Dimethyl Sulfoxide → (3RS, 4S)-4-(Biphenyl-4-yloxy)-5-methyl-1-pyridin-3-yl-hex-1-yn-3-ol

Temperature

10 °C

Oxalyl chloride (1.65 ml) was added dropwise to a solution of dimethyl sulfoxide (2.25 ml) in dry dichloromethane (120 ml) at −65° C. The resulting solution was stirred for 10 minutes and then a solution of (2S)-2-(biphenyl-4-yloxy)-3-methylbutan-1-ol (3.40 g, Example 8b)) in dry dichloromethane (30 ml) was added dropwise at −65° C. The mixture was stirred for a further 15 minutes and then triethylamine (12 ml) was added dropwise. The mixture was allowed to warm to 10° C. with stirring. The mixture was then diluted with isohexane (250 ml), stirred for 10 minutes, filtered and concentrated under reduced pressure. The residue was dissolved in dry tetrahydrofuran (20 ml) and added at −20° C. to a solution of 1-lithio-2-pyridin-3-ylacetylene [generated by the addition of n-butyllithium (2.5 M in hexanes, 8.4 ml) to a solution of pyridylacetylene (2.0 g) (J. Amer. Chem. Soc. 1935, 57, 1284) in tetrahydrofuran (80 ml) at −60° C. with stirring for 20 minutes]. The mixture was allowed to warm to room temperature and after 30 minutes was poured into water (200 ml). The mixture was extracted with ethyl acetate, the combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (4:1) to give the sub-title compound as an oil and as a 3:1 mixture of diastereomers (4.38 g).

1. stirringThe mixture was stirred for a further 15 minutes
2. stirringwith stirring
3. stirringstirred for 10 minutes
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. dissolutionThe residue was dissolved in dry tetrahydrofuran (20 ml)
7. additionadded at −20° C. to a solution of 1-lithio-2-pyridin-3-ylacetylene [
8. additiongenerated by the addition of n-butyllithium (2.5 M in hexanes, 8.4 ml) to a solution of pyridylacetylene (2.0 g) (J. Amer. Chem. Soc. 1935, 57, 1284) in tetrahydrofuran (80 ml) at −60° C.
9. stirringwith stirring for 20 minutes]
10. temperatureto warm to room temperature and after 30 minutes
11. additionwas poured into water (200 ml)
12. extractionThe mixture was extracted with ethyl acetate
13. dry with materialthe combined organic extracts dried over anhydrous magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure
16. customThe residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (4:1)

ORD record

ord-80c4397a93d44ee1ba0d618b6e2210ed

Source dataset

uspto-grants-2001_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06300352B1