3-Hydroxypyridine → HCID 18433351, compound

Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (6.80 g. 39.0 mmol) in tetrahydrofuran (THF) (25 mL) was added drop-wise at ambient temperature to a stirring solution of triphenylphosphine (10.23 g, 390 mmol) in THF (100 mL). The resulting solution was allowed to stir at ambient temperature for 30 min. 4-Hydroxy-1-methylpiperidine (3.05 g, 26.5 mmol) and 3-hydroxypyridine (3.71 g, 39.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 h. The solution was concentrated by rotary evaporation, and the resulting residue was dissolved in CHCl3 (100 mL). The suspension was cooled in an ice-water bath, and a solution of 1 M HCl (75 mL) was added with stirring. The aqueous phase was separated. The organic phase was extracted with water (3×75 mL). The combined aqueous extracts were cooled in an ice-water bath, basified with 1 M NaOH solution (125 mL) to pH ˜11 and extracted with CHCl3 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude product was dissolved in CHCl3 (75 mL), and the CHCl3 solution was extracted with 1 M NaOH solution (4×25 mL) to remove residual 3-hydroxypyridine. The CHCl3 phase was separated, and the combined NaOH layers were back extracted with CHCl3 (3×50 mL). All CHCl3 extracts were combined, dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified by vacuum distillation using a test-tube distillation apparatus, collecting the fraction with bp 83-93° C. at 0.10-0.075 mm Hg. Further purification by a second vacuum distillation yielded 120 mg (2.4%) of a colorless oil, bp 72-75° C. at 0.75 mm Hg. The compound exhibits a Ki of 4897 nM.

1. stirringthe reaction mixture was stirred at ambient temperature for 18 h
2. concentrationThe solution was concentrated by rotary evaporation
3. dissolutionthe resulting residue was dissolved in CHCl3 (100 mL)
4. temperatureThe suspension was cooled in an ice-water bath
5. additiona solution of 1 M HCl (75 mL) was added
6. stirringwith stirring
7. customThe aqueous phase was separated
8. extractionThe organic phase was extracted with water (3×75 mL)
9. temperatureThe combined aqueous extracts were cooled in an ice-water bath
10. extractionextracted with CHCl3 (6×50 mL)
11. dry with materialThe combined organic extracts were dried (Na2SO4)
12. filtrationfiltered
13. concentrationconcentrated by rotary evaporation
14. dissolutionThe crude product was dissolved in CHCl3 (75 mL)
15. extractionthe CHCl3 solution was extracted with 1 M NaOH solution (4×25 mL)
16. customto remove residual 3-hydroxypyridine
17. customThe CHCl3 phase was separated
18. extractionthe combined NaOH layers were back extracted with CHCl3 (3×50 mL)
19. dry with materialdried (Na2SO4)
20. filtrationfiltered
21. concentrationconcentrated by rotary evaporation
22. distillationThe resulting oil was purified by vacuum distillation
23. distillationdistillation apparatus
24. customcollecting the fraction with bp 83-93° C. at 0.10-0.075 mm Hg
25. customFurther purification
26. distillationby a second vacuum distillation

ORD record

ord-01134fd5dd994aee8be602fc9c42cc66

Source dataset

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06627648B1