3-Ethynylpyridine → (3RS, 4S)-4-(4-Bromophenoxy)-1-pyridin-3-yl-hex-1-yn-3-ol

Temperature

-70 °C

Freshly activated (dried in oven at 300° C.) powdered molecular sieves (20 g, 3 Å, <5 micron) were added to (2S)-2-(4-bromophenoxy)-1-butanol (5.24 g, Example 87b)) and pyridinium dichromate (12.07 g) in anhydrous dichloromethane (200 ml). This mixture was treated with anhydrous acetic acid (2 drops) and stirred under nitrogen for 2 hours. Celite® (10 g) was added to the reaction mixture which was stirred for 20 minutes. Isohexane (100 ml) was added to this and the mixture filtered. The filtrate was concentrated under reduced pressure and the residue obtained was triturated in diethyl ether. This was filtered through anhydrous magnesium sulfate and the filtrate concentrated under reduced pressure. The residue obtained was assumed to be (2S)-2-(4-bromophenoxy)-1-butanal and dissolved in anhydrous tetrahydrofuran (40 ml). n-Butyl-lithium (5.88 ml, 2.5M solution in hexanes) was added dropwise to a solution of pyridin-3-ylacetylene (1.6g, J. Amer. Chem. Soc. 1935, 57, 1284) in anhydrous tetrahydrofuran (80 ml) at −70° C., under nitrogen. After stirring for 20 minutes the solution of the (2S)-2-(4-bromophenoxy)-1-butanal in tetrahydrofuran was added dropwise, maintaining the reaction temperature at −70° C.. The reaction mixture was then allowed to warm slowly to 0° C. and poured into brine (200 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic fractions were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an oil which was purified by flash column chromatography over silica eluting with isohexane : ethyl acetate (2:1). This gave the sub-title compound as an oil (3.42 g).

1. custom(dried in oven at 300° C.)
2. additionwere added to (2S)-2-(4-bromophenoxy)-1-butanol (5.24 g, Example 87b)) and pyridinium dichromate (12.07 g) in anhydrous dichloromethane (200 ml)
3. additionThis mixture was treated with anhydrous acetic acid (2 drops)
4. additionCelite® (10 g) was added to the reaction mixture which
5. stirringwas stirred for 20 minutes
6. additionIsohexane (100 ml) was added to this and the mixture
7. filtrationfiltered
8. concentrationThe filtrate was concentrated under reduced pressure
9. customthe residue obtained
10. customwas triturated in diethyl ether
11. filtrationThis was filtered through anhydrous magnesium sulfate
12. concentrationthe filtrate concentrated under reduced pressure
13. customThe residue obtained
14. additionwas added dropwise
15. temperatureto warm slowly to 0° C.
16. customThe organic layer was separated
17. extractionthe aqueous layer was extracted with ethyl acetate
18. dry with materialdried over anhydrous magnesium sulfate
19. filtrationAfter filtration
20. concentrationthe filtrate was concentrated under reduced pressure
21. customto give an oil which
22. customwas purified by flash column chromatography over silica eluting with isohexane : ethyl acetate (2:1)

ORD record

ord-e91f4b0944de47aea8137cce61a088c9

Source dataset

uspto-grants-2001_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06300352B1