WO2016088101A1 - 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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WO2016088101A1
WO2016088101A1 PCT/IB2015/059377 IB2015059377W WO2016088101A1 WO 2016088101 A1 WO2016088101 A1 WO 2016088101A1 IB 2015059377 W IB2015059377 W IB 2015059377W WO 2016088101 A1 WO2016088101 A1 WO 2016088101A1
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formula
compound
process according
solvent
group
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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
    • 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
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • 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 a compound of Formula V, a process for its preparation, and its 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 a compound of Formula V, a process for its preparation, and its use for the preparation of tedizolid phosphate.
  • the processes of the present invention are industrially viable and produce tedizolid phosphate having high purity and yield.
  • ambient temperature refers to a temperature in the range of about 20°C to about 25 °C.
  • halogen refers to chloro, bromo, or iodo.
  • Ci-6 alkyl refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec- pentyl, 3-pentyl, n-hexyl, iso-hexyl, 2,3-dimethylbutyl, or neo-hexyl.
  • aryl refers to a monocyclic aromatic hydrocarbon.
  • An example of an aryl is phenyl.
  • aralkyl refers to a methylene substituted aryl group.
  • An example of an aralkyl is benzyl.
  • heterocycle refers to a non-aromatic ring containing one or more hetero atoms selected from the group consisting of oxygen (O), and boron (B).
  • O oxygen
  • B boron
  • An example of a heterocyclic ring is 4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl.
  • Ri is Ci_ 6 alkyl
  • Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
  • R 2 and R 3 each independently are Ci-6 alkyl, aryl, or aralkyl, or R 2 and R 3 are taken together with the oxygen atoms to which they are attached to form a 5- or 6-membered heterocyclic ring, which is optionally substituted with Ci-6 alkyl, aryl, or aralkyl,
  • a second aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a third aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • a fourth aspect of the present invention provides a process for the preparation of a compound of Formula VII,
  • Ri is 0-6 alkyl
  • a fifth aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
  • Ri is Ci-6 alkyl
  • a sixth aspect of the present invention provides a compound of Formula V.
  • a seventh aspect of the present invention provides use of a compound of Formula
  • the compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent.
  • an iodinating agent is iodine.
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
  • the solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, ⁇ , ⁇ -dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
  • reaction of the compound of Formula II with the iodinating agent is carried out for about 1 hour to about 25 hours, for example, for about 1 hour to about 10 hours.
  • reaction of the compound of Formula II with the iodinating agent is carried out at a temperature of about 5°C to about 35°C, for example, of about 10°C to about 30°C.
  • the compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula III may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula III is reacted with the compound of Formula IV to obtain the compound of Formula V in the presence of a base, a phase transfer catalyst, and a solvent.
  • the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and pyridine.
  • the phase transfer catalyst is selected from the group consisting of tetra-n- butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether.
  • the solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N-dimethylformamide, acetonitrile, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include n-hexane, n-heptane, cyclohexane, toluene, and xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula III with the compound of Formula IV is carried out for about 15 minutes to about 8 hours, for example, for about 30 minutes to about 4 hours.
  • reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 15°C to about 40°C, for example, of about 25°C to about 35°C.
  • the compound of Formula V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula V may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula V is reacted with the compound of Formula VI to obtain the compound of Formula VII in the presence of a base and a solvent.
  • An example of a base is n-butyl lithium.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, ⁇ , ⁇ -dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • reaction of the compound of Formula V with the compound of Formula VI is carried out for about 15 hours to about 25 hours, for example, for about 20 hours to about 22 hours.
  • reaction of the compound of Formula V with the compound of Formula VI is carried out at a temperature of about -78°C to about 40°C, for example, of about -65°C to about 30°C.
  • the compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VII is protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent.
  • the protecting agent is selected from the group consisting di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
  • the solvent is selected from the group consisting of dimethylsulfoxide, N,N- dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include toluene, benzene, and p-xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • An example of a catalyst is 4-(N,N-dimethylamino)pyridine.
  • the protection of the compound of Formula VII with the protecting agent is carried out for about 5 hours to about 12 hours, for example, for about 6 hours to about 8 hours.
  • the protection of the compound of Formula VII with the protecting agent is carried out at a temperature of about 20°C to about 70°C, for example, of about 25°C to about 55°C.
  • the compound of Formula VIII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VIII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VIII is 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.
  • 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 mixtures thereof.
  • ethers examples include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • hydrocarbons examples include benzene, toluene, and p-xylene.
  • the coupling of the compound of Formula IX with the compound of Formula X is carried out for about 15 minutes to about 7 hours, for example, for about 30 minutes to about 6 hours.
  • 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 and a solvent to obtain the compound of Formula XII.
  • the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
  • the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
  • ketones include acetone and methyl ethyl ketone.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out for about 1 hour to about 7 hours, for example, for about 2 hours to about 4 hours.
  • the deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25 °C to about 35°C.
  • the compound of Formula XII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula XII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XII is phosphorylated in the presence of a
  • phosphorylating agent is phosphorus oxy chloride.
  • An example of a base is triethylamine.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and 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 used in step (a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
  • the solvent used in step (a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • 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 used in step (b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • alcohols examples include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
  • the deprotection of the compound of Formula B in the presence of the 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 the 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 IR spectrum was recorded using a Perkin Elmer ® instrument.
  • the dichloromethane layer was washed with deionized water (500 mL), then dried over anhydrous sodium sulfate, and then concentrated under vacuum at 30°C to 35°C. Hexanes (600 mL) were added to the residue, and then the obtained slurry was stirred for 3 hours at 20°C to 25°C. The solid was filtered under vacuum, then washed with hexanes (100 mL). The solid was dried under vacuum at 40°C to 45°C for 10 hours to afford the title compound.
  • Methyl (3-fluoro-4-iodophenyl)carbamate (Formula V, 50 g, Example 2) was dissolved in anhydrous tetrahydrofuran (350 mL) at 20°C to 25 °C, and then the solution was cooled to -65°C to -60°C under nitrogen atmosphere.
  • n-Butyl lithium ( 1.6 M in hexane, 45.5 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes.
  • Example 5 Preparation oftert-butyl ⁇ (5R)-3-r3-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 ⁇ is tert-butoxycarbonyl and R? and together with the oxygen atom they are attached to form a 5 membered heterocyclic ring)
  • Ethyl acetate:hexanes ( 1 : 1 , 500 mL) were added to the mixture, and the resulting slurry was stirred at ambient temperature for 2 hours. The solid was filtered, and then the mother liquor was concentrated under vacuum to obtain a residue. Ethyl acetate :hexanes (9: 1 , 400 mL) were added to the residue, then it was stirred at ambient temperature until complete dissolution. Activated carbon (3 g) and silica gel (60- 120 mesh, 6 g) were added to the reaction mixture while stirring, and then the mixture was stirred at ambient temperature for 45 minutes. The solution was filtered through a Hyflo .
  • dichloromethane layer was washed with a saturated sodium bicarbonate solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to dryness.
  • Activated carbon (3 g) was added to the solution at ambient temperature, and then the mixture was stirred for 1 hour. The solution was filtered through a Hyflo ® , and then the bed was washed with methanol: dichloromethane (1 : 1, 100 mL). The filtrate was concentrated under vacuum to dryness.
  • Tetrahydrofuran 75 mL was added to (5R)-3- ⁇ 3-fluoro-4-[6-(2-methyl-2H- tetrazol-5 -yl)pyridin-3 -yl]phenyl ⁇ -5 -(hydroxymethyl)- 1 ,3 -oxazolidin-2-one (Formula XII, 3 g, Example 7) while stirring under inert atmosphere.
  • the reaction mixture was cooled to -5°C in an ice bath, and then triethylamine (3.4 mL) was added to the mixture.
  • Phosphorous oxy chloride (2.3 mL) was added to the reaction mixture at -5°C to 0°C over 10 minutes to 15 minutes.
  • the reaction mixture was stirred at 0°C to 5°C for 4 hours to 5 hours.
  • the reaction mixture was slowly poured into another flask containing deionized water (110 mL) precooled to 0° to 5°C. The temperature was maintained below 10°C during addition.
  • the yellow slurry thus obtained was stirred overnight at ambient temperature.
  • the solid obtained was filtered, then washed with deionized water (15 mL) and methanol (30 mL). The solid was dried at 45°C for 6 hours to afford the title compound.
  • the reaction mixture was stirred for 2 hours at -65 °C to -70°C.
  • the reaction mixture was warmed to ambient temperature.
  • Dichloromethane (20 mL) and an aqueous solution of sodium bisulfate (0.5 g in 20 mL deionized water) were added to the reaction mixture.
  • the organic layer was separated, and 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 the organic layer was used as such for the next step.

Abstract

The present invention provides processes for the preparation of tedizolid phosphate. The present invention further provides a compound of Formula V, a process for its preparation, and its use for the preparation of tedizolid phosphate. The processes of the present invention 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 a compound of Formula V, a process for its preparation, and its 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 a compound of Formula V, a process for its preparation, and its use for the preparation of tedizolid phosphate.
The processes of the present invention 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.
Figure imgf000003_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000003_0002
Formula II
with an iodinating agent to obtain a compound of Formula III;
Figure imgf000004_0001
Formula III
b) reacting the compound of Formula III with a compound of Fonnula IV,
Figure imgf000004_0002
Formula IV
wherein X is halogen,
to obtain a compound of Fonnula V;
Figure imgf000004_0003
Formula V
c) reacting the compound of Formula V with a compound of Fonnula VI,
Figure imgf000004_0004
Formula VI
wherein Ri is Ci_6 alkyl,
to obtain a compound of Formula VII;
Figure imgf000004_0005
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000005_0001
Formula VIII
wherein Pi is a protecting group selected from the group consisting of tert- butoxycarbonyl, benzyloxycarbonyl, and benzyl;
e) 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 a compound of Formula V,
Figure imgf000006_0003
Formula V
wherein the process comprises reacting a compound of Fonnula III
Figure imgf000006_0004
Formula III
with a compound of Fonnula IV,
Figure imgf000006_0005
Formula IV wherein X is halogen.
A third aspect of the present invention provides a process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000007_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula III
Figure imgf000007_0002
Formula IV
wherein X is halogen,
to obtain a compound of Formula V; and
Figure imgf000007_0003
Formula V
b) converting the compound of Formula V into tedizolid phosphate of Formula I.
A fourth aspect of the present invention provides a process for the preparation of a compound of Formula VII,
Figure imgf000008_0001
Formula VII
wherein the process comprises reacting a compound of Formula V
Figure imgf000008_0002
Formula V
with a compound of Formula VI,
Figure imgf000008_0003
Formula VI
wherein Ri is 0-6 alkyl.
A fifth 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) reacting a compound of Formula V
Figure imgf000008_0005
Formula V with a compound of Formula VI,
Figure imgf000009_0001
Formula VI
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VII; and
Figure imgf000009_0002
b) converting the compound of Formula VII into tedizolid phosphate of Formula I.
A sixth aspect of the present invention provides a compound of Formula V.
Figure imgf000009_0003
Formula V
A seventh aspect of the present invention provides use of a compound of Formula
V
Figure imgf000009_0004
Formula V
for the preparation of tedizolid phosphate of Formula I.
The compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent. An example of an iodinating agent is iodine.
The base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
The solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, Ν,Ν-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
The reaction of the compound of Formula II with the iodinating agent is carried out for about 1 hour to about 25 hours, for example, for about 1 hour to about 10 hours.
The reaction of the compound of Formula II with the iodinating agent is carried out at a temperature of about 5°C to about 35°C, for example, of about 10°C to about 30°C.
The compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula III may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula III is reacted with the compound of Formula IV to obtain the compound of Formula V in the presence of a base, a phase transfer catalyst, and a solvent.
The base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and pyridine.
The phase transfer catalyst is selected from the group consisting of tetra-n- butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether.
The solvent is selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, N,N-dimethylformamide, acetonitrile, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include n-hexane, n-heptane, cyclohexane, toluene, and xylene. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The reaction of the compound of Formula III with the compound of Formula IV is carried out for about 15 minutes to about 8 hours, for example, for about 30 minutes to about 4 hours.
The reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 15°C to about 40°C, for example, of about 25°C to about 35°C.
The compound of Formula V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula V may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula V is reacted with the compound of Formula VI to obtain the compound of Formula VII in the presence of a base and a solvent.
An example of a base is n-butyl lithium.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, Ν,Ν-dimethylformamide, N-methylpyrrolidone, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The reaction of the compound of Formula V with the compound of Formula VI is carried out for about 15 hours to about 25 hours, for example, for about 20 hours to about 22 hours.
The reaction of the compound of Formula V with the compound of Formula VI is carried out at a temperature of about -78°C to about 40°C, for example, of about -65°C to about 30°C.
The compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VII is protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent.
The protecting agent is selected from the group consisting di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
The solvent is selected from the group consisting of dimethylsulfoxide, N,N- dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include toluene, benzene, and p-xylene.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
An example of a catalyst is 4-(N,N-dimethylamino)pyridine.
The protection of the compound of Formula VII with the protecting agent is carried out for about 5 hours to about 12 hours, for example, for about 6 hours to about 8 hours.
The protection of the compound of Formula VII with the protecting agent is carried out at a temperature of about 20°C to about 70°C, for example, of about 25°C to about 55°C.
The compound of Formula VIII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VIII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VIII is 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 mixtures thereof.
Examples of ethers include 1,4-dioxane, diethyl ether, diisopropyl ether, and tetrahydrofuran.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
Examples of hydrocarbons include benzene, toluene, and p-xylene. The coupling of the compound of Formula IX with the compound of Formula X is carried out 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 and a solvent to obtain the compound of Formula XII.
The deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
The solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
Examples of ketones include acetone and methyl ethyl ketone.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out for about 1 hour to about 7 hours, for example, for about 2 hours to about 4 hours.
The deprotection of the compound of Formula XI in the presence of the deprotecting agent is carried out at a temperature of about 15°C to about 60°C, for example, of about 25 °C to about 35°C. The compound of Formula XII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula XII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula XII is phosphorylated in the presence of a
phosphorylating agent, a base, and a solvent to obtain tedizolid phosphate of Formula I.
An example of a phosphorylating agent is phosphorus oxy chloride.
An example of a base is triethylamine.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
The phosphorylation of the compound of Formula XII in the presence of the phosphorylating agent is carried out for about 2 hours to about 10 hours, for example, for about 3 hours to about 6 hours.
The phosphorylation of the compound of Formula XII in the presence of the phosphorylating agent is carried out at a temperature of about -10°C to about 10°C, for example, of about -7°C to about 8°C.
Tedizolid phosphate of Formula I may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Tedizolid phosphate of Formula I may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
Alternatively, the compound of Formula XII is phosphorylated to obtain 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 imgf000016_0001
Formula B
b) deprotecting the protected compound of Formula B in the presence of an acid and a solvent to obtain tedizolid phosphate of Formula I.
An example of the catalyst used in step (a) is tetrazole.
The oxidizing agent used in step (a) is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
The solvent used in step (a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The reaction of the compound of Formula XII with di-tert-butyl N,N- diisopropylphosphoramidite in 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 used in step (b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tert-butanol.
The deprotection of the compound of Formula B in the presence of the 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 the 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 IR spectrum was recorded using a Perkin Elmer® instrument.
The chromatographic purity was recorded using an Acquity® H-class UPLC, PDA Detector.
EXAMPLES
Example 1 : Preparation of 3-fluoro-4-iodoaniline (Formula III)
Sodium bicarbonate (113.4 g) was dissolved in deionized water (1 L) at 20°C to 25°C. The mixture was stirred for 20 minutes at ambient temperature. 3-Fluoro aniline (Formula II, 100 g) was added to the solution at 20°C to 25°C. The reaction mixture was cooled to 10°C to 15°C, followed by the addition of iodine (183 g) in small lots over a period of 1.5 hours. The reaction mixture was stirred for 1 hour at 10°C to 15°C, and then further stirred for 14 hours to 16 hours at 20°C to 25 °C. The solid was filtered, then washed with deionized water (100 mL). The wet solid obtained was dried at 50°C to 55°C to afford the title compound.
Yield: 166.2 g
Example 2: Preparation of methyl (3-fluoro-4-iodophenyl)carbamate (Formula V)
3-Fluoro-4-iodoaniline (Formula III, 100 g, Example 1) was dissolved in dichloromethane (1 L) under inert atmosphere at ambient temperature. Sodium bicarbonate (71 g) and tetra-n-butylammonium bromide (10 g) were added to the solution while stirring at ambient temperature. Methyl chloroformate (Formula IV, when X=chloro; 72 g) was added to the reaction mixture at ambient temperature over 30 minutes. The reaction mixture was stirred for 3 hours at ambient temperature. Deionized water (1 L) was added to the reaction mixture, and then the mixture was stirred at ambient temperature for 20 minutes. The layers were separated. The dichloromethane layer was washed with deionized water (500 mL), then dried over anhydrous sodium sulfate, and then concentrated under vacuum at 30°C to 35°C. Hexanes (600 mL) were added to the residue, and then the obtained slurry was stirred for 3 hours at 20°C to 25°C. The solid was filtered under vacuum, then washed with hexanes (100 mL). The solid was dried under vacuum at 40°C to 45°C for 10 hours to afford the title compound.
Yield: 104.4 g ^-NMR CCDCIB): δ 7.58-7.62 (t, 1H), 7.36-7.39 (dd, 1H), 6.84-6.86 (dd, 1H), 3.78 (s, 3H)
Mass (m/z): 296.3 [M+H]+
IR (KBr, cm"1): 3363, 1709, 1598, 1537, 1410, 1071, 864
Example 3 : Preparation of (5R)-3-(3-fluoro-4-iodophenyn-5-(hydroxymethyl)- 1.3- oxazolidin-2-one (Formula VII)
Methyl (3-fluoro-4-iodophenyl)carbamate (Formula V, 50 g, Example 2) was dissolved in anhydrous tetrahydrofuran (350 mL) at 20°C to 25 °C, and then the solution was cooled to -65°C to -60°C under nitrogen atmosphere. n-Butyl lithium ( 1.6 M in hexane, 45.5 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes. (R)-(-)-Glycidyl butyrate (Formula VI, when Ri= n-propyl, 24.66 g) was slowly added to the reaction mixture under nitrogen atmosphere at -65°C to -60°C, and then the mixture was stirred for 1 hour. The reaction mixture was allowed to attain ambient temperature, and was then stirred for 20 hours at 20°C to 25 °C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (5.0 g in 50 mL of deionized water) was added to the reaction mixture. Tetrahydrofuran was recovered under vacuum at 40°C to 45°C, followed by the addition of deionized water (500 mL) at 40°C to 45°C. The reaction mixture was allowed to attain ambient temperature, and was then stirred for 2 hours. The solid obtained was filtered, and then washed with deionized water (50 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.
Yield: 48.55 g
Example 4: Preparation oftert-butyl r(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1.3- oxazolidin-5-νΠ methyl carbonate (Formula VIII. when Ρ is tert-butoxycarbonyl)
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-l,3-oxazolidin-2-one (Formula VII, 10 g, Example 3) was dissolved in toluene (150 mL) at ambient temperature. Di-tert-butyl dicarbonate (8.5 g) was added to the reaction mixture at ambient temperature, followed by the addition of 4-(N,N-dimethylamino)pyridine (DMAP) (0.37 g). The reaction mixture was heated to 45°C to 50°C for 7 hours. The reaction mixture was allowed to attain ambient temperature, then deionized water (50 mL) was added to the mixture. The layers were separated, and the toluene layer was dried over anhydrous sodium sulfate. The toluene layer was concentrated under vacuum to dryness to afford the title compound as off-white solid.
Yield: 1 1 . 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-r3-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 and R? and 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 dimethylsulfoxide (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 then nitrogen gas was bubbled through the reaction mixture at ambient temperature for 45 minutes to 50 minutes. [l, -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 the mixture. 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 to the mixture, and the resulting slurry was stirred at ambient temperature for 2 hours. The solid was filtered, and then the mother liquor was concentrated under vacuum to obtain a residue. Ethyl acetate :hexanes (9: 1 , 400 mL) were added to the residue, then it was stirred at ambient temperature until complete dissolution. Activated carbon (3 g) and silica gel (60- 120 mesh, 6 g) were added to the reaction mixture while stirring, and then the mixture was stirred at ambient temperature for 45 minutes. The solution was filtered through a Hyflo . The mother liquor was concentrated under vacuum, and then hexanes (500 mL) were added. The resulting slurry was stirred vigorously at ambient temperature for 2 hours. The solid obtained was filtered, then dried at 40°C to 45 °C for 5 hours to afford the title compound.
Yield: 18.9 g
¾-NMR (DMSO-d6): δ 7.65-7.67 (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 [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yl]phenyl}-2-oxo-1.3-oxazolidin-5-yl]methyl carbonate (Formula XI. when Pi is tert-butoxycarbonyl)
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 the mixture was 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, 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 ¾-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-[6-(2-methyl-2H-tetrazol-5-ynpyridin-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 the mixture. The reaction mixture was stirred at ambient temperature for 3 hours. Dichloromethane (250 mL) and deionized water (500 mL) were added to the mixture, and then the resulting solution was stirred for 15 minutes to 20 minutes at ambient temperature. The layers were separated, and the
dichloromethane layer was washed with a saturated sodium bicarbonate solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then concentrated under vacuum to dryness. 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, and then gradually cooled to ambient temperature to obtain a suspension. The suspension was cooled to 0°C to 5°C, and it was 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 to the mixture, and then the solution was stirred at ambient temperature for 1 hour. The solution was filtered through a Hyflo®, and then the bed was washed with methanol: dichloromethane (1 : 1, 50 mL). The mother liquor was concentrated under vacuum to dryness. Dichloromethane in hexanes (20%, 150 mL) was added, and the resulting slurry was stirred at ambient temperature for 0.5 hour. The solid was filtered, 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 inert atmosphere. The reaction mixture was cooled to -5°C in an ice bath, and then triethylamine (3.4 mL) was added to the mixture.
Phosphorous oxy chloride (2.3 mL) was added to the reaction mixture at -5°C to 0°C over 10 minutes to 15 minutes. The reaction mixture was stirred at 0°C to 5°C for 4 hours to 5 hours. The reaction mixture was slowly poured into another flask containing deionized water (110 mL) precooled to 0° to 5°C. The temperature was maintained below 10°C during addition. The yellow slurry thus obtained was stirred overnight at ambient temperature. The solid obtained was filtered, then washed with deionized water (15 mL) and methanol (30 mL). The solid was dried at 45°C for 6 hours to afford the title compound.
Yield: 2.95 g
Example 9: Preparation of di-tert-butyl r(5R)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yl]phenyl}-2-oxo-1.3-oxazolidin-5-yl]methyl phosphate (Formula B)
(5Pv)-3 - {3 -Fluoro-4- [6-(2-methyl-2H-tetrazol-5 -yl)pyridin-3 -yl]phenyl} -5 -
(hydroxymethyl)- l,3-oxazolidin-2 -one (Formula XII, 1 g, Example 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 solution, andthen 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 -65 °C to -70°C. The reaction mixture was warmed to ambient temperature. Dichloromethane (20 mL) and an aqueous solution of sodium bisulfate (0.5 g in 20 mL deionized water) were added to the reaction mixture. The organic layer was separated, and 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 the organic layer was used as such for the next step.
Example 10: Preparation of r(5j?)-3-{3-fluoro-4-r6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- vHphenyl}-2-oxooxazolidin-5-vHmethyl hydrogen phosphate (Formula I)
Di-tert-butyl [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl phosphate (Formula B, Example 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 give a residue. Ethanol (12 mL) and diethyl ether (10 mL) were added to the residue, and then the mixture was stirred for 2 hours at ambient temperature. The solid obtained was filtered, and the wet solid 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:
A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000025_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000025_0002
Formula II
with an iodinating agent to obtain a compound of Formula III;
Figure imgf000025_0003
Formula III
b) reacting the compound of Formula III with a compound of Formula IV,
Figure imgf000025_0004
Formula IV
wherein X is halogen,
to obtain a compound of Formula V;
Figure imgf000026_0001
Formula V
c) reacting the compound of Formula V with a compound of Formula VI,
Figure imgf000026_0002
Formula VI
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VII;
Figure imgf000026_0003
Formula VII
d) protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII,
Figure imgf000026_0004
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,
R30 OR3
\
B— B
/ \
R20 OR2
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 imgf000027_0001
Formula IX
f) coupling the compound of Formula IX with a compound of Formula X,
Figure imgf000027_0002
Formula X
wherein X is halogen,
in the presence of a palladium catalyst to obtain a compound of Formula XI;
Figure imgf000027_0003
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 imgf000027_0004
Formula XII
h) phosphorylating the compound of Formula XII in the presence of a
phosphorylating agent to obtain tedizolid phosphate of Formula I. A process for the preparation of a compound of Formula V,
Figure imgf000028_0001
Formula V
wherein the process comprises reacting a compound of Formula III
Figure imgf000028_0002
Formula III
with a compound of Formula IV
Figure imgf000028_0003
Formula IV
wherein X is halogen.
A process for the preparation of tedizolid phosphate of Formula I.
Figure imgf000028_0004
Formula I
wherein the process comprises:
a) reacting a compound of Formula III
Figure imgf000028_0005
Formula III with a compound of Fonnula IV,
Figure imgf000029_0001
Formula IV
wherein X is halogen,
to obtain a compound of Formula V; and
Figure imgf000029_0002
Formula V
b) converting the compound of Formula V into tedizolid phosphate of Fonnula I.4. A process for the preparation of a com ound of Formula VII,
Figure imgf000029_0003
Formula VII
wherein the process comprises reacting a compound of Fonnula V
Figure imgf000029_0004
Formula VI
wherein Ri is Ci-6 alkyl.
5. A process for the preparation of tedizolid phosphate of Formula I,
Figure imgf000030_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula V
Figure imgf000030_0002
Formula V
with a compound of Formula VI,
Figure imgf000030_0003
Formula VI
wherein Ri is Ci-6 alkyl,
to obtain a compound of Formula VII; and
Figure imgf000030_0004
Formula VII
b) converting the compound of Formula VII into tedizolid phosphate of Formula I.
6. The process according to claim 1, wherein the compound of Formula II is reacted with an iodinating agent to obtain the compound of Formula III in the presence of a base and a solvent.
7. The process according to claim 1, wherein the iodinating agent is iodine.
8. The process according to claim 6, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.
9. The process according to claim 6, wherein the solvent is selected from the group consisting of water, acetonitrile, dimethylsulphoxide, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
10. The process according to any one of claim 1, 2, or 3, wherein the compound of Formula III is reacted with the compound of Formula IV to obtain the compound of Formula V in presence of a base, a phase transfer catalyst, and a solvent.
1 1. The process according to claim 10, 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.
12. The process according to claim 10, wherein the phase transfer catalyst is selected from the group consisting of tetra-n-butylammonium bromide, tetra-n- butylammonium chloride, tetra-n-butylammonium iodide, and 18-crown-6-ether. 13. The process according to claim 10, 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 any one of claim 1, 4, or 5, wherein the compound of Formula V is reacted with the compound of Formula VI to obtain the compound of Formula VII in the presence of a base and a solvent.
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 a mixture thereof.
17. The process according to claim 1, wherein the compound of Formula VII is
protected with a protecting agent to obtain the compound of Formula VIII in the presence of a catalyst and a solvent.
18. The process according to claim 17, wherein the protecting agent is selected from the group consisting di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, and benzyl bromide.
19. The process according to claim 17, wherein the solvent is selected from the group consisting of dimethylsulfoxide, Ν,Ν-dimethylformamide, ethers, hydrocarbons, halogenated hydrocarbons, and mixtures thereof.
20. The process according to claim 17, wherein the catalyst is 4-(N,N- dimethylamino)pyridine.
21. The process according to claim 1 , 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.
22. The process according to claim 21 , wherein the palladium catalyst is [ 1 , Γ - bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex.
23. The process according to claim 21, wherein the base is potassium acetate.
24. The process according to claim 21, wherein the solvent is selected from the group consisting of dimethylsulphoxide, acetonitrile, N,N-dimethylformamide, 1,4- dioxane, and tetrahydrofuran.
25. The process according to claim 1, 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.
26. The process according to claim 25, 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).
27. The process according to claim 25, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, triethyl amine, and N,N-diisopropylamine.
28. The process according to claim 25, wherein the solvent is selected from the group consisting of water, Ν,Ν-dimethylformamide, ethers, alcohols, hydrocarbons, and a mixture thereof. The process according to claim 1, wherein the compound of Formula XI is deprotected in the presence of a deprotecting agent and a solvent to obtain the compound of Formula XII.
The process according to claim 29, wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid and hydrochloric acid.
The process according to claim 29, wherein the solvent is selected from the group consisting of ketones, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
The process according to claim 1, wherein the compound of Formula XII is phosphorylated in the presence of a phosphorylating agent, a base, and a solvent to obtain tedizolid phosphate of Formula I.
The process according to claim 32, wherein the phosphorylating agent is phosphorus oxy chloride.
The process according to claim 32, wherein the base is triethylamine.
The process according to claim 32, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
The process according to claim 1, wherein the compound of Formula XII is phosphorylated to obtain tedizolid phosphate of Formula I by
a) reacting the compound of Formula XII with di-tert-butyl NN- diisopropylphosphoramidite in the presence of a catalyst and a solvent followed by the oxidation with an oxidizing agent to obtain a protected compound of Formula B; and
Figure imgf000033_0001
Formula B
b) deprotecting the protected compound of Formula B in the presence of an acid and a solvent to obtain tedizolid phosphate of Formula I.
37. The process according to claim 36, wherein the catalyst is tetrazole.
38. The process according to claim 36, wherein the oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloroperbenzoic acid.
39. The process according to claim 36, wherein the solvent in step (a) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
40. The process according to claim 36, wherein the acid is trifluoroacetic acid. 41. The process according to claim 36, wherein the solvent in step (b) is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and mixtures thereof.
42. A compound of Formula V.
Figure imgf000034_0001
Formula V
43. Use of a compound of Formula V
Figure imgf000034_0002
Formula V
for the preparation of tedizolid phosphate of Formula I.
PCT/IB2015/059377 2014-12-05 2015-12-04 Processes for the preparation of tedizolid phosphate and its intermediates WO2016088101A1 (en)

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CN106146560A (en) * 2016-07-12 2016-11-23 扬子江药业集团有限公司 A kind of process for purification of high-purity phosphoric acid specially azoles amine
CN106749074A (en) * 2016-11-14 2017-05-31 沈阳药科大学 A kind of preparation method of Fang oxazolidinones intermediate
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

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US20100093669A1 (en) * 2008-10-10 2010-04-15 Trius Therapeutics Methods for preparing oxazolidinones and compositions containing them
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Publication number Priority date Publication date Assignee Title
CN106146560A (en) * 2016-07-12 2016-11-23 扬子江药业集团有限公司 A kind of process for purification of high-purity phosphoric acid specially azoles amine
CN106749074A (en) * 2016-11-14 2017-05-31 沈阳药科大学 A kind of preparation method of Fang oxazolidinones intermediate
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