WO2016009401A2 - Préparation du phosphate de tédizolid - Google Patents

Préparation du phosphate de tédizolid Download PDF

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Publication number
WO2016009401A2
WO2016009401A2 PCT/IB2015/055428 IB2015055428W WO2016009401A2 WO 2016009401 A2 WO2016009401 A2 WO 2016009401A2 IB 2015055428 W IB2015055428 W IB 2015055428W WO 2016009401 A2 WO2016009401 A2 WO 2016009401A2
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WIPO (PCT)
Prior art keywords
compound
formula
tedizolid phosphate
tedizolid
phosphate
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PCT/IB2015/055428
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English (en)
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WO2016009401A3 (fr
Inventor
Abhishek Sud
Pramod CHAUDHARI
Rakeshwar Bandichhor
Vilas Hareshwar Dahanukar
Venkata Annapurna Sasi Kala CHEEMALAPATI
Dasameswara Rao KAVITAPU
Jaydeepkumar Dahyabhai Lilakar
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Dr. Reddy's Laboratories Limited
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Publication of WO2016009401A2 publication Critical patent/WO2016009401A2/fr
Publication of WO2016009401A3 publication Critical patent/WO2016009401A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present application relates to processes for the preparation of tedizolid phosphate.
  • the drug compound having the adopted name tedizolid phosphate has a chemical name (5R)-3- ⁇ 3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl] phenyl ⁇ - 5-(phosphonooxymethyl)-1 ,3-oxazolidin-2-one, and is represented by structure of formula (I).
  • Tedizolid is used to treat patients with acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis.
  • ABSSSSI acute bacterial skin and skin structure infections
  • U.S. Patent No. 7,816,379 generically and specifically discloses tedizolid and pharmaceutically acceptable salts thereof. Further, it discloses process for preparation of tedizolid and its intermediates.
  • U.S. Patent No. 8,604,209 discloses an alternative process for preparation of tedizolid by treating benzyl (4-(2-(2-methyltetraZol-5-yl) pyridin-5-yl)-3-fluorphenyl) carbamate with glycidyl ester in the presence of a strong base or an organolitihium salt.
  • the present application relates to process for the preparation of tedizolid phosphate, which includes one or more of the following steps:
  • X is halogen such as CI, Br or I
  • X is halogen such as CI, Br or I
  • X is halogen such as CI, Br or I
  • P is selected from H or a hydroxyl protecting group such as acetyl, benzoyl, benzyloxy carbonyl.
  • R is alkyl (e) deprotecting compound of formula (VIII) wherein P is a hydroxy protecting group to provide tedizolid of formula (IX);
  • the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:
  • the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:
  • the present application provides substantially pure tedizolid phosphate.
  • the present application relates to process for the preparation of tedizolid phosphate, which includes one or more of the following steps:
  • X is halogen such as CI, Br or I
  • X is halogen such as CI, Br or I
  • X is halogen such as CI, Br or I
  • P is selected from H or a hydroxyl protecting group such as acetyl, benzoyl, benzyloxy carbonyl.
  • R is alkyl (e) deprotecting compound of formula (VIII) when P is a hydroxy protecting group to provide tedizolid of formula (IX);
  • Step (a) involves converting 4-halo-3-fluoroaniline compound of formula (II) to a compound of formula (IV):
  • X is halogen such as CI, Br or I
  • Step (a) may be effected by reacting 4-halo-3-fluoroaniline compound of formula (II) with epihalohydrin of formula (III).
  • Step (a) may be carried out in presence of Lewis acids such as for example, aluminum trichloride, aluminum tribromide, boron trichloride, boron trifluoride, zinc chloride, ferric chloride, stannic chloride, titanium tetrachloride, bismuth triflate and the like, or any other suitable reagent.
  • Lewis acids such as for example, aluminum trichloride, aluminum tribromide, boron trichloride, boron trifluoride, zinc chloride, ferric chloride, stannic chloride, titanium tetrachloride, bismuth triflate and the like, or any other suitable reagent.
  • step (a) may be carried out without using reagent.
  • Step (a) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; n
  • Step (b) involves converting a compound of formula (IV) to a compound of formula (V)
  • X is halogen such as CI, Br or I;
  • Suitable reagents that may be used in step (b) include but not limited to 1 ,1 '- Carbonyldiimidazole (CDI), dimethyl carbonate, phosgene, ethylchloroformate and the like or any other suitable reagent.
  • CDI Carbonyldiimidazole
  • dimethyl carbonate phosgene, ethylchloroformate and the like or any other suitable reagent.
  • Step (b) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof.
  • ethers such as for example, diethyl ether, diisoprop
  • step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
  • Step (c) involves converting a compound of formula (V) to a compound of formula (VI)
  • X is halogen such as CI, Br or I
  • P is selected from H or a hydroxyl protecting group such as acetyl, benzoyl, benzyloxy carbonyl.
  • Suitable reagents that may be used in step (c) include but not limited to alkaline or alkaline earth metal salt of carboxylic acids such as for example sodium acetate, potassium acetate, sodium propionate, sodium benzoate, potassium benzoate and the like or any other suitable reagent.
  • alkaline or alkaline earth metal salt of carboxylic acids such as for example sodium acetate, potassium acetate, sodium propionate, sodium benzoate, potassium benzoate and the like or any other suitable reagent.
  • Step (c) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to: ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, N- methylpyrrolidone, pyridine,
  • step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
  • Step (d) involves reacting compound of formula (VI) with compound of formula (VII) to provide compound of formula (VIII)
  • R is alkyl
  • Suitable reagents that may be used in step (d) include, but not limited to copper (II) acetate, palladium acetate, zinc acetate, Tetrakis(triphenylphosphine)palladium, Pd(N,N-Dimethyl (N- Heterocyclic carbene)Pd(allyl)CI Complexes, Phenanthroline-Palladium(ll) Complex, Bis[tri(o-tolyl)phosphine]palladium(ll) or the like or any other suitable reagents.
  • Suitable bases that may be used in step (d) include, but are not limited to organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like; inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t- butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like or any other suitable bases known in the art.
  • organic bases such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like
  • inorganic bases including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t- butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like or any other suitable bases known
  • Step (d) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to: ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, and the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; aromatic hydrocarbons, such as for example,
  • step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
  • Isolation of compound of formula (VI II) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (e) involves deprotecting compound of formula (VIII) when P is a hydroxy protecting group to provide tedizolid of formula (IX)
  • Suitable reagents that may be used in step (e) include, but are not limited to, acids, bases, resins, and any mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures.
  • Suitable acids that may be used in step (e) include, but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
  • Suitable bases that may be used in step (e) include, but are not limited to: ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like;
  • Suitable resins that may be used in step (e) include, but are not limited to, ion exchange resins, such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulfonic, methanesulfonic, p- toluenesulfonic, and the like or any other suitable reagents.
  • Step (e) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to: water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like;
  • Suitable temperatures for the reaction of (e) may be less than 160°C, less than 130°C, less than 100°C, less than 80°C, less than 60°C, less than 40°C, less than 20°C or any other suitable temperatures.
  • step (e) may be isolated directly from the reaction mixture itself after the reaction is complete in step (e), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
  • Isolation of compound of formula (IX) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (f) involves converting tedizolid of formula (IX) to tedizolid phosphate.
  • Step (f) may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like
  • step (f) may be isolated directly from the reaction mixture itself after the reaction is complete in step (f), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
  • Isolation of tedizolid phosphate may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • steps (a) to (e) or any two or more steps may be carried out as in- situ i.e. without isolating the intermediates in each stage.
  • the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:
  • Providing a solution or suspension of crude tedizolid phosphate in step a) includes:
  • Suitable solvents which can be used in step (a) include but are not limited to water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin
  • Step (b) involves adding alkali or alkaline earth metal hydroxide or alkoxide,
  • Suitable alkali or alkaline earth metal hydroxide or alkoxide that may be used in step (b) include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert- butoxide, calcium methoxide and the like or any other suitable reagents that can form alkali or alkaline earth metal salt with tedizolid phosphate.
  • Alkali or alkaline earth metal hydroxide in step (b) may be directly added to the reaction mixture or may be added by dissolving alkali or alkaline earth metal hydroxide in suitable solvent as mentioned in step (a) in the form of solution.
  • Step (c) involves optionally treating the reaction mixture with carbon.
  • Suitable carbons that may be used in step (c) include but not limited to acidic carbon or basic carbon or neutral carbon and the like.
  • Step (d) involves isolating alkali or alkaline earth metal salt of tedizolid phosphate.
  • alkali or alkaline earth metal salt of tedizolid phosphate may be carried out using methods known in the art such as removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • Step (e) involves converting alkali or alkaline earth metal salt of tedizolid phosphate to tedizolid phosphate.
  • Suitable reagents that may be used for converting alkali or alkaline earth metal salt of tedizolid phosphate to tedizolid phosphate include but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, formic acid and the like.
  • Suitable solvents that may be used in step (e) include but are not limited to water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example,
  • Step (f) involves isolating substantially pure tedizolid phosphate.
  • substantially pure tedizolid phosphate may be carried out using methods known in the art such as removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:
  • Providing a solution or suspension of crude tedizolid phosphate in step a) includes:
  • Suitable solvents used in step (a) include but are not limited to water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, aceton
  • Step (b) involves adding sodium hydroxide or sodium alkoxide solution
  • Suitable sodium alkoxide that may be used in step (b) include but not limited to sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like
  • Sodium hydroxide or sodium alkoxide used in step (b) may be directly added to the reaction mixture or may be added by dissolving sodium hydroxide or sodium alkoxide in suitable solvent as mentioned in step (a) in the form of solution.
  • Step (c) involves optionally treating the reaction mixture with carbon.
  • Suitable carbons that may be used in step (c) include but not limited to acidic carbon or basic carbon or neutral carbon and the like.
  • Step (d) involves isolating disodium salt of tedizolid phosphate at less than
  • the isolation of disodium salt of tedizolid phosphate may be carried out using methods known in the art such as removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.
  • Isolation of disodium salt of tedizolid phosphate may be carried out at temperature less than 25 °C or less than 20 °C or less than 15 °C or less than 13 °C or less than 10 °C or less than 8 °C or less than 5 °C or less than 3 °C.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • Step (e) involves converting disodium salt of tedizolid phosphate to tedizolid phosphate.
  • Suitable reagents that may be used for converting disodium salt of tedizolid phosphate to tedizolid phosphate include but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, formic acid and the like.
  • Suitable solvents that may be used in step (e) include but are not limited to water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example,
  • Step (f) involves isolating substantially pure tedizolid phosphate.
  • substantially pure tedizolid phosphate may be carried out using methods known in the art such as removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • High performance liquid chromatography (HPLC) method employed for the analysis of the tedizolid phosphate and disodium salt of tedizolid phosphate involves the use of C18 or equivalent column. Additional parameters are as shown in Table-1 .
  • the present application provides substantially pure tedizolid phosphate.
  • the number of carbon atoms present in a given group or compound is designated “C x -C y ", where x and y are the lower and upper limits, respectively.
  • a group designated as “CrC 8 " contains from 1 to 8 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of any substituents, such as alkoxy substitutions or the like.
  • C C 6 alcohols include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.
  • aliphatic hydrocarbon is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
  • a liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic.”
  • C 5 -C 8 aliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isoo
  • C 3 -C 6 esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.
  • ether is an organic compound containing an oxygen atom -O- bonded to two carbon atoms.
  • C 2 -C 6 ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.
  • halogenated hydrocarbon is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like.
  • C 3 -C 6 ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.
  • a “nitrile” is an organic compound containing a cyano -(C ⁇ N) bonded to another carbon atom.
  • C 2 -C 6 nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.
  • Crude tedizolid phosphate as used herein refers tedizolid phosphate having chemical purity of less than that of substantially pure tedizolid phosphate as determined by HPLC.
  • Substantially pure tedizolid phosphate as used herein refers tedizolid phosphate having chemical purity of about 98% or about 98.5% or about 99% or about 99.1% or about 99.2% or about 99.3% or about 99.4% or about 99.5% or about 99.6% or about 99.7% or about 99.8% or about 99.9% as determined by High performance liquid chromatography (HPLC) and/or having any individual impurity less than about 0.05% or less than about 0.07% or less than about 0.10% or less than about 0.15% as determined by HPLC.
  • HPLC High performance liquid chromatography
  • Example 5 Preparation of (R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl acetate.
  • Example 7 Preparation of Tedizolid phosphate disodium salt.
  • Example 8 Preparation of Tedizolid phosphate disodium salt.
  • Example 9 Preparation of Tedizolid phosphate disodium salt.
  • Tedizolid disodium salt (5 g) was dissolved in water (50 mL) at 28 °C and the obtained solution was filtered. Filtrate was charged into round bottom flask and tetrahydrofuran (50 mL) was added. Reaction mass pH was adjusted to 1 .3 with 2N hydrochloric acid solution (15 mL) at 10 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with water (25 mL) & methanol (25 mL) and dried under reduced pressure to afford title compound.
  • Example 12 Preparation of Tedizolid phosphate from Tedizolid phosphate disodium salt.
  • Tedizolid disodium salt (1 .4 g) was dissolved in water (14 mL) at 28 °C and the obtained solution was filtered. Filtrate was charged into round bottom flask and tetrahydrofuran (14 mL) was added. Reaction mass pH was adjusted to 1 .3 with 2N hydrochloric acid solution (4 mL) at 10 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with water (7 mL) & methanol (7 mL) and dried under reduced pressure to afford title compound.
  • Example 13 Preparation of Tedizolid phosphate disodium salt.
  • Reaction mass was filtered and the obtained filtrate was added drop wise to a round bottom flask containing acetone (160 mL) at 29 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with acetone (20 mL) and dried under vacuum. The obtained dried compound dissolved in water (20 mL) at 28 °C and carbon was added to the reaction mixture. Reaction mass was filtered and washed with water (20 mL). Filtrate was slowly added to the acetone (1 60 mL) at 29 °C and stirred at same temperature for 1 hour 15 minutes. Separated solid was filtered, washed with acetone (20 mL) and dried to afford title compound.

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Abstract

La présente invention concerne des procédés de préparation du phosphate de tédizolid.
PCT/IB2015/055428 2014-07-18 2015-07-17 Préparation du phosphate de tédizolid WO2016009401A2 (fr)

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