WO2017078097A1 - Procédé de fabrication d'antibiotique à base d'aminoglycoside - Google Patents

Procédé de fabrication d'antibiotique à base d'aminoglycoside Download PDF

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Publication number
WO2017078097A1
WO2017078097A1 PCT/JP2016/082667 JP2016082667W WO2017078097A1 WO 2017078097 A1 WO2017078097 A1 WO 2017078097A1 JP 2016082667 W JP2016082667 W JP 2016082667W WO 2017078097 A1 WO2017078097 A1 WO 2017078097A1
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WIPO (PCT)
Prior art keywords
formula
compound represented
group
positions
compound
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Application number
PCT/JP2016/082667
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English (en)
Japanese (ja)
Inventor
高橋　良昭
英二郎 梅村
Original Assignee
Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
公益財団法人 微生物化学研究会
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Application filed by Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社, 公益財団法人 微生物化学研究会 filed Critical Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
Publication of WO2017078097A1 publication Critical patent/WO2017078097A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel method for producing aminoglycoside antibiotics.
  • MRSA microporous swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine-resistant swine, and the development of therapeutic drugs is actively being carried out.
  • aminoglycoside antibiotics have a broad antibacterial spectrum from Gram-positive bacteria to Gram-negative bacteria and have an excellent bactericidal activity, and thus are promising to overcome various resistant bacteria including MRSA. Expected to be a drug, research into its derivatives is ongoing.
  • Patent Document 1 discloses (2S) -2-hydroxyarbekacin as a part of the present inventors as an aminoglycoside antibiotic that exhibits a broad antibacterial spectrum and excellent antibacterial activity and can avoid severe nephrotoxicity. It is disclosed. Patent Document 1 describes that the final substance (2S) -2-hydroxyarbekacin was produced using the synthetic intermediate (2S) -2-hydroxydibekacin.
  • an object of the present invention is to provide a novel method for stably producing (2S) -2-hydroxydibekacin.
  • the manufacturing method of the compound represented by Formula (15) characterized by using the compound represented by Formula (1) as a raw material or a synthetic intermediate is provided.
  • the manufacturing method of the compound represented by Formula (15) characterized by using the compound represented by Formula (16) as a raw material or a synthetic intermediate is provided.
  • high purity (2S) -2-hydroxydibekacin can be stably produced by using 2-hydroxykanamycin C or 2-hydroxykanamycin B as a raw material or a synthetic intermediate.
  • the amino group of the compound represented by the formula (1) is protected with a tert-butoxycarbonyl group to obtain the compound represented by the formula (2).
  • the compound represented by the formula (7) is reacted with a base to epoxidize the 3 ′ and 4 ′ positions and deprotect the hydroxyl groups at the 2, 2 ′′, 4 ′′ and 6 ′ positions, A hydroxyl group at the 2 ′′, 4 ′′ and 6 ′ positions is protected with an acetyl group to obtain a compound represented by the formula (8).
  • the compound represented by the formula (9) is benzylsulfonylated at the 3 ′ position, and the compound represented by the formula (10) is eliminated by the elimination reaction of the 3′-position benzylsulfonyloxy group and the 4′-position iodine. Get.
  • the amino group of the compound represented by the formula (16) is protected with a benzyloxycarbonyl group to obtain the compound represented by the formula (17).
  • the compound represented by the formula (21) is treated by the Tipson-Cohen reaction to obtain the compound represented by the formula (22) by the elimination reaction at the 3 ′ and 4 ′ positions.
  • the compound represented by the formula (22) is subjected to base treatment and / or acid treatment to deprotect the 2, 2 ′′, 4 ′′ and 6-positions, and represented by the formula (23). A compound is obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention fournit un procédé qui est caractéristique en ce qu'une 2-hydroxykanamycine C ou une 2-hydroxykanamycine B est mise en œuvre en tant que matière première ou produit semi-ouvré synthétique, et qui est destiné à fabriquer de manière stable une (2S)-2-hydroxydibékacine.
PCT/JP2016/082667 2015-11-02 2016-11-02 Procédé de fabrication d'antibiotique à base d'aminoglycoside WO2017078097A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015216165A JP2019001718A (ja) 2015-11-02 2015-11-02 アミノグリコシド系抗生物質の製造方法
JP2015-216165 2015-11-02

Publications (1)

Publication Number Publication Date
WO2017078097A1 true WO2017078097A1 (fr) 2017-05-11

Family

ID=58662113

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/082667 WO2017078097A1 (fr) 2015-11-02 2016-11-02 Procédé de fabrication d'antibiotique à base d'aminoglycoside

Country Status (2)

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JP (1) JP2019001718A (fr)
WO (1) WO2017078097A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS608299A (ja) * 1983-06-28 1985-01-17 Fujisawa Pharmaceut Co Ltd ５−デ−ｏ−メチルスポラリシンｂまたはその塩類の製造法
WO2007142150A1 (fr) * 2006-06-02 2007-12-13 Meiji Seika Kaisha, Ltd. Nouvel antibiotique de type aminoglycoside
WO2009069800A1 (fr) * 2007-11-30 2009-06-04 Meiji Seika Kaisha, Ltd. Nouvel antibiotique de type aminoglycoside, son procédé de production et son utilisation pharmaceutique
CN101575354A (zh) * 2009-05-26 2009-11-11 北京化工大学 阿贝卡星及其中间体地贝卡星的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS608299A (ja) * 1983-06-28 1985-01-17 Fujisawa Pharmaceut Co Ltd ５−デ−ｏ−メチルスポラリシンｂまたはその塩類の製造法
WO2007142150A1 (fr) * 2006-06-02 2007-12-13 Meiji Seika Kaisha, Ltd. Nouvel antibiotique de type aminoglycoside
WO2009069800A1 (fr) * 2007-11-30 2009-06-04 Meiji Seika Kaisha, Ltd. Nouvel antibiotique de type aminoglycoside, son procédé de production et son utilisation pharmaceutique
CN101575354A (zh) * 2009-05-26 2009-11-11 北京化工大学 阿贝卡星及其中间体地贝卡星的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RAKHIT,S. ET AL.: "Facile synthesis of purpurosamine C, a component of the antibiotic gentamicin Cla", JOURNAL OF CARBOHYDRATES, NUCLEOSIDES, NUCLEOTIDES, vol. 2, no. 2, 1975, pages 153 - 157 *
YONETA,T. ET AL.: "An improved synthesis of 3', 4'-dideoxykanamycin B", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 52, no. 4, 1979, pages 1131 - 1134, XP055379556 *

Also Published As

Publication number Publication date
JP2019001718A (ja) 2019-01-10

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