Electric Literature of 399-94-0, A common heterocyclic compound, 399-94-0, name is 1-Bromo-2,5-difluorobenzene, molecular formula is C6H3BrF2, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
a) Preparation of (2R)-2′,5′-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250 ml) was vigorously stirred. The color of iodine was disappeared and the inner temperature rose up to 65 C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55 C. over 45 min. The resulting mixture was stirred at 55 C. for 30 min. then at r.t. for 1 hr. The mixture was cooled down to -5 C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150 ml) dropwise over 40 min. And the resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was cooled down to 5 C. and saturated NH4Cl aq. (100 ml) was added carefully. The whole was diluted with H2O (600 ml) and extracted with EtOAc (400 ml+200 ml*2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1~5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. Physical form: colorless oil; FAB-MS: m/z 271(M+H)+; 1H-NMR(CDCl3) delta1.42~1.90(9H,m),3.32~3.40(1H*1/2,m),3.69~3.77(1H*1/2,m),3.86~3.94(1H*1/2,m), 4.66(1H*1/2,t,J=3.6 Hz),4.75(1H*1/2,t,J=3.6 Hz),4.87(1H*1/2,q,J=6.6 Hz), 5.11(1H*1/2,q,J=6.9 Hz),7.08~7.25(2H,m),7.49~7.55(1 H,m).
The synthetic route of 399-94-0 has been constantly updated, and we look forward to future research findings.
Reference:
Patent; Basilea Pharmaceutica AG, a Swiss Company; US6300353; (2001); B1;,
Bromide – Wikipedia,
bromide – Wiktionary