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WO2016088103A1 - A process for the preparation of tedizolid phosphate - Google Patents

A process for the preparation of tedizolid phosphate Download PDF

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Publication number
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
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solvent
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Rakesh Singh
Atul Sharma
Mahavir Singh Khanna
Mohan Prasad
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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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

The present invention provides a process for the preparation of tedizolid phosphate.

Description

A PROCESS FOR THE PREPARATION OF TEDIZOLID PHOSPHATE
Field of the Invention
The present invention provides a process for the preparation of tedizolid phosphate.
Background of the invention
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.
Figure imgf000002_0001
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 Nos. 7,816,379 and 8,604,209 disclose processes for the preparation of tedizolid phosphate.
U.S. Patent No. 8,426,389 discloses a crystalline form of tedizolid phosphate.
Summary of the Invention
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.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to a temperature in the range of about 20°C to about 25 °C. The term "halogen," as used herein, refers to chloro, bromo, or iodo.
The term "Ci-6 alkyl," as used herein, 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.
The term "aryl," as used herein, refers to a monocyclic aromatic hydrocarbon. An example of an aryl is phenyl.
The term "aralkyl," as used herein, refers to a methylene substituted aryl group. An example of an aralkyl is benzyl.
The term "heterocycle," as used herein, 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,
Figure imgf000003_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000003_0002
Formula II
with a compound of Formula III,
Figure imgf000003_0003
Formula III wherein X is halogen,
to obtain a compound of Formula IV;
Figure imgf000004_0001
Formula IV
b) reacting the compound of Formula IV with a compound of Fonnula V,
Figure imgf000004_0002
Formula V
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VI;
Figure imgf000004_0003
c) reacting the compound of Formula VI with an iodinating agent to obtain a compound of Formula VII;
Figure imgf000004_0004
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII.
Figure imgf000005_0001
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
coupling a compound of Formula VIII with a compound of Formula A,
Figure imgf000005_0002
Formula A
wherein R2 and R3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R2 and R3 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,
in the presence of a palladium catalyst and a phosphine ligand to obtain a compound of Formula IX,
Figure imgf000005_0003
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
reacting the compound of Formula IX with an alkali metal azide in the presence of ammonium chloride, to obtain a compound of Formula X,
Figure imgf000005_0004
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
g) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI,
Figure imgf000006_0001
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
h) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000006_0002
Formula XII
i) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Formula I. The compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in the presence of a base and a solvent.
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.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include n-hexane, n-heptane, cyclohexane, toluene, and xylene. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The 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.
The 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, Ν,Ν-dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The 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.
The 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.
The 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.
The 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.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include toluene, benzene, and p-xylene.
Examples of halogenated hydrocarbons 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 [Ι, - 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.
Examples of ethers include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol. Examples of hydrocarbons 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.
Examples of alkali metal azides include sodium azide and potassium azide.
The solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulphoxide, alcohols, and mixtures thereof.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The 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.
The 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.
Examples of methylating agents include methanol and methyl iodide.
The solvent is selected from the group consisting of N,N-dimethylformamide, ethers, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
Examples of halogenated hydrocarbons 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. Examples of ketones include acetone and methyl ethyl ketone.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of alcohols 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, a base, and a solvent to obtain tedizolid phosphate of Formula I.
An example 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.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of 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.
Alternatively, the compound of Formula XII is phosphorylated to obtain tedizolid phosphate of Formula I by
a) reacting the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in the presence of a catalyst and a solvent followed by oxidation with an oxidizing agent to obtain a protected compound of Formula B; and
Figure imgf000013_0001
Formula B
b) deprotecting the protected compound of Formula B in the presence of an acid and a solvent to obtain tedizolid phosphate of Formula I.
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.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The 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.
The 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.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of alcohols 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.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Methods
The chromatography purity was recorded using an Acquity® H-class UPLC, PDA Detector.
EXAMPLES
Example 1 : Preparation of methyl (3-fluorophenyl)carbamate (Formula IV)
3-Fluoroaniline (Formula II, 100 g) was dissolved in dichloromethane (500 mL) under inert atmosphere at ambient temperature . Sodium bicarbonate ( 151.3 g) was added to the mixture while stirring at ambient temperature. Methyl chloroformate (Formula III, when X=chloro; 127.6 mL) was added to the reaction mixture at ambient temperature over 40 minutes to 45 minutes. The reaction mixture was stirred for 2 hours to 3 hours at ambient temperature. Deionized water (500 mL) was added to the reaction mixture, and then the mixture was stirred at ambient temperature for 15 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). 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.
Yield: 140 g
Example 2: Preparation of (5R)-3-(3-fluorophenyl)-5-(hvdroxymethyl)-1.3-oxazolidin-2- one (Formula VI)
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. (R)-(-)-Glycidyl butyrate (Formula V, when Ri= n-propyl, 60.25 g) was slowly added to the reaction mixture under nitrogen atmosphere at -65°C to -60°C, and then the mixture was stirred for 20 hours at 20°C to 25 °C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (7 g in 70 mL of deionized water) was added to the reaction mixture.
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.
Yield: 72.1 g
Example 3: Preparation of (5R)-3-(3-fluoro-4-iodophenyl)-5-(hvdroxymethyl)-1.3- oxazolidin-2-one (Formula VII)
(5R)-3-(3-Fluorophenyl)-5-(hydroxymethyl)-l,3-oxazolidin-2-one (Formula VI, 5 g, Example 2) was dissolved in trifluoroacetic acid (25 mL) at ambient temperature, and then the mixture was stirred for 10 minutes. N-Iodosuccinimide (5.59 g) was added to the reaction mixture at ambient temperature, and then the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under vacuum to obtain a residue. Deionized water (50 mL) was added to the residue, followed by the addition of ethyl acetate in hexanes (20%, 30 mL). 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.
Yield: 7.9 g
Example 4: Preparation oftert-butyl r(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1.3- oxazolidin-5-νΠ methyl carbonate (Formula VIII. when Ρ is tert-butoxycarbonyl)
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-l,3-oxazolidin-2-one (Formula VII, 10 g, Example 3) was dissolved in toluene (150 mL) at ambient temperature. Di-tert-butyl dicarbonate (8.5 g) was added to the reaction mixture at ambient temperature, followed by the addition of 4-(N,N-dimethylamino)pyridine (DMAP) (0.37 g). The reaction mixture was heated to 45°C to 50°C for 7 hours. The reaction mixture was allowed to attain ambient temperature, and then deionized water (50 mL) was added to the reaction mixture. The layers were separated, and the toluene layer was dried over anhydrous sodium sulfate. The toluene layer was concentrated under vacuum to dryness to afford the title compound as off-white solid.
Yield: 11.1 g
Example 5: Preparation oftert-butyl {(5R)-3-r4-(6-cvanopyridin-3-yl)-3-fluorophenyll-2- oxo-1.3-oxazolidin-5-yl}methyl carbonate (Formula IX. when Ρ is tert-butoxycarbonyl)
Tert-butyl [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl carbonate (Formula VIII, 50 g, Example 4) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine-2-carbonitrile (Formula A, wherein R2 and R3 together with the oxygen atom to which they are attached to form a 5 membered heterocyclic ring, 33 g) were dissolved in dimethylsulphoxide (300 mL) at ambient temperature. 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). The solution was stirred at ambient temperature for 10 minutes, and the organic layer was separated. The organic layer was washed twice with deionized water (200 mL each). The ethyl acetate layer was recovered at 50°C to 55°C to obtain a residue. The residue was suspended in methanol (500 mL) at 50°C to 55°C, followed by the addition of deionized water (200 mL). The mixture was stirred for 10 minutes at 50°C to 55°C, followed by its cooling to 20°C to 25°C. The mixture was stirred at 20°C to 25°C for 2 hours. The solid was filtered, then washed with deionized water (50 mL). The wet solid was dried overnight at 50°C to 55°C to obtain the title compound. Yield: 45.3 g
Example 6: Preparation of tert-butyl r(5R)-3-{3-fluoro-4-r6-(2H-tetrazol-5-yl)pyridin-3- vHphenyl}-2-oxo-1.3-oxazolidin-5-vHmethyl carbonate (Formula X. when P^ is tert- butoxycarbonyl)
Tert-butyl {(5R)-3-[4-(6-cyanopyridin-3-yl)-3-fluorophenyl]-2-oxo-l,3- oxazolidin-5-yl} methyl carbonate (Formula IX, 25 g, Example 5) was dissolved in N,N- dimethylformamide (150 mL), followed by the addition of sodium azide (6.87 g) and ammonium chloride (5.65 g) under nitrogen atmosphere. The reaction mixture was heated to 95°C to 100°C and then stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to ambient temperature followed by the addition of deionized water (1L). The mixture was stirred at ambient temperature for 3 hours. The solid obtained was filtered, and then washed twice with deionized water (100 mL each). The wet solid was dried overnight at 60°C to 65°C to afford the title compound.
Yield: 25.8 g
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 Ρ is tert-butoxycarbonyl)
Method A: 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, 15 g, Example 6) was suspended in dichloromethane (450 mL), followed by the addition of methanol (7.25 mL) and triphenylphosphine (10.1 g) at ambient temperature under nitrogen atmosphere. Diethyl azodicarboxylate (7.62 g) was slowly added to the reaction mixture at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 hours. After completion of the reaction, 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.
Yield: 12.5 g
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. After completion of the reaction, deionized water (500 mL) was added, and then the mixture was stirred for 2 hours at ambient temperature. The solid was filtered and then washed with deionized water (50 mL) at ambient temperature. The wet solid was dried at 60°C to 65 °C to afford the title compound as a mixture of two isomers and used as such for the next step.
Example 8: Preparation of (5R)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- vHphenyl}-5-(hvdroxymethyl)-1.3-oxazolidin-2-one (Formula XII)
Tert-butyl [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl carbonate (Formula XI, 11 g, Example 7, Method A) was dissolved in dichloromethane (110 mL) at ambient temperature, and then trifluoroacetic acid (110 mL) was added to the mixture. The reaction mixture was stirred at ambient temperature for 3 hours. Dichloromethane (250 mL) and deionized water (500 mL) were added to the mixture, and then the resulting solution was stirred for 15 minutes to 20 minutes at ambient temperature. The layers were separated, and the
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. Methanol: dichloromethane (1 : 1, 500 mL) was added to the 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. Methanol (75 mL) was added to the dried material, then the mixture was heated to 70°C, and then gradually cooled to ambient temperature to obtain a suspension. The suspension was cooled to 0°C to 5°C, and then stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, and then washed with cold methanol (3 x 25 mL). The solid was dried at 45 °C for 6 hours to 7 hours to afford a crude compound (4.4 g). The crude compound (4.2 g) was dissolved in methanol: dichloromethane (1 : 1, 350 mL) at ambient temperature. Activated carbon (1 g) was added to the mixture, and then the solution was stirred at ambient temperature for 1 hour. The solution was filtered through a Hyflo®, and then the bed was washed with methanol: dichloromethane (1 : 1, 50 mL). The mother liquor was concentrated under vacuum to dryness. Dichloromethane in hexanes (20%, 150 mL) was added to the dried material, and the resulting slurry was stirred at ambient temperature for 0.5 hour. The solid obtained was filtered, and then dried at 45 °C for 6 hours to afford the title compound as an off-white solid.
Yield: 3.2 g
Example 9: Preparation of [(5j?)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yl]phenyl}-2-oxooxazolidin-5-yl]methyl hydrogen phosphate (Formula I)
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.
Yield: 2.95 g
Example 10: Preparation of di-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 phosphate (Formula B)
(5Pv)-3 - {3 -Fluoro-4- [6-(2-methyl-2H-tetrazol-5 -yl)pyridin-3 -yl]phenyl} -5 - (hydroxymethyl)- l,3-oxazolidin-2 -one (Formula XII, 1 g, Example 8) was added to a mixture of tetrahydrofuran (10 mL) and dichloromethane (5 mL). Tetrazole (0.6 g) and di-tert-butyl-N,N-diisopropylphosphoramidite (2.3 g) were added to the solution, and then the mixture was stirred for 16 hours at ambient temperature. After completion of the reaction, the 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.
Example 11 : Preparation of r(5j?)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- vHphenyl}-2-oxooxazolidin-5-vHmethyl hydrogen phosphate (Formula I)
Di-tert-butyl [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl phosphate (Formula B, Example 10) was added to trifluoroacetic acid (15 mL), and then the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was concentrated in vacuum at 45 °C to 50°C to obtain a residue. Ethanol (12 mL) and diethyl ether (10 mL) were added to the residue, and then the mixture was stirred for 2 hours at ambient temperature. The solid obtained was filtered, and the wet solid obtained was dried overnight under vacuum at 45°C to 50°C to afford the title compound.
Yield: 0.43 g
Chromatographic purity: 99.92 %

Claims

We claim:
1. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000022_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000022_0002
Formula II
with a compound of Formula III,
Figure imgf000022_0003
Formula III
wherein X is halogen.
to obtain a compound of Formula IV;
Figure imgf000022_0004
Formula IV
b) reacting the compound of Fonnula IV with a compound of Fonnula V,
Figure imgf000023_0001
Formula V
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VI;
Figure imgf000023_0002
Formula VI
c) reacting the compound of Formula VI with an iodinating agent to obtain a compound of Formula VII;
Figure imgf000023_0003
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000023_0004
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
e) coupling a compound of Formula VIII with a compound of Formula A,
Figure imgf000024_0001
Formula A
wherein R2 and R3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R2 and R3 are taken together with the oxygen atoms to which they are attached to form a 5- to 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl, or aralkyl,
in the presence of a palladium catalyst and a phosphine ligand to obtain a compound of Formula IX,
Figure imgf000024_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
f) reacting the compound of Formula IX with an alkali metal azide in the
presence of ammonium chloride to obtain a compound of Formula X,
Figure imgf000024_0003
Formula X
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
g) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI,
Figure imgf000025_0001
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
h) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000025_0002
Formula XII
i) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Formula I.
2. The process according to claim 1, wherein the compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in the presence of a base and a solvent.
3. The process according to claim 2, wherein 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.
4. The process according to claim 2, wherein the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N- dimethylformamide, acetonitrile, and mixtures thereof.
5. The process according to claim 1, wherein 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.
6. The process according to claim 5, wherein the base is n-butyl lithium.
7. The process according to claim 5, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, Ν,Ν-dimethylformamide, N- methylpyrrolidone, and mixtures thereof.
8. The process according to claim 1, wherein the compound of Formula VI is reacted with an iodinating agent to obtain the compound of Formula VII in the presence of an acid.
9. The process according to claim 1, wherein the iodinating agent is N- iodosuccinimide.
10. The process according to claim 8, wherein the acid is trifluoroacetic acid.
1 1. The process according to claim 1, wherein 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.
12. The process according to claim 1, wherein the protecting agent is selected from the group consisting di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
13. The process according to claim 1 1, wherein the solvent is selected from the group consisting of dimethylsulfoxide, Ν,Ν-dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
14. The process according to claim 1 1, wherein the catalyst is 4-(N,N- dimethylamino)pyridine.
15. The process according to claim 1, wherein 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. 16. The process according to claim 1, wherein 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 [ 1 , Γ - bis(diphenylphosphino)ferrocene]palladium(II) dichloride.
17. The process according to claim 1, wherein the phosphine ligand is selected from the group consisting of triphenylphosphine, tri(o-tolyl)phosphine, diphenylphosphino ethane, diphenylphosphino propane, and diphenylphosphino ferrocene.
18. The process according to claim 15, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethyl amine, and N,N-diisopropylamine.
19. The process according to claim 15, wherein the solvent is selected from the group consisting of water, Ν,Ν-dimethylformamide, dimethylsulphoxide, ethers, alcohols, hydrocarbons, and mixtures thereof.
20. The process according to claim 1, wherein 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.
21. The process according to claim 1, wherein the alkali metal azide is selected from the group consisting of sodium azide and potassium azide.
22. The process according to claim 20, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulphoxide, alcohols, and mixtures thereof.
23. The process according to claim 1, wherein the compound of Formula X is N- methylated with the methylating agent to obtain the compound of Formula XI in the presence of diethyl azodicarboxylates and triphenylphosphine in a solvent. 24. The process according to claim 1, wherein the compound of Formula X is N- methylated with the methylating agent to obtain the compound of Formula XI in the presence of a base and a solvent.
25. The process according to any one of claims 1, 23, or 24, wherein the methylating agent is selected from the group consisting of methanol and methyl iodide.
26. The process according to claim 23 or 24, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, ethers, halogenated solvents, and mixtures thereof.
27. The process according to claim 24, wherein 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 process according to claim 1, wherein 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 process according to claim 1, wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
The process according to claim 28, wherein the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
The process according to claim 1, wherein the compound of Formula XII is phosphorylated in the presence of a phosphorylating agent, a base, and a solvent to obtain tedizolid phosphate of Formula I.
The process according to claim 1, wherein the phosphorylating agent is phosphorus oxy chloride.
The process according to claim 31, wherein the base is triethylamine.
The process according to claim 31, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
The process according to claim 1, wherein the compound of Formula XII is phosphorylated to obtain tedizolid phosphate of Formula I by
a) reacting the compound of Formula XII with di-tert-butyl NN- diisopropylphosphoramidite in the presence of a catalyst and a solvent followed by the oxidation with an oxidizing agent to obtain a protected compound of Formula B; and
Figure imgf000028_0001
Formula B
b) deprotecting the protected compound of Formula B in the presence of an acid and a solvent to obtain tedizolid phosphate of Formula I.
36. The process according to claim 35, wherein the catalyst is tetrazole.
37. The process according to claim 35, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
38. The process according to claim 35, wherein the solvent in step a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
39. The process according to claim 35, wherein the acid is trifluoroacetic acid. 40. The process according to claim 35, wherein the solvent in step b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
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