168828-89-5

Basic information

• Product Name: DeacetaMide Linezolid PhthaliMide
• Synonyms: (S)-2-[[3-[3-Fluoro-4-(4-Morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]Methyl]-1H-isoindole-1,3(2H)-dione;2-[[(5S)-3-[3-fluoro-4-(4-Morphol;(S)-2-((3-fluoro-4-Morpholiophenyl)-2-oxooxazolidin-5-yl)Methyl)isoindoline-1,3-dione;(S)-2-((3-(3-Fluoro-4-Morpholinophenyl)-2-oxooxazolidin-5-yl)Methyl)isoindoline-1,3-dione;Linezolid DesacetaMide PhthaliMide;(S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]pthalamide;DeacetaMide Linezolid PhthaliMide;(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide
• CAS NO: 168828-89-5
• Molecular Formula: C₂₂H₂₀FN₃O₅
• Molecular Weight: 425.4097032
• EINECS: 1533716-785-6
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Linezolid intermediate
• Mol File: 168828-89-5.mol
• Article Data: 20

Chemical Properties

• Melting Point: 205-207 °C
• Boiling Point: 619.13 °C at 760 mmHg
• Flash Point: 328.238 °C
• Appearance: /
• Density: 1.44
• Storage Temp.: 2-8°C
• Solubility: Acetonitrile (Slightly, Sonicated), Chloroform (Slightly), DMSO (Slightly), Meth
• PKA: 5.73±0.40(Predicted)
• CAS DataBase Reference: DeacetaMide Linezolid PhthaliMide(CAS DataBase Reference)
• NIST Chemistry Reference: DeacetaMide Linezolid PhthaliMide(168828-89-5)
• EPA Substance Registry System: DeacetaMide Linezolid PhthaliMide(168828-89-5)

Safety Data

• Hazardous Substances Data: 168828-89-5(Hazardous Substances Data)

Usage

Chemical Properties

Off-white Crystals

Uses

Linezolid (L466500) intermediate.

Synthetic route

3-fluoro-4-(morpholin-4-yl)-phenyl isocyanate (224323-51-7) + (S)-N-glycidylphthalimide (161596-47-0) → 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)

Conditions	Yield
With lithium bromide at 120℃; for 4h; Temperature; Solvent;	96.51%
With lithium bromide In N,N-dimethyl-formamide at 60℃; for 4h; Reagent/catalyst; Solvent;	90.11%

2-[(5R)-(2-oxo-5-oxazolidinyl)-methyl]-1H-isoindole-1,3(2H)-dione (352524-58-4) + 4-(2-fluoro-4-bromophenyl)morpholine (513068-89-8) → 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)

Conditions	Yield
With copper(l) iodide; N,N-dimethyl-ethanamine; potassium carbonate In dichloromethane at 110℃; for 20h; Reagent/catalyst; Solvent; Temperature;	92.8%
With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; potassium carbonate In 1,4-dioxane at 110℃; for 20h; Goldberg Reaction; Inert atmosphere;	76%

(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone + potassium phtalimide (1074-82-4) → 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)

Conditions	Yield
at 140 - 145℃; for 2h;	92%
In N,N-dimethyl-formamide for 5h; Reflux;	62%
In N,N-dimethyl-formamide for 5h; Heating / reflux;

potassium phtalimide (1074-82-4) + (R)-methyl methanesulfonate (174649-09-3) → 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)

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 3h;	87.7%
In N,N-dimethyl-formamide at 120℃; for 2h;
In N,N-dimethyl-formamide at 120℃; for 2h;	27 g

(S)-3-Chloro-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl-3-fluoro-4-morpholinophenylcarbamate (1373348-82-3) → 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)

Conditions	Yield
With potassium carbonate In acetone at 20℃; for 8h;	86%

methyl (3-fluoro-4-morpholinophenyl)carbamate (212325-40-1) + (S)-N-glycidylphthalimide (161596-47-0) → 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)

Conditions	Yield
With lithium tert-butoxide In N,N-dimethyl-formamide at 25 - 85℃; Temperature; Solvent; Reagent/catalyst;	85%
With lithium tert-butoxide In ethyl acetate at 25 - 75℃; Solvent; Temperature; Reagent/catalyst;	70%

benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate (168828-81-7, 1027135-00-7) + (S)-N-glycidylphthalimide (161596-47-0) → 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)

Conditions	Yield
Stage #1: benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate With lithium tert-butoxide In tetrahydrofuran; N,N-dimethyl-formamide at 5℃; for 0.5h; Inert atmosphere; Stage #2: (S)-N-glycidylphthalimide In tetrahydrofuran; N,N-dimethyl-formamide at 5 - 20℃; for 24h; Reagent/catalyst; Temperature; Inert atmosphere;	84%

(R)-(-)-epichlorohydrin (51594-55-9) + potassium phtalimide (1074-82-4) + methyl chloroformate (79-22-1) + 3-fluoro-4-(morpholinyl)aniline (93246-53-8) → 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)

Conditions	Yield
Stage #1: (R)-(-)-epichlorohydrin; 3-fluoro-4-(morpholinyl)aniline In butan-1-ol at 20℃; Cooling; Stage #2: methyl chloroformate With sodium hydrogencarbonate In butan-1-ol at 0 - 5℃; Stage #3: potassium phtalimide In N,N-dimethyl-formamide at 95 - 100℃; for 3h;	83%

C21H22FN3O4 + 1,1'-carbonyldiimidazole (530-62-1) → 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)

Conditions	Yield
With dmap In acetonitrile at 80℃; for 1.5h; Inert atmosphere;	70.51%

N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline (874340-08-6) + 1,1'-carbonyldiimidazole (530-62-1) → 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)

Conditions	Yield
In dichloromethane at 20℃; for 20h;
In dichloromethane

phthalimide (136918-14-4) → 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)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / isopropyl alcohol / 5 h / Reflux 2: triethylamine / tetrahydrofuran / 20 °C / Inert atmosphere 3: potassium carbonate / dichloromethane / 20 °C 4: potassium carbonate / acetone / 8 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: methylamine / isopropyl alcohol / 5 h / 60 °C 1.2: 10 - 30 °C 2.1: lithium tert-butoxide / N,N-dimethyl-formamide / 25 - 85 °C View Scheme
Multi-step reaction with 3 steps 1: methylamine / isopropyl alcohol / 5 h / 60 °C 2: sodium methylate / methanol / 10 - 30 °C 3: lithium tert-butoxide / ethyl acetate / 25 - 75 °C View Scheme

(S)-3-chloro-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl chloroformate (1373348-79-8) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 20 °C 2: potassium carbonate / acetone / 8 h / 20 °C View Scheme

2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (148857-42-5) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 20 °C / Inert atmosphere 2: potassium carbonate / dichloromethane / 20 °C 3: potassium carbonate / acetone / 8 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium methylate / methanol / 10 - 30 °C 2: lithium tert-butoxide / ethyl acetate / 25 - 75 °C View Scheme

N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholin-4-yl)aniline (868405-66-7) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide 2: dichloromethane View Scheme
Multi-step reaction with 5 steps 1: 1,1'-carbonyldiimidazole / dichloromethane / 24 h / 20 - 30 °C 2: N,N-dimethyl-formamide / 120 °C 3: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 4: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 5: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 5 steps 1: dichloromethane / 24 h / 25 - 30 °C 2: N,N-dimethyl-formamide / 120 °C 3: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 4: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 5: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 20 h / 20 °C 2: N,N-dimethyl-formamide / 5 h / Reflux View Scheme

3-fluoro-4-(morpholinyl)aniline (93246-53-8) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol 2: N,N-dimethyl-formamide 3: dichloromethane View Scheme
Multi-step reaction with 6 steps 1: tert-butyl alcohol / 16 h / Reflux 2: 1,1'-carbonyldiimidazole / dichloromethane / 24 h / 20 - 30 °C 3: N,N-dimethyl-formamide / 120 °C 4: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 5: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 6: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; toluene / 1 h / 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 2.2: 20 °C / Cooling 3.1: triethylamine / dichloromethane / 45 °C 4.1: N,N-dimethyl-formamide / 3 h / 80 °C View Scheme

3-fluoro-4-(morpholinyl)aniline (93246-53-8) + (S)-N-glycidylphthalimide (161596-47-0) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide 2: dichloromethane View Scheme
Multi-step reaction with 2 steps 1: ethanol / 16 h / 60 °C / Inert atmosphere 2: dmap / acetonitrile / 1.5 h / 80 °C / Inert atmosphere View Scheme

3,4-difluoronitrobenzene (369-34-6) → 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)

Conditions	Yield
Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 6 h / 40 - 50 °C / Reflux 2: hydrogen / Raney nickel / methanol / 8 h / 45 - 50 °C / 2942.29 Torr / Autoclave 3: tert-butyl alcohol / 16 h / Reflux 4: 1,1'-carbonyldiimidazole / dichloromethane / 24 h / 20 - 30 °C 5: N,N-dimethyl-formamide / 120 °C 6: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 7: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 8: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 4 h / 10 - 20 °C 2.1: hydrogen / methanol / 10 h / 20 °C / 3750.38 Torr / Inert atmosphere; Autoclave 3.1: sodium hydrogencarbonate / water; toluene / 1 h / 0 - 20 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 4.2: 20 °C / Cooling 5.1: triethylamine / dichloromethane / 45 °C 6.1: N,N-dimethyl-formamide / 3 h / 80 °C View Scheme
Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 6 h / 40 °C / Reflux 2: hydrogen / methanol / 8 h / 45 - 50 °C / 3000.3 Torr / Autoclave; Inert atmosphere 3: tert-butyl alcohol / 16 h / Reflux 4: dichloromethane / 24 h / 25 - 30 °C 5: N,N-dimethyl-formamide / 120 °C 6: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 7: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 8: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / ethyl acetate / 25 - 80 °C 2.1: 5%-palladium/activated carbon; hydrogen / methanol / 22 - 35 °C / 225.02 - 1500.15 Torr 3.1: isopropyl alcohol / 28 - 88 °C 3.2: 35 - 38 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / ethyl acetate / 24 h / 20 °C 2.1: palladium 10% on activated carbon; ammonium formate / acetone / 8 h / 50 °C 3.1: sodium hydrogencarbonate / acetone; water / 0 - 20 °C 4.1: lithium tert-butoxide / N,N-dimethyl-formamide; tetrahydrofuran / 0.5 h / 5 °C / Inert atmosphere 4.2: 24 h / 5 - 20 °C / Inert atmosphere View Scheme

3-fluoro-4-(4-morpholinyl)nitrobenzene (2689-39-6) → 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)

Conditions	Yield
Multi-step reaction with 7 steps 1: hydrogen / Raney nickel / methanol / 8 h / 45 - 50 °C / 2942.29 Torr / Autoclave 2: tert-butyl alcohol / 16 h / Reflux 3: 1,1'-carbonyldiimidazole / dichloromethane / 24 h / 20 - 30 °C 4: N,N-dimethyl-formamide / 120 °C 5: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 6: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 7: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogen / methanol / 10 h / 20 °C / 3750.38 Torr / Inert atmosphere; Autoclave 2.1: sodium hydrogencarbonate / water; toluene / 1 h / 0 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 3.2: 20 °C / Cooling 4.1: triethylamine / dichloromethane / 45 °C 5.1: N,N-dimethyl-formamide / 3 h / 80 °C View Scheme
Multi-step reaction with 7 steps 1: hydrogen / methanol / 8 h / 45 - 50 °C / 3000.3 Torr / Autoclave; Inert atmosphere 2: tert-butyl alcohol / 16 h / Reflux 3: dichloromethane / 24 h / 25 - 30 °C 4: N,N-dimethyl-formamide / 120 °C 5: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 6: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 7: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1.1: 5%-palladium/activated carbon; hydrogen / methanol / 22 - 35 °C / 225.02 - 1500.15 Torr 2.1: isopropyl alcohol / 28 - 88 °C 2.2: 35 - 38 °C View Scheme
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; ammonium formate / acetone / 8 h / 50 °C 2.1: sodium hydrogencarbonate / acetone; water / 0 - 20 °C 3.1: lithium tert-butoxide / N,N-dimethyl-formamide; tetrahydrofuran / 0.5 h / 5 °C / Inert atmosphere 3.2: 24 h / 5 - 20 °C / Inert atmosphere View Scheme

(R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol (168828-82-8) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 2: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 45 °C 2: N,N-dimethyl-formamide / 3 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 2: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme

(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone → 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)

Conditions	Yield
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 120 °C 2: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 3: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 4: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 120 °C 2: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 3: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 4: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme

(R)-(3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl acetate (496031-56-2) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 2: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 3: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme
Multi-step reaction with 3 steps 1: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 2: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 3: N,N-dimethyl-formamide / 2 h / 120 °C View Scheme

benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate (168828-81-7, 1027135-00-7) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 1.2: 20 °C / Cooling 2.1: triethylamine / dichloromethane / 45 °C 3.1: N,N-dimethyl-formamide / 3 h / 80 °C View Scheme

(R)-(-)-epichlorohydrin (51594-55-9) + potassium phtalimide (1074-82-4) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) + 3-fluoro-4-(morpholinyl)aniline (93246-53-8) → 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)

Conditions	Yield
Stage #1: (R)-(-)-epichlorohydrin; 3-fluoro-4-(morpholinyl)aniline In isopropyl alcohol at 28 - 88℃; Stage #2: N,N-dimethyl-formamide at 35 - 38℃; Stage #3: potassium phtalimide Further stages;	234 g

N-ethoxycarbonyl-3-fluoro-4-morpholinyl aniline (565176-83-2) + (S)-N-glycidylphthalimide (161596-47-0) → 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)

Conditions	Yield
With triethylamine at 90 - 95℃; for 6h; Reagent/catalyst; Concentration;	40 g

methyl (3-fluoro-4-morpholinophenyl)carbamate (212325-40-1) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1.17 h / -10 °C 1.2: 4.67 h / -10 - 55 °C 2.1: 2 h / 140 - 145 °C View Scheme

potassium phtalimide (1074-82-4) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 3 h / 80 °C 2: sodium azide; (Dichloroiodo)benzene / ethyl acetate / 12 h / 0 - 80 °C / Inert atmosphere 3: potassium carbonate; N,N-dimethyl-ethanamine; copper(l) iodide / dichloromethane / 20 h / 110 °C View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 5 h / 70 °C 2: sodium azide; (Dichloroiodo)benzene / ethyl acetate / 12 h / 0 - 80 °C / Inert atmosphere 3: potassium carbonate; N,N-dimethyl-ethanamine; copper(l) iodide / dichloromethane / 20 h / 110 °C View Scheme

C12H13NO4 → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium azide; (Dichloroiodo)benzene / ethyl acetate / 12 h / 0 - 80 °C / Inert atmosphere 2: potassium carbonate; N,N-dimethyl-ethanamine; copper(l) iodide / dichloromethane / 20 h / 110 °C View Scheme

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%

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) + acetic anhydride (108-24-7) → linezolid (165800-03-3)

Conditions	Yield
Stage #1: 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione With hydrazine In methanol; water at 60℃; for 1h; Stage #2: acetic anhydride With triethylamine at 0 - 20℃; for 2h;	89.1%
Stage #1: 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione With hydrazine hydrate In methanol at 30 - 70℃; Stage #2: acetic anhydride at 10 - 30℃; Concentration;	145 g
Stage #1: 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione With hydrazine hydrate In methanol for 1h; Reflux; Stage #2: acetic anhydride With triethylamine at 10 - 30℃; for 1h;	9 g
Stage #1: 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione With hydrazine hydrate In methanol for 2h; Reflux; Stage #2: acetic anhydride In dichloromethane at 0 - 10℃;

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) + methylamine (74-89-5) → N-[[3-(3-fluoro-4-morphol-4-ylphenyl)-2-oxazolone-5-yl]methyl]-2-methylaminobenzamide

Conditions	Yield
In water; acetone for 6h; Reagent/catalyst; Solvent; Reflux;	66.39%

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) → linezolid (165800-03-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol / 1 h / Reflux 2: toluene / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol / 1 h / Reflux 2: triethylamine / dichloromethane / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol / 1 h / Reflux 2: ethyl acetate / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol / 1 h / Reflux 2: ethyl acetate / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 4 h / Reflux 2: triethylamine / ethyl acetate / 2 h / 20 °C View Scheme

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)-5-chloro-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]thiophen-2-carboxamide

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol 2: triethylamine / toluene / 12 h / 20 - 45 °C View Scheme

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-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]benzamide (1390617-34-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol 2: triethylamine / toluene / 12 h / 20 - 45 °C View Scheme

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) → 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
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / methanol 2.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 0.5 h / 0 - 20 °C 2.2: 4 h / 0 - 20 °C View Scheme

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) → 4-amino-5-chloro-2-ethoxy-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]benzamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / methanol 2.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 0.5 h / 0 - 20 °C 2.2: 4 h / 0 - 20 °C View Scheme

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) → 5-(aminosulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxy benzamide (1390617-37-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / methanol 2.1: chloroformic acid ethyl ester; triethylamine / dichloromethane / 0.5 h / 0 - 20 °C 2.2: 4 h / 0 - 20 °C View Scheme

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-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-3,4-dimethoxybenzamide (1390617-32-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol 2: triethylamine / toluene / 12 h / 20 - 45 °C View Scheme

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) → 2-benzyl-(S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]acrylamide (1390617-33-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol 2: triethylamine / toluene / 12 h / 20 - 45 °C View Scheme

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) → 2-chloro-(S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol 2: triethylamine / toluene / 12 h / 20 - 45 °C View Scheme

Upstream product

• 874340-08-6 N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline 
• 530-62-1 1,1'-carbonyldiimidazole 
• 1074-82-4 potassium phtalimide 
• 136918-14-4 phthalimide 
• 1373348-79-8 (S)-3-chloro-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl chloroformate 
• 1373348-82-3 (S)-3-Chloro-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl-3-fluoro-4-morpholinophenylcarbamate 
• 148857-42-5 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione 
• 868405-66-7 N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholin-4-yl)aniline 
• 93246-53-8 3-fluoro-4-(morpholinyl)aniline 
• 161596-47-0 (S)-N-glycidylphthalimide 
• 174649-09-3 (R)-methyl methanesulfonate 
• 369-34-6 3,4-difluoronitrobenzene 
• 2689-39-6 3-fluoro-4-(4-morpholinyl)nitrobenzene 
• 168828-82-8 (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol 

Downstream Products

• 165800-03-3 linezolid 
• 1390617-34-1 (S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]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 
• 1390617-37-4 5-(aminosulfonyl)-N-(S)-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-2-methoxy benzamide 
• 1390617-32-9 (S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]-3,4-dimethoxybenzamide 
• 1390617-33-0 2-benzyl-(S)-N-[[3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl]methyl]acrylamide 
• 1497427-33-4 (S)-N-[[3-[3-fluoro-4-morpholinophenyl]-2-oxo-5-oxazolidinyl]methyl]hexanamide 
• 1497427-32-3 (S)-N-[[3-[3-fluoro-4-morpholinophenyl]-2-oxo-5-oxazolidinyl]methyl]pentanamide 
• 168828-90-8 (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine 

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.

Process for the preparation of linezolid

The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (S)-glycidyl phthalimide intermediates, which are used in the preparation of Linezolid.

A novel method for preparation of linezolid, (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide

Background: Linezolid (I) [(S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide] is a synthetic antibiotic used for the treatment of serious infections caused by grampositive bacteria that are resistant to other antibiotics. Linezolid empirical formula is C16H20FN3O4and its molecular weight is 337.35. It is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia, although it may be used for a variety of other infections. Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. Lohray et al., in 1999, have reported a synthetic method for Linezolid starting from D-mannitol, the chemical synthesis of Linezolid by alternate route has attracted several research groups in the past 15years. Methods: An improved and economically viable process is described to prepare Linezolid wherein methyl 3-fluoro-4-morphinolino phenyl carbamate (V) is reacted with R-epichlorohydrin in the presence of n-butyllithium in hexane to obtain (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (IV) which reacts with potassium phthalimide in presence of polar solvent to give (S)-2-[3-(3-3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidine-5-yl methyl]-isoindole-1,3-dione (III), which is subsequently converted to Linezolid. Results: Linezolid was obtained via only four steps with yield 90% and high purity. This process avoids formation and use of sensitive intermediates. It is an improved process for the preparation of an intermediate (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (formula IV). Conclusion: Linezolid was successfully synthesized from (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic ester via R-epichlorohydrin and potassium phthalimide and developed new intermediate (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one (IV). The present method relates to a novel, cost effective and industrially viable process. Thus, the process described is less cumbersome by way of reduced reaction stages, high purity and quantity of the yield. In comparison with previously reported synthetic strategies, this novel approach is believed to be the shortest and the most efficient synthetic route to date.