New Process For Synthesis Of (r)-n-(3 - Fluoro - 4 - Morpholino Phenyl) - Oxazolone -5 - Methyl Alcohol

The new synthetic technology of (R)-N-(3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinylmethanol was studied. 3-Fluoro-4-morpholinyl- nitrobenzene was prepared by 3,4-difluoro-nitrobenzene and morpholine. 3-Fluoro-4-morpholinyl-nitrobenzene reacted with Fe in water to afford 3-Fluoro-4-morpholinylaniline. Then the interaction of 3-Fluoro-4-morpholinylaniline and phosgene gave 3-Fluoro -4-morpholinylphenuyl-isocyanate. Finally, the reaction of 3-Fluoro-4-morpholiny-lphenuyl-isocyanate with ( R)-glycidyl butyrate gave a new product, which was catalyzed by sodium methoxide and reacted with methanol to synthesize ( R)-N-(3-Fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinylmethanol. Catalysts were applied as Na₂CO₃ and Fe, which could be obtained easily and cheap, instead of diisoproprlethylamine and Pd/C. Phosgene as the raw material was used instead of benzyl chloroformate. The new method had many advantages such as the simple operation steps, the low price materials and the lowering production cost.Using morpholine and 3,4-difluoro-nitrobenzene for the synthesis of 3-fluoro -4-morpholinly-nitrobenzene. We study the effects of raw material ratio, reaction temperature and reaction time on the production yields, the optimum synthesis conditions were n(3,4-difluoro-nitrobenzene ): n(morpholine) : n ( sodium carbonate )=1:1.4:0.052, reaction temperature 78℃ ,and reaction time 6h .the production yields were over 98% .the purity was over 99.5% (mol). The complex was characterized by UV-Vis, IR,¹HNMR and elemental analysis. The optimum conditions for 3-Fluoro-4-morpholinylaniline were n(3-fluoro-4-morpholinly-nitro-benzene ): n(Fe) =1:4.52. reaction in water temperature 96℃ ,and reaction time 5h .the production yields were over 90% .Determination solubility of 3-Fluoro-4-morpholinylaniline in water, acetone, ethyl acetate, tetrachloromethane, trichloromethane, DMF, ethanol, benzene, and toluene were researched by dynamic method. Results of these measurements were correlated with two parameters equation separately. The average ralative deviation of correlations was 6.255%. It can provide reliable data of solubility of3-Fluoro^-morpholinylaniline for slection of the reation media, the separated way, the purification and the reclamation of the product. Using the data, the reaction media of the product had been modified. The consumption was reduced, and the yield of the product was increased.A spectrophotometry method for 3-fluoro-4-morpholinly -nitrobenzene—the intermediate product of linezolid was developed. The detection wavelength was set at 357 nm ,A good linear relationship between the absorbance and the quantity of 3-fluoro-4-morpholinly -nitrobenzene in the rang from 0.895mg/L to23.27 mg/L with the regression equation y=0.0587x—0.0025 (n=7) (r=0.9992) the average recovery was 99.3% and RSP was 0.69% (n=6) .The method was simple rapid and accurate.