4-Cyanophenylboronic acid → 3'-Fluoro-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile

HRID 391484Notes

Reaction equation

HRID 391484 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:30][C:28]1[CH:29]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:27]=1

Participants

5

Reactant 2

HCID 27343264-Cyanophenylboronic acidHCID 58993701tert-Butyl 4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate

Product 1

HCID 589936983'-Fluoro-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl 4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol), 4-cyanophenylboronic acid (93 mg, 0.63 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.02 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.7 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 48 mg (46%). 1H-NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m, 1H), 7.11-7.13 (m, 1H), 7.08 (s, 1H), 6.84-6.86 (s, 1H), 4.40 (s, 2H), 3.45 (s, 2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H), 2.17-2.20 (m, 2H), 1.88-1.94 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 163.3 (d, J=247.6 Hz), 144.2, 142.5, 141.2, 132.7, 128.4, 127.8, 127.3, 126.2, 121.3, 118.7, 114.2, 114.0, 113.1, 111.7, 80.1, 72.3, 42.7, 41.9, 33.6. Mass spec.: 401.28 (MH)+. Accurate mass spec.: m/z 401.2026 [MH]+, Δ=0.8 ppm.

Workup

  1. customsealed
  2. customAfter flushing with nitrogen, 0.7 mL of a 1 N potassium hydroxide aqueous solution
  3. additionwas introduced
  4. temperatureAfter cooling to room temperature
  5. concentrationthe reaction mixture was concentrated
  6. additiontreated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h
  7. customThe solvent was removed in vacuo
  8. washAfter washing the column with several volumes of methanol
  9. washthe product was eluted
  10. washby washing the column with 2 M ammonia in methanol
  11. concentrationconcentrated
  12. customto afford 48 mg (46%)

Sources & evidence

ORD record
ord-a3e6631d1a674f22b873ec1d0fa946e6
Source dataset
uspto-grants-2013_02
Patent number
US08383821B2

Reaction notes

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