WO2016088102A1 - Processes for the preparation of tedizolid phosphate and its intermediates - Google Patents

Processes for the preparation of tedizolid phosphate and its intermediates Download PDF

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Publication number
WO2016088102A1
WO2016088102A1 PCT/IB2015/059378 IB2015059378W WO2016088102A1 WO 2016088102 A1 WO2016088102 A1 WO 2016088102A1 IB 2015059378 W IB2015059378 W IB 2015059378W WO 2016088102 A1 WO2016088102 A1 WO 2016088102A1
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formula
compound
group
process according
solvent
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PCT/IB2015/059378
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French (fr)
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the present invention provides processes for the preparation of tedizolid phosphate.
  • the present invention further provides compounds of Formula IX and Formula X, processes for their preparation, and their use 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 processes for the preparation of tedizolid phosphate.
  • the present invention further provides compounds of Formula IX and Formula X, processes for their preparation, and their use in the preparation of tedizolid phosphate.
  • the processes of the present invention are industrially viable and produce high purity tedizolid phosphate in high 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 atoms selected from the group consisting of oxygen (O), and boron (B).
  • O oxygen
  • B boron
  • An example of a heterocyclic ring is 4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl.
  • Ri is Ci_6 alkyl
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • R 2 and R 3 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,
  • a second aspect of the present invention provides a process for the preparation of a compound of Formula IX,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • R 2 and R 3 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,
  • a third aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • R 2 and R 3 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,
  • a fourth aspect of the present invention provides a process for the preparation of a compound of Formula X,
  • 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 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,
  • a fifth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • R 2 and R 3 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,
  • a sixth aspect of the present invention provides a process for the preparation of a compound of Formula X,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • a seventh aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • An eighth aspect of the present invention provides a process for the preparation of a compound of Formula XI,
  • 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,
  • a ninth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • a tenth aspect of the present invention provides a process for the preparation of a compound of Formula XI,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • An eleventh aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • a twelfth aspect of the present invention provides a compound of Formula IX,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl.
  • a thirteenth aspect of the present invention provides a compound of Formula X,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl.
  • a fourteenth aspect of the present invention provides use of a compound of Formula IX,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • a fifteenth aspect of the present invention provides use of a compound of Formula X,
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
  • the compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent.
  • An example of an iodinating agent is iodine.
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
  • the solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, ⁇ , ⁇ -dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
  • reaction of the compound of Formula II with the iodinating agent is carried out for about 1 hour to about 25 hours, for example, for about 1 hour to about 10 hours.
  • reaction of the compound of Formula II with the iodinating agent is carried out at a temperature of about 5°C to about 35°C, for example, of about 10°C to about 30°C.
  • the compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula III 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 III is reacted with the compound of Formula IV to obtain the compound of Formula V in the presence of a base, a phase transfer catalyst, 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 phase transfer catalyst is selected from the group consisting of tetra-n- butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether.
  • 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
  • reaction of the compound of Formula III with the compound of Formula IV 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 III with the compound of Formula IV 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 V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula V 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 V is reacted with the compound of Formula VI to obtain the compound of Formula VII 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 V with the compound of Formula VI 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 V with the compound of Formula VI 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 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 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 the 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 110°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 either diethyl azodicarboxylates and triphenylphosphine in a solvent or in the presence of a base and a solvent.
  • methylating agents include methanol and methyl iodide.
  • the solvent is selected from the group consisting of N,N-dimethylformamide, ethers, halogenated solvents, 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 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 mixtures 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 out for about 2 hours to about 10 hours, for example, for about 3 hours to about 6 hours.
  • 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.
  • An example of the catalyst used in step (a) is tetrazole.
  • the oxidizing agent used in step (a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
  • the solvent used 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.
  • step (a) examples 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.
  • step (a) 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.
  • 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. 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 NMR spectrum was recorded using a Bruker ® Avance III (400 MHz) NMR spectrometer.
  • Mass spectrum was recorded using a MASS (API2000) LC/MS-MS system, Q Trap ® LC/MS-MS system (Applied Biosystems ® ) .
  • the IR spectrum was recorded using a Perkin Elmer ® instrument.
  • the dichloromethane layer was washed with deionized water (500 mL), then dried over anhydrous sodium sulfate, and then concentrated under vacuum at 30°C to 35°C. Hexanes (600 mL) were added to the residue, and the resulting slurry was stirred for 3 hours at 20°C to 25°C. The obtained solid was filtered under vacuum and then washed with hexanes (100 mL). The solid obtained was dried under vacuum at 40°C to 45°C for 10 hours to afford the title compound.
  • Methyl (3-fluoro-4-iodophenyl) carbamate (Formula V, 50 g, Example 2) was dissolved in anhydrous tetrahydroiuran (350 mL) at 20°C to 25 °C, and then the solution was cooled to -65°C to -60°C under a nitrogen atmosphere. n-Butyl lithium ( 1.6 M in hexane, 45.5 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes.
  • 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 was 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 it, followed by the addition of deionized water (1L).
  • Example 7 Preparation oftert-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 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 the suspension was 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-dimethylformamide (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.
  • 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 the another flask containing deionized water (110 mL) precooled to 0° to 5°C. The temperature 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 to the reaction mixture.
  • the organic layer was separated, and then washed with an aqueous solution of sodium bicarbonate (0.5 g in 20 mL deionized water), followed by 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.

Abstract

The present invention provides processes for the preparation of tedizolid phosphate. The present invention further provides compounds of Formula IX and Formula X, processes for their preparation, and their use for the preparation of tedizolid phosphate. The processes of the present invention are industrially viable and produce high purity tedizolid phosphate in high yield.

Description

PROCESSES FOR THE PREPARATION OF TEDIZOLID PHOSPHATE AND ITS
INTERMEDIATES
Field of the Invention
The present invention provides processes for the preparation of tedizolid phosphate. The present invention further provides compounds of Formula IX and Formula X, processes for their preparation, and their use 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 processes for the preparation of tedizolid phosphate. The present invention further provides compounds of Formula IX and Formula X, processes for their preparation, and their use in the preparation of tedizolid phosphate.
The processes of the present invention are industrially viable and produce high purity tedizolid phosphate in high 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 atoms 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.
Figure imgf000003_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000003_0002
Formula II
with an iodinating agent to obtain a compound of Formula III;
Figure imgf000004_0001
Formula III
b) reacting the compound of Fonnula III with a compound of Formula IV,
Figure imgf000004_0002
Formula IV
wherein X is halogen,
to obtain a compound of Fonnula V;
Figure imgf000004_0003
Formula V
c) reacting the compound of Formula V with a compound of Formula VI,
Figure imgf000004_0004
Formula VI
wherein Ri is Ci_6 alkyl,
to obtain a compound of Formula VII;
Figure imgf000004_0005
Formula VII d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000005_0001
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
e) coupling the 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
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 imgf000006_0001
Formula X
g) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI;
Figure imgf000006_0002
Formula XI
h) deprotecting the compound of Fonnula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000006_0003
Formula XII
i) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Formula I.
A second aspect of the present invention provides a process for the preparation of a compound of Formula IX,
Figure imgf000006_0004
Formula IX wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising coupling a compound of Formula VIII
Figure imgf000007_0001
Formula VIII
with a compound of Formula A
Figure imgf000007_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.
A third aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000007_0003
Formula I
wherein the process comprises:
a) coupling a compound of Formula VIII,
Figure imgf000008_0001
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a compound of Formula A,
Figure imgf000008_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; and
Figure imgf000008_0003
Formula IX
b) converting the compound of Formula IX into tedizolid phosphate of Formula I.
A fourth aspect of the present invention provides a process for the preparation of a compound of Formula X,
Figure imgf000008_0004
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
wherein the process comprises:
a) coupling a compound of Formula VIII
Figure imgf000009_0001
Formula VIII
with a compound of Formula A,
Figure imgf000009_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; and
Figure imgf000009_0003
b) reacting the compound of Formula IX with an alkali metal azide in the
presence of ammonium chloride to obtain the compound of Formula X.
A fifth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000010_0001
Formula I
wherein the process comprises:
a) coupling a compound of Formula VIII,
Figure imgf000010_0002
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a compound of Formula A,
Figure imgf000010_0003
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 imgf000010_0004
b) reacting the compound of Formula IX with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000011_0001
Formula X
c) converting the compound of Formula X into tedizolid phosphate of Formula I.
A sixth aspect of the present invention provides a process for the preparation of a compound of Formula X,
Figure imgf000011_0002
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising reacting a compound of Formula IX
Figure imgf000011_0003
Formula IX
with an alkali metal azide in the presence of ammonium chloride.
A seventh aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000012_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000012_0002
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000012_0003
Formula X
b) converting the compound of Formula X into tedizolid phosphate of Formula I. An eighth aspect of the present invention provides a process for the preparation of a compound of Formula XI,
Figure imgf000012_0004
Formula XI wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000013_0001
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000013_0002
Formula X
b) N-methylating the compound of Formula X with a methylating agent to obtain the compound of Formula XI.
A ninth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000013_0003
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000014_0001
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride, to obtain a compound of Formula X;
Figure imgf000014_0002
Formula X
b) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI; and
Figure imgf000014_0003
Formula XI
c) converting the compound of Formula XI into tedizolid phosphate of Formula I. A tenth aspect of the present invention provides a process for the preparation of a compound of Formula XI,
Figure imgf000014_0004
Formula XI wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising N-methylating a compound of Formula X
Figure imgf000015_0001
Formula X
with a methylating agent.
An eleventh aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000015_0002
Formula I
wherein the process comprises:
a) N-methylating a compound of Formula X,
Figure imgf000015_0003
Formula X
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a methylating agent to obtain a compound of Formula XI; and
Figure imgf000016_0001
Formula XI
b) converting the compound of Formula XI into tedizolid phosphate of Formula I. A twelfth aspect of the present invention provides a compound of Formula IX,
Figure imgf000016_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl.
A thirteenth aspect of the present invention provides a compound of Formula X,
Figure imgf000016_0003
Formula X
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl.
A fourteenth aspect of the present invention provides use of a compound of Formula IX,
Figure imgf000016_0004
Formula IX wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
for the preparation of tedizolid phosphate of Formula I.
A fifteenth aspect of the present invention provides use of a compound of Formula X,
Figure imgf000017_0001
Formula X
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
for the preparation of tedizolid phosphate of Formula I.
The compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent.
An example of an iodinating agent is iodine.
The base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
The solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, Ν,Ν-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
The reaction of the compound of Formula II with the iodinating agent is carried out for about 1 hour to about 25 hours, for example, for about 1 hour to about 10 hours.
The reaction of the compound of Formula II with the iodinating agent is carried out at a temperature of about 5°C to about 35°C, for example, of about 10°C to about 30°C.
The compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula III 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 III is reacted with the compound of Formula IV to obtain the compound of Formula V in the presence of a base, a phase transfer catalyst, 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 phase transfer catalyst is selected from the group consisting of tetra-n- butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether.
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 III with the compound of Formula IV 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 III with the compound of Formula IV 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 V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula V 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 V is reacted with the compound of Formula VI to obtain the compound of Formula VII 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 V with the compound of Formula VI 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 V with the compound of Formula VI 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 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 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 the 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 110°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 either 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 solvents, 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 mixtures 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 out 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 the compound 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 imgf000024_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 used in step (a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
The solvent used 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 NMR spectrum was recorded using a Bruker® Avance III (400 MHz) NMR spectrometer.
The Mass spectrum was recorded using a MASS (API2000) LC/MS-MS system, Q Trap® LC/MS-MS system (Applied Biosystems®) .
The IR spectrum was recorded using a Perkin Elmer® instrument.
The chromatographic purity was recorded using an Acquity® H-class UPLC, PDA Detector.
EXAMPLES
Example 1 : Preparation of 3-fluoro-4-iodoaniline (Formula IIP
Sodium bicarbonate (113.4 g) was dissolved in deionized water (1 L) at 20°C to 25°C. The mixture was stirred for 20 minutes at ambient temperature. 3-Fluoro aniline (Formula II, 100 g) was added to the solution at 20°C to 25°C. The reaction mixture was cooled to 10°C to 15°C, followed by the addition of iodine (183 g) in small lots over a period of 1.5 hours. The reaction mixture was stirred for 1 hour at 10°C to 15°C, and then further stirred for 14 hours to 16 hours at 20°C to 25°C. The solid obtained was filtered, and then washed with deionized water (100 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.
Yield: 166.2 g
Example 2: Preparation of methyl (3-fluoro-4-iodophenyl) carbamate (Formula V)
3-Fluoro-4-iodoaniline (Formula III, 100 g, Example 1) was dissolved in dichloromethane (1 L) under inert atmosphere at ambient temperature. Sodium bicarbonate (71 g) and tetra-n-butylammonium bromide (10 g) were added while stirring at ambient temperature. Methyl chloroformate (Formula IV, when X=chloro; 72 g) was added to the reaction mixture at ambient temperature over 30 minutes. The reaction mixture was stirred for 3 hours at ambient temperature. Deionized water (1 L) was added to the reaction mixture, and then the mixture was stirred at ambient temperature for 20 minutes. The layers were separated. The dichloromethane layer was washed with deionized water (500 mL), then dried over anhydrous sodium sulfate, and then concentrated under vacuum at 30°C to 35°C. Hexanes (600 mL) were added to the residue, and the resulting slurry was stirred for 3 hours at 20°C to 25°C. The obtained solid was filtered under vacuum and then washed with hexanes (100 mL). The solid obtained was dried under vacuum at 40°C to 45°C for 10 hours to afford the title compound.
Yield: 104.4 g
Example 3: Preparation of (5R)-3-(3-fluoro-4-iodophenyl)-5-(hvdroxymethyl)-1.3- oxazolidin-2-one (Formula VII)
Methyl (3-fluoro-4-iodophenyl) carbamate (Formula V, 50 g, Example 2) was dissolved in anhydrous tetrahydroiuran (350 mL) at 20°C to 25 °C, and then the solution was cooled to -65°C to -60°C under a nitrogen atmosphere. n-Butyl lithium ( 1.6 M in hexane, 45.5 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes. (R)-(-)-Glycidyl butyrate (Formula VI, when Ri= n-propyl, 24.66 g) was slowly added to the reaction mixture under a nitrogen atmosphere at -65°C to -60°C and then the mixture was stirred for 1 hour. The reaction mixture was allowed to attain ambient temperature, then was stirred for 20 hours at 20°C to 25 °C under nitrogen atmosphere. After completion of the reaction, an ammonium chloride solution (5.0 g dissolved in 50 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 2 hours. The solid obtained was filtered, and then washed with deionized water (50 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.
Yield: 48.55 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 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 an 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 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 was 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 it, followed by the addition of deionized water (1L). The solution was stirred at ambient temperature for 10 minutes, and then 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 cooling to 20°C to 25°C. The mixture was stirred at 20°C to 25°C for 2 hours. The solid was filtered, and then washed with deionized water (50 mL), and then the wet solid was dried overnight at 50°C to 55°C to obtain the title compound. Yield: 45.3 g
^-NMR (DMSO-d6): δ 8.97 (s, IH), 8.24-8.26 (dd, IH), 8.14-8.16 (dd, IH), 7.67-7.79 (m, IH), 7.51-7.54 (m, IH), 7.30-7.31 (dd, IH), 4.96-5.02 (m, IH), 4.30-4.36 (m, 2H), 4.21-4.28 (m, IH), 3.90-3.92 (m, IH), 1.41 (s, 9H)
Mass (m/z): 414.3 [M+H]+
IR (in KBr, οηι_1):3451, 2987, 1748, 1628, 1226, 1088, 849
Example 6: Preparation oftert-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 a nitrogen atmosphere. The reaction mixture was heated to 95 °C to 100°C, and was 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 (1 L). The mixture was stirred at ambient temperature for 3 hours. The solid obtained was filtered, and then was 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
i-NMR (DMSO-d6): δ 8.88 (s, IH), 8.22-8.24 (dd, IH), 8.14-8.16 (dd, IH), 7.50-7.77 (m, 2H), 7.30-7.31 (m, IH), 4.97-5.03 (m, IH), 4.22-4.37 (m, 2H), 4.14-4.18 (m, IH), 3.89-3.92 (m, IH)
Mass (m/z): 457.3 [M+H]+
IR (in KBr, cm"1 ): 3430, 2979, 1748, 1627, 1284, 1158, 857
Example 7: Preparation oftert-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 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 the suspension was 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-dimethylformamide (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- yl]phenyl}-5-(hydroxymethyl)-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 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 solution 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 solution, 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 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 r(5j?)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- vHphenyl}-2-oxooxazolidin-5-vHmethyl 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 the another flask containing deionized water (110 mL) precooled to 0° to 5°C. The temperature 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 to the reaction mixture. The organic layer was separated, and then washed with an aqueous solution of sodium bicarbonate (0.5 g in 20 mL deionized water), followed by 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 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, andthen the mixture was stirred for 2 hours at ambient temperature. The solid obtained was filtered, and the wet solid 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 imgf000033_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000033_0002
Formula II
with an iodinating agent to obtain a compound of Formula III;
Figure imgf000033_0003
Formula III
b) reacting the compound of Formula III with a compound of Formula IV,
Figure imgf000033_0004
Formula IV
wherein X is halogen,
to obtain a compound of Formula V;
Figure imgf000034_0001
Formula V
c) reacting the compound of Formula V with a compound of Formula VI,
Figure imgf000034_0002
Formula VI
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VII;
Figure imgf000034_0003
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000034_0004
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
e) coupling the compound of Formula VIII with a compound of Formula A,
Figure imgf000035_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 imgf000035_0002
Formula IX
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 imgf000035_0003
Formula X
g) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI;
Figure imgf000035_0004
Formula XI h) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000036_0001
Formula XII
i) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Formula I.2. A process for the preparation of a compound of Formula IX,
Figure imgf000036_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising coupling a compound of Formula VIII
Figure imgf000036_0003
Formula VIII
with a compound of Formula A,
Figure imgf000036_0004
Formula A 12 wherein R2 and R3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R2 and R3
13 are taken together with the oxygen atoms to which they are attached to form a 5 - to
14 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl,
15 or aralkyl,
16 in the presence of a palladium catalyst and a phosphine ligand.
1 3. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000037_0001
4 wherein the process comprises:
5 a) coupling a compound of Formula VIII,
Figure imgf000037_0002
7 Formula VIII
8 wherein Pi is a protecting group selected from the group consisting of tert-
9 butoxycarbonyl, benzyloxycarbonyl, and benzyl,
10 with a compound of Formula A,
Figure imgf000037_0003
12 Formula A
13 wherein R2 and R3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R2 and
14 R3 are taken together with the oxygen atoms to which they are attached to form
15 a 5- to 6-membered heterocyclic ring, which is optionally substituted with Ci-6
16 alkyl, aryl, or aralkyl, in the presence of a palladium catalyst and a phosphine ligand to obtain a compound of Formula IX; and
Figure imgf000038_0001
Formula IX
b) converting the compound of Formula IX into tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula X,
Figure imgf000038_0002
Formula X
wherein P! is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
wherein the process comprises:
a) coupling a compound of Formula VIII
Figure imgf000038_0003
Formula VIII
with a compound of Formula A,
Figure imgf000038_0004
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; and
Figure imgf000039_0001
Formula IX
b) reacting the compound of Formula IX with an alkali metal azide in the
presence of ammonium chloride to obtain the compound of Formula X.
5. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000039_0002
Formula I
wherein the process comprises:
a) coupling a compound of Formula VIII,
Figure imgf000039_0003
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a compound of Formula A,
Figure imgf000040_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 imgf000040_0002
b) reacting the compound of Formula IX with an alkali metal azide in the
presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000040_0003
Formula X
c) converting the compound of Formula X into tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula X,
Figure imgf000040_0004
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising reacting a compound of Formula IX
Figure imgf000041_0001
Formula IX
with an alkali metal azide in the presence of ammonium chloride.
7. A process for the preparation of tedizolid phosphate of Formula I
Figure imgf000041_0002
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000041_0003
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000042_0001
Formula X
b) converting the compound of Formula X into tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula XI,
Figure imgf000042_0002
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
wherein the process comprises:
a) reacting a compound of Formula IX
Figure imgf000042_0003
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X; and
Figure imgf000042_0004
b) N-methylating the compound of Formula X with a methylating agent to obtain the compound of Formula XI.
9. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000043_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula IX,
Figure imgf000043_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with an alkali metal azide in the presence of ammonium chloride to obtain a compound of Formula X;
Figure imgf000043_0003
Formula X
b) N-methylating the compound of Formula X with a methylating agent to obtain a compound of Formula XI; and
Figure imgf000044_0001
Formula XI
c) converting the compound of Fonnula XI into tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula XI,
Figure imgf000044_0002
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising N-methylating a compound of Formula X
Figure imgf000044_0003
Formula X
with a methylating agent.
A process for the reparation of tedizolid phosphate of Formula I.
Figure imgf000044_0004
Formula I
wherein the process comprises: a) N-methylating a compound of Formula X,
Figure imgf000045_0001
Formula X
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a methylating agent to obtain a compound of Formula XI; and
Figure imgf000045_0002
Formula XI
b) converting the compound of Formula XI into tedizolid phosphate of Formula I. 12. The process according to claim 1, wherein the compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent.
13. The process according to claim 1, wherein the iodinating agent is iodine.
14. The process according to claim 12, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
15. The process according to claim 12, wherein the solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
16. The process according to claim 1, wherein the compound of Formula III is reacted with the compound of Formula IV to obtain the compound of Formula V in presence of a base, a phase transfer catalyst, and a solvent.
17. The process according to claim 16, 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.
18. The process according to claim 16, wherein the phase transfer catalyst is selected from the group consisting of tetra-n-butylammonium bromide, tetra-n- butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether. 19. The process according to claim 16, wherein the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N- dimethylformamide, acetonitrile, and mixtures thereof.
20. The process according to claim 1, wherein the compound of Formula V is reacted with the compound of Formula VI to obtain the compound of Formula VII in the presence of a base and a solvent.
21. The process according to claim 20, wherein the base is n-butyl lithium.
22. The process according to claim 20, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, Ν,Ν-dimethylformamide, N- methylpyrrolidone, and mixtures thereof.
23. 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.
24. 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.
25. The process according to claim 23, wherein the solvent is selected from the group consisting of dimethylsulfoxide, Ν,Ν-dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
26. The process according to claim 23, wherein the catalyst is 4-(N,N- dimethylamino)pyridine.
27. The process according to any one of claims 1, 2, 3, 4, or 5, 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.
28. The process according to any one of claims 1, 2, 3, 4, or 5, 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 [ Ι, - bis(diphenylphosphino)ferrocene]palladium(II) dichloride.
29. The process according to any one of claims 1, 2, 3, 4, or 5, wherein the phosphine ligand is selected from the group consisting of triphenylphosphine, tri(o- tolyl)phosphine, diphenylphosphino ethane, diphenylphosphino propane, and diphenylphosphino ferrocene.
30. The process according to claim 27, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethyl amine, and N,N-diisopropylamine.
31. The process according to claim 27, wherein the solvent is selected from the group consisting of water, Ν,Ν-dimethylformamide, dimethylsulphoxide, ethers, alcohols, hydrocarbons, and mixtures thereof.
32. The process according to any one of claims 1, 4, 5, 6, 7, 8, or 9, 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.
33. The process according to any one of claims 1, 4, 5, 6, 7, 8, or 9, wherein the alkali metal azide is selected from the group consisting of sodium azide and potassium azide.
34. The process according to claim 32, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulphoxide, alcohols, and mixtures thereof.
35. The process according to any one of claims 1, 8, 9, 10 or 1 1, wherein 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.
36. The process according to any one of claims 1, 8, 9, 10 or 11, wherein the compound of Formula X is N-methylated with a methylating agent to obtain the compound of Formula XI in the presence of a base and a solvent.
37. The process according to any one of claims 1, 8, 9, 10, or 11, wherein the
methylating agent is selected from the group consisting of methanol and methyl iodide.
38. The process according to claim 35 or 36, wherein the solvent is selected from the group consisting of N,N-dimethylformamide, ethers, halogenated solvents, and mixtures thereof.
39. The process according to claim 36, 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.
40. 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.
41. The process according to claim 1, wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
42. The process according to claim 40, wherein the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
43. 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.
44. The process according to claim 1, wherein the phosphorylating agent is phosphorus oxy chloride.
45. The process according to claim 43, wherein the base is triethylamine.
46. The process according to claim 43, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
47. 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 imgf000049_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.
48. The process according to claim 47, wherein the catalyst is tetrazole.
49. The process according to claim 47, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
50. The process according to claim 47, wherein the solvent in step (a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
51. The process according to claim 47, wherein the acid is trifluoroacetic acid. 52. The process according to claim 47, wherein the solvent in step (b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
53. A compound of Formula IX,
Figure imgf000049_0002
Formula IX wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl.
54. A compound of Formula X,
Figure imgf000050_0001
Formula X
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzy l.
55. Use of a compound of Formula IX,
Figure imgf000050_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
for the preparation of tedizolid phosphate of Formula I.
56. Use of a compound of Formula X,
Figure imgf000050_0003
Formula X
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
for the preparation of tedizolid phosphate of Formula I.
PCT/IB2015/059378 2014-12-05 2015-12-04 Processes for the preparation of tedizolid phosphate and its intermediates WO2016088102A1 (en)

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