WO2005044824A2 - Procedes de preparation de cephalosporine de type 3-(2-substitue vinyle) de grande purete - Google Patents

Procedes de preparation de cephalosporine de type 3-(2-substitue vinyle) de grande purete Download PDF

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Publication number
WO2005044824A2
WO2005044824A2 PCT/IB2004/003571 IB2004003571W WO2005044824A2 WO 2005044824 A2 WO2005044824 A2 WO 2005044824A2 IB 2004003571 W IB2004003571 W IB 2004003571W WO 2005044824 A2 WO2005044824 A2 WO 2005044824A2
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Prior art keywords
cefditoren pivoxil
process according
organic solvent
mixture
acid
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PCT/IB2004/003571
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English (en)
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WO2005044824A3 (fr
Inventor
Yatendra Kumar
Mohan Prasad
Kaptan Singh
Ashok Prasad
Santosh Richhariya
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Ranbaxy Laboratories Limited
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Priority to EP04798757A priority Critical patent/EP1689755A2/fr
Priority to JP2006538976A priority patent/JP2007510709A/ja
Publication of WO2005044824A2 publication Critical patent/WO2005044824A2/fr
Publication of WO2005044824A3 publication Critical patent/WO2005044824A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to processes for preparing highly pure amorphous and crystalline forms of 3-(2-substituted vinyl) cephalosporin.
  • the present invention relates to processes for preparation of highly pure amorphous and crystalline forms of cefditoren pivoxil and pharmaceutical compositions comprising highly pure amorphous and crystalline forms of cefditoren pivoxil.
  • the present invention also relates to methods of treating infections using highly pure amorphous and crystalline forms of cefditoren pivoxil.
  • Cefditoren pivoxil of Formula I (also known as ME- 1207), which is a pivaloxymethyl
  • cefditoren also known as ME- 1206
  • ME- 1206 is a third generation cephalosporin derivative belonging to the class of 3-(2-substituted vinyl) cephalosporin, which was first developed by Meiji Seika of Japan with the aim of producing active cephalosporins with potent and broad-spectrum activity (U.S. Patent No. 4,839,350).
  • Cefditoren pivoxil is highly active, not only against a variety of gram-positive and gram-negative bacteria, but also against some resistant strains of bacteria.
  • Cefditoren pivoxil of Formula I is chemically known as [6R-[3(Z),6a,7b(Z)]]-7-[[(2-Amino-4- thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, pivaloyloxy-methyl ester.
  • U.S. Patent No. 4,839, 350 describes a process for preparing amorphous form of cefditoren pivoxil.
  • 6,342,493 describes a process for preparing orally administrable compositions that include particles composed of a homogeneous mixture of a crystallographically stable, amorphous, water soluble substance of cefditoren pivoxil and a water soluble high molecular weight polymer.
  • the process involves mixing crystalline cefditoren pivoxil and a water soluble, high molecular weight polymer in an acidic solution followed by basification of the acidic solution to precipitate a yellow-colored powdery composition that contains amorphous cefditoren pivoxil and high molecular weight polymer.
  • Many technical problems are believed to exist in this process, such as the need for strict production controls and requirements to carry out the operation.
  • Japanese Patent Application No. 2001-131071 A2 describes a process for preparing amo ⁇ hous cefditor ⁇ n pivoxil by precipitation, spray-drying, and freeze-drying. Also described is a process of converting crystalline cefditoren pivoxil to amorphous cefditoren pivoxil by milling. This process provides a product that has purity in the range of 93 to 98%. For precipitation, spray drying and freeze-drying, no particular form of cefditoren pivoxil is reported.
  • cefditoren pivoxil has negligible solubility at the specified volume in the given solvents, suggesting that it is the amorphous form of cefditoren pivoxil that is used for spray-drying, freeze-drying or precipitation.
  • highly pure amorphous and crystalline forms of cefditoren pivoxil produced by a simple, cost-effective process that is easily scalable to commercial level.
  • the cefditoren pivoxil has a purity greater than 98.5% and contains less than 1.0% of the E- isomer impurity and less than 1% of the ⁇ -isomer impurity.
  • Embodiments of the compound may include one or more of the following features.
  • the compound may be in amorphous form. In amorphous form, the compound may have a XRD pattern as depicted in Figure I.
  • the compound may be in a crystalline form. In the crystalline form, the compound may have a XRD pattern as depicted in Figure II.
  • a process for preparing crystalline cefditoren pivoxil from amorphous cefditoren pivoxil In another general aspect there is provided a process for preparing crystalline cefditoren pivoxil from amorphous cefditoren pivoxil.
  • the process includes (a)(i) adding amorphous cefditoren pivoxil to an organic solvent optionally containing water and/or (ii) adding an organic solvent optionally containing water to amorphous cefditoren pivoxil; (b) crystallizing the product from the reaction mixture; and (c) isolating crystalline cefditoren pivoxil.
  • the organic solvent may be one or more of an alcohol, a ketone, an ester, a cyclic ether, a nitrile, a glycol, a chlorinated hydrocarbon, or a mixture thereof.
  • the alcohol may be one or more of ethanol, methanol, isopropyl alcohol, n-butanol, iso-butanol, amyl alcohol or a mixture thereof.
  • the ester may be one or more of ethyl formate, methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate or a mixture thereof.
  • the ketone may be one or more of acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone or a mixture thereof.
  • the cyclic ether may be one or more of tetrahydrofuran, 1,4-dioxane or a mixture thereof.
  • the glycol may be one or more of propylene glycol, ethylene glycol or a mixture thereof.
  • the chlorinated hydrocarbon may be one or more of methylene chloride, ethylene chloride, chloroform or a mixture thereof.
  • the organic solvent may contain about 0.01 to about 50% by weight of water.
  • the reaction mixture may be stirred at a temperature of about -20°C to about 100°C to crystallize.
  • the crystallization temperature may be kept in the range of about 0°C to about 60°C.
  • the cefditoren pivoxil obtained may be highly pure cefditoren pivoxil having a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • a process for preparing an amorphous form of cefditoren pivoxil from crystalline cefditoren pivoxil includes: (a) dissolving crystalline cefditoren pivoxil in a first organic solvent; (b) adding a second organic solvent to the solution or adding the solution to the second organic solvent in optional order of succession to precipitate cefditoren pivoxil; and (c) isolating the amorphous cefditoren pivoxil from the reaction mixture.
  • the first organic solvent may be at least one water- immiscible or partially miscible solvent.
  • the at least one water-immiscible or partially miscible solvent may be an alcohol, a ketone, an ester, a chlorinated hydrocarbon or a mixture thereof.
  • the second organic solvent may be an alkyl ether, a hydrocarbon or a mixture thereof.
  • the cefditoren pivoxil obtained may be highly pure cefditoren pivoxil having a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the dissolution of crystalline cefditoren pivoxil in the first organic solvent maybe effected by initially dissolving crystalline cefditoren pivoxil in a third organic solvent.
  • the third organic solvent may be one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • a process for preparing an amorphous form of cefditoren pivoxil includes the steps of: (a) dissolving crystalline cefditoren pivoxil in a first organic solvent; (b) removing the first organic solvent from the reaction mixture; and (c) isolating the amorphous form of cefditoren pivoxil.
  • the first organic solvent may be at least one water- immiscible or partially miscible solvent.
  • the at least one water-immiscible or partially miscible solvent may be an alcohol, a ketone, an ester, a chlorinated hydrocarbon or a mixture thereof.
  • the process may further include applying heating to dissolve the crystalline form in the first organic solvent.
  • the first organic solvent may be removed under reduced pressure.
  • the first organic solvent may be removed by spray-drying the solution of crystalline cefditoren pivoxil.
  • the cefditoren pivoxil obtained may be highly pure cefditoren pivoxil having a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ -isomer impurity is less than 1%.
  • a process for preparing a highly pure amorphous form of cefditoren pivoxil from crystalline form includes the steps of: (a) dissolving a crystalline form of cefditoren pivoxil in an organic solvent optionally containing water; and (b) freeze drying or lyophilizing the solution to get highly pure amo ⁇ hous form of cefditoren pivoxil.
  • the cefditoren pivoxil obtained is highly pure cefditoren pivoxil and has a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the organic solvent may be at least one water- immiscible or partially miscible solvent.
  • the at least one water-immiscible or partially miscible solvent may be an alcohol, a ketone, an ester, a chlorinated hydrocarbon or a mixture thereof.
  • the process may further include applying heating to dissolve the crystalline form in the organic solvent.
  • a process for preparing a highly pure amo ⁇ hous form of cefditoren pivoxil from crystalline form includes the steps of: (a) dissolving the crystalline cefditoren pivoxil in an acid, optionally in the presence of a water miscible organic solvent; (b) adding water to the solution in an amount sufficient to precipitate the cefditoren pivoxil from the solution; and (c) isolating the highly pure amo ⁇ hous cefditoren pivoxil from the solution.
  • the cefditoren pivoxil obtained is highly pure cefditoren pivoxil and has a purity greater than 98.5%, the E- isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the acid may be at least one of an organic acid or an inorganic acid.
  • the organic acid may be one or more of Cl-12 alkyl or aryl carboxylic acids, Cl-10 alkyl or aryl sulphonic acids or a mixture thereof.
  • the Cl-10 alkyl or aryl carboxylic acid may be one or more of formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, benzoic acid, mono-, di- or trisubstituted benzoic acids, phenyl acetic acid, substituted phenyl acetic acid or a mixture thereof.
  • the Cl-12 alkyl or aryl sulphonic acid may be one or more of methanesulphonic acid, p-toluenesulphonic acid, benzenesulphonic acid or a mixture thereof.
  • the inorganic acid may be one or more of hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid or a mixture thereof.
  • the acid may contains a water miscible organic solvent.
  • the water miscible organic solvent may be one or more of dimethylformamide, dimethylacetamide, tetrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • the mixture of amo ⁇ hous and crystalline form of cefditoren pivoxil is prepared directly from the reaction mixture, from the crystalline form or from the amo ⁇ hous form of cefditoren pivoxil and the cefditoren pivoxil obtained is highly pure cefditoren pivoxil and has a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • Embodiments of this process may include one or more of the features described above.
  • a pharmaceutical composition that includes a highly pure amo ⁇ hous or crystalline form of cefditoren pivoxil and a pharmaceutically acceptable carrier.
  • the cefditoren pivoxil is highly pure cefditoren pivoxil and has a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 - isomer impurity is less than 1%.
  • a method of treating infections caused by gram positive, gram negative and resistant strains of bacteria includes administering to a mammalian host in need thereof a therapeutically effective amount of the highly pure amo ⁇ hous or crystalline form of cefditoren pivoxil.
  • the cefditoren pivoxil is highly pure cefditoren pivoxil and has a purity greater than 98.5%, the E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. For example, some of the reactions described herein can be characterized as one pot reactions.
  • List of Figures Figure I is an X-ray powder diffraction (XRD) pattern of highly pure amo ⁇ hous form of cefditoren pivoxil.
  • Figure II is an X-ray powder diffraction (XRD) pattern of highly pure crystalline form of cefditoren pivoxil.
  • Figure III is an X-ray powder diffraction (XRD) pattern of a mixture of highly pure crystalline and amo ⁇ hous cefditoren pivoxil.
  • the present invention provides highly pure amo ⁇ hous cefditoren pivoxil having purity greater than 98.5% and containing less than 1.0% of the unwanted E-isomer impurity and less than 1% of the ⁇ 2 -isomer impurity.
  • Figure I shows an XRD pattern of the amo ⁇ hous form of cefditoren pivoxil.
  • highly pure cefditoren pivoxil refers to cefditoren pivoxil in amo ⁇ hous or crystalline form having purity not less than 98.5% and containing less than 1.0% of the E-isomer impurity and less than 1% of the ⁇ 2 -isomer impurity. More preferably the purity is not less than 99.0% which has less than 0.5% of E-isomer impurity and less than 0.5% of ⁇ -isomer impurity.
  • highly pure cefditoren pivoxil refers to cefditoren pivoxil having purity not less than 99.20% and containing less than 0.1% of E-isomer impurity and less than 0.5% of ⁇ 2 -isomer impurity.
  • the present invention also provides a highly pure crystalline cefditoren pivoxil having purity greater than 98.5% and containing less than 1.0% of the unwanted E-isomer impurity and less than 1% of the ⁇ -isomer impurity.
  • Figure II shows an XRD pattern of the crystalline form.
  • the present invention further provides an efficient, one-step process for preparing a crystalline form of cefditoren pivoxil from amo ⁇ hous cefditoren pivoxil.
  • the process includes the steps of: a) adding amo ⁇ hous cefditoren pivoxil to an organic solvent optionally containing water; b) crystallizing the product from the reaction mixture; and c) isolating crystalline cefditoren pivoxil.
  • Amo ⁇ hous cefditoren pivoxil can be prepared according to the process described in copending PCT Application No. PCT/LB2004/002648, which is inco ⁇ orated by reference herein in its entirety.
  • the amo ⁇ hous material can be added to an organic solvent optionally containing water or, alternatively, the organic solvent with optional water can be added to the amo ⁇ hous material in an optional order of succession.
  • the resultant reaction mixture thereafter can be stirred at a temperature of about -20 °C to about 100 °C to complete crystallization.
  • the crystalline material can be isolated from the reaction mixture by conventional methods known to one of ordinary skill in the art.
  • the obtained crystalline form of cefditoren pivoxil typically exhibits an XRD pattern as depicted in Figure II.
  • Organic solvents used in preparing crystalline cefditoren pivoxil can be, for example, ethanol, methanol, isopropyl alcohol, n-butanol, iso-butanol, amyl alcohol, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, 1,4- dioxane, propylene glycol, ethylene glycol, methylene chloride, ethylene chloride, chloroform or mixtures thereof.
  • the solvent can contain up to about 0.01 % to about 50 % by weight of water. Typically, the crystallization temperature can be kept between about 0 °C to 60 °C.
  • the isolated crystalline cefditoren pivoxil then can be optionally dried under vacuum to get highly pure cefditoren pivoxil having a purity greater than 98.5%, wherein the unwanted E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the present invention also encompasses a process for preparing a highly pure amo ⁇ hous form of cefditoren pivoxil from crystalline cefditoren pivoxil.
  • the process includes the steps of: a) dissolving crystalline cefditoren pivoxil in a first organic solvent; b) adding a second organic solvent to the solution or adding the solution to the second organic solvent, in optional order of succession, to precipitate cefditoren pivoxil; and c) isolating the amo ⁇ hous cefditoren pivoxil from the reaction mixture.
  • the first organic solvent can be a water-immiscible or partially miscible solvent, including, for example, iso-butanol, n-butanol, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone, methylene chloride, ethylene chloride, chloroform or a mixture thereof.
  • a water-immiscible or partially miscible solvent including, for example, iso-butanol, n-butanol, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone, methylene chloride, ethylene chloride,
  • the second organic solvent can be, for example, diisopropyl ether, diethyl ether, toluene, xylene, heptane, hexane, cyclohexane, cycloheptane, petroleum ether or a mixtures thereof.
  • common techniques for example, seeding with amo ⁇ hous material or cooling the reaction mass, also can be effectively utilized.
  • the precipitated product then can be isolated from the reaction mass and dried under vacuum to get amo ⁇ hous form of cefditoren pivoxil having purity greater than 98.5%, wherein the unwanted E-isomer is less than 1.0% and the ⁇ 2 -isomer impurity is less than 1%.
  • the dissolution of crystalline cefditoren pivoxil in the first organic solvent can be effected by initially dissolving crystalline cefditoren pivoxil in a third organic solvent, for example, dimethylformamide, dimethylacetamide, tefrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof. Water and a first organic solvent then can be added to this solution in optional order of succession to obtain a biphasic solution. The organic layer can be separated and washed successively with water to remove the traces of the third organic solvent.
  • a third organic solvent for example, dimethylformamide, dimethylacetamide, tefrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • Water and a first organic solvent then can be added
  • a solution of crystalline cefditoren pivoxil in first organic solvent can thus be effectively prepared.
  • the present invention also encompasses a process for preparing a highly pure amo ⁇ hous form of cefditoren pivoxil in a method that include the steps of: a) dissolving crystalline cefditoren pivoxil in a first organic solvent; b) removing the solvent from the reaction mixture; and c) isolating amo ⁇ hous form of cefditoren pivoxil.
  • the first organic solvent can be a water-immiscible or partially miscible solvent, for example, iso-butanol, n-butanol, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone, methylene chloride, ethylene chloride, chloroform or a mixture thereof. If required, optional heating can be utilized to dissolve the crystalline form completely in the first organic solvent.
  • Dissolution of crystalline cefditoren pivoxil in a first organic solvent can be effected by initially dissolving crystalline cefditoren pivoxil in a second organic solvent, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof. Water and the first organic solvent then can be added to this solution in optional order of succession to obtain a biphasic solution. The organic layer can be separated and washed successively with water to remove the traces of the second organic solvent.
  • a second organic solvent for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • Water and the first organic solvent then can be added to this solution in optional order
  • a solution of crystalline cefditoren pivoxil in a first organic solvent can thus be effectively prepared.
  • the solvent can be concentrated under vacuum of about 100 mm to about 0.01 mm of Hg. h particular, the solvent can be removed by vacuum distillation of the solution with optional heating at a temperature of about 0 °C to 100 °C to effect faster removal of the solvent.
  • the solvent can also be removed by spray-drying the solution of crystalline cefditoren pivoxil using a spray-dryer.
  • a suitable spray dryer is the mini-spray Dryer (Model: Buchi 190 Switzerland), which operates on the principle of nozzle spraying in a parallel flow, i.e., the product is sprayed in the same direction as the drying gas flow.
  • the drying gas can be air or inert gases, for example, nitrogen, argon or carbon dioxide.
  • the drying gas is nitrogen.
  • the present invention also provides a process for preparing a highly pure amo ⁇ hous form of cefditoren pivoxil from crystalline form using the following steps: a) dissolving a crystalline form of cefditoren pivoxil in an organic solvent optionally containing water; and b) freeze drying or lyophilizing the solution to obtain a highly pure amo ⁇ hous form of cefditoren pivoxil.
  • a solution of crystalline cefditoren pivoxil in organic solvent optionally containing water is prepared as described above.
  • dissolution of crystalline cefditoren pivoxil in a suitable organic solvent can be effected by initially dissolving crystalline cefditoren pivoxil in a second organic solvent, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • Water and the suitable organic solvent can be added to this solution in optional order of succession to obtain a biphasic solution.
  • the organic layer can be separated and washed successively with water to remove the traces of the second organic solvent.
  • a solution of crystalline cefditoren pivoxil in a suitable organic solvent can thus be effectively prepared.
  • the solution of cefditoren pivoxil then is freeze-dried by conventional techniques to obtain the amo ⁇ hous cefditoren pivoxil.
  • the amo ⁇ hous form can then be dried under vacuum.
  • Another aspect of the invention encompasses a process for preparing highly pure amo ⁇ hous form of cefditoren pivoxil from the crystalline form of cefditoren pivoxil.
  • This process includes the following steps: a) dissolving crystalline cefditoren pivoxil in an acid, optionally in presence of a water miscible organic solvent; b) adding water to the solution, sufficient to precipitate cefditoren pivoxil out from the solution; and c) isolating highly pure amo ⁇ hous cefditoren pivoxil from the solution.
  • Crystalline cefditoren pivoxil can be dissolved in an acid optionally containing a water-miscible organic solvent to form a clear solution.
  • the solution optionally can be treated with charcoal or clarified or filtered to remove foreign particulate matter.
  • the solution also can be obtained by gently warming the mixture.
  • Water can be added to the solution at a rate sufficient to slowly precipitate the cefditoren pivoxil. After complete addition of water, the mixture can be chilled or partially concentrated to remove the organic solvent. The separated amo ⁇ hous form can then be filtered and dried as per the methods described earlier.
  • the acid can be an organic acid, for example, of C 1-1 alkyl or aryl carboxylic acids, or C O alkyl or aryl sulphonic acids (e.g., formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, benzoic acid, mono or di or tri substituted benzoic acids, phenyl acetic acid, substituted phenyl acetic acid, methanesulphonic acid, p-toluenesulphonic acid, benzenesulphonic acid and the like) or a mixture thereof.
  • the acid can be an inorganic acid, for example, hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid and the like, or a mixture thereof.
  • the water miscible organic solvent can be, for example, dimethylformamide, dimethylacetamide, tefrahydrofuran, 1,4-dioxane, methanol, acetone, acetonitrile, ethanol, isopropanol or a mixture thereof.
  • the present invention also provides a process for converting a mixture of amo ⁇ hous and crystalline forms of cefditoren pivoxil to a highly pure amo ⁇ hous form of cefditoren pivoxil.
  • a mixture of the amo ⁇ hous and the crystalline forms of cefditoren pivoxil can be prepared directly from the reaction mixture or from the crystalline form or from the amo ⁇ hous form of cefditoren pivoxil by the process already described in the specification with little variations in reaction temperature, quantity of solvent, reaction time, spray-drying temperature, flow rate of inert gas during spray-drying and the like.
  • the mixture of amo ⁇ hous and crystalline cefditoren pivoxil is then converted to the amo ⁇ hous form by any of the techniques already described in the above embodiments.
  • the present invention also relates to pharmaceutical compositions and dosage forms that include one or more highly pure amo ⁇ hous and/or crystalline forms of cefditoren pivoxil.
  • Such pharmaceutical compositions can be used as an antibacterial in the treatment of infections caused by gram positive, gram negative and resistant strains of bacteria.
  • the pharmaceutical compositions of the present invention also can contain a pharmaceutically acceptable carrier.
  • the invention also relates to methods of treating infections caused by gram positive, gram negative and resistant strains of bacteria. The methods include administering to a mammalian host in need thereof a therapeutically effective amount of one or more highly pure amo ⁇ hous and/or crystalline forms of cefditoren pivoxil. Provided below are illustrative examples of the inventions described herein.
  • Examples EXAMPLE 1 PREPARATION OF CEFDITOREN PIVOXIL (FORMULA T) Iodomethyl pivalate (10 g) was added in one lot to a stirred mixture of cefditoren sodium (20 g) in DMF (120 mL) at -15 °C. The reaction mixture was stirred at about -10 °C to -15 °C for 60 min. Subsequently, the reaction mixture was quenched by pouring the reaction mixture into a solvent mixture of deionized water and ethyl acetate.
  • ⁇ 2 -isomer 0.76% rR in KBr (cm -l): 2974, 2934, 1787, 1752, 1678, 1534, and 1369.
  • EXAMPLE 2 PREPARATION OF CRYSTALLINE CEFDITOREN PIVOXIL Denatured spirit (150 mL) was added to the product obtained in Example 1 (15 g) and the heterogeneous mixture was stirred at about 30 °C to about 35 °C for about 2-3 hrs until crystallization was complete. The product was filtered under reduced pressure and dried under vacuum to yield crystalline cefditoren pivoxil.
  • EXAMPLE 3 PREPARATION OF CRYSTALLINE CEFDITOREN PIVOXIL
  • the product obtained in Example 1 (2.0 g) was suspended in aqueous ethanol (90% v/v, 20 mL) at about 30-32 °C for 3.0 hrs to complete crystallization.
  • the crystalline product was filtered and washed with aqueous ethanol (90%v/v, 5 mL) and dried at about 35-40 °C under vacuum to yield crystalline cefditoren pivoxil.
  • EXAMPLE 5 PREPARATION OF AMORPHOUS CEFDITOREN PTVOXIL FROM CRYSTALLINE CEFDITOREN PTVOXIL Crystalline cefditoren pivoxil (20.0 g) was dissolved in DMF (100 mL) at ambient temperature. This solution was added to a pre-cooled mixture of ethyl acetate (600 mL) and water (400 mL) at about 5-10 °C. The resultant mixture was stirred for about 10-15 minutes and the layers were separated.
  • EXAMPLE 7 PREPARATION OF AMORPHOUS CEFDITOREN PTVOXIL FROM CRYSTALLINE CEFDITOREN PTVOXIL
  • Step A Preparation of mixture of crystalline and amo ⁇ hous cefditoren pivoxil from crystalline cefditoren pivoxil
  • Crystalline cefditoren pivoxil (2.0 g) was dissolved in acetic acid (4.0 mL) at ambient temperature. This solution was added to pre-cooled water (60 mL) at about 5- 10°C. The resultant mixture was stirred for about 10 to 15 minutes at about 5-10 °C. The separated solids were filtered and washed with a copious amount of water. The product was then dried to yield a mixture of crystalline and amo ⁇ hous cefditoren pivoxil (1.7 g).
  • Step B Conversion of mixture of crystalline and amo ⁇ hous cefditoren pivoxil to amo ⁇ hous cefditoren pivoxil
  • DMF dimethyl methyl acetate
  • ethyl acetate 50 mL
  • water 35 mL
  • the resultant mixture was stirred for about 10 to 15 minutes and the layers were separated.
  • the organic layer obtained was subjected to spray drying using a mini spray-dryer (Buchi Model 190) at an inlet temperature of about 75 °C and an outlet temperature of about 55 °C with a feed rate of 15 mL per minute.
  • Cefditoren pivoxil (1.45 g) was thus obtained in an amo ⁇ hous form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention se rapporte à un procédé de préparation de formes amorphes et cristallines de cefditoren pivoxil de grande pureté, et à des compositions pharmaceutiques comportant des formes amorphes et cristallines de cefditoren pivoxil de grande pureté. La présente invention se rapporte également à un procédé de traitement d'infections à l'aide de formes amorphes et cristallines de cefditoren pivoxil de grande pureté. Le cefditoren pivoxil de grande pureté présente une pureté supérieure à 98,5 % et renferme moins de 1,0 % d'impuretés de type isomère E et moins de 1 % d'impuretés de type isomère ?2.
PCT/IB2004/003571 2003-11-07 2004-11-01 Procedes de preparation de cephalosporine de type 3-(2-substitue vinyle) de grande purete WO2005044824A2 (fr)

Priority Applications (2)

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EP04798757A EP1689755A2 (fr) 2003-11-07 2004-11-01 Procedes de preparation de cephalosporine de type 3-(2-substitue vinyle) de grande purete
JP2006538976A JP2007510709A (ja) 2003-11-07 2004-11-01 高純度３−（２−置換ビニル）セファロスポリンの製法

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IN1368/DEL/2003 2003-11-07
IN1368DE2003 2003-11-07

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WO2005044824A3 WO2005044824A3 (fr) 2005-07-14

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Cited By (5)

* Cited by examiner, † Cited by third party
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WO2006024900A1 (fr) * 2004-08-31 2006-03-09 Ranbaxy Laboratories Limited Cefditoren pivoxil de grande purete
EP1954653A2 (fr) * 2005-11-23 2008-08-13 Merck & Co., Inc. Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
US7459550B2 (en) 2003-07-04 2008-12-02 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of Cefditoren
WO2014189308A1 (fr) * 2013-05-23 2014-11-27 영진약품공업 주식회사 Nouvelle forme cristalline du cefditoren pivoxil, et son procédé de préparation
CN107422056A (zh) * 2017-08-17 2017-12-01 山东裕欣药业有限公司 一种特戊酸碘甲酯的气相色谱检测方法及其制备方法

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CN101560216B (zh) * 2009-05-27 2011-06-15 上海交通大学 头孢妥仑酯的制备方法
CN106117244B (zh) * 2016-06-24 2018-10-19 瑞阳制药有限公司 头孢妥仑匹酯的精制方法
CN106243128B (zh) * 2016-07-30 2018-09-04 济南康和医药科技有限公司 一种头孢妥仑匹酯的精制方法
CN109053768A (zh) * 2018-08-07 2018-12-21 中国医药集团总公司四川抗菌素工业研究所 一种无定型头孢妥仑酯的制备方法
CN109336904B (zh) * 2018-11-21 2020-06-09 山东罗欣药业集团股份有限公司 一种头孢妥仑匹酯的制备方法
CN110251467A (zh) * 2019-06-26 2019-09-20 北京济美堂医药研究有限公司 一种无定形态头孢妥仑匹酯组合物的制备方法

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EP1051978A1 (fr) * 1998-01-07 2000-11-15 Meiji Seika Kaisha, Ltd. Compositions de cephalosporine amorphes, stables du point de vue cristallographique et procede de preparation de ces compositions
JP2001131071A (ja) * 1999-10-29 2001-05-15 Meiji Seika Kaisha Ltd 非晶質および非晶質を含有する医薬組成物

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459550B2 (en) 2003-07-04 2008-12-02 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of Cefditoren
WO2006024900A1 (fr) * 2004-08-31 2006-03-09 Ranbaxy Laboratories Limited Cefditoren pivoxil de grande purete
EP1954653A2 (fr) * 2005-11-23 2008-08-13 Merck & Co., Inc. Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
EP1954653A4 (fr) * 2005-11-23 2010-11-03 Merck Sharp & Dohme Procede de generation de solide amorphe pour agents pharmaceutiques insolubles dans l'eau
WO2014189308A1 (fr) * 2013-05-23 2014-11-27 영진약품공업 주식회사 Nouvelle forme cristalline du cefditoren pivoxil, et son procédé de préparation
KR101561963B1 (ko) * 2013-05-23 2015-10-22 영진약품공업 주식회사 세프디토렌 피복실의 신규 결정 형태 및 이의 제조 방법
CN107422056A (zh) * 2017-08-17 2017-12-01 山东裕欣药业有限公司 一种特戊酸碘甲酯的气相色谱检测方法及其制备方法
CN107422056B (zh) * 2017-08-17 2020-04-24 山东裕欣药业有限公司 一种特戊酸碘甲酯的气相色谱检测方法及其制备方法

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AR046229A1 (es) 2005-11-30

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