WO2008041100A1 - Procédé amélioré pour la préparation d'antibiotiques céphalosporines - Google Patents

Procédé amélioré pour la préparation d'antibiotiques céphalosporines Download PDF

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Publication number
WO2008041100A1
WO2008041100A1 PCT/IB2007/002917 IB2007002917W WO2008041100A1 WO 2008041100 A1 WO2008041100 A1 WO 2008041100A1 IB 2007002917 W IB2007002917 W IB 2007002917W WO 2008041100 A1 WO2008041100 A1 WO 2008041100A1
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WO
WIPO (PCT)
Prior art keywords
methyl
cephem
aminothiazol
formula
carboxylic acid
Prior art date
Application number
PCT/IB2007/002917
Other languages
English (en)
Inventor
Palanisamy Senthilkumar Udayampalayam
Sundaravadivelan Sivakumaran
Prabhat Kumar Sahoo
Original Assignee
Orchid Chemicals & Pharmaceuticals Limited
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 Orchid Chemicals & Pharmaceuticals Limited filed Critical Orchid Chemicals & Pharmaceuticals Limited
Publication of WO2008041100A1 publication Critical patent/WO2008041100A1/fr

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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
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid

Definitions

  • the present invention relates to an improved process for the preparation of cephalosporin antibiotics, which have a wide range of anti-bacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotic of the formula (I)
  • US patent Nos. 4,767,852 and 5,003,073 disclose a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4- carboxylic acid derivative with 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate of the formula (II) (MAEM),
  • solvents such as chlorinated hydrocarbons, ethers or esters such as ethyl acetate or in a mixture of such solvent with water.
  • US patent 5,026,843 discloses a process for preparing ceftriaxone disodium comprising reacting 7-amino-3- ⁇ [(2,5-dihydro-6-hydroxy-2-methyl-5- oxo-l ⁇ -triazin-S-ytythioJmethylJ-S-cephem ⁇ -carboxylic acid with 2- mercaptobenzothiazolyl 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate in an aqueous solution in suitable solvents, in the presence of an amine and the obtained aqueous solution is treated with a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-tert- butylcyclohexylamine and N,N-dibenzylethylenediamine.
  • a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropyl
  • the solvent used for the condensation is selected from acetone, acetonitrile, carbon tetrachloride, methylene chloride, toluene, methanol, ethanol, iso- propanol, dioxane, iso-propyl ether, N-methyl pyrrolidone and dimethyl formamide (DMF) and the base used is triethylamine.
  • WO 00/68234 discloses a process for the preparation of cefpodoxime acid, comprising condensation of 7-amino-3-methoxymethyl-3-cephem-4- carboxylic acid with MAEM in the presence of an organic solvent and an organic base and optionally in the presence of water.
  • US 5,527,906 describes a process for the preparation of Ceftriaxone disodium hemiheptahydrate involving condensation of 7-amino-3- ⁇ [(2,5- dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thio]methyl ⁇ -cephem-4- carboxylic acid derivative with MAEM using NaHCO 3 in aqueous acetone.
  • this patent motivates the direct isolation of sodium salt of cephalosporin after acylation or condensation reaction, this patent yields a product in which the sodium content in final product is not consistent, as it utilizes the inorganic base for condensation.
  • the primary objective of the invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (I), which is simple, high yielding and cost effective.
  • Another objective of the present invention is to provide a process for the preparation of number of cephalosporin antibiotics, in which the by-products are removed and the same can be recycled using simple & industrially viable technique.
  • the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I)
  • step (ii) adding water or acetone to the step (i) mass, (iii) optionally filtering the by-product, and (iv) isolating the compound of formula (I).
  • the water miscible organic solvent used in step (i) is selected from acetone, tetrahydrofuran (THF), acetonitrile, Isopropyl alcohol or mixtures thereof.
  • condensation reaction is carried out in aqueous solvent, wherein the water to solvent ratio varies from 0% to 100%, preferably 30% to 70%.
  • the compound of formula (I) is isolated from the reaction mass as sodium salt if required by the addition of excess acetone.
  • the compound of formula (I) is isolated from the reaction mass as acid (R 2 is COOH) by the addition of water.
  • the by-product 2- mercaptobenzothiazole (MBT) is precipitated; accordingly the present invention provides a simple technique of recovering the MBT.
  • the compound of formula (I) is isolated from the reaction mass by adjusting the pH. Surprisingly the compound thus isolated does not contain any detectable limit of MBT, whereas the literature processes yields the compound of formula (I) that contains the said MBT as an impurity. Owing to the toxic nature of MBT, the presence of MBT in the final API is not advisable in terms of pharmacopoeia requirement. Since the present invention obviates the problem associated with prior art process, it is economically and industrially viable.
  • the use of conjugate base of an organic acid like sodium 2-ethyl hexonate or sodium acetate obviates the use of organic amine during condensation step and hence provides a process to isolate the sodium salt directly.
  • One of the problems associated with acylation or condensation stage is degradation of final API and the degradation is directly associated with the basicity of the base used.
  • the use of inorganic base like sodium carbonate or strong organic bases like sodium methoxide is not advisable, as they tend to degrade the final API. Because of the less basic nature of sodium 2-ethyl hexanoate, the degradation of the final API is minimized and it also provides direct isolation of sodium salt. Hence the process of the present invention is commercially more viable over the existing prior art processes.
  • the compound of formula (I) obtained is a syn-isomer.
  • the starting material, 7-amino cephem derivative of formula (III) is prepared by utilizing the technique known in the prior art.
  • the commercially important cephalosporin compounds of formula (I) that can be manufactured by the process of this invention includes Cefetamet, Cefotaxime, Cefditoren, Ceftizoxime, Cefepime, Ceftriaxone, Cefixime, Cefdinir, Cefquinome, Cefpodoxime, Cefteram, Cefoselis, Cefuzonam and the like or its sodium salt or its hydrated form of sodium salt. If required the compound of formula (I) is converted into its pharmaceutically acceptable salt or ester by utilizing the process known in prior art.
  • the compound of formula (I) or its solvates or its salt can be formulated by conventional method.
  • a stable parenteral aqueous solution comprising pharmaceutically acceptable ⁇ - lactam antibiotic, and/or EDTA, and/or sodium citrate, which is preferably suitable for intramuscular and intravenous administration.
  • cefetamet sodium thus obtained is converted to Cefetamet pivoxil as follows; Preparation of Cefetamet Pivoxil
  • Cephalosporin antibiotic is prepared directly.
  • the present invention is eco-friendly and economical as product isolation is very simple.
  • the by-product (MBT) is isolated from the reaction mass in almost pure form, which can be further, purified or converted into bis-benzothiazole di-sulfide and can be reused.

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

Abstract

La présente invention porte plus particulièrement sur un procédé pour la préparation d'antibiotiques céphalosporines de la Formule (I) dans laquelle R1 représente l'hydrogène, le trityle, l'alkyle comme CH3, CRaRbCOORc où Ra et Rb représentent indépendamment l'hydrogène ou le méthyle et Rc représente l'hydrogène ou l'alkyle en C1-C6 ; R2 représente l'ion carboxylate ou COORd, où Rd représente l'hydrogène, l'ester ou un contre-ion qui forme un sel ; R3 représente l'hydrogène, CH3, CH2OCH3, CH2OCOCH3, CH=CH2, Formule (II).
PCT/IB2007/002917 2006-10-04 2007-10-03 Procédé amélioré pour la préparation d'antibiotiques céphalosporines WO2008041100A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1836CH2006 2006-10-04
IN1836/CHE/2006 2006-10-04

Publications (1)

Publication Number Publication Date
WO2008041100A1 true WO2008041100A1 (fr) 2008-04-10

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101792456A (zh) * 2010-03-11 2010-08-04 池州东升药业有限公司 一种头孢他美酯盐酸盐的制备方法
CN102659817A (zh) * 2012-05-08 2012-09-12 浙江普洛得邦制药有限公司 一种头孢地尼的制备方法
CN104513256A (zh) * 2013-10-07 2015-04-15 鲁南贝特制药有限公司 一种头孢妥仑匹酯的制备方法
CN109180704A (zh) * 2018-11-19 2019-01-11 齐鲁安替制药有限公司 一种头孢妥仑匹酯的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399094A2 (fr) * 1989-05-23 1990-11-28 S.B.D. SYNTHETIC AND BIOLOGICAL DEVELOPMENTS S.r.l. Procédé pour la préparation de ceftriaxone
WO2004037833A1 (fr) * 2002-10-24 2004-05-06 Orchid Chemicals & Pharmaceuticals Ltd Procede de preparation d'antibiotiques cephalosporines
US20040242557A1 (en) * 2003-06-02 2004-12-02 Ramesh Dandala Process for preparing cefdinir
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399094A2 (fr) * 1989-05-23 1990-11-28 S.B.D. SYNTHETIC AND BIOLOGICAL DEVELOPMENTS S.r.l. Procédé pour la préparation de ceftriaxone
WO2004037833A1 (fr) * 2002-10-24 2004-05-06 Orchid Chemicals & Pharmaceuticals Ltd Procede de preparation d'antibiotiques cephalosporines
US20040242557A1 (en) * 2003-06-02 2004-12-02 Ramesh Dandala Process for preparing cefdinir
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

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101792456A (zh) * 2010-03-11 2010-08-04 池州东升药业有限公司 一种头孢他美酯盐酸盐的制备方法
CN102659817A (zh) * 2012-05-08 2012-09-12 浙江普洛得邦制药有限公司 一种头孢地尼的制备方法
CN102659817B (zh) * 2012-05-08 2014-07-02 浙江普洛得邦制药有限公司 一种头孢地尼的制备方法
CN104513256A (zh) * 2013-10-07 2015-04-15 鲁南贝特制药有限公司 一种头孢妥仑匹酯的制备方法
CN109180704A (zh) * 2018-11-19 2019-01-11 齐鲁安替制药有限公司 一种头孢妥仑匹酯的合成方法

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