168828-84-0

Usage

Uses

Used in Pharmaceutical Industry:
(R)-5-(Azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone is used as an impurity in the production of Linezolid (L466500), an antimycobacterial agent. It plays a role in the synthesis process of Linezolid, contributing to its overall effectiveness as a medication.
Additionally, it is referred to as Linezolid USP Related Compound A, indicating its relevance in the United States Pharmacopeia (USP) standards for the quality and purity of pharmaceutical products. This highlights the importance of understanding and controlling the presence of impurities like (R)-5-(Azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone in the manufacturing process to ensure the safety and efficacy of Linezolid as an antimycobacterial treatment.

InChI:InChI=1/C14H17FN5O3/c1-18(17-16)12-9-20(14(21)23-12)11-4-2-3-10(15)13(11)19-5-7-22-8-6-19/h2-4,12H,5-9H2,1H3/q+1/t12-/m1/s1

Synthetic route

(R)-methyl methanesulfonate (174649-09-3) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 85℃;	97.23%
With sodium azide In N,N-dimethyl-formamide at 60℃; Reflux;	95%
With sodium azide In tetrahydrofuran; water for 8h; Reflux;	93%

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

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

(R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl 4-methylbenzenesulfonate (168828-83-9) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 80 - 85℃; for 4h;	90%

(5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 85℃; for 12h;	87%
With sodium azide In N,N-dimethyl-formamide at 85℃; for 12h;	86%

(R)-5-azidomethyl-1,3-oxazolidin-2-one (677726-40-8) + 4-(2-fluoro-4-bromophenyl)morpholine (513068-89-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With copper(l) iodide; potassium carbonate; rac-diaminocyclohexane In 1,4-dioxane at 110℃; for 23h;	84%

(S)-3-azido-1-chloropropan-2-yl 3-fluoro-4-morpholinophenylcarbamate (1373348-81-2) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With potassium carbonate In acetone at 20℃; for 8h;	83%

(R)-5-azidomethyl-1,3-oxazolidin-2-one (677726-40-8) + 4-(2-fluoro-4-iodophenyl)morpholine (1250999-09-7) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With trans-1,2-Diaminocyclohexane; potassium carbonate; copper(l) chloride In 1,4-dioxane at 110℃; for 15h; Inert atmosphere; Darkness;	82%
With potassium carbonate; trans-1,2-Diaminocyclohexane; copper(l) chloride In 1,4-dioxane at 110℃; for 15h; Inert atmosphere; Darkness; Sealed vessel;	82%

(S)-3-azido-1-chloropropan-2-yl chloroformate (1373348-78-7) + 3-fluoro-4-(morpholinyl)aniline (93246-53-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With potassium carbonate In acetone at 20℃;	82%

(R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol (168828-82-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Stage #1: (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; Stage #2: With sodium azide In N,N-dimethyl-formamide at 80℃; Further stages.;	79%
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 4 h / 0 °C 2: NaN3 / dimethylformamide / 75 °C View Scheme
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 2 h / 20 °C 2: sodium azide / dimethylformamide / 6 h / 65 °C View Scheme

(R)-N-(3-fluoro-4-morpholinylphenyl)oxiranylmethyl carbamic acid ethyl ester (1223581-08-5) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With sodium azide; ammonium chloride In methanol; water at 80 - 85℃; for 4h;	76%

3-chloro-2-((phenoxycarbonyl)oxy)propyl azide (881012-11-9) + 3-fluoro-4-(morpholinyl)aniline (93246-53-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;

3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-1-ol → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: aq. NaHCO3 / acetone 2.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 3.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 3.2: NaBH4 / methanol 3.3: 86 percent / CuSO4 / methanol 4.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 5.1: Et3N / CH2Cl2 / 4 h / 0 °C 6.1: NaN3 / dimethylformamide / 75 °C View Scheme

(3-fluoro-4-morpholin-4-yl-phenyl)-(3-oxo-propyl)-carbamic acid benzyl ester (912552-55-7) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

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

(3-fluoro-4-morpholin-4-yl-phenyl)-(3-hydroxy-propyl)-carbamic acid benzyl ester (912552-54-6) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 2.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 2.2: NaBH4 / methanol 2.3: 86 percent / CuSO4 / methanol 3.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 4.1: Et3N / CH2Cl2 / 4 h / 0 °C 5.1: NaN3 / dimethylformamide / 75 °C View Scheme

((S)-2,3-Dihydroxy-propyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (912552-56-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

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

3-fluoro-4-(morpholinyl)aniline (93246-53-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: NaI; Na2CO3 / dimethylformamide / 65 °C 2.1: aq. NaHCO3 / acetone 3.1: 95 percent / (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - -60 °C 4.1: nitrosobenzene; D-proline / acetonitrile / 24 h / -20 °C 4.2: NaBH4 / methanol 4.3: 86 percent / CuSO4 / methanol 5.1: 96 percent / sodium hydride / tetrahydrofuran / 0 °C 6.1: Et3N / CH2Cl2 / 4 h / 0 °C 7.1: NaN3 / dimethylformamide / 75 °C View Scheme
Multi-step reaction with 3 steps 1: Et3N / tetrahydrofuran / 2 h / 20 °C 2: sodium azide / dimethylformamide / 6 h / 65 °C View Scheme
Multi-step reaction with 4 steps 1: 70 percent / sodium bicarbonate / acetone; H2O 2: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 3: 35.423 g / triethylamine / CH2Cl2 / 20 h 4: sodium azide / dimethylformamide / 16 h / 75 °C View Scheme

3,4-difluoronitrobenzene (369-34-6) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: N,N-diisopropylethylamine / acetonitrile / 17 h / Heating 2: H2 / PtO2 / methanol / 3 h / 20 °C / 1471.02 Torr 3: Et3N / tetrahydrofuran / 2 h / 20 °C 4: sodium azide / dimethylformamide / 6 h / 65 °C View Scheme
Multi-step reaction with 6 steps 1: 98 percent / N,N-diisopropylethylamine / ethyl acetate 2: ammonium formate / 10percent Pd/C 3: 70 percent / sodium bicarbonate / acetone; H2O 4: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 5: 35.423 g / triethylamine / CH2Cl2 / 20 h 6: sodium azide / dimethylformamide / 16 h / 75 °C View Scheme
Multi-step reaction with 6 steps 1.1: methanol / 25 - 30 °C 2.1: hydrogen / palladium 10% on activated carbon / methanol / 20 - 30 °C / Autoclave 3.1: sodium carbonate / toluene; acetone / 0 - 5 °C 4.1: butan-1-ol; n-butyllithium / hexane; tetrahydrofuran / -15 - 30 °C / Inert atmosphere 4.2: -10 - 15 °C 5.1: triethylamine / dichloromethane / 20 - 30 °C 6.1: sodium azide / N,N-dimethyl-formamide / 60 °C / Reflux View Scheme

3-fluoro-4-(4-morpholinyl)nitrobenzene (2689-39-6) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2 / PtO2 / methanol / 3 h / 20 °C / 1471.02 Torr 2: Et3N / tetrahydrofuran / 2 h / 20 °C 3: sodium azide / dimethylformamide / 6 h / 65 °C View Scheme
Multi-step reaction with 5 steps 1: ammonium formate / 10percent Pd/C 2: 70 percent / sodium bicarbonate / acetone; H2O 3: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 4: 35.423 g / triethylamine / CH2Cl2 / 20 h 5: sodium azide / dimethylformamide / 16 h / 75 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogen / palladium 10% on activated carbon / methanol / 20 - 30 °C / Autoclave 2.1: sodium carbonate / toluene; acetone / 0 - 5 °C 3.1: butan-1-ol; n-butyllithium / hexane; tetrahydrofuran / -15 - 30 °C / Inert atmosphere 3.2: -10 - 15 °C 4.1: triethylamine / dichloromethane / 20 - 30 °C 5.1: sodium azide / N,N-dimethyl-formamide / 60 °C / Reflux View Scheme

(5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-carbaldehyde-2-oxazolidinone → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBH4 / methanol / 0 °C 2: Et3N 3: NaN3 / dimethylsulfoxide / 80 °C View Scheme

(R)-2-(3-Fluoro-4-morpholin-4-yl-phenylamino)-1-{(4R,5R)-5-[(R)-2-(3-fluoro-4-morpholin-4-yl-phenylamino)-1-hydroxy-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-ethanol (905945-96-2) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: CH2Cl2 / Ambient temperature 2: 2N HCl / Ambient temperature 3: lead tetraacetate (LTA) / tetrahydrofuran / 0 °C 4: NaBH4 / methanol / 0 °C 5: Et3N 6: NaN3 / dimethylsulfoxide / 80 °C View Scheme

C28H32F2N4O8 (239438-43-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: lead tetraacetate (LTA) / tetrahydrofuran / 0 °C 2: NaBH4 / methanol / 0 °C 3: Et3N 4: NaN3 / dimethylsulfoxide / 80 °C View Scheme

C31H36F2N4O8 (239438-39-2) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 2N HCl / Ambient temperature 2: lead tetraacetate (LTA) / tetrahydrofuran / 0 °C 3: NaBH4 / methanol / 0 °C 4: Et3N 5: NaN3 / dimethylsulfoxide / 80 °C View Scheme

benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate (168828-81-7, 1027135-00-7) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) n-butyllithium / 1.) THF, hexane, -78 deg C, 35 min, 2.) THF, hexane, -78 deg C, 1 h 2: 35.423 g / triethylamine / CH2Cl2 / 20 h 3: sodium azide / dimethylformamide / 16 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: butan-1-ol; n-butyllithium / hexane; tetrahydrofuran / -15 - 30 °C / Inert atmosphere 1.2: -10 - 15 °C 2.1: triethylamine / dichloromethane / 20 - 30 °C 3.1: sodium azide / N,N-dimethyl-formamide / 60 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C 1.3: 0.17 h / 20 °C 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / -78 °C 1.2: -78 - 20 °C 2.1: triethylamine / dichloromethane 3.1: sodium azide / N,N-dimethyl-formamide / 70 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / -30 - -20 °C 1.2: -30 - 50 °C 2.1: triethylamine / dichloromethane / 0 - 5 °C 3.1: sodium azide / N,N-dimethyl-formamide / 2 h / 25 - 85 °C View Scheme

C8H10FNO3S (1201594-21-9) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bis(1,5-cyclooctadiene)nickel(0); sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere 2.1: N-iodo-succinimide; trifluoroacetic acid / 14 h / 23 °C / Inert atmosphere 2.2: 23 °C 3.1: trans-1,2-Diaminocyclohexane; potassium carbonate; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness View Scheme
Multi-step reaction with 3 steps 1: sodium t-butanolate / bis(1,5-cyclooctadiene)nickel (0); 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere; Sealed vessel 2: trifluoroacetic acid; N-iodo-succinimide / 14 h / 23 °C / Inert atmosphere; Sealed vessel 3: potassium carbonate / trans-1,2-Diaminocyclohexane; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness; Sealed vessel View Scheme

phenyl N,N-dimethylsulfamate (66950-63-8) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: Inert atmosphere 2.1: bis(1,5-cyclooctadiene)nickel(0); sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere 3.1: N-iodo-succinimide; trifluoroacetic acid / 14 h / 23 °C / Inert atmosphere 3.2: 23 °C 4.1: trans-1,2-Diaminocyclohexane; potassium carbonate; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness View Scheme

N-(2-fluorophenyl)-morpholine → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-iodo-succinimide; trifluoroacetic acid / 14 h / 23 °C / Inert atmosphere 1.2: 23 °C 2.1: trans-1,2-Diaminocyclohexane; potassium carbonate; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid; N-iodo-succinimide / 14 h / 23 °C / Inert atmosphere; Sealed vessel 2: potassium carbonate / trans-1,2-Diaminocyclohexane; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness; Sealed vessel View Scheme

phenol (108-95-2) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: Inert atmosphere 2.1: Inert atmosphere 3.1: bis(1,5-cyclooctadiene)nickel(0); sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere 4.1: N-iodo-succinimide; trifluoroacetic acid / 14 h / 23 °C / Inert atmosphere 4.2: 23 °C 5.1: trans-1,2-Diaminocyclohexane; potassium carbonate; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness View Scheme

N-ethoxycarbonyl-3-fluoro-4-morpholinyl aniline (565176-83-2) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C 1.3: 0.5 h / 20 °C 2.1: triethylamine / dichloromethane / 18 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 4 h / 80 - 85 °C View Scheme

2-fluorophenol (367-12-4) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions

Yield

Multi-step reaction with 4 steps 1: sodium hydride / 1,2-dimethoxyethane; mineral oil / 15 h / 23 °C / Inert atmosphere 2: sodium t-butanolate / bis(1,5-cyclooctadiene)nickel (0); 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere 3: trifluoroacetic acid; N-iodo-succinimide / 14 h / 23 °C / Inert atmosphere; Sealed vessel 4: potassium carbonate / trans-1,2-Diaminocyclohexane; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness; Sealed vessel View Scheme

2-fluorophenyl diethylcarbamate (459408-52-7) → (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0)

Conditions

Yield

Multi-step reaction with 3 steps 1: sodium t-butanolate / bis(1,5-cyclooctadiene)nickel (0); 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride / 1,4-dioxane / 3 h / 80 °C / Inert atmosphere 2: trifluoroacetic acid; N-iodo-succinimide / 14 h / 23 °C / Inert atmosphere; Sealed vessel 3: potassium carbonate / trans-1,2-Diaminocyclohexane; copper(l) chloride / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere; Darkness; Sealed vessel View Scheme

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

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

(R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) + thioacetic acid (507-09-5) → linezolid (165800-03-3)

Conditions	Yield
Stage #1: (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one; tiolacetic acid at 23℃; for 7h; Stage #2: With potassium hydroxide In water at 23℃;	90%
at 23℃; for 7h; Inert atmosphere;	90%
Ambient temperature;	86%
at 20℃; for 15h;	85%
at 20℃; for 15h;

C33H52N2O10 + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C48H70FN7O13

Conditions	Yield
With copper(l) iodide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 4h;	86%

acetic anhydride (108-24-7) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → linezolid (165800-03-3)

Conditions	Yield
With palladium on activated charcoal; hydrogen In methanol at 20℃; under 1034.32 Torr; for 3h;	85%
With hydrogen; palladium 10% on activated carbon In dichloromethane under 1103.36 Torr; for 6h;	80%
Stage #1: acetic anhydride; (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one With hydrogen; acetic acid; palladium 10% on activated carbon In ethyl acetate at 25 - 35℃; under 1551.49 Torr; for 3h; Stage #2: With sodium carbonate In water; ethyl acetate for 0.166667h; Product distribution / selectivity;	78%

ethylenesulfonyl fluoride (677-25-8) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → PH-027

Conditions	Yield
In ethyl acetate at 100℃; for 16h; Sealed tube;	85%

C40H69NO13 (677726-20-4) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C54H85FN6O16

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 2h;	80%

N-(3,6,9,12-tetraoxapentadec-14-ynyl)-2,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-isoindol (1308299-12-8) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → (R)-1-(1-(1-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2,5,8,11-tetraoxatridecan-13-yl)-2,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methanoisoindole (1309042-01-0)

Conditions	Yield
With copper(l) iodide; triethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere;	75%

(R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) + acetylene (74-86-2) → PH-027

Conditions	Yield
In 1,2-dimethoxyethane at 90℃; for 12h;	74%

dimethyl acetylenedicarboxylate (762-42-5) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → 1-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester (503026-28-6)

Conditions	Yield
In 1,2-dimethoxyethane at 90℃; for 24h;	73%

3-butyn-1-yl p-toluenesulfonate (23418-85-1) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C25H28FN5O6S (677726-23-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 2h;	63%

methyl ethynyl ketone (1423-60-5) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → (R)-5-(5-Acetyl-[1,2,3]triazol-1-ylmethyl)-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one + (R)-5-(4-Acetyl-[1,2,3]triazol-1-ylmethyl)-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (503026-25-3)

Conditions	Yield
In 1,2-dimethoxyethane at 90℃; for 24h;	A 5% B 62%

C33H57NO10 (677726-42-0) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C47H73FN6O13

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 15h;	56%

3,6,9,12-tetraoxapentadec-14-yn-1-ol (87450-10-0) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → (R)-3-(3-fluoro-4-morpholinophenyl)-5-((4-(13-hydroxy-2,5,8,11-tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (1308299-13-9)

Conditions	Yield
With copper(l) iodide; triethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere;	54%

2-(N-methyl-N-prop-2-yn-1-ylamino)ethanol (13105-72-1) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C20H27FN6O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 16h;	50.6%

C43H78N2O12 (677727-50-3) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C57H94FN7O15

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 4h;	50%

C42H74N2O12 + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C56H90FN7O15

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 4h;	50%

C42H76N2O13 (677727-53-6) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C56H92FN7O16

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 4h;	50%

pent-1-yn-5-ol (5390-04-5) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C19H24FN5O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; copper(l) iodide In tetrahydrofuran at 20℃; for 16h;	48.7%

1,11-bis(2-propyn-1-oxy)-3,6,9-trioxaundecane (159428-42-9) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → C42H54F2N10O11 (1308299-19-5)

Conditions	Yield
With copper(l) iodide; triethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere;	47%

4-amino-1-(3,6,9,12-tetraoxapentadec-14-ynyl)pyrimidin-2(1H)-one (1308299-10-6) + (R)-5-azidomethyl-3-(3-fluoro-4-(morpholin-4-yl)phenyl)oxazolidin-2-one (168828-84-0) → (R)-5-((4-(13-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,5,8,11-tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (1308299-15-1)

Conditions	Yield
With copper(l) iodide; triethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere;	46%

Upstream product

• 168828-90-8 (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine 
• 105-58-8 Diethyl carbonate 
• 530-62-1 1,1'-carbonyldiimidazole 
• 224323-51-7 3-fluoro-4-(morpholin-4-yl)-phenyl isocyanate 
• 459408-52-7 2-fluorophenyl diethylcarbamate 
• 367-12-4 2-fluorophenol 
• 1373348-81-2 (S)-3-azido-1-chloropropan-2-yl 3-fluoro-4-morpholinophenylcarbamate 
• 1373348-78-7 (S)-3-azido-1-chloropropan-2-yl chloroformate 
• 93246-53-8 3-fluoro-4-(morpholinyl)aniline 
• 565176-83-2 N-ethoxycarbonyl-3-fluoro-4-morpholinyl aniline 
• 168828-83-9 (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl 4-methylbenzenesulfonate 
• 108-95-2 phenol 
• 66950-63-8 phenyl N,N-dimethylsulfamate 
• 1201594-21-9 C₈H₁₀FNO₃S 

Downstream Products

• 677726-23-7 C₂₅H₂₈FN₅O₆S 
• 912359-80-9 (S)-[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]aminomethane 
• 1430414-17-7 C₂₀H₁₉F₄N₃O₅S 
• 1430414-18-8 C₂₀H₂₀F₃N₃O₅S 
• 1430414-06-4 C₂₀H₂₁ClFN₃O₅S 
• 1430414-16-6 C₂₀H₂₀Cl₂FN₃O₅S 
• 1430414-15-5 C₂₀H₂₀ClF₂N₃O₅S 
• 1430414-14-4 C₁₈H₂₀FN₃O₅S₂ 
• 1430414-13-3 C₂₁H₂₁F₄N₃O₅S 
• 1430414-12-2 C₂₄H₂₄FN₃O₇S₃ 
• 1430414-11-1 C₂₃H₂₃FN₄O₅S 
• 1430414-10-0 C₂₀H₂₄FN₅O₆S₂ 
• 1430414-09-7 C₂₆H₂₆FN₃O₆S 
• 1430414-08-6 C₂₀H₂₀ClF₂N₃O₅S 

Relevant academic research and scientific papers

Synthesis of covalent bonding MWCNT-oligoethylene linezolid conjugates and their antibacterial activity against bacterial strains

Nowadays, infectious diseases caused by drug-resistant bacteria have become especially important. Linezolid is an antibacterial drug active against clinically important Gram positive strains; however, resistance showed by these bacteria has been reported. Nanotechnology has improved a broad area of science, such as medicine, developing new drug delivery and transport systems. In this work, several covalently bounded conjugated nanomaterials were synthesized from multiwalled carbon nanotubes (MWCNTs), a different length oligoethylene chain (Sn), and two linezolid precursors (4and7), and they were evaluated in antibacterial assays. Interestingly, due to the intrinsic antibacterial activity of the amino-oligoethylene linezolid analogues, these conjugated nanomaterials showed significant antibacterial activity against various tested bacterial strains in a radial diffusion assay and microdilution method, including Gram negative strains asEscherichia coli(11 mm, 6.25 μg mL?1) andSalmonella typhi(14 mm, ≤0.78 μg mL?1), which are not inhibited by linezolid. The results show a significant effect of the oligoethylene chain length over the antibacterial activity. Molecular docking of amino-oligoethylene linezolid analogs shows a more favorable interaction of theS2-7analog in the PTC ofE. coli.

Modular click chemistry libraries for functional screens using a diazotizing reagent

Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties1. Copper(i)-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur(vi) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions2–4, providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups5. The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide6–11 (FSO2N3), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science.

PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF LINEZOLID AND ITS COMPOSITIONS

The present invention relates to a process for the preparation of crystalline form I of linezolid, comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature. The present invention also relates to the use of crystalline form I of linezolid prepared by the method of the present invention for preparing pharmaceutical compositions.

PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES

A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.

Novel promising linezolid analogues: Rational design, synthesis and biological evaluation

A new series of 5-substituted oxazolidinones derived from linezolid, having urea and thiourea moieties at the C-5 side chain of the oxazolidinone ring, were prepared and their in vitro antibacterial activity was evaluated. The compound 10f demonstrated high antimicrobial activity, comparable to that of linezolid against Staphylococcus aureus.

A facile solvent-free synthesis of chiral oxazolidinone derivatives catalyzed by MgI2 etherate: An approach to enantiopure synthesis of linezolid

A highly efficient and stereoselective cycloaddition of aryl isocyanates with chiral oxiranes catalyzed by MgI2 etherate under solvent-free conditions was developed to prepare the chiral oxazolidinone derivatives. This methodology has been applied into the practical synthesis of antibacterial drug linezolid.

AMINATION OF ARYL ALCOHOL DERIVATIVES

Embodiments of the invention provide methods and materials for chemical cross-coupling reactions that utilize aryl alcohol derivatives as cross-coupling partners. Embodiments of the invention include methods for the amination of aryl sulfamates and carbamates, which are attractive cross-coupling partners, particularly for use in multistep synthesis. Illustrative embodiments include versatile means to use simple derivatives of phenol as precursors to polysubstituted aryl amines, as exemplified by a concise synthesis of the antibacterial drug linezolid.

An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: A short and efficient synthesis of Linezolid

A short, concise and efficient synthesis of Linezolid was accomplished through a convergent scheme utilizing either (S)-1-azido-3-chloropropan-2-yl chloroformate or (S)-1- phthalimido-3- chloropropan-2-yl chloroformate as a key starting material. The synthesis demonstrates utility of (S)-1-azido-3- chloropropan-2-yl chloroformate and/or (S)-1-phthalimido-3-chloropropan-2-yl chloroformate to facilitate the expeditious construction of 3-aryl-5- (substituted methyl)-2- oxazolidinones and offers the possibility of accessing related 2-oxazolidinone members easily as well as making additional analogues of Linezolid. ARKAT-USA, Inc.

PROCESS FOR THE PREPARATION OF LINEZOLID

The present invention provides an improved process for the preparation of Linezolid of formula (D. The present invention relates to preparation of intermediate (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl |-2-oxo-5-oxazolidinyl] methanol of formula (II), Linezolid amine of formula (Ia) and their use in the preparation of Linezolid. The present invention further provides process for the preparation of Form I of Linezolid of formula (I).

PROCESSES FOR THE PREPARATION OF LINEZOLID

Disclosed herein a process for preparing linezolid, wherein the resultant linezolide is devoid of impurities and involve easy and economical process. The present invention further relates to preparation of linezolid by employing an azide intermediate and process for said intermediate.