WO2005021567A1 - Derives o-alkyle de macrolides et d'azalides et processus d'obtention stereoselectif - Google Patents

Derives o-alkyle de macrolides et d'azalides et processus d'obtention stereoselectif Download PDF

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Publication number
WO2005021567A1
WO2005021567A1 PCT/HR2003/000047 HR0300047W WO2005021567A1 WO 2005021567 A1 WO2005021567 A1 WO 2005021567A1 HR 0300047 W HR0300047 W HR 0300047W WO 2005021567 A1 WO2005021567 A1 WO 2005021567A1
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WIPO (PCT)
Prior art keywords
derivative
azalide
macrolide
membered
methyl
Prior art date
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PCT/HR2003/000047
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English (en)
Inventor
Davor Kidemet
Gorjana Lazarevski
Marko Derek
Marija Leljak
Original Assignee
Pliva - Istrazivacki Institut D.O.O.
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.)
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Application filed by Pliva - Istrazivacki Institut D.O.O. filed Critical Pliva - Istrazivacki Institut D.O.O.
Priority to AU2003267675A priority Critical patent/AU2003267675A1/en
Publication of WO2005021567A1 publication Critical patent/WO2005021567A1/fr

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    • 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

Definitions

  • the present invention relates to a process for regioselective O-alkylation of macrolide and azalide derivatives applicable in a large scale. Specifically, the invention relates to regioselective alkylation of macrolide and azalide derivatives having vicinal diol system, using diazoalkanes in the presence of transition-metal halides and of boric acid as catalysts, respectively. In another aspect, the invention relates to macrolide and azalide derivatives obtained according to abovementioned method, pharmaceutically acceptable salts and solvates and use thereof as antibacterial agents or intermediates for the synthesis of other antibacterial agents.
  • the present invention relates to a process for selective alkylation of macrolide and azalide derivatives applicable in a large scale. Specifically, the invention relates to regioselective alkylation of macrolide and azalide derivatives having vicinal diol system, using diazoalkanes in the presence of transition-metal halides and of boric acid, respectively.
  • the invention relates to macrolide and azalide derivatives obtained according to abovementioned method, pharmaceutically acceptable salts and solvates and use thereof as antibacterial agents or intermediates for the synthesis of other antibacterial agents.
  • pharmaceutically acceptable salts and solvates and use thereof as antibacterial agents or intermediates for the synthesis of other antibacterial agents.
  • the present invention relates to process for regioselective O-alkylation of macrolide and azalide derivatives, specifically 11-O-alkyl derivatives represented by formula (I) (I)
  • A is 14-membered macrolide derivative and 15-membered azalide derivative, and R 1 is C1-C4 alkyl group
  • A is 14-membered macrolide derivatives and 15-membered azalide derivatives
  • R 2 is a hydrogen or C1-C3 alkyl groups
  • transition-metal halides and of boric acid as catalysts respectively, preferably H 3 BO 3 , TiCl and SnCl in suitable inert organic solvent.
  • Representative 14-membered macrolides include clarithromycin (J. Antibiot. 43 (1990) 544-549), roxithromycin (J. Antibiot 39 (1986) 660), and 15-membered azalide derivatives include azithromycin (J. Chem. Research (S) (1988) 152, J. Chem. Research (M) (1988) 1239),2'- ⁇ ,3'-N-dicarbobenzoxy-azithromycin (J. Antibiotics 45 (1992) 527), 9-deoxo-9a-aza-9a-homoerythromycin (J. Chem. Soc. Perkin Trans.
  • Macrolide and azalide derivatives formula (I) are dissolved in suitable inert organic solvent (e.g. but not limited to, lower alcohols, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, dichloromethane,ethyl-acetate, dimethyl sulfoxide, ethers), preferably acetone or ethanol or N,N-dimethylformamide.
  • suitable inert organic solvent e.g. but not limited to, lower alcohols, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, dichloromethane,ethyl-acetate, dimethyl sulfoxide, ethers
  • suitable inert organic solvent e.g. but not limited to, lower alcohols, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacet
  • reactione mixture one equivalent or less of transition-metal halide or boric acid, preferably boric acid or TiCl 4 or SnCl 2 , was added and the resulting mixture is stirred at a temperature from -20°C to the reflux temperature of the solvent, preferably room temperature, for 1 hour. Then, ether solution of the coresponding diazoalkane was added dropwise. The reaction mixture was stirred at said temperature until TLC analysis showed complete conversion. Isolation by using standard methods (extraction, precipitation and like) afforded excusively desired 11-O-alkil- macrolide and azalide derivatives. Representative compounds of the present invention were assayed in vitro for antibacterial activity. The results of this assay as minimum inhibitory concentrations (MIC) are reported in Table 1.
  • Diazomethane was prepared according to the method and apparatus described in J. Org.
  • Diazald (Diazald) and potassium hydroxide.
  • Solution of Diazald in diethylether was added dropwise in solution of KOH in water and ethanol.
  • the yellow condensate of diazomethane was continuously introduced into the reaction mixture.
  • Diazomethane was prepared according to the method described in Org. Synth. Coll. Vol. 2 (1943) 165, starting from N-methyl-N-nitrosourea which was portionwise added to the mixture of 40% aq. KOH and ether (diethyl or diisopropyl-ether) at 0 °C while vigorous stirring. The phases were separated and upper organic layer containing diazomethane was used for methylation.
  • Example 1 The compound of example 1 was obtained in the same manner as described in Example 1 Method II by using different solvents and salts as indicated in Table 2. Quantitative analysis of final mixtures was performed by LC-MS method
  • Clarithromycin J. Antibiot. 43 (1990) 544-549
  • (1.00 g, 1.34 mmol) and SnCl 2 2H 2 O 0.307 g, 1.36 mmol
  • DMF 10 mL
  • Solution of diazomethane in diethylether from Method B (cca 6 mmol) was added and resulting mixture was stirred at r.t.for 4 hours.
  • the mixture was diluted with aq. NaHCO 3 (50 mL) and extracted with ethyl-acetate (3 x 30 mL). The organic layer was dried over Na 2 SO 4 , and concentrated to afford mixture of title and starting compounds (24 % : 73 % LC-MS).

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  • 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

La présente invention concerne un processus stéréosélectif par O-alkylation de dérivés macrolides et azalides, en particulier de dérivés de 11-0 alkyle représentés par la formule (I) dans laquelle A est un dérivé macrolide à 13 éléments et un dérivé azalide à 15 éléments, et R1 est un groupe C1-C4 alkyle. Ce procédé consiste à faire réagir un dérivé macrolide ou azalide à système hydroxyle vicinal avec un diazoalkane représenté par la formule R2 - CH N2 - dans laquelle R2 est un hydrogène ou un groupe C1-C3 alkyle - en présence d'halogénures de métal de transition et d'acide borique comme catalyseurs, respectivement, de préférence H3B03, TiC14 et SnC12, dans un solvant organique inerte approprié. Cette invention concerne également des nouveaux composants représentés par la formule (I).
PCT/HR2003/000047 2003-09-02 2003-09-04 Derives o-alkyle de macrolides et d'azalides et processus d'obtention stereoselectif WO2005021567A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003267675A AU2003267675A1 (en) 2003-09-02 2003-09-04 O-alkyl macrolide and azalide derivatives and regioselective process for their preparation

Applications Claiming Priority (2)

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US49981703P 2003-09-02 2003-09-02
US60/499,817 2003-09-02

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WO2005021567A1 true WO2005021567A1 (fr) 2005-03-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801642A (zh) * 2016-03-11 2016-07-27 北京理工大学 一种制备6,11-双-o-甲基红霉素a的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080819A1 (fr) * 1981-11-30 1983-06-08 Taisho Pharmaceutical Co. Ltd Dérivés de 11-0-alkylérythromycine A
EP0467331A1 (fr) * 1990-07-18 1992-01-22 PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija dionicko drustvo Dérivés O-méthyliques d'azithromycine A, procédé et composés intermédiaires pour leur production et leur utilisation à la préparation des produits pharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080819A1 (fr) * 1981-11-30 1983-06-08 Taisho Pharmaceutical Co. Ltd Dérivés de 11-0-alkylérythromycine A
EP0467331A1 (fr) * 1990-07-18 1992-01-22 PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija dionicko drustvo Dérivés O-méthyliques d'azithromycine A, procédé et composés intermédiaires pour leur production et leur utilisation à la préparation des produits pharmaceutiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERTHO G ET AL: "Solution conformation of methylated macrolide antibiotics roxithromycin and erythromycin using NMR and molecular modeling. Ribosome-bound conformation determined by TRNOE and formation of cytochrome P450-metabolite complex", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, BUTTERWORTH & CO., GUILDFORD, GB, vol. 22, 1998, pages 103 - 127, XP002219406, ISSN: 0141-8130 *
EVTUSHENKO E V: "Regioselective methylation of methyl glycopyranosides with diazomethane in the presence of transition-metal chlorides and of boric acid", CARBOHYDRATE RESEARCH, ELSEVIER SCIENTIFIC PUBLISHING COMPANY. AMSTERDAM, NL, vol. 316, no. 1-4, 15 March 1999 (1999-03-15), pages 187 - 200, XP004171913, ISSN: 0008-6215 *
MORIMOO S ET AL: "Chemical modifications of erythromycins. II. Synthesis and antibacterial activity of o-alkyl derivatives of erythromycin A", JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO, JP, vol. 43, 1990, pages 286 - 294, XP002093093, ISSN: 0021-8820 *
WADDELL S T ET AL: "Synthesis and antibacterial activity of O-methyl derivatives of azalide antibiotics: I. 4, 11 and 12-OMe derivatives via direct methylation", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 5, 3 March 1998 (1998-03-03), pages 549 - 554, XP004136902, ISSN: 0960-894X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801642A (zh) * 2016-03-11 2016-07-27 北京理工大学 一种制备6,11-双-o-甲基红霉素a的方法
CN105801642B (zh) * 2016-03-11 2019-03-26 北京理工大学 一种制备6,11-双-o-甲基红霉素a的方法

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