 1.85 mmol) dropwise via syringe. The reaction was stirred at −78° C. for 10 minutes, warmed to room temperature for 5 minutes, and cooled back to −78° C. A solution of ethyl cyanocarbonate (188 mg, 1.90 mmol) in THF (1 mL) was added via syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with aqueous NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/heptane) to provide the title compound (448 mg, 58% yield). MS (ES+) 459.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81 (dd, J=8.42, 2.32 Hz, 1H), 6.75 (dd, J=11.34, 2.32 Hz, 1H), 6.20 (s, 2H), 4.49 (q, J=7.07 Hz, 2H), 3.89 (s, 3H), 3.66-3.72 (m, 2H), 2.29 (s, 3H), 1.44 (t, J=7.07 Hz, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).

Workup

  1. temperaturewarmed to room temperature for 5 minutes
  2. temperaturecooled back to −78° C
  3. customThe cooling bath was removed
  4. stirringthe reaction mixture was stirred at room temperature for 30 minutes
  5. customThe reaction was quenched with aqueous NH4Cl solution
  6. additiondiluted with EtOAc
  7. washThe organic layer was washed with water and brine
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by flash chromatography (0-20% EtOAc/heptane)

Sources & evidence

ORD record
ord-d2f19b8d5d734dc9ad4dd28eabce5235
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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