Diethyl Ether → Methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate

HRID 2410748Notes

Reaction equation

HRID 2410748 reaction equation
[NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:31]=[N-:32]

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 33557Sodium AzideHCID 23668193Sodium NitriteHCID 86663019Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate

Product 1

HCID 86663020Methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinateYield 275.9%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (2.00 gm, 4.76 mmol) was dissolved in trifluoroacetic acid (26 mL) and the yellow solution was cooled in an ice-bath. Powdered sodium nitrite (0.657 gm, 9.52 mmol) was added with stirring to give a dark red mixture. After 30 minutes, powdered sodium azide (3.09 gm, 47.6 mmol) was added followed by diethyl ether (26 mL). The light red mixture was stirred in the ice-bath for 30 minutes. The reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to about 50 mL on the rotary evaporator. The resulting solid was collected by filtration and washed three times with EtOAc to give methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (5.86 gm, 72% yield). Removal of the solvent from the filtrate followed by flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 2% MeOH) afforded another 1.58 gm of product. MS (ESI) m/z 446 and 448 (M+H). 1H NMR (CDCl3) δ ppm 7.82-7.80 (3H, m), 7.49-7.53 (2H, m), 4.02 (3H, s), 3.69-3.88 (4H, m), 3.57-3.70 (2H, m), 3.40-3.53 (2H, m).

Workup

  1. temperaturethe yellow solution was cooled in an ice-bath
  2. customto give a dark red mixture
  3. customThe reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution)
  4. washThe organic phase was washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated to about 50 mL on the rotary evaporator
  7. filtrationThe resulting solid was collected by filtration
  8. washwashed three times with EtOAc

Sources & evidence

ORD record
ord-20b793b9645a41348e77894f21018f86
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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