Dichloromethane → (4-Methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]amine

HRID 570221Notes

Reaction equation

HRID 570221 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[N:7]=2)=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 27343872-(Trifluoromethyl)benzeneboronic acidHCID 86657407(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine

Product 1

HCID 86657408(4-Methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]amine

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine (7.26 g, 22.9 mmol, prepared as described in STEP A above) in DME (100 mL) and water (50 mL) was treated with 2-trifluoromethylphenylboronic acid (5.66 g, 29.8 mmol), and Cs2CO3 (11.2 g, 34.4 mmol). The resulting mixture was degassed via heating under a stream of Ar. Cl2Pd(dppf).DCM (1.13 g, 1.38 mmol) was added, and the mixture was heated to 80° C. for 4 h. The cooled mixture was diluted with water (100 mL) and extracted twice with EtOAc (150 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield (4-methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amine as a yellow oil, which solidified upon standing. 1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.8 Hz, 1H), 7.57-7.63 (m, 1H), 7.47-7.55 (m, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.85-6.91 (m, 3H), 6.57 (s, 1H), 5.11 (t, J=5.2 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N2OF6: 427.1 (M+H); Measured: 427.2.

Workup

  1. customThe resulting mixture was degassed
  2. temperaturevia heating under a stream of Ar
  3. extractionextracted twice with EtOAc (150 mL)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=30 mL/min

Sources & evidence

ORD record
ord-3188b201f8f64155b4a31a7304ffe1d2
Source dataset
uspto-grants-2015_05
Patent number
US09023846B2

Reaction notes

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