898543-06-1

Basic information

• Product Name: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one.HCl
• Synonyms: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one.HCl;4-[4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one hydrochloride;4-[4-[(5S)-5-(Aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholinone hydrochloride;(S)-4-(4-(5-(aMinoMethyl)-2-oxooxazolidin-3-yl)phenyl)Morpholin-3-one hydrochloride;4-{4-[(5S)-5-aMinoMethyl)-2-oxo-1,3-oxazolidin-3-yl} Mor-pholin -3-one hydrochloride;3-Morpholinone, 4-[4-[(5S)-5-(aMinoMethyl)-2-oxo-3-oxazolidinyl]phenyl]-, hydrochloride;4-{4-[(5S)-5-aMinoMethyl)-2-oxo-1,3-oxazolidin-3-yl}Morpholin-3-one;Rivaroxaban interMediate A
• CAS NO: 898543-06-1
• Molecular Formula: C₁₄H₁₇N₃O₄*ClH
• Molecular Weight: 328
• EINECS: 1806241-263-5
• Product Categories: Intermediates;Intermediate of Rivaroxaban
• Mol File: 898543-06-1.mol

Chemical Properties

• Boiling Point: 593.9 °C at 760 mmHg
• Flash Point: 313 °C
• Appearance: /
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Water (Slightly)
• PKA: 8.96[at 20 ℃]
• Water Solubility: 184.9g/L at 20℃
• CAS DataBase Reference: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one.HCl(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one.HCl(898543-06-1)
• EPA Substance Registry System: (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one.HCl(898543-06-1)

Safety Data

• Hazardous Substances Data: 898543-06-1(Hazardous Substances Data)

Usage

Flammability and Explosibility

Nonflammable

InChI:InChI=1S/C14H17N3O4.ClH/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;1H/t12-;/m0./s1

Synthetic route

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-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Stage #1: 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione With methylamine In N,N-dimethyl-formamide at 60 - 65℃; for 5h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 40℃; Temperature; Solvent;	96%
Stage #1: 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione With methylamine In methanol; water at 25 - 65℃; for 5h; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃; for 0.5h; pH=1 - 2; Temperature;	92%
Stage #1: 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione With methylamine In ethanol; water at 40 - 60℃; for 8h; Stage #2: With hydrogenchloride In water at 15℃; for 2h;	89.7%

(S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one (1414932-73-2) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With hydrogenchloride In water at 0 - 15℃; for 0.75h; pH=2; Temperature; pH-value;	92.4%

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-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Stage #1: 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione; methylamine In ethanol for 1h; Reflux; Large scale; Stage #2: With hydrogenchloride In ethanol at 50 - 60℃; pH=2 - Ca. 3; Large scale;	90.3%

4-{4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (1372665-04-7) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Stage #1: 4-{4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one With palladium 10% on activated carbon; hydrogen In methanol at 40℃; for 6h; Stage #2: With hydrogenchloride In methanol for 4h; Reagent/catalyst;	90.2%

2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (446292-07-5) + 1,1'-carbonyldiimidazole (530-62-1) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Stage #1: 2-((2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione; 1,1'-carbonyldiimidazole With dmap In tetrahydrofuran for 12h; Reflux; Stage #2: With hydrogenchloride In water at 20℃; Concentration;	89.1%

C18H23N3O6 → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With hydrogenchloride In ethanol at 55℃; for 2h;	85%

(S)-4-(4-((3-amino-2-hydroxypropyl)amino)phenyl)morpholin-3-one hydrochloride (1403383-55-0) + 1,1'-carbonyldiimidazole (530-62-1) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Stage #1: (S)-4-(4-((3-amino-2-hydroxypropyl)amino)phenyl)morpholin-3-one hydrochloride With potassium carbonate In 4-methyl-2-pentanone at 4℃; Inert atmosphere; Reflux; Stage #2: 1,1'-carbonyldiimidazole In 4-methyl-2-pentanone at 20℃; for 15h; Stage #3: With hydrogenchloride In water; 4-methyl-2-pentanone	80.1%

1-{(R)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-ylmethyl}-3;5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide (1403383-52-7) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With hydrogenchloride; water In ethanol at 50℃; for 2h; Inert atmosphere;	33.1%

4-[4-(N-(3-chloro-(2R)-2-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (1252018-10-2) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonia / water / 4 h / 20 °C 2.1: potassium carbonate / 4-methyl-2-pentanone / 4 °C / Inert atmosphere; Reflux 2.2: 15 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: acetonitrile / 3 h / 20 °C / Inert atmosphere 2: sodium iodide / sulfolane / 20 h / 110 °C 3: sulfolane / 72 h / 50 °C / Inert atmosphere 4: hydrogenchloride; water / ethanol / 2 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 2 h / 100 °C 2: potassium carbonate / ethanol / 2 h / 60 °C 3: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1.1: methanol / 10 h / Reflux 2.1: dmap / tetrahydrofuran / 12 h / Reflux 2.2: 20 °C 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-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium iodide / sulfolane / 20 h / 110 °C 2: sulfolane / 72 h / 50 °C / Inert atmosphere 3: hydrogenchloride; water / ethanol / 2 h / 50 °C / Inert atmosphere View Scheme

4-[4-((R)-5-(iodomethyl)-2-oxo-oxazolidin-3-yl)phenyl]-morpholin-3-one (1252018-26-0) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfolane / 72 h / 50 °C / Inert atmosphere 2: hydrogenchloride; water / ethanol / 2 h / 50 °C / Inert atmosphere View Scheme

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-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 4 h / Reflux 2.1: methylamine / ethanol; water / 2 h / 65 °C 2.2: 65 °C / pH 2.7 View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / dichloromethane / 5 h / 20 °C 2.1: methylamine / methanol / 6 h / 25 °C / Reflux 2.2: 1 h / 25 - 30 °C / pH 2 - 3 View Scheme
Multi-step reaction with 2 steps 1.1: dichloromethane / 8 h / 25 - 30 °C 2.1: methylamine / water; methanol / 5 h / 25 - 65 °C 2.2: 0.5 h / 25 - 30 °C / pH 1 - 2 View Scheme
Multi-step reaction with 2 steps 1.1: dmap / tetrahydrofuran / 25 h / Reflux; Large scale 2.1: ethanol / 1 h / Reflux; Large scale 2.2: 50 - 60 °C / pH 2 - Ca. 3 / Large scale View Scheme

4-(4-aminophenyl)morpholin-3-one (438056-69-0) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethanol / 9 h / 80 °C 2.1: tetrahydrofuran / 4 h / Reflux 3.1: methylamine / ethanol; water / 2 h / 65 °C 3.2: 65 °C / pH 2.7 View Scheme
Multi-step reaction with 3 steps 1.1: isopropyl alcohol; water / Reflux 2.1: potassium carbonate / dichloromethane / 5 h / 20 °C 3.1: methylamine / methanol / 6 h / 25 °C / Reflux 3.2: 1 h / 25 - 30 °C / pH 2 - 3 View Scheme
Multi-step reaction with 3 steps 1: ethanol / 24 h / Reflux 2: dichloromethane / 44 h / 20 °C 3: hydrogenchloride / methanol / 1 h / 20 °C View Scheme

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-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With hydrogenchloride In methanol at 20℃; for 1h;	26.5 g

tert-butyl N-[(R)-2-hydroxy-3-{4-(3-oxomorpholin-4-yl)phenylamino}propyl]carbamate (1429333-95-8) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 44 h / 20 °C 2: hydrogenchloride / methanol / 1 h / 20 °C View Scheme

[4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester (1313613-18-1) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium tert-butoxide / N,N-dimethyl-formamide; methanol / 18 h / 0 - 25 °C 2: hydrogenchloride / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: lithium tert-butoxide / tetrahydrofuran / 48 h / 0 - 25 °C 2: hydrogenchloride / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: lithium tert-butoxide / N,N-dimethyl-formamide; tetrahydrofuran / 44 h / 20 °C / Cooling with ice 2: hydrogenchloride / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: lithium tert-butoxide; lithium chloride / tetrahydrofuran / 4 h / 50 °C / Inert atmosphere 2: hydrogenchloride / water / 0.75 h / 0 - 15 °C / pH 2 View Scheme

2-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With methylamine In dichloromethane; water at 20 - 45℃; for 15h; Solvent;	58 g

para-nitrophenyl bromide (586-78-7) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetonitrile / 18 h / 60 °C 1.2: 2 h / 60 °C 2.1: iron; acetic acid / acetonitrile / 3 h / 30 °C 3.1: ethanol / 12 h / Reflux 4.1: N,N-dimethyl-formamide / 2 h / 100 °C 5.1: potassium carbonate / ethanol / 2 h / 60 °C 6.1: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme

4-{4-[(5R)-5-(chloromethyl)-2-oxo-1,3-oxazole-3-yl]phenyl}morpholin-3-one → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 2 h / 60 °C 2: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme

4-chlorobenzonitrile (100-00-5) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetonitrile / 6 h / 60 °C 1.2: 2 h / 60 °C 2.1: iron; acetic acid / acetonitrile / 3 h / 30 °C 3.1: ethanol / 12 h / Reflux 4.1: N,N-dimethyl-formamide / 2 h / 100 °C 5.1: potassium carbonate / ethanol / 2 h / 60 °C 6.1: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme

4-(4-nitrophenyl)-3-morpholinone (446292-04-2) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: iron; acetic acid / acetonitrile / 3 h / 30 °C 2: ethanol / 12 h / Reflux 3: N,N-dimethyl-formamide / 2 h / 100 °C 4: potassium carbonate / ethanol / 2 h / 60 °C 5: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme

4-Fluoronitrobenzene (350-46-9) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetonitrile / 18 h / 60 °C 1.2: 2 h / 60 °C 2.1: iron; acetic acid / acetonitrile / 3 h / 30 °C 3.1: ethanol / 12 h / Reflux 4.1: N,N-dimethyl-formamide / 2 h / 100 °C 5.1: potassium carbonate / ethanol / 2 h / 60 °C 6.1: hydrogenchloride / ethanol / 2 h / 55 °C View Scheme

ethyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: lithium tert-butoxide / dichloromethane / 0.5 h / 5 - 20 °C / Reflux; Large scale 1.2: 12 h / Large scale 2.1: hydrogenchloride / water; ethanol / 1.5 h / 20 °C / pH 2 - 3 / Large scale View Scheme

4-{4-[(R)-5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
With hydrogenchloride In ethanol; water at 20℃; for 1.5h; pH=2 - 3; Large scale;	1.45 kg

1,4-phenylenediamine (106-50-3) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: pyridine / tetrahydrofuran / 5 h / 10 - 20 °C 2.1: tetrabutylammomium bromide; potassium carbonate / dichloromethane / 5 h / 0 - 20 °C 3.1: isopropyl alcohol / 17 h / Reflux 4.1: methanol / 10 h / Reflux 5.1: dmap / tetrahydrofuran / 12 h / Reflux 5.2: 20 °C View Scheme

N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrabutylammomium bromide; potassium carbonate / dichloromethane / 5 h / 0 - 20 °C 2.1: isopropyl alcohol / 17 h / Reflux 3.1: methanol / 10 h / Reflux 4.1: dmap / tetrahydrofuran / 12 h / Reflux 4.2: 20 °C View Scheme

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

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 7 h / 0 - 5 °C 2.1: methylamine / ethanol; water / 8 h / 40 - 60 °C 2.2: 2 h / 15 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 7 h / 0 - 5 °C 2.1: methylamine / ethanol; water / 8 h / 40 - 60 °C 2.2: 15 °C / pH 1 - 2 View Scheme

methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (1252018-07-7) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium chloride; lithium hexamethyldisilazane / tetrahydrofuran / 12 h / 30 °C / Inert atmosphere 2: hydrogenchloride / water / 0.75 h / 0 - 15 °C / pH 2 View Scheme

4-bromo-aniline (106-40-1) → 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: copper(l) iodide; N,N`-dimethylethylenediamine; potassium carbonate / toluene / Inert atmosphere 2: sodium hydrogencarbonate / dichloromethane / 4 h / 25 °C 3: lithium tert-butoxide; lithium chloride / tetrahydrofuran / 4 h / 50 °C / Inert atmosphere 4: hydrogenchloride / water / 0.75 h / 0 - 15 °C / pH 2 View Scheme

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;

5-Chlorothiophene-2-carboxylic acid (24065-33-6) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
Stage #1: 5-Chlorothiophene-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one hydrochloride In N,N-dimethyl-formamide at 34℃; for 4h;	96.3%
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 2.83333h; Reagent/catalyst; Cooling with ice;	95.2%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h; pH=8 - 9; Large scale;	94.7%

5-chlorothiophene-2-carboxylic acid chloride (89166-94-9) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
With triethylamine In water; acetone; toluene at 30 - 35℃; for 2h; Temperature; Concentration;	93.3%

5-chlorothiophene-2-carbonyl chloride (42518-98-9) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
With sodium carbonate In water; acetone; toluene at 8 - 53℃;	93.12%
With sodium carbonate In water; acetone; toluene at 10 - 53℃; for 0.5h; High pressure;	90%
With potassium carbonate In dichloromethane at 25 - 30℃; for 5h;	88%

5-chlorothiophene-2-carbonyl chloride (42518-98-9) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → 5-chloro-N-({(5)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide (482306-32-1)

Conditions	Yield
With potassium carbonate In acetone for 2h; Heating;	85%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + 4-nitrophenyl 5-chlorothiophene-2-carboxylate (1450877-56-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
With triethylamine In dimethyl sulfoxide at 35 - 40℃; Reagent/catalyst; Solvent; Temperature;	82.7%
With triethylamine In dimethyl sulfoxide; acetonitrile at 35 - 40℃;	82.7%

4,5-dichlorothiophene-2-carbonyl chloride (89283-13-6) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → (S)-4,5-dichloro-N-[[2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]-2-thiophenecarboxamide

Conditions	Yield
With sodium carbonate In water; acetone at 20℃;	82.1%
With sodium carbonate In water; toluene at 8 - 20℃; for 2h;

formic acid (64-18-6) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide (1616563-62-2)

Conditions	Yield
Stage #1: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one hydrochloride With ammonia In dichloromethane for 0.25h; Stage #2: formic acid In water; toluene at 110 - 120℃;	80%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + 4-Fluoronitrobenzene (350-46-9) → (S)-4-(4-(5-(((4-nitrophenyl)amino)methyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one

Conditions	Yield
With potassium carbonate In ethyl acetate for 24h; Reflux;	75.4%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + 2-{2-[1-(5-chlorothiophen-2-yl)-N-{4-[(5S)-5-{[(5-chlorothiophen-2-yl)formamido]methyl}-2-oxo-1,3-oxazolidin-3-yl]phenyl}formamido]ethoxy}acetic acid (1151893-81-0) → 5-chloro-N-(4-((S)-5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)-N-(2-(2-oxo-2-((((S)-2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)amino)ethoxy)ethyl)thiophene-2-carboxamide

Conditions	Yield
Stage #1: 2-{2-[1-(5-chlorothiophen-2-yl)-N-{4-[(5S)-5-{[(5-chlorothiophen-2-yl)formamido]methyl}-2-oxo-1,3-oxazolidin-3-yl]phenyl}formamido]ethoxy}acetic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 20℃; Cooling with ice; Stage #2: With triethylamine In N,N-dimethyl-formamide at 10 - 20℃; Stage #3: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one hydrochloride In N,N-dimethyl-formamide at 30 - 35℃;	48.6%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 10h; Inert atmosphere;	42.6%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + bis(trichloromethyl) carbonate (32315-10-9) → C29H32N6O9

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 4h;	14%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + 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
With triethylamine In tetrahydrofuran at 0 - 20℃;	13.1%

4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) + 3-chlorothiophene-2-carbonyl chloride (86427-02-3) → Rivaroxaban (366789-02-8)

Conditions	Yield
Stage #1: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one hydrochloride With triethylamine In 1-methyl-pyrrolidin-2-one for 0.25h; Stage #2: 3-chlorothiophene-2-carbonyl chloride In 1-methyl-pyrrolidin-2-one at 10 - 82℃;

methyl 5-chloro-2-thiophenecarboxylate (35475-03-7) + 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (898543-06-1) → Rivaroxaban (366789-02-8)

Conditions	Yield
at 120℃; for 48h; Product distribution / selectivity; Inert atmosphere; Heating;

Upstream product

• 106-40-1 4-bromo-aniline 
• 1252018-07-7 methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate 
• 1414932-73-2 (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one 
• 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 
• 1372665-04-7 4-{4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one 
• 106-50-3 1,4-phenylenediamine 
• 446292-07-5 2-((2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione 
• 530-62-1 1,1'-carbonyldiimidazole 
• 1327778-39-1 ethyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate 
• 350-46-9 4-Fluoronitrobenzene 
• 446292-04-2 4-(4-nitrophenyl)-3-morpholinone 
• 100-00-5 4-chlorobenzonitrile 
• 586-78-7 para-nitrophenyl bromide 

Downstream Products

• 865479-71-6 5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 
• 482306-32-1 5-chloro-N-({(5)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide 
• 1770812-37-7 (S)-4,5-dichloro-N-[[2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]-2-thiophenecarboxamide 
• 1415566-28-7 N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 
• 1365267-35-1 N,N'-bis[{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl]urea 
• 1429334-00-8 (S)-N-[{3-(4-(3-oxomorpholin-4-yl)phenyl)-2-oxo-1,3-oxazolidin-5-yl}methyl]acetamide 
• 366789-02-8 Rivaroxaban 
• 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 
• 446292-10-0 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one 

Relevant articles and documents

Preparation of intermediates (by machine translation)

In the method of manufacturing a method of manufacturing problems [to] [ribarokisaban[ribarokisaban][ribarokisaban[ribarokisaban] which, in particular, intermediate compounds on an industrial scale manufacturing method is excellent in operability. [Solution] water-miscible organic solvent other than alcohols in, 2 - ({(5S) -2 - [4 - (3 - oxo--4 - morpholinyl) - phenyl] - 1, 3 - oxazolidine -3 - oxo -5 - yl} methyl) - 1, 3 (2H) dione is reacted with methylamine - 1H - isoindole, 2 layers separated from the solution 4 - {4 - [(aminomethyl) - 1, 3 - oxazolidine -3 - oxo (5S) -5 - -2 - yl] - phenyl} morpholine hydrochloride is precipitated on the production of -3 -, and method of manufacturing the compound [ribarokisaban[ribarokisaban]. Figure 4 [drawing] (by machine translation)

Preparation and application of key intermediate of rivaroxaban

The invention provides preparation and application of a key intermediate of rivaroxaban. Experiment conditions of a Gabriel method are optimized, and results show that a specific solvent is a key parameter which affects the purity and the yield of a rivaroxaban intermediate. The rivaroxaban prepared by the invention is high in yield and good in purity, and is capable of meeting quality standards of raw material medicines without recrystallization.

Preparation method of rivaroxaban intermediate

The invention discloses a preparation method of a Rivaroxaban intermediate. The preparation method includes the following steps that (1) in existence of an organic lithium salt or the organic lithiumsalt and an inorganic lithium salt, a compound in a following formula I is reacted with a compound in a following formula II to obtain a compound in a following formula III; and (2) the compound in the formula III is subjected to an acidification reaction in existence of inorganic acid HX, the Rivaroxaban intermediate shown in a following formula IV is obtained, wherein R in the compound in the formula I is selected from methyl, isopropyl, normal-butyl and phenyl or benzyl, and the inorganic acid HX is selected from hydrochloric acid or sulfuric acid. The preparation method is easy to operateand high in yield, and industrial production and patent medicine quality control are convenient.

Preparation method and use of rivaroxaban intermediate

The present invention relates to a preparation method of a rivaroxaban intermediate I. The method provided by the invention has the advantages of greatly shortening the reaction time, easy preparationby scale, simple operation, good stability, high purity, low environmental pollution and suitable for industrial production.

(S)- {1 - (chloromethane ester) - 2 - [2 - (1, 3 - two oxygen different indole) yl] ethyl} halide salt and its preparation method

The present invention discloses a compound (S)-{1-(chloroformate)-2-[2-(1,3-dioxo-isoindol)yl]ethyl}halogenation salt represented by a formula VI, and a preparation method thereof, wherein X represents a halogen. According to the present invention, the compound is used for preparing the rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban intermediate, and the obtained product is firstly obtained through the method in the present invention; and the preparation method is mature and reliable, and can be suitable for industrial large-scale production. The formula VI is defined in the specification.

4 - (4 - a ammonia alkenyl phenyl) - 3 - morpholone and its preparation method

The present invention discloses a compound 4-(4-methylamino alkenyl phenyl)-3-morpholinone represented by a formula III, and a preparation method thereof. According to the present invention, the compound is used for preparing the rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban intermediate, and the obtained product is firstly obtained through the method in the present invention; and the operation of the preparation method is simple, the yield is up to about 90%, and the product purity is good. The formula III is defined in the specification.

NOVEL MORPHOLINE DIPHOSPHATE SALT, AND METHOD FOR MANUFACTURING HIGH PURITY RIVAROXABAN USING SAME

The present invention relates to a method of producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide (hereinafter, andPrime;rivaroxabanandPrime;, chemical formula 1) with high purity in an economical and mass-producible manner by using novel 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one disphosphate salts (hereinafter, andPrime;morpholine disphosphate saltsandPrime;, chemical formula 2).COPYRIGHT KIPO 2017

A method for synthesizing [...] (by machine translation)

The invention discloses a method for synthesizing [...], from 4 - (4 - a ammonia alkenyl phenyl) - 3 - morpholone with (S)- {1 - (chloromethane ester) - 2 - [2 - (1, 3 - two oxygen different indole) yl] ethyl} halide salt to ring-closure reaction, to make the key intermediate (S)- 2 - {[2 - oxo - 3 - (4 - (3 - oxo-morpholine) phenyl) oxazolidine - 5 - yl] methyl} isoindole - 1, 3 - dione, then the key intermediate to remove the amino protecting base 4 - {4 - [(5 S) - 5 - (aminomethyl) - 2 - oxo - 1, 3 - oxazolidine - 3 - yl] phenyl} morpholine - 3 - one hydrochloride, with 2 - chloro formyl - 5 - [...][...] further reaction. This invention prepares mild condition, the process is simple, low cost, high yield, is suitable for industrial production. (by machine translation)

A method for the preparation of key intermediate the advantage cuts down Sha Ban

The invention relates to a preparation method of a rivaroxaban key intermediate, particularly a preparation method of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholone hydrochloride (compound 4), which comprises the following steps: reacting dibenzyl ammonia with R-epoxy chloropropane to obtain N,N-dibenzyl epoxypropane (compound 1), reacting the compound 1 with 4-(4-aminophenyl)morpholinyl-3-one to obtain a compound 2, reacting the compound 2 with N,N-carbonyl-diimidazole to obtain a compound 3, and catalyzing the compound 3 with palladium on carbon to obtain the 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholone hydrochloride.

A process for preparing 4 - (4 - aminophenyl) - 3 - morpholinon method (by machine translation)

The invention discloses a process for preparing 4 - (4 - aminophenyl) - 3 - morpholone (type IV) method, which belongs to the field of chemical synthesis. The specific method comprises: intermediate N - (4 - aminophenyl) - 2 - (2 - halo ethoxy) acetamide (type III) by the one-step cyclization reaction systems benefit cuts down Sha Ban key intermediate 4 - (4 - aminophenyl) - 3 - morpholone (type IV), wherein X represents halogen. The prepared 4 - (4 - aminophenyl) - 3 - morpholinon purity is good, the reaction yield is high, can be as high as 87% of the left and right, and the preparation process avoids the use of expensive metal palladium on nitro reduction, the operation is simple, and is suitable for industrial production. (by machine translation)