Ethylene carbonate → 4-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl-methyl)-benzonitrile hydrochloride

Temperature

20 °C

To 3-fluoro-4-hydroxybenzonitrile (5 g) was added xylene (10 mL), at 20° C. To the resulting mixture was added ethylene carbonate (3.44 g) and tetra-n-butylammonium iodide (0.71 g). The reaction mixture was heated to 125° C.±5° C., over twenty minutes, and maintained at this temperature for five hours. For convenience, the reaction mixture was cooled to 20° C., over approximately fifteen and an half hours, and was analysed for water content (typically <0.1% w/w). To the cooled reaction mixture was added triethylamine (7.1 mL) and 4-methylpentan-2-one (16 mL). The reaction mixture was then cooled to −10° C., over approximately twenty minutes, after which trimethylamine hydrochloride (0.70 g) was added, followed by a solution of para-toluenesulfonyl chloride (7.34 g), dissolved in 4-methylpenatan-2-one (40 mL). During the addition, the reaction temperature was maintained at −10° C.±5° C. When the addition was complete, the reaction mixture was warmed to 20° C. Water (30 mL) was added and the reaction mixture was heated to 72° C., at which temperature the layers were separated and the lower (aqueous) layer was discarded. To the retained (organic) layer was added 1 M hydrochloric acid (30 mL), and the reaction mixture was again heated to 72° C. The layers were separated and the lower (aqueous) layer was discarded. For convenience, the upper (organic) layer was cooled to 20° C. over eighteen hours. The reaction mixture was then cooled to 5° C. over approximately ten minutes, after which the crude product was isolated by filtration and washed (on the filter) with 4-methylpenatan-2-one (5 mL, at 5° C.). The damp solid was then dried in vacuo, at 35° C., for approximately twenty-four hours. This provided the title compound as a white crystalline solid (7.3 g; 60% yield).

1. customat 20° C
2. temperatureThe reaction mixture was heated to 125° C.±5° C., over twenty minutes
3. temperaturemaintained at this temperature for five hours
4. customTo the cooled reaction mixture
5. temperatureThe reaction mixture was then cooled to −10° C., over approximately twenty minutes
6. additionDuring the addition
7. temperaturethe reaction temperature was maintained at −10° C.±5° C
8. additionWhen the addition
9. temperaturethe reaction mixture was warmed to 20° C
10. temperaturethe reaction mixture was heated to 72° C., at which temperature the layers
11. customwere separated
12. additionwas added 1 M hydrochloric acid (30 mL)
13. temperaturethe reaction mixture was again heated to 72° C
14. customThe layers were separated
15. temperatureFor convenience, the upper (organic) layer was cooled to 20° C. over eighteen hours
16. temperatureThe reaction mixture was then cooled to 5° C. over approximately ten minutes
17. customafter which the crude product was isolated by filtration
18. washwashed (on the
19. filtrationfilter) with 4-methylpenatan-2-one (5 mL, at 5° C.)
20. customThe damp solid was then dried in vacuo, at 35° C., for approximately twenty-four hours

ORD record

ord-c8e79f4b42d747fabdf1137dd229268b

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07928225B2