3-Hydroxypyridine → HCID 57284020, compound

Temperature

2.5 °C

Under a nitrogen atmosphere, diethyl azodicarboxylate (4.65 g, 26.70 mmol) was added to a cold (0-5° C.), stirring solution of triphenylphosphine (7.00 g, 26.70 mmol) in dry tetrahydrofuran (60 mL, distilled from sodium and benzophenone). The mixture was stirred at 0-5° C. for 15 min. The resulting yellow solution was treated drop-wise at 0-5° C. with a solution of (3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (2.50 g, 13.35 mmol) in dry THF (20 mL) producing a thick yellow mixture. At 0-5° C., 3-hydroxypyridine (2.54 g, 26.70 mmol) was added in one portion. The resulting yellow solution was allowed to stir and warm to ambient temperature over 24 h. The solution was diluted with CH2Cl2 (150 mL) and washed with saturated K2CO3 solution (2×100 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give a viscous, light-yellow gel. The crude product was purified by column chromatography on silica gel (302 g), eluting with CHCl3—CH3OH (95:5, v/v). Selected fractions containing the product (Rf 0.44) were combined and concentrated to afford 2.50 g of a light-yellow oil, that contained solids. Impure fractions were combined and concentrated to give 16 g of solids. The solids were triturated with pentane (4×75 mL) in an ultrasonic bath, and the pentane filtrate was concentrated to give 3.40 g of an oil. The oil was chromatographed on silica gel (180 g), eluting with CHCl3-acetone (4:1, v/v). Selected fractions containing the product (Rf 0.29) were combined and concentrated to afford 1.23 g of a light-yellow oil. The 2.50 g lot was triturated with pentane (2×50 mL) in an ultrasonic bath and the pentane filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (50 g), eluting with CHCl3-acetone (4:1, v/v). Selected fractions containing the product were combined and concentrated to give 0.58 g of a light-yellow oil. Impure fractions from the latter column were combined and concentrated, and the residue was chromatographed on silica gel (50 g) to give 0.28 g of a light-yellow oil. All purified materials were combined, concentrated and dried under high vacuum to yield 1.83 g (51.9%) of a light-yellow oil.

1. customproducing a thick yellow mixture
2. stirringto stir
3. temperaturewarm to ambient temperature over 24 h
4. washwashed with saturated K2CO3 solution (2×100 mL)
5. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated by rotary evaporation
8. custombriefly dried under high vacuum
9. customto give a viscous, light-yellow gel
10. customThe crude product was purified by column chromatography on silica gel (302 g)
11. washeluting with CHCl3—CH3OH (95:5
12. additionSelected fractions containing the product (Rf 0.44)
13. concentrationconcentrated

ORD record

ord-6e96046aadad4527b37c3fd13e6bc8d6

Source dataset

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06627648B1