Phosphorus oxychloride → tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

HRID 627050Notes

Reaction equation

HRID 627050 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19]

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 796472,6-DifluoroanilineHCID 118380491lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Product 1

HCID 118380511tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylateYield 65%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (589 mg, 2.18 mmol, Eq: 1.00) and 2,6-difluoroaniline (480 mg, 0.4 mL, 3.72 mmol, Eq: 1.71) in pyridine (7 mL) (ice-bath) was added dropwise phosphoryl trichloride (660 mg, 0.4 mL, 4.3 mmol, Eq: 1.97). The cooling bath was removed and the resulting yellow/orange suspension was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (1×5 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1)). After the combined fractions were concentrated, the off-white solid was treated with 5% MeOH/ether (˜10 mL) to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (532 mg).

Workup

  1. customThe cooling bath was removed
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. additionthe residue was treated with water (20 mL)
  4. extractionThe resulting mixture was extracted with EtOAc (2×20 mL)
  5. washthe combined organic layers were washed with brine (1×5 mL)
  6. customThe crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1))
  7. concentrationAfter the combined fractions were concentrated
  8. additionthe off-white solid was treated with 5% MeOH/ether (˜10 mL)

Sources & evidence

ORD record
ord-a1bffcb7e4c64680900e3397b38d936a
Source dataset
uspto-grants-2016_04
Patent number
US09309248B2

Reaction notes

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