Potassium Carbonate → (R)-methyl-6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate

HRID 2173780Notes

Reaction equation

HRID 2173780 reaction equation
F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:13][CH:14]([CH3:34])[CH2:15][C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][C@@H:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH:14]([CH3:34])[CH3:13])=[N:3][CH:4]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 13758765Methyl 6-fluoropyridine-3-carboxylateHCID 67980925(R)-3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride

Product 1

HCID 67980699(R)-methyl-6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinateYield 107.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A 1.0 L round bottom flask was charged with methyl 6-fluoronicotinate (14.2 g, 91.6 mmol), (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (30.0 g, 87.3 mmol), potassium carbonate (36.2 g, 262 mmol) and N,N-dimethylformamide (300 mL). The reaction was heated to 110° C. and stirred for 15 hours. The reaction was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with water (5×) and brine (1×), dried over sodium sulfate, filtered and concentrated to provide (R)-methyl-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g) as a light brown solid. 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J=6.24 Hz, 3H) 1.02 (d, J=6.24 Hz, 3H) 1.67-1.92 (m, 3H) 3.86 (s, 3H) 4.68-4.84 (m, 1H) 6.36 (d, J=8.97 Hz, 1H) 6.65 (br. s., 1H) 7.42-7.47 (m, 2H) 7.55-7.59 (m, 2H) 7.66-7.69 (m, 4H) 8.00 (dd, J=8.97, 2.15 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H). MS (M+1): 443.4.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. filtrationfiltered
  3. additionThe filtrate was diluted with ethyl acetate and saturated ammonium chloride
  4. customThe layers were separated
  5. extractionthe aqueous was extracted with ethyl acetate
  6. washThe combined organic layers were washed with water (5×) and brine (1×)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-4d3805f2ad71430981dfc7fe88ebe926
Source dataset
uspto-grants-2015_06
Patent number
US09056834B2

Reaction notes

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