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WO2013072923A1 - Procédé de préparation de linézolide cristallin - Google Patents

Procédé de préparation de linézolide cristallin Download PDF

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Publication number
WO2013072923A1
WO2013072923A1 PCT/IN2012/000621 IN2012000621W WO2013072923A1 WO 2013072923 A1 WO2013072923 A1 WO 2013072923A1 IN 2012000621 W IN2012000621 W IN 2012000621W WO 2013072923 A1 WO2013072923 A1 WO 2013072923A1
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WO
WIPO (PCT)
Prior art keywords
linezolid
crystalline form
stable
solvents
acetate
Prior art date
Application number
PCT/IN2012/000621
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English (en)
Inventor
Shriprakash Dhar DWIVEDI
Ashok Prasad
Kuldeep Natwarlal Jain
Original Assignee
Cadila Healthcare Limited
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Filing date
Publication date
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Publication of WO2013072923A1 publication Critical patent/WO2013072923A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the invention relates to an improved process for the preparation of crystalline linezolid.
  • the invention relates to an improved process for the preparation of crystalline Form-I of linezolid substantially free from crystalline Form-Il of linezolid.
  • the present invention relates to a stable crystalline Form-I of linezolid.
  • the invention also relates to pharmaceutical compositions that include the stable crystalline Form-I of linezolid.
  • Linezolid [(S)-N-[[3-(3-flouro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl] acetamide is an antimicrobial agent.
  • Linezolid is an oxazolidinone, having the empirical Formula CJ6H20FN3O4 and the following structure (I):
  • 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 and related compounds, processes for their preparation and their therapeutic uses were also disclosed in U.S. Patent No. 5,837,870 and International (PCT) Publications WO 95/07271 arid WO 99/24393 as well as in reference articles like J. Med. Chem. 39(3), 673-679, and Tetrahedron Lett. 40(26), 4855, 1999.
  • U.S. Patent Nos. 6,444,813 and 6,559,305 disclose crystal Form II of linezolid.
  • the US '305 patent further discloses that the crystal Form II is characterized by powder X-ray diffraction pattern andian infrared (IR) spectrum.
  • IR infrared
  • polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic.
  • chemical reactivity e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more
  • the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing.
  • 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).
  • a present crystalline form can overcome the problems like thermodynamic stability, solubility, storage, compressibility etc important for Formulation and product manufacturing and doesn't degrade to crystalline Form-II of linezolid.
  • the crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern as shown in FIG1, IR spectrum as shown in FIG.2, and differential scanning calorimetry endothermic peak as shown in FIG3.
  • the crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2 ⁇ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.
  • FIG.2 shows DSC analysis of crystalline Form-I of linezolid of the present invention characterized by having an endothermic peak in the range of about 181°C- 184°C.
  • the crystalline Form-I of linezolid of present invention is also characterized by IR analysis.
  • FIG.3 shows Infrared spectrum of Linezolid with characteristics peaks at about 3336, 2968, 2816, 1743, 1662, 1516, 1471, 1452, 1423, 1228, 1117, 937, 754 and -1
  • a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid having particle size d0.9 from 30 m to 200 ⁇ .
  • stable pharmaceutical composition of linezolid crystalline Form-I comprising a therapeutically effective amount of stable micronized crystalline Form-I of linezolid having particle size d0.9 less than about 25 ⁇ .
  • FIG 1 - represents the PXRD of crystalline Form of linezolid as per Example-6.
  • FIG 2 - represents the DSC of crystalline Form of linezolid as per Example-6.
  • FIG 3 - represents the IR spectrum of crystalline Form of linezolid as per Example-6.
  • FIG 4 - represents the PXRD of crystalline Form-II of linezolid as per Example-7.
  • FIG 5 - represents the PXRD comparison of crystalline Form of linezolid during stability up to 6 Months.
  • stable refers to crystalline linezolid Form-I that includes either of the following:
  • crystalline Form-I does not convert to Form-II or any other solid form when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months.
  • crystalline Form-I does not convert to Form-II or any other solid form when stored up to about six months or more.
  • the stable crystalline Form-I does not show an X-ray powder diffraction peak at a diffraction angle (2 ⁇ ) of about 23.5° when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months and containing less than about 0.15% (wt/wt) any single individual impurities like linezolid amine or linezolid alcohol or linezolid acetyl or desflouro and (R)-isomer by area percentage of HPLC temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months.
  • the term "obtain” or “obtaining” may include decantation or unloading from hydrogenator or pressure reactor.
  • the product obtained may be further or additionally dried to achieve the desired moisture values and remove traces of solvents atleast under ICH limits.
  • the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • micronized may include reduction in particle size of linezolid crystalline Form-I obtained as such by the process of present invention.
  • the term “micronized” includes particle size d0.9 of linezolid crystalline Form-I less than about 25 ⁇ .
  • micronized linezolid crystalline Form-I may be prepared by unit operation that involves reduction of particle size like jet-milling, ball-milling, multi-milling, shifting, sieving and the like.
  • amount may include the values from ⁇ 0.2° in case of 2-
  • the term "about” may include the values from ⁇ 3°C in case of differential scanning calorimetry.
  • the present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein.
  • “comprises” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited.
  • the terms “having” and “including” are also to be construed as open ended unless the context suggest otherwise.
  • pure When a molecule or other material is identified herein as “pure”, it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of substantially pure crystalline linezolid, “pure” also means about 99% of one crystalline form free from crystalline Form-II, as appropriate or in the case of crystalline solids.
  • Embodiments of the process may include one or more of the following features.
  • the solution or suspension may be obtained by dissolving or suspending linezolid in a suitable solvent.
  • a solution may be obtained directly from a reaction mixture in a process in which linezolid is formed.
  • the solvent containing linezolid may be heated to obtain a solution in hydrogenator or pressure reactor. It can be heated from about 35°C to about reflux temperature of the solvent used, for example from about 35°C to about 120°C.
  • Impurity "linezolid amine” is (S)-[N-[3-(3-flouro-4-mo holinylphenyl)-2-oxo-5- oxazolidinyl] methyl]amine.
  • Impurity "desflouro” is (S)-N-[3-(4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]acetamide.
  • Impurity "linezolid alcohol” is (R)-[N-[3-(3-flouro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol.
  • the stable linezolid crystalline Form-I is having particle size d0.9 in the range of 30 ⁇ to 200 ⁇ .
  • stable micronized linezolid crystalline Form-I there is provided stable micronized linezolid crystalline Form-I.
  • the micronized linezolid crystalline Form-I is having particle size d0.9 less than about 25 ⁇ , particularly less than 15 ⁇ .
  • the embodiments of the invention includes micronization of linezolid crystalline Form-I having particle size d0.9 in the range of 30 ⁇ to 200 ⁇ .
  • crystalline Form-I of linezolid substantially free from Form-II of linezolid.
  • substantially free herein means crystalline form of linezolid prepared by the process of the present invention contains 1% or less of crystalline Form-II of linezolid, particularly contains 0.5% or less of.
  • crystalline Form-II of linezolid more particularly less contains no detectable quantity of crystalline Form-II of linezolid, measured by X-ray powder diffraction pattern.
  • the crystalline Form-I of linezolid of the present invention is characterized by its powder X-ray diffraction pattern as shown in FIG.1, IR spectrum as shown in FIG.2, and differential scanning calorimetry endothermic peak as shown in FIG3.
  • Form-II of linezolid is characterized by having peaks at about 23.5°C which is not present in crystalline form of linezolid prepared by the process of present invention.
  • the crystalline Form-I of linezolid of present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2 ⁇ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.
  • FIG.2 shows DSC analysis of crystalline Form-I of linezolid of present invention characterized by having an endothermic peak in the range of about 181°C-184°C.
  • FIG.3 shows Infrared spectrum of Linezolid with characteristics peaks at about 3336, 2968, 2816, 1743, 1662, 1516, 1471, 1452, 1423, 1228, 1 117, 937, 754 and -1
  • an improved process for the preparation of crystalline Form-I of linezolid comprising heating linezolid in one or more of suitable solvent in a hydrogenator and obtaining crystalline Form-I of linezolid.
  • the crystalline Form-I of linezolid may be prepared by heating linezolid in one or more of suitable solvent selected from diisopropyl ether, methyl tert- butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like in a hydrogenator.
  • the reaction involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen.
  • the reaction mixture may be further cooled before filtration and washing the wet-cake with heptane.
  • the crystalline Form-I of linezolid is obtain by drying wet-cake at 70°C to 75°C in a vacuum oven.
  • the suitable solvent in step (a) comprises one or more of acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, toluene, xylene, methylene dichloride, chlorobenzene or mixtures thereof.
  • methylene dichloride In particular, methylene dichloride.
  • Embodiments of the process includes acetylating linezolid amine of Formula (II) in methylene dichloride with acetic anhydride below 5°C. Particularly, at 0°C to 5°C and reaction mixture may be maintained for 30 minutes in step (a). The linezolid product obtain in the reaction mixture may be isolated as residue by complete removal of methylene dichloride. In general, the methylene dichloride layer may be washed with 10% sodium bicarbonate solution at room temperature before subjecting to complete removal of the solvent. Embodiments of the process further include removing traces of methylene dichloride by co-distillation with toluene to provide linezolid residue.
  • the suitable solvent in step (c) comprises one or more of aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like, halogenated hydrocarbons like methylene dichloride, chlorobenzene, ethylene dichloride and the like, esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, nitriles like acetonitrile, propionitrile and the like, aprotic polar solvents like N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrroIidone, dimethylsulfoxide and the like.
  • aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like
  • halogenated hydrocarbons like methylene dichloride, chlorobenzene, ethylene dichloride and the like
  • esters like ethyl acetate, methyl a
  • Embodiments of the process include heating linezolid residue in suitable solvent, particularly aromatic hydrocarbons like toluene or xylene below 80°C.
  • the linezolid residue may be heated at about 35°C to about 80°C, More particular, at about 50°C to 55°C.
  • the reaction mixture may be cooled after heating at about 50°C to 55°C in toluene or xylene to obtain linezolid wet-cake by filtration.
  • the wet-cake may be again heated in suitable solvent comprises of esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate below 80°C, Particularly at about 70°C to 80°C.
  • the precipitated linezolid when filtered at above 15°C provides better yield and purity.
  • the precipitated linezolid may be filtered at about 18°C to 22°C and dried at 65°C to 70°C to obtain pure linezolid substantially free from linezolid amine, linezolid alcohol, desflouro and linezolid acetyl impurities. Further, linezolid is substantially free from its (R)-isomer.
  • the pure linezolid may be converted to crystalline Form-I of linezolid by crystallizing linezolid in one or more of suitable solvent selected from diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like in a hydrogenator.
  • suitable solvent selected from diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like in a hydrogenator.
  • the reaction involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen.
  • the reaction mixture may be further cooled before filtration and washing the wet-cake with heptane.
  • the crystalline Form-I of linezolid is obtain by drying wet-cake at 70°C to 75°
  • the halogenated hydrocarbon solvent comprises one or more of methylene dichloride, ethylene dichloride, chloroform, chlorobenzene and the like.
  • methylene dichloride ethylene dichloride, chloroform, chlorobenzene and the like.
  • the aromatic hydrocarbon solvent comprises one or more of toluene, o-xylene, m-xylene, p-xylene, ethylbenzene and the like.
  • the alkyl ester is one or more of toluene, o-xylene, m-xylene, p-xylene, ethylbenzene and the like.
  • solvent comprises one or more of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like.
  • the suitable solvent in step (e) comprises one or more of diisopropyl ether, methyl tert-butyl ether, diethyl ether, petroleum ether, heptane, hexane, cyclohexane and the like.
  • step (f) involves heating linezolid in heptane at about 105°C to 110°C under 3 Kg pressure in presence of nitrogen.
  • the reaction mixture may be further cooled before filtration and washing the wet-cake with heptane.
  • Crystalline form of linezolid is obtain by drying wet-cake at 70°C to 75°C in a vacuum oven.
  • a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of linezolid having particle size d0.9 from 30 ⁇ to 200 um.
  • stable pharmaceutical composition comprising a therapeutically effective amount of stable micronized crystalline Form-I of linezolid having particle size d0.9 less than about 25 ⁇ .
  • stable linezolid crystalline Form-I having bulk density of about 0.40 g/mL and tapped density of about 0.60 g/mL.
  • stable micronized linezolid crystalline Form-I having bulk density of about 0.28 g/mL and tapped density of about 0.40 g/mL.
  • the crystalline Form of linezolid can be characterized by PXRD, DSC, IR as follows:
  • Powder X-ray Diffraction was measured by using a Rigaku D/MAX 2200 VPC diffraction meter, the powder x-ray diffraction pattern was measured at room 10 temperature using a CuKa filled tube (40kV, 40 mA) as the x-ray source with a wide- angle goniometer, a scattering slit, an diverging slit, a graphite secondary monochromator and a scintillation counter. Data collection was done in 20 continuous scan mode at a scan speed of 37minute in scan steps of 0.02° in the range of 2° to 40°.
  • the crystalline Form of linezolid of present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2 ⁇ at about 7.3, 13.4, 14.6, 17.9, 18.3, 19.8, 20.9, 22.1, 25.3, 27.6, 28.3 and 29.6 degrees.
  • the crystalline form of linezolid is further characterized by X-ray powder diffraction pattern substantially as depicted in FIG.1
  • I/Io is in between 21 to 35
  • I/Io is in between 36 to 50
  • FIG.3 represents the IR spectra of crystalline Form-I of linezolid.
  • Example-2 N-carbobenzoxy-3-fluoro-4-morpholinyI aniline To a suspension of 100 g of 3-fluoro-4-morpholinyl-nitrobenzene in 1 L of methanol under nitrogen, was added 28 g of Raney Nickel in an autoclave. The reaction mixture was bubbled with H gas at room temperature initially and further under 5
  • reaction mixture was quenched in 134 g of saturated aqueous ammonium chloride solution, followed by 500 mL of toluene, and the aqueous layer extracted with toluene.
  • the combined organic layers were washed with 360 mL of brine.
  • the organic layer was treated with 4 g activated charcoal and stirred for 30 minute and filtered. The filtrate was concentrated under vacuum at 60°C to remove toluene completely.
  • the reaction mixture was stirred at 25°C and treated with 10% sodium bicarbonate solution (280 mL, 28g). The separated organic layer was washed with water and allowed to settle for 30 minutes. The organic layer was treated with 5 g activated carbon and stirred for 30 minutes. The reaction mixture was filtered and methylene dichloride was completely removed under vacuum below 50°C. The residue (linezolid oil) was co- distilled with 100 mL toluene to obtain 83 g Linezolid as a residue. The residue was cooled to room temperature and 300 mL toluene was added to it. The reaction mixture was heated at 50°C to 55°C for 3 hours and cooled to room temperature.
  • Linezolid (50 g) obtained in Example-5 and n-heptane (1 L) was heated at 105°C to 110°C for 4 hours in an autoclave.
  • the pressure of autoclave was set to 3 Kg with nitrogen pressure and reaction mixture was continuously stirred.
  • the reaction mixture was cooled to 25°C and nitrogen pressure was released.
  • the product thus obtained was filtered and washed with 100 mL n-heptane.
  • the wet-cake was dried in hot air oven at 65°C to 70°C to obtain 98 g (98%) linezolid crystalline form having purity by HPLC 99.9%.
  • Impurity profile Linezolid Amine (Not detected), Desflouro (0.04%), Linezolid Alcohol (Not detected), Linezolid Acetyl (Not detected). R-Isomer (Not detected) Form-II content: Not detected.
  • Example-7 Micronized linezolid (crystalline Form-I)
  • the sample was charged for stability at 40°C/75%RH.
  • the purity of micronized crystalline Form-I of linezolid was 99.9% by HPLC.
  • Linezolid crystalline Form-I was characterized by X- ray powder diffraction as shown in FIG 1, IR spectrum as shown in FIG.2 and DSC analysis as shown in FIG.3.
  • Linezolid (Example-6) with more than 99.95% enantiomeric purity, less than 0.05% of the R enantiomer, (10 grams) was mixed with ethyl acetate (100 mL) and heated to 60°C to 65°C with constant stirring. The linezolid was completely dissolved and the mixture was stirred for an additional 30 minutes. The temperature was maintained at 55°C in the flask and one neck of the flask is un-stoppered to allow slow evaporation of the solvent. A gentle stream of nitrogen is blown across the open neck to aid in evaporation. Solids spontaneously precipitated from solution and the volume is reduced by about 25% of the initial volume. The flask is sealed and mixed for 90 minutes while maintaining the mixture at 55°C.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une forme I cristalline stable de linézolide.
PCT/IN2012/000621 2011-09-19 2012-09-18 Procédé de préparation de linézolide cristallin WO2013072923A1 (fr)

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Cited By (5)

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CN104262280A (zh) * 2014-09-22 2015-01-07 山东华生化学股份有限公司 一种利奈唑酮的制备方法
CN104370847A (zh) * 2013-08-16 2015-02-25 浙江医药股份有限公司新昌制药厂 一种利奈唑胺晶型i的制备方法
WO2015068121A1 (fr) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Procédé pour la préparation de la forme cristalline i de linézolide et ses compositions
CN114163395A (zh) * 2021-12-07 2022-03-11 中国人民解放军空军军医大学 一类手性噁唑啉酮衍生物及合成方法及其在制备利奈唑胺和利伐沙班中的应用
CN116675685A (zh) * 2022-02-25 2023-09-01 东北农业大学 含吡啶联噁唑烷酮类化合物及其合成方法和应用

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CN104262280B (zh) * 2014-09-22 2016-07-20 山东华生化学股份有限公司 一种利奈唑酮的制备方法
CN114163395A (zh) * 2021-12-07 2022-03-11 中国人民解放军空军军医大学 一类手性噁唑啉酮衍生物及合成方法及其在制备利奈唑胺和利伐沙班中的应用
CN114163395B (zh) * 2021-12-07 2023-10-10 中国人民解放军空军军医大学 一类手性噁唑啉酮衍生物及合成方法及其在制备利奈唑胺和利伐沙班中的应用
CN116675685A (zh) * 2022-02-25 2023-09-01 东北农业大学 含吡啶联噁唑烷酮类化合物及其合成方法和应用

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