WO2013190559A1

WO2013190559A1 - Improved processes for the preparation of linezolid crystalline form iii

Info

Publication number: WO2013190559A1
Application number: PCT/IN2012/000434
Authority: WO
Inventors: Dodda Mohan Rao
Original assignee: Symed Labs Limited
Priority date: 2012-06-19
Filing date: 2012-06-19
Publication date: 2013-12-27

Abstract

We have surprisingly and unexpectedly found that linezolid crystalline Form III can be prepared in an improved, efficient and cost effective process, in high purity and with high yield, by reacting the solution of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride with acetic anhydride, optionally in the presence of an organic base, to produce a reaction mass containing linezolid, followed by layer separation and subsequent carbon treatment to the resulting organic layer to form a filtrate, adding water to the resulting filtrate, and subsequent removal of methylene chloride solvent by distillation, optionally seeding the reaction mass during the distillation process, to produce the crystalline Form III of linezolid.

Description

IMPROVED PROCESSES FOR THE PREPARATION OF LINEZOLID

CRYSTALLINE FORM III

FIELD OF THE INVENTION

The present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of highly pure linezolid crystalline Form III.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,688,792 (hereinafter referred to as the '792 patent), assigned to Pharmacia & Upjohn Company, discloses a variety of oxazine and thiazine oxazolidinone derivatives and their stereochemical^ 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:

The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia). Linezolid is marketed by Pfizer under the trade names Zy vox (in the United States, United Kingdom, Australia, and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).

The synthesis of linezolid was first described in the '792 patent. Similar processes for the preparation of linezolid are also described in U.S. Patent No. 5,837,870, PCT Publication No. WO 99/24393, J. Med. Chem. 39(3), 673-679, 1996 (hereinafter referred to as the 'JMC Article'), and Tetrahedron Lett., 40(26), 4855, 1999.

Linezolid is known to exhibit polymorphism and three crystalline forms (Forms I, II & III) are so far known.

U.S. Patent No. 6,559,305 (hereinafter referred to as the '305 patent), assigned to Pharmacia & Upjohn Company, 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 peaks expressed as 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, 1 123, 11 16, 1078, 1066, 1049, 907, 852 and 758 cm^"1.

The '305 patent further states that when linezolid was originally produced, for example, as per the processes exemplified in the '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. Crystal Form II differs from Form I in its IR spectrum, X-ray powder diffraction spectrum (XRPD) and melting point.

It is well known that linezolid is the (S)-enantiomer of N-[[3-[3-fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]]methyl]acetamide (hereinafter also referred to as the "(S)-enantiomer"). During the preparation of Linezolid, a certain amount of the undesired (R)-enantiomer will also be formed, of which as much as possible should be removed. When the Crystal Form I of linezolid is crystallized, it concentrates the undesired (R)-enantiomer in its crystal lattice.

It will of course be appreciated that the enantiomeric purity of chiral drugs is of eminent concern in the medical field and methods of increasing the amount of the desired enantiomers are constantly sought. In the case of linezolid, the (R)-enantiomer is considered as an impurity and it is desired to keep its concentration as low as possible. In providing a solution to this problem, it is most surprising and unexpected that crystal Form I crystallizes with an increased/higher concentration of the undesired (R)-enantiomer while crystal Form II crystallizes with the exact opposite result, i.e. it has a reduced /lower concentration of the undesired (R)-enantiomer."

Therefore, the crystal Form I is an impure form and contains unacceptable amounts of undesired R-enantiomer since it is formed due to the formation of pseudoracemic solid solution of the enantiomers (see column-4 and lines 37 to 42 of the '305 patent). Since it crystallizes with an increased/higher concentration of the undesired (R)-enantiomer, the crystal Form I is not suitable for pharmaceutical formulations and therapeutic use thereof. Moreover, the crystal Form II of linezolid also suffers from disadvantages since it is not a thermodynamically stable form.

. U.S. Patent No. 7,714,128 B2 (hereinafter referred to as the ' 128 patent), assigned to Symed Labs Limited (the present applicant), discloses a novel, stable and enantiomerically pure crystalline form (Form III) of linezolid, process for the preparation and pharmaceutical compositions thereof. According to the Ί28 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, 1 197, 1 176, 1 1 16, 1082, 1051 , 937, 923, 904, 869, 825 and 756 cm^-1.

Advantageously, the crystalline Form III of linezolid has good flow properties and is consistently reproducible, does not have the tendency to convert to other forms and it has been found to be thermally more stable than Form I or Form II. Furthermore, Form III bulk solid is more compact and less electrostatic than Form II and hence which is more readily subjected to any treatment under the usual conditions of the pharmaceutical technology, in particular, of formulation on an industrial scale.

Various processes for the preparation of linezolid crystalline Form III are described and exemplified in the Ί28 patent. As per the process exemplified in example 1 of the Ί28 patent, the linezolid crystalline Form III is prepared by heating linezolid (obtained by the process described in the '792 patent) at 130°C to 140°C under nitrogen atmosphere for 4 hours.

As per the process exemplified in example 2 of the ' 128 patent, the linezolid crystalline Form III is prepared by suspending linezolid Form II (with 99.8% ee) in toluene, the resulting suspension is refluxed for 3 hours, followed by cooling the mass to 25°C and then filtering the solid to produce linezolid crystalline Form III.

As per the process exemplified in example 3 of the ' 128 patent, the linezolid crystalline Form III is prepared by mixing linezolid (obtained by the process described in the '792 patent) with isopropyl alcohol, the resulting mixture is heated to 80°C and then stirred for 10 minutes at the same temperature to form a clear solution, the resulting solution is cooled to 0°C, followed by stirring for 1 hour 30 minutes at 0°C and filtering the solid to produce linezolid crystalline Form III.

As per the process exemplified in example 5 of the ' 128 patent, the linezolid crystalline Form III is prepared by slow addition of acetic anhydride to a mixture of (S)-N- [[3-[3-fluoro-4-[4-mo holinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine and ethyl acetate at ambient temperature, the resulting mass is stirred for 1 hour at ambient temperature, followed by filtration of the solid and then drying under reduced pressure at 50°C to produce linezolid crystalline Form III.

A need still remains for improved, cost effective, commercially viable and environmentally friendly processes of preparing linezolid crystalline Form III with high yield and high chemical and enantiomeric purity.

SUMMARY OF THE INVENTION

We have surprisingly and unexpectedly found that linezolid crystalline Form III can be prepared in an improved, efficient and cost effective process, in high purity and with high yield, by reacting the solution of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]- 2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride with acetic anhydride, optionally in the presence of an organic base, to produce a reaction mass containing linezolid, followed by layer separation and subsequent carbon treatment to the resulting organic layer to form a filtrate, adding water to the resulting filtrate, and subsequent removal of methylene chloride solvent by distillation, optionally seeding the reaction mass during the distillation process, to produce the crystalline Form III of linezolid.

We have further surprisingly and unexpectedly found that linezolid crystalline Form III can be prepared in an improved, efficient, cost effective and environmentally friendly process, in high purity and with high yield, by providing a solution of linezolid in water at a temperature of about 80°C to about 95°C, allowing the solution to cool at room temperature (25-30°C), and recovering the highly pure crystalline Form III of linezolid from the resulting mass.

The crystalline Form III of linezolid can also be prepared by providing n suspension of linezolid and water, heating the suspension at a temperature of about 60°C to about 80°C, optionally seeding the suspension with linezolid crystalline Form III, cooling the suspension to below 30°C, and recovering the highly pure crystalline Form III of linezolid from the suspension.

Provided herein are efficient, cost effective, industrially advantageous and commercially viable processes for the preparation of linezolid crystalline Form III, in high yield and with high chemical and enantiomeric purity. The processes disclosed herein are more convenient to operate at lab scale and in commercial scale operations.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Linezolid Crystalline Form III.

Figure 2 is a characteristic infra red (IR) spectrum of Linezolid Crystalline Form III.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a process for the preparation of linezolid crystalline Form III, comprising:

a) providing a first solution of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]amine in methylene chloride;

b) optionally, adding a base to the first solution to form a second solution;

e) combining the first solution obtained step-(a) or the second solution obtained in step-(b) with acetic anhydride to produce a reaction mass containing linezolid; d) separating the organic layer (methylene chloride layer) from the reaction mass obtained in step-(c);

e) optionally, subjecting the organic layer obtained in step-(d) to carbon treatment or silica gel treatment to obtain a filtrate;

f) optionally, adding water to the organic layer obtained in step-(d) or to the filtrate obtained in step-(e) to produce a reaction mixture; and

g) removing the methylene chloride solvent from the organic layer obtained in step-(d), or from the filtrate obtained in step-(e) or from the reaction mixture obtained in step-(f), by distillation or evaporation to produce highly pure crystalline Form III of linezolid.

As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

In one embodiment, disclosed herein is an efficient, convenient, commercially viable and consistently reproducible processes for the preparation of linezolid crystalline Form III and the crystalline Form III obtained by this processes is substantially free from other solid state forms of linezolid detectable, by the spectral methods typically used.

The use of specific solvent (methylene chloride or a mixture thereof with water) and particular isolation techniques disclosed herein for isolating the crystalline Form III of linezolid, allows the product to be easily isolated and purified, thereby producing the crystalline Form III with high yield and high chemical, chiral and polymorphic purity.

Step-(a) of providing a solution of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2- oxo-5-oxazolidinyl]methyl]amine includes dissolving or extracting the (S)-N-[[3-[3- fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride, or obtaining an existing solution from a previous processing step.

In one embodiment, the (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]amine is dissolved or extracted in methylene chloride at a temperature of 0°C to the boiling temperature of the solvent, and more specifically at a temperature of • about 20°C to about 40°C.

In another embodiment, the solution in step-(a) is also prepared by reacting (S)-N- [[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide with hydrazine hydrate in an alcohol solvent, preferably methanol, at reflux temperature to produce a reaction mass containing (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- ^■ oxazolidinyl]methyl]amine, the resulting mass is cooled to 25-30°C and then stirred with water to form a clear solution, followed by usual work up such as a filtration, a carbon treatment, a washing, an extraction, a pH adjustment, an evaporation or a combination thereof. In one embodiment, the work-up includes dissolving or extracting the resulting (S)-N-[[3-[3-fluoro-4-[4-mo holinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride at a temperature of 0°C to the boiling temperature of the solvent, and more specifically at a temperature of about 20°C to about 40°C.

Alternatively, the solution in step-(a) is prepared by treating an acid addition salt of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine with a base to liberate (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]amine free base, followed by dissolving or extracting the (S)-N-[[3-[3-fluoro-4-[4- morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride.

The acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, di-p-toluoyl-L-(+)-tartaric acid, malic acid, ascorbic acid, and the like. A specific acid addition salt of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2- oxo-5-oxazolidinyl]methyl]amine is hydrochloride salt.

The treatment of an acid addition salt with base is carried out in a solvent selected from the group consisting of water, an ester, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ether, and mixtures thereof.

The base can be an inorganic or an organic base. Specifically, the base is an organic base. Specific organic bases are triethyl amine, tributyl amine, diisopropylethyl amine, diethyl amine, tert-butyl amine, N-methylmorpholine, pyridine, 4-(N,N- dimethylamino)pyridine, and l-alkylimidazole.

Exemplary inorganic bases include, but are not limited to, hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific inorganic bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate; and more specifically sodium hydroxide, sodium bicarbonate, potassium hydroxide, sodium carbonate and potassium carbonate. In one embodiment, the addition of base in step-(b) is carried out at a temperature of about 0°C to the boiling temperature of the solvent used, specifically at a temperature of about 5°C to about 35°C, and more specifically at a temperature of about 10°C to about 30°C.

In another embodiment, the base used in step-(b) is an organic or inorganic base selected from the group as described above. Specifically, the base used in step-(b) is an organic base, and more specifically triethyl amine.

Combining of the solution with acetic anhydride in step-(c) is done in a suitable order, for example, the solution is added to the acetic anhydride, or alternatively, the acetic anhydride is added to the solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of below 30°C for at least 5 minutes, specifically at a temperature of about 0°C to about 20°C for about 10 minutes to about 1 hour, and most specifically at a temperature of about 10°C to about 15°C for about 15 minutes to about 30 minutes. After completion of the addition process, the resulting mass is stirred at a temperature of below 35°C for at least 10 minutes and specifically at a temperature of about 10°C to about 30°C for about 15 minutes to about 2 hours to form the reaction mass containing linezolid.

In one embodiment, the reaction mass containing the linezolid obtained, after completion of the reaction, in step-(c) may be subjected to usual work up such as a filtration, a carbon treatment, a washing, a layer separation, an extraction, a pH adjustment^ an evaporation or a combination thereof.

In a preferred embodiment, the reaction mass containing the linezolid obtained in step-(c) is washed with water, followed by layer separation and then collecting the organic layer by the methods known in the art.

In one embodiment, the organic layer obtained in step-(d) is subjected to carbon treatment or silica gel treatment.

The carbon treatment or silica gel treatment in step-(e) is carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 5 minutes, specifically at a temperature of about 20°C to about 30°C for about 5 minutes to about 30 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing linezolid by removing charcoal or silica gel. Preferably, a finely powdered carbon is an active carbon. In one embodiment, a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

In one embodiment, the addition of water in step-(f) is carried out at a temperature of about 0°C to the boiling temperature of the solvent used, specifically at a temperature of about 15°C to about 35°C, and more specifically at a temperature of about 20°C to about 30°C.

Removal of solvent in step-(g) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain highly pure crystalline Form III of linezolid.

Specifically, the removal of solvent in step-(g) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.

In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

In a preferred embodiment, the distillation process is performed at atmospheric pressure and at a temperature of about 45°C to about 90°C, and most specifically at a temperature of about 50°C to about 80°C.

In another embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum at above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD").

Another suitable method is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled conditions. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it. In one embodiment, the organic layer or the reaction mixture that is to be subjected to distillation in step-(g) is optionally seeded with crystalline Form III of linezolid at the time before or during the distillation process. Specifically, the organic layer or the reaction' mixture is seeded with crystalline Form III of linezolid when the volume of the organic solvent reaches around 33 percent of the initial volume by distilling off methylene chloride.

In another embodiment, the solid obtained in step-(g) is optionally co-distilled with an ester solvent to remove the traces of methylene chloride, followed by water washings at higher temperature (60 - 65°C) and then recovering the highly pure crystalline Form III of linezolid. Exemplary ester solvents used for co-distillation process include, but are not limited to, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, and mixtures thereof. A most specific ester solvent is ethyl acetate.

The solid recovering is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

According to another aspect, there is provided a process for the preparation of linezolid crystalline Form III, comprising:

a) providing a solution of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]amine in methylene chloride;

b) combining the solution obtained step-(a) with acetic anhydride to produce a reaction mass containing linezolid;

c) separating the organic layer (methylene chloride layer) from the reaction mass obtained in step-(b); and

d) removing the methylene chloride solvent from the organic layer obtained in step-(c) by distillation or evaporation to produce highly pure crystalline Form III of linezolid.

The process steps-(a), (b), (c) and (d) can be carried out by the methods and conditions as disclosed herein above.

a) providing a solution of linezolid in water at a temperature of about 80°C to about 95°C; b) maintaining the solution under stirring at about 80°C to about 95°C; c) cooling the solution obtained in step-(b) slowly at a temperature of below about 35°C to cause crystallization; and

d) recovering the highly pure crystalline Form III of linezolid from the reaction mass obtained in step-(c).

Step-(a) of providing a solution of linezolid includes dissolving linezolid in water, or obtaining an existing solution from a previous processing step.

In one embodiment, the linezolid is dissolved in water at a temperature of about 85°C to about 95°C, specifically at about 88°C to about 92°C, and most specifically at about 90°C.

The solution in step-(a) is prepared by reacting (S)-N-[[3-[3-fluoro-4-[4- morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine with acetic anhydride, optionally in the presence of a base, in a suitable solvent to produce a reaction mass containing linezolid, followed by usual work up such as a filtration, a carbon treatment, a washing, an extraction, a pH adjustment, a layer separation, an evaporation or a combination thereof. In one embodiment, the work-up includes dissolving or extracting the resulting linezolid in water at a temperature of about 80°C to about 95°C, and specifically at about 88°C to about 92°C. The suitable solvent may be selected from the group consisting of an alcohol, a ketone, an ester, a chlorinated hydrocarbon solvent, a hydrocarbon, a polar aprotic solvent, and mixtures thereof. In another embodiment, the base is an organic or inorganic base selected from the group as described above. Specifically, the base used in step-(b) is an organic base, and more specifically triethyl amine.

In another embodiment, the solution in step-(b) is stirred at a temperature of about 85°C to about 95°C for about 15 minutes to about 4 hours, specifically at about 88°C to about 92°C for about 20 minutes to about 3 hours; and most specifically at about 90°C for about 2 hours.

The solution obtained in step-(a) or step-(b) is optionally subjected to carbon treatment or silica gel treatment as per the methods as described hereinabove.

In one embodiment, the crystallization in step-(c) is carried out by allowing the solution to cool at room temperature (25-30°C) for about 30 minutes to about 4 hours, and more specifically for about 1 hour 30 minutes to about 3 hours. The recovering in step-(d) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, the crystalline Form III of linezolid is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

a) providing a suspension of linezolid in water at a temperature of about 60°C to about 80°C;

b) maintaining the suspension under stirring at about 60°C to about 80°C;

c) optionally, seeding the suspension obtained in step-(b) with linezolid Form III;

d) cooling the suspension obtained in step-(b) or step-(c) gradually to a temperature of below about 35°C; and

e) recovering the highly pure crystalline Form III of linezolid from the resulting mass obtained in step-(d).

Step-(a) of providing a suspension of linezolid includes suspending linezolid in water at room temperature (25-30°C), followed by heating the suspension at a temperature of about 60°C to about 80°C, or obtaining an existing suspension from a previous processing step and then heating at a temperature of about 60°C to about 80°C.

In one embodiment, the suspension is heated at a temperature of about 60°C to about 70°C, and specifically at a temperature of about 60°C to about 65°C.

The suspension in step-(a) is prepared by reacting (S)-N-[[3-[3-fluoro-4-[4- morphOlinyl]phenyl]-2-Oxo-5-oxazolidinyl]methyl]amine with acetic anhydride, optionally in the presence of a base, in a suitable solvent to produce a reaction mass containing linezolid, followed by usual work up such as a filtration, a carbon treatment, a washing, an extraction, a pH adjustment, a layer separation, an evaporation or a combination thereof. In one embodiment, the work-up includes suspending or admixing the resulting linezolid with water, followed by heating the suspension at a temperature of about 60°C to about 80°C, and specifically at about 60°C to about 65°C.

In another embodiment, the suspension in step-(b) is stirred at a temperature of about 60°C to about 80°C for about 10 minutes to about 4 hours, specifically at about 60°C^y' to about 70°C for about 15 minutes to about 3 hours; and most specifically at about 60°C to about 65 °C for about 20 minutes to about 1 hour.

The suspension in step-(d) is initially cooled under stirring at a temperature of about 25°C to about 35°C for at least 5 minutes, and specifically at a temperature of about 25°C to about 30°C for about 10 minutes to about 30 minutes. The resulting suspension is further cooled under stirring at a temperature of below about 20°C for at least 10 minutes, and specifically at a temperature of about 5°C to about 15°C for about 15 minutes to about 1 hour.

The recovering in step-(e) is carried out by the methods as described hereinabove. The highly pure crystalline Form III of linezolid obtained by the processes described hereinabove 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 25°C to about 90°C, and specifically at about 75°C to about 85°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 conditions 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. Drying equipment selection is well within the ordinary skill in the art.

In one embodiment, the crystalline Form III of linezolid obtained by the processes disclosed hereinabove is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.60, 9.57, 13.73, 14.96, 18.23, 18.97, 21.28, 22.43, 25.66, 27.04, 27.91 and 29.92 ± 0.2 degrees substantially in accordance with Figure 1; and an infra red (FT-IR) spectrum having main bands at about 3339, 1743, 1663, 1546, 1517, 1472, 1453, 1424, 1400, 1381 , 1335, 1274, 1257, 1229, 1213, 1 199, 1 177, 1 1 17, 1081 , 1050, 936, 923, 904, 871, 824 and 756 ± 2 cm^"1 substantially in accordance with Figure 2.

The term "highly pure linezolid crystalline Form III" refers to the linezolid crystalline Form III having total purity, which includes both chemical and enantiomeric purity, greater than about 99.8%, specifically greater than about 99.9%, and more specifically greater than about 99.95% (measured by HPLC). For example, the total purity of linezolid crystalline form III obtained by the process disclosed herein can be about 99.9% to about 99.99% as measured by HPLC.

The highly pure crystalline Form III of linezolid obtained by the processes disclosed herein has very good flow properties and which is consistently reproducible, does not have the tendency to convert to other forms, and is found to be more stable. The crystalline Form III of linezolid obtained by the processes disclosed herein exhibits properties making it suitable for formulating linezolid.

Unless otherwise specified, the crystalline Form III of linezolid used for seeding in the above processes can be obtained by the processes described in the U.S. Patent No. 7,714, 128 B2, or obtained by the processes exemplified in examples 2 and 3 disclosed hereinafter.

Unless otherwise specified, the linezolid as used herein as starting material, may be taken in the form of a solid or a liquid wherein the solid is a crystalline form or an amorphous form or a solvate or a mixture thereof, can be obtained by the processes described in the prior art, for example, the processes described in the U.S. Patent No. 5,688,792 and 6,559,305; and PCT Publication No. WO2007/026369 A l .

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper-Κα radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA. Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm^"1 to 650 cm^"1.

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 C 18, 250 mm x 4.6 mm, 5μπι or Equivalent; Detector wavelength = 254 nm; Flow Rate = 0.5 ml/minute; Injection volume = 20μί; 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, 5μη or Equivalent; Detector wavelength = 254 nm; Flow Rate = 1.5 mL/minute; Injection volume = ΙΟμί; Gven 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 Linezolid Crystalline Form III of N-[[(5S)-3-[3-Fluoro-4-[4- morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyljacetamide (Linezolid)

Step-I: Preparation of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyI]amine

Methanol (260 ml) and hydrazine hydrate (26 ml) were added to (S)-N-[[3-[3-fluoro-4-[4- morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]phthalimide at 25-30°C, the resulting mixture was heated to reflux (68°C/78°C) and then maintained for 2 hours at the same temperature. The reaction mass was cooled to 25-30°C, followed by the addition of water (500 ml) and stirring for 10 minutes at 25-30°C to form a clear solution. Activated carbon (4 g) was added to the solution and then stirred for 5 minutes at 25-30°C. The resulting mixture was filtered through hyflo bed and the bed was washed with water (50 ml). The resulting filtrate was extracted three times with methylene chloride (150 ml x 3), and the bottom organic layer was separated and then washed with water (150 ml x 3) to yield 480 ml of methylene chloride layer containing the (S)-N-[[3-[3-Fluoro-4-[4- morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.

Step-II: Linezolid Crystalline Form III

Triethyl amine (12.5 ml) was added to the methylene chloride layer (obtained in step-I) at 25-30°C and the resulting solution was cooled to 15°C, followed by slow addition of acetic anhydride (12.5 ml) for 10 minutes. The temperature of the reaction mass was raised to 25- 30°C and then stirred for 1 hour at the same temperature. The reaction mass was washed with water (50 ml x 2), the resulting organic layer was separated and then subjected to carbon treatment by stirring the organic layer with activated carbon (2.5 g) for 5 minutes at 25-30°C. The resulting mixture was filtered through hyflo bed and the bed was washed with methylene chloride (25 ml). Water (200 ml) was added to the resulting filtrate, followed by removal of methylene chloride solvent by ordinary distillation at 80°C. During the distillation process, the reaction mass was seeded with 0.5 g of crystalline form III of linezolid when the volume of bottom methylene chloride layer reaches around 75 ml. The resulting mass was cooled to 25-30°C and then stirred for 15 minutes at the same temperature. The separated solid was filtered, washed with water (50 ml) and then dried the material at 80-85°C for 4 hours to produce 23 g of linezolid crystalline Form III. Example 2

Preparation of Linezolid Crystalline Form III

Triethyl amine (12.32 ml) and methylene chloride (220 ml) were added to (S)-N-[[3-[3- fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (22 g) at 25-30°C, the resulting solution was cooled to 10-15°C, followed by slow addition of acetic anhydride at 12-14°C for 10 to 15 minutes. During the addition process, the temperature of the reaction mass raised up to 22°C. The resulting mass was stirred for 10 to 15 minutes at 10-15°C, followed by raising the temperature to 25-30°C and then stirring the mass for 1 hour at the same temperature. The reaction mass was washed with water (50 ml x 2), followed by separation of the organic layer and subsequently stirring the organic layer with activated carbon (2.5 g) for 5 minutes at 25-30°C. The resulting mixture was filtered through hyflo bed and the bed was washed with methylene chloride (20 ml), followed by removal of solvent by ordinary distillation at 55-60°C to produce a solid. The resulting solid was co-distilled two times with ethyl acetate (35 ml x 2) under vacuum at 65-75°C. Water (1 10 ml) was added to the resulting solid, followed by heating the mixture at 60- 65°C and then stirring for 20 to 25 minutes at the same temperature. The resulting mass was cooled to 25-30°C and then stirred for 10 minutes at the same temperature, followed by cooling the mass to 10°C and then stirring for 10 to 15 minutes at the same temperature. The separated solid was filtered, washed with water (50 ml) and then dried the material at 80-85°C for 4 hours to produce 21.5 g of highly pure linezolid crystalline Form III [Purity by HPLC: 99.95%; Chiral Purity by HPLC: (S)-isomer = 99.989%; (R)-isomer = 0.01 1%; and Melting Point: 177.8°C - 178.5°C].

Example 3

Preparation of Linezolid Crystalline Form III

Water (500 ml) was added to linezolid crystalline Form II (50 g) [Purity by HPLC: 99.89%; Chiral Purity by HPLC: (R)-isomer = 0.2%] at 25-30°C, the contents were heated to dissolve at 90°C and then stirred for 2 hours at the same temperature to form a solution. The resulting solution was allowed to cool slowly to 25-30°C without any external aid (about 1 hour 30 minutes to 2 hours). The separated solid was filtered, washed with water (50 ml) and then dried the material at 85-90°C for 4 hours to produce 45 g of linezolid crystalline Form III [Purity by HPLC: 99.95%; Chiral Purity by HPLC: (R)-isomer = 0.01%].

Claims

We claim:

1. A process for the preparation of linezolid crystalline Form III, comprising:

a) providing a solution of linezolid in water at a temperature of about 80°C to about 95°C;

b) maintaining the solution under stirring at about 80°C to about 95°C;

c) cooling the solution obtained in step-(b) slowly at a temperature of below about 35°C to cause crystallization; and

2. The process of claim 1, wherein the solution in step-(a) is provided: by dissolving linezolid in water at a temperature of about 85°C to about 95°C; or by reacting (S)-N- [[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine with acetic anhydride, optionally in the presence of a base, in a suitable solvent to produce a reaction mass containing linezolid, followed by work up and then dissolving or extracting the resulting linezolid in water at a temperature of about 85°C to about 95°C.

3. The process of claim 1, wherein the solution in step-(b) is stirred at a temperature of about 85°C to about 95°C for about 15 minutes to about 4 hours; wherein the solution obtained in step-(a) or step-(b) is optionally subjected to carbon treatment or silica gel treatment; wherein the crystallization in step-(c) is carried out by allowing the solution to cool at room temperature (25-30°C) for about 30 minutes to about 4 hours; and wherein the recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.

4. A process for the preparation of linezolid crystalline Form III, comprising:

b) optionally, adding a base to the first solution to form a second solution;

c) combining the first solution obtained step-(a) or the second solution obtained in step-(b) with acetic anhydride to produce a reaction mass containing linezolid; d) separating the organic layer (methylene chloride layer) from the reaction mass obtained in step-(c); e) optionally, subjecting the organic layer obtained in step-(d) to carbon treatment or silica gel treatment to obtain a filtrate;

g) removing the methylene chloride solvent from the organic layer obtained in step- id), or from the filtrate obtained in step-(e) or from the reaction mixture obtained in step-(f), by distillation or evaporation to produce the highly pure crystalline Form III of linezolid.

The process of claim 4, wherein the solution in step-(a) is provided by the following methods:

i) dissolving or extracting the (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]amine in methylene chloride; or

ii) reacting the (S)-N-[[3-[3-fluoro-4-[4-moφholίnyl]phenyl]-2-o o-5-oxazolidinyl] methyljphthalimide with hydrazine hydrate in an alcohol solvent at reflux temperature to produce a reaction mass containing (S)-N-[[3-[3-fluoro-4-[4- mo holinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, the resulting mass is cooled to 25-30°C and then stirred with water to form a clear solution, followed by work up and then dissolving or extracting the (S)-N-[[3-[3-fluoro-4-[4- mo holinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in methylene chloride; or iii) treating an acid addition salt of (S)-N-[[3-[3-fluoro-4-[4-moφholinyl]phenyΓJ-2- oxo-5-oxazolidinyl]methyl]amine with a base to liberate (S)-N-[[3-[3-fluoro-4-[4- morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine free base, followed by dissolving or extracting the (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]amine in methylene chloride.

The process of claim 4, wherein the base used in step-(b) is an organic or inorganic base; and wherein the removal of solvent in step-(g) is accomplished by complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain the highly pure crystalline Form III of linezolid.

The process of claim 6, wherein the base is an organic base; wherein the removal of solvent in step-(g) is carried out by distillation, wherein the distillation process is performed at atmospheric pressure or at reduced pressure; and wherein the evaporation is performed in a pilot plant Rota vapor, a Vacuum Paddle Dryer or in an agitated thin film dryer ("ATFD").

8. The process of claim 7, wherein the organic base is triethyl amine; and wherein the distillation process is performed at atmospheric pressure and at a temperature of about 45°C to about 90°C.

9. The process of claim 4, wherein the organic layer or the reaction mixture that is to be subjected to distillation in step-(g) is seeded with crystalline Form III of linezolid when the volume of the organic solvent reaches around 33 percent of the initial volume by distilling off methylene chloride; wherein the solid obtained in step-(g) is optionally co-distilled with an ester solvent to remove the traces of methylene chloride, followed by water washings at higher temperature (60 - 65°C) and then recovering the highly pure crystalline Form III of linezolid; and wherein solid obtained in step-(g) is recovered by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

10. A process for the preparation of linezolid crystalline Form III, comprising:

1 1. A process for the preparation of linezolid crystalline Form III, comprising:

b) maintaining the suspension under stirring at about 60°C to about 80°C;

c) optionally, seeding the suspension obtained in step-(b) with linezolid Form III; d) cooling the suspension obtained in step-(b) or step-(c) gradually to a temperature of below about 35°C; and e) recovering the highly pure crystalline Form III of linezolid from the resulting mass obtained in step-(d).

12. The process of claim 11, wherein the suspension in step-(a) is provided: by suspending linezolid in water at room temperature (25-30°C), followed by heating the suspension at a temperature of about 60°C to about 80°C; or by reacting (S)-N-[[3-[3-fluoro-4-[4- mo holinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine with acetic anhydride, optionally in the presence of a base, in a suitable solvent to produce a reaction mass containing linezolid, followed by suspending or admixing the resulting linezolid with water, and then heating the suspension at a temperature of about 60°C to about 80°C.

13. The process of claim 1 1 , wherein the suspension in step-(b) is stirred at a temperature of about 60°C to about 80°C for about 10 minutes to about 4 hours; wherein the suspension in step-(d) is initially cooled under stirring at a temperature of about 25°C to about 35°C for at least 5 minutes, and further cooled under stirring at a temperature of about 5°C to about 15°C for about 15 minutes to about 1 hour; and wherein the recovering in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.

14. The process of any one of claims 1 , 4, 10 and 1 1 , wherein the highly pure crystalline Form III of linezolid obtained is further dried, under vacuum or at atmospheric pressure, at a temperature of about 25°C to about 90°C; and wherein the drying is performed in a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor.

15. The process of any one of claims 1, 4, 10 and 1 1, wherein the crystalline Form III of linezolid obtained is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.60, 9.57, 13.73, 14.96, 18.23, 18.97, 21.28, 22.43, 25.66, 27.04, 27.91 and 29.92 ± 0.2 degrees substantially in accordance with Figure 1 ; and an infra red (FT-IR) spectrum having main bands at about 3339, 1743, 1663, 1546, 1517, 1472, 1453, 1424, 1400, 1381, 1335, 1274, 1257, 1229, 1213, 1 199, 1 177, 1 117, 1081, 1050, 936, 923, 904, 871, 824 and 756 ± 2 cm^"1 substantially in accordance with Figure 2.