WO2016088103A1 - Procédé de préparation de phosphate de tédizolide - Google Patents

Procédé de préparation de phosphate de tédizolide Download PDF

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WO2016088103A1
WO2016088103A1 PCT/IB2015/059379 IB2015059379W WO2016088103A1 WO 2016088103 A1 WO2016088103 A1 WO 2016088103A1 IB 2015059379 W IB2015059379 W IB 2015059379W WO 2016088103 A1 WO2016088103 A1 WO 2016088103A1
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formula
compound
process according
group
solvent
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PCT/IB2015/059379
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Rakesh Singh
Atul Sharma
Mahavir Singh Khanna
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention provides a process for the preparation of tedizolid phosphate.
  • Tedizolid phosphate chemically [(5i?)-3- ⁇ 3-fluoro-4-[6-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yl]phenyl ⁇ -2-oxooxazolidin-5-yl]methyl hydrogen phosphate, is represented by Formula I.
  • Tedizolid phosphate is indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria.
  • U.S. Patent No. 8,426,389 discloses a crystalline form of tedizolid phosphate.
  • the present invention provides a process for the preparation of tedizolid phosphate.
  • the process of the present invention uses non-toxic and inexpensive reagents, is industrially viable, and produces tedizolid phosphate having high purity and yield.
  • ambient temperature refers to a temperature in the range of about 20°C to about 25 °C.
  • halogen refers to chloro, bromo, or iodo.
  • Ci-6 alkyl refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec- pentyl, 3-pentyl, n-hexyl, iso-hexyl, 2,3-dimethylbutyl, or neo-hexyl.
  • aryl refers to a monocyclic aromatic hydrocarbon.
  • An example of an aryl is phenyl.
  • aralkyl refers to a methylene substituted aryl group.
  • An example of an aralkyl is benzyl.
  • heterocycle refers to a non-aromatic ring containing one or more hetero atom selected from the group consisting of oxygen (O) and boron (B).
  • An example of a heterocyclic ring is 4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl.
  • a first aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Ri is Ci-6 alkyl
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • R 2 and R3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R 2 and R 3 are taken together with the oxygen atoms to which they are attached to form a 5- or 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl, or aralkyl,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and pyridine.
  • the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N-dimethylformamide, acetonitrile, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include n-hexane, n-heptane, cyclohexane, toluene, and xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula II with the compound of Formula III is carried out for about 15 minutes to about 8 hours, for example, for about 30 minutes to about 4 hours.
  • reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • the compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula IV may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula IV is reacted with the compound of Formula V to obtain the compound of Formula VI in the presence of a base and a solvent.
  • An example of a base is n-butyl lithium.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, ⁇ , ⁇ -dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula IV with the compound of Formula V is carried out for about 15 hours to about 25 hours, for example, for about 20 hours to about 22 hours.
  • reaction of the compound of Formula IV with the compound of Formula V is carried out at a temperature of about -78°C to about 40°C, for example, of about -65°C to about 30°C.
  • the compound of Formula VI may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VI is reacted with an iodinating agent to obtain the compound of Formula VII in the presence of an acid.
  • An example of an iodinating agent is N-iodosuccinimide.
  • An example of an acid is trifluoroacetic acid.
  • reaction of the compound of Formula VI with the iodinating agent is carried out for about 2 hours to about 8 hours, for example, for about 3 hours to about 6 hours.
  • reaction of the compound of Formula VI with the iodinating agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • the compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VII is protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent.
  • the protecting agent is selected from the group consisting of di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
  • the solvent is selected from the group consisting of dimethylsulfoxide, N,N- dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include toluene, benzene, and p-xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • An example of a catalyst is 4-(N,N-dimethylamino)pyridine.
  • the protection of the compound of Formula VII with the protecting agent is carried out for about 5 hours to about 12 hours, for example, for about 6 hours to about 8 hours.
  • the protection of the compound of Formula VII with the protecting agent is carried out at a temperature of about 20°C to about 70°C, for example, of about 25°C to about 55°C.
  • the compound of Formula VIII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VIII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VIII is coupled with the compound of Formula A to obtain the compound of Formula IX in the presence of a palladium catalyst, a phosphine ligand, a base, and a solvent.
  • the palladium catalyst is selected from the group consisting of palladium(II) acetate, palladium(II) bromide, palladium(II) chloride, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), tetrakis(tri(o-tolyl)phosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), and [ ⁇ , - bis(diphenylphosphino)ferrocene]palladium(II) dichloride .
  • the phosphine ligand is selected from the group consisting of triphenylphosphine, tri(o-tolyl)phosphine, diphenylphosphino ethane, diphenylphosphino propane, and diphenylphosphino ferrocene.
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethyl amine, and N,N- diisopropylamine .
  • the solvent is selected from the group consisting of water, N,N- dimethylformamide, dimethylsulphoxide, ethers, alcohols, hydrocarbons, and mixtures thereof.
  • ethers examples include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • hydrocarbons examples include benzene, toluene, and p-xylene.
  • the coupling of the compound of Formula VIII with the compound of Formula A is carried out for about 2 hours to about 15 hours, for example for about 4 hours to about 10 hours.
  • the coupling of the compound of Formula VIII with the compound of Formula A is carried out at a temperature of about 15°C to about 100°C, for example, of about 20°C to about 90°C.
  • the compound of Formula IX may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula IX may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula IX is reacted with an alkali metal azide in the presence of ammonium chloride and a solvent to obtain the compound of Formula X.
  • alkali metal azides examples include sodium azide and potassium azide.
  • the solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulphoxide, alcohols, and mixtures thereof.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • reaction of the compound of Formula IX with the alkali metal azide is carried out for about 1 hour to about 6 hours, for example, for about 3 hours to about 5 hours.
  • reaction of the compound of Formula IX with the alkali metal azide is carried out at a temperature of about 75°C to about 150°C, for example, of about 90°C to about 1 10°C.
  • the compound of Formula X may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula X may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula X is N-methylated with a methylating agent to obtain the compound of Formula XI in the presence of diethyl azodicarboxylates and
  • triphenylphosphine in a solvent, or in the presence of a base and a solvent.
  • methylating agents examples include methanol and methyl iodide.
  • the solvent is selected from the group consisting of N,N-dimethylformamide, ethers, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1,2-dichloroethane.
  • the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • the N-methylation of the compound of Formula X with the methylating agent is carried out for about 2 hours to about 10 hours, for example, for about 4 hours to about 8 hours.
  • the N-methylation of the compound of Formula X with the methylating agent is carried out at a temperature of about 15°C to about 40°C, for example, of about 25°C to about 35°C.
  • the compound of Formula XI may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula XI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XI is deprotected in the presence of a deprotecting agent and a solvent to obtain the compound of Formula XII.
  • the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
  • the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
  • ketones include acetone and methyl ethyl ketone.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out for about 1 hour to about 7 hours, for example, for about 2 hours to about 4 hours.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25 °C to about 35°C.
  • the compound of Formula XII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula XII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XII is phosphorylated in the presence of a
  • phosphorylating agent is phosphorus oxy chloride.
  • An example of a base is triethylamine.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and a mixture thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • the phosphorylation of the compound of Formula XII in the presence of the phosphorylating agent is carried for about 2 hours to about 10 hours, for example, for about 3 hours to about 6 hours.
  • the phosphorylation of the compound of Formula XII in the presence of the phosphorylating agent is carried out at a temperature of about -10°C to about 10°C, for example, of about -7°C to about 8°C.
  • Tedizolid phosphate of Formula I may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Tedizolid phosphate of Formula I may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XII is phosphorylated to obtain tedizolid phosphate of Formula I by
  • An example of the catalyst used in step a) is tetrazole.
  • the oxidizing agent in step a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
  • the solvent in step a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in step a) is carried out for about 1 hour to about 30 hours, for example, for about 2 hours to about 10 hours.
  • reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in step a) is carried out at a temperature of about -70°C to about 10°C, for example, of about -65 °C to about 5°C.
  • the compound of Formula B may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula B may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • An example of the acid used in step b) is trifluoroacetic acid.
  • the solvent used in step b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • the deprotection of the compound of Formula B is carried out for about 30 minutes to about 3 hours, for example, for about 45 minutes to about 2 hours.
  • the deprotection of the compound of Formula B is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • Tedizolid phosphate of Formula I may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. Tedizolid phosphate of Formula I may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the combined dichloromethane layers were washed with deionized water (200 mL).
  • the dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to obtain a residue.
  • Hexane (1L) was added to the residue, and the resulting slurry was stirred overnight at ambient temperature.
  • the solid was filtered under vacuum, and then washed with hexanes (200 mL). The solid was dried under vacuum at 40°C for 10 hours to obtain the title compound.
  • Methyl (3-fluorophenyl)carbamate (Formula IV, 70 g, Example 1) was dissolved in anhydrous tetrahydrofuran (420 mL) at ambient temperature, and then the solution was cooled to -65°C to -60°C under nitrogen atmosphere. n-Butyl lithium (1.6 M in hexane, 272 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes.
  • Tetrahydrofuran was recovered under vacuum at 40°C to 45°C, followed by the addition of deionized water (500 mL) at 40°C to 45°C.
  • the reaction mixture was allowed to attain ambient temperature and then was stirred for two hours.
  • the solid obtained was filtered, and then washed with deionized water (70 mL).
  • the wet solid was dried at 50°C to 55°C to afford the title compound.
  • the resulting biphasic system was stirred at ambient temperature for 15 minutes, then cooled to 0°C to 5°C, and then stirred for another 1 hour at 0°C to 5°C.
  • the solid obtained was filtered, then washed with deionized water (40 mL), and then washed with ethyl acetate in hexanes (20%, 30 mL). The solid was dried at 40°C to 45 °C for 4 hours to afford the title compound as an off- white solid.
  • Tri(o-tolyl)phosphine (7.75 g) was added to the reaction mixture, followed by the addition of potassium carbonate (35.15 g) under nitrogen atmosphere at ambient temperature. The reaction mixture was stirred at ambient temperature, and then nitrogen gas was bubbled through the reaction mixture for 40 minutes to 45 minutes. Palladium(II) acetate (2.85 g) was added to the reaction mixture under nitrogen atmosphere, and then the mixture was stirred for 10 minutes at ambient temperature. The reaction mixture was heated to 80°C to 85°C, and then stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and then ethyl acetate (400 mL) was added to the mixture, followed by the addition of deionized water (1L).
  • Example 7 Preparation of tert-butyl r(5R)-3- ⁇ 3-fluoro-4-r6-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yllphenyl ⁇ -2-oxo-1.3-oxazolidin-5-yllmethyl carbonate (Formula XI. when ⁇ is tert-butoxycarbonyl)
  • the solvent was evaporated from the reaction mixture at 30°C to 35°C to obtain a solid.
  • the solid was suspended in a mixture of methanol (150 mL) and water (150 mL), and then stirred at ambient temperature for 2 hours. The solid was filtered, and then washed with water (50 mL). The wet solid was dried at 60°C to 65°C to afford the title compound as a mixture of two isomers and was used as such for the next step.
  • Method B Tert-butyl [(5R)-3- ⁇ 3-fluoro-4-[6-(2H-tetrazol-5-yl)pyridin-3- yl]phenyl ⁇ -2-oxo-l,3-oxazolidin-5-yl]methyl carbonate (Formula X, 10 g, Example 6) was suspended in N,N-dimethyl formamide (100 mL), followed by the addition of sodium hydroxide (1.314 g). Methyl iodide (4.66 g) was slowly added to the reaction mixture at 0°C to 5°C. The reaction mixture was stirred at 20°C to 25°C for 5 hours to 6 hours.
  • dichloromethane layer was washed with a saturated sodium bicarbonate solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to dryness to obtain a residue.
  • Activated carbon (3 g) was added to the solution at ambient temperature, and then the mixture was stirred for 1 hour. The solution was filtered through a Hyflo ® , and then the bed was washed with methanol: dichloromethane (1 : 1, 100 mL). The filtrate was concentrated under vacuum to dryness.
  • Tetrahydrofuran 75 mL was added to (5R)-3- ⁇ 3-fluoro-4-[6-(2-methyl-2H- tetrazol-5 -yl)pyridin-3 -yl]phenyl ⁇ -5 -(hydroxymethyl)- 1 ,3 -oxazolidin-2-one (Formula XII, 3 g, Example 8) while stirring under inert atmosphere.
  • the reaction mixture was cooled to -5°C in an ice bath, and then triethylamine (3.4 mL) was added to the mixture.
  • Phosphorous oxy chloride (2.3 mL) was added to the reaction mixture at -5°C to 0°C over 10 minutes to 15 minutes.
  • the reaction mixture was stirred at 0°C to 5°C for 4 hours to 5 hours.
  • the reaction mixture was slowly poured into a flask containing deionized water (110 mL) precooled to 0° to 5°C. The temperature of the reaction mixture was maintained below 10°C during addition.
  • the yellow slurry thus obtained was stirred overnight at ambient temperature.
  • the solid obtained was filtered, then washed with deionized water (15 mL) and methanol (30 mL). The solid was dried at 45 °C for 6 hours to afford the title compound.
  • reaction mixture was cooled to -70°C to -65°C, followed by the addition of m-chloroperbenzoic acid (0.7 g). The reaction mixture was stirred for 2 hours at -70°C to -65 °C. The reaction mixture was warmed to ambient temperature. Dichloromethane (20 mL) and an aqueous solution of sodium bisulfate (0.5 g in 20 mL deionized water) were added. The organic layer was separated, then washed with an aqueous solution of sodium bicarbonate (0.5 g in 20 mL deionized water), and then washed with deionized water (20 mL). The separated organic layer was dried with anhydrous sodium sulfate (2 g) at ambient temperature, and the organic layer was used as such for the next step.
  • dichloromethane (20 mL) and an aqueous solution of sodium bisulfate (0.5 g in 20 mL deionized water) were added. The organic layer was separated, then was

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Abstract

La présente invention concerne un procédé de préparation de phosphate de tédizolide.
PCT/IB2015/059379 2014-12-05 2015-12-04 Procédé de préparation de phosphate de tédizolide WO2016088103A1 (fr)

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CN107353304A (zh) * 2017-07-12 2017-11-17 浙江普洛得邦制药有限公司 磷酸泰地唑胺三羟甲基氨基甲烷盐及其晶型a、制备方法和应用
CN112957332A (zh) * 2021-02-04 2021-06-15 海南通用康力制药有限公司 注射用磷酸特地唑胺及其质量标准
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

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CN107353304A (zh) * 2017-07-12 2017-11-17 浙江普洛得邦制药有限公司 磷酸泰地唑胺三羟甲基氨基甲烷盐及其晶型a、制备方法和应用
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US11566023B2 (en) 2020-06-18 2023-01-31 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US12116361B2 (en) 2020-06-18 2024-10-15 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
CN112957332A (zh) * 2021-02-04 2021-06-15 海南通用康力制药有限公司 注射用磷酸特地唑胺及其质量标准

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