Diisopropylethylamine → HCID 86726829, compound

Temperature

45 °C

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (0.028 g, 0.11 mmol), HATU (0.056 g, 0.15 mmol) and DIPEA (0.051 mL, 0.29 mmol) in 1,2-dichloroethane (0.4 mL) was added a solution of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-4-yl acetate (0.050 g, 0.10 mmol) in 1,2-dichloroethane (0.5 mL). The reaction mixture was stirred at 45° C. for 1 h and then at ambient temperature overnight. The reaction mixture was diluted with EtOAc (40 mL) and H2O (3 mL). The layers were separated and the organic layer was washed with H2O (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in THF (1.3 mL) and MeOH (0.4 mL) and to this was added 1 M aq. NaOH (1 mL) and the resulting mixture was stirred for 2.5 h at ambient temperature. The reaction mixture was diluted with EtOAc (40 mL) and neutralized by the addition of 1 M aq. HCl to adjust the pH to ˜7. The layers were separated, the organic layer was washed with H2O (3×3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in 4 M HCl in 1,4-dioxane (2 mL) and stirred at ambient temperature for 30 min. The volatile organic solvents were removed under reduced pressure and the residue was re-dissolved in MeOH (5 mL) and neutralized by the addition of saturated NH4OH. The crude reaction mixture was purified by mass triggered preparative-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the two 7-hydroxyl diastereoisomers of the title compound as two peaks.

1. customat ambient temperature
2. customovernight
3. customThe layers were separated
4. washthe organic layer was washed with H2O (3×3 mL)
5. extractionThe combined aqueous phases were extracted with EtOAc (3 mL)
6. washThe combined organic extracts were washed with brine (3 mL)
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. dissolutionThe crude product was dissolved in THF (1.3 mL)
11. additionMeOH (0.4 mL) and to this was added 1 M aq. NaOH (1 mL)
12. stirringthe resulting mixture was stirred for 2.5 h at ambient temperature
13. additionThe reaction mixture was diluted with EtOAc (40 mL)
14. additionneutralized by the addition of 1 M aq. HCl
15. customThe layers were separated
16. washthe organic layer was washed with H2O (3×3 mL)
17. extractionthe combined aqueous phases were extracted with EtOAc (3 mL)
18. washThe combined organic extracts were washed with brine (3 mL)
19. dry with materialdried over Na2SO4
20. filtrationfiltered
21. concentrationconcentrated under reduced pressure
22. dissolutionThe crude product was dissolved in 4 M HCl in 1,4-dioxane (2 mL)
23. stirringstirred at ambient temperature for 30 min
24. customThe volatile organic solvents were removed under reduced pressure
25. dissolutionthe residue was re-dissolved in MeOH (5 mL)
26. additionneutralized by the addition of saturated NH4OH
27. customThe crude reaction mixture
28. customwas purified by mass
29. washeluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.)

ORD record

ord-9833882bd0e24854bf7d613a57eb1d0c

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09200004B2