168828-90-8

Basic information

• Product Name: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine
• Synonyms: -3-(3-fluoro-4-morpholinophenyl);(5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one;(S)-(-)-5-Aminomethyl-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one;(S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one;(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine;Deacetyl Linezolid;InterMediate of Linezolid;(5S)-5-(AMinoMethyl)-3-[3-fluoro-4-(4-Morpholinyl)phenyl]-2-oxazolidinone
• CAS NO: 168828-90-8
• Molecular Formula: C₁₄H₁₈FN₃O₃
• Molecular Weight: 295
• EINECS: 1806241-263-5
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Impurities;Intermediates & Fine Chemicals;Pharmaceuticals;Linezolid intermediate
• Mol File: 168828-90-8.mol
• Article Data: 51

Chemical Properties

• Boiling Point: 480.02 °C at 760 mmHg
• Flash Point: 244.107 °C
• Appearance: /
• Density: 1.319
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 8.96±0.29(Predicted)
• CAS DataBase Reference: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine(168828-90-8)
• EPA Substance Registry System: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine(168828-90-8)

Safety Data

• Hazardous Substances Data: 168828-90-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-white Solid

Uses

An impurity of Linezolid (L466500), as antimycobacterial agent. Linezolid USP Related Compound C.

Synthetic route

(R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With water; triphenylphosphine In tetrahydrofuran at 70℃;	100%
With hydrogen In methanol at 40 - 60℃; under 3750.38 Torr; for 3h; Temperature; Pressure; Reagent/catalyst; Autoclave;	98%
With palladium on activated charcoal; hydrogen; acetic acid In methanol for 2h;	81%

linezolid (165800-03-3) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With hydrogenchloride In methanol Reflux;	99%
With pyridine; hydroxylamine hydrochloride In ethanol for 48h; Sealed tube;

2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione (168828-89-5) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With hydrazine hydrate In ethanol for 4h; Solvent; Reflux;	95.4%
With hydrazine hydrate In methanol for 1h; Reflux;	90%
With hydrazine hydrate In methanol for 1h; Reflux;	71%

(S)-5-((benzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (1236077-61-4) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With hydrogen; acetic acid; 5% Pd(II)/C(eggshell) In methanol at 40℃; under 7355.72 - 8826.87 Torr;	95%
With ammonium formate; palladium 10% on activated carbon In methanol at 65℃; for 8h;

(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholino phenyl)-isooxazol-2-one (565176-85-4) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In acetone at 25℃; under 37503.8 Torr; for 5h; Product distribution / selectivity;	93%
With hydrogen; palladium 10% on activated carbon In acetone at 25℃; under 37503.8 Torr; for 5h; Product distribution / selectivity;	93%

(S)-5-((allylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (1215006-07-7) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Stage #1: (S)-5-((allylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one With 1,3-dimethylbarbituric acid; palladium diacetate; triphenylphosphine In ethanol at 35℃; for 5h; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water pH=1; Stage #3: With sodium hydroxide In water pH=10;	81%

(R)-[3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-5-oxazolidinyl]methyl p-iodobenzenesulfonate → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With ammonia In methanol at 70℃; under 3750.38 Torr; for 20h;	67.7%

(R)-[3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-5-oxazolidinyl]methyl p-bromobenzenesulfonate → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With ammonia In methanol at 80℃; under 4500.45 Torr; for 20h;	67.6%

(R)-[3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-5-oxazolidinyl]methyl p-fluorobenzenesulfonate → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With ammonia In methanol at 75℃; under 5250.53 Torr; for 20h;	65.8%

(R)-[3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-5-oxazolidinyl]methyl p-chlorobenzenesulfonate → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With ammonia In methanol at 90℃; under 4500.45 Torr; for 20h;	65.5%

4-Nitro-benzenesulfonic acid (R)-3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (198410-26-3) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With ammonia In methanol

3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-1-ol → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: aq. NaHCO3 / acetone 2.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 3.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 3.2: NaBH4 / methanol 3.3: 86 percent / CuSO4 / methanol 4.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 5.1: Et3N / CH2Cl2 / 4 h / 0 °C 6.1: NaN3 / dimethylformamide / 75 °C 7.1: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme

(3-fluoro-4-morpholin-4-yl-phenyl)-(3-oxo-propyl)-carbamic acid benzyl ester (912552-55-7) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 1.2: NaBH4 / methanol 1.3: 86 percent / CuSO4 / methanol 2.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 3.1: Et3N / CH2Cl2 / 4 h / 0 °C 4.1: NaN3 / dimethylformamide / 75 °C 5.1: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme

(3-fluoro-4-morpholin-4-yl-phenyl)-(3-hydroxy-propyl)-carbamic acid benzyl ester (912552-54-6) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 2.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 2.2: NaBH4 / methanol 2.3: 86 percent / CuSO4 / methanol 3.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 4.1: Et3N / CH2Cl2 / 4 h / 0 °C 5.1: NaN3 / dimethylformamide / 75 °C 6.1: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme

((S)-2,3-Dihydroxy-propyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (912552-56-8) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 2: Et3N / CH2Cl2 / 4 h / 0 °C 3: NaN3 / dimethylformamide / 75 °C 4: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme

3-fluoro-4-(morpholinyl)aniline (93246-53-8) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: NaI; Na2CO3 / dimethylformamide / 65 °C 2.1: aq. NaHCO3 / acetone 3.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 4.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 4.2: NaBH4 / methanol 4.3: 86 percent / CuSO4 / methanol 5.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 6.1: Et3N / CH2Cl2 / 4 h / 0 °C 7.1: NaN3 / dimethylformamide / 75 °C 8.1: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme
Multi-step reaction with 4 steps 1.1: NaHCO3 2.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 2.2: hexane; tetrahydrofuran / -78 - 20 °C 3.1: Et3N 4.1: NH3 / methanol View Scheme
Multi-step reaction with 4 steps 1: Et3N / tetrahydrofuran / 2 h / 20 °C 2: sodium azide / dimethylformamide / 6 h / 65 °C 3: triphenylphosphine; H2O / tetrahydrofuran / 11 h / 40 °C View Scheme

(R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol (168828-82-8) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 4 h / 0 °C 2: NaN3 / dimethylformamide / 75 °C 3: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme
Multi-step reaction with 2 steps 1: Et3N 2: NH3 / methanol View Scheme
Multi-step reaction with 3 steps 1: Et3N / tetrahydrofuran / 2 h / 20 °C 2: sodium azide / dimethylformamide / 6 h / 65 °C 3: triphenylphosphine; H2O / tetrahydrofuran / 11 h / 40 °C View Scheme

(R)-methyl methanesulfonate (174649-09-3) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaN3 / dimethylformamide / 75 °C 2: hydrogen / Pd/C / ethyl acetate / 12 h / 760 Torr View Scheme
Multi-step reaction with 2 steps 1: sodium azide / dimethylformamide / 6 h / 65 °C 2: triphenylphosphine; H2O / tetrahydrofuran / 11 h / 40 °C View Scheme
Multi-step reaction with 2 steps 1: sodium azide / dimethylformamide / 16 h / 75 °C 2: H2 / Pd/C / ethyl acetate View Scheme

3,4-difluoronitrobenzene (369-34-6) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N,N-diisopropylethylamine 2.1: ammonium formate / 10 percent Pd/C / methanol; tetrahydrofuran 3.1: NaHCO3 4.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 4.2: hexane; tetrahydrofuran / -78 - 20 °C 5.1: Et3N 6.1: NH3 / methanol View Scheme
Multi-step reaction with 6 steps 1: N,N-diisopropylethylamine / acetonitrile / 17 h / Heating 2: H2 / PtO2 / methanol / 3 h / 20 °C / 1471.02 Torr 3: Et3N / tetrahydrofuran / 2 h / 20 °C 4: sodium azide / dimethylformamide / 6 h / 65 °C 5: triphenylphosphine; H2O / tetrahydrofuran / 11 h / 40 °C View Scheme
Multi-step reaction with 7 steps 1: 98 percent / N,N-diisopropylethylamine / ethyl acetate 2: ammonium formate / 10percent Pd/C 3: 70 percent / sodium bicarbonate / acetone; H2O 4: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 5: 35.423 g / triethylamine / CH2Cl2 / 20 h 6: sodium azide / dimethylformamide / 16 h / 75 °C 7: H2 / Pd/C / ethyl acetate View Scheme

3-fluoro-4-(4-morpholinyl)nitrobenzene (2689-39-6) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ammonium formate / 10 percent Pd/C / methanol; tetrahydrofuran 2.1: NaHCO3 3.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 3.2: hexane; tetrahydrofuran / -78 - 20 °C 4.1: Et3N 5.1: NH3 / methanol View Scheme
Multi-step reaction with 5 steps 1: H2 / PtO2 / methanol / 3 h / 20 °C / 1471.02 Torr 2: Et3N / tetrahydrofuran / 2 h / 20 °C 3: sodium azide / dimethylformamide / 6 h / 65 °C 4: triphenylphosphine; H2O / tetrahydrofuran / 11 h / 40 °C View Scheme
Multi-step reaction with 6 steps 1: ammonium formate / 10percent Pd/C 2: 70 percent / sodium bicarbonate / acetone; H2O 3: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 4: 35.423 g / triethylamine / CH2Cl2 / 20 h 5: sodium azide / dimethylformamide / 16 h / 75 °C 6: H2 / Pd/C / ethyl acetate View Scheme

benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate (168828-81-7, 1027135-00-7) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 1.2: hexane; tetrahydrofuran / -78 - 20 °C 2.1: Et3N 3.1: NH3 / methanol View Scheme
Multi-step reaction with 4 steps 1: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 2: 35.423 g / triethylamine / CH2Cl2 / 20 h 3: sodium azide / dimethylformamide / 16 h / 75 °C 4: H2 / Pd/C / ethyl acetate View Scheme
Multi-step reaction with 4 steps 1.1: butan-1-ol; n-butyllithium / hexane; tetrahydrofuran / -15 - 30 °C / Inert atmosphere 1.2: -10 - 15 °C 2.1: triethylamine / dichloromethane / 20 - 30 °C 3.1: sodium azide / N,N-dimethyl-formamide / 60 °C / Reflux 4.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 15 - 20 °C / Autoclave View Scheme

(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-({[(1S)-1-phenylethyl]amino}methyl)-1,3-oxazolidin-2-one (1027321-41-0) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
With palladium 10% on activated carbon; ammonium formate In methanol at 20℃; Inert atmosphere;

(R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl 4-methylbenzenesulfonate (168828-83-9) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5 h / 70 °C 2: ammonium formate / palladium 10% on activated carbon / methanol / 8 h / 65 °C View Scheme
With sodium diformamide; N,N-dimethyl-formamide at 85℃; for 2h; Inert atmosphere;	18.87 g

N-ethoxycarbonyl-3-fluoro-4-morpholinyl aniline (565176-83-2) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C 1.3: 0.5 h / 20 °C 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: 5 h / 70 °C 4.1: ammonium formate / palladium 10% on activated carbon / methanol / 8 h / 65 °C View Scheme

1-chloro-2-fluoro-4-nitrobenzene (350-31-2) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: Neat (no solvent) 2.1: ammonium formate / palladium 10% on activated carbon / tetrahydrofuran; methanol / 20 °C / Inert atmosphere; cooling with ice 3.1: toluene / -20 °C / Inert atmosphere; Reflux 4.1: Tributylphosphine oxide; lithium bromide / o-xylene / 1 h / Reflux 5.1: hydrogenchloride; water / 0.25 h / 20 °C 5.2: pH 8 - 9 View Scheme
Multi-step reaction with 5 steps 1.1: Neat (no solvent) 2.1: ammonium formate / palladium 10% on activated carbon / tetrahydrofuran; methanol / 20 °C / Inert atmosphere; cooling with ice 3.1: toluene / -20 °C / Inert atmosphere; Reflux 4.1: Tributylphosphine oxide; lithium bromide / toluene / 1 h / Inert atmosphere; Reflux 5.1: hydrogenchloride / dichloromethane; water / 1 h / 20 °C 5.2: pH 7 / cooling with ice View Scheme

3-fluoro-4-(morpholin-4-yl)-phenyl isocyanate (224323-51-7) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Tributylphosphine oxide; lithium bromide / o-xylene / 1 h / Reflux 2.1: hydrogenchloride; water / 0.25 h / 20 °C 2.2: pH 8 - 9 View Scheme
Multi-step reaction with 2 steps 1.1: Tributylphosphine oxide; lithium bromide / toluene / 1 h / Inert atmosphere; Reflux 2.1: hydrogenchloride / dichloromethane; water / 1 h / 20 °C 2.2: pH 7 / cooling with ice View Scheme
Multi-step reaction with 2 steps 1: lithium bromide; Tributylphosphine oxide / toluene / 0.25 h / Inert atmosphere; Reflux 2: hydrogenchloride; water / dichloromethane / 0.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium halide / 4 h / 80 °C 2.1: sodium azide / N,N-dimethyl-formamide / 3 h / 85 °C 2.2: 20 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1: MgI2 etherate / neat (no solvent) / 20 - 65 °C 2: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 3: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme

4-chlorobenzonitrile (100-00-5) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: fluorine; sulfuric acid 2.1: Neat (no solvent) 3.1: ammonium formate / palladium 10% on activated carbon / tetrahydrofuran; methanol / 20 °C / Inert atmosphere; cooling with ice 4.1: toluene / -20 °C / Inert atmosphere; Reflux 5.1: Tributylphosphine oxide; lithium bromide / o-xylene / 1 h / Reflux 6.1: hydrogenchloride; water / 0.25 h / 20 °C 6.2: pH 8 - 9 View Scheme
Multi-step reaction with 6 steps 1.1: fluorine; sulfuric acid 2.1: Neat (no solvent) 3.1: ammonium formate / palladium 10% on activated carbon / tetrahydrofuran; methanol / 20 °C / Inert atmosphere; cooling with ice 4.1: toluene / -20 °C / Inert atmosphere; Reflux 5.1: Tributylphosphine oxide; lithium bromide / toluene / 1 h / Inert atmosphere; Reflux 6.1: hydrogenchloride / dichloromethane; water / 1 h / 20 °C 6.2: pH 7 / cooling with ice View Scheme

(S)-(E,Z)-5-((benzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (1330034-71-3) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Stage #1: (S)-(E,Z)-5-((benzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one With hydrogenchloride; water at 20℃; for 0.25h; Stage #2: With sodium hydroxide In water pH=8 - 9;

(S)-(E,Z)-5-((4-chlorobenzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (1345879-82-4) → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Stage #1: (S)-(E,Z)-5-((4-chlorobenzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one With hydrogenchloride In dichloromethane; water at 20℃; for 1h; Stage #2: With sodium hydroxide In dichloromethane; water pH=7; Product distribution / selectivity; cooling with ice;
With hydrogenchloride; water In dichloromethane at 20℃; for 0.5h;

C20H21FN2O6S → (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8)

Conditions	Yield
Stage #1: C20H21FN2O6S With sodium diformamide In N,N-dimethyl-formamide at 85℃; for 2h; Inert atmosphere; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 85℃; for 2.5h; Inert atmosphere; Stage #3: With sodium hydroxide In dichloromethane; water; N,N-dimethyl-formamide at 20℃; Inert atmosphere;
Stage #1: C20H21FN2O6S With sodium diformamide In N,N-dimethyl-formamide at 85℃; for 2h; Inert atmosphere; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 85℃; for 2.5h; Inert atmosphere; Stage #3: With sodium hydroxide In dichloromethane; water; N,N-dimethyl-formamide at 20℃; Inert atmosphere;

(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) + N-[(2S)-2-acetoxy-3-chloropropyl]acetamide (183905-31-9) → (R)-1-acetamido-3-((((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)amino)propan-2-yl acetate

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2h;	97.9%

2-furanoic acid (88-14-2) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)furan-2-carboxamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12.5h;	95%

(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → 7-methoxy-2-methyl-N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-quinolinecarboxamide

Conditions	Yield
Stage #1: 7-methoxy-2-methylquinoline-3-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine In dichloromethane at 20℃; for 12h;	95%

2-methoxy-4-amino-5-ethylsulphonyl benzoic acid (71675-87-1) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → 4-amino-5-(ethylsulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxybenzamide (1390617-35-2)

Conditions	Yield
Stage #1: 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine In dichloromethane at 0 - 20℃; for 4h;	93%

acetyl chloride (75-36-5) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → linezolid (165800-03-3)

Conditions	Yield
With triethylamine In ethyl acetate at 20℃; for 2h;	92.8%
With triethylamine In dichloromethane at 0 - 20℃; for 1h;	85%
With triethylamine In dichloromethane at 20℃; Inert atmosphere;	73 mg
With triethylamine In N,N-dimethyl-formamide at 2℃;	9.8 g

(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; water; N,N-dimethyl-formamide at 20℃; for 0.0833333h;	92%

(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) + N′-(2,2-dichloro-1-methylethylidene)-4-methylbenzenesulfonohydrazide (91257-99-7) → (R)-3-(3-fluoro-4-morpholinophenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (1170353-86-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol at 0℃; Inert atmosphere;	91%

benzoic acid (65-85-0) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → N-(3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine benzoate (1609632-44-1)

Conditions	Yield
In methanol; water; isopropyl alcohol at 80℃;	89.5%

acetic acid (64-19-7) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one acetate

Conditions	Yield
Stage #1: (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine With hydrogen; palladium 10% on activated carbon In ethyl acetate at 50℃; under 608.041 - 912.061 Torr; for 20h; Stage #2: acetic acid Product distribution / selectivity;	89%

acetic anhydride (108-24-7) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → linezolid (165800-03-3)

Conditions	Yield
With triethylamine In ethyl acetate at 20 - 40℃; under 608.041 - 912.061 Torr; for 2h; Product distribution / selectivity;	88%
With triethylamine In ethyl acetate at 25℃; for 2h; Product distribution / selectivity;	88%
at 0℃;	88%

3,4-dimethoxy-3-cyclobutene-1,2-dione (5222-73-1) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-3-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylamino)-4-methoxycyclobut-3-ene-1,2-dione (1308299-21-9)

Conditions	Yield
With triethylamine In methanol at 20℃; pH=7.5;	88%

5-chlorothiophene-2-carbonyl chloride (42518-98-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-5-chloro-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]thiophen-2-carboxamide

Conditions	Yield
With triethylamine In toluene at 20 - 45℃; for 12h;	87%

NSC 373853 (107089-76-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → C22H24FN5O5S (1280555-25-0)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 6h;	85%

(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) + 3,4-dimethoxybenzoic acid chloride (3535-37-3) → (S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-3,4-dimethoxybenzamide (1390617-32-9)

Conditions	Yield
With triethylamine In toluene at 20 - 45℃; for 12h;	83%

4-(4-methylsulfanyl-phenyl)-4-oxo-butyric acid (7028-67-3) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-4-oxo-4-(4-thiomethyl)phenylbutanamide (675609-11-7)

Conditions	Yield
Stage #1: 4-(4-methylsulfanyl-phenyl)-4-oxo-butyric acid; (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; water at 0 - 20℃; for 24h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 0.25h;	79%

acetyl chloride (75-36-5) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (S)-N-acetyl-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide + linezolid (165800-03-3)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 2h;	A 8% B 79%

2-oxo-4-hydroxy-6-methyl-cyclohex-3-ene carboxylic acid methyl ester (39493-62-4) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → methyl 4-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylamino)-6-methyl-2-oxocyclohex-3-enecarboxylate (1147846-91-0)

Conditions	Yield
Reflux;	77%

methyl 4-bromocrotonate (1117-71-1) + carbon dioxide (124-38-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → methyl 2-(3-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-2-oxooxazolidin-4-yl)acetate

Conditions	Yield
With caesium carbonate; N,N,N',N'-tetramethylguanidine In N,N-dimethyl-formamide at 20℃; for 30h; Michael Addition; Schlenk technique; Sealed tube;	74%

ethyl furan-2-carboxycyanoimidate + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]furan-2-yl-cyanoamidine

Conditions	Yield
In methanol Heating / reflux;	73%

chloroacetyl chloride (79-04-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → 2-chloro-(S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]acetamide

Conditions	Yield
With triethylamine In toluene at 20 - 45℃; for 12h;	71%
Stage #1: (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine With triethylamine In dichloromethane for 0.25h; Stage #2: chloroacetyl chloride In dichloromethane at 20℃; for 18h; Cooling with ice;
With potassium carbonate In acetone at 20℃;
With potassium carbonate In acetone at 20℃;

4-Fluorobenzenesulfonyl chloride (349-88-2) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (R)-[{N-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl] 4-fluorobenzensulfonamide (1280555-38-5)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0℃; for 6h;	70%

4-chlorobenzenesulfonyl chloride (98-60-2) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (R)-[{N-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl] 4-chlorobenzensulfonamide (1280555-37-4)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0℃; for 6h;	70%

benzenesulfonyl chloride (98-09-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (R)-[{N-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl] benzensulfonamide (1280555-36-3)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0℃; for 6h;	70%

p-toluenesulfonyl chloride (98-59-9) + (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (168828-90-8) → (R)-[{N-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl] 4-methylbenzensulfonamide (1280555-41-0)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0℃; for 6h;	70%

Upstream product

• 1352030-06-8 N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine 
• 952680-48-7 (3-fluoro-4-morpholin-4-yl-phenyl)carbamic acid tert-butyl ester 
• 1385053-40-6 C₁₈H₂₅FN₂O₄ 
• 93246-53-8 3-fluoro-4-(morpholinyl)aniline 
• 513068-96-7 3-(3-fluoro-4-morpholin-4-yl-phenyl)-5-hydroxymethyl-oxazolidin-2-one 
• 858344-36-2 methanesulfonic acid 3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-oxazolidin-5-ylmethyl ester 
• 212325-40-1 methyl-(3-fluoro-4-morpholinophenyl)carbamate 
• 1345879-80-2 C₁₁H₁₁ClFNO₂ 
• 455-86-7 3,4-Difluorobenzoic acid 
• 1345879-78-8 3-fluoro-4-morpholinobenzoylazide 
• 165800-03-3 linezolid 

Downstream Products

• 216868-96-1 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]methyldithiocarbamate 
• 165800-03-3 linezolid 
• 1147846-91-0 methyl 4-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylamino)-6-methyl-2-oxocyclohex-3-enecarboxylate 
• 1147846-92-1 ethyl 4-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylamino)-6-methyl-2-oxocyclohex-3-ene-1-carboxylate 
• 1147846-93-2 methyl 4-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methylamino)-2-oxo-6-phenylcyclohex-3-ene-1-carboxylate 
• 1170353-86-2 (R)-3-(3-fluoro-4-morpholinophenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one 
• 1390617-37-4 5-(aminosulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxy benzamide 
• 1390617-35-2 4-amino-5-(ethylsulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxybenzamide 
• 1390617-34-1 (S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]benzamide 
• 1390617-33-0 2-benzyl-(S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]acrylamide 
• 1390617-32-9 (S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-3,4-dimethoxybenzamide 

Relevant articles and documents

Linezolid preparation method

The invention relates to a linezolid preparation method. 3-fluoro-4-morpholinyl aniline is taken as a starting material and subjected to a reaction with (S)-(+)-N-(2,3-ethoxypropyl) phthalimide, an intermediate 1 is generated and subjected to a cyclization reaction with a carbonylation agent, an intermediate 2 is generated, an ammonolysis reaction and an acetylation reaction are performed, and a target compound is obtained. The problems of poor safety, strict conditions, many impurities and low yield, which are not suitable for industrial production, of a linezolid preparation method in the prior art are solved, the starting material of the route is cheap and available, the operation is simple, hazardous reagents are avoided, the solvent is easily recycled and reused, reaction yield is higher, purity of a final product is up to 99.9% or higher, and the linezolid preparation method is suitable for industrial production.

cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD-5) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD-6), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.

Method of preparing linezolid

The invention relates to a method of preparing an oxazolidine antibacterial agent-linezolid. The method includes: enabling (S, E)-N-benzal-1-(ethylene oxide-2-group)-methylamine and morpholino fluoro-phenyl carbamate to react in a non-nucleophilic agent under action of alkali and catalyst to obtain a high-purity imine intermediate; subjecting the intermediate to hydrolysis and acylation to generate linezolid. The method is high in yield, simple to operate, mild in reaction condition and suitable for industrial production.