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

Temperature

20 °C

To 3-fluoro-4-hydroxybenzonitrile (10 g) was added ethylene carbonate (6.85 g), potassium iodide (1.2 g) and xylene (21 mL), at 20° C. The reaction mixture was heated to 140° C.±5° C., over thirty minutes, and maintained at this temperature for twelve hours. For convenience, the reaction mixture was cooled to 20° C., over approximately eight hours. To the cooled reaction mixture was added triethylamine (7.1 mL) and 4-methyl-pentan-2-one (14.25 mL). The reaction mixture was then cooled to −10° C., over approximately five minutes, after which trimethylamine hydrochloride (1.4 g) was added, followed by a solution of para-toluenesulfonyl chloride (14.6 g), dissolved in 4-methylpenatan-2-one (80 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 (60 mL) was added and the reaction mixture was heated to 75° 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 (60 mL), and the reaction mixture was again heated to 75° C. The layers were separated and the lower (aqueous) layer was discarded. For convenience, the upper (organic) layer was cooled to 20° C. over approximately fourteen hours. The reaction mixture was then cooled to 5° C. over approximately ten minutes, after which the product was isolated by filtration and washed (on the filter) with 4-methylpenatan-2-one (10 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 (16.9 g; 69% yield).

1. customat 20° C
2. temperatureThe reaction mixture was heated to 140° C.±5° C., over thirty minutes
3. temperaturemaintained at this temperature for twelve hours
4. customTo the cooled reaction mixture
5. temperatureThe reaction mixture was then cooled to −10° C., over approximately five 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 75° C., at which temperature the layers
11. customwere separated
12. additionwas added 1 M hydrochloric acid (60 mL)
13. temperaturethe reaction mixture was again heated to 75° C
14. customThe layers were separated
15. temperatureFor convenience, the upper (organic) layer was cooled to 20° C. over approximately fourteen hours
16. temperatureThe reaction mixture was then cooled to 5° C. over approximately ten minutes
17. customafter which the product was isolated by filtration
18. washwashed (on the
19. filtrationfilter) with 4-methylpenatan-2-one (10 mL, at 5° C.)
20. customThe damp solid was then dried in vacuo, at 35° C., for approximately twenty-four hours

ORD record

ord-0feca235dff64a9c97338b1990364c01

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07928225B2