(4-Methoxyphenyl)boronic acid → 2-(4-Methoxyphenyl)-6-(((4-phenylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine

HRID 656516Notes

Reaction equation

HRID 656516 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:3]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:38][CH:37]=1

Participants

5

Reactant 2

HCID 201262(4-Methoxyphenyl)boronic acidHCID 57557581Tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate

Product 1

HCID 237251762-(4-Methoxyphenyl)-6-(((4-phenylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridineYield 42.8%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol); 4-methoxyphenyl boronic acid (128.0 mg, 0.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) were combined in dry tetrahydrofuran (3 mL) in a sealed tube. The mixture was flushed with nitrogen then 0.75 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:2, 3 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. Concentration and preparative HPLC afforded 41.0 mg (34%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.99 (d, 2H, J=8.0 Hz), 7.86 (s, 1H), 7.31-7.49 (m, 5H), 7.24 (s, 1H), 7.01 (d, 2H, J=8.0 Hz), 4.61 (s, 2H), 3.84 (s, 3H), 3.34 (s, 2H), 3.32-3.60 (m, 2H), 2.85-2.97 (m, 2H), 2.53-2.57 (m, 2H), 2.20-2.26 (m, 2H). Mass spec.: 457.18 (MH)+.

Workup

  1. customThe mixture was flushed with nitrogen
  2. addition0.75 mL of a 1 N potassium hydroxide aqueous solution was introduced
  3. temperatureAfter cooling to room temperature
  4. concentrationthe reaction mixture was concentrated
  5. additiontreated with a trifluoroacetic acid/methylene chloride mixture (1:2, 3 mL) for 1 h
  6. customThe solvent was removed in vacuo
  7. washAfter washing the column with several volumes of methanol
  8. washthe product was eluted
  9. washby washing the column with 2 M ammonia in methanol
  10. concentrationConcentration and preparative HPLC

Sources & evidence

ORD record
ord-e13f98bc56d042f6b3328b98fb7df8d2
Source dataset
uspto-grants-2011_12
Patent number
US08071778B2

Reaction notes

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