N-[[(5S)-3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16. 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filling. Alter stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starling material is consumed. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43-40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20°-25° and then filtered through Celite, washing the pad with ethyl acetate. The flitrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reducedpressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractionsare pooled and concentrated to give the title compound, mp 140.0°-140.5°; [α]25 D -6.6° (c 1.0, CHCl3). is consumed The reaction mixture is stirred for 1 hr at 20°-25° filtered through Celite washing the pad with ethyl acetate The flitrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reducedpressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]- acetamide (PREPARATION 17, 0.280 g, 1.11 mmol) is dissolved in a mixture of acetic acid (20 ml) and trifluoroacetic acid (5 ml) and then treated with iodine monochloride (2.343 g, 14.43 mmol) at 20-25°. The mixture is stirred at 20-25° under nitrogen. After about 24 hr the reaction mixture is diluted with ether and the solids collected under reduced pressure through a medium-porosity sintered glass filter, washing with ether. The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel, and washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, mp 185.5-186.5°; [α]25D -37.6° (c 1.0, DMF). the solids collected under reduced pressure through a medium-porosity sintered glass filter washing with ether The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine The organic phase is separated dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16, 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filling. After stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starting material is consumed. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43.40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20-25° and then filtered through Celite, washing the pad with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reducedpressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractionsare pooled and concentrated to give the title compound, mp 140.0-140.5°; [α]25D -6.6° (c 1.0, CHCl3). is consumed The reaction mixture is stirred for 1 hr at 20-25° filtered through Celite washing the pad with ethyl acetate The filtrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reducedpressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16, 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filling. After stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starting material is consumed. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43.40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20-25° and then filtered through Celite, washing the pad with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reducedpressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractionsare pooled and concentrated to give the title compound, mp 140.0-140.5°; [α]25D -6.6° (c 1.0, CHCl3). is consumed The reaction mixture is stirred for 1 hr at 20-25° filtered through Celite washing the pad with ethyl acetate The filtrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reducedpressure

Conditions: temp:1.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-fluorophenylcarbamic acid 2-methylpropyl ester (300.0 g, 1.42 mol), (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (556.1 g, 2.87 mol, 2.02 eq), methanol (90.03 g, 2.81 mol, 1.98 eq) and N,N-dimethylformamide (500 ml) is added a slurry of lithium t-amylate (401.3 g, 4.27 mol, 3.00 eq) in heptane (1 liter) while maintaining −4 to 7° C., followed by heptane (100 ml). The mixture is then stirred at 19 to 20° C. for 21 h. The reaction mixture is then added to a mixture of ammonium chloride (228 g, 4.26 mol, 3.00 eq), water (2.0 liter) and toluene (1.0 liter) while maintaining 8 to 10° C. The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml). The precipitate is collected by vacuum filtration and washed with heptane (1 liter) and water (1 liter) and dried in a nitrogen stream to give 252.4 g of crude product. This is triturated in acetonitrile (1 kg) at 90° C. and the slurry concentrated under reduced pressure to 800 ml total volume. Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume. Water (1 liter) and heptane (1 liter) are added and the precipitate collected by vacuum filtration, washed with water (750 ml) and heptane (250 ml) and dried in a nitrogen stream to give the title compound (225.7 g, 63.0%). while maintaining 8 to 10° C The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml) The precipitate is collected by vacuum filtration washed with heptane (1 liter) and water (1 liter) dried in a nitrogen stream to give 252.4 g of crude product This is triturated in acetonitrile (1 kg) at 90° C. the slurry concentrated under reduced pressure to 800 ml total volume Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume Water (1 liter) and heptane (1 liter) are added the precipitate collected by vacuum filtration washed with water (750 ml) and heptane (250 ml) dried in a nitrogen stream

Conditions: temp:1.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-fluorophenylcarbamic acid 2-methylpropyl ester (300.0 g, 1.42 mol), (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (556.1 g, 2.87 mol, 2.02 eq), methanol (90.03 g, 2.81 mol, 1.98 eq) and N,N-dimethylformamide (500 ml) is added a slurry of lithium t-amylate (401.3 g, 4.27 mol, 3.00 eq) in heptane (1 liter) while maintaining −4 to 7° C., followed by heptane (100 ml). The mixture is then stirred at 19 to 20° C. for 21 h. The reaction mixture is then added to a mixture of ammonium chloride (228 g, 4.26 mol, 3.00 eq), water (2.0 liter) and toluene (1.0 liter) while maintaining 8 to 10° C. The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml). The precipitate is collected by vacuum filtration and washed with heptane (1 liter) and water (1 liter) and dried in a nitrogen stream to give 252.4 g of crude product. This is triturated in acetonitrile (1 kg) at 90° C. and the slurry concentrated under reduced pressure to 800 ml total volume. Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume. Water (1 liter) and heptane (1 liter) are added and the precipitate collected by vacuum filtration, washed with water (750 ml) and heptane (250 ml) and dried in a nitrogen stream to give the title compound (225.7 g, 63.0%). while maintaining 8 to 10° C The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml) The precipitate is collected by vacuum filtration washed with heptane (1 liter) and water (1 liter) dried in a nitrogen stream to give 252.4 g of crude product This is triturated in acetonitrile (1 kg) at 90° C. the slurry concentrated under reduced pressure to 800 ml total volume Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume Water (1 liter) and heptane (1 liter) are added the precipitate collected by vacuum filtration washed with water (750 ml) and heptane (250 ml) dried in a nitrogen stream

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16, 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filing. After stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starting material is cushioned. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43.40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20°-25° and then filtered through Celite, washing the pad with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reduced pressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractions are pooled and concentrated to give the title compound, mp 140.0°-140.5°; [α]25D -6.6° (c 1.0, CHCl3). The reaction mixture is stirred for 1 hr at 20°-25° filtered through Celite washing the pad with ethyl acetate The filtrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reduced pressure

Conditions: temp:1.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-fluorophenylcarbamic acid 2-methylpropyl ester (300.0 g, 1.42 mol), (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (556.1 g, 2.87 mol, 2.02 eq), methanol (90.03 g, 2.81 mol, 1.98 eq) and N,N-dimethylformamide (500 ml) is added a slurry of lithium t-amylate (401.3 g, 4.27 mol, 3.00 eq) in heptane (1 liter) while maintaining −4 to 7° C., followed by heptane (100 ml). The mixture is then stirred at 19 to 20° C. for 21 h. The reaction mixture is then added to a mixture of ammonium chloride (228 g, 4.26 mol, 3.00 eq), water (2.0 liter) and toluene (1.0 liter) while maintaining 8 to 10° C. The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml). The precipitate is collected by vacuum filtration and washed with heptane (1 liter) and water (1 liter) and dried in a nitrogen stream to give 252.4 g of crude product. This is triturated in acetonitrile (1 kg) at 90° C. and the slurry concentrated under reduced pressure to 800 ml total volume. Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume. Water (1 liter) and heptane (1 liter) are added and the precipitate collected by vacuum filtration, washed with water (750 ml) and heptane (250 ml) and dried in a nitrogen stream to give the title compound (225.7 g, 63.0%). while maintaining 8 to 10° C The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml) The precipitate is collected by vacuum filtration washed with heptane (1 liter) and water (1 liter) dried in a nitrogen stream to give 252.4 g of crude product This is triturated in acetonitrile (1 kg) at 90° C. the slurry concentrated under reduced pressure to 800 ml total volume Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume Water (1 liter) and heptane (1 liter) are added the precipitate collected by vacuum filtration washed with water (750 ml) and heptane (250 ml) dried in a nitrogen stream

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16. 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filling. Alter stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starling material is consumed. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43-40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20°-25° and then filtered through Celite, washing the pad with ethyl acetate. The flitrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reducedpressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractionsare pooled and concentrated to give the title compound, mp 140.0°-140.5°; [α]25 D -6.6° (c 1.0, CHCl3). is consumed The reaction mixture is stirred for 1 hr at 20°-25° filtered through Celite washing the pad with ethyl acetate The flitrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reducedpressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]- acetamide (PREPARATION 17, 0.280 g, 1.11 mmol) is dissolved in a mixture of acetic acid (20 ml) and trifluoroacetic acid (5 ml) and then treated with iodine monochloride (2.343 g, 14.43 mmol) at 20-25°. The mixture is stirred at 20-25° under nitrogen. After about 24 hr the reaction mixture is diluted with ether and the solids collected under reduced pressure through a medium-porosity sintered glass filter, washing with ether. The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel, and washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, mp 185.5-186.5°; [α]25D -37.6° (c 1.0, DMF). the solids collected under reduced pressure through a medium-porosity sintered glass filter washing with ether The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine The organic phase is separated dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl azide (PREPARATION 16, 8.200 g, 34.71 mol) in ethyl acetate (100 ml) is treated with palladium on carbon (10%, 0.820 g) under nitrogen. The atmosphere is then replaced with hydrogen (balloon) via repeated evacuation and filling. After stirring under hydrogen for 17 hr, TLC in methanol/chloroform (5/95) reveals the azide starting material is consumed. The atmosphere is replaced with nitrogen and then pyridine (6 ml) and acetic anhydride (4.1 ml, 43.40 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hr at 20-25° and then filtered through Celite, washing the pad with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue taken-up in dichloromethane. The addition of ether affords a precipitate. After standing in the refrigerator overnight the solids are collected by vacuum filtration, washed with cold hexane, and dried under reducedpressure to give the title compound as a solid. The crude product is purified by chromatography over silica gel, eluting with methanol/chloroform (5/95). The appropriate fractionsare pooled and concentrated to give the title compound, mp 140.0-140.5°; [α]25D -6.6° (c 1.0, CHCl3). is consumed The reaction mixture is stirred for 1 hr at 20-25° filtered through Celite washing the pad with ethyl acetate The filtrate is concentrated under reduced pressure The addition of ether affords a precipitate After standing in the refrigerator overnight are collected by vacuum filtration washed with cold hexane dried under reducedpressure

Conditions: temp:1.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-fluorophenylcarbamic acid 2-methylpropyl ester (300.0 g, 1.42 mol), (S)—N-[2-(acetyloxy)-3-chloropropyl]acetamide (556.1 g, 2.87 mol, 2.02 eq), methanol (90.03 g, 2.81 mol, 1.98 eq) and N,N-dimethylformamide (500 ml) is added a slurry of lithium t-amylate (401.3 g, 4.27 mol, 3.00 eq) in heptane (1 liter) while maintaining −4 to 7° C., followed by heptane (100 ml). The mixture is then stirred at 19 to 20° C. for 21 h. The reaction mixture is then added to a mixture of ammonium chloride (228 g, 4.26 mol, 3.00 eq), water (2.0 liter) and toluene (1.0 liter) while maintaining 8 to 10° C. The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml). The precipitate is collected by vacuum filtration and washed with heptane (1 liter) and water (1 liter) and dried in a nitrogen stream to give 252.4 g of crude product. This is triturated in acetonitrile (1 kg) at 90° C. and the slurry concentrated under reduced pressure to 800 ml total volume. Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume. Water (1 liter) and heptane (1 liter) are added and the precipitate collected by vacuum filtration, washed with water (750 ml) and heptane (250 ml) and dried in a nitrogen stream to give the title compound (225.7 g, 63.0%). while maintaining 8 to 10° C The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml) The precipitate is collected by vacuum filtration washed with heptane (1 liter) and water (1 liter) dried in a nitrogen stream to give 252.4 g of crude product This is triturated in acetonitrile (1 kg) at 90° C. the slurry concentrated under reduced pressure to 800 ml total volume Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume Water (1 liter) and heptane (1 liter) are added the precipitate collected by vacuum filtration washed with water (750 ml) and heptane (250 ml) dried in a nitrogen stream