1-Bromo-2-Chloroethane → 1-(2,2-Difluorobenzo[D][1,3]dioxol-5-YL)cyclopropanecarbonitrile

Temperature

10 °C

A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0° C. was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a % conversion >99% was observed (typically after 2.5-3 h), the reaction mixture was cooled to 10° C. and was charged with water (461 mL) at such a rate as to maintain a temperature <25° C. The temperature was adjusted to 20-25° C. and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50-60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50-60° C. The resulting mixture was cooled to 20-25° C. and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).

1. customA stock solution of 50% w/w NaOH was degassed via nitrogen
2. customsparge for no less than 16 h
3. customAn appropriate amount of MTBE was similarly degassed for several hours
4. customTo a reactor purged with nitrogen
5. additionwas charged
6. customdegassed MTBE (143 mL)
7. customthe mixture was degassed via nitrogen
8. customsparge for 30 min
9. customEnough degassed MTBE
10. additionis charged
11. customto degassing
12. additionTo the stirring mixture at 23.0° C. was charged
13. customdegassed 50% w/w NaOH (143 mL) over 10 min
14. aliquotBefore sampling
15. customto separate
16. aliquotThe top organic phase was sampled for analysis
17. customtypically after 2.5-3 h
18. additionwas charged with water (461 mL) at such a rate as
19. temperatureto maintain a temperature <25° C
20. customwas adjusted to 20-25° C.
21. customthe phases separated
22. customsufficient time should be allowed for complete phase separation
23. extractionThe aqueous phase was extracted with MTBE (123 mL)
24. washthe combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL)
25. concentrationThe solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C
26. additionThe solution was charged with ethanol (256 mL)
27. concentrationagain concentrated to 164 mL under vacuum at 50-60° C
28. additionEthanol (256 mL) was charged
29. concentrationthe mixture concentrated to 164 mL under vacuum at 50-60° C
30. temperatureThe resulting mixture was cooled to 20-25° C.
31. additiondiluted with ethanol to 266 mL in preparation for the next step

ORD record

ord-8745074c02e54dbc92991164fccdb036

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09254291B2