Preparation of (R)-N-[3-(3-fluoro-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol methanesulfonate_Industrial additives

Background and overview^[1]

(R)-N-[3-(3-Fluoro-(4-morpholinyl)phenyl)-2-oxo-5-zolidinyl]methanol mesylate is synthesized from linezolid intermediate. Among the lower-level antibacterial agents, linezolid is a recently synthesized class of antibacterial agents with antimicrobial activity against many pathogenic microorganisms.

Preparation^[1]

Step (1): 3-fluoro-4-morpholinonitrobenzene

In the presence of acetonitrile solvent (115ml), 3,4-difluoronitrobenzene (100g) was slowly added to morpholine (76.6g) and triethylamine (23ml) at 40-50°C. in the mixture. The reaction was heated at reflux temperature for 6 hours and cooled to 25-30°C. Water (600 ml) was then slowly added to the reaction mass, followed by cooling to 0-5°C. The reaction mixture was stirred for 1 hour. The solid was filtered to give 134 g of 3-fluoro-4-morpholinonitrobenzene.

Step (2): 3-fluoro-4-morpholinoaniline

Methanol (1.35 L) and 3-fluoro-4-morpholinonitrobenzene (134 g) were added to the autoclave, followed by Raney Nickel (20.5 g). The system was nush with nitrogen and hydrogen. The hydrogen pressure is set to 4·0kg/cm^-2. The reaction mixture was stirred at 45-50°C under H₂ pressure for 8 hours, and the reaction was followed by TLC until completion. The reaction mixture was filtered through Celite and the filtrate was distilled/evaporated completely under U/vacuum at a temperature <50°C. Cool the reaction to 25-30°C. DM water (ml) was added thereto. Stir for 1 hour at 25-30°C. The solid was filtered to obtain 105 g of 3-fluoro-4-morpholinylaniline.

Step (3): N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline

Mix 3-fluoro-4-morpholinoaniline (100 g) and R-epichlorohydrin (59 g), add tert-butanol (500 ml) and heat to reflux temperature for 16 hours. The solvent was distilled to give 156 g of N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline.

Step (4): (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl)-oxazolidin-2-one

Dissolve N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline (156 g) in dichloromethane (1.5 L) at room temperature Carbonyldiimidazole (87.4 g) was added and stirred at 25-30°C for 24 hours. Then wash with water three times (750ml×3). Dry with Na₂SO₄. Dichloromethane was distilled to obtain 156 g of crude (5R)-5-(chloromethyl)-3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxazolidinone, obtained from n-Butyl acetate reverse osmosis fungicide ester (100 ml) was further isolated and crystallized to give 83 g of (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl)-oxazole Alkane-2-one.

Step (5): (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinylmethylacetate

Combine (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl)-oxazolidin-2-one (83 g) with sodium acetate (43 g) Mix and add dimethylformamide (320ml). The reaction was heated to 120°C and stirred for 8-10 hours. Then cool it to 25-30°C. The inorganic salt was filtered and washed with DMF (10 ml). Add DM water (1.0 L) to the round bottom flask. Add the above reactants to the water slowly over 60 minutes at 20-05°C and stir at 20-25°C for 30 minutes. The precipitated solid was filtered and the material was dried at 50°C for 5-6 hours to obtain 65 g of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazole Alkyl methyl acetate.

Step (6): (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinylmethanol

Mix (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinylmethylacetate (62 g) and tetrahydrofuran (300 ml) , cool to 0-5℃. Sodium tert-butoxide (17.5 g) was added slowly at 0-5°C, followed by DM water (620 ml) at 10-15°C. The reaction was stirred at 10-15°C for 30 minutes. After the reaction was completed, dichloromethane (300 ml) was added, and the mixture was further extracted with dichloromethane (120 ml). The solvent was completely evaporated under U/vacuum. The precipitated solid was crystallized from hexanes (150 ml). The solid separated was filtered and washed with hexane. The material was dried at 50-55°C to obtain 50 g of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinylmethanol.

Step (7): (R)-N-[3-(3-fluoro-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol methanesulfonate

Combine (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinylmethanol (50 g) and tris in dichloromethane (250 ml). Ethylamine (42.6 g) was cooled in an ice bath and treated with methanesulfonyl chloride (38.2 g). The mixture was stirred at 0-5°C for 30 minutes. The precipitated product was filtered and washed with cold DM water (250 ml). The material was dried at 50-55°C to obtain 40 g of (R)-N-[3-(3-fluoro-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol mesylate.

References

[1][Chinese invention] CN201280009854.5 New preparation method of linezolid and its new intermediates