446292-10-0

Basic information

• Product Name: 3-MORPHOLINONE, 4-[4-[(5S)-5-(AMINOMETHYL)-2-OXO-3-OXAZOLIDINYL]PHENYL]-
• Synonyms: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one;Des(5-chloro-2-carboxythienyl) Rivaroxaban;Rivaroxaban Intermediate 3;4-{4-[(5S)-5-aminomethyl)-2-oxo-1,3-oxazolidin-3-yl}morpholin-3-on;4-[4-[(5S)-5-(AMinoMethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-Morpholinone;4-{4-[(5S)-5-(aMinoMethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}Morpholin-3-one;Rivaroxaban interMediate C;Rivaroxaban Aminomethyl Impurity
• CAS NO: 446292-10-0
• Molecular Formula: C₁₄H₁₇N₃O₄
• Molecular Weight: 291.305
• EINECS: 1312995-182-4
• Product Categories: Amines;Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Aromatics;Intermediates
• Mol File: 446292-10-0.mol
• Article Data: 39

Chemical Properties

• Melting Point: 148.3-149.8 °C
• Boiling Point: 580.4 °C at 760 mmHg
• Flash Point: 304.8 °C
• Appearance: White solid
• Density: 1.348 g/cm³
• Vapor Pressure: 1.83E-13mmHg at 25°C
• Refractive Index: 1.598
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 8.96±0.29(Predicted)
• CAS DataBase Reference: 3-MORPHOLINONE, 4-[4-[(5S)-5-(AMINOMETHYL)-2-OXO-3-OXAZOLIDINYL]PHENYL]-(CAS DataBase Reference)
• NIST Chemistry Reference: 3-MORPHOLINONE, 4-[4-[(5S)-5-(AMINOMETHYL)-2-OXO-3-OXAZOLIDINYL]PHENYL]-(446292-10-0)
• EPA Substance Registry System: 3-MORPHOLINONE, 4-[4-[(5S)-5-(AMINOMETHYL)-2-OXO-3-OXAZOLIDINYL]PHENYL]-(446292-10-0)

Safety Data

• Hazardous Substances Data: 446292-10-0(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

InChI:InChI=1/C14H17N3O4/c15-7-12-8-17(14(19)21-12)11-3-1-10(2-4-11)16-5-6-20-9-13(16)18/h1-4,12H,5-9,15H2/t12-/m0/s1

Synthetic route

4-{4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (1372665-04-7) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With palladium on activated charcoal; hydrogen In methanol at 40 - 50℃; under 37503.8 Torr; for 20h; Solvent; Reagent/catalyst;	100%
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 50℃; for 18h; Inert atmosphere;	92.6%
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol at 50℃; under 4200.42 Torr;	2.56 g

4-{4-[(S)-5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one (1414932-72-1) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With isobutylamine In toluene for 3h; Product distribution / selectivity; Reflux;	99.7%
With isobutylamine In toluene for 3h; Concentration; Solvent; Time; Temperature; Reagent/catalyst; Heating; Reflux;	99.7%
With hydrogenchloride; triethylamine In ethanol; water at 22 - 65℃; for 1h;	95%
With hydrogenchloride In water for 0.333333h; Time;

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
In dichloromethane; water pH=8; Concentration;	96.7%
With potassium carbonate In methanol at 25 - 30℃; for 0.5h;	56%
With potassium carbonate In methanol at 25 - 30℃; for 0.5h;	56%
With potassium carbonate In water at 20℃; for 2h;

2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (446292-08-6) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With hydrazine hydrate In methanol at 80℃; for 2.5h;	96.1%
With ethanolamine In toluene at 75 - 85℃; for 2h; Solvent; Temperature;	95.87%
With hydrazine hydrate In ethanol for 2h; Reflux;	95.4%

4-{4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one (1349248-79-8) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol at 40℃; for 24h;	96%
With 5%-palladium/activated carbon; hydrogen In ethyl acetate for 12h;	91%
With palladium 10% on activated carbon; hydrogen In methanol under 1500.15 - 3000.3 Torr; for 4h;	90.9%
With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 45℃; under 3750.38 - 6000.6 Torr; for 8h; Autoclave;	80%
With water; triphenylphosphine In tetrahydrofuran at 10 - 65℃;	18 g

2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (446292-07-5) + methylamine (74-89-5) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Stage #1: 2-((2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione With dmap; 1,1'-carbonyldiimidazole In tetrahydrofuran for 12h; Reflux; Stage #2: methylamine In ethanol; water for 8h; Reflux;	92.2%

tert-butyl {(5S)-3-[4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methylcarbamate (1416129-92-4) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With hydrogenchloride; water In ethanol at 20℃; for 24h; Solvent;	90%
With hydrogenchloride In ethanol; water at 20℃; for 24h; Solvent;	90%

(S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one (1414932-73-2) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With hydrogenchloride; water In ethanol at 20℃; for 24h; Solvent;	90%
With hydrogenchloride In ethanol; water at 20℃; for 24h; Solvent; Time;	90%

C14H14N2O5 → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Stage #1: C14H14N2O5 With ammonium hydroxide In methanol for 0.5h; Stage #2: With methanol; sodium tetrahydroborate at 0 - 20℃; for 2.5h;	87.5%

2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (446292-08-6) + methylamine (74-89-5) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
In methanol; water for 2h; Reflux;	85%

2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (446292-08-6) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 2,3-dihydrophthalazine-1,4-dione (1445-69-8)

Conditions	Yield
With hydrazine hydrate In ethanol at 65℃; for 3h;	A 73% B 12.7%

2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (446292-07-5) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 24 h / 60 °C 2: aq. MeNH2 / ethanol / 1 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: toluene / 3 h / Industry scale; Reflux 2.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 2.2: 58 - 60 °C / pH 2.7 / Industry scale View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 20 h / 30 °C 2: hydrazine hydrate / methanol / 1 h / Reflux View Scheme

4-(4-aminophenyl)morpholin-3-one (438056-69-0) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / ethanol; H2O / 27 h / Heating 2: 87 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 24 h / 60 °C 3: aq. MeNH2 / ethanol / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: water / ethanol / 36 h / 60 °C / Industry scale 2.1: toluene / 3 h / Industry scale; Reflux 3.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 3.2: 58 - 60 °C / pH 2.7 / Industry scale View Scheme
Multi-step reaction with 4 steps 1: toluene / 20 °C / Reflux 2: MgI2*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 3: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 4: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme

2-Anilinoethanol (122-98-5) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydroxide / ethanol; water / 0.5 h / 38 - 45 °C / pH 10 - 13 / Industry scale 2.1: nitric acid; sulfuric acid / sulfolane / 2 h / -5 - 30 °C 3.1: hydrogen / Raney Ni / methanol / 24 h / 40 - 50 °C 4.1: water / ethanol / 36 h / 60 °C / Industry scale 5.1: toluene / 3 h / Industry scale; Reflux 6.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 6.2: 58 - 60 °C / pH 2.7 / Industry scale View Scheme
Multi-step reaction with 7 steps 1: sodium hydroxide / ethanol; water 2: sulfuric acid; nitric acid / water 3: 5%-palladium/activated carbon; hydrogen / ethanol / 40 °C 4: toluene / 20 °C / Reflux 5: MgI2*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 6: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 7: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme

4-(4-nitrophenyl)-3-morpholinone (446292-04-2) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogen / Raney Ni / methanol / 24 h / 40 - 50 °C 2.1: water / ethanol / 36 h / 60 °C / Industry scale 3.1: toluene / 3 h / Industry scale; Reflux 4.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 4.2: 58 - 60 °C / pH 2.7 / Industry scale View Scheme
Multi-step reaction with 5 steps 1: 5%-palladium/activated carbon; hydrogen / ethanol / 40 °C 2: toluene / 20 °C / Reflux 3: MgI2*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 4: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 5: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme
Multi-step reaction with 4 steps 1: ammonium formate / water / 30 - 90 °C 2: water / 8 h / 80 °C 3: dmap / 6 h / 80 - 85 °C 4: methylamine / water / 5 h / 35 °C View Scheme

4-phenyl-3-morpholinone (29518-11-4) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: nitric acid; sulfuric acid / sulfolane / 2 h / -5 - 30 °C 2.1: hydrogen / Raney Ni / methanol / 24 h / 40 - 50 °C 3.1: water / ethanol / 36 h / 60 °C / Industry scale 4.1: toluene / 3 h / Industry scale; Reflux 5.1: methylamine / ethanol / 4 h / 65 °C / Industry scale 5.2: 58 - 60 °C / pH 2.7 / Industry scale View Scheme
Multi-step reaction with 6 steps 1: sulfuric acid; nitric acid / water 2: 5%-palladium/activated carbon; hydrogen / ethanol / 40 °C 3: toluene / 20 °C / Reflux 4: MgI2*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 5: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 6: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme

4-{4-[(5R)-5-(chloromethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (1252018-28-2) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 2: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 5 h / Reflux 2: hydrazine hydrate / methanol / 1 h / Reflux View Scheme

4-(4-isocyanatophenyl)morpholin-3-one (1325210-64-7) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: MgI2*etherate / tetrahydrofuran / 20 - 80 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 12 h / 85 °C 3: 5%-palladium/activated carbon; hydrogen / ethyl acetate / 12 h View Scheme
Multi-step reaction with 2 steps 1: lithium bromide; Triphenylphosphine oxide / 1-methyl-pyrrolidin-2-one / 7 h / 90 - 95 °C 2: potassium hydroxide / water / Reflux View Scheme

4-[4-(N-(3-chloro-(2R)-2-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (1252018-10-2) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloromethane / 20 h / 30 °C 2: N,N-dimethyl-formamide / 5 h / Reflux 3: hydrazine hydrate / methanol / 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: chloroform / 20 h / 30 °C 2: N,N-dimethyl-formamide / 5 h / Reflux 3: hydrazine hydrate / methanol / 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 5 h / Reflux 2: dichloromethane / 20 h / 30 °C 3: hydrazine hydrate / methanol / 1 h / Reflux View Scheme

[4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester (1313613-18-1) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium tert-butoxide / dichloromethane / 24 h / Reflux 2: isobutylamine / toluene / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 0.17 h / 0 °C 1.2: 18 h / 30 °C 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 0.17 h / 0 °C 1.2: 18 h / 30 °C 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

dodecyl (4-(3-oxomorpholin)phenyl)carbamate (1414932-71-0) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium tert-butoxide / dichloromethane / 36 h / Reflux 2: isobutylamine / toluene / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: n-butyllithium / dichloromethane / 36 h / Heating; Reflux 2: isobutylamine / toluene / 3 h / Heating; Reflux View Scheme

4-{4-[(5S)-5-(N-benzylaminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morphoIin-3-one (1424942-78-8) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; acetic acid In methanol at 45℃; under 3750.38 - 6000.6 Torr; for 8h; Autoclave;	15.5 g

4-[4-{(R)-2,3-dihydroxy-propylamino}phenyl]morpholin-3-one (1447919-65-4) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanol / 48 h / 30 °C 1.2: 2 h / Reflux 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: methanol / 48 h / 30 °C 1.2: 2 h / Reflux 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme
Multi-step reaction with 4 steps 1: triethylamine / chloroform / 1 h / -5 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 10 h / 80 °C 3: sodium azide / water; N,N-dimethyl-formamide / 10 h / 0 - 40 °C 4: 5%-palladium/activated carbon; hydrogen / ethanol / 24 h / 40 °C View Scheme

butyric acid-2(R)-2-hydroxy-3-[4-(3-oxo-morpholin-4-yl)phenylamino]-propyl ester (1446022-14-5) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanol / 48 h / 30 °C 1.2: 2 h / Reflux 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: methanol / 48 h / 30 °C 1.2: 2 h / Reflux 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme
Multi-step reaction with 5 steps 1: dichloromethane / 48 h / 30 °C 2: sodium methylate; methanol / 1 h / 30 °C 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: dichloromethane / 48 h / 30 °C 2: sodium methylate; methanol / 1 h / 30 °C 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

butyric acid-2-oxo-5(R)-3-[4-(3-oxomorpholin-4-yl)-phenyl]oxazolidin-5-yl-methyl ester (1446022-15-6) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium methylate; methanol / 1 h / 30 °C 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium methylate; methanol / 1 h / 30 °C 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

4-(4-((R)-5-benzyloxymethyl-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one (1117893-59-0) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

4-(4-(R)-3-benzyloxy-2-hydroxy-propylamino)phenyl-morpholin-3-one (1117893-58-9) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: dichloromethane / 44 h / 30 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: dichloromethane / 44 h / 30 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

acetic acid-1-benzyloxymethyl-2-[(R)-4-(3-oxo-morpholin-4-yl)phenylamino]-ethylester (1447919-68-7) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: chloroform / 2 h / 50 °C 2: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 0 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 4: triethylamine / dichloromethane / 18 h / 0 - 20 °C 5: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 6: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: chloroform / 2 h / 50 °C 2: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 0 °C 3: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 4: triethylamine / dichloromethane / 18 h / 0 - 20 °C 5: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 6: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

acetic acid-1-benzyloxymethyl-2-{[(R)-(3-oxo-morpholin-4-yl)-phenyl]-chlorocarbonyl-amino} ethyl ester (1447919-69-8) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 0 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: lithium tert-butoxide; methanol / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 0 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 3000.3 - 3750.38 Torr / Autoclave 3: triethylamine / dichloromethane / 18 h / 0 - 20 °C 4: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

4-(4-((R)-5-((phenyloxycarbonyloxy)methyl)-2-oxo-oxazolidin-3-yl)phenyl)-morpholin-3-one (1447919-71-2) → 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium methylate; methanol / 4 h / 30 °C 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium carbonate / N,N-dimethyl-formamide / 2 h / 90 °C 4: palladium 10% on activated carbon; hydrogen / ethyl acetate / 18 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium methylate; methanol / 4 h / 30 °C 2: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C 4: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 1500.15 - 3000.3 Torr View Scheme

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 5-chlorothiophene-2-carbonyl chloride (42518-98-9) → Rivaroxaban (366789-02-8)

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 3h; Product distribution / selectivity;	100%
With triethylamine In tetrahydrofuran at 20℃; for 3h; Reagent/catalyst; Solvent; Time; Concentration; Temperature;	100%
With sodium carbonate In water; acetone; toluene at 8 - 53℃; for 0.5h;	98.7%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + formic acid (64-18-6) → N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide (1616563-62-2)

Conditions	Yield
In toluene at 110 - 120℃; Solvent;	96%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 2-Thiophenecarbonyl chloride (5271-67-0) → N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Conditions	Yield
With 4-methyl-morpholine In water; acetonitrile at -5 - 20℃; for 2.5h; Reagent/catalyst;	96%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 5-Chlorothiophene-2-carboxylic acid (24065-33-6) → Rivaroxaban (366789-02-8)

Conditions	Yield
With 4-methyl-morpholine; hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 2.83333h;	95.2%
With ortho-iodophenylboronic acid In dichloromethane at 30℃; for 48h; Reagent/catalyst; Time; Concentration; Temperature; Solvent; Dean-Stark;	85%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	68.9%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + N-(Benzyloxycarbonyl)sarcosine (39608-31-6) → C25H28N4O7 (947181-22-8)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	92%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + C11H6ClN3O2S → Rivaroxaban (366789-02-8)

Conditions	Yield
With triethylamine at 10 - 25℃;	90.3%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 4-chloro-benzoyl chloride (122-01-0) → 4-chloro-N-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-benzamide

Conditions	Yield
With pyridine; aminomethylpolystyrol resin at 20℃; for 3.5h;	89%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + O-acetylsalicyloyl chloride (5538-51-2) → C23H23N3O7

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	73%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 2-(methylcarbamoyl)benzoic acid. (6843-36-3) → (S)-N1-methyl-N2-((2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)oxazolidin-5-yl)methyl)phthalamide

Conditions	Yield
Stage #1: 2-(methylcarbamoyl)benzoic acid. With sodium hydrogencarbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: With isobutyl chloroformate In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #3: 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one In N,N-dimethyl-formamide for 8h;	65%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + (S)-2-(((2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)oxazolidin-5-yl)methyl)carbamoyl)benzoic acid (1365267-37-3) → N,N'-bis[{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl]benzene-1,2-diamide (1365267-36-2)

Conditions	Yield
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate; acetonitrile at 5℃; for 2.16667h; pH=8;	62.8%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 4-nitrophenyl 5-chlorothiophene-2-carboxylate (1450877-56-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
With potassium carbonate In dichloromethane at 25 - 30℃;	55.5%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) → 2-[2-({4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}amino)ethoxy]acetohydrazide

Conditions	Yield
With hydrazine hydrate In methanol at 80℃; for 12h; Temperature; Solvent;	49.5%
With hydrazine hydrate In methanol at 80℃; for 12h;	49.5%
With hydrazine hydrate In methanol at 90℃; for 12h;	49.5%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 2-thiophenylcarboxylic acid (527-72-0) → N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Conditions	Yield
Stage #1: 2-thiophenylcarboxylic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one In dichloromethane at 20℃; for 6h; Inert atmosphere;	48%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) → (S)-4-(4-(((2-oxooxazolidin-5-yl)methyl)amino)phenyl)morpholin-3-one

Conditions	Yield
In water at 130℃; for 12h; Temperature; Time; Solvent; Autoclave;	46%
With water at 130℃; for 12h; Sealed tube;	46%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 5-chlorothien-2-ylsulfonyl chloride (2766-74-7) → 5-Chloro-thiophene-2-sulfonic acid {(R)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide

Conditions	Yield
With pyridine In tetrahydrofuran at 20℃; for 4h;	43%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + bis(trichloromethyl) carbonate (32315-10-9) → N,N'-bis[{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl]urea (1365267-35-1)

Conditions	Yield
Stage #1: 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one; bis(trichloromethyl) carbonate With triethylamine In tetrahydrofuran at 20℃; Cooling; Stage #2: With sodium carbonate In tetrahydrofuran	38.8%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 5-bromothiophene-2-carboxylic acid (7311-63-9) → 5-bromo-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Conditions	Yield
Stage #1: 5-bromothiophene-2-carboxylic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one In dichloromethane at 20℃; for 6h; Inert atmosphere;	37%
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + (5-fluorothiophen-2-yl)formyl chloride → (S)-5-fluoro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide

Conditions	Yield
With pyridine at 0 - 23℃; for 1h; Inert atmosphere;	37%

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (446292-10-0) + 6-chloropicolinic acid (4684-94-0) → 6-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)pyridine-2-carboxamide

Conditions	Yield
Stage #1: 6-chloropicolinic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one In dichloromethane at 20℃; for 6h; Inert atmosphere;	27%

Upstream product

• 446292-08-6 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 
• 74-89-5 methylamine 
• 446292-07-5 2-((2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione 
• 1414932-73-2 (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one 
• 635301-86-9 [4-(3-oxo-morpholin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester 
• 1416129-92-4 tert-butyl {(5S)-3-[4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methylcarbamate 
• 1252018-07-7 methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate 
• 1411775-00-2 4-(4-{[(2R)-3-(dibenzylamino)-2-hydroxypropyl]amino}phenyl)morpholin-3-one 
• 1429334-08-6 4-{4-[(5S)-5-(tritylaminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one 
• 1429334-05-3 4-[4-{(R)-2-hydroxy-3-azidopropylamino}phenyl]morpholin-3-one 
• 1429334-02-0 N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]acetamide 
• 1429334-00-8 (S)-N-[{3-(4-(3-oxomorpholin-4-yl)phenyl)-2-oxo-1,3-oxazolidin-5-yl}methyl]acetamide 
• 1429333-99-2 4-{4-[(R)-2-hydroxy-3-((3,4-dimethoxybenzylidene)amino)propylamino]phenyl}morpholin-3-one 
• 1429333-96-9 (5S)-5-{[(3,4-dimethoxybenzylidene)amino]methyl}-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-2-one 

Downstream Products

• 366789-02-8 Rivaroxaban 
• 1415566-28-7 N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 
• 1429334-00-8 (S)-N-[{3-(4-(3-oxomorpholin-4-yl)phenyl)-2-oxo-1,3-oxazolidin-5-yl}methyl]acetamide 
• 1616563-62-2 N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide 
• 1616563-61-1 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 

Relevant articles and documents

Oxazolidinone derivative and preparation method thereof

The invention relates to a preparation method of an oxazolidinone compound impurity 5-chloro-nitrogen-[[(5S)-2-oxo-3-[4-acetamidophenyl]-1, 3- oxazolidine-5-yl]methyl] thiophene-2-methanamide (formulaI) in rivaroxaban. According to a preparation method, 4-aminoacetanilide (formula II) and (S)-N-epoxypropyl phthalimide (formula III) are used as raw materials, and the impurity is obtained through ring opening coupling, ring closing, protecting group removal and condensation reaction. The compound represented by formula I can be applied to rivaroxaban bulk drug quality control and qualitative and quantitative research and detection of impurities.

Rivaroxaban intermediate preparation method

The invention provides a preparation method of a Rivaroxaban intermediate compound in a formula I. The method includes dissolving a compound in a formula II in an organic solvent; and carrying out ammonolysis reaction by taking C3-4 alkyl primary ammonia as an ammonia source to obtain the compound in the formula I. The preparation method is safer, economical, simple and convenient, environment-friendly and suitable for industrialization.

A [...] synthesis process

The invention relates to the technical field of heterocyclic chemistry, specifically to the technical field of nitrogen-oxygen heterocyclic chemistry. Specifically speaking, the invention discloses a novel synthetic process for rivaroxaban. According to the process, the R group of a compound with a structure as shown in a formula (I) is removed so as to obtain a compound with a structure as shown in a formula (II) or an acid salt thereof, and the compound with the structure as shown in the formula (II) or the acid salt thereof reacts with a compound with a structure as shown in a formula (III) under the action of alkali so as to prepare rivaroxaban, wherein the formulas are described in the specification, and R in the formulas is a C1-20 aliphatic/aromatic hydrocarbon group.