JP2936404B2 - Method for producing penam-3-carboxylic acid derivative and penam-2,3-dicarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing a penam-3-carboxylic acid derivative or a salt thereof and to a penum-2,3-dicarboxylic acid derivative useful as an intermediate.

[0002]

2. Description of the Related Art It has a broad antibacterial spectrum, that is, it exhibits excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is particularly stable against β-lactamase and excellent against resistant bacteria. Penam-2,3 has an antibacterial activity and is an intermediate for producing a penum-3-carboxylic acid derivative useful as a medicament for humans and animals.
It is not known to use dicarboxylic acids.

[0003]

[Problems to be Solved by the Invention] Production of penam-3-carboxylic acid derivatives having a wide antibacterial spectrum, being stable against β-lactamase, and exhibiting excellent antibacterial activity against resistant bacteria The development of a law was desired.

[0004]

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

Embedded image Wherein R ^1a represents a phenylacetylamino group, a phenoxyacetylamino group or an acetylamino group;
² represents an optionally substituted aryl or heterocyclic group; R ⁴ represents an optionally protected carboxyl group or a carboxylate group; and n represents 0 or 1. By subjecting the penum-2,3-dicarboxylic acid derivative or a salt thereof represented by the general formula [II]

[0005]

Embedded image Wherein a penam-3-carboxylic acid derivative or a salt thereof represented by the formula “wherein R ^1a , R ² , R ⁴ and n are the same as above” can be produced, and the following general formula [I]

Embedded image Wherein R ^1a represents a phenylacetylamino group, a phenoxyacetylamino group or an acetylamino group;
² represents an optionally substituted aryl or heterocyclic group; R ^3a represents a hydrogen atom or a carboxyl protecting group;
⁴ represents a carboxyl group or a carboxylate group which may be protected; and n represents 0 or 1. The present inventors have found that a penum-2,3-dicarboxylic acid derivative or a salt thereof represented by the general formula (1) is a useful intermediate, 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, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, se
a linear or branched C _1-5 alkyl group such as c-butyl, tert-butyl and pentyl; an aryl group includes, for example, phenyl, naphthyl, indanyl and the like; a halogen atom includes, for example, a fluorine atom, A heterocyclic group includes, for example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, chlorine atom, bromine atom, iodine atom and the like;
Benzimidazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 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
At least one heteroatom selected from oxygen, nitrogen and sulfur atoms such as [1,2-b] [1,2,4] triazinyl, pyrrolidinyl, morpholinyl, quinuclidinyl and 2,3,4-tritetrahydroquinolyl 4 members containing 5
Means a 6-membered, 6-membered or fused heterocyclic group, and the heterocyclic group containing a nitrogen atom may be quaternized.

The substituent of the aryl or heterocyclic group in R ² includes, for example, a lower alkyl group; vinyl,
Lower alkenyl groups such as aryl, propenyl and butenyl; lower alkynyl groups such as ethynyl and propynyl; halogen atoms; hydroxyl groups; C _1-8 acyl groups such as acetyl, propionyl, butyryl, toluyl; C such as acetyloxy and benzoyloxy; _1-8 acyloxy group; amino group; lower alkoxy group such as methoxy and ethoxy; aryloxy group such as phenoxy; hydroxy lower alkyl group such as hydroxymethyl; sulfo group; lower alkyl substitution such as methylamino, ethylamino and dimethylamino Amino group; cyano group; nitro group; carboxyl group; lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl; lower alkylthio groups such as methylthio and ethylthio; heterocyclic thio groups; heterocyclic thio lower alkyl groups Pyridinium, imidazolium, quinolinium, 1-cyclic ammonio group such as methyl pyrrolidinium; and pyridinium methyl imidazolium methyl, include groups such as cyclic ammonio-lower alkyl groups such as quinolinium methyl, in R ² The aryl or heterocyclic group may be substituted with one or more substituents selected from the above substituents. In addition, as a heterocyclic group of a heterocyclic thio group, the same group as the above-mentioned heterocyclic group can be mentioned.

Examples of the carboxyl-protecting group for R ^3a and R ⁴ include those conventionally known in the field of penicillins and cephalosporins, and include, for example, catalytic reduction, chemical reduction and other relaxation. Ester-forming group that is eliminated by treatment under mild conditions, or ester-forming group that is easily eliminated in vivo, or organic silyl group or organic phosphorus group that is easily eliminated by treatment with water or alcohol Alternatively, an ester forming group such as an organic tin group may be used. Of 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-hydroxy-3,5-
Aralkyl groups such as di (tert-butyl) benzyl, phenethyl, diphenylmethyl, trityl, bis (p-methoxyphenyl) methyl; phthalidyl group; 2-iodoethyl;
Halo-lower alkyl groups such as 2,2,2-trichloroethyl; acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, Acyloxy lower alkyl groups such as -pivaloyloxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-n-propyl; (5-methyl-
(5-lower alkyl-2-oxo-1,3-dioxol-4-yl) lower alkyl groups such as 2-oxo-1,3-dioxol-4-yl) methyl; methoxymethyl, ethoxymethyl, propoxymethyl, Lower alkoxy groups such as isopropoxymethyl; and alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl and 1-propoxycarbonyloxyethyl.

When the groups R ^{1a to} R ⁴ and their substituents have groups such as an amino group, a mono-lower alkyl-substituted amino group, a hydroxyl group and a carboxyl group, these groups are usually It may be protected by a known protecting group. Protecting groups for amino group and mono-lower alkyl-substituted amino group include, for example, formyl, te
rt-butoxycarbonyl, tert-amyloxycarbonyl, trityl, trimethylsilyl, benzylidene, 2,
Examples include commonly known amino protecting groups such as 2,2-trichloroethoxycarbonyl, p-nitrobenzylidene, hexahydro-1H-azepin-1-ylmethylene, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phthaloyl.

Examples of the hydroxyl-protecting group include formyl, acetyl, benzyl, tetrahydropyranyl, benzyloxycarbonyl, trimethylsilyl and p-nitrobenzyloxycarbonyl. Examples of the carboxyl protecting group include the carboxyl protecting groups described above.

Examples of the salts of the compounds of the formulas [I], [I '] and [II] include commonly known salts of a basic group such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group. Can be Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with halogen anions such as chloroanion and bromoanion; and salts with formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like. Salts with carboxylic acids; or methanesulfonic acid,
Salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; calcium; , Salts with alkaline earth metals such as magnesium; 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, when the molecule has an ammonium group or a pyridinio group in the molecule, each of these groups may usually form an inner salt with the above-mentioned carboxylate group in R ⁴ . The general formulas [I], [I '] and
When isomers (for example, optical isomers, geometric isomers, tautomers, and the like) are present in the compound of [II] and salts thereof, the present invention includes all such isomers,
It also includes all crystalline forms and hydrates and solvates. Next, the production method of the present invention and the production method of the intermediate will be explained including the production method of penam-3-carboxylic acid as a whole.

[0013]

(Equation 1)

(Equation 2) Wherein R ^1a , R ² , R ^3a and R ⁴ have the same meanings as described above, and R ¹ is an optionally protected acylamino group; R ^1b is penicillin and cephalosporin an acyl group which is usually used in the field of system compound; R ^4a
Represents a carboxyl group which may be protected as in R ⁴ ; X ¹ and Y each represent a leaving group. "

The general formulas [Ia] to [Ie], [IIa], [IIb] and [I
Examples of the salts of the compounds of the formulas [II] to [IX] include the same salts as the salts of the compounds of the formula [I]. The leaving group for X ¹ and Y includes a halogen atom; a lower alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy; and phenylsulfonyloxy;
And arylsulfonyloxy groups such as tolylsulfonyloxy.

(1) The compound of the general formula [IV] or a salt thereof is
It can be obtained by reacting a compound of the general formula [IX] or a salt thereof with a compound of the general formula [III] or a salt thereof in the presence or absence of a base or a deoxidizing agent. 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; dimethyl sulfoxide; and hexamethylphosphoric triamide. May be used as a mixture of two or more. As the base used in this reaction, 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 (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene or Grignard reagents such as methylmagnesium bromide or 2,4,6-trimethylphenylmagnesium bromide, etc. And deoxidizing agents include propylene oxide and molecular sieves. General formula [III]
The amount of the compound or a salt thereof is 1 to 2 moles compared to the compound of the general formula [IX] or a salt thereof. The amount of the base or deoxidizing agent used as required is 0.01 to 0.01 to the compound of the general formula [IX] or a salt thereof, respectively.
2.0 times mol. This reaction is usually performed at -70 to 150 ° C for 5 minutes.
It may be carried out for minutes to 5 hours.

(2) The compound of the general formula [VI] or a salt thereof is
It can be obtained by reacting a compound of the general formula [IV] or a salt thereof with a compound of the general formula [V], a hydrate thereof or a reactive derivative such as hemiacetal in the presence or absence of a base. it can. 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. Examples of the base used in this reaction include the same bases as described in (1). 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
It is 0.001 to 1-fold the molar amount of the compound of the general formula [IV] or a salt thereof. This reaction is usually carried out at −30 to 100 ° C. for 5 minutes to
All you need to do for 5 hours.

(3) The compound of the general formula [VII] or a salt thereof is obtained by reacting a compound of the 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 obtained by 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, as described in (1), 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 the same bases as described in (1). The amount of the halogenating agent or the sulfonylating agent to be used is 1 to 5 moles per 1 mole of the compound of the general formula [VI] or a salt thereof. The amount of the base used as needed is 1 to 5 moles per 1 mole of the compound of the general formula [VI] or a salt thereof. This reaction is
Usually, it may be carried out at −20 to 50 ° C. for 5 minutes to 5 hours.

(4) The compound of the general formula [Ia] or a salt thereof is
It can be obtained by subjecting the 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-imidazolidone and the like, and these solvents may be used as a mixture of two or more. Examples of the base used in this reaction include the same bases as described in (1).
This reaction can be performed 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 compared to the compounds of the formula [VII] or a salt thereof. In addition, the amount of the silylating agent used if necessary is 1 to the compound of the general formula [VII] or a salt thereof.
~ 3 times the mole. This reaction is usually carried out at -78 to 50 ° C for 5 minutes.
It may be carried out for minutes to 12 hours.

(5) The compound of the general formula [Ib] or a salt thereof is
It can be obtained by subjecting a compound of the general formula [Ia] 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 Groups in Organic Synthesis (P
rotective Groups in Organic Synthesis)
Theodra W Green John Wiley and Sons Incorporated
ley & Sons, Inc.)] or a method analogous thereto.

(6) The compound of the general formula [Ic] or a salt thereof is
It can be obtained by subjecting a compound of the general formula [Ib] or a salt thereof to an oxidation reaction. Specifically, for example, Journal of the Organic Chemistry (JO
rg. Chem.) Volume 35, pp. 2430 to 2433 (1970) or a method analogous thereto.

(7) The compound of the formula [IIa] or a salt thereof can be obtained by subjecting the compound of the formula [Ic] 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; dimethyl sulfoxide; hexamethylphosphoric triamide; water; Acetic acid; esters such as ethyl acetate; and pyridine. 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. Further, the amount of the acid used as needed is 0.00 to the compound of the general formula [Ic] or a salt thereof.
It is 1 to 10 times mol. The reaction is usually carried out at 0 to 100 ° C. for 1
It may be carried out for minutes to 12 hours. The compound of the general formula [IIb] or a salt thereof can also be obtained by subjecting the compound of the general formula [Ib] or a salt thereof to a similar decarboxylation reaction.

(8) The compound of the formula [IIb] or a salt thereof can be obtained by subjecting the compound of the formula [IIa] or a salt thereof to a usual reduction reaction known in the art. Specifically, for example, Journal of the Chemical Society Perkin Transactions I (J. Chem. Soc. Perkin.Trans.I), pages 932 to 937 (1
973) or the method described in JP-B-56-24675 or a method analogous thereto.

(9) The compound of the general formula [Id] or a salt thereof is
The acyl group of the compound of the general formula [IIb] or a salt thereof can be obtained by subjecting the compound to a usual deacylation reaction known in the art or by removing an amino protecting group.
Specifically, a compound of the general formula [IIb] or a salt thereof is reacted with a halogenating agent such as phosphorus pentachloride to give an imino halide, and then reacted with an alcohol to give an imino ether, which is further hydrolyzed. By the general formula [I
d) 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 [Id] or a salt thereof can be obtained by the method described in JP-A-45-40899 or a method similar thereto.

(10) The compound of the general formula [Ie] or a salt thereof is prepared by adding the compound of the general formula [VIII] or a salt thereof to a compound of the general formula [Id] or a reactive derivative thereof in the presence of a solvent. It can be obtained by reacting a salt or a reactive derivative thereof. Examples of the reactive derivative of the compound of the general formula [Id] or a salt thereof include trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilanyl, and dimethoxysilanediyl. Organic silyl groups such as dimethoxyphosphinyl, 1,3,2-dioxophosphorane-
2-yl, 4-methyl-1,3,2-dioxophosphoran-2-yl or 1,3,2-dioxophosphan-2
And compounds in which an organic phosphorus group such as -yl is bonded to an amino group which is a reaction site. Examples of the reactive derivative of the compound of the general formula [VIII] include JP-A-56-127375 and JP-A-59-127375.
Acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, active thioloesters, acid azides and the general formula [V
III] and a reactive derivative of the Vilsmeier reagent. Solvents used in this reaction include:
The solvent 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 ethanol and isopropanol; N, N
Amides such as 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; 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, and the base used as necessary includes, for example, the same bases as mentioned in (1). When the compound of the general formula [VIII] is used as a salt with a free acid or a nitrogen-containing organic base, a suitable condensing agent is used. As the condensing agent used, for example,
N, N 'such as N, N'-dicyclohexylcarbodiimide
-Disubstituted carbodiimides. The amount of the compound of the general formula [VIII] 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 [Id] or a salt or a reactive derivative thereof. It is about 1.5 times mol. This reaction is usually carried out at -50 to
It may be carried out at 80 ° C. for 5 minutes to 30 hours.

In each of the steps described above, the introduction and elimination of the protecting group can be appropriately carried out by a conventional method, and the compounds of the general formulas [Ia] to [Ie], [IIa], [IIb] and [III] to When the compound of [IX] or a salt thereof has an isomer, each can be isolated and purified by a conventional method.
When a group active in the reaction is present in the groups of R ^1a , R ² , R ^3a and R ^4a , the reaction may be protected with a usual protecting group. The group can also be eliminated. Further, for example, esterification, hydrolysis, addition, acylation, oxidation, reduction, cyclization, halogenation, alkylation, amination, thiolation, quaternization, aryloxylation, sulfonylation or alkylamino The compound of the present invention can also be derived to other compounds of the present invention by commonly known methods such as chemical conversion, and by appropriately combining these methods.

Next, the compound of the general formula [IX] or a salt thereof, which is a raw material, is prepared, for example, from Journal of the Chemical Society Perkin Transactions I.
(J. Chem. Soc. Perkin.Trans.I) pp. 150-155 (1980
) Or a method known per se or the like can be appropriately combined. Further, the compound of the general formula [III] or a salt thereof is disclosed in, for example,
It can be obtained by the method described in 2-228083 and the like.

[0027]

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, Z; Benzyloxycarbonyl Unless otherwise specified, carriers used in column chromatography are Kieselgel 60 manufactured by Merck, Art
7734 (Kieselgel 60, Art.7734) was used. Further, the mixing ratio in the eluent is a volume ratio. (Note that the configurations at the 2- and 3-positions of the penum skeleton are deduced.)

Reference Example 1 α-bromophenylacetic acid diphenylmethyl ester 13.9
g and 60 ml of N, N-dimethylformamide,
Under ice cooling, (3R, 4R) -3-phenylacetamide-4
-8.6 g of mercapto-2-azetidinone is added,
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. When the solvent is distilled off under reduced pressure, (3R, 4
R) -4- [1-Phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamide-2
19.2 g of azetidinone (98.2% yield) are obtained. IR (KBr) cm ^-1 ; vc = o 1760, 1740, 1660 Similarly, the compounds of Table 2 were obtained.

[0029]

[Table 2]

Reference Example 2 (3R, 4R) -4- [1- (p-hydroxyphenyl) -1-
47 g of ((diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone is dissolved in 235 ml of methylene chloride, 8.2 ml of pyridine and 9.6 ml of acetic anhydride are added at room temperature, and the mixture is stirred at the same temperature for 12 hours. The reaction solution is added to 100 ml of water, adjusted to pH 2.5 with 2N hydrochloric acid, and then the organic layer is separated. After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent; chloroform: acetone = 10: 1),
(3R, 4R) -4- [1- (p-acetoxyphenyl) -1-
(Diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone 43.5 g (yield 77.3
%). IR (KBr) cm ^-1 ; νc = o 1760,1740,1660

Reference Example 3 19.2 g of (3R, 4R) -4- [1-phenyl-1- (diphenylmethoxycarbonyl) methylthio] -3-phenylacetamido-2-azetidinone, p-nitrobenzyl glyoxylic acid / 1 water 8.0 g of Japanese product and methylene chloride
Add 1,8-diazabicyclo [5.
4.0] Undec-7-ene (DBU) 0.05 ml after adding
Stir at room temperature for 2 hours. The reaction solution is added to 200 ml of water, adjusted to pH 3 with 2N hydrochloric acid, and the organic layer is separated. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure,
(3R, 4R) -1- [1-hydroxy-1- (p-nitrobenzyloxycarbonyl) methyl] -4- [1-phenyl-1- (diphenylmethoxycarbonyl) methylthio]-
There are obtained 26.0 g (yield 97.4%) of 3-phenylacetamido-2-azetidinone. IR (KBr) cm ^-1 ; vc = o 1760, 1750, 1660 Similarly, compounds of Table 3 were obtained.

[0032]

[Table 3]

Reference Example 4 (3R, 4R) -1- [1-hydroxy-1- (p-nitrobenzyloxycarbonyl) methyl] -4- [1-phenyl-1- (diphenylmethoxycarbonyl) methylthio]-
A mixture of 10.0 g of 3-phenylacetamide-2-azetidinone and 100 ml of tetrahydrofuran was added under ice-cooling for 2,2.
6.28 ml of 6-lutidine were added, followed by thionyl chloride.
2.15 ml are added dropwise over 5 minutes. After stirring at the same temperature for 30 minutes, the precipitate is removed by filtration 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 10 ml of 15% n-butyllithium hexane solution) was added at the same temperature. Is added dropwise over 10 minutes, and the mixture is further stirred at the same temperature for 10 minutes. The reaction solution was mixed with 300 ml of water and ethyl acetate 1
Add to a mixture of 00 ml and 6 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-phenylacetamido-2-phenyl-2-diphenylmethoxycarbonyl. 5.5 g (56.4% yield) of penum-3α-carboxylic acid p-nitrobenzyl ester are obtained. This compound was a 1: 1 mixture of 2α-form and 2β-form from NMR. IR (KBr) cm ^-1 ; νc = o 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), 6.95-7.45 (23H, m), 7.95-8.18 (2H,
m) Similarly, the compounds in Table 4 were obtained.

[0034]

[Table 4-1]

[0035]

[Table 4-2]

[0036]

[Table 4-3]

[0037]

[Table 4-4]

Reference Example 5 6β-phenylacetamido-2-phenyl-2-diphenylmethoxycarbonylpenam-3α-carboxylic acid p-
Aluminum chloride was added to a mixture of 9.8 g of nitrobenzyl ester, 50 ml of methylene chloride and 50 ml of anisole at -30 ° C.
A solution of 4 g and 50 ml of anisole is added dropwise over 5 minutes. After stirring at the same temperature for 20 minutes, the reaction solution is added to a mixture of 200 ml of water 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, and 2N
After adjusting the pH to 2.0 with 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) are obtained. IR (KBr) cm ^-1 ; νc = o 1770, 1750, 1650 NMR (CDCl ₃ ) δ value; 3.38 (2H, s), 4.40 (1H, d, J = 15 Hz), 4.67
(1H, d, J = 15Hz), 5.50 (1H, m), 5.71 (1H, d, J = 4Hz), 6.03 (1H,
s), 7.00 to 7.60 (14H, m), 8.03 (2H, d, J = 9 Hz) The compounds in Table 5 were obtained in the same manner.

[0039]

[Table 5]

Reference Example 6 17 g of 6β-phenylacetamido-2- (p-benzyloxycarbonyloxymethylphenyl) -2-diphenylmethoxycarbonylpenam-3α-carboxylic acid p-nitrobenzyl ester, 85 ml of methylene chloride and 85 ml of anisole A solution of 10 g of aluminum chloride and 30 ml of anisole is added dropwise to the mixture at -30 ° C over 5 minutes. −20
After stirring at 10 ° C. for 10 minutes, the reaction is added to a mixture of 200 ml of water 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: ethanol = 50: 1). This is dissolved in a mixed solution of 50 ml of water and 50 ml of ethyl acetate, adjusted to pH 2.0 with 2N sulfuric acid, and then the organic layer is separated. After washing with water and saturated saline solution in that order, it is dried over anhydrous sodium sulfate. If the solvent is distilled off under reduced pressure, 6β-phenylacetamide-2-
(p-benzyloxycarbonyloxymethylphenyl)-
6.8 g (49.2% yield) of 2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester are obtained. IR (KBr) cm ^-1 ; νc = o 1790,1750,1660 After obtaining the above compound, further column chromatography
(Eluent: chloroform: methanol = 10: 1) was dissolved in a mixed solution of 50 ml of water and 50 ml of ethyl acetate, adjusted to pH 2.0 with 2N sulfuric acid, and the organic layer was separated. After washing with water and saturated saline solution in that order, it is dried over anhydrous sodium sulfate. If the solvent is distilled off under reduced pressure, 6β
-Phenylacetamide-2- (p-hydroxymethylphenyl) -2-carboxypenam-3α-carboxylic acid p-
5.0 g (44.7% yield) of nitrobenzyl ester are obtained. IR (KBr) cm ^-1 ; νc = o 1785, 1745, 1650 NMR (d ₆ -DMSO) δ value; 3.57 (2H, s), 4.42 (2H, s), 4.52 to 5.60
(6H, m), 5.78 (1H, s), 6.77 ~ 7.76 (11H, m), 8.09 (2H, d, J = 9H
z), 8.69 (1H, d, J = 7Hz)

Reference Example 7 2β-phenylacetamido-2- (p-nitrobenzyloxycarbonyl) -2- (thiophen-2-yl) penam-3α-carboxylic acid diphenylmethyl ester 2 g,
2 g of 5% palladium-carbon is added to a mixture of 10 ml of water and 10 ml of ethyl acetate, and hydrogenated at room temperature and normal pressure for 2 hours. After completion of the reaction, 5% palladium-carbon was removed by filtration and the pH was adjusted with 2N hydrochloric acid.
After adjusting to 2, 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 ; νc = o 1780,1740,1660

Reference Example 8 A mixture of 3.1 g of 6β-phenylacetamido-2-phenyl-2-carboxypenam-3-carboxylic acid p-nitrobenzyl ester and 30 ml of methylene chloride was added with m-chloride under ice-cooling.
1.06 g of chloroperbenzoic acid are added in portions 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 was separated and washed sequentially with water and saturated saline,
Dry 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 is dissolved in a mixture 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 washing sequentially with water and saturated saline, drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, 6β-
Phenylacetamide-2-phenyl-2-carboxypenam-3α-carboxylic acid p-nitrobenzyl ester-
2.5 g (78.6% yield) of 1-oxide are obtained. IR (KBr) cm ^-1 ; νc = o 1790,1745,1670,1630 NMR (CDCl ₃ ) δ value; 3.56 (1H, s), 3.62 (1H, s), 4.96-5.30 (4
H, m), 5.88-6.12 (2H, m), 7.05-7.40 (13H, m), 8.03 (2H, d,
J = 9 Hz) Similarly, the compounds in Table 6 were obtained.

[0043]

[Table 6]

Example 1 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),
6β-phenylacetamido-2α-phenylpenam-
0.5 g of 3α-carboxylic acid p-nitrobenzyl ester-1-oxide (compound I) (20.5% yield) and 6β-phenylacetamido-2β-phenylpenum-3α-carboxylic acid p-nitrobenzyl ester-1-oxide (compound II)
0.55 g (22.5% yield) is obtained. (Compound I) IR (KBr) cm ^-1 ; vc = o 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 ~ 7.33 (13H, m), 7.95 (2
(Compound II) IR (KBr) cm ^-1 ; vc = o 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 (13
H, m), 8.07 (2H, d, J = 9 Hz) The compounds in Table 7 were obtained in the same manner.

[0045]

[Table 7-1]

[0046]

[Table 7-2]

[0047]

[Table 7-3]

[0048]

[Table 7-4]

[0049]

[Table 7-5]

Example 2 A mixture of 200 mg of 6β-phenylacetamide-2α- (p-hydroxymethylphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide and 2 ml of N, N-dimethylformamide was cooled with ice. Below, after sequentially adding triphenylphosphine 93 and 116 mg of carbon tetrabromide,
Stir for 30 minutes at the same temperature. Furthermore, after sequentially adding 93 mg of triphenylphosphine and 116 mg of carbon tetrabromide, the mixture is stirred at the same temperature for 30 minutes. Then, at the same temperature, 75 mg of sodium salt of 5-mercapto-1,2,3-thiadiazol and 25 mg of potassium carbonate are sequentially added, and the mixture is stirred at the same temperature for 2 hours. The reaction solution is added to a mixture of 10 ml of water and 10 ml of ethyl acetate, and the organic layer is separated. The extract is washed successively 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 = 10: 1) to give 6β-phenylacetamide-2α- ｛p-
[(1,2,3-thiadiazol-5-yl) thiomethyl] phenyl} penam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide (120 mg, yield 52.2%) was obtained. IR (KBr) cm ^-1 ; v c = o 1795,1750,1670 The following compound was obtained in the same manner.・ 6β-phenylacetamide-2β- ｛p-[(1,
2,3-thiadiazol-5-yl) thiomethyl] phenyl @ penam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide IR (KBr) cm ^-1 ; vc = o 1790,1750,1675

Example 3 6β-phenylacetamido-2α-phenylpenam-
To a mixture of 500 mg of 3α-carboxylic acid p-nitrobenzyl ester-1-oxide, 2 ml of methylene chloride and 2 ml of N, N-dimethylformamide was added 0.1 g of phosphorus tribromide at -30 ° C, and the mixture was stirred at the same temperature for 30 minutes. I do. 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, 10 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 6β-
Phenylacetamide-2α-phenylpenam-3α-
Carboxylic acid p-nitrobenzyl ester 300 mg (yield 62.5
%). IR (KBr) cm ^-1 ; νc = 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), 5.55-5.80 (2H, m), 6.15 (1H,
d, J = 8Hz), 7.00 (2H, d, J = 10Hz), 7.25 (10H, s), 8.05 (2H, d, J
= 10 Hz) In the same manner, the compounds in Table 8 were obtained.

[0052]

[Table 8-1]

[0053]

[Table 8-2]

[0054]

[Table 8-3]

[0055]

[Table 8-4]

[0056]

[Table 8-5]

Example 4 6β-Phenylacetamide-2α- (p-benzyloxycarbonyloxymethylphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester 390 mg, methylene chloride 1.95 ml and anisole 1.95 ml After adding a solution of 230 mg of aluminum chloride and 1.0 ml of anisole at -30 ° C, the mixture was stirred for 30 minutes under ice-cooling. 5 ml of reaction solution
And 5 ml of ethyl acetate, and the organic layer is separated. The extract is washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: toluene:
Purification with ethyl acetate = 5: 1) yields 6β-phenylacetamide-2α- (p-hydroxymethylphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester 190m
g (60.7% yield). IR (KBr) cm ^-1 ; vc = o 1780, 1740, 1660 The following compounds were obtained in the same manner. o6β-phenylacetamide-2β- (p-hydroxymethylphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester IR (KBr) cm ^-1 ; vc = o 1780,1745,1660

Example 5 6β-phenylacetamido-2- (pyridin-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 5 minutes. After stirring at the same temperature for 20 minutes, the reaction solution is
Add to a mixture of 20 ml and 20 ml of ethyl acetate. After adjusting the pH to 1.5 with 2N hydrochloric acid and stirring at room temperature for 1 hour, 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
100 mg (yield 14.1%) of-(pyridin-3-yl) penam-3α-carboxylic acid p-nitrobenzyl ester (Compound II) are obtained. (Compound I) IR (KBr) cm ^-1 ; vc = o 1780, 1745, 1660 NMR (CDCl ₃ ) δ value; 3.61 (2H, s), 4.75 (1H, d, J = 6 Hz), 4.89 (1
H, d, J = 6Hz), 5.10 ~ 5.52 (3H, m), 5.67 (1H, dd, J = 4Hz, J = 9H
z), 6.35 (1H, m), 7.00 to 7.68 (9H, m), 8.00 to 8.62 (4H, m) (Compound II) IR (KBr) cm- ¹ ; vc = o 1780, 1745, 1660 NMR (CDCl ₃ ) δ value; 3.66 (2H, s), 4.70 (1H, d, J = 14Hz), 4.90
(1H, d, J = 14Hz), 5.05-5.40 (3H, m), 5.50 (1H, dd, J = 4Hz, J =
9Hz), 6.50 (1H, d, J = 9 Hz), 7.00 to 7.60 (9H, m), 8.05 (2H, d, J
= 9 Hz), 8.33 to 8.57 (2H, m) Similarly, the compounds in Table 9 were obtained.

[0059]

[Table 9-1]

[0060]

[Table 9-2]

Example 6 A mixture of 110 mg of 6β-phenylacetamido-2α- (p-hydroxymethylphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester and 1 ml of N, N-dimethylformamide was added under ice-cooling with triethanolamine. Phenylphosphine 53
mg and 67 mg of carbon tetrabromide are added, followed by stirring at the same temperature for 30 minutes. Further, after adding 53 mg of triphenylphosphine and 67 mg of carbon tetrabromide, the mixture is stirred at the same temperature for 30 minutes. The reaction solution was added to a mixture of 5 ml of water and 5 ml of ethyl acetate, and the organic layer was separated and washed sequentially with water and saturated saline.
Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 1 ml of pyridine was added to the obtained residue under ice-cooling.
Stir at the same temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was added with 3 ml of diethyl ether and 3 ml of ethyl acetate.
Add 6 ml and remove the precipitate to obtain 6β-phenylacetamido-2α- [p- (1-pyridiniomethyl) phenyl].
130 mg (92.8% yield) of penum-3α-carboxylic acid p-nitrobenzyl ester bromide are obtained. IR (KBr) cm ^-1 ; v c = o 1780,1745,1660 The following compounds were obtained in the same manner. 6β-phenylacetamide-2β- [p- (1-pyridiniomethyl) phenyl] penam-3α-carboxylic acid p-nitrobenzyl ester bromide IR (KBr) cm ^-1 ; vc = o 1785,1745,1665

Reference Example 9 6β-phenylacetamido-2α- (p-acetoxyphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester 200 mg, N, N-dimethylaniline 0.13 ml and methylene chloride 6 ml At 30 ° C add 100 mg of phosphorus pentachloride and stir at -30 to -20 ° C for 3 hours. Then -50
Cool to 0 ° C, add 0.42 ml of methanol, and stir 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 sodium hydrogen carbonate solution. 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; toluene: ethyl acetate = 2: 1) to give 6β-amino-2α- (p-acetoxyphenyl) penam- 110 mg (68.8% yield) of 3α-carboxylic acid p-nitrobenzyl ester are obtained. IR (KBr) cm ^-1 ; νc = o 1760,1745

REFERENCE EXAMPLE 10 To a mixture of 32-aminothiazol-4-ylacetic acid hydrochloride (32 mg) and N, N-dimethylformamide (0.5 ml) was added triethylamine (0.02 ml) under ice-cooling. 6β-amino-2α- (p-acetoxyphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester 50 m
g, hydroxybenzotriazole 20 mg and N, N'-
30 mg of dicyclohexylcarbodiimide is added and stirred at the same temperature for 5 hours. The reaction solution was mixed with 5 ml of water and 5 ml of ethyl acetate.
PH 7.5 with saturated aqueous sodium hydrogen carbonate solution.
Adjust to 0. 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; chloroform: acetone = 10: 1) to give 6β- (2-aminothiazol-4-yl).
Acetamide-2α- (p-acetoxyphenyl) penam-
30 mg of 3α-carboxylic acid p-nitrobenzyl ester (yield
45.5%). IR (KBr) cm ^-1 ; vc = o 1770, 1740, 1660 Similarly, compounds of Table 10 were obtained.

[0064]

[Table 10-1]

[0065]

[Table 10-2]

Reference Example 11 6β-phenylacetamido-2α-phenylpenam-
170 mg of 3α-carboxylic acid p-nitrobenzyl ester, N,
0.125 ml of N-dimethylaniline and 3.4 ml of methylene chloride
90 mg of phosphorus pentachloride was added to the mixture at −30 ° C., and −35 to
Stir at −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 sodium hydrogen carbonate solution. The organic layer was separated, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate to obtain 6β-amino-2α-phenylpenam-3.
A solution containing α-carboxylic acid p-nitrobenzyl ester is obtained. The solution was cooled to -20 ° C and D-α- (4-
After addition of 133 mg of ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetyl chloride, the mixture was added at 0 ° C.
And stir for 10 minutes. The reaction solution is added to 5 ml of water, 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. 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- [α- (4-ethyl-2,3. -Dioxo-1-piperazinecarboxamide)
Phenylacetamide] -2α-phenylpenam-3α
-Carboxylic acid p-nitrobenzyl ester 160 mg (yield 69.5
%). IR (KBr) cm ^-1 ; νc = o 1780,1740,1705,1670 NMR (CDCl ₃ ) δ value; 1.08 (3H, t, J = 7 Hz), 3.31 to 3.70 (4H, m),
3.85-4.15 (2H, m), 4.64 (1H, d, J = 12Hz), 4.86 (1H, d, J = 12H
z), 5.06 (1H, d, J = 8Hz), 5.18 (1H, d, J = 8Hz), 5.46 (1H, d, J = 7
Hz), 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 = 7 Hz) In the same manner, the compounds in Table 11 were obtained.

[0067]

[Table 11-1]

[0068]

[Table 11-2]

[0069]

[Table 11-3]

[0070]

[Table 11-4]

Example 7 6β-Phenylacetamide-2α- (p-acetoxyphenyl) penam-3α-carboxylic acid p-nitrobenzyl ester 120 mg, ethyl acetate 5 ml and water 5 ml in a mixture of 5%
100 mg of palladium-carbon is added and hydrogenated at room temperature and normal pressure for 2 hours. Add 17 mg of sodium bicarbonate, and at the same temperature
After stirring for 5 minutes, 5% palladium-carbon is removed by filtration, and the aqueous layer is separated. Purification by column chromatography [LC-SORB (LC-SORB) 40-60 manufactured by Chemco, eluent; 10% acetonitrile aqueous solution] gives 6β-phenylacetamide-2α- (p-acetoxyphenyl) penam-3α-carboxylic acid Of sodium salt (yield 33.3%). IR (KBr) cm ^-1 ; νc = o 1760,1640,1590 NMR (d ₆ -DMSO) δ value; 2.31 (3H, s), 3.63 (2H, s), 4.55 (1H, d,
J = 7Hz), 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 (2
(H, d, J = 9 Hz), 8.83 (1 H, d, J = 9 Hz) In the same manner, the compounds shown in Tables 12 and 13 were obtained.

[0072]

[Table 12-1]

[0073]

[Table 12-2]

[0074]

[Table 12-3]

[0075]

[Table 12-4]

[0076]

[Table 12-5]

[0077]

[Table 12-6]

[0078]

[Table 13-1]

[0079]

[Table 13-2]

[0080]

[Table 13-3]

[0081]

[Table 13-4]

[0082]

[Table 13-5]

Example 8 6β-Phenylacetamido-2α- (thiophene-2
-Yl) penam-3α-carboxylic acid diphenylmethyl ester 80 mg, methylene chloride 0.4 ml and anisole 0.4 ml
A mixture of 77 mg of aluminum chloride and 0.4 ml of anisole is added dropwise to the mixture at −30 ° C. 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 water (1 ml), and further added sodium hydrogen carbonate (12 m).
After adding g, the mixture is stirred for 10 minutes under ice cooling. The aqueous layer was separated and subjected to column chromatography [LC Solve (LC-SO
RB) 40-60 Chemco, eluent; 5% acetonitrile aqueous solution] to give 6β-phenylacetamide-2α.
33 mg (yield 55.0%) of the sodium salt of-(thiophen-2-yl) penam-3α-carboxylic acid are obtained. IR (KBr) cm ^-1 ; νc = o 1760,1650,1600 NMR (d ₆ -DMSO) δ value; 3.52 (2H, s), 4.47 (1H, d, J = 7Hz), 5.30
(1H, d, J = 7Hz), 5.36 (1H, d, J = 4Hz), 5.46 (1H, dd, J = 4Hz, J = 8
Hz), 6.83 (1H, m), 7.00 to 7.45 (7H, m), 8.65 (1H, d, J = 8 Hz). 6β-phenylacetamido-2β- (thiophene-
2-yl) penam-3α-carboxylic acid sodium salt IR (KBr) cm ^-1 ; νc = o 1765,1650,1605 NMR (d ₆ -DMSO) δ value; 3.57 (2H, s), 4.26 (1H, d, J = 5Hz), 5.20
~ 5.62 (3H, m), 6.80 ~ 7.39 (8H, m), 8.43 (1H, d, J = 8Hz)

Reference Example 14 D-6β- [α- (4-ethyl-2,3-dioxo-1-
Piperazinecarboxamide) phenylacetamide] -2
To a mixture of 70 mg of sodium salt of α- (p-acetoxyphenyl) penam-3α-carboxylic acid and 0.5 ml of water was added 80 mg of protease (Type XIII, manufactured by Sigma) at room temperature, and saturated sodium bicarbonate was added at the same temperature. Stir for 5 hours while adjusting the pH to 7 with an aqueous solution. 0.3 ml of ethyl acetate was added to the reaction solution, and
The pH was adjusted to 2.2 with 1N hydrochloric acid, and the resulting precipitate was collected by filtration to give D-6β- [α- (4-ethyl-2,3-dioxo-).
1-piperazinecarboxamide) phenylacetamide]
50 mg of 2α- (p-hydroxyphenyl) penam-3α-carboxylic acid are obtained (79.4% yield). IR (KBr) cm ^-1 ; νc = o 1770,1735,1710,1675,1650 NMR (d ₆ -DMSO) δ value; 1.12 (3H, t, J = 8 Hz), 3.08 to 4.27 (7H,
m), 4.95 (1H, d, J = 8 Hz), 5.04 to 5.92 (5H, m), 6.36 (2H, d, J = 9
Hz), 7.15-7.70 (7H, m), 9.40 (1H, m), 10.04 (1H, d, J = 7Hz)

Example 9 6β-phenylacetamide-2α- (quinoline-6-
Il) Penam-3α-carboxylic acid sodium salt is dissolved in water and 6 mg of 6β-phenylacetamido-2α- (quinolin-6-yl) penam-3α-carboxylic acid prepared by adding equimolar 1N hydrochloric acid and N , N-dimethylformamide (1 ml) was added with methyl iodide (0.02 ml), and the mixture was stirred at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, and 3.8 mg of sodium hydrogen carbonate and 1 ml of water were added to the obtained residue.
Solvent (LC-SORB) 40-60, manufactured by Chemco, eluent; 20% acetonitrile aqueous solution], the purification of 6β-phenylacetamide-2α- (1-methyl-6-quinolinio) penam-3α-carboxylic acid 12 mg (60% yield) of the inner salt is obtained. IR (KBr) cm ^-1 ; vc = o 1760, 1650, 1600 The following compound was obtained in the same manner.・ 6β-phenylacetamide-2α- (1-methyl-
Intramolecular salt of 3-pyridinio) penam-3α-carboxylic acid IR (KBr) cm ^-1 ; νc = o 1770,1660,1600 6β- [2- (Z)-(2-aminothiazole-4)
-Yl) -2-methoxyiminoacetamide] -2α-
(1-methyl-3-pyridinio) penam-3α-carboxylic acid inner salt IR (KBr) cm ⁻¹ ; νc = o 1780, 1730, 1660 NMR (d ₆ -DMSO) δ value; 3.97 (3H, s ), 4.10 (3H, s), 4.38 (1H, d,
J = 10Hz), 4.52 (1H, d, J = 10Hz), 5.65-5.92, (2H, m), 6.97 (1
H, s), 8.10-8.40 (2H, m), 8.81 (1H, m), 9.18 (1H, m), 9.73 (1
(H, d, J = 8Hz)

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ identification code FI A61K 31/43 A61K 31/43 C07D 499/70 C07D 499/70 Z Examiner Junko Uchida (56) References JP-A-2-72180 (JP, A) JP-A-63-183588 (JP, A) JP-A-62-228083 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 499/00-499 / 82 A61K 31/00-31/80 CAPLUS (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula Wherein R ^1a represents a phenylacetylamino group, a phenoxyacetylamino group or an acetylamino group;
² represents an optionally substituted aryl or heterocyclic group; R ⁴ represents an optionally protected carboxyl group or a carboxylate group; and n represents 0 or 1. Wherein the penam-2,3-dicarboxylic acid derivative or a salt thereof represented by the general formula (1) is subjected to a decarboxylation reaction. A method for producing a penam-3-carboxylic acid derivative or a salt thereof represented by the formula: wherein R ^1a , R ² , R ⁴ and n are the same as above. (2) Wherein R ^1a represents a phenylacetylamino group, a phenoxyacetylamino group or an acetylamino group;
² represents an optionally substituted aryl or heterocyclic group; R ^3a represents a hydrogen atom or a carboxyl protecting group;
⁴ represents a carboxyl group or a carboxylate group which may be protected; and n represents 0 or 1. And a salt thereof.