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WO2002044193A1 - Procédé permettant d'obtenir de l'azaérythromycine - Google Patents

Procédé permettant d'obtenir de l'azaérythromycine Download PDF

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Publication number
WO2002044193A1
WO2002044193A1 PCT/ES2001/000452 ES0100452W WO0244193A1 WO 2002044193 A1 WO2002044193 A1 WO 2002044193A1 ES 0100452 W ES0100452 W ES 0100452W WO 0244193 A1 WO0244193 A1 WO 0244193A1
Authority
WO
WIPO (PCT)
Prior art keywords
azaerythromycin
catalyst
obtaining
hydrogenation
deoxo
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.)
Ceased
Application number
PCT/ES2001/000452
Other languages
English (en)
Spanish (es)
Inventor
Ramon Asensio Dominguez
Luis Angel Diaz Tejo
Felipe Requena Perez
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.)
Ercros Industrial SA
Original Assignee
Ercros Industrial SA
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 Ercros Industrial SA filed Critical Ercros Industrial SA
Priority to AU2002220757A priority Critical patent/AU2002220757A1/en
Publication of WO2002044193A1 publication Critical patent/WO2002044193A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals

Definitions

  • Azaerythromycin [formula I] (9-deoxo-9a-aza-9a-homoer ⁇ tromycin A) is a key intermediate for the synthesis of azithromycin [formula II] (9-deoxo-9a-aza-9a-methyl- 9a- homoerithromycin A).
  • the present invention describes a process for its preparation from 6,9-iminoether [formula III] (9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza omoerythromycin A) by hydrogenation low pressure catalytic
  • Azithromycin is a macrolide antibiotic obtained by chemical synthesis from erythromycin A, it is more stable than this and has a broad spectrum of action that includes gram negative bacteria and intracellular microorganisms. It is described in patents US 4474768 and US 4517359.
  • azithromycin is obtained by reductive methylation of azaerythromycin with a mixture of formic acid and aqueous formaldehyde under chloroform reflux (Eschweiler-Clarke reaction).
  • azithromycin is obtained by oxidation of azaerythromycin to obtain the N-oxide derivative, followed by methylation and catalytic hydrogenation.
  • erythromycin (9-deoxo-9a-aza-9a-homoerythromycin A) is described in US 4328334. Its synthesis from erythromycin A consists of several stages:
  • EP 0879823 describes the synthesis of azithromycin from the iminoether directly in the same reactor.
  • the yields range between 50 and 87%;
  • hydrogenations are carried out at 60-70 bar using radius as catalyst and acetic acid as solvent.
  • the object of the present invention is a new method of obtaining azaerithromycin that is simpler, cheaper and more industrializable than those described to date.
  • 6,9-iminoether of erythromycin can be catalytically reduced at low pressure (less than 5 bar), after a pH adjustment with an appropriate acid and using alcohol solvents of 1 -3 carbon atoms or mixtures of these with water. Under the right conditions a high purity azaerythromycin is obtained with a good yield.
  • the 6,9-iminoether of erythromycin A is catalytically reduced at low pressure (between 1-5 bar) to obtain azaerythromycin.
  • the solvent for the reaction alcohols of 1-3 carbon atoms or mixtures thereof with water are used. It has been found that in these solvents and after a pH adjustment with a suitable acid (such as perchloric acid or hydrochloric acid), the reaction proceeds relatively quickly (3-4 hours) under mild temperature conditions (25 -45 ° C). Furthermore, in hydroalcoholic media, 6,9-iminoether does not evolve towards 9,11 -iminoether described in WO 94 26758. The product obtained had crystallized directly in basic aqueous solution. Heating the suspension between 35-45 ° C improves the crystallization performance.
  • the solvents used are low molecular weight alcohols or mixtures thereof with water;
  • the catalyst can be used several times, without detecting yield losses and / or noble metal;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un procédé permettant d'obtenir de l'azaérythromycine représentée par la formule (I), à partir de 6,9-iminoéther de l'érythromycine A, qui est réduit par catalyse à basse pression (moins de 5 bars), après un ajustement de pH avec un acide approprié et en utilisant, comme dissolvants, des alcools à 1-3 atomes de carbone ou des mélanges desdits alcools avec de l'eau. Dans les conditions appropriées, on obtient une azaérythromycine de grande pureté présentant un bon rendement.
PCT/ES2001/000452 2000-11-30 2001-11-26 Procédé permettant d'obtenir de l'azaérythromycine Ceased WO2002044193A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002220757A AU2002220757A1 (en) 2000-11-30 2001-11-26 Method for obtaining azaerythromycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200002858A ES2179756B1 (es) 2000-11-30 2000-11-30 Procedimiento de obtencion de azaeritromicina.
ESP200002858 2000-11-30

Publications (1)

Publication Number Publication Date
WO2002044193A1 true WO2002044193A1 (fr) 2002-06-06

Family

ID=8495813

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2001/000452 Ceased WO2002044193A1 (fr) 2000-11-30 2001-11-26 Procédé permettant d'obtenir de l'azaérythromycine

Country Status (4)

Country Link
AU (1) AU2002220757A1 (fr)
ES (1) ES2179756B1 (fr)
PT (1) PT102564B (fr)
WO (1) WO2002044193A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304407C (zh) * 2004-09-03 2007-03-14 南京圣和药业有限公司 一种阿奇霉素的精制方法
WO2007017898A3 (fr) * 2005-05-24 2007-04-26 Kopran Res Lab Ltd Procede de recuperation d'un catalyseur pt/c dans la preparation de dihydrate d'azithromycine
WO2007015265A3 (fr) * 2005-05-24 2007-12-06 Kopran Res Lab Ltd Fabrication de 6,9-imino ether
WO2007029266A3 (fr) * 2005-05-24 2007-12-06 Kopran Res Lab Ltd Procede de preparation de 9-deoxo-9a-aza-homoerythromycine
CN109575092A (zh) * 2018-12-19 2019-04-05 宜昌东阳光药业股份有限公司 一种阿奇霉素重排杂质内酰胺的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328334A (en) * 1979-04-02 1982-05-04 Pliva Pharmaceutical And Chemical Works 11-Aza-10-deoxo-10-dihydroerythromycin A and derivatives thereof as well as a process for their preparation
WO1994026758A1 (fr) * 1993-05-19 1994-11-24 Pfizer Inc. Intermediaire s'appliquant a l'azithromycine
EP0879823A1 (fr) * 1997-05-19 1998-11-25 Hovione Inter Ltd. Préparation de l'azithromycine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328334A (en) * 1979-04-02 1982-05-04 Pliva Pharmaceutical And Chemical Works 11-Aza-10-deoxo-10-dihydroerythromycin A and derivatives thereof as well as a process for their preparation
WO1994026758A1 (fr) * 1993-05-19 1994-11-24 Pfizer Inc. Intermediaire s'appliquant a l'azithromycine
EP0879823A1 (fr) * 1997-05-19 1998-11-25 Hovione Inter Ltd. Préparation de l'azithromycine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304407C (zh) * 2004-09-03 2007-03-14 南京圣和药业有限公司 一种阿奇霉素的精制方法
WO2007017898A3 (fr) * 2005-05-24 2007-04-26 Kopran Res Lab Ltd Procede de recuperation d'un catalyseur pt/c dans la preparation de dihydrate d'azithromycine
WO2007015265A3 (fr) * 2005-05-24 2007-12-06 Kopran Res Lab Ltd Fabrication de 6,9-imino ether
WO2007029266A3 (fr) * 2005-05-24 2007-12-06 Kopran Res Lab Ltd Procede de preparation de 9-deoxo-9a-aza-homoerythromycine
CN109575092A (zh) * 2018-12-19 2019-04-05 宜昌东阳光药业股份有限公司 一种阿奇霉素重排杂质内酰胺的合成方法
CN109575092B (zh) * 2018-12-19 2022-05-10 宜昌东阳光生化制药有限公司 一种阿奇霉素重排杂质内酰胺的合成方法

Also Published As

Publication number Publication date
ES2179756A1 (es) 2003-01-16
AU2002220757A1 (en) 2002-06-11
PT102564A (pt) 2002-05-31
PT102564B (pt) 2004-07-30
ES2179756B1 (es) 2004-10-01

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