PROCESS FOR PREPARING CRYSTALLINE FORM OF LINEZOLID
FIELD OF THE INVENTION

The present invention provides a process for preparing crystalline form of Linezolid.

BACKGROUND OF THE INVENTION

Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA).

Chemically, linezolid is (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl] acetamide. The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:

Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).

WO9507271 (Barbachyn et al, 1994), US5688792 and EP0717738 first claimed and disclosed Linezolid and its process of preparation. There is no disclosure about polymorphism of Linezolid in these patents.

J. Med. Chem., 39(3), 673-9 (1996) discloses preparation of Linezolid, purified by column chromatography and recrystallized from ethyl acetate and hexane as white crystals, m.p. 181.5-182.5 °C.

US6559305 (Bergren, 2000) and US6444813 cover and disclose Linezolid crystal "Form II" and its process of preparation comprising mixing greater than 98% enantiomerically pure Linezolid in a solvent or a mixture of solvents, particularly ethyl acetate, at a temperature below 80 °C and separating Linezolid crystal "Form II".

WO2012114354 (Alia, Raghu Mitra et al, 2011) describes anhydrous Linezolid crystalline Form-II comprising less than 0.5% of water content, characterised by its XRPD and IR spectra and its process of preparation comprising mixing Linezolid in n-butyl acetate at a temperature of 90-95 °C for 40-45 min.

WO2011050826 (Westheim et al, 2009) relates to a process for making a crystalline Form A of Linezolid comprising dissolving Linezolid in solvent selected from alcohols, cyclic ethers and aliphatic esters, followed by addition of an anti-solvent and seeded with crystals of crystalline Form A of Linezolid.

WO2005035530 (Mohan Rao et al, 2003) describes the crystalline Form III of Linezolid, which was obtained by heating Linezolid at 130-140 °C, refluxing in a solvent such as toluene or xylene or by crystallization from a seeded solution in a solvent.

The drawbacks of the above mentioned patent applications are that process temperature is high or seeding is required to get desired polymorph that may not lead to consistency in getting the desired polymorph. The process for preparing crystalline form of Linezolid has operating temperature more than 90°C, which may lead to the decomposition of the product and produce product of inferior quality.

There are various other forms of Linezolid given in prior art.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.

The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale. The inventors of the present invention during their continuous efforts developed a simple and operation friendly process for preparing pure crystalline form of Linezolid.

OBJECT OF THE INVENTION

The main object of the present invention is to provide simple, operational and environmental friendly process for preparing pure crystalline form of Linezolid.

Another object of the present invention is to provide highly pure crystalline form of Linezolid that provides good yields of the product.

Yet another object of the present invention is to provide pure crystalline form of Linezolid prepared without usage of anti-solvents and seeding.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides process for preparing crystalline Form of Linezolid comprising

a) adding an organic solvent to Linezolid residue at below about 50 °C, cooling and filtering the resultant slurry;

b) washing the slurry obtained in a) with an organic solvent and

c) drying of the product to get crystalline form of Linezolid.

In another aspect of the present invention relates to the process for the preparation of crystalline form of Linezolid, characterized by the infrared spectra (IR spectra) and X-ray powder diffraction patterns (XRPD).

BRIEF DESCRIPTION OF DRAWINGS

Figure- 1: Represents X-ray powder diffraction pattern (XRPD) of crystalline Form of
Linezolid.

Figure- 2: Represents infrared absorption spectrum (IR spectrum) of crystalline Form of
Linezolid

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a simple, operational and environmental friendly process for preparing pure crystalline form of Linezolid.

Linezolid used for the synthesis of polymorph can be made by the following process for the preparation of Linezolid, which is depicted in Scheme 1.

Scheme 1

According to one embodiment of the present invention, the process for the preparation of linezolid involves the acetylation of the non isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-
(morpholin-4-yl) phenyl] -1,3 -oxazolidin-2-one in organic solvent with acetic anhydride to give linezolid residue.

According to one embodiment of the present invention, the organic solvent for acetylation for preparing Linezolid is selected from polar solvent such as dichloromethane and the like and non polar solvents such as toluene, chloroform, preferably dichloromethane and/or chloroform.

According to another embodiment, the present invention provides a process for preparing crystalline Form of Linezolid comprising

a) adding an organic solvent to Linezolid residue at below about 50 °C, cooling and filtering the resultant slurry;

b) washing the slurry obtained in a) with an organic solvent and

c) drying of the product to get crystalline form of Linezolid.

Suitable organic solvents used for the crystallization are selected from non polar solvents such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene and xylene, preferably n-hexane, n-heptane, cyclohexane, methylcyclohexane.

According to yet another embodiment of the present invention, the slurry is cooled at a temperature range of 10-30°C, preferably 20-25 °C and dried at temperature range of 35-75°C, preferably 45-60 T.

X-ray powder diffraction diagram

The X-ray powder diffraction profile of the crystalline form was measured on Shimadzu Model No XRD-7000 equipped with solid-state detector. Copper radiation of 1.54 A° may be used for the analysis.

The XRPD pattern of the figure has a vertical axis that is intensity unit and a horizontal axis that is 29 angle in degrees.

In one embodiment, the crystalline Form of Linezolid is characterized by X-ray powder diffraction pattern having peaks at 9.47, 13.78, 14.17, 16.70, 17.60, 19.39, 19.90, 21.49, 22.31,22.80, 23.44, 25.22, 26.87, 28.65, 37.05 and 44.07 ± 0.2° 20 values. The crystalline form of Linezolid is characterized by X-ray diffraction pattern diagram as represented in Figure-1.

The IR analysis was done on Perkin Elmer SPECTRUM ONE FT-IR spectrometer in DRIFT mode, or using mineral oil mull technique. The sample was scanned from 450 to 4000 cm'1.

The crystalline form of Linezolid is characterised by the characteristic IR peaks of stretching and bending as represented in Figure-2.

In another embodiment the crystalline Form of Linezolid is further characterized by Infrared spectrum having peaks at 3363,1747,1675,1536,1516,1474,1445,1410,1375,1328,1273, 1252,1236,1220,1144, 1116,1077,1065,1049, 906, 851 and 756 cm'1.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1: Preparation of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-
1,3-oxazoIidin-2-one

methyl (3-fluoro-4-morpholinophenyl)carbamate (100 g) was added to the glass flask having THF (400 ml) at 25-30°C and cooled to 0-5°C. 2.5 M n-butyl lithium solution (250 ml) was slowly added to the reaction mixture at 0 - 5°C over a period of 120 min and the reaction mixture was stirred for 20 - 30 min at 0 - 5°C. R-Epichlorohydrin (52 g) was slowly added at 0 - 5°C over a period of 60 min to the reaction mixture, stirred for 180 min at 0 - 5°C and raised the temperature of the reaction mixture to 25 - 30°C. The reaction mixture was stirred at 25 - 30°C for 12 h, distilled out THF under reduced pressure at below 45°C to get the product as residue. Dichloromethane (400 ml) and DM water (250 ml) were added to the reaction mixture under nitrogen atmosphere at 25-30°C .The organic layer was separated and dichloromethane (200 ml) was added to the aqueous layer. The reaction mixture was stirred for 10-15 min at 25-30°C and the organic layer was separated. The combined organic layer was added into the reactor and washed with DM water (100 ml) at 25-30°C. Dichloromethane was distilled at atmospheric pressure to get the residue and traces of dichloromethane were removed under reduced pressure at below 50°C. Methanol (300 ml) was added at below 50°C, cooled the reaction mass to 5-10°C, filtered the solid obtained and dried at 50-55°C to obtain the title compound of 92 g.

Example 2: Preparation of (S)-2-[3-{3-fluoro-4-(morpholin-4-yl)phenyl}-2oxo-oxazolidin-5-yl methyl]-isoindole-l,3-dione

DMF (300 ml) was charged into a glass flask at ambient temperature and charged (5R)-5-(chloromethyl)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-l,3-oxazolidin-2-one (100 g) into the glass flask at ambient temperature. Potassium phthalimide (250 g) was added at 25-30°C to the reaction mixture, raised the temperature to 140-145°C, maintained at the same temperature for 120 min and cooled to 25-30°C. DM water (400 ml) was slowly added to the reaction mixture at 25-30°C over a period of 60 min and stirred the slurry obtained for 30-45min at 25-30°, the solid was filtered and washed with DM water (200 ml) to get crude solid of (S)-2- [3 - {3 -fluoro-4-(morpholin-4-yl)phenyl] -2oxo-oxazolidin-5 -yl methyl] -isoindole-l,3-dione. This crude solid was added to methanol (500 ml), refluxed for 60 min and cooled to 25-30°C. The solid obtained was filtered, washed with methanol (100 ml) and the solid was added to ethyl acetate (500 ml), refluxed for 60 min and cooled to 25-30°C. The solid obtained was filtered and washed with ethyl acetate (100 ml) to obtain the title product in pure form (85 g).

Example 3: Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid)

Methanol (100 ml) was charged into the glass flask and DM water (400 ml) was added to Methanol at ambient temperature. (S)-2-[3-{3-fluoro-4-(morpholin-4-yl)phenyl]-2oxo-oxazolidin-5-yl methyl]-isoindole-1,3-dione (100 g) was added to aqueous methanol at 25-30°C. Methyl amine solution (47 g) was added to the reaction mixture at 25-30°C, stirred, the temperature was slowly raised to 80-85°C and further stirred for 2-3 hours at 80-85°C. The reaction mixture was cooled to 25-30°C and dichloromethane (50 ml) was added to it, the reaction mixture was stirred for 15 min and separated the two layers. MDC was distilled out by atmospheric pressure completely to get the residual product (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30°C over a period of 60 min. The reaction mixture was stirred for 60 min at 25-30°C.The reaction was checked for its completion by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with D M Water (200 ml). The dichloromethane layer was filtered through hyflo and dichloromethane was distilled out completely under vacuum below 40°C. Cyclohexane (500 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid was filtered, washed with cyclohexane (200 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) form (53g)-

Example 4: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one residue obtained in example 3, was added dichloromethane (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min and stirred the reaction mixture for 60 min at 25-30°C.The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with D M Water (100 ml), filtered through hyflo and dichloromethane was distilled out completely under vacuum below 40°C. n-Heptane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid obtained was filtered, washed with n-Heptane (100 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) form (12g).

Example 5: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one residue obtained in example 3, was added dichloromethane (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min and stirred the reaction mixture for 60 min at 25-30°C. The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with D M Water (100 ml), the dichloromethane layer was filtered through hyflo and dichloromethane was distilled out completely under vacuum below 40°C. N-Hexane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid obtained was filtered, washed with N-Hexane (100 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) form (11 g).

Example 6: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one residue obtained in example 3, was added chloroform (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min, the reaction mixture was stirred for 60 min at 25-30°C. The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to the reaction mixture, stirred for 15 min and the two layers were separated. The organic layer was washed with D M Water (100 ml), the organic layer was filtered through hyflo and distilled out chloroform completely under vacuum below 40°C. Cylcohexane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C,stirred for 60 min, the solid was filtered, washed with Cyclohexane (100 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl] -2-oxo-1,3 -oxazolidin-5 -yl} methyl)acetamide (Linezolid) form (11.5 g).

Example7: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one residue obtained in example 3, was added chloroform (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min and the reaction mixture was stirred for 60 min at 25-30°C. The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The organic layer was washed with D M Water (100 ml), filtered the organic layer through hyflo and chloroform was distilled out completely under vacuum below 40°C. Heptane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid obtained was filtered, washed with Heptane (100 ml) and dried at 50-60°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide(Linezolid) form (11.5 g).

Example 8: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one residue obtained in example 3, was added chloroform (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min, stirred the reaction mixture for 60 min at 25-30°C.The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The organic layer was washed with D M Water (100 ml), filtered through hyflo and distilled out chloroform completely under vacuum below 40°C. N-hexane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid was filtered, washed with N-hexane (100 ml) and dried at 50-60°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) form (12g).

Example 9: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fiuoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one residue obtained in example 3, was added chloroform (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min, stirred the reaction mixture for 60 min at 25-30°C. The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to the reaction mixture, stirred for 15 min and the two layers were separated. The organic layer was washed with D M Water (100 ml), filtered through hyflo and distilled out Chloroform completely under vacuum below 40°C. Methylcyclohexane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid obtained was filtered, washed with Methylcyclohexane (100 ml) and dried at 50-60°C to furnish pure N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) form (11 g).

Example 10: Preparation of Crystalline Form of Linezolid

To 20 g of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl] -1,3 -oxazolidin-2-one residue obtained in example 3, was added dichloromethane (100 ml) and acetic anhydride (6.5 g) was slowly added at 25-30°C over a period of 60 min, stirred the reaction mixture for 60 min at 25-30°C. The completion of the reaction was checked by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mass, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with D M Water (100 ml), filtered through hyflo and distilled out dichloromethane completely under vacuum below 40°C. Methylcyclohexane (200 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid was filtered, washed with Methylcyclohexane (100 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3 -fluoro-4-(morpholin-4-yl)phenyl] -2-oxo-1,3 -oxazolidin-5 -yl} methyl)acetamide (Linezolid) form (12 g).

We claim:

1. A process for preparing crystalline Form of Linezolid comprising

a) adding an organic solvent to Linezolid residue at below about 50 °C, cooling and filtering the resultant slurry;

b) washing the slurry obtained in a) with an organic solvent and

c) drying of the product to get crystalline form of Linezolid.

2. The process according to claim la), wherein the linezolid residue is prepared comprising the acetylation of the non isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one in organic solvent with acetic anhydride.

3. The process according to claim 2, wherein the organic solvent from polar solvent such as dichloromethane and the like and non polar solvents such as toluene, chloroform, preferably dichloromethane and/or chloroform.

4. The process according to claims la) and lb), wherein the organic solvent are non polar solvent selected from n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, xylene, preferably n-hexane, n-heptane, cyclohexane, methylcyclohexane.

5. The process according to claim 1, wherein the slurry is cooled at a temperature range of 10-30°C, preferably 20-25 °C and dried at temperature range of 35-75°C, preferably 45-60 °C.

6. Crystalline form of Linezolid according to claim 1 having a powder X-ray diffraction pattern substantially in accordance with Figure-1.

7. Crystalline form of Linezolid according to claim 6 having powder X-ray diffraction pattern characterised by the peaks at 9.47,13.78,14.17,16.70,17.60,19.39,19.90,21.49,22.31, 22.80,23.44,25.22,26.87,28.65,
37.05 and 44.07 ± 0.2° 20 values

8. Crystalline form of Linezolid according to claim 1 having IR spectrum substantially in accordance with Figure-2.

9. Crystalline form of Linezolid according to claim 8 having IR peaks at 3363,1747,1675,1536,1516,1474,1445,1410,1375,1328,1273,1252,1236,1220,1144,1116,1077,1065,1049,906, 851 and 756 cm"1

10. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.