EP1660505A2 - Procede de preparation selective de l'isomere z de cedfitorene et de ses sels et esters pharmaceutiquement acceptables - Google Patents

Procede de preparation selective de l'isomere z de cedfitorene et de ses sels et esters pharmaceutiquement acceptables

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Publication number
EP1660505A2
EP1660505A2 EP04744275A EP04744275A EP1660505A2 EP 1660505 A2 EP1660505 A2 EP 1660505A2 EP 04744275 A EP04744275 A EP 04744275A EP 04744275 A EP04744275 A EP 04744275A EP 1660505 A2 EP1660505 A2 EP 1660505A2
Authority
EP
European Patent Office
Prior art keywords
formula
cefditoren
compound
process according
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04744275A
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German (de)
English (en)
Inventor
Yatendra Kumar
Mohan Prasad
Kaptan Singh
Ashok Prasad
Santosh Richhariya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1660505A2 publication Critical patent/EP1660505A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • cefditoren pivoxil is a third generation cephalosporin developed with an aim of producing active cephalosporins with potent and broad-spectrum activity (European Patent No. 175610).
  • 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.
  • FORMULA la European Patent No. 175610 describes a process for preparation of cefditoren and its pharmaceutically acceptable salts and esters. The process described is non-selective and gives more than 20% of unwanted E-isomer, which is then separated by means of column chromatography. The yield of cefditoren or its sodium salt or its pivaloxymethyl ester is reported to be very low.
  • U.S. Patent No. 6,288,223 describes a process for the selective preparation of the Z-isomer of 3-2 (substituted vinyl)cephalosporins. The process described uses stringent conditions for deprotection of the protected amino and carboxyl functionalities. The process isolates every intermediate followed by its purification and therefore is very time consuming and expensive.
  • U.S. Patent No. 5,616,703 describes a process for separation of cephalosporin isomers by forming aminp salts. The process described therein produces the intermediates in which the unwanted E isomer is more than 20%, which is then depleted by forming amine salts. In this process the yield of the intermediate is diminished and the unwanted E- isomer discarded after separation.
  • 7-ATCA 7-amino-3-[(4-methylthiazol-5-yl)vinyl]-3- cephem-4-carboxylic acid
  • Z-enriched 7-ATCA of Formula IX having less than 2% of unwanted E-isomer obtained without carrying out purification steps.
  • crystalline hydrates of sodium and potassium salts of cefditoren having specific XRD pattern exemplified in Figure 1 and Figure 2.
  • a process for preparation of 7-ATCA of Formula IX from 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (hereinafter referred to as PCMCC esters) of Formula II wherein the process can be carried out in single reaction vessel without the need to isolate any intermediate.
  • esters of PCMCC of Formula II such as p-methoxybenzyl ester (hereinafter referred to as GCLE) or diphenylmethyl ester are treated with an alkali or alkaline earth metal halide, such as an iodide or bromide, and a phosphorous-containing compound of Formula III which is P(YR) n , wherein Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R can be to C straight or branched chain alkyl, alkenyl, allcynyl or C 6 to Cio aryl or aralkyl in an organic solvent to get intermediate phosphonium salt of Formula IN, which is reacted in-situ with an organic or inorganic base to get an ylide of Formula N.
  • GCLE p-methoxybenzyl ester
  • diphenylmethyl ester diphenylmethyl ester
  • FORMULA IX In a second step, 7-ATCA is treated with optionally 2-amino protected, activated esters of 2-methoxyimino-2-(2-aminothiazole-4-yl)acetic acid of Formula X, wherein Z can be substituents of Formula Xa, Xb, Xc, Xd and R e is monovalent or divalent amino protecting group such as trityl (triphenylmethyl), acetyl, benzhydryl or acetamidophenyl, R can be Ci to C 7 straight or branched chain alkyl, alkenyl, alkynyl or C 6 to do aryl or aral yl; Ri is C ⁇ - 6 straight or branched chain alkyl, cycloalkyl, aryl, aralkyl or a heterocycle residue, in the presence of an organic solvent and a base to get cefditoren acid, which can be converted to its sodium salt of Formula lb.
  • the first step of preparation of 7-ATCA having less than 1% of unwanted E- isomer includes five operations (i) through (v), which are carried out in-situ without isolating any intermediate.
  • PCMCC ester of Formula II is treated with alkali or alkaline earth metal halide, such as iodide or bromide, and a phosphorous-containing compound of Formula III in organic solvent optionally containing water, at a temperature of about -10 to about 50°C.
  • alkali or alkaline earth metal halide such as iodide or bromide
  • a phosphorous-containing compound of Formula III in organic solvent optionally containing water, at a temperature of about -10 to about 50°C.
  • the molar ratio of alkali or alkaline earth metal halide and compound of Formula III used can be selected in the range of from about 0.98 to about 1J5 per mole of Formula II.
  • the organic solvent can be selected from, for example, chlorinated hydrocarbons such as methylene chloride, chloroform, ethylene chloride or ethylene bromide; ethers such as tetrahydrofuran, diisopropyl ether, 1,4-dioxane or diethyl ether; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; and lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol or mixtures thereof.
  • chlorinated hydrocarbons such as methylene chloride, chloroform, ethylene chloride or ethylene bromide
  • ethers such as tetrahydrofuran, diisopropyl ether, 1,4-dioxane or diethyl ether
  • ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone
  • lower alcohols such as
  • the base used in this step can be an inorganic compound such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or organic salts such as sodium methoxide, potassium t-butoxide, sodium ethoxide, or organic ammonium compounds such as triethylamine, dicyclohexylamine or diphenylamine.
  • the organic layer can be separated from the aqueous layer and dried over anhydrous sodium sulphate, magnesium sulphate or a suitable drying agent known to a person skilled in the art. After adjusting the volume of the organic layer with solvent used earlier, it can be used as such in (iii). In (iii), to the organic layer obtained in (ii) which contains a solution of ylide of
  • the ratio of chlorinated hydrocarbon to lower alkanol can vary from about 1:1 to about 1:0.25.
  • the above reaction mass containing a mixture of solvents in the mentioned ratio- containing product of step (ii) is cooled to about -50 to about -5°C and to it added 4- methylthiazole-5-carboxaldehyde of Formula NI.
  • the reaction mixture is stirred for 15 to 35 hours at about -50 to about 30°C.
  • it is quenched by addition of water, followed by washing of the organic layer with sodium bisulphite solution to reduce aldehydic and related impurities generated during the reaction.
  • DPTC of Formula Nil is treated with a phenol or its ether for deprotection of the carboxyl-protecting group at a temperature of about 0 to about 100°C.
  • the reaction can be carried out in presence of an organic solvent such as lower alkanol, chlorinated hydrocarbon or acetone. However, the reaction can be carried out without using any solvent.
  • a phenol or its ether can be, for example, anisole, 2-cresol, 3-cresol, 4-cresol, resorcinol, catechol, 2-mercapto ⁇ henol, 3-mercaptophenol, and 2-methoxyphenol.
  • an acid catalyst which can be selected from a group comprising trifluoroacetic acid, formic acid or Lewis acids such as aluminium chloride, boron trifluoride, and anhydrous zinc chloride can be used.
  • n-butyl acetate can be added to the reaction mixture and the organic layer can be extracted with sodium bicarbonate solution.
  • the sodium salt of the product is extracted in the aqueous layer, which after separating the layers is washed with n-butyl acetate to remove traces of deprotecting agent.
  • the aqueous layer obtained above can be used as such in the next operation without isolating the product, MPTC of Formula NIII.
  • Deprotection of an amino group is a well-known art in the field of, for example, production and purification of penicillins and cephalosporins. Deprotection mostly involves deacylation, for which several processes are available (European Patent No. 175610, PCT patent application WO 02/18618, US patent application 20020006642 and US patent application 20020058302).
  • dichloromethane can be added to quench the reaction and the layers can be separated.
  • the aqueous layer can be acidified to adjust the pH between about 4.5 to about 5.
  • Cefditoren acid of Formula I can precipitate, and which can be filtered and purified using a solvent or by column chromatography.
  • acetone and sodium 2-ethylhexanoate at a temperature of about 15 to about 30°C to produce a sodium salt of cefditoren.
  • the sodium salt can precipitate from the reaction mass as crystalline solid.
  • acetone can be optionally added to the reaction mass and the product can be filtered.
  • the sodium salt of cefditoren thus obtained can have an HPLC purity above 98% wherein the E-isomer as determined by HPLC can be less than or equal to 1%.
  • the crystalline sodium salt can have up to about 6.5 to about 7% moisture, which suggests that it could be a novel dihydrate of the cefditoren sodium.
  • a potassium salt of cefditoren can be prepared from cefditoren acid.
  • the potassium salt can contain up to about 6 to about 7% intrinsic moisture, which suggests that it is in dihydrate form.
  • cefditoren acid such as calcium, magnesium, zinc, copper, nickel, manganese, rubidium, cobalt, strontium and the like can be prepared using appropriate salt-forming agents known to a person skilled in the art.
  • These crystalline forms of cefditoren salts can be very good candidates for development of parenteral dosage forms of cefditoren owing to their high solubilities and stabilities in aqueous conditions.
  • the sodium or potassium salt of cefditoren or cefditoren acid can be dissolved in an organic solvent and reacted with halomethyl pivalate of Formula XI wherein the halo group is chloro or bromo or iodo, at a temperature of about -25 to about 35°C.
  • cefditoren pivoxil is obtained by a suitable aqueous work-up followed by extraction with organic solvent. Any organic solvent may be used for extraction which is known to a person of ordinary skill in the art.
  • the solution of cefditoren pivoxil in organic solvent is partially concentrated by evaporation of solvent under vacuum.
  • the product can be then precipitated from the concentrated solution by addition of an anti-solvent selected from, for example, n-hexane, diethyl ether, diisopropyl ether, cyclohexane and cycloheptane.
  • an anti-solvent selected from, for example, n-hexane, diethyl ether, diisopropyl ether, cyclohexane and cycloheptane.
  • the precipitated product is then filtered and can be purified by further crystallization or by column chromatography using hexane-ethyl acetate as eluent.
  • the compound of Formula XI can be selected from, for example, iodomethyl pivalate, bromomethyl pivalate, chloromethyl pivalate.
  • the organic solvents can be selected from, for example, dimethylformamide, dimethylacetamide, dimethylsulphoxide, tetrahydrofuran, 1,4-dioxane. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • Example 1 Preparation of 7-ATCA To a stirred mixture of 4-methoxybenzyl 3-(chloromethyl)-8-oxo-7- [(phenylacetyl)amino]-5-thia-l-azabicyclo[4J.0]oct-2-ene-2-carboxylate (10 g, 20.5 mmol) in 60 ml of water and 60 ml of chloroform, was added sodium iodide (3.23 g, 21.5 mmol) and triphenyl phosphine (5.65 g, 21.5 mmol). The heterogeneous mixture was stirred at 25 - 30°C for 3 hrs. The bottom organic layer was separated and cooled to 0 - 5°C.
  • Reaction mixture was stirred for 20- 24 hours at -10 to -15°C after end of which it was quenched by addition of water (100 ml) followed by washing of organic layer with sodium bisulfite solution. Organic layer was concentrated under reduced pressure to get a brown coloured residue. Phenol (50 ml) was added to the residue to get a clear solution. This solution was stirred at 40-50°C for 10-12 hours and n-butyl acetate (100 ml) was added to the reaction mass followed by cooling to 5-10°C. Organic portion was extracted with sodium bicarbonate solution (0J7 Molar, 2 x 100 ml).
  • Example 2A Preparation of Cefditoren Sodium A suspension of 7-ATCA of Formula IX (5.0 g, 15.4 mmol) and S-(l,3- benzothiazol-2-yl)-(2-amino-lJ-thiazol-4-yl)(methoxyimino)ethanethioate (6.1 g, 18.6 mmol) in aqueous THF (60 ml) was stirred at 0 - 5°C. Triethylamine (2.3 ml) was added slowly at 0-5 °C over 15-20 minutes. The mixture was stirred at 0-5 °C for 2-3 hours. Reaction was quenched by addition of dichloromethane followed by layer separation.
  • Aqueous layer was diluted with acetone to 50 ml.
  • Sodium 2-ethylhexanoate (3.3 g, 19.8 mmol) was added to aqueous acetone solution at 20-25°C.
  • acetone 50 ml slowly to the reaction mass in order to complete crystallization. Filtered the crystallized product under suction and washed with acetone (2 x 10 ml). Product was vacuum dried to get 6.5 g of off-white title compound in 75% yield.
  • Example 2B Preparation of Cefditoren Potassium A suspension of 7-ATCA (1.0 g, 3.09 mmol) and S-(l,3-benzothiazol-2-yl)-(2- amino-lJ-thiazol-4-yl)(methoxyimino)ethanethioate (1J4 g, 3.82 mmol) in aqueous tetrahydrofuran (12 ml) was stirred at 0 - 5°C. Triethylamine (0.34 g) in THF (1.0 ml) was added slowly at 0 - 5°C over 15 - 20 min. The mixture was stirred at 0 - 5°C for 2 - 3 hrs.
  • Example 3 Preparation of Cefditoren Pivoxil To a stirred mixture of cefditoren sodium (20 g) in dimethylformamide (120 ml) at- 15°C, iodomethyl pivalate (10 g) was added in one lot. Reaction mixture was stirred at -10 to -15°C for 60 min. Subsequently it was quenched by pouring reaction mixture in de- ionized water and ethyl acetate. Ethyl acetate layer was washed sequentially by water, 0.5% NaHCO 3 and 0.1% HC1 and finally by water. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure till residual volume is about 120 ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne un procédé sélectif de préparation de l'isomère Z de cefditorène de formule I et de ses sels et esters pharmaceutiquement acceptables. Le cefditorène possède un large spectre d'activité anti-bactérienne contre les bactéries gram positif et gram négatif.
EP04744275A 2003-08-14 2004-08-13 Procede de preparation selective de l'isomere z de cedfitorene et de ses sels et esters pharmaceutiquement acceptables Withdrawn EP1660505A2 (fr)

Applications Claiming Priority (2)

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IN1004DE2003 2003-08-14
PCT/IB2004/002648 WO2005016936A2 (fr) 2003-08-14 2004-08-13 Procede de preparation selective de l'isomere z de cedfitorene et de ses sels et esters pharmaceutiquement acceptables

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Families Citing this family (12)

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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
WO2005100369A1 (fr) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Depletion d'e-isomeres dans la preparation de cephalosporines (vinyle susbstitue en 2)-3 enrichies en z
JP4064948B2 (ja) 2004-06-04 2008-03-19 明治製菓株式会社 ３−アルケニルセフェム化合物及び製造方法
JPWO2011093294A1 (ja) * 2010-01-27 2013-06-06 日本化学工業株式会社 セファロスポリン誘導体の製造方法
CN104513256B (zh) * 2013-10-07 2018-07-31 鲁南贝特制药有限公司 一种头孢妥仑匹酯的制备方法
CN103665002B (zh) * 2013-12-18 2016-02-03 成都医路康医学技术服务有限公司 一种头孢妥仑匹酯的制备方法
CN104788471B (zh) * 2015-03-23 2017-06-27 浙江华方药业股份有限公司 一种头孢妥仑匹酯母核的合成方法
CN105175432B (zh) * 2015-09-09 2017-05-24 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
CN106366097A (zh) * 2016-08-19 2017-02-01 陕西思尔生物科技有限公司 一种头孢妥仑匹脂的制备方法
CN108997377B (zh) * 2018-07-27 2020-04-28 湖北凌晟药业有限公司 一种e型7-atca的制备方法
CN110655527A (zh) * 2019-09-20 2020-01-07 北京济美堂医药研究有限公司 一种高纯度头孢妥仑匹酯制备方法
CN113788844A (zh) * 2021-09-08 2021-12-14 湖北凌晟药业有限公司 一种e型头孢妥仑钠的制备方法

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JPS62205088A (ja) * 1986-03-03 1987-09-09 Meiji Seika Kaisha Ltd 新規セフエム化合物
TW209223B (fr) * 1989-09-26 1993-07-11 Yamanouchi Pharma Co Ltd
AT400436B (de) * 1992-11-10 1995-12-27 Biochemie Gmbh Neues verfahren zur herstellung von 3-vinylcephalosporinverbindungen
EP0723965B1 (fr) * 1993-09-29 2001-05-30 Meiji Seika Kaisha Ltd. Nouveaux derives de cephalosporine
DE69427312T2 (de) * 1993-11-17 2001-08-23 Biochemie Gmbh Trennung von Cephalosporinisomeren
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TR200000310T2 (tr) * 1997-06-24 2000-08-21 Meiji Seika Kaisha, Ltd. Bir 3-(2-değiştirilmiş-vinil)-sefalosporin' in z-izomeri' nin seçici üretimine mahsus bir yöntem.
WO2003091230A1 (fr) * 2002-04-26 2003-11-06 Orchid Chemicals & Pharmaceuticals Limited Procede de preparation du produit intermediaire 4-methylthiazol-5-carbaldehyde

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WO2005016936A3 (fr) 2005-08-11
WO2005016936A2 (fr) 2005-02-24

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