WO2016009401A2

WO2016009401A2 - Preparation of tedizolid phosphate

Info

Publication number: WO2016009401A2
Application number: PCT/IB2015/055428
Authority: WO
Inventors: Abhishek Sud; Pramod CHAUDHARI; Rakeshwar Bandichhor; Vilas Hareshwar Dahanukar; Venkata Annapurna Sasi Kala CHEEMALAPATI; Dasameswara Rao KAVITAPU; Jaydeepkumar Dahyabhai Lilakar
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2014-07-18
Filing date: 2015-07-17
Publication date: 2016-01-21
Anticipated expiration: 2017-01-18
Also published as: WO2016009401A3

Abstract

The present application relates to processes for the preparation of tedizolid phosphate.

Description

PREPARATION OF TEDIZOLID PHOSPHATE

INTRODUCTION

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).

(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.

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 reported processes for preparation of tedizolid phosphate suffer from one or more drawbacks such as low yield and purity, involving usage of toxic reagents and tedious workup procedures.

Hence, there is always need to provide commercially viable, simple, economical, cost effective and robust processes for the preparation of tedizolid phosphate. SUMMARY

In the first embodiment, the present application relates to process for the preparation of tedizolid phosphate, which includes one or more of the following steps:

(a) converting 4-halo-3-fluoroaniline compound of formula (II) to a compound of formula (I

wherein X is halogen such as CI, Br or I

(b) converting a compound of formula (IV) to a compound of formula (V);

wherein X is halogen such as CI, Br or I;

(c) converting a compound of formula (V) to a compound of formula (VI);

wherein 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.

(d) reacting compound of formula (VI) with a compound of formula (VII) to provide a compound of formula (VIII)

(VIII)

wherein X and P are as defined above, R is alkyl (e) deprotecting compound of formula (VIII) wherein P is a hydroxy protecting group to provide tedizolid of formula (IX); and

(IX)

(f) converting tedizolid of formula (IX) to tedizolid phosphate.

In the second embodiment, the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:

(a) providing a solution or suspension of crude tedizolid phosphate in a

solvent,

(b) adding alkali or alkaline earth metal hydroxide or alkoxide,

(c) optionally treating with carbon,

(d) isolating alkali or alkaline earth metal salt of tedizolid phosphate,

(e) converting alkali or alkaline earth metal salt of tedizolid phosphate to

tedizolid phosphate, and

(f) isolating substantially pure tedizolid phosphate.

In the third embodiment, the present application provides process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:

(a) providing a solution or suspension of crude tedizolid phosphate in a

solvent,

(b) adding sodium hydroxide or sodium alkoxide,

(c) optionally treating with carbon,

(d) isolating disodium salt of tedizolid phosphate at less than 25°C,

(e) converting disodium salt of tedizolid phosphate to tedizolid phosphate, and

(f) isolating substantially pure tedizolid phosphate.

In the fourth embodiment, the present application provides substantially pure tedizolid phosphate. DETAILED DESCRIPTION

wherein X is halogen such as CI, Br or I

(b) converting a compound of formula (IV) to a compound of formula (V);

wherein X is halogen such as CI, Br or I;

(c) converting a compound of formula (V) to a compound of formula (VI);

(VIII)

wherein X and P are defined above, R is alkyl (e) deprotecting compound of formula (VIII) when P is a hydroxy protecting group to provide tedizolid of formula (IX); and

(IX)

(f) converting tedizolid of formula (IX) to tedizolid phosphate.

Step (a) involves converting 4-halo-3-fluoroaniline compound of formula (II) to a compound of formula (IV):

wherein 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. Optionally step (a) may be carried out without using reagent.

Step (a) may be carried out in a suitable solvent. Suitable solvents that may be used 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, acetonitrile, propionitrile, or the like; and any mixtures thereof. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Step (b) involves converting a compound of formula (IV) to a compound of formula (V)

Where in 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.

Step (b) may be carried out in a suitable solvent. Suitable solvents that may be used 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.

The product of 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)

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.

Step (c) may be carried out in a suitable solvent. Suitable solvents that may be used 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, Ν,Ν-dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

The product of 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)

(VIII)

wherein X and P are defined above, 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.

Step (d) may be carried out in a suitable solvent. Suitable solvents that may be used 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, Ν,Ν-dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; and any mixtures of two or more thereof.

The product of 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)

(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 that may be used 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; polar aprotic solvents, such as for example, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

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.

The product of 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 that may be used 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, Ν,Ν-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; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.

The product of 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.

Optionally 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.

(a) providing a solution or suspension of crude tedizolid phosphate in a

solvent,

(b) adding alkali or alkaline earth metal hydroxide or alkoxide,

(c) optionally treating with carbon,

(d) isolating alkali or alkaline earth metal salt of tedizolid phosphate,

(e) converting alkali or alkaline earth metal salt of tedizolid phosphate to

tedizolid phosphate, and

(f) isolating substantially pure tedizolid phosphate.

Providing a solution or suspension of crude tedizolid phosphate in step a) includes:

i) direct use of a reaction mixture containing crude tedizolid phosphate that is obtained in the course of its synthesis; or

ii) dissolving crude tedizolid phosphate in a solvent or

iii) adding solvent to the crude tedizolid phosphate. 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, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof.

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.

The isolation of 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, acetonitrile, propionitrile, or the like; and any mixtures thereof.

Step (f) involves isolating substantially pure tedizolid phosphate.

The isolation of 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.

(a) providing a solution or suspension of crude tedizolid phosphate in solvent,

(b) adding sodium hydroxide or sodium alkoxide,

(c) optionally treating with carbon,

(d) isolating disodium salt of tedizolid phosphate at less than 25°C,

(e) converting disodium salt of tedizolid phosphate to tedizolid phosphate, and

(f) isolating substantially pure tedizolid phosphate.

ii) dissolving crude tedizolid phosphate in a solvent or.

iii) adding solvent to the crude tedizolid phosphate

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, acetonitrile, propionitrile, or the like; and any mixtures thereof.

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

25°C

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.

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.

Step (f) involves isolating substantially pure tedizolid phosphate.

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 .

Table-1

Column YMC TRIART C18,150^*4.6mm;5.(^m

Flow rate 1 .0 mL /min

Injection volume 10.0μΙ_

Diluent Mix Water and Acetonitrile in the ratio of 1 :1

Sample 0.5 mg/mL

concentration

Column oven 40°C

temperature

Run time 60 minutes

Detector 254 nm

wavelength

Mobile Phase Preparation of Buffer: Dissolve about 1 .36g of KH₂P0₄ and 2.0 preparation mL of TEA in 1000ml of MQ water. Adjust pH to 6.5 with dil.H3P04.Filter and degas.

Preparation of Mobile phase-A : 100% Buffer

Preparation of Mobile phase-B : Mix the volumes of

Acetonitrile and water in the ratio of 90:10 v/v

Gradient

program

In the fourth embodiment, the present application provides substantially pure tedizolid phosphate.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. In general, 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. For example, a group designated as "CrC₈" 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.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "C C₆ 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.

An "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." Examples of C₅-C₈ 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, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C₃-C₆ 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.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two carbon atoms. "C₂-C₆ 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.

A "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.

A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C₃-C₆ 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. "C₂-C₆ 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.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.

EXAMPLES

Example 1 : Preparation of (R)-1-((4-bromo-3-fluorophenyl)amino)-3- chloropropan-2-ol

4-bromo-3-fluoroaniline (0.5 g), (R)-epichlorohydrin (0.27 g) acetonitrile (10 mL) was charged into round bottom flask and stirred for 5 minutes. Bismuth triflate (0.17) g was charged into the reaction mass, resultant reaction mixture was heated to 78 °C and stirred at 78°C for 20 hours. Reaction mass was concentrated under reduced pressure and the obtained crude compound was purified using column chromatography to afford title compound.

Yield: 0.6 g

Example 2: Preparation of (R)-1-((4-bromo-3-fluorophenyl)amino)-3- chloropropan-2-ol

4-bromo-3-fluoroaniline (4 g) and water (40 mL) was charged into round bottom flask at 28°C and stirred for 5 minutes. (R)-epichlorohydrin (2.6 g) was charged into the reaction mass, resultant reaction mixture was heated to 51 °C and stirred at 51 °C for 33 hours. Reaction mass was diluted with ethyl acetate (60 mL) and stirred for 15 minutes. Organic layer was separated and dried using sodium sulfate. The obtained organic layer was concentrated under reduced pressure and the obtained crude compound was purified using column chromatography to afford title compound.

Yield: 4.3 g

Example 3: Preparation of (R)-3-(4-bromo-3-fluorophenyl)-5-(chloromethyl) oxazolidin-2-one

(R)-1 -((4-bromo-3-fluorophenyl)amino)-3-chloropropan-2-ol (2 g), 1 ,1 '- Carbonyldiimidazole (1 .45 g) and dichloromethane (20 mL) was charged into round bottom flask at 28°C and the resultant reaction mixture was stirred under nitrogen atmosphere at 28°C for 16 hours. Reaction mass was diluted with dichloromethane (20 mL) and washed with water (20 mL). Organic layer was dried using sodium sulfate and concentrated under reduced pressure. The obtained crude compound was purified using column chromatography to afford title compound.

Yield: 1 .9 g

Example 4: Preparation of (R)-(3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5- yl)methyl acetate

(R)-3-(4-bromo-3-fluorophenyl)-5-(chloromethyl)oxazolidin-2-one (200 mg) and N, N-dimethylformamide (5 mL) was charged into round bottom flask and stirred for 5 minutes. Potassium acetate (102 mg) was added to the reaction mass at 28°C, the resultant reaction mixture was heated to 80°C and stirred at 80°C for 1 1 hours. Water (10 mL) was added to the reaction mass at 28°C and the reaction mass was extracted with ethylacetate (10 mL). The obtained organic layer was dried with sodium sulfate and concentrated under reduced pressure. The obtained crude compound was purified using column chromatography to afford title compound.

Yield: 200 mg

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.

(R)-(3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl acetate (0.5 g) and potassium carbonate (0.63 g) was added to the solution of 2-(2-methyl-2H- tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.52 g) & mixture of dioxane and water 5:1 (15 mL) at 28°C under nitrogen atmosphere and stirred at 28°C for 45 minutes. [1 ,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (0.12 g) was added to the reaction mass, resultant reaction mixture was heated to 90°C and stirred at 90°C for 4 hours. Reaction mass was cooled to 28°C, filtered and washed with dioxane (5 mL). Filtrate was concentrated under reduced pressure and the obtained crude was diluted with mixture of dichloromethane and water 9:1 (5 mL). Layers were separated and organic layer was washed with brine solution (5 mL). Organic layer was dried using sodium sulfate, concentrated under reduced pressure and the obtained crude compound was purified using column chromatography to afford title compound. Yield: 0.35g

Example 6: Preparation of tedizolid

Potassium carbonate (0.31 g) was added portion wise to the solution containing (R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2- oxooxazolidin-5-yl)methyl acetate (0.3 g) and mixture of dichloromethane & methanol 1 :1 (15 mL) at 28°C under nitrogen atmosphere. The resultant reaction mixture was stirred at 28°C for 24 hours. Reaction mass was concentrated under reduced pressure and the obtained crude was diluted with dichloromethane& methanol 9:1 (10 mL). Reaction mass was washed with brine solution (5 mL), Organic layer was dried using sodium sulfate. Organic layer was concentrated under reduced pressure and the obtained crude compound was purified using column chromatography to afford title compound.

Yield: 0.2 g

Example 7: Preparation of Tedizolid phosphate disodium salt.

Crude tedizolid phosphate (5 g) and water (100 mL) was charged into round bottom flask and cooled to 10 °C. Reaction mass pH was slowly adjusted to 8.52 with 2N sodium hydroxide solution (10 mL). Acidic carbon (2.5 g) was added to the reaction mass and stirred at 10 °C for 40 minutes. Reaction mass was filtered and washed with water (100 mL). Resultant filtrate was added slowly to a round bottom flask containing pre-cooled acetone (800 mL) at 13 °C and stirred at same temperature for 1 hour 10 minutes. Separated solid was filtered, washed with pre- cooled acetone (20 mL) and dried to afford title compound.

Purity by HPLC: 99.84%, 0.03% (0.897 RRT) and 0.08 (1 .33 RRT)

Example 8: Preparation of Tedizolid phosphate disodium salt.

Crude tedizolid phosphate (2 g) and water (20 mL) was charged into round bottom flask and cooled to 10 °C. Reaction mass pH was slowly adjusted to 8.57 with 1 N sodium hydroxide solution (8 mL). Basic carbon (0.5 g) was added to the reaction mass and stirred at 10 °C for 55 minutes. Reaction mass was filtered and washed with water (20 mL). Resultant filtrate was added slowly to a round bottom flask containing pre-cooled acetone (160 mL) at 10 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with pre-cooled acetone (20 mL). Wet compound dissolved in water (10 mL) and the reaction mass was filtered. Resultant filtrate was slowly added to pre-cooled acetone (80 mL) at 12 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with pre-cooled acetone (10 mL) and dried to afford title compound.

Yield: 1 .7 g; Purity by HPLC: 99.83%, 0.08% (0.897 RRT) and 0.07 (1 .33 RRT)

Example 9: Preparation of Tedizolid phosphate disodium salt.

Crude tedizolid phosphate (20 g) and water (600 mL) was charged into round bottom flask and cooled to 10 °C. Reaction mass pH was slowly adjusted to 8.33 with 2N sodium hydroxide solution (45 mL). Acidic carbon (8 g) was added to the reaction mass and stirred at 1 1 °C for 60 minutes. Reaction mass was filtered and washed with water (400 mL). Resultant filtrate was added slowly to a round bottom flask containing pre-cooled acetone (4 L) at 12 °C and stirred at same temperature for 1 hour 30 minutes. Separated solid was filtered, washed with pre-cooled acetone (200 mL) and dried under vacuum to afford title compound.

Yield: 20.1 g; Purity by HPLC: 99.72%, 0.16% (0.897 RRT) and 0.12 (1 .33 RRT) Example 10: Preparation of Tedizolid phosphate dipotassium salt.

Crude tedizolid phosphate (2 g) and water (20 mL) was charged into round bottom flask and cooled to 1 1 °C. Reaction mass pH was slowly adjusted to 8.9 with 2N potassium hydroxide solution (4.0 mL). Acidic carbon was added to the reaction mass and stirred at 1 1 °C for 40 minutes. Reaction mass was filtered and washed with water (20 mL). Resultant filtrate was added slowly to a round bottom flask containing pre-cooled acetone (160 mL) at 12 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with pre-cooled acetone (20 mL). Wet compound dissolved in water (100 mL) and the reaction mass was filtered. Resultant filtrate was slowly added to pre-cooled acetone (400 mL) at 12 °C and stirred at same temperature for 50 minutes. Separated solid was filtered, washed with pre-cooled acetone (20 mL) and dried to afford title compound.

Yield: 0.8 g; Purity by HPLC: 98.1 1 % Example 11 : Preparation of Tedizolid phosphate from 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.

Yield: 3.7 g; Purity by HPLC: 99.83%, 0.09% (0.897 RRT) and 0.07 (1 .33 RRT)

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.

Yield: 1 .2 g; Purity by HPLC: 99.87%, 0.05% (0.897 RRT) and 0.07 (1 .33 RRT)

Example 13: Preparation of Tedizolid phosphate disodium salt.

Crude tedizolid phosphate (2 g) and water (20 mL) was charged into round bottom flask at 29 °C. Reaction mass pH was slowly adjusted to 8.5 with 1 N sodium hydroxide solution (4 mL). Carbon (0.3 g) was added to the reaction mass and stirred at 29 °C for 60 minutes. Reaction mass was filtered and washed with water (20 mL). Resultant filtrate was added drop wise to a round bottom flask containing acetone (1 60 mL) at 29 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with acetone (1 0 mL) and dried under vacuum at 40 °C. The obtained compound dissolved in water (10 mL) at 29 °C and carbon was added to the reaction mixture. Reaction mass was filtered and washed with water (10 mL). Filtrate was slowly added to the acetone (80 mL) at 29 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with acetone (5 mL) and dried to afford title compound.

Yield: 0.8 g; Purity by HPLC: 99.63%, 0.29% (0.897 RRT) and 0.04 (1 .33 RRT) Example 14: Preparation of Tedizolid phosphate disodium salt.

Crude tedizolid phosphate (2 g) and methanol (24 mL) was charged into round bottom flask at 29 °C. Sodium methoxide solution (25%; 2.62 mL) was added slowly to the reaction mixture at 28 °C and stirred at same temperature for 60 minutes. Separated solid was filtered, washed with methanol (10 mL) & acetone (10 mL) and dried. The dried compound and water (20 mL) was charged into round bottom flask. Reaction mixture pH was adjusted to 1 1 with 1 N sodium hydroxide solution (4 mL). Darco G-carbon (2 g) was added to the reaction mass at 30 °C and stirred at same temperature for 60 minutes. 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.

Yield: 0.9 g; Purity by HPLC: 99.61 %, 0.34% (0.897 RRT) and 0.05 (1 .33 RRT)

Claims

CLAIMS:

1 . A process for the preparation of tedizolid phosphate including one or more of the following steps:

(a) converting 4-halo-3-fluoroaniline compound of formula (II) to a compound of formula (IV):

wherein X is halogen such as CI, Br or I;

(b) converting a compound of formula (IV) to a compound of formula (V);

wherein X is halogen such as CI, Br or I;

(c) converting a compound of formula (V) to a compound of formula (VI);

(VIII)

wherein X and P are defined above

(e) deprotecting compound of formula (VIII) wherein P is a hydroxy protecting group to provide tedizolid of formula (IX); and

(IX)

(f) converting tedizolid of formula (IX) to tedizolid phosphate.

2. The process as claimed in claim 1 , wherein compound of formula (II) used in step (a) is 4-bromo-3-fluoroaniline.

3. The process as claimed in claim 1 , wherein compound of formula (III) used in step (a) is (R)-epichlorohydrin.

4. The process as claimed in claim 1 , wherein compound of formula (IV) is converted to compound of formula (V) using reagent selected from 1 ,1 '-Carbonyldiimidazole (CDI), dimethyl carbonate, phosgene or ethylchloroformate.

5. The process as claimed in claim 1 , wherein compound of formula (IV) is converted to compound of formula (V) using 1 ,1 '-Carbonyldiimidazole (CDI).

6. The process as claimed in claim 1 , wherein hydroxyl protecting group of compound of formula (VI) is acetyl and X is bromine.

7. The process as claimed in claim 1 , wherein compound of formula (VII) is 2-(2- methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine.

8. The process as claimed in claim 1 , wherein compound (VIII) is (R)-(3-(3-fluoro-4- (6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl acetate

9. A process for the preparation of substantially pure tedizolid phosphate, which includes one or more of the following steps:

(a) providing a solution or suspension of crude tedizolid phosphate in solvent,

(b) adding alkali or alkaline earth metal hydroxide or alkoxide,

(c) optionally treating with carbon, (d) isolating alkali or alkaline earth metal salt of tedizolid phosphate,

(e) converting alkali or alkaline earth metal salt of tedizolid phosphate to

tedizolid phosphate, and

(f) isolating substantially pure tedizolid phosphate.

10. The process as claimed in claim 9, wherein alkaline earth metal hydroxide or alkoxide used in step (b) is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide.

1 1 . The process as claimed in claim 9, wherein alkaline alkali or alkaline earth metal salt of tedizolid phosphate is disodium salt of tedizolid phosphate or di potassium salt of tedizolid phosphate.

12. The process as claimed in claim 9, wherein alkaline alkali or alkaline earth metal salt of tedizolid phosphate is isolated at 20-25°C.

13. The process as claimed in claim 9, wherein alkaline alkali or alkaline earth metal salt of tedizolid phosphate is isolated at 10-20°C.

14. Tedizolid phosphate having a chemical purity of about 99.50% as determined by HPLC.

15. Tedizolid phosphate having any individual impurity less than 0.15% as determined by HPLC.