Dimethylformamide → 1-Methyl-4-(6-(((4-phenylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine-2-yl)piperazine

HRID 656517Notes

Reaction equation

HRID 656517 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.CC(C)([O-])C.[Na+].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CN(C)C=O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:2]2[CH:3]=[C:4]([C:30]([F:32])([F:33])[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)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[N:7]=2)[CH2:43][CH2:42]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 531671-MethylpiperazineHCID 23676156Sodium t-butoxideHCID 57557581Tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate

Product 1

HCID 248005771-Methyl-4-(6-(((4-phenylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine-2-yl)piperazineYield 38.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.21 mmol), sodium tert-butoxide (22 mg, 0.23 mmol), N-methyl piperizine (18 mg, 0.18 mmol), (+/−) 2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (93 mg, 0.15 mmol), and tris(dibenzylideneacetone)dipalladium (0) (7.0 mg, 0.007 mmol) were combined in dry toluene (2 mL) and dimethylformamide (0.5 mL) in a sealed tube. The mixture was then 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, 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. Concentration and preparative HPLC afforded 31.0 mg (26%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.27-7.46 (m, 5H), 6.99 (s, 1H), 6.74 (s, 1H), 4.40-4.53 (m, 2H), 4.40 (s, 2H), 3.50-3.55 (m, 4H), 3.10-3.50 (m, 6H), 2.83-2.96 (m, 5H), 2.51-2.55 (m, 2H), 2.15-2.22 (m, 2H), Mass spec.: 449.24 (MH)+.

Workup

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

Sources & evidence

ORD record
ord-9d7722dce17045c5b69232140c5adf68
Source dataset
uspto-grants-2011_12
Patent number
US08071778B2

Reaction notes

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