Phenylboronic Acid → 3-Amino-biphenyl-2-carbonitrile

HRID 2036780Notes

Reaction equation

HRID 2036780 reaction equation
[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].C([O-])(=O)C.[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]#[N:5]

Participants

5

Reactant 3

HCID 66827Phenylboronic AcidHCID 517044Potassium AcetateHCID 98130382-Amino-6-bromobenzonitrile

Product 1

HCID 463118033-Amino-biphenyl-2-carbonitrile

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

2-Amino-6-bromo-benzonitrile (1.0 Kg, 5.07 moles) and toluene (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer under inert atmosphere. Potassium acetate (996 g, 10.16 moles) and phenylboronic acid (866, 7.10 moles) were added into the solution and the solution was degassed with nitrogen for 30 min. After this time, dichloro-bis(triphenylphosphine) palladium (II) (17.8 g, 0.025 moles) was added to the reaction mixture at ambient temperature. The mixture was heated to 110° C., where it stirred for 17 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was completed. The reaction mixture was filtered through a celite bed. The filtrate was transferred back to the reactor and concentrated hydrochloric acid (˜35%, 2 L, 2 vol) was charged to the reactor at ambient temperature. The HCl salt of the title compound precipitated out from the reaction and was collected by filtration. The HCl salt was transferred into the 20 L reactor and then made basic with 10% NaOH solution (pH 8-9). The resulting product was extracted with ethyl acetate (10 L, 10 vol). The ethyl acetate layer was washed with water (5 L, 5 vol) and then the solvent was evaporated under vacuum to give a residue. Hexanes (5 L, 5 vol) were added to the residue at 35-40° C., and the resulting slurry was cooled to ambient temperature. Once at the prescribed temperature, the product was collected by filtration to provide a pale yellow solid (802 g, 81.4%, 99% by HPLC). 1H NMR (DMSO-D6, 400 MHz, δ ppm); 7.43-7.52 (m, 5H), 7.33-7.37 (m, 1H), 6.83 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.1 (s, 2H). ES-MS: [M++1]=194.23.

Workup

  1. customequipped with mechanical stirrer under inert atmosphere
  2. customthe solution was degassed with nitrogen for 30 min
  3. filtrationThe reaction mixture was filtered through a celite bed
  4. additionwas charged to the reactor at ambient temperature
  5. customThe HCl salt of the title compound precipitated out from the reaction
  6. filtrationwas collected by filtration
  7. extractionThe resulting product was extracted with ethyl acetate (10 L, 10 vol)
  8. washThe ethyl acetate layer was washed with water (5 L, 5 vol)
  9. customthe solvent was evaporated under vacuum
  10. customto give a residue
  11. temperaturethe resulting slurry was cooled to ambient temperature
  12. filtrationOnce at the prescribed temperature, the product was collected by filtration
  13. customto provide a pale yellow solid (802 g, 81.4%, 99% by HPLC)

Sources & evidence

ORD record
ord-e102401db5bb4caba8961331643b05f7
Source dataset
uspto-grants-2013_11
Patent number
US08575184B2

Reaction notes

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