DESC:CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201841010686, filed on March 22, 2018, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION
The present invention relates to novel, cost effective and industrially advantageous processes for the production of an oxazolidinone antibacterial agent and its intermediate, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, with a reduced number of synthetic steps, reduction in the chemical waste and thereby increasing the overall yield of the product.

BACKGROUND OF THE INVENTION
U.S. Patent No. 5,688,792 (hereinafter referred to as the US‘792 patent), assigned to Pharmacia & Upjohn Company, discloses a variety of oxazine and thiazine oxazolidinone derivatives and their stereochemically isomeric forms, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms and acid-fast organisms. Among them, Linezolid, a member of the oxazolidinone class of drugs and chemically named as N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). Linezolid is represented by the following structural formula I:
Various processes for the preparation of Linezolid and its penultimate intermediate, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, were described in U.S. Patent Nos. US 5,688,792, US 7,429,661, US 7,307,163; PCT Publication Nos. WO 2012/114355, WO 2013/190559, WO 2014/045292, WO2014/174522 and WO 2015/162622; Chinese Patent Application Publication Nos. CN 103103229, CN 103382200, CN 102229577, CN 102850228 and CN 102898394; and Journal Articles: J. Med. Chem. 39(3), 673-679, 1996.
The synthesis of Linezolid was first described in the US‘792 patent. According to the US‘792 patent, the Linezolid is prepared by a process as depicted in scheme 1:

The synthesis of Linezolid as described in the US‘792 patent involves the following main reaction steps: a) 3-Fluoro-4-morpholinyl aniline is reacted with benzyl chloroformate in the presence of sodium bicarbonate to produce N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline; b) the N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline is reacted with a solution of (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane at a temperature of –78°C under nitrogen atmosphere, followed by tedious work-up and isolation methods to produce the (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone; c) the (5R)-5-(Hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone is reacted with methanesulfonyl chloride in the presence of triethylamine in methylene chloride solvent under nitrogen atmosphere to produce (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate; d) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate is reacted with sodium azide to produce (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl azide, or alternatively (ii) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate intermediate is reacted with potassium phthalimide to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide; e) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl azide intermediate is hydrogenated in the presence of 10% palladium/carbon to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, or (ii) the (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide intermediate is reacted with aqueous methyl amine to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine; and f) the amino-methyl-oxazolidinone intermediate is then subjected to acetylation with acetic anhydride to produce Linezolid.
However, the processes described in the US’792 patent suffer from the following disadvantages and limitations: i) the processes involve the use of highly flammable and dangerous reagent like n-butyl lithium in hexanes, which is an explosive and pyrophoric reagent; ii) handling of n-butyl lithium is very difficult at lab scale and in commercial scale operations since n-butyl lithium is stored and available as solutions in highly flammable liquids like alkanes (hexanes) and exposure to air or water causes flash fire or explosion; iii) the reaction between N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline (Benzyl ester intermediate) and (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane or lithium tert-butoxide should be performed at extremely low temperatures (–78°C to –16°C) under very strict control of reaction conditions; processes involving extremely low temperatures are undesirable for large-scale operations since they require special equipment and an additional reactor, adding to the cost, thereby making the processes commercially unfeasible; iv) the processes involve the use of additional process steps (SIX), longer reaction times, nitrogen atmosphere, thereby leading to low overall yields of the product; v) the processes require the use of highly toxic and/or expensive reagents like benzyl chloroformate, sodium azide and (R)-glycidyl butyrate, Palladium on Carbon; vi) the processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, multiple isolation /re-crystallizations; vii) the processes involve the use of multiple and excess amounts of hazardous solvents like n-hexane, heptanes and dioxane; viii) the processes involve the use of highly hazardous reagents like phosgene, methanesulfonyl chloride and pyridinium p-toluenesulfonate; ix) the processes require the use of slow, expensive and time-consuming column chromatographic purifications - methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible; x) the overall processes generate a large quantity of chemical waste which is difficult to treat.
The aforesaid problems have been solved by the commercially viable, industrially advantageous and environmentally friendly processes for the preparation of Linezolid using novel intermediates as disclosed in the U.S. Patent Nos. 7,307,163 and 7,429,661 (assigned to the present applicant), which involve the use of reduced number of reaction steps (five reaction steps) to produce Linezolid (starting from the key starting material “3-Fluoro-4-morpholinyl aniline”).
U.S. Patent No. 7,307,163 B2 (hereinafter referred to as the US‘163 patent) discloses a novel, commercially viable and industrially advantageous process for the preparation of Linezolid and its intermediates. The US‘163 patent discloses a process for the preparation of 5-aminomethyl substituted oxazolidinone intermediate of formula I which is represented by the following scheme 2:

The specific process for the preparation of Linezolid as disclosed in the US’163 patent is depicted in the below scheme 3:

As per the process described in US‘163 patent, Linezolid is prepared by the following main reaction steps: i) 3-Fluoro-4-morpholinyl aniline is reacted with (R)-epichlorohydrin to produce N-[3-chloro-2(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline; ii) carbonylating the N-[3-chloro-2(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline with a carbonylating agent (preferably N,N-carbonyldiimidazole) in an aprotic solvent to produce (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone; iii) reacting the resulting chloromethyl-oxazolidinone compound with potassium phthalimide to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide, iv) reacting the resulting phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in an alcoholic solvent (preferably methanol, ethanol or isopropyl alcohol) to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (hereinafter referred to as 5-aminomethyl substituted oxazolidinone intermediate); or alternatively the chloromethyl-oxazolidinone compound obtained in step-(ii) with an azide source like sodium azide followed by catalytic hydrogenation in presence of palladium on carbon catalyst to produce the 5-aminomethyl substituted oxazolidinone intermediate; the resulting 5-aminomethyl substituted oxazolidinone intermediate is finally acetylated with an acetylating agent like acetic anhydride to produce Linezolid.
U.S. Patent No. 7,429,661 B2 (hereinafter referred to as the US‘661 patent) discloses another novel, commercially viable and industrially advantageous process for the preparation of Linezolid and its intermediates. The process for the preparation of 5-aminomethyl substituted oxazolidinone intermediate described in the US’661 patent is depicted in the below scheme 4:

The process for the preparation of 5-aminomethyl substituted oxazolidinone intermediate described in the US’661 patent is depicted in the below scheme 5:

As per the process described in US‘661 patent, Linezolid is prepared by the following main reaction steps: i)(a) N-[3-chloro-2(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline is reacted with potassium phthalimide to produce N-[3-phthalimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline, or alternatively (b) 3-fluoro-4-morpholinyl aniline is reacted with (S)-N-2,3-epoxypropyl phthalimide to produce N-[3-phthalimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline; ii) the resulting N-[3-phthalimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline is subjected to carbonylation with a carbonylating agent, preferably N,N-carbonyldiimidazole, in an aprotic solvent to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide; iii) reacting the resulting phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in an alcoholic solvent (preferably methanol, ethanol or isopropyl alcohol) to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, which is finally acetylated with an acetylating agent like acetic anhydride to produce Linezolid.
U.S. Patent No. 6,559,305 (hereinafter referred to as the US‘305 patent) discloses two crystal forms (Form I & Form II) of Linezolid. According to the ‘305 patent, the crystalline Form II of Linezolid is characterized by a powder X-ray diffraction spectrum having 2-theta angle positions at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61, 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees; and an IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287,1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078,1066, 1049, 907, 852 and 758 cm-1. The US‘305 patent further states that when Linezolid was originally produced, for example, as per the processes exemplified in the US‘792 patent (example 5) and J. Med. Chem. 39 (3), 673-679, 1996, the crystal form was Form I, which is characterized by having melting point of 181.5-182.5°C, and an IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm-1.
U.S. Patent No. 7,714,128 B2 (hereinafter referred to as the US‘128 patent) discloses a novel, stable and enantiomerically pure crystalline form (Form III) of Linezolid and processes for preparation thereof. According to the US‘128 patent, the crystalline Form III of Linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 ± 0.2 degrees; and an IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm-1.
PCT Publication No. WO 2012/114355 describes a process for the preparation of Linezolid which involves 8 reaction steps starting from the key starting material 3-Fluoro-4-morpholinyl aniline, which is depicted in the below scheme 6:

In the processes for the preparation of Linezolid described in the prior art, the 5-aminomethyl substituted oxazolidinone intermediate, namely (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, is a key penultimate intermediate.
As per the processes described in the US‘792 patent, the preparation of 5-aminomethyl substituted oxazolidinone intermediate starting from the key starting material 3-Fluoro-4-morpholinyl aniline is carried out in a sequence of 5 reaction steps. As per the processes described in the US‘163 and US’661 patents, the preparation of 5-aminomethyl substituted oxazolidinone intermediate starting from the key starting material 3-Fluoro-4-morpholinyl aniline is carried out in a sequence of 4 reaction steps. According to WO 2012/114355, the preparation of 5-aminomethyl substituted oxazolidinone intermediate starting from the key starting material 3-Fluoro-4-morpholinyl aniline is carried out in a sequence of 7 reaction steps.
The object of the present invention is to provide a novel, cost effective, and industrially advantageous process of preparing Linezolid and its key penultimate intermediate 5-aminomethyl substituted oxazolidinone with a reduced number of reaction steps, reduction in the chemical waste and thereby increasing the overall yield of the product, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The present inventors have surprisingly and unexpectedly found that Linezolid and its penultimate intermediate, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, can be prepared, with a reduced number of reaction steps and with high yield and purity, by reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone with ammonia, preferably with ammonia gas under pressure, in a suitable solvent, optionally in the presence of a base, to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, followed by acetylation with a suitable acetylating agent to produce Linezolid or a polymorphic form thereof.
In one aspect, provided herein is a novel, cost effective, and industrially advantageous process for the preparation of Linezolid intermediate, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, by reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone with ammonia, preferably with ammonia gas under pressure, in a suitable solvent, optionally in the presence of a base and/or a suitable catalyst.
In another aspect, provided herein is a novel, cost effective, and industrially advantageous process for the preparation of Linezolid by reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone with ammonia, preferably with ammonia gas under pressure, in a suitable solvent, optionally in the presence of a base and/or a suitable catalyst to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, followed by acetylation with a suitable acetylating agent to produce Linezolid with high yield and purity.
The processes for the preparation of Linezolid and its intermediate disclosed herein have the following advantages over the processes described in the prior art:
i) the overall process involves a reduced number of process steps, shorter reaction times and less expensive reagents thereby making the process cost effective;
ii) the process avoids the use of additional and unnecessary reaction steps, thereby avoiding the use of additional and expensive reagents like potassium phthalimide, sodium azide, methanesulfonyl chloride, Palladium on Carbon, hydrazine hydrate, methylamine;
iii) the overall yield of the Linezolid and its intermediate is increased and the purity of the product is increased without additional purifications;
iv) the process avoids the use of tedious and cumbersome procedures like prolonged reaction time periods, extremely low temperatures (–78°C to –16°C), multiple process steps, column chromatographic purifications, multiple isolations, additional and excess amounts of solvents;
v) the process avoids the use of explosive, dangerous and difficult to handle reagents like n-butyl lithium and lithium tert-butoxide;
vi) the process avoids the use of highly inflammable and toxic solvents like hexane, dioxane and heptanes;
vii) the process avoids the use of additional and excess amounts of solvents, multiple isolation steps, column chromatographic purifications;
viii) the process involves easy work-up methods and simple isolation processes, and there is a reduction in chemical waste.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel, cost effective, and industrially advantageous process for the preparation of Linezolid of formula I:

or an enantiomeric form or a mixture of enantiomeric forms thereof, which comprises:
a) reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone of formula III:

or an enantiomeric form or a mixture of enantiomeric forms thereof, with ammonia in a suitable solvent, optionally in the presence of a suitable base, to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:

or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof; and
b) acetylation of the amino-methyl-oxazolidinone compound of formula II obtained in step-(a) with an acetylating agent, optionally in the presence of a base, in a suitable solvent to produce highly pure Linezolid or a polymorphic form, or a mixture of polymorphic forms, thereof.
The structural formulae of the compounds I, II and III designated herein each contains one chiral centre and thus exists as two optical isomers, i.e. enantiomers (R & S-isomers). Unless otherwise specified, the process disclosed herein encompasses the preparation of both enantiomers and mixtures thereof in all proportions.
Unless otherwise specified, the (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone employed as starting material in the present invention can be prepared by the processes known in the art, for example, but are not limited to, as per the processes described in the U.S. Patent No. 7,307,163.
Unless otherwise specified, the term ‘base’ as used herein includes organic bases and inorganic bases. Exemplary inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, sodium amide, potassium amide, and mixtures thereof. Exemplary organic bases include, but are not limited to, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, and the like.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds of formula I, II and III obtained by, or employed in, the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, a polar aprotic solvent, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof. Specifically, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, acetone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by the methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature of the solvent used; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC. For example, “room temperature” can refer to a temperature of about 25ºC to about 30ºC.
In one embodiment, the reaction in step-(a) is carried out in the presence of a reaction inert solvent. Exemplary solvents used in step-(a) include, but are not limited to, an alcohol, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. Most preferred solvents are acetonitrile, methanol, N,N-dimethylformamide, dimethyl sulfoxide and mixtures thereof.
In one embodiment, the ammonia in step-(a) is used in the form of ammonia gas under pressure or in the form of liquor ammonia or in the form of ammonia saturated in an organic solvent.
In a preferred embodiment, the reaction in step-(a) is advantageously carried out with ammonia gas under pressure of about 1 Kg/Cm2 to about 50 Kg/Cm2, specifically under pressure of about 5 Kg/Cm2 to about 30 Kg/Cm2, and most specifically under pressure of about 10 Kg/Cm2 to about 20 Kg/Cm2.
In one embodiment, the reaction in step-(a) is optionally carried out in the presence of a base, wherein the base is an organic base or an inorganic base.
In a preferred embodiment, the reaction in step-(a) is carried out in the presence of an inorganic base. Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium amide, potassium amide, and mixtures thereof. A most specific inorganic base is sodium carbonate or potassium carbonate.
In another embodiment, the reaction in step-(a) is optionally carried out in the presence of a catalytic amount of sodium iodide or potassium iodide.
The time period required for completion of the reaction in step-(a) will ordinarily depend on the reaction temperature, pressure and the solvent employed in the reaction.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 20ºC to the reflux temperature of the solvent used, specifically at a temperature of about 40ºC to the reflux temperature of the solvent used, and more specifically the reflux temperature of the solvent used. The reaction time may vary from about 1 hour to about 60 hours, and specifically from about 2 hours to about 40 hours.
The reaction mass containing the (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, distillation, filtration, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce Linezolid of formula I, or the amino-methyl-oxazolidinone compound of formula II may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the amino-methyl-oxazolidinone compound of formula II obtained in step-(a) is optionally subjected to carbon treatment.
In one embodiment, the amino-methyl-oxazolidinone compound of formula II may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the amino-methyl-oxazolidinone compound of formula II obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the acetylation of the amino-methyl-oxazolidinone compound of formula II in step-(b) is carried out by the methods known in the art, for example, as per the processes described in the U.S. Patent Nos. US5,688,792, US7,429,661, US7,307,163, US9,586,913, US7,714,128, and WO2013/190559.
Exemplary acetylating agents used in step-(b) include, but are not limited to, acetic anhydride, acetyl chloride and the like. A most specific acetylating agent is acetic anhydride.
Exemplary solvent used for acetylation in step-(b) include, but are not limited to, water, an alcohol, a ketone, an ether, an ester, a nitrile, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used for acetylation in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-proply acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
Most specifically, the solvent used for acetylation in step-(b) is selected from the group consisting of dichloromethane, methanol, ethanol, isopropyl alcohol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
The base used in step-(b) is an organic base or an inorganic base.
In one embodiment, the acetylation in step-(b) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 10°C to about 50°C, and more specifically at a temperature of about 20°C to about 40°C. The reaction time may vary from about 20 minutes to about 5 hours.
The reaction mass containing the Linezolid of formula I obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, distillation, filtration, decolorization, a carbon treatment or a combination thereof, followed by isolation and/or recrystallization from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
In one embodiment, the solvent used for work up, isolation and/or recrystallization of Linezolid obtained by the process described herein is selected from the group as described hereinabove.
The solid separated is collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
In one embodiment, the Linezolid solid obtained by the processes described in the present invention is in the form of crystalline Form II.
In another embodiment, the Linezolid solid obtained by the processes described in the present invention is in the form of crystalline Form III.
The term “Linezolid Crystalline Form III”, as used herein is intended to mean the Linezolid Form III as disclosed in the U.S. Patent No. 7,714,128.
The term “Linezolid Crystalline Form II”, as used herein is intended to mean the Linezolid Form II as disclosed in the U.S. Patent No. 6,559,305.
The highly pure Linezolid or a polymorphic form thereof obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 110°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
The highly pure Linezolid or a polymorphic form or a mixture of polymorphic forms thereof obtained by the process disclosed herein has a total purity (including both chemical and enantiomeric purities) of greater than about 99.5%, specifically greater than about 99.8%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.
According to another aspect, there is provided a novel, cost effective, and industrially advantageous process for the preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:

or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof, comprising reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone of formula III:

or an enantiomeric form or a mixture of enantiomeric forms thereof, with ammonia in a suitable solvent, optionally in the presence of a suitable base, to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof.
In one embodiment, the reaction of the compound of formula III with ammonia is carried out in the presence of a reaction inert solvent. Exemplary solvents include, but are not limited to, an alcohol, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. Most preferred solvents are acetonitrile, methanol, N,N-dimethylformamide, dimethyl sulfoxide and mixtures thereof.
In one embodiment, the ammonia is used in the form of ammonia gas under pressure or in the form of liquor ammonia or in the form of ammonia saturated in an organic solvent.
In a preferred embodiment, the reaction is advantageously carried out with ammonia gas under pressure of about 1 Kg/Cm2 to about 50 Kg/Cm2, specifically under pressure of about 5 Kg/Cm2 to about 30 Kg/Cm2, and most specifically under pressure of about 10 Kg/Cm2 to about 20 Kg/Cm2.
In one embodiment, the reaction is carried out in the presence of a base, wherein the base is an organic base or an inorganic base.
In a preferred embodiment, the reaction is carried out in the presence of an inorganic base. Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium amide, potassium amide, and mixtures thereof. A most specific inorganic base is sodium carbonate or potassium carbonate.
In another embodiment, the reaction is optionally carried out in the presence of a catalytic amount of sodium iodide or potassium iodide.
The time period required for completion of the reaction will ordinarily depend on the reaction temperature, pressure and the solvent employed in the reaction.
In one embodiment, the reaction of the compound of formula III with ammonia is carried out at a temperature of about 20ºC to the reflux temperature of the solvent used, specifically at a temperature of about 40ºC to the reflux temperature of the solvent used, and more specifically the reflux temperature of the solvent used. The reaction time may vary from about 1 hour to about 60 hours, and specifically from about 2 hours to about 40 hours.
The reaction mass containing the (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II obtained may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, distillation, filtration, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the amino-methyl-oxazolidinone compound of formula II obtained is subjected to carbon treatment.
In one embodiment, the amino-methyl-oxazolidinone compound of formula II may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the amino-methyl-oxazolidinone compound of formula II obtained by the process described herein is selected from the group as described hereinabove.
The amino-methyl-oxazolidinone compound of formula II obtained by the process disclosed herein has a total purity (including both chemical and enantiomeric purities) of greater than about 98%, specifically greater than about 99.8%, more specifically greater than about 99.9% as measured by HPLC.
INSTRUMENTAL DETAILS:
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC using Shimadzu LC-2010 CHT system with LC solutions software or its equivalent under the following conditions: Column = Kromasil 100 C18, 250 mm x 4.6 mm, 5µm or Equivalent; Detector wavelength = 254 nm; Flow Rate = 0.5 ml/minute; Injection volume = 20µL; Oven temperature = 40°C; Run time = 30 minutes; Diluent = Acetonitrile; Elution = Isocratic; Mobile Phase = Water (400 ml) : acetonitrile (600 ml) : triethyl amine (1.8 ml) : acetic acid (1.3 ml).
HPLC Method for measuring Chiral Purity:
The chiral purity was measured by HPLC using Shimadzu LC-2010 CHT system with LC solutions software or its equivalent under the following conditions: Column = Chiralpak AD-H, 250 mm x 4.6 mm, 5µm or Equivalent; Detector wavelength = 254 nm; Flow Rate = 1.5 mL/minute; Injection volume = 10µL; Oven temperature = 25°C; Run time = 30 minutes; Diluent = Mobile phase; Elution = Isocratic; Mobile Phase = n-hexane (700 ml) : ethanol (300 ml) : diethyl amine (1 ml).

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine
Acetonitrile (200 ml) was taken into a reaction flask, followed by the addition of (5R)-5-(Chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone (5 g), potassium carbonate (2.4 g) and potassium iodide (catalytic amount) while stirring at 25-30ºC. The resulting mixture was taken into an autoclave at 25-30ºC, followed by purging ammonia gas under pressure of 15 Kg/cm2 at 25-30ºC until saturation for about 30 to 40 minutes. The reaction mixture was heated to 85°C while stirring and then maintained for 35 to 40 hours. After completion of the reaction (checked by TLC), the reaction mass was cooled to 25-30ºC, the undissolved material was filtered and then washed with acetonitrile (30 ml). The mother liquors were taken and distilled off the solvent under reduced pressure to give 4.5 g of pure (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine.
Example 2
Preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine
(5R)-5-(Chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone (5 g) was dissolved in acetonitrile (200 ml) while stirring at 25-30ºC. The resulting solution was taken into an autoclave at 25-30ºC, followed by purging ammonia gas under pressure of 15 Kg/cm2 at 25-30ºC until saturation for about 30 to 40 minutes. The reaction mixture was heated to 85°C while stirring and then maintained for 35 to 40 hours. After completion of the reaction (checked by TLC), the reaction mass was cooled to 25-30ºC and then distilled off the solvent completely under reduced pressure to give pure (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.

Example 3
Preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine
Methanol (400 ml) was taken into a reaction flask, followed by the addition of (5R)-5-(Chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone (5 g), potassium carbonate (2.4 g) and potassium iodide (catalytic amount) while stirring at 25-30ºC. The resulting mixture was taken into an autoclave at 25-30ºC, followed by purging ammonia gas under pressure of 15 Kg/cm2 at 25-30ºC until saturation for about 30 to 40 minutes. The reaction mixture was heated to 65°C while stirring and then maintained for 40 to 45 hours. After completion of the reaction (checked by TLC), the reaction mass was cooled to 25-30ºC, the undissolved material was filtered and then washed with methanol (30 ml). The mother liquors were taken and distilled off the solvent completely under reduced pressure to give pure (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine.

Example 4
Preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]amine
(5R)-5-(Chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone (5 g) was dissolved in methanol (400 ml) while stirring at 25-30ºC. The resulting solution was taken into an autoclave at 25-30ºC, followed by purging ammonia gas under pressure of 15 Kg/cm2 at 25-30ºC until saturation for about 30 to 40 minutes. The reaction mixture was heated to 65°C while stirring and then maintained for 40 to 45 hours. After completion of the reaction (checked by TLC), the reaction mass was cooled to 25-30ºC and then distilled off the solvent completely under reduced pressure to give pure (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.
,CLAIMS:1. A process for the preparation of Linezolid of formula I:

or an enantiomeric form or a mixture of enantiomeric forms thereof, which comprises:
a) reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone of formula III:

or an enantiomeric form or a mixture of enantiomeric forms thereof, with ammonia in a suitable solvent, optionally in the presence of a suitable base, to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:

or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof; and
b) acetylation of the amino-methyl-oxazolidinone compound of formula II obtained in step-(a) with an acetylating agent, optionally in the presence of a base, in a suitable solvent to produce highly pure Linezolid or a polymorphic form, or a mixture of polymorphic forms, thereof.

2. The process of claim 1, wherein the ammonia in step-(a) is used in the form of ammonia gas under pressure or in the form of liquor ammonia or in the form of ammonia saturated in an organic solvent; wherein the solvent used in step-(a) is selected from the group consisting of an alcohol, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof; wherein the base used in step-(a) is an organic base or inorganic base; wherein the reaction in step-(a) is optionally carried out in the presence of a catalytic amount of sodium iodide or potassium iodide; wherein the reaction in step-(a) is carried out at a temperature of about 20ºC to the reflux temperature of the solvent used; wherein the amino-methyl-oxazolidinone compound of formula II obtained in step-(a) is optionally subjected to carbon treatment; wherein the acetylating agent used in step-(b) is acetic anhydride or acetyl chloride; the solvent used for acetylation in step-(b) is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a nitrile, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof; and wherein the Linezolid solid obtained by the processes described in the present invention is in the form of crystalline Form II or crystalline Form III.
3. The process of claim 2, wherein the ammonia in step-(a) is used in the form of ammonia gas under pressure of about 1 Kg/Cm2 to about 50 Kg/Cm2; wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the base used in step-(a) is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium amide, potassium amide, and mixtures thereof; wherein the reaction in step-(a) is carried out at a temperature of about 40ºC to the reflux temperature of the solvent used; and wherein the solvent used for acetylation in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-proply acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
4. The process of claim 3, wherein the ammonia in step-(a) is used in the form of ammonia gas under pressure of about 10 Kg/Cm2 to about 20 Kg/Cm2; wherein the solvent used in step-(a) is selected from the group consisting of acetonitrile, methanol, N,N-dimethylformamide, dimethyl sulfoxide and mixtures thereof; wherein the inorganic base used in step-(a) is sodium carbonate or potassium carbonate; wherein the reaction in step-(a) is carried out at the reflux temperature of the solvent used; and wherein solvent used for acetylation in step-(b) is selected from the group consisting of dichloromethane, methanol, ethanol, isopropyl alcohol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
5. A process for the preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:

or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof, comprising reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-morpholinyl)phenyl]-2-oxazolidinone of formula III:

or an enantiomeric form or a mixture of enantiomeric forms thereof, with ammonia in a suitable solvent, optionally in the presence of a suitable base, to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II or a salt thereof, or an enantiomeric form or a mixture of enantiomeric forms thereof.
6. The process of claim 5, wherein the ammonia is used in the form of ammonia gas under pressure or in the form of liquor ammonia or in the form of ammonia saturated in an organic solvent; wherein the solvent used is selected from the group consisting of an alcohol, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof; wherein the base used is an organic base or inorganic base; wherein the reaction is optionally carried out in the presence of a catalytic amount of sodium iodide or potassium iodide; wherein the reaction is carried out at a temperature of about 20ºC to the reflux temperature of the solvent used; and wherein the amino-methyl-oxazolidinone compound of formula II obtained is optionally subjected to carbon treatment.
7. The process of claim 6, wherein the ammonia is used in the form of ammonia gas under pressure of about 1 Kg/Cm2 to about 50 Kg/Cm2; wherein the solvent used is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the base used is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium amide, potassium amide, and mixtures thereof; and wherein the reaction is carried out at a temperature of about 40ºC to the reflux temperature of the solvent used.
8. The process of claim 7, wherein the ammonia in step-(a) is used in the form of ammonia gas under pressure of about 10 Kg/Cm2 to about 20 Kg/Cm2; wherein the solvent used in step-(a) is selected from the group consisting of acetonitrile, methanol, N,N-dimethylformamide, dimethyl sulfoxide and mixtures thereof; wherein the inorganic base used in step-(a) is sodium carbonate or potassium carbonate; and wherein the reaction in step-(a) is carried out at the reflux temperature of the solvent used.