Triphenylphosphine → 4-Chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile

To a solution of triphenylphosphine (263 mg, 1.002 mmol) in THF (2 mL) was added DIAD (0.195 mL, 1.002 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybenzyl)amino)acetamide (160 mg, 0.334 mmol) in TIIF (1.000 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 3 h. LC-MS indicated the desired peak. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg) as a yellow solid. TFA (1 mL) was added to the above obtained solution of 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg, 0.065 mmol) and ANISOLE (0.028 mL, 0.260 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed completion. Solvent was evaporated and purification via flash chromatography (0-10% MeOH in DCM, 24 g) gave 4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg) as a yellow oil.

1. stirringThe reaction mixture was then stirred at room temperature for 3 h
2. extractionThe aqueous layer was extracted with EtOAc
3. washthe combined organic layer was washed with water, brine
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. customPurification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g)

ORD record

ord-61e306e2fd6a4d7d8f23872da263398e

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273057B2