WO1983002614A1 - Derives de l'acide 5,6-cis-carbapenem-3-carboxylique et leur procede de preparation - Google Patents

Derives de l'acide 5,6-cis-carbapenem-3-carboxylique et leur procede de preparation Download PDF

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Publication number
WO1983002614A1
WO1983002614A1 PCT/JP1982/000031 JP8200031W WO8302614A1 WO 1983002614 A1 WO1983002614 A1 WO 1983002614A1 JP 8200031 W JP8200031 W JP 8200031W WO 8302614 A1 WO8302614 A1 WO 8302614A1
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Prior art keywords
group
reaction
acid
cis
compound
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PCT/JP1982/000031
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English (en)
Japanese (ja)
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Ltd. Takeda Chemical Industries
Hideaki Natsugari
Yoshihiro Matsushita
Kouichi Yoshioka
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Takeda Chemical Industries Ltd
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Priority to PCT/JP1982/000031 priority Critical patent/WO1983002614A1/fr
Priority to EP82108210A priority patent/EP0074599A1/fr
Publication of WO1983002614A1 publication Critical patent/WO1983002614A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • 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 5,6-cis-force babenemu 3-force boric acid derivative having excellent antibacterial activity and 3-ratatamase inhibitory activity, and a method for producing the same.
  • a vanem compound having a basic skeleton represented by, a compound having a 1-hydroxyl-methyl group at the 6-position and a cis configuration at the 5 and 6-positions is a natural compound. It was found to have a strong antibacterial activity and a strong ⁇ -lactamase inhibitory activity (for example, Japanese Patent Application Laid-Open Nos. 55-104296 and 56-54996).
  • the present invention has a 1-methyl group which may be substituted with an optionally protected hydroxyl group at the 6-position of the above-mentioned vanem skeleton, and the cis-configuration at the 5 and 6-positions.
  • R 1 represents a hydrocarbon group or a heterocyclic group
  • R 2 represents a hydrogen atom or a hydroxyl-protecting group
  • n represents 0, 1 or 2.
  • R 1 is an acetamido or acetamido-ete group and represents a hydrogen atom or a sulfonic acid group
  • n represents 2.
  • This relates to 5, 6-potassium vanem-3-potassium acid derivatives represented by :), pharmacologically acceptable salts thereof, and methods for producing these.
  • R 2 has the same meaning as described above, R 3 represents a hydrogen atom or a carboxy protecting group, and X represents a deprotecting group. 3 ⁇ 4 or a salt thereof and a compound represented by the formula
  • the hydrocarbon group represented by R 1 for example A key, 5 / Croix key, alkenyl-le, Shikuroa Quai Two, alkynyl, ⁇ Lee, ⁇ la key group or the like is used.
  • the alk is preferably a linear or branched lower alk having 1 to 6 carbon atoms. Examples thereof include meth, eth, n-butyl, isobrovi, n-butyl, isobutyl and sec. —Buchi A ⁇ tert-Buchi, n-pliers, isobench, n-hexyl, isohexyl, etc. are used.
  • cycloalkyl those having 3 to 8 carbon atoms are preferable, and for example, ⁇ cloprobi, cyclobutyl, cyclobench, cyclohexyl, cyclohepty, adamantyl and the like are used.
  • a straight chain or a lower case having 2 to 6 carbon atoms of a chain is preferred, such as bi-, aryl and isobutene.
  • aki- ⁇ straight-chain or branched lower alkyls having 2 to 6 carbon atoms, such as ethyl-; u, 1-brovinii, 2-brobi-
  • 3 ⁇ 4 is used.
  • 1-cyclobromo-, 1-cyclobutene, 1-cyclovente, 2-cyclopentene-3-cyclovente ⁇ , 1-cyclohexyl, 2-cyclohexene, 3
  • Those having 3 to 8 carbon atoms, such as —cyclohexyl 1 —cycloheptenyl, 1, -cyclohexadi ⁇ —, etc. are preferably used, and those having 4 to 6 carbon atoms are preferred.
  • heterocyclic group represented by R 1 examples include a 5- to 8-membered ring containing one to several heteroatoms such as a nitrogen atom (which may be oxidized), an oxygen atom and a yellow atom.
  • the condensed ring or the like having a bond at a carbon atom is used.
  • hydrocarbon groups and heterocyclic groups represented by R 1 may have one to several identical or different substituents.
  • alk, alk, and alkynole are, for example, cycloalkyl, cycloa; wk-, aryl, heterocyclic group, alkoxy group, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , u, ⁇ ⁇ , ⁇ ⁇ , ⁇ ⁇ , ⁇ ⁇ Snorrejo-Sai Kishi,
  • ni 0, 1, 2 or 3
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an alkyl, a squiaki, an alkene, an araki, an aryl, a heterocyclic group, a Coxycarbo, oxy or oxo with R 4 and R 5 together
  • Examples of the substitution group include aki, avoxy, aka, a! I, Araki, Meadow, Aki Chi, Ari Chio, Araki Chi, Aki Ho, Ali Sho, Alakis V Ho, Trinoperogenoaki, Hydroki ,
  • the alkoxy is preferably a linear or branched lower alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy and n-bromo.
  • Xy isopropoxy *, 11-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n, benchoxy, isopentoxy, nf ⁇
  • ⁇ ⁇ either.
  • fluorine, chlorine, bromine and iodine are used.
  • quaternary ammonium group for example, bilidium, quinolium and the like are used (as the ash group, for example, fomi, akicarbyl, arylcarbyl) , Aralkyl carboxy-A ⁇ heterocyclic group acetyl, etc.
  • the amino group When an amino group is present in the substituent of the hydrocarbon group or the heterocyclic group represented by R 1 , the amino group may be substituted or protected, and when an amino group is present, these amino groups may be substituted or protected. May also be protected.
  • substituent of the amino group include ash, alkyl, hydroxyaky, aranolekyl, aryy, heterocyclic group, amidino group, amimethylene group, carbamoy group, sulphonic acid group, axinolephony, Laxonil, Aryls Noleh, Akoxyka / 1, Aralkil Kishikaburu, Aryak Kishika Norepo / Tokyo, etc.
  • the amino group together with the 3 ⁇ 4 substituent, For example, a cyclic amino group such as pyrrolidino, biperidino, moholino, and biverazino may be formed.
  • a cyclic amino group such as pyrrolidino, biperidino, moholino, and biverazino may be formed.
  • the protecting group for the amino group those used for this purpose in the field of ⁇ -lactam and peptide synthesis are conveniently employed.
  • aromatic ash groups such as phthaloy, ⁇ -trobenzoyl, ⁇ -ter-butylbenzene, p-tert-butylbenzenesho- ⁇ benzeneshonii, toenshenho, etc., for example, homi, acechi, Aliphatic groups such as brobi, horrloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfone, ethaneshoni, trifluoroacetic, male, succinic, etc., for example, methoxycarbonyl, ethoxycarbonyl Two A ⁇ t—Butoxyka Boni, Isobrofo.
  • the ester group is an amino group such as a trioxy, 2-nitrophenothio, pendylidene, 412 trobenzylidene, or triquinolesili, benzyl, ⁇ -trobenzy, etc.
  • the protecting group is used. The choice of the protecting group is not particularly limited in the present invention. As the protecting group for the carboxy group, 3-latatam and all those which can be used as the protecting group for the ordinary carboxylic group in the field of organic chemistry can be used.
  • any one which can be used as a protecting group for a hydroxyl group in the field of 3-lactam and organic chemistry can be used, for example, acetyl, chloroacetyl and other ester residues, 2, 2, and 2 — trichloroethoxycarbonyl, 2-trimethylsiloxydoxycabonyl esterified carboxyl residue, tert — butyl, penzyl, p — — trobenzyl, tririch, methoxymethyl Ae V residue, trimethytri, tert-butydimethysil, etc.
  • R 2 represents a hydrogen atom or a hydroxyl-protecting group.
  • R 2 for example, those described above and the like are used.
  • protective groups that form an ether bond such as, for example, -methoxyethoxymethy, methoxime, and methylthiomethy ⁇ groups, are frequently used.
  • R 3 represents a hydrogen atom or a carboxyl protecting group.
  • protecting group for the carboxy group represented by R 3 for example, those described above and the like are used.
  • p-trovenge, 0-trobenzil, p-methoxybenzide, etc. are commonly used.
  • the leaving group represented by X includes:
  • n is the same as defined above).
  • a disubstituted phosphoroxy group such as diphenylphosphoroxy group and jetiphosphoryloxy group may be used.
  • the compound of interest (I) may be used as it is, but may be used as it is, but by a method known per se. It can be used in the form of an acceptable salt.
  • non-toxic cations such as sodium and potassium, for example, aginine, o
  • basic amino acids such as tin, lysine, histidine, etc., for example, N-methyldalcamin, diethanamine, triethanolamine And trishydroxymethyaminomethane may be used by forming 3 ⁇ 4 with any of the hydroxyhydroxyamines.
  • it contains a basic group in R 1
  • salts with organic acids such as, for example, sulfuric acid, tartaric acid, and methanesulfonic acid
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, for example, agine
  • acidic amino acids such as aspartic acid and glutamic acid.
  • the compound (I) of the present invention may exist in a racemic form (dl form) as in the case of the starting compound (I), and the racemic form is also included in the present invention. It can be used as a drug as a racemate as it is, or as a racemate, separated into i-form or one-body.
  • the desired 5, 6-cis-cabervenem compound (I) or a salt thereof is a valuable antibiotic that is active against various Gram-positive and Gram-negative bacteria. It is used as an antimicrobial agent to treat infections caused by Gram-positive or Gram-negative bacteria, such as Stabilococcus oleus, Escherichia coli, Tarebzyra bunoymo, etc. Used safely.
  • the antimicrobial agent of the present invention is further added to animal feed as a fungicide, for example, to preserve the feed. For example, to destroy and inhibit the growth of harmful * bacteria on medical and dental equipment and for industrial use, e.g. water-based paint and
  • Object of the Invention ⁇ (I) or a salt thereof can be used alone or in combination with other active ingredients in any of various pharmaceutical preparations, for example, kabse, tablet, powder or solution , Suspensions or elixirs. They can be administered intravenously, intravenously or intramuscularly.
  • Tablets for oral administration may contain conventional forms such as binders such as sylob, arabian gum, gelatin, sorbitol, tragacanth or bolibi
  • binders such as sylob, arabian gum, gelatin, sorbitol, tragacanth or bolibi
  • fillers such as lactose, sugars, corn starch, calcium phosphate, sovito or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato flour or nato It may contain a wetting agent that can be used, such as lithium lauryl sulfate.
  • the drug can be coated by a method well known in the art.
  • Oral liquid preparations can be water or oily suspensions, solutions, emulsions, water, oils, elixirs or any dry product which can be in any color or dissolved in water or other suitable solvent before use. Good.
  • compositions may be presented in unit use form in a container supplemented with an ampoule or preservative.
  • the compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous solvents, and auxiliary agents such as suspending, stabilizing and / or dispersing agents. It may be appropriately contained.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-containing water, before use.
  • a suitable form that is absorbed by the mucous membranes or bronchial tissue of the nose and throat such as powder, liquid spray or inhalant, rosein, and throat paint.
  • it may be used as a liquid or semi-solid capsule or as a drop.
  • a softening agent, cream, lotion, bint, powder or the like may be used as an external preparation using a hydrophobic or hydrophilic base.
  • composition may contain other active ingredients.
  • a stabilizer such as a stabilizer, a binder, an antioxidant, a preservative, a lubricant, a suspending agent, a thickener or a flavoring agent may be contained.
  • the composition may contain other active ingredients.] 3 It can also provide a broader antibacterial activity.
  • livestock it may be formulated as a long acting or rapidly releasing intra-mammary preparation in the base.
  • the compound ⁇ (I) of the present invention can be used as a therapeutic agent for bacterial infection, for example, in mammals, such as respiratory tract infection, urinary tract infection, purulent disease, biliary tract infection, intestinal infection,
  • 3 ⁇ 4 ⁇ Can be used for treatment of gynecological and surgical infections.
  • the daily dosage depends on the condition of the breather and the weight of the host being treated, the mode and frequency of administration, the parenteral route suitable for common infections and the oral route for intestinal infections.
  • the daily consumption of 1) is 1 day l or more?
  • the patient's body weight l kg per kg of active ingredient is from about 15 to 60.
  • the preferred daily dose for adult humans is about 10 to about 200 ⁇ as the active ingredient! ?, Divided into 2 to 4 times each day, and inject a small amount of about 2.5 to about 10 once
  • composition comprising compound (I) can be administered in solid or liquid oral form, for example, in several unit dosage forms.
  • the compositions in liquid or solid unit use contain from 0.5 to 99% of the active substance. A preferred range is about 10-60%.
  • the composition contains about 15 to 150 active ingredients at a minimum. However, it is generally preferred to use a dosage in the range of about 250 to: I 00.
  • the compound (I) of the present invention or the clay thereof has a ⁇ -lactamase a harmful effect in addition to the above-mentioned uses, and thus may be used in combination with a ⁇ 1actam antibiotic.
  • 3-pactam antibiotics include, for example, benzylpenicillin, phenoxymethinolepeniline, carberin, ambiline, amoxicillin, and all Lin All ⁇ -silin antibiotics include, for example, cephalolysin, cephalotin, cephazolin, verrex 5 / n, cefoxitin, cefacetry, cefamand, cefmenokim, cefsulodin, cef-tiam, cef-tish Cephalosbolin antibiotics such as taxime, cefavirin, ceftizoglyph, cefradine, and cephaloglysin can be used.
  • the boronic acid derivative (I) or its 3 ⁇ 4 can be produced by expanding the compound (I) or its ⁇ with the compound ( ⁇ ).
  • the salt of the compound (I) those as described for the salt of the above (I) can be used. Can be.
  • the compound (II) may be used as it is, but it does not participate in the reaction. For example, lithium, sodium, and potassium.
  • the reaction may be carried out as an earth metal salt. 1 to 10 moles, preferably 1 to 5 moles of compound (I) or a salt thereof is reacted with 1 mole of compound (1) or a salt thereof. Usually, the reaction is performed in a solvent.
  • Solvents include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, tris such as acetonitrile, ethers such as dimethyl ethane and tetrahydrobran, dimethylformamide, dimethyl sulfoxide and the like. And hexamethylphosphoramide are preferably used.
  • bases include, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, Diisobrovirethylamine and viridin rudo are preferred.
  • the compound (summer) is converted to an alkali metal ⁇ , an alkaline earth metal salt or the like as described above, and converted to a compound (I) or a salt thereof. You may make it react.
  • the amount of the group to be used depends on the type of the compound (I), (I :) and the solvent used, and other reaction conditions]. Preferably it is 1 to 5 m.
  • the reaction temperature is in the range of 150 to 40 !, preferably 130 t;
  • the reaction time varies depending on the kind of the compound (I) or a salt thereof, the kind of the compound (I) or its kind, the reaction temperature and the like, but is 1 to 72 hours, preferably 1 to 24 hours.
  • the obtained target compound (I) can be isolated and purified by a method known per se, for example, digestion, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography: 5 or the like. .
  • (_ CI FI For example, an organic solvent that is not mixed with water, such as ethyl acetate, and water are added to the reaction mixture, the organic solvent layer is separated, washed with water, dried with a desiccant, and then evaporated to remove the solvent. be able to.
  • the compound ( ⁇ ) thus obtained can be further purified, if necessary, by a conventional method such as preparative thin-layer chromatography, column chromatography, and recrystallization.
  • the protecting group can be removed if necessary.
  • a method for removing the protecting group a method using an acid, a method using a hydroxyl group, a method using hydrazine, a method using reduction, an imino halogenating agent, and then an imino etherifying agent are used, depending on the type of the protecting group.
  • a conventional method such as a hydrolysis method can be appropriately selected and carried out.
  • the acid varies depending on the type of the protecting group and other conditions.
  • Acidic ion-exchange resins and the like are used in addition to organic acids such as fonic acid and ⁇ -entosphone test.
  • the base may be, for example, an alkali metal such as sodium or potassium or a hydroxide of an alkaline earth metal such as potassium or magnesium, depending on the type of the protecting group and other conditions.
  • alkali metal such as sodium or potassium
  • a hydroxide of an alkaline earth metal such as potassium or magnesium
  • inorganic bases such as carbonates, metal oxides, organic amines, and organic groups such as quaternary ammonia
  • basic ion exchange resins are used.
  • a solvent is used in the above method using an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used.
  • metals such as tin and zinc or metal compounds such as chromium dichloride and chromium oxide, and sulfuric acid and boron Organic such as acid and hydrochloric acid And an acid such as an inorganic acid, and a method of reducing in the presence of a metal catalyst for corrosion reduction.
  • Platinum catalysts such as platinum sponge, platinum black, platinum oxide, and colloidal platinum; palladium oxide, palladium oxide, palladium sulfate, palladium carbonate, palladium carbonate, palladium carbonate, palladium carbonate, palladium carbonate, palladium palladium, palladium palladium, palladium palladium, etc.
  • the iron in the case of the reduction process by metallic and ⁇ , inorganic acids Yobigisan such as a metal compound ⁇ and hydrochloric acid such as chromium, ⁇ , the method according ⁇ reduction organic acids such Burobion acid used is usually a solvent
  • inorganic acids Yobigisan such as a metal compound ⁇ and hydrochloric acid such as chromium, ⁇
  • the method according ⁇ reduction organic acids such Burobion acid used is usually a solvent
  • alcohols such as methanol, ethanol, * robby alcohol, isobrovir alcohol, etc., and ethyl acetate are frequently used.
  • water, acetone, and the like are commonly used.
  • the acid itself can be used as a solvent.
  • the reaction temperature in the method using an acid, the method using a base, and the method using a reduction is usually about the same as heating under cooling. Also, by reacting with an iminono, a logenizing agent and then an iminoatelating agent, and then hydrolyzing as necessary].
  • an imino halogenating agent used in the method of removing a protecting group For example, phosphorus trichloride, pentachloride, tribromide, thiocyanate, thionyl chloride, phosgene and the like are used.
  • the reaction temperature is not particularly limited, it is usually carried out usually at room temperature or under cooling.
  • alcohols or metal alkoxides are used as the iminoetherating agent used for the reaction product thus obtained.
  • alcohols methanol, ethanol, brovanol, isobrono "phenol, and ⁇ -butanol are used.
  • akanos such as tert-butanol or the like, or their alkyl moieties are methoxy, ethoxy, Compounds substituted with an alkoxy group such as propoxy, isobroboxy, butoxy, etc. are used.
  • the metal alkoxides include the above-mentioned alcohols such as sodium oxalate and sodium oxalate derived from alcohol.
  • Alkaline earth metal aquoxides such as metal alkoxides, calcium alkoxides, and barium alkoxides are used.
  • the protecting group is a residue of an organic carboxylic acid.]) A free amino group, a hydroxy group, a carboxy group, a carboxyl group, a sulfone When there is a substituent such as an acid group, a treatment for further increasing the effect of the adjacent group of these groups to increase the reactivity of the power ball group and remove the protective group to obtain a favorable result is advantageous. It is.
  • the group on the carbon adjacent to the carbonyl group described above is a free amino group
  • the free amino group is converted into a thiolide group and then removed.
  • a method of removing a protecting group by applying a known method used for a method of decomposing a tide bond may be used.
  • the degree of reaction of this reaction is not particularly limited, and is appropriately selected depending on the kind of the protecting group, the kind of the elimination method, and the like. It is preferable that the reaction is carried out under cooling or moderate heating.
  • the protective group for the carboxyl group in the target product (I) is a halogenoaki group, an aralkyl group or a benzhydryl group
  • a reducing agent used in this reaction, when the protecting group of the carboxyl group is a halogenoaki group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl, for example, zinc and sulfuric acid are used.
  • Hydrogen and platinum oxide, platinum black, platinum sponge, palladium-carbon, palladium when the protecting group is, for example, an aralkyl group or a benzhydryl group, such as benzyl, p-nitrobenzene.
  • CMPI _ Preferred is a catalytic reduction catalyst such as mu-black, barium palladium barium monosulfate, barium barium monocarbonate, reduction-nicke, Raney nickel, Urushibara-nickel, or metal sulfide such as sodium sulfide or lithium sulfide. It is.
  • metal sulfide such as sodium sulfide or lithium sulfide. It is.
  • removal by light irradiation can be performed by electrolytic reduction in the case of p-methoxybenzene group.
  • the reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it is involved in the reaction.
  • the reaction temperature is usually from about 40 to about ⁇
  • the reaction time is usually from 5 minutes to 12 hours, depending on the type of the raw material compound and the base agent.
  • the protecting group of the amino group in the target product (I) is, for example, “!!” pr benzyl group, 0-nitrobenzene group; i group, p-group.
  • a methoxybenzoxycarbonyl group or a benzyloxycarbonyl group it is removed by the above-mentioned protective group removal reaction of the carboxyl group, and the hydroxyl-protecting group for the purpose (I) is acetoxyl group.
  • the hydroxyl-protecting group for the purpose (I) is acetoxyl group.
  • a lower aliphatic hydroxy group as in the following, it can be removed by treating with an aqueous solvent in the presence of the group.
  • water or a mixed solvent of water and alcohols such as methanol and ethanol, or ethers such as tetrahydrofuran and dioxane, and any organic solvent is preferable.
  • the reaction is not particularly limited as long as it does not affect the ring, but is performed using, for example, sodium metal carbonate such as sodium carbonate and potassium carbonate, etc.
  • the reaction temperature is 0 or room temperature.
  • the reaction time depends on the type of starting compound. It is usually 1 to 6 hours, depending on the reaction temperature and the reaction temperature.
  • a trialkyl tertiary alkyl group such as tert-butyl dimethylsilyl is used as a protective group for a hydroxyl group, for example, a fluorine ion such as tetrabutylammonium fluoride or fluorinated lithium is used.
  • ethers such as tetrahydrofuran and dioxane are suitable.
  • the reaction is carried out at around room temperature for 10 to 18 hours.
  • R 1 is a group having a carboxy group
  • the derivative in the carboxylic group may be converted to a carboxy group, but this case is of course within the scope of the present invention. Included.
  • the thus-obtained compound (I) from which the protecting group has been eliminated can be converted to a desired salt by a conventional method.
  • the compound (I) Since the compound (I) has a carboxy group and a carboxyl group, it can act on a base to form a salt. Therefore, the chemical compound (I) may be collected as water.] What is obtained as salt may be used as a salt or Ttfe salt. Further, the compound (I) obtained in the unfriendly form may be referred to as 3 ⁇ 4. As a method for freeing compound (I), which can be obtained as 3 ⁇ 4, for example, a method using an acid or the like is used.
  • the acid used varies depending on the type of the protecting group and other conditions, but examples of the acid include inorganic acids such as sulfuric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, sulfuric acid, and p-toensone Ay.
  • Acid is frequently used.
  • an acidic ion exchange resin is used.
  • the solvent for example, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane, etc., water or a mixed solvent is often used. This method is generally performed at room temperature, but may be performed with cooling or heating. The reaction time depends on the temperature, type of solvent and temperature, Generally, it is preferable to finish in a single hour.
  • the resulting free compound (I) can be isolated by known means as described above.
  • the Amino group ⁇ Mi de, Urei de, amidino, guaiacolsulfonate - converted to Gino group In the case of having a hydroxyl group, the hydroxyl group can be converted to an phenyloxy group, a halogen atom, or an azide group, and when n is 0 or 1, a sulfur atom can be oxidized. You can also.
  • the reaction for converting an amino group to an amide group, a perido group, an amidino group or a guadino group can be achieved by various known methods.
  • the conversion reaction to the amide group can be abrupt by contacting the amide with the acylating agent under a solvent.
  • the solvent to be used is not particularly limited, but is preferably a chlorinated hydrocarbon such as chloroform and methylene chloride, and ethers such as tetrahydrofuran and dioxane.
  • the acylating agent to be used is not particularly limited as long as it can convert a normal amino compound, but fatty acids such as anhydrous anhydride and brobion anhydride, fatty acid anhydride ⁇ ., Acetyl chloride, brobio -Examples include fatty acid halide derivatives such as lucid chloride, n-butylidyl bromide, isoptilidid chloride, and methoxalyl chloride.
  • the reaction is preferably carried out in the presence of a base, and the group used is preferably an organic base such as tritamine or pyridine or a fatty acid argari metal such as sodium or potassium phosphate. .
  • the reaction temperature is not particularly limited, but is preferably around 0 " ⁇ 40 ⁇ .
  • the time required for the reaction varies depending on the type of the acylating agent and the reaction temperature, but is usually from 0.5. (5 hours) ⁇
  • the conversion reaction to a laid group is carried out in the presence of a solvent, a substituted isocyanate,
  • Oi.:FI It is carried out by reacting substituted isothiocyanates.
  • substituted isocyanate include methyl isocyanate, ethyl isocyanate, phenyl isocyanate, and p-bromophenyl isocyanate.
  • methisothiocyanate, phenylthioisothiocyanate and the like can be used.
  • the reaction temperature is around 0 to 40, and the reaction time is usually 0.5 to 5 hours.
  • the conversion to an amidino group is carried out by reacting with dioxane, THF, DMF-chloroform, acetone, acetate, or a solvent such as imidoesters.
  • imid esthetics include, but are not limited to, methyl imidate, methyl imidate, methyl vacimidate, meth; vaimidate, methubuenylase imidate, meth N-formimidate, methN —Ethyl imimidate, meth N′-isopropionate; u imimidate can be used.
  • the reaction temperature is from 0 to 25 !, and the reaction time is usually 1 to 6 hours.
  • the conversion to the gua-dino group can be carried out in water, dimethylformamide, hexamethylenephosphoramide, in any solvent, such as 0-alk or 0-arylbusoidurea, or S-aki or S-arypsoidurea. It is performed by reacting it with a kind.
  • Pseudoureas include: 0-methidoid urea, S-methylpseudourea, 0-2,4-dichlorophenipseudourea, S- ⁇ -two-port buenibuside thiourea, 0-, -trimethybusoidurea, etc. Can be used.
  • the reaction temperature is from 0 ° to around 40, and the reaction time is usually from 1 to 24 hours.
  • the compound (I) thus obtained can be isolated and purified by a method known per se.
  • the reaction that converts a hydroxyl group to an acyloxy group, a halogen atom, or an azide group This can be achieved by various known methods.
  • the conversion reaction to an amino group can be carried out in the same manner as the above-mentioned reaction for converting an amino group to an amide group.
  • Conversion to a halogen atom is achieved by hapgenization according to a conventional method.
  • Halogenating agents used include, for example, thiol chloride, thiocyanate bromide, oxalic chloride, carbon tetrachloride-triphenyl-phosphine, carbon tetrabromide triphenyl phosphite. Are used.
  • Suitable solvents used are, for example, ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene and toluene.
  • the reaction temperature is preferably 0 to room temperature, and the reaction time is usually 15 minutes to 5 hours.
  • the conversion reaction to an azide group can be achieved by reacting with a hydrogen azidide or azide diphenylate in the presence of a phos: 7-in derivative and a diester of azodicarbonate.
  • phosphine derivative to be used for example, triphenylphosphine and tri-II-dithiophosphine are preferable.
  • azodicarboxylic acid diester for example, azodicarbonic acid dimethyl ester, azodicarboxylic acid boronic acid ester, etc. Is used.
  • solvent to be used for example, halogenated hydrocarbons such as methylene dioxide and chloroform, and ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction temperature is preferably 0 t! 60, and the reaction time is preferably 5 minutes to 5 hours.
  • the compound (I) thus obtained can be isolated and purified by a method known per se.
  • the oxidation reaction of the sulfur atom can be performed by a method known per se.
  • a mild oxidizing agent that acts substantially on the bones of bones such as perbenzoic acid, ozone, and phen-dichloroi; dyed, hydrogen peroxide, sodium meta-peroxide, Performed using sodium hypochlorite
  • the compound ( ⁇ :) in the present application can be manufactured, for example, by the following method or a method similar thereto.
  • R 7 is a protecting group for a hydrogen atom or an amide group
  • R 8 is a protecting group for a hydrogen atom or a hydroxyl group
  • R 7 and R 8 are
  • R 9 represents a hydrocarbon group or a heterocyclic group
  • R 9 represents a hydrocarbon group or a heterocyclic group.
  • the starting material is 4- (2-hydroxyhexyl) azetidine-1-one (BJ, Christensen, et al., Jana Seibu Organic Chemistry), which is known as a starting material. Cliemistry), the 45 vol, if Shirukere even interfere with the following reaction with 1130 (1980 :) amide group compounds and Korisanmoto is protected (V :) is use. protecting group R 7 There are no restrictions on the choice, for example, trimethinoresilyl, t-butyl; dimethinoresilinole, any organosilyl group or cyclic ethers such as 2-tetrahydrovira!]? R 7 and R 8 are
  • R 10 Is then the ones such as described for R 1 is used, the J divided for example methyl, E Ji, lower alkyl groups as Isopuropi group, further E 10 and R 11 is 3 carbon atoms -? 6 ⁇ Those linked by a kylene group may be used frequently.
  • compounds in which both R 10 and R 11 are methyl groups have already been described in the literature]) (B. G. Christensen et al., Journal of Organic Chemistry, 45, 1130 (1980)).
  • the first step is to obtain (VI by sulfating the 3-position of V) VI
  • N-substituted thiomes can be used (wherein E 9 is as defined above)
  • a hydrocarbon group or a heterocyclic group as described in the above Bi can be used.
  • Substituted phenyl group, heterocyclic group such as 2-pyridyl group, 2-benzothiazo- / re group, methyl group, ethyl group, isof group.
  • Lower alkyl groups such as a propyl group and an n-propynole group can be commonly used. ( ⁇ means that there are theoretically two diastereomers with respect to the 3-position substituent. — ⁇ ⁇ —
  • Isomers can be separated by column chromatography, recrystallization, or any other operation! It can be isolated and used for the next step reaction, but the mixture can be used for the next step reaction without isolation.
  • the second step is a step of quinolelating the 3-position of (VI) to obtain (V).
  • the same strong salt groups and were use in the first step using a solvent 3 ⁇ 4, - 7 8 0 from 3 C.
  • treatment with 1 to 20 moles of ketone per monole gives (W).
  • the conversion reaction of (V) ⁇ ⁇ 3 ⁇ 4) ⁇ (3 ⁇ 4) on 1 ⁇ is (Conversion to (V) ⁇ (W in the same vessel without isolating ⁇ (labeled as 2 'process in the above figure))
  • the mixture is treated at a temperature of 178.
  • the third step is a step in which) is reduced to selectively obtain 3,4-cis-substituted azetidinones (: 3 ⁇ 4U).
  • the reducing agent for example chromatic ⁇ scan's compound, - Ggeru compounds, mercury compounds, such as zinc compounds are used, preferably expression 3 ⁇ 4 2 S n3 ⁇ 4 or R 12 S n H 3
  • R 12 represents a hydrocarbon group.
  • the hydrocarbon group in H 12 is I Table, those such as described for R 1 is used, and]? Divided e.g. Mechinore, E Ji / Les, n one Puropinore, isopropylidene Honoré 'n one butyl Le, t Buchinore , N-Pentyl ruthenium, a lower alkyl group having 16 carbon atoms, for example, a phenyl group, a lower aki group (meth, ethynole group, etc.)-Substituted phenyl group can be used.
  • triphenyl-tin hydride tri-n-butynoles hydride, diphenyl-tin hydride, di-n-butyltin hydride, triethyltin hydride, trimethyltin hydride, hydrogen
  • n-butyltin chloride can be used, for example, triphenyltin hydride and tri- ⁇ -butyltin hydride are preferred.
  • the reducing agent is usually used in an amount of 1 mole to 10 moles, preferably 1.2 to 5 moles per mole.
  • This reaction is suitably carried out in the presence of a free radical initiator such as 0.1-0.5 monosodium azobis-succinyl octyl-tolyl or di-butyric acid.
  • a free radical initiator such as 0.1-0.5 monosodium azobis-succinyl octyl-tolyl or di-butyric acid.
  • Light irradiation may be performed instead of using a free radical initiator.
  • the reaction may be carried out in a solvent which does not participate in the reaction, although the reducing agent itself may be used as a solvent.
  • Ketones such as aceton, methylethylketone, ketones such as dioxane and tetrahydrobran, phenols, methanol, and alcohols such as ethanol, aromatics such as benzene, benzene, and xylene. Hydrocarbons and the like can be used as the solvent.
  • the reaction temperature can usually be carried out from 0 ⁇ 1 3 0 3 C, in particular 1 0 1 0 0 preferably der, in an atmosphere of inert gas such as required Ruraba nitrogen or Anoregon.
  • the reaction time varies depending on the type of the starting compound, the reaction temperature, the amount of the reducing agent used, etc. I have time.
  • the desired compound (W) having a 3,4-cis configuration can be preferentially obtained, but a small amount of a compound having a 3,4-trans configuration is produced as a by-product.
  • Isolation of (:) from the reaction mixture is performed according to a conventional method. For example, (3 ⁇ 4! Can be easily isolated by distilling off the solvent and subjecting the residue to recrystallization or column chromatography.
  • the fourth step is to protect the newly formed hydroxyl group and obtain (K) by
  • protecting group represented by R 2 those described above are used.
  • a protecting group that forms an ether bond such as a 9-methoxymethoxymethyl group, a methoxymethyl group and a 'methylthiomethyl group. It is suitable. Of these, for example, a / 9-methoxetoxymethinole group is preferable as the protecting group of [ ⁇ ].
  • the reaction for introducing a protecting group can be achieved by a known method.
  • ⁇ ⁇ toxethoxymethyl lid, methoximethic lid, methylthiethylmethinolex Lido-like halogenated alkyl is converted to triethylamine, diisopropion / 1 / ethyflamin, pyridine, ⁇ -butyllithium, hydrogenated sodium in the presence of dichloromethane, chloroform, .
  • the conversion from () to (XVU) is achieved in substantially the same way as the conversion from (3 ⁇ 41) to (K), and the conversion from (XVS) to (K) is the conversion from (w to :).
  • the fifth step is the step of removing the protecting groups R 7 and R 8 of CK) to obtain (X). Removal of protecting groups 7 and R 8 ′ is accomplished by applying various known deprotection methods. For example, if (K) is a compound derived from (XVD), removal of the protecting groups It is carried out by hydrolysis in a solvent such as an aqueous acetic acid solution at a temperature of 0 ° C to 75 ° C for a reaction time of 5 minutes to 16 hours.
  • a solvent such as an aqueous acetic acid solution
  • the sixth step is a step of converting the hydroxyxeti group of (X) into a carboxyl group by an oxidation reaction to obtain (XI).
  • the oxidation reaction is carried out in a solvent such as acetone, aqueous THF, aqueous dioxane, etc. from -10 ° C to 40 ° C. It can be carried out in a temperature range of C for 10 minutes to 24 hours using various known oxidation systems such as Jones reagent, potassium permanganate, silver oxide and the like.
  • (X) acetone 10 in any solvent It is preferable to carry out an oxidation reaction using a Jones reagent 'at a temperature of C to 30 for 10 minutes to 8 hours.
  • (XVi) [The symbols in the parentheses are the same as above], and can also be converted to (XE) by the following: Conversion from (X) to, for example, DMS0'pyridin, ace-tri- DMS 0—anhydride, chromium anhydride ⁇ -pyridine, cyclohexyl; I / cabodimide-DMS 03 ⁇ 4 in a solvent such as ⁇ , dichloronorethane, etc .; Oxidation at a temperature of 3] is carried out.
  • the conversion from (XI) obtained in this way is substantially the same as the conversion from (X) to (XE). Achieved.
  • (XI can also be obtained by subjecting (K) to an anonymous oxidation reaction (indicated as step 6 'in the scheme)
  • an anonymous oxidation reaction for example, compounds in which (K) is derived from (XVI)
  • [XI] is obtained.
  • deprotected (X :) is generated in the middle, and the oxidation reaction proceeds in the next step.
  • the target compound (: I) of the present application is (including any one-body, ⁇ -body, and body).?, And the optically active (V) is used to produce the optically active (: I).
  • the ⁇ -isomer it is preferable to carry out the division using (XI)
  • the division can be carried out by various known methods, for example, the crystallization method or [ has an optical activity corresponding to ⁇ , for example, fractional crystallization of diastereomeric salts formed by reaction with quinine, busine, efedrin, strychnine, monolefin, etc., chromatographic It is divided by the physical separation method by Phi et al.
  • the seventh step is a step of activating the carboxy group of (XE), and then extending two carbon atoms to obtain CM ′).
  • the reaction is carried out by reacting with a magnesium salt of a malonic acid derivative represented by the following formula at 0, C; ⁇ 50 for 1 to 48 hours.
  • the eighth step is a step of diazotizing (I) to obtain (XBU).
  • Jiazo reaction is, for example, ⁇ Seto - DOO Rinore, Jikuronoremetan, T HP 1 Rudono such solvent, for example Application Benefits Echinorea Mi down, Jechinoreami down, in the presence of a base such as pins lysine (:. S One to two moles per mole, for example: -Reaction with any azide, such as: -Norboxoxybenzenesnorrezo-luazide, P-toluenesulfonazide, methanes-noreazide.
  • the temperature is -10 to 40.
  • C the reaction time is usually 1 to 48 hours.
  • the ninth step is a step of removing the protecting group (H 2 :) of (Xffl) to obtain ( ⁇ ), but it is not essential to remove the protecting group in this step, and it is not pharmaceutically acceptable. If it can be tolerated, it may remain in the target compound (I.
  • the protective group can be removed in any step after this step.
  • the removal of such a protecting group is carried out by applying various known deprotection methods.
  • R 2 is a 9-methoxetoxymethinole group, for example, clofenolhonolem, dichloromethane
  • This can be done by contacting a solvent such as THF with, for example, titanium tetrachloride or bromide.
  • the amount of noreic acid used was 1 to 30 moles per ⁇ 1 monolayer, and the reaction temperature was -1.0 to 40.
  • c ⁇ The reaction time is 5 minutes to 10:00 o
  • Step 10 is a step of cyclizing to obtain (XV).
  • This oxidation reaction is carried out by cyclizing ⁇ in a solvent such as benzene, tonoleene, or TH: F, for example, in the presence of a catalyst such as copper sulfate, copper powder, rhodium acetate, or palladium acetate. ! Is done.
  • the reaction temperature is 5 0 from 1 1 0 a c, the reaction time is from 1 to 5 hours Der '), I usually nitrogen or Anoregon.
  • Cormorant 3 ⁇ 4 dividing line in the fog BS care of inert gas.
  • the cyclization reaction is carried out by irradiating (XI with, for example, benzene, THF, carbon tetrachloride, and methyl alcohol) in a solvent at ⁇ 10 to 40. You can do it.
  • the first step is a step of activating (XV) with an activator to obtain (IE).
  • X is a substituted sulfonoxy group
  • (XV) 1 to 3 monoles of 1 monole, for example, p-tonoreensenolenoic anhydride, .V 12 trophenenolenosolephonic anhydride, 2,4,1 Trisopropinolephenylsnolefonic acid, methansnolefonic anhydride ⁇ ,-tonoleensnolefinorenolechloride, bromophenylsnolefonichloride
  • What kind of snolefonyl chloride for example, Methane, chlorophonolem, acetonitrinole, dimethoxyethane, TELF
  • any solvent for example, tri'ethinoleamine, disop-mouth hinoletylamine, pyridine, 4-dimethino
  • the reaction is performed in the presence of a base. Usually, the reaction temperature is - 20 a C from 40 5 C, the reaction time is 5 hours 0.5.
  • X is a halogen place • If the cow, the X is Choku ⁇ sulfo - sulfo in the reaction in the case of Ruokishi group - Honoré agent algebraic) to a halogenating agent (e.g., old Kizari Kurori de, (C6H 5 3 C, (CH 5 ⁇ PBr 2 , (C 6 H 5 0 3 Br 2, etc. Chioninorekurori de) using, X of be converted from by reacting the same ⁇ conditions (XV) to (H).
  • a halogenating agent e.g., old Kizari Kurori de, (C6H 5 3 C, (CH 5 ⁇ PBr 2 , (C 6 H 5 0 3 Br 2, etc. Chioninorekurori de
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-miscible organic solvent and water are added to the reaction mixture, and the organic solvent layer is separated. It can be obtained by taking out, washing with water, drying with a desiccant, and then distilling off the solvent.
  • the starting material ( ⁇ ) is not limited, and any starting material ( ⁇ :) suitable for the purpose of the present application can be used.
  • Cis-111 [31-diazo-31- (4-1-to-penzinoleoxycarbo >)-12-oxo 7 "mushroom.” 1-3 "(1-hydroxy-11-methy; ⁇ et) buzetidine
  • One 2-one (benzene solvate) 1.1 7 ⁇ (2,5 m moi) and rhodium (IE) acetate 60 «anhydrous benzene! 2 Deoxygenate the suspension through star element for approximately 0 minutes. The mixture is then heated for 45 minutes in a nitrogen atmosphere with stirring 8. After the reaction solution is cooled, the mixture is filtered using a cerite, and the solvent is distilled off under reduced pressure to obtain the title compound as a blue foam (0.91, 100).
  • Lithium salt of S-dimethinoleamino-3-mecaptoviridazine! Add 6 1 ⁇ (1.04 rnmol) and stir at 0 for 2 hours. Dilute the reaction solution with succinic acid and add it to a saline solution under ice-cooling to separate the Arisuto layer. The Arisuto layer was washed with water and dried (2Ta 2 SO).
  • ruthenate 412 tropene diester in 25 s anhydrous tris-acetate under a nitrogen atmosphere at 0 with disopropidamine 0.12 ⁇ (0 69 nmoi), then add 0.14 (0.68 mmol) of diphen-lin chloride and stir for 90 minutes, then add Jial 50 ⁇ (5 mmol) and E-2-2- Acetamide ethylene chloride; silver of t 6 7 ⁇ (0 ⁇ 7 Sminoi) is added and stirred for 2 hours, and the precipitate is filtered off. The water In addition, remove the insoluble part.
  • V / IrO IE m 1 1760,, 700, 1620
  • ⁇ ⁇ nm CE j.): 230 (396), 310 (444) ⁇ (10 10, ⁇ 20 ) ⁇ : 1.30, 1.44 (3 ⁇ , sx2, one C3 ⁇ 4x2), 2.09 (3 ⁇ , s,- COCE 3 ), 3.02 C 1 H, ⁇ , J 18, 10 Hz, ⁇ c ⁇ -), 3.72 (l H, a, J-6 Hz, cs-co ⁇ ),
  • E-2-acetamide A-6-1 (1-hydroxy ⁇ -meth / eth) 17-1-year-old azabicyclo [3,2, 0 ] Heptoh-2-ene Sodium sodium borate, 5,5- ⁇ -S3- (3-2-1aceto-d-bininolechio) -6- (1-1-hydroxy-1-methinoleet) -1-71 1-azabicyclo [3,
  • the column After concentrating the aqueous layer, the column is subjected to force column chromatography using DIAION: SP-20 (manufactured by Kasei Co., Ltd.)-(3. ⁇ , 3% R ⁇ ), and eluted with 3 acetone Collect the fractions and freeze-dry to give the title compound as a colorless powder
  • NME (90MHZ, D 2 O) : 1.43, 1 ⁇ 56 ( each 3H, 8x2,
  • DIAION SP—20 (San'i-Daisei f ⁇ ⁇ )
  • Column chromatography H 2 o, 3% acetate, and fractions eluted with 3% acetone were collected and lyophilized to give the title compound as a colorless powder (25 ⁇ ) can get.
  • 5,6-cis-force ⁇ ' ⁇ nemu 3-force / ⁇ bonic acid derivative (I) has excellent antibacterial activity and -lactamase inhibition, and is useful for humans and dogs, cats, cattle, cows, horses, As a remedy for infectious diseases caused by Gram-positive or negative bacteria in mammals including mice, guinea pigs, etc., as a preservative for animal feed, industrial water, and as a disinfectant for sanitary equipment. Used in combination with ⁇ -lactam antibiotics to prevent the degradation of the antibiotic

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Abstract

Dérivés de l'acide 5,6-cis-carbapénem-3-carboxylique représentés par la formule générale suivante:$(8,)$(où R1 représente un groupe hydrocarbyl ou un groupe hétérocyclique, R2 représente un atome d'hydrogène ou un groupe de protection hydroxyle et n représente 0, 1 ou 2, à condition que lorsque R1 représente un groupe acétamidoéthyl ou un groupe acétamidoéthényl et R2 représente un atome d'hydrogène ou un groupe d'acide sulphonique, n est égal à 2), ou leurs sels, et procédé de préparation des composés (I) illustrés par le schéma suivant:$(8,)$(où R3 représente un atome d'hydrogène ou un groupe de protection carboxyle, X représente un groupe éliminable, et les autres symboles sont identiques à ceux définis ci-dessus). Les composés (I) ont d'excellents effets antibactériens et d'inhibition de la lactamase beta, et sont utilisés en tant que médicaments pour l'homme et les animaux domestiques.
PCT/JP1982/000031 1981-09-09 1982-02-02 Derives de l'acide 5,6-cis-carbapenem-3-carboxylique et leur procede de preparation WO1983002614A1 (fr)

Priority Applications (2)

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PCT/JP1982/000031 WO1983002614A1 (fr) 1982-02-02 1982-02-02 Derives de l'acide 5,6-cis-carbapenem-3-carboxylique et leur procede de preparation
EP82108210A EP0074599A1 (fr) 1981-09-09 1982-09-07 Dérivés de 5,6-cis-carbapénème, leurs préparation et utilisation

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PCT/JP1982/000031 WO1983002614A1 (fr) 1982-02-02 1982-02-02 Derives de l'acide 5,6-cis-carbapenem-3-carboxylique et leur procede de preparation

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3312533A1 (de) * 1982-04-09 1983-10-13 Bristol-Myers Co., 10154 New York, N.Y. Carbapenem-derivate, verfahren zu ihrer herstellung und pharmazeutische mittel, die diese verbindungen enthalten
US11084833B2 (en) 2016-10-10 2021-08-10 The Johns Hopkins University Antibacterial agents against D,D- and L,D-transpeptidases

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5476593A (en) * 1977-11-12 1979-06-19 Beecham Group Ltd Antibacterial polycyclic compounds*their manufacture and medical composition containing them
JPS5527169A (en) * 1978-08-14 1980-02-27 Merck & Co Inc Manufacture of thienamycin and intermediate
JPS5533494A (en) * 1978-08-25 1980-03-08 Beecham Group Ltd Betaalactum antibacterial*its manufacture and composition
GB2047700A (en) * 1979-04-16 1980-12-03 Kowa Co Antibiotic and process for producing the same
JPS56127381A (en) * 1980-03-10 1981-10-06 Takeda Chem Ind Ltd Beta-lactam compound and its preparation
JPS56127382A (en) * 1980-03-10 1981-10-06 Takeda Chem Ind Ltd Beta-lactam compound and its preparation
JPS5711982A (en) * 1980-06-26 1982-01-21 Kowa Co Novel antibiotic and its preparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5476593A (en) * 1977-11-12 1979-06-19 Beecham Group Ltd Antibacterial polycyclic compounds*their manufacture and medical composition containing them
JPS5527169A (en) * 1978-08-14 1980-02-27 Merck & Co Inc Manufacture of thienamycin and intermediate
JPS5533494A (en) * 1978-08-25 1980-03-08 Beecham Group Ltd Betaalactum antibacterial*its manufacture and composition
GB2047700A (en) * 1979-04-16 1980-12-03 Kowa Co Antibiotic and process for producing the same
JPS56127381A (en) * 1980-03-10 1981-10-06 Takeda Chem Ind Ltd Beta-lactam compound and its preparation
JPS56127382A (en) * 1980-03-10 1981-10-06 Takeda Chem Ind Ltd Beta-lactam compound and its preparation
JPS5711982A (en) * 1980-06-26 1982-01-21 Kowa Co Novel antibiotic and its preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3312533A1 (de) * 1982-04-09 1983-10-13 Bristol-Myers Co., 10154 New York, N.Y. Carbapenem-derivate, verfahren zu ihrer herstellung und pharmazeutische mittel, die diese verbindungen enthalten
US11084833B2 (en) 2016-10-10 2021-08-10 The Johns Hopkins University Antibacterial agents against D,D- and L,D-transpeptidases

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