Water → 2-Cyanophenylboronic acid

Temperature

-78 °C

Dissolve 2-bromobenzonitrile (melt in water bath at 65° C. before use, 6.733 kg, 37.0 mol, 1 eq) in THF (52.5 L) in a cryogenic reactor and cool to −78° C. Add triisopropylborate (13.96 kg, 74 mol, 2 eq). Allow the mixture to cool to −78° C. again. Add hexyllithium (2.5M in hexane, 15.38 kg, 55.5 mol, 1.5 eq) over a period of 2 h (max internal temp=69° C.). After the addition, stir for 1 h at −75° C. Add the mixture (−74° C.) to water (48 L, 5° C.) over a period of 15 min with stirring to give a slightly yellow emulsion (−1° C.). Warm the mixture to 23° C. and stir at this temperature for 90 min. Separate the layers. Extract the aqueous layer with isopropyl acetate (24 L). Combine the organic layers and re-extract with brine (22 L). Combine the aqueous layers and acidify to pH 1 with 1M sulfuric acid (31 L). Extract the product twice with isopropyl acetate (41 L and 39 L). Combine the organic layers and stir overnight with brine (21 L) at 2° C. Collect the organic solution (90 L) and distill under reduced pressure at 50-60° C. to reduce the volume to 10 L. Strip the suspension with isopropyl acetate (11 L). Add methylcyclohexane (20 L) at 25° C. Cool the suspension to -7° C. Collect the precipitated product by filtration. Wash the filter cake with a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L). Dry the filter cake on the rotovap at reduced pressure at 50° C. to obtain 2.997 kg of title compound as a white powder; 55% yield (poor yield due to some material sticking to the reactor wall). 1H NMR (solvent-dx): § 7.53 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.62 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.73 (m, 2H).

1. temperatureAllow the mixture to cool to −78° C. again
2. additionAfter the addition
3. stirringwith stirring
4. customto give a slightly yellow emulsion (−1° C.)
5. temperatureWarm the mixture to 23° C.
6. stirringstir at this temperature for 90 min
7. customSeparate the layers
8. extractionExtract the aqueous layer with isopropyl acetate (24 L)
9. extractionCombine the organic layers and re-extract with brine (22 L)
10. extractionExtract the product twice with isopropyl acetate (41 L and 39 L)
11. stirringCombine the organic layers and stir overnight with brine (21 L) at 2° C
12. customCollect the organic solution (90 L)
13. distillationdistill under reduced pressure at 50-60° C.
14. customat 25° C
15. temperatureCool the suspension to -7° C
16. customCollect the precipitated product
17. filtrationby filtration
18. washWash the filter cake
19. additionwith a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L)
20. customDry the filter cake on the rotovap at reduced pressure at 50° C.

ORD record

ord-86d457b7685f442495b3939968821234

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07625932B2