JPS62215586A - 1-sulfo-2-azetidinone derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:(3S,4S)-cis-3-Amino-4-carbamoyloxymethyl-2-azetidinone-1- sulfonic acid expressed by formula I (R<1> represents H or lower alkyl; R<2> represents H or ester residue), a salt or ester thereof. USE:An antimicrobial agent against Gram-negative bacteria, germicide for preservation of feed against decay, bactericide used on a medical or dental apparatus and industrial germicide used in white water in a paper mill, etc. PREPARATION:Sodium ( 3S, 4S )-cis-3-benzoyloxycarboxamide-4-carbamonyloxy methyl-2-azetidinone-1-sulfonate is catalytically reduced to obtain a compound expressed by formula I or a compound expressed by formula I (R<3> represents amino-protecting group) or salt thereof is sulfonated and then the protecting group and, if necessary, ester residue are eliminated to obtain the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1-sulfo-
2-Azetidinone derivatives, their salts or esters, and their production methods. 1-Sulfo-2-azetidinone derivatives recently isolated from nature are attracting attention due to their unique structure and antibacterial activity [Nature (Nature) Volume 289, Page 590 (1981), 2
Volume 91.

489 pages (1981) Ko. Also, JP-A-55-1640
72 and JP-A-56-125362 disclose l-sulfo-lactams with various changes in the acylamino group at the 3-position of the β-lactam ring.
2-azetidinone derivatives are disclosed with some 4-position substituents.

As a result of extensive research aimed at obtaining novel and useful l-sulfo-2-azededinone derivatives, the present inventors found that the formula [wherein R1 represents a hydrogen atom or a lower alkyl group, and represents a protective group for a] The compound represented by (3S.

4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid (hereinafter referred to as "compound [A]"), its salt or ester and the formula [wherein R1 is the same as above] R4 represents a hydrogen atom or a protecting group for an amino group, and R5 represents an ester residue. , formula % formula % [Symbols in the formula have the same meanings as above] (3s.

l-sulfo-2-azetidinone derivatives, salts or esters thereof having 4S)-coordination can be obtained, and the obtained compounds [■], salts or esters thereof have antibacterial properties that are strong against Gram-negative bacteria including Pseudomonas aeruginosa. The present invention was completed based on the findings of the present invention that the present invention exhibits action and is extremely stable against β-lactamases produced by microorganisms.

That is, the present invention provides (1) a compound [■], a salt or ester thereof, (2
) Compound [II or a salt thereof is sulfonated, and then the protecting group and, if necessary, the ester residue is removed. , the production of a compound [II[], its salt or ester, which is characterized by reacting the salt or ester thereof with a carboxylic acid [■] or a reactive derivative thereof, and then removing the protecting group and, if necessary, the ester residue. Regarding the law.

In the formulas [1], [II] and [01], R1
The alkyl of the lower alkyl group represented by is preferably one having 1 to 4 carbon atoms, such as methyl, ethyl, n
-propyl, n-butyl, isopropyl, isobutyl, etc. are used.

The ester residues represented by R2 in the formulas [1] and [III] and R5 in the formula [+] are:
For example, biologically active ester residues, such as methoxymethyl, which have the effect of increasing blood concentration and prolonging efficacy. ethoxymethyl, isopropoxymethyl,
α-(C
,-,)alkoxy(C,-,)alkyl method, for example, (C+-,)amyl such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, α-(Cz-11)acyloxy(Cz-11) such as α-acetoxyethyl ,−,)
Alkyl groups, such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, etc.
-,)alkoxycarbonyloxy(C+-,)alkyl groups, etc. are used, as well as ester residues usually used as protecting groups for carboxyl groups, such as t-butyl,
Penzhytril, benzyl, p-nitrobenzyl, p
-methoxybenzyl, p-nitrophenyl, β-trimethylsilylethyl, β, β, β-trichloroethyl, trialkylsilyl (eg, t-butyldimethylsilyl, isopropyldimethylsilyl, etc.), and the like are used. As an ester residue as a protecting group for a carboxyl group,
For example, t-butyl, benzhytryl, p-nitrobenzyl and the like are particularly preferred.

In the above formulas [+1 and [111], the protecting group for the amino group represented by R3 and R4, respectively, is usually β-
Those used for this purpose in the synthesis of lactam-based antibacterial compounds are conveniently employed. For example, formyl, acetyl, and monochloroacetyl.

Acyl groups such as dichloroacedel, trichloroacetyl, trifluoroacetyl, etc., such as thi-butoxycarbonyl, 2-cyanoethoxycarbonyl, β.

Esterified carboxyl groups such as β, β-trichloroethoxycarbonyl, β-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, as well as e.g. Protecting groups for amino groups such as alkylsilyl are used. Among them, formyl, monochloroacetyl, trityl and the like are particularly preferred.

The object compound [11[] of the present application may be used with its sulfo group and carboxyl group free, but it can be converted to a non-toxic cation such as sodium or potassium, or a base such as arginine, ornidine, lysine, histidine, etc. by a conventional method. It may also be used by forming a salt with a polyhydroxyalkylamine such as N-methylglucamine, jetanolamine, triethanolamine, or trishydroxymethylaminomethane. The amino group at the 2-position of the thiazole ring may also be used in its free form, but
Salts with organic acids such as acetic acid, tartaric acid and methanesulfonic acid, such as hydrochloric acid and hydrobromic acid, in a conventional manner.

It may be used by forming salts with inorganic acids such as sulfuric acid and phosphoric acid, for example, salts with acidic amino acids such as aspartic acid and glutamic acid. Furthermore, the carboxyl group can also be used by forming an ester with a biologically active ester residue as described in the explanation of R2 and R5 above. Moreover, the object compound [11[] of the present application may be used as a racemate, but (3S.

An optically active substance having 4S)-coordination is a substance that exhibits essential antibacterial activity, and this application describes compounds having this (3S,4S)-coordination [[11], their salts, esters, and their production methods. This is what we provide.

The target compound [111] or its salts or esters are valuable antibiotics active mainly against Gram-negative bacteria, and are used as medicines for humans and livestock, and as antibacterial agents to treat infections caused by various bacteria. Safely used as an agent. Furthermore, the compounds of the invention [[[] or salts or esters are added to animal feed as fungicides, for example to preserve feed. Also used as a disinfectant to destroy and inhibit the growth of harmful bacteria, e.g. on medical and dental equipment, and as an industrial disinfectant to inhibit the growth of harmful bacteria, e.g. in the white water of water-based paints and paper mills. As an agent, a solution! Compound [[[] or its salt or ester 0 per million parts
．． It can be used in aqueous compositions at concentrations ranging from 1 to 100 parts.

The compound [11[] of the present invention, its salt or ester is
It can be used alone or in combination with other active ingredients in the formulation of any of a variety of pharmaceutical preparations, for example as capsules, tablets, powders, solutions, suspensions or elysids. They can be administered orally, intravenously or intramuscularly.

Tablets for oral administration may contain the usual excipients such as binders such as syrup, gum arabic, zelalbyrolidone, fillers such as lactose, sugars, corn starch, calcium phosphate, sorbitol, glycine, etc., lubricants such as magnesium stearate, talc, It may contain polyethylene glycol, silica, etc., disintegrants such as potato starch, or available wetting agents such as sodium lauryl sulfate. Tablets can be coated by methods well known in the art. Oral liquid preparations include aqueous or oily suspensions,
It may be in the form of a solution, emulsion, syrup, elixir, etc., or it may be a dry product that is dissolved in water or other suitable solvent before use. Such liquid preparations may contain suspending agents such as sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
hydrogenated edible oils such as almond oil, fractionated coconut oil, oily esters, etc., such as aluminum stearate gel;
Propylene glycol or 1-rua I and 1-lua
It can contain propyl p-hydroxybenzoate, sorbic acid, etc. Suppositories can employ common suppository bases such as cocoa butter or other glycerides.

Injectable compositions may be presented in unit dosage form in ampoules or in containers with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous solvents, optionally containing auxiliary agents such as suspending agents, stabilizing agents and/or dispersing agents. You may do so. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable solvent, eg, sterile pyrogen-free water, before use.

They can also be formulated into suitable forms that are absorbed by the mucous membranes of the nose and throat or the bronchial tissues, such as powders, liquid sprays or inhalants, roseine, throat paints, and the like. For ocular or otic pharmaceutical administration, it may be used in liquid or semisolid form as capsules or as drops. Furthermore, it may be used as an external preparation using a hydrophobic or hydrophilic base such as an ointment, cream, lotion, paint, or powder.

In addition to the carrier, it may also contain other ingredients such as stabilizers, binders, antioxidants, preservatives, wetting agents, suspending agents, thickening agents, or flavoring agents.

Additionally, the compositions may contain active ingredients to provide a broader spectrum of antimicrobial activity.

For livestock, it may be formulated as a mammary formulation in a long-acting or fast-release matrix.

The compound [■] of the present invention, its salt or ester can be used as a therapeutic agent for bacterial infections, for example, for treating respiratory infections in mammals.
It can be used to treat urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, surgical infections, etc. The daily dosage depends on the condition of the patient being treated and the weight of the host, the method of administration (preferably parenteral for general infections and oral for intestinal infections) and frequency. Generally, the daily oral dosage will consist of about 15 to 300 IIlg of active ingredient per kg of patient body weight in one or more applications per day. The preferred daily dosage for adult humans is about 10 to about 150 mg of active ingredient per kg of body weight.
approximately 2.5 to approximately 75 times each time, divided into 2 to 4 times daily.
It is appropriate to administer parenterally in an amount of mg/kg.

Compositions containing Compound [111], its salts or esters, may be administered in several unit dosage forms, such as solid or liquid orally ingestible.

The composition per unit use, liquid or solid, contains 0.00% active substance.
Contains 5-99%. The preferred range is about lθ to 60%
It is. The compositions generally contain about 15 to 1500 active ingredients.
Contains mg. However, generally around 250
It is preferred to use dosages in the range ˜1000 mg.

The object compound [In], its salt, or ester can be produced, for example, by sulfonating the compound [11 or its salt, and then removing the protecting group and, if necessary, the ester gL group.

The raw material compound [1] can be used as a free substance, or sulfonation in the compound window is to introduce a sulfo group into the 1-position of the compound [11 or a salt thereof. This is carried out by reacting with a reactive derivative of sulfuric anhydride. Examples of reactive derivatives of sulfuric anhydride include sulfuric anhydride-pyridine, sulfuric anhydride-picoline, sulfuric anhydride-lutidine, sulfuric anhydride-N,
Adducts such as N-dimethylformamide, sulfuric anhydride-dioxane, sulfuric anhydride-trimethylamine, sulfuric anhydride-chlorosulfonic acid, or mixtures of sulfuric acid-acetic anhydride are used. In the above sulfonation reaction, about 1 to 10 mol, preferably about 1 to 5 mol of sulfuric anhydride or a reactive derivative thereof is used per 1 mol of compound [1]. The reaction temperature is about -20 to about 80°C, preferably 0 to 60°C. Usually solvents are preferably used, such as water or ethers such as dioxane, tetrahydrofuran, diethyl ether, esters such as ethyl acetate, ethyl formate, halogenated hydrocarbons such as chloroform, dichloromethane, etc. Common organic solvents such as hydrocarbons such as benzene, toluene, and n-hexane, and amides such as N,°N-dimethylformamide and N,N-dimethylacetamide are used alone or in combination. . Raw materials used [I
], depending on the sulfonating agent, reaction temperature, and type of solvent, the reaction usually completes in several tens of minutes to several tens of hours, but sometimes several days are required. After the completion of the reaction, the reaction product can be obtained with any purity by purification and separation means known per se, such as solvent extraction, recrystallization, and chromatography, but the reaction mixture can also be used as a raw material for the next step. can.

Next, the protecting group and, if necessary, the ester residue are removed from the obtained sulfonation reaction product to obtain the desired product. Here, the ester residue to be removed if necessary is generally used as a protecting group for a carboxyl group and can be easily removed after the sulfonation reaction, and simultaneously with the removal of the protecting group for the amino group represented by R3, Alternatively, it may be removed before or after removal of the protecting group for the amino group. Also,
Depending on the type, the amino group-protecting group and the carboxyl group-protecting group may be eliminated under the reaction conditions of the sulfonation, and in this case, there is no need to perform a new elimination step. As a method for removing the protecting group for the amino group and the protecting group for the carboxyl group, depending on the type of the protecting group, for example, a method using an acid, a method using a base, a method using a reduction, etc. can be selected as appropriate. . In the case of a method using an acid, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, etc., depending on the type of protecting group and other conditions. In addition to organic acids such as p-toluenesulfonic acid, acidic ion exchange resins and the like are used. In the case of a method using a base, the base may be an inorganic base such as a hydroxide or carbonate of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium, although it depends on the type of protecting group and other conditions. , such as metal alkogizides, organic amines,
In addition to organic bases such as quaternary ammonium salts, basic ion exchange resins and the like are used. When a solvent is used in the above acid or base method, 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 protecting group and other conditions, but for example, metals such as tin or zinc or metal compounds such as chromium dichloride or chromium acetate are combined with organic compounds such as acetic acid, propionic acid, hydrochloric acid, etc. A method using an acid such as an inorganic acid, a method of reduction in the presence of a metal catalyst for catalytic reduction, etc. are used. Catalysts used in the catalytic reduction method include platinum catalysts such as platinum wire, platinum sponge, platinum black, platinum oxide, and colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, and palladium carbonate. Examples include palladium catalysts such as barium, palladium on carbon, palladium silica gel, and colloidal palladium, and nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, and urushihara nickel. In the case of a reduction method using a metal and an acid, a metal compound such as iron or chromium and an inorganic acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid or propionic acid are used. The reduction method is usually carried out in a solvent, and for example, in the catalytic reduction method, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, ethyl acetate, etc. are often used. Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent. The reaction temperature in the acid method, the base method, and the reduction method is usually carried out under cooling or heating. Further, in order to remove a protecting group containing a silyl group, a compound containing a fluorine ion such as tetrabutylammonium fluoride or potassium fluoride can be used. Furthermore, when the protecting group for the amino group is a monochloroacetyl group, it can be easily removed by using, for example, thiourea or sodium N-methyldithiocarbamate.

Furthermore, the object compound of the present application can be produced by reacting compound [A], its salt or ester with carboxylic acid [11] or its reactive derivative, and then removing the protecting group and, if necessary, the ester residue. can.

Compound [A] may be used in its free state, but it may also be used as a salt or ester as described for compound [I[1]. Carboxylic acid [11] is used not only as a free carboxyl group but also as a reactive derivative of a carboxyl group. As a reactive derivative of carboxylic acid [R1,
For example, acid halides, acid anhydrides, active amides, active esters, active thioesters, etc. are used, and specific examples of such reactive derivatives are as follows.

(2) Acid halide: As the acid halide, for example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride; Examples of the acid anhydride include monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid (e.g., acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.) mixed acid anhydride. , aromatic carboxylic acid (for example, benzoic acid, etc.) mixed acid anhydride, symmetrical acid anhydride, etc. are used.

3) Active amide: As the active amide, for example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc. are used.

4) Active ester: Examples of the active ester include methyl ester, ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2.4-
In addition to esters such as dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, and mesylphenyl ester, ■-hydroxy-IH-2-
Esters with pyridone, N-hydroxyphthalimide, N-hydroxyphthalimide, etc. are used.

5) Active thioester: Here, the active thioester is, for example, 2-pyridylthiol. Thioesters with heterocyclic thiols such as 2-penzthiazolyl diol, etc. may be used.

Various reactive derivatives as mentioned above include carboxylic acid [11]
It is selected as appropriate depending on the types of R', IN' and R5.

In this method, first, 1 mol or more of carboxylic acid [U] or a reactive derivative thereof is reacted with 1 mol of compound [A], its salt or ester, preferably 1 to 4 mol. This reaction is usually carried out in a solvent. As the solvent, water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, or other general organic solvents that do not participate in the reaction are used. Among these, the hydrophilic solvent is water) -: abr al city + 71 ten sushit, -7S 4su -h ++,
When using -1'' in its free state, it is preferable to carry out the reaction in the presence of a condensing agent, such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(
4-diethylaminocyclohexyl)carbodiimide,
N-ethyl-N'-(3-dimethylaminobrobyl)carbodiimide and the like are used. Also, for example, alkali metal carbonates, trimethylamine, triethylamine, tributylamine, trialkylamines such as N-methylmorpoline and N-methylbiberidine, N,N-dialkylanilines, N,N-dialkylbenzylamines, pyridine, picoline, lutidine, 1.5-diazabicyclo[4,
3,0conon-5-ene, 1,4-diazabicyclo[2
, 2,2 cooctane, 1,8-diazabicyclo[5,4
This reaction can be carried out in the presence of a base such as undecene-7], and a liquid condensing agent that is similar to a base can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. The reaction is completed in several minutes to several tens of hours.

The product obtained in this reaction can be isolated and purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography, etc. The reaction mixture may be used as a raw material for the next step without further treatment.

The product obtained by the above acylation reaction is then used as a raw material for the step of removing the protecting group and, if necessary, the ester residue. This elimination step is carried out in the same manner as the aforementioned step of eliminating the protective group and, if necessary, the ester residue after sulfonation.

Furthermore, the object compound of the present application can be obtained by reacting, for example, compound [A] [for example, a salt or ester thereof represented by the formula with a compound represented by the formula υ [wherein R4 has the same meaning as above] or a reactive derivative thereof. , the resulting formula [wherein R' is a compound represented by the same meanings as above, a salt or ester thereof, and the formula %[] [wherein R1 is a compound represented by the same meanings as above or a salt thereof] It can also be produced by subjecting them to dehydration condensation and then removing the protecting group and, if necessary, the ester residue. The reaction between the above compounds [IV] and [V] is the reaction between the compounds [IV] and [V].
A] can be carried out in the same manner as the reaction between carboxylic acid [■], and the dehydration condensation reaction between compounds [■] and [■] can be carried out according to the method described in, for example, JP-A-52-125190. It can be done. Furthermore, it is advantageous to remove the protecting group and the ester residue in the same manner as described above.

The object compound [III] of the present invention from which the protecting group and, if necessary, the ester residue have been removed is isolated and purified by means known per se as described above.

In addition, since compound [I[1] has an amino group in addition to a sulfo group and a carboxyl group, it can generally form a salt by interacting with a base or an acid. Therefore, compound [II
[] is sometimes collected as a salt, and the obtained salt may be made into a free form or may be used as pond salt. Furthermore, the compound [TI[] obtained in free form may be used as a salt. As a method for converting compound [I[] obtained as a salt with a base into a free form, for example, a method using an acid is used. The acid used varies depending on the type of protecting group and other conditions, but 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 often used. Ru. In addition, acidic ion exchange resins and the like are used. Further, as the solvent, for example, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane, water, or a mixed solvent is often used.

This method is usually carried out at room temperature, but may also be carried out under cooling or heating. The reaction time varies depending on the type of acid and solvent and the temperature, but it is generally preferable to complete the reaction in a short time. The resulting free compound [11[] can be isolated by known means as described above. Furthermore, the compound [II[
] can be converted into an ester.

Note that the raw material compounds [+], [A
] and [■] can be produced, for example, by the method shown below or a method based thereon.

Method 1) (racemic) [■] (3S, 4S) [IX] [X] [X[] [XIIco[XIII] Method 2) [XVcoRI RI[XIX
] ■ [XX] CICII, C0CII, CO, Et + II,
NC3NII, -> [XXI] [
XXI[][XXII[co[XXIV] [wherein, DMB represents a 2,4-dimethoxybenzyl group, C
bz represents a benzyloxycarbonyl group, El represents an ethyl group, PNI3 represents a p-nitrobenzyl group, and R1 has the same meaning as above.

Cis-3-amino-4-methoxycarbonyl-1-(2,4-dimethoxybenzyl)-2-azetidinone [■], which is the starting material in the above method l), is described, for example, in the Journal・Society (Journal or theAmerica)
It is a known compound described in vol. 99, p. 2352 (1977), etc., and can be easily obtained. Compound [I[] is
For example, it can be manufactured by the above method 3) or a method similar thereto. Regarding the specific method,
For example, Japanese Patent Application No. 56-194311 and Japanese Patent Application No. 57-1943
-011965 etc.

The raw material compound [11, [A],
[■) may be used as a raw material for the reaction of the present invention after being separated and purified by the above-mentioned known methods or as a reaction mixture.

The present invention will be further explained in detail in the following experimental examples, working examples, and reference examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed.

Unless otherwise specified, elution in column chromatography in Examples and Reference Examples was performed using TLC (ThinLaye
The analysis was carried out under observation using chromatography (thin layer chromatography). In the TLC observation, Merck's GO was used as the TLC plate, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used as the detection method. Another detection method is to spray 48% hydrobromic acid onto a spot on a TLC plate, heat it to hydrolyze it, spray it with ninhydrin reagent, and then heat it again to change the color from red to reddish-purple. The elution fractions containing the target product were confirmed and collected. When two or more types of developing solvents are used, unless otherwise specified, the first solvent used is used to elute the by-product, and the second solvent used is used to elute the target product. In the column chromatography purification using "Amberlite", water was first used as the developing solvent, and then an aqueous ethanol solution was used while gradually increasing the concentration, unless otherwise specified in the Examples and Reference Examples. A sodium solution containing the target product was used as a desiccant.

“Amberlight” is manufactured by Rohm and Haas (Rohm & Haas)
hm & l1ass Co, in U, S, A
"Dowex" is manufactured by Dow Chemical Co., Ltd., and "Dowex" is manufactured by Dow Chemical Co. The NMrt reactor is EM390 (90 MI (z
) or 'r60((i.

It was measured with a MIIZ)fi spectrometer, and all δ values were expressed in ppm. The symbols in Examples and Reference Examples have the following meanings.

S: singlet d
: Doublet (doub 1et)q :
quartet ABq: A
B-type quartet (A BtYI) equartet) d, d, : double doublet (doub
ledoubLeL) m: multiplet
br,: broad cons
tant) Hz: hertz (llerz) mg= milligram (milligram) g, gram (
gram) -2 milliliter Ph
: Phenyl MeOII : Methanol CHCla : Chloroform DMSO : Dimethylsulroxide Experimental Examples For the target products obtained in Examples 2 and 4, M T C
(n+cg/d) was measured by the following method and summarized in the table below.

Measurement method The MIC of the test compound was determined using the agar dilution method.
ion method). That is, sequentially weighted aqueous solutions t and oi of the test compound were poured into a Petri dish, and then Trypticase soy agar was poured into a Petri dish.
agar) Pour 9.0d and mix. On the mixed agar plate, a suspension solution of the test bacteria (approximately 108 CF'U/d
) to paint the floor.

After one-night incubation at 37°C, the lowest concentration of the test compound that completely inhibits the growth of the test bacteria is determined at the minimum inhibitory concentration (MIC).
1nhibiLoryconcentration).

Test bacteria (1) Enterobacter cloacani (Enterobacter
ctercloacae) I FOl 2937 (
2) Talebsiella pneumoniae (Klebsiel)
lapneumoniae) TN l 711 (3
) Pseudomonas aeruginosa
Asaeruginosa) GN 3407 Results (mCg/form) Reference Example 1 Cis-3-amino-4-methoxycarbonyl-1-(2
, 4-dimethoxybenzyl)-2-azetidinone23.
54 g and 16.17 g of p-toluoyl-di-monotartrate monohydrate were added to 600a4 acetonitrile, heated to dissolve, filtered and allowed to cool. When the precipitated crystals were filtered and washed with cooled acetonitrile, the salt 20.3
g is obtained. Add this to acetonitrile 300711i2
Recrystallize from to obtain 16.3 g of salt.

Melting point 165-168℃ [α几 +71.9°(cm 0 , 985, MeO
[1] Mix this salt with 100 J of water and 20 J of tetrahydrofuran.
Dissolve in the 0h4 mixture and add 6.1 g of sodium hydrogen carbonate. Next, carbobenzoxy chloride 4.2- is added dropwise while stirring under water cooling. 1 hour under water cooling, 1 hour at room temperature
After stirring for an hour, tetrahydrofuran is distilled off under reduced pressure at a bath temperature of 30°C or lower.

Add 400 g of ethyl acetate and 200 g of water to the residue and shake. The aqueous layer is re-extracted with 2001 nl of ethyl acetate, and the extracts are combined and washed twice with 2% aqueous sodium bicarbonate. Then, the mixture is washed with brine and IN hydrochloric acid 1 saline solution in order, and after drying, the solvent is distilled off under reduced pressure, and 3LJ of ether is added to the residue. The formed crystals are collected by filtration, heated to 50 ml of ethyl acetate to dissolve them, and 50 d of hexane are added to the filtered solution and allowed to cool. When the precipitated colorless product is filtered, (3S, 4S)-cis-3-
6.45 g (37.5%) of benzyloxycarboxamide-4-methoxycarbonyl-1-(2,4-dimethoxybenzyl)-2-azetidinone are obtained.

Melting point 120-121'c [α]22+ 24.4° (cm 1.08.(j-I
C1,)■Rν Nuji 5-'cm-': 3300.1
? 70.1745,1695aX Elemental analysis value Ctd-1t-N to q (%)
H (%) N (%) Calculated value 61.67 5.65 6.54 Actual value 61.50 5.59 6.37 Reference example 2 (33,4S)-cis-3-benzyloxycarboxamide-4-methoxy Dissolve 12.8 g of carbonyl, 1-(2゜4-dimethoxybenzyl)-2-azetidinone in 300 g of tetrahydrofuran, and while stirring under cooling with water, dropwise add a solution of 28 g of sodium hydroxide dissolved in 150 d of cold water over 10 minutes. . After dropping, cool with water for 1
Stir at room temperature for 3 hours. Tetrahydrofuran is distilled off under reduced pressure at a bath temperature of 30°C or less, water is added to the residue, and the mixture is filtered. Washing with water and ethyl acetate yields 44 g of crude crystals. Combine the mother liquor and washing solution, shake and separate the ethyl acetate layer. The aqueous layer was re-extracted with ethyl acetate, and the ethyl acetate layers were combined with IN hydrochloric acid.

Wash with saline solution. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the crude crystals obtained earlier were combined with the residue and recrystallized from ethyl acetate to give (38°4S)-cis-3.
9.1 g (76%) of -benzyloxycarboxamide-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-azetidinone are obtained as colorless crystals.

Melting point 137-138°C [α12” +32.7° (C=l, CII
C+3) 11L Shinuji'-'''cm-': 3480.
3345.1740.1715ax NM(L(CDC13)δ: 3.5-3.9(311
, C, -11°C, -C1i,) ,'A, 711(
311,s, 0C113), 3.79 (:(Il
, S,OCI+,).

4.35 (211,s,N,-ell,), 4.9-5
．． 2(ill, m, C, -H).

5.07 (211,s, C11ta), 6.06 (i
ll, d, J=1011z, Cs-N11).

6.3-6.6 (211, m, aromatic proton), 7.
1-7.3 (ill.

m, aromatic proton), 7.32 (511, s, -
IJ) :) ) Elemental analysis value Ct 1Hz 4N t
C (%) as Oa! -1(%) N(
%) Calculated value 62.99 6.04 7.00 Actual value 62.92 5.90 7.03 Reference example 3 (3S,4S)-cis-3-benzyloxycarboxamide-1-(2,4-dimethoxybenzyl )-2.0 g of 4-hydroxymethyl-2-azetidinone is dissolved in 40 methylene chloride, and 0.52 d of chlorosulfonyl isocyanate is added while stirring under water cooling. After stirring for 30 minutes under water cooling, chlorosulfonyl isocyanate 0.3
Add 5d and stir for another 10 minutes. A solution of 1.26 g of sodium sulfite dissolved in 301 n1 of water was added to the reaction solution under water cooling, and the mixture was stirred at room temperature for 1 hour. Methylene chloride was distilled off under reduced pressure and the residue was extracted with chloroform.

The extract is washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the residue was filtered to obtain 2.46 g of crude crystals. By recrystallizing Kiyo from ethyl acetate-hexane, (3S,
4S)-cis-3-benzyloxycarboxamide-4
-Carbamoyloxymethyl-1-(2,4-dimethoxybenzyl)-2-azededinone as colorless crystals.
72 g (77.7%) are obtained.

Melting point 179-111! 0°C [a]'jo4゛5+ 34,5' (c-0,
8,DMSO)InshiKB'cm-':34
10,3300,1760.1710aX NMrt(d@-DMSO)δ: 3.74(al
l, s, 0CIt+).

3, 76 (all, s, 0CIIs), 3.7~
4, :a(311,m, C4-Il, C4-C
11t).

4, 2f) (211, ABQ, J = 1511z,
N + -CIlt), 4, 92 (111,,
d, d, j= 5.1QIlz, c, -1t),
5.05 (211,s, C1l, I'h), 7
, 35 (511, s.

Ph), 7.87 (111, d, J = 1011z, C
3-N11) Elemental analysis value C□IItsNiO7 as C
(%)■! (%) N (%) Calculated value 59. ．． 59 5.68 9.48 Actual value 59,30 5.70 9.57 Reference example 4 (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-1-(2,4
-dimethoxybenzyl)-2-azetidinone 1.60g
, potassium persulfate 1.41g and dipotassium phosphate 0
．． 85 g was suspended in a mixture of 36 molar acetonitrile and 18 liters of water, and stirred for 80 minutes at a bath temperature of 95° C. under an argon atmosphere. Acetonitrile was distilled off under reduced pressure, and 10 ml of brine was added to the residue, followed by extraction with a mixed solution of ethyl acetate and tetrahydrofuran. The extract is washed with 5% sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the solidified residue was recrystallized from ethyl acetate.
426 mg (40.3%) of (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azetidinone is obtained as pale yellow crystals. After concentrating the mother liquor, purification by silica gel column chromatography (70 g, developing solution: CIf C13MeOH-ethyl acetate, 85:10°5) further yielded 353II1.
g crystals (colorless) are obtained.

Total yield 779+ng (73,6%) Melting point 191-
192℃ [αkoni”+60.6° (cm 1,, MeO
H) IRνK"cm-': 3400.3300.175
5. (sh).

I+1ax 1745, 1695 NMIt(d, -DMSO) δ: 3.70-4.
25 (311, C, -El.

C, -C1l, ) , 4.95(ill , d, d
, J = 5.10112. C5-11), 5.
05 (2I1.s, Cl1-Ph), 6.47
(2+1. br, s, C0N11z), 7.
33 (511, s.

Ph), 7.92 (Hl, d, J = 1011
z, C3-Ni1), 8.30(ltl, br
,s.

N, -11) Elemental analysis value CI 31-I Is N s C (%) as Os ((%) N (%) Calculated value 53.23 5.15 14.32 Actual value 52.83 5.02 14 .26 Reference Example 5 293 mg of (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azededinone was dissolved in dioxane 10d, and sulfuric anhydride-
Add 477 mg of pyridine complex and stir at room temperature for 14 hours. Dioxane was distilled off under reduced pressure, and 20 d of water and 20 ml of DOWEX 50W (Na) were added to the residue, followed by stirring at room temperature for 1 hour. The resin is filtered off and the filtrate is concentrated under reduced pressure.

The residue was subjected to Amberlite XAD-2 column chromatography, eluting sequentially with water, 5% ethanol and 10% ethanol. When both parts containing the target product are combined, concentrated under reduced pressure and lyophilized, (3S,4S)-cis3
270 mg (64%) of sodium -benzyloxycarboxamide-4-carbamoyloxymethyl-2-azetidinone-1-sulfonate are obtained as a colorless powder.

[αkoε5 +29.4 ° (cm0.715.water)
I Rv KBrcn+-': 3500, 3370, 3
320,1795゜max x 1760.1730.169O NMR (d, -DMSO) δ: 3.85 to 4.40
(311,C,-11°C4-Cl1-), 4,
92 (111, d, d, J = 5.10112.
C3-If), 6.1G~6,65(ill, C
0NIl*), 7.35 (511,s, Ph)
, 7, 98 (lIl, d, J = 1011z,
C, -111) Elemental analysis value Cl31-114N, Nao @S ・l
! -C as H10 (%) H (%) N (%) Calculated value 36.97 4.06 9.95 Actual value 37.24 4.13 10.02 (3S, 4S
)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2=azetidinone 674 m
Dissolve g in methanol 50g, add 5% palladium on carbon 3
Add 00o+g and stir for 30 minutes at room temperature under hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was mixed with a mixture of tetrahydrofuran and water (1:1) 20-
2-(2-chloroacetamido-4-thiazolyl)
Add 162 g of -(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acedel chloride hydrochloride. After stirring for 30 minutes under water cooling, 100 ml of brine was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (60 g, developing solution: ethyl acetate), both fractions containing the target product were collected, and the solvent was distilled off under reduced pressure. When ether was added to the residue and the resulting colorless solid was collected by filtration, (3S,4S)-cis-3-(2
-(2-chloroacetamide-4-deazolyl)-2-(
1.25 g of Z)-[1-methyl-1-(4-nitrobenzyloxycarbonyl)ethoxyiminoacetamide)-4-carbamoyloxymethyl-2-azetidinone (
87%) obtained.

Melting point 190-195℃ (decomposition) [α℃ +34.5° (c = 0, 145, MeO
H) I Rv KB'cm-': 3450, 3300.
1753, 1740 (sh).

aX 1690.166O NMR (d, -DMSO) δ: 1.51 (311,
S, C113), 1.53 (311, s, ells)
, :(,8~4 ,4 (311,C,-11,C,
-C1,),4,37 (211,s,clcllt
), 5.2-5.45 (311, C3-H, C11tP
h), 6.53 (211, br, s, cONllt),
7.38 (111,s, proton at 5-position of thiazole ring),
7.62 (2+1.d, J = 8■2.aromatic proton).

8.07 (211, dJ=811z, aromatic proton)
, 8.50 (III.

br, s, N, -H), 9.23 (III, d, J=9
11z,C,-N11) Example 1 (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azedidinone = 422 mg of sodium 1-sulfonate was dissolved in water lO-
and tetrahydrofuran for 10 hours, add 422 mg of IO% palladium on carbon, and stir at room temperature under hydrogen atmosphere for 1 hour.
Stir for an hour.

The catalyst was filtered off, and a mixture of water and tetrahydrofuran (1:1
) Wash at 30°C. Combine the filtrate and washing liquid, add 202 mg of baking soda while stirring under water cooling, and then add 2-(2-chloroacetamido-4-deazolyl)-2-(Z)-(p-
Add 614 mg of nitrobenzyloxycarbonylmethoxyimino)acetyl chloride hydrochloride. 30 under water cooling
After stirring for a minute, the pH was adjusted to 5 with IN hydrochloric acid and the pH was adjusted to 30 °C under reduced pressure.
Concentrate to -.

To the residual solution, 10 d of tetrahydro7ran was added, followed by 129 mg of sodium N-methyldithiocarbamate, and the mixture was stirred at room temperature. 129 mg of sodium N-methyldithiocarbamate was added after 40 minutes and after 80 minutes, and the mixture was stirred for a total of 2 hours. Tetrahydrofuran is distilled off under reduced pressure, and the remaining aqueous solution is washed with ether and concentrated again under reduced pressure. Amberlite XAD-
2 (200y, 12), water, 5% ethanol, 10% ethanol.

Elution was performed sequentially with 15% ethanol and 20% ethanol, and both fractions containing the target product were collected, concentrated under reduced pressure, and lyophilized to yield (3S,4S)-cis-3-[2-(2-amino-4 -thiazolyl)-2-(Z)-(p-nitrobenzyloxycarbonylmethoxyimino)acetamide]
-4-Carbamoyloxymethyl-2-azetidinone-
Sodium 1-sulfonate as pale yellow powder for 50 h
g (76%) obtained.

[(Z], +IO, l' (C=1.water) I R
v I< B rcm-': 1760, 1720 (b
r, sh), 1870ax NMR (d, -DMSO) δ: 3.9-4.4 (3+
1. C, -11, C, -C11,), 4.78 (2
1+, s, 0CI1. -COOCIIm),
5.28 (ill, d, d, J= 4, 5.101
12. C, -II), 5.35 (211, S, 0
CII! -COOCIll).

6.45 (211, br, s, C0NL), 6.76 (
111,s, proton at 5-position of thiazole ring), 7.18(
211, br, s, thiazole ring 2-position amino group), 7.
68 (211, d, J-811z, aromatic proton).

8, 19 (211, d, J = 811z, aromatic proton), 9.18 (III, d.

-J = 1011z, C, -III) Elemental analysis value C+
*■IIIIN? N aO+*S t ・2 Hto as C (%) 14 (% ) N (%) Calculated value 34.60 3.36 14.87 Actual value 34.44 3. IQ 14.82 Example 2 (3S,4S)-cis-3-[2-(2-amino-4-
350 mg of sodium thiazolyl')-2-(Z)-(p-nitrobenzyloxycarbonylmethoxyimino)acetamide]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonate was dissolved in 20 d of water and diluted with lO
Add 350 mg of % palladium on carbon and stir for 1 hour at room temperature in a hydrogen atmosphere. Filter off the catalyst and wash with water. Combine the filtrate and washing liquid, add 40 NL of DOWEX 50W (H), and stir for 1 hour under water cooling. The resin is filtered off and washed with water and a mixture of water and acetone. The filtrate and washing liquid were combined and concentrated under reduced pressure, and the residue was washed with Amberlite XAD-2 (15
0rJ) was subjected to column chromatography and eluted with 5% ethanol. Both fractions containing the target product are concentrated under reduced pressure and then lyophilized to yield (3S,4S)-cis-3-[2-(2-amino-4-deazolyl)-2-
(Z)-(carboxymethoxyimino)acetamide]-
4-carbamoyloxymethyl-2-azededinone-1
- 164 mg (61%) of sulfonic acid are obtained as a colorless powder.

[α] 45° (c=l, DMSO) I Rv
KBrcm-': 176Q, 17 to 5.167Q, 16
4Q118X NMR (d, = DMSO) δ: 3.9-4.4 (31
1,C,-11゜C4-Cl11), 4,66(
2+1. s, No-Cl1t), 5.28(i
ll, d, d, J ~4.5.1011z, c, +-
! I), 6.92 (III, s, thiazole ring 5-position
ton), 9.33 (ill, d, J= 1011z,
ca-N++) Example 3 (3S,4S)-cis-3-(2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(4-nitrobenzyloxy) Dissolve 1.13 g of carbonyl)ethoxyimino]acetamide)-4-carbamoyloxymethyl-2-azededinone in N,N-dimethylformamide, cool to -78°C, and add sulfuric anhydride-N,N-dimethylformamide complex solution. (1,56M
e degrees) Add 2.08 degrees. After stirring for 3 hours under water cooling, at -78°C, the above complex solution; i0.23d was added and stirred for another 1 hour under water cooling. Add 0.2 pyridine to the reaction solution.
When 9rJ is added and then ether tooy is added, a candy-like substance is precipitated. The supernatant ether layer was discarded, the precipitated candy-like substance was dissolved in water, and DOWEX 5 (IW(Na)3
Add 0d and stir at room temperature for 1 hour.

The resin is filtered off, and the filtrate is concentrated under reduced pressure to about 30 rJ. Add 232 mg of sodium N-methyldithiocarbamate to the residual solution and stir at room temperature. After 1 hour and 2 hours, 232 mg of sodium N-methyldithiocarbamate was added, and the mixture was stirred for a total of 3 hours. After washing the reaction solution with ether, it was concentrated under reduced pressure, and the residue was subjected to column chromatography using Amberlite XAD-2 (18 (ld)).
Elution was performed sequentially with 10% ethanol, 15% ethanol, and 20% ethanol, and both fractions containing the target product were collected, concentrated under reduced pressure, and lyophilized. Amino-4-deazolyl)-2-(Z
)-[1-Methyl~1-(4-nitrobenzyloxycarbonyl)ethquinimino]acetamide)-4-carbamoyloxymethyl-2-azededinone-1-sulfonate sodium as pale yellow powder (579 mg (46,4
%) obtained [αcoD +6.5 ° (c= 1
, water) I RνK"am-': 1760.1725
．． 1670aX NMR (d, -DMSO) δ: 1.47 (611,
S, 2X C113).

3,95~4,35(3+1.C,-11,C4-C
l+ri, 5.20-5.45 (311.

C, -Il, 0CII, ) , 6.43 (21+, b
r, s, C0NI1. ), 6.68(lit,
s.

thiazole ring 5-position proton), 7.23 (211,b
r, s, thiazole ring 2-position amino group), 7.63 (21
1, d, J=811z.

aromatic proton), 8.11 (211, d, J=811
z, aromatic proton), 9.00 (111, d, J=9
11z, C3-N11) Elemental analysis value Ct+HttNvN
aO+tS 2・2! -C as HtO (%) H (%) N (%) Calculated value 36.21 3.91 14.08 Actual value 36.36 3.73 14.05 Example 4 (3S,4S)-cis-3- (2-(2-amino-4-
Thiazolyl)-2-(Z)-[1-methyl-1-(4-
344 mg of sodium nitrobenzyloxycarbonyl)ethoxyiminocoacetamide)-4-carbamoyloxymethyl-2-azetidinone-1-sulfonate was added to 1 part of water.
71n! 1 and 344 mg of 1O% palladium on carbon.
and stir for 50 minutes at room temperature under hydrogen atmosphere. Filter off the catalyst, wash with water, combine the filtrate and washing liquid, and add 4 liters of baking soda over water.
After adding 2 mg, wash with ethyl acetate. Add 40 ml of DOWEX 50 W (1-N) to the aqueous solution and stir for 1 hour under water cooling.

The resin is filtered off and the filtrate is concentrated under reduced pressure. The residue was subjected to column chromatography using Amberlite XAD-2 (150d) with water, 5% ethanol and 10%
Elute sequentially with % ethanol.

Both fractions containing the target product are collected, concentrated under reduced pressure, and lyophilized to yield (3S,4S)-cis-3-42-(2-amino-
4-thiazolyl)-2-(Z)-(1-carboxy-1
185 mg (70%) of medylethoxyimino)acetamide]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid are obtained as a colorless powder.

[α]25+34.3° (c=1, water) I Rv
KBrcm-': 1760.1715 (br,), 16
35ax NMR (d, -DMSO) δ: 1.46 (611,
S, 2X C113).

Claims (2)

[Claims] (1) (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, or a salt or ester thereof. (2) (3S,4S)-cis- characterized by catalytic reduction of sodium (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azetidinone-1-sulfonate. 3-amino-
4-carbamoyloxymethyl-2-azetidinone-1
- A method for producing sulfonic acid or its sodium salt.