856866-72-3

Usage

Novel antibacterial drugs

Tedizolid belongs to the second generation oxazolidinone antibiotics, being an analog of linezolid as well as a kind of protein synthesis inhibitors, acting on the bacterial ribosomal 50S subunit and causing inhibition of bacterial protein synthesis. Compared with linezolid, the efficacy of the two is basically the same, but linezolid required to be taken for 2 times a day and for 10 continuous days while Tedizolid only takes 1 time daily and continuous taking for 6 days. On June 20, 2014, the US FDA had approved a new antimicrobial drug Tedizolid (trade name: Sivextro) for the treatment of skin infections in adult patients. Sivextro is approved for the treatment of acute bacterial skin and skin infections caused by certain sensitive bacteria such as Staphylococcus aureus (including methicillin-resistant strains and methicillin-sensitive strains), various streptococci and Enterococcus faecalis (ABSSSI). Sivextro is administered intravenously and orally. Tedizolid phosphate is a second-generation oxazolidinone antibiotic developed by Dong-A Pharmaceutical, licensed to Cubist Pharmaceuticals and Bayer for commercial development. Sivextro is designed for the treatment of serious or life-threatening infections, and its listing applications are eligible for Qualified Infectious Disease Products (QIDP) and have obtained the approve of FDA for accelerated review. Sivextro's QIDP eligibility gives the drug exclusive five-year market exclusivity, in addition to its market exclusivity under the Food, Drug, and Cosmetic Act. The safety and efficacy of Sivextro were evaluated in two clinical trials involving 1315 ABSSSI adult patients. Subjects were randomized to Sivextro or another antibiotic linezolid approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). The results showed that its clinical efficacy is equivalent to linezolid. However, it will cause less gastrointestinal adverse reactions and thrombocytopenia adverse reactions than linezolid. The incidence of drug resistance is also lower. Tedizolid has been shown to be more tolerant than vancomycin. The most common side effects identified in clinical trials include nausea, headache, diarrhea, vomiting and dizziness. The safety and efficacy of Sivextro have not been evaluated in patients with reduced white blood cell levels (neutropenia), so alternative therapies should be considered for these patients. Sivextro is marketed by Cubist Pharmaceuticals, Inc., based in Lexington, Massachusetts. Status of intellectual property: Compound patent ZL200480037612.2, protection period 2024.12.17 expires. This information was edited by Xiao Nan from lookchem (2015-08-14).

Indications

Tedizolid phosphate is an oxazolidinone compound used in the treatment of acute bacterial skin and skin structure infections caused by the following gram-positive bacteria-sensitive strains: Staphylococcus aureus (including Methicillin-resistant and methicillin-susceptible strains), pyogenic streptococci, Streptococcus lactis, Streptococcus angustifolia (including Angina, Streptococcus intermedius and Streptococcus constellation), and Enterococcus faecalis.

State of Intellectual Property

(A) Administrative protection, new drug protection and new drug monitoring period On August 9, 2013, Bayer Pharmaceuticals has filed a new drug application with CFDA. (B) Domestic patent 1. Patented compounds East Asia Pharmaceutical has applied for the compound patent in China under the application number is ZL200480037612.2. The date of application is December 17, 2004; the protection period will expire at 2024.12.17. Three subsequent divisional applications were further filed with the application numbers being 201010508824.1 (preparation), 201110304983.4, 201210155386.4. On October 9, 2009, the Teresius Therapeutics Company has applied for a preparation method patent with the patent number of 200980140144.4. 2. Crystal patent On February 3, 2010, Teulius Therapeutics applied for a crystalline form patent of free acid with the application number of 201080014363.0. Form I of the disclosed free acid has the advantage that it is more stable than the disodium salt and has no moisture absorption. 3. Formulation Composition Patents The above-mentioned patent 200480037612.2 and its divisional application patent have disclosed the Tedizolid powder, tablet, capsule and injection. The above-mentioned patent 201080014363.0 have disclosed the prescription of Tedizolid tablets and freeze-dried preparations.

Biological Activity

tedizolid is an oxazolidinone antimicrobial agent with mic50 value of 0.5 μg/ml for mssa, mrsa, vr e. faecium and vr e. faecalis and 0.25 μg/ml for msse, mrse, pssp and prsp [1].the resistant gram-positive infection is a serious global health problem. for instant, the methicillin-resistant s. aureus (mrsa) has spread all over the world with rates ranging from 18 to 26 cases among 100,000 people. besides that, there come out a serious of resistant strains such as the linezolid-resistant s. aureus (lrsa) and the vancomycin-resistant s. aureus (vrsa). due to the unfavorable outcomes of the existed antibiotics, alternative treatments have been developed. tedizolid is a synthetic antibiotic that works based on the inhibition of protein synthesis. it binds to the 50s ribosome and inhibits the formation of the 70s complex [1].tedizolid showed potent bacteriostatic activity against many resistant gram-positive pathogens such as mssa, mrsa, s. pyogenes and s. pneumoniae. for the enterococcal and staphylococcal isolates, tedizolid displayed more than 4-fold higher potency than that of linezolid. it also showed inhibitory effects on a panel of 169 linezolid-resistant staphylococcal isolates with 79.2% inhibition at concentration of ≤ 4μg/ml. the mic values of tedizolid against linezolid-resistant staphylococci were in a range from 0.06 to 16 mg/l. besides that, tedizolid was found to be the inhibitors of human monoamine oxidase with ic50 values of 8.7 and 5.7 μm for mao-a and mao-b, respectively [1, 2 and 3].when treated in vivo, tedizolid was the active moiety converted from the pro-drug tedizolid phosphate. it was found that granulocytes could affect the antistaphylococcal effect of tedizolid. in neutropenic mice, the administration of tedizolid for 24 hours or 48 hours caused ed50 values of 25.2 and 35.7 mg/kg/day, respectively [1 and 4].

references

[1] kanafani z a, corey g r. tedizolid (tr-701): a new oxazolidinone with enhanced potency. expert opinion on investigational drugs, 2012, 21(4): 515-522.[2] rodríguez-avial i, culebras e, betriu c, et al. in vitro activity of tedizolid (tr-700) against linezolid-resistant staphylococci. journal of antimicrobial chemotherapy, 2012, 67(1): 167-169.[3] flanagan s, bartizal k, minassian s l, et al. in vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. antimicrobial agents and chemotherapy, 2013, 57(7): 3060-3066.[4] louie a, liu w, kulawy r, et al. in vivo pharmacodynamics of torezolid phosphate (tr-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant staphylococcus aureus strains in a mouse thigh infection model. antimicrobial agents and chemotherapy, 2011, 55(7): 3453-3460.

Synthetic route

C23H29FN6O3Si → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
With cesium fluoride In tetrahydrofuran at 20℃; for 1h;	99%

3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester (1220910-89-3) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert.-butyl lithium; (R)-glycidyl butyrate In tetrahydrofuran at 0 - 30℃; for 15h; Reagent/catalyst; Large scale;	95%

3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester (1220910-89-3) + (R)-glycidyl butyrate (60456-26-0) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Stage #1: 3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester With potassium tert-butylate; lithium tert-butoxide In tetrahydrofuran; acetonitrile at 25℃; for 2h; Inert atmosphere; Stage #2: (R)-glycidyl butyrate In tetrahydrofuran; acetonitrile for 3h;	86.7%
Stage #1: 3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1.41667h; Inert atmosphere; Stage #2: (R)-glycidyl butyrate With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at 20℃; for 15h; Inert atmosphere; cooling with ice;	85%
Stage #1: 3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester With lithium hexamethyldisilazane In tetrahydrofuran at 10 - 15℃; for 2h; Inert atmosphere; Large scale; Stage #2: (R)-glycidyl butyrate With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at 0 - 15℃; Inert atmosphere; Large scale;	84.4%

2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1056039-83-8) + (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (444335-16-4) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
With palladium diacetate; potassium carbonate; triphenylphosphine In 1,4-dioxane at 20℃; Reagent/catalyst; Solvent; Temperature; Reflux; Inert atmosphere;	84%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine In 1,4-dioxane; water for 4h; Reagent/catalyst; Solvent; Suzuki Coupling; Inert atmosphere; Reflux;	78%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 12h; Solvent; Reflux; Inert atmosphere;	63.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate Suzuki Coupling;
Stage #1: 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine; (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 60℃; for 5h; Suzuki Coupling; Inert atmosphere; Large scale; Stage #2: With L-Cysteine; triethylamine at 60℃; for 16h; Inert atmosphere; Darkness; Large scale;

(5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (444335-16-4) + 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (380380-64-3) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions

Yield

Stage #1: (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; bis(pinacol)diborane In dimethyl sulfoxide at 80℃; for 14h; Inert atmosphere; Stage #2: 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 70℃; for 3h; Inert atmosphere;

83%

(5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one (487041-08-7) + 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1056039-83-8) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
With palladium diacetate; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 6h; Catalytic behavior; Reagent/catalyst; Temperature; Suzuki Coupling; Sealed tube; Inert atmosphere; Green chemistry;	77.6%

(5R)-3-[3-fluoro-4-(tributylstannyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one + 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (380380-64-3) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; lithium chloride In N,N-dimethyl-formamide at 90℃; for 4h; Temperature; Reagent/catalyst;	48%
With lithium chloride; bis-triphenylphosphine-palladium(II) chloride In 1-methyl-pyrrolidin-2-one at 20 - 120℃; for 4h;	26%
With bis-triphenylphosphine-palladium(II) chloride; lithium chloride In 1-methyl-pyrrolidin-2-one at 120℃; for 4h; Stille coupling; Inert atmosphere;	26%
With bis-triphenylphosphine-palladium(II) chloride; lithium chloride at 120℃; for 4h;

2,5-dibromopyridine (624-28-2) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions

Yield

Multi-step reaction with 4 steps 1: sodium cyanide / N,N-dimethyl-formamide / 7 h / 150 °C / Inert atmosphere 2: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 3 h / 110 °C / Inert atmosphere 3: sodium hydroxide / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; lithium chloride / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C / Inert atmosphere View Scheme

2-Cyano-5-bromopyridine (97483-77-7) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 3 h / 110 °C / Inert atmosphere 2: sodium hydroxide / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3: bis-triphenylphosphine-palladium(II) chloride; lithium chloride / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C / Inert atmosphere View Scheme

meta-fluoroaniline (372-19-0) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran / 2 h / 0 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.17 h / -78 °C / Inert atmosphere 2.2: 26 h / -78 - 20 °C / Inert atmosphere 3.1: N-iodo-succinimide; trifluoroacetic acid / 3 h / 20 °C 4.1: potassium carbonate; palladium diacetate / N,N-dimethyl-formamide; water / 6 h / 90 °C / Sealed tube; Inert atmosphere; Green chemistry View Scheme
Multi-step reaction with 5 steps 1: ethanol / 12 h / Reflux 2: triethylamine / N,N-dimethyl-formamide / 4 h / 65 °C 3: trifluorormethanesulfonic acid; N-iodo-succinimide / dichloromethane / 2 h / 0 °C 4: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h 5: lithium chloride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 4 h / 90 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydrogencarbonate / dichloromethane / 20 - 25 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.17 h / -65 - -60 °C / Inert atmosphere 2.2: 20 h / -65 - 25 °C / Inert atmosphere 3.1: trifluoroacetic acid; N-iodo-succinimide / 0.17 h / 20 - 25 °C 3.2: 4 h / 20 - 25 °C 4.1: dmap / toluene / 7 h / 45 - 50 °C 5.1: tris-(o-tolyl)phosphine; potassium carbonate / dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere 5.2: 5.17 h / 20 - 85 °C / Inert atmosphere 6.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 7.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 7.2: 3 h / 20 - 25 °C View Scheme

N-(carbobenzyloxy)-3-fluoroaniline (149524-47-0) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.17 h / -78 °C / Inert atmosphere 1.2: 26 h / -78 - 20 °C / Inert atmosphere 2.1: N-iodo-succinimide; trifluoroacetic acid / 3 h / 20 °C 3.1: potassium carbonate; palladium diacetate / N,N-dimethyl-formamide; water / 6 h / 90 °C / Sealed tube; Inert atmosphere; Green chemistry View Scheme

(5R)-3-(3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (149524-42-5) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-iodo-succinimide; trifluoroacetic acid / 3 h / 20 °C 2: potassium carbonate; palladium diacetate / N,N-dimethyl-formamide; water / 6 h / 90 °C / Sealed tube; Inert atmosphere; Green chemistry View Scheme
Multi-step reaction with 3 steps 1: trifluorormethanesulfonic acid; N-iodo-succinimide / dichloromethane / 2 h / 0 °C 2: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h 3: lithium chloride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 4 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; N-iodo-succinimide / 0.17 h / 20 - 25 °C 1.2: 4 h / 20 - 25 °C 2.1: dmap / toluene / 7 h / 45 - 50 °C 3.1: tris-(o-tolyl)phosphine; potassium carbonate / dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere 3.2: 5.17 h / 20 - 85 °C / Inert atmosphere 4.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 5.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 5.2: 3 h / 20 - 25 °C View Scheme

5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (380380-64-3) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 2: potassium carbonate; palladium diacetate / N,N-dimethyl-formamide; water / 6 h / 90 °C / Sealed tube; Inert atmosphere; Green chemistry View Scheme
Multi-step reaction with 2 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate / tetrahydrofuran / 20 - 70 °C / Inert atmosphere; Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 2.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; potassium carbonate / 1,4-dioxane; water / 1 h / 70 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 2.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1.1: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 4 h / 70 °C / Inert atmosphere; Large scale 2.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane / 5 h / 60 °C / Inert atmosphere; Large scale 2.2: 16 h / 60 °C / Inert atmosphere; Darkness; Large scale View Scheme

(3-fluoro-phenyl)-carbamic acid methyl ester (72755-13-6) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.17 h / -65 - -60 °C / Inert atmosphere 1.2: 20 h / -65 - 25 °C / Inert atmosphere 2.1: trifluoroacetic acid; N-iodo-succinimide / 0.17 h / 20 - 25 °C 2.2: 4 h / 20 - 25 °C 3.1: dmap / toluene / 7 h / 45 - 50 °C 4.1: tris-(o-tolyl)phosphine; potassium carbonate / dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere 4.2: 5.17 h / 20 - 85 °C / Inert atmosphere 5.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 6.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 6.2: 3 h / 20 - 25 °C View Scheme

(5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one (487041-08-7) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: dmap / toluene / 7 h / 45 - 50 °C 2.1: tris-(o-tolyl)phosphine; potassium carbonate / dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere 2.2: 5.17 h / 20 - 85 °C / Inert atmosphere 3.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 4.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 4.2: 3 h / 20 - 25 °C View Scheme

tert-butyl [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl carbonate → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: tris-(o-tolyl)phosphine; potassium carbonate / dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere 1.2: 5.17 h / 20 - 85 °C / Inert atmosphere 2.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 3.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 3.2: 3 h / 20 - 25 °C View Scheme

tert-butyl {(5R)-3-[4-(6-cyanopyridin-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl carbonate → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 4 h / 95 - 100 °C / Inert atmosphere 2.1: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 5 h / 20 - 25 °C / Inert atmosphere 2.2: 3 h / 20 - 25 °C View Scheme

tert-butyl [(5R)-3-{3-fluoro-4-[6-(2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl carbonate → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Stage #1: tert-butyl [(5R)-3-{3-fluoro-4-[6-(2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl carbonate With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 20 - 25℃; for 5h; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane at 20 - 25℃; for 3h; Further stages;

(2R)-2-hydroxy-3-[(3-fluorophenyl)amino]propyl butanoate → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl-formamide / 4 h / 65 °C 2: trifluorormethanesulfonic acid; N-iodo-succinimide / dichloromethane / 2 h / 0 °C 3: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h 4: lithium chloride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 4 h / 90 °C View Scheme

(5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (444335-16-4) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / 6 h / 60 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 0.5 h 3.1: bis[2-(diphenylphosphino)phenyl] ether; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran; hexane / 12 h / 20 °C 4.1: cesium fluoride / tetrahydrofuran / 1 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / 6 h / 60 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 0.5 h 3.1: bis[2-(diphenylphosphino)phenyl] ether; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran; hexane / 12 h / 20 °C 4.1: cesium fluoride / tetrahydrofuran / 1 h / 20 °C View Scheme

(R)-3-(4-bromo-3-fluoro-phenyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-oxazolidin-2-one (1188330-70-2) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h 2.1: bis[2-(diphenylphosphino)phenyl] ether; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran; hexane / 12 h / 20 °C 3.1: cesium fluoride / tetrahydrofuran / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h 2.1: bis[2-(diphenylphosphino)phenyl] ether; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran; hexane / 12 h / 20 °C 3.1: cesium fluoride / tetrahydrofuran / 1 h / 20 °C View Scheme

C16H23ClFNO3SiZn → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: bis[2-(diphenylphosphino)phenyl] ether; bis(1,5-cyclooctadiene)nickel (0) / tetrahydrofuran; hexane / 12 h / 20 °C 2: cesium fluoride / tetrahydrofuran / 1 h / 20 °C View Scheme

2-fluoro-4-(benzyloxycarbonyl)aminophenylboronic acid (874290-59-2) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; potassium carbonate / 1,4-dioxane; water / 1 h / 70 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 2.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme

(4-bromo-3-fluorophenyl)carbamic acid benzyl ester (510729-01-8) → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 10 - 15 °C / Inert atmosphere 2.1: potassium phosphate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 35 - 85 °C / Inert atmosphere 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 3.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 3 steps 1.1: cobaltocene / tetrahydrofuran / 20 - 30 °C / Inert atmosphere; Large scale 2.1: tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate / tetrahydrofuran / 20 - 70 °C / Inert atmosphere; Large scale 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 3.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere; Cooling with acetone-dry ice 1.2: Inert atmosphere 2.1: tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; potassium carbonate / 1,4-dioxane; water / 1 h / 70 °C / Inert atmosphere 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 3.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme

C14H11BrFNO2Zn → (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate / tetrahydrofuran / 20 - 70 °C / Inert atmosphere; Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / 10 - 15 °C / Inert atmosphere; Large scale 2.2: 0 - 15 °C / Inert atmosphere; Large scale View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridine-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate

Conditions	Yield
With triethylamine; trichlorophosphate In tetrahydrofuran at 0℃; for 3h;	97%
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one With triethylamine; trichlorophosphate In tetrahydrofuran at 0 - 2.2℃; for 3.73333h; Stage #2: With water In tetrahydrofuran at 11.9℃; for 1h; cooling with ice/salt;	96%
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one With triethylamine In tetrahydrofuran at 0℃; Stage #2: With trichlorophosphate In tetrahydrofuran at 1 - 2℃; for 3h;	84.8%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + 4-(2,2-bis(diisopropoxyphosphoryl)ethyl)benzoic acid → (R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl 4-(2,2-bis(diisopropoxyphosphoryl)ethyl)benzoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	95%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + benzyl alcohol (100-51-6) → dibenzyl (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid

Conditions	Yield
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one With N-ethyl-N,N-diisopropylamine; trichlorophosphate In tetrahydrofuran at 0 - 20℃; for 4h; Stage #2: benzyl alcohol With N-ethyl-N,N-diisopropylamine at 0 - 20℃; for 8h;	84%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + dibenzyl N,N-diisopropylphosphoroamidate (124575-22-0) → dibenzyl (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid

Conditions	Yield
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one; dibenzyl N,N-diisopropylphosphoroamidate With 1H-tetrazole In dichloromethane at 25 - 30℃; for 0.5h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 5 - 10℃; for 0.5h;	83.1%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + methanesulfonyl chloride (124-63-0) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (856867-59-9)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 0.5h;	82%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	82%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate (990-91-0) → dibenzyl (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid

Conditions	Yield
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one With sodium hydride In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; Cooling with ice; Stage #2: dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate In tetrahydrofuran at 20℃; for 10h; Inert atmosphere;	82%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + tetraisopropyl (2-(4-(azidocarbonyl)phenyl)ethane-1,1-diyl)bis(phosphonate) → C38H50FN7O10P2

Conditions	Yield
With dmap In N,N-dimethyl-formamide at 80℃; for 3h;	81%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyloxazolidin-2-one

Conditions	Yield
With diethylamino-sulfur trifluoride; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere;	75%
With diethylamino-sulfur trifluoride; triethylamine In dichloromethane for 24h;

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + di-tert-butyl diisopropylphosphoramide (137348-86-8) → (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid di-tert-butyl ester

Conditions	Yield
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one; di-tert-butyl diisopropylphosphoramide With 1H-tetrazole In tetrahydrofuran; dichloromethane at 20℃; for 15h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran; dichloromethane at -78℃; for 4h;	71%
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one; di-tert-butyl diisopropylphosphoramide With 1H-tetrazole In tetrahydrofuran; dichloromethane at 20℃; for 15h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran; dichloromethane at -78℃; for 2h;	68%
Stage #1: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one; di-tert-butyl diisopropylphosphoramide With 1H-tetrazole In tetrahydrofuran; dichloromethane at 20 - 25℃; for 16h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran; dichloromethane at -70 - 25℃; for 2h;

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + isoxazol-3-ol (5777-20-8) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(isoxazol-3-yl)oxymethyloxazolidin-2-one (717116-80-8)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 12h; Mitsunobu reaction; Inert atmosphere;	51%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → C34H29F2N12O8P (1256966-02-5)

Conditions	Yield
With triethylamine; trichlorophosphate In tetrahydrofuran at 20 - 25℃; for 16h; Inert atmosphere;	20%

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) + BOC-glycine (4530-20-5) → C24H26FN7O6

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In DMF (N,N-dimethyl-formamide) at 20℃; for 10h;
With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere;

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodium phosphate

Conditions	Yield
Multi-step reaction with 2 steps 1: triethyl phosphate; trichlorophosphate / 2 h / 20 °C / Inert atmosphere 2: sodium methylate / methanol / 2 h / 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(methoxymethyl)oxazolidin-2-one

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: methanol / 24 h / 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(dimethylaminomethyl)oxazolidin-2-one

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 30 h / 60 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,4]triazol-1-yl)methyloxazolidin-2-one

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 48 h / 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-one (700370-32-7) + (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-2-yl)methyloxazolidin-2-one

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium hydride / N,N-dimethyl-formamide; mineral oil / 48 h / 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one (1293990-05-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one (1293990-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: 10% palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)-2-methoxyacetamide (1293990-07-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: 10% palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)furan-2-carboxamide (1293990-08-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: 10% palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)thiopene-2-carboxamide (1293990-09-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: 10% palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere View Scheme

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one (856866-72-3) → (S)-2-(benzyloxy)-N-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (1293990-10-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: 10% palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 4: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere View Scheme

Upstream product

• 487041-08-7 (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one 
• 1056039-83-8 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 
• 372-19-0 meta-fluoroaniline 
• 149524-47-0 N-(carbobenzyloxy)-3-fluoroaniline 
• 149524-42-5 (5R)-3-(3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one 
• 380380-64-3 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine 
• 444335-16-4 (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one 
• 510729-01-8 (4-bromo-3-fluorophenyl)carbamic acid benzyl ester 
• 874290-59-2 2-fluoro-4-(benzyloxycarbonyl)aminophenylboronic acid 
• 1188330-70-2 (R)-3-(4-bromo-3-fluoro-phenyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-oxazolidin-2-one 
• 1220910-89-3 3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester 
• 72755-13-6 (3-fluoro-phenyl)-carbamic acid methyl ester 
• 97483-77-7 2-Cyano-5-bromopyridine 
• 624-28-2 2,5-dibromopyridine 

Downstream Products

• 1835340-19-6 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridine-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 
• 1293990-05-2 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidin-2-one 
• 1293990-06-3 (S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidin-2-one 
• 1293990-07-4 (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)-2-methoxyacetamide 
• 1293990-08-5 (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)furan-2-carboxamide 
• 1293990-09-6 (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)thiopene-2-carboxamide 
• 1293990-10-9 (S)-2-(benzyloxy)-N-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide 
• 1293990-11-0 (S)-N-((3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)-2-hydroxyacetamide 

Relevant academic research and scientific papers

Refining process of tedizolid and preparation method of tedizolid phosphate

The invention belongs to the field of medicine synthesis, and discloses a refining process of tedizolid. According to the invention, a mixed solution of dichloromethane, toluene and ethanol is prepared, tedizolid generated through Suzuki reaction is purified through steps of liquid separation, filtration and the like, and the obtained tedizolid pure product is used for tedizolid phosphate synthesis. While the purity of tedizolid is ensured, the consumption of tedizolid in the refining process is reduced, the yield of tedizolid is improved, the utilization rate of raw materials is improved, the production cost is saved, the tedizolid with higher purity participates in synthesis of tedizolid phosphate, the side reaction in the tedizolid phosphate synthesis process is reduced, the purification difficulty of tedizolid phosphate is reduced, and the purity and the yield of tedizolid phosphate are improved. The method is suitable for refining tedizolid compounds, and is especially suitable for refining an intermediate tedizolid in a tedizolid phosphate synthesis process.

Purification method of tedizolid phosphate

The invention relates to the technical field of medicinal chemistry, in particular to a purification method of tedizolid phosphate. The method comprises the following steps: firstly, crude tedizolid phosphate is creatively mixed with absolute ethyl alcohol, impurities with lower polarity than tedizolid phosphate in the crude tedizolid phosphate are dissolved in the absolute ethyl alcohol, then the impurities are removed by filtering, and tedizolid phosphate is left in a filtered solid; and other impurities can be removed by combining the subsequent steps of converting tedizolid phosphate solid into tedizolid phosphate disodium salt, acidifying, crystallizing and the like. The tedizolid phosphate obtained through purification is high in purity, the sodium hydroxide solution is clear, and a high-boiling-point solvent which is difficult to remove does not need to be used in the purification process of the purification method. The method is simple, convenient and beneficial to industrial production.

Preparation method of tedizolid phosphate and intermediate thereof

The invention discloses a preparation method of tedizolid phosphate and an intermediate thereof. The preparation method of a tedizolid phosphate intermediate II comprises the following steps: 1, in anorganic solvent, under a condition of presence of a catalyst and zinc powder, performing a reaction on 3-fluorine-4-bromophenyl amino benzyl formate so as to obtain a solution of a tedizolid phosphate intermediate III; and 2, in an organic solvent, under a condition of presence of a palladium catalyst and a base, performing a coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step 1 with 2-methyl-5-(5-bromopyridine-2-yl) tetrazole, so as to obtain the tedizolid phosphate intermediate II. The preparation method disclosed by the invention is free of toxic reagent, mild in reaction condition, safe to operate, environmentally friendly, high in yield, high in prepared product purity and low in production cost. Tedizolid phosphate prepared from the tedizolid phosphate intermediate II disclosed by the invention is high in yield, high in purity, capable of meeting raw material medicine standards and applicable to industrial production.

Preparation method of high-purity tedizolid phosphate

The invention discloses a preparation method of high-purity tedizolid phosphate. The preparation method comprises the following steps: 1, with 2-methyl-5-(5-bromopyridin-2-yl)tetrazole as a starting material and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) as a catalyst, and reacting the starting material and the catalyst with bis(pinacolato)diboron to generate a compound as shown in a formula 1, namely bromine-converted pinacol borate; 2, subjecting a compound shown in a formula 3 and (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one to Suzuki coupling under the catalyticaction of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to obtain (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl]-5-one; and 3, preparing tedizolid phosphate from a compound as shown in a formula 5 under the condition of phosphorylation of phosphorus oxychloride.

Preparation method of tedizolid phosphate

The invention belongs to the field of pharmaceutical and chemical industry, and specifically relates to a preparation method of tedizolid phosphate. The compound shown as a formula Z1 is a tedizolid phosphate precursor, and is obtained in a cyclization reaction through catalyst catalysis by using X3 as a raw material. The preparation method of the compound shown as the formula Z1 comprises the following steps: carrying out the cyclization reaction on a compound shown as a formula X2 and a compound shown as a formula R under the existence of a catalyst and a solvent, so as to obtain the compound shown as a formula Z1; carrying out a phosphorylation reaction on the compound shown as the formula Z1 so as to obtain tedizolid phosphate. According to the preparation method disclosed by the invention, the compound with high boiling point such as DMPU is prevented from being used as the catalyst, and the dissolubility of the reaction system is improved through the addition of a mixed solvent,so that the reaction time is greatly shortened, and the compound is applicable for industrial production.

Nickel catalyzed tedizolid phosphate synthesis method

The invention discloses a nickel catalyzed tedizolid phosphate synthesis method. The method includes that methyl tetrazolium bromopyridine serving as an electrophilic reagent and N-oxazolidinone phenyl zinc halide serving as a nucleophilic reagent are subjected to nickel catalyzed Negishi coupling reaction and in-situ deprotection to obtain pharmaceutically active molecular tedizolid through a two-step one-pot process, and tedizolid is subjected to phosphoric acid esterification to obtain tedizolid phosphate. The method has advantages that 1) by in-situ synthesis and utilization of the organiczinc reagent, a complex step of metal reagent separation is avoided; 2) a cheap nickel catalyzing system is applied to establishment of a tedizolid phosphate core framework for the first time, and efficiency of nickel catalyzed Negishi coupling reaction is equivalent to that of palladium catalyzed Suzuki coupling reaction in current industrial synthesis of tedizolid phosphate. The remarkable advantages are beneficial to improvement of efficiency in tedizolid phosphate synthesis and production cost reduction, and the nickel catalyzed tedizolid phosphate synthesis method has a promising industrial application prospect.

Novel oxazolidinone compound as well as preparation method and medical application thereof

The invention relates to a novel oxazolidinone compound as well as a preparation method and a medical application thereof, and in particular relates to a novel oxazolidinone compound which is of formula (I) as shown in the specification, a preparation method of the compound, a medicinal composition with the compound, and an application of the compound as a treatment agent, particularly an application of the compound in preparing medicines for treating microorganism infection. Substituent groups of the formula (I) are defined same as those in claims.

Method for preparing tedizolid phosphate

The invention discloses a method for preparing tedizolid phosphate, wherein the method specifically includes the steps: with N-[3-fluoro-4-[6-(2-methyl-2H-tetrazole-5-yl)-3-pyridyl]phenyl]benzyqcarbamate as a starting raw material, in the presence of R1-O-M, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, carrying out a reaction with R-glycidyl butyrate, and then esterfying with POCl3 phosphoric acid to obtain a tedizolid phosphate crude product; and adjusting the pH value to 7-9 with an alkali solution, converting the tedizolid phosphate crude product into a salt, and adjusting the pH value to 1-2 with hydrochloric acid to obtain the refined tedizolid phosphate. The method has the advantages of mild reaction conditions, relatively low cost, simple and convenient operation, less side reaction, high yield, good reaction reproducibility, economy and environmental protection, and is suitable for industrialized production.

One-pot synthesized tedizolid

The invention relates to a preparation method of tedizolid indicated in the formula I. The preparation method includes: taking 5-bromine-2-(2-methyl-2H-tetrazole-5-radical) pyridine indicated in the formula II as a raw material to be reacted with boric acid indicated in the formula III to obtain 2-(2-methyl-2H-tetrazole-5-radical)-5-(4,4,5,5-tetramethyl-1,3-dioxane-2-radical) pyridine indicated in the formula IV under the action of a palladium catalyst; allowing compound without separation to be directly in Suzuki coupling reaction with (5R)-3-(4-bromine-3-fluorophenyl)-5-hydroxymethyl oxazolane-2-ketone indicated in the formula V under the action of the palladium catalyst to obtain the tedizolid indicated in the formula I. The preparation method of the one-pot synthesized tedizolid is easy in obtaining of the raw materials, simple in production process, short in production cycle, less in discharge of three wastes (waste gas, waste water and industrial residue), and a one-pot method is high in yield and has great practical value.

Method for preparing tedizolid phosphate

The invention relates to the technical field of preparation of tedizolid phosphate, and especially relates to a preparation method of tedizolid phosphate. According to the invention, 3-fluoroaniline is taken as a raw material, and is subjected to a nucleophilic substitution reaction with (R)-(-)-glycidyl butyrate, then a cyclization reaction and hydrolysis are carried out, protective group is removed to obtain a compound (VI); the compound (VI) is subjected to an iodination reaction and the nucleophilic substitution reaction to obtain a compound (VIII); the compound (VIII) and 2-(1-methyl-tetrazolium-5-group)-5-bromopyridine (IX) are reacted, and then a target product (I) is obtained with phosphoric acid. The method has the advantages of short route, mild reaction condition, and easy post-treatment, and is more suitable for industrial production requirement.