Sodium Carbonate → HCID 87070217, compound

HRID 2410849Notes

Reaction equation

HRID 2410849 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].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]

Participants

4

Reactant 3

HCID 10340Sodium CarbonateHCID 2773253(2-(Benzyloxy)phenyl)boronic acidHCID 53419616Methyl 3-amino-2,6-dibromoisonicotinate

Product 1

HCID 87070217HCID 87070217, compoundYield 74%

Conditions

Temperature
110 °C

Procedure

A flask containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (3.00 g, 9.68 mmol), 2-benzyloxybenzeneboronic acid (2.52 g, 11.1 mmol), tetrakistriphenylphosphine palladium (0) (0.533 g, 0.461 mmol) and Na2CO3 (2.64 g, 24.9 mmol) was flushed with nitrogen. Toluene (24 mL) and methanol (8 mL) were added and the reaction was heated at 110° C. for 23 h. This was partitioned between EtOAc and aq. sat. sodium bicarbonate solution. The organic phase was washed with sat. aq. sodium bicarbonate solution and brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with hexane containing 0 to 15% EtOAc afforded methyl 3-amino-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.80 gm, 6.78 mmol, 74% yield) as a solid. This was quickly dissolved in TFA (40 mL) and the yellow solution cooled in an ice-bath. Sodium nitrite (0.935 g, 13.6 mmol) was added with stirring to give a dark red mixture. After 30 min, solid sodium azide (4.40 g, 67.8 mmol) was added over 5 min followed by Et2O (40 mL). This was stirred in the ice-bath for 30 min and then partitioned between H2O and EtOAc. The organic phase was separated and most of the solvent was removed. The residue was diluted with EtOAc, washed with aq. sat. NaHCO3 solution and brine and then dried over sodium sulfate. The solution was concentrated to about 50 ml volume and the solid was with EtOAc, to leave methyl 3-azido-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.70 gm, 4.39 mmol, 65% yield) as a solid. 1,2-Dichloroethane (3 mL), rhodium octanoate dimer (0.171 g, 0.220 mmol), and crushed 4A° molecular sieves (2.70 g) were added and the mixture was heated at 80° C. for 48 h. It was diluted with a mixture of 25% MeOH in DCM and filtered. The solid was washed with additional 25% MeOH in DCM and the solvents removed from the combined filtrates. The residue was suspended in MeOH and filtration followed by washing with MeOH left methyl 9-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.84 g, 97% yield) as a solid. MS (ESI) m/z 411.0 (M+H). 1H NMR (500 MHz, chloroform-d) d ppm 9.63 (1H, br. s.), 7.98 (1H, s), 7.77 (2H, d, J=7.32 Hz), 7.48 (3H, m), 7.34 (1H, m), 7.16 (1H, d, J=7.93 Hz), 6.85 (1H, d, J=7.93 Hz), 5.48 (2H, s), 4.09 (3H, s).

Workup

  1. additionA flask containing
  2. customwas flushed with nitrogen
  3. additionToluene (24 mL) and methanol (8 mL) were added
  4. customThis was partitioned between EtOAc and aq. sat. sodium bicarbonate solution
  5. washThe organic phase was washed with sat. aq. sodium bicarbonate solution and brine
  6. dry with materialdried with sodium sulfate
  7. customRemoval of the solvent
  8. washstep gradient elution with hexane containing 0 to 15% EtOAc

Sources & evidence

ORD record
ord-3cf30cd80b8b4e9c8f0f9110d7d497ec
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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