JP2860421B2 - Novel penam derivatives and their salts - Google Patents

Description

The present invention relates to a novel penam-3-carboxylic acid derivative or a salt thereof, and more particularly, to a general formula: Wherein R ¹ is α-aminophenylacetyl, α- (4
-Ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (4-ethyl-2,
3-dioxo-1-piperazinecarboxamido) benzothienylacetyl, 2-thienyl-2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) acetyl, 2- (2-aminothiazol-4-yl)- 2
-Methoxyiminoacetyl, α- (cis-2-cyanovinyl) thioacetyl, α- [3- (4-phenylphenylcarbonyl) -3-methyl-1-ureido] -α-phenylacetyl and α-{[4- ( 4-chlorophenylimidazole) -2-yl] carboxamide} -α-
An amino group substituted with an acyl group selected from a phenylacetyl group; R ² is thienyl, furyl, thiazolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroquino which may be substituted with a lower alkyl group; R ³ is a hydrogen atom; R ⁴ is a carboxyl group or a carboxylate group which may be protected; and n is 0 or a ril or imidazo [1,2, -b] [1,2,4] triazinyl group. Or 1 is indicated. The present invention relates to a novel penum-3-carboxylic acid derivative or a salt thereof.

An object of the present invention is to provide a broad antibacterial spectrum, that is, exhibiting excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, particularly stable against β-lactamase, and excellent against even resistant bacteria. An object of the present invention is to provide a novel compound which has activity and is useful as a medicine for humans and animals.

Still another object of the present invention is to provide compounds useful as intermediates of other penum derivatives.

[Prior Art] Conventionally, in a penum derivative represented by the general formula [I], R ¹ is α-aminophenylacetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-. Phenylacetyl, α- (4-ethyl-2,3
-Dioxo-1-piperazinecarboxamido) benzothienylacetyl, 2-thienyl-2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) acetyl, 2- (2-aminothiazol-4-yl) -2 −
Methoxyiminoacetyl, α- (cis-2-cyanovinyl) thioacetyl, α- [3- (4-phenylphenylcarbonyl) -3-methyl-1-ureido] -α-phenylacetyl and α-{[4- (4 -Chlorophenylimidazole) -2-yl] carboxamide {-amino group substituted with an acyl group selected from α-phenylacetyl group, and R ² may be optionally substituted with a lower alkyl group. Thienyl, furyl, thiazolyl , Pyridyl, quinolyl, 1,2,3,4-tetrahydroquinolyl or imidazo [1,2, -b] [1,2,4] triazinyl groups are not known.

[Problems to be Solved by the Invention] Under such circumstances, a penum derivative having a broad antibacterial spectrum, being stable against β-lactamase, and exhibiting an excellent antibacterial activity even against resistant bacteria. Development was desired.

[Means for Solving the Problems] The present inventors have made intensive studies to solve the above problems, and as a result, have found that a penam-3-carboxylic acid derivative represented by the general formula [I] or a salt thereof has an intended purpose. The inventors have found that the present invention has been achieved, and have completed the present invention.

 Hereinafter, the present invention will be described in detail.

In the present specification, unless otherwise specified, a lower alkyl group means, for example, a straight or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. the chain _C 1 _{~ 5} alkyl group; the aryl group, for example,
Phenyl, naphthyl, indanyl and the like; a halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a heterocyclic group includes, for example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, imidazolyl, benzimidazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiazizolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,4-triazinyl, imidazo [1,2-b] [1,2,4] triazinyl, pyrrolidinyl, morpholinyl, quinuclidinyl, 2,
A 4-, 5-, 6- or fused heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, such as 3,4-tritetrahydroquinolyl, Heterocyclic groups containing atoms may be quaternized.

Examples of the substituent of the thienyl, furyl, thiazolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroquinolyl or imidazo [1,2, -b] [1,2,4] triazinyl group for R ² include lower groups. And an alkyl group.

Examples of the protecting group of the optionally protected carboxyl group of R ⁴ include those conventionally known in the field of penicillin and cephalosporin-based compounds, and include, for example, catalytic reduction, chemical reduction or other moderation. Ester-forming group that is eliminated by treatment under a variety of conditions, or an ester-forming group that is easily eliminated in vivo, or an organic silyl group, organic phosphorus group, or organic group that is easily eliminated by treatment with water or alcohol Ester-forming groups such as tin groups.

Among these carboxyl protecting groups, suitable protecting groups include, for example, lower alkyl groups; aryl groups; allyl groups; benzyl, 4-methoxybenzyl,
4-nitrobenzyl, 3,4-dimethoxybenzyl, 4-
Aralkyl groups such as hydroxy-3,5-di (tert-butyl) benzyl, phenethyl, diphenylmethyl, trityl, bis (p-methoxyphenyl) methyl; phthalidyl groups; 2-iodoethyl, 2,2,2-trichloroethyl Halo-lower alkyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-pivaloyloxyethyl, Acyloxy lower alkyl groups such as -acetoxy-n-propyl and 1-pivaloyloxy-n-propyl; (5-lower alkyl-2) such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl −
Oxo-1,3-dioxol-4-yl) lower alkyl groups; alkoxy lower alkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl and isopropoxymethyl; and methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1- And alkoxycarbonyloxy lower alkyl groups such as ethoxycarbonyloxyethyl and 1-propoxycarbonyloxyethyl.

When each of these groups R ^{1 to} R ⁴ and their substituents has a group such as an amino group, a hydroxyl group and a carboxyl group, these groups are protected with a generally known protecting group. You may.

Examples of the amino-protecting group include formyl, te
rt-butoxycarbonyl, tert-amyloxycarbonyl, trityl, trimethylsilyl, benzylidene, 2,2,
Examples include commonly known amino protecting groups such as 2-trichloroethoxycarbonyl, p-nitrobenzylidene, hexahydro-1H-azepin-1-ylmethylene, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and phthaloyl groups.

Examples of the hydroxyl-protecting group include formyl, acetyl, benzyl, tetrahydropyranyl, benzyloxycarbonyl, trimethylsilyl and p-nitrobenzyloxycarbonyl. As the protective group of the carboxyl group, for example, it includes the same carboxyl protecting group as those described in R ^4.

In addition, as the salt of the compound of the general formula [I] of the present invention,
Examples of the salt include a commonly known basic group such as an amino group or a salt in an acidic group such as a hydroxyl group or a carboxyl group. Next, salts of the basic group include, for example, salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with halogen anions such as chloro anion and bromo anion; formic acid, citric acid, trichloroacetic acid, trifluoro Salts with carboxylic acids such as acetic acid; or methanesulfonic acid,
Salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like, and salts in the acidic group, for example, salts with alkali metals such as sodium and potassium; calcium; , Magnesium or other salts with alkaline earth metals; ammonium salts; or trimethylamine, triethylamine, tributylamine, pyridine, N, N-
Dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β
-Phenethylamine, 1-ephenamine and N, N'-
Examples thereof include salts with a nitrogen-containing organic base such as dibenzylethylenediamine.

Further, in the case of having an ammonium group or a pyridinio group in the molecule, each of these groups is usually as described above.
It may form an inner salt with the carboxylate group in R ⁴ .

Further, in the compound of the general formula [I] and a salt thereof,
When isomers exist (eg, optical isomers, geometric isomers, tautomers, and the like), the present invention includes all such isomers and includes all crystalline forms and hydrates and solvates. Things are also included.

 Next, a method for producing the compound of the present invention will be described.

The compound of the general formula [I] and a salt thereof can be usually produced by a combination of known methods, and for example, can be produced according to the following production route.

In the formula, R ¹ , R ² and R ⁴ have the same meanings as described above, R ^1a represents a phenylacetylamino group, a phenoxyacetylamino group or an acetylamino group; R ^1b represents R ¹
R ^2a represents a phenyl group which may be substituted with a group selected from a lower alkyl group, a halogen atom, a C _1-8 acyl group and a hydroxy lower alkyl group; R ^3a represents a carboxyl-protected group; group; R ^4a is the same protected or unprotected carboxyl group and R ^4; R ^4b is a carboxyl protecting group; X _1, X ₂ and Y represents a leaving group.

The general formulas [Ia], [Ib], [Ic], [Id], [II],
[III], [IV], [VI], [VII], [VIII], [I
X], [X], [XII], [XIII], [XIV] or [X
Examples of the salt of the compound of the formula [V] include the same salts as the salts of the compound of the formula [I].

Examples of the leaving group for X ¹ , X ² and Y include a halogen atom; a lower alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy; and an arylsulfonyloxy group such as phenylsulfonyloxy and tolylsulfonyloxy. No.

As the carboxyl protecting group for R ^3a , R ^4a and R ^4b , the same protecting groups as described for R ⁴ can be mentioned.

The production method of the compound of the general formula [I] will be described in more detail according to the above production route.

(1) The compound of the general formula [IV] or a salt thereof is obtained by combining the compound of the general formula [II] or a salt thereof with a compound of the general formula [III] in the presence or absence of a base or a deoxidizing agent or It can be obtained by reacting the salt.

This reaction can be carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, tetrahydrofuran, dioxane, 1,2- Ethers such as dimethoxyethane and diethyl ether; amides such as N, N-dimethylformamide; halogenated hydrocarbons such as methylene chloride and chloroform; ketones such as acetone; nitriles such as acetonitrile; dimethylsulfoxide; Methyl phosphate triamide and the like may be mentioned, and these solvents may be used as a mixture of two or more kinds.

The base used in this reaction includes alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, potassium tert.
-Butoxide, diethylamine, triethylamine, diisopropylethylamine, lithium diisopropylamide, lithium bistrimethylsilylamide, lithium hexamethyldisilylamide, dicyclohexylamine, pyridine, 2,6-lutidine, N-methylpiperidine, N-methylmorpholine, tetramethylguanidine ,
1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U), Grignard reagents such as 1,5-diazabicyclo [4.3.0] non-5-ene or methylmagnesium bromide or 2,4,6-trimethylphenylmagnesium bromide, and the like. Examples include propylene oxide and molecular sieves.

The amount of the compound of the general formula [III] or a salt thereof to be used is 1 to 2 moles compared to the compound of the general formula [II] or a salt thereof.

Further, the amount of the base or deoxidizing agent used as needed is based on the compound of the general formula [II] or a salt thereof.
Each is 0.01 to 2.0 times mol.

This reaction may be usually performed at -70 to 150 ° C for 5 minutes to 5 hours.

(2) reacting a compound of the general formula [IX] or a salt thereof with a compound of the general formula [II] and a compound of the general formula [VIII] or a salt thereof in the presence or absence of a base Can be obtained by

This reaction can be performed in the presence or absence of a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, for example,
The same solvents as described in (1) are mentioned, and these solvents may be used as a mixture of two or more kinds.

As the base used in this reaction, for example,
The same base as described in (1) can be mentioned.

The amount of the compound of the general formula [VIII] or a salt thereof to be used is 1 to 2 times that of the compound of the general formula [II] or a salt thereof.

The amount of the base used as needed is 0.001 to 1 mole per mole of the compound of the general formula [II] or a salt thereof.

This reaction may be usually carried out at -50 to 100 ° C for 5 minutes to 5 hours.

(3) The compound of the general formula [VI] or a salt thereof is obtained by adding the compound of the general formula [V], a hydrate or a hemihydrate thereof to the compound of the general formula [IV] or a salt thereof in the presence or absence of a base. It can be obtained by reacting a reactive derivative such as acetal.

This reaction can be carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, tetrahydrofuran, dioxane, 1,2- Ethers such as dimethoxyethane and diethyl ether; amides such as N, N-dimethylformamide; halogenated hydrocarbons such as methylene chloride and chloroform; dimethyl sulfoxide; esters such as ethyl acetate; and fragrances such as benzene and toluene. Group hydrocarbons, and these solvents may be used as a mixture of two or more.

As the base used in this reaction, for example,
The same base as described in (1) can be mentioned.

The amount of the compound of the general formula [V] to be used is 1 to 5 moles compared to the compound of the general formula [IV] or a salt thereof.

The amount of the base used as needed is 0.001 to 1-fold the molar amount of the compound of the general formula [IV] or a salt thereof.

This reaction may be usually carried out at −30 to 100 ° C. for 5 minutes to 5 hours.

(4) The compound of general formula [VII] or a salt thereof is obtained by reacting a compound of general formula [VI] or a salt thereof with a halogenating agent or a sulfonylating agent in the presence or absence of a base. Can be.

This reaction can be performed in the presence or absence of a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, for example,
The same solvents as described in (1) are mentioned, and these solvents may be used as a mixture of two or more kinds.

Examples of the halogenating agent used in this reaction include thionyl chloride, phosphorus pentachloride, and bromine, and examples of the sulfonylating agent include methanesulfonyl chloride and p-toluenesulfonyl chloride.

Examples of the base used as needed include, for example,
The same base as described in (1) can be mentioned.

The amount of the halogenating agent or the sulfonylating agent to be used is 1 to 1 with respect to the compound of the general formula [VI] or a salt thereof, respectively.
It is 5 times mol.

The amount of the base used as needed is 1 to 5 moles per 1 mole of the compound of the formula [VI] or a salt thereof.

This reaction may be usually performed at -20 to 50 ° C for 5 minutes to 5 hours.

(5) (i) a compound of the general formula [XII] or a salt thereof,
It can be obtained by subjecting a compound of the general formula [VII] or a salt thereof to a ring closure reaction in the presence of a base.

This reaction can be carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, tetrahydrofuran, dioxane, 1,2- Ethers such as dimethoxyethane and diethyl ether; amides such as N, N-dimethylformamide; halogenated hydrocarbons such as methylene chloride and chloroform; dimethyl sulfoxide; nitriles such as acetonitrile; hexamethylphosphoric triamide; , 3-Dimethyl-2-
Examples thereof include imidazolidone, and these solvents may be used as a mixture of two or more kinds.

As the base used in this reaction, for example,
The same base as described in (1) can be mentioned.

This reaction can be carried out in the presence of a silylating agent, if necessary. Examples of the silylating agent include trimethylsilyl chloride and N, O-bistrimethylsilylacetamide.

The amount of the base to be used is 1 to 3 moles relative to the compound of the formula [VII] or a salt thereof.

The amount of the silylating agent used if necessary is 1 to the compound of the general formula [VII] or a salt thereof.
About 3 times the molar amount.

This reaction may be usually carried out at -78 to 50 ° C for 5 minutes to 12 hours.

(Ii) The compound of the general formula [Id] or a salt thereof can be obtained by subjecting the compound of the general formula [X] or a salt thereof to a ring closure reaction in the presence of a base.

This reaction can be performed in the presence or absence of a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, for example,
The same solvents as described in (i) may be mentioned, and these solvents may be used as a mixture of two or more kinds.

As the base used in this reaction, for example,
The same base as described in (i) can be mentioned.

The amount of the base to be used is 0.5 to 3 moles compared to the compound of the formula [X] or a salt thereof.

This reaction may be carried out usually at −30 to 100 ° C. for 5 minutes to 10 hours.

(6) The compound of the general formula [XIII] or a salt thereof can be obtained by subjecting the compound of the general formula [XII] or a salt thereof to an elimination reaction of a carboxyl protecting group commonly known in the art.

Specifically, for example, a method using anisole and aluminum chloride and a method using Protective Group in Organic Synthesis (Protective Group)
s in Organic Synthesis) [Theodra W Green] John Wiley & Sons, Inc. (John Wiley & Sons, I
nc.)] or a method analogous thereto.

(7) The compound of the general formula [XIV] or a salt thereof can be obtained by subjecting the compound of the general formula [XIII] or a salt thereof to an oxidation reaction.

More specifically, for example, Journal of the Organic Chemistry (J. Org. Chem.) Vol. 35, No. 243
The method described on page 0 to page 2433 (1970) or a method analogous thereto can be used.

The compound of the general formula [X] or a salt thereof can also be obtained by subjecting the compound of the general formula [IX] or a salt thereof to a similar oxidation reaction.

(8) The compound of the general formula [Ia] or a salt thereof can be obtained by subjecting the compound of the general formula [XIV] or a salt thereof to a decarboxylation reaction in the presence or absence of an acid.

This reaction can be carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, tetrahydrofuran, dioxane, 1,2- Ethers such as dimethoxyethane and diethyl ether; amides such as N, N-dimethylformamide; halogenated hydrocarbons such as methylene chloride and chloroform; ketones such as acetone; nitriles such as acetonitrile; dimethylsulfoxide; hexamethyl Phosphoric acid triamide;
Water; alcohols such as methanol and ethanol;
Acetic acid; esters such as ethyl acetate; pyridine; and the like. These solvents may be used as a mixture of two or more kinds.

Acids used in this reaction include, for example, mineral acids such as hydrochloric acid and sulfuric acid; organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and mesitylenesulfonic acid; tin tetrachloride, zinc chloride, aluminum chloride, trichloride and the like. Lewis acids such as boron fluoride and titanium tetrachloride; or acidic ion exchange resins.

The amount of the acid used as needed is 0.001 to 10 times the molar amount of the compound of the general formula [XIV] or a salt thereof.

This reaction may be usually carried out at 0 to 100 ° C. for 1 minute to 12 hours.

Further, the compound of the general formula [Ib] or a salt thereof can also be obtained by subjecting the compound of the general formula [XIII] or a salt thereof to a similar decarboxylation reaction.

(9) The compound of general formula [Ib] or a salt thereof is obtained by subjecting a compound of general formula [Ia] or a salt thereof or a compound of general formula [Id] or a salt thereof to a usual reduction reaction known in the art. Can be obtained by:

Specifically, for example, Journal of the Chemical Society Perkin Transactions 1
(J. Chem. Soc. Perkin. Trans. 1) pages 932 to 937 (197
3 years) or the method described in JP-B-56-24675 or a method analogous thereto.

(10) The compound of general formula [XV] or a salt thereof can be obtained by removing the acyl group or amino protecting group of the compound of general formula [Ib] or a salt thereof.

Specifically, a compound of the general formula [Ib] or a salt thereof is reacted with a halogenating agent such as phosphorus pentachloride to form an imino halide, and then reacted with an alcohol to form an imino ether, which is further hydrolyzed. Can be derived to a compound of the general formula [XV] or a salt thereof.
Further, Journal of the Chemical Society (J. Chem. Soc.) Vol. 83, p. 320 (1903), Canadian Patent No. 770125, British Patent No. 1041985, Japanese Patent Publication No. 49-40479
The compound of the general formula [XV] or a salt thereof can be obtained by the method described in JP-B No. 45-40899 or a method similar thereto.

(11) The compound of the general formula [Ic] or a salt thereof is prepared by adding a compound of the general formula [XI] or a salt thereof to a compound of the general formula [XV] or a salt or a reactive derivative thereof in the presence of a solvent. By reacting a reactive derivative of

Examples of the reactive derivative of the compound of the general formula [XV] or a salt thereof include trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilanyl, and dimethoxysilanediyl. Organic silyl group such as, or dimethoxyphosphinyl, 1,3,2-
Dioxophosphoran-2-yl, 4-methyl-1,3,2-
Examples include compounds in which an organic phosphorus group such as dioxophosphoran-2-yl or 1,3,2-dioxophosphan-2-yl is bonded to an amino group which is a reaction site.

Examples of the reactive derivative of the compound represented by the general formula [XI] include acid halides, acid anhydrides, mixed acid anhydrides described in JP-A-56-127375, JP-A-59-93085, and JP-A-63-135477. Active acid amides, active esters, active thioloesters, acid azides and reactive derivatives of the compound of the general formula [XI] with the Vilsmeier reagent are mentioned.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; ethers such as tetrahydrofuran, diethyl ether and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform. Nitriles such as acetonitrile; alcohols such as methanol, ethanol and isopropanol; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; aromatic hydrocarbons such as benzene and toluene;
Esters such as methyl acetate and ethyl acetate; ketones such as acetone; dimethyl sulfoxide; and pyridine. These solvents may be used as a mixture of two or more kinds.

This reaction can also be carried out in the presence of a base. Examples of the base used as needed include (1)
And the same bases as mentioned in the above.

When the compound of the general formula [XI] is used as a salt with a free acid or a nitrogen-containing organic base, a suitable condensing agent is used.

Examples of the condensing agent used include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide.

The amount of the compound of the general formula [XI] or a salt thereof or a reactive derivative thereof to be used is 0.9 times or more, preferably 0.9 mol or more with respect to the compound of the general formula [XV] or a salt or a reactive derivative thereof. It is about 1.5 times mol.

This reaction may be carried out usually at -50 to 80C for 5 minutes to 30 hours.

In each of the steps described above, introduction and elimination of a protecting group can be appropriately performed by a conventional method, and the general formula [Ia]
~ [Id], [II], [IV], [VI], [VII], [I
X], [X], [XII], [XIII], [XIV] or [X
When the compound of the formula V] or a salt thereof has an isomer, it can be isolated and purified by a usual method.

When there is a group active in the reaction among the groups of R ^1a , R ² , R ^2a , R ^3a , R ^4a and R ^4b , the reaction may be protected by a usual protecting group during the reaction. The protecting group can be removed by a conventional method.

Further, for example, esterification, hydrolysis, addition, acylation, oxidation, reduction, cyclization, halogenation, alkylation,
Derivation of the compound of the present invention into other compounds of the present invention by commonly known methods such as amination, thiolation, quaternization, aryloxylation, sulfonylation or alkylamination, and by appropriately combining these methods. You can also.

Next, the compound of the general formula [II] or a salt thereof, which is a raw material for producing the compound of the present invention, can be obtained, for example, from Journal of the Chemical Society, Perkin Transactions 1 (J. Chem. Soc.). .Perkin.Trans.1)
It can be obtained by appropriately combining the methods described on pages 150 to 155 (1980) or the methods known per se.

The compound of the formula [III] or a salt thereof can be obtained, for example, by the method described in JP-A-62-228083.

Furthermore, the compound represented by the general formula [VIII] or a salt thereof can be obtained from Chemical Abstracts
It can be obtained by appropriately combining the methods described in Vol. 48, 7584 g or the like, or methods known per se.

When the compound of the present invention is used as a medicine, a carrier usually used for preparation is appropriately used, and a tablet,
It is prepared into capsules, powders, syrups, granules, suppositories, ointments or injections. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, weight, and condition of the patient. Usually, for adults, oral or parenteral (for example, injection administration, drip or rectum site) 0.1 ~ 100mg / kg / day by 1 ~ 1
It may be administered in several divided doses.

[Effect of the Invention] Next, the antibacterial activity of the representative compound of the present invention will be described.

1. Antibacterial activity Test method: Japanese Society of Chemotherapy standard method [Chemothera
py) Vol. 29, No. 1, pp. 76-79 (1981)], and cultured at 37 ° C. for 20 hours with peptone broth (manufactured by Eiken Chemical Co., Ltd.), and the amount of bacteria was 10 One platinum loop of the bacterial solution prepared at ⁶ cells / ml was inoculated into a Heart Infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) containing the drug, and cultured at 37 ° C. for 20 hours. Observe the presence or absence of growth and determine the minimum concentration at which the growth of the bacteria was inhibited.
C (μg / ml).

Table 1 shows the results. The symbol * in Table 1 means a β-lactamase producing strain.

The following symbols used in the table of test compounds have the following meanings.

Me; methyl group; Et; ethyl group The configuration at the 2- and 3-positions of the penum skeleton is estimated.

[Examples] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

The symbols used in the reference examples and examples have the following meanings.

Me; methyl; Ac; acetyl; PNB; p-nitrobenzyl DPM; diphenylmethyl Unless otherwise specified, the carrier used in the column chromatography was Kieselgel 60, art 7334 (Kieselgel 60, Art.7734) manufactured by Merck. Using. Further, the mixing ratio in the eluent is a volume ratio. (Note that the configuration at the 2- and 3-positions of the penum skeleton is estimated.) Reference Example 1 α-bromophenylacetic acid diphenylmethyl ester 1
To a mixture of 3.9 g and 60 ml of N, N-dimethylformamide was added (3R, 4R) -3-phenylacetamide- under ice-cooling.
8.6 g of 4-mercapto-2-azetidinone are added and then 5.08 ml of triethylamine are added dropwise over 5 minutes. After stirring at the same temperature for 30 minutes, the reaction solution is added to a mixture of 300 ml of water and 300 ml of ethyl acetate. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure,
19.2 g (yield 98.2%) of (3R, 4R) -4- [1-phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone is obtained.

IR (KBr) cm ^-1 ; v _{c =} 1760, 1740, 1660 Similarly, compounds of Table 2 were obtained.

Reference Example 2 19.2 g of (3R-4R) -4- [1-phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone, glyoxylic acid p
After adding 0.05 ml of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) to a mixture of -nitrobenzyl ester monohydrate 8.0 g and methylene chloride 150 ml under ice-cooling. Stir at room temperature for 2 hours. The reaction solution was added to 200 ml of water, and 2
After adjusting the pH to 3 with N hydrochloric acid, the organic layer is separated. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, (3R, 4R) -1- [1-hydroxy-1- (p-nitrobenzyloxycarbonyl) methyl] -4- [1-
26.0 g (97.4% yield) of phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone is obtained.

IR (KBr) cm ^-1 ; v _{c =} 1760, 1750, 1660 Similarly, compounds of Table 3 were obtained.

Reference Example 3 6.5 g of (3R-4R) -3-phenylacetamido-4-mercapto-2-azetidinone and α-bromocinnamic acid p
Dissolve 10 g of -nitrobenzyl ester in 100 ml of N, N-dimethylformamide, add 0.62 g of potassium tert-butoxide at -50 ° C, and stir at -50 to -40 ° C for 1 hour.
The reaction solution is added to 300 ml of ice water and 300 ml of ethyl acetate, and the organic layer is separated and washed successively with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to give (3R,
4R) -3-Phenylacetamido-4- [2-bromo-
2- (p-nitrobenzyloxycarbonyl) -1-phenylethylthio] -2-azetidinone 9.0 g (yield 54.5
%).

IR (KBr) cm ^-1 ; v _{c =} 1770,1730,1650 Reference Example 4 (3R, 4R) -3-phenylacetamido-4- [2-
Bromo-2- (p-nitrobenzyloxycarbonyl)
-1-phenylethylthio] -2-azetidinone (8.8 g) was dissolved in methylene chloride (70 ml), and 3.1 g of m-chloroperbenzoic acid (purity 80%) was added in portions over 10 minutes under ice-cooling. Stir for 30 minutes at the same temperature. The reaction solution was added to 50 ml of water,
Adjust to pH 7.0 with saturated aqueous sodium bicarbonate. The organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 2: 1) to give (3R, 4R) -3-phenylacetamide-4- { 6.5 g of [2-bromo-2- (p-nitrophenylbenzyloxycarbonyl) -1-phenyl] ethylsulfinyl} -2-azetidinone (yield 73
%).

IR (KBr) cm ^-1 ; v _{c =} 1780,1750,1680 Example 1 (3R, 4R) -1- [1-hydroxy-1- (p-nitrobenzyloxycarbonyl) methyl] -4- [1 -Phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone
To a mixed solution of 10.0 g and 100 ml of tetrahydrofuran was added 3.28 ml of 2,6-lutidine under ice-cooling, and then 2.15 ml of thionyl chloride was added dropwise over 5 minutes. After stirring at the same temperature for 30 minutes, the precipitate is removed, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in anhydrous tetrahydrofuran (200 ml), N, O-bistrimethylsilylacetamide (3.48 ml) is added under ice cooling, and the mixture is stirred at room temperature for 15 minutes. Then, the reaction solution was cooled to -78 ° C, 12 ml of hexamethylphosphoric triamide was added, and a solution of lithium hexamethyldisilylamide (4 ml of hexamethyldisilazane, 20 ml of tetrahydrofuran and 15% -n-butyllithiumhexane) was added at the same temperature. (Prepared from 10 ml of solution) over 10 minutes, and further stirred at the same temperature for 10 minutes. The reaction is added to a mixture of 300 ml of water, 100 ml of ethyl acetate and 27 ml of 6N hydrochloric acid. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give 6β
5.5 g (yield 56.4%) of p-nitroacetamide-2-phenyl-2-diphenylmethoxycarbonylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

This compound was analyzed by NMR for 2α-form and 2β-form.
It was a 1: 1 mixture of bodies.

IR (KBr) cm ^-1 ; ν _{c =} 1780,1740,1725,1680 NMR (CDCl ₃ ) δ value; 3.28 (1H, s), 3.34 (1H, s), 4.80 to 5.80 (5H, m), 6.80 (1H, s), 6.95 to 7.45 (23H, m), 7.95 to 8.18 (2H, m) The compounds in Table 4 were obtained in the same manner.

Example 2 To a mixture of 6β-phenylacetamido-2-phenyl-2-diphenylmethoxycarbonylpenam-3α-carboxylic acid p-nitrobenzyl ester 9.8 g, methylene chloride 50 ml and anisole 50 ml at −30 ° C. aluminum chloride 5.4 g And a solution of 50 ml of anisole are added dropwise over 5 minutes. After stirring at the same temperature for 20 minutes, the reaction solution was
And 200 ml of ethyl acetate. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: methanol = 100: 1 to 10: 1). This was dissolved in a mixture of 50 ml of water and 50 ml of ethyl acetate,
After adjusting the pH to 2.0 with 2N sulfuric acid, the organic layer is separated. After washing with water and saturated saline solution in that order, it is dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, amorphous 6β
-Phenylacetamide-2-phenyl-2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester 4.2 g (55.5% yield) is obtained.

IR (KBr) cm ^-1 ; ν _{c =} 1770, 1750, 1650 NMR (CDCl ₃ ) δ value; 3.38 (2H, s), 4.40 (1 H, d, J = 15 Hz), 4.67 (1 H, d, J = 15Hz), 5.50 (1H, m), 5.71 (1H, d, J = 4Hz) 6.03 (1H, s), 7.00 ~ 7.60 (14H, m), 8.03 (2H, d, J = 9Hz) And the compound of Table-5 were obtained.

Example 3 6 A mixture of 2 g of β-phenylacetamido-2- (p-nitrobenzyloxycarbonyl) -2- (thiophen-2-yl) penam-3α-carboxylic acid diphenylmethyl ester, 10 ml of water and 10 ml of ethyl acetate was added. % Of palladium-carbon is added and hydrogenated at room temperature and normal pressure for 2 hours. After completion of the reaction, 5% palladium-carbon is removed, the pH is adjusted to 2 with 2N hydrochloric acid, and the organic layer is separated. After sequentially washing with water and saturated saline and drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to give 6β-phenylacetamido-2-carboxy-2- (thiophen-2-yl) penam-3α-. 1.45 g (89% yield) of carboxylic acid diphenylmethyl ester are obtained.

IR (KBr) cm ^-1 ; v _{c =} 1780,1740,1660 Example 4 3.1 g of 6β-phenylacetamido-2-phenyl-2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester and 30 ml of methylene chloride 1.06 g of m-chloroperbenzoic acid is added portionwise to the above mixture under ice-cooling over 10 minutes. After stirring at the same temperature for 30 minutes, the mixture is added to 50 ml of ice water. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; chloroform: methanol = 100: 1 to 10: 1).
To purify. This is dissolved in a mixed solution of 30 ml of water and 30 ml of ethyl acetate, adjusted to pH 2.0 with 2N sulfuric acid, and then the organic layer is separated. After sequentially washing with water and saturated saline, drying over anhydrous sodium sulfate, and evaporating the solvent under reduced pressure,
2.5 g of 6β-phenylacetamido-2-phenyl-2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide (78.6% yield) is obtained.

IR (KBr) cm ^-1 ; ν _{c =} 1790,1745,1670,1630 NMR (CDCl ₃ ) δ value; 3.56 (1H, s), 3.62 (1H, s), 4.96 to 5.30 (4H, m), 5.88 to 6.12 (2H, m), 7.05 to 7.40 (13H, m) 8.03 (2H, d, J = 9 Hz) In the same manner, the compounds in Table 6 were obtained.

Example 5 A mixture of 2.5 g of 6β-phenylacetamido-2-phenyl-2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide and 30 ml of ethyl acetate is refluxed for 20 minutes. After cooling to room temperature, 30 ml of water is added and the pH is adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer is separated, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1 to 2: 1) to give 6β-phenylacetamido-2α-phenylpenam-3α. -Carboxylic acid p-nitrobenzyl ester-
0.5 g of 1-oxide (compound I) (20.5% yield) and 6
β-phenylacetamido-2β-phenylpenam-3
0.55 g (yield 22.5%) of α-carboxylic acid p-nitrobenzyl ester-1-oxide (compound II) is obtained.

(Compound I) IR (KBr) cm ^-1 ; v _{c =} 1790, 1750, 1680 NMR (CDCl ₃ ) δ value; 3.57 (2H, s), 4.88 (1H, d, J = 13 Hz), 5.08 (1H , d, J = 13Hz), 5.22 (1H, d, J = 7Hz), 5.49 (1H, d, J = 7Hz), 6.06 (1H, dd, J = 5Hz, J = 10Hz), 6.90 to 7.33 (13H , m), 7.95 (2H, d, J = 9Hz) ( compound ^{II) IR (KBr) cm -1} ; ν c = 0 1790,1745,1670 NMR (CDCl 3) δ value; 3.58 (2H, s), 4.62 (1H, d, J = 11Hz), 4.98-5.30 (4H, m), 6.08 (1H, dd, J = 5Hz, J = 9Hz), 7.03-7.46 (13H, m), 8.07 (2H, d, J = 9 Hz) Similarly, the compounds in Table 7 were obtained.

Example 6 6β-phenylacetamide-2α-phenylpenam-3α-carboxylic acid p-nitrobenzyl ester-1-
To a mixture of 500 mg of oxide, 2 ml of methylene chloride and 2 ml of N, N-dimethylformamide, at −30 ° C., 0.1 ml of phosphorus tribromide
And stirred for 30 minutes at the same temperature. The reaction solution is added to a mixture of 20 ml of water and 20 ml of ethyl acetate while adjusting the pH to 7.0 with a saturated aqueous solution of sodium carbonate. The organic layer is separated, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 ml of diethyl ether was added to the obtained residue.
-Phenylacetamide-2α-phenylpenam-3α
-Carboxylic acid p-nitrobenzyl ester 300 mg (yield 6
2.5%).

IR (KBr) cm ^-1 ; ν _{c =} 1790, 1745, 1650 NMR (CDCl ₃ ) δ value; 3.64 (2H, s), 4.60 (1H, d, J = 14 Hz), 4.83 (1H, d, J = 14Hz), 5.08 (2H, s), 5.55 to 5.80 (2H, m), 6.15 (1H, d ,, J = 8Hz), 7.00 (2H, d, J = 10Hz), 7.25 (10H, s), 8.05 (2H, d, J = 10Hz) In the same manner, the compound of Table-8 was obtained.

Example 7 6β-phenylacetamido-2- (pyridine-3-
Yl) -2-diphenylmethoxycarbonylpenam-3
To a mixture of 1 g of carboxylic acid p-nitrobenzyl ester, 5 ml of methylene chloride and 5 ml of anisole, a solution of 540 mg of aluminum chloride and 5 ml of anisole is added dropwise at −30 ° C. over a period of 5 minutes. After stirring at the same temperature for 20 minutes, the reaction solution is added to a mixture of 20 ml of water and 20 ml of ethyl acetate. After adjusting the pH to 1.5 with 2N hydrochloric acid and stirring for 1 hour at room temperature, the pH is adjusted to 7.0 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1) to give 6β-phenylacetamido-2α- (pyridin-3-yl). Penam-3α-carboxylic acid p-nitrobenzyl ester (Compound I) 220 mg (30.0% yield) and 6β-phenylacetamido-2β- (pyridin-3-yl) penam-3α
-Carboxylic acid p-nitrobenzyl ester (Compound II)
100 mg (14.1% yield) are obtained.

(Compound I) IR (KBr) cm ^-1 ; v _{c =} 1780, 1745, 1660 NMR (CDCl ₃ ) δ value; 3.61 (2H, s), 4.75 (1H, d, J = 6 Hz), 4.89 (1H , d, J = 6Hz), 5.10 ~ 5.52 (3H, m), 5.67 (1H, dd, J = 4Hz, J = 9Hz), 6.35 (1H, m), 7.00 ~ 7.68 (9H, m), 8.00 ~ 8.62 (4H, m) (Compound II) IR (KBr) cm ^-1 ; νc ₌ 1780,1745,1660 NMR (CDCl ₃ ) δ value; 3.66 (2H, s), 4.70 (1H, d, J = 14Hz), 4.90 (1H, d, J = 14Hz), 5.05 to 5.40 (3H, m), 5.50 (1H, dd, J = 4Hz, J = 9Hz), 6.50 (1H, d, J = 9Hz), 7.00 7.67.60 (9H, m), 8.05 (2H, d, J = 9 Hz), 8.33 to 8.57 (2H, m) The compounds in Table 9 were obtained in the same manner.

Example 8 6β-phenylacetamido-2α-phenylpenam-3α-carboxylic acid p-nitrobenzyl ester 170 m
g, N, N-dimethylaniline 0.125 ml and methylene chloride
At −30 ° C., 90 mg of phosphorus pentachloride was added to 3.4 ml of the mixture,
Stir at −35 to −30 ° C. for 3 hours. Then, the mixture is cooled to -50 ° C, 0.4 ml of methanol is added, and the mixture is stirred at -10 ° C for 2 hours. The reaction solution is added to 3 ml of water, stirred for 1 minute under ice cooling, and adjusted to pH 7 with a saturated aqueous solution of sodium hydrogen carbonate.
The organic layer is separated, washed with saturated saline, and dried over anhydrous magnesium sulfate to obtain a solution containing 6β-amino-2α-phenylpenam-3α-carboxylic acid p-nitrobenzyl ester. The solution was cooled to -20 ° C,
After adding 133 mg of D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetyl chloride, the mixture is stirred at 0 ° C. for 10 minutes, the reaction mixture is added to 5 ml of water, and a saturated aqueous solution of sodium hydrogen carbonate is added. Adjust to pH 7 with.
The organic layer is separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: acetone = 15: 1) to give D-6β-
160 mg (yield 69.5%) of [α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetamide] -2α-phenylpenam-3α-carboxylic acid p-nitrobenzyl ester are obtained.

IR (KBr) cm ^-1 ; ν _{c =} 1780,1740,1705,1670 NMR (CDCl ₃ ) δ value; 1.08 (3H, t, J = 7 Hz), 3.31 to 3.70 (4H, m), 3.85 to 4.15 (2H, m), 4.64 (1H, d, J = 12Hz), 4.86 (1H, d, J = 12Hz), 5.06 (1H, d, J = 8Hz), 5.18 (1H, d, J = 8Hz), 5.46 (1H, d, J = 7Hz), 5.57 to 5.82 (2H, m), 6.75 (1H, d, J = 10Hz), 7.05 (2H, d, J = 8Hz), 7.23 (5H, s), 7.33 (5H, s) 8.05 (2H, d, J = 8Hz), 9.82 (1H, d, J = 7Hz) Similarly, the compounds in Table-10 were obtained.

Example 9 To a mixture of 120 mg of 6β-phenylacetamide-2α- (p-acetoxyphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester, 5 ml of ethyl acetate and 5 ml of water was added 100 mg of 5% palladium-carbon, Hydrogenate at normal pressure for 2 hours. Add 17mg of sodium bicarbonate,
After stirring at the same temperature for 10 minutes, 5% palladium-carbon is removed, and the aqueous layer is separated. Column chromatography [LC-SORB 40-60 manufactured by Kecom, eluent; 1
0% acetonitrile aqueous solution], 6β-phenylacetamido-2α- (p-acetoxyphenyl)
32 mg of sodium salt of penum-3α-carboxylic acid (yield 3
3.3%).

IR (KBr) cm ^-1 ; v _{c =} 1760, 1640, 1590 NMR (d ₆ -DMSO) δ value; 2.31 (3H, s), 3.63 (2H, s), 4.55 (1H, d, J = 7 Hz) ), 5.15 (1H, d, J = 7Hz), 5.48 (1H, dd, J = 5Hz, J = 9Hz), 5.69 (1H, d, J = 5Hz), 7.12 (2H, d, J = 9Hz), 7.42 (5H, s), 7.65 (2H, d, J = 9 Hz), 8.83 (1 H, d, J = 9 Hz), and the compounds in Table 11 and Table 12 were obtained in the same manner.

Example 10 6β-phenylacetamido-2α- (thiophene-
2-yl) penam-3α-carboxylic acid diphenylmethyl ester 80 mg, methylene chloride 0.4 ml and anisole 0.4
A mixture of 77 mg of aluminum chloride and 0.4 ml of anisole is added dropwise at −30 ° C. to the mixture of ml. After stirring at the same temperature for 15 minutes, the reaction solution is added to a mixture of 3 ml of water and 3 ml of ethyl acetate, and adjusted to pH 2 with 2N sulfuric acid. The organic layer was separated, washed with water, added with 1 ml of water, and further added with sodium hydrogen carbonate 1
After adding 2 mg, the mixture is stirred under ice cooling for 10 minutes. The aqueous layer was separated and subjected to column chromatography [LC Solve (LC-
SORB) manufactured by 40-60 Chemco, eluent; 5% acetonitrile aqueous solution] to give 6β-phenylacetamide-2.
33 mg (yield 55.0%) of the sodium salt of α- (thiophen-2-yl) penam-3α-carboxylic acid are obtained.

IR (KBr) cm ^-1 ; ν _{c =} 1760,1650,1600 NMR (d ₆ -DMSO) δ value; 3.52 (2H, s), 4.47 (1H, d, J = 7 Hz), 5.30 (1H, d , J = 7Hz), 5.36 (1H, d, J = 4Hz), 5.46 (1H, dd, J = 4Hz, J = 8Hz), 6.83 (1H, m), 7.00 to 7.45 (7H, m), 8.65 ( (1H, d, J = 8 Hz) Similarly, the following compound was obtained.

6β-phenylacetamido-2β- (thiophene-
2-yl) penam -3α- sodium salt IR of the carboxylic acid _{^{(KBr) cm -1; ν c}} = 0 1765,1650,1605 NMR (d 6 -DMSO) δ value; 3.57 (2H, s), 4.26 (1H , d, J = 5 Hz), 5.20-5.62 (3H, m), 6.80-7.39 (8H, m), 8.43 (1H, d, J = 8 Hz) Example 11 6β-phenylacetamido-2α- (quinoline-6
20-mg of 6β-phenylacetamido-2α- (quinolin-6-yl) penam-3α-carboxylic acid prepared by dissolving the sodium salt of -yl) penam-3α-carboxylic acid in water and adding equimolar 1N hydrochloric acid; To a mixture of 1 ml of N, N-dimethylformamide is added 0.02 ml of methyl iodide, and the mixture is stirred at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, 3.8 mg of sodium hydrogen carbonate and 1 ml of water were added to the obtained residue, and column chromatography [LC Solve (LC-SORB) 40-60, manufactured by Chemco, eluent; 20%
Acetonitrile aqueous solution] to give 6β-phenylacetamido-2α- (1-methyl-6-quinolinio)
Inner salt of henam-3α-carboxylic acid 12mg (60% yield)
Get.

IR (KBr) cm ^-1 ; v _{c =} 1760, 1650, 1600 In the same manner, the following compound was obtained.

6β-phenylacetamido-2α- (1-methyl-
Intramolecular salt of 3-pyridinio) penam-3α-carboxylic acid IR (KBr) cm ^-1 ; vc _{= 0} 1770,1660,1600 6β- [2- (Z)-(2-aminothiazole-4-
Yl) -2-methoxyiminoacetamide] -2α-
Internal salt of (1-methyl-3-pyridinio) penam-3α-carboxylic acid IR (KBr) cm ^-1 ; νc ₌ 1780,1730,1660 NMR (d ₆ -DMSO) δ value; 3.97 (3H, s), 4.10 (3H, s), 4.38 (1H, d, J = 10 Hz), 4.52 (1H, d, J = 10 Hz), 5.65 to 5.92 (2H, m), 6.97 (1H, s), 8.10 to 8.40 (2H, m), 8.81 (1H, m), 9.18 (1H, m), 9.73 (1H, d, J = 8Hz)

Continuation of the front page Examiner Seiko Tamura (56) Reference JP-A-62-228083 (JP, A) JP-A-52-113991 (JP, A) JP-A-48-52792 (JP, A) Chem. Lett. , 1977 PP. 1394-1402 Tetrahedron Let t. , 1984, 25 (49), pp. 5593-5596 Tetrahedron Let t. , 1972, 29 pp. 2923-2926 Supervised by Japan Compendium Association, 11th revision Japanese Pharmacopoeia commentary, Hirokawa Shoten, 1986, pp. C-1467-c-1469 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 499/68-499/84 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (1)

(57) [Claims] (1) General formula Wherein R ¹ is α-aminophenylacetyl, α- (4
-Ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (4-ethyl-2,
3-dioxo-1-piperazinecarboxamido) benzothienylacetyl, 2-thienyl-2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) acetyl, 2- (2-aminothiazol-4-yl)- 2
-Methoxyiminoacetyl, α- (cis-2-cyanovinyl) thioacetyl, α- [3- (4-phenylphenylcarbonyl) -3-methyl-1-ureido] -α-phenylacetyl and α-{[4- ( 4-chlorophenylimidazole) -2-yl] carboxamide} -α-
An amino group substituted with an acyl selected from a phenylacetyl group; R ² is a thienyl, furyl, thiazolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroquinolyl which may be substituted with a lower alkyl group; Or an imidazo [1,2-b] [1,2,4] triazinyl group; R ³ is a hydrogen atom; R ⁴ is an optionally protected carboxyl or carboxylate group; and n is 0 or 1 Is shown. ] The penam-3-carboxylic acid derivative represented by these, or its salt.