WO1983002614A1 - 5,6-cis-carbapenem-3-carboxylic acid derivatives and process for their preparation - Google Patents

Abstract

Derivatives of 5,6-cis-carbapenem-3-carboxylic acid represented by the following general formula: $ (8,) $ (where R1 represents a hydrocarbyl group or a heterocyclic group, R2 represents a hydrogen atom or a hydroxyl protecting group and n represents 0, 1 or 2, provided that when R1 represents an acetamidoethyl group or an acetamidoethenyl group and R2 represents a hydrogen atom or a sulphonic acid group, n is equal to 2), or their salts, and process for preparing the compounds (I) illustrated by the following diagram: $ (8,) $ (where R3 represents a hydrogen atom or a carboxyl protecting group, X represents an eliminable group, and the other symbols are identical to those defined above). The compounds (I) have excellent antibacterial and beta-lactamase inhibiting effects, and are used as medicaments for humans and domestic animals.

Description

 Details

5, 6— ^ Sulfuric acid Lubabenemu 3-Sulfuric acid derivative and its production method

 TECHNICAL FIELD The present invention relates to a novel 5,6-cis-force babenemu 3-force boric acid derivative having excellent antibacterial activity and 3-ratatamase inhibitory activity, and a method for producing the same.

Background technology

 A vanem compound having a basic skeleton represented by, a compound having a 1-hydroxyl-methyl group at the 6-position and a cis configuration at the 5 and 6-positions is a natural compound. It was found to have a strong antibacterial activity and a strong ^ -lactamase inhibitory activity (for example, Japanese Patent Application Laid-Open Nos. 55-104296 and 56-54996).

However, the 2-position substituent of such a compound which has a 1-hydroxy-1-methylethyl group at the 6-position and has a cis configuration at the 5 and 6-positions found in nature is very limited. Therefore, there has been a demand for the development of compounds having various substituents at the 2-position along with a stereoselective and general synthesis method of these natural compounds. However, according to the systematic nomenclature, the basic skeleton of the above-mentioned force-bavenem compounds should be referred to as 7-year-old oxo-1-azabicyclo [3,2,0] buta-2-ene.

 O FI

, V / IPO For the sake of simplicity, except for the experimental part, it shall be named “Rikibabenem” as described above, which is derived from Benam, which is widely used in ba-sylin chemistry.

 Disclosure of the invention

The present invention has a 1-methyl group which may be substituted with an optionally protected hydroxyl group at the 6-position of the above-mentioned vanem skeleton, and the cis-configuration at the 5 and 6-positions. New 新 規 formula

[In the formula, R ¹ represents a hydrocarbon group or a heterocyclic group, R ² represents a hydrogen atom or a hydroxyl-protecting group, and n represents 0, 1 or 2. However, R ¹ is an acetamido or acetamido-ete group and represents a hydrogen atom or a sulfonic acid group, and n represents 2. This relates to 5, 6-potassium vanem-3-potassium acid derivatives represented by :), pharmacologically acceptable salts thereof, and methods for producing these.

The present inventors have conducted various studies and found that the formula

[Wherein, R ² has the same meaning as described above, R ³ represents a hydrogen atom or a carboxy protecting group, and X represents a deprotecting group. ¾ or a salt thereof and a compound represented by the formula

R ¹ S (0) _n H (Ϊ)

[The symbols in the formula are as defined above]

5 [The symbols in the formula the same meanings as defined] represented by 6 - cis one Karupapene beam - ₃ - that carboxylic acid窸導compound or a salt thereof can be obtained in a high yield, resulting et al formula (I ) Were found to have excellent antibacterial activity and ^ -lactamase a harmful effect, and based on these, the present invention was completed. That is, the present invention

 (1) 5, 6-cis on the other hand Babenemu 3-carbonic acid derivative (I) or its

 (2) 5, 6-cis-l-bavanem-13-force boric acid derivative (ID or its derivative) characterized by reacting compound (I) or a salt thereof with compound (I)

 About.

In the above formula, the hydrocarbon group represented by R ^1, for example A key, 5 / Croix key, alkenyl-le, Shikuroa Quai Two, alkynyl, § Lee, § la key group or the like is used. Here, the alk is preferably a linear or branched lower alk having 1 to 6 carbon atoms. Examples thereof include meth, eth, n-butyl, isobrovi, n-butyl, isobutyl and sec. —Buchi A \ tert-Buchi, n-pliers, isobench, n-hexyl, isohexyl, etc. are used. As the cycloalkyl, those having 3 to 8 carbon atoms are preferable, and for example, ^ cloprobi, cyclobutyl, cyclobench, cyclohexyl, cyclohepty, adamantyl and the like are used. As the case, a straight chain or a lower case having 2 to 6 carbon atoms of a chain is preferred, such as bi-, aryl and isobutene.

(ΟΜΡΙ -, 2-metallic, 2-butenyl, 3-butenyl, etc. are used. Examples of the aki- ^ include straight-chain or branched lower alkyls having 2 to 6 carbon atoms, such as ethyl-; u, 1-brovinii, 2-brobi-

¾ is used. Examples of 1-cyclobromo-, 1-cyclobutene, 1-cyclovente, 2-cyclopentene-3-cyclovente = ■, 1-cyclohexyl, 2-cyclohexene, 3 Those having 3 to 8 carbon atoms, such as —cyclohexyl 1 —cycloheptenyl, 1, -cyclohexadi ヱ —, etc. are preferably used, and those having 4 to 6 carbon atoms are preferred. For example, Hue, α-Naphth, β- 亍 Futi, Bib = =, and Antry are used, but Hue and Nahti are frequently used. As araki, for example, penzil, 7: enechi, Hue-provi, naphthymeth, etc. are used. Examples of the heterocyclic group represented by R ¹ include a 5- to 8-membered ring containing one to several heteroatoms such as a nitrogen atom (which may be oxidized), an oxygen atom and a yellow atom. The condensed ring or the like having a bond at a carbon atom is used. Zil, 2—, 3— or 4 bilges, N—oxide 2—, 3— or 4 bilges, 2—, 3 or 4 2 —, 3 — or 4-Tiovilla-, pyrazi-, 2-, 4-or 5-thiazoli, 2-, 4-1 or 5-Oxazoli A \ 3-, 4-or 5-Isothiazoli, 3-, 4-1 Or 5—isoxazoli, 2—, 4 1 or 5—imidazoli, 3—, 4 1 or 5—virazoli, 3 1 or 4— Biridazier, K-Issue Kisido 3 or 4-Pyridazi-, 2-, 4- or 5-Bilimidyl, N-ο 贿 _ Oxido 2-, 4-previously 5-pyrimidini, piberazini, 4-one or 5- (1,2,3-thiadiazolyl), 3-one or 5- (1,2,4-thiadiazolyl), 1,3 , 4-Asian diazoli, 1, 2, 5-thiadiazolyl, 4-or 5-(1, 2, 3-oxadiazoli), 3 1 or 5-(1, 2, 4-year old,, 1, 3, 4-) 1,2,5—one year old, 1,2,3—or 1,

2, 4—triazolyl, 1Η or 2Η—tetrazolil, pyrido [2,

3—d] birimidi, benzovira, 1,8—, 1,5—, 1,6—, 1,7—, 2,7—or 2,6—naphthyridyl, quinoli, thieno [2, 3—b] billiards are frequently used.

These hydrocarbon groups and heterocyclic groups represented by R ¹ may have one to several identical or different substituents. For example, among the carboxy group represented by R ¹ , alk, alk, and alkynole are, for example, cycloalkyl, cycloa; wk-, aryl, heterocyclic group, alkoxy group,シ, キ, ヽ, ヽ, ノ, 、, 、, バ, u, ス ル, ス ル, ス ル, ス ルSnorrejo-Sai Kishi,

-Toro, Amino, Caboxy, Amino Bonil, Alkyl, Talent, Mekabut, Akaki, Aminoaki ^ Chi, Ashamino Aki / U Chio, Araki Chit , Aryl thio, heterocyclic ring, quaternary ammonium, etc.] may be substituted. Specific examples of the substituted radical include, for example,

-C-I (CH ₂ ) _m -R ⁶

 R5

ΟΜΡΙ W [In the formula, ni represents 0, 1, 2 or 3, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an alkyl, a squiaki, an alkene, an araki, an aryl, a heterocyclic group, a Coxycarbo, oxy or oxo with R ⁴ and R ⁵ together, R ⁶ is a hydrogen atom, aki, ^ chloroaki, aryl, heterocyclic group, halogen, cyano, hydroxy, acrekoxy, Ally, Akiyoki, Power / Moi, Hydroxysnorehoni, ATV, Sulfo = / ι ^, Yuriyho, Nytro, Amino, Caboxy, Acoxica Boni, Amino Carboni, A1 Kirchi Talent Bo, Ashi, Mekabut, Aki Chio, Amino Aki Chio, Asil Amino Akio, Araki Chio, Ali Chi, Heterocyclic Chi, Fourth Indicates a class ammo. ] Etc. are also used. A cycloalkyl, a cycloalkyl, an aralkyl, an aryl, a heterocyclic group, a quaternary ammonium represented by R ¹ , or represented by the above-mentioned alkyl, alkyl, or alkyl; Examples of the substitution group include aki, avoxy, aka, a! I, Araki, Meadow, Aki Chi, Ari Chio, Araki Chi, Aki Ho, Ali Sho, Alakis V Ho, Trinoperogenoaki, Hydroki ,,,,,,,,,,,,,,,,,,,,,, Or Diaminoaminoalkyl is used. Here, the alkoxy is preferably a linear or branched lower alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy and n-bromo. Xy, isopropoxy *, 11-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n, benchoxy, isopentoxy, nf ΟΜΡΓ For example, one can use ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ~~~~~~~~ either. As the halogen, fluorine, chlorine, bromine and iodine are used. As the quaternary ammonium group, for example, bilidium, quinolium and the like are used ^{(as the} ash group, for example, fomi, akicarbyl, arylcarbyl) , Aralkyl carboxy-A \ heterocyclic group acetyl, etc. are used, etc., and so on, for example, aceti, brovi, n-butyri, isobutyri, n-pentanoy, n-hexanoy U, 4-hydroxy.droxybenzoyl, 4-methoxybenzoyl, phenylase, 4-hydroxy5 / pueraseti, 4-methoxyphenylase, 2-thiercabo, 2-brinoreca B =, 2 —, 4 mono or 5 — thiazolyacetyl, 2 — or 3-cesium, 2 — or 3 — free, 2 — amino-4 or 5 — thiazolyl acetyl, etc. Cycloalkyl, As the ke, cyclo / ke / no, aryl, araki, and heterocyclic groups, those described above can be used.

When an amino group is present in the substituent of the hydrocarbon group or the heterocyclic group represented by R ¹ , the amino group may be substituted or protected, and when an amino group is present, these amino groups may be substituted or protected. May also be protected. Examples of the substituent of the amino group include ash, alkyl, hydroxyaky, aranolekyl, aryy, heterocyclic group, amidino group, amimethylene group, carbamoy group, sulphonic acid group, axinolephony, Laxonil, Aryls Noleh, Akoxyka / 1, Aralkil Kishikaburu, Aryak Kishika Norepo / Tokyo, etc. are used here (Ashi, Achill, Akoxy, The aryl / V-kill, aryl, and heterocyclic groups are as described above). The amino group, together with the ¾ substituent, For example, a cyclic amino group such as pyrrolidino, biperidino, moholino, and biverazino may be formed. As the protecting group for the amino group, those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed. For example, aromatic ash groups such as phthaloy, ρ-trobenzoyl, ρ-ter-butylbenzene, p-tert-butylbenzenesho- \ benzeneshonii, toenshenho, etc., for example, homi, acechi, Aliphatic groups such as brobi, nochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfone, ethaneshoni, trifluoroacetic, male, succinic, etc., for example, methoxycarbonyl, ethoxycarbonyl Two A \ t—Butoxyka Boni, Isobrofo. Xicarbo-, 2-cyanoethoxyka-\ 2,2,2-trik Τ3 mouth ethoxyka-, 2-trimethysilethoxykaboni, Benzoxykaboni, 2-methylsho-ethoxykabo, ρ-Nitro. PENJI KIKABONI /, τ-METHOD ベ ン BENZY オ OKIBO ボ, DIPHENYLMETHOXYCABONI, METHOXIMETHOXAVOBO, ACETIMETHOXYCABONYL, ISOVOL OXOKABO, FEFOXYcarbonyl, etc. The ester group is an amino group such as a trioxy, 2-nitrophenothio, pendylidene, 412 trobenzylidene, or triquinolesili, benzyl, ρ-trobenzy, etc. The protecting group is used. The choice of the protecting group is not particularly limited in the present invention. As the protecting group for the carboxy group, 3-latatam and all those which can be used as the protecting group for the ordinary carboxylic group in the field of organic chemistry can be used. For example, methyl, ethyl, η-blobi, isobrovir , Tert-buty, erami, benji, p --- trovenge Nore, 0-Nitrobenzil, p-Methoxybenzyl, Penzhydryl, Fenasil, Phenyl, p-Nitrofufenii; V, Methoxymethoxy, Ethoxymethyl, Benzi-methyloxymethyl, Acetethoxymethi, Vivaloyl 2,2-methyl-2-methyl-methyl, 2-methyl-2-methyl-methyl, methylthiomethyl, tri-methyl, 2,2,2—trichloro-ethyl, 2-hydroxy-methyl, tri-methyl-ethyl, dimethyl, Acetylmethi AP —-trobenzylmethi, p-mesibenzoylmethi, phthalimidmethyl, buzi-bioximeti, 1,1-dimethylbrobi, 3-methi 1-3bibute-, sakunimimidome, 3,5-di tert-butyl 4-hydroxybenzene, methyl, benzenesulfo-methyl, phenylthiomethy, dimethyaminoethyl, bi Gin 11-year-old cysidoid 2 —Methyl, methyl meth-methyl, bis (p-methoxy-methyl), 2—ester residues such as cyano-1,1 dimethyl, silyl group, etc. are used Furthermore, as the protecting group for the hydroxyl group, any one which can be used as a protecting group for a hydroxyl group in the field of 3-lactam and organic chemistry can be used, for example, acetyl, chloroacetyl and other ester residues, 2, 2, and 2 — trichloroethoxycarbonyl, 2-trimethylsiloxydoxycabonyl esterified carboxyl residue, tert — butyl, penzyl, p — — trobenzyl, tririch, methoxymethyl Ae V residue, trimethytri, tert-butydimethysil, etc. silylete residue, 2 — tetrahydrovira , 4-Methoxy-4-tetrahydrobib-acetate residue, sulfonic acid group, etc. In the present invention, the selection of the protecting group is based on the amino group and the carboxy group. Similarly, there is no particular limitation. In the above formula, R ² represents a hydrogen atom or a hydroxyl-protecting group. As the hydroxyl-protecting group represented by R ² , for example, those described above and the like are used. For example, protective groups that form an ether bond, such as, for example, -methoxyethoxymethy, methoxime, and methylthiomethy ^ groups, are frequently used.

In the above formula, R ³ represents a hydrogen atom or a carboxyl protecting group.

As the protecting group for the carboxy group represented by R ³ , for example, those described above and the like are used. For example, p-trovenge, 0-trobenzil, p-methoxybenzide, etc. are commonly used.

In the above formula (ί), the leaving group represented by X includes:

n is the same as defined above). For example, 1-toluenesulfoxy, p-nitropheny; 1 / sulfonic-5, p-bromophenoxy, methanesulfonyl, halogen, such as substituted sulfonoxy, chloro, bromo, etc. For example, a disubstituted phosphoroxy group such as diphenylphosphoroxy group and jetiphosphoryloxy group may be used.

 In the above formula, 11 represents 0, 1 or 2.

When the carboxyl group at the 3-position or the carboxyl group is contained in R ¹ , the compound of interest (I) may be used as it is, but may be used as it is, but by a method known per se. It can be used in the form of an acceptable salt. For example, non-toxic cations such as sodium and potassium, for example, aginine, o; basic amino acids such as tin, lysine, histidine, etc., for example, N-methyldalcamin, diethanamine, triethanolamine And trishydroxymethyaminomethane may be used by forming ¾ with any of the hydroxyhydroxyamines. Also, it contains a basic group in R ¹

(ο:, ί? ι ヽ

― In some cases, salts with organic acids such as, for example, sulfuric acid, tartaric acid, and methanesulfonic acid, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, for example, agine, It may be used by forming salts with acidic amino acids such as aspartic acid and glutamic acid.

 The compound (I) of the present invention may exist in a racemic form (dl form) as in the case of the starting compound (I), and the racemic form is also included in the present invention. It can be used as a drug as a racemate as it is, or as a racemate, separated into i-form or one-body.

 Specific examples of the purpose (I) include a compound represented by the following formula.

目的物の 5 , 6 —シス—カ バーベネム化合物（ I )またはその塩は、 種々のグラム一陽性及びグラム—陰性細菌に対して活性な価攛ある抗生 物質であ]?、 人及び家畜の医薬として利用され、 と わけグラム -陽性 またはグラム -陰性細菌例えばスタブィロコッカス · ォ一レウス、 ェシ エリ ヒア . コリー、 タ レブジーラ · ブノィモ -ー¾どによって引起され る感染を処理する抗菌剤として安全に使用される。 本凳明の抗菌剤は、 更に、 例えば飼料を防腐するために殺菌剤として動物供袷飼料に添加さ れる。 例えば、 医科及び歯科装置上の有害 *細菌の生長を破かい及び阻 止するために及び工業用例えば水を基にしたペイント及びベーバーミ

The desired 5, 6-cis-cabervenem compound (I) or a salt thereof is a valuable antibiotic that is active against various Gram-positive and Gram-negative bacteria. It is used as an antimicrobial agent to treat infections caused by Gram-positive or Gram-negative bacteria, such as Stabilococcus oleus, Escherichia coli, Tarebzyra bunoymo, etc. Used safely. The antimicrobial agent of the present invention is further added to animal feed as a fungicide, for example, to preserve the feed. For example, to destroy and inhibit the growth of harmful * bacteria on medical and dental equipment and for industrial use, e.g. water-based paint and

(OMPI · As a germicide to stop the growth of harmful bacteria in white water of a million mils of solution! ) Antibiotics 0.1 to: Can be used in aqueous compositions at concentrations in the range of L00 parts.

 Object of the Invention ^ (I) or a salt thereof can be used alone or in combination with other active ingredients in any of various pharmaceutical preparations, for example, kabse, tablet, powder or solution , Suspensions or elixirs. They can be administered intravenously, intravenously or intramuscularly.

 Tablets for oral administration may contain conventional forms such as binders such as sylob, arabian gum, gelatin, sorbitol, tragacanth or bolibi

-Pyrrolidone, fillers such as lactose, sugars, corn starch, calcium phosphate, sovito or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato flour or nato It may contain a wetting agent that can be used, such as lithium lauryl sulfate. The drug can be coated by a method well known in the art. Oral liquid preparations can be water or oily suspensions, solutions, emulsions, water, oils, elixirs or any dry product which can be in any color or dissolved in water or other suitable solvent before use. Good.

 ¾ Liquid preparations include suspending agents such as sorbitol, methyl sesame, glucose, sugar syrup, gelatin, hydroxyxethyl cellulose, caboximethic rose, aremi stearylate: = ■ ゥMuddy or hydrogenated edible oils containing almond oil, fractionated coconut oil, oily broth, brovirene glycol or ethanol, preservatives such as methyl or brovi-p—hydroxybenzoate or sorbic acid You can also have. Suppositories are common suppository substrates such as cocoa 'putter

(O FI ヽ Or other glycerides can be used.

 Injectable compositions may be presented in unit use form in a container supplemented with an ampoule or preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous solvents, and auxiliary agents such as suspending, stabilizing and / or dispersing agents. It may be appropriately contained. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-containing water, before use.

 It can also be formulated in any suitable form that is absorbed by the mucous membranes or bronchial tissue of the nose and throat, such as powder, liquid spray or inhalant, rosein, and throat paint. For pharmaceutical administration to the eye or ear, it may be used as a liquid or semi-solid capsule or as a drop. Further, a softening agent, cream, lotion, bint, powder or the like may be used as an external preparation using a hydrophobic or hydrophilic base.

 In addition to the carrier, other components such as a stabilizer, a binder, an antioxidant, a preservative, a lubricant, a suspending agent, a thickener or a flavoring agent may be contained. In addition, the composition may contain other active ingredients.] 3 It can also provide a broader antibacterial activity.

 For livestock, it may be formulated as a long acting or rapidly releasing intra-mammary preparation in the base.

 The compound ^ (I) of the present invention can be used as a therapeutic agent for bacterial infection, for example, in mammals, such as respiratory tract infection, urinary tract infection, purulent disease, biliary tract infection, intestinal infection,

¾ ^ Can be used for treatment of gynecological and surgical infections. The daily dosage depends on the condition of the breather and the weight of the host being treated, the mode and frequency of administration, the parenteral route suitable for common infections and the oral route for intestinal infections. In general, the daily consumption of 1) is 1 day l or more? In one or more applications, the patient's body weight l kg per kg of active ingredient is from about 15 to 60. The preferred daily dose for adult humans is about 10 to about 200 ^^ as the active ingredient! ?, Divided into 2 to 4 times each day, and inject a small amount of about 2.5 to about 10 once

5 It is appropriate to give.

 The composition comprising compound (I) can be administered in solid or liquid oral form, for example, in several unit dosage forms. The compositions in liquid or solid unit use contain from 0.5 to 99% of the active substance. A preferred range is about 10-60%. The composition contains about 15 to 150 active ingredients at a minimum. However, it is generally preferred to use a dosage in the range of about 250 to: I 00.

 The compound (I) of the present invention or the clay thereof has a β-lactamase a harmful effect in addition to the above-mentioned uses, and thus may be used in combination with a ^ 1actam antibiotic. Examples of 3-pactam antibiotics include, for example, benzylpenicillin, phenoxymethinolepeniline, carberin, ambiline, amoxicillin, and all Lin All ■ -silin antibiotics include, for example, cephalolysin, cephalotin, cephazolin, cevarex 5 / n, cefoxitin, cefacetry, cefamand, cefmenokim, cefsulodin, cef-tiam, cef-tish Cephalosbolin antibiotics such as taxime, cefavirin, ceftizokim, cefradine, and cephaloglysin can be used.

 5,6-cis-force pavenem 3-force of the object of the present application The boronic acid derivative (I) or its ¾ can be produced by expanding the compound (I) or its 氇 with the compound (Ϊ).

As the salt of the compound (I), those as described for the salt of the above (I) can be used. Can be. The compound (II) may be used as it is, but it does not participate in the reaction. For example, lithium, sodium, and potassium. The reaction may be carried out as an earth metal salt. 1 to 10 moles, preferably 1 to 5 moles of compound (I) or a salt thereof is reacted with 1 mole of compound (1) or a salt thereof. Usually, the reaction is performed in a solvent. Solvents include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, tris such as acetonitrile, ethers such as dimethyl ethane and tetrahydrobran, dimethylformamide, dimethyl sulfoxide and the like. And hexamethylphosphoramide are preferably used. The addition of a base favors the reaction. Such bases include, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, Diisobrovirethylamine and viridin rudo are preferred. Further, instead of using a base in this reaction, the compound (summer) is converted to an alkali metal ^, an alkaline earth metal salt or the like as described above, and converted to a compound (I) or a salt thereof. You may make it react. The amount of the group to be used depends on the type of the compound (I), (I :) and the solvent used, and other reaction conditions]. Preferably it is 1 to 5 m. The reaction temperature is in the range of 150 to 40 !, preferably 130 t; The reaction time varies depending on the kind of the compound (I) or a salt thereof, the kind of the compound (I) or its kind, the reaction temperature and the like, but is 1 to 72 hours, preferably 1 to 24 hours. The obtained target compound (I) can be isolated and purified by a method known per se, for example, digestion, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography: 5 or the like. .

(_ CI FI For example, an organic solvent that is not mixed with water, such as ethyl acetate, and water are added to the reaction mixture, the organic solvent layer is separated, washed with water, dried with a desiccant, and then evaporated to remove the solvent. be able to. The compound (ί) thus obtained can be further purified, if necessary, by a conventional method such as preparative thin-layer chromatography, column chromatography, and recrystallization.

When the object (I) thus obtained has a protecting group, the protecting group can be removed if necessary. As a method for removing the protecting group, a method using an acid, a method using a hydroxyl group, a method using hydrazine, a method using reduction, an imino halogenating agent, and then an imino etherifying agent are used, depending on the type of the protecting group. After that, if necessary, a conventional method such as a hydrolysis method can be appropriately selected and carried out. Here, in the case of the method using an acid, the acid varies depending on the type of the protecting group and other conditions. Acidic ion-exchange resins and the like are used in addition to organic acids such as fonic acid and ρ-entosphone test. In the case of the method using a base, the base may be, for example, an alkali metal such as sodium or potassium or a hydroxide of an alkaline earth metal such as potassium or magnesium, depending on the type of the protecting group and other conditions. In addition to inorganic bases such as carbonates, metal oxides, organic amines, and organic groups such as quaternary ammonia, basic ion exchange resins are used. When a solvent is used in the above method using an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used. In the case of the reduction method, it depends on the type of the protecting group and other conditions.) For example, metals such as tin and zinc or metal compounds such as chromium dichloride and chromium oxide, and sulfuric acid and boron Organic such as acid and hydrochloric acid And an acid such as an inorganic acid, and a method of reducing in the presence of a metal catalyst for corrosion reduction. Platinum catalysts such as platinum sponge, platinum black, platinum oxide, and colloidal platinum; palladium oxide, palladium oxide, palladium sulfate, palladium carbonate, palladium carbonate, palladium carbonate, palladium palladium, palladium palladium, palladium palladium, etc. Catalysts, reduced nickel, nickel oxide, Raney-nicke, Urushibara-nickel, and the like. The iron in the case of the reduction process by metallic and黢, inorganic acids Yobigisan such as a metal compound饬and hydrochloric acid such as chromium,醉酸, the method according _ό reduction organic acids such Burobion acid used is usually a solvent For example, in the case of the method by catalytic reduction, alcohols such as methanol, ethanol, * robby alcohol, isobrovir alcohol, etc., and ethyl acetate are frequently used. In the method using a metal and an acid, water, acetone, and the like are commonly used. However, when the drum is a liquid, the acid itself can be used as a solvent. The reaction temperature in the method using an acid, the method using a base, and the method using a reduction is usually about the same as heating under cooling. Also, by reacting with an iminono, a logenizing agent and then an iminoatelating agent, and then hydrolyzing as necessary]. As an imino halogenating agent used in the method of removing a protecting group, For example, phosphorus trichloride, pentachloride, tribromide, thiocyanate, thionyl chloride, phosgene and the like are used. Although the reaction temperature is not particularly limited, it is usually carried out usually at room temperature or under cooling. As the iminoetherating agent used for the reaction product thus obtained, alcohols or metal alkoxides are used. As alcohols, methanol, ethanol, brovanol, isobrono "phenol, and η-butanol are used. First, akanos such as tert-butanol or the like, or their alkyl moieties are methoxy, ethoxy, Compounds substituted with an alkoxy group such as propoxy, isobroboxy, butoxy, etc. are used. Examples of the metal alkoxides include the above-mentioned alcohols such as sodium oxalate and sodium oxalate derived from alcohol. Alkaline earth metal aquoxides such as metal alkoxides, calcium alkoxides, and barium alkoxides are used. In addition, for example, the protecting group is a residue of an organic carboxylic acid.]) A free amino group, a hydroxy group, a carboxy group, a carboxyl group, a sulfone When there is a substituent such as an acid group, a treatment for further increasing the effect of the adjacent group of these groups to increase the reactivity of the power ball group and remove the protective group to obtain a favorable result is advantageous. It is. As an example of such a case, for example, when the group on the carbon adjacent to the carbonyl group described above is a free amino group, the free amino group is converted into a thiolide group and then removed. A method of removing a protecting group by applying a known method used for a method of decomposing a tide bond may be used. The degree of reaction of this reaction is not particularly limited, and is appropriately selected depending on the kind of the protecting group, the kind of the elimination method, and the like. It is preferable that the reaction is carried out under cooling or moderate heating.

 Specifically, in the case where the protective group for the carboxyl group in the target product (I) is a halogenoaki group, an aralkyl group or a benzhydryl group, it can be achieved by contacting with a reducing agent. As the reducing agent used in this reaction, when the protecting group of the carboxyl group is a halogenoaki group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl, for example, zinc and sulfuric acid are used. Hydrogen and platinum oxide, platinum black, platinum sponge, palladium-carbon, palladium, when the protecting group is, for example, an aralkyl group or a benzhydryl group, such as benzyl, p-nitrobenzene.

_ CMPI _ Preferred is a catalytic reduction catalyst such as mu-black, barium palladium barium monosulfate, barium barium monocarbonate, reduction-nicke, Raney nickel, Urushibara-nickel, or metal sulfide such as sodium sulfide or lithium sulfide. It is. In addition, in the case of 0--trobenzy group, removal by light irradiation can be performed by electrolytic reduction in the case of p-methoxybenzene group. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it is involved in the reaction. However, alcohols such as methanol, ethanol, tetrahydrofuran and dioxane can be used. Preferred are ethers, fatty acids such as severe acids, and mixed solvents of these organic solvents and water. The reaction temperature is usually from about 40 to about ^β , and the reaction time is usually from 5 minutes to 12 hours, depending on the type of the raw material compound and the base agent. In addition, the protecting group of the amino group in the target product (I) is, for example, “!!” pr benzyl group, 0-nitrobenzene group; i group, p-group. In the case of a methoxybenzoxycarbonyl group or a benzyloxycarbonyl group, it is removed by the above-mentioned protective group removal reaction of the carboxyl group, and the hydroxyl-protecting group for the purpose (I) is acetoxyl group. In the case of a lower aliphatic hydroxy group as in the following, it can be removed by treating with an aqueous solvent in the presence of the group. Although not particularly limited, water or a mixed solvent of water and alcohols such as methanol and ethanol, or ethers such as tetrahydrofuran and dioxane, and any organic solvent is preferable. ¾ ¾ group The reaction is not particularly limited as long as it does not affect the ring, but is performed using, for example, sodium metal carbonate such as sodium carbonate and potassium carbonate, etc. The reaction temperature is 0 or room temperature. The reaction time depends on the type of starting compound. It is usually 1 to 6 hours, depending on the reaction temperature and the reaction temperature. In addition, when a trialkyl tertiary alkyl group such as tert-butyl dimethylsilyl is used as a protective group for a hydroxyl group, for example, a fluorine ion such as tetrabutylammonium fluoride or fluorinated lithium is used. By processing]? Is removed. As the solvent to be used, ethers such as tetrahydrofuran and dioxane are suitable. The reaction is carried out at around room temperature for 10 to 18 hours.

In the removal reaction of the protecting group, when R ¹ is a group having a carboxy group, the derivative in the carboxylic group may be converted to a carboxy group, but this case is of course within the scope of the present invention. Included.

 The thus-obtained compound (I) from which the protecting group has been eliminated can be converted to a desired salt by a conventional method.

Since the compound (I) has a carboxy group and a carboxyl group, it can act on a base to form a salt. Therefore, the chemical compound (I) may be collected as water.] What is obtained as salt may be used as a salt or Ttfe salt. Further, the compound (I) obtained in the unfriendly form may be referred to as ¾. As a method for freeing compound (I), which can be obtained as ¾, for example, a method using an acid or the like is used. The acid used varies depending on the type of the protecting group and other conditions, but examples of the acid include inorganic acids such as sulfuric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, sulfuric acid, and p-toensone Ay. Acid is frequently used. 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 is often used. This method is generally performed at room temperature, but may be performed with cooling or heating. The reaction time depends on the temperature, type of solvent and temperature, Generally, it is preferable to finish in a single hour. The resulting free compound (I) can be isolated by known means as described above.

When the thus desired product obtained (I) has a § amino group liberated in the substituent represented by R ^1, the Amino group § Mi de, Urei de, amidino, guaiacolsulfonate - converted to Gino group In the case of having a hydroxyl group, the hydroxyl group can be converted to an phenyloxy group, a halogen atom, or an azide group, and when n is 0 or 1, a sulfur atom can be oxidized. You can also.

The reaction for converting an amino group to an amide group, a perido group, an amidino group or a guadino group can be achieved by various known methods. The conversion reaction to the amide group can be abrupt by contacting the amide with the acylating agent under a solvent. The solvent to be used is not particularly limited, but is preferably a chlorinated hydrocarbon such as chloroform and methylene chloride, and ethers such as tetrahydrofuran and dioxane. The acylating agent to be used is not particularly limited as long as it can convert a normal amino compound, but fatty acids such as anhydrous anhydride and brobion anhydride, fatty acid anhydride ^., Acetyl chloride, brobio -Examples include fatty acid halide derivatives such as lucid chloride, n-butylidyl bromide, isoptilidid chloride, and methoxalyl chloride. The reaction is preferably carried out in the presence of a base, and the group used is preferably an organic base such as tritamine or pyridine or a fatty acid argari metal such as sodium or potassium phosphate. . The reaction temperature is not particularly limited, but is preferably around 0 "^ 40 ^β . The time required for the reaction varies depending on the type of the acylating agent and the reaction temperature, but is usually from 0.5. (5 hours) ゥ The conversion reaction to a laid group is carried out in the presence of a solvent, a substituted isocyanate,

Oi.:FI It is carried out by reacting substituted isothiocyanates. Examples of the substituted isocyanate include methyl isocyanate, ethyl isocyanate, phenyl isocyanate, and p-bromophenyl isocyanate. For example, methisothiocyanate, phenylthioisothiocyanate and the like can be used. The reaction temperature is around 0 to 40, and the reaction time is usually 0.5 to 5 hours. The conversion to an amidino group is carried out by reacting with dioxane, THF, DMF-chloroform, acetone, acetate, or a solvent such as imidoesters. Examples of imid esthetics include, but are not limited to, methyl imidate, methyl imidate, methyl vacimidate, meth; vaimidate, methubuenylase imidate, meth N-formimidate, methN —Ethyl imimidate, meth N′-isopropionate; u imimidate can be used. The reaction temperature is from 0 to 25 !, and the reaction time is usually 1 to 6 hours. The conversion to the gua-dino group can be carried out in water, dimethylformamide, hexamethylenephosphoramide, in any solvent, such as 0-alk or 0-arylbusoidurea, or S-aki or S-arypsoidurea. It is performed by reacting it with a kind. Pseudoureas include: 0-methidoid urea, S-methylpseudourea, 0-2,4-dichlorophenipseudourea, S-ρ-two-port buenibuside thiourea, 0-, -trimethybusoidurea, etc. Can be used. The reaction temperature is from 0 ° to around 40, and the reaction time is usually from 1 to 24 hours. The compound (I) thus obtained can be isolated and purified by a method known per se.

The reaction that converts a hydroxyl group to an acyloxy group, a halogen atom, or an azide group This can be achieved by various known methods. The conversion reaction to an amino group can be carried out in the same manner as the above-mentioned reaction for converting an amino group to an amide group. Conversion to a halogen atom is achieved by hapgenization according to a conventional method. Halogenating agents used include, for example, thiol chloride, thiocyanate bromide, oxalic chloride, carbon tetrachloride-triphenyl-phosphine, carbon tetrabromide triphenyl phosphite. Are used. Suitable solvents used are, for example, ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene and toluene. The reaction temperature is preferably 0 to room temperature, and the reaction time is usually 15 minutes to 5 hours. The conversion reaction to an azide group can be achieved by reacting with a hydrogen azidide or azide diphenylate in the presence of a phos: 7-in derivative and a diester of azodicarbonate. As the phosphine derivative to be used, for example, triphenylphosphine and tri-II-dithiophosphine are preferable.], And as the azodicarboxylic acid diester, for example, azodicarbonic acid dimethyl ester, azodicarboxylic acid boronic acid ester, etc. Is used. As the solvent to be used, for example, halogenated hydrocarbons such as methylene dioxide and chloroform, and ethers such as tetrahydrofuran and dioxane are preferable. The reaction temperature is preferably 0 t! 60, and the reaction time is preferably 5 minutes to 5 hours. The compound (I) thus obtained can be isolated and purified by a method known per se.

 The oxidation reaction of the sulfur atom can be performed by a method known per se. For example, a mild oxidizing agent that acts substantially on the bones of bones, such as perbenzoic acid, ozone, and phen-dichloroi; dyed, hydrogen peroxide, sodium meta-peroxide, Performed using sodium hypochlorite

O iFI _ " It is. In particular, for example, perbenzoic acid, m-chloroperbenzoic acid and the like are suitable. In general, when one equivalent is used for the compound (I) (n = 0), su-foxide ( _n = 1) is obtained, and when two or more equivalents are used, su-fon ( n-2) is obtained. The reaction is usually carried out in an inert solvent such as dichloromethane, chloroform, carbon tetrade, or the like, at a temperature of about 130 to 25, while the reaction for sulfoxide is about 3 minutes to 3 hours, about 1 to 9 hours for sulfone. The S-purified product can be isolated and purified by various known methods. However, in the case of sulfoxide, two diastereomeric variants having different S-0 bonds are generated. There is. These isomers can be separated by known methods such as column chromatography and recrystallization.

 The compound (Ϊ :) in the present application can be manufactured, for example, by the following method or a method similar thereto.

. ? I-, '

Wherein R ² and R ³ are as defined above, R ⁷ is a protecting group for a hydrogen atom or an amide group, R ⁸ is a protecting group for a hydrogen atom or a hydroxyl group, or R ⁷ and R ⁸ are And R ⁹ represents a hydrocarbon group or a heterocyclic group, and R ⁹ represents a hydrocarbon group or a heterocyclic group. ]

ΟϊνίΡΙ According to the above scheme, the starting material is 4- (2-hydroxyhexyl) azetidine-1-one (BJ, Christensen, et al., Jana Seibu Organic Chemistry), which is known as a starting material. Cliemistry), the 45 vol, if Shirukere even interfere with the following reaction with 1130 (1980 :) amide group compounds and Korisanmoto is protected (V :) is use. protecting group R ⁷ There are no restrictions on the choice, for example, trimethinoresilyl, t-butyl; dimethinoresilinole, any organosilyl group or cyclic ethers such as 2-tetrahydrovira!]? R ⁷ and R ⁸ are

~ 0.

 RIO Rll

 CXVD

[Wherein, ¹⁰ and R ¹¹ are the same or different and each represents a zR elementary group]

しては、 前記 R¹ で述べた ごときものが用いられ、 と J?わけたとえばメチル，ェチ ，ィソプロピ ル基のよう 低級アルキ 基、 さらに E¹⁰と R¹¹が炭素数 3 - 6個のァ キレン基で結合しているものが繁用されてもよい。 のうち R¹⁰ および R¹¹が共にメチ 基の化合物はすでに文献上記載されてお]) (ビ 一 . ジー . ク リステンセンら ， ジャーナル ォブ オーガニック ケミ ス ト リ ー ， 45巻， 1130頁（ 1980年） , 4一（ 2 -ヒ ドロキ シェチル )ァゼチジン一 2 -オンと 2 , 2 -ジメ トキシプロパンとを三 フッ化ホウ素ェ—テラート ， ρ—トノレエンスノレホン酸 どのよう 酸触 媒？？在下に反応させて得られる。 他の（χν は上記反応で 2 ， 2 -ジメ トキシプロノ ンの代])に、 ケト ン類（ ジェチ ケト ン ， メチノレエチ T ケ ト ン ， ジィ ソプロ ピノレケ ト ン ， シク ロフ"ロノ"？ノ ン ， シクロブタノ ン ， シ クロべンタ ノ ン ， シク ロへキサノ ン ど を用いることによって容易に 得られる。 Can be combined at the same time. R ¹⁰ ,

Is then the ones such as described for R ¹ is used, the J divided for example methyl, E Ji, lower alkyl groups as Isopuropi group, further E ¹⁰ and R ¹¹ is 3 carbon atoms -? 6 § Those linked by a kylene group may be used frequently. Among them, compounds in which both R ¹⁰ and R ¹¹ are methyl groups have already been described in the literature]) (B. G. Christensen et al., Journal of Organic Chemistry, 45, 1130 (1980)). ), 4- (2-hydroxyshethyl) azetidin-l-one and 2,2-dimethoxypropane are combined with boron trifluoride etherate, ρ-tonoreensnolefonic acid What is the acid catalyst? Other (χν is 2,2-dimethoxyprononone in the above reaction)) and ketones (jetiketon, methinoleet T ketone) Tonson, Gysopropynolekton, Siklov “Rono”? It can be easily obtained by using nonon, cyclobutanone, cyclopentanone, cyclohexanone and the like.

 It is preferred to use (XVU) in the following reactions.

 The first step is to obtain (VI by sulfating the 3-position of V) VI

In carrying out the reaction of this step, (V) 1 to 3 moles of lithium diisopropylamide, lithium isopropylinole hex / reamine, sodium amide, hydrogen amide, hydrogen Chemistry REAME What is a tetrahydrofuran (THF, dimethoxetane 'atenore, dimethinolehonolemamide, dimethinoresulfoxide (DMS0)) in the presence of a strong ¾ group Reaction with 1 mol of sulfenolating agent at a temperature from C to 0 ° C gives (VI. Examples of the sulfenolating agent include compounds of formula (H ⁹ s ₂ )

The formula R ⁹ S- _{S_〇?.} Cormorant replacement Chisaisu Hone of R ⁹

Equation E ⁹ S—like Ν or R ⁹ S-N

N-substituted thiomes can be used (wherein E ⁹ is as defined above)

¾¾ J ο

As R ⁹ , a hydrocarbon group or a heterocyclic group as described in the above Bi can be used. Particularly, for example, a phenyl group, a lower alkyl group (eg, methyl, ethynole group, etc.)-Substituted phenol group, a halogeno group (Cross-mouth, bromo, etc.) Substituted phenyl group, heterocyclic group such as 2-pyridyl group, 2-benzothiazo- / re group, methyl group, ethyl group, isof group. Lower alkyl groups such as a propyl group and an n-propynole group can be commonly used. (Ή means that there are theoretically two diastereomers with respect to the 3-position substituent. — Ϋ́ ϋ—

 Isomers can be separated by column chromatography, recrystallization, or any other operation! It can be isolated and used for the next step reaction, but the mixture can be used for the next step reaction without isolation.

The second step is a step of quinolelating the 3-position of (VI) to obtain (V). Is in carrying out the reaction of this step, the same strong salt groups and were use in the first step, using a solvent ¾, - 7 8 0 from ³ C. At temperatures up to C (VI), treatment with 1 to 20 moles of ketone per monole gives (W). The conversion reaction of (V) → ί ¾) → (¾) on 1 は is (Conversion to (V) → (W in the same vessel without isolating π (labeled as 2 'process in the above figure)) In this case, using (V) the same strong base and solvent as used in the first step, the mixture is treated at a temperature of 178. C to 0 to obtain (V) 1 By adding one mole of the monophenylene-sulfonating agent to the monole, it is possible to obtain 20 moles of acetone in one mole :). (V) 2 moles to 3 moles per 1 mole are suitable, and there may be two diastereomers due to the 3-substituent in theory.In this reaction, these isomers are separated by column chromatography and re-used. It can be isolated and used for the next step reaction, but it can be used in the next step reaction without isolation as a mixture. It is possible.

 The third step is a step in which) is reduced to selectively obtain 3,4-cis-substituted azetidinones (: ¾U).

The hitting to react ¾ embodiment of the present process, the reducing agent for example chromatic ^ scan's compound, - Ggeru compounds, mercury compounds, such as zinc compounds are used, preferably expression ¾ ² S n¾ or R ¹² S n H ₃

(In the formula, R ¹² represents a hydrocarbon group.)

This is done by using an organotin compound such as The hydrocarbon group in H ¹² is I Table, those such as described for R ¹ is used, and]? Divided e.g. Mechinore, E Ji / Les, n one Puropinore, isopropylidene Honoré 'n one butyl Le, t Buchinore , N-Pentyl ruthenium, a lower alkyl group having 16 carbon atoms, for example, a phenyl group, a lower aki group (meth, ethynole group, etc.)-Substituted phenyl group can be used. More specifically, triphenyl-tin hydride, tri-n-butynoles hydride, diphenyl-tin hydride, di-n-butyltin hydride, triethyltin hydride, trimethyltin hydride, hydrogen Although n-butyltin chloride can be used, for example, triphenyltin hydride and tri-η-butyltin hydride are preferred. The reducing agent is usually used in an amount of 1 mole to 10 moles, preferably 1.2 to 5 moles per mole. This reaction is suitably carried out in the presence of a free radical initiator such as 0.1-0.5 monosodium azobis-succinyl octyl-tolyl or di-butyric acid. Light irradiation may be performed instead of using a free radical initiator. The reaction may be carried out in a solvent which does not participate in the reaction, although the reducing agent itself may be used as a solvent. Ketones such as aceton, methylethylketone, ketones such as dioxane and tetrahydrobran, phenols, methanol, and alcohols such as ethanol, aromatics such as benzene, benzene, and xylene. Hydrocarbons and the like can be used as the solvent. The reaction temperature can usually be carried out from 0 ^ 1 3 0 ³ C, in particular 1 0 1 0 0 preferably der, in an atmosphere of inert gas such as required Ruraba nitrogen or Anoregon. The reaction time varies depending on the type of the starting compound, the reaction temperature, the amount of the reducing agent used, etc. I have time. By this reaction, the desired compound (W) having a 3,4-cis configuration can be preferentially obtained, but a small amount of a compound having a 3,4-trans configuration is produced as a by-product. Isolation of (:) from the reaction mixture is performed according to a conventional method. For example, (¾! Can be easily isolated by distilling off the solvent and subjecting the residue to recrystallization or column chromatography.

 The fourth step is to protect the newly formed hydroxyl group and obtain (K) by

As the protecting group represented by R ² , those described above are used. For example, a protecting group that forms an ether bond, such as a 9-methoxymethoxymethyl group, a methoxymethyl group and a 'methylthiomethyl group, is used. It is suitable. Of these, for example, a / 9-methoxetoxymethinole group is preferable as the protecting group of [观]. The reaction for introducing a protecting group can be achieved by a known method. For example, in the case of the above-mentioned protecting group forming an edenole bond, β → toxethoxymethyl lid, methoximethic lid, methylthiethylmethinolex Lido-like halogenated alkyl is converted to triethylamine, diisopropion / 1 / ethyflamin, pyridine, η-butyllithium, hydrogenated sodium in the presence of dichloromethane, chloroform, . carbon tetrachloride, THI ^1, ether, dimethyl Tokishietan, § Se Tonito Rinore, DMF DMS 0 which solvent, one 2 0 'Ji from 1 0 0 and ¹ gamma 2 hours at a temperature 0. [delta] of (H; and The amount of the alkylating agent and the group used depends on the type, starting compound, solvent, and reaction temperature. 2 0 moles, preferably 1 Monoreka ^ et 5 mode.

The (Κ :) obtained in this way can also be expressed as —3 '— ca ■ 3 OR 2

R ⁹ S 8

 OR

 )> 〇 N (JX

 'E

 CX)

[The symbols in the formula are as defined above.]

 It can also be obtained from (S J via (XViU. The above reaction is to protect (水 i) the water ^ group, obtain (XVtt, and reduce it with to obtain (K)).

The conversion from () to (XVU) is achieved in substantially the same way as the conversion from (¾1) to (K), and the conversion from (XVS) to (K) is the conversion from (w to :). The fifth step is the step of removing the protecting groups R ⁷ and R ⁸ of CK) to obtain (X). Removal of protecting groups ⁷ and R ⁸ ′ is accomplished by applying various known deprotection methods. For example, if (K) is a compound derived from (XVD), removal of the protecting groups It is carried out by hydrolysis in a solvent such as an aqueous acetic acid solution at a temperature of 0 ° C to 75 ° C for a reaction time of 5 minutes to 16 hours.

 The sixth step is a step of converting the hydroxyxeti group of (X) into a carboxyl group by an oxidation reaction to obtain (XI). The oxidation reaction is carried out in a solvent such as acetone, aqueous THF, aqueous dioxane, etc. from -10 ° C to 40 ° C. It can be carried out in a temperature range of C for 10 minutes to 24 hours using various known oxidation systems such as Jones reagent, potassium permanganate, silver oxide and the like. In particular, (X) acetone 10 in any solvent. It is preferable to carry out an oxidation reaction using a Jones reagent 'at a temperature of C to 30 for 10 minutes to 8 hours.

In the conversion reaction from (X) to (XI), (X is — 4r—

0-R ²丄 Ni

 (XVi), [The symbols in the parentheses are the same as above], and can also be converted to (XE) by the following: Conversion from (X) to, for example, DMS0'pyridin, ace-tri- DMS 0—anhydride, chromium anhydride 漦 -pyridine, cyclohexyl; I / cabodimide-DMS 0¾ in a solvent such as ^, dichloronorethane, etc .; Oxidation at a temperature of 3] is carried out. The conversion from (XI) obtained in this way is substantially the same as the conversion from (X) to (XE). Achieved.

(XI can also be obtained by subjecting (K) to an anonymous oxidation reaction (indicated as step 6 'in the scheme) For example, compounds in which (K) is derived from (XVI) In this case, when the oxidation reaction is carried out in a solvent at a temperature of −10 ³ C to 30 = C using a dione's reagent in a solvent for 10 minutes to 8 hours, [XI] is obtained. In this reaction, deprotected (X :) is generated in the middle, and the oxidation reaction proceeds in the next step.

The target compound (: I) of the present application is (including any one-body, ^ -body, and body).?, And the optically active (V) is used to produce the optically active (: I). However, in the case of the ^ -isomer, it is preferable to carry out the division using (XI) The division can be carried out by various known methods, for example, the crystallization method or [ has an optical activity corresponding to π, for example, fractional crystallization of diastereomeric salts formed by reaction with quinine, busine, efedrin, strychnine, monolefin, etc., chromatographic It is divided by the physical separation method by Phi et al.

 The seventh step is a step of activating the carboxy group of (XE), and then extending two carbon atoms to obtain CM ′).

 In carrying out the reaction of this step, first, (XU is dissolved in, for example, T HF or dimethoxetane in any solvent, 1 to 2 mol, for example, 1,1'-carbo-diyl in 1 mol of (XI). Midazo- or 1,1'-canolevo-bis (2-methyimidazo-A) Any reagent is reacted with O'C at 50 to give imidazolide and then without isolation of imidazolide, (XI) 1 The following formula of 1 to 3 monoles per mole

CR ³ OGOCHo COO) oMg-(XK '

[Wherein, Ε ³ is as defined above]

 The reaction is carried out by reacting with a magnesium salt of a malonic acid derivative represented by the following formula at 0, C; ^ 50 for 1 to 48 hours.

 The eighth step is a step of diazotizing (I) to obtain (XBU).

Jiazo reaction is, for example, § Seto - DOO Rinore, Jikuronoremetan, T HP ¹ Rudono such solvent, for example Application Benefits Echinorea Mi down, Jechinoreami down, in the presence of a base such as pins lysine (:. S One to two moles per mole, for example: -Reaction with any azide, such as: -Norboxoxybenzenesnorrezo-luazide, P-toluenesulfonazide, methanes-noreazide. The temperature is -10 to 40. C, the reaction time is usually 1 to 48 hours.

The ninth step is a step of removing the protecting group (H ² :) of (Xffl) to obtain (ΧΙΌ), but it is not essential to remove the protecting group in this step, and it is not pharmaceutically acceptable. If it can be tolerated, it may remain in the target compound (I. In addition, if necessary, the protective group can be removed in any step after this step. The removal of such a protecting group is carried out by applying various known deprotection methods. When R ² is a 9-methoxetoxymethinole group, for example, clofenolhonolem, dichloromethane, This can be done by contacting a solvent such as THF with, for example, titanium tetrachloride or bromide. The amount of noreic acid used was 1 to 30 moles per ααιυ 1 monolayer, and the reaction temperature was -1.0 to 40. c 、 The reaction time is 5 minutes to 10:00 o

 Step 10 is a step of cyclizing to obtain (XV).

This oxidation reaction is carried out by cyclizing ααν in a solvent such as benzene, tonoleene, or TH: F, for example, in the presence of a catalyst such as copper sulfate, copper powder, rhodium acetate, or palladium acetate. ! Is done. The reaction temperature is 5 0 from 1 1 0 ^a c, the reaction time is from 1 to 5 hours Der '), I usually nitrogen or Anoregon. Cormorant ¾ dividing line in the fog BS care of inert gas. The cyclization reaction is carried out by irradiating (XI with, for example, benzene, THF, carbon tetrachloride, and methyl alcohol) in a solvent at −10 to 40. You can do it.

The first step is a step of activating (XV) with an activator to obtain (IE). (Wherein X is a substituted sulfonoxy group, (XV) 1 to 3 monoles of 1 monole, for example, p-tonoreensenolenoic anhydride, .V 12 trophenenolenosolephonic anhydride, 2,4,1 Trisopropinolephenylsnolefonic acid, methansnolefonic anhydride 薆,-tonoleensnolefinorenolechloride, bromophenylsnolefonichloride What kind of snolefonyl chloride, for example, Methane, chlorophonolem, acetonitrinole, dimethoxyethane, TELF In any solvent, for example, tri'ethinoleamine, disop-mouth hinoletylamine, pyridine, 4-dimethinoreamininopyridine. The reaction is performed in the presence of a base. Usually, the reaction temperature is - 20 ^a C from 40 ⁵ C, the reaction time is 5 hours 0.5. (X is a halogen place • If the cow, the X is Choku換sulfo - sulfo in the reaction in the case of Ruokishi group - Honoré agent algebraic) to a halogenating agent (e.g., old Kizari Kurori de, (C6H _{5 3 C, (CH 5 ^ PBr 2} , (C 6 H 5 0 3 Br 2, etc. Chioninorekurori de) using, X of be converted from by reacting the same镁conditions (XV) to (H). (H) Is also a di-substituted phosphoryloxy group, a phosphorylating agent (eg, diphen-]) phosphoric acid chloride, dimethyl) is substituted for the sulfolating agent in the above-mentioned reaction wherein X is a substituted sulfonyloxy group. (XV) can be converted to (E) by the same reaction using) phosphoric acid chloride, jetty] phosphoric acid chloride and the like.

 After completion of the reaction, the target compound of this step (is collected from the reaction mixture according to a conventional method. For example, a water-miscible organic solvent and water are added to the reaction mixture, and the organic solvent layer is separated. It can be obtained by taking out, washing with water, drying with a desiccant, and then distilling off the solvent.

 ί π) can be subjected to the next step reaction without performing the above isolation operation o

 In the above examples, the starting material (π) is not limited, and any starting material (π :) suitable for the purpose of the present application can be used.

 Specific examples will be given later as reference examples.

ノ __ΟΜΡΙ,

«, — Ϋ ― BEST MODE FOR CARRYING OUT THE INVENTION

Reference example

 5, 6 -cis 1 6-1 (I-hydroxy-1 meth / ^ eth -1 -1 azabi r r 3,2,0] Nito Penji Esthe

 Cis-111 [31-diazo-31- (4-1-to-penzinoleoxycarbo =>)-12-oxo 7 "mushroom." 1-3 "(1-hydroxy-11-methy; ^ et) buzetidine One 2-one (benzene solvate) 1.1 7 ^ (2,5 m moi) and rhodium (IE) acetate 60 «anhydrous benzene! 2 Deoxygenate the suspension through star element for approximately 0 minutes. The mixture is then heated for 45 minutes in a nitrogen atmosphere with stirring 8. After the reaction solution is cooled, the mixture is filtered using a cerite, and the solvent is distilled off under reduced pressure to obtain the title compound as a blue foam (0.91, 100).

IR ¹ : 3500, 1780-1720

, 1 0 Hz , >C< _H ) , 4.25 ( 1 H , ID , >CH-liH - ) , 4.70 ( 1 H , s , >NCH< 二 ） ， 5.30 (2H， ΑΒ<ι , J= 16， 13 H z , - 0 C H₂ Ar ) , 7.55( 2H , d , J = 9 H z , arom. H) , 8.27( 2H, a , J = 9Hz , arom . H ) 本化合物をベンゼンで処理すると無色結晶（ 1 3モ のベンゼンを 含む）と る。 その物性は次の通 1?であった。 点 55 - 60 (軟化 I R ^ :¹ : 3550， 1780- 1720 Ή R d 90MHz, CDCI ₃ ^ 1.28, 1.5 3 (3Η, sχ2, -CH ₃ χ2), 1.9 (1Η, Η, -ΟΗ), 2.63 (1Η, 4α, j = 19, 7Ηζ, > C <^), 3.67 (lH, d, J = 6Hz,> CHC0-), 3.96 (jH, ddL,

, 10 Hz,> C < _H ), 4.25 (1H, ID,> CH-liH-), 4.70 (1H, s,> NCH <2), 5.30 (2H, ΑΒ <ι, J = 16, 13 H z, -.. 0 CH 2 Ar), 7.55 (2H, d, J = 9 H z, arom H), 8.27 (2H, a, J = 9Hz, arom H) colorless when the compound is treated with benzene Crystals (containing 13 mo benzene). Its physical properties were as follows. Points 55-60 (softening IR ^: ¹ : 3550, 1780-1720

Elemental analysis Civ Hisiis 0 ₇ 1/3 C6 H ₆ Total value: c 58.76; H 5.19; N 7.21

 Laughter: c 58.74; s 5.17 N 7.02

 In the next step reaction, a crude compound obtained by distilling the solvent was used.

 Example 1

 5, 6-1-3-ethylthio 1-1 (1-hydroxy 1-methyl) 1-oxo-) Asa 'bisik mouth [3, 2, 0] hept 1-2 1-2-force / 1/1 Bon-zen 41-1-Trobenzil ester

 5, 6-cis 4 1 [3 1 diazo 1 3 1 (4 1 2 1 mouth pens A; oki power) 1-2 oxop pi -3 -1 (1 hydro!) 5,6-cis-6- (1-hydroxy-1-methazine) prepared according to the method of Reference Example from methyrueti / 1 /) azetidine-2 one-year-old (benzene solvate) 234 ^ (0.5mnioi) 1) 1-Azabicyclo [3,2,0] heptane-3,7,1-diene-2-one-force boric acid 4-Acetate solution Add 0.11 Ml (0.63 mmoi) of diisoprobiecinoleamin, and then add 0.13 W (0.63 mmoi) of jibwe- / renrin chloride, and stir for 90 minutes. To this mixture is added diisopropitinoreamin 0.22 »(1.3 m πιο 、), then ethyl mercaptan 0.1 W (1.3 fflmoi) and stir at 0 for Ί7 hours. The solvent is distilled off under pressure, the residue is dissolved in vinegar, washed with water, dried (Na ^ SC ^) and the solvent is distilled off. The residue was subjected to force column chromatography using hexane residue (hexane, hexane-hydrogen ethynole-1: 1) to give the title compound as colorless crystals (100 ^). .

Point 7 — 80 ° (softening), 1 3 3 — 1 3 5 ° C (remelting) '' IE 15: 1770, 1740, 1 690

UT λ ^ ° ^Η nm (Ej): 262 (247), 317.5 (244)

HME (60MHz, CDC13 1.27, 1.47 ( each 3 H, s X 2, one _{CH 3 x2), 1.30 (3H} , -t? J = 7Hz, -CH 2 CH3), 2.87

(2H, 4 J = 7Hz, 1 c CH ₃ ), 2.8-3.2 (1 H, m

 H

 \ z), 3.57 (lH, d, J = 6Hz: CH-CO-), 3.9-

H

 4.4 (2 H, m, c, ^ E-BC), 5.30 (2Η, ΑΒ,

J = 22, 1Ηζ, -oc¾Ar), 7.57 (2H, d., J = 8sz arom.Η), 8.10 (2H, a., J = 8Hz, arom.Η) Elemental analysis C ₁₉ H ₂₂ Bf ₂ ° 6 S, H ₂ 0

 Calculated: C 53.76; H 5.695 it 6.59 Found: c 54.12 H 5.36; ir 6.27 Example 2

 5, 6-cis-1-31-thio-1-6- (1-hydroxy-methyl / ^-ethynole) 1,3-hydroxy-1,3,2,0] heptoto 21-one-two-one Lithium

 題 の 混合 混合 混合 混合〗〗〗〗〗〗〗〗 混合 混合〗 混合〗 混合〗 混合 混合 混合 混合 混合 混合 混合〗 混合 混合 混合 混合 混合 混合 混合 混合 混合 混合〗 混合 混合 混合. Add% P (i-C70 ^) and hydrogenate at room temperature under normal pressure for 1.5 hours. Add 1 Q% Pa-c70 ^ and hydrogenate for another 3 hours. After combining and distilling off tetrahydrofuran under reduced pressure, the resulting aqueous solution is concentrated with ethyl acetate and concentrated under reduced pressure. Column chromatography using XAD-2-(H20), collecting fractions having an absorption at 297 nm with πv spectrum and freeze-drying to give the title compound as a colorless powder

C PI (21) is obtained.

I ^R ^ a ^rl: 1750

ϋ ^{ν A} L ^{2 nm (E} ): 2 9 7 (2 6 8)

NE (9 OMH z, D ₂ O) ^: 1.38 (3H, t, J = 7 Hz,

-c¾ CH ₃ ), "3, 1.53 (each 3H, sx2,-CH ₃ x2), 2.98

(2H, <i, -CH ₉ CH ₃ ), 3.23 (1 H, dd, J = j 7,

10Hz, 3.83 (lH, d, J = 6Hz, CH-CO-),

 3.98 (1 H, ad, j = 17, 9 Hz,〉, 4.3-4.δ (1H, m,> CH-iT)

 Example 3

 5, 6 cis-1 3-(2-Hydroxyshethio) 1-61 (1-Hydrox 1-Methyl /! ヱ ノ ノ)-7 1-year-old xo 1-azabicyclo [3, 2, 0] heptoe 21- 2-Rubonic acid 412 Benzyl ester

5, 6-cis 4-1-1 5,6-cis-6- (1-hydroxy-1--1-methinoleethyl) -1-azabicyclo prepared from azetidin-2-one (benzene solvate) 35 1 ^ (0.75 mmoi) according to the method of Reference Example [3,2,0] Hetane-3,7-diene-2-cabonic acid 4- ■ = trobene / 1-ester-acetate-tri-30 solution ^: under nitrogen atmosphere At 0, add 0.165 miool of diisoprophidine and then add 0.195 »(0.93 mol) of diphenylphosphoric acid chloride. Add 0,255 (1.44 minol) of diisoprobamine to this mixture, then add 0.105 «(1.4 nimol) of 2-mecaptoethanol and stir for 16 hours. Diesel. The reaction solution SuShun Echiru

(ΟΜΡΙ And add it to a saline solution under ice-cooling to separate the posterior layer. The organic ϋ layer washed with water, dried (ira ₂ S0 ₄₎ After the solvent was distilled off, and the residue Furoriji - Ru use force column chromatography (hexane one ^ acid E Ji / v ^ - 3:! 1 )

The title compound is obtained as colorless crystals (142).

） ： 265(262)， 318(280 ) IT MR ( 60MHz , CDCI₃ ) 9： 1.27 , 1.49 (各々 3Ε , s 2 , 一 C¾x2), 1.95 ( 2H , ¾. s. , -OH χ 2 ) , 2.9-3.1 ( 3Η , m , -SCH₂CH₂- , g ) , .3.55 ( 1 H , d , J = 6Hz , ヽ CH - C 0 -） , 3.6~4.3 ( 4H , m , -S CH ₂C¾ - OH , CH-2i< , Melting point 1 29, 33 X (decomposition)

): 265 (262), 318 (280) IT MR (60MHz, CDCI ₃ ) 9: 1.27, 1.49 (3Ε, s2, one C¾x2), 1.95 (2H, ¾. S., -OHχ2), 2.9-3.1 (3Η, m, -SCH ₂ CH _2- , g), .3.55 (1 H, d, J = 6 Hz, ヽ CH-C 0-), 3.6 ~ 4.3 (4H, m, -S CH ₂ C¾-OH, CH-2i <,

), 5.32 (2Η, ΑΒ <Ι, J = 24, 15Ηζ, -OGH ₂ AD,

 7.60 C2H, a, J = 8Hz, arom.Η), 8.2 8.2 (2Η, d, J = 8Hz, arom.Η)

Elemental analysis value C ₁₉ Hgg ίΓ ₂ 0 ₇ S

 Calculated: C 54.02; E 5.25; N 6.63

 Found: c 53.77 H 5.16; N 6.20

Actual translation 4

 5,6-cis-1- (2-hydroxyethylthio) -1-61- (1-hydroxy-1-methyl); u) I-oxo-1 1-azabicro [3,2,

0] Hept--21-Sodium sodium borate

4 twelve preparative port Penji Este 9 13 Uedai Kanorepon acid (0. 29 m mol), sodium hydrogen carbonate _{37 (0 .44 m 0 l)} , 1 0% in a mixture of Tetorahi mud Blanc 9 and water 9 Add P4-C91 ^ and hydrogenate at room temperature under normal pressure for 2 hours. Filter off the sensitizer, wash with a small amount of water, and filtrate And the washings are combined, and tetrahydrofuran is distilled off under reduced pressure. The resulting aqueous solution is washed with Chinole and compressed under reduced pressure. Amber lysate! : AD-2 the used column chromatography - (H ₂ 0) is subjected to, and lyophilized to collect minute ί having absorption in 2 9 8.nm in Y V-spectrum target title compound powder ^ color powder (3 It is obtained as 3¾.

IR ^ ¹ : 1 750 σ n I, (E): 298 (248)

_{NM R (9 OMHz, D 2} o) ί: 1.45, 1.60 ( each 3H, βχ2, - 0 (I Η, dd, j 6Hz,

 Η

ヽ-CE - CO -), 3.8 - 4.1 (3H,,,, -SCH 2 CH 2 0H),

 H

 4.45 (1 H, m, ^ CH-H) Example 5

5, 6 1 cis 1 3 1 [3-1 (4-trovenge xycarbo) aminopropio]-6-(1-hydroxy 1-methyl ethynole)-axoxo 1-azabi sik π [3, 2, 0] hepto 2 1-2 1-Carvone 4-1 = Tropendi Esthe

5, 6-cis-4- (3-diazo-31- (4--1 = benzyloxy) = 2-oxo propyl)-3-(!-Hydroxy 1-method ) Azetidin-2-one (benzene solvate) 5,6 -cis-16- (1-hydroxy-1-methinetinol) -1 I-asa prepared from 250 ^ (0.53 minoi) according to the method of Reference Example 'Bisic mouth [3,2,0] hepta 3,7-dione-one-strength solution of carboxylic acid 4-212-trobene di-ester in anhydrous acetonitrile / 25 »solution under nitrogen atmosphere, 0 at disoprophet The amine 0.11 (0.63 mmol) is:

 OMPI_

, Νϊ δ Add diphe-phosphoric acid 0.13 »(0.63 mmoi) and stir for 90 minutes. This mixture is mixed with diisopropylpropionamine 0.14

Add «^ (0.8 mmol), then add 3- (4-l-pentoxy) -amino-pappin 79 ^ (0.64 mnol), stir at 0 for 3 hours, and add diisopropylethylamine. 0 .07ff

(0.4 mmol) Add 3- (4-butene benzyloxy-norrevo-〃) and add 89 ミ ノ '(0.32 mmol) of aminopropanethio and stir for another 16 hours. The reaction mixture is diluted with ethyl acetate and added to a saline solution under ice-cooling to separate a nucleated layer. After washing the nucleated layer with water and drying (e ^ SO ^), the solvent is distilled off, and the residue is subjected to column chromatography using a phlegm (齚-齚 -hexane = 2: 1) to give the title compound. Is obtained as a pale yellow foam (138).

I s β » ¹ : 1 T 70

τ τ λ ^ ° ^Η _nm (E): 264 (280), 318 (164) ER (90MHz, CDCI ₃ ) d: L29 ,! .51 (3H, sx2, one Cx2, respectively), t.8-2.0 (2H, m, -SCH2CH2CH2-, 2.01

(1 H, s, -0 H), ₂了 3.4 (5H, m, -SCH ₂ CH ₂ CH2lT,

 ^ c ~), 3.59 (l H, d, j = 6 Hz, CH-CO-), 4.0-- 4.5

C 2H, m,, CH-¾X), 5.18 (2H, s,

-0CH ₂ Ar), 5.31 (2Η, ΑΒα, J = 24, 15Hz, -OCHoAr),

7.2-8.3 (8S, n, arom.H)

Real judge 6

)に付す。 ϋ Vスぺク ト で 298 η ηに吸収をもつ分闺を集め、 凍結乾燥すると檩題化合物が無色 粉末（ 28^ )として得られる。 5,6— ^ S-3-1- (3-aminoprobithio) -1-6-1 (1-hydroxy / 1-methyl / 1 / ethyl-1) -7-oxo-1 1-asa-bicyclo [3,2,0 Heptow 21 Title power Tetrahydrochloride of bouronic acid 4 1 2 mouth benzene 1 3 (0.22ππποΐ) Pfuran 25 «r, pH 7.0 i¾ 瑗 mouth liquid I 2r ^ and water 1 2 Add 0% P <ic134 to the mixture of W and hydrogenate at room temperature under normal pressure for 90 minutes. Add〗 0 100 ^ and hydrogenate for another 2 hours, then filter off the catalyst and wash with a small amount of water. The filtrate and washing solution are combined, and tetrahydrofuran is distilled off under reduced pressure. The resulting aqueous solution g Shun Echiru in wash净後and瀵', Amberlite XAD - 2 color Mukuroma preparative chromatography (Eta ₂ 0 using,

). The fractions having an absorption at 298 η η are collected by ϋV spectrum and freeze-dried to give the title compound as a colorless powder (28 ^).

^IR "I ^{1 1740}

υ ν n _m (E): 298 (246)

NMR (90MH2, D ₂ O) ^: 1.44, 1.57 (3 H, s x2,

-CH ₃ 2), J.9 -2.3 (2H, in, -SCH ₂ CH ₂ CH _2- ), 2.9-3.4 (5H, m, -SCH ₂ CH ₂ CH ₂ H <, ^ C ^ ~), 3.86 (1 H, d,

J = 6Hz, CE-co-) , 3.8- 4.2 (1 H, ffi, ^ c H), 4.3 one 4.6 (1 H, JD, ^ CE-E ^)

Real 7

 5, 6 1 cis 1 3 1 (2-moholinothio)-6-(1-benzo 1-methylethyl) 1-1-oxobi j-azabicyclo [3, 2, 0] hept-21 2-1-carboxylic acid 4-benzene / u-ester

5, 6 -cis-4-1 (3-1) 3-1 (4-1-1-2-year-old xo-probi) 1-3-1-1-1- / 1) azetidin-2-one (benzene solvate) 234

5,6-cis-6 prepared from (0, 5 mol) according to the method of Reference Example.

)を加え、 次 で ジフエ- リ ン酸クロリ ド 0 , ί 3 » （ 0 . 6 3 mnoi )を加えて 9 0 分間かきまぜる。 この混合 にジイ ソプロピノレエチ ァミ ン 0 . 1 ( 0 . 8 mmol )を加え、 次 で 2 -乇 ホリノェチ メ 力プタン 9 * ( 0 . 64 mmoi)を加え、 6 . 5時間かきまぜる。 さらにジィ yプロビルェチ ァ ミン 0 . 0了《4 ( 0 . 4 ιηπ:οΐ )と 2—モノレホリノ ェチ メノレカプタン 4 7^( 0 . 3 2 mm 01 ) 追加し j 5時間かきま ぜた後、反応液を酢酸ェチ で希釈し、 食塩水中に氷冷下加えて有機層 を分取する。有棱詹を水洗、 乾燥（ a₂so₄)後、溶媒を留去し、 残留 物をフ リ ジー を用 るカラムク口マ トグラフィ— （酢酸ェチ ) に 付すと檩題化合物が無色結晶（ t 0 0 )として得られる。 . PI 1-(, 1-hydroxy-1-! Methinetin)-\ azabicyclo [3,2,0] heptane-1,3,7-dione-2 mono-rubonic acid 4-1-trovendyl acetate anhydrous 2 0 Dissolve the solution in a nitrogen atmosphere at 0.

), Then add diphenyl chloride 0, ί3 »(0.63 mnoi) and stir for 90 minutes. To this mixture, add 0.1 (0.8 mmol) of diisopropinolethiamine, then add 9 * (0.64 mmoi) of 2- 乇 horinetic metheptane, and stir for 6.5 hours. Furthermore, add y y provirethamine 0.0 to 4 <0.4 (0.4 ιηπ: οΐ) and 2-monoreholinöch menolecaptan 4 7 ^ (0.3 2 mm 01) j After stirring for 5 hours, react Dilute the solution with ethyl acetate and add to saline under ice-cooling to separate the organic layer. Yu棱詹washed with water, dried (a ₂ so _4), the solvent was distilled off, and the residue disadvantageous Gee Ru use the Karamuku port Ma Togurafi - as the eluent (acetic E h)檩題compound colorless crystals ( t 0 0).

 Melting point t 2-1 7 3 'C

 I R ^ l: 1 760

_{U γ λΕ¾0Η η m (Ε)} : 265 (228), 320 (260) NUR (6 OMRz, CDG1 3) 5: 1.26, 1.51 (^ 3H, sx2,

_{-CH 3 2), 1.78 (1} H, s, - OH), 2.32-3.08 (1 1 H, m, one _{sc 2 CH 2 -, X ::} ,, one ^{- 1 Η f 06), 3.51} -4.38 (5Η in, ~ SCH _S C¾1 ^ ヽ ,, X ヽ^H g ,, z GE-, CH-CO-),

5.32 (2H, ABa, j = 24, 15Hz, -0CH2Ar), 7.59 (2H, ά, J = 8Hz, arom.H), 8J9 (2H, 4, j = 8Hz, arom.Ξ) Value C ₂ 3 H ₂₉ Έ _Ζ 0 S

 Calculated value: c 55.18; H6.0; N8.39

__OMPI Lol data: c 54.73; H6.03; N8.17

 Example 8

 5, 6 1 cis 1 3 1 (2-mo holino thio) 1 6-1 (1 ド キ-------) Hepto-2-one boric acid

Add 0.105 ^ to a mixture of the title carboxylic acid 41-to-pentene diester 10 (0.2 mmoi), tetrahydrofuran 20 pH 7.0, phosphate buffer 10 W and water j. Hydrogenate at room temperature under normal pressure for 2 hours. After filtering off the catalyst and washing with a small amount of water, the filtrate and washing solution are combined, and tetrahydrofuran is distilled off under reduced pressure. The obtained aqueous solution is washed with ethyl acetate and concentrated under reduced pressure. Anba concentrate - Ru use Reye preparative force Ramukuroma Togurafi over subjected to _{(Η 2 0, 1 0 EtOH} ), the title compound and lyophilized to collect fractions having absorption in 2 9 4 nm in Y Upsilon bitch Torr Is obtained as a colorless powder (12 * ^).

 U λ 2 ° n m C E j ^): 2 9 4 (1 6 5)

N MR (90MHz, D2O) 1.44 , 1.57 ( each _{3 E, s x2, -CH 3} x 2), 2.91 -3.62 (1 1 H, ID, -SCH 2 CH 2 -,, -H 0), 3.79- 4.24 (5H, m, -SCH ₂ C¾-2,,

 CH CO-), 4.51 (1 H, m, CH)

Example 9

 5, 6 1 cis 1 3 1 (4 1 pyrimethylmethyl) 1 6-1 (1-hydroxy 1-methinetinol)-7 1 oxo 1 1 1 azabi sik mouth [3, 2, 0] (2) Ichino (2) One-strength boric acid (4) 12 Trobenzi Esthe //

5, 6 — cis 4 −1 [3 dia.

· '.,. Power- — 2-oxo ^ propyl) 1-31 (, 1-hydroxy 1-methyl 1) azetidin-12-one (benzene solvate) 2 34 «(0.5 mmol) reference example 5,6-cis-6- (1-hydroxy-methyl / ethyl) 1-azabox mouth [3,2,0] heptane-3,7-dione-1-force rubonic acid prepared according to the method of (4) Acetonitrile solution of benzene in anhydrous acetonitrile 20 Β solution ^: Under nitrogen atmosphere, add disopropiet / Uamine 0 · ί 1 * ^ (0.63 mmol) at 0, then add diphene Add 0. 3 W (0.65 mmol) of phosphoric chloride and stir for 90 minutes. To this mixture is added 0.04 (0.4 mmoi) of diisobenzene, and then 4-mecaptomethypyridine 8 O ² ^ (0.64 ααοΐ), and the mixture is stirred for 9'0 minutes. Further, add 0.04 g of diisopropy uamine (0.4 mmoi) and 40 ^ (0.32 mmol) of 4-mecaptomethypyridine and stir for 18 hours. Dilute, add to saline under ice-cooling, and separate the aqueous layer. The Ariyang layer was washed with water and dried (iTa ₂ SO ₄ ), the solvent was distilled off, and the residue was subjected to column chromatography using florisinole (ethyl acetate / U-hexane-2: 1) to leak. The compound is obtained as colorless crystals (104). ϋ point 1 8 1-I 8 2

 ^ „∑3r one 1.

IS ^ _{m & ∑} m: 1 7 7 0 πν λ Ι ^Ά n _m (Ε): 262 (29!), ³¹⁵ (293) '

1ί Μ R (90 MHz, MS0 -d 6): 1 · 1 3, 20 ( each 3H, s x2,

-c¾ χ 2), 3.0-3.29 (1Η, m, ^ rc ^), 3.57 (1Η, d,

^ = 6Ηζ,> CH-CO-), 3.94-4.37 (2H, m, χ, CH-1), 4.17 (2Η, s, -SCH2-), 4.63 (1Η, s,

-ΟΗ, 5.31 (2Η, ΑΒ <1, J = 21, ί5Ηζ, -0CH ₂ Ar), 7.30

'' C? V:? I -8.69 (8 H, m, aromH)

Elemental analysis C £ ₃ H23 N ₃ 0 ₆ S

 Calculated: C 58.83; H 4.93; N 8.95.

 Found: C 58.76; H 4.98; u 8.94

 Example 10

 5, 6-cis-1 3— (4-Bilymethythio) -1 6— (1-Hydroxy-methylethyl) -1 7-oxo-1 1-azabicyclo [3,2,0] hepto-2-ene-1 2 One-pot sodium acid sodium salt

 Title O-Pentyl benzyl ester 200 * ^ (0.42 mmol), tetrahydrofuran 40 PH 7.0 Phosphate buffer 10 Ml ^ and water 20 mixed with t O% P Add <ic 200 and hydrogenate at room temperature under normal pressure for 3 hours. After filtering off the catalyst and enzymatically enriching it with Shaoi water, the filtrate and washing solution are combined, and tetrahydrobran is distilled off under reduced pressure. The obtained permanent solution is washed with acetic acid and concentrated under reduced pressure. The concentrated solution is subjected to column chromatography using Amberlite® AD-2 (separated by column chromatography) and freeze-dried to obtain the title compound as S-free powder (58 ^).

E R ^{1: 1} 750 '

): 262 (144), 298 (252)

_{HMR (90MHz, D 2 0>} ^ :: 11..3355 ,, 11..4499 (( each each people 33 HH ,, eβ X> 2, -CH 3 x2), 3.07 (1 H, ad,),

3.75 (1 H, dd, j = 17, 9Hz, c H), 3.76 (1 H, d, J = 6 H z, CH - CO -), 4.25 (2H, s, - SCH 2 -), 4.30 ( 1 H, m, ^ CH-li.), 7.62 (l H, d, J = 6 Hz _i arom .H¾

8.6 I (1H, d, J = 6Hz, arom.H)

Elemental analysis value C ₁₆ Η _{17 1} ί ₂ 0 ₄ SNa.3H ₂ 0

GMPI Calculated value: a 5.60

 Measured value: 5.40

 mm 11

 5, 6 1 cis 1 3 1 (2-bimethylmethinoretio) 1 6 1 (1-hydroxy-1-methinoreti) 1-oxo-1 1-azabicyclo [3,2,0] heptoh 21-21 Acid 4--Gluene benzoate 5, 6-Cis 4-1 [3-Diazo 1-3-1 (4-Gluten benzoic acid ball) 1-2-Oxoprobi] 1-3-1-Hydroxy -5-, 6-cis-β- (1-hydroxymethine) prepared according to the method of Reference Example from azetidine-l-one (benzene solvate) 23 ^ (0.5 minol) ! /) 1 t-azabicyclo [3,2,0] heptane-3,7-diene 1 2 1 ^ ^ bonic acid 4 1-tongue solution At the bottom, add 0.11 »(0.63 mmol) of diisopropylamine and then add 0.13 of diphenylphosphoryl chloride. Add (0.665 moi) and mix for 90 minutes: ^ Mix the mixture ^ Add diisopropinoleetinoreamin 0. t4 Mi (0.8 mmoi), then add 2-menolecaptomethyviridine 8 0

C 0.64 mmol) and stir for 90 minutes. Further, add 0.04 (0.4 mmol) of diisoprovirethamine and 40 ^ (0.32 mmoi) of 2-methylpyrdomethyi 7-pyridine and stir for 4 hours. Dilute with water and add to saline under ice-cooling to separate the nucleated layer. The bridged layer Eisen, dried (a ₂ S0 _4), the solvent was暂去the residual furo Li di - Karamuku Mato chromatography using chromatography (hexane Mune錢Echiru =:! T) in subjecting the檩題The compound is obtained as colorless crystals (102).

Point 8 Ryoichi 8 8. c R "> ^ max- ^T cm 1 750

 u Y): 263 (307), 318 (279)

_{N MR (60MHz, CDCI 3)} ί: 1.25, 1.52 ( each _{3H, sx2, -CH 3 x 2} ), 1.93 (1 H, 8, -OH), 3.2 (I Η, dd, J = /

9 Hz,), 3.59 (1 H, d, J = 6 Hz, ^ CH-CO-),

3.86-4.40 (4Η, m,,-SC¾-),

 5.37 (2H, AB4, J = 24, 15Hz, -OC Ar), 7.1 8- 8.39 (8H, ID, aromH)

Elemental analysis value _{H 2ί 3 0 6 S · ½} Η 2 0

 Calculated values: c 57.73; H5.05; B8.78

 Obtained values: c 57.81; H 5.05; S 8.80

 Example 12 '

 5, 6-^ 1 3 1 (2-pyridimethylthio) 1 5 1 (1-hydroxyl 1-methynoleethynole) 1-oxo- 1 1 azabicyclo [3,2,0] hept-2 -2-force sodium borate

The title carboxylic acid 4-l-pentopenestenole 90 ^ (0.19 mmol), tetrahydro 7-lan! 8 et PH 7.0 Add 0% P <!-C90 ^ to a mixture of 9 W phosphate buffer and 9 W water, and add fluorine for 4 hours at room temperature under normal pressure. The catalyst is filtered off, washed with a small amount of water, the filtrate and the washing solution are combined, and tetrahydrofuran is distilled off under reduced pressure. The obtained aqueous solution is quenched with ethyl acetate and concentrated under reduced pressure. The concentrate Diaion HP - 20 using (manufactured by Mitsubishi of Narusha) Karamukuroma Togurafi _{- (E 2 0, 10S6 ΕΐΟΗ} ) was attached to one of the fractions eluting with 0% EtOH lyophilizing the title compound ^ is ^ Obtained as colored powder (23).

 R ^^ & x m one: 1 750

CMFI HT λ¾ ° nm C): 264 (172), 298 (256)

_{NMR (90 H2, D 2 O} ) ^: 1.33, 1.42 ( each _{3 H, s X2, -CH 3} x2), 3.i3 (l H, <m, J = 17, 1 0Hz, ^ c ^), 3.74 (1 H, dd), 3.75 (1 H, Λ,

j = 6Hz, ^ CH-CO-), 4.30 (2 H, s, -SCH _2- ), 4.31

(H, m, CH-N), 7.40-8.6 (4H, a, arom.H) Example 13

 5, 6 1-3-[3-1 (6-dimethylamino) = 1) 6-1 (1-hydroxy 1-meth)-1-year-old 1-aza [3,2,0] butene 21-butene 4-acid

5, 6 1 cis 1 4 1 [3 1 diazo 1 3 1 (4 1-g benzyloxy force ubonyl) 1 2 oxopbyl] 1 3 — (1-hydridoxy 1-meth echinole) azetidine 1,6-one- (one-benzene) solubilizer (2,3,4 ^ (0.5 inmol)), prepared according to the method of Reference Example, 5,6-cis- (1-hydroxy-1-methynoleeth) -I-azabiq Mouth [3,2,0] heptane-1,3,2-dione-2-force Boronic acid 4-to-2 mouth Benze Este / ^ in anhydrous acetonitrile 2 solution under nitrogen atmosphere, 0 at disopropinolethiamine 0 ♦ Add 1 1 (0.63 ol), then add diphene / u-lin chloride 0.3. 3 W (0.3 3 3 mnoi) and mix ⁴ times for 90 minutes. Lithium salt of S-dimethinoleamino-3-mecaptoviridazine! Add 6 1 ^ (1.04 rnmol) and stir at 0 for 2 hours. Dilute the reaction solution with succinic acid and add it to a saline solution under ice-cooling to separate the Arisuto layer. The Arisuto layer was washed with water and dried (2Ta ₂ SO).

C PI The title compound is obtained as pale yellow crystals (60). Point 1 78 — 1 79 ° C (decomposed)

： 1 760 IR

: 1 760

ϋ V λ ^ ° ^Η _ffl (EJ ^): 267 (482), 312.5 (356) Elemental analysis CH ₂₅ N ₅ 0 ₆ .

 Calculated value: C 55.30; H 5.04 N 14.02

 Found: c 55.14 H 4.96; H 13.65

 Example 14

 5, δ-cis 1- [3- (1- (6-dimethyaminoviridazi-norre) thio]] 1- 6- (1-hydroxy-1-methy) -1-oxo-1 1-azabicyclo [3,2,0] Heptoe 21-force

Title A mixture of tetrahydrofuran 20 of cannolebonic acid and a mixture of tetrahydrofuran 20 of 105 ^ (0.21 m moi), methanol 5 PH 7.0 L And add hydrogen at room temperature under normal pressure for 2 hours. The solvent is filtered off and washed with a small amount of water. The organic solvent is distilled off under reduced pressure. The resulting aqueous solution was washed with齚E Ji and amber Lai preparative c concentrate concentrated under reduced pressure XAD - 2 subjected to use Ru column chroma preparative chromatography (H ₂ 0,5% EtOH), and Y V scan By collecting the kuokuri with a yield of 292 _nm in a vector and freeze-drying, the nuclear title compound is obtained as a colorless powder (4ί »).

IE vl: 1 750

HMR (90 ΜΞ z, D _Q 0) ^: 1.30, 1.50 (3 H, s χ2,

 -c¾ x 2), 258 (lH, ad, j = l7, l OHz, ^ c¾-), 3.26 (6H, s, -H (CH3) 2), 3.61 (1H, da, j = 17, 9Hz,

fo: .m c ^〉, 3.79 (l H, d, j = 6 Hz, -CH-co-), 4.3

(1H, m, ^ CE-IK.), 7.22 (1H, Λ, J = 8H2, arom.H), 7.70 (lH, d, J = 8Hz, aroin.H)

Actual 15

 5,6-cis-1- (E-21-acetamidobi-thio) -1-61- (1-hydroxy-1-methyl) -oxo-1,1-azabicyclo [3,2,0] 2- force 4-nitrobenzene ester ^^

 5, 6-cis-4-1! : 3-diazo 1-3-1 (4- 1-year-old penji-ki-ki-bo-)-1 21-year-old quinoprop) -3-1 (1-hydroxy-1 -methyl / 1-ethyl A azetidine 1-one on (Pen-Zen solvate) 5,6-cis-1-1 (1-methylethyl)> 1-1-azabicro [3,2] prepared from 234 ^ (0.5 mmol) according to the method of Reference Example. , 0] heptane-1,3,7-dione-1,2-butyric acid ruthenate 412 tropene diester in 25 s anhydrous tris-acetate under a nitrogen atmosphere at 0 with disopropidamine 0.12 ^ (0 69 nmoi), then add 0.14 (0.68 mmol) of diphen-lin chloride and stir for 90 minutes, then add Jial 50 ^ (5 mmol) and E-2-2- Acetamide ethylene chloride; silver of t 6 7 ^ (0 · 7 Sminoi) is added and stirred for 2 hours, and the precipitate is filtered off. The water In addition, remove the insoluble part.

ェチ ）に と檩題化合物が淡黄色結晶（ 1 55 ）として得ら: n¾。 ¾, dried (iTa ^ S0 _4), and evaporated to remove the solvent. Column chromatography using residual ^ -fluoridation-(ethyl ethyl hexane-2: 1,

The title compound was obtained as pale yellow crystals (155): n¾.

 ¾i point 1 82-t 83 (decomposition)

V / IrO IE m ¹ : 1760,, 700, 1620

u Y λ ^Μθ0Η _nm (E): 229.5 (375), 262 (367)

max \ ^cm

 322.5 (371)

NH (90 MHz, DMS0-d ₆ ) d:]. \ 5, 1.33 (3 H, s 2, 1 CH ₃ x2), 1.93 (3H, s, -C0CE ₃ ), 2.9-3.3 (1 H, m,

^ c ^), 3.55 (1H, (i, j = 6Hz, CH-co-), 3.9-4.3

 H

(2H, m, C ^ „, ^ CE-B), 4.7 (l H, 4, -OH), 5.37 (2H, AB4, J = 21, 1 H z,-OC¾ Ar), 5.87C 1H, d , J = 14 H z, -S-CH = CH-N <), 7.07 (i H, d4, J = 14, t 3 E 2, -S-CH = CH-iTH-), 7.75 (2H, d , J * = 8H2, & Tom.H), 8.20 (2H, d., J = 8Hz, arom.H), 10.28

 Elemental analysis CsiH lis O? S Calculated: c 54.665 H 5.02 N 9.1 1

 Found: C 54.58;. B: 5.26 N 8.92

Example 16

 5, 6-cis 1-31 (E-2-Acetamidovinicho) 1-6-1 (1-Hydroxyl 1-Metech) 1-year-old Kisso 1—Azabisik mouth [3,

2,0] Hebut-1-ene-sodium sodium borate: ^ 福 題-4-Nito-benzodiestenole of boronic acid 1550 ^ (0.33 mmol) tetrahydrofuran 1 Add sodium hydrogen carbonate 36 ^ and 10 Pi-C 150 ^ to a solution of water 5 and water 15 and add hydrogen for 4 hours at room temperature under normal pressure (10 Pd-c is added after 1 hour during the reaction). 150, 3 hours later add 50 ^). After filtering off the catalyst and purifying with a small amount of water, the filtrate and the washing liquid are combined, and the nucleated solvent is distilled off under reduced pressure. The resulting 7j solution is washed with ethyl acetate.

-f. ϊ,: π Then, concentrate under reduced pressure. The concentrate Diaion HP - 20 fractions with column chromatography absorbed 230 and 3 ί 0 m in UV-spectrum subjected to _{(Η 2 0, 5 E OH} ) using (≡¾ Kasei Co., Ltd.) And then freeze-dried to give the title compound as a colorless powder (75).

 IR. 1745, 1570, 1615

 m x

nm CE j .) ： 230 ( 396 ) , 310 ( 444) ίί Μ Ε ( 10 ΟΜΗζ , κ₂ 0 ) ί： 1.30 , 1.44 (各々 3 Η， sx2， 一 C¾x2) , 2.09 ( 3 Η， s , - COCE₃ )， 3.02 C 1 H , <ϋ , J= 18 , 10Hz , ^c^-) , 3.72( l H , a , J-6Hz， cs-co~), ϋ Υ

nm CE j.): 230 (396), 310 (444) ίί (10 10, κ ₂₀ ) ί: 1.30, 1.44 (3 Η, sx2, one C¾x2), 2.09 (3 Η, s,- COCE ₃ ), 3.02 C 1 H, <ϋ, J = 18, 10 Hz, ^ c ^-), 3.72 (l H, a, J-6 Hz, cs-co ~),

 H

3.75 (iH, <i <i , J = 8, 9Hz, / C H), Ca .4.3 (1 H, m, ^ CH-ir), 6.07 (1 H, i, J = 13 H z, -SCH = CH-N), 7.14 (l H, (i, J = l 3 Hz, -SCH = CH-iT)

 5, 6-cis-3-1 (E-2-acetamide): A-6-1 (1-hydroxy ί-meth / eth) 17-1-year-old azabicyclo [3,2, 0 ] Heptoh-2-ene Sodium sodium borate, 5,5-^-S3- (3-2-1aceto-d-bininolechio) -6- (1-1-hydroxy-1-methinoleet) -1-71 1-azabicyclo [3,

2,0] Hept-1-ene-2-carboxylic acid sodium carboxylic acid 63 3 ^ water 8 »Add 0-5 m-chlorostricted benzoic acid (80 purity) 45 and stir for 30 minutes. After the reaction mixture has been treated with acid,

^ co. 5) and concentrate under reduced pressure. The concentrate was subjected to column chromatography (¾ο) using Diion Hi> -20 (manufactured by Mitsubishi Kasei Co., Ltd.), and purified to obtain two isomers (A, B) related to the sulfoxide of the title compound. ) Are each obtained as a colorless powder. Isomer A (This product distills off before isomer B by column chromatography.) Yield fi 26.5 «y (319)

_{NME (D 2 0, 1 0} θΜΗζ) ί: 1.34, 1.45 ( each _{3 H, s 2, CH 3} X2), 2.15 (3H, s, ~ C0CH 3), 3.14 (1 H, dd,

J-17, 1 1 Hz, 6HZ,

 ^ CH-CO-), 3.84 (lH, dcL, J = 17, 8Hz, C ^),; -Ca.4.6 (1H, m, ^ CH-K), 6.30C1H, d, J = 14Hz, -SCH = CH-U <), 7.55 (1H, d, J = 14Hz, -SCH = CH-N <), isomer B

 Yield 34.2 ^

^RR ^ „? ¹ : ¹ : 17 0, 1700, 1 620

FY λ ^Η 2θna (E) ^): 244 (409), 290 (352)

 max 1Π3

Ή MR {D ₂ 0 y 100 MHz) (?: 1.34, 1.45 (32, s x2,

-C¾ x 2), 2.15 (3H, s, -C0CH ₃ ) ', 3.05 (1 H, a.α, J = 17, 11 Hz, ^ C-), 3.8 i (l H, d, j = 6Hz,

 H

 / CH-CO-), 3.90 (1H, d d., J = 17, 9Hz, ^ C ^), Ca.4.5 (1H, m,> CH-NC), 6.39 (1H, d, J = HHz, -SCH = CH-iT:), 7.55 C l H, d, J = l 4 E z, -SCH = CH-iTC)

 5, 6 1 ^ Sue 3--(3-acetamidoprovirthio)-6-(hydroxy-method) 1-7-1-1-azabisik mouth [3, 2, 0] hept-2-en-2- Power Sodium borate

5, 6-cis-3- (3-aminoprobithio) -6-1 (1-hydro ΟίνΙΡΙ) 17-oxo-one-one-one-one-mouth- [3,2,0] heptoh-2-ene-2-force Water 6.5% of boric acid 20 ^ and 6.5-tetrahydrophenone »To the solution, add a solution of charcoal water, sodium 15 and water 4.2 W in water, then add a solution of anhydrous 8.6 µm in 1.66 s of tetrahydrofuran and stir for 20 minutes. After the reaction mixture is concentrated under reduced pressure with concentrated ethyl acetate, it is subjected to column chromatography (H ₂ o) using Diaion HP-20 (manufactured by Mitsui Chemicals, Inc.). The fractions that absorb at 299 nm are collected on a solid and lyophilized to give the title compound as a colorless powder (10).

ίί R (iQ0MHz, D.O): 1.33, 1.44 (3H, S X2, ~ CH ₃ X 2 respectively), 1.7-2.0 (2H,, -SC¾C CE _2- ), 2.02 (3, s, one C0CH) ₃ ), 2.8-4.0 (6Η, m, -SCH ₂ CH ₂ CH2 1 c¾1), 3.74 (ίH, d, j = 6Hz, ^ CH-CO-), 4.20-

4.43 (1Η, m, CH-H)

Fine 19

 5, 6-cis-3-1 (2-honolemimidaminothio) -1 61- (1-hydroxy-1-methyi; ^ ethinole) -oxo-1 1-azabicyclo [3,2, G] heptoto 21 En 2 Boric acid

 5, 6-cis-1 31 (2-aminoethyl) 1 6-1 (hydroxyl-1-methine): 7-oxo-1 1-azabicyclo [3,2,0] heptoto-2-ene-2 Power rubonic acid 44o PH 7.0 release

11. Add 2N-NaOH to the 1W solution under ice-cooling to adjust the pH to 8.5. Add 5 minutes to this solution with a small amount of benjihomie medium salt And add. During the addition, keep the pH of the reaction solution at 8.5 with 2N-NaOH. After stirring for 5 minutes, the reaction mixture is adjusted to NHCi-CpH 7.0 · and washed with ethyl acetate. After concentrating the aqueous layer, the column is subjected to force column chromatography using DIAION: SP-20 (manufactured by Kasei Co., Ltd.)-(3.ο, 3% R 了), and eluted with 3 acetone Collect the fractions and freeze-dry to give the title compound as a colorless powder

(32 ^).

^{IR ^ ll ^ 1 - 1 75} 0, 1 7 1 5

^ 20 _{n in (E} J): _{296 (230} )

_{NME (90MHZ, D 2 O)} : 1.43, 1 · 56 ( each 3H, 8x2,

 H

-CH ₃ X2), 3.0-3.4 (3Η, m, -SCH ₂ CH _2- , / C ~), 3.6-H

4.2 (3 H, m, -sc¾CH ₂ ii, ½) ヽ, 3.8 o 77 (11 H, d,

J = 6Hz, ^ CH-CO-), 4.4 (1H, in, CH-1), 8.00 (1H, s, ^] J-CH = N-)

 5, 6-cis 3-(3-homodiaminopropylthio)-6-(1-hydroxy 1-methech) 1-asa bicyclo 1: Asa bicyclo £: 3, 2,, 0] hept-2-en-2-force boric acid

 5, 6-cis-1 31 (3-aminoprovirthio) 1 6- (1-hydroxyl 1-methyldithio) -1 7-oxo-1 1-asa'bi, cyclo [3,2,0] heptoh 2 -En- 2-novolonic acid 30 <D p E 7.0 Lin buffer-

Add 2-aOH to the 7.5 solution under ice-cooling to adjust to pE 8.5. To this solution, add a small amount of Penji / Rehomymidate Shio-Jun Salt over a few minutes. During the addition, keep the pH of the reaction solution at 8.5 with 2 W-NaOH. After stirring for 6 minutes, the reaction mixture is adjusted to 7.0 with 1 w-HCi, and washed with ethyl acetate. After concentrating the aqueous layer, DIAION: SP—20 (San'i-Daisei fΟΪ Π) Column chromatography (H ₂ o, 3% acetate), and fractions eluted with 3% acetone were collected and lyophilized to give the title compound as a colorless powder (25 ^) can get.

in df ¹ : 1 750, 1 7 1 5

U Υ λ ^Ε 2 ° ηιπ (Ε ^17Β ): 298 (261)

 m tea

_{? NURC 9 QMHz, D 2 0} ): 1.41, 1.58 ( each 3 H, sx 2, one _{CH 3 X2), t.9 2.3 (} 2H, m, -SCH 2 CH2CH 2 -), 2.9 - 3.4 (5H, m, -SCH ₂ CH ₂ CH ₂ -1T <, honor), 3.85 (1 H, d,

J = 6Hz, ^ CH-CO-), 3.5-4.1 (1H, m, c ^:>, 4.4

(1 H, m CH-N <), 7.95 (1 H

 Industrial use.

 5,6-cis-force ヽ 'ぺ nemu 3-force / ^ bonic acid derivative (I) has excellent antibacterial activity and -lactamase inhibition, and is useful for humans and dogs, cats, cattle, cows, horses, As a remedy for infectious diseases caused by Gram-positive or negative bacteria in mammals including mice, guinea pigs, etc., as a preservative for animal feed, industrial water, and as a disinfectant for sanitary equipment. Used in combination with β-lactam antibiotics to prevent the degradation of the antibiotic

Claims

The scope of the claims  I expression One R '

[In the formula, El represents a hydrocarbon group or a heterocyclic group, H ² represents a hydrogen atom or a protecting group for a hydroxyl group, and n represents 0, 1 or 2. However, when R ¹ is a psetamidoethyl or psetamidoether-〃 group and E ² represents a hydrogen atom or a sulfonic acid group, n represents 2. The 5,6-cis-force vanem-3-force nolevonic acid derivative or a salt thereof represented by the formula: 2.

[In the formula, E ² represents a hydrogen atom or a hydroxyl group protecting group, R ³ represents a hydrogen atom or a carboxyl protecting group, and X represents a leaving group. Or a compound represented by the formula El S (0) _n H [Wherein, Ri represents a hydrocarbon group or a heterocyclic group, and ϋ represents 0, 1 or 2. A compound of the formula -Η "

 A method for producing a 5,6-cis-potene-3-3-carboxylic acid derivative or a salt thereof represented by the formula: wherein the symbols are as defined above.  O PI —