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WO1998006723A1 - Sels d'amine - Google Patents

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Publication number
WO1998006723A1
WO1998006723A1 PCT/EP1997/004439 EP9704439W WO9806723A1 WO 1998006723 A1 WO1998006723 A1 WO 1998006723A1 EP 9704439 W EP9704439 W EP 9704439W WO 9806723 A1 WO9806723 A1 WO 9806723A1
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WO
WIPO (PCT)
Prior art keywords
cefixime
salt
dicyclohexylamine
formula
compound
Prior art date
Application number
PCT/EP1997/004439
Other languages
English (en)
Inventor
Ludwig Miller
Hubert Sturm
Original Assignee
Biochemie Gesellschaft Mbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biochemie Gesellschaft Mbh filed Critical Biochemie Gesellschaft Mbh
Priority to AU46168/97A priority Critical patent/AU4616897A/en
Publication of WO1998006723A1 publication Critical patent/WO1998006723A1/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

Definitions

  • the present invention relates to cephalosporins, in particular to cefixime of formula
  • Cefixime e.g. in form of the trihydrate is an orally available cephalosporin having e.g. excellent antibacterial properties; see e.g. H. Yamanaka et al., J. Antibiotics (1985), 38 (12), p. 1738-1751.
  • the last step in the production of cefixime is described therein to be performed by acidic cleavage of protecting groups from protected cefixime, e.g. from cefixime wherein one or both -COOH groups are protected, e.g.
  • cefixime of formula I was found in form of a salt with dicyclohexylamine which is particularly useful in the purification of cefixime, and which may be isolated in excellent purity, e.g. in crystalline form, containing less than 5%, even less than 3% of by-products.
  • the isolated salt may be converted into cefixime of high purity, e.g. in form of a solvate, e.g.hydrate, e.g. trihydrate without any further purification.
  • the present invention provides cefixime of formula I in form of a salt with dicyclohexylamine.
  • a salt of a compound of formula I with dicyclohexylamine includes a solvate, e.g. a hydrate, e.g. a trihydrate thereof.
  • cefixime in form of a salt with dicyclohexylamine may crystallize.
  • the present invention provides cefixime of formula I in form of a crystalline salt with dicyclohexylamine.
  • cefixime in form of a bis-dicyclohexylammonium salt may crystallize.
  • a bis-dicyclohexyiammoium salt of cefixime is believed to be composed of about 1.6 to 2.4, e.g. 1.8 to 2.2, such as 1.9 to 2.1 such as 2 mol of dicyclohexylamine per mol of cefixime of formula I.
  • cefixime of formula I in form of a bis- dicyclohexylammonium salt, e.g. of formula
  • a compound of formula I in form a salt with dicyclohexylamine may be produced as follows: Cefixime of formula I, e.g. in free form, in form of a solvate, e.g. hydrate, e.g. trihydrate; in form of a salt, e.g. an acid addition salt, such as an acid addition salt as obtainable in a process for the production of a compound of formula I by cleavage of protection groups, e.g. a salt of a compound of formula I with hydrochloric acid, formic acid, acetic acid, a toluenesulphonic acid a methansulphonic acid; or a mixed salt of a compound of formula I, e.g.
  • a salt and solvate e.g. hydrate, e.g. trihydrate may be suspended or dissolved in a solvent or solvent system, e.g. in an organic solvent, e.g. in the presence of water.
  • An appropriate organic solvent includes any solvent wherein a compound of formula I may exist in form of a salt with dicyclohexylamine, e.g. in form of a solvate, such as ketones, e.g. an alkyl ketone, preferably a dialkyl ketone such as acetone, diethyl ketone and methylisobutyl ketone; an alcohol, preferably an alkyl alcohol, e.g.
  • a nitrile preferably an alkyl nitrile having altogether 2 to 5 carbon atoms, for example acetonitrile
  • an carboxylic acid ester for example an alkyl ester of an alkyl carboxylic acid, the carboxylic acid having altogether 1 to 8, e.g. 1 to 6 carbon atoms, e.g. acetic acid, propionic acid, such as acetic acid-(C-i to C 4 )alkylester
  • an amide of a carboxylic acid e.g. an N-dialkylamide, such as dimethylformamide.
  • a solvent system comprising mixtures of individual solvents, e.g.
  • alkyl includes (C,. ⁇ 2 )alkyl, e.g. (Ci. 8 )alkyl, such as (C ⁇ )alkyl, e.g. (C ⁇ )alkyl.
  • Water may be present in the organic solvent or solvent system which may support solubility of cefixime in a form as described above, e.g. in form of an acid addition salt.
  • acetone e.g. in the presence of water may be used as organic solvent (system). In case that acetone/water is used the ratio is in principle not critical, but preferably a small amount of water in respect with acetone may be used.
  • an appropriate acetone:water ratio includes 1 :1 or less up to 20:1 or more, such as 2:1 to 10:1 , e.g. 3:1 to 6:1.
  • suspension or solution comprising a compound of formula I in a form as described above and an organic solvent with or without water may be combined with dicyclohexyl amine of formula
  • dicycohexyl amine e.g. by addition of dicycohexyl amine to the solution or suspension, e.g. as such, or in solution or suspension of a solvent, e.g. in a solvent as described above.
  • An amount of diclyhexyl amine sufficient to result in a salt of a compound of formula I with dicyclohexyl amine may be used, e.g. per equivalent of cefixime one equivalent of dicyclohexyl amine and more, e.g. 2.0 to 5.0, such as 2.2 to 4.0 equivalents may be added.
  • a compound of formula I e.g.
  • a compound of formula I in form of a salt with dicyclohexylamine may crystallize and may be isolated as usual, for example by filtration.
  • An anti-solvent for example an ether or a hydrocarbon or a ketone, e.g. acetone in big excess, may be added to the reaction mixture, e.g. in case that a compound of formula I in form of a salt with dicyclohexylamine is too readily soluble in the solvent or solvent system.
  • an isolated compound of formula I in form of a salt with dicyclohexylamine may be resuspended in a solvent or solvent system wherein a salt of a compound of formula I is preferably insoluble ore only slightly soluble and wherein impurities are soluble, such as organic solvents as described above to effect further purification.
  • the present invention provides a process for the production of a compound of formula I in form of a salt with dicyclohexylamine, comprising the steps (i) suspending or dissolving a compound of formula I, e.g. in free form, in form of a solvate, in form of a salt, or in form of a salt and a solvate in a solvent, (ii) treating the suspension or solution obtained in step (i) with dicyclohexylamine, and (iii) isolating a compound of formula I in form of a salt with dicyclohexylamine obtained in step (ii).
  • cefixime e.g. a composition containing cefixime and by-products, e.g. in free form, in form of a solvate, in form of a salt and in form of a salt and a solvate, e.g. as obtainable by acidic cleavage of protecting groups from protected cefixime, e.g. from cefixime wherein one or both - COOH groups are protected may contain considerable amounts of by-products, e.g. 6%, 7% and more.
  • cefixime in form of a salt with dicyclohexylamine may be obtained according to a process of the present invention, e.g. from impure cefixime, in highly pure, e.g.
  • cefixime in form of a salt with dicyclohexylamine may thus decrease considerably the content of by-products of an impure cefixime used as starting compound and may thus be used in the purification of impure cefixime.
  • cefixime in form of a salt with dicyclohexylamine in the purification of impure cefixime.
  • Cefixime e.g. in free form or in solvate, e.g. hydrate, e.g. trihydrate form may be obtained from a compound of formula I in form of a salt with dicyclohexylamine, e.g. in salt and solvate form, for example as follows:
  • Cefixime in form of a salt with dicyclohexylamine may be dissolved or suspended in water or a mixture of water and an organic solvent.
  • An appropriate organic solvent includes any organic solvent wherein cefixime in free form or in solvate form may exist, preferably an organic solvent as described above for the formation of a compound of formula I with a salt with dicyclohexylamine, more preferably a ketone, e.g. a dialkylketone, such as acetone and an alcohol, e.g. an alkyl alcohol, such as ethanol; and water, with or without the presence of an organic solvent as described above.
  • a solution of cefixime in the form of a salt with dicyclohexylamine in the solvent system used may be formed, which may be filtered, e.g.in the presence of carbon, e.g. activated carbon and/or a filter assistant agent and/or through an adsorber resin.
  • Cefixime in free form or in solvate form may precipitate by combination of a solution or suspension of cefixime in form of a salt with dicyclohexylamine with an acidic agent, e.g. by addition of an acid, to an pH where cefixime may exist in free form or in solvate form.
  • An appropriate pH includes a pH of (about) 1.5 to 4, e.g. 2 to 3.
  • An acidic agent includes an appropriate acidic agent which is able to convert cefixime in form of a salt with dicyclohexylamine into cefixime in free form or solvate form, preferably an inorganic acid, such as phosphoric acid or sulphuric acid; an acidic ion exchange resin may e.g. be used.
  • Cefixime in free or solvate form may crystallize and may be isolated, e.g. as usual, e.g. by filtration.
  • Dicyclohexylamine may be removed, e.g. partially, e.g. prior to isolation of cefixime, e.g. by extraction from the reaction mixture, e.g. prior to crystallisation of cefixime.
  • the pH of the reaction mixture may be adjusted to 8 to 11 , e.g. ⁇ 9, such as 9 to 11 , e.g. 10 to 11 , e.g. by use of a base, preferably an inorganic base, such as e.g. an alkali, e.g. sodium and potassium or earth alkali hydroxide and carbonate, preferably a hydroxide.
  • Dicyclohexylamine may be extracted into an organic solvent which is able to form a two-phase system with water and which is able to dissolve dicyclohexylamine, e.g. partially, in a two-phase system with water, including e.g. a halogented hydrocarbon, such as methylene chloride, a ketone, such as methyl isobutylketone and an ester of a carboxylic acid, such as ethyl acetate, isopropyl acetate, n-butyl acetate, for example as usual.
  • Water may be added to the reaction mixture, if not present in an amount sufficient to form a two phase system in the reaction mixture.
  • Dicyclohexylamine may also be removed from the reaction mixture by use of an ion exchange resin, adsorber resin and an ion retardation resin, such as AG 11 A8 ⁇ from Biorad; Dianion Snake cage resin ® from Mitsubishi, styrene-divinylbenzene copolymerisates, e.g.Dianion HP 20 ® , Dianion HP 21 ® , Dianion SP 207 ® , Amberlite XAD 1180 ® , XAD 1600 ® , XAD 16 ® or adsorber resins CG 161 ® , e.g. by stirring the reaction mixture in the presence of such a resin or by pouring the reaction through a bed of such a resin.
  • an ion exchange resin, adsorber resin and an ion retardation resin such as AG 11 A8 ⁇ from Biorad
  • Dianion Snake cage resin ® from Mitsubishi
  • the pH of the reaction mixture may be adjusted again to 1.5 to 4, e.g. 2 to 3 as described above, e.g. in the presence of an organic solvent, preferably in the presence of a ketone, such as an alkylketone, e.g. a dialkylketone, e.g. acetone; or an alcohol, such as an alkyl alcohole, e.g.ethanol.
  • Cefixime e.g. in free or solvate, e.g. hydrate, e.g. trihydrate form may be obtained, e.g. in crystalline form, and may be isolated, e.g. as usual.
  • the present invention provides a process for the conversion of cefixime in form of a salt with dicyclohexylamine into cefixime comprising the steps (i) combining an acidic agent with cefixime in form of a salt with dicyclohexylamine in a solvent, and (ii) isolating cefixime obtained in step (i).
  • Cefixime in form of a salt with dicyclohexylamine may be obtained in substantially pure form, but depending on the content of the impurities of impure cefixime used as starting compound for its production, it may still contain considerable amounts of impurities, e.g. impure cefixime in form of a salt with dicyclohexylamine, e.g. a composition containing cefixime and, e.g. more than 2% byproducts may be obtained. It was now surprisingly found that the conversion of cefixime in form of a salt with dicyclohexylamine into cefixime may considerably decrease the amount of impurities, e.g.
  • Cefixime may be obtained from the conversion step in highly pure form, e.g. crystalline form and may contain low amounts of by-products, e.g. below 1.2%, even below 0.7%.
  • the present invention provides a process for the depletion of by-products in a composition containing cefixime and by-products, comprising converting cefixime into a salt with dicyclohexylamine and isolating cefixime in form of salt with dicyclohexylamine, and/or converting cefixime in form of a salt with dicyclohexylamine into cefixime and isolating cefixime.
  • the present invention provides the use of a process for converting cefixime in form of a salt with dicyclohexylamine, e.g. a crystalline salt, e.g. a bis-dicyclohexylammonium salt, into cefixime in the purification of cefixime.
  • the present invetnion provides a process for the purification of impure cefixime comprising the steps
  • Such a process has the advantage that impurities of an impure cefixime, e.g. a composition containing cefixime and by-products used as starting material, e.g. in the range of about 6% and more may be decreased to a content of e.g. 0.7% and below.
  • impurities of an impure cefixime e.g. a composition containing cefixime and by-products used as starting material, e.g. in the range of about 6% and more may be decreased to a content of e.g. 0.7% and below.
  • a salt of a compound of formula I with dicyclohexylamine according to the present invention may be produced easily, even without the use of halogenated solvents, if desired and may decrease considerably the content of by-products, if used in any purification process according to the present invention.
  • a process according to the present invention may be used on technical scale.
  • a salt of the present invention may thus be used in the purification of impure cefixime.
  • Purified cefixime in form of a trihydrate obtained according to the present invention may be used, if desired after further purification, as an antibacterial agent in the same dosages and in the same applications as purified cefixime in form of a trihydrate obtainable according to known (purification) processes.
  • Cefixime is also known under the chemical names [6R-(6 ⁇ ,7 ⁇ (Z)]-7- ⁇ [(2-amino-4-thiazolyl)[(carboxymethoxy)imino]acetyl]amino ⁇ -3-ethenyl-8-oxo-5- thia-1-azybicyclo[4.2.0]oct-2-ene-2-carboxylic acid; or
  • Example 1 Production of cefixime in form of a bis-dicyclohexylammonium salt 15 g of dicyclohexylamine are added dropwise to a suspension of 15 g of impure cefixime in form of a trihydrate (content of by-products: 5.76%), obtainable according to example Ab) in a mixture of 60 ml of acetone and 15 ml of water. A solution is obtained. 540 ml of acetone are added dropwise within 30 minutes at 20°.
  • Cefixime in form of a bis-dicyclohexylammonium salt crystallises. The crystal suspension is stirred for ca. one hour at room temperature, cooled to 0° and stirred for 2 hours at 0°.
  • Example 2 Production of cefixime in form of a trihydrate
  • a solution of 5 g of cefixime in form of a bis-dicyclohexylammonium salt (content of by-products: 2.59 %), obtainable according to example 1 in 50 ml of water is mixed with 1 g of activated carbon, stirred for 10 minutes at room temperature, and filtered. The filtrate is diluted with 20 ml of ethanol and the pH is adjusted to 2.5 by dropwise addition of 2 ml of sulphuric acid within ca. 45 minutes.
  • Cefixime in form of a trihydrate crystallises. The reaction mixture is stirred for ca. 1 hour at room temperature for ca. 1 hour at 0°. Crystalline cefixime in form of a trihydrate is filtrated off, washed with water and dried. Yield: 2.78 g in form of a white, crystalline powder. Content of by-products: 0.62 %
  • Example 3 Production of cefixime in form of a trihydrate
  • a solution of 5 g of cefixime in form of a bis-dicyclohexylammonium salt (content of by-products: 2.59%), obtainable according to example 1 in 50 ml of water is mixed with 25 ml of methylene chloride and cooled to 0°. 6.1 ml of 2 M NaOH are added dropwise under stirring and the phases are separated.
  • the methylene chloride phase contains dicyclohexylamine.
  • the aqueous phase is washed with methylene chloride, treated with 1 g of activated carbon, stirred for 10 minutes in an ice bath and filtrated. Isolation of crystalline cefixime in form of a trihydrate from the filtrate is performed after adjustment of the pH to 2.5 as described in Example 2, according to the method as described in Example 2. Yield: 2.78 g Content of by-products: 1.13%

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

Abstract

Cette invention concerne un céfixime qui se présente sous forme d'un sel contenant du dicyclohexylamine, par exemple, un sel de bis-dicyclohexylammonium. Cette invention concerne également un procédé de préparation de ce sel, ainsi que son utilisation dans la purification de céfixime.
PCT/EP1997/004439 1996-08-14 1997-08-13 Sels d'amine WO1998006723A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46168/97A AU4616897A (en) 1996-08-14 1997-08-13 Amine salts

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA1468/96 1996-08-14
AT146896A AT404251B (de) 1996-08-14 1996-08-14 Neues kristallines salz von cefixim

Publications (1)

Publication Number Publication Date
WO1998006723A1 true WO1998006723A1 (fr) 1998-02-19

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PCT/EP1997/004439 WO1998006723A1 (fr) 1996-08-14 1997-08-13 Sels d'amine

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AT (1) AT404251B (fr)
AU (1) AU4616897A (fr)
ID (1) ID18027A (fr)
WO (1) WO1998006723A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT405402B (de) * 1997-12-04 1999-08-25 Biochemie Gmbh Kristalline salze von 7-(2-(aminothiazol-4-yl)-2 -(tert.butoxycarbonylmethoxyimino)acetamido)- 3-vinyl-3-cephem-4-carbonsäure
WO1999051607A3 (fr) * 1998-04-02 2000-01-27 Biochemie Gmbh Procede de purification d'un derive de cephalosporine
US6313289B1 (en) * 1997-01-16 2001-11-06 Biochemie Gesellschaft M.B.H. Purification process
US6350869B1 (en) * 1997-04-04 2002-02-26 Biochemie Gesellschaft M.B.H. Crystalline amine salt of cefdinir
US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7662955B2 (en) * 2003-03-20 2010-02-16 Orchid Chemicals And Pharmaceuticals Ltd. Process for the preparation of cefoxitin
US7705142B2 (en) 2005-03-29 2010-04-27 Hetero Drugs Limited Process for the preparation of cefixime
CN102311452A (zh) * 2011-09-22 2012-01-11 山东罗欣药业股份有限公司 头孢克肟晶体、其制备方法及含有该晶体的片剂组合物
US9163342B2 (en) 2009-07-31 2015-10-20 Rockwool International A/S Method for manufacturing a mineral fiber-containing element and element produced by that method
WO2016142902A1 (fr) * 2015-03-11 2016-09-15 Lupin Limited Céfixime à aire de surface réduite et haute stabilité
CN109734726A (zh) * 2019-01-30 2019-05-10 山东省分析测试中心 一种三水合头孢克肟晶体的精制方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030630A2 (fr) * 1979-11-19 1981-06-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 7-acylamino-3-vinyl céphalosporanique, procédé pour leur préparation, compositions pharmaceutiques les contenant; leurs produits de départ et leur préparation
WO1995033753A1 (fr) * 1994-06-03 1995-12-14 Marcham Trading & Investment Ltd. Procede pour la preparation du cefixime trihydrate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030630A2 (fr) * 1979-11-19 1981-06-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 7-acylamino-3-vinyl céphalosporanique, procédé pour leur préparation, compositions pharmaceutiques les contenant; leurs produits de départ et leur préparation
WO1995033753A1 (fr) * 1994-06-03 1995-12-14 Marcham Trading & Investment Ltd. Procede pour la preparation du cefixime trihydrate

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313289B1 (en) * 1997-01-16 2001-11-06 Biochemie Gesellschaft M.B.H. Purification process
US6350869B1 (en) * 1997-04-04 2002-02-26 Biochemie Gesellschaft M.B.H. Crystalline amine salt of cefdinir
AT405402B (de) * 1997-12-04 1999-08-25 Biochemie Gmbh Kristalline salze von 7-(2-(aminothiazol-4-yl)-2 -(tert.butoxycarbonylmethoxyimino)acetamido)- 3-vinyl-3-cephem-4-carbonsäure
WO1999051607A3 (fr) * 1998-04-02 2000-01-27 Biochemie Gmbh Procede de purification d'un derive de cephalosporine
US6825345B2 (en) 1998-04-02 2004-11-30 Sandoz Gmbh Process for purification of a cephalosporin derivative
US7825241B2 (en) 2002-08-13 2010-11-02 Sandoz Ag Cefdinir intermediate
US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7662955B2 (en) * 2003-03-20 2010-02-16 Orchid Chemicals And Pharmaceuticals Ltd. Process for the preparation of cefoxitin
US7705142B2 (en) 2005-03-29 2010-04-27 Hetero Drugs Limited Process for the preparation of cefixime
US9163342B2 (en) 2009-07-31 2015-10-20 Rockwool International A/S Method for manufacturing a mineral fiber-containing element and element produced by that method
CN102311452A (zh) * 2011-09-22 2012-01-11 山东罗欣药业股份有限公司 头孢克肟晶体、其制备方法及含有该晶体的片剂组合物
CN102311452B (zh) * 2011-09-22 2013-07-03 山东罗欣药业股份有限公司 头孢克肟晶体、其制备方法及含有该晶体的片剂组合物
WO2016142902A1 (fr) * 2015-03-11 2016-09-15 Lupin Limited Céfixime à aire de surface réduite et haute stabilité
CN109734726A (zh) * 2019-01-30 2019-05-10 山东省分析测试中心 一种三水合头孢克肟晶体的精制方法
CN109734726B (zh) * 2019-01-30 2020-09-15 山东省分析测试中心 一种三水合头孢克肟晶体的精制方法

Also Published As

Publication number Publication date
ATA146896A (de) 1998-02-15
AT404251B (de) 1998-10-27
ID18027A (id) 1998-02-19
AU4616897A (en) 1998-03-06

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