LINEZOLID FORM-III

CROSS REFERENCE

This application claims priority from Indian Patent Application No. 201641031561 filed in Indian Patent Office on September 16, 2016.

FIELD OF INVENTION

The invention relates to a novel process for preparation of crystalline Linezolid Form-Ill.

BACKGROUND OF THE INVENTION

Linezolid is chemically known as (5)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2- oxo-5-oxazolidinyl] methyl] acetamide. It is represented by the following structure of formula I:

LINEZOLID (Formula I)

Linezolid and its process for the preparation were first disclosed in U.S. Patent No.

5,688,792.

Linezolid is an antibacterial agent, effective against many gram positive and gram negative bacteria and is used to treat many serious infections caused by these pathogens such as streptococci, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) among others. It is well known in the art that Linezolid exhibits polymorphism. Till now various crystalline forms of Linezolid have been disclosed in the prior art such as Form-I, Form-II, Form- III and Form-IV.US 2006/0111350 discloses various polymorphic forms and hydrates.

Crystalline Form-I of Linezolid characterized by melting point of 181.5 - 182.5 °C and by IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm ^"1 was first described by J. Med. Chem. 39(3), 673-679, 1996. Crystalline Linezolid Form-II has been disclosed in U.S. Patent No. 6,559,305 and is characterized by 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 and powder X-ray diffraction spectrum having 2-theta values 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.

PCT Publication No. WO 2005/035530 describes Linezolid Form-Ill by XRD peaks having 2-theta values 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 degrees and by 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 .

US 2006/0142283 claims a crystalline Form-IV characterized by a powder X-ray diffraction (PXRD) pattern with 2-theta values at about 13.5, 18.0, 21.1, 22.2 and 25.4+0.2 degrees.

Though many polymorphic forms of Linezolid have been known in the art but Linezolid Form-Ill possesses good commercial valued due to its good thermal stability favouring its utility for preparation of solid pharmaceutical dosage forms. In PCT publication WO2005/035530 crystalline Linezolid Form-Ill is prepared by directly heating Linezolid at 90°C -200°C. In one preparation process this document discloses mixing the Linezolid with a solvent at its boiling point wherein solvent may be selected from toluene, xylene, chloroform, methylene dichloride, acetonitrile, water, methanol, ethanol, propanol, isopropyl alcohol, ter-butyl alcohol, acetone, mehyl ethyl ketone, ethyl acetate, diethyl ether and methyl tert. Butyl ether. This document has preferably used toluene, xylene and isopropyl alcohol. In another PCT publication WO 2013190559 water has been used as solvent at about 80°C to about 95 °C for crystallization process to obtain crystalline Linezolid Form-Ill. This document also discloses a process wherein the suspension of the Linezolid in water is seeded with crystals of Linezolid Form- III. Yet another PCT publication WO2016/113751 discloses a process for preparation of Linezolid Form- III by suspending crystalline Linezolid in a solvent at 25-30° C and heating the solution to 75-80° C, cooling the reaction mass to 25-30° C and recovering the crystalline Linezolid Form-Ill wherein the solvent used may be selected from a cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropanol or 1-butanol; toluene, xylene, chloroform, methylene dichloride, acetonitrile, acetone and methyl ethyl ketone.

Although above prior arts have disclosed preparation methods for this compound but due to its commercial value there is always a need for an improved process for industrial scale preparation of this compound.

OBJECT OF THE INVENTION The object of the invention is to provide a novel process for the preparation of crystalline Linezolid Form- III. SUMMARY OF THE INVENTION

Accordingly, a novel process for preparation of crystalline Linezolid Form-Ill is disclosed.

In one aspect, the invention provides a process for preparation of crystalline Linezolid Form-Ill comprising the steps of:

a) obtaining a suspension of Linezolid in an organic solvent and heating at elevated temperature with stirring to obtain a clear solution; b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering solid and washing with an organic solvent;

e) drying the solid to obtain crystalline Linezolid Form- III. In general embodiment, the organic solvent in step (a) and step (d) may be selected from the organic solvents selected from Methyl isobutyl ketone, Mono chlorobenzene, 1,2-Dichlorobenzene, Fluorobenzene, Bromobenzene, Iodobenzene and Di, Tri, Tetra, Penta and Hexa substituted halo benzene or mixture thereof. In one embodiment the organic solvent used in step (a) and step (d) is Methyl isobutyl ketone.

In another embodiment the organic solvent used in step (a) and step (d) is Mono chlorobenzene.

In another embodiment the organic solvent used in step (a) and step (d) is Mono chlorobenzene, wherein in step (a) the solvent Mono chlorobenzene is used in presence of catalytic amount of Triethylamine. In general embodiment the elevated temperature in step (a) is in between 110°C to 130 °C. In one embodiment when Methyl isobutyl ketone is used as solvent, the suspension in step (a) is heated to a temperature between 105°C to 110° C to obtain the clear solution. In another embodiment when Mono chlorobenzene is used as solvent, the suspension in step (a) is heated to a temperature between 120° C to 130 ⁰ C to obtain the clear solution.

In another embodiment when Mono chlorobenzene alongwith Triethylamine is used, the suspension in step (a) is heated to a temperature between 120° C to 125 ° C to obtain the clear solution.

In a general embodiment, the suspension in step (a) is stirred at elevated temperature for 60 to 90 minutes.

The drying in step e) may be done by initial suck drying for 10 to 15 minutes followed by drying under vacuum at 60 to 65°C.

In one embodiment, the invention provides a process for preparation of crystalline Linezolid Form- III comprising the following steps: a) obtaining a suspension of Linezolid in Methyl isobutyl ketone and heating to a temperature between 105 to 110°C with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Methyl isobutyl ketone;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III. In another embodiment the invention provides a process for preparation of crystalline Linezolid Form- III comprising the following steps: a) obtaining a suspension of Linezolid in Mono chlorobenzene and heating to a temperature between 120 to 130° C with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Mono chlorobenzene;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III.

In another embodiment the invention provides a process for preparation of crystalline Linezolid Form- III comprising the following steps: a) obtaining a suspension of Linezolid in Mono chlorobenzene & Triethylamine and heating to a temperature between 120 to 125° C with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Mono chlorobenzene;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III.

The drying in step e) in any of the above processes may be done by initial suck drying for 10 to 15 minutes followed by drying under vacuum at 60 to 65 °C.

The crystalline Linezolid Form-Ill obtained by any of the above processes is highly pure with HPLC purity greater than or equal to 99.5%, or greater than or equal to 99.9% or greater than or equal to 99.97%.

The crystalline Linezolid Form-Ill obtained by any of the above processes is highly pure and comprises level of single unknown impurity less than 0.05%. BRIEF DESCRIPTION OF THE DRAWINGS

Figure- 1 represents HPLC chromatogram of the highly pure Crystalline Linezolid Form- III obtained in Example- 1.

Figure-2 represents HPLC chromatogram of the highly pure Crystalline Linezolid Form- III obtained in Example-2.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a novel process for the preparation of crystalline Linezolid Form-Ill.

Linezolid is chemically (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl] acetamide which is represented by structural formula I as shown below:

LINEZOLID (Formula I) The source Linezolid used to prepare crystalline Linezolid Form-Ill in the present invention can be Linezolid obtained by any of the processes known in the prior art.

Without any limitation, the source Linezolid which can be used in the present invention as a starting material for preparation of crystalline Linezolid Form- III can be obtained by the process as disclosed in U.S. Patent No. 5,688,792, International Patent Publication No. WO 2012/114355 Al (Applicant's own process) or by any other process known in the art. The invention provides highly pure crystalline Linezolid Form-Ill. The crystalline Linezolid Form-Ill is prepared by heating the source Linezolid obtained by any known prior art process in presence of an organic solvent. Accordingly, in general embodiment, theinvention provides a novel process for the preparation of crystalline Linezolid Form-Ill which comprises the steps of: a) obtaining a suspension of Linezolid in an organic solvent and heating at elevated temperature with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with the organic solvent;

e) drying the solid to obtain crystalline Linezolid Form- III. Step a):

The source Linezolid used in step a) can be obtained by any of the processes available in the prior art. The suspension of source Linezolid in step a) is prepared in an organic solvent. In one embodiment the suspension is prepared in a single solvent. In another embodiment the suspension is prepared in a mixture of two or more organic solvents.

The organic solvent for the preparation of suspension of source Linezolid in step a) may be selected from Methyl isobutyl ketone, Mono chlorobenzene, 1,2- Dichlorobenzene,Fluorobenzene,Bromobenzene, Iodobenzene and Di, Tri, Tetra, Penta and Hexa substituted halo benzene or mixture thereof.

In one embodiment, the organic solvent used in above step a) is Methyl isobutyl ketone. In another embodiment, the organic solvent used in above step a) is Mono chlorobenzene. In another embodiment, the organic solvent used in above step a) is Mono chlorobenzene & Triethyl amine, wherein Mono chlorobenzene is used in presence of catalytic amount of Triethylamine. The suspension of source Linezolid in the organic solvent is heated to an elevated temperature such as between 110°C to 130°C; followed by stirring at the same temperature until a clear solution is obtained.

In one embodiment the suspension of source Linezolid in step a) is heated to 105° C to 110 ⁰ C, followed by stirring at the same elevated temperature for about 60- 90 minutes until a clear solution is obtained.

In another embodiment the suspension of source Linezolid in step a) is heated to 120°C to 130°C, followed by stirring at the same elevated temperature for about 60- 90 minutes until a clear solution is obtained.

In another embodiment the suspension of source Linezolid in step a) is heated to 120°C to 125°C, followed by stirring at the same elevated temperature for about 60- 90 minutes until a clear solution is obtained.

Step b):

In step b) the clear solution obtained in step a) is cooled to 25-30°C. Step c):

In step c), the solution is stirred for 60 to 90 minutes at 25-30° C to cause crystallization. The crystallization results in precipitated solid.

Step d):

In step d) the crystalline solid obtained in step c) is filtered and washed with an organic solvent or mixture of organic solvents. The organic solvent for washing of solid in this step may be selected from Methyl isobutyl ketone, Mono chlorobenzene, 1,2-Dichlorobenzene, Fluorobenzene, Bromobenzene, Iodobenzene and Di, Tri, Tetra, Penta and Hexa substituted halo benzene or mixture thereof.

In one embodiment, the organic solvent used for washing in this step is Methyl isobutyl ketone.

In another embodiment, the organic solvent for washing in this step is Mono chlorobenzene.

Any conventional filtration technique known in the art can be used for filtration of the solid.

Step e):

After washing, the crystalline solid obtained in step d) is dried to obtain highly pure crystalline Linezolid Form-III.The drying can be performed by initial suck drying of wet solid for 10 to 15 min to obtain a cake followed by vacuum drying of the wet cake at 60 to 65°C which provides final product crystalline Linezolid Form- III. The crystalline Linezolid Form-Ill obtained by the process of the invention is highly pure having HPLC purity equal to or greater than 99.5%.

In one embodiment of the invention the HPLC purity of crystalline Linezolid Form- III obtained by the above process is equal to or greater than 99.9%.

In another embodiment of the invention the HPLC purity of crystalline Linezolid Form- III obtained by the above process is equal to or greater than 99.97%.

The crystalline Linezolid Form- III obtained by the process of the invention is highly pure having any single unknown impurity less than 0.05%. Accordingly in one preferred embodiment, the invention provides a process for the preparation of crystalline Linezolid Form-Ill comprising the steps of: a) obtaining a suspension of Linezolid in Methyl isobutyl ketone and heating to a temperature between 105 to 110°C with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Methyl isobutyl ketone;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III.

In another embodiment of the invention, the process for the preparation of crystalline Linezolid Form-Ill comprises the steps of: a) obtaining a suspension of Linezolid in Mono chlorobenzene and heating to a temperature between 120 to 130° C with stirring to obtain a clear solution; b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Mono chlorobenzene;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III

In another embodiment of the invention, the process for the preparation of crystalline Linezolid Form-Ill comprises the steps of: a) obtaining a suspension of Linezolid in Mono chlorobenzene and Triethylamine and heating to a temperature between 120 to 125° C with stirring to obtain a clear solution;

b) cooling the solution obtained in step (a) to 25-30° C;

c) stirring the solution at 25-30° C for 60-90 minutes;

d) filtering the solid and washing with Mono chlorobenzene;

e) drying the solid to obtain highly pure crystalline Linezolid Form- III The drying step e) of the process of any of above embodiments may be done by initial suck drying of wet solid for 10 to 15 min followed by drying under vacuum at 60 to 65° C. Without any limitation, the above described processes of the invention are further explained and exemplified by the following examples.

EXAMPLES

Example 1;

150.0mL of Methyl isobutyl ketone was added to 30.0g of Linezolid in a 500.0mL round bottom flask. The total content in the flask was heated to 105-110°C and stirred at the same temperature (105-110°C) until the solution becomes clear. Then the whole reaction mass was cooled to 25-30° C and stirred for 60-90 minutes. The precipitated solid mass was then filtered and washed with 30.0mL of Methyl isobutyl ketone. The washed solid was then suck dried for 10-15 minutes followed by drying of the wet cake under vacuum at 60-65 ⁰ C.

Yield of the crystalline Linezolid Form-Ill obtained was 28.0g (93.35 w/w), with HPLC purity of 99.95%.

Example 2:

lOO.OmL of Mono chlorobenzene was added to 50. Og of Linezolid in a 250.0mL round bottom flask. The total content in the flask was heated to 120-130 °C and stirred at the same temperature (120 to 130°C) until the solution becomes clear. Then the whole reaction mass was cooled to 25-30 °C and stirred for 60-90 minutes. The precipitated solid mass was then filtered and washed with 50.0mL of Mono chlorobenzene. The filtered solid was then suck dried for 10-15 minutes followed by drying of the wet cake under vacuum at 60-65 °C. Yield of the linezolid crystalline form-Ill obtained was 46.0g (92.0 w/w), with HPLC purity of 99.97%. Example 3:

50.0mL of Mono chlorobenzene& 0.25ml of Triethylamine was added to 25. Og of Linezolid in a 250. OmL round bottom flask. The total content in the flask was heated to 120-125°C and stirred at the same temperature (120 to 125°C) until the solution becomes clear. Then the whole reaction mass was cooled to 25-30 °C and stirred for 30-60 minutes. The precipitated solid mass was then filtered and washed with 12.5mL of Mono chlorobenzene. The filtered solid was then suck dried for 10- 15 minutes followed by drying of the wet cake under vacuum at 80-85 °C. Yield of the linezolid crystalline form-Ill obtained was 24.5g (98.0 w/w), with HPLC purity of 99.91%.