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 928508Notes

Reaction equation

HRID 928508 reaction equation
[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

Participants

8

Reactant 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

Product 1

HCID 574775973 Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrileYield 83.6%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

Method C. 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]pyrimidin (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).

Workup

  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)

Sources & evidence

ORD record
ord-fbf36be4f4ae41fb9e9d64ca96bddba9
Source dataset
uspto-grants-2016_03
Patent number
US09290506B2

Reaction notes

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