WO2004011471A1 - Procede d'elaboration de cepheme esters - Google Patents

Procede d'elaboration de cepheme esters Download PDF

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Publication number
WO2004011471A1
WO2004011471A1 PCT/IB2003/002967 IB0302967W WO2004011471A1 WO 2004011471 A1 WO2004011471 A1 WO 2004011471A1 IB 0302967 W IB0302967 W IB 0302967W WO 2004011471 A1 WO2004011471 A1 WO 2004011471A1
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WO
WIPO (PCT)
Prior art keywords
group
process according
methyl
formula
alkyl
Prior art date
Application number
PCT/IB2003/002967
Other languages
English (en)
Inventor
Yatendra Kumar
Mohan Prasad
Kaptan Singh
Satyananda Misra
Original Assignee
Ranbaxy Laboratories 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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to AU2003249494A priority Critical patent/AU2003249494A1/en
Publication of WO2004011471A1 publication Critical patent/WO2004011471A1/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

Definitions

  • the present invention relates to a process for the preparation of cephem esters.
  • Cephem esters having a physiologically labile group are used as prodrugs for oral administration of cephalosporin antibiotics.
  • the preparation of cephem esters from the corresponding cephem free acid or salts thereof results in the formation of undesired ⁇ 2 - isomer of the cephem ester of Formula A along with the desired ⁇ 3 - isomer of Formula B.
  • the ⁇ 2 - isomer is formed as a result of ⁇ 3 ⁇ ⁇ 2 isomerization under basic conditions, which are necessary for the completion of the esterification reaction.
  • the removal of the ⁇ 2 - isomer from the cephem ester is very difficult due to the structure similarity of ⁇ 2 and ⁇ 3 - isomers and also entails decrease in yield.
  • Several processes have been reported to overcome this problem in the synthesis of cephem esters by minimizing isomerization. J. Org. Chem. 1986, 51, 4723 and J. antibiotics,
  • U.S. Patent No. 5,498,787 teaches the use of quaternary ammonium or quaternary phosphonium salts as catalysts for eliminating the formation of ⁇ 2 -isomer of cephem esters.
  • PCT patent application WO 02/16372 uses crown ether catalysts to achieve similar results for the preparation of cefuroxime axetil.
  • the present invention provides an inexpensive and efficient process for preparing cephem esters while minimizing the concomitant formation of the corresponding ⁇ 2 -isomer.
  • the present invention provides a process for the preparation of cephem ester of formula I,
  • R is cyano, phenyl, cyclohexadienyl, heterocyclyl, heterocyclylthio, or a heterocyclylamido group, wherein the phenyl or the heterocyclic ring may be further substituted by an alkyl, hydroxy, a ino, aminoalkyl, halo or a carboxyalkyl group;
  • A is mono or disubstituted methylene group, -CH, — -CH- -CH-
  • Ri is alkyl, alkoxyalkyl or carboxyalkyl
  • R' is hydrogen, alkyl, alkenyl, alkynyl, alkoxymethyl, alkylthiomethyl, alkanoyloxymethyl, carbamoyloxymethyl, or a heterocyclylthiomethyl group, wherein the heterocyclic ring may be further substituted by hydroxy, alkyl, carboxyalkyl, sulfonylalkyl or carbamoyl; and R" is alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, alkanoyloxyalkyl or alkoxycarbonyloxyalkyl, comprising reacting a compound of Formula II,
  • the heterocyclyl group may be a 5 or 6 membered heterocyclic ring containing up to four hetero atoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • R examples include 4-hydroxyphenyl, 2-aminomethylphenyl, 2-amino-4-thiazolyl, 2-furanyl, 2-thienyl, 4-pyridinyl, IH-tetrazolyl, 5-amino-l,2,4-thiadiazol-3-yl, 5-methyl- l,3,4-thiadiazol-2-yl, 5-carboxy-lH-imidazol-4-yl, 4-hydroxy-6-methyl-3-pyridinyl, 3,5- dichloro-4-oxo-l(4H)-pyridinyl, and 4-ethyl-2,3-dioxo-l-piperazinyl.
  • R' examples include methyl, 2-(4-methyl-5-thiazolyl)ethenyl, acetoxymethyl, methoxymethyl, chloro, l-methyl-lH-tetrazol-5-ylthio, lH-l,2,3-triazol-4-ylthio, 5- methyl- 1, 3, 4-thiadiazol-2-yl, l,2,3-thiadiazol-5-ylthio and l,2,5,6-tetrahydro-2-methyl-5,6- dioxo- 1 ,2,4-triazin-3 -ylthio .
  • R" examples include 1-acetoxyethyl, pivaloyl, pivaloyloxymethyl, 1- (isopropoxycabonyloxy)ethyl and 1 -(cyclohexyloxycabonyloxy)ethyl.
  • Halogen X in R"X is selected from the group consisting of chloro, bromo and iodo.
  • the reaction can be carried out in the presence of an amine, for example triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, pyridine, N- methylpiperidine N-methyl pyrrolidine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture(s) thereof.
  • an amine for example triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, pyridine, N- methylpiperidine N-methyl pyrrolidine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture(s) thereof.
  • DBU 1,8-di
  • Suitable inorganic bases which may be used in the process include sodium carbonate, potassium carbonate and sodium bicarbonate.
  • Suitable phosphate buffers which may be used in the process include disodium hydrogenphosphate, dipotassium hydrogenphosphate and sodium hydrogen phosphate. It is convenient to employ about 0.5 to about 2.5 molar equivalents of the phosphate buffer with respect to the inorganic base.
  • the reaction can be carried out in the presence of a solvent which is inert under the reaction conditions, for example dimethylformamide, dimethylacetamide, dimethylsulphoxide, hexamethylphosphoric triamide, tetrahydrofuran, dichloromethane, ethylacetate, acetonitrile and mixture(s) thereof.
  • a solvent which is inert under the reaction conditions
  • the reaction can be carried out at ambient temperature or with cooling, for example at temperatures ranging from about -10°C to about 0°C.
  • the process of the present invention consistently gives cephem esters in high yield and purity.
  • the reaction mixture was poured into ethylacetate (300ml) followed by the addition of water (300ml).
  • the organic layer was separated and then washed successively with aqueous hydrochloric acid, aqueous sodium thiosulphate and finally with aqueous sodium chloride.
  • the ethyl acetate layer obtained above was concentrated to about 40 ml at 30-35°C

Landscapes

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

Abstract

La présente invention concerne un procédé d'élaboration de céphème esters.
PCT/IB2003/002967 2002-07-25 2003-07-24 Procede d'elaboration de cepheme esters WO2004011471A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003249494A AU2003249494A1 (en) 2002-07-25 2003-07-24 Process for the preparation of cephem esters

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN772DE2002 2002-07-25
IN772/DEL/2002 2002-07-25

Publications (1)

Publication Number Publication Date
WO2004011471A1 true WO2004011471A1 (fr) 2004-02-05

Family

ID=30776586

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/002967 WO2004011471A1 (fr) 2002-07-25 2003-07-24 Procede d'elaboration de cepheme esters

Country Status (2)

Country Link
AU (1) AU2003249494A1 (fr)
WO (1) WO2004011471A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010097675A1 (fr) * 2009-02-27 2010-09-02 Dhanuka Laboratories Ltd. Procédé de préparation amélioré pour le cefpodoxime proxétil
CN102161669A (zh) * 2011-02-21 2011-08-24 江苏济川制药有限公司 一种除去头孢替坦二钠中杂质△2-isomer的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498787A (en) * 1994-04-20 1996-03-12 Standard Chemical & Pharmaceutical Co., Ltd. Method for preparing cephalosporin derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498787A (en) * 1994-04-20 1996-03-12 Standard Chemical & Pharmaceutical Co., Ltd. Method for preparing cephalosporin derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DEMUTH TP ET AL: "synthesis and antibacterial activity of new C-10 quinolonyl-cephem esters", THE JOURNAL OF ANTIBIOTICS, vol. 44, no. 2, 1994, pages 200 - 209, XP009018960 *
MOBASHERY ET AL: "preparation of ceph-3-em esters unaccompanied by delta3 to delta2 isomerization of the cephalosporin", JOURNAL OF ORGANIC CHEMISTRY, vol. 51, 1986, USA, pages 4723 - 4726, XP002257956 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010097675A1 (fr) * 2009-02-27 2010-09-02 Dhanuka Laboratories Ltd. Procédé de préparation amélioré pour le cefpodoxime proxétil
CN102161669A (zh) * 2011-02-21 2011-08-24 江苏济川制药有限公司 一种除去头孢替坦二钠中杂质△2-isomer的方法

Also Published As

Publication number Publication date
AU2003249494A1 (en) 2004-02-16

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