1,4-Dioxane → 3 Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

HRID 334236

Reaktionsgleichung

Reaktionsgleichung von HRID 334236
[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[C:26]2[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=2[N:28]=[CH:29][N:30]=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5]1

Komponenten

8

Edukt 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 467367974-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo(2,3-d)pyrimidineHCID 594201653-Cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile

Produkt 1

HCID 574775973 Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrileAusbeute 83,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittel2×HCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

Into a 25 ml round bottom flask equipped with a stir bar, condenser, thermocouple and 3-way valve was charged 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 0.697 g, 2.21 mmol, 1.3 equiv), 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3a, 0.506 g, 1.69 mmol), 1,4-dioxane (4.44 mL), water (4.44 mL), and sodium bicarbonate (NaHCO3, 0.666 g, 7.93 mmol, 4.7 equiv) at room temperature. The resulting mixture was degassed four times backfilling with nitrogen each time before tetrakis(triphenylphosphine)palladium(0) (91.6 mg, 0.079 mmol, 0.047 equiv) was added. The resulting reaction mixture was degassed four times backfilling with nitrogen each time. The reaction was then warmed to 90° C. for 2-6 h. When TLC and HPLC showed that the coupling reaction was deemed complete, the reaction mixture was allowed to cool to room temperature followed by dilution with water (5 mL) and ethyl acetate (10 mL). The two layers were separated, and the aqueous layer was back extracted with ethyl acetate (10 mL). The combined organic fractions were washed with water (10 mL) and saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to give the crude product (9) as an amber oil. The crude product was purified by flash column chromatography (SiO2, 0% to 40% ethyl acetate/hexane gradient elution) to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 617 mg, 737.9 mg theoretical, 83.6% yield) as a yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and m/e 459 (M++Na).

Aufarbeitung

  1. customInto a 25 ml round bottom flask equipped with a stir bar, condenser
  2. customThe resulting mixture was degassed four times
  3. additionwas added
  4. customThe resulting reaction mixture
  5. customwas degassed four times
  6. customWhen TLC and HPLC showed that the coupling reaction
  7. temperatureto cool to room temperature
  8. customThe two layers were separated
  9. extractionthe aqueous layer was back extracted with ethyl acetate (10 mL)
  10. washThe combined organic fractions were washed with water (10 mL) and saturated aqueous NaCl solution (10 mL)
  11. dry with materialdried over magnesium sulfate (MgSO4)
  12. concentrationconcentrated under reduced pressure
  13. customto give the crude product (9) as an amber oil
  14. customThe crude product was purified by flash column chromatography (SiO2, 0% to 40% ethyl acetate/hexane gradient elution)

Quellen und Nachweise

ORD-Eintrag
ord-b7554c20c2e242f9a195163b202634c1
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08883806B2

Verknüpfte Notizen

Wird geladen…