Sodium Carbonate → Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate

HRID 2410747Notes

Reaction equation

HRID 2410747 reaction equation
[NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:14]1([C:20]([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:21])=[CH:27][CH:26]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 2773546[4-(Morpholine-4-carbonyl)phenyl]boronic acidHCID 53419616Methyl 3-amino-2,6-dibromoisonicotinate

Product 1

HCID 86663019Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinateYield 24%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of methyl 3-amino-2,6-dibromoisonicotinate (11.4 g, 36.6 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (8.7 g, 33.3 mmol), and powdered sodium carbonate (8.12 g, 77 mmol) in a mixture of toluene (90 mL) and methanol (30 mL) was degassed and then backfilled with nitrogen twice. Tetrakis(triphenylphosphine)-palladium(0) (1.93 g, 1.67 mmol) was added and the reaction was degassed and backfilled with nitrogen. After stirred in a 110° C. oil bath for 64 hr, the reaction was cooled and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, and then dried over sodium sulfate and the solvents removed. The residue was suspended in EtOAc and the solid was collected by filtration and washed with EtOAc to give methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)-isonicotinate (3.29 gm, 24%). Flash silica gel chromatography of the filtrate (step gradient elution with hexane containing 10 to 20% EtOAc and then methylene chloride containing 1 to 4% MeOH) gave additional 4.63 g (33%) of pure product and 2.2 g of material that contained 65% of the product according to LC/MS. MS (ESI) m/z 418 and 420 (M−H). 1H NMR (CDCl3) δ ppm 7.83 (1H, s), 7.68 (2H, d, J=8.24 Hz), 7.52 (2H, d, J=7.93 Hz), 5.93 (2H, br. s.), 3.92 (3H, s), 3.78 (4H, br. s.), 3.62 (2H, br. s.), 3.46 (2H, br. s.).

Workup

  1. customwas degassed
  2. customthe reaction was degassed
  3. temperaturethe reaction was cooled
  4. custompartitioned between EtOAc and saturated aqueous sodium bicarbonate
  5. customThe organic phase was separated
  6. washwashed with saturated aqueous sodium bicarbonate, brine
  7. dry with materialdried over sodium sulfate
  8. customthe solvents removed
  9. filtrationthe solid was collected by filtration
  10. washwashed with EtOAc

Sources & evidence

ORD record
ord-0d8d7c18d1f648de8e4f9286cf48b245
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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