FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"PROCESS FOR THE PREPARATION OF (S)-N [[3-(3-FLUORO-4-(4-MORPHOLINYL) PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL]
ACETAMIDE"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED





PRIORITY
[0001] This application claims the benefit under Indian Provisional Application
853/MUM/2005, filed on July 15, 2005, and entitled "PROCESS FOR THE PREPARATION OF (S)-N [[3-(3-FLUORO-4-(4-MORPHOLINYL) PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL] ACETAMIDE", the contents of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
[0002] The present invention generally relates to a process for the preparation of (S)-
N [[3-(3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide.
2. Description of the Related Art
[0003] Linezolid, also known as (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-
5-oxazolidinyl]methyl]acetamide, can be represented by the structure of general Formula I:

[0004] Linezolid is a synthetic antibacterial agent of the oxazolidinone class.
Linezolid has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents, therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the
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majority of strains. Linezolid is commercially sold under the trade name Zyvox®. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 986-87, monograph 5526; and Physician's Desk Reference, "Zyvox," 58th Edition, pp. 2808-2815 (2004).
[0005] U.S. Patent No. 5,688,792 ("the '792 patent"), herein incorporated by
reference, discloses linezolid and a process for its preparation.
SUMMARY OF THE INVENTION
[0006] In accordance with one embodiment of the present invention, a process
comprising (a) providing a solution of linezolid in organic solvent having a boiling point of
less than about 150°C; (b) addition of an anti solvent having boiling point more than 50°C and
recovering linezolid.
[0007] In accordance with a second embodiment of the present invention, linezolid
having a x-ray powder diffraction (XRD) pattern substantially in accordance with Figure 1
and/or an infra red (IR) spectrum substantially in accordance with Figure 2 prepared by a
process comprising (a) providing a solution of linezolid in organic solvent having a boiling
point of less than about 150°C; (b) addition of an anti solvent having boiling point more than
50°C and recovering linezolid.
[0008] In accordance with a third embodiment of the present invention, a
pharmaceutical composition is provided comprising a therapeutically effective amount of
linezolid having a x-ray powder diffraction (XRD) pattern substantially in accordance with
Figure 1 and/or an infra red (IR) spectrum substantially in accordance with Figure 2 prepared
by a process comprising (a) providing a solution of linezolid in organic solvent having a
boiling point of less than about 150°C; (b) addition of an anti solvent having boiling point
more than 50°C and recovering linezolid.
[0009] In accordance with a fourth embodiment of the present invention, a
pharmaceutical composition is provided comprising a therapeutically effective amount of
linezolid having a x-ray powder diffraction (XRD) pattern substantially in accordance with
Figure 1.
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DEFINITIONS
[0010] The term "treating" or "treatment" of a state, disorder or condition as used
herein means: (1) preventing or delaying the appearance of clinical symptoms of the state,
disorder or condition developing in a mammal that may be afflicted with or predisposed to the
state, disorder or condition but does not yet experience or display clinical or subclinical
symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition,
i.e., arresting or reducing the development of the disease or at least one clinical or subclinical
symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or
condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be
treated is either statistically significant or at least perceptible to the patient or to the physician.
[0011] The term "therapeutically effective amount" as used herein means the amount
of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
[0012] The term "buffering agent" as used herein is intended to mean a compound
used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
[0013] The term "sweetening agent" as used herein is intended to mean a compound
used to impart sweetness to a preparation. Such compounds include, by way of example and
without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol,
sucrose, fructose and other such materials known to those of ordinary skill in the art.
[0014] The term "binders" as used herein is intended to mean substances used to cause
adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin,
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liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
[0015] When needed, other binders may also be included in the present invention.
Exemplary binders include starch, polyethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
[0016] The term "diluent" or "filler" as used herein is intended to mean inert
substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
[0017] The term "glidant" as used herein is intended to mean agents used in tablet and
capsule formulations to improve flow-properties during tablet compression and to produce an
anti-caking effect. Such compounds include, by way of example and without limitation,
colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc,
combinations thereof and other such materials known to those of ordinary skill in the art.
[0018] The term "lubricant" as used herein is intended to mean substances used in
tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
[0019] The term "disintegrant" as used herein is intended to mean a compound used in
solid dosage forms to promote the disruption of the solid mass into smaller particles which are
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more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
[0020] The term "wetting agent" as used herein is intended to mean a compound used
to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.
[0021] Most of these excipients are described in detail in, e.g., Howard C. Ansel et al,
Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
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BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 is a characteristic x-ray diffraction pattern of linezolid of the present
invention.
[0023] Figure 2 is a characteristic infra red spectrum of linezolid of the present
invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] The present invention is directed to a process for preparing linezolid having a
x-ray powder diffraction (XRD) pattern substantially in accordance with Figure 1 and/or an
infra red (IR) spectrum substantially in accordance with Figure 2. In one embodiment, a
process for preparing linezolid includes at least (a) providing a solution of linezolid in organic
solvent having a boiling point of less than about 150°C; (b) addition of an anti solvent having
boiling point more than 50°C and recovering linezolid.
[0025] In step (a) of the process of the present invention, a solution is prepared
containing at least linezolid in organic solvent having a boiling point of less than about
150°C. In step (b) of the process of the present invention, addition of anti solvent having
boiling point more than 50°C and recovering linezolid.
[0026] Suitable organic solvents for use herein include those having a boiling point
lower than about 150°C, and preferably lower than about 100°C. Useful solvents include, but
are not limited to, chlorinated solvents, e.g., methylene chloride, ethylene chloride,
chloroform, and the like; alcoholic solvents, e.g., methanol, ethanol, isopropanol and the like;
aliphatic or cyclic ethers, e.g., tetrahydrofuran, monoglyme and the like and mixtures thereof.
[0027] Suitable anti solvents for use herein include those having a boiling point
greater than about 50°C and preferably greater than about 100°C. Representative examples of
such anti-solvents include, but are not limited to, o-xylene, m-xylene, p-xylene, mesitylene,
diphenyl ether, n-heptane and the like and mixture thereof. Preferably, the anti-solvent is o-
xylene, m-xylene, p-xylene and mixture thereof.
[0028] Following the addition of the anti solvent to the solution, the low boiling
solvent is removed, e.g., either by evaporating in rotatory evaporator or under stirring. The
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low boiling solvent can be removed at a temperature ranging from about 30°C to about
120°C, preferably from about 50°C to about 80°C and more preferably from about 60°C to
about 70°C. Next, linezolid is isolated by known techniques, e.g., filtration. The linezolid
thus obtained will have a x-ray powder diffraction (XRD) pattern substantially in accordance
with Figure 1 and/or an infra red (IR) spectrum substantially in accordance with Figure 2.
[0029] Another aspect of the present invention is directed to pharmaceutical
compositions containing at least the linezolid of the present invention. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The linezolid of the present invention also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The dosage forms may contain the linezolid of the present invention as is or, alternatively, may contain the linezolid of the present invention as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.
[0030] Capsule dosages can contain the linezolid of the present invention within a
capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a
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coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
[0031] Tableting compositions may have few or many components depending upon
the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
[0032] Other excipients contemplated by the present invention include binders, such
as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet
and dry granulation and direct compression tableting processes; disintegrants such as sodium
starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants
like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners;
preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
[0033] In one embodiment, the linezolid of the present invention for use in the
pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. The particle sizes of the linezolid of the present invention can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state the linezolid of the present invention into any of the foregoing desired particle size range.
[0034] Actual dosage levels of the linezolid of the present invention may be varied to
obtain an amount of the linezolid of the present invention that is effective to obtain a desired
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therapeutic response for a particular composition and method of administration for treatment of a mammal. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the linezolid of the present invention administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc.
[0035] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLE 1
[0036] Preparation of Linezolid
[0037] A 1 liter distillation flask was charged with a solution of linezolid in methylene
chloride (30 grams in 300 ml)) and o-xylene as an anti solvent was added and stirred for 20 to 25 minutes. Methylene chloride was distilled out of the solution in a rotatory evaporator at a bath temperature of 60°C to 70°C. During distillation solids began to precipitate out. After completion of the distillation, the precipitated solids were isolated by filtration and dried to provide linezolid (25 g, 83%) having a characteristic infra red spectra and x ray powder diffraction pattern shown in Figures 1 and 2.
EXAMPLE 2
[0038] Preparation of Linezolid
[0039] A 1 liter distillation flask was charged with a solution of linezolid (30 g) in
methylene chloride (150 ml) and tetrahydrofuran (300 ml) and o-xylene (120 ml) as an anti solvent was added and stirred for 20 to 25 minutes. Methylene chloride and tetrahydrofuran were distilled out of the solution in a rotatory evaporator by raising the bath temperature up to 120°C. During distillation, solids began to precipitate out. After completion of the
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distillation, the precipitated solids were isolated by filtration and dried to provide linezolid (23 g, 76.6%) having a characteristic infra red spectra and x ray powder diffraction pattern shown in Figures 1 and 2.
[0040] While the above description contains many specifics, these specifics should not
be construed as limitations of the invention, but merely as exemplifications of preferred embodiments thereof. Those skilled in the art will envision many other embodiments within the scope and spirit of the invention as defined by the features and advantages appended hereto.

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WE CLAIM:
1. A process for the preparation of linezolid comprising (a) providing a solution of
linezolid in organic solvent having a boiling point of less than about 150°C; (b) addition of an
anti solvent having boiling point more than 50°C and recovering linezolid.
2. The process of claim 1, wherein linezolid having a x-ray powder diffraction (XRD)
pattern substantially in accordance with Figure 1 and/or an infra red (IR) spectrum
substantially in accordance with Figure 2.
3. The process of Claim 1, wherein the anti solvent has a boiling point of more than
about 100°C.
4. The process of Claim 1, wherein the anti-solvent is selected from the group
consisting of o-xylene, m-xylene, p-xylene, mesitylene, diphenyl ether, n-heptane and mixture
thereof.
5. The process of Claim 1, wherein the organic solvent has a boiling point lower than about150°C.
6. The process of Claim 1, wherein the organic solvent has a boiling point lower than about 100°C.

7. The process of Claim 1, wherein the organic solvent is selected from the group consisting of a chlorinated solvent, alcoholic solvent, aliphatic or cyclic ether and mixtures thereof.
8. The process of Claim 6, wherein the chlorinated solvent is selected from the group consisting of methylene chloride, ethylene chloride, chloroform, and the mixtures thereof.
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9. The process of Claim 6, wherein the alcoholic solvent is selected from the group
consisting of methanol, ethanol, isopropanol and mixtures thereof.
10. The process of Claim 6, wherein the aliphatic or cyclic ether solvent is selected from the group consisting of tetrahydrofuran, monoglyme and mixtures thereof.
11. The process of Claim 1, wherein the step of providing the solution comprises adding the organic solvent to linezolid and then adding the anti solvent.
12. Linezolid prepared by the process of Claim 1.
13. A pharmaceutical composition comprising a therapeutically effective amount of
linezolid prepared by the process of claim 1 and one or more pharmaceutically acceptable
excipients.

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ABSTRACT
[0041] A process is provided comprising (a) providing a solution of linezolid in
organic solvent having a boiling point of less than about 150°C; (b) addition of an anti solvent having boiling point more than 50°C and recovering linezolid.
1 7 JUL 2006