WO2016088100A1 - 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
WO2016088100A1
WO2016088100A1 PCT/IB2015/059374 IB2015059374W WO2016088100A1 WO 2016088100 A1 WO2016088100 A1 WO 2016088100A1 IB 2015059374 W IB2015059374 W IB 2015059374W WO 2016088100 A1 WO2016088100 A1 WO 2016088100A1
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formula
compound
process according
group
tert
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PCT/IB2015/059374
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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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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention provides processes for the preparation of tedizolid phosphate.
  • the present invention further provides compounds of Formula VIII, Formula IX, and Formula XI, 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 VIII, Formula IX, and Formula XI, processes for their preparation, and their use for the preparation of tedizolid phosphate.
  • 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.
  • a first aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Ri is Ci-6 alkyl
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • R 2 and 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 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 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 third aspect of the present invention provides a process for the preparation of a compound of Formula VIII,
  • Pi is a protecting group selected from the group consisting of tert-butoxy carbonyl, benzyloxycarbonyl, and benzyl,
  • a fourth 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 fifth 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;
  • P2 and P3 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, comprising reacting a compound of Formula VIII
  • 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 sixth 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 seventh 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,
  • 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,
  • An eighth 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;
  • P 2 and P 3 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 ninth aspect of the present invention provides a process for the preparation of a compound of Formula XII,
  • 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 tedizolid phosphate of Formula I,
  • 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 compound of Formula VIII
  • 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;
  • P2 and P3 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.
  • a thirteenth aspect of the present invention provides a compound of Formula XI
  • 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
  • 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
  • Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • P 2 and P 3 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, for the preparation of tedizolid phosphate of Formula I.
  • a sixteenth aspect of the present invention provides use of a compound of Formula
  • 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 the compound of Formula III to obtain the compound of Formula IV in the presence of a base and a solvent.
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and pyridine.
  • the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N-dimethylformamide, acetonitrile, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include n-hexane, n-heptane, cyclohexane, toluene, and xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula II with the compound of Formula III is carried out for about 15 minutes to about 8 hours, for example, for about 30 minutes to about 4 hours.
  • reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • the compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula IV may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula IV is reacted with the compound of Formula V to obtain the compound of Formula VI in the presence of a base and a solvent.
  • An example of a base is n-butyl lithium.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, ⁇ , ⁇ -dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
  • ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula IV with the compound of Formula V is carried out for about 15 hours to about 25 hours, for example, for about 20 hours to about 22 hours.
  • reaction of the compound of Formula IV with the compound of Formula V is carried out at a temperature of about -78°C to about 40°C, for example, of about -65°C to about 30°C.
  • the compound of Formula VI may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VI is reacted with an iodinating agent to obtain the compound of Formula VII in the presence of an acid.
  • An example of an iodinating agent is N-iodosuccinimide.
  • An example of an acid is trifluoroacetic acid.
  • reaction of the compound of Formula VI with the iodinating agent is carried out for about 2 hours to about 8 hours, for example, for about 3 hours to about 6 hours.
  • reaction of the compound of Formula VI with the iodinating agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • the compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VII is protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent.
  • the protecting agent is selected from the group consisting 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 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 reacted with the compound of Formula A to obtain the compound of Formula IX in the presence of a palladium catalyst, a base and a solvent.
  • a palladium catalyst is [ 1, 1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex.
  • An example of a base is potassium acetate.
  • the solvent is selected from the group consisting of dimethylsulphoxide, acetonitrile, ⁇ , ⁇ -dimethylformamide, 1,4-dioxane, and tetrahydrofuran.
  • the reaction of the compound of Formula VIII with the compound of Formula A is carried out for about 15 minutes to about 6 hours, for example for about 30 minutes to about 4 hours.
  • reaction of the compound of Formula VIII with the compound of Formula A is carried out at a temperature of about 15°C to about 80°C, for example, of about 20°C to about 70°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 coupled with the compound of Formula X to obtain the compound of Formula XI in the presence of a palladium catalyst, a base and a solvent.
  • the palladium catalyst is selected from the group consisting of
  • 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, ethers, alcohols, hydrocarbons, and a mixture 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 IX with the compound of Formula X is carried for about 15 minutes to about 7 hours, for example, for about 30 minutes to about 6 hours.
  • the reaction of the compound of Formula IX with the compound of Formula X is carried out at a temperature of about 25°C to about 100°C, for example, of about 30°C to about 80°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 to obtain the compound of Formula XII in a solvent.
  • the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
  • the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
  • ketones include acetone and methyl ethyl ketone.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out for about 1 hour to about 7 hours, for example, for about 2 hours to about 4 hours.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25 °C to about 35°C.
  • the compound of Formula XII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula XII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XII is phosphorylated in the presence of a
  • phosphorylating agent is phosphorus oxy chloride.
  • An example of a base is triethyl amine.
  • 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.
  • the phosphorylation of the compound of Formula XII in the presence of the phosphorylating agent is carried out at a temperature of about -10°C to about 10°C, for example, of about -7°C to about 8°C.
  • Tedizolid phosphate of Formula I may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Tedizolid phosphate of Formula I may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XII is phosphorylated to obtain tedizolid phosphate of Formula I by:
  • An example of the catalyst used in step a) is tetrazole.
  • the oxidizing agent in step a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
  • the solvent in step a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in the presence of a catalyst in step a) is carried out for about 1 hour to about 30 hours, for example, for about 2 hours to about 10 hours.
  • reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in the presence of a catalyst 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 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 in the presence of an acid 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 in the presence of an acid is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
  • Tedizolid phosphate of Formula I may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. Tedizolid phosphate of Formula I may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the 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 chromatographic purity was recorded using an Acquity ® H-class UPLC, PDA Detector.
  • Methyl (3-fluorophenyl)carbamate (Formula IV, 70 g, Example 1) was dissolved in anhydrous tetrahydrofuran (420 mL) at ambient temperature and the solution was cooled to -65°C to -60°C under nitrogen atmosphere.
  • n-Butyl lithium (1.6 M in hexane, 272 mL) was slowly added to the above solution under a nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes.
  • reaction mixture was warmed to ambient temperature, and then stirred for 20 hours at 20°C to 25 °C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (7 g dissolved in 70 mL of deionized water) was added to the reaction mixture.
  • Tetrahydrofuran was recovered under vacuum at 40°C to 45 °C, followed by the addition of deionized water (500 mL) at 40°C to 45°C. The reaction mixture was allowed to attain ambient temperature and was then stirred for 2 hours. The solid obtained was filtered, then washed with deionized water (70 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.
  • Deionized water 50 mL was added to the residue, followed by the addition of ethyl acetate in hexanes (20%, 30 mL). The resulting biphasic system was stirred at ambient temperature for 15 minutes, then cooled to 0°C to 5°C, and then stirred for another 1 hour at 0°C to 5°C. The solid obtained was filtered, then washed with deionized water (40 mL) and 20% ethyl acetate in hexanes (30 mL). The solid was dried at 40°C to 45°C for 4 hours to afford the title compound as an off-white solid.
  • the solid obtained was filtered, 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, 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.
  • 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 7) while stirring under an inert atmosphere.
  • the reaction mixture was cooled to -5°C in an ice bath, 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 another flask containing deionized water (110 mL) precooled to 0°C 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 dissolved in 20 mL deionized water) were added to the mixture.
  • the organic layer was separated, then washed with an aqueous solution of sodium bicarbonate (0.5 g dissolved in 20 mL deionized water), followed by deionized water (20 mL).

Abstract

The present invention provides processes for the preparation of tedizolid phosphate. The present invention further provides compounds of Formula (VIII), Formula (IX), and Formula (XI), processes for their preparation, and their use for the preparation of tedizolid phosphate. The processes of the present invention use non-toxic and inexpensive reagents, are industrially viable, and produce tedizolid phosphate having high purity and 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 VIII, Formula IX, and Formula XI, 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 VIII, Formula IX, and Formula XI, processes for their preparation, and their use for the preparation of tedizolid phosphate.
The processes of the present invention use non-toxic and inexpensive reagents, are industrially viable, and produce tedizolid phosphate having high purity and yield. Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to a temperature in the range of about 20°C to about 25 °C.
The term "halogen," as used herein, refers to chloro, bromo, or iodo.
The term "Ci-6 alkyl," as used herein, refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec- pentyl, 3-pentyl, n-hexyl, iso-hexyl, 2,3-dimethylbutyl, or neo-hexyl.
The term "aryl," as used herein, refers to a monocyclic aromatic hydrocarbon. An example of an aryl is phenyl.
The term "aralkyl," as used herein, refers to a methylene substituted aryl group. An example of an aralkyl is benzyl.
The term "heterocycle," as used herein, refers to a non-aromatic ring containing one or more hetero 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.
A first aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000003_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000003_0002
Formula II with a compound of Formula III,
Figure imgf000004_0001
Formula III
wherein X is halogen,
to obtain a compound of Formula IV;
Figure imgf000004_0002
Formula IV
b) reacting the compound of Formula IV with a compound of Formula V,
Figure imgf000004_0003
Formula V
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VI;
Figure imgf000004_0004
c) reacting the compound of Formula VI with an iodinating agent to obtain a compound of Formula VII;
Figure imgf000004_0005
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) reacting 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 to obtain a compound of Formula IX;
Figure imgf000005_0003
Formula IX
f) coupling the compound of Formula IX with a compound of Formula X,
Figure imgf000005_0004
Formula X
wherein X is halogen, in the presence of a palladium catalyst to obtain a compound of Formula XI;
Figure imgf000006_0001
Formula XI
g) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000006_0002
Formula XII
h) 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 tedizolid phosphate of Formula I.
Figure imgf000006_0003
Formula I
wherein the process comprises:
a) protecting a compound of Formula VII
Figure imgf000006_0004
Formula VII with a protecting agent to obtain a compound of Formula VIII
Figure imgf000007_0001
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
b) reacting the compound of 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 to obtain a compound of Formula IX;
Figure imgf000007_0003
Formula IX
c) coupling the compound of Formula IX with a compound of Formula X,
Figure imgf000007_0004
Formula X
wherein X is halogen, in the presence of a palladium catalyst to obtain a compound of Formula XI; and
Figure imgf000008_0001
Formula XI
d) converting the compound of Formula XI into tedizolid phosphate of Formula I.
A third aspect of the present invention provides a process for the preparation of a compound of Formula VIII,
Figure imgf000008_0002
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert-butoxy carbonyl, benzyloxycarbonyl, and benzyl,
comprising protecting a compound of Formula VII
Figure imgf000008_0003
Formula VII
with a protecting agent.
A fourth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000008_0004
Formula I wherein the process comprises:
a) protecting a compound of Formula VII
Figure imgf000009_0001
Formula VII
with a protecting agent to obtain a compound of Formula VIII
Figure imgf000009_0002
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
b) converting the compound of Formula VIII into tedizolid phosphate of Formula
I.
A fifth aspect of the present invention provides a process for the preparation of a compound of Formula IX,
Figure imgf000009_0003
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
P2 and P3 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, comprising reacting a compound of Formula VIII
Figure imgf000010_0001
with a compound of Formula A
Figure imgf000010_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.
A sixth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000010_0003
Formula I
wherein the process comprises:
a) reacting a compound of Formula VIII,
Figure imgf000010_0004
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
with a compound of Formula A,
O OR
\ /
B— B
/ \
O OR
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 to obtain a compound of Formula IX; and
Figure imgf000011_0001
Formula IX
b) converting the compound of Formula IX into tedizolid phosphate of Formula I.
A seventh aspect of the present invention provides a process for the preparation of a compound of Formula XI,
Figure imgf000011_0002
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising coupling a compound of Formula IX,
Figure imgf000012_0001
Formula IX
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,
with a compound of Formula X,
Figure imgf000012_0002
Formula X
wherein X is halogen,
in the presence of a palladium catalyst.
An eighth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000012_0003
Formula I
wherein the process comprises:
a) coupling a compound of Formula IX,
Figure imgf000012_0004
Formula IX wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
P2 and P 3 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,
with a compound of Formula X,
Figure imgf000013_0001
Formula X
wherein X is halogen,
in the presence of a palladium catalyst to obtain a compound of Formula XI; and
Figure imgf000013_0002
Formula XI
b) converting the compound of Formula XI into tedizolid phosphate of Formula I.
A ninth aspect of the present invention provides a process for the preparation of a compound of Formula XII,
Figure imgf000013_0003
Formula XII
wherein the process comprises deprotecting a compound of Formula XI,
Figure imgf000014_0001
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl,
in the presence of a deprotecting agent.
A tenth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000014_0002
Formula I
wherein the process comprises:
a) deprotecting a compound of Formula XI,
Figure imgf000014_0003
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000014_0004
Formula XII b) converting the compound of Formula XII into tedizold phosphate of Formula I.
An eleventh aspect of the present invention provides a compound of Formula VIII
Figure imgf000015_0001
Formula VIII
wherein 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
Figure imgf000015_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
P2 and P3 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.
A thirteenth aspect of the present invention provides a compound of Formula XI
Figure imgf000015_0003
Formula XI
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 VIII
Figure imgf000016_0001
Formula VIII
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
IX,
Figure imgf000016_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
P2 and P3 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, for the preparation of tedizolid phosphate of Formula I.
A sixteenth aspect of the present invention provides use of a compound of Formula
XI
Figure imgf000016_0003
Formula XI
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 the compound of Formula III to obtain the compound of Formula IV in the presence of a base and a solvent.
The base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and pyridine.
The solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N-dimethylformamide, acetonitrile, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include n-hexane, n-heptane, cyclohexane, toluene, and xylene.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The reaction of the compound of Formula II with the compound of Formula III is carried out for about 15 minutes to about 8 hours, for example, for about 30 minutes to about 4 hours.
The reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
The compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula IV may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula IV is reacted with the compound of Formula V to obtain the compound of Formula VI in the presence of a base and a solvent.
An example of a base is n-butyl lithium.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, Ν,Ν-dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The reaction of the compound of Formula IV with the compound of Formula V is carried out for about 15 hours to about 25 hours, for example, for about 20 hours to about 22 hours.
The reaction of the compound of Formula IV with the compound of Formula V is carried out at a temperature of about -78°C to about 40°C, for example, of about -65°C to about 30°C.
The compound of Formula VI may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VI is reacted with an iodinating agent to obtain the compound of Formula VII in the presence of an acid.
An example of an iodinating agent is N-iodosuccinimide.
An example of an acid is trifluoroacetic acid.
The reaction of the compound of Formula VI with the iodinating agent is carried out for about 2 hours to about 8 hours, for example, for about 3 hours to about 6 hours.
The reaction of the compound of Formula VI with the iodinating agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25°C to about 35°C.
The compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VII is protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent. The protecting agent is selected from the group consisting 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 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 reacted with the compound of Formula A to obtain the compound of Formula IX in the presence of a palladium catalyst, a base and a solvent.
An example of a palladium catalyst is [ 1, 1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex.
An example of a base is potassium acetate.
The solvent is selected from the group consisting of dimethylsulphoxide, acetonitrile, Ν,Ν-dimethylformamide, 1,4-dioxane, and tetrahydrofuran. The reaction of the compound of Formula VIII with the compound of Formula A is carried out for about 15 minutes to about 6 hours, for example for about 30 minutes to about 4 hours.
The reaction of the compound of Formula VIII with the compound of Formula A is carried out at a temperature of about 15°C to about 80°C, for example, of about 20°C to about 70°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 coupled with the compound of Formula X to obtain the compound of Formula XI in the presence of a palladium catalyst, a base and a solvent.
The palladium catalyst is selected from the group consisting of
tetrakis(triphenylphosphine)palladium (0), tetrakis(tri(o-tolyl)phosphine)palladium (0), and bis(dibenzylideneacetone)palladium(0).
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, ethers, alcohols, hydrocarbons, and a mixture 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 IX with the compound of Formula X is carried for about 15 minutes to about 7 hours, for example, for about 30 minutes to about 6 hours. The reaction of the compound of Formula IX with the compound of Formula X is carried out at a temperature of about 25°C to about 100°C, for example, of about 30°C to about 80°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 to obtain the compound of Formula XII in a solvent.
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 triethyl amine.
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 tedizolid phosphate of Formula I by:
a) reacting the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in the presence of a catalyst and a solvent followed by oxidation with an oxidizing agent to obtain a protected compound of Formula B; and
Figure imgf000023_0001
Formula B
b) deprotecting the compound of Formula B in the presence of an acid and a solvent to obtain tedizolid phosphate of Formula I.
An example of the catalyst used in step a) is tetrazole.
The oxidizing agent in step a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
The solvent in step a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in the presence of a catalyst 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 the presence of a catalyst 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 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 in the presence of an acid 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 in the presence of an acid 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 chromatographic purity was recorded using an Acquity® H-class UPLC, PDA Detector.
EXAMPLES
Example 1 : Preparation of methyl (3-fluorophenyl)carbamate (Formula IV)
3-Fluoroaniline (Formula II, 100 g) was dissolved in dichloromethane (500 mL) under an inert atmosphere at ambient temperature. Sodium bicarbonate (151.3 g) was added to the mixture while stirring at ambient temperature. Methyl chloroformate (Formula III, when X=chloro; 127.6 mL) was added to the reaction mixture at ambient temperature over 40 minutes to 45 minutes. The reaction mixture was stirred for 2 hours to 3 hours at ambient temperature. Deionized water (500 mL) was added to the reaction mixture, and then the mixture was stirred at ambient temperature for 15 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined dichloromethane layers were washed with deionized water (200 mL). The dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to obtain a residue. Hexane (1 L) was added to the residue, and then the slurry was stirred overnight at ambient temperature. The solid was filtered under vacuum, and then washed with hexanes (200 mL). The solid obtained was dried under vacuum at 40°C for 10 hours to obtain the compound of Formula IV.
Yield: 140 g
Example 2: Preparation of (5R)-3-(3-fluorophenyl)-5-(hydroxymethyl)-1.3-oxazolidin-2- one (Formula VI)
Methyl (3-fluorophenyl)carbamate (Formula IV, 70 g, Example 1) was dissolved in anhydrous tetrahydrofuran (420 mL) at ambient temperature and the solution was cooled to -65°C to -60°C under nitrogen atmosphere. n-Butyl lithium (1.6 M in hexane, 272 mL) was slowly added to the above solution under a nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes. (R)-(-)-Glycidyl butyrate (Formula V, when Ri= n-propyl, 60.25 g) was slowly added to the reaction mixture under nitrogen atmosphere at -65 °C to -60°C, and then stirred for 1 hour. The reaction mixture was warmed to ambient temperature, and then stirred for 20 hours at 20°C to 25 °C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (7 g dissolved in 70 mL of deionized water) was added to the reaction mixture.
Tetrahydrofuran was recovered under vacuum at 40°C to 45 °C, followed by the addition of deionized water (500 mL) at 40°C to 45°C. The reaction mixture was allowed to attain ambient temperature and was then stirred for 2 hours. The solid obtained was filtered, then washed with deionized water (70 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.
Yield: 72.1 g
Example 3: Preparation of (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1.3- oxazolidin-2-one (Formula VII)
(5R)-3-(3-Fluorophenyl)-5-(hydroxymethyl)-l,3-oxazolidin-2-one (Formula VI, 5 g, Example 2) was dissolved in trifluoroacetic acid (25 mL) at ambient temperature, and then the mixture was stirred for 10 minutes. N-Iodosuccinimide (5.59 g) was added to the reaction mixture at ambient temperature and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under vacuum.
Deionized water (50 mL) was added to the residue, followed by the addition of ethyl acetate in hexanes (20%, 30 mL). The resulting biphasic system was stirred at ambient temperature for 15 minutes, then cooled to 0°C to 5°C, and then stirred for another 1 hour at 0°C to 5°C. The solid obtained was filtered, then washed with deionized water (40 mL) and 20% ethyl acetate in hexanes (30 mL). The solid was dried at 40°C to 45°C for 4 hours to afford the title compound as an off-white solid.
Yield: 7.9 g
Example 4: Preparation oftert-butyl [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1.3- oxazolidin-5-νΠ methyl carbonate [Formula VIII. when Ρ is tert-butoxycarbonyll
(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, then deionized water (50 mL) was added. The layers were separated, and the toluene layer was dried over anhydrous sodium sulfate. The toluene layer was concentrated under vacuum to dryness to afford the title compound as off-white solid.
Yield: 11.1 g ^-NMR CCDCIB): δ 7.67-7.71 (t, 1H), 7.45-7.48 (dd, 1H), 7.04-7.07 (dd, 1H), 4.86-4.90 (m, 1H), 4.30-4.33 (m, 2H), 3.84-3.88 (m, 1H), 1 .48 (s, 9H)
Mass (m/z): 438.4 [M+H]+
Chromatographic purity : 98. 13%
Example 5 : Preparation oftert-butyl {(5R)-3-[3-fluoro-4-(4.4.5.5-tetramethyl- 1.3.2- dioxaborolan-2-yl)phenyll-2-oxo- 1.3-oxazolidin-5-yl}methyl carbonate [Formula IX. when Ρ is tert-butoxycarbonyl. R? and R^ together with the oxygen atom they are attached to form a 5 membered heterocyclic ring!
Tert-butyl [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl carbonate (Formula VIII, 25 g, Example 4) was dissolved in dimethyl sulfoxide (250 mL) at ambient temperature. Bis(pinacolato)diboron (Formula A, when R2 and R3 together with the oxygen atom they are attached to form a 5 membered heterocyclic ring; 17.42 g) was added to the reaction mixture, followed by the addition of potassium acetate ( 1 1 .21 g). The reaction mixture was stirred at ambient temperature and nitrogen gas was bubbled through the reaction mixture at ambient temperature for 45 minutes to 50 minutes . [ 1 , Γ - Bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (4.67 g) was added to the reaction mixture under inert atmosphere, and then the reaction mixture was heated to 60°C. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to ambient temperature, and then ethyl acetate (600 mL) was added to it. The solution was stirred at ambient temperature for 15 minutes, and then filtered through a Hyflo®. The mother liquor was washed twice with deionized water ( 1 L and 0.6 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum. Ethyl acetate:hexanes ( 1 : 1 , 500 mL) were added, and then the slurry was stirred at ambient temperature for 2 hours. The solid was filtered, and the mother liquor was concentrated under vacuum to obtain a residue. Ethyl acetate:hexanes (9: 1 , 400 mL) were added to the residue, and then the mixture was stirred at ambient temperature until complete dissolution. Activated carbon (3 g) and silica gel (60- 120 mesh, 6 g) were added with stirring, then the reaction mixture was stirred at ambient temperature for 45 minutes. The solution was filtered through a Hyflo®. The mother liquor was concentrated under vacuum, and hexanes (500 mL) were added. The resulting slurry was stirred vigorously at ambient temperature for 2 hours. The solid was filtered, then dried at 40°C to 45°C for 5 hours to afford the title compound. Yield: 18.9 g
^-NMR (DMSO-d6): 57.65-7.67 (t, 1H), 7.44-7.47 (dd, 1H), 7.34-7.36 (dd, 1H), 4.96- 4.97 (m, 1H), 4.29-4.34 (m, 2H), 4.25-4.27 (m, 2H), 4.15-4.19 (m, 1H), 3.82-3.86 (m, lH), 1.41 (s, 9H), 1.29 (s, 9H)
Mass (m/z): 438.7 [M+H]+
Chromatographic purity: 94.36 %
Example 6: 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-butoxycarbonyll
N,N-Dimethylformamide:water (9: 1, 280 mL) was added to tert-butyl {(5R)-3-[3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-l,3-oxazolidin-5- yl}methyl carbonate (Formula IX, 16 g, Example 5) at ambient temperature. 5-Bromo-2- (2-methyl-2H-tetrazol-5-yl)pyridine (Formula X, when X=bromo, 7.03 g) was added to the reaction mixture, followed by the addition of sodium carbonate (15.52 g) while stirring. Nitrogen gas was bubbled through the reaction mixture at ambient temperature for 45 minutes to 50 minutes, followed by the addition of
tetrakis(triphenylphosphine)palladium (0) (4.23 g). The reaction mixture was heated to 70°C, and then stirred at the same temperature for 4 hours to 5 hours. After completion of the reaction, ethyl acetate (500 mL) was added to the reaction mixture, and then the reaction mixture was filtered through a Hyflo®. The mother liquor was washed with deionized water (2 x 1 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated to dryness under vacuum. Methanol (500 mL) was added to the mixture, and then the solution was concentrated to a volume of 250 mL by distillation. Deionized water (70 mL) was added to the remaining solution, and then the solution was stirred at ambient temperature for 3 hours. The solid obtained was filtered, and then washed with methanol: water (3:2, 150 mL). The solid was dried at 45 °C for 5 hours to 6 hours to afford the title compound as off-white solid.
Yield: 13.5 g
^-NMR (DMSO-d6): δ 8.94 (s, 1H), 8.18-8.24 (dd, 1H), 7.74-7.78 (m, 1H), 7.67-7.71 (m, 1H), 7.51-7.53 (dd, 1H), 5.00 (m, 1H), 4.49 (s, 3H), 4.22-4.38 (m, 3H), 1.42(s, 9H)
Mass (m/z): 471.6 [M+H]+ Chromatographic purity: 95.3 %
Example 7: Preparation of (5R)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yllphenyl}-5-(hvdroxymethyl)-1.3-oxazolidin-2-one (Formula XII)
Tert-butyl [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl carbonate (Formula XI, 11 g, Example 6) was dissolved in dichloromethane (110 mL) at ambient temperature, and then
trifluoroacetic acid (110 mL) was added to it. The reaction mixture was stirred at ambient temperature for 3 hours. Dichloromethane (250 mL) and deionized water (500 mL) were added, 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 saturated sodium bicarbonate solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to dryness.
Methanol: dichloromethane (1 : 1, 500 mL) was added to the residue. Activated carbon (3 g) was added to the solution at ambient temperature, and then the mixture was stirred for 1 hour. The solution was filtered through a Hyflo®, and then the bed was washed with methanol: dichloromethane (1 : 1, 100 mL). The filtrate was concentrated under vacuum to dryness. Methanol (75 mL) was added to the mixture, and then the mixture was heated to 70°C, 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, 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, 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, and then the 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
Chromatographic purity: 99.3 % Example 8: 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 7) while stirring under an inert atmosphere. The reaction mixture was cooled to -5°C in an ice bath, 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 another flask containing deionized water (110 mL) precooled to 0°C 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 9: 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)
(5R)-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 7) 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 above solution and 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 dissolved in 20 mL deionized water) were added to the mixture. The organic layer was separated, then washed with an aqueous solution of sodium bicarbonate (0.5 g dissolved 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 used as such for the next step. Example 10: Preparation of r(5i?)-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 9) was added to trifluoroacetic acid (15 mL), and then the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was concentrated in vacuum at 45 °C to 50°C to obtain a residue. Ethanol (12 mL) and diethyl ether (10 mL) were added to the residue and the mixture was stirred for 2 hours at ambient temperature. The solid obtained was filtered, and then the wet solid obtained was dried under vacuum overnight 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 imgf000032_0001
Formula I
wherein the process comprises
a) reacting a compound of Formula II
Figure imgf000032_0002
Formula II
with a compound of Formula III,
Figure imgf000032_0003
Formula III
wherein X is halogen,
to obtain a compound of Formula IV;
Figure imgf000032_0004
Formula IV
b) reacting the compound of Formula IV with a compound of Formula V,
Figure imgf000032_0005
Formula V wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VI;
Figure imgf000033_0001
Formula VI
c) reacting the compound of Formula VI with an iodinating agent to obtain a compound of Formula VII;
Figure imgf000033_0002
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000033_0003
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
e) reacting the compound of Formula VIII with a compound of Formula A,
Figure imgf000033_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 to obtain a compound of Formula IX;
Figure imgf000034_0001
Formula IX
f) coupling the compound of Formula IX with a compound of Formula X,
Figure imgf000034_0002
Formula X
wherein X is halogen,
in the presence of a palladium catalyst to obtain a compound of Formula XI;
Figure imgf000034_0003
g) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain a compound of Formula XII; and
Figure imgf000034_0004
h) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Fonnula I. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000035_0001
Formula I
wherein the process comprises:
a) protecting a compound of Formula VII
Figure imgf000035_0002
Formula VII
with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000035_0003
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
b) reacting the compound of Formula VIII with a compound of Formula A,
Figure imgf000035_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 to obtain a compound of Formula IX;
Figure imgf000036_0001
Formula IX
c) coupling the compound of Formula IX with a compound of Formula X,
Figure imgf000036_0002
Formula X
wherein X is halogen,
in the presence of a palladium catalyst to obtain a compound of Formula XI; and
Figure imgf000036_0003
Formula XI
d) converting the compound of Formula XI into tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula VIII,
Figure imgf000036_0004
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert-butoxy carbonyl, benzyloxycarbonyl, and benzyl,
comprising protecting a compound of Formula VII
Figure imgf000037_0001
Formula VII
with a protecting agent.
4. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000037_0002
Formula I
wherein the process comprises:
a) protecting a compound of Formula VII
Figure imgf000037_0003
Formula VII
with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000037_0004
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
b) converting the compound of Formula VIII into tedizolid phosphate of Formula I.
5. A process for the preparation of a compound of Formula IX,
Figure imgf000038_0001
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
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,
comprising reacting a compound of Formula VIII
Figure imgf000038_0002
Formula VIII
with a compound of Formula A
Figure imgf000038_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 - to 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl, or aralkyl
in the presence of a palladium catalyst. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000039_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula VIII
Figure imgf000039_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 imgf000039_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- to 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl, or aralkyl,
in the presence of a palladium catalyst to obtain a compound of Formula IX; and
Figure imgf000039_0004
Formula IX
b) converting the compound of Formula IX into tedizolid phosphate of Formula I.7. A process for the preparation of a compound of Formula XI,
Figure imgf000040_0001
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
comprising coupling a compound of Formula IX
Figure imgf000040_0002
Formula IX
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,
with a compound of Formula X,
Figure imgf000040_0003
Formula X
wherein X is halogen,
in the presence of a palladium catalyst. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000041_0001
Formula I
wherein the process comprises:
a) coupling a compound of Formula IX,
Figure imgf000041_0002
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
Pv2 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,
with a compound of Formula X,
Figure imgf000041_0003
Formula X
wherein X is halogen,
in the presence of a palladium catalyst to obtain a compound of Formula XI; and
Figure imgf000041_0004
Formula XI
b) converting the compound of Formula XI into tedizold phosphate of Formula I. 9. A process for the preparation of a compound of Formula XII,
Figure imgf000042_0001
Formula XII
wherein the process comprises deprotecting 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,
in the presence of a deprotecting agent.
10. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000042_0003
Formula I
wherein the process comprises:
a) deprotecting a compound of Formula XI,
Figure imgf000042_0004
Formula XI wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
in the presence of a deprotecting agent to obtain compound of Formula XII; and
Figure imgf000043_0001
Formula XII
b) converting the compound of Formula XII into tedizold phosphate of Formula I. 1 1. The process according to claim 1, wherein the compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in presence of a base and a solvent.
12. The process according to claim 1 1, 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.
13. The process according to claim 1 1, wherein the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N, N- dimethylformamide, acetonitrile, and mixtures thereof.
14. The process according to claim 1, wherein the compound of Formula IV is reacted with the compound of Formula V to obtain the compound of Formula VI in the presence of a base and a solvent.
15. The process according to claim 14, wherein the base is n-butyl lithium.
16. The process according to claim 14, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, Ν,Ν-dimethylformamide, N- methylpyrrolidone, and mixtures thereof.
17. The process according to claim 1, wherein the compound of Formula VI is reacted with an iodinating agent to obtain the compound of Formula VII in the presence of an acid.
18. The process according to claim 1, wherein the iodinating agent is N- iodosuccinimide.
19. The process according to claim 17, wherein the acid is trifluoroacetic acid. 20. The process according to any one of claim 1, 2, 3, or 4, 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.
21. The process according to any one of claim 1, 2, 3, or 4, wherein the protecting agent is selected from the group consisting di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
22. The process according to claim 20, wherein the solvent is selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
23. The process according to claim 20, wherein the catalyst is 4-(N,N- dimethylamino)pyridine.
24. The process according to any one of claim 1, 2, 5, or 6, wherein the compound of Formula VIII is reacted with the compound of Formula A to obtain the compound of Formula IX in the presence of a palladium catalyst, a base, and a solvent. 25. The process according to any one of claim 1, 2, 5, or 6, wherein the palladium catalyst is [ 1, l '-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex.
26. The process according to claim 24, wherein the base is potassium acetate.
27. The process according to claim 24, wherein the solvent is selected from the group consisting of dimethylsulphoxide, acetonitrile, N,N-dimethylformamide, 1,4- dioxane, and tetrahydrofuran.
28. The process according to any one of claim 1, 2, 7, or 8, wherein the compound of Formula IX is coupled with the compound of Formula X to obtain the compound of Formula XI in the presence of a palladium catalyst, a base, and a solvent. 29. The process according to any one of claim 1, 2, 7, or 8, wherein the palladium catalyst is selected from the group consisting of tetrakis(triphenylphosphine)palladium (0), tetrakis (tri (o- tolyl)phosphine)palladium (0), and bis(dibenzylideneacetone)palladium(0).
30. The process according to claim 28, 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 28, wherein the solvent is selected from the group consisting of water, Ν,Ν-dimethylformamide, ethers, alcohols, hydrocarbons, and mixtures thereof.
32. The process according to any one of claim 1, 9, or 10, wherein the compound of Formula XI is deprotected in the presence of a deprotecting agent to obtain the compound of Formula XII in a solvent.
33. The process according to any one of claim 1, 9, or 10, wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
34. The process according to claim 32, wherein the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and a mixture thereof.
35. 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.
36. The process according to claim 1, wherein the phosphorylating agent is phosphorus oxy chloride.
37. The process according to claim 35, wherein the base is triethylamine.
38. The process according to claim 35, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
39. The process according to claim 1, wherein 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 NN- diisopropylphosphoramidite in the presence of a catalyst and a solvent followed by oxidation with an oxidizing agent to obtain a protected compound of following Formula B; and
Figure imgf000046_0001
Formula B
b) deprotecting the protected compound of Formula B in the presence of an acid and a solvent to obtain the compound of Formula I.
40. The process according to claim 39, wherein the catalyst is tetrazole.
41. The process according to claim 39, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chlorobenzoic acid.
42. The process according to claim 39, wherein the solvent in step a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
43. The process according to claim 39, wherein the acid is trifluoroacetic acid.
44. The process according to claim 39, wherein the solvent in step b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
45. A compound of Formula VIII,
Figure imgf000046_0002
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl.
46. A compound of Formula IX,
Figure imgf000047_0001
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
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.
47. A compound of Formula XI,
Figure imgf000047_0002
Formula XI
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl.
48. Use of a compound of Formula VIII,
Figure imgf000047_0003
Formula VIII
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.
49. Use of a compound of Formula IX,
Figure imgf000048_0001
Formula IX
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl; and
P2 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,
for the preparation of tedizolid phosphate of Formula I.
50. Use of a com ound of Formula XI,
Figure imgf000048_0002
Formula XI
wherein Pi is a protecting group selected from the group consisting tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl,
for the preparation of tedizolid phosphate of Formula I.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090192197A1 (en) * 2003-12-18 2009-07-30 Dong-A Pharm. Co., Ltd. Novel oxazolidinone derivatives
US20100093669A1 (en) * 2008-10-10 2010-04-15 Trius Therapeutics Methods for preparing oxazolidinones and compositions containing them
US20100227839A1 (en) * 2009-02-03 2010-09-09 Trius Therapeutics Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin- 5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090192197A1 (en) * 2003-12-18 2009-07-30 Dong-A Pharm. Co., Ltd. Novel oxazolidinone derivatives
US20100093669A1 (en) * 2008-10-10 2010-04-15 Trius Therapeutics Methods for preparing oxazolidinones and compositions containing them
US20100227839A1 (en) * 2009-02-03 2010-09-09 Trius Therapeutics Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin- 5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US11566023B2 (en) 2020-06-18 2023-01-31 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

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