WO1985001502A1 - 7-oxo-1-azabicyclo ad3.2.0 bd hept-2-ene-2-carboxylic acid derivatives, process for their preparation, and their use - Google Patents

7-oxo-1-azabicyclo ad3.2.0 bd hept-2-ene-2-carboxylic acid derivatives, process for their preparation, and their use Download PDF

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Publication number
WO1985001502A1
WO1985001502A1 PCT/JP1983/000319 JP8300319W WO8501502A1 WO 1985001502 A1 WO1985001502 A1 WO 1985001502A1 JP 8300319 W JP8300319 W JP 8300319W WO 8501502 A1 WO8501502 A1 WO 8501502A1
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group
reaction
oxo
formula
reference example
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PCT/JP1983/000319
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English (en)
French (fr)
Japanese (ja)
Inventor
Koichi Yoshioka
Norikazu Tamura
Hideaki Natsugari
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Takeda Chemical Industries, Ltd.
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Priority to PCT/JP1983/000319 priority Critical patent/WO1985001502A1/ja
Priority to JP59199316A priority patent/JPS6089486A/ja
Priority to EP84111442A priority patent/EP0137403A3/en
Priority to CA000464131A priority patent/CA1263117A/en
Publication of WO1985001502A1 publication Critical patent/WO1985001502A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present invention relates to a novel 7-oxo 1-azabicyclo [3 • 2 • 0] hepta-21-en "rubonic acid derivative which is extremely stable against in vivo enzymes and has a strong antibacterial action (as used herein). Is the cal
  • Japanese Patent Application Laid-Open No. 54-157,595 describes that 7-oxo-1-azabicyclo [3.2.0] hepta-2-ene-12-carboxylic acid has an 11-position at the 6-position.
  • (Lower alkylthio) A compound having a dimethyl group is described and is known to exhibit antibacterial activity.
  • the present inventors have been intensively studying for the purpose of obtaining a compound which is stable against in vivo enzymes and has an excellent antibacterial action.
  • X is a lower alkylene group or a lower alkenyl group which may have a hydroxyl group
  • Y is (1) a lower alkyl group (2) a cycloalkyl group having 3 to 8 carbon atoms (3 )
  • Lower alkenyl group (4) aryl group (5) aralkyl group or (6) 3- to 8-membered heterocyclic group, or a group represented by the formula Y—SO 2 —X—
  • the present invention relates to an antibacterial composition containing a compound represented by the general formula (: I) or a salt thereof.
  • X is, for example, ethylene, propylene, butylene, hydroxyethylene, hydroxymethylethylene, 1-hydroxy-2-methynoleethylene, hydroxyxetinoreethylene, 1-hydroxy-2-ethylethylene
  • a lower alkylene group having 2 to 4 carbon atoms which may have a hydroxyl group, such as ethenylene, propenylene, '1-butenylene, 2-butenylene and the like.
  • Y represents (1) for example, ⁇ I>, ethyl, n-propyl, isopropyl, n-butynole, iso " ⁇ > le, tert-butynole, ⁇ -pentynole, ⁇ -hexynole, y A straight-chain or branched lower alkyl group having 1 to 6 carbon atoms such as sohexyl, (2) for example, 'cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl A cycloalkyl group having 3 to 8 carbon atoms such as, cycloheptyl and cyclooctyl; (3) a lower alkenyl having 2 to 4 carbon atoms such as vinyl, propenyl, 1-butenyl, 2-butenyl, and 3-butenyl; (4) aryl groups such as phenyl and naphthyl (preferably having 6 to 10 carbon atoms); ( 5 )
  • a nitrogen atom which may, SansoHara element comprises five 1 a hetero atom such as a sulfur atom, or indicate a benzene ring condensed with from 3 may be 8-membered heterocyclic group, Or a substructure,
  • Y— S0 2 — X— is a combination of X and Y, for example,
  • lower alkyl groups having 1 to 6 carbon atoms include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutynole, sec-butynole, tert-butynole, n-pentynole
  • a linear or branched lower alkyl group having 1 to 6 carbon atoms such as n-hexyl, isohexyl, etc. is used as a cycloalkyl group having 3 to 8 carbon atoms.
  • Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like are used.
  • alkenyl group having 2 to 6 carbon atoms for example, vinyl, aryl, isopropynanol, 2 —A straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms such as methallyl, 2-butenyl and 3-butenyl is used.
  • phenyl, naphthyl, ⁇ -naphthyl, biphenyl, anthryl and the like are used.
  • one heteroatom such as a nitrogen atom, an oxygen atom and a sulfur atom which may be oxidized is used.
  • the 3- to 8-membered heterocyclic group which may be condensed with a benzene ring the same as those defined in the above ⁇ are used, respectively.
  • the substituent in the optionally substituted carboxy group represented by R include: (1) phenyl (2), for example, 4-fluorophenyl, 2-chlorophenyl, 2,4-dichloro.
  • Mono- or di-halogen-substituted phenyl groups such as phenyl '4-bromophenyl, 2-chloro-substituted 4-bromophenyl and 4-chlorophenyl, 3aminophenyl group, ⁇ protected phenyl-substituted phenyl Radicals, such as methoxy, ethoxy, ⁇ -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, ⁇ -hexynoleoxy, isohexyloxy, etc.
  • a lower alkoxy group having 1 to 6 carbon atoms for example, 'methoxycarbonyl, ethoxycarbonyl, n-propoxyl-carbonyl, isopropoxy Sylcarboninole, ⁇ -butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-n-ethoxycarbonyl, n-hexoxycarbonyl, n-hexyloxycarbonyl Lower alkoxycarbonyl group having 1 to 6 carbon atoms, such as lupinyl, isohexyloxy force, luponyl, and a 3 to 8 membered heterocyclic group (the same as defined in Y above is used) ® (a ) Iminomethyl, 1-Iminoethyl, 2—Iminoethyl, 1-Iminopropyl, 2-Iminopropyl, 3—Iminopropyl, 1-Iminobutyl,
  • 93 a formyloxy group, such as an alkenyloxy group having 2 to 7 carbon atoms, such as acetoxy, memeonolinoleoxy, ⁇ -butyryloxy, isobutyrinoleoxy, ⁇ -pentanoyloxy, ⁇ -hexanoyloxy; ⁇ for example benzoyloxy Aryloxycarbonyloxy groups such as, 4-hydroxybenzoinoleoxy, 4-methoxybenzoyloxy, etc .; @for example, phenylacetoxy, 4-hydroxyphenylacetoxy, 4-methoxyphenylacetoxy Aralkylcarbonyl'reoxy groups, such as: ⁇ eg '2—thienylcarbonyloxy, 2-furinolecal Heterocyclic carbonyloxy groups such as dioxy, etc .; for example, 2 —, — or 5 monothiazolyl acetoxy, 2 — or 3 — diphenyl acetoxy, 2 — or 3
  • Amino-substituted lower alkyl (1 to 6 carbon atoms) amino group such as methyliminomethylamino, n-methylaminomethylamino, n-propyliminomethylamino, 1-methyliminoethylamino,
  • 1-Ci-C6 lower alkylamino group-substituted lower alkyl (Ci-C6) amino group such as 1-ethyliminoethylamino, 1-n-propynoleminoethylamino, etc., for example, methylthio, ethylthio, ⁇ - Lower alkylthio groups having 1 to 6 carbon atoms, such as propylthio, isopropylthio, ⁇ -butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, ⁇ -hexylthio, and isohexylthio; Arylthio groups such as phenylthio, naphthylthio, etc., and carbamoyl groups or lower alkyls having 1 to 6 carbon atoms such as methylcarbamoyl, ethylcarbamoyl, ⁇
  • Rubamoyl group, ®Rubamoylamino group, ⁇ G) phenyl carno Moylamino group for example, ', methylcarha' moylamino, ethylcarbamoyl, chinethylcarno moinoreamino, propylcarpamoinoreamino, dibutinole / 'moinoreamino, n-hexisolenoreno Mono or di (lower alkyl group having 1 to 6 carbon atoms) substitution ability such as noramino, etc.
  • Alkyl-substituted imino groups ⁇ carboxyl groups, @protected carboxyl groups, @halogens such as fluorine, chlorine, bromine and iodine, @> amino groups, and ( ⁇ ) protected amino groups are used.
  • examples of the leaving group represented by Z include a phenylsulfonyloxy group, a p-tonolenesnolephoninoleoxy group and a p-nitrate
  • a lower alkylsulfonyloxy group having 1 to 6 carbon atoms such as a nylsulfonyloxy group, for example, a methanesulfonyloxy group or an ethanesulfonyloxy group, for example, a halogen such as chlorine or bromine, for example, diphenylphosphoryloxy, etc.
  • a diaryl phosphoryloxy group for example, a di (substituted alkyl group having 1 to 6 carbon atoms) substituted phosphoryloxy group such as a getyl phosphoryloxy group is used.
  • R Further examples of R are as follows.
  • an aromatic acyl group such as phthaloyl, P-nitrobenzoyl, p-tert-butylbenzoyl; — Aromatic sulfonyl groups such as tert-butynolebenzen-snolehoninole, p-n-norenoene-snolehoninole, and benzenesulfonyl; for example, honoremil, acetyl, propionyl, aminoacetyl, methylamino acetyl, mono Aliphatic acyl groups such as chloroacetinol, dichloroacetinole, trichloroacetinole, trifluorophenol, acetyl, maleyl, succinyl, etc .;
  • Le W1PO Aliphatic sulfol groups such as rufonyl, ethanesulfonyl and the like; for example, methoxy canephore, ethoxycarbinole, t-butoxycanoleboninole, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, 2,2 Ethoxy canoleboninole, 2-trimethoxy benzoyl benzoyl, ethoxy canole bonyl, benzyloxy carbonyl, 2-methinolesulfonyl ethoxy carbonyl boninole, p-nitrobenzolenole canon bonole, Esterified carboxyl groups such as p-methoxybenzyloxy carbonylcarbonyl, diphenylmethinoleoxycarbonyl, methoxymethyloxylcamolebonyl, acetylmethyloxycanolebonyl, isobornyloxycarbonyl, phenyloxycarbon
  • any of ⁇ -lactam and those which can be usually used as a carboxyl-protecting group in the field of organic chemistry can be used.
  • any of those which can be used as a protecting group for a hydroxyl group in the field of lactam and lactam and organic chemistry can be used, for example, ester residues such as acetyl and chloroacetyl; Esterified carboxyl residues such as 2,2-trichloroethoxycanoleboninole and 2-trimethinolesilinoletoethoxycarbonyl; for example, tert-butynole, benzyl, p-ditropendinole, trityl, methoxime Ether residues such as tinole, methylthiomethyl, ⁇ -methoxethoxymethyl; for example, trimethylsilole and tert-butyldimethylsilole, such as siloleneter residues; for example, 2-tetrahydrobiranyl, 4-methoxy Acetal residues such as 4-tetrafluoroviranyl
  • compound (I) When the carboxyl group at the 2- position or R contains a carboxyl group, compound (I) may be used as it is, but may be used in the form of a pharmacologically acceptable salt by a method known per se. Can also.
  • non-toxic cations such as sodium and potassium, such as arginine, ordinine,
  • the wipo Basic amino acids such as lysine and histidine, for example, polyhydroxyalkyls such as N-methylglutamine, diethanolamine, triethanolamine, trishydroxymethylamine, and amines, etc. May be used after forming a salt thereof.
  • R contains a basic group (for example, an amino group)
  • a salt with an organic acid such as acetic acid, tartaric acid, or methanesulfonic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphorus
  • a salt with an inorganic acid such as an acid, for example, a salt with an acidic amino acid such as arginine, aspartic acid or glutamic acid may be used.
  • the compound (I) of the present invention or a salt thereof may exist in a racemic form as in the case of the raw material compound ⁇ , but this racemic form may be used as it is, or a racemic form may be optically resolved to obtain an optically active form (: d form). , Body, etc.) as a medicine.
  • the compound ⁇ ) of the present invention or a salt thereof has an antibacterial activity against various Gram-positive and Gram-negative bacteria, and is used as a pharmaceutical for humans and homes, and is particularly Gram-positive (eg, Staphylococcus). It is useful as an antimicrobial agent for treating infections caused by 'Aureus' or Gram-negative bacteria (Escherichia coli, Klebsiella nymmoniae). Further, the antimicrobial agent of the present invention may be added to animal feed as a bactericide for preserving the feed, and can also be used as a bactericide on medical and dental equipment.
  • the compound (I) of the present invention or a salt thereof may be used alone or in combination with other active ingredients (eg, cephalosporin antibiotics, penicillin antibiotics) in any of various pharmaceutical preparations. Together, they are used, for example, as tablets, capsules, powders, solutions, suspensions or elixirs. These formulations can be administered orally or parenterally (eg, intravenous injection, muscle --Can be administered.
  • active ingredients eg, cephalosporin antibiotics, penicillin antibiotics
  • Formulations for oral administration include known pharmaceutically acceptable excipients (eg, starch, lactose, calcium carbonate, calcium phosphate, etc.) and binders (eg, starch, gum arabic, carboxymethylcellulose). Tablets, etc., mixed with a lubricant (eg, magnesium stearate, talc, etc.) and a disintegrant (eg, carboxymethyl calcium, talc, etc.), and Capsules, powders, fine granules, and granules can be prepared. Oral liquid preparations may be used as solutions, aqueous or oily suspensions, emulsions, syrups and elixirs, or may be dry products which are dissolved in ice or other suitable solvent before use.
  • excipients eg, starch, lactose, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethylcellulose
  • Tablets, etc. mixed with a
  • Such liquid preparations may include suspending agents (eg, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin), preservatives (eg, methyl p-hydroxybenzoate, propyl p-hydroxy). Benzoate).
  • suspending agents eg, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin
  • preservatives eg, methyl p-hydroxybenzoate, propyl p-hydroxy).
  • Benzoate Suppositories, ordinary suppositories substrate, for example, cocoa 'butter - or other c injectable formulations which can be used glycidyl Serai de a solution in oily or aqueous vehicles, suspension, emulsion or powder form And may optionally contain adjuvants such as suspending, stabilizing and z-dispersing agents. If the preparation for injection is in powder form, use it after dissolving in an appropriate solvent, for example, distilled water from which pyrogen
  • the injectable preparation may contain other active ingredients (for example, penicillin antibiotics, cephalosporin antibiotics, etc.) to exert a broad spectrum antibacterial activity.
  • active ingredients for example, penicillin antibiotics, cephalosporin antibiotics, etc.
  • the compound (I) of the present invention or a salt thereof may be used as a therapeutic agent for bacterial infection, for example, in mammals for respiratory infection, urinary tract infection, purulent disease, biliary tract infection, intestinal
  • the daily dose is about 10 to about 200 Z (body weight) as compound U), and it is about 5 to about 100 Zk ⁇ body weight once every 2 to 4 times a day.
  • the amount is administered, for example, by intravenous injection.
  • the compound (I) of the present invention or a salt thereof has an inhibitory activity on lactamase in addition to the above-mentioned uses, and therefore may be used in combination with a 3-latatam antibiotic.
  • 9-lactam antibiotics include penicillin antibiotics such as benzylpenicillin, phenoxymethinolepenicillin, carpenicillin, ampicillin, amoxicillin, and sulpenicillin.
  • cephalolizine, cepharotin, cefazolin, cephalexin, cefoxitin, cefacetry 0 /, cefamandole, cefmenoxime, cefsulodin, cefotiam, cefotaxime, cefapidin, ceftizoxime, And cephalosporin antibiotics such as cephaloglysin, etc. are used, and are prepared in the usual manner for injections, dry syrups, granules, tablets, capsules, etc. It is preferably used in the form of a salt or hydrate as an injection.
  • the compound ⁇ ) of the present invention can be used in an amount of 1 ⁇ 10 to 10 times (weight) based on 1 / 9-lactam antibiotic 1; Preference is given to a ratio of 8, for example 1/5 or 1 ⁇ 6, and the compounds according to the invention generally have a daily weight of 20 to: L 50 ⁇ 9 (body weight), for example 1 to 6 times, It is usually administered in 2 to 4 divided doses.
  • Compound (I) or a salt thereof of the present invention can be easily produced by a method known per se. That is, it can be produced by reacting the compound (II) or a salt thereof with the compound (I) or a salt thereof and subjecting it to a deprotecting group reaction if necessary.
  • the compound (II) and the compound (D may be used as they are.
  • alkali metal salts such as lithium, sodium and potassium, for example, alkaline earth metals such as calcium and magnesium It may be subjected to the reaction as a metal salt, a silver salt, etc.
  • the compound ( ⁇ ) or a salt thereof may be used as they are.
  • a solvent such as dichloromethane and chloroform
  • nitriles such as acetonitrile, dimethoxetane and tetrahydrofuran.
  • Ethers such as dimethylformamide, dimethylsulfoxide, and hexamethyl phosphoroamide.
  • a base may be added to promote the reaction advantageously.
  • bases include, for example, sodium bicarbonate, sodium bicarbonate, sodium carbonate, sodium carbonate, sodium hydride, lithium hydride, sodium hydride.
  • the amount of the base to be added is generally about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound GD1.
  • Reaction temperature is -50.
  • To 4 (about f C, preferably about ⁇ 30 to 20 ° C.)
  • the reaction time is about 1 to 72 hours, preferably about 1 to 24 hours.
  • compound (I) or a salt thereof thus obtained has a protecting group
  • the protecting group can be removed by a method known per se, if necessary.
  • the reaction for removing the protecting group is specifically described.
  • the protecting group for the carboxyl group in compound (I) or a salt thereof is a halogenoalkyl group, an aralkyl group, a benzhydryl group, or the like
  • the compound is brought into contact with a reducing agent. Achieved.
  • the group is, for example, a halogenoalkyl group such as 2,2-dibromoethyl, 2,2,2-trichloroethyl, zinc and acetic acid are preferred, and the protecting group is, for example, benzyl, P-nitrobenzyl And hydrogen when it is an aralkyl group or a benzhydryl group such as, for example, platinum oxide, platinum black, platinum sponge, palladium-carbon, palladium-black, and ⁇ . Radium barium monosulfate.
  • a catalytic reduction catalyst such as radium barium monocarbonate, reduced nickel, Raney nickel, Urushibara nickel or an alkali metal sulfide such as sodium sulfide or sulfur sulfide is suitable.
  • radium barium monocarbonate reduced nickel, Raney nickel, Urushibara nickel or an alkali metal sulfide such as sodium sulfide or sulfur sulfide is suitable.
  • 0-nitrobenzyl group removal by light irradiation can be performed, and in the case of p-methoxybenzyl group, removal by electrolytic reduction can be performed.
  • the reaction is performed in the presence of a solvent.
  • Examples of the solvent used include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; lower (2 to 7 carbon atoms) fatty acids such as acetic acid and ⁇ propionic acid; A mixed solvent of water and water is preferred.
  • the reaction temperature is usually
  • reaction time is usually about 5 minutes to 12 hours.
  • the protecting group of the amino group in the compound (I) or a salt thereof is, for example, a P-nitrobenzoleoxycanoleboninole group, an o-benzenzoleoxycanolebonyl group, a P-methoxybenzylo group
  • a xycarbonyl group, a benzyloxycarbonyl group or the like it is removed in the same manner as in the above-mentioned protective group removal reaction of the carboxyl group.
  • the protecting group of the hydroxyl group in the compound (I) or a salt thereof is a lower alkanol (2 to 7 carbon atoms) oxy group such as acetoxy, it can be removed by treating with a base in an aqueous solvent.
  • the solvent used is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction.
  • OMPI A mixed solvent of water and an organic solvent such as alcohols such as methanol'ethanol or ethers such as tetrahydrofuran and dioxane is preferable.
  • the base to be used is not particularly limited as long as it does not affect the / 3-lactam ring.
  • the reaction is carried out using alkali metal carbonates such as sodium carbonate and potassium carbonate. .
  • the reaction temperature is
  • the reaction time varies depending on the type of the starting compound, the reaction temperature and the like, but is usually about 1 to 6 hours.
  • a tri-lower (carbon number 1 to 6) alkylsilyl group such as tert-butyldimethylsilyl is used as a hydroxyl-protecting group, for example, tetrabutylammonium fluoride or potassium fluoride is used. It is removed by treating with fluorine ion such as.
  • ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction is completed in about 10 to 18 hours at around room temperature.
  • the compound (D) Since the compound (D) has a carboxyl group, it can generally act with a base to form a salt. Therefore, the compound (1) may be collected as a salt, and the compound obtained as a salt may be in a free form or as another salt. Further, the compound (I) obtained in a free form may be converted into a salt.
  • a method of releasing the compound (I) obtained as a salt for example, a method using an acid and the like are used.
  • the acid used depends on the type of protecting group and other conditions. For example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, and P-toluenesulfonic acid are commonly used. Is done.
  • an acidic ion exchange resin is used.
  • a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane, etc., water, or a mixed solvent thereof is often used. This method is generally performed at room temperature, but may be performed under cooling or heating.
  • the reaction time is generally about tens of minutes to about one hour.
  • the compound (1) or a salt thereof obtained in this manner is isolated by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, and close chromatography. It can be purified.
  • this amino group is further converted to an amide group (eg, acetoamide group, propionamide group, etc.), ureido group, imino-substituted lower alkyl (having 1 to 6 carbon atoms) amino group, a lower Arukirui amino-substituted lower alkyl (1 to 6 carbon atoms) amino groups having 1 to 6 carbon atoms, can be converted into Guanijino group.
  • an amide group eg, acetoamide group, propionamide group, etc.
  • ureido group eg, imino-substituted lower alkyl (having 1 to 6 carbon atoms) amino group
  • a lower Arukirui amino-substituted lower alkyl (1 to 6 carbon atoms) amino groups having 1 to 6 carbon atoms can be converted into Guanijino group.
  • amino group-substituted lower alkyl (C1 to C6) amino group and the C1 to C6 lower alkylamino-substituted lower alkyl (C1 to C6) amino group the same as those described above are used.
  • this hydroxyl group can be further converted to an acyloxy group (eg, acetoxy, propionyloxy, etc.), a halogen, or an azide group. .
  • an acyloxy group eg, acetoxy, propionyloxy, etc.
  • a halogen e.g., acetoxy, propionyloxy, etc.
  • the amino group is an amide group, a ureido group, an imino group-substituted lower alkyl (1 to 6 carbon atoms) amino group, a C1 to 6 lower alkylamino-substituted lower alkyl (1 to 6 carbon atoms) amino group
  • the reaction for conversion to a guanidino group can be achieved by various known methods.
  • the conversion reaction of an amino group into an amide group can be carried out by contacting with an acylating agent in the presence of a solvent.
  • the solvent used is not particularly limited, but halogenated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane are preferred.
  • the acylating agent used is not particularly limited as long as it can acylate a normal amino compound. Examples thereof include lower fatty acid anhydrides such as anhydrous acetic acid and propionic anhydride;
  • lower (carbon number) such as acetyl chloride, propionyl chloride, ⁇ -butyryl bromide, isoptyryl bromide, methoxalyl chloride, etc.
  • Fatty acid halide derivatives can be mentioned.
  • This reaction is suitably carried out in the presence of a base.
  • the base to be used include organic bases such as triethylamine and pyridine, and bases such as sodium acetate and potassium acetate. Alkali metal salts of fatty acids are preferred.
  • the reaction temperature is not particularly limited, but is preferably around 0 ° to 40 ° C. The time required for the reaction varies depending on the type of the acylating agent and the reaction temperature, but is usually about 30 minutes to 5 hours.
  • the conversion of an amino group to a peri-radical group is carried out in the presence of a solvent in the presence of a substituted isocyanate.
  • Suitable substitutions may be, for example, methyl, ethyl, phenyl, P-bromophenyl, etc.
  • the reaction temperature is around 0 ° to 40 ° C, and the reaction time is usually about 30 minutes to 5 hours.
  • the conversion reaction of an amino group into an amino-substituted lower alkyl (1 to 6 carbon atoms) amino group or a lower alkyl amino group substituted with 1 to 6 carbon atoms lower alkyl (1 to 6 carbon atoms) is carried out by reacting with a solvent such as dioxane, tetrahydrofuran, dimethylformamide, chloroform, aceton, acetonitrile, 7, for example, with imidoesters.
  • Suitable imidoesters include, for example, methylformimide, ethylhonoleimidate, benzylformimidate, methylacetoimidate, methylacetoimidate, methylphenylimidate, methylphenylimidate.
  • the reaction temperature is around 0 ° to 2 and the reaction time is usually about 1 to 6 hours.
  • the conversion reaction of the amino group to the guanidino group is carried out in a solvent such as water, dimethylformamide, hexamethylenephosphoramide, for example, 0-alkyl or 0-arylpseurea or S-alkyl.
  • the reaction is carried out by reacting with thiol or S-arylpsoid thioureas. Examples of the above pseudoureas include 0-methyl pseudourea,
  • busotide ureas such as S-methylpseudourea, 0-2,4-digluropruspure urine 0-N, N-trimethylpseudeurea, are S-p-ditrophenylpsoye Dothiourea and the like are used.
  • the reaction temperature is from 0 ° C to about 40 ° C, and the reaction time is usually from 1 force to 24 hours.
  • the reaction for converting a hydroxyl group into an acyloxy group, a halogen atom or an azide group can be achieved by various known methods.
  • the reaction for converting a hydroxyl group to an acyloxy 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 can be achieved by halogenation according to a conventional method.
  • As the halogenating agent to be used for example, thioyl chloride, thionyl bromide, oxalyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine and the like 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 (or around room temperature, and the reaction time is usually about 15 minutes to 5 hours.
  • the conversion of the hydroxyl group to the azide group is carried out in the presence of a phosphine derivative and an azodicarboxylic acid ester.
  • the reaction is achieved by reacting with hydrogen hydride or azide difluorophenylate.
  • triphenylphosphine and tri-n-butylphosphine are preferable, and as azodicarboxylic acid diester, for example, azodicarboxylic acid dimethyl ester, azodicarboxylic acid getyl ester and the like are used.
  • Suitable solvents used are, for example, halogenated hydrocarbons such as dichloromethane and chloroform, and ethers such as tetrahydrofuran and dioxane.
  • the reaction temperature is preferably about 0 to 60 ° C., and the reaction time is preferably about 5 minutes to 5 hours.
  • the compound (I) or a salt thereof thus obtained is isolated and purified by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc. be able to.
  • the starting compound (I) used in the present invention can be produced by a method known per se or a method similar thereto. For example, it can be manufactured by the method shown in the figure below or a method similar to it,
  • R 1 , X, Y and Z have the same meanings as above, X ′ represents a lower alkylene group or an alkenylene group which may have a protected hydroxyl group, and R 2 represents a hydrogen atom or an amino group.
  • R 3 is a protecting group for a hydrogen atom or a hydroxyl group, or R 2 and K 3 are bonded to each other to form a hydrocarbon group or a heterocyclic group, and R 4 is a hydrocarbon group or a heterocyclic group. Is shown).
  • the lower alkylene group or lower alkenylene group in the lower alkylene group or lower alkenylene group which may have a protected hydroxyl group represented by X ′ is the same as defined for X. .
  • protecting group for the hydroxyl group in the lower alkylene group which may have a protected hydroxyl group represented by X and the protecting group for the hydroxyl group represented by R 3 , the same as those described above are used.
  • protecting group for the amide group represented by R 2 include trimethyl i-yl and t-butyl dimethyl.
  • Tri-substituted (lower alkyl groups having 1 to 6 carbon atoms) such as V-ril, and 5- to 6-membered cyclic ether groups such as 2-tetrahydropyran are used.
  • Hydrocarbon group or multiple heterocyclic group represented by R 2 and 3 are bonded to each other, a hydrocarbon group or heterocyclic group represented by R 4 are the same as those defined in the K is used.
  • the protecting group R 2 for the amino group and the protecting group R 3 for the hydroxyl group are not particularly limited in their selection as long as they do not hinder the reaction under j, for example, trimethylsilyl group, t-butyldimethylsilyl group,
  • R 5 and R 6 each represent a hydrocarbon group.
  • the amide group and the hydroxyl group may be simultaneously protected by forming a compound represented by
  • the hydrocarbon group represented by R 5 and R 6 the same one as defined in the above R is used, and particularly, a hydrocarbon group having 1 to 3 carbon atoms such as methyl, ethyl-, or isopropyl group is used.
  • Lower alkyl groups, and those in which R 5 and R 6 are linked by an alkylene group having 3 to 6 carbon atoms are frequently used. (Both “XVH” and “R 6.” , Both of which are methyl groups, have already been described in the literature (B. G. Christensen, et al., Journal of Organic and Chemistry.
  • This compound is composed of 4-2-hydroxethyl) azetidine-l-one and 2,2-dimethoxybutane.
  • an acid catalyst such as boron trifluoride etherate and P-toluenesulfonic acid.
  • R 5 and R 6 are groups other than the methyl group 1, ketones such as getyl ketone and methyl may be used instead of the 2,2-dimethoxypropane used in the above reaction.
  • OMPI It can be easily produced by using L-tilchyl ketone, diisopropyl ketone, cyclopropanone, clobutanone, cyclopentanone, cyclohexanone). In the following reaction, it is preferable to use (as a starting compound.
  • Step 1 is a step of sulfenylating the 3- position of (IV) with a sulfenylating agent to obtain (V).
  • a sulfenylating agent to be used include disulfides represented by the formula (R 4 S) 2 ,
  • R 4 in the formula I is as defined above.
  • the sulfenyl amide may be used in an approximately equimolar amount with respect to 1 mol of (JV).
  • the reaction is usually performed in a solvent in the presence of a base.
  • a base examples include strong bases such as lithium diisopropylamide, lithium isoprovir chlorohexylamine, sodium amide, and hydrogenating hydride.
  • Suitable solvents include, for example, tetrahydrofuran, dimethoxyethane, ether, dimethylformamide, dimethylsulfoxide and the like.
  • the amount of the base to be added is suitably about 1 to 3 mol per 1 mol of (IV).
  • the reaction temperature is about 180 ° C to 0 ° C.
  • the reaction time is about 30 minutes to 6 hours.
  • (V) can theoretically have two diastereomers with respect to the 3-position substituent. These isomers can be isolated by operations such as column chromatography and recrystallization, and each can be used in the next step reaction.
  • the second step is a step of alkylating the 3- position of (V :) with an alkylating agent to produce (VI).
  • alkylyl used include a compound represented by the formula Y—S—XA, wherein A is a halogen atom, a P-toluenesulfonyl group, a methanesulfonyl group, a trifluoromethanesulfonyl group or an oxo group; Is as defined above].
  • halogen atom represented by A for example, chlorine, bromine, iodine and the like are used.
  • reaction of this step the same strong base and solvent as those used in the first step were used, and at a temperature of about 180 to 0 ° C, about 1 to 20 moles of 1 mole of [V) was used.
  • the reaction is carried out by reacting an alkylide.
  • the above (lr)-(V)-(:) conversion reaction converts (: V) to I)-(W) in the same vessel without isolation (. Display :) is also possible.
  • the same strong base and solvent as those used in the first step (I?) Were used, and the amount was about 1 y.
  • (IV) by adding approximately 1 mole of the sulfhydrating agent to 1 mole, and then adding about 1 to 20 moles of the alkylating agent. ) Can be obtained.
  • the amount of the strong base used is suitably 2 to 3 mol per 1 mol of (IV).
  • the resulting (71) may theoretically have two diastereomers due to the 3-position substituent.
  • the third coloration is a step for preparing a (VI) is reacted with a reducing agent selectively 3, 4-cis-substituted ⁇ Zechijinon (3 ⁇ 4 a).
  • WIPO Suitable reducing agents include, for example, organotin compounds, nickel compounds, mercury compounds, zinc compounds and the like.
  • hydrocarbon group represented by R 7 the same groups as those described for R can be used. Particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and n-pentyl
  • a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl group, etc.)-Substituted phenyl group is used.
  • triphenyltin hydride and tri-n-butyltin hydride are preferred.
  • the reducing agent is used usually in an amount of about 1 to 10 mol, preferably about 1.2 to 5 mol, per 1 mol.
  • This reaction is suitably carried out in the presence of a free-radical initiator such as 0.1 to 0.5 mol of azobisbisbutyronitrile or di-tert-butyl peroxide.
  • a free-radical initiator such as 0.1 to 0.5 mol of azobisbisbutyronitrile or di-tert-butyl peroxide.
  • Light irradiation may be performed instead of using the free radical initiator.
  • the reaction may be carried out using the solvent itself, but is usually performed in a solvent that does not participate in the reaction.
  • Suitable solvents include, for example, ketones such as acetone and methyldiol ketone, ethers such as dioxane and tetrahydrobran, alcohols such as methanol and ethanol, and aromatic hydrocarbons such as benzene, toluene and xylene. Hydrogens etc. — ⁇
  • the reaction temperature may be usually about 0 1 3 0 ° C, particularly about 1 (Power et al 1 0 0 ° c is preferred. In If necessary nitrogen or in an atmosphere of an inert gas such as argon. the reaction time is about 2 4 hours 1 by. this reaction, primarily 3, 4-position compounds with cis Haisuppon (a) the power to generate a small amount of 3, compounds having a 4-Bok lance arrangement ( The isolation of CW a) from the reaction mixture is carried out according to a method known per se. For example, (Wa) can be easily isolated by evaporating the solvent of the reaction mixture and subjecting the residue to a recrystallization method or column chromatography. (Hb) is produced by directly alkylating the 3-position of IV) with an alkylating agent (second step).
  • the conversion reaction from [IV) force to ⁇ b) is achieved by the same method as the conversion reaction from [V) force to W). -That is, using the same strong base and solvent as used in the second step, at a temperature of about 180 ° to 0 °, about 20 moles of alkylating agent were reacted with 1 mole of (I?). To obtain Wb).
  • each of the 3,4-cis form and the 3,4-trans form or a mixture of both can be used.
  • this hydroxyl group is subjected to a protection reaction to produce (3 ⁇ 4).
  • the protecting group for the hydroxyl group in ( ⁇ 1) the same ones as described above are used, and examples thereof include ethers such as ⁇ -methoxy i / ethoxy methyl group, methoxymethyl group, methylthiomethyl group and the like.
  • Protecting groups that form a bond are preferred. Among these, for example, a methoxyquinine methyl group is preferable.
  • the introduction reaction of the protecting group can be achieved by a method known per se. Further, for example, in the case of the above-mentioned protecting group forming an ether bond, —methokitoquine methyl chloride,
  • the reaction is carried out by reacting an alkyl halide such as methoxymethyl chloride and methylthiomethyl chloride. This reaction is carried out in the presence of a base such as, for example, triethylamine, diisopropylpropylamine, pyridine, ⁇ -butyllithium, hydrogenated sodium, and the like.
  • a base such as, for example, triethylamine, diisopropylpropylamine, pyridine, ⁇ -butyllithium, hydrogenated sodium, and the like.
  • the amount of the alkyl halide and the base used in this reaction is about 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol).
  • the reaction is usually performed in a solvent.
  • Solvents used include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ether, dimethoxetane, acetonitrile, dimethylformamide, dimethylsulfoxide, and the like.
  • the reaction temperature is about 120 ° to 100 ° C.
  • the reaction time is about 30 minutes to 72 hours.
  • the 3-position substituent of ( «) and the thio group of (group represented by the formula Y.—S—X—) are oxidized with an oxidizing agent to be converted to a sulfonyl group to produce (: ⁇ ) It is a process.
  • the oxidation reaction of this thio group is a mild oxidizing agent that does not act on the lactam ring, such as perbenzoic acid, ozone, phenyldichloroiodide, hydrogen peroxide, sodium metaperoxide, and hypochlorous acid. This is performed using acid sodium or the like. Among them, for example, perbenzoic acid, m-chloroperbenzoic acid and the like are particularly preferable.
  • the oxidizing agent is used in an amount of about 2 mol or more per 1 mol.
  • the reaction is usually carried out in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride and the like.
  • the reaction temperature is about —30. From a 2 5 ° C.
  • the reaction time is about 10 minutes to 10 hours.
  • the sixth step is to remove the protecting group R 2 and R 3 of (K), is a step for preparing a (X). Removal of the protecting group R 2 and R 3 is carried out by applying various known deprotection methods. For example, when (IX) is a compound derived from, the protecting group is removed at a temperature of about 0 ° to 75 ° C in a solvent such as aqueous acetic acid.
  • the reaction is carried out by acid hydrolysis with a reaction time of 5 minutes to 16 hours at d4-degree.
  • the hydroxyethyl group at the 4-position of X) is converted to a hydroxymethyl group by an oxidation reaction to produce a): 3 ⁇ 4.
  • the acid ib reaction can be carried out using various known oxidizing agents such as diones reagent, potassium permanganate, silver oxide and the like.
  • the reaction is performed in a solvent such as 7k tetrahydrofuran, aqueous dioxane, and acetone.
  • the reaction temperature is in the range of 110 ° C to 40 ° C.
  • the reaction time ranges from 10 minutes to 24 hours. About 10 ° to 30 °, especially in solvents such as acetone. It is preferable to carry out the oxidation reaction at a temperature of C for about 10 minutes to about 8 hours using a Dijon's reagent.
  • the target compound (I) includes both the optically active compound and the racemic compound.
  • the optically active compound (I) can be produced from the optically active compound (W).
  • Optical resolution can be achieved by various methods of ⁇ !, such as crystallization or by reacting (3 :) with optically active amines such as, for example, quinine, brunun, ephedrine, strychnine, morphine.
  • Optical separation is performed by the fractional crystallization method of the diastereomer salt, the physical separation method using chromatography, etc.
  • the carboxyl group for the 4-position substitution in () is converted to 3 ⁇ 4ft, and then two carbon atoms are extended to produce (an).
  • reaction is carried out as t a) with, for example, 1,1-carbodium midazole or
  • the amount of the magnesium salt of the imidazolide reagent and the malonic acid derivative used in the reaction is about 1 to 2 moles per mole of D (the former is about 1 to 2 moles, and the latter is about 1 to 3 moles. as tetrahydrofuran.
  • the reaction temperature is carried out in a solvent such as dimethyl Tokishetan about 0 ° 5 0 ° takes place in C. the reaction time from is about 1 48 hours.
  • the ninth step is a reaction for producing (XI) by thiazotizing (II).
  • This diazotization reaction is carried out by reacting 3 ⁇ 4 ⁇ with an azide compound such as ⁇ -carboxybenzenesulfonyl azide, ⁇ -toluenesulfonyl azide, methanesulfonyl azide in the presence of a base such as triethylamine, getylamine or pyridine.
  • the amount of the base is usually used in a large excess with respect to ⁇ ;
  • the amount of the azide compound is about 1 to 2 times the molar amount with respect to (K;
  • the reaction is usually performed with acetonitrile and dichloromethan.
  • the reaction is carried out in a solvent such as tan, tetrahydrofuran, etc.
  • the reaction temperature is about 110.
  • the pressure is 40 ° C, and the reaction time is usually about 1 to 48 hours.
  • Step 10 is a step of removing the protecting group for the hydroxyl group of ( ⁇ ), but it is not essential to remove the protecting group in this step, provided that it is pharmaceutically acceptable.
  • the protecting group may remain in the target compound (I), and if necessary, the protecting group may be removed in any step after this step.
  • the protecting group of the hydroxyl group is /?-Methoxyethoxymethyl group, for example, in a solvent such as chloroform, dichloromethane, or tetrahydrofuran, for example, titanium tetrachloride Acids, such as zinc and zinc bromide It is performed by reacting with _ 6 _.
  • the amount of Lewis acid used is about 1 to 30 times the mole of (XI), and the reaction temperature is about 11 ( ⁇ to 40 ° C).
  • the reaction time is about 5 minutes to 10 hours. .
  • the first step is a step of subjecting (xm to a cyclization reaction to produce (x).
  • This cyclization reaction is carried out in a solvent such as benzene, toluene, tetrahydrofuran or the like, for example, copper sulfate, copper powder
  • a solvent such as benzene, toluene, tetrahydrofuran or the like, for example, copper sulfate, copper powder
  • the reaction is carried out by cyclization in the presence of a catalyst such as rhodium acetate, noradium acetate, etc.
  • the reaction is performed at about 50 ° to 110 ° C.
  • the reaction time is about 1 to 5 hours.
  • the cyclization is usually carried out in a solvent such as benzene, tetrahydrofuran, carbon tetrachloride or getyl ether, for example, in an atmosphere of an inert gas such as nitrogen or argon. It can be carried out by irradiating with light at a temperature of from 40 ° to 40 ° for 30 minutes to 2 hours.
  • a solvent such as benzene, tetrahydrofuran, carbon tetrachloride or getyl ether
  • an atmosphere of an inert gas such as nitrogen or argon. It can be carried out by irradiating with light at a temperature of from 40 ° to 40 ° for 30 minutes to 2 hours.
  • the 12th step is a step of activating XV with a excretory agent to produce I.
  • P-toluenesulfonic acid anhydride p-nitrophenyl phenylsulfonic acid anhydride, 2,4-triisopropylmonophenylsulfonic acid anhydride, methanesulfonic acid bran water
  • P-toluene Sulfonyl diluents such as sulfoyuric chloride and p-bromophenylsulfonyl chloride can be used in a solvent such as, for example, dichloromethane, chloroform, formacetonitrile, dimethoxyethane, tetrahydrofuran and the like.
  • the reaction is carried out in the presence of a base such as min, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
  • a base such as min, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
  • the reaction temperature is about ⁇ 20 ° to 40 ° C.
  • the reaction time is about 30 minutes to 5 hours.
  • ⁇ in (II :) is a disubstituted phosphoryloxy group
  • a phosphorylating agent C eg diphenylphosphoric acid Reaction under the same conditions using a lid, dimethyl phosphate, acetyl phosphate chloride, etc.
  • reaction product thus obtained or a salt thereof can be isolated and purified by a means known per se, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
  • Double double double doublet t triplet q: quartet
  • IR «» -1 3320, 1750-1720, 1350, 1120
  • aqueous layer is extracted with ethyl acetate
  • the organic layers are combined, washed successively with 20 carbon dioxide rim, water (3 times), aqueous sodium hydrogen carbonate and water (3 times), dried (Na 2 SO 4 ), and dried. Is concentrated to about 10 ⁇ . Then, benzene 10 is added, and the solvent is distilled off to obtain a benzene solvate 66 w of the title compound as a white foam.
  • I M- 1 3 330, 2 140, 1760, 1720, 1650, 1340, 1130
  • Reference Example 3 2,3-1,4 Trans obtained in 2 1 -3-[ ⁇ ((2-Methoxyethoxyethoxy)) 1 -2 -Methinoresnolehonyllechinole] 1-4-[3-(4
  • the title compound 2884 can be obtained as an oil from the same method as in Reference Example 7 from —w-benzoyloxycarbonyl) 1 2 —oxopropyl] azetidin-12-one 311 w.
  • the aqueous layer is washed with ethyl acetate, concentrated under reduced pressure, and the concentrated solution is subjected to column chromatography using an Amberlite XAD-2 (eluate, H 20 ). The fractions that absorb at 298 nm in the UV spectrum are collected and lyophilized to give powder 21.
  • the product further Diaion HP - 2 0 the use Karamuku port Mato chromatography (eluent, H 2 0) title compound when purified by (1 2) is obtained as a colorless powder.
  • IRM 1 3400, 1750, 1720, 1300,
  • the title compound (20 ⁇ :) is obtained as a pale yellow powder by treating the 4-butanol benzyl ester 51 ⁇ obtained in the above (a) in the same manner as in Example 1 (cj).
  • Clopentyl-3,3-dioxide ) 1-7-oxo-1 1-azabisik In the mouth 3 ⁇ 2.
  • IR c 1 3400, 1770, 1700, 1640,
  • the title compound (14 ⁇ ) is obtained as a pale-yellow powder from the 4- (2-to-open-end benzyl ester 52, obtained in the above aj, in the same manner as in Example 1).
  • UV nm 2 3 0, 2 6 5, 3 2 6
  • the title compound (19) is obtained as a colorless powder from the 412-to-mouth benzyl ester 59 obtained in the above (a), in the same manner as in Example 1 ().
  • the MI C (meg) of a representative example of the target compound [I] obtained in the examples was measured by the following method.
  • the MIC of the test compound was determined by the agardiluion method. That is, 1.0 of a 7K solution of a test compound, which has been sequentially diluted, is poured into a Petri dish, and then the trypticase 'soy' gas is added.
  • Staphylococcus' Ole Reus S. aureus DA 209P
  • the MIC C minimum inhibitory concentration of the test compound is shown in Table 1 c
  • the stability in a mouse kidney homogenate was measured by the following method.
  • test compound After mixing well with 200 ° C, keep the temperature at 30 ° C. Every 25 minutes, collect 25 ⁇ of the mixture, add it to methanol 25 cooled by ice melting, and stop the reaction between the kidney enzyme and the test compound. The amount of test compound remaining depends on the proteus vulgaris (GN4 4 13) and the inhibitory effect on lactamase produced by entrobacter cloacac N 12 82 It is determined by measurement (as described in Journal of Ant-fciotics, 34, 212-217 (1981)).
  • the compound of the present invention 7-oxo-11-azavinclo (: 3 ⁇ 2 ⁇ 0) ′ ′ pta-2-ene-2-carboxylic acid derivative (: I), is an excellent antibacterial agent and is capable of infecting humans or livestock with bacteria. It is used for the treatment and prevention of the disease.

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PCT/JP1983/000319 1983-09-28 1983-09-28 7-oxo-1-azabicyclo ad3.2.0 bd hept-2-ene-2-carboxylic acid derivatives, process for their preparation, and their use WO1985001502A1 (en)

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PCT/JP1983/000319 WO1985001502A1 (en) 1983-09-28 1983-09-28 7-oxo-1-azabicyclo ad3.2.0 bd hept-2-ene-2-carboxylic acid derivatives, process for their preparation, and their use
JP59199316A JPS6089486A (ja) 1983-09-28 1984-09-21 ７‐オキソー１‐アザビシクロ〔３．２．０〕ヘプター２‐エン‐２‐カルボン酸誘導体，その製造法及び用途
EP84111442A EP0137403A3 (en) 1983-09-28 1984-09-26 Carbapenems, their production and use
CA000464131A CA1263117A (en) 1983-09-28 1984-09-27 Carbapenems, their production and use

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54145695A (en) * 1978-05-06 1979-11-14 Beecham Group Ltd Alkylcarbapenems*their manufacture and composition
JPS54157595A (en) * 1978-05-06 1979-12-12 Beecham Group Ltd Carbapenem derivative*its manufacture and composition
JPS5716891A (en) * 1980-03-27 1982-01-28 Merck & Co Inc 1-carbapenems and manufacture thereof through silyl substituted dithioacetals of intermediates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54145695A (en) * 1978-05-06 1979-11-14 Beecham Group Ltd Alkylcarbapenems*their manufacture and composition
JPS54157595A (en) * 1978-05-06 1979-12-12 Beecham Group Ltd Carbapenem derivative*its manufacture and composition
JPS5716891A (en) * 1980-03-27 1982-01-28 Merck & Co Inc 1-carbapenems and manufacture thereof through silyl substituted dithioacetals of intermediates

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