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WO2001053305A1 - Procédés de préparation de dérivés de carbapenem - Google Patents

Procédés de préparation de dérivés de carbapenem Download PDF

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Publication number
WO2001053305A1
WO2001053305A1 PCT/JP2001/000439 JP0100439W WO0153305A1 WO 2001053305 A1 WO2001053305 A1 WO 2001053305A1 JP 0100439 W JP0100439 W JP 0100439W WO 0153305 A1 WO0153305 A1 WO 0153305A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
substituted
formula
alkyl group
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/JP2001/000439
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English (en)
Japanese (ja)
Inventor
Toshiro Sasaki
Takashi Ando
Kunio Atsumi
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.)
Meiji Seika Kaisha Ltd
Original Assignee
Meiji Seika Kaisha Ltd
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 Meiji Seika Kaisha Ltd filed Critical Meiji Seika Kaisha Ltd
Priority to AU2001227095A priority Critical patent/AU2001227095A1/en
Publication of WO2001053305A1 publication Critical patent/WO2001053305A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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 provides a novel process for producing 2- (7-methylthioimidazo [5,1-b] thiazolyl-2-yl) capilluvanem derivatives having excellent antibacterial activity and a wide spectrum, and intermediates thereof. About.
  • a carbenem derivative having a substituted imidazo [5,11b] thiazolyl group at the 2-position on the carbamine ring is a laculinase-producing bacterium, MRS A (methicillin-resistant It has strong antibacterial activity against Staphylococcus aureus, resistant Pseudomonas aeruginosa, PRSP (benicillin-resistant pneumococcus), enterococci and Haemophilus influenzae, and high against DHP-1 (renal dehydrobeptidase-1) It has been reported that it has stability. The following methods are disclosed as methods for producing these derivatives.
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 3 represents a protecting group for a carboxyl group or a group capable of being hydrolyzed in a living body
  • R 1 represents a lower alkyl group.
  • R represents also represent a group in vivo can be hydrolyzed, refers to salts of Cal Bokishiru group or Anion-carboxylic acid as _C0 2 R.
  • the compound of the formula (X) and the reagent such as trialkyltin chloride used for preparing the compound belong to the organotin compound and have high toxicity. Further, the palladium catalyst and the phosphine ligand used in the reaction of the compound of the formula (IX) with the compound of the formula (X) were expensive.
  • the present invention is directed to a method for advantageously producing a lubabenem derivative having a substituted imidazo [5,1-b] thiazole group at the 2-position on the lavenenem ring in terms of safety and economy, and its production. Its purpose is to provide intermediates used in the method.
  • the present inventors have treated certain substituted imidazo [5,1-b] thiazols, which are intermediates for the production of sorbanem derivatives, with a Grignard reagent and combined the resulting mixture with other intermediates for the production. By reacting, we have found that carbane derivatives can be produced efficiently, safely and inexpensively.
  • the present invention is based on this finding.
  • the process according to the invention comprises a compound of the formula (III):
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 2 is substituted by a lower alkyl group optionally substituted by one or more halogen atoms, or a halogen atom or lower alkyl group (this alkyl group may be substituted by one or more halogen atoms)
  • R 3 represents a carboxyl protecting group or a group that can be hydrolyzed in vivo.
  • X represents a halogen atom.
  • IT is a lower alkyl group optionally substituted with one or more halogen atoms, or a halogen atom, a lower alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • a lower alkoxy group optionally substituted by an atom and one NR 5 R 6 (R 5 and R 6 may be the same or different and represent a lower alkyl group, or R 5 and R f Together represent a — (C IL) lake—group (n is an integer from 2 to 6) which may be substituted with one or more groups which may be the same or different and are selected from the group consisting of Represents a phenyl group, and I 1 , R 2 and R 3 have the same meanings as defined in the formula (II I).
  • R 1 represents a hydrogen atom or a hydroxyl-protecting group
  • R represents a hydrogen atom or a group capable of being hydrolyzed in a living body, or forms a pharmaceutically acceptable salt.
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • Lower alkyl group lower alkyl group, lower alkyl group, lower alkyl group, lower alkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower alkyloxy group, lower alkyloxy group, lower alkyloxy group Cycloalkyloxycarbonyloxy lower alkyl group, lower cycloalkyloxycarbonyloxy (lower cycloalkyl) methyl group, lower cycloalkyl lower alkyloxycarbonyloxy lower alkyl group Group, adamantyloxycarbonyloxy lower alkyl group, 2-indaniloxycarbonyloxy lower alkyl group which may have a substituent on the aromatic ring, aryl lower alkyloxycarbonyl group Xyl-lower alkyl group, aryloxy lower alkyl group, ponyloxy-lower alky
  • R 4 is a substituted lower alkyl group, or a halogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, wherein one or more hydrogen atoms on the ring are the same or different, —NR S R 6 (R s and R f may be the same or different and each represents a lower alkyl group, or R s and R 6 together form a — (CH 2 ) group (n is an integer of 2 to 6)
  • a production method characterized by representing a phenyl group which may be substituted with a group selected from the group consisting of the group represented by.
  • Preferred specific examples of the compound of the formula (I) include:
  • the compound of formula (I) is dissolved or suspended in an inert solvent such as tetrahydrofuran, getyl ether, dioxane, dimethoxetane, toluene, benzene, dichloromethane, hexamethylphosphoric acid triamide, and the like. 70 ° C., preferably at 180 ° C.
  • alkyl magnesium chloride alkyl magnesium bromide, alkyl magnesium oxide, aryl magnesium bromide, etc., preferably methyl magnesium
  • a Grignard reagent such as chloride and ethylmagnesium bromide
  • the mixture was mixed with tetrahydrofuran, getyl ether, dioxane, dimethyloxetane, toluene, benzene, dichloromethane, and hexamethyl phosphate triamide.
  • a compound of formula (I) such as alkyl magnesium chloride, alkyl magnesium bromide, alkyl magnesium chloride, aryl magnesium bromide, etc., preferably methyl magnesium chloride, ethyl magnesium bromide.
  • a compound of formula (III) can be obtained.
  • the obtained compound of the formula (III) may be purified, if necessary, by precipitation, crystallization, or gel filtration using Sephadex or the like, or silica gel column chromatography, and used in the next step.
  • the compound of formula (III) is then subjected to the steps of forming an ordinary ring of pentane, removing the protecting group if necessary, introducing an ester residue which can be hydrolyzed in vivo, and Z Alternatively, the compound can be converted to a compound of the formula (IV) by performing a step of forming a pharmaceutically acceptable salt in CO 2 R.
  • the step of forming the carbane ring is carried out under Wittig cyclization conditions well known in the art, that is, the compound represented by the formula (III) dissolved in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, or dioxane, If necessary, the reaction can be carried out by adding a catalytic amount of an additive (preferably hydroquinone) and reacting at room temperature to reflux temperature for 10 minutes to 24 hours.
  • an additive preferably hydroquinone
  • the step of removing the protecting group is performed by performing the deprotection reaction of the protecting groups R 1 and R 3 in one or more steps before or after performing the above-mentioned ring closing reaction depending on the type of the protecting group. Become.
  • a mineral acid such as hydrochloric acid
  • an organic acid such as formic acid, acetic acid or citric acid
  • a Lewis acid such as aluminum chloride
  • R 1 is a silyl protecting group (for example, t-butyldimethylsilyl group, trimethylsilyl group, or triethylsilyl group)
  • a fluorine ion reagent for example, tetrabutylammonium fluoride
  • R ′ is an aryloxycarbonyl group and R 3 is an aryl group
  • it can be easily removed by using various palladium complexes (for example, tetrakis (triphenylphosphine) palladium (0) and the like). it can.
  • R 3 to produce a compound of formula (IV) is an ester residue which can be hydrolyzed in vivo may be prepared according to the following steps.
  • bases in this reaction include organic bases such as diisoprovirethylamine, diazabicyclo [2,2,2] indene and 2,6-lutidine, and inorganic bases such as sodium hydroxide, Examples include potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
  • R "_Y is, for example, benzoyloxymethyl chloride, 11- (benzoyloxy) ethyl chloride, 11- (2-methylbenzoyloxy) ethyl chloride, 4-t-butylbenzoyl chloride 2,4,6-trimethylbenzoyloxymethyl chloride, 4- (N, N-di-n-propylaminosulfonyl) ben Vyloxymethyl chloride 1- [4- (N, N-di-n-propylaminosulfonyl) benzoyloxy] ethyl chloride, 2-naphthylcarboxyloxymethyl chloride, 1-adamantylcarbonyloxymethyl chloride 1- (1-adamantylcarbonyloxy) ethyl, cyclohexyl (cyclohexyloxycarbonyloxy) methylo-dide, (1R, 2S, 5R)-( 1) 1-menthyloxycarbonyloxymethyl chloride, (1
  • the compound represented by the formula (XII) thus obtained can be isolated and purified by precipitation, crystallization or gel filtration using Sephadex or the like, or silica gel column chromatography. can do.
  • Kiichi C 0 2 step of forming a pharmaceutically acceptable salt thereof in R can therefore performed with conventional methods.
  • a compound represented by the formula (XII) is suspended in water, and under ice-cooling, 1.0 equivalent of an aqueous solution of sodium hydrogencarbonate or potassium hydrogencarbonate is added. And then freeze-dried as it is or by precipitation or crystallization using an organic solvent such as acetonitrile or acetone.
  • an organic solvent such as acetonitrile or acetone.
  • Example 1 2- Mode 7-methylthioimidazo "5, 1-b] thiazol 2- (tree n-butylsyl)-7-methylthioimidazo [5, 1-b] thiazole 0. Cool 2.5 g of 23 g of tetrahydrofuran to 150 ° C, 0.11 g of N-succinimide was added. After stirring at the same temperature for 4 hours, 50 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a dilute aqueous sodium bicarbonate solution, a dilute aqueous sodium thiosulfate solution, and a saturated aqueous sodium chloride solution.
  • This reaction mixture was added to 100 ml of a saturated aqueous solution of ammonium chloride, and extracted with 100 ml of ethyl acetate.
  • the organic layer was sequentially washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • the residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate) to obtain 0.39 g of the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des procédés permettant de préparer, de manière efficace, sûre et à bas coût, des dérivés de carbapenem comportant des groupes imidazo[5,1-b]thiazolyle substitués en position 2 du cycle carbapenem, ainsi que les produits intermédiaires destinés à être utilisés dans le cadre desdits procédés. L'invention concerne, en particulier, un procédé de préparation des composés représentés par la formule générale (III), qui consiste à faire réagir un mélange réactionnel, obtenu par le traitement d'un composé représenté par la formule générale (I) avec un réactif de Grignard, avec un composé par la formule générale (II). Dans lesdites formules, X représente un halogéno; R1 représente H ou un groupe protecteur hydroxyle; R2 désigne un alkyle éventuellement substitué ou un aryle éventuellement substitué; R3 représente un groupe protecteur carboxyle ou un groupe hydrolysable in vivo; et R4 désigne un alkyle éventuellement substitué ou un phényle éventuellement substitué.
PCT/JP2001/000439 2000-01-24 2001-01-24 Procédés de préparation de dérivés de carbapenem Ceased WO2001053305A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001227095A AU2001227095A1 (en) 2000-01-24 2001-01-24 Processes for the preparation of carbapenem derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000015105A JP2005231997A (ja) 2000-01-24 2000-01-24 カルバペネム誘導体の製造法
JP2000-15105 2000-01-24

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WO2001053305A1 true WO2001053305A1 (fr) 2001-07-26

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004055027A1 (fr) * 2002-12-13 2004-07-01 Meiji Seika Kaisha, Ltd. Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production
WO2006077919A1 (fr) * 2005-01-19 2006-07-27 Meiji Seika Kaisha, Ltd. Dérivé d'imidazothiazole et méthode de synthèse dudit dérivé
US7482445B2 (en) 2003-06-18 2009-01-27 Meiji Seika Kaisha, Ltd. Crystalline carbapenem intermediate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010316A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0089139A2 (fr) * 1982-03-16 1983-09-21 Beecham Group Plc Antibiotiques, leur préparation et leur utilisation
EP0760370A1 (fr) * 1995-03-10 1997-03-05 Meiji Seika Kabushiki Kaisha Nouveaux derives de carbapeneme
WO1998032760A1 (fr) * 1997-01-28 1998-07-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2000006581A1 (fr) * 1998-07-27 2000-02-10 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010316A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0089139A2 (fr) * 1982-03-16 1983-09-21 Beecham Group Plc Antibiotiques, leur préparation et leur utilisation
EP0760370A1 (fr) * 1995-03-10 1997-03-05 Meiji Seika Kabushiki Kaisha Nouveaux derives de carbapeneme
WO1998032760A1 (fr) * 1997-01-28 1998-07-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2000006581A1 (fr) * 1998-07-27 2000-02-10 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUTHIKONDA R.N. ET AL.: "Structure-activity relationships in the 2-arylcarbapenem series: synthesis of 1-methyl-2-aryl-cabapenems", J. MED. CHEM., vol. 30, no. 5, 1987, pages 871 - 880, XP002942200 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004055027A1 (fr) * 2002-12-13 2004-07-01 Meiji Seika Kaisha, Ltd. Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production
US7524951B2 (en) 2002-12-13 2009-04-28 Meiji Seika Kaisha, Ltd. Intermediates of 2-substituted carbapenem derivatives and process for production thereof
US7563901B2 (en) 2002-12-13 2009-07-21 Meiji Seika Kaisha, Ltd. Intermediates of 2-substituted carbapenem derivatives and process for production thereof
US7482445B2 (en) 2003-06-18 2009-01-27 Meiji Seika Kaisha, Ltd. Crystalline carbapenem intermediate
WO2006077919A1 (fr) * 2005-01-19 2006-07-27 Meiji Seika Kaisha, Ltd. Dérivé d'imidazothiazole et méthode de synthèse dudit dérivé
US7662841B2 (en) 2005-01-19 2010-02-16 Meiji Seika Kaisha, Ltd. Imidazothiazole derivatives and process for producing the same
CN101137661B (zh) * 2005-01-19 2011-06-15 明治制果株式会社 咪唑并噻唑衍生物及其制备方法
JP4964599B2 (ja) * 2005-01-19 2012-07-04 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 イミダゾチアゾール誘導体およびその製造方法
KR101344137B1 (ko) 2005-01-19 2013-12-20 메이지 세이카 파루마 가부시키가이샤 이미다조티아졸 유도체 및 그의 제조방법

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AU2001227095A1 (en) 2001-07-31
JP2005231997A (ja) 2005-09-02

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