Benzyl azide → HCID 86726524, compound

Temperature

25 °C

Add isopropylmagnesium chloride (368 mL, 736.00 mmol) drop-wise to a solution of 2-but-3-ynoxytetrahydropyran (113.50 g, 736.00 mmol) in tetrahydrofuran (1.4 L) at 15° C., maintaining the internal temperature less than 20° C. Remove the ice-water bath, allow the temperature to warm to 25° C., and hold at that temperature for 20 min to ensure gas evolution is complete. Heat the reaction mixture to 30-35° C., and add benzyl azide (70 g, 525.71 mmol) drop-wise to the mixture over 2 h while ensuring benzyl azide concentration in the reaction mixture does not rise to appreciable levels by a method such as LCMS. After a 4 h stir, cool the reaction mixture to 25° C., and quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition. After a 16 h stir, dilute with methyltert-butyl ether (200 mL), separate the layers, and stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h. When greater than 98% conversion is achieved by a method such as LCMS, raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL). Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL). Concentrate the combined organic layers in vacuo, and purify the resulting crude product by silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (53 g, 50%) as an off-white solid. MS (m/z): 204.1 (M+1).

1. temperaturemaintaining the internal temperature less than 20° C
2. customRemove the ice-water bath
3. temperatureHeat the reaction mixture to 30-35° C.
4. concentrationbenzyl azide concentration in the reaction mixture
5. temperaturecool the reaction mixture to 25° C.
6. customquench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition
7. stirringAfter a 16 h stir
8. additiondilute with methyltert-butyl ether (200 mL)
9. customseparate the layers
10. stirringstir the organic layer with 3M hydrochloric acid (600 mL) for 4 h
11. temperatureraise the pH of the reaction mixture to pH>10
12. additionvia dropwise addition of 6 M sodium hydroxide (ca. 350 mL)
13. extractionExtract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL)
14. concentrationConcentrate the combined organic layers in vacuo
15. custompurify the resulting crude product by silica gel column chromatography
16. washeluting with ethyl acetate

ORD record

ord-a7944a6fa76940f18852799bff4c21c5

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969555B2