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Chemical Structure| 856866-72-3 Chemical Structure| 856866-72-3
Chemical Structure| 856866-72-3

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Tedizolid is an oxazolidinone-class antibiotic used to treat for acute bacterial skin and skin structure infections, working by inhibition of protein synthesis by binding to the 50S ribosomal subunit of the bacteria.

Synonyms: DA-7157; Torezolid

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Buschfort, Friederike ;

Abstract: Severe sepsis and septic shock are among the most urgent problems of modern medicine, accounting for 20-80% of illnesses and a mortality rate of 22-76% in ICU patients. The joint project "DiabKON" (Diagnostic Therapy Control), from which this dissertation emerged, attempts to improve the treatment of intensive care patients through controlled therapy. The focus is on therapy monitoring, in which a renewed administration of antibiotics should depend on the timely determination of the concentration in the patient's blood. The project was funded by the German Federal Ministry of Education and Research under the funding measure "KMU-innovativ: Medizintechnik" (FKZ 13GW0354 A-F). The aim of this work was to establish immunoassays that allow the rapid, cost-effective and quantitative determination of the antibiotics and from human blood samples. The results of the two immunoassays should be comparable with the reference method LC-MS/MS. To this end, monoclonal antibodies were first generated by immunizing mice with the antibiotics bound to carrier proteins. Spleen cells from mice with the highest antibody titer were then fused with myeloma cells to form hybridoma cells. Selection of the best positive clones was then performed by direct competitive ELISA over multiple rounds of screening. Assay development for and included optimization of the assay procedure with testing of multiple assay formats and establishment of a standard curve for quantitative detection. Optimization of the reagents used also significantly improved the stability of the assay and thus the reliability of the measurement. Following development, verification and validation of the two tests enabled all the required performance parameters of the assays to be determined. It was found that both assays met all regulatory requirements in terms of accuracy, analytical sensitivity, stability and reproducibility. The method comparisons showed very good comparability to the reference method LC-MS/MS. Both tests can be performed fully automatically on the DRG:HYBRiD-XL instrument from DRG Instruments GmbH. They are used for rapid quantitative detection of concentrations of and in the blood and thus allow close and timely control of therapy. The findings of this work contribute to the development of further tests against commonly used , which can then be used for therapy monitoring of treatment.

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Product Details of Tedizolid

CAS No. :856866-72-3
Formula : C17H15FN6O3
M.W : 370.34
SMILES Code : O=C1O[C@@H](CO)CN1C2=CC=C(C3=CC=C(C4=NN(C)N=N4)N=C3)C(F)=C2
Synonyms :
DA-7157; Torezolid
MDL No. :MFCD19442562
InChI Key :XFALPSLJIHVRKE-GFCCVEGCSA-N
Pubchem ID :11234049

Safety of Tedizolid

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H228-H315-H319
Precautionary Statements:P240-P210-P241-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313
Class:4.1
UN#:1325
Packing Group:

Application In Synthesis of Tedizolid

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 856866-72-3 ]

[ 856866-72-3 ] Synthesis Path-Upstream   1~16

  • 1
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  • [ 856866-72-3 ]
YieldReaction ConditionsOperation in experiment
48% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; lithium chloride In N,N-dimethyl-formamide at 90℃; for 4 h; In a 100 ml reaction flask,Compound 7 (5.0 g, 10 mmol) and 50 ml of DMF were added,2- (1-methyl-tetrazol-5-yl) -5-bromopyridine (2.65, 11 mmol)Lithium chloride (1.7 g),1,1'-bis (diphenylphosphino) ferrocene] palladium chloride (1.0 g),The mixture was stirred at 90 ° C for 4 hours,After completion of the reaction,To room temperature,And extracted three times with water / ethyl acetate (V / V = 1: 1)The organic layers were combined,Dried over anhydrous sodium sulfate,And concentrated to give 1.7 g of the compound (1)The yield was 48percent
26% With lithium chloride In 1-methyl-pyrrolidin-2-one at 20 - 120℃; for 4 h; In 150ml of 1-methyl-2-pyrrolidone was dissolved 37g of (R)-3- (4- tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7g of 2- (2-methyltetrazol-5-yl)-5-bromopyridine, 10.44g of lithium chloride and 2.9g of dichlorobistriphenylphospine palladium (I I) at room temperature and then stirred at the temperature of 120 C for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8g of the title compound. Yield 26percent. 1H NMR (DMSO-d6) 5 8.90 (s, lH), 8. 18 (m, 2H), 7.70 (m, 2H), 7.49 (dd, 1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.46 (s, 3H), 4.14 (t, lH), 3. 88 (dd, lH), 3.68 (m, lH), 3. 58 (m, lH)
26% With bis-triphenylphosphine-palladium(II) chloride; lithium chloride In 1-methyl-pyrrolidin-2-one at 120℃; for 4 h; Inert atmosphere To a solution of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol 5 (37.0 g, 74.0 mmol) in NMP (150 mL) was added 2-(2-methyltetrazol-5-yl)-5-bromopyridine 9 (19.7 g, 81.9 mmol), LiCl (10.4 g, 245 mmol) and Pd(PPh3)2Cl2 (2.90 g, 4.13 mmol). The reaction mixture was stirred for 4 h at 120 °C. After being cooled to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was further purified by column chromatography to obtain the title compound (8 g, 26percent). Mp: 201 °C. 1H NMR (DMSO-d6): δ 8.90 (s, 1H), 8.18 (m, 2H), 7.70 (m, 2H), 7.49 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.74 (m, 1H), 4.46 (s, 3H), 4.14 (t, J = 8.8 Hz, 1H), 3.88 (m, 1H), 3.68 (m, 1H), 3.58 (m, 1H). 13C NMR (DMSO-d6): δ 163.56, 159.03, 154.06, 149.18, 144.78, 140.30, 136.96, 131.42, 130.73, 121.89, 118.36, 113.81, 105.18, 73.39, 61.52, 45.96, 39.63. IR (neat, cm-1): 3251.40, 1746.23, 1619.91, 1473.35, 1406.82. [M + H]+: 371.02. HRMS [EI-MS]: m/z, calculated for [C17H15FN6O3] 370.1190, found, 370.1100 [C17H15FN6O3].
References: [1] Patent: CN105859780, 2016, A, . Location in patent: Paragraph 0038.
[2] Patent: WO2005/58886, 2005, A1, . Location in patent: Page/Page column 28; 29.
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039.
[4] Patent: CN107400126, 2017, A, . Location in patent: Paragraph 0036.
  • 2
  • [ 1056039-83-8 ]
  • [ 444335-16-4 ]
  • [ 856866-72-3 ]
YieldReaction ConditionsOperation in experiment
84% With palladium diacetate; potassium carbonate; triphenylphosphine In 1,4-dioxane at 20℃; Reflux; Inert atmosphere Under stirring, 1,4-dioxane (400 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 83.3 mmol, 1.0 equiv), bis(pinacolato)diboron (25.3 g, 100 mmol, 1.2 equivalents), potassium acetate (20.4 g, 208 mmol, 2.5 eq) and bis(triphenylphosphine)palladium dichloride (1.17 g, 1.4 mmol, 0.015 eq) was added in sequence to the reaction vessel. The solution was warmed to reflux under nitrogen and TLC followed 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine for complete reaction. After the reaction is completed, it is cooled to below 20 °C. (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one (21.7 g, 75.0 mmol, 0.9 eq.), potassium carbonate (34.5 g, 250 mmol, 3.0 equiv), palladium acetate (0.14 g, 0.62 mmol, 0.0075 equiv) and triphenylphosphine (0.65 g, 2.5 mmol, 0.03 equiv) was added in sequence to the reaction vessel and nitrogen protected. Warming to reflux, TLC tracks 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxoboran-2-yl)pyridine until reaction is complete. After the reaction was completed, it was cooled to room temperature and stirred for 16 hours. It was filtered under reduced pressure and the cake was rinsed with water (200 ml) and methanol (200 ml). The filter cake was collected and air dried at 80° C. to give 25.8 g (compound I) as an off-white powder in a yield of 84percent.
78% With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine In 1,4-dioxane; water for 4 h; Inert atmosphere; Reflux At room temperature, 1.0 g of the compound of formula I, 1.2 g of the compound of formula II, 0.8 g of potassium carbonate, 60 mgTricyclohexylphosphine and 72 mg of tris (dibenzylideneacetone) dipalladium (Pd2 (dba) 3) catalyst were added followed by 4 mL of water and 15 mL1,4-dioxane, after a vacuum and nitrogen replacement after heating to reflux, insulation in the reflux state SUZUKI coupling anti-When the SUZUKI coupling reaction was complete (about 4 hours), the reaction was terminated, and the reaction solution was filtered while hot with diatomaceous earth so that the collectedCrystallization of the filtrate naturally cool, l. 0g obtained tidiazolamide crystals (off-white solid), HPLC purity of 99.5percent, the molar yield of 78percent.
63.7% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 12 h; Reflux; Inert atmosphere In 3000 ml of the four port in the round-bottom flask, is provided with the mechanical stirring, reflux condensation tube, thermometer, under the protection of argon is added to the round-bottom flask 1500 ml toluene, 100g (5R) - 3 - (4-bromo-3-fluoro-phenyl) - 5-hydroxy methyl oxazolidine-2-one, 105g2 - (2-methyl -2H-tetrazol-5-yl) pyridine-5-boronic acid frequency ester, 28g two chlorine pairs (triphenyl phosphine) palladium, opening stirring to the solid dissolved, add prepared 140g the potassium carbonate solution dissolving a small amount of water, heating to reflux, the reaction stirred 12 hours, cooling to room temperature. Filtering, the filter cake is washed with water after washing with ethanol mixed solution of methanol used for washing. The filter cake vacuum 45 °C drying 48 hours, shall be 81.3g product. Yield: 63.7percent.
References: [1] Patent: CN107382995, 2017, A, . Location in patent: Paragraph 0007; 0014; 0015; 0016; 0117; 0018; 0019-0022.
[2] Patent: CN106146485, 2016, A, . Location in patent: Paragraph 0040; 0041; 0042.
[3] Patent: CN105418681, 2016, A, . Location in patent: Paragraph 0048; 0049.
[4] RSC Advances, 2016, vol. 6, # 63, p. 58088 - 58098.
  • 3
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  • [ 60456-26-0 ]
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YieldReaction ConditionsOperation in experiment
86.7%
Stage #1: With potassium <i>tert</i>-butylate; lithium tert-butoxide In tetrahydrofuran; acetonitrile at 25℃; for 2 h; Inert atmosphere
Stage #2: for 3 h;
In a 1L three-necked bottle, 50 g of a compound of Formula X3, 400 ml of tetrahydrofuran and 400 ml of acetonitrile were added.Nitrogen gas, temperature 25°C, solids insolubleThen, 9.9 g of lithium tert-butoxide and 13.9 g of potassium tert-butoxide were added, and the solid matter dissolved.The reaction solution changed from colorless to yellow,After stirring for 2 hours, the reaction solution was added dropwiseR-(-)-glycidol butyric acid and compound of formula R 19.7 g,After completion of the addition, the reaction was incubated for 3 hours, and the sample was subjected to a TLC (developing solvent: chloroform/methanol = 10/1). After the spot of the compound of Formula X3 disappeared, the sample was dropped.Add dilute hydrochloric acid prepared from concentrated hydrochloric acid and water, adjust the pH to 8, fully stir for 30 minutes, the water bath temperature is 35°C to 55°C, and the vacuum degree -0.07MPa to -0.1MPa is concentrated under reduced pressure to stop flow.
85%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1.41667 h; Inert atmosphere
Stage #2: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at 20℃; for 15 h; Inert atmosphere; cooling with ice
A 5-L, three-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a 500-mL addition funnel and a nitrogen-inlet adapter. The flask was dried with a heat gun under a flow of nitrogen to an internal temperature of 60°C. The flask was charged with intermediate 7 (110.0 g, 0.272 mol, AMRI lot No. DUG-AF-202Q)) and anhydrous THF (2.2 L, 20 vol). The slurry was stirred and a light green solution formed. The addition funnel was charged with 1.0 M lithium hexamethyldisilazide (299 mL, 0.286 mol, 1.05 eq.). The LiHMDS solution was added dropwise to the solution of intermediate 7 over approximately 25 minutes. A red solution formed. The solution was stirred one hour at room temperature and then DMPU (34.9 g, 0.272 mol, 1 eq) was added, and the mixture turned to a yellow slurry. The batch was cooled in an ice bath to 5.7°C. R-(-)-Glycidyl butyrate (41.25 g, 0.286 mol, 1.05 eq) was then added in one portion. The mixture was stirred in the ice bath for 0.5 hour and then was warmed to room temperature and stirred overnight. The reaction formed a tan slurry at this point, and HPLC analysis after 15 hours indicated that there was approximately 87percent TR-700, 1.6percent intermediate 7, and approximately 7percent of the butyrate ester of TR-700. A small amount of sodium methoxide in methanol (11 mL, 0.1 vol) was added, and the batch was stirred for 1 hour to remove the residual ester. The in-process HPLC analysis at this point showed there was approximately 90.7percent TR-700 and 0.2percent of the butyrate ester. The reaction was quenched by the addition of 10percent w/w ammonium chloride solution (1.1 L, 10 vol). A modest exothermic event from 22°C to 25°C was observed upon addition of the ammonium chloride solution. The two-phase mixture was distilled to a pot temperature of 700C (atmospheric pressure) to remove approximately 2.2 L of the THF. This formed a thick slurry which is diluted with water (550 mL, 5 volumes). The slurry was cooled to room temperature (23.6°C) and was filtered. The filter cake was washed with water (1.1 L, 10 vol) and methanol (550 mL, 5 vol) to give TR-700 as a white solid. The wet cake was dried overnight in a vacuum oven at 500C to give 89.7 g of TR-700 (89percent yield) that was 97.8percent (AUC) by HPLC analysis. The TR-700 was further purified by reslurrying in 2.7 L (30 vol) of 4: 1 methanol/water at 700C, cooling to 230C, filtering and washing with methanol (180 ml). This removed some of the over-alkylated product that is observed. The purified TR- 700 was recovered in 96percent yield (85percent overall yield), and the purity was improved to 98.4percent (AUC) by HPLC analysis. The palladium content was 10 ppm.
References: [1] Patent: CN107722056, 2018, A, . Location in patent: Paragraph 0058; 0060; 0062; 0063; 0064; 0068.
[2] Patent: WO2010/42887, 2010, A2, . Location in patent: Page/Page column 19-20.
  • 4
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YieldReaction ConditionsOperation in experiment
95% With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert.-butyl lithium; (R)-glycidyl butyrate In tetrahydrofuran at 0 - 30℃; for 15 h; Large scale To the kettle was added tetrahydrofuran (20 L)And benzyl N- [3-fluoro-4- [6- (2-methyl- 2H- tetrazolium- 5 -yl) -3-pyridyl] phenyl] carbamateCompound (II) (1 Kg, 2.47 mol),0 ~ 30 ° C After mixing,1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidone was added sequentially (DMPU, 0.63 Kg, 4.94 mol, 2 equivalents),Lithium tert-butoxide (0.396 Kg, 4.94 mol, 2 equivalents)Add R-glycidyl butyrate(0.39 Kg, 2.72 mol, 1.1 equivalents)0 ~ 30 ° C for 15 hours.After the reaction,The reaction was quenched by adding a mass-volume ammonium chloride solution (1 Kg / 10 L)Concentrated under reduced pressure,The residue was added to methanol (10 L)Stirred for 0.5 hours to give suction filtration,The filter cake was washed with methanol,45 ~ 50 ° C under vacuum to give a white solid(5R) -3- (4- (6- (2-methyl- 2H- tetrazolium- 5-yl) -3-pyridyl) -3- fluorophenyl) -5-hydroxymethyl oxazoline -2-one Compound (III) (0.87 Kg, yield: 95percent).
References: [1] Patent: CN106317114, 2017, A, . Location in patent: Paragraph 0024; 0025; 0026; 0027.
  • 5
  • [ 444335-16-4 ]
  • [ 380380-64-3 ]
  • [ 856866-72-3 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; bis(pinacol)diborane In dimethyl sulfoxide at 80℃; for 14 h; Inert atmosphere
Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 70℃; for 3 h; Inert atmosphere
DMSO (100 ml) was added to a 250 ml reaction flask,(5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one(10 g, 34.5 mmol), pinacolate (17.52 g, 69 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (1.41 g, 1.73 mmol)And potassium acetate (13.5 g, 138 mmol), and the temperature was raised to 80 ° C under a nitrogen atmosphere,For 14 hours. The heating was stopped, the solution was cooled to room temperature, and extracted with water / ethyl acetate 3 times. The organic layers were combined and the organic layer was washed with saturated waterBrine, dried over anhydrous sodium sulfate and concentrated by suction filtration. The concentrated product of the above step was added to a 250 ml reaction flask,1,4-dioxane (100 ml) was added,5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine(8.28 g, 34.5 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (0.56 g, 0.69 mmol)And cesium carbonate aqueous solution (50 ml, containing 33.72 g of cesium carbonate, 103.5 mmol),Under nitrogen protection,The temperature was raised to 70 ° C,The reaction was carried out for 3 hours,Dichloromethane was added for extraction.The separated organic phase was washed with saturated brine,Anhydrous sodium sulfate dehydration,filter,Concentrated in vacuo and purified by column chromatography,10.6 g of a solid was obtained,The yield was 83.0percentHPLC purity was 98.34percent (area normalization method).
References: [1] Patent: CN105418678, 2016, A, . Location in patent: Paragraph 0070; 0071; 0072; 0073; 0074; 0075.
  • 6
  • [ 487041-08-7 ]
  • [ 1056039-83-8 ]
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YieldReaction ConditionsOperation in experiment
77.6% With palladium diacetate; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 6 h; Sealed tube; Inert atmosphere; Green chemistry To a solution of 5 (1.03 g, 3.06 mmol) and potassium carbonate (1.27 g, 9.18 mmol) in degassed N,N-dimethylformamide (DMF) (5 mL) and H2O (5 mL) was added 12 (1.05 g, 3.67 mmol) followed by palladium acetate (0.07 g, 0.31 mmol) and the reaction mixture was heated at 90 °C for 6 h in a sealed tube under argon. The reaction mixture was cooled to room temperature, poured into the ice water. The crude solid was filtered and purified by column chromatography (2 percent CH3OH in CH2Cl2) to obtain the title compound (0.88 g, 77.6 percent). ee>99percent. mp: 199–201 °C. [α]D20= −46 (c=0.5, DMSO). The 1H-NMR and 13C-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.19–8.23 (m, 2H), 7.68–7.76 (m, 2H), 7.51–7.53 (m, 1H), 5.24 (t, 1H J=5.6 Hz), 4.75–4.76 (m, 1H), 4.47 (s, 3H), 4.15 (t, 1H, J=8.6 Hz), 3.90–3.92 (m, 1H), 3.69–3.72 (m, 1H), 3.60–3.63 (m, 1H). 13C-NMR (100 MHz, DMSO-d6) δ: 163.9, 159.3 (J=244 Hz), 154.3, 149.4, 145.1, 140.5, 137.2, 131.6, 130.9, 122.1, 118.6 (J=13 Hz), 114.0, 105.4 (J=28 Hz), 73.5, 61.6, 46.0. ESI-HRMS m/z: Calcd for C17H16FN6O3 (M+H)+: 371.1262. Found: 371.1254.
References: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146.
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References: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146.
[2] Patent: CN105859780, 2016, A, .
[3] Patent: WO2016/88103, 2016, A1, .
  • 8
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References: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146.
[2] Patent: CN105859780, 2016, A, .
[3] Patent: WO2016/88103, 2016, A1, .
  • 9
  • [ 444335-16-4 ]
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References: [1] Patent: CN107827927, 2018, A, .
[2] Patent: CN107827927, 2018, A, .
  • 10
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References: [1] Patent: CN107827927, 2018, A, .
[2] Patent: CN107827927, 2018, A, .
  • 11
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References: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039.
  • 12
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References: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039.
  • 13
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References: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146.
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References: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146.
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References: [1] Patent: WO2016/88103, 2016, A1, .
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References: [1] Patent: WO2016/88103, 2016, A1, .
 

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