Tetrahydrofuran → HCID 178447657, compound

HRID 1046586Notes

Reaction equation

HRID 1046586 reaction equation
[C:1]([Si:5]([CH3:25])([CH3:24])[C:6]1[C:11]([F:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)[N:9]=[C:8](F)[C:7]=1[F:23])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH:27]([CH3:37])[C@:28]([CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1)([OH:30])[CH3:29].C1COCC1.N1([Si:48]([CH3:51])([CH3:50])[CH3:49])C=CN=C1>CCOC(C)=O>[Si:5]([C:6]1[C:7]([F:23])=[C:8]([N:35]2[CH2:34][CH2:33][NH:32][C@H:31]([C@:28]([O:30][Si:48]([CH3:51])([CH3:50])[CH3:49])([CH:27]([CH3:37])[CH3:26])[CH3:29])[CH2:36]2)[N:9]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)[C:11]=1[F:12])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:24])[CH3:25]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 28925(Trimethylsilyl)imidazoleHCID 66797442(2R)-3-methyl-2-(piperazin-2-yl)butan-2-olHCID 178454989HCID 178454989, compound

Product 1

HCID 178447657HCID 178447657, compoundYield 378.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A 500 ml glass pressure vessel was charged with tert-butyl-dimethyl-[2,3,5-trifluoro-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)-4-pyridyl]silane (26.80 g, 73.53 mmol), (2R)-3-methyl-2-piperazin-2-yl-butan-2-ol (19 g, 110.3 mmol), THF (53 mL) and imidazol-1-yl-trimethyl-silane (51.57 g, 53.72 mL, 367.7 mmol). An identical experiment was run in parallel. The containers was sealed and the mixture was heated and stirred at 95° C. overnight. Lc/Ms after this time showed a mixture consisting of 73% of the desired (S,R)-diastereoisomer and 18% of the (R,R)-diastereoisomer. Both reaction mixtures were cooled, combined and diluted with EtOAc (500 ml). The solution was washed with saturated sodium bicarbonate (2×200 ml). The combined aqueous layers are extracted 3 times with ethyl acetate (200 ml). The combined organics were washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to give 163.874 g of viscous brown oil. The diastereoisomers were separated on silica gel, eluting with 10-95% ethyl acetate in petroleum ether containing 2% triethylamine). This gave the required (S,R) -diastereoisomer as an orange foam (60.1 g, 69%); 1H NMR (CDCl3) 0.001 (9H, s), 0.32 (6H, s), 0.76-0.84 (9H, m), 1.11 (4H, m), 1.45 (4H, m), 1.72 (1H, m), 1.90 (1H, s), 2.61 (1H, m), 2.74 (2H, m), 2.97 (1H, m), 3.11 (1H, m), 3.64 (1H, m), 3.82 (1H, m), 3.96 (1H, m), 7.09 (1H, m), 8.48 (1H, m), 8.74 (1H, m), 11.31 (1H, brs); 19F NMR (decoupled) −113.45, −108.39; MS ES(+) 589.3 (M+1). The (R,R)-diastereoisomer was isolated as an orange foam (22%); 1H NMR (CDCl3) 0.001 (9H, s), 0.33 (6H, s), 0.72-0.88 (10H, m), 1.07 (3H, m), 1.45 (5H, m), 1.86 (1H, m), 2.54 (1H, m), 2.74 (2H, m), 2.94 (1H, m), 3.07 (1H, m), 3.63 (1H, m), 3.73 (1H, m), 3.96 (1H, m), 7.04 (1H, m), 8.46 (1H, m), 8.69 (1H, m), 11.35 (1H, brs); 19F NMR (decoupled) −113.78, −108.4; MS ES(+) 589.3 (M+1).

Workup

  1. customThe containers was sealed
  2. temperaturethe mixture was heated
  3. customBoth reaction mixtures
  4. temperaturewere cooled
  5. washThe solution was washed with saturated sodium bicarbonate (2×200 ml)
  6. extractionThe combined aqueous layers are extracted 3 times with ethyl acetate (200 ml)
  7. washThe combined organics were washed with brine (200 ml)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c042b5182ced46258195f2e04517698f
Source dataset
uspto-grants-2013_10
Patent number
US08569337B2

Reaction notes

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