Preparation and application of 1-bromo-3-fluoro-5-pyrrolidinebenzene_Kain Industrial Additive

Background and overview^[1]

1-Bromo-3-fluoro-5-pyrrolidine benzene is a pharmaceutical intermediate, which can be prepared by nucleophilic substitution of 1-bromo-3,5-difluorobenzene and pyrrolidine. 1-Bromo-3-fluoro-5-pyrrolidinebenzene can be used to prepare phenyl (4-(3-(pyrrolidin-1-yl)-5-fluorophenyl])piperazin-l-yl)methanone, An anti-amyloid compound.

Preparation^[1]

Add 1-bromo-3,5-difluorobenzene (1.00g, 5.18mmol), pyrrolidine (0.47mL, 5.7mmol), DEPEA (1.4mL, 7.77mmol) and NMP (6.9mL) to the tube middle. The tube was sealed and stirred at 100°C overnight. The reaction mixture was diluted with water and EtOAc. The aqueous layer was back extracted with EtOAc (3x). The combined organic layers were then washed with H₂O, 1N HCl (2x), saturated NaHCO₃, H₂O and brine, then Dry with Na₂SO₄. The material was filtered and concentrated under reduced pressure to obtain 1.178 g of solid, a crude yellow solid.

Apply^[1]

Add 1-bromo-3-fluoro-5-pyrrolidinebenzene (2.49mmol), benzoylpiperazine hydrochloride (0.6778g, 2.99mmol) and NaOt-Bu (0.7179g, 7.47mmol) to the tube. The tube was evacuated and flushed with argon for three cycles. Toluene (7.5 mL) and NMP (4.5 mL) were then added and the mixture was degassed with argon for 30 min. Then Pd₂(dba)₃ (0.0456g, 0.0498mmol) and BINAP (0.0620g, 0.0996mmol) were added, the tube was sealed and heated at 80°C overnight. After cooling, the mixture was diluted with water and EtOAc. The aqueous layer was back extracted with EtOAc (3x). Then the combined organic layers were washed with H₂O, 1N HCl (2x), and then with saturated NaHCO₃, H₂O and Wash with brine and then dry over Na₂SO₄. The material was filtered and concentrated under reduced pressure to give an oil. Purification of this material by flash chromatography (35% EtOAc/hexanes) afforded 0.0881 g (8.8% yield) of phenyl (4-(3-(pyrrolidin-1-yl)-5-fluorophenyl]) Piperazin-l-yl)methanone.