Ethyl Acetate → tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-cyanoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

HRID 913952Notes

Reaction equation

HRID 913952 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]OS(C)(=O)=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:7]=2)[CH:3]=1.[C-:48]#[N:49].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)[CH2:12][C:48]#[N:49])[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[N:7]=2)[CH:3]=1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 8929Sodium CyanideHCID 57545940HCID 57545940, compound

Product 1

HCID 67402367tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-cyanoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylateYield 37.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(methylsulfonyloxy)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (155 mg, 0.218 mmol) in DMF was added NaCN (21.37 mg, 0.436 mmol) and the reaction was stirred at R.T for 1 h. LC/MS showed no reaction. The reaction was heated at 50 C for another hour, LC/MS showed no reaction either. The reaction was again heated at 80 C for another hour, no reaction was observed. It was stirred at 80 C over the weekend. LC/MS showed product along with staring material. It was stirred at 80 C for 6 h, LC/MS showed the reaction was complete. The reaction was then partitioned between Et2O and H2O, the phase was separated and the aqueous phase was extracted with Et2O, the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. It was purified by Biotage LC (30% EtOAc/Hex) to title compound (52.2 mg, 0.081 mmol, 37.3% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.0 (s, 1H),), 7.53 (m, 1H), 7.32 (m, 2H), 7.05 (m, 2H), 6.63 (s, 1H), 5.61 (s, 2H), 5.04 (m, 1H), 3.68 (m, 2H), 3.57 (t, J=8.05 Hz, 2H), 3.45 (m, 2H), 3.05-2.96 (m, 3H), 2.74 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.42 (s, 9H), 0.9 (t, J=8.42 Hz, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.63 (d, J=245.7 Hz), 155.0, 144.8, 129.9, 128.9, 128.0, 124.0, 122.8, 119.3, 117.2, 115.5, 115.4, 81.9, 79.5, 79.0, 73.4, 67.8, 42.5, 41.4, 32.4, 28.6, 25.3, 17.9, 1.35. LC/MS (HPLC method 3): tR=4.16 min, 643.1 (MH)+.

Workup

  1. customno reaction
  2. temperatureThe reaction was heated at 50 C for another hour
  3. customno reaction either
  4. temperatureThe reaction was again heated at 80 C for another hour
  5. stirringIt was stirred at 80 C over the weekend
  6. stirringIt was stirred at 80 C for 6 h
  7. customThe reaction was then partitioned between Et2O and H2O
  8. customthe phase was separated
  9. extractionthe aqueous phase was extracted with Et2O
  10. washthe combined organic phases were washed with water and brine
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-9ef10bf23a8644f08242cf2a7ba87876
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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