JPH0224832B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel penem-3-carboxylic acid derivative having the following, a pharmacologically acceptable salt thereof, and a method for producing the same. In the above formula, R ¹ is a 1-hydroxy lower alkyl group, a 1-acyloxy lower alkyl group, a 1-alkylsulfonyloxy lower alkyl group, a 1-arylsulfonyloxy lower alkyl group, or a 1-
represents a trialkylsilyloxy lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group,
R ³ is a hydrogen atom, a protecting group for an amino group, or a formula

[Formula] represents a group (wherein R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group), A represents a branched lower alkylene group, and R ⁴ represents a hydrogen atom or a lower alkyl group. Indicates a carboxyl group protecting group. In the general formula (1), R ¹ is preferably, for example, hydroxymethyl, 1-hydroxyethyl, 1-
Hydroxy lower alkyl groups such as hydroxypropyl, 1-hydroxy-1-methylethyl, 1-hydroxybutyl; e.g. acetoxymethyl,
1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-isobutyryloxyethyl, 1-acetoxypropyl,
Lower aliphatic acyloxy lower alkyl groups such as 1-acetoxy-1-methylethyl, 1-acetoxybutyl or e.g. benzyloxycarbonyloxymethyl, 1-benzyloxycarbonyloxyethyl, 1-(P-nitrobenzyloxycarbonyloxy) Ethyl, 1-(P-nitrobenzyloxycarbonyloxy)propyl, 1
-(P-nitrobenzyloxycarbonyloxy)
-Acyloxy lower alkyl groups such as aralkyloxycarbonyloxy lower alkyl groups such as 1-methylethyl, 1-(P-nitrobenzyloxycarbonyloxy)butyl; e.g. methanesulfonyloxyethyl, 1-methanesulfonyloxyethyl, 1- Propanesulfonyloxyethyl, 1-methanesulfonyloxypropyl, 1-
Lower alkylsulfonyloxy lower alkyl groups such as ethanesulfonyloxypropyl, 1-methanesulfonyloxy-1methylethyl, 1-methanesulfonyloxybutyl; e.g. benzenesulfonyloxymethyl, 1-benzenesulfonyloxyethyl, 1-(P- arylsulfonyloxy lower alkyl groups such as toluenesulfonyloxy)ethyl, 1-benzenesulfonyloxypropyl, 1-benzenesulfonyloxy-1-methylethyl, 1-benzenesulfonyloxybutyl or e.g. trimethylsilyloxymethyl, 1-trimethylsilyloxyethyl , 1-
tert-butyldimethylsilyloxyethyl, 1-
tert-butyldimethylsilyloxypropyl, 1
-tert-butyldimethylsilyloxy-1-methylethyl, trialkylsilyloxy lower alkyl group such as 1-tert-butyldimethylsilyloxybutyl, R ² is preferably a hydrogen atom or e.g. methyl, ethyl, n - a linear or branched lower alkyl group such as propyl, isopropyl, n-butyl, isobutyl, and R ³
is preferably a hydrogen atom, an aralkyloxycarbonyl group such as benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, or a formula

[Formula] group (wherein R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, etc.), and A is preferably, for example, 1-methylethylene, 1-ethylethylene, 1-propylethylene, 1-isopropylethylene, 1-butylethylene, 2-methylethylene, 2-ethylethylene, 2-propylethylene, 2-isopropylethylene, 2-butylethylene, 1-methyltrimethylene, 1-ethyltrimethylene, 1-propyltrimethylene, 1-isopropyltrimethylene,
1-Butyltrimethylene, 2-methyltrimethylene, 2-ethyltrimethylene, 2-propyltrimethylene, 2-isopropyltrimethylene, 2-
Butyltrimethylene, 3-methyltrimethylene,
3-ethyltrimethylene, 3-propyltrimethylene, 3-isopropyltrimethylene, 3-butyltrimethylene, 1-methyltetramethylene, 1
-Ethyltetramethylene, 2-methyltetramethylene, 2-ethyltetramethylene, 3-methyltetramethylene, 3-ethyltetramethylene, 4-
Methyltetramethylene, 4-ethyltetramethylene, 1,1-dimethylethylene, 1,1-diethylethylene, 2,2-dimethylethylene, 2,2
-diethylethylene, 1,1-dimethyltrimethylene, 1,1-diethyltrimethylene, 2,2dimethyltrimethylene, 2,2-diethyltrimethylene, 3,3-dimethyltrimethylene, 3,3-
Diethyltrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,3
-dimethyltrimethylene, 1,1-dimethyltetramethylene, 1,1-diethyltetramethylene,
2,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 3,3-diethyltetramethylene, 4,
4-dimethyltetramethylene, 4,4-diethyltetramethylene, 1,2-dimethyltetramethylene, 1,2-diethyltetramethylene, 1,3-
Dimethyltetramethylene, 1,3-diethyltetramethylene, 2,3-dimethyltetramethylene,
A branched lower alkylene group such as 1,4-dimethyltetramethylene, 2,4-dimethyltetramethylene, 3,4-dimethyltetramethylene, 1,4-diethyltetramethylene, and R ⁴ is preferably is a hydrogen atom; for example, a linear or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; for example, 2-iodoethyl,
Halogeno lower alkyl groups such as 2,2-dibromoethyl, 2,2,2-trichloroethyl; e.g. methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl Lower alkoxymethyl groups; for example, lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxyethyl; for example, 1-methoxycarbonyloxyethyl, 1 -ethoxycarbonyloxyethyl, 1-
n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-
1-lower alkoxycarbonyloxyethyl groups such as butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl; aralkyl groups such as benzyl, P-methoxybenzyl, 0-nitrobenzyl, P-nitrobenzyl;
It is a benzhydryl group or a phthalidyl group. Furthermore, as a particularly preferred compound in the general formula (1), R ¹ is a 1-hydroxyethyl group, R ² is a hydrogen atom, and R ³ is a hydrogen atom, a formimidoyl group, or an acetimidoyl group. and A is 1-methylethylene, 2-methylethylene, 1-ethylethylene, 2-ethylethylene,
1,1-dimethylethylene, 2,2-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-ethyltrimethylene, 2
-Ethyltrimethylene, 3-ethyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,3-
Dimethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1-ethyltetramethylene, 2-ethyltetramethylene, 3-ethyltetramethylene, 4-ethyltetra methylene, 1,1-dimethyltetramethylene,
1,2 dimethyltetramethylene, 1,3-dimethyltetramethylene, 2,3-dimethyltetramethylene, 1,4-dimethyltetramethylene, 2,4
- An ethylene group, trimethylene group or tetramethylene group having 1 or 2 methyl or ethyl branches in the carbon chain, such as dimethyltetramethylene, 3,4-dimethyltetramethylene, R ⁴
is a hydrogen atom or a pivaloyloxymethyl group. 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 ⁴ is a hydrogen atom can be made into a pharmacologically acceptable salt form, if necessary. Such salts include lithium, sodium, potassium,
Examples include salts of inorganic metals such as calcium and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium salts and potassium salts are preferred. The compound having the general formula (1) of the present invention belongs to penem derivatives in which a double bond exists between the 2- and 3-positions of the penicillin ring, and is a novel compound having an amino-substituted alkylmercapto group at the 2-position. They are a group of compounds that exhibit excellent antibacterial activity and are useful as pharmaceuticals, or are important synthetic intermediates for compounds that exhibit these activities. Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below. (1) 2-(2-amino-1-methylethylthio)-
6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium salt or potassium salt. (2) 2-[2-(P-nitrobenzyl)oxycarbonylamino-1-methylethylthio]-6-
(1-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid P-nitrobenzyl ester. (3) 2-(2-aminopropylthio)-6-(1-
(hydroxyethyl) penem-3-carboxylic acid and its sodium or potassium salt. (4) 2-[2-(P-nitrobenzyl)oxycarbonylaminopropylthio]-6-(1-tert-
butyldimethylsilyloxyethyl) penem-
3-Carboxylic acid P-nitrobenzyl ester. (5) 2-(2-amino-1-ethylethylthio)-
6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium salt or potassium salt. (6) 2-(2-aminobutylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (7) 2-(2-amino-1,1-dimethylethylthio)-6-(1-hydroxyethyl)penem-
3-carboxylic acid and its sodium or potassium salt. (8) 2-(2-amino-2-methylpropylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (9) 2-(2-amino-1,2-dimethylethylthio)-6-(1-hydroxyethyl)penem-
3-carboxylic acid and its sodium or potassium salt. (10) 2-(3-amino-1-methylpropylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (11) 2-(3-amino-2-methylpropylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (12) 2-(3-aminobutylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (13) 2-(3-amino-1,1-dimethylpropylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium salt or potassium salt. (14) 2-(3-amino-2,2-dimethylpropylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium salt or potassium salt. (15) 2-(3-amino-3-methylbutylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (16) 2-(3-amino-1-methylbutylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (17) 2-(4-amino-1-methylbutylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (18) 2-(4-amino-2-methylbutylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acids and their sodium or potassium salts. (19) 2-(4-amino-1-methylpentylthio)-6-(1-hydroxyethyl)penem-3
- Carboxylic acids and their sodium or potassium salts. (20) 2-(2-formimidoylamino-1-
Methylethylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (21) 2-(2-acetimidoylamino-1-
Methylethylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (22) 2-(2-formimidoylaminopropylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (23) 2-(2-acetimidoylaminopropylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium salt or potassium salt. (24) 2-(2-formimidoylamino-1-
Ethylethylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (25) 2-(3-formimidoylamino-1-
Methylpropylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (26) 2-(4-formimidoylamino-1-
Methylbutylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid and its sodium or potassium salt. (27) 2-(2-amino-1-methylethylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acid pivaloyloxymethyl ester. (28) 2-(2-aminopropylthio)-6-(1
-hydroxyethyl)penem-3-carboxylic acid pivaloyloxymethyl ester. (29) 2-(3-amino-1-methylpropylthio)-6-(1-hydroxyethyl)penem-3
-Carboxylic acid pivaloyloxymethyl ester. (30) 2-(4-amino-1-methylbutylthio)
-6-(1-hydroxyethyl)penem-3-
Carboxylic acid pivaloyloxymethyl ester. As mentioned above, this exemplified compound has stereoisomers, and among these isomers, preferred are the (5R, 6S) coordination or the (5R, 6S) coordination.
6R) Compounds with coordination and the substituent at the 6-position is 1
-Hydroxyethyl group or 1-tert-butyldimethylsilyloxyethyl group, examples include compounds whose coordination is R coordination. The novel compound (1) according to the present invention can be produced by the method shown below. In the above formula, R ¹ , R ² , R ³ , R ⁴ and A have the same meanings as described above, and R ⁷ is a 1-acyloxy lower alkyl group, 1-alkylsulfonyloxy lower alkyl group, 1-arylsulfonyl It represents an oxy lower alkyl group or a 1-trialkylsilyloxy lower alkyl group, and R ⁸ is a protecting group for an amino group, preferably benzyloxycarbonyl, P-
Denotes an aralkyloxycarbonyl group such as nitrobenzyloxycarbonyl, where R ⁹ represents a protecting group for the carboxyl group, where each substituent in R ⁷ and R ⁹ corresponds to the corresponding group in R ¹ and R ⁴ described above. Including those who do. X represents an acyloxy group such as acetoxy, propionyloxy, benzoyloxy, an alkylsulfonyl group such as methanesulfonyl or ethanesulfonyl, or an arylsulfonyl group such as benzenesulfonyl or P-toluenesulfonyl; Y represents chlorine;
Indicates a halogen atom such as bromine, iodine, Z
is a tri-lower alkylphosphonio group such as tri-n-butylphosphonio or a trisubstituted phosphonio group such as an arylphosphonio group such as triphenylphosphonio, or a cation such as a dimethylphosphonio group with a lithium or sodium ion. shows a diesterified phosphono group with The first step is the step of producing a compound having the general formula (3), in which the compound having the general formula (2) is converted into a compound having the general formula (3). (In the formula, R ² , R ⁸ and A have the same meaning as described above, and M represents an alkali metal atom such as sodium or potassium.) This is a step of reacting with a trithiocarbonate alkali metal salt having the following formula. In carrying out the reaction of this step, the triothiocarbonate alkali metal salt having the general formula (8) used as a raw material is prepared using the general formula (8) according to a conventional method. (wherein R ² , R ⁸ and A have the same meanings as defined above), carbon disulfate and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or sodium methoxide; It can be produced using alkali metal alkoxides such as sodium ethoxide and potassium ethoxide. The reaction is achieved by contacting the compound having the general formula (2) with 1 to 1.5 molar amount of the compound having the general formula (8) obtained as described above in the presence of a solvent. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include water, methanol, ethanol,
Alcohols such as n-propanol, acetone, Kents such as methyl ethyl ketone, dialkyl fatty acid amides such as dimethylformamide and dimethylacetamide, and mixed solvents of these organic solvents and water are suitable. Although the reaction temperature is not particularly limited, it is usually suitably carried out at 0 to 50°C. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 10 minutes to 2 hours. After the reaction is completed, the target compound (3) of this step is collected from the reaction mixture according to a conventional method. For example, a water-immiscible organic solvent such as ethyl acetate and water are added to the reaction mixture, the organic solvent layer is separated, washed with water, dried with a desiccant, and then the solvent is distilled off from the organic solvent layer. It can be obtained by 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 second step is a step of producing a compound having the general formula (4), in which the compound having the general formula (3) is added to the compound having the general formula OHC-COOR ⁹ (10) (wherein R ⁹ has the same meaning as above). show.)
This is a step in which a glyoxylic acid ester derivative having the following is subjected to an addition reaction. In carrying out the reaction of this step, the reaction is achieved by bringing the compound having the general formula (3) into contact with the compound having the general formula (10) in the presence of a solvent. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, and dimethylformamide and dimethylacetamide. Dialkyl fatty acid amides such as these and mixed solvents of these organic solvents are suitable. This addition reaction may be promoted in the presence of a base, but the bases used for this purpose include:
Examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, and sodium aluminum silicate molecular sieves. The reaction temperature is not particularly limited and is usually between room temperature and around 100°C, but if the above base is used, it is preferable to heat it around room temperature, and when it is not used, it is preferably heated around the reflux temperature of the solvent. If necessary, it can be carried out under an atmosphere of an inert gas such as nitrogen. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 1 to 6 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, it can be obtained by removing insoluble matter from the reaction mixture if necessary, washing with water, drying, and distilling off the solvent and excess reagents. 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 third step is a step of producing a compound having general formula (5), and is a step of halogenating a compound having general formula (4). In carrying out the reaction of this step, the reaction is achieved by bringing the compound having the general formula (4) into contact with a halogenating agent in the presence of a solvent.
There are no particular limitations on the halogenating agent used in the reaction, but thionyl halides such as thionyl chloride and thionyl bromide, phosphorus oxyhalides such as phosphorus oxychloride, phosphorus pentachloride, and phosphorus pentabromide may be used. Preferred examples include phosphorus halides or oxalyl halides such as oxalyl chloride. This reaction is preferably carried out in the presence of a base, and the base used for this purpose is preferably an organic base such as triethylamine, diisopropylethylamine, pyridine or lutidine. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction temperature is not particularly limited, but a relatively low temperature is desirable in order to suppress side reactions, preferably around -15°C or room temperature, and if necessary, in an atmosphere of an inert gas such as nitrogen. can be done. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 10 to 30 minutes. 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, the corresponding chlorine compound can be converted into a bromine or iodine compound by treatment with an inorganic bromide or iodide salt such as lithium bromide or potassium iodide in an organic solvent such as ether. . The fourth step is a step of producing a compound having general formula (6), and a step of converting a compound having general formula (5) into a phosphorus-ylide compound. In carrying out the reaction of this step, the reaction is achieved by bringing the compound having the general formula (5) into contact with a phosphine compound or phosphite compound and a base in the presence of a solvent.
Examples of the phosphine compound used in the reaction include tri-lower alkylphosphine such as tri-n-butylphosphine or triarylphosphine such as triphenylphosphine;
Suitable reagents for the phosphite compound include phosphite tri-lower alkyl esters such as phosphite triethyl ester or phosphite di-lower alkyl ester alkali metal salts such as phosphite dimethyl ester sodium salt. I can give it to you. The base used is triethylamine when using a phosphine compound,
Diisopropylethylamine, pyridine, 2,6
An organic base such as -lutidine is preferred, and when a phosphite compound is used, an alkali metal hydride such as sodium hydride or a lower alkyllithium compound such as n-butyllithium is preferred. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include aliphatic hydrocarbons such as hexane and cyclohexane, ethers such as tetrahydrofuran and dioxane, benzene, and toluene. aromatic hydrocarbons, and dialkyl fatty acid amides such as dimethylformamide and dimethylacetamide. The reaction temperature is not particularly limited, but it is usually suitably carried out at 30 to 100°C, and if necessary, it can be carried out in an atmosphere of an inert gas such as nitrogen. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 1 to 50 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, a water-immiscible organic solvent such as ethyl acetate and water are added to the reaction mixture, the organic solvent layer is separated, washed with water, dried with a desiccant, and then the solvent is distilled off from the organic solvent layer. It can be obtained by The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. The fifth step is a step of producing a penem-3-carboxylic acid derivative having general formula (7), and is a step of heating a compound having general formula (6) to cause a ring-closing reaction. In carrying out the reaction of this step, the reaction is achieved by heating the compound having the general formula (6) in the presence or absence of a solvent. There are no particular limitations on the solvent used in the reaction, but
Ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, xylene are preferred. There are no particular limitations on the heating reaction temperature, but it is usually preferable to carry out the reaction at 100 to 200°C, and if necessary, in the presence of a solvent, in an atmosphere of an inert gas such as nitrogen or argon, or In the absence of a solvent, the reaction can be carried out in a reaction vessel under reduced pressure. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 5 to 12 hours. After the reaction is completed, the target compound (7) 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 (7) thus obtained can be further purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. The sixth step is the compound of general formula (1) which is the object compound of the present invention.
In the step of producing a penem-3-carboxylic acid derivative having the formula (7), the compound having the general formula (7) is optionally subjected to a reaction for removing the protecting group ^R9 of the carboxyl group and
A reaction in which the corresponding protecting groups contained in R ⁷ and R ⁸ are removed to restore the hydroxyl group and amino group or lower alkylamino group, and the R ₂ -NH- group of the obtained compound is converted to the formula

It consists of a process of carrying out an appropriate combination of reactions for converting into the group [Formula] (wherein R ² , R ⁵ and R ⁶ have the same meanings as described above). That is, the compound having the general formula (7) can be converted into a carboxylic acid derivative by removing the protecting group R ⁹ of the carboxyl group according to a conventional method. 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 (7)
This can be achieved by contacting a compound having a reducing agent in which the substituent R ⁹ 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 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 hours. 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. Further, in compound (7), when the substituent R ⁷ is an acyloxy lower alkyl group or a trialkylsilyloxy lower alkyl group, and the substituent R ⁸ is a protecting group for an amino group or a lower alkylamino group, as desired, As described below, each protecting group can be removed according to a conventional method to convert the compound to the corresponding hydroxyl group, amino group, or lower alkylamino group, and the compound thus obtained can be It can also be subjected to the reaction for removing the carboxyl group protecting group R ⁹ described above. That is, the reaction for producing a compound in which the substituent R ¹ represents a hydroxy lower alkyl group among the compounds having the general formula (1) is the reaction for producing a compound in which R ⁷ of the compound having the general formula (7) represents an acyloxy lower alkyl group. Alternatively, it can be achieved by removing the acyl or trialkylsilyl protecting group of the hydroxyl group from a compound representing a trialkylsilyloxy lower alkyl group. When R ⁷ is a lower aliphatic acyloxy lower alkyl group such as 1-acetoxyethyl, the reaction can be carried out by treating the corresponding compound (7) 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 normal hydrolysis reactions, but water, water and methanol, ethanol,
A mixed solvent with an organic solvent such as an alcohol such as n-propanol or an ether such as tetrahydrofuran or 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 lower alkyl group such as 1-benzyloxycarbonyloxyethyl or 1-(P-nitrobenzyloxycarbonyloxy)ethyl, the reaction is performed with the corresponding compound.
(7) can be carried out by contacting with a reducing agent. The type of reducing agent and reaction conditions used in this reaction are as follows:
This is similar to the case of removing the aralkyl group, which is R ⁹ , and therefore, the carboxyl group protecting group R ⁹ can also be removed at the same time. Furthermore, when the above substituent R ⁷ is a tri-lower alkylsilyloxy lower alkyl group such as 1-tert-butyldimethylsilyloxyethyl,
The reaction can be carried out by treating the corresponding compound (7) with tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction takes place around room temperature.
This is preferably carried out by treating for 10 to 18 hours. Among the compounds having the general formula (1), substituents
The reaction for producing an amino or lower alkylamino compound in which R ³ represents a hydrogen atom is performed using benzyloxycarbonyl or P-nitrobenzyloxycarbonyl, in which R ⁸ is a protecting group for the amino group, in a compound having the general formula (7). This is achieved by removing these protecting groups from a compound representing an aralkyloxycarbonyl group such as by a reduction reaction. The type of reducing agent and reaction conditions used in this reduction reaction are the same as those for removing the aralkyl group of the carboxyl group protecting group R ⁹ described above, so in such a case, both protecting groups should be removed at the same time. can do. Among the compounds having the general formula (1), substituents
R ³ is

[Formula] Group (wherein R ⁵ and R ⁶ have the same meanings as defined above)
An amino or lower alkylamino compound in which R ₃ is a hydrogen atom is defined by the general formula (In the formula, R ⁵ and R ⁶ have the same meanings as described above, and R ¹⁰ is methyl, ethyl, n-propyl,
Indicates an alkyl group such as isopropyl. ) is achieved by contacting with an imidoester having There are no particular limitations on the solvent used in the reaction, but when using a compound having the general formula (1) above in which R ³ and R ⁵ are hydrogen atoms as a raw material, phosphorus kept at a pH of around 8 is used. The use of acid buffers is preferred. The reaction temperature is preferably relatively low, from 0°C to around room temperature, and the reaction time is usually 10 minutes to 2 hours. After carrying out the above various reactions, the target compound for each reaction is collected from the reaction mixture according to a conventional method,
If necessary, it can be further purified by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. The above general formula (2) which is a starting material for the production method of the present invention
A 4-acyloxy or 4-sulfonylazetidin-2-one compound having the formula can be synthesized by the method exemplified below. In the above formula, R ¹¹ represents a carboxyl group protecting group such as an alkyl group such as methyl, ethyl, or tert-butyl, or an aralkyl group such as benzyl, and R ¹²
is P-nitrobenzyloxycarbonyl or
Indicates a hydroxyl protecting group such as tert-butyldimethylsilyl. The known compound 6α-
Bromopenicillanic acid ester (12) (JPClayton;
J. Chem. Soc. (C), 1969, p. 2123) with trimethyloxonium tetrafluoroborate followed by a base such as basic alumina can lead to the ring-opened compound (13). Compound (13)
is obtained by treatment with a Grignard reagent such as methylmagnesium bromide or a dialkyl copper lithium such as dimethylcopper-lithium, or by treatment with zinc in the presence of a dialkyl aluminum halide such as diethyl aluminum chloride. Compound (14) is obtained by reacting the rate anion with acetaldehyde. The 1'-hydroxyl group of compound (14) is protected to form compound (15), which is treated with mercuric acetate in acetic acid and further oxidized with potassium permanganate.
Starting compound 2a can be obtained, and 4-methylsulfonylazetidin-2-one compound 2b can be obtained by oxidizing compound (15) with potassium periodate in the presence of potassium permanganate. In the above reaction starting from compound (12), the coordination at the 1' position of the hydroxyethyl group in the 3-position side chain of the azetidinone ring is mainly S coordination. Treatment with an organic acid in the presence of triphenylphosphine and azodicarboxylic acid diethyl ester results in an inverted,
A 1′R-coordinated acyloxy compound can be obtained, and when this is treated with an alcohol-alkali metal alkoxide such as methanol-sodium methoxide according to a conventional method, a 1′R-coordinated hydroxyl group on the 3-position side chain can be obtained. Compound (14) can be converted to compound (14), which is used in the following reaction. Furthermore, in this reaction, by reacting compound (13) with an aliphatic aldehyde other than acetaldehyde, a compound in which a 1-hydroxyethyl group other than a 1-hydroxyethyl group is introduced into the 3-position of the azetidinone ring is obtained. be able to. The penem-3-carboxylic acid derivatives of the present invention having the general formula (1) exhibit excellent antibacterial activity or are important synthetic intermediates for compounds exhibiting such antibacterial activity. Among them, the activity of compounds exhibiting antibacterial activity was measured by the agar plate dilution method, and it was found that, for example, Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, as well as Bacillus enterica, Shigella, Klebsiella pneumoniae, M. mutiformis, and Pseudomonas aeruginosa It showed activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as. Such compounds are therefore useful as antibacterial agents to treat bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, etc. The dosage varies depending on age, body weight, symptoms, etc., as well as the dosage form and number of administrations, but it is usually 1 dose for adults.
Approximately 250 to 3000 mg per day is administered once or in divided doses. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 7 (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio [thiocarbonyl]thioazetidin-2-one 1-Methyl-
Add 168 mg (0.59 mol) of 2-(P-nitrobenzyloxycarbonylamino)ethanethiol,
After stirring for 5 minutes, add 45 mg of carbon disulfide at the same temperature.
(0.59 mmol) and stirred for 5 minutes, then added 45 mg (0.59 mmol) of carbon disulfide at the same temperature and stirred for 10 minutes. Then, at the same temperature, 154 mg of (3R.4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was added.
(0.54 mmol) and slowly raise the bath temperature to 0°C over about 1 hour. After the reaction was completed, the solution was made slightly acidic by adding one drop of acetic acid, diluted with ethyl acetate, washed with saturated brine, dried, the solvent was distilled off, and the residue was subjected to column chromatography using 10 g of silica gel. Elution was performed with a mixed solvent of ~15% ethyl acetate-benzene to obtain 237 mg (yield 77%) of the desired product as a yellow oil. Elemental analysis value as C ₂₃ H ₃₅ N ₃ O ₆ S ₃ Si Calculated value: C, 48.14; H, 6.15; N, 7.32; S, 16.76 Actual value: C, 48.35; H, 6.11; N, 7.14; S, 16.59 IR spectrum ν ^CHCl3 _nax cm−1: 3460, 3420, 1780,
1735 nmr spectrum ( _CDCl3 ) δppm: 0.08 (6H,
S), 0.85 (9H, S), 1.15 (3H, d, J=6
Hz), 1.34 (3H, d, J = 7Hz), 3.13 (1H, t,
J=3Hz), 3.43 (2H, t, J=7Hz), ~4.2
(2H, m), 5.16 (2H, S), 5.38 (1H, br, t,
J=7Hz), 5.62 (1H, d, J=3Hz), 6.9
(1H, br.), 7.50 (2H, d), 8, 23 (2H, d) Reference example 8 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1 -[-hydroxy(P-nitrobenzyloxycarbonyl)methyl]-4-[[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl ]Thioazetidin-2-one 230mg (0.40mmol), P-nitrobenzylglyoxylate hydrate 182mg
(0.80 mmol) was heated under reflux in 5 ml of benzene for 10 hours. After the reaction, the solvent was distilled off, and the residue was subjected to column chromatography using 10 g of silica gel and eluted with a 7-10% ethyl acetate-benzene mixed solvent to obtain 234 mg of the target product as a yellow oil (yield,
75%) obtained. Elemental analysis value C ₃₂ H ₄₂ N ₄ O ₁₁ S ₃ Si Calculated value: C, 49.09; H, 5.41; N, 7.16; S, 12.28 Actual value: C, 49.23; H, 5.38; N, 7.02; S, 12.05 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3530, 3450, 1782,
1760, 1736 nmr spectrum (CDCl ₃ ) δppm: 0.05 (3H,
S), 0.08 (3H, S), 0,85 (9H, S), 1.18
(3H, d, J=6Hz), 1.36 (3H, d, J=7
Hz), 3.4 (3H, m), 4.2 (3H, m), 5.1 to 5.7
(6H, m), 6.2 (1H, m), 7.50 (2H, d), 7.55
(2H, d), 8.23 (4H, d) Reference example 9 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[1-methyl-2- (P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thio-1-[1-(P-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]1-[1-hydroxy(P-nitrobenzyloxycarbonyl)methyl]-4-[[[1-methyl-2 -(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one 223 mg
(0.285 mmol) was dissolved in 5 ml of tetrahydrofuran, and at -15℃, 34 mg (0.31 mmol) of 2.6-lutidine was dissolved in 5 ml of tetrahydrofuran.
Then 37 mg (0.31 mmol) of thionyl chloride was added,
Stir for 15 minutes at the same temperature. Furthermore, 60 mg (0.56 mmol) of 2.6-lutidine and 183 mg (0.70 mmol) of triphenylphosphine were added, and the
Stir for 35 hours at °C. After the reaction is completed, the mixture is diluted with ethyl acetate, washed with water, and then dried. The solvent was distilled off, and the residue was subjected to column chromatography using 10 g of silica gel and eluted with a 15-20% ethyl acetate-benzene mixed solvent to give 159 mg (yield, 54%).
The desired product is obtained as a yellow oil. Elemental analysis value C ₅₀ H ₅₅ N ₄ O ₁₀ PS ₃ Si Calculated value: C, 58.46; H, 5.40; N, 5.45; P, 3.01 Actual value: C, 58.19; H, 5.51; N, 5.28; p, 2.86 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1760, 1734,
1623 Example 1 (5R,6S)-2-[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1-tert-butyldimethylsilyloxyethyl ] Penem-3-carboxylic acid P-nitrobenzyl ester and its (5S)-isomer (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl ]Thio-1
-[1-(p-nitrobenzyloxycarbonyl)
155 mg of triphenylphosphoranylidenemethyl)azetidin-2-one and 10 mg of hydroquinone are heated in 15 ml of xylene at 130°C for 7.5 hours under a nitrogen stream. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was separated by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (3:
1)], 81 mg (yield, 73%) of the target product, and 16 mg (yield, 14%) of its (5S)-isomer were obtained as oils. From the nmr spectra, it was determined that the 2-position substituent was unsaturated. It is a 1:1 mixture of stereoisomers based on the same carbon atoms. Elemental analysis value as C ₃₂ H ₄₀ N ₄ O ₁₀ S ₂ Si Calculated value: C, 52.44; H, 5.50; N, 7.65; S, 8.75 Actual value: C, 52.69; H, 5.44; N, 7.38; S, 8.51(5S)-isomer Actual value: C, 52.55; H, 5.67; N, 7.37
;S, 8.54 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3460, 1798, 1735,
1700 (sh.) (5S) - isomer: 3450, 1798, 1735, 1700 (sh.) UV spectrum λ ^THF _nax nm: 265 (ε25900), 340
(ε10500) (5S)-anisotropic: 265 (ε25400), 336 (ε9900) nmr spectrum (CDCl ₃ ) δppm: 0.03, 0.06
(6H, S) 0.83 (9H, S), 1.23 (3H, d, J=
6Hz), ~1.3 (3H, m), 3.45 (3H, m), 3.71,
3.73 (1H, dd, J=4.2Hz) 4.2 (2H, m), 5.18
(1H, d, J=14.5Hz), 5.17 (2H, s), ~5.4
(1H, m), 5.38 (1H, d, J=14.5Hz), 5.61
(1H, br, s), 7.48 (2H, d), 7.60 (2H,
d), 8.16 (4H, d), (5S) -isomer: 0.12 (6H,
s), 0.88 (9H, s), 1.40 (6H, d, J=6
Hz), ~3.5 (3H, m), 3.87 (1H, dd, J=10,
4Hz), ~4.4 (2H, m), 5.16 (2H, S), ~5.3
(1H, m), 5.22 (1H, d, J=14.5Hz), 5.42
(1H, d, J = 14.5Hz), 5.61, 5.68 (1H, 1:
1, d, J = 3.5Hz) 7.47 (2H, d) 7.61 (2H,
d), 8.18 (4H, d) Example 2 (5R, 6S)-2-[[1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1 -Hydroxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester (5R,6S)-2-[[1-methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]
thio]-6-[(R)-1-tert-butyldimethylsiliolxyel]penem-3-carboxylic acid p-
80 mg (0.109 mmol) of nitrobenzyl ester, 65 mg (1.09 mmol) of acetic acid, and 114 mg (0.437 mmol) of tetra(n-butyl)ammonium fluoride are left in 4.5 ml of tetrahydrofuran at room temperature for 24 hours. After the reaction is completed, the mixture is diluted with ethyl acetate and washed with water and then with aqueous sodium bicarbonate. After drying, the solvent was distilled off and the resulting crystalline residue was washed with ethyl acetate, melting point 195.
18 mg of stereoisomer A with ~198 °C (yield, 27%)
I got it. After concentrating the washings of the crystals, the crystals were purified by thin layer chromatography on silica gel [developing solvent: ethyl acetate-chloroform (3:1)] to obtain 32 mg of an oil containing the other stereoisomer B as the main component. rate,
47%). Physical data of crystalline isomer A Elemental analysis value C ₂₆ H ₂₆ N ₄ O ₁₀ S ₂ S ₂ Calculated value: C, 50.48; H, 4.24; N, 9.06; S, 10.37 Actual value: C, 50.33; H , 4.18; N, 9.13; S, 10.19 IR spectrum ν ^nujol _nax cm ^-1 : 3450, 3290, 1775,
1690 Specific optical rotation [α] _D +92.4° (C=0.38, THF) nmr spectrum (d ₇ -DMF) δppm: 1.32
(3H, d, J=6Hz), 1.42 (3H, d, J=6.5
Hz), ~3.5 (3H, m) 3.95 (1H, dd, J=7.15
Hz), ~4.2 (2H, m), 5.28 (2H, s), 5.37
(1H, d, J = 14.5Hz), 5.65 (1H, d, J =
14.5Hz), 5.85 (1H, d, J = 1.5Hz), 7.69 (2H,
d), 7.81 (2H, d), 8.27 (4H, d) nmr spectrum of oily isomer B (d ₇ -DMF)
δppm: 1.32 (3H, d, J = 6Hz), 1.46 (3H,
d, J=6.5Hz) 3.95 (1H, dd, J=7.15Hz),
~4.2 (2H, m), 5.28 (2H, m), 5.37 (1H, d,
J = 14.5Hz), 5.65 (1H, d, J = 14.5Hz), 5,
87 (1H, d, J = 1.5Hz), 7.69 (2H, d), 7.81
(2H, d) 8.27 (4H, d). Example 3 (5R,6S)-2-[[2-amino-1-methylethyl)thio]-6-[(R)-1-hydroxyethyl]penem-3-carboxylic acid (5R,6S)-2-[[1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]penemcarvone obtained in Example 2 46 mg of acid p-nitrobenzyl ester (1:1 mixture of stereoisomers A and B) in 4 ml of tetrahydrofuran and 0.1 M
- It was dissolved in 4 ml of phosphate buffer (PH7.1), 120 mg of 10% palladium-carbon was added, and the mixture was stirred under normal pressure of hydrogen for 5.5 hours. After the reaction is completed, the reaction mixture is filtered,
The catalyst was washed with 4 ml of the above phosphate buffer, and the combined solution and washing solution were washed with ethyl acetate. Approximately 4ml of water layer
Concentrate at room temperature under reduced pressure until
Chromatography was performed using 15 ml of HP20AG (manufactured by Mitsubishi Kasei Corporation), and the fractions eluted with 4-5% acetone-water were collected and lyophilized to obtain the desired product in powder form.
11.5 mg (yield 51%) was obtained. UV spectrum λ ^H2O _nax nm: 254 (ε, 4900), 322
(ε, 6500) IR spectrum ν ^KBr _nax cm ^-1 : 3400 (br), 1767, 1585 Specific rotation [α] _D +120° (C=0.54, H ₂ O) nmr spectrum (D ₂ O) δppm (ext .TMS):
1.31 (3H, d, J = 6Hz), 1.42, 1.46 (3H,
1:1, d, J=7Hz), 2.8-3.8 (3H, m),
3.96 (1H, dd, J=6, 1.5Hz), 4.3 (1H, m),
5.69, 5.72 (1H, 1:1, d, J = 1.5Hz) Example 4 (5R, 6S)-2-[[2-amino-1-methylethyl)thio)-6-[(R)-1 -Hydroxyethyl]penem-3-carboxylic acid (5R,6S)-2-[[1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]penemcarvone obtained in Example 2 The acid p-nitrobenzyl ester (crystalline isomer A) was subjected to a reduction reaction in the same manner as in Example 3 to remove the protecting group, and the desired amino acid was obtained in a yield of 53%. UV spectrum λ ^H2O _nax nm (ε): 251 (5200), 320
(6000) IR spectrum ν ^KBr _nax cm ^-1 : 3400, 1770, 1580 nmr spectrum (D ₂ O) δppm: 1.31 (3H,
d, J = 6Hz), 1.42 (3H, d, J = 7Hz), 2.8
~3.8 (3H, m), 3.96 (1H, dd, J=6, 1.5
Hz), 4.3 (1H, m), 5.69 (1H, d, J = 1.5Hz) Reference example 10 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4- [[[2-(p
-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl]thioazetidin-2-one By the same operation as in Reference Example 7, 2-methyl-2-
(p-nitrobenzyloxycarbonylamino)
Trithiocarboxylic acid sodium salt prepared from propanethiol and carbon disulfate and (3R,4R)-4
-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]yield as a yellow oil by reaction with azetidin-2-one
Got it at 80%. IR spectrum ^CHCl3 _nax cm ^-1 : 3450, 3420, 1780,
1735 Reference example 11 (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-hydroxy(P-nitrobenzyloxycarbonyl)
Methyl]-4-[[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl]thioazetidin-2-one In the same manner as described in Reference Example 8, (3S, 4R)-3
-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl]thioazetidin-2-one yield 87
% of the target compound was obtained. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3530, 6450, 1780,
1760, 1740 Reference example 12 (3S,4R)-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl ]Thio-1-[1-
(p-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one By the same operation as described in Reference Example 9 (3S,
4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-hydroxy(p-nitrobenzyloxycarbonyl)methyl]-4-
The desired product was obtained from [[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl]thioazetidin-2-one in a yield of 60%. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1760, 1735,
1625 Example 5 (5R,6S)-2-[[2-(P-nitrobenzyloxycarbonylamino)propyl]thio]-
6-[(R)-1-tert-butyldimethylsilyloxy]penem-3-carboxylic acid p-nitrobenzyl ester and its (5S)-isomer In the same manner as described in Example 1, (3S, 4R) −
[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]thiocarbonyl]thio-1-[1-(p-nitro Heating benzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one in xylene yields the desired trans isomer (70% yield) and its (5S)-cis isomer (14% yield). I got it. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3440, 1790, 1725,
1702, (5S)-isomer: 3430, 1785, 1722, 1700 nmr spectrum ( _CDCl3 ) δppm: 0.04 (3H,
S), 0.07 (3H, S), 0.79 (9H, S), 1.16 (3H,
d, J = 6Hz), 1.24 (3H, d, J = 6.5Hz),
3.19 (9H, d, J = 6.5Hz), 3.60~3.75 (1H,
m), 3.85-4.45 (2H, m), 5.03 (1H, d, J
=8.5Hz), 5.19 (2H, S), 523, 5.40 (2H,
ABq, J=14Hz), 5.65 (1H, d, J=1.8Hz),
7.50 (2H, d), 7.65 (2H, d), 8, 22 (4H,
d) (5S)-isomer: 0.12 (6H, s), 0.88 (9H,
s), 1.31 (3H, d, J=6Hz), 1.42 (3H, d,
J=6Hz), 3.18 (2H, d, J=6Hz), 3.87
(1H, dd, J=10.4Hz), 3.9~4.5 (2H, m),
4.99 (1H, d, J=8Hz), 5.16 (2H, S),
5.22, 5.42 (2H, ABq, J=14Hz), 5.68 (1H,
d, J=4Hz), 7.47 (2H, d), 7.61 (2H,
d), 8.18 (4H, d) Example 6 (5R, 6S)-2-[[2-(P-nitrobenzyloxycarbonylamino)propyl]thio]-
6-[(R)-1-hydroxyethyl]penem-
3-carboxylic acid P-nitrobenzyl ester By the same operation as described in Example 3 (5R,
6S)-2-[[2-(p-nitrobenzyloxycarbonylamino)propyl]thio]-6-[(R)-
1-tert-Butyldimethylsilyloxy]penem-3-carboxylic acid p-nitrobenzyl ester was desilylated to obtain the desired product in 80% yield. UV spectrum λ ^EtoH _nax nm: 264, 338 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3430, 1790, 1730,
1700 nmr spectrum ( _d7 -DMF) δppm: 1.29
(6H, d, J = 6.5Hz), 3.25 (2H, d, J = 6
Hz), 3.7-4.5 (3H, m), 5.30 (2H, s), 5.42,
5.60 (2H, ABq, J = 14Hz), 5.91 (1H, d, J
= 1.5Hz), 7.53 (1H, d, J = 9Hz), 7.73
(2H, d), 7.87 (2H, d) 8.34 (4, d). Example 7 (5R,6S)-2-[(2-(aminopropyl)thio]-6-[(R)-1-hydroxyethyl]penem-3-carboxylic acid By the same operation as described in Example 4 (5R,
6S)-2-[[2-(P-nitrobenzyloxycarbonylamino)propyl]thio]-6-[(R)-
1-Hydroxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester is subjected to a reduction reaction,
The target amino acid was obtained with a yield of 55%. UV spectrum λ ^H3O _nax nm (ε): 254 (4600), 320
(5700) IR spectrum ν ^KBr _nax cm ^-1 : 3400, 1770, 1570 nmr spectrum (D ₂ O) δppm: 1.31 (3H,
d, J = 6.5Hz), 1.41 (3H, d, J = 6.5Hz),
2.8-3.3 (2H, m), 3.5 (1H, m), 3.95 (1H,
dd, J = 6.18Hz), 4.3 (1H, m), 5.69 (1/2H,
d, J=1.8Hz), 5.72 (1/2H, d, J=1.8Hz). Reference example 13 (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1
-Methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one 6.61 g (23,1 mmol) of (R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol was added to a solution of 518 mg (22.5 mmol) of metallic sodium dissolved in 100 ml of methanol at -10°C.
and stirred for 5 minutes, then 1.76g of carbon disulfide
(23.1 mmol) and stir for 10 minutes. Then, at the same temperature, (3R,4R)-4-acetoxy-3-[(R)-
1-tert-butyldimethylsilyloxyethyl]
Add 6.46 mg (22.5 mmol) of azetidin-2-one, and raise the bath temperature to 0°C in about 1 hour. Acetic acid approx.
After adding 300 mg, dilute with ethyl acetate, wash with saturated saline, and dry. The solvent was distilled off and the residue was subjected to column chromatography using 200 g of silica gel. 10.8 g (yield: 84%) of the target product was obtained as a yellow oil. Elemental analysis value as C ₂₃ H ₅₅ O ₆ S ₃ Si Calculated value: C, 48.14; H, 6.15; N, 7.32; S, 16.76 Actual value: C, 48.22; H, 6.12; N, 7.18; S, 16.55 IR Spectrum ν ^CHCl3 _nax cm ^-1 : 3460, 3420, 1780,
1735 NMR spectrum ( _CDCl3 ) δppm: 0.08
(6H, s), 0.85 (9H, s), 1.15 (3H, d, J
= 6Hz), 1.34 (3H, d, J = 7Hz), 3.13 (1H,
t, J = 3Hz), 3.43 (2H, t, J = 7Hz), ~
4.2 (2H, m), 5.16 (2H, s), 5.38 (1H, br,
t, J = 7Hz), 5.62 (1H, d, J = 3Hz), 6.9
(1H, br.), 7.50 (2H, d), 8, 23 (2H, d) Reference example 14 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1 -[1-Hydroxy(P-nitrobenzyloxycarbonyl)
methyl]-4-[[[(R)-1-methyl-2-(P
-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1-
10.8 g (18.8 mmol) of methyl-2-(P-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one and 8.53 g of p-nitrobenzylglyoxylate hydrate
(37.6 mmol) was heated under reflux in 100 ml of benzene for 20 hours. After the reaction is complete, the solvent is distilled off and the residue is subjected to column chromatography using 150 g of silica gel. After eluting 1.62 g (15%) of the starting material with a 15% acetone-hexane mixed solvent, the fraction eluted with a 30% acetone-hexane mixed solvent was collected, and 12.6 g (yield) of the target product was obtained as a yellow oil.
85%) obtained. Elemental analysis value as C ₃₂ H ₄₂ N ₄ O ₁₁ S ₃ Si Calculated value: C, 49.09; H, 5.41; N, 7.16; S, 12.28 Actual value: C, 49.15; H, 5.38; N, 6.91; S, 12.07 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3530, 3450, 1782,
1760, 1736 NMR spectrum ( _CDCl3 ) δppm: 0.05
(3H, s), 0.08 (3H, s), 0.85 (9H, s),
1.18 (3H, d, J = 6Hz), 1.36 (3H, d, J =
7Hz), 3.4 (3H, m), 4.2 (3H, m), 5.1 to 5.7
(6H, m), 6.2 (1H, m), 7.50 (2H, d), 7.55
(2H, d), 8.23 (4H, d) Reference example 15 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1
-Methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thio-1-[1-(p-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-hydroxy(p-nitrobenzyloxycarbonyl)methyl]-4-[[[(R)- 1-Methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thioazetidin-2-one
12.6g (1.61mmol) in 150ml of tetrahydrofuran
2.00 g of 2.6-lutidine dissolved in -15℃
(18.7 mmol) then 2.11 g of thionyl chloride
(1.77 mmol) and stirred at the same temperature for 15 minutes. Furthermore, 3.45 g (3.22 mmol) of 2.6-lutidine and 12.6 g (48.1 mmol) of triphenylphosphine are added, and the mixture is stirred at 65° C. for 35 hours under a nitrogen stream. After the reaction is completed, the mixture is diluted with ethyl acetate, washed with water, and then dried. The solvent was distilled off and the residue was subjected to column chromatography using 250 g of silica gel to obtain a concentration of 15-20%.
Elute with a mixed solvent of ethyl acetate and benzene to obtain the target product.
10.9 g (yield 66%) was obtained as a yellow oil. Elemental analysis value C ₅₀ H ₅₅ N ₄ O ₁₀ PS ₃ Si Calculated value: C, 58.46; H, 5.40; N, 5.45; S, 3.01 Actual value: C, 58.59; H, 5.22; N, 5.33; S, 2.95 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1760, 1734,
1623 Example 8 (5R,6S)-2-[[(R)-1-methyl-2-
(p-nitrobenzyloxycarbonylamino)
ethyl]thio]]-6-[(R)-1-tert-butyldimethylsilyloxyethyl]penem-3-
Carboxylic acid p-nitrobenzyl ester and its (5S)-isomer (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[[(R)-1-
9.90 g of methyl-2-(p-nitrobenzyloxycarbonylamino)ethyl]thio]thiocarbonyl]thio-1-[1-(p-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one, Hydroquinone 570
mg is heated in 1000 ml of xylene at 127-130°C for 13.5 hours under nitrogen flow. After the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 150 g of silica gel, eluting with 5% ethyl acetate-benzene to obtain the cis isomer [(5S, 6S) isomer]
1.60 g (23% yield) was obtained as an oil. Further elution with 5-10% ethyl acetate-benzene yielded 5.24 g of trans isomer [(5R,6S) isomer] (yield 74
%) was obtained. The trans isomer was recrystallized from benzene to obtain a pure product with a melting point of 163-164°C. Elemental analysis value as C ₃₂ H ₄₀ N ₄ O ₁₀ S ₂ Si Calculated value: C, 52.44; H, 5.50; N, 7.65; S, 8.75 Actual value: Trans isomer: C, 52.70; H,
5.39; N, 7.43; S, 8.55; cis isomer: C,
52.58; H; 5.44; N, 7.41; S, 8.52 IR spectrum, trans isomer ν ^KBr _nax cm ^-1 :
3400 (br.), 1785, 1735, 1690; Cis isomer ν ^CHCl3 _nax cm ^-1 : 3450, 1798, 1735, 1700 (Sh.) Specific rotation, trans isomer: [α] ²⁵ _D +29.6° (C=0.47, CHCl ₃ ) NMR spectrum (CDCl ₃ ) δppm, trans isomer: 0.03, 0.06 (6H, s), 0.83 (9H, s),
1.23 (3H, d, J=6Hz), ~1.3 (3H, m)
3.45 (3H, m), 3.71 (1H, dd, J=4, 1.5
Hz), 4.2 (2H, m), 5.17 (2H, s), 5.18 (1H,
d, J=14.5Hz), 5.38 (1H, d, J=14.5Hz),
~5.4 (1H, m), 5.61 (1H, d, J = 1.5Hz),
7.48 (2H, d), 7.60 (2H, d) 8.16 (4H, d);
Cis-isomer: 0.12 (6H, s) 0.88 (9H.S),
1.40 (6H, d, J=6Hz), ~3.5 (3H, m),
3.87 (1H, dd, J=10, 3.5Hz), ~4.4 (2H,
m), 5.16 (2H, s), ~5.3 (1H, m), 5.22
(1H, d, J = 14.5Hz), 5.42 (1H, d, J =
14.5Hz), 5.61 (1H, d, J = 3.5Hz), 7.47 (2H,
d), 7.61 (2H, d), 8.18 (4H, 4) Example 9 (5R, 6S)-2-[[(R)1-methyl-2-(P
-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester (5R,6S)-2-[[(R)1-methyl-2-(p
3.39 g
(4.63 mmol), acetic acid 2.78 g (46 mmol), tetra(n-butyl)ammonium fluoride 3.62 g
(1.39 mmol) was dissolved in 66 ml of tetrahydrofuran and stirred at room temperature for 15 hours. After the reaction is complete, dilute with ethyl acetate, wash with water and then with aqueous sodium bicarbonate. The crystalline residue obtained by distilling off the solvent was recrystallized from ethyl acetate to obtain 1.98 g of the desired product having a melting point of 158-160°C. The liquid was subjected to column chromatography to obtain an additional 0.36 g of target crystals (melting point: 158-160°C). Total yield: 2.34 g (82% yield) This compound is similar to isomer B described in Example 5.
The NMR spectra matched. Elemental analysis value as C ₂₆ H ₂₆ N ₄ O ₁₀ S ₂ Calculated value: C, 50.48; H, 4.24; N, 9.06; S, 10.37 Actual value: C, 50.42; H, 4.19; N, 8.95; S, 10.33 IR spectrum ν ^KBr _nax cm ^-1 : 3520, 3330, 1780,
1710 Specific rotation [α] ²⁵ _D +70.0° (C = 0.47, DMF) NMR spectrum (d ₇ −DMF) δppm: 1.32,
(3H, d, J=6Hz), 1.46 (3H, d, J=6.5
Hz), 3.95 (1H, dd, J=7.15Hz), 4.17 (1H,
m), 5.28 (2H, s), 5.37 (1H, d, J = 14.5
Hz), 5.65 (1H, d, J = 14.5Hz), 5.87 (1H,
d, J=1.5Hz), 7.69 (2H, d), 7.81 (2H,
d), 8.27 (4H, d) Example 10 (5R,6S)-2-[[(R)-2-amino-1-methylethyl]thio]-6-[(R)-1-hydroxyethyl] penem-3-carboxylic acid (5R,6S)-2-[[(R)1-methyl-2-(p
-nitrobenzyloxycarbonylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]
2.19 g of penem-3-carboxylic acid p-nitrobenzyl ester was added to 200 ml of tetrahydrofuran and
Dissolve in 200ml of 0.1M phosphate buffer (PH7.1) and add 10
Add 4g of % palladium-carbon and hydrogenate at atmospheric pressure, 5
Stir for hours. After the reaction was completed, the reaction mixture was filtered, the catalyst was washed with 50 ml of the above phosphate buffer solution, and the combined solution and washing solution were washed twice with ethyl acetate. The aqueous layer was concentrated to about 200 ml under reduced pressure at room temperature, subjected to column chromatography using 50 ml of Diaion Hp20AG, and the fractions eluted with 5% acetone-water were collected and freeze-dried. The target product was subjected to the same column chromatography.
604 mg (yield 56%) was obtained as a colorless powder. IR spectrum ν ^KBr _nax cm ^-1 : 3400 (br.), 1775,
1580 Specific rotation [α] ²⁵ _D +14.34° (C=0.47, H ₂ O) NMR spectrum (D ₂ O) δppm (ext・
TMB): 1.31 (3H, d, J = 6Hz), 1.46 (3H,
d, J=7Hz), 3.1-3.8 (3H, m), 3.96 (1H,
dd, J=6, 1.5Hz), 4.26 (1H, m), 5.69
(1H, d, J = 1.5Hz). Example 11 (5R,6S)-2-[[(R)2-[(formimidoyl)amino]-1-methylethyl]thio]-6
-[(R)-1-hydroxyethyl]penem-3
-carboxylic acid (5R,6S)-2-[[(R)-2-amino-1-methylethyl]ethyl]thio]-6-[(R)-1-hydroxyethyl]penem-3-carboxylic acid 50 mg
(0.16mmol) in 0.1M phosphate buffer (PH7.1) 10
ml, and adjust the pH to 8.5 by adding 2N sodium hydroxide solution dropwise while stirring in ice water. Add 236 mg (2.47 mmol) of methylformimidate hydrochloride in small portions over 5 minutes. At the same time, keep the pH at 8.5 by dropping 2N sodium hydroxide solution. After stirring for 5 minutes, 2N hydrochloric acid solution was added to adjust the pH to 7.0, and this solution was subjected to column chromatography using Diaion HP20AG (20 ml). After eluting inorganic salts and impurities with water, the fractions eluted with 3% to 5% acetone-water were collected and lyophilized to obtain 17 mg (yield 31%) of the N-formimidoyl derivative as a colorless powder. . IR spectrum ν ^KBr _nax cm ^-1 : 3400 (br), 1770, 1720
(Sh), 1580 Specific optical rotation [α] ²⁵ _D +124.1° (C=0.34, H ₂ O) NMR spectrum (D ₂ O) δppm: 1.30 (3H,
d, J=6Hz), 1.34 (3H, d, J=7Hz), 3.2
~3.7 (3H, m), 3.90 (1H, dd, J=6, 1.5
Hz), 4.26 (1H, m) 5.72 (1H, d, J = 1.5
Hz), 7.83 (1H, s) Reference example 1 (3S,4R)-3-[(S)-1-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4- Methylthio-azetidin-2-one (3S,4R)-3-bromo-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-
4-methylthioazetidin-2-one (1.96g,
6.38 mmol), acetaldehyde (843 mg, 3 equivalents)
was dissolved in 20 ml of tetrahydrofuran, and this solution was mixed with zinc (625 mg, 1.5 equivalents) and diethylaluminum chloride (6.68 ml, 1.5 equivalents, 15% hexane solution).
into a solution of 15 ml of tetrahydrofuran under stirring, 15 ~
Add for 40 min at 20°C. After stirring for 1 hour, water and then ethyl acetate were added, the resulting white precipitate was separated using Celite, and the liquid was extracted with ethyl acetate. Processed by conventional methods, crude target material
2.05 g are obtained as an oil. This was separated by silica gel column chromatography (approximately 30 g, developed with chloroform-ethyl acetate (5:1)) to obtain 1.04 g (yield, 60%) of the desired product as a colorless oil. This product is a mixture of 1'S and 1'R coordination for the 3-position side chain, and the ratio is 4:1. Elemental analysis value C ₁₂ H ₁₉ O ₄ As NS Calculated value: C, 52.74; H, 6.96; N, 5.13; S, 11.72 Actual value: C, 52.81; H, 7.21; N, 5.43; S, 11.78 IR spectrum ν ^liq _nax cm ^-1 : 3450, 1760, 1710,
1380, 1360, 1225 nmr spectrum (CDCl ₃ ) δppm, 1′S system:
1.30 (3H, d, J=6Hz), 1.93 (3H, s),
2.05 (3H, s), 3.14 (1H, dd, J=6.3Hz),
3.72 (3H, s), 4.12 (1H, m), 4.92 (1H, d,
J = 3Hz); 1'R system: 1.26 (3H, d, J = 6Hz),
1.93 (3H, s), 2.05 (3H, s), 2.16 (3H, s),
3.14 (1H, dd, J=6.3Hz), 3.72 (3H, s),
4.12 (1H, m), 5.04 (1H, d, J = 3Hz). Reference example 2 (3S,4R)-3-[(R)-1-benzoyloxyethyl]-1-(1-methoxycarbonyl-
2-Methylprop-1-enyl)-4-methylthioazetidin-2-one (3S,4R)-3-[(S)-1-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthio-azetidin-2-one (105mg, 0.38mmol ), triphenylphosphine (201 mg, 2 equivalents), benzoic acid (94
mg, 2 equivalents) was dissolved in 2 ml of tetrahydrofuran, and azodicarboxylic acid diethyl ester (134 mg, 2 equivalents) was dissolved in tetrahydrofuran (1 ml).
Add the solution gradually over 10 minutes at 20℃ and leave it as is.
Continue stirring for 1.5 hours. The solvent was distilled off, and the residue was dissolved in 3 ml of a mixed solution of benzene-ethyl acetate (6:1).
Dissolve it in a cold place, separate the crystals that precipitate, and separate the liquid by thin layer chromatography (developing agent, benzene: ethyl acetate = 5:1) to obtain the desired product.
119 mg (yield, 82%) was obtained as an oil. This product contains a small amount of the 1' isomer. Elemental analysis value C ₁₉ H ₂₃ NO ₅ Calculated value as S: C, 60.48; H, 6.10; N, 3.71; S, 8.49. Actual value: C, 59.20; H, 6.36; N, 3.52; S, 8.68. IR Spectrum ν ^liq _nax cm ^-1 : 1765, 1720, 1380,
1360, 1270. nmr spectrum (CDCl ₃ ) δppm, principal component (1'R system): 1.49 (3H, d, J = 6Hz), 1.95 (3H,
s), 2.03 (3H, s), 2.17 (3H, s), 3.33 (1H,
dd, J=7.3Hz), 3.74 (3H, s), 5.14 (1H,
d, J = 3Hz), 5.63 (1H, dq, J = 7.6Hz),
7.54 (3H, m), 8.10 (2H, m); subcomponent (1′S
system): 1.52 (3H, d, J = 6Hz), 1.95 (3H,
s), 2.03 (3H, s), 2.17 (3H, s), 3.33 (1H,
dd, J=7.3Hz), 3.74 (3H, s), 4.96 (1H,
d, J = 3Hz), 5.63 (1H, dq, J = 7.6Hz),
7.54 (3H, m), 8.10 (2H, m). Reference example 3 (3S,4R)-3-[(R)-1-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one (3S,4R)-3[(R)-1-benzoyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one 91 mg (0.24 mmol) Dissolve in methanol and add 7.17 mg of sodium to this.
A solution of (0.31 mmol) dissolved in 0.65 ml of methanol was added at 0°, and the mixture was stirred at room temperature (18° to 20°C) for 5 hours. After the reaction is complete, make it slightly acidic with acetic acid, add 20 ml of ethyl acetate, and wash with water. After drying,
Distill the solvent. The obtained residue is purified by preparative thin layer chromatography using silica gel [developing solvent: benzene-ethyl acetate (2:1)] to obtain a pure product. According to the nmr spectrum, this product is a mixture of 1′R and 1′S, and the ratio is approximately 4:1.
It is. Obtain 50 mg (yield, 74.4%) as an oil. Elemental analysis value as C ₁₂ H ₁₉ NO ₄ S Calculated value: C, 52.74; H, 6.96; N, 5.13; S, 11.72 Experimental value: C, 53.03; H, 7.33; N, 4.68; S, 11.39 IR spectrum ν ^liq _nax cm ^-1 : 3450 (br), 1750, 1720 nmr spectrum (CDCl ₃ ) δppm, Principal component (1'R system): 1.26 (3H, d, J = 6Hz),
1.93 (3H, s), 2.05 (3H, s) 2.15 (3H, s),
3.10 (1H, dd, J=6.3Hz), 3.72 (3H, s),
4.23 (1H, dq, J = 6.6Hz), 5.03 (1H, d, J
= 3 Hz); Subcomponent (1'S system): 1.29 (3H, d, J
=6Hz), 1・93 (3H, s), 2.05 (3H, s),
2.15 (3H, s), 3.10 (1H, dd, J=6.3Hz),
3.72 (3H, s), 4.23 (1H, dq, J=6.6Hz),
4.90 (1H, d, J=3Hz). Reference example 4 (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidine- 2-on (3S,4R)-3[(R)-1 obtained in Reference Example 3
-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one 5.65 g (20.8 mmol), imidazole 2.54 g
(37.3 mmol) was dissolved in 110 ml of dimethylformamide, and 53.3 g (35.3 mmol) of tert-butyldimethylchlorosilane was added at 0°C, followed by stirring overnight at room temperature. After the reaction is complete, add 200ml of benzene and wash with water. After drying, the solvent was distilled off and the resulting residue was
The product was subjected to column chromatography using double the amount of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (10:1) to obtain 7.95 g (yield 94%) of the desired product as a colorless oil. At the same time, 370mg (6%) of raw materials
was recovered. From the nmr spectrum, the product is 3
It is a mixture of 1'R and 1'S coordination isomers of the side chain, and the ratio is about 4:1. Elemental analysis value C ₁₈ H ₃₃ NO ₄ As SSi Calculated value: C, 55.81; H, 8.53; N, 3.62; S, 8.29 Actual value: C, 55.44; H, 8.70; N, 3.42; S, 8.45 IR spectrum ν ^liq _nax cm ^-1 : 1760, 1720 nmr spectrum (CDCl ₃ ) δppm; Principal component (1'R system): 0.10 (6H, s), 0.84 (9H, s), 1.23
(3H, d, J=6Hz), 1.92 (3H, s), 2.05
(3H, s) 2.16 (3H, s) 3.05 (1H, dd, J=
5.3Hz) 3.71 (3H, s) 4.23 (1H, m)), 5.09
(1H, d, J=2Hz); Subcomponent (1′S system): 0.10
(6H, s), 0.84 (9H, s) 1.28 (3H, d, J=
6Hz) 1.92 (3H, s), 2.05 (3H, s) 2.16 (3H,
s), 3.20 (1H, m), 3.71 (3H, s), 4.23 (1H,
m) 4.96 (1H, d, J = 3Hz). Reference example 5 (3S,4R)-4-acetoxy-3[(R)-1-
tert-butyldimethylsilyloxyethyl]-
1-(1-methoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one (3S,4R)-3[(R)- obtained in Reference Example 4
tert-butyldimethylsilyloxyethyl]-1
-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidine-2
-3.85g of mixture mainly composed of
(9.95mmol), mercuric acetate 5.08g (15.9mmol)
Dissolve in 38 ml of acetic acid under a nitrogen atmosphere at a bath temperature of 95 to 100℃.
Heat and stir for 20 minutes. After the reaction is completed, acetic acid is distilled off under reduced pressure, and the resulting white residue is stirred at 0°C with the addition of a mixed solvent of water and ethyl acetate (approximately 1:1). The ethyl acetate layer was washed with water, and after drying, the solvent was distilled off. The resulting residue was subjected to column chromatography using 30 g of silica gel, and eluted with a mixed solvent of benzene-ethyl acetate (5:1). , objective 3.50
g (yield, 88%) was obtained as an oil. This product contains a small amount of the 1'S coordination isomer at the 3-position side chain as shown by the nmr spectrum. Elemental analysis value as C ₁₉ H ₃₃ NO ₆ Si Calculated value: C, 57.14; H, 8.27; N, 3.51 Actual value: C, 56.80; H, 8.44; N, 3.29 IR spectrum ν ^liq _nax cm ^-1 : 1780, 1755, 1725 nmr spectrum (CDCl ₃ ) δppm; Principal component (1'R system); 0.10 (6H, s), 0.90 (9H, s), 1.32
(3H, d, J=6Hz), 1.94 (3H, s), 2.06
(3H, s), 2.22 (3H, s), 3.23 (1H, dd, J
=6.15Hz), 3.80 (3H, s), 4.26 (1H, m),
6, 32 (1H, d, J = 1.5Hz); Subcomponent (1'S system); 0.10 (6H, s), 0.90 (9H,
s), 1.34 (3H, d, J=6Hz), 1.94 (3H,
s), 2.06 (3H, s), 2.22 (3H, s), 3.34 (1H,
m), 3.80 (3H, s), 4.26 (1H, m), 6.25 (1H,
d, J=1.5Hz) Reference example 6 (3S,4R)-4-acetoxy-3[(R)-1-
tert-butyldimethylsilyloxyethyl]azetidin-2-one (3S,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl) obtained in Reference Example 5 Azetidine-
3 g (7.5 mmol) of a mixture containing 2-one as the main component
was dissolved in 300 ml of acetone, and 6.43 g (30.1 mmol) of sodium metaperiodate and 120 mg of potassium permanganate were dissolved in 150 ml of water and 150 ml of 0.1M phosphate buffer (PH7.02). Around ℃
Add over 30 minutes and stir at the same temperature for 4 hours. After the reaction is complete, the precipitate is separated, about 25 ml of buffer is added to the solution to adjust the pH to 6.8, and the acetone is removed at low temperature under reduced pressure, followed by extraction with benzene. The benzene layer is collected, dried, and the solvent is distilled off to obtain a crystalline solid. Recrystallization from n-hexane yielded 0.934 g (43.3%) of the desired product as needle crystals having a melting point of 104-106°C. Elemental analysis value as C ₁₃ H ₂₅ O ₄ Si Calculated value: C, 54.32; H, 8.77; N, 4.87 Actual value: C, 54.04; H, 8.79; N, 4.71 IR spectrum ν ^nujol _nax cm ^-1 : 3175, 1783, 1743. Specific rotation [α] ²⁰ _D +48.8° (C = 0.41, CHCl ₃ ) nmr spectrum (CDCl ₃ ) δppm: 0.07 (6H,
s), 0.88 (9H, s), 1.25 (3H, d, J=6.5
Hz), 2.13 (3H, s), 3.20 (1H, dd, J=3.5,
1.5Hz), 4.3 (1H, m) 5.98 (1H, d, J = 1.5
Hz), 7.24 (1H, br).

Claims (1)

[Claims] 1 formula Penem-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof, wherein R ¹ is a 1-hydroxy lower alkyl group,
1-acyloxy lower alkyl group, 1-alkylsulfonyloxy lower alkyl group, 1-arylsulfonyloxy lower alkyl group or 1-trialkylsilyloxy lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group,
R ³ is a hydrogen atom, a protecting group for an amino group, or −CR ⁶ =
NR ⁵ group (in the formula, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group), A represents a branched lower alkylene group,
R ⁴ represents a hydrogen atom or a carboxyl group protecting group. 2 R ¹ is a 1-hydroxyethyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom, formimidoyl group or acetimidoyl group, and A is methyl or ethyl having 1 to 2 carbon atoms. The penem-3-carboxylic acid derivative according to claim 1, which is an ethylene group, trimethylene group or tetramethylene group having a branch, and R ⁴ is a hydrogen atom or a pivaloyloxymethyl group, and its pharmacologically acceptable salt.