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WO2013190559A1 - Procédés perfectionnés pour la préparation de forme cristalline iii du linézolide - Google Patents

Procédés perfectionnés pour la préparation de forme cristalline iii du linézolide Download PDF

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Publication number
WO2013190559A1
WO2013190559A1 PCT/IN2012/000434 IN2012000434W WO2013190559A1 WO 2013190559 A1 WO2013190559 A1 WO 2013190559A1 IN 2012000434 W IN2012000434 W IN 2012000434W WO 2013190559 A1 WO2013190559 A1 WO 2013190559A1
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Prior art keywords
linezolid
temperature
crystalline form
form iii
solution
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PCT/IN2012/000434
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English (en)
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Dodda Mohan Rao
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Symed Labs Limited
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Priority to PCT/IN2012/000434 priority Critical patent/WO2013190559A1/fr
Publication of WO2013190559A1 publication Critical patent/WO2013190559A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of highly pure linezolid crystalline Form III.
  • 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.
  • 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).
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin- resistant Staphylococcus aureus
  • Linezolid 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).
  • 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.
  • 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 .
  • Crystal 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.
  • 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").
  • (S)-enantiomer N-[[3-[3-fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]]methyl]acetamide
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step-(c) 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);
  • step e) optionally, subjecting the organic layer obtained in step-(d) to carbon treatment or silica gel treatment to obtain a filtrate;
  • step 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;
  • step-(d) 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.
  • reflux temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the base used in step-(b) is an organic or inorganic base selected from the group as described above.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a finely powdered carbon is an active carbon.
  • a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.
  • 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.
  • step-(g) 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.
  • 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.
  • 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.
  • 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").
  • ATFD agitated thin film dryer
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step-(a) b) combining the solution obtained step-(a) with acetic anhydride to produce a reaction mass containing linezolid;
  • step-(c) 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.
  • step-(b) 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
  • Step-(a) of providing a solution of linezolid includes dissolving linezolid in water, or obtaining an existing solution from a previous processing step.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step-(a) or step-(b) is optionally subjected to carbon treatment or silica gel treatment as per the methods as described hereinabove.
  • 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.
  • the crystalline Form III of linezolid is recovered by filtration employing a filtration media of, for example, a silica gel or celite.
  • step-(b) optionally, seeding the suspension obtained in step-(b) with linezolid Form III;
  • step-(b) or step-(c) cooling the suspension obtained in step-(b) or step-(c) gradually to a temperature of below about 35°C;
  • 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.
  • 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.
  • 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.
  • 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.
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • 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.
  • 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.
  • FT-IR infra red
  • high purity 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).
  • 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.
  • 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.
  • 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 .
  • the X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper- ⁇ 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.
  • 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 .
  • Step-I Preparation of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl]methyI]amine
  • 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).
  • 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.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention porte sur un procédé de préparation de forme cristalline III du linézolide qui est de façon étonnante et inattendue, un procédé perfectionné, efficace et rentable de préparation de forme cristalline III du linézolide de pureté élevée avec un rendement de production élevé, par la réaction de la solution de (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phényl]-2-oxo-5-oxazolidinyl]méthyl]amine dans du chlorure de méthylène avec de l'anhydride acétique, éventuellement en présence d'une base organique, pour produire une masse réactionnelle contenant du linézolide, suivie d'une séparation de couches et d'un traitement au charbon subséquent de la couche organique ainsi obtenue pour former un filtrat, de l'ajout d'eau au filtrat ainsi obtenu et de l'élimination subséquente du solvant chlorure de méthylène par distillation, et éventuellement de l'ensemencement de la masse réactionnelle pendant le processus de distillation, pour produire la forme cristalline III du linézolide.
PCT/IN2012/000434 2012-06-19 2012-06-19 Procédés perfectionnés pour la préparation de forme cristalline iii du linézolide WO2013190559A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051360A1 (fr) * 2016-09-16 2018-03-22 Lee Pharma Limited Nouveau procédé de préparation de linézolide cristallin de forme iii

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688792A (en) * 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US20060128703A1 (en) * 2003-10-16 2006-06-15 Symed Labs Limited Novel crystalline form of linezolid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688792A (en) * 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US20060128703A1 (en) * 2003-10-16 2006-06-15 Symed Labs Limited Novel crystalline form of linezolid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051360A1 (fr) * 2016-09-16 2018-03-22 Lee Pharma Limited Nouveau procédé de préparation de linézolide cristallin de forme iii

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