Pyridine → HCID 73332703, compound

Temperature

0 °C

To a stirred solution of (R)-1-((2R,3 S,5R)-5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-3-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)ethanol (21 mg, 0.030 mmol) in anhydrous DCM (1.75 mL) under nitrogen was added pyridine (5 μL, 5 mg, 0.060 mmol) and Dess-Martin periodinane (19 mg, 0.045 mmol). After 1.5 hours, the mixture was filtered and concentrated under reduced pressure. The resultant oily film was dissolved in anhydrous THF (2.0 mL) and cooled to 0° C. Then 3M methylmagnesium bromide (˜0.10 mL, 0.30 mmol) in THF was added portionwise until all of the ketone intermediate was consumed. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide a yellow oily film. The oily film was dissolved in formic acid (1.8 mL) and saturated aqueous potassium hydrogen sulfate (0.2 mL). The reaction mixture was stirred at 50° C. for 1 hour, then allowed to cool to room temperature. The mixture was then poured into saturated aqueous sodium bicarbonate (30 mL), and extracted with EtOAc (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant white solid was dissolved in methanol (10 mL) and treated with 5N NaOH (0.5 mL). After stirring at room temperature for 15 minutes, the mixture was poured into water and neutralized with 1N aqueous HCl to pH 6. The mixture was extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 20 g (2×10 g in series) silica gel cartridge eluted with 0-10% methanol in DCM over 20 column volumes. The combined product fractions were concentrated under reduced pressure, dissolved in MeCN and water, frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C26H26ClN3O4 479.16, observed m/e: 480.10 (M+H)+ (Rt 2.22/4 min). 1H NMR δ (ppm)(DMSO-d6): 7.92 (s, 1H), 7.74 (m, 6H), 7.49 (t, J=8.0 Hz, 2H), 7.39 (dd, J=7.5, 7.5 Hz, 1H), 5.30 (s, 1H), 5.02 (heptet, J=5.5 Hz, 1H), 4.25 (m, 1H), 3.74 (m, 1H), 3.29 (t, J=10.0 Hz, 1H), 2.92 (d, J=10 Hz, 1H), 2.60 (m, 1H), 1.64 (q, J=11.5 Hz, 1H), 1.18 (s, 3H), 1.15 (s, 3H).

1. filtrationthe mixture was filtered
2. concentrationconcentrated under reduced pressure
3. dissolutionThe resultant oily film was dissolved in anhydrous THF (2.0 mL)
4. customwas consumed
5. additionThe reaction mixture was poured into water (30 mL)
6. extractionextracted with EtOAc (2×30 mL)
7. dry with materialThe combined organic layers were dried over sodium sulfate
8. concentrationconcentrated under reduced pressure
9. customto provide a yellow oily film
10. temperatureto cool to room temperature
11. extractionextracted with EtOAc (2×30 mL)
12. dry with materialThe combined organic layers were dried over sodium sulfate
13. concentrationconcentrated under reduced pressure
14. dissolutionThe resultant white solid was dissolved in methanol (10 mL)
15. additiontreated with 5N NaOH (0.5 mL)
16. stirringAfter stirring at room temperature for 15 minutes
17. additionthe mixture was poured into water and neutralized with 1N aqueous HCl to pH 6
18. extractionThe mixture was extracted with EtOAc (2×40 mL)
19. washThe combined organic layers were washed with brine (30 mL)
20. dry with materialdried over sodium sulfate
21. concentrationconcentrated under reduced pressure
22. customThe resultant residue was chromatographed
23. washeluted with 0-10% methanol in DCM over 20 column volumes
24. concentrationThe combined product fractions were concentrated under reduced pressure
25. dissolutiondissolved in MeCN
26. temperaturewater, frozen at −78° C.

ORD record

ord-773f397da4714948b0d0e668ebcd58f3

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09382243B2