"PROCESS FOR THE PREPARATION OF LINEZOLID CRYSTALLINE FORM-I"

FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of Linezolid crystalline form-Il. The invention also provides a cost effective process for large scale production of Linezolid crystalline form-II. More particularly, the present invention relates to a stable crystalline Form-II of Linezolid.

Background of the invention:

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). Linezolid is marketed by "Pfizer'" under the trade names "Zyvox" and it is chemically known as (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide having the formula (1).

Linezolid is described in the "Merck Index" (13 edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°C. Linezolid was first disclosed in US5688792 and its process describes by using of R -glycidylbutyrate which results in the formation of (R)- N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages has to be converted to various intermediary compounds to finally form Linezolid.

Linezolid is known to exhibit polymorphism, i.e. US 5,688,792 (the 792 patent) and J. Med. Chem. 39(3), 673-679, 1996 are disclosed a process for polymorphic Form-I.

The 792 patent described process involves the use of silica gel column with eluting a gradient of 2- 10% methanol/ethyl acetate (v/v).
J. Med. Chem. 39(3), 673-679, 1996 described process, which involves the use of ethyl acetate and hexane to recrystallize the Linezolid.

U.S. Patent Nos. 6,444,813 and 6,559,305 (the US '305) discloses crystal Form II of Linezolid. The US'305 patent further discloses that the crystal Form II is characterized by powder X-ray diffraction pattern and infrared (IR) spectrum.

Several processes for the preparation of crystalline Form of Linezolid have been disclosed, for example in U.S. Patent Nos. 7,649,096 B2, 7,718,799 B2, 7,718,800 B2, 7,732,597 B2, and 7,714,128 B2.

The publications WO 2007/116284 Al, WO 2009/063505 A2, WO 2010/031769 Al, WO 2010/081404 Al, WO 2010/084514 A2, WO2011/029460 Al and WO 2011/77310 Al, discloses various processes for the synthesis of Linezolid and its crystalline form.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates. The solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing. For example, an amorphous form may form hydrates more readily or may be more difficult to filter and wash free of impurities than a crystalline form (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms). Thus, a present crystalline form-II can overcome the problems like thermodynamic stability, solubility, storage and compressibility.

There is consequently a need for an alternative method for the preparation of Linezolid form-II. Also there is a constant need to have the cost effective and industrial friendly process for the preparation of the solid state form in substantially pure Linezolid having stable Form-II.

SUMMARY OF THE INVENTION

In one aspect of the present invention is to provide a process for the preparation of Linezolid crystalline form-II comprising the steps of;

a) reacting the compound of formula(III) with epichlorohydrin in presence of a base,
b) treating the product of step a) with substituted phthalimide to give a compound of formuIa(V),
c) deprotecting the compound of formula (V); followed by acylation ,and
d) isolating the Linezolid crystalline form-II with hydrocarbon solvent.
The above synthetic process is illustrated as per the following Scheme-I

In another aspect of the present invention is to provide an improved process for the preparation of Linezolid crystalline form-II comprising the steps of;

a) reacting the compound of formula(III) with (S)-Glycidylphthalimide of formula(IX) to give a compound of formula(VI),
b) subjecting the compound of formula(VI) with aqueous methyl amine,
c) acylating the product of step b), and
d) isolating the Linezolid crystalline form-II with hydrocarbon solvent.

The above synthetic process is illustrated as per the following Scheme-II

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1: X-ray powder diffraction (PXRD) of Linezolid Crystalline Form-II
Fig 2: Differential scanning calorimetry (DSC) of Linezolid Crystalline Form-II Detailed Description of the Invention The present invention relates to a process for the preparation of Linezolid crystalline form-II. One embodiment of the present invention is to provide a process for the preparation of Linezolid crystalline form-II comprising the steps of;
a) reacting the compound of formula(III) with epichlorohydrin in presence of a base,
b) treating the product of step a) with substituted phthalimide to give a compound of formula(V),
c) deprotecting the compound of formula (V); followed by acylation ,and
d) isolating the Linezolid crystalline form-II with hydrocarbon solvent. According to the present invention, the compound of formula (III) is reacts with epichlorohydrin in presence of base and solvent at a suitable temperature, most preferably 50-55 °C to give a (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4- morpholinyl)phenyl]-2-oxazolidinone; further it is treated with substituted potassium phthalimide in presence of a solvent to give (S)-2-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-yl-methyl]-5-^-isoindole-l,3-dione(Formula-V),wherein X=halogen, cyano, amine, nitro or amine/amine derivatives. The compound of formula (V) is reacted with hydrazine hydrate or aqueous methylamine to give (S)-5-Aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyI)-oxazolidin-2-one, which is subsequently acylated with acetic anhydride in presence of a solvent to give a residue and it was recrystallized with hydrocarbon solvent to give Linezolid crystalline form-11.

According to the embodiment, the base is selected from triethylamine, lithium tertiary butoxide, diisoprorpyl amine, n-butyl lithium and sodium hydride.

According to the embodiment, the solvent is selected from cyclic ethers such as tetrahydrofuran; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; acetonitrile; chlorinated solvents such as dichloromethane, chloroform, dichloroethane; alcohols such as methanol, ethanol, t-amyl alcohol, t-butyi alcohol Isopropyl alcohol and water (or) mixtures thereof. Preferable solvent is selected from tetrahydrofuran, methanol, isopropyl alcohol and N, N-dimethylformamide; hydrocarbon solvent is selected from cyclohexane, cycloheptane, hexane, pentane and heptane.

The reaction is performed at or below boiling temperature of the solvent used, more preferably between 10°C and boiling temperature of the solvent used and even more preferably at boiling temperature of the solvent used.

According to the embodiment, substituted phthalimide of formula (IV) Wherein X=chlorine, bromine, iodine, cyano, amine, nitro or amine/amine derivatives.

Another embodiment of the present invention is (S)-2-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-yl-methyl]-5-X-isoindole-l,3-dione of Formula-V.

Wherein X=chlorine, bromine, iodine, cyano, amine, nitro or amine/amine derivatives.

In yet another embodiment of the present invention is to provide a process for the preparation of Linezolid crystalline form-II comprising the steps of;
a) reacting the compound of formula(III) with (S)-Glycidylphthalimide of formula(IX) to give a compound of formula(VI),
b) subjecting the compound of formula(VI) with aqueous methyl amine,
c) acylating the product of step b), and
d) isolating the Linezolid crystalline form-II with hydrocarbon solvent.

According to the embodiment, the reaction between formula (III) with (S)-Glycidylphthalimide of formula (IX) is carried out in presence of base and solvent at suitable temperature to give a compound of formula(VI); further it is subjected to deprotection with hydrazine hydrate (or) aqueous methyl amine to give (S)-5-

Aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one,which is subsequently acylated with acetic anhydride in presence of a solvent to give a residue and it was recrystallized with hydrocarbon solvents to give Linezolid crystalline form-II.

According to the embodiment, the base is selected from triethylamine, lithium tertiary butoxide, diisoprorpyl amine, n-butyl lithium and sodium hydride.

According to the embodiment, the solvent is selected from cyclic ethers such as tetrahydrofuran; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; acetonitrile, ethylacetate; chlorinated solvents such as dichloromethane, chloroform, dichloroethane; alcohols such as methanol, ethanol, t-amyl alcohol, t-butyl alcohol, Isopropyl alcohol and water (or) mixtures thereof, hydrocarbon solvent is selected from cyclohexane, cycloheptane, hexane, pentane and heptane.

The reaction is performed at room temperature or below boiling temperature of the solvent used, more preferably between 10°C and boiling temperature of the solvent used and even more preferably at boiling temperature of the solvent used. Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried.

According to the present invention, the crystalline form-II of Linezolid having HPLC purity is not less than 99.5%.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Experimental procedure:

Example-1: Preparation of (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)oxazolidin-2-one.
To a solution of 50g (0.15moles) (3-fluoro-4-morpholin-4-yl phenyl) carbamic acid benzyl ester in tetrahydrofuran (500 ml), 95 ml (0.15moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at -30 to -40°C. The solution was stirred for 30 min at -30 to -40°C. 18 g (0.19 moles) of R-epichlorohydrin was added over 30-40 min at -30 to -20°C. The reaction mixture was continuously stirred and the temperature was slowly raised to 50-55°C. The reaction was continued (~4 hrs) at 50-55°C till the conversion 74%. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500ml) and washed with water (300ml x 2). The methylene chloride layer was concentrated to get an oily residue, hexanes (100 ml) was added to the residue, stirred for 5min and decanted to give solid residue. Another lot of hexanes (150 ml) was added, stirred for 15 min and decanted. (This hexane layers contained un-reacted starting material). A mixture of isopropanol (30ml) and hexanes (120ml) was added to the residue under stirring. The solid was filtered and the wet cake was washed with a mixture of hexanes (40ml) and isopropanol (10ml) at 25-30°C. The wet cake was dried at 40-45°C to yield 30.2g of (5R)-5-chloromethyl-3-(3-f!uoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one. The pure sample was obtained by re-crystallization from isopropanol.

Example-2: Preparation of (S) [2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione To a solution of 500 g (1.59 moles) of 5-chloro-methyl-3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one in dimethyl formamide (1000 ml), 500 g (2.17) moles) of 4-nitropthalimide potassium was added at 25-30°C. The suspension was heated at 130-140°C and the stirring was continued by monitoring the progress of qualitative HPLC analysis till the starting material was less than 2% (2 hrs). The suspension was cooled to 30°C and poured into water (2000ml). The resulting solid was collected by filtration. The wet cake was suspended in ethyl acetate (1000 ml) at 25-30°C and stirred for 30-40 min. The slurry was filtered and washed the wet cake with ethyl acetate (500 ml) to yield 500 g (chromatographic purity: 99%) of (S) [2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione
Example-3: Preparation of (5R)-5-chloromethyI-3-(3-fluoro-4-morpholin-4-yl-phenyl)oxazolidin-2-one
To a solution of 38.lg (0.15moles) (3-fluoro-4-morpholin-4-yl phenyl) carbamic acid methyl ester in tetrahydrofuran (380 ml), 95 ml (0.15moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at 0 to -10°C. The solution was stirred for 30min at 0 to -10°C. 18 g (0.19 moles) of R-epichlorohydrin was added over 30-40 min at 0 to -10°C. The stirring was continued and the temperature was slowly raised to 50-55°C. The reaction was continued (~4 hrs) at 50-55°C till the conversion was about 75%. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500ml) and washed with water (300ml x 2). The methylene chloride layer was concentrated to get an oily residue. Isopropanol (100ml) was added to the residue and stirred for 15min at 50-55°C. The resulting product slurry was stirred for 30min. The product was filtered and washed the wet cake with pre-cooled isopropanol (25ml). The wet cake was dried at 40-45°C to yield 30g (purity 96%, 3% of (3-fluoro-4-morpholin-4-yl phenyl) carbamic acid methyl ester) of (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)oxazolidin-2-one. Pure sample was obtained by re-crystallization from isopropanol.
ExampIe-4: Preparation of (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one
To a solution of 40.2g (0.15moles) (3-fluoro-4-morpholin-4-yl phenyl) carbamic acid ethyl ester in tetrahydrofuran (400ml), 95ml (0.15moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at -10 to 0°C. The solution was stirred for 30 min at -10 to 0°C, 18 g (0.19 moles) of R-epichlorohydrin was added to the reaction mixture over 30-40 min at 0 to -10°C. The stirring was continued and the temperature was slowly raised to 50-55°C. The reaction was continued (~4 hrs) at 50-55°C till the conversion was about 75%. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500ml) and washed with water (300ml x 2). The methylene chloride layer was concentrated to get an oily residue. Isopropanol (100ml) was added to the residue and stirred for 15min at 50-55°C. The resulting product slurry was stirred for 30min. The product was filtered and washed the wet cake with pre-cooled isopropanol (25ml). The wet cake was dried at 40-45°C to yield 30.4g of (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one. Pure sample was obtained by re-crystallization from isopropanol.
Example- 5: Preparation of crystalline Linezolid form-II.
To the mixture of Methanol (100 ml) ,DM water (400 ml) and (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione (100 g 0.212 moles ) were added methyl amine solution (47 g) to the reaction mixture at 25-30°C, stirred and the temperature was slowly raised to 80-85°C and stirred for 2-3 hours at 80-85°C. The reaction mixture was cooled to 25-30°C and dichloromethane (500 ml) was added to it and stirred the reaction mixture for 15 min and separated the two layers. MDC was distilled out by atmospheric pressure completely to get the residual product (5S)-5-(amino methyl)-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. After completion, 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 DM Water (200 ml). The dichloromethane layer was filtered through hyflo and distilled out dichloromethane 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, filtered the solid, washed with cyclohexane (200 ml) and dried the solid at 45-55°C to furnish pure crystalline form-II of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}rnethyl)acetamide (Linezolid) (53 g 75%).

Example- 6: Preparation of crystalline Linezolid form-I
To a mixture of Methanol (50 ml), DM water (200 ml) and (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-l,3-dione (50 g 0.117moles ) methyl amine solution (25 g) was added to the reaction mixture at 25-30°C, stirred, the temperature was slowly raised to 80-85°C and stirred for 2-3 hours at 80-85°C. The reaction mixture was cooled to 25-30°C and dichloromethane (250 ml) was added to it. The reaction mixture was stirred for 15 min and two layers were separated. Charged purified water (300 ml) to the MDC layer and mixture was acidified to pH 2.0-3.0 with dilute hydrochloric acid, stirred the reaction mixture for 10-15 min and two layers were separated. Charged MDC (200 ml) to the aqueous layer and mixture was basified to pH 10.0-11.0 with aqueous ammonia solution. Stirred the reaction mixture for 10-15 min and two layers were separated. The MDC layer was distilled out by atmospheric pressure completely to get the residual product, (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l, 3-oxazolidin-2-one. Methyl acetate (1000 ml) was added to the residue followed by addition of 4-Dimethyl amino pyridine (3.0 g) and acetic anhydride (12.5g) was slowly added at 0-5°C over a period of 60 min. The reaction mixture was stirred for 120 min at 0-5°C.The reaction was checked for its completion by HPLC/TLC. The resultant Solid was filtered, washed with Methyl acetate (25 ml) and dried at 45-55°C to furnish pure crystalline Linezolid form-I.

WE CLAIM:

1. A process for the preparation of Linezolid crystalline form-II comprising the steps of;
a) reacting the compound of formula(III) with epichlorohydrin in presence of a base,
b) treating the product of step a) with substituted phthalimide to give a compound of formula(V),
c) deprotecting the compound of formula (V); followed by acylation ,and
d) isolating the Linezolid crystalline form-11 with hydrocarbon solvent.

2. A process for the preparation of Linezolid crystalline form-II comprising the steps of;
a) reacting the compound of formula(III) with (S)-Glycidylphthalimide of formula(IX) , optionally in presence of a base to give a compound of formula(VI),
b) subjecting the compound of formula(VI) with aqueous methyl amine,
c) acylating the product of step b), and
d) isolating the Linezolid crystalline form-II with hydrocarbon solvent.

3. The process according to claim 1 and 2, the base is selected from triethylamine, lithium tertiary butoxide, diisoprorpyl amine, n-butyl lithium and sodium hydride; hydrocarbon solvent is selected from cyclohexane, cycloheptane, hexane or heptane.

4. The process according to claim 1 and 2, wherein the acylation has been carried out in presence of acetic anhydride and an solvent to give Linezolid crystalline form-II

5. The process according to claim 4, the solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, toluene or xylene.

6. The process according to claim 1 and 2, the isolated crystalline form-II of Linezolid is dried at a temperature about range of 40°C to 65°C.

7. The crystalline form-II of Linezolid according to any preceding claims having a particle size D90 in the range of 25 um to 200 ^m.

8. The process according to claim 7, wherein the particle size D90 is less than 50