Methyl iodide → tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

HRID 913925Notes

Reaction equation

HRID 913925 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[H-].[Na+].I[CH3:47]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][O:13][CH3:47])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 57545941HCID 57545941, compound

Product 1

HCID 57545988tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (25 mg, 0.039 mmol) in dimethylformamide (0.5 mL) at 0° C. was added sodium hydride (60%, 3.15 mg, 0.079 mmol). After 5 min, the reaction was treated with iodomethane (4.93 μL, 0.079 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×). then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% ethyl acetate/n-hexane) gave 22 mg (86%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.9, 5.2 Hz, 2H), 7.02 (dd, J=8.9, 8.5 Hz, 2H), 6.74 (s, 1H), 5.67 (d, J=10.7 Hz, 1H), 5.63 (d, J=10.7 Hz, 1H), 5.06 (dd, J=7.3, 2.7 Hz, 1H), 3.50-3.80 (m, 6H), 3.48 (d, J=9.2 Hz, 1H), 3.41 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 3.06 (m, 2H), 2.23 (m, 1H), 2.07 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.69 (bs, 1H), 1.44 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=245 Hz), 155.1, 145.7, 138.84, 138.82, 130.8, 128.9 (d, J=7.7 Hz), 128.1, 124.3, 122.8, 122.2, 118.3, 115.2 (d, J=21), 81.9, 79.4, 78.7, 77.9, 76.1, 67.7, 59.4, 41.4, 40.2 (br), 32.4, 32.0, 28.6, 17.9, −1.4. Mass spec.: 648.38 (MH)+.

Workup

  1. customThe ice bath was removed
  2. waitcontinued for 1 h
  3. customquenched by the cautious addition of saturated ammonium chloride
  4. additionThe reaction was diluted with diethyl ether
  5. customthe layers separated
  6. washThe ethereal was washed with water (2×)
  7. dry with materialthen brine, dried over magnesium sulfate
  8. concentrationconcentrated
  9. customColumn chromatography (25% ethyl acetate/n-hexane) gave 22 mg (86%) as a colorless film

Sources & evidence

ORD record
ord-8f4233ae6b914cf890d7eda1542338c8
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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