JPH10130272A - Method for producing 2-carboxypenam derivative or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject derivative useful as an antimicrobial agent in a high yield by reacting a specific compound with a specific carboxyamidine. SOLUTION: (A) A compound of formula I [R<1> is a (substituted) phenyl; R<2> is a (protected) sulfo or sulfonato; R<3> is a (protected) carboxyl or carboxylato] or its salt is reacted with (B) benzotriazole-1-carboxyamidine or its salt or 1H-pyrazole-1-carboxyamidine or its salt to give the objective derivative of formula II [R<4> is guanidino] such as (3R,5R,6R)-3-carboxy-6-[D-α-(2- fluoro-4-hydroxyphenyl)-α-sulfoacetamido]-3-(3-guanidino-2-oxoimidazolidin-1-yl)-7- oxo-4-thia-1-azabicyclo[3.2.0]heptane monosodium salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a 2-carboxypenam derivative or a salt thereof useful as an antibacterial agent.

[0002]

2. Description of the Related Art General formula [2]

Embedded image During the "formula, R ^1, a halogen atom or a protected or unprotected good hydroxyl radical optionally substituted phenyl group; R ² is an optionally protected sulfo group or a sulfonate group; R ³ is And R ⁴ represents a guanidino group, respectively. ”A method for producing a 2-carboxypenam derivative or a salt thereof represented by the formula: No. 6,086,045. However, the method described in this publication is not sufficient as an industrial production method because it involves a low yielding step.

[0003]

SUMMARY OF THE INVENTION It has been desired to develop a method for obtaining a desired product in a high yield in an industrial process for producing a 2-carboxypenam derivative or a salt thereof.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have obtained the general formula [1]

Embedded image Wherein R ¹ , R ² and R ³ have the same meanings as described above, or a salt thereof, and benzotriazole-1-carboxyamidine or a salt thereof, or 1H-pyrazole-1. -By reacting with carboxamidine or a salt thereof to obtain 2-
The present inventors have found that a carboxypenam derivative or a salt thereof can be obtained in a high yield, and have completed the present invention.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the present specification, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom unless otherwise specified.

Examples of the carboxyl-protecting group include carboxyl-protecting groups conventionally known in the field of penicillin and cephalosporin compounds, and include, for example, catalytic reduction, chemical reduction or treatment under other mild conditions. Such as an ester forming group which is easily removed in vivo; or an organic silyl group, an organic phosphorus group or an organic tin group which is easily removed by treatment with water or alcohol. Ester forming groups and the like. Among these protecting groups, suitable protecting groups include, for example, lower alkyl groups such as methyl, ethyl, propyl and tert-butyl; benzyl, 4-methoxybenzyl, 4-nitrobenzyl and 3,4-dimethoxy Aralkyl groups such as benzyl, 4-hydroxy-3,5-di (tert-butyl) benzyl, phenethyl, diphenylmethyl, triphenylmethyl or bis (methoxyphenyl) methyl; phthalidyl groups; 2-iodoethyl or 2, Two,
Halo-lower alkyl groups such as 2-trichloroethyl and the like; acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl,
Acyloxy-lower alkyl groups such as 1-acetyloxyethyl, 1-pivaloyloxyethyl, 1-acetyloxy-n-propyl or 1-pivaloyloxy-n-propyl; 5-methyl-2-oxo-1,3 −
5-lower alkyl-2-oxo-1,3-dioxol-4-yl lower alkyl groups such as dioxol-4-yl-methyl; lower alkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl or isopropoxymethyl An oxy lower alkyl group; or a lower alkoxycarbonyloxy lower alkyl group such as methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl or 1-propoxycarbonyloxyethyl.

Examples of the hydroxyl-protecting group include formyl, acetyl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, allyloxycarbonyl, benzyloxycarbonyl, trimethylsilyl and tert-butylmethylsilyl. Examples of the sulfo-protecting group include lower alkyl groups such as methyl, ethyl, propyl and tert-butyl.

The protecting group for the amino group includes, for example, p
-Nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, tert
-Butyloxycarbonyl group and the like. Examples of the guanidino group-protecting group include nitro, 4-methoxyphenylsulfonyl and 2,4,6-trimethylphenylsulfonyl groups. Next, the present invention will be described in more detail.

[0009]

(Equation 1)

Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. The compound of the general formula [2] or a salt thereof is a compound of the general formula [1] or a salt thereof. It can be produced by reacting a salt with benzotriazole-1-carboxamidine or a salt thereof or 1H-pyrazole-1-carboxamidine or a salt thereof in the presence or absence of a base.

The salts of the 2-carboxypenam derivatives of the general formulas [1] and [2] include salts of a generally known basic group such as amino group or guanidino group or acidic group such as carboxyl group or sulfo group. Salts. Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid; salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid or trifluoroacetic acid; or methanesulfonic acid, benzenesulfonic acid, Salts with sulfonic acids such as p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid and the like, and salts in an acidic group include, for example, salts with an alkali metal such as sodium or potassium; Salts with alkaline earth metals; ammonium salts; or trimethylamine, triethylamine, tri-n-butylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, Benzylamine, N
And salts with nitrogen-containing organic bases such as -benzyl-β-phenethylamine or N, N'-dibenzylethylenediamine.

The salts of benzotriazole-1-carboxamidine and 1H-pyrazole-1-carbamidine include salts of amidino groups which are generally known. Examples of the salt of the amidino group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid. Listed and preferred salts include p-toluenesulfonate and hydrochloride.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride and chloroform; and tetrahydrofuran and dioxane. Ethers; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ketones such as acetone; alcohols such as methanol and ethanol; nitriles such as acetonitrile; dimethylsulfoxide Sulfoxides, water, etc., and these solvents may be used alone or in combination of two or more.

The base optionally used in this reaction includes, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide; an alkali hydrogen carbonate such as sodium hydrogen carbonate; an alkali carbonate such as sodium carbonate or potassium carbonate. An alkali acetate such as sodium acetate; potassium tert-butoxide, triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, 2,6-lutidine, N-methylpiperidine, N-methylmorpholine, tetramethylguanidine or 1,8- And inorganic or organic bases such as diazabicyclo [5.4.0] undec-7-ene.

The amount of benzotriazole-1-carboxamidine or a salt thereof or 1H-pyrazole-1-carboxamidine or a salt thereof is 1 to 15 times the molar amount of the compound of the formula [1] or a salt thereof. is there. The amount of the base to be used is 0.1 to 10-fold the molar amount of the compound of the general formula [1].

The reaction temperature and the reaction time can be appropriately selected according to the starting materials and the solvent used, and are not particularly limited, but are usually 0 to 70 ° C, preferably 20 to 50 ° C, and 5 minutes to 5 minutes.
It should be carried out for 24 hours.

In general formula [1] or a salt thereof in the above-mentioned production method, isomers (for example, optical isomers,
When geometric isomers and tautomers are present), these isomers can be used, and various crystal forms, hydrates and solvates of the above compounds can be used.

The thus-obtained compound of the general formula [2] or a salt thereof is converted into a compound by a generally known method, for example,
A compound of the general formula [2] having a protected guanidino group or a salt thereof can be obtained by the method described in “Basic and Experimental Peptide Synthesis”, pp. 61-64, Maruzen Co., Ltd., 1985. Next, a method for producing a compound of the general formula [1] or a salt thereof as a raw material will be described.

[0019]

(Equation 2)

Wherein R ⁵ represents a phenyl, p-methylphenyl, p-methoxyphenyl, thienyl or furyl group, and R ¹ , R ² and R ³ each have the same meaning as described above. . "

Examples of the salts of the compounds of the general formulas [3] and [5] include the same salts as those described as the salts of the compound of the general formula [2]. Salts of the compound of the general formula [4] include, for example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; or trimethylamine, triethylamine, tributylamine, pyridine , N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine,
Dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine or N,
And a salt with a nitrogen-containing organic base such as N'-dibenzylethylenediamine.

The reactive derivative of the compound of the general formula [3] or a salt thereof includes, for example, trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl,
Organic silyl groups such as trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilanyl or dimethoxysilanediyl or dimethoxyphosphinyl, 1,3,2-dioxophosphoran-2-yl, 4-
Compounds in which an organic phosphorus group such as methyl-1,3,2-dioxophosphoran-2-yl or 1,3,2-dioxophospholinan-2-yl is bonded to an amino group which is a reaction site. Can be

The reactive derivative of the compound of the formula [4] or a salt thereof includes, for example, acid halides, acid anhydrides, mixed acid anhydrides, active acid amides described in JP-A-59-93085 and the like. Active ester, active thioloester or acid azide or compound of general formula [4] and Vilsmeier
Reactive derivatives with reagents and the like are included.

The compound of the general formula [5] or a salt thereof can be prepared by converting the compound of the general formula [3] or a salt thereof or a reactive derivative thereof into a compound of the general formula [4] in the presence or absence of a base. It can be obtained by reacting with a salt thereof or a reactive derivative thereof.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; and solvents such as tetrahydrofuran, dioxane and dimethoxyethane. Ethers; N, N-
Amides such as dimethylformamide and N, N-dimethylacetamide; ketones such as acetone; alcohols such as methanol and ethanol; esters such as ethyl acetate; nitriles such as acetonitrile;
And water. These solvents may be used alone or in combination of two or more.

The base optionally used in this reaction includes, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide; an alkali hydrogen carbonate such as sodium hydrogen carbonate; an alkali carbonate such as sodium carbonate; sodium acetate Alkali acetate such as potassium ter
t-butoxide, triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, 2,6
Inorganic or organic bases such as -lutidine, N-methylpiperidine, N-methylmorpholine, tetramethylguanidine or 1,8-diazabicyclo [5.4.0] undec-7-ene.

In this reaction, a condensing agent may be used. Examples of the condensing agent include N, N-disubstituted carbodiimides such as N, N-dicyclohexylcarbodiimide; and 1,1'-carbonyldiimidazole. .

The amount of the compound represented by the general formula [4] or a salt thereof or a reactive derivative thereof is 1.0 to 1.5 times the molar amount of the compound of the general formula [3] or a salt thereof or a reactive derivative thereof. is there. The reaction temperature and the reaction time can be appropriately selected according to the starting materials and the solvent to be used, and are not particularly limited. However, the reaction is usually carried out at −70 to 40 ° C. for 10 minutes to 48 hours.

The compound of the general formula [1] or a salt thereof can be produced by subjecting the compound of the general formula [5] or a salt thereof to a generally known elimination reaction of an amino protecting group. As the elimination reaction, for example, a compound of the general formula [5] or a salt thereof is treated with hydrazine, substituted hydrazine or hydroxyamine in the presence of an acid to obtain a compound of the general formula [1]
Or a reaction to obtain a compound thereof or a salt thereof.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include alcohols such as methanol and ethanol; esters such as ethyl acetate; and tetrahydrofuran and dioxane. Ethers; amides such as N, N-dimethylformamide; and water. These solvents may be used alone or in combination of two or more.

The substituted hydrazine used in this reaction includes phenylhydrazine, p-methoxyphenylhydrazine, p-methylphenylhydrazine, p-nitrophenylhydrazine, 2,4-dinitrophenylhydrazine, p-methylphenylsulfonylhydrazine and And semicarbacid hydrochloride.

Examples of the acid used in this reaction include mineral acids such as sulfuric acid and hydrochloric acid; sulfonic acids such as p-toluenesulfonic acid; and organic carboxylic acids such as acetic acid.

The amounts of the substituted hydrazine and hydroxylamine are 1 to 3 moles compared to the compounds of the formula [5]. The amount of the acid to be used is 0.1 to 3 moles per 1 mole of the compound of the general formula [5]. The reaction temperature and reaction time
The method can be appropriately selected according to the starting materials and the solvent to be used, and is not particularly limited.

In the method for producing the compound of the present invention and the method for producing the starting compound described above, when there are active groups other than the reaction site, these groups may be protected in advance and then eliminated after the reaction. After completion of the reaction, the reaction target product can be used for the next reaction without isolation, and can be isolated and purified by a usual method such as recrystallization or column separation.

[0035]

EXAMPLES Next, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The wave number of IR indicates absorption of carbonyl.

Reference Example 1 (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-3- [3- (p-methylbenzylideneamino)
Dissolve 60 g of 2-oxoimidazolidin-1-yl] -7-oxo-6-phenylacetamido-4-thia-1-azabicyclo [3.2.0] heptane in 600 ml of methylene chloride, and add -60 ° C. Then, 37.8 g of N, N-dimethylaniline and then 27.8 g of phosphorus pentachloride are added, and the mixture is stirred at -20 ° C for 30 minutes. The reaction mixture was cooled to -60 ° C, 37.1 g of methanol was added,
After stirring for 1 hour under ice cooling, the precipitated crystals were collected by filtration.
(R, 5R, 6R) -6-amino-3-diphenylmethyloxycarbonyl-3- [3- (p-methylbenzylideneamino) -2-oxoimidazolidin-1-yl] -7
44 g of -oxo-4-thia-1-azabicyclo [3.2.0] heptane monohydrochloride are obtained. IR (KBr) cm ^-1 : 1800,1730,1710

Reference Example 2-1 D-α- (2-fluoro-4-hydroxyphenyl)-
15.2 g of α-sulfoacetic acid / dicyclohexylamine salt / 1/2 hydrate was suspended in 152 ml of methylene chloride, and N,
7.9 g of N-diisopropylethylamine are added, followed by dropwise addition of 8.0 g of trimethylsilyl chloride. After stirring the reaction mixture at room temperature for 1 hour, thionyl chloride 3.5 g at -30 ° C
And the mixture is stirred for 1 hour under ice cooling.

Reference Example 2-2 (3R, 5R, 6R) -6-amino-3-diphenylmethyloxycarbonyl-3- [3- (p-methylbenzylideneamino) -2-oxoimidazolidin-1-yl]
-7-oxo-4-thia-1-azabicyclo [3.2.
0] 13 g of heptane monohydrochloride is suspended in 130 ml of methylene chloride, and 16.3 g of tri-n-butylamine is added. The solution is cooled to -60 ° C, the reaction mixture prepared in Reference Example 2-1 is added dropwise thereto, and the mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered off. 200 ml of water was added to the filtrate, the organic layer was separated, washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 150 ml of ethanol was added to the obtained residue, and the precipitated crystals were collected by filtration to give (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- [D-α- (2-Fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- [3
-(P-methylbenzylideneamino) -2-oxoimidazolidin-1-yl] -7-oxo-4-thia-1-
15.1 g of azabicyclo [3.2.0] heptane-1 tri-n-butylamine salt are obtained. IR (KBr) cm ^-1 : 1800,1740,1690

Reference Example 3 (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- [D-α- (2-fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- [3-
5.0 g of (p-methylbenzylideneamino) -2-oxoimidazolidin-1-yl] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane / 1 tri-n-butylamine salt in methanol After dissolving in 50 ml, 1.3 g of 2,4-dinitrophenylhydrazine monohydrochloride is added, and the mixture is stirred at room temperature for 1.5 hours, and the precipitated crystals are collected by filtration. The obtained precipitated crystals were dissolved in methylene chloride (100 ml), water (100 ml) and methanol.
The suspension is suspended in 50 ml of a mixed solution, adjusted to pH 6.5 with a saturated aqueous solution of sodium hydrogen carbonate, and the insoluble matter is filtered off. The filtrate was adjusted to pH 2 with 6N hydrochloric acid, and the precipitated crystals were collected by filtration. (3R, 5R, 6
R) -3- (3-Amino-2-oxoimidazolidin-
1-yl) -3-diphenylmethyloxycarbonyl-
6- [D-α- (2-fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane tetrahydrate 3.
Get 4g. IR (KBr) cm ^-1 : 1780,1735,1670

Example 1-1 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-diphenylmethyloxycarbonyl-6- [D-α- (2 -Fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane tetrahydrate (500 mg) was dissolved in dimethyl sulfoxide (2.5 ml), and the mixture was dissolved at room temperature. After adding 45.4 mg of potassium carbonate and 440 mg of benzotriazole-1-carboxyamidine / p-toluenesulfonate, the mixture is stirred at 50 ° C. for 10 hours. The reaction mixture was cooled to room temperature, 25 ml of water was added, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to give (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- [D-α- (2
-Fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- (3-guanidino-2-oxoimidazolidin-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] 442 mg of heptane 5.5 hydrate are obtained. IR (KBr) cm ^-1 : 1785,1735,1685

Example 1-2 (3R, 5R, 6R) -3-diphenylmethyloxycarbonyl-6- [D-α- (2-fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- (3 -Guanidino-2-oxoimidazolidin-1-yl) -7
-Oxo-4-thia-1-azabicyclo [3.2.0] heptane pentahydrate (250 mg) was suspended in methylene chloride (2.5 ml) and anisole (0.2 ml).
A 0.7 ml solution of nitromethane containing 05 mg is added and stirred at the same temperature for 1 hour. 12.5 ml of water and 5 m of ethyl acetate were added to the reaction mixture.
After adding l, the pH is adjusted to 5.0 with a saturated aqueous sodium hydrogen carbonate solution, the insolubles are filtered through celite, and the aqueous layer is separated. The separated aqueous layer was washed with ethyl acetate, concentrated under reduced pressure to 5 ml, and subjected to reverse phase column chromatography (eluent;
(3R, 5R, 6R) -3-carboxy-6- [D-α- (2-fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- (3-guanidino-2) -Oxoimidazolidin-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane monosodium salt (120 mg) is obtained. IR (KBr) cm ^-1 : 1776,1684,1627 NMR (D ₂ O) δ value; 3.41 (1H, d, J = 12.5 Hz), 3.61 (4H, s), 4.61
(1H, d, J = 12.5Hz), 5.36 (1H, s), 5.47 (1H, d, J = 4Hz), 5.60 (1
(H, d, J = 4Hz), 6.60-6.86 (2H, m), 7.56-7.85 (1H, m)

Example 2 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6- [D
-Α- (2-fluoro-4-hydroxyphenyl) -α
-Sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane disodium salt 1.0 g
Is dissolved in 5 ml of water, 2.6 g of 1H-pyrazole-1-carboxamidine hydrochloride is added, and the mixture is stirred at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature, adjusted to pH 4.5 with a saturated aqueous solution of sodium hydrogen carbonate, and purified by reversed-phase column chromatography (eluent: water) to give (3R, 5R, 6).
R) -3-Carboxy-6- [D-α- (2-fluoro-4-hydroxyphenyl) -α-sulfoacetamide]
-3- (3-Guanidino-2-oxoimidazolidin-
480 mg of 1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane monosodium salt are obtained.

Example 3 (3R, 5R, 6R) -3- (3-Amino-2-oxoimidazolidin-1-yl) -3-carboxy-6- [D
-Α- (2-fluoro-4-hydroxyphenyl) -α
-Sulfoacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane disodium salt 200 m
g was dissolved in 1 ml of water, and 240 mg of benzotriazole-1-carboxyamidine / p-toluenesulfonate was added, followed by stirring at 50 ° C. for 7 hours. After cooling the reaction mixture to room temperature, insolubles are removed by filtration. The obtained filtrate was purified by reverse phase column chromatography (eluent: water) to give (3R,
5R, 6R) -3-carboxy-6- [D-α- (2-
Fluoro-4-hydroxyphenyl) -α-sulfoacetamide] -3- (3-guanidino-2-oxoimidazolidin-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane・ 120 mg of monosodium salt
Get.

[0044]

According to the production method of the present invention, the compound represented by the general formula [2]
A carboxypenam derivative or a salt thereof can be obtained in a high yield, and is suitable as an industrial production method.

Claims (2)

[Claims] 1. A compound of the general formula [1] During the "formula, R ^1, a halogen atom or a protected or unprotected good hydroxyl radical optionally substituted phenyl group; R ² is an optionally protected sulfo group or a sulfonate group; R ³ is And a carboxyl group or a carboxylato group which may be protected, respectively. ”And a salt thereof, and benzotriazole-1
Wherein the compound is reacted with carboxamidine or a salt thereof or 1H-pyrazole-1-carboxamidine or a salt thereof. Wherein R ⁴ represents a guanidino group, and R ¹ , R ² and R ³ have the same meaning as described above.
-A method for producing a carboxypenam derivative or a salt thereof. 2. The 2-carboxypenam derivative or a salt thereof according to claim 1, wherein the compound of the general formula [1] or a salt thereof is reacted with benzotriazole-1-carboxamidine or a salt thereof. Manufacturing method.