Methyl 6-formylpyridine-3-carboxylate → HCID 67980582, compound

HRID 2406949Notes

Reaction equation

HRID 2406949 reaction equation
[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:30][CH:31]([CH3:33])[CH2:32][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:28])([F:29])[F:13])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1

Participants

6

Reactant 3

HCID 586269Methyl 6-formylpyridine-3-carboxylateHCID 27827094'-(Trifluoromethyl)[1,1'-biphenyl]-4-amineHCID 178418816HCID 178418816, compound

Product 1

HCID 67980582HCID 67980582, compoundYield 39.2%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of methyl 6-formylnicotinate (0.200 g, 1.21 mmol) in tetrahydrofuran (8 mL) containing activated molecular sieves was added 4′-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol). The reaction was heated to 90° C. and stirred overnight. The reaction was concentrated to dryness and the residue was dissolved in tetrahydrofuran (8 mL). The solution was cooled to 0° C. Zinc chloride (3.52 mL, 1M in diethyl ether, 3.52 mmol) was added, followed by isobutylmagnesium bromide (1.47 mL, 2.0M in THF, 3.52 mmol). The reaction was stirred at 0° C. for 2 hours. The reaction was quenched with saturated ammonium chloride. The mixture was diluted with dichloromethane and water. The layers were separated and the aqueous was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (210 mg, 39%) as a yellow oil. 1H NMR (400 MHz, CD3OD, δ): 9.09 (s, 1H), 8.31 (d, 1H), 7.72-7.57 (m, 5H), 7.41 (d, 2H), 6.65 (d, 2H), 4.61-4.52 (m, 1H), 3.94 (s, 3H), 1.92-1.73 (m, 2H), 1.1.72-1.61 (m, 1H), 1.05 (d, 3H), 0.91 (d, 3H).

Workup

  1. concentrationThe reaction was concentrated to dryness
  2. dissolutionthe residue was dissolved in tetrahydrofuran (8 mL)
  3. temperatureThe solution was cooled to 0° C
  4. stirringThe reaction was stirred at 0° C. for 2 hours
  5. customThe reaction was quenched with saturated ammonium chloride
  6. additionThe mixture was diluted with dichloromethane and water
  7. customThe layers were separated
  8. extractionthe aqueous was extracted again with dichloromethane
  9. dry with materialThe combined organic layers were dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification by column chromatography

Sources & evidence

ORD record
ord-b1f06747736541a5b962b6c9e63ad8db
Source dataset
uspto-grants-2014_08
Patent number
US08809342B2

Reaction notes

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