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

Abstract

Compounds represented by formula (I), (wherein X represents a lower alkenylene or lower alkylene group optionally containing a hydroxy group, Y represents (1) a lower alkyl group, (2) a C3-8 cycloalkyl group, (3) a lower alkenyl group, (4) an aryl group, (5) an aralkyl group, or (6) a 3- to 8-membered hetero cyclic group, or X and Y of the Y-SO2-X group are bound to each other and represent (II), (wherein $(1,5)$ represents an integer of 0 to 3, and m and n each represent an integer of 0 to 6, with the sum of m and n being 2 to 6), and R represents an optionally substituted hydrocarbyl group or a 3- to 8-membered heterocyclic group) or the salts thereof, process represented by the scheme (III), (wherein Z represents an eliminatable group, COOR1 represents an optionally protected carboxyl group, and other symbols are as defined above) and antibacterial composition containing compound (I) or its salt.

Description

 Specification

 7-oxo-l-azabicyclo [3.2.0] hepta-2-ene-2-carboxylic acid derivatives, their production and use

 Technology 1_

 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

OOH Nem compounds are

OOH

7-oxo 1-azabicyclo [3. 2. 0] hepta-2-en-2-carboxylic acid), its production method and use.

 Background technology

In recent years, various ⁷ -oxo-1-azabisic [3.2.0] hept- ^2- en-2-carboxylic acid derivatives having antibacterial activity have been produced.

 For example, 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.

 However, when these compounds are taken into the body, they are rapidly degraded by in vivo enzymes (for example, dehydropeptidase, which is a renal enzyme), inactivated, and have the antibacterial action inherent in the compounds. It has the disadvantage that it cannot be fully demonstrated.

 Disclosure of the invention

 O PI

,. , 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.

 (In the formula, X is a lower alkylene group or a lower alkenyl group which may have a hydroxyl group, and 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—

X and Y combine to form

/ (CH ₂ ) m, ^ (CH ₂ ) m _0H

S0 ₂ CH (CH ₂ ) or S0 ₂ C- (CH ₂ ) i- (CH ₂ ) _n- ^/ (CH ₂ ) /

[Wherein, is an integer of 0 to 3, m and n are each an integer of ^{6 to 6} , and the sum of m and n is 2 to 6.] A hydrocarbon group or a 3- to 8-membered heterocyclic group), or a salt thereof, which meets the above-mentioned object, and as a result of further study, the present invention was completed. .

 That is, the present invention

 (1) a compound represented by the general formula (I) or a salt thereof,

(2) —General

Wherein Z is a leaving group, COO Ri is a carboxyl group which may be protected, and X and Y have the same meanings as defined above. -— Salt and general formula

 Reacting with a compound represented by RSH (I) wherein R represents an optionally substituted hydrocarbon group or a 3- to 8-membered heterocyclic group, or a salt thereof, and deprotecting as necessary A method for producing a compound represented by the general formula (I) or a salt thereof, which is characterized by subjecting the compound to a group reaction:

 (3) The present invention relates to an antibacterial composition containing a compound represented by the general formula (: I) or a salt thereof.

In the above general formula, X is, for example, ethylene, propylene, butylene, hydroxyethylene, hydroxymethylethylene, 1-hydroxy-2-methynoleethylene, hydroxyxetinoreethylene, 1-hydroxy-2-ethylethylene And 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. And Y represents (1) for example, ^ I>, ethyl, n-propyl, isopropyl, n-butynole, iso "^> le, tert-butynole, π-pentynole, η-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 ) aralkyl groups such as benzyl, phenethyl and phenylpropyl (preferably carbon number). 7 to 10), or (6) for example, 1- or 2-aziridinyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3 REA

O PI 1-Chenyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-Pyridyl, N-Oxido 2-, 3- or 4-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-Monobilanyl, 2-, 3- or 4-thioviranyl, pyrazinyl, 2-, 4- or 5-thiazolyl.

2-, 4-mono- or 5-oxazolyl, 3-, 4-mono- or 5-isothiazolyl, 3-, 4-mono- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4 1- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-year-old xido 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, N-oxyd 2-, 4- or 5- Pyrimidinyl, piperazinyl, 4- or 5- (1,2,3-thiadiazolyl), 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 1. 2,5—thiadiazolyl, 4 or 5— (1,2,3—oxadiazolyl), 3— or 5— (1.2,4—oxadiazolyl), 1,3,4—oxadiazolyl, 1 , 2,5-oxaxaziryl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H—tetrazolyl ，, benzothiylzolinole, indolinyl, benzopyranyl, 1,8-, 1,5-, 1,6—, 1,7—, 2,7— or 2,6-naphthyridinyl, quinolyl, etc. of Okishido reduction is optionally 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,

 ΟΜΡΙ

ゝ -WT O ΝΑΤΙΟ One one

 (3 ~ ψγ-sick u-p-thousand) ~ (3-Thiacyclo pentyl (3-Thiacyclo ^ syl)

_{3, three} to; ^ Kishido) methyl-3, 3 -: ^ Kishido) Echiru -3, 3 - ,: ¾ · Kishido) Puropinore

Equation of

(CH ₂ ) m

 ヽ

so ₂ CH- (CH ₂ ) ^-ヽ (CH ₂ ) _n z (where is an integer from 0 to 3, m and n are each an integer from 0 to 6, and the sum of m and n is 2 to 6)) or, for example,

 (1-Hydroxy-3— (1-Hydroxy-1 3— (1-Hydroxy-4—

 Thiacyclofuthino 3, Thiashik π Pentyl Thiacyclo sinole

 3—i ^ oxide) -3,3—: ^ oxide) 1 4 4—dioxide)

 (1-Hydroxy-3- (1-Hydroxy-4-1 (1-Hydroxy-3-

 Chiashik C ^ Shinore Chiashik π ^ ^ Chiashik π ^ ^

 —3,3—oxide) 1,4,4-dioxide) 1,3,3— ': ^ oxide)

OH

S0 ₂

CH₂ CH₂ CH₂-

CH ₂ CH ₂ CH _2-

((1-hydroxy-1 3— ((1-hydroxy-4— ((1-hydroxy-1 3—

 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

 —3,3—didiacid) methyl) -4 4 '': ^ oxide) ethyl :) -3,3— ί¾ "oxide" propyl)

ΟΜΡΙ Equations, (C ⁿ H2 ₂ ) ノ mr ヽ · Οϋ

 S inO, C (The symbols in the formula are as defined above.)

 \

(CH _{2) I} / ^C )-represents a group represented by the formula: wherein R is an optionally substituted lower alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, From 1 to 5 hydrocarbon groups such as lower alkenyl groups and aryl groups, or 1 to 5 heteroatoms such as optionally oxidized nitrogen, oxygen and sulfur atoms; A 3- to 8-membered heterocyclic group which may be condensed with a benzene ring.

In the above, 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. As the 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. For example, phenyl, naphthyl, β-naphthyl, biphenyl, anthryl and the like are used. In addition, one heteroatom such as a nitrogen atom, an oxygen atom and a sulfur atom which may be oxidized is used. As the 3- to 8-membered heterocyclic group which may be condensed with a benzene ring, the same as those defined in the above Υ are used, respectively. Examples of 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, 基 protected phenyl-substituted phenyl Radicals, such as methoxy, ethoxy, π-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, π-hexynoleoxy, isohexyloxy, etc. A lower alkoxy group having 1 to 6 carbon atoms, for example, 'methoxycarbonyl, ethoxycarbonyl, n-propoxyl-carbonyl, isopropoxy Sylcarboninole, π-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, A lower alkyl group having 1 to 6 carbon atoms substituted by an imino group such as 2-iminobutyl, 3-iminobutyl, 4-iminobutyl, etc. (b) For example, methyl, ethynole, n -Professional Pill, isopropynole, n-butynole, isobutynole, tert-butynole, n-pentyl, n-hexyl, etc. Lower alkyl groups having 1 to 6 carbon atoms, (c) amino group, (d) protected (E) lower-groups having 2 to 7 carbon atoms, such as acetinole, propioninole, butylinole, isobutylinole, n-pentanoinole, n-hexanoyl, and n-heptanol. Arcanoy Or a 3- to 8-membered heterocyclic group substituted by 1 to 3 groups such as a group or (ί) oxo group (as the 3- to 8-membered heterocyclic group, the same ones as defined in the above 上 記 are used. ), ⑨③ a formyloxy group, such as an alkenyloxy group having 2 to 7 carbon atoms, such as acetoxy, puionolinoleoxy, η-butyryloxy, isobutyrinoleoxy, η-pentanoyloxy, η-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 — furylacetoxy, 2 — amino -4 or 5 -Acyloxy group such as heterocyclic acetoxy group such as thiazolyl acetoxy, etc. ®Methylamino, ethylamino, propylamino, η-butylamino, isobutylamino, tert-butynoleamino, n-heptinoleamino, n-hexinoleamino, Dimethylamino, Jethylamino, Metylethylamino, Di (n-propynole) amino, Methinole n-Propinoleamino, Etinole n-Propinoleamino, Di (n-butyl) amino, Di (n-heptyl) amino Mono or di (minus 1 carbon) such as mino, di (n-hexyl) amino 6 lower alkyl groups) substituted amino groups, such as iminomethylamino, 1-iminoethylamino, 2-iminoethylamino, 1-iminopropylamino, 1-iminobutylamino, etc. Amino-substituted lower alkyl (1 to 6 carbon atoms) amino group, such as methyliminomethylamino, n-methylaminomethylamino, n-propyliminomethylamino, 1-methyliminoethylamino, One one

 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, π- Lower alkylthio groups having 1 to 6 carbon atoms, such as propylthio, isopropylthio, π-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, π-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, π-pentylcarbamoyl, and isohexcarbamoyl. 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. Rubamoylamino group, ⑬azide group, ⑩hydroxyl group, @> protected hydroxyl group, @ ィ minino group, @ For example, methylimino, ethylimino, n-propylimino, isopropinomino, n-butylimino, isobutinoremino, sec—butinoremino, tert—butinoremino, n-pentinoremino, i Low carbon number of 1 to 6 such as sopentinorei mino, π-hexinolemino, isohexylinomino, 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. Can be

 In the above formula (B), examples of the leaving group represented by Z include a phenylsulfonyloxy group, a p-tonolenesnolephoninoleoxy group and a p-nitrate

OMPI

,, WHO Mouth A phenylenolesnolephoninoleoxy group, a p-bromophenylsnolephoninoleoxy group, a p-phenylphenylsulfonyloxy group, etc., which may be substituted with methyl, nitro or phos, or a halogen. 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. Further examples of R are as follows.

NH H H 3

CH g

O PI — One

 Two

H ₃ H ₅ NH

 H

OMPI

One —

 As the protecting group for the amino group, those used for this purpose in the field of lactam and peptide synthesis are appropriately used. For example, 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 .;

OMPI

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, phenyloxycarbonyl, etc. And, for example, Trityl, 2-ditropenylthio, benzylidene, 412 trobenzylidene, eg ^ "lower alkyl (1 to 6 carbon atoms) silyl, benzyl, p, such as triethylsilyl, methylethylsilyl, etc. —A protective group for an amino group other than an acyl group, such as nitrobenzyl, is used In the present invention, the selection of the protective group is not particularly limited.

As the carboxyl-protecting group, any of β-lactam and those which can be usually used as a carboxyl-protecting group in the field of organic chemistry can be used. — Butinore, -tert—Aminore, Benzinole, p—Nitrobenzinole, o—Nitrobenzinole, p—Methoxybenzinole, Benz Hydrinole, Fenasinole, Fenisole, ρ—Nitrofeninole, Meximetinole , Ethoxymecinole, benzyloxymecinole, acetoximetyl, pinoroyloxymethyl, 2-methylsulfoninoleetinole, 2-trimethylinolesinoleleethyl, methinolethiomethyl, trityl, 2,2, 2 — trichloroethyl, 2 — odoethinole, trimethylinole, Dimethylsilinole, acetinolemethyl, p-nitroben OPI Zylmethyl, p-mesylbenzoylmethyl 'phthalanolmidometyl, pionyloxymethyl, 1,1-dimethylpropyl, 3-methyl-3-butyr, succinimidemethyl, 3,5-di-tert-butyl-141-ethyl Droxybenzinole, mesylmethinole, benzenes-norefoninolemethinole, phenylthiomethyl, iminomethyl> reaminoethyl, 11-iminoethylaminoethyl, dimethylaminoaminoethyl, pyridin-11-oxamide-12-methyl, Methinolesulfinyl methinoles, bis (ρ-methoxyxinoleno) methinoles, ester residues such as 2-cyano-1,1, 1-dimethylethyl, and silyl groups are used.

 Further, as the protecting group for the hydroxyl group, 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, β-methoxethoxymethyl; for example, trimethylsilole and tert-butyldimethylsilole, such as siloleneter residues; for example, 2-tetrahydrobiranyl, 4-methoxy Acetal residues such as 4-tetrafluoroviranyl; sulfonic acid groups Is used. In the present invention, the choice of the protecting group for the pre-group is not particularly limited, similarly to the protecting groups for the amino group and the carboxyl group.

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. For example, non-toxic cations such as sodium and potassium, such as arginine, ordinine,

OMPI

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. When 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 ω, 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 α) 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.

 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.

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). 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 pyrogens have been removed, before use.

 Furthermore, the injectable preparation may contain other active ingredients (for example, penicillin antibiotics, cephalosporin antibiotics, etc.) to exert a broad spectrum antibacterial activity. 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

OMPI

. wipo It can be used to treat infections, obstetrics and gynecology infections, and surgical infections. 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. Suitably 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. Examples of such 9-lactam antibiotics include penicillin antibiotics such as benzylpenicillin, phenoxymethinolepenicillin, carpenicillin, ampicillin, amoxicillin, and sulpenicillin. Also, for example, 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. In such a case, the compound α) of the present invention can be used in an amount of 1Ζ10 to 10 times (weight) based on 1 / 9-lactam antibiotic 1; Preference is given to a ratio of 8, for example 1/5 or 1Ζ6, 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.

 Pa

ΟΜΡΙ In this reaction, the compound (II) and the compound (D may be used as they are. For example, 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. In this reaction, the compound (Ϊ) or a salt thereof

 About 1 to 10 mol, preferably about 1 to 5 mol, of the compound (I) or a salt thereof is used per 1 mol. The reaction is usually performed in a solvent. Suitable solvents include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, dimethoxetane and tetrahydrofuran. Ethers such as dimethylformamide, dimethylsulfoxide, and hexamethyl phosphoroamide. Further, a base may be added to promote the reaction advantageously. Such bases include, for example, sodium bicarbonate, sodium bicarbonate, sodium carbonate, sodium carbonate, sodium hydride, lithium hydride, sodium hydride. , Sodium methoxide, triethylamine, diisopropylethylamine, pyridine and the like are preferred. 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.

 When 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.

 Further, the reaction for removing the protecting group is specifically described. When 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. Carboxyl group protection as a reducing agent used in this reaction

O PI IPO When 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 ヽ. 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. In the case of 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

 It is from 0 ° to around 4 (f C. The 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 In the case of 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.

 When 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. For example, the reaction is carried out using alkali metal carbonates such as sodium carbonate and potassium carbonate. . The reaction temperature is

It is performed at 0 ° C. or about room temperature. 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. When 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. As the solvent to be used, ethers such as tetrahydrofuran and dioxane are preferable. The reaction is completed in about 10 to 18 hours at around room temperature.

 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. As 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. In addition, an acidic ion exchange resin is used. As the solvent, for example, 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.

O PI

W1PO 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.

When a free amino group is present in the substituent represented by R of compound (I), 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.

 As the 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.

 When a hydroxyl group is present in the substituent represented by R in compound (I), this hydroxyl group can be further converted to an acyloxy group (eg, acetoxy, propionyloxy, etc.), a halogen, or an azide group. .

 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;

O PI For example, lower (carbon number) such as acetyl chloride, propionyl chloride, π-butyryl bromide, isoptyryl bromide, methoxalyl chloride, etc.

 2 to 7) Fatty acid halide derivatives can be mentioned. This reaction is suitably carried out in the presence of a base. Examples of 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.

-By reacting 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) The reaction 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. Medium, ethyl N-methylformimidate, methyl N-ethylformimidate, methinole N-isopropylformimidate

OMPI

Movie— Can be. 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,

 Examples of the above-mentioned 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.

O PI For example, 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.

O PI

, / W1PO 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,

 1st process

 (3) (1)

(XI) (XiV)

O PI

[Wherein, 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).

 In the above, 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. .

As the 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. Examples of the 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.

According to the above scheme, as a starting material, for example, 4-((2-hydroxyhexyl) azetidine-1-one (be-di-one) Stensen et al., Journal of 'Organic' Chemistry ', Vol. 45, Vol. 113, p.

Compound (I) obtained by subjecting an amide group and a hydroxyl group of (0) to a protection reaction by a known method 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,

² -—Tetrahydrobilanyl group and the like are used. Further, R ² and R ³ combine to form compound (17) with the formula

(In the formula, 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 Here, as 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.

Organic Chemistry), Vol. 45, p. 110, p. 1980)) ₀ This compound is composed of 4-2-hydroxethyl) azetidine-l-one and 2,2-dimethoxybutane. For example, it is produced by reacting in the presence of an acid catalyst such as boron trifluoride etherate and P-toluenesulfonic acid. When 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). Examples of the sulfenylating agent to be used include disulfides represented by the formula (R ⁴ S) ₂ ,

Thiosulfonates represented by the formula R ⁴ S— S0 ₂ R ⁴ , imids represented by the formula R ⁴ S—

And R ⁴ in the formula I is as defined above. -In this reaction, 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. Examples of the base to be used 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.

OMPI

, WIPO _ _ However, the mixture can be used for the next step reaction without isolation.o

苐 The second step is a step of alkylating the ^3- position of (V :) with an alkylating agent to produce (VI). Examples of the 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].

 As the halogen atom represented by A, for example, chlorine, bromine, iodine and the like are used.

 In the 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. In this case, 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. In this case, 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. In this reaction, these heterologous organisms can be isolated by operations such as column chromatography and recrystallization, and each can be used for the next step reaction. If used as a mixture without isolation, can do. The third coloration is a step for preparing a (VI) is reacted with a reducing agent selectively 3, 4-cis-substituted § Zechijinon (¾ _a).

O PI

WIPO Suitable reducing agents include, for example, organotin compounds, nickel compounds, mercury compounds, zinc compounds and the like.

R ⁷ ) ₃ SnH,

(R ⁷⁾ ₂ SnH ₂ or

R ⁷ S nH ₃

 [Wherein, represents a hydrocarbon group]

Is used. As the 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 For example, 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. More specifically, triphenyltin hydride, tri-n-butyltin hydride, dibutyltin hydride, di-n-butyltin hydride, triethyltin hydride, trimethyltin hydride, trimethyltin hydride, τ-butylinated n-butyltin Is used. Of these, 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. 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. — Δ―

No. 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).

 In the following fourth to 12th reaction steps, each of the 3,4-cis form and the 3,4-trans form or a mixture of both can be used.

 In the fourth step, when (: W) has a hydroxyl group, this hydroxyl group is subjected to a protection reaction to produce (¾). As 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,

ΟΜΡΙ 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, π-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.

In the fifth step, 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 (: Κ) 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.

O PI

"WIPO One _OA

The reaction is carried out by acid hydrolysis with a reaction time of ⁵ minutes to 16 hours at d4-degree.

 In the seventh section, the hydroxyethyl group at the 4-position of X) is converted to a hydroxymethyl group by an oxidation reaction to produce a): ¾.

 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). In the case of (1), it is preferable to perform optical resolution using () (racemate) of the obtained intermediate material. 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.

 In the eighth step, the carboxyl group for the 4-position substitution in () is converted to ¾ft, and then two carbon atoms are extended to produce (an).

 The reaction is carried out as t a) with, for example, 1,1-carbodium midazole or

 Reaction with an imidazolide reagent such as 1,1-carbonylbis-2-methylimidazole) to give imidazolide, and without isolating the imidazolide

(OMPI Formula [0 (: 0 (: 11 ₂ (00 :) ₂ Mg

[Wherein R ¹ has the same meaning as described above] with a magnesium i / dimethyl salt of a malonic acid derivative represented by the following formula:

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 ¾Π with an azide compound such as Ρ-carboxybenzenesulfonyl azide, Ρ-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 Μ; 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 (ΧΙ), 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. When 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 (Γ 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 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.- The 12th step is a step of activating XV with a excretory agent to produce I.

 (I) when Z is a substituted sulfonyloquine group, (XV) about 1 mol

One to ^three times the moles of 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. Usually, the reaction temperature is about −20 ° to 40 ° C. The reaction time is about 30 minutes to 5 hours. [When Z of E is a nitrogen atom, the reaction in the case where Z is a substituted sulfonyl group; Bruno instead of Suruhoyuru agent, halogenated agents (eg, Okizarirukuro Li _{de, (C 6 H 5) 3} PC1 2, CC 6 H 5 a PBr 2, (C 6 H 5 0) 3 ΡΒ r 2, Chioniruku b And the reaction can be carried out under the same conditions to convert from XV) to (II). In the case where ζ in (II :) is a disubstituted phosphoryloxy group, instead of the sulfonylating agent in the reaction where 化 剤 is a substituted sulfonyloxy group, a phosphorylating agent C, eg diphenylphosphoric acid Reaction under the same conditions using a lid, dimethyl phosphate, acetyl phosphate chloride, etc.

 Can be converted to (II).

 The 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.

 Hereinafter, the present invention will be described in more detail with reference to Test Examples, Reference Examples, and Examples. Symbols used in Reference Examples and Examples have the following meanings.

 s: Singlet d: Doublet dd: Double doublet d dd:

 Double double doublet t: triplet q: quartet

ABq: AB type quartet m: Multiplet J: Coupling constant

 b: Wide

 The fillers for column chromatography in Reference Examples and Examples were Florisil (100 to 200 mesh, Florisin, USA), Diaion HP 20 (Mitsubishi Corporation) Amberlite XAD-2 (Rohm & And Haas, USA) and silica gel (Kiesel gel, 30-200 Mem, Merck, West Germany) manufactured by Dansei were used.

O PI BEST MODE FOR CARRYING OUT THE INVENTION

Reference example 1

 7— (1-Hydroxy-1-3-thiacyclopentyl) -1-7-F X-nilthio 8-oxo-1,2,2-dimethyl-1-3-oxa-1 1-azabisik

 [4. 2. 0]

Diisopropyl § Mi emissions 3.4 ^ anhydrous Te preparative La arsenide Dorofuran 3 0 ^ under a nitrogen atmosphere to a solution of is added hexane 1 5 one 7 8 1 5 ₀ n-Buchiruriumu / to. To this solution is added a solution of anhydrous tetrahydrofuran 10 ^ of 8-5.5-oxo-2,2-dimethyl-3-oxal-1-azavinclo [4.2.0] octane 1.5.5 over a period of 10 minutes. Stir for 15 minutes. Diphenyl disulphide 2.18? Add 10 parts of anhydrous tetrahydrofuran solution over 10 minutes and stir for 15 minutes, then add 3-thiacic pentanone 2.0 for 5 minutes and stir for 30 minutes. The reaction solution is placed in acetic acid (2 ^)-water (60 ^) under ice-cooling: ¹ ", the organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed successively with 0.5-5 aqueous solution of sodium hydroxide and water, dried (Na ₂ SO ₄ ), and the solvent is distilled off. The residue was subjected to column chromatography using a silica gel (ethyl hexane monoacetate = 3: 1, 1: 1) to give the title compound.

 3.0 3 ^ is obtained as an oil 0

IR ^N ^ M →: 3450, 1740

_{NMR (9 OMHz, CDC1 3)} s: l.40, 1.56 ( each 3 Η, s X 2) 1.5- 1.9 (2Η, m), 2.2 - 2.4 (2 Η, m), 2.8 - 3.2 (Η, m ), 3.8-4.2 (3Η, m), 7.1-7.9 (5 Η, m)

Reference example 2

 7— (1—hydroxy-1-3-thiacyclopentyl) -1-8-oxo-2,

O PI 2-dimethyl-3-oxa-1-azabisic mouth [4.2.0] octane 7- (1-hydroxy-13-thiacyclopentyl) obtained in Reference Example 1 17-f-I-2thio-1-8-oxo 1,2-Dimethyl-1-3-azaxcyclo [4.2.0] octane 3.0 3, Rhozobisi sobuti mouth trinole 300 w and tri-n-butyltin hydride 8.5 The solution of acetone in 80 ^ is refluxed under a nitrogen atmosphere. After 5 hours, add more tri-n-butyltin hydride 5.0, reflux for 14 hours, add more π-butyltin hydride 4.0 ^, and return for 5 hours. Evaporation of the solvent and treatment with isopropyl ether gives 1.36 of the 6,7-cis isomer of the title compound as colorless crystals. The mother liquor was subjected to column chromatography using silica gel (ethyl hexane monoacetate = 1: 1) to further show the 6,7-cis isomer of the title compound and the 7,6-cis isomer of the title compound. Each of the isomers is obtained as colorless crystals. -6, 7-cis isomer: melting point 1 1 3— 1. 1 5

l ^{R v} max — ¹ : 3 4 3 0, 1 7 4 0

_{NMR (9 0 MH Z, CDC13} ) 3: 1.40, 1.74 ( each 3H, s X 2), 1.6 - 2.2 (2 H, m), 2.5 - 3.2 (6 Η, 77:), 3.3 6 (1 Η, d, J = 6 Hz), 3.7- 4.1 (3Η, m)

Elemental analysis value As C ₁₂ H ₁₉ NO ₃ S

 Calculated value): C5 6.01; H7.44; N5.44

 Obtained value (%): C56.28; H7.35; N5.40

 6, 7 — trans isomer:

 IR KB

m _a , j ¹ : 3 4 5 0, 1 7 2 0

_{NMR (9 0MH z, CDC1 3} ) 3: 1.4 0, 1.6 9 ( each 3H, sx 2), 1.6 - 2.0 (2 H, m), 2.3 - 3.2 (7 H, m), 3.5 - 4.0

OMH crane (3H,)

Reference example 3

 6,7-cis-1 7- [1- (2-methoxytoximetoxy) -13-thiacyclopentyl] -18-oxo-1,2,2-dimethyl-3-oxa-1-azabicyclo [4,2,0] Octane

6,7-cis-1 7- (1-hydroxy-13-thiacyclopentyl) -18-oxo-1,2,2-dimethyl-13-oxa1-1-azabicyclo [4.2.0] obtained in Reference Example 2. To a solution of octane 370 in dichloromethan7, add 0.75 of diisopropylethylamine and 0.49 of 2-methoxetoxymethyl chloride, and allow to stand at room temperature for 140 hours. Da. Wash with acetic acid and water sequentially, dry (Na ₂ SO ₄ ) and evaporate the solvent to obtain the title compound as an oil. ·

X- ¹ :.

_{NMR (9 OMHz, CDC1 3)} s: 1.38, 1.7 1 ( each 3H),

1.7 (2 H, m), 2.0 - 3.2 (6 Η, m), 3.1 7 (1 Η, d, J = 5 Η ζ), 3.38 (3H, s), 3.3- 3.9 (7 Η, m), 4.9 (2 Η, bs) Reference example 4

 6, 7—Sys 7—! 1- (2-Methoxyethoxymethoxy) 1-3-thiacyclopentyl-3,3-dioxide] -18-oxo-1,2,2-dimethyl-1-3-oxa1-1-azabisik [4.2.0] Octane

6,7-cis-1 7- [1- (2-methoxetoxymethoxy) -13-thiacyclopentyl] obtained in Reference Example 3-8-oxo-1 2,2-dimethyl-1-3-oxa1-1-azabicyclo [4 · 2. 0] Octane is dissolved in dichloromethane 20 and metabenzoic perbenzoic acid 800 w is added under ice cooling and stirred for 1 hour. Wash the reaction solution with saturated aqueous sodium hydrogen carbonate solution and water sequentially After purification, dry (Na ₂ SO ₄ ) and evaporate the solvent. Force used resulting residue by silica force gel Ramukuroma preparative chromatography (acetic Echiruku every mouth Holm = 1: 1 and acetic acid Echiru) as the eluent to give the title compound ⁴ 6 ⁹ ^ is obtained as an oil.

IR _m -i: 1 750, 1 320, 1 1 20

 NMR (9 OMHz, CDClg) <ϊ: l.38, 1.69 (3Η, sx2), 1.9 (2H, m), 2.55 (2H, m), 3.36 (3H, s), 3.0-4.0 (1 2 H, m), 4.8 6 (2 H, s)

Reference example 5

 3,4-cis-1-4-carboxymethyl-1-3- [1— (2-methoxytoximethoxy) -1-3-thiacyclopentyl-1,3,3-dioxide] azetidine-1 2-one

 6,7-cis-1 7- [1- (2-methoxethoxymethoxy) -1-3-thiacyclopentyl-13,3-dioxide obtained in Reference Example 4〗 1-8-oxo-1,2,2-dimethyl-3-oxa 1-Azabicyclo [4.2.0] octane 540 ^ ^ in acetone solution under ice cooling, Jones reagent

Add 0.8 and stir for 5 hours. To the reaction mixture, slowly add 0.5 mg of V-propanol and stir for 10 minutes. After diluting the reaction mixture with dichloromethane, the insolubles are removed by filtration using celite, and the filtrate is concentrated. The residue in chloroform 2 0 ^ was added, dried (MgSO _4), the solvent was distilled off to give the title compound 4 2 1 w is obtained as an oil.

 I R m-i: 350 0-2 800, 1 76 0-1 7 3 0

_{NMR (9 0 MH Z, CDClg} ) δ: 2.4 - 4.0 (1 3 Η, m), 3.36 (3Η, s), 4.1 5 (lH, m), 4.8 (2H, s), 7.2 (1 H, bs ), 8.1 (1 H, bs)

OMPI Reference example 6

 3,4—cis 1—3— [1— (2-Methoxyethoxymethoxy) 1—3—thiacylcyclopentyl 3,3—dioxide] 1—4 1 3— (4—2 mouth benzyloxycarbo 2) -2-oxopropyl] azetidine 1-one

3,4-1, cis-1,4-carboxy i-methyl-13-! Obtained in Reference Example 5: 1-C2-methoxeteki i-meth) 3-1, thia i-clopentyl-3,3-dioxide] azetidine-1 2 To a solution of 421 w of anhydrous tetrahydrofuran in 15 m, add 1,1'-carbodiimidazole 236 at room temperature and stir for 6 hours. To this solution, add the magnesium salt of malonic acid mono- ⁴ -nitrobenzyl ester 759, and stir at room temperature for 17 hours. Ethyl acetate is added to the reaction solution, washed with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried (Na ₂ SO ₄ ), and the solvent is distilled off. The residue was chromatographed on silica gel (ethyl chloroformate = 1: 1 and ethyl acetate) to give the title compound 448 as a pale yellow oil.

IR «» ^-1 : 3320, 1750-1720, 1350, 1120

_{NMR (9 OMHz, CDC1 3)} : 2.6 (2H, m), 3.30 (3Η,

 s), 3.59 (2Η, s), 3.2-3.9 (1 lH, m), 4.2 (1H, m), 4.76 (2H, s), 5.26 (2H, s), 6.86 (1H, bs) )

7.55 (2H, d?, 8.22 C 2H, cf)

Reference Example 7

 3,4-cis-1 4— [3-Diazo 3— (4-2 Trobenzoyloxycarbonyl) 1 2-oxopropyl] 1 3— [1— (2-Methoxyethoxymethoxy) 1 3— Thiacyclopentyl-3,3-dioxide] ase

OMPI

W1PO Chijin 1 2—year-old

 3,4-cis-13- [11- (2-methoxetoxymethoxy) -13-thiacyclopentyl-3,3-dioxide] -1-4 obtained in Reference Example 6

[3-(4-12-benzyloxycarbonyl)-1-oxo-propyl] azetidine-1-470-^ acetonitrile in anhydrous 14-solution in 14 me with p-toluenesulfonylazi de 2 0 3 ^ anhydrous § Se Toni Application Benefits Honoré 2 ^ solvent solution are added, followed by addition of preparative Ryechiruami emissions 0 - ⁴ 5. After stirring at room temperature for 1 hour, add ethyl acetate to the reaction mixture, wash with saturated saline, and dry.

(Na ₂ SO ₄ ). The solvent is distilled off, and the residue is subjected to column chromatography (ethyl acetate) using a silica gel to give the title compound 442 w as a pale yellow foam.

IR y cm ~ ^l : 3330, 2140, 1.760, 1720, 1640,

1 3 5 0, 1 1 2 0

_{NMR (9 OMHz, CDC1 3)} s: 2.6 (2H, m), 3.3 1 (3H,

s), 3.0-3.9 (11H, m), 4.2 (1H, m), 4.83 (2H, bs), 5.36 (2H, s), 6.40 (1H, bs), 7.54 (2 H, d, J = 9H Z), 8.2 4 (2H, d, J = 9H Z)

Reference Example 8

 3, 4 1cis 1 4 1 [3-diazo 1 3-(4-2-trobenzoyloxy carbonyl)-1-2-oxopropyl] 1-3-(1-hydroxy 3-cyclopentyl 3, 3-dioxin D) Azetidine one 2—on

3,4-cis- [3-diazo-l- (4-nitrobenzyloxycarbonyl) -l-oxopropyl-3-l! Obtained in Reference Example 7! 1-(2-methoxyquinone) 1-3-thiazic pentyl-1,3-dioxin] azetidine-1-2-one 9 7 ^ dried dichloromethan 1 8 dissolved oi Liquid to stir 1 hour added titanium tetrachloride I. ³ 0 in a nitrogen atmosphere o hands. Add 30 ^ of ethyl acetate to the reaction mixture and stir for an additional hour. The reaction solution is added to 50% aqueous calcium carbonate, and the insoluble material is removed by filtration using celite. The organic layer is separated. After the 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.

IIII α: 3400, 2140, 1750, 1720, 1650 NMR (9 OMHz, acetate d ₆ + CDCl ₃ ) δ: 2.5 (2Η, m),

3.3-3.8 (6H, m), 3.59 (1H, d, J = _6Hz ), 4.4

 (1H, m), 5.5 1 (2H, s), 6.7-9 (1H, bs), 7.46

(S, peak due to benzene solvent), 7.71 (2H, d, J = 9 H Z), 8.3 8 (2H, d, J = 9 H z)

Reference Example 9

 7- (1-hydroxy-1-41thiacyclohexyl) -1-7-phenylthio-8-oxo-1,2,2-dimethyl-3,3-hydroxy-1,1-azabicyclo

 [4.2.0] Octane

 In the same manner as in Reference Example 1, 8-oxo-1,2,2-dimethyl-3,3-hydroxy-1,4-azabic mouth [4.2.0] octane 620 ^, diphenolenosulfide 960 and The title compound 1.192 is obtained as colorless crystals from 4-thiacyclohexanone 5 11.

Melting point 1 9 1-1 9 2 τ

IR;, ¹ : 350 0, 1 730

NMR (9 OMHz, CDl ₃ ) 3: 1 · 38, 1.48 (3Η, s X 2),

Ο ΡΙ 1.6 (2H, m), 1.7-3.3 (8 H, m), 3.7-4.2 (3 H, m),

7.1-7.9 (5 H, m)

Elemental analysis value As C ₁₉ H ₂₅ N0 ₃ S ₂

 Calculated value (%): C 60.13; H 6.64; N 3.69; S 16.89

 Obtained value (): C 60.39; H 6.49; N 3.68; S 1 7.17

 Reference example 10

7— (1—Hydroxy 4-thiacyclohexynole) -1—8—2,2-Dimethyl—1,3—oxa—1—Azabicyclo [4.2.0] octane 7— (1 obtained in Reference Example 9 —Hydroxy-1-hexyl hexyl) — 7-F: π-dithio-1-2-oxo-1,2,2-dimethyl-3-oxa1-1—azabisik [4.2.0] octane 1.19.2 ⁶ of the title compound in a manner similar to how the reference example 2, 7- cis form (5 ⁴ 2 w) and ^6, 7 -. trans form (2 2 2) as colorless crystals.

 6, 7—cis-form

Melting point 1 3 3— 1 3 4

IR RE ^ _OT - ¹ : _{3400, 1740}

NMR (9 OMHz, CDC) « 5: 1.3 8, 1.73 ( each 3H, s χ 2), 1.6 - 3.3 (1 0 Η, m), 3.2 0 (1 Η, d, J = 6H Z), 3.6- 3.9 (3 Η, m)

Elemental analysis value C ₁₃ H ₂₁ N0 ₃ S

 Calculated value (%): C 57.54; H 7.80; N 5.16; Sl 1.81

 Obtained value (de: C 57.30: H 7.85; N 5.42; S 12.05

 6, 7—Transformer

IR file ^ ^-1 : 3500, 1720

_{NMR (9 0 MHz, CDC1 3} ) δ: ι.4 0, 1 · 7 1 ( each 3H, s χ 2), 1.6 - 3.3 (1 0 H, m), 2.8 1 (1 H, d, J = 2H Z), 3.5 5

(lH,), 3.7—3.9 (2H, m) Reference example 1 1

 6, 7—Sys 1 7—! : 1- (2-'methoxhetoxymethoxy) -1 4-thiacyclohexyl] -18-oxo-1,2,2-dimethyl-3-oxa1-1-azabicyclo [4.2.0] octane

6,7-cis-1 7- (1-hydroxy-4-thicyclohexyl) -18-oxo-1,2,2-dimethyl-3-oxa1-1 obtained from Reference Example 10 1-azabisik [4.2. [0] octane was used to obtain the title compound in the same manner as in Reference Example 3. 1 ... 1 ⁷ "

 NMR (9 OMHz, CDCU) S: 1.38, -1.71 (3H, sX2)

1.5-3.1 (10H, m), 3.38 "H, S), 3.0-4.0 (8H, m), 4.93 (2H, s) Reference example 1 2

 6, 7-cis 7- [1- (2-Methoxyethoxymethoxy) -1 41-thiacyclohexyl-4,4-dioxide] -1-8-oxo-1,2,2-dimethyl-3-oxa1-1-azabicyclo I 4 .0] octane

 In the same manner as in Reference Example 4, 6,7-cis-17- [11- (2-methoxyshethoxymethoxy) -14-thiacyclo ^ xyl] -18-oxo-1,2,2-dimethyl-3-oxa1-1 —Azabicyclo [4.2.0] octane gives the title compound 780 w as an oil.

1 7 4ひ， 1 3 1 5, 1 1 3 0 IR

1 7 4 h, 1 3 1 5, 1 1 3 0

_{NMR (9 OMHz, CDC1 3)} ^: ι.3 8, 1.7 0 ( each 3Ή, s χ 2)

 1.6-3.0 (8Η, m), 3.1-4.0 (10 0, m), 3.3 6 (3Η,

WIPO s), 5.0 1 (2H, s)

 Reference Example 1 3

 3,4-cis-1-4-carboxymethyl 3- (1- (2-methoxyethoxy) —4-thiacyclohexyl-1,4,4-diethyl oxide) azetidine-1-one

⁶ In the same manner as in Reference Example 5, 7-cis one ⁷ - [1- (2-main Toki cerevisiae Tokishime butoxy) Kishiru 4 to single 4-Chiashiku b, 4 Jiokishi de] - 8- Okishi one 2, 2-Dimethyl-3-oxa-1-azabicyclo [4 · 2.0〗 octane 472 w gives the title compound 362 as an oil.

Reference example 1 4

 3, 4 -cis 1-3-[1-(2-Methoxy.ethoxymethoxy) 1-4 1 Thiacyclohexynole 1-4, 4-dioxide] 1-4-[3-(4-Torobenzyloxy) Carbonyl) -2-oxopropyl] azetidine-2-one

 In the same manner as in Reference Example 6, 3,4-cis-1-carboxime

 3— [1— (2-Methoxyethoxyethoxy) 14-thiacyclohexyl-4,4-dioxide] azetidine-1 2-one The title compound 3 2 4 is a pale yellow oil from 3 6 2w Obtained as a product.

I R: 3320, 1 750-1 720, 1 350, 1 1 20

_{NMR (9 0 MHz, CDC1 3} ) «5: 2.0 - 3.0 (6 H, m), 3.3 4

 (3H, s), 3.6 3 (2H, s), 3.1-3.9 (9H, m), 4.2

ClH, m), 4.9 2 ( 2 H, s), 5.3 0 (2 H, s), 6.5 (1 H, b), 7.5 4 (2 H, d, J = 9 H z), 8.23 (2 H , d, J = 9

H _z )

OMPI

k¾? NATlO¾! Reference example 1 5

 3,4-cis-1 4 [3-Diazo 3- (4-1-2-benzyloxycarbonyl) -2-oxopropyl] -1 3-[-11- (2-methoxhetoxy methoxy) 1 4-thiacylhexyl 1 4 , 4-dioxide] azetidine-1-one

3 In the same manner as in Reference Example 7, 4-cis one ³ - (1 - (2-main Toki cerevisiae Tokishime butoxy) hexyl one 4 to single 4-Chiashiku b, 4 Jiokishi de] - - [3- (12-Port benzyloxycarbonyl) -12-oxopro-pyru]] azetidine-12-one 704, yields the title compound 724 as a pale yellow foam.

 I R V

¹ : 3320, 2140, 176 0 , 1 720 , 1 650 ,

¹ : 3320, 2140, 176 0, 1 720, 1 650,

1 350, 1 1 20

_{NMR (90 MHz, CDCl 3)} 3: 2.1 - 3.0 (6 H, m), 3.3 6

 (3H, s), 3.3-3.9 (9 H, m), 4.2 (1 H, m), 4.9 3

 (2H, s), 5.38 (2H, s), 6.4 (1H, bs), 7.54 (2

H, d, J = 9Hz) , 8.26 (2H, d, J = 9 H z)

Reference Example 1 6

 6, 7—Trans 1-7— (1-Hydroxy 1 2-Methylthioethyl)

― 8 一 1 一 2,2 ジ 2 3 ー 3—1 一 1 ビ 1 ビ 2 ビ 1 4 2] 0 octane

Diisopropyl Sopuropiruami down 0.6 8 ^ under a nitrogen atmosphere in anhydrous te door La human Dorofura down 1 0 solution of hexane in one ⁷ 8 hand 1 5 de 0 n- butyllithium / / to 3.0

 Add. To this solution is added 8-oxo-1,2,2-dimethyl-3-oxa

Add a solution of 1-azabicyclo [4.2.0] octane 310 in 7j tetrahydrofuran 1 over ⁵ minutes, and stir for 10 minutes.

OMPI

,, WIPO, Pressure to give a methylthio § Seto aldehyde arsenide de ³ 60® over ⁵ minutes to the reaction solution, after stirring for 30 minutes, a saturated chloride Anmoniumu water was added, Dosu to room temperature. Separate the organic layer and extract the aqueous layer with ethyl acetate. The organic layers were combined, 0.5 N hydroxide isocyanatomethyl Riumu solution was successively washed with water, dried (N a ₂ S0 _4), and evaporated to remove the solvent. The residue was subjected to column chromatography using silica gel (ethyl hexane monoacetate = 1: 1 to 1: 2) to give two types of stereochemistry based on the configuration of the hydroxyl group at the 7-position of the title compound. A mixture of isomers A and B (263), and one of the stereoisomers A (21) are each obtained as an oil. The following is the configuration of the substituted hydroxyl group (or protected hydroxyl group). The two stereoisomers based on are tentatively called isomers A and B. A mixture of isomers A and B:

L ^ ^v ^ ma- «» ^-1 : 3 4 4 0, 1 7 3 0

 NMR (9θΜΗζ, CDCI3) «5: 1.45, 1.78 (3H, sχ2), 1.5-2.1 (2Η, m), 2.18 (3Η, s), 2.6-3.2 (3Η, m), 3.6 (1 Η, m), 3.7-4.0 (2 Η, m), 4.1 (1 Η, πι) isomer Α:

 1 R cm- ^: 3 4 4 0, 1 7 3 0

NMR (9 0 MHz, CD and _{'1 3) s: 1.4 0} , 1.7 3 ( each 3 H, sX2), 1.5 - 2.1 (2 H, m), 2.1 2 (3 H, s), 2.6 - 3.2 ( 3 H, m), 3.6 (1 H., m), 3.7-4.0 (2 H, m), 4.0 (1 H, m) Reference example 1 Ί

 6, 7—Transform 1 7— [1- (2-Methoxyxetoxime) 1

2-Methylthioethyl] 18-year-old 1,2-dimethyl-13-oxa-11-azabicyclo [4.2.0] octane (isomer A) One - 6 In the same manner as in Reference Example 3, 7-trans one ⁷ - (1-hydroxy shea one 2- Mechiruchioechiru) Single 8- Okiso one 2, 2-dimethyl-one 3-O hexa one 1- Azabishikuro [4.2.0] octane (isomer A) 211 gives the title compound as an oil.

Ϊ́χ- ¹ : 1 7 5 <3

NMR (9 0 MHz, and _{CD '1 3) δ: 1.40} , 1.7 3 ( each 3 Η, s χ 2), 1.6 - 2.1 (2 Η, m), 2.1 5 (3 H, s), 2.79 (2H , d, J = 6 Hz), 3.38 (3H, s), 3.1-3 (9 H, m), 4.79 (2H, s)

Reference Example 1 8

 6,7-trans- 1 7- [1- (2-methoxethoxymethoxy) -l-methylsulfonylethyl] -18-oxo-l, 2-dimethyl-2-ox-l-l-azabisik mouth [4.2 [0] octane (isomer A)

 In the same manner as in Reference Example 4, 6,7-trans-17- [11- (2-methoxyethoxymethoxy) -12-methylthioethyl] -18-oxo1-2, obtained by Reference Example 17 The title compound 255 is obtained as an oil from 2-dimethyl-13-oxa-11-azabicyclo [4.2.0] octane. ■

^IR - ¹ : 1 7 "

NMR (90 MHz, CD CI ₃ ) s: ι · 40, 1.71 (3H, s χ 2, respectively),

 1.6-2.1 (2Η, m), 3.0 3 (3Η, s), 3.36 (3Η, s), 3.1 -4.0 (1 OH, m), 4.45 (1Η, m), 4.86 (2Η, m) ) Reference example 1 9

 3,4-trans-4-carboxymethyl-3- (1- (2-methoxyethoxymethoxy) -1-methylsulfonylethyl) azetidine-1 2

O PI One on (isomer A)

⁶ In the same manner as in Reference Example 5, 7-preparative lance one ⁷ - [1- (2-main Tokishe Tokishime Toushishi) Single 2- methylation sulfonyl E chill] one 8-O Kiso one 2, 2,1-Dimethyl-3-oxa-1-azabicyclo [4 • 2 • 0] octane 255 w gives the title compound 190 as an oil.

 1 R V ^: 350 0-280 0, 1 76 0-1 700

_{NMR (9 θΜΗζ, CDC1 3)} 3: 3.0 0 (3Η, s), 3.3 6 (3H, s), 2.6 - 4.2 (1 0 H, m), 4.5 (1 H, m), 4.8 8 (2 H , s), suku (/ no nosu (/ no)

 Reference Example 20

 3, 4-1-3-[1-(2-methoxyethoxyethoxy) 1

2-Methinolesulfoninoleethyl] -14- [31- (412-trobendinoleoxycarbonyl) -2-oxopropyl] azetidine-12-one (isomer A)

 3,4-Transnth-4-carboxymethyl-13- [11- (2-methoxyethoxymethoxy) -12-methylsulfonylethyl] azetidine-12-one 19 From 0, the title compound 1 58 is obtained as a pale yellow oil.

IR Li _{^{N ^ a a cm- 3 3 2}} 0, 1 7 6 0 - 1 7 1 5, 1 350, 1 1 30 NMR (9 OMHz, CD CI 3 ": 2 · 9 6 (3 Η, s), 3.0 (2H, m), 3.35 (3Η, s), 3.56 (2Η, s), 3.1-3.8 (7Η, m), 4.0 (1Η, m), 4.45 (1Η, m) , 4.87 (2Η, s), 5.26 (2Η, s), 6.25 (1Η, bs), 7.48 (2Η, d, J = 9 Hz), 8.2 1 (2Η, d, J = 9Η _Ζ )

Reference Example 2 1

OMPI 3, 4-trans 1-4-1 [3-diazo 3- (4-nitrobenzyloxycarbonyl) -1 2-oxopropyl] ー 3— [1— (2-methoxyethoxymethoxy) 1-2-methinole Sulfoninoleethyl] azetidine-1-one (isomer A)

 In the same manner as in the method of Reference Example 7, 3,4-trans-1--3- (1- (2-methoxyethoxymethoxy) -12-methylsulfonyletyl) -14-1 [3— ( [Xycarbonyl) -l-oxopropyl] azetidin-l-one 158w gives the title compound 148 as a pale yellow oil.

IR V N e ^-i: 3350, 2140, 1760, 1720, 1640, 1350, 1120

_{NMR (9 OMHz, CDC1 3)} δ: 2.9 7 (-3H, s), 2.9- 3.3 (3H, m), 3.3 3 (3 H, s), 3.3 - 3.8 (6 H, m), 4.0 (lH , m), 4.5 (1H, m), 4.86 (2H, s), 5.34 (2H, s), 6.3 (1H, bs), 7.52 (2H, d), 8.23 (2H, d, J = 9H _Z )

Reference Example 2 2

 6, 7—Trans 1 7— [: 1— (2-Methoxy methoxy) 1—2—Methyl Thioethyl] —8—Oxo 1 2,2—Dimethyl 1—3—Oxa 1—1—Azabisik mouth [4. 2.0] octane (mixture of isomers Α and Β)

In the same manner as in Reference Example 3, the 6,7-trans-7- (1-hydroxy-1-2-methylthioethyl) -1-8-oxo-1,2,2-dimethyl-1-3-oxa-1 obtained in Reference Example 16 1-Azabicyclo [4.2.0] octane (mixture of isomers A and B) 263 gives the title compound as an oil. R and NMR spectra are the same as those of the compound obtained in Reference Example 17.

Reference Example 2 3

 6, 7 — Trans 1 7 — [1 (2-Methoxy toxic) 1 2 -Metinoresnorelephoninoletin] 8 —Oxo 1 2, 2 —Dimethyl 1 3 — Age 1 1 —Azabicik mouth [42.0] octane (mixture of isomers A and B)

 6,7 Trans obtained in Reference Example 2 2 7- [11- (1- (2-methoxyethoxyethoxy)] 1-2-methylthioethyl] -18-oxo-1 2,2-Dimethyl-3-year-old 1 —The title compound 303 is obtained as an oil from azabicyclo [4.2.0:] octane in the same manner as in Reference Example 4.

_T- D Ne at.

i ^K "max ^m 7 4 5

 NMR (9θΜΗζ, CD CI 3) s: i.40, 1.71 (3H, sx2), 1.6-2.1 (2H, m), 2.97 (3H, s), 3.36 (3H , s), 3.1-4.0 (10H, m), 4.45 (1H, m), 4.86 (2H, s) Reference example 24

 3, 4 1 trans 1 4-carboxymethyl 1 3-[1-(2-methoxyethoxyethoxy) 1 2-methinolesulfoninoletin] azetidine 1 2-one (isomer A and B) Mixture)

 In the same manner as in Reference Example 5, 6, 7-transfer 7- [11- (2-methoxyethoxyethoxy) 12-methinoresnorelephoninoletin] 18-oxo1-2,

2-dimethyl-1 3-oxa-1 1-azabicyclo [4.2.0] octane

 From 303, the title compound 2333w is obtained as an oil. Reference Example 2 5 3, 4 1 Trans 3 1 [1 (2-methoxyethoxyethoxy) 1

O PI 2—Methylsolephonylethynole] 1 4- 1 [3— (4-Dibenzyloxycarbonyl) 1 2-oxopropyl] azetidin-1 2-one (isomer)

 Mixture of A and B)

Reference Example 6 and 3 in the same manner, 4 Ichito lance one ⁴ Ichiriki Rupokishime Chiru ³ - [1 - (2 - main Tokishe Tokishime butoxy) one 2 - methylsulfonyl E chill] Azechijin one 2 - title from the on-2 3 3 Symbol Compound 181 is obtained as a pale yellow oil.

^{IR - 1: 3 3 3 0} , 1 7 6 0 -1 7 1 0, 1 3 5 0, 1 120 NMR (9 0 MHz, CDU1 3) 3: 2.9 7 (3H, s), 2.8- 3.3

 (3H, m), 3.3 3 (3H, s), 3.56 (2Η, s), 3.3—

3.9 (6H, m), 4.0 (lH, m), 4.40 (1H, m), 4.86 (2H, s), 5.25 (2H, s), 6.3 (1H, bs), 7.5 1 (2 _{H, d, J = 9H Z} ), 8.2 1 (2 H, d, J = 9 H z)

Reference Example 2 6

 3, 4 — trans 1 4 — [3 — diazo 1 3 — (4-nitrobenzyloxycarbonyl) 1 2 — oxopropyl] -3 — [1 — (2 — methoxyethoxymethoxy) 1 2 — methylsulfonyl Ethyl] azetidine-1-one (mixture of isomers A and B)

 3, 4—Transance 13— [11- (2—Methoxyethoxymethoxy) 1-2—Methylsulfoninoleethyl] —4 [3— (4-1Nitrobenzyloxycarbonyl) as in Reference Example 7. 1) 2-Oxopropyl] azetidine-2 -one 18 1 gives the title compound 1666 as a pale yellow oil.

M- ¹ ： 3 330, 2 140, 1 7 60， 1 720, 1 650, 1 3 4 0 , 1 1 3 0 I

M- ¹ : 3 330, 2 140, 1760, 1720, 1650, 1340, 1130

O PI _{NMR (9 0 MHz, CDC1 3} ) δ: 2.9 7 (3Η, s), 2.8- 3.3

(3H, m), 3.35 (3H, s), 3.3-3.9 (6H, m), 4.05 (lH, m), 4.46 (1H, m), 4.87 (2H, s), 5.3 5 (2H, s), 6.2 (1 H, bs), 7.5 1 (2H, d, J = 9 H z), 8.2 4 (2 H, d, J = 9H Z)

 Reference Example 2 7

 6, 7—trans- 1 7 — (2-methylthioacetyl) -1 8-oxo-1,2,2-dimethyl-13-oxa-1 1-azabicyclo [4 • 2 • 0] octane

Under a nitrogen stream, the dimethyl Chirusuruhokishi de 0.2 ⁴ one 7 8 ° c was dissolved in Jikurorome data down 5, anhydrous bets Riffle silos acetate 0.3 6 mg Axis Rorome data down 1 ^ solution was added to this mixture in 1 0 Stir for a minute. 6,7-trans-1- 7- (1-hydroxy-1-2-methylthioethyl) -1-8-oxo-12,2-dimethyl-3-oxa-1-azabicyclo obtained in Reference Example 16 0.0 Octane (mixture of isomers A and B) A solution of 420 in dichloromethane 2 is added over 10 minutes. After stirring for 30 minutes, add 0.68 of triethylamine over 10 minutes and stir at room temperature for 1.5 hours. The reaction solution is poured into water, extracted with dichloromethane, washed with water, and dried (Na ₂ SO ₄ ). The solvent is distilled off, and the residue is subjected to column chromatography using silica gel (hexane monoethyl acetate = 3: 1) to give the title compound (331 w) as an oil. R R ^v ^ rnax ^m ~ ^X : ^{1 7 5 0.} 1 7 0 0

 NMR (90 MHz, CDCI3) ^: 1.40, 1.69 (3H, s x 2 each),

2.0 7 (3 H, s) , 1.5 - 2.0 (2 H, m), 3.3 3 (2 H, ABq, J = 1 9.8, 1 3.8 H z), 3.7 - 4.2 (3 H, m) 4.2 5 ( lH, .d,

O PI

f WIPO J = 2.5 Hz)

Reference Example 2 8

 6, 7 — trans 1 7 — (1-hydroxy 1 2 — methylthioethyl) -8 — oxo 2, 2 — dimethyl 3 — oxa 1 1 — azabi sik mouth [4 · 2. Body B)

 6,7-trans-17- (2-methylthioacetyl) -18-oxo-1,2,2-dimethyl-13-oxar 1-azabisik mouth obtained in Reference Example 2 7 [4.2.0] octane To 23 mi solution of 429 ^ in anhydrous getyl ether, at room temperature under nitrogen atmosphere, add potassium iodide 334 and 1M potassium tris-sec-butyl borohydride tetrahydrofuran solution 4.9 for 30 minutes. Stir. I M calcium tri-sec-butyl hydridotetrahydrofuran solution 2.0 ^ Add and mix for 1 hour.

 Add 2.0. After stirring for 2 hours, add 0.49 acetic acid and 10 ^ ethyl acetate, and filter off insolubles. After evaporating the solvent, ethyl acetate 20

, And the organic layer is washed successively with sodium bicarbonate water and water, and dried (Na ₂

S0 ₄₎ to. The solvent is distilled off, and the residue is subjected to column chromatography using silica gel (ethyl acetate-hexane = 1: 2 to 2: 1) to give the title compound (330) as colorless prisms.

Melting point 1 0 6 — 1 0 7 ° C

NMR (90 MHz, CD Cl ₃ ) "5: 1.0, 1.71 (3Η, sχ2 respectively),

2. 1 2 (3 Η, s), 1.5-2. 1 (2 Η, m), 2.3-3.2 (3 Η, m), 3.5-4.2 (4 Η, m)

Elemental analysis value C _n His NO ₃ S

Calculated value (de: C53.85; H7.81: N5.71; S S3.07 f OMPI Obtained: C 54.03; H 7.92; N 5.70; S 12.77

 Reference Example 29

 6,7-trans-1- 7- [11- (2-methoxetoxymethoxy) -12-methylthioethyl] -18-oxo-1,2,2-dimethyl-3-3-year-old 1-azabicyclo [4.2.0] Octane (isomer B)

 Reference Example 28 6,7-Transition 7- (1-Hydroxy-1-2-Methylthioethyl) obtained in Reference Example 8-18-Kizo-1,2,2-Dimethyl-3-Oxa-1-Azabisik mouth [4.2 [0] The title compound is obtained as an oil from octane (isomer B) 4444 in the same manner as in Reference Example 3.

I ^R -i ^{: 1 7 5 Q}

 NMR (9 OMHz, CDC ": 1.40, 1.71 (3Η, sχ2 respectively),

1.6-2.1 (2H, m), 2.76 (2H, d, J = 6Η _Ζ ), 3.38

(3Η, s), 3.1-4.3 (9Η, m), 4.8 (2Η, s) Reference example 30

 6, 7—Trans 1 7— [1 (2—Methoxyxetoxime) 1

2-Methylsulfonylethyl] 18-year-old 2,2-Dimethyl-13-oxa1-1-azavicik mouth [4.2.0] octane (isomer B)

 Reference Example 29 6,7-Transone obtained in 9 7- [1— (2—Methoxyethoxymethoxy) 1-2-Methylthioethyl] -18-Oxo-1,2,2-dimethyl-3-Oxa-1 From 1-azabicyclo [4.2.0] octane force, the title compound 507 was obtained as an oil in the same manner as in Reference Example 4.

IR «« ^-1 : 1 7 5 0, 1 3 5 0, 1 1 0

NMR (9 OMHz, CD CI 3) s: l. 0, 1.70 (3H, sx2), 1.6-2.1 (2H, m), 2.96 (3H, s), 3.08 (1H, dd,

OH J = 1.5, 7.5 Hz), 3.36 (3H, s), 3.3—4.0 (9H, m),

4.44 (lH, ddd, J = 7.5, 7.5, 4.5 H z), 4.83 (2H, s)

Reference example 3 1

 3, 4 1 trans 1 4 1 carboxymethyl-3 — [1 — (2 — methoxy ethoxymethoxy) 1 2 — methylsulfonyletyl] azetidine 1 2 1 one (isomer B)

Reference ^! 6,7-trans-7- [11- (2-methoxyethoxymethoxy) -12-methylsulfonyleti] -18-oxo-1,2,2-dimethyl-13-oxar obtained by 30 The title compound 1992 can be obtained as an oil from 1-azabic mouth [4.2.0] octane 207 w in the same manner as in Reference Example 5. ^{-lR lj} m ^ x — ¹ · 3 5 0 0 -2 8 0 0, 1 7 6 0-1 7 0 0

NM (9 θΜΗζ, CD CI ₃ ) 3.0 0 (3 H, s), 3.36 (3H, s), 2.6-3.9 (9 H, m), 4.05 (1 H, m), 4.5 2 (1 H , m), 5.8 2 (2H, bs), 7.0 (1H, bs), 7.5 (1H, bs) Reference example 3 2

 3, 4 — Trans 1 3 — [1 — (2 — methoxyl toxic) 1 2 — methinoresnolehoninoletinoch] 1 4 — [3 — (412 trobenzinoleoxycarbonyl) 1 2 —oxopropyl] azetidine 1 2 —one (isomer B)

Reference Example 31 3,4 1-Transition 14-Carboxymethyl-14- (11- (2-Methoxyxethoxymethoxy) 1-2-Methylsulfonylethyl) azetidine- ² -one obtained in 1 Thus, the title compound 142 was obtained as an oil in the same manner as in Reference Example 6.

OMPI IR ^spec ^ i: 3440, 1 760-1 720, 1 350, 1 140 NMR (90 MHz, CD CI ₃ ) <5: 2.94 (3 H, s), 2.7-3.3 (3H, m)), 3.33 (3H, s), 3.56 (2H, s), 3.3-3.8 (6H, m), 4.1 (1H, m), 4.5 (lH, m), 4.80 (2H, s) ), 5.26 (2H, s), 6.25 (1H, s), 7.51

(2H,, 8.2 1 (2H, d, J = 9 _Hz )

 Reference example 3 3

 3,4—Trans 1—4— [3—Diazo 3— (4-Nitrobenzyloxycarbonyl) 1-2—Oxopropyl] 1 3— [1—1 (2-Methoxyethoxymethoxy) 1-2—Me Tylsulfonylethyl] azetidine-1-one (isomer B)

 Reference Example 3 2,3-1,4 Trans obtained in 2 1 -3-[Γ ((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.

IR CM ¹ ": 3 4 4 0, 2 1 4 0, 1 7 6 0, 1 7 2 0, 1 640,

1 3 5 0, 1 1 3 0

NMR (90 MHz, CD '1 ₃ ) 3: 3.96 (3 H, s), 2.ί-3. ^ (3H, m), 3.3 3 (3 H, s), 3.3-3.8 (6 H, m), 4.1

(lH, m), 4.5 (1H, m), 4.8 1 (2H, s), 5.36 (2H, s), 6.39 (1H, s), 7.53 (2H, d, J = 9 H _z ) ₅ 8.23 (2H, d, J = 9H _Z )

Reference example 3 4

7- (1-hydroxy 2-methylthioethyl) — 8 —Oxo-1,2,2-dimethyl-3 —Oxa1-1—azabicyclo [42.0] octane

Reference Example 1 Method and ⁸ in the same manner - Okiso one ^2, 2-dimethyl-3-year old Kisa 1 - Azabishikuro [. 4 - 2 0] octane 1.0 0 ^ title compound from 1.8 8 as colorless crystals. (This product is mostly obtained as a mixture of two isomers A and B, but only a small part is isolated as each isomer).

Melting point 83-85. c (mixture of isomers A and B)

1 ^{R v} m ^ x ^<M ~ ^l : 3 5. . , 173 (mixture of isomers A and B)

_{NMR (9 θΜΗζ, CDC1 3)} δ:

Isomer A: 0.7 9, 1.5 8 (31 ^ s X 2 each), 1.6-2.0 (2 Η, m), 2.15 (3 Η, s), 2.89 (2 Hd, J = 7.5 Η _ζ ) ,

3.3-4.0 (3 Η, m, 4.3 1 Cl H, dd, J = 7.5,

4.8 Η _ζ ), 7.2-7.6 (5 m, m)

Isomer Β: 1.47, 1.76 (3Η, s X 2), 1.9 1 (3Η, s), 1.6-2.0 (2Η, m), 2.96 (2Η, m), 3.7-4.0 (respectively) 3 Η, m), 4.1 3 (1 Η, dd, J = 10.5, 5.1 Η _ζ ), 7.2-7.7 (5

Η, m)

As Elemental analysis _{C 17 .H 23 N0 3 S 2} ( isomer A, the mixture of B)

 Calculated value (): C57.76; H6.56rN3.96; S18.1

 Obtained: C57.69; H6.68; N4.14S18.38

Reference Example 3 5

6,7-cis-7- (1-hydroxy-1-2-methylthioethyl) -18-oxo-1,2,2-dimethyl-3, oxa-1,1-aza, bis (1-20) octane ⁷ — (1 —hydroxy-2 — methylthioethyl) obtained in Reference Example 3 4

-7-Phenylthio-1-oxo-2,2-dimethyl-2,3-methyl-1- 1-azabicyclo mouth [4.2.0] octane 1.32 from 1.32 in the same manner as in Reference Example 2 560 are obtained as colorless crystals. At this time, a mixture of 6,7-cis-form and trans-form, 16 5, and 6,7-trans-form 89 are obtained.

Melting point 9 1 1 9 2.5 I ^{R v} Sa ^CiS_1: 3 4 2 0, 1 7 2 0

NMR (9 0 MHz, CD Ji _{1 3) «5: l.3 8} , 1.7 2 ( each 3H, sx 2), 2.1 5 (3 H, s), 1.5 - 2.2 (2 H, m), 2.6 8 (2 H, d,

J = 6 Hz), 3.3 3 (1 H, dd, J = 6.8, 5.3 H _z ), 3.6 — 4.0 (3 H, m), 4.1 2 (1 H, m)-Elemental analysis C _n H _{As 19} NO ₃ S

 Calculated value (): C 53.85; H 7.81; N 5.71: S I 3.07

 Obtained value (: C 53.85; H 7.81; N 5.82; S

The IR and NMR spectra of the 5,6-trans form obtained here agree with those obtained in Reference Example 16.

OMPI WIPO --Reference example 36

 6, 7-cis 7 _ [1- (2-methoxyethoxymethoxy) 1 2—

Methylthioethyl j-1-8-oxo-2,2-dimethyl-3-oxa-1

—Azabicyclo [4 · 2.0 J octane

 Reference Example 35 6,7-cis-1 7- (1-hydroxy-2-methylthioethyl) -1,8-oxo-1,2,2-dimethyl-3-oxa-11 obtained in 5

The title compound is obtained as an oil in the same manner as in Reference Example 3 using azabichrome [4.2.0 J octane 274].

 A "

_{NMRC 9 θΜΗζ, CDC1 3 δ:} 1.37, 1.70 ( each 3 H, sx 2),

 2.1 4 (3 Η, s, 1.5 to 2.l (2 H, m, 2.7 δ 2 ti, dd,

 J = 5.3, 5.3 Ηζ, 3.3 8 C 3, s, 3.4 to 4.0 (8H, m,

 4.2 (lH, m, 4.8 7 2H, m

Reference example 3 7.

 6, 7-cis 1 7- [1- (2-Methoxyethoxymethoxy 1-2-Methylsulfonylethyl J-18-Oxo1-2,2-Dimethyl-13-Oxa-1

1-azabicyclo [4.2.0] octane

 Reference Example 36 6-, 7-cis-1-7- to 1-C2-methoxetoxymethoxy) 1-2-methylthioethyl J—8-oxo-12,2-dimethyl—3-oxa-1-azavinclo [4 ・ 2. J Octane laser, reference example

In the same manner as in the method of 4, the title compound 310 is obtained as an oil.

_{NMRC 9 OMHz, CDC1 3;:} 1.3 6, 1.6 9 ( each 3 fl, s), l.5~

2.2 C 2H, m, 3.0 1 (3ϋ, s;, 3.36 (3H, s, 3.1 to 4.0 (10H, m), 4.5 lH, mj, 4.90 CH, AB q, J = 6,12Hz) ^ One —

 Reference example 3 8.

 3,4-cis-14-carboxymethyl-3- [1-1 (2-methoxyxethoxymethoxy-2-methylsulfonylethylazetidine-12-one

6,7-cis- 7-[:: 11- (2-methoxyethoxyethoxymethoxy-12-methylsulfonyleethyl J-18-oxo-1 2,2'-dimethyl-3 obtained in Reference Example 3 7 - using Okisa one 1- Azabishikuro [4, 2 · 0 J octane 2 6, in the same manner as in reference example 5, the title compound ² 0 5 is obtained as an oil-like product -. -. IR III CLA cm ~ ^l : 350 000 to 280 000, 170 000 to: 170 000

_{NMR (9 θΜΗζ, CD 1 3} δ: 2.8 5 (2H, m, 3.0 0 (3H, sj, 3.3 6 (3H, s), 3. of ~ 4.0 (7H, n -, 4.1 (lH, m 4.4 ( lH, m), 4.86 (2H, s, 6.2 (lH, bsJ, 6.9 (lH, bsj) Reference example 3 9.

 3, 4—i Sue 3— [1- (2-Methoxy oxime ethoxy 1 2-Methinoresnorelephonyletinole J — 4— [3-(4-Nitrobenzinoleoxycanole Bonyl 1-oxopropyl Jazetidine 1 2-one

 The 3,4-cis-14-carboxymethyl-13- [1- (2- (methoxyethoxyethoxymethoxy-2-methylsulfonylacetylazetidine-12-one) 2-30 ^ obtained in Reference Example 38 was obtained. In the same manner as in Reference Example 6, the title compound 187 is obtained as an oil.

IR レ ^ | CM ¹ 1 3 32 0, 1 7 6 0, 1 7 2 0, 1 3 5 0

 1 1 3 0

_{NMR C 9 OMHz, CDC 1 3} ) δ: 2.9 6 (3H, s;, 3.1 1 (2 Η, d, J two 7Hz, 3.3 3 f 3Η, s ;, 3.5 7 (2Η, s, 3 · 1~ 4.0 (7H, m, 4.1 C lH, m;, 4.4 C lH, m, 4.8 3 (2 H, s,

5.2 5 (2H, s, 6.3 3 (lH, bs, 7.5 0 C 2H, d, J = 9iiz),

6.2 0 C 2R, d, J = 9Hz)

Reference example 4 0.

 3, 4-cis-1 4- [3-diazo-3- (4-nitrobenzenesiloxy-carbonyl) -1,2-oxopropyl] -1 3- [1- (2-methoxyethoxy methoxy-1,2- Tylsulfonylacetyl Jazetidin-1-one 3,4-su-3- [1-((2-methoxyethoxymethoxy) -2-methylsulfonylacetyl obtained in Reference Example 39! 4-41 [3 — (412 T-benzyloxycarbonyl-12-oxopropyl Jazetidin-12-one 87 ^ in the same manner as in Reference Example 7 to give the title compound 172

^ Is obtained as an oil. -IB an ¹

： 3 2 20 , 2 1 4 0 , 1 7 5 0 , 1 7 1 5 ,

: 3 2 20, 2 1 4 0, 1 7 5 0, 1 7 1 5,

 1 6 5 0, 1 3 5 0

_{NMR (9 θΜΗζ, CDC1 3 δ} : 2.9 6 (3H, s;, 3.3 5 (3H, s,

3.2 ~ 4.0 (9H, m, 4.15 (lH, m;, 4.35 (lH, m),

 4.8 7 C 2 H, ABq, J = l 0.5, 7.5 Hz;, 5.3 3 (2H, s J), 6.2 1 (lH, bs;, 7.5 1 (2H, d, J = 9 Hz;, 8.2 3 (2 H, d, J = z)

 5, 6-cis-1- (2-acetamidoethylthio-16- (1—hydroxy-13-thiacyclopentyl-13,3-dioxo-17-oxo-1--1-azabicyclo [3. 2.0 J Hept-12-1-2-carboxylic acid sodium salt.

 (a) 5, 6-cis-6- (1—hydrazine £ — 3-thiazic σpentinole-3-3-thiacyclopentyl-3,3-dioxyd-1-azazaclo

Ο ΡΙ [3 ・ 2,0 J Manufacture of 1,3,7-dione-2-butyruvonic acid hepto-bent benzyl ester

 3,4 -cis-4-[3 -diazo-3-(4 -2 benzoyloxycarbonyl)-1 -2-oxopropyl J-3-(1 -hydroxy 3 -thiazic mouth obtained in Reference Example 8 Pentyl-3,3-dioxide azetidin-1 2-one 60 "if {Benzene solvate J and rhodium (11 acetate 5 W anhydrous tetrahydrofuran 4π ^, mixed with anhydrous benzene 6π ^ for 10 minutes) Deoxygenate through nitrogen, then heat the mixture at 80 ° C. for 7 minutes while stirring under a nitrogen atmosphere, and evaporate the solvent after the reaction to give the title compound quantitatively as a foam.

 : 3 4 7 0, 1 7 7 0, 1 7 4 0, 1 3 5 0,

 1 1 2 0

NMR (9 0 MHz, Aseton one _{d 6) δ: 2.4~ 3.3 (} 8 H, m, 3.6 9 (lH, d, J = 6 z), 3.9 (lH, m, 4.2 3 (lH, s, 4.8 6 (2H, bsj, 7.18 (2H, d, 7.74 (2H, d, J = 9 Hz)

 (b) 5, 6 —cis-1 3 — (2-acetamidoethylthio 1-6 — (1 —hydroxy ^ −3 —thiacic pentyl 1,3,3 —dioxide-17 —oquino 1-azabicyclo [3. 2.0 J Hept-1-ene-2-carboxylic acid 4-Nitrobenzyl ester production.

3,4-Ic-S—4— [3-Diazo-3 -— (4-2-B-benzoyloxycarbonyl-2-oxopropyl) -1 3— (1—Hydroxy i / I 3— obtained in Reference Example 8 5,6—cis-16— (1—) produced from thia / pentopentyl-1,3,3 dioxin azetidin-2-2-one (benzene solvate) 60 ^ according to the method (a) above. Hydroxy i / — 3 —thiacyclopentyl-1,3,3-dioxide-11—azabi σ [3.2.0;) hebutane --A solution of 1,3,7-dione-12-carboxylic acid 412 trobenzyl ester in anhydrous 6π ^ 6π ^ under nitrogen atmosphere. Apply diisopropylethylenamine 0.016π ^ with C [], then add diphenylphosphoric acid chloride 0.019 and stir for ² hours. This mixture is stirred at 0 ° C with isopropylethylamine 0.01 Sm ^ and N-acetylcysteamine 11 for 1 hour. The reaction - was distilled 1 left ^{for four} hours, the solvent is 20 ° C, the residue was diluted with acetic acid Echiru, 7K washed, dried (Na ₂ S0 _4), evaporated. The residue was subjected to column chromatography using fluorescein (aceton-chloroform-form = 1: 1) to give the title compound (23) as an oil.

IR V CM ¹ : 338 0, 1770, 1700, 1650,

 1 3 3 0, 1 1 2 0

UV λ H nm: 26 9, 32 0

NMR 9θΜΒζ, CCD ₃ ^ CO: 1.90 (3ϋ, s;, 2.7 (2H, m, 2.8 to 3.810H, m, 4.08 (lH,, .4 (1H, m,

5.3 8 C 2H, ABq, J = 22, 14 Hz, 7.4 (lH, mj, 7.78 C 2H, d, J = 9 Hz, 8.25 (2H, d, J = 9 Hz

 (cj 5,6-cis-13- (2-acetamidoethylthio-16- [1-hydroxy-3-thiacic-pentyl-3,3-dioxide-17-oxo-11-azabizik 3.2) 0 J-Hept-1-ene-2-carbonic acid sodium salt production

5,6-cis-1- (2-acetamidoethylthio) -16-C1-hydroxy-13-thiacyclopentyl-3,3-dioxide-17-oxo-1-1-azabicyclo obtained in (b) above 3 ・ 2.0 J Hept 1-2-1-ene Rubinic acid 4-12 Trobenzyl ester 5 7 Tetrahydrofura Down 5 m ^, pH 7. 0-phosphate buffer 2.6 m ^ and water 2.6m £ 1 ₀ 0 Pd-C5 were added under normal pressure at room temperature混台solution is added 1.5 hours hydrogen. The catalyst is filtered off and washed with a small amount of water. The filtrate and washing solution are combined, and tetrahydrofuran is distilled off under reduced pressure. 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.

 IR 3 0, 1 7 5 0, 1 6 4 0

UV: 298 (134;-

_{NMR (9 θΜΗζ, D 2 O} δ: 2.0 1 (3 Η, s), 2.5 C 2 Η, m), 2.8 ~ 3.9 C 1 0 Η, m), 4.0 0 1 Η, d, J = 6 Η ζ ), 4.4 1Η, m)

Example 2.

 5,6-cis-13- (2-pyrimidinylthio) -16- (1-hydroxy-3-thiacyclopentyl-3,3-dioxide:) 17-oxo-1-azabiro [3. 2.0 J hept-2-ene-1 2-potassium sodium salt

 (a) 5, 6 -cis-1 3-(2-pyrimidinylthio 1-6-(1 -hid sigma-1 -thiasignopentyl-1, 3,3-dioxin-7-oxo-1-azavinclo [3.2. 0 J-hepto-2-ene-2-carboxylic acid 412 To produce benzyl esters.

3,4-cis-14- [3-diazo-3- (4--2-to σbenzyloxycarbonyl 2-oxopropyl J-13— [1—) obtained in Reference Example 7 (2-Methoxyxethoxymethoxyl-3-thiacycline pentyl-3,3-dioxide) azetidin-2-one 100 ^ from Reference Example 8 and Example 1 (5,6 produced in the same manner as in Example 1a). —Cis 6— (1-Hydroxy mouth 3—Thiacycline pentyl-3,3-dioxide-11-azabicyclo [3.2,0] heptane 1-3,7-dione-12-dicarboxylic acid

溶液に窒素雰囲気 下、 0°Cでジイ ソプロピルェチルァミン 0.0 14π ^を加え、 ついでフエ ニルリン酸クロリ ド 0.017ι ^を加えて 9 0分間かきまぜる。 この混合 物に 2 -メルカプトピ リ ミジンのリチウム塩 2 0 ^を加えて 0。じで 1 8 時間かきまぜる。 反応液を酢酸ェチルで希釈し、 氷水中に加え有機層を 分取する。 有機層を水洗.，乾燥（Na₂S0₄J)後、 溶媒を留去し、残留物を フロ リジールを用いるカラムクロマトグラフ-ィ ー（ァセトン一クロロホ ルム = 1 : 1 ) に 1"と、 題記化合物（5 が'/ *Κ物として得られる。 —Anhydrous acetonitrile of benzyl ester

Under a nitrogen atmosphere, add diisopropylethylamine 0.014π ^ to the solution at 0 ° C, then add phenylphosphoric acid chloride 0.017ι ^, and stir for 90 minutes. To this mixture was added 20 ^ lithium salt of 2-mercaptopyrimidine to 0. Stir for 18 hours. Dilute the reaction solution with ethyl acetate and add to ice water to separate the organic layer. The organic layer was washed with water, dried (Na ₂ SO ₄ J), the solvent was distilled off, and the residue was subjected to column chromatography (acetone-chloroform = 1: 1) using Florisil to 1 ", The title compound (5 is obtained as a '/ * Κ product.

IR on ^-1 : 34 5 0, 1 7 8 0, 1 7 1 0

UV λ ^ III ⁰ _γ ^Η nm: ^{262, 3.18}

NMR (9 OMHz, CDC1 ₃ 2.4 (2Η, m), 3.1-3.8 (6H, m)

 3.8 6 (1Η, d, J = 6 Hz, 4.5 (1Η, m, 5.36 (2Η, ABq, J = 25, 1Ηζ, 7.09 (lH, t, J = dz, 7.6 1 C 2Η, d, J = 9 Hz, 8.2 1 C 2H, d, J = 9 Hz, 8.5 6 (2 J, J = 5 Hz (b) 5, 6-cis-1 3-(2-pyrimidinylthio) 1 6-(: 1—Hydroxyxy 3-Thiacyclopentyl-13,3-dioxide-17-oxo-1-azabicyclo !: 3,2,0! Hept-2-ene-2-carboxylic acid Preparation of sodium carboxylic acid salt

 From the 4-nitrobenzyl ester 50 ^ obtained in (a) above, the title compound (6 was converted to pale yellow powder in the same manner as in Example 1 ().

Ο ΡΙ can get.

IR ^ml : 3 400, 1 750

 UV: 290 (1 06 J)

_{NMR (90 MHz, D 2 0} δ: 2.5~2.8 (2H, m, 3.1~4.0

 (6H, m), 4.26 (1H, d, J = 6Hz, 4.5 (1H, m), 7.56 (lH, t, J = 5Hz, 8.89 (2H, d, J = 5Hz

 Example 3.

 5,6-cis-1- (2-aminoethylthio-16- (1-hydroxy-13-thiacyclopentyl-3,3-dioxide-7-oxo-1-1-azabicyclo [3.2.0] heptー 2 ェ 1 — 2 力 -rubonic acid

(a) 5, 6-£ 1-3-[2-(4- 2- benzyloxycarbonylaminoethylthio)-1-6-(1 -hydroxy. 1-3-Thiacyclopentyl-1, 3-3 -doxydoku -7-Oxo 1-1-azabicro [3 · 2 · 0) Hept 1-2-1-2-Rubinic acid 4-2 U

 3,4-cis-14- [3-diazo-3-((412-port benzyloxycarbonyl-2-oxo-propyl)]-3— [1- (2- (2-methoxyquinone) obtained in Reference Example 7 The title compound (8a) can be obtained as an oily product from (tox))-3-thiacyclopentyl-3,3-dioxide Jazetidin-2-one 18 3 ^ in the same manner as in Example 2 (a).

IR V COT ¹ : 3 4 0 0, 1 7 7 0, 1 7 1 0

 UV λ ^ nm: 2 6 8, 3 18

NMR (90顧_{z, (CD 3 2 CO;} §: 1.9 5 (2H, m), 2.5~3.1 (10H, m, 3.5 9 (lH, d, J = 6 Hz, 3.9 (lH, m;, 4.73 (2H, s), 4.8 7 (2H, ABq, J = 29, 14Hz, 6.8 (lH, bs 7.1 2 C 2H, d, J = 9Hz;, 7.59 C 2H, d, J = 9Hz, 7.7 1

(4H, d, J = 9Hz

(b) 5,6-cis-1- (2-aminoethylthio-6- (1-hydroxy-1-3-thiacic-pentyl-3,3-dioxide-17-oxo-1--1-azabicyclo [3.2 0:! Hept-2-ene-2

Above (and from 4 two preparative port base Njiruesuteru ⁸ 7 obtained in aj in the same manner of Example 1 (c) title I匕合product (18 as a colorless powder ^{IE, - 1:. 3 4} 0 0, 1 7 5 5

^nm ( ; ： 2 9 5 ( 1 0 9 ； U

^nm (;: ²⁹⁵ (10 9;

_{NMR (9 OMHz, D 2 0} δ: 2.6 (2 H, m, 3.0~ 40 (1 θΗ, m, 4.1 5 C lH, d, J = 6 Hz), 4.5 (lH f .m)

Example 4.

 5, 6-cis-1- (2-formimididoylaminoethylthio-16- (1-hydroxy-3-thiacyclopentyl-13,3-dioxide) -7-oxo-11-azabicyclo [3.2.0J Hept-2-ene-2-carboxylic acid.

 5,6-i-su-3-(: 2-Aminoethylthio-6-C 1-hydroxyl obtained in Example 3 £ —3-Thiacyclopentyl-13,3-dioxido—7-oxo-11-azabicyclo [ 3.2. 0] Heptot-2-ene-2 monobasic rubonic acid 18 ρΗ 7.0 Phosphate buffer solution 3.5m £ To a solution of 1N aqueous sodium hydroxide solution under ice cooling, add pH 8.5 Add benzylformimide hydrochloride 63 3 to this solution in small portions over a period of 10 minutes while maintaining the ρΗ of the solution at 1ΝτΚ sodium hydroxide aqueous solution at 8.5, after stirring for 5 minutes. Then, the reaction mixture is adjusted to pH 7.0 with hydrochloric acid and washed with ethyl acetate.

>, WIPO After concentration, the mixture is subjected to column chromatography using Diaion HP-20, fractions eluted with 3% acetate are collected, and lyophilized to obtain the title compound (12) as a colorless powder.

IRM ¹ : 3400, 1750, 1720, 1300,

1 1 2 0

_{NMJR, (90MHz, D 2 0} δ: 2.6 (2 H, m, 3.0~ 0 (1 OH, m),

4.1 3 (lH, d _f J = 6H.z), 4.5 (lH, m, 7.9 5 (lH, s

 Example 5.

 5,6-cis-1- (2-acetamidoethylthio-16- (1-hydroxy-14-thiacyclohexyl-14,4-dioxide-17-oxo-1-1-azabicyclo [3.2] 0 J-hep-2-ene-2-potassium sodium salt

 (aj 5, 6-cis—3— (2-acetamidoethylthio 16— (1—hydroxy ^ —4 thiachlorohexyl 1,4,4 dioxide 17—oxoxo 1—azabinclo [ 3.2.0 Production of 2-heptan-2-carboxylic acid _ 4-nitrobenzyl ester

 Reference Example 15 3,4-1,4- (3-diazo-3-(-nitrobenzyloquincarbonyl:)-12-oxopropyl) -13- [1- (2-methoxhetoxime) obtained in Reference Example 15ー 4—Cleaning

 The title compound (18 ^;) is obtained as a foam from 4 (1-dioxide) azetidin-2-one 67 in the same manner as in Example 2 (aj).

 IR ^^ 3x ^ '340 0, 1770, 1690, 1650,

 1 3 5 0, 1 1 4 0

UV λ ^ ∞ nm: 2 6 8, 3 19

ΟΜΡΙ NMR (9 OMHz, acetone one _{d 6) δ: 1.9 0 (} 3H, s, 2.1~3.7

， 4.4 ( lfi,m)， 5.4 0 2 H , ABq , J=24 , 14Hz , 7.4 ( lH , , 7.7 8 C 2 H , d , J = 9Hz , 8.2 3 C 2H, d , J B Z) (14H, m), 3, 8 4 (lH, d

, 4.4 (lfi, m), 5.40H, ABq, J = 24, 14Hz, 7.4 (lH,, 7.78C2H, d, J = 9Hz, 8.23C2H, d, JBZ)

(b) 5,6-cis-13- (2-acetamidoethylthio) -16- (11-hydroxy-14-thiacyclohexyl_4,4-dioxide-17-oxo-l-azavinclo [ 3.2.0] Production of sodium salt of hept-2-ene-2-carboxylate

 From the 4-nitrobenzyl ester 40 obtained in the above (a), the title compound (12) is obtained as a colorless powder in the same manner as in the method of Example 1 (c).

IR ^^ cm ¹ : 3400, 1750, 1.640

UV ^nm (: 3. (U 16 "

_{NMR (9 θΜΗζ, ϋ 2 0} δ: 2.1 3 (3 Η, s;, 2.2~ 3.9 (14Η, m) 3.9 7 (lH, d, J = 6Hz, 4.4 (lH, m)

Example 6.

 5, 6 — trans 3 — (: 2—acetamidoethylthio 6 — (: 1 — hydroxy-1 2 —methylsulfonyl-methyl-7-oxo-1 1 —azabicyclo [3 • 2. 2-ene-1-carboxylic acid sodium salt (isomer A

 (a) 5, 6 — trans 3 — (2-acetamidoethylthio 16 — (: 1-hydroxy-2-methylsulfonyletyl 17-oxo-1 1 —azabicyclo [3 · 2.0 J hept Production of 1-2--1--2-carboxylic acid 4-4-2 σ-benzylester

Reference example 2 1, 3, 4 — trans— 1 r 3 — diazo — 3 — (: 4-Nitrobenzyloquincarbonyl-1-2-oxopropyl J—3— [1- (2-Methoxyxyethoxymethoxy-12-methylsulfonylethyl:! Azetidin-2-one (isomer A) From Example 21, the title compound ⁴ 1 ^ is obtained as a white foam in the same manner as in Example 2 (the method of aj).

IR CTH " ¹ : 3 4 40, 1 7 9 0, 1 7 0 0, 1 6 4 0,

 1 3 4 0, 1 1 3 0

 UV "-nra: 2 6 9, 3.2 1

 (bj 5, 6-trans-1- (2-acetamidoethylthio-6- (1-hydroxy-1--2-methylsulfonylethyl-7-oxo-1--1-azabicyclo [3.2.0] heptose) 2-en-2-fluorosulfonic acid sodium salt (Production of isomer A

From the resulting 4 two Bok port Ben glycol ester 5 2 ^m 9 above (a), in the same manner as in Example 1 (c), the title compound (16) as a pale yellow powder.

IR COT " ¹ 1 3 4 0 0, 1 7 6 0, 1 6 3 0

 U nmCE ^: 300 (1 1 2;

NMR (9 θΜΗζ, D ₂₀ <5: 2.1 3 (3H, s, 3.31 (2Η, s,

 2.9 to 4.0 (9H, m), 4.35 (1H, m;), 4.70 (lH, m)

Example 7.

 5, 6-trans-3- (2-acetamidoethylthio-16- (1-hydroxy-12-methylsulfonylechinole) -7-oxo-11-1-asa'bicyclo [32.0: ! Heptot-2-ene sodium 2-ruthenate sodium salt (mixture of isomers A and B)

 (a) 5, 6-trans-3- (2-acetamidoethylthio-16- (1-hydroxy-1--2-methylsulfonyletyl-17-oxo-1-aza)

OMPI Production of bicyclo [3.2.0] hept-2-ene-1-2-carboxylic acid 412-mouth benzyl ester

 3,4—trans-4-1 obtained in Reference Example 26 [3-diazo-3-(

4-122 σ-benzyloxycarbonyl) 1-2-oxopropyl] 1-3- [1- (2-methoxetoxymethoxy-12-methylsulfonylethyl) azetidin-12-one (isomer Α and Β The title compound 28 is obtained as a white foam in the same manner as in Example 2 (a).

_{^{IR v ^ x l: 3 4}} 3 0, 1 7 70, 1 70 0, 1 64 0,

 1 3 4 0, 1 1 1 0

 UV λ nm: 2 6 8, 3 2 1

 (b) 5, 6-trans-1- (2-acetamidoethylthio-16- (1-hydroxy-2-methylsulfonyletyl-17-.oxo-1-1-azabicro [3.20: ! Heptot-2-ene sodium 2-Rubonate sodium salt (mixture of isomers A and B)

 In the same manner as in Example 1 (4), the title compound (15 ^ was obtained as a pale yellow powder using the method of Example 1 (4) using 4.12 σ-benzyl ester 44 »¾ obtained in (a) above. .

R ^ ma- ^m : 3400, 1755, 1630

 UV:

3 0 0 C 1 47 ；

3 0 0 C 1 47;

_{NMR (90MHz, D 2 0)} ^: 2.1 0 3 H, s, 3.3 1 (2H, s;,

 2.9 to 4.0 (9H, m), 4.35 (lH, m, 4.70lH, m

 Example 8.

 5, 6-cis-1 3— (: 2-piperazinethylthio-6— (1-hydroxy-3-3-thiacyclopentyl-3,3-dioxide) 1-7-oxo

0MPI IPO 1 1-azavinclo [3 · 2. 0] heptoe 2- 2-en-2-capronic acid (aj5,6-cis-l3- {C2-4- (4-1-2 trobenzyloxycarbonyl) pipet Radinoethylthio-6- (1-hydroxy-3-thiacycline pentyl-3,3-dioxide) -17-oxo-1 1-azabisik σ [3.2,0 J heptoe-2—ene1-2—force Manufacture of rubonic acid 4-12 trobenzyl ester

 3,1-cis-4-1 [3-diazo-3- (4--2-to-mouth benzyloquincarbonyl-12-oxopropyl) -13- [11- (2-methoxethoxymethoxy :) obtained in Reference Example 7 The title compound (55) is obtained as an oil in the same manner as in Example 2 (a) from 3-thiacyclopentyl-3,3-dioquindo Jazetidin-12-one 150 force.

IR ^^ COT ¹ : 3350, 1770, 1-7110

 UV ^: 268, 320

NMR (9 θΜΗζ, acetone one _{d 6) δ: 2.3~ 4.0 (} 20H, m), 4.07

 lH, d, J = 6Hz), 4.4 C lH, m, 5.23 2H, s), 5.38

 C 2H, ABq, J = 24, 15Hz;, 7.63 [2H, d, J = 9Hz,

 7.74 (2H, d, J = 9 Hz), 8.21 (2H, d, J = 9 Hz)

 (b) 5, 6 -cis-1 3-(2 -piperazinethylthio 1-6-(1 -hydroxyl 3 -thiacyclopentyl-3,3 -dioxide)-7 -oxo 1 -azabi Production of black [3.2.0 J hept-2-ene-2-carboxylic acid]

 From the 4-nitrobenzyl ester 55 obtained in (a) above, the title compound (8.6 is obtained as a pale yellow powder in the same manner as in Example 1 ().

IR ^ cm " ¹ : 3 4 4 0, 1 7 5 5

OMPI

W1PO — T —

UV nm (E): 2 9 9 10

NMIIC 9 OMHz, D ₂₀ §: 2.5 to 4.0 (2θΗ, m), 4.15 (lH, d,

 J = 6 Hz, 4.5 (1 H, m)

Example 9.

 5, 6-cis-3-(2-hydroxyshethylthio)-1-6-(1-hydroxy)-1-3-thiacyclopentyl-1, 3-3-dioxide-7-oxo

— 1-azabicyclo [3 ・ 2,0 J-hept-2-ene-2-force sodium levenoate sodium salt

 (a) 5, 6—Sulfur 3— (: 2—Hydroxyshetylthio) 1—6— (1-Hydroxy-3-Thiacyclopentyl-3,3-dioxide — 7—Oxo-1—Azavinclo [ 3.2.0] Heptot-2-ene-2-carboxylic acid Preparation of 4,12-Trobendinole ester-3,4-cis-1 4- [3-diazo-1-(obtained in Reference Example 7) 4- (2) benzoyloxycarbonyl) 1-2-oxopropyl J—3— [11

 (2-Methoxyethoxyethoxymethoxy-3-Thiacyclopentyl-1,3,3

—Dioxide :! The title compound (34 ^) is obtained as a foam from azetidine-1-one 150 in the same manner as in Example 2 (a).

IR ^ cm " ¹ : 3450, 1 75 5

UV λ nm: 2 6 7, 3 2 0

NMR (9 OMHz, acetone one _{d 6 δ: 2.5 (2Η,} m;, 2.8~ 3.9 [8H,

 m, 3.7 3 C 2,, t, J = Qiiz), 4.0 7 (lH, d, J = 6 Hz),

 4.4 (lH, m, 5.3 8 (2 H, ABq, J = 23, 12Άζ), 7.78 (2 H, d, J = 9 Hz;, 8.2 1 C 2H, d, J = 9 Hz;

 (b) 5, 6-cis-1-(: 2-hydroxyshetylthio) -6-1-1-hydroquinine-3-thiacic pentyl-3,3-dioki i / do-7-oki

>, IPO, Saw 1-Azabichrome [3 ・ 2 ・ 0 J Hept-1-ene-12-Carboxylic acid sodium salt production

 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).

 IR: 3 4 2 0, 1 7 5 5

： 3 0 0 ( 9 1 U

: 3 0 0 (9 1

NMJft (9 OMHz, D ₂ 0 <5 2.65 C 2H, m, 2.9-4.0 (6H, m,

3.1 7 C 2H, t, J = 6Hz, 3.9 1 (2 H, t, J 6Bz) _t 4.1 6

 (lH, d, J = 6Hz, 4.5 (lH, m

Example 1 o.

 5, 6-cis. 1-3-Ethylthio 1- 6- (1.-Hydroxy / 1- 3-Thiacyclopentyl-3,3-Dioxod 17-Oxo-11- 1-azabicyclo [3. Sodium 2-carboxylic acid sodium salt

(aj 5, 6—cis 1—3-ethylthio 6— (1—hydroxy 1—thia

 Clopentyl-3,3-dioxide :) 1-7-oxo-1 1-azabisik In the mouth 3 · 2.

 3,4-I-cis-4- (3-Diazo-3— (4-2-sigmabenzyloxycarbonyl-1-2-oxopropyl J—3 -— [1-—) obtained in Reference Example 7

C 2—Methoxy ethoxy methoxy 13-thiacycline pentyl 13, 3-dioxide: 1azetidine-12-one 8 was also obtained from the title compound in the same manner as in Example 2 (a;). (Obtained as an 8 W oil.

IR cm " ¹ : 1 7 6 0

UV: 2 6 7, 3 2 1

O PI WIPO, ― O―

NMR C 9 OMHz, acetone 1 d ₆ ): 1.26 (3 H, t, J = 7 Hz),

 2.5 6 C 2H, q, J = 7H;, 2.6 C 2H, m), 2.9 to 3.4 (6 H,, 4.07 C 1 H, d, J = 6 Hz), 4.45 (lfi, m), 5.3 8 (2H, ABq, J = 22, 1 Hz), 7.78 C 2H, d, J = 9 Hz), 8.2 3 (2H, d, J = 9 Hz)-

(b) 5,6-cis-1-ethylthio-6- (1-hydroxy-3-thiacyclopentyl-3,3-dioxydocu-7-oxo-1-1-azabisik mouth !: 3,2,0 J The 4-nitro σ-benzyl ester 40 obtained in the above-mentioned 0) of 2-en-2-carboxylic acid sodium salt was converted to the title compound (4 ^) in the same manner as in Example 1 (c;). Is obtained as a pale yellow powder o

 IR:,: 3440, 1750

UV ¾0 _{nm C} Ej ^: 3 0 2 (1 0 4)

NMR C 90 t z, ₂₀ d: i.4 o (3H, t, J = 7 Hz, 2.6 (2H, m, 3.00 (2H, q, J = 7 Hz, 3.2 to 4.0 (6H, m , 4.1 2

 lH, d, J = 6Hz, 4.4 C lH, m

Example 1 1.

 5, 6-Lance 1 3- (: 2-acetamidoethylthio 16- (1-hydroxy-12-methylsulfonyletyl 17-oxo-1 1-azabicyclo [3.2.0 J 2-ene-1-carboxylic acid sodium salt (isomer

 (aj 5, 6-trans-1- (2-acetamidoethylthio) -1-6- (1-hydroxy-2-methinolesnorephonylethyl) -17-oxo-1-1-azabicyclo [3.2.0 J heptamine 2-ene 2-carboxylic acid 4-nitro

v W "I" PO Manufacture of benzoyl ester

 Reference Example 33 3,4 1-trans-1- 4- (3-diazo-3- (4-nitrobenzoyloxycarbonyl) —2-oxopropyl) 1-3- [1- (2- The title compound (32 is a white foam) was prepared in the same manner as in Example 2 (a), except that methoxyl ethoxymethoxy J-12-methylsulfonylethyl! Azetidin-12-one 103 isomer is obtained. Obtained as a product.

IR c ¹ : 3400, 1770, 1700, 1640,

3 5 0, 1 1 2 0

UV λ ^E m ^t a ⁰ x ^{H Γ} nm 2 6 8, 3 2 1

(b) 5, 6-trans-3- (2-acetamidoethylthio-6-(: 1-hydroxy-2-methylsulfonylethyl-17-oxo-11-azabicyclo!); 32.0 ! Hept-1-ene-2-carboxylic acid sodium salt (: Production of isomer B

 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).

 c ^ p— _ι

 I RE C7B: 3400, 1755, 1630

U ^{V n} ) ^ 0 0 (1 5 5)

NMR (9θΜΗζ, D ₂₀ ) δ: 2.15 (3Η, s, 3.33 (3H, s,

2.9 to 4.0 C 9H, m, 4, 4 (lH, m, 4.8 (lH, m

Example 1 2.

5, 6-cis-1- (2-acetamidoethylthio-1-6-1-hydroquinone 2-methylsulfonyleethyl-17-oxo-1-1-azabizik

Mouth [3.2.0] Heptot-2-ene-2-carboxylic acid sodium salt (a) 5,6-cis-13- (2-acetamidoethylthio-16- (1-1

O PI

W1PO, Production of hydroxy-1-methylsulfonylacetyl 7-oxo-11-azabicyclo [3 · 2 · 0 J-hept-2-ene-12-carboxylic acid 4-nitrobenzyl ester

 (a) 3,4-su-4-(: 3-diazo-13- (4-to-2 mouth benzyloxycarbonyl-12-oxopropizole) obtained in Reference Example 40-1,3- [1-C2-me The title compound C 25 ^ is obtained as a powder in the same manner as in Example 2 (X) from the oxime xymethoxy-12-methylsulfonylethyl Jazetidin-12-one 8Q power.

IR ^ ^ illζa in cm ^-1 : 3440, 1765, 1695, 1640,

 1 3 4 0, 1 1 3 0

UV ^ t _a ^H nm: -2 6 7, 3 2 0

 (b) 5,6-cis-1- (2-acetamidoethylthio-16- (1-hydroxy-2-methylsulfonylethyl-7-oxo.1-1-azabicyclo [3.2.0] hepto-1) Manufacture of sodium 2-butyric acid sodium salt

 Using the above-mentioned method (a), the title compound (16 is obtained as a white foam using the same method as in Example 1 (4).

IR Li cm- ¹ : 3400, 1760, 1640

UV _{nm C} E; ¾

： 2 9 9 1 6 9

: 2 9 9 1 6 9

NMR (9 OMHz _f D ₂₀ ) δ: 2.15 {3H, s, 3.3 1 C 3H, s,

 3.0 to 4.1 9H, m, 4.45 C lH, m, 4.8 (lH, m)

Example 1 3.

 5, 6-cis-l3-[(: E)-2-acetamidovinylthio J-6- (: 1-hydroxyl-3-thiacyclopentyl-13,3-dioxide) 17-

O PI Oxo-1 1-azabichrome [3.2.0] hept-2-ene-2-carbonic acid sodium salt

 (aj 5, 6-cis-1 3 — [(1-2-acetamidovinylthio :) 1-6— (1-hydroquinone 13-thiacyclopentyl-3,3-dioxyd 7-oxo-1 1-azavinclo [3 [2 • 0] hept-1-2-ene-2-force Production of 4-nitrobenzyl rubonic acid ester

 3,4-cis-4- (3-diazo-3-((412-to-open-benzyloxycarbonyl-12-oxo-propyl) -13- [11- (2-methoxyethoxy) obtained in Reference Example 7) From the 13-thiadiclopentyl-3,3 dioxide Jazetidin-12-one 123, the title compound (45 ^ was converted into a foam in the same manner as in Example 2 (a). can get.

IR ^^ cro " ¹ : 1 7 65, ¹ 690, 1.6 2 0

nm ： 2 3 0 , 2 6 5 , 3 2 6 UV

nm: 2 3 0, 2 6 5, 3 2 6

_{NMR (9 oMHz, CD 3 COCD} 3 ^: i.9 7 (3H, s;, 2.4 5 C 2H, m, 2.7~ 3.9 (6H, m, 4.0 6 (lH, d, J = 6Hz, 4.4

 (1 H, mj), 5.3 8 (2H, ABq, J = 22, 14 Hz, 5.9 7 (lH, d, J = l 4 Hz;, 7.1 7 (lH, dd, J ^ l 4, 13 Hz) , 7.7 3 (2 H, d, J = 9 Hz, 8.2 1 C 2H, d, J = 9 Hz, 9.7 6 (1 H, d, J = 13 Hz;

 (bj 5, 6—cis 1 3 — [(: 1—2—acetamidovinylthio J— 6— (1—hydroxy i—3—thiaΐclopentyl-3,3-dioxo-7—oxazo 1—azabi i /Chloro[3.2.0]heptoh-2-ene-2-force Production of sodium rubonate salt

 The title compound (19 was obtained as a colorless powder from the 4-benzyl benzyl ester 69 obtained in the above (a) in the same manner as in Example 1 (

Ο ΡΙ ― —

It is.

IR ^ ^ml : 1 7 5 5, 1 6 7 0, 1 6 2 0

UV nm (Ε: 2 2 9 C 312, 3 0 6 (3 12

；

;

_{NMR C 9 OMHz, D 2 0J} S: 2.2 0 (3H, s, 2.6 5 C 2H, m), 3.0~4.0 [6H, m, 4.1 2 [lH, d, J = 6H.z) , 4.5 0 ( lH, m]

6.1 5 (lH, d, J = 13Hz), 7.28 lH, d, J = l 3Hz

Example 14.

 5, 6-cis-3-((Z-2-acetamidovinylthio-6- [1hydroxy-13-thiacyclopentyl-3,3-dioxide) -17-oxo-1-1-azabisik σ [3.2 0 J-Hept-12-2-Sodium sulfonate

 (a) 5,6-cis-13-[(Z—2-acetamidovinylthio) -16- (1—hydroxy-3-thiacyclopentyl-13,3-dioxide) 17-oxo-11-1—azabicyclo [ 3 · 2.0:! Heptoh-2-ene-2-force Manufacture of rubenic acid 412 trobenzyl ester

3,4-cis-14- [3-diazo-3-4-2-butanol obtained in Reference Example 7 benzyloxycarbonyl-2- (oxopropyl) -13- [1-1- [2-methoxyethoxymethoxy] ΐ) — 3-Thiacycline pentyl-1,3,3-dioxin Jazetidin-12-one 9 Q ^{II L} , to give the title compound (27 ^) as a foam in the same manner as in Example 2 (aj). Can be

m ¹ ： 1 7 7 5 , 1 7 0 0 . 1 6 3 0 IR

m ¹ : 1 7 7 5, 1 7 0 0 .1 6 3 0

UV λ ^ ^e _a ° ^H nm: 2 3 7, 2 6 3, 3 2 6

_{NMRC 9θΜΗζ, CD 3 COC 3 δ} : 2 .0 6 3Η, s;, 2.4 5 C Η, m, 2.8- 3.9 C 6H, m, 4.0 8 lH, d, J = 6Hz), 4.4 0 C lH, m , 5.4 2 2H, ABq, J = 24-1 Hz J, 5.46 (lH, d, J = 8 Hz), 7.28 C 1Η, dd, J = 8, 12 Hz;, 7.78 C 2Η, d, J = 9 Hz, 8.2 3 C 2Η, d, J = 9 Hz;, 9.10 (lH, m )

(bj 5, 6-cis-l3- [Aji- 2-acetamidovinylthio-J-l 6- (1-hydroquinine-3-thiacyclopentyl-3,3-dioxide)-7-oxo-1-l-azavinclo [3・ 2 ・ 0] Heptoto-2-ene Production of sodium salt of rubonate

 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 ().

IR v K ⁱ B ^OA n ¹

1 ¹ max 7 6 0, 1 6 8 0, 1 6 3 0

UV max ( ^{1 β} ί ¹ (1 ^¾ ) 2 3 3 (291), 30 5 (274

NMRC 90ΜΗζ, D ₂₀ ) δ 2.26 (3Η, s, 2.65 (2Η, m, 3.0-4.0 (6H, m, 4.13 (lH, d, J = 6Hz)), 4.50

 (lH, mj, 5.86 (lH, d, J = 8H.z), 7.30 (1 Η, d, J = 8 Hz

Example 1 5.

 5, 6 —cis 3 — (2 —acetamidoethylthio 1 6 — (1 —hydroquinone 3 —thiashik mouth pentyl 3, 3 —dioxo 1 7 —oxo 1 1 azabi i 3. 2.0 J Hept 1-2-en-2-carboxylate sodium salt 250 to a sterile vial (17m ^ internal volume) and cap. When used, close the sterile vial. Then, add 11 ^ of distilled water from which pyrogen has been removed to prepare a solution for injection.

Example 16.

5, 6— 6S—3— (2-formimidyluaminoethylthio) 1 6- (1—Hydroquinone 3—Tianck-mouthed pentyl—1,3,3-Dioxide - 7- Okiso one 1 Azabishikuro [3 · 2 · 0 J hept-2-E down Ichiriki carboxylic acid 2 5 0 to _c when used for the sealing plug was added to a sterile vial (internal capacity 12Pai ^ sterile vial sealing plug And distilled water from which pyrogen has been removed is added thereto to obtain a solution for injection.

Test 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.

 (a Measurement 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.

を塗沫する。 3 7°Cで 1 8時間培養（incubation した後、 試験菌の増殖を完全に阻害する試 験化合物の最低濃度を、 最小阻害濃度（MI C： minimal inhitory concentration ) とする。 (Trypticase soy agar) 9. Pour and mix Om ^. A suspension of the test organism on the mixed agar plate (: about 10 ⁸

Paint. 3. Incubate at 37 ° C for 18 hours (incubation). The minimum concentration of the test compound that completely inhibits the growth of the test bacteria is defined as the minimal inhibitory concentration (MIC).

 () Test bacteria

 (1) Staphylococcus' Ole Reus (S. aureus DA 209P

(2) Escherichia-Collie (E. col 0-111

 (3) Citropactor 'Freundi i f C. F reundi i IFO 12681

(4) Pneumoniae DT

 (Results

 The MIC C minimum inhibitory concentration of the test compound is shown in Table 1 c

'― O PI Table 1. MIC values (meg)

 Test example 2.

 With respect to the representative example of the target compound obtained in the examples, the stability in a mouse kidney homogenate was measured by the following method.

 Measuring method

Mouse kidney 5 09- cooled 0.05M phosphate buffer (pH 6.9) © 200? ^ Triturated in, the resulting kidney homogenate save one ² 0 ° C. This mouse kidney homogenate

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)).

(b result Table 2 shows the half-life of the test compound.

 Table 2. Test compounds 1 2 12 13

 Example 半 Half-life (min :)

 〉 120〉 120〉 120〉 120

 .% mcin)

Industrial applicability

 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.

ΟΜΡΙ

Claims

 U general formula Y—S 0

[In the formula, X represents a lower alkylene group or a lower alkenylene group which may have a hydroxyl group, and γ represents a (υlower alkyl group (a cycloalkyl group having ^{3 to 8} carbon atoms; a lower alkyl group (3 lower alkenyl groups) Group (4) aryl group (5 aralkyl group or (63 to 8 membered heterocyclic group, or a partial structural formula, Y—S02—X is a compound of the formula X S0 ₂ CH— (CH ₂ or .S 0 ₂ C-(CR ₂ ) _£  \ (CH no (Wherein is an integer from 0 to 3, m and n are each an integer from 0 to 6 and the sum of m and π represents 2 to 6), and R is A hydrocarbon group or a 3- to 8-membered heterocyclic group ", or a salt thereof.  (2) General formula

[In the formula, X represents a lower alkylene group or an alkenylene group which may have a hydroxyl group, and Y represents (υa lower alkyl group (2 cycloalkyl group having 3 to 8 carbon atoms (3 lower alkenyl group) (4 aryl group or (3- to 8-membered heterocyclic group or a partial structural formula, Y—S 0 ₂ ΟΜΡΙ wipo, X— combines X and Y to form the formula CH ₂ ; _mX S0 ₂ CH- (CH ₂ one still S0 ₂ , (01 ₂ no (

(Wherein, is an integer from 0 to 3, m and n are each an integer from 0 to 6, and the sum of m and n represents 2 to 6, and Z is a leaving group. C ¹ OR ¹ represents a carboxyl group which may be protected: a compound represented by! Or a salt thereof and a general formula [In the formula, R represents an optionally substituted hydrocarbon group or a 3- to 8-membered heterocyclic group: reacting with a compound represented by! Or a salt thereof, and subjecting the compound to a deprotecting group reaction if necessary. General-expression -R characterized by the following:

[The symbols in the formula are as defined above] or a method for producing a salt thereof. (3 General formula

[In the formula, X is a lower alkylene group or a lower alkenylene group which may have a hydroxyl group, and (1) a lower alkyl group (2) a cycloalkyl group having 3 to 8 (3 :) lower alkenyl groups; group) Ryoriichirumoto the [5) Araruki group or ^{(6) 3} to ^8-membered heterocyclic group, or a partial structural formula, YS 0 ₂ OMPI —X— is the formula CH ₂ where X and Y combine S0 ₂ ( ^CH 2

(Wherein is an integer of 0 to 3, m and π are each an integer of 0 to 6, and the sum of m and n is 2 to 6), and ϋ is Shows good hydrocarbon groups or 3- to 8-membered heterocyclic groups: An antibacterial composition comprising the compound represented by the formula: or a salt thereof.