WO2004106353A1 - Process for selective alkylation of macrolide and azalide derivatives - Google Patents

Process for selective alkylation of macrolide and azalide derivatives Download PDF

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Publication number
WO2004106353A1
WO2004106353A1 PCT/HR2003/000048 HR0300048W WO2004106353A1 WO 2004106353 A1 WO2004106353 A1 WO 2004106353A1 HR 0300048 W HR0300048 W HR 0300048W WO 2004106353 A1 WO2004106353 A1 WO 2004106353A1
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WO
WIPO (PCT)
Prior art keywords
macrolide
azalide
derivatives
selective alkylation
transition
Prior art date
Application number
PCT/HR2003/000048
Other languages
French (fr)
Inventor
Davor Kidemet
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.)
Filing date
Publication date
Application filed by Pliva - Istrazivacki Institut D.O.O. filed Critical Pliva - Istrazivacki Institut D.O.O.
Priority to AU2003264910A priority Critical patent/AU2003264910A1/en
Publication of WO2004106353A1 publication Critical patent/WO2004106353A1/en

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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
    • 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

  • the present invention relates to a process for selective alkylation of macrolide and azalide derivatives. 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 present invention relates to a process for preparing 11-O-alkyl macrolide and azalide derivatives comprising reacting an macrolide or azalide derivative with vicinal hydroxyl system with diazoalkane having the formula:
  • R is a hydrogen or C1-C3 alkyl groups in the presence of transition-metal halides and of boric acid, respectively.
  • Macrolide and azalide derivatives 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).
  • 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-dimethylacetamide, pyridine, dichloromethane,ethyl-acetate, dimethyl

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a process for selective alkylation of macrolide and azalide derivatives comprising reacting an macrolide or azalide derivative having a vicinal hydroxyl system with diazoalkane of the formula: R-CHN2 wherein R is a hydrogen or C1-C3 alkyl group in the presence of transition-metal halides and of boric acid, respectively.

Description

PROCESS FOR SELECTIVE ALKYLATION OF MACROLIDE AND AZALIDE
DERIVATIVES
This application claims priority to U.S. Provisional Application 60/474,348 filed May 30, 2003.
TECHNICAL FIELD
The present invention relates to a process for selective alkylation of macrolide and azalide derivatives. 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.
BACKGROUND OF THE INVENTION
A series of alkyl derivatives of macrolide and azalide antibiotics have been described in the literature. Among them O-Me derivatives of erythromycin (clarithromycin) (US Patent No. 4,331,803) and azithromycin (US Patent No. 5,250,518) have significant biolgical activities. The process for making this derivatives in general is a multistep procedure. Because macrolide and azalide compounds posses a few different hydroxyl groups it is difficult to alkylate one hydroxyl group selectively in the presence of other unprotected hydroxyl groups (see e.g. J. Antibiot. 46 (1993) 647; J. Antibiot. 43 (1990) 286). Various protecting groups have been described in the literature (See e.g. J. Antibiot. 45 (1992) 527, J. Antibiot. 37 (1984) 187, J. Antibiot. 46 (1993) 1163, US Patent Nos. 5,872,229; 5,719,272; 5,929,219). Selective synthesis of 12-OMe-azithromycin has been described in WO 99/20639. However, the substitution at the 11-O-position with alkyl groups is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Therefore, there is considerable effort directed towards discovering more efficient and cleaner and one step method of introducing alkyl supstituents in the 11 -position of macrolide and azalide derivatives that have unprotected other hydroxyl groups. The method is suitable to all macrolide and azalide compounds having vicinal diol system. Regioselective alkylation of vicinal hydroxyl groups with diazoalkanes in the presence of transition-metal halides and of boric acid, respectively, is known in the literature. See for example,. Carbohydr. Res. 316 (1999) 187-200; Helv. Chim. Acta 79 (1996) 2114-2136; Chem. Pharm. Bull. 18 (1970) 677-686. However, there are no known reports of regioselective alkylation of 11 -hydroxyl group of macrolide and azalide derivatives with diazoalkanes in the presence of transition-metal halides and of boric acid, respectively.
DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing 11-O-alkyl macrolide and azalide derivatives comprising reacting an macrolide or azalide derivative with vicinal hydroxyl system with diazoalkane having the formula:
R - CH N2 wherein
R is a hydrogen or C1-C3 alkyl groups in the presence of transition-metal halides and of boric acid, respectively.
Macrolide and azalide derivatives 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). To reaction mixture transition-metal halide or boric acid was added and the resulting mixture is stirred at a temperature from -20°C to the reflux temperature of the solvent for 1 hour. Then, ether solution of the coresponding diazoalkane was added dropwise. The reaction micture 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-derivatives.

Claims

1. A process for selective alkylation of macrolide and azalide derivatives comprising reacting an macrolide or azalide derivative having a vicinal hydroxyl system with diazoalkane of the formula:
R - CH N2 wherein
R is a hydrogen or C1-C3 alkyl group in the presence of transition-metal halides and of boric acid, respectively.
PCT/HR2003/000048 2003-05-30 2003-09-04 Process for selective alkylation of macrolide and azalide derivatives WO2004106353A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003264910A AU2003264910A1 (en) 2003-05-30 2003-09-04 Process for selective alkylation of macrolide and azalide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47434803P 2003-05-30 2003-05-30
US60/474,348 2003-05-30

Publications (1)

Publication Number Publication Date
WO2004106353A1 true WO2004106353A1 (en) 2004-12-09

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Application Number Title Priority Date Filing Date
PCT/HR2003/000048 WO2004106353A1 (en) 2003-05-30 2003-09-04 Process for selective alkylation of macrolide and azalide derivatives

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CN (1) CN100381453C (en)
AU (1) AU2003264910A1 (en)
WO (1) WO2004106353A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103923142B (en) * 2014-04-30 2017-01-11 浙江震元制药有限公司 Preparation method of roxithromycin intermediate
CN105801642B (en) * 2016-03-11 2019-03-26 北京理工大学 A method of preparing the bis--O- erythromycin A of 6,11-
WO2018150421A1 (en) * 2017-02-14 2018-08-23 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Cyclization processes of hydroxyalkenoic aicds and products thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020639A2 (en) * 1997-10-16 1999-04-29 Pliva, Farmaceutska Industrija ,Dionicko, Drustvo NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9011409A (en) * 1990-07-18 1995-10-31 Pliva Pharm & Chem Works O-methyl azitromycin derivates, methods and intermediates for their preparation and methods for preparation of pharmaceuticals products which comprise them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020639A2 (en) * 1997-10-16 1999-04-29 Pliva, Farmaceutska Industrija ,Dionicko, Drustvo NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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 *

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Publication number Publication date
CN1798755A (en) 2006-07-05
AU2003264910A1 (en) 2005-01-21
CN100381453C (en) 2008-04-16

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