Potassium Phosphate, Tribasic → Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)isonicotinate

HRID 2410720Notes

Reaction equation

HRID 2410720 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.[NH2:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:43][CH:42]=2)=[N:39][C:38](Br)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].COC1C=CC(B(O)O)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:43][CH:42]=2)=[N:39][C:38]([C:16]2[CH:15]=[CH:14][C:19]([O:20][CH3:21])=[CH:18][CH:17]=2)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 201262(4-Methoxyphenyl)boronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 86663009Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate

Product 1

HCID 66599449Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)isonicotinateYield 392%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Procedure

A flask containing dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (132 mg, 0.322 mmol), methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (665 mg, 1.61 mmol), 4-methoxyphenylboronic acid (293 mg, 1.93 mmol), palladium(II) acetate (36.1 mg, 0.161 mmol), and potassium phosphate tribasic (1025 mg, 4.83 mmol) was flushed with nitrogen. Tetrahydrofuran (16 mL) was added and the reaction was heated at reflux overnight. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried with sodium sulfate and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 0 to 10% EtOAc) afforded 556 mg of methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)-isonicotinate as a yellow oil. MS (ESI) m/z 441.2 (M+H). 1H NMR (CDCl3) δ ppm 8.01 (1H, s), 7.92 (2H, d, J=8.85 Hz), 7.67 (2H, d, J=8.85 Hz), 7.44-7.48 (2H, m), 7.40 (2H, t, J=7.63 Hz), 7.35 (1H, d, J=7.32 Hz), 7.10 (2H, d, J=8.85 Hz), 6.94 (2H, d, J=8.85 Hz), 5.94 (2H, br. s.), 5.13 (2H, s), 3.95 (3H, s), 3.83 (3H, s).

Workup

  1. customwas flushed with nitrogen
  2. additionTetrahydrofuran (16 mL) was added
  3. temperaturethe reaction was heated
  4. temperatureat reflux overnight
  5. customThe reaction was partitioned between EtOAc and water
  6. customThe organic phase was separated
  7. washwashed with brine
  8. dry with materialdried with sodium sulfate
  9. customthe solvent removed
  10. washRadial silica gel chromatography (step gradient elution with hexane containing 0 to 10% EtOAc)

Sources & evidence

ORD record
ord-b4decbf0b32a457f839909abcab2d5ba
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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