Water → HCID 59420135, compound

Temperature

95 °C

Into a 100 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-c]pyrimidine (3b, 3.30 g, 0.0129 mol), (3S)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((S)-24, 5.12 g, 0.0146 mol, 1.13 equiv), 1,4-dioxane (33.4 mL, 0.428 mol), water (16.7 mL, 0.929 mol) and potassium carbonate (K2CO3, 8.03 g, 0.0581 mol, 4.5 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) (1.49 g, 0.00129 mol, 0.10 equiv). The mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 21 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 (20 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 (50 mL). The combined organic fractions were washed with 20% aqueous brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution) afford (3S)-3-cyclopentyl-3-{4-[7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propanenitrile ((S)-25, 4.11 g, 5.27 g theoretical, 78% yield) as colorless oil, which was solidified upon standing at room temperature. For (S)-25: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.71 (d, 1H, J=3.8 Hz,), 7.12 (d, 1H, J=3.8 Hz), 6.76 (s, 1H), 4.53 (td, 1H, J=19.4, 4.3 Hz), 3.68 (m, 2H), 3.52 (m, 2H), 3.26 (dd, 1H, J=9.6, 17.3 Hz), 3.19 (dd, 1H, J=4.3, 17.2 Hz), 2.41 (m, 1H), 1.80 (m, 1H), 1.63-1.09 (m, 13H); C22H28N6O2 (MW, 408.50), LCMS (EI) m/e 409 (M++H).

1. customInto a 100 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 mixture was degassed four times
5. temperaturethe reaction mixture was cooled to room temperature
6. additionbefore being diluted with ethyl acetate (45 mL) and water (20 mL)
7. stirringThe resulting mixture was stirred until the majority of solids
8. customThe two layers were separated
9. extractionthe aqueous layer was extracted with ethyl acetate (50 mL)
10. washThe combined organic fractions were washed with 20% aqueous brine (50 mL)
11. dry with materialdried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution)

ORD record

ord-9272cd11ca214d719ef59226199017c7

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09000161B2