Tetrahydrofuran → 1-(2-Aminopyridin-3-yl)ethanol

To a dry flask (dried with a heat gun under argon purge) was added dry THF (400 mL) and MeLi-LiBr (137 mL of a 1.5 M solution in Et2O, 204.9 mmol) via cannula. This solution was cooled to −78° C. when a solution of 2-aminopyridine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL) was added dropwise via a pressure equalizing addition funnel over ˜45 min with vigorous stirring (exotherm observed, orange color persisted). Upon complete addition, the solution was allowed to stir for 1 hour at −78° C., at which time TLC (KMnO4 stain with heat) indicated that most of the starting material had been converted to product. The reaction was quenched very carefully with water (200 mL; dropwise initially), diluted with EtOAc (200 mL) and allowed to warm to rt. The layers were separated and the aqueous layer was extracted with 3% MeOH in EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desired racemic product as a yellow oil that solidified under high vac over several days. This material was separated into its respective enantiomers (>98% ee) by SFC with a chiralcel OD-H (20×250 mm) column (10% EtOH/0.1% isopropylamine in heptane/0.1% isopropylamine).

1. customTo a dry flask (dried with a heat gun under argon
2. custompurge)
3. additionwas added dry THF (400 mL) and MeLi-LiBr (137 mL of a 1.5 M solution in Et2O, 204.9 mmol) via cannula
4. additionwas added dropwise via a pressure
5. additionaddition funnel over ˜45 min
6. additionUpon complete addition
7. customThe reaction was quenched very carefully with water (200 mL
8. additiondropwise initially), diluted with EtOAc (200 mL)
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with 3% MeOH in EtOAc
11. dry with materialThe combined extracts were dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc)

ORD record

ord-b0988497415649d58633ccc387509d59

Source dataset

uspto-grants-2009_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07504413B2