Water → (4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Temperature

82 °C

Into a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 700 mg, 2.61 mmol), 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 935 mg, 2.97 mmol, 1.13 equiv), 1,2-dimethoxyethane (DME, 10 mL, 96 mmol), water (5 mL, 0.28 mol) and potassium carbonate (K2CO3, 1.82 g, 7.84 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol, 0.010 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 82° C. The reaction mixture was stirred at 82° C. for 6 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (10 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic fractions were washed with aqueous brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution) to afford racemic 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 0.97 g, 1.1 g theoretical, 88.6% yield) as colorless oil, which solidified upon standing at room temperature in vacuo. For 20: 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.45 (d, 1H, J=3.8 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.22 (s, 2H), 4.23 (ddd, 1H, J=10.0, 8.6, 4.0 Hz), 3.10 (dd, 1H, J=17.0, 8.6 Hz), 2.92 (dd, 1H, J=17.0, 4.0 Hz), 2.56 (m, 1H), 2.00-1.25 (m, 8H), 1.12 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421 (M++H).

1. customInto a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve
2. customThe resulting reaction mixture
3. customwas degassed three times
4. customThe resulting reaction mixture
5. customwas degassed four times
6. temperaturethe reaction mixture was cooled to room temperature
7. additionbefore being diluted with ethyl acetate (45 mL) and water (10 mL)
8. stirringThe resulting mixture was stirred until the majority of solids
9. customThe two layers were separated
10. extractionthe aqueous layer was extracted with ethyl acetate (1×25 mL)
11. washThe combined organic fractions were washed with aqueous brine (2×25 mL)
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution)

ORD record

ord-8f99796044044799a19bc7360373baff

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08883806B2