Chlorotrimethylsilane → 2-[(Benzylmethylamino)methyl]-1-pyridin-3-ylcyclohexanol hydrochloride

温度

-10 °C

50 ml n-butyllithium solution (2.5 mol/l in hexane) were added dropwise to a solution of 12.1 ml 3-bromopyridine in 180 ml analytical grade diethyl ether at a temperature of −45 to −50° C. in the course of 30 minutes. After a further 20 minutes at this temperature, 25.2 g 2-[(benzylmethylamino)methyl]cyclohexanone, dissolved in 50 ml analytical grade diethyl ether, were added dropwise in the course of 30 minutes, with continued cooling, and the mixture was subsequently stirred for a further 60 minutes. The cooling was then removed and 54 ml water were added, while warming the reaction mixture from −20 to 0° C., the phases were separated, the aqueous phase was extracted twice with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, the combined organic phases were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (33.0 g) was chromatographed on silica gel first with acetone/ethyl acetate (V:V=1:2) and then again with pure ethyl acetate, the product fraction obtained (23.6 g) was dissolved in 230 ml ethyl acetate, and 2.74 ml water and 19.3 ml chlorotrimethylsilane were added and the mixture, from which an oil settled out, was concentrated to dryness. The residue was taken up in 90 ml water and 17.9 ml sodium hydroxide solution (32 percent strength by weight), the mixture was extracted twice with 90 ml ethyl acetate each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. 23.6 g of crude product were again obtained, to which, after dissolving in 230 ml acetone, 2.74 ml water and 19.3 ml chlorotrimethylsilane, dissolved in 100 ml acetone, were added. The supernatant was decanted off from the solid formed and the residue was heated to 50° C. with 230 ml acetone. After cooling, the supernatant was decanted off again and the residue was dried in vacuo (50 mbar) at 50° C. 28.8 g 2-[(benzylmethylamino)methyl]-1-pyridin-3-yl-cyclohexanol hydrochloride were obtained.

1. additionwere added dropwise in the course of 30 minutes, with continued cooling
2. customThe cooling was then removed
3. addition54 ml water were added
4. customthe phases were separated
5. extractionthe aqueous phase was extracted twice with a mixture of equal volumes of tetrahydrofuran and ethyl acetate
6. dry with materialthe combined organic phases were dried over magnesium sulfate
7. filtrationfiltered
8. concentrationthe filtrate was concentrated
9. customThe crude product obtained (33.0 g)
10. customwas chromatographed on silica gel first with acetone/ethyl acetate (V:V=1:2)
11. customagain with pure ethyl acetate, the product fraction obtained (23.6 g)
12. concentrationwas concentrated to dryness
13. extraction17.9 ml sodium hydroxide solution (32 percent strength by weight), the mixture was extracted twice with 90 ml ethyl acetate each time
14. dry with materialthe combined extracts were dried over magnesium sulfate
15. filtrationfiltered
16. concentrationthe filtrate was concentrated
17. custom23.6 g of crude product were again obtained, to which
18. additionwere added
19. customThe supernatant was decanted off from the solid
20. customformed
21. temperatureAfter cooling
22. customthe supernatant was decanted off again
23. customthe residue was dried in vacuo (50 mbar) at 50° C

ORDレコード

ord-e91904f6e63446478a02da3c168c8b90

出典データセット

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07384961B2