(Trimethylsilyl)imidazole → HCID 178447656, compound

HRID 2178292Notes

Reaction equation

HRID 2178292 reaction equation
[Si:1]([C:8]1[C:13]([Cl:14])=[C:12](F)[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1([Si:31]([CH3:34])([CH3:33])[CH3:32])C=CN=C1.[CH3:35][CH:36]([CH3:46])[C@:37]([CH:40]1[CH2:45][NH:44][CH2:43][CH2:42][NH:41]1)([OH:39])[CH3:38]>C1COCC1.C(OCC)(=O)C>[Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([N:44]2[CH2:43][CH2:42][NH:41][C@H:40]([C@:37]([O:39][Si:31]([CH3:34])([CH3:33])[CH3:32])([CH:36]([CH3:46])[CH3:35])[CH3:38])[CH2:45]2)[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 28925(Trimethylsilyl)imidazoleHCID 66797442(2R)-3-methyl-2-(piperazin-2-yl)butan-2-olHCID 178454988HCID 178454988, compound

Product 1

HCID 178447656HCID 178447656, compoundYield 59%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

3-(4-(tert-butyldimethylsilyl)-5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (132.7 g, 348 mmol) was dissolved in anhydrous THF (265 mL). Imidazol-1-yl(trimethyl)silane (254 mL) was added followed by (2R)-3-methyl-2-(piperazin-2-yl)butan-2-ol (90 g, 522 mmol). The mixture was divided into four glass pressure vessel's and the sealed containers heated and stirred at 95° C. for 48 hours. The crude mixtures were cooled, combined and diluted with ethyl acetate (1.7 L). The solution was washed with saturated sodium bicarbonate (2×500 ml). The combined aqueous layers were back-extracted with ethyl acetate (500 ml). The combined organics were washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo to give a viscous brown oil. The diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether). This gave the required (S,R)-diastereoisomer as a yellow foam (125.3 g, 59%); 1H NMR (CDCl3) 0.01 (9H, s), 0.42 (6H, s), 0.78-0.89 (15H, m), 1.09-1.13 (3H, m), 1.74 (1H, m), 2.61 (1H, m), 2.80-2.99 (4H, m), 3.12 (1H, m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m), 8.81 (1H, m), 12.75 (1H, brs); 19F NMR (decoupled) −108.9; MS ES 605.2 (M+). The (R,R)-diastereoisomer was isolated as a yellow foam (27.5 g, 13%); 1H NMR (CDCl3) 0.00 (9H, s), 0.38 (6H, m), 0.76-0.80 (15H, m), 0.85 (3H, s), 1.85 (1H, m), 2.50 (1H, m), 2.90-3.13 (4H, m), 3.42 (1H, m), 3.56 (1H, m), 3.91 (1H, m), 7.08 (1H, m), 8.51 (1H, m), 8.76 (1H, m), 12.70 (1H, brs); 19F NMR (decoupled) −109.0; MS ES 605.2 (M+).

Workup

  1. temperaturethe sealed containers heated
  2. temperatureThe crude mixtures were cooled
  3. washThe solution was washed with saturated sodium bicarbonate (2×500 ml)
  4. extractionThe combined aqueous layers were back-extracted with ethyl acetate (500 ml)
  5. washThe combined organics were washed with brine (500 ml)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a viscous brown oil
  10. customThe diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether)

Sources & evidence

ORD record
ord-a0575742ea644f57bdcf53a06d92ecb4
Source dataset
uspto-grants-2015_06
Patent number
US09067932B2

Reaction notes

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