Sodium hydride → 3-Amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester

HRID 2264948Notes

Reaction equation

HRID 2264948 reaction equation
[CH:1]1([NH:4][C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[H][H]>>[CH3:18][O:17][C:15]([C:14]1[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[C:11]=1[NH2:12])=[O:16]

Participants

5

Reactant 4

HCID 24758Sodium hydrideHCID 60984Methyl bromoacetateHCID 595964594-Cyclopropylamino-nicotinonitrileHCID 178418361HCID 178418361, compound

Product 1

HCID 595965463-Amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl esterYield 50.3%

Procedure

To a stirred solution of 4-cyclopropylamino-nicotinonitrile (2.15 g, 13.51 mmol) and methyl bromoacetate (1.53 mL, 16.21 mmol, 1.2 eq) at 0° C. was added sodium hydride (60% in mineral oil: 1.35 g, 33.78 mmol, 2.5 eq) portion wise over 15 min. After the evolution of hydrogen gas had subsided, the reaction mixture was warmed to ambient temperature and stirred under N2 for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and poured into EtOAc. The biphasic layers were separated, and the organic layer was washed with 50% aq. brine, sat. NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 25% MeOH in EtOAc) to give the desired product as an orange solid (1.57 g, 50.3%). 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.01 (d, J=1.0 Hz, 1H), 8.24 (t, J=5.1 Hz, 1H), 7.29 (dd, J=6.0 Hz, J=1.0 Hz, 1H), 6.34-6.09 (br s, 2H), 3.85 (s, 3H), 3.35 (m, 1H), 1.14-1.03 (m, 2H), 0.80-0.70 (m, 2H); LC-MS (method D): [M+H]+=232.0, RT=1.31 min.

Workup

  1. customThe reaction mixture was quenched with saturated NH4Cl solution (10 mL)
  2. additionpoured into EtOAc
  3. customThe biphasic layers were separated
  4. washthe organic layer was washed with 50% aq. brine, sat. NaHCO3 solution, and brine
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue was absorbed onto silica
  9. custompurified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 25% MeOH in EtOAc)

Sources & evidence

ORD record
ord-82a8b3135dd840fd91c08de8edb5f375
Source dataset
uspto-grants-2010_12
Patent number
US07855216B2

Reaction notes

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