JPH0154354B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula The present invention relates to a method for producing a novel penem-3-carboxylic acid derivative and a salt thereof.

In the above formula, R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, or an R ³ A- group (wherein R ³ is a hydroxyl group,
It represents an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, a mercapto group, an alkylthio group, an amino group or an acylamino group, and A may be substituted with a trifluoromethyl group or a phenyl group. Indicates a good alkylene group. ), and R ² represents a hydrogen atom or a protecting group for a carboxyl group. ).

In the general formula (1), R ¹ is preferably a hydrogen atom such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
Straight or branched lower alkyl groups such as tert-butyl, n-pentyl, isopentyl,
For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
Straight chain or branched lower alkoxy group such as sec-butoxy, tert-butoxy or R ³ A
- group (wherein R ³ is a hydroxyl group, such as a lower alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, lower aliphatic acyloxy such as acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy) groups or acyloxy groups such as benzyloxycarbonyloxy, aralkyloxycarbonyloxy groups such as p-nitrobenzyloxycarbonyloxy, lower alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, e.g. Arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, tri-lower alkylsilyloxy groups such as trimethylsilyloxy, tert-butyldimethylsilyloxy, mercapto groups such as methylthio, ethylthio, n-propylthio, isopropyl It represents a lower alkylthio group such as thio, an amino group or a lower aliphatic acylamino group such as acetylamino, propionylamino, n-butyrylamino, isobutyrylamino, and A represents, for example, methylene, ethylene, ethylidene, trimethylene, propylidene, Tetramethylene, butylidene, pentamethylene, pentylidene, 2,2,2
- Indicates an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group such as trifluoroethylidene, 3,3,3-trifluoropropylidene, and benzylidene. ), and R ² is preferably a hydrogen atom, such as a linear or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, such as 2-iodoethyl, Halogeno lower alkyl groups such as 2,2-dibromoethyl, 2,2,2-trichloroethyl, such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl Lower alkoxymethyl groups, e.g. lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, n-butyloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, e.g. 1-
1- such as methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl A lower alkoxycarbonyloxyethyl group, for example an aralxy group such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, a benzhydryl group or a phthalidyl group.

Further, particularly preferred compounds in the general formula (1) include R ¹ being a hydrogen atom, an ethyl group, α-hydroxyethyl, α-acetoxyethyl, α-propionyloxyethyl, α-n-butyryloxyethyl, α -Aminoethyl, α-acetylaminoethyl, α-propionylaminoethyl, α-n
-Hydroxy group at α position, such as butyryl aminoethyl,
An ethyl group or a methoxy group substituted with an amino group, an aliphatic acyloxy group having 2 to 4 carbon atoms, or an aliphatic acylamino group having 2 to 4 carbon atoms, and R ² is a hydrogen atom or pivaloyloxy. Examples include compounds that are methyl groups.

As shown in the general formula (1) above, compound (1) is usually a thiol type It is not a thioketone type.

In addition, in the compound having the above general formula (1), there are optical isomers and stereoisomers based on asymmetric carbon atoms, and all of these isomers are represented by a single formula, but this However, the scope of the present invention is not limited. However, it is preferable to select a compound in which the carbon atom at position 5 has the same coordination as that of penicillins, that is, the R coordination.

Furthermore, in the general formula (1), the carboxylic acid compound in which R ² is a hydrogen atom can be made into a salt form, if necessary. Such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium.
Preferred are sodium and potassium salts.

The compound having the general formula (1) of the present invention is an important synthetic intermediate for penem compounds that exhibit excellent antibacterial activity.

Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below.

(1) 2-thioxopenam-3-carboxylic acid or its sodium salt or potassium salt (2) 2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester (3) 6-(1-tert-butyldimethylsilyloxyethyl) -2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester (4) 6-(1-hydroxyethyl)-2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester (5) 6-(1-hydroxyethyl) -2-thioxopenam-3-carboxylic acid or its sodium salt or potassium salt (6) 6-methoxy-2-thioxopenam-3-carboxylic acid or its sodium salt or potassium salt (7) 6-ethyl-2-thioxopenam-3- Carboxylic acid or sodium salt or potassium salt (8) 6-(1-acetoxyethyl)-2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester (9) 6-(1-p-nitrobenzyloxycarbonylethyl)- 2-Thioxopenam-3-carboxylic acid p-nitrobenzyl ester As mentioned above, this exemplary compound has stereoisomers, but among these isomers, the (5R,6S) coordination is preferable. and (5R,
6R) Compounds with coordination and α of the 6-position substituent
Compounds having a substituent such as a hydroxyl group, an acetoxy group, an amino group, or an acetamido group at the position thereof are R-coordinated.

The object compound (1) of the present invention can be produced by the method shown below.

In the above formula, R ¹ and R ² have the same meanings as described above, and R ⁴ is a hydrogen atom, an alkyl group, an alkoxy group, or an R ⁷ A- group (wherein R ⁷ is an alkoxy group, an acyloxy group, an alkyl represents a sulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, or an acylamino group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group. R ⁵ is methyl,
represents a lower alkyl group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, R ⁶ represents a carboxyl group protecting group,
and Y represents a halogen atom, B is a single bond,
It represents a lower alkylene group such as methylene or ethylene, which may have a lower alkyl group such as methyl, ethyl, or propyl as a substituent, or an o-phenylene group. Here, each substituent in R ⁴ corresponds to the corresponding group in R ¹ described above, and includes those in which either the hydroxyl group or the mercapto group is protected, and the protecting group for the carboxyl group in R ⁶ is It corresponds to the corresponding group in R ² .

The first step of the present invention is a step of producing a compound having general formula (4), in which a compound having general formula (2) is reacted with carbon disulfide in the presence of a base, and then a compound having general formula (3) is produced. This is a process of reacting compounds.

In carrying out the reaction of this step, the reaction is carried out by treating the compound having the general formula (2) with a base in the presence of a solvent, reacting it with carbon disulfide, and then reacting the compound having the general formula (3) with a base. This is achieved by reacting with a compound. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but
Tetrahydrofuran, ethers such as diethyl ether, N,N-dimethylformamide,
Fatty acid dialkylamides such as N,N-dimethylacetamide and mixed solvents of these organic solvents are suitable. Examples of the base used in this reaction include bases such as lithium dipropylamide and lithium hexamethyldisilazane. The reaction temperature is not particularly limited and is usually -
It is suitably carried out at a temperature of 78° to -20°C, and can be carried out in an atmosphere of an inert gas such as nitrogen.
The time required for the reaction is approximately 5 minutes to 1 hour for the reaction with the base and 10 minutes to 2 hours for the reaction with carbon disulfide.
time, the reaction time with the compound having general formula (3) is 10
The duration ranges from minutes to 5 hours.

After the reaction is completed, the target compound (4) of this step is collected from the reaction mixture according to a conventional method. For example, after terminating the reaction by adding glacial acetic acid to the reaction mixture, a water-immiscible organic solvent such as ethyl acetate and water are added, and the organic solvent layer is separated and sequentially treated with dilute aqueous sodium bicarbonate solution and water. It can be obtained by washing, drying with a desiccant, and then distilling off the solvent from the organic solvent layer.

The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc.

The second step is a step of producing a compound having general formula (5), and is a step of halogenating compound (4) by treating it with a halogenating agent.

In carrying out the reaction of this step, the reaction is achieved by reacting the compound having the general formula (4) with a halogenating agent in the presence of a solvent.
The halogenating agent used in the reaction is not particularly limited, but suitable examples include chlorine, bromine, sulfuryl chloride, and sulfuryl bromide. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include methylene chloride, chloroform, carbon tetrachloride, 1,2
-Dichloroethanes are preferred. Although the reaction temperature is not particularly limited, a relatively low temperature is desirable in order to suppress side reactions, and it is preferable to carry out the reaction at a temperature of -20°C to around room temperature. The time required for the reaction mainly depends on the type of raw material compound and the reaction temperature, but it is about 1 minute to 1 minute.
It's time.

After the reaction is completed, the target compound (5) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent and excess reagent from the reaction mixture. Usually, the obtained target compound is used in the next reaction step without further purification.

In addition, in the target compound (5) thus obtained, the halogen atom represented by the substituent Y can be converted to another halogen atom by a known method. For example, converting the corresponding chlorine compound into a bromine or iodine compound by treating it with an inorganic bromide or iodide salt such as lithium bromide or potassium iodide in an organic solvent such as ether or acetone. Can be done.

The third step is the compound of general formula (1) which is the object compound of the present invention.
In the step of producing a 2-thioxopenam-3-carboxylic acid derivative having the formula (5), a compound having the general formula (5) is subjected to a ring-closing reaction in the presence of a base to obtain a compound having the general formula (6) (step a), and then Using the obtained compound (6) as desired, protect the carboxyl group.
It consists of a step (b step) in which R ⁶ is removed and the corresponding protecting groups contained in R ⁴ are removed to restore the hydroxyl group, mercapto group, or amino group.

In carrying out this step, the initial reaction for producing the penam derivative having the general formula (6) is as follows:
This is achieved by contacting the compound having the general formula (5) with a base in a solvent. The solvent used in the reaction is not particularly limited, but includes halogenated carbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, alcohols such as methanol, ethanol, and propanol, ethyl ether, Ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, methyl acetate and ethyl acetate. Esters such as and mixed solvents of these organic solvents and water are suitable. The base used in this reaction is not particularly limited as long as it acts as a nucleophile to thiocarbonyl bonds and cleaves them, but examples include methylamine, ethylamine, n-propylamine, n-butylamine. aliphatic primary amines such as aniline, arylamines such as p-chloroaniline, organic bases such as aralkylamines such as benzylamine, phenethylamine, ammonia such as sodium methoxide-methanol, sodium ethoxide -alkali metal alkoxides such as ethanol, potassium-tert-butoxide-tert-butanol -alcohols, inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, caustic potash, caustic soda are preferred. Although there are no limitations on the reaction temperature, it is usually preferable to carry out the reaction at a temperature of -20°C to around room temperature. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 30 minutes to 12 hours.

After the reaction is completed, the target compound (6) of this step is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent from the reaction mixture, add an organic solvent that is immiscible with water and water to the residue, separate the organic solvent, wash it with water, dry it with a desiccant, and then remove the organic solvent from the organic solvent layer. It can be obtained by distilling off the solvent.

Compound (6) thus obtained can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc.

When the compound (6) obtained here is a 5S coordination isomer, it can be easily obtained by heating in an organic solvent such as toluene, xylene, dimethylformamide, or dimethylacetamide.
Can be converted to isomer with 5R coordination.

Next, the obtained compound (6) can be converted into a carboxylic acid derivative by carrying out a treatment for removing the carboxyl group protecting group R ⁶ according to a conventional method, if necessary. Removal of the protecting group varies depending on the type of protecting group, but is generally removed by methods known in the art. Preferably, the reaction is performed according to the general formula (6)
This can be achieved by contacting a compound having a reducing agent in which the substituent R ⁶ is a protecting group that can be removed by reduction treatment, such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group. As the reducing agent used in this reaction, zinc and acetic acid are preferred when the protecting group for the carboxyl group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl. , hydrogen and palladium when the protecting group is, for example, an aralkyl group such as benzyl, p-nitrobenzyl, or a benzhydryl group.
Catalytic reduction catalysts such as carbon or alkali metal sulfides such as sodium or potassium sulfide are preferred. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and acetic acid are used. Fatty acids such as and mixed solvents of these organic solvents and water are suitable. The reaction temperature is usually around 0°C to room temperature, and the reaction time varies depending on the raw material compound and the type of reducing agent, but is usually 5 minutes to 12 minutes.
It's time.

After the reaction is completed, the target compound of the carboxyl protecting group removal reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing insoluble matter precipitated from the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent.

The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc.

Furthermore, when the substituent R ⁷ in compound (6) is an acyloxy group, a trialkylsilyloxy group, an acylthio group, or an acylamino group, the respective protecting groups can be removed according to a conventional method as described below, if desired. It is also possible to remove and convert the compound to the corresponding hydroxyl group, mercapto group or amino group, and then subject the obtained compound to the above-mentioned reaction for removing the carboxyl group protecting group R ⁶ .

That is, the reaction for producing a compound in which the substituent R ³ represents a hydroxyl group among the compounds having the general formula (1) is the reaction for producing a compound in which the substituent R 3 represents ^{a hydroxyl group.}
is achieved by removing the acyl or trialkylsilyl protecting group of the hydroxyl group from a compound representing an acyloxy group or trialkylsilyloxy group. When R ⁷ is a lower aliphatic acyloxy group such as acetoxy, the reaction can be carried out by treating the corresponding compound (6) with a base in the presence of an aqueous solvent. The solvent used is not particularly limited as long as it is a solvent used in ordinary hydrolysis reactions, but water or water and alcohols such as methanol, ethanol, and n-propanol, or tetrahydrofuran,
A mixed solvent with an organic solvent such as an ether such as dioxane is suitable. The base used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring, but alkali metal carbonates such as sodium carbonate and potassium carbonate are preferably used. It is done using The reaction temperature is not particularly limited, but a temperature of about 0° C. to room temperature is suitable in order to suppress side reactions. The time required for the reaction varies depending on the type of raw material compound, reaction temperature, etc., but is usually 1 to 6 hours. Furthermore, when the above substituent R ⁷ is an aralkyloxycarbonyloxy group such as benzyloxycarbonyloxy or p-nitrobenzyloxycarbonyloxy, the reaction can be carried out by contacting the corresponding compound (6) with a reducing agent. It can be carried out by The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group, which is the carboxyl group protecting group R ⁶ described above, and therefore the carboxyl group protecting group R ⁶ must also be removed at the same time. Can be done.

In addition, when the above substituent R ⁷ is a tri-lower alkylsilyloxy group such as tert-butyldimethylsilyloxy, the reaction is performed with the corresponding compound (6).
This can be carried out by treating with tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction is suitably carried out by treating at around room temperature for 10 to 18 hours.

Among the compounds having the general formula (1), substituents
The reaction for producing a compound in which R ³ represents a mercapto group is achieved by removing the acyl protecting group of the mercapto group from a compound having the general formula (6) in which R ⁷ represents an acylthio group. .
As the acylthio group, a lower aliphatic acylthio group such as acetylthio is suitable, and the reaction can be carried out by treating the corresponding compound (6) with a base in the presence of an aqueous solvent. The reaction conditions for this reaction are the same as those for removing the acyl protecting group of the hydroxyl group described above.

Among the compounds having the general formula (1), substituents
The reaction for producing a compound in which R ³ represents an amino group is
This is achieved by removing the aralkyloxycarbonyl group of the amino group from a compound having general formula (6) in which R ⁷ represents an aralkyloxycarbonylamino group. As the aralkyloxycarbonylamino group, an aralkyloxycarbonylamino group such as benzyloxycarbonylamino or p-nitrobenzyloxycarbonylamino is suitable, and the reaction is the same as in the case of removing the carboxyl protecting group described above.

After carrying out the various conversion reactions described above, the target compound for each reaction is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent from the reaction mixture under reduced pressure, add an organic solvent that is immiscible with water and water to the residue, separate the organic solvent layer, wash it with water, dry it with a desiccant, and then add the organic solvent to the residue. It can be obtained by distilling off the solvent from the solvent layer.

The target compound thus obtained can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. The reaction for removing the carboxyl group protecting group R ⁶ can also be carried out in the same manner as the reaction described above.

In the compound having the general formula (6), a substituent
5 in compounds where R ⁴ has a substituent other than a hydrogen atom
When the position and the 6-position are cis-coordinates, it can be converted into a trans isomer by the method shown below, if desired.

The first step is a step of producing a compound having general formula (8), and is a step of treating compound (7) with a trifluoromethanesulfonyl compound to sulfonylate it.

In carrying out this step, the reaction is achieved by reacting the compound having the general formula (7) with a trifluoromethanesulfonyl compound in the presence of a solvent. Preferred examples of the sulfonylating agent used in the reaction include trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride. The solvent used is not particularly limited as long as it does not participate in this reaction, and examples include ether, tetrahydrofuran, ethers such as dioxane, dichloromethane,
Examples include halogenated hydrocarbons such as chloroform and dichloroethane. This reaction is preferably carried out in the presence of a base, and the base used is preferably an organic base such as triethylamine or pyridine. The reaction temperature is not particularly limited, but -
A temperature of about 70° to room temperature is suitable. The time required for the reaction varies depending on the reaction temperature, etc., but is usually 10 minutes to 5 hours.

After the reaction is completed, the target compound (8) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

The second step is a step of producing a compound having general formula (9), and is a step of heat-treating compound (8) to isomerize it.

In carrying out this step, the reaction is achieved by heating the compound having the general formula (8) in the presence of a solvent and a small amount of hydroquinone. The solvent to be used is not particularly limited as long as it does not participate in this reaction, and examples include aromatic hydrocarbons such as toluene and xylene, and amides such as N,N-dimethylformamide and N,N-dimethylacetamide. can give.

The reaction temperature is usually 120 to 160°C, and the reaction time is 30 minutes to 20 hours.

After completion of the reaction, the target compound (9) of this reaction is collected from the reaction mixture according to a conventional method. For example, compound (9)
can be obtained by distilling off the solvent from the reaction mixture.

The target compound thus obtained can be purified by conventional methods such as recrystallization, column chromatography, etc., if necessary.

The third step is a step of producing a compound having general formula (10), and is a step of removing the trifluoromethanesulfonyl group of compound (9).

In carrying out this step, the reaction is achieved by reacting the compound having the general formula (9) with a base in the presence of a solvent. The solvent used in the reaction is not particularly limited, but includes halogenated carbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, alcohols such as methanol, ethanol, and propanol, ethyl ether, Ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, methyl acetate and ethyl acetate. Esters such as and mixed solvents of these organic solvents and water are suitable. The base used in this reaction is not particularly limited as long as it acts as a nucleophile to thiosulfonyl bonds and cleaves them, but examples include methylamine,
aliphatic primary amines such as ethylamine, n-propylamine, n-butylamine, arylamines such as aniline, p-chloroaniline, organic bases such as aralkylamines such as benzylamine, phenethylamine, ammonia, Alkali metal alkoxide-alcohols such as sodium methoxide-methanol, sodium ethoxide-ethanol, potassium-tert-butoxide-tert-butanol; Bases are preferred. There are no particular limitations on the reaction temperature, but
Usually, it is preferable to carry out the reaction at a temperature of -20°C to around room temperature. The time required for the reaction mainly depends on the type of raw material compound,
It takes about 30 minutes to 12 hours, although it varies depending on the reaction temperature.

After the reaction is completed, the target compound (10) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure, adding a mixed solvent of ethyl acetate and hexane to the residue to separate the precipitate, and then distilling off the solvent from the liquid.

Compound (10) thus obtained can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc.

The 2-thioxopenam derivative having general formula (1) produced by the method of the present invention is an important intermediate for producing penem-3-carboxylic acid derivatives having excellent antibacterial activity.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 2-(3,3-dimethyl-2,4-dioxo-
1,3-dithiane-2-ylidene)-2-(4-
Methylthio-2-oxoazetidin-1-yl)acetic acid p-nitrobenzyl ester A hexane solution of n-butyllithium (2.08 ml, 1.63 mmole/ml) was added to a solution of hexamethyldisilazane (619 μ) in tetrahydrofuran (10 ml) at room temperature and stirred for 30 minutes. After cooling this solution to -78°C, a solution of 2-(4-methylthio-2-azetidinon-1-yl)acetic acid p-nitrobenzyl ester (500 mg) in tetrahydrofuran (10 ml) was added, and after stirring for 20 minutes, two Carbon sulfide (146μ
), 2,2-dimethylmalonic acid dichloride (324 mg) was added, and the mixture was stirred at -78°C for 1 hour. After adding acetic acid (1.5 ml) to the reaction mixture, add ethyl acetate, wash with water and brine in that order, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (eluent solvent: benzene-ethyl acetate = 2:1) to obtain 338 mg of the target compound.

Infrared absorption spectrum ν ^CHCl3 _nax cm ^-1 : 1782, 1715 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 1.52 (3H, s), 1.61 (3H, s), 2.13 (3H, s),
3.12 (1H, dd, J = 2.0Hz, 15.0Hz), 3.37 (1H,
dd, J=4.0, 15.0Hz), 5.28(1H, dd, J=2.0,
4.0Hz), 5.34 (2H, s), 7.54, 8.21 (4H, A ₂ B ₂ ,
J=9.0Hz) Example 2 2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester 2-(3,3-dimethyl-2,4-dioxo-
A solution of p-nitrobenzylesteryl 1,3-dithiane-2-ylidene)-2-(4-methylthio-2-oxoazetidin-1-yl)acetate (150 mg) in dichloromethane (3 ml) containing equimolar chlorine was added. Add carbon chloride solution, 2-(3,3-dimethyl-
2,4-Dioxo-1,3-dithian-2-ylidene)-2-(4-chloro-2-oxoazetidin-1-yl)acetic acid p-nitrobenzyl ester is produced. The crude 4-chloroazetidinone derivative thus obtained was dissolved in dichloromethane (2 ml), and triethylamine (47μ) was added under ice-cooling and stirring.
and 30% methanol solution of methylamine (98μ
) and stir for 15 minutes. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent solvent: ethyl acetate) to obtain 60 mg of the target compound.

Infrared absorption spectrum ν ^CHCl3 _nax cm ^-1 : 1792, 1750 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 3.49 (1H, dd, J=16.3, 2.0Hz), 3.91 (1H, dd,
J=16.3, 4.0Hz), 5.31 (2H, s), 5.40 (1H,
s), 5.88 (1H, dd, J=4.0, 2.0Hz), 7.50, 8.19
(4H, _A2B2 , _J =9.0Hz) Example 3 2-(1,5-dioxo-1.5-dihydro-2,
4-benzodithiepin-3-ylidene)-2-
[3-(1-tert-butyldimethylsilyloxyethyl)-4-methylthio-2-oxoazetidin-1-yl]acetic acid p-nitrobenzyl ester [3-(1-tert-butyldimethylsilyloxyethyl)-4-methylthio-2-oxoazetidin-1-yl]acetic acid p-nitrobenzyl ester (2.24g), hexamethyldisilazane (1.99g)
ml), n-butyllithium hexane solution (5.82
ml, 1.63 mmol/ml), carbon disulfide (427 μ), and phthaloyl chloride (750 μ), and after reaction treatment in the same manner as in Example 1, purification using silica gel column chromatography (methylene chloride),
3.02g of target compound is obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 0.05 (6H, s), 0.85 (9H, s), 1.24 (3H, d, J
= 6.0Hz), 2.17 (3H, s), 3.22 (1H, dd, J =
2.5, 4.0Hz), 4.0~4.5 (1H, m), 5.18 (1H, d,
J = 2.5Hz), 5.28, 5.47 (2H, AB-q, J = 13
Hz), 7.5-8.4 (8H, m) Example 4 (8R, 6S, 5S)-6-(1-tert-butyldimethylsilyloxyethyl)-2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester 2-(1,5-dioxo-1,5-dihydro-
2,4-benzodithiepin-3-ylidene)-2
-[3-(1-tert-Butyldimethylsilyloxyethyl)-4-methylthio-2-oxoazetidin-1-yl]acetic acid p-nitrobenzyl ester (3.0 g) was added with an equimolar amount of chlorine in the same manner as in Example 2. After chlorination, dissolve in ether (120 ml),
Pass in ammonia gas for 10 minutes under ice cooling. After distilling off the ether, extract with ethyl acetate and wash with saturated brine. The solvent was distilled off and the residue was purified by silica gel chromatography (ethyl acetate elution).
1.87 g of the target compound is obtained.

Nuclear magnetic resonance spectrum ( _CDCl3 ) δ _ppn : 0.12 (6H, s), 0.85 (9H, s), 1.36 (3H, d, J
= 6.0Hz), 3.83 (1H, dd, J = 10, 4 ⁺ ), around 4.2 (1H, m), 5.22 (3H, s), 5.91 (1H, d, J =
4Hz), 7.40, 8.10 (4H, A ₂ B ₂ , J = 8.5Hz) Infrared absorption spectrum ν ^CHCl3 _nax cm ^-1 : 1785, 1750, 1603, 1520, 1348 Reference example 1 (5S, 6S, 8R) -2 -Trifluoromethanesulfonylthio-6-(1-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p-nitrobenzyl ester (5S,6S,8R)-6-(1-tert-butyldimethylsilyloxyethyl)-2-thioxopenam-3-carboxylic acid p-nitrobenzyl ester (500 mg) was added to a solution of methylene chloride (5 ml) with triethylamine under ice cooling. (154μ), trifluoromethanesulfonyl chloride (187mg) and cooled on ice for 1 hour.
Stir for an hour. Add appropriate amounts of ethyl acetate and water to disperse the organic layer, wash with water, dry, and then evaporate the solvent. The residue was fractionated and purified using a silica gel Rover column (developing solvent: benzene:ethyl acetate = 97:3) to obtain 280 mg (44%) of the target compound.

Infrared absorption spectrum ν ^CHCl3 _nax cm ^-1 : 1785, 1690, 1605, 1350, 1320 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 0.07 (3H, s), 0.12 (3H, s), 0.81 (9H, s) ，
1.41 (3H, d, J = 6.0Hz), 3.85 (1H, dd, J =
4.0, J=10.0Hz), 4.10~4.54 (1H, m), 5.17,
5.43 (2H, AB-q, J=13.2Hz), 5.68 (1H, d,
J=4.0Hz), 7.57, 8.18 (4H, _A2B2 , J=9.3Hz) Reference example 2 (5R, _6S ,8R)-2-trifluoromethanesulfonylthio-6-(1-tert-butyldimethylsilyl (oxyethyl)penem-3-carboxylic acid p-nitrobenzyl ester (5S,6S,8R)-2-trifluoromethanesulfonylthio-6-(1-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p-
Nitrobenzyl ester (360 mg) was added to a small amount of p-
Heat under reflux in xylene (60 ml) in the presence of hydroquinone under a nitrogen stream for 5 hours. After cooling, the solvent was distilled off, and the residue was fractionated and purified using a silica gel Rover column (developing solvent: benzene: ethyl acetate = 40:1).
Then, 220 mg (61%) of the target compound is obtained.

Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1790, 1720, 1690, 1605, 1350, 1330, 1120 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 0.05 (3H, s), 0.07 (3H, s), 0.84 ( 9H,s),
1.23 (3H, d, J = 6.0Hz), 3.78 (1H, dd, J =
2.0, J=4.0Hz), 4.05~4.45 (1H, m), 5.20,
5.39 (2H, AB-q, J=13.5Hz), 5.67 (1H, d,
J = 2.0Hz), 7.59, 8.18 (4H, A ₂ B ₂ , J = 8.4Hz) Reference example 3 (5R, 6S, 8R) -6-(1-tert-butyldimethylsilyloxyethyl)-2-thioxopenam -3-carboxylic acid p-nitrobenzyl ester (5R,6S,8R)-2-trifluoromethanesulfonylthio-6-(1-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p
-Nitrobenzyl ester (63 mg) was dissolved in methylene chloride (1 ml), and a methylene chloride (0.1 ml) solution of triethylamine (15.1 μ) and 30% methylamine-methanol solution (13.9 μ) was added under ice cooling. Stir at the same temperature for 4 hours. Concentrate under reduced pressure, add appropriate amounts of ethyl acetate and water, separate the organic layer, dry, concentrate, and fractionate and purify the residue using a silica gel chromatography column (developing solvent: benzene: ethyl acetate = 1:1) to obtain the target compound ( 10mg) can be obtained.

Infrared absorption spectrum ν ^CHCl3 _nax cm ^-1 : 1785, 1750, 1602, 1520, 1348 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 0.05 (3H, s), 0.07 (3H, s), 0.86 (9H, s) ，
1.29 (3H, d, J = 6.0Hz), 3.63 (1H, dd, J =
2.0, J=4.0Hz), 4.13-4.53 (1H, m), 5.28
(2H, s), 5.35 (1H, s), 5.82 (1H, d, J=
2.0Hz), 7.50 _, 8.22 (4H, _A2B2 , J=8.7Hz).

Claims (1)

[Claims] 1. General formula [In the formula, R ⁴ is a hydrogen atom, an alkyl group, an alkoxy group, or an R ⁷ A- group (wherein, R ⁷ is an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, represents an acylthio group, an alkylthio group, or an acylamino group, A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group), R ⁵ represents a lower alkyl group, and R ⁶ represents a carboxyl group. Represents a protecting group. ] After treating the compound with a base,
carbon disulfide is reacted, and then a compound having the general formula XCO-B-COX (wherein B represents a single bond, a lower alkylene group or an O-phenylene group, and X represents a halogen atom) general formula (wherein R ⁴ , R ⁵ , R ⁶ and B have the same meanings as above) is produced, and then reacted with a halogenating agent to produce a compound having the general formula (In the formula, Y represents a halogen atom, R ⁴ , R ⁶
and B have the same meanings as above. ) and then react this compound with a base to form the general formula (In the formula, R ⁴ and R ⁶ have the same meanings as above.) Then, if desired, the obtained compound is added to a carboxyl group-protecting group.
A general formula characterized by subjecting to a reaction for removing R ⁶ and a reaction for restoring a hydroxyl group, an amino group, or a mercapto group by removing the corresponding protecting groups contained in R ⁴ [In the formula, R ¹ is a hydrogen atom, an alkyl group, an alkoxy group, or an R ³ A- group (wherein, R ³ is a hydroxyl group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group) mercapto group, alkylthio group, amino group or acylamino group, A represents an alkylene group optionally substituted with a trifluoromethyl group or a phenyl group), and R ² represents a hydrogen atom or a protected carboxyl group. represents a group. ] A method for producing a 2-thioxopenam derivative and a salt thereof.