JPS595189A - Carbapenem-3-carboxylic acid derivative and penem-3-carboxylic acid derivative and their preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, alkyl, alkoxy, R<5>A-group (R<5> is hydroxyl, alkoxy, acyloxy; A is trifluoromethyl, alkylene); R<2> is lower alkyl; R<3> is 4-8-membered cyclic aliphatic amine which may contain O and/or S atoms in the ring; R<4> is H, carboxyl-protecting group; X is methylene, thio] or its salt. EXAMPLE:( 5R,6S )-2-[ 1-( Pyrrolidin-3-yl )ethylthio ]-6-[ (R)-1-hydroxyethyl]carbapenem-3-carboxylic acid. USE:Antibacterial. PREPARATION:For example, the reaction of a compound of formula II (R<8> is H, alkyl; R<10> is protecting group) with a sulfonic acid in the presence of a base is followed by the reaction with a mercaptan of formula III (R<9> is R<3> protected in its N atom) and deprotection to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel carbapenem-3-carboxylic acid derivatives having the general formula,
This invention relates to penem-3-carboxylic acid derivatives, their pharmacologically acceptable salts, and their production methods.

In the above formula, B is a hydrogen atom, an alkyl group, an alkoxy group,
Acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, trialkylsilyloxy group,
It represents a mercapto group, an alkylthio group, an ami/amino group, or an acylamino group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group. )
, R2 represents a lower alkyl group, and R3 is a 4-membered to 8-membered atom which may contain an oxygen atom or a sulfur atom in the ring.
The remainder of the membered cyclic aliphatic amine represents a hydrogen atom or a lower alkyl group. ], R4 represents a hydrogen atom or a protecting group for a carboxyl group, and X represents a methylene group or a thio group.

Suitable compounds in the general formula (1) include R, for example, a hydrogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Be0-butyl, t
Straight-chain or branched lower alkyl groups such as ert-butyl, n-pentyl, isopentyl; e.g. methoxy, ethoxy, n-propoquine, isopropoxy, n
-butoxy, isophyloxy, ec-butoxy, t
A linear or branched lower alkoxy group such as art-butoxy or an RA- group (wherein R5 is a hydroxyl group; e.g. methoxy, ethoxy, n
- lower alkoxy groups such as propoxy, isopropoxy; for example, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy; or lower aliphatic acyloxy groups such as benzyloxycarbonyloxy, p-nitrobenzyloxycarbonyloxy; Acyloxy groups such as aralkyloxycarbonyloxy7 groups; lower alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy; arylsulfonyloxy groups such as benzenesulfonyloxy, p-)luenesulfonyloxy; ; For example, trimethylsilyloxy,
tri-lower alkylsilyloxy groups such as tert-butyldimethylsilyloxy; mercapto groups; lower alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio; ami7 groups or e.g. acetylamino, propionylamino, n- A represents a lower aliphatic acylamino group such as butyrylamino and isobutyrylamino, and A represents, for example, methylene, ethylene, ethylidene, trimethylene, propylidene, impropylidene, tetramethylene, butylidene, pentamethylene, pentylidene, 2,2.2- Trifluoroethylidene, 3
, 3° represents an alkylene group which may be substituted with a trifluoromethyl group such as 3-trifluoropropylidene, benzylidene, or a phenyl group. )! and R2 is, for example, methyl, ethyl, n-propyl, isopropyl, n
-6!0 is a linear or branched lower alkyl group such as butyl, isobutyl, 5ea-butyl, tert-butyl, and R3 is, for example, azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, A four-membered ring that may contain an oxygen atom or a sulfur atom, such as oxazolidine, thiazolidine, tetrahydroxazine, tetrahydrothiazine, hexahydroxazepine, hexahydrothiazepine, octahydroxapsin, and octahydrothiazosine. A B-type cycloaliphatic amine residue in which the nitrogen atom is substituted with 6- (wherein R and R are the same or different and represent a hydrogen atom or a lower alkyl group such as methyl or ethyl) R4 is a hydrogen atom;
For example, methyl, ethyl, n-furovir, isoflovir,
Straight-chain or branched lower alkyl groups such as n-butyl, isobutyl, tert-butyl; for example 2-iodoethyl, 2,2-dibromoethyl, 2,2. 2
-halogeno-lower alkyl groups such as trichloroethyl; lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, n-probogysimethyl, impropoxymethyl, n-butoxymethyl, imbutoxymethyl; e.g. acetoxymethyl, phlopionyl; Lower aliphatic acyloxymethyl groups such as oxymethyl, n-butyryloxymethyl, imbutyryloxymethyl, pivaloyloxymethyl; e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1
1-Lower alkoxycarbonyloxyethyl groups such as -n-7'roboxycarbonyloxyethyl, 1-impropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-imbutoxycarbonyloxyethyl: for example, benzyl, Compounds which are an aralkyl group such as p-methoxybenzyl, 0-nitrobenzyl, p-nitrobenzyl; a benzhydryl group or a phthalidyl group, or a methylene group or a thio group can be mentioned.

More preferred compounds in the general formula flll include R as a hydrogen atom, an ethyl group, α-hydroxyethyl, α
-acetoxyethyl, α-propionyloxyethyl,
α-n-butyryluoquinethyl, α-aminoethyl, α
- a taethyl group in which the α-position is substituted with a hydroxyl group, an amine 7 group, a lower aliphatic acyloxy group or a lower aliphatic acyl amine 7 group, such as acetyl amide/ethyl, α-propionyl amine/ethyl, α-n-butyryl aminoethyl; 1-hydroxy-17methy/l/ethyl, 1-acetoxy-1-
Methyl ethyl, 1-propionyloxy-1-methylethyl, 1-ny phenyloquine-1-methylethyl,
1-amino-1-methylethyl, 1-acetylamide/-
A hydroxyl group, an amino group, a lower aliphatic acyloquine group, or a lower aliphatic anolamino group in the α position, such as 1-methylethyl, 1-7'rohyonylamino-1-methylethyl, 1-n-butyrylami/-1-methylethyl is an isopropyl group or a methoxy group substituted with a group, R is a methyl group or an ethyl group, and R is 3-azetidinyl, 3
-pyrrolidinyl, s-piperidyl, 4-piperidyl, 5
-(1,3-oxa/lylenyl 15-(1,3-thiazolidinyl), 2-morpholinyl, 2-(thiomorpholinyl) group or the nitrogen atom of these cyclic amine residues is 6- (wherein R and R are the same) or differently represents a hydrogen atom or a methyl group], R is a hydrogen atom or a pivaloyloxymethyl group, and X is a methylene group or a thio group. .

Particularly suitable compounds in the general formula fil include:
R is a hydrogen atom or a 1-hydroxyethyl group, R
is a methyl group, R is 3-azedecynyl, 3-pyrrolidinyl, 3-piperidyl, 4-piperidyl, 5-(1.
3-oxazolidinyl], 5-(1,3-thiazolidinyl), 2-morpholinyl, 2-thiomorpholinyl group, or a group in which the nitrogen atom of these cyclic amine residues is substituted with a formimidoyl group or acetimidoyl group Examples include compounds in which R and R are a hydrogen atom or a pivaloyloxymethyl group, and X is a 4-methylene group or a thio group.

The compound having the general formula (1) according to the present invention is a new compound, and is a broad-spectrum antibiotic having extremely remarkable effects on the treatment of infectious diseases such as Clam-positive bacteria and Clam-positive bacteria.

, chenamycin not only shows strong antibacterial activity against clam-positive bacteria, but also green 1iii! It is an antibiotic that exhibits strong activity against a wide range of Clam-positive bacteria, including Bacteria. In recent years, a method for synthesizing chenamycin and its derivatives has been established at Merck & Co., making it possible to synthesize new compounds, and since then many chenamycin derivatives have been synthesized (JP-A-55-27169; JP-A-Sho 56- 5478 etc.).

On the other hand, there are also many reports on the synthesis of penem compounds, which are analogs of chenamycin, in which the methylene group at the 1-position of chenamycin is replaced with a sulfur atom. However, in any case, there are almost no compounds known in the literature that surpass chenamycin in antibacterial activity.

.

As a result of many years of research into the synthesis of penem and chenamycin-related compounds, the present inventors found that when a carbape or penem skeleton has a lower alkylthio group at the 2-position, at the α-position of the alkyl group, We have discovered that by introducing a thyroaliphatic amine substituent that may contain an oxygen atom or a sulfur atom in the ring, strong antibacterial activity can be expressed. Furthermore, it has been revealed that some of the compounds according to the present invention have stronger antibacterial activity than chenamycin, which is said to be a strong antibacterial agent even in conventional amounts.

In addition, in the compound having the general formula (1), optical isomers and stereoisomers based on asymmetric carbon atoms exist,
Although all of these isomers are shown in a single formula, this is not intended to limit the scope of the present description. However, compounds can preferably be selected in which the carbon atom at position 5 has the same <f, ie R, configuration as chenamycin.

In addition, the carboxylic acid compound represented by the general formula (1) (where R is a hydrogen atom) can be made into a pharmacologically acceptable salt form if necessary. Such salts include lithium, sodium, Examples include ammonium salts such as carlylammonium, diimpropylammonium, and trienal ammonium, but sodium salts, potassium salts are preferred.

The compound having the general formula (1) of the present invention is a compound similar to penem or chenamycin, and at the 2nd position,
It is a group of novel compounds having a lower alkylthio group substituted with a cycloaliphatic amine containing an oxygen or sulfur atom, and these compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals, or their It is an important synthetic intermediate for active compounds.

Among the compounds having the general formula (1) obtained by the present invention, examples of compounds having excellent antibacterial activity include the following carboxylic acid compounds and their sodium salts, potassium salts, and piparoyloxymethyl esters. be able to.

H Specific compounds where X in the above formula is a methylene group or thio are illustrated below.

As mentioned above, this exemplified compound has stereoisomers, and among these stereoisomers, preferred are (
Compounds with sR,6s) coordination or (SR,6R) coordination, and compounds with R coordination for the 8-position substituent 1-hydroxyethyl, and compounds with the α-position carbon of the 2-position 1 substituent are unsaturated. In the case of a stereogenic carbon, examples include compounds in which it is in the R configuration.

Among the novel compounds (1) according to the present invention, the compound (1a) in which X is a methylene group can be obtained by the method shown below.
(3) (51(la) In the above Me formula, R1, R2, R5 and R4 have the same meanings as described above, and R8 is a hydrogen atom, an alkyl group, an alkoxy group or an RA- group (in the formula, R is hydroxyl group, alkoxy group, acylox7 group, arylsulfonyloquine group,
Arylsulfonyloxy group, trialkylsilyloxy group, acylthio group, r) L/kylthio group, acylami 7 group, aralkylami/group or aralkyloxycarbonyl amine 7 group, A is substituted with trifluoromethyl group or phenyl group Indicates an alkylene group that may be substituted. ), R represents a carboxyl group protecting group,
R represents an alkanesulfonyl group, an arylsulfonyl group, a sialylphosphoryl group, or a diarylphosphoryl group, and R is a cycloaliphatic group forming a 4- to 8-membered ring which may contain an oxygen atom or a yellow atom in the ring. An amine residue in which the nitrogen atom has a protective group.

In this synthesis method, in the presence of a base, a compound having the general formula (2),
A compound having general formula (3) is produced by reacting alkanesulfonic anhydride, arylsulfonic anhydride, dialkylphosphoryl halide and diarylphosphoryl halide, and the obtained compound (3) is reacted in the presence of a base without isolation. A compound having the general formula (5) is produced by reacting a mercaptan having the general formula (4), and then, if desired, the obtained compound is subjected to a reaction for removing the protecting group R10 of the carboxyl group, and is included in R and R. The corresponding protecting groups are removed to restore the hydroxyl group, amino group, cyclic amide group and mercapto group (wherein R and R have the same meanings as described above). This is a reaction for producing a compound (1a) in which X is a methylene group among the target compounds of the present invention having the general formula (11).

To carry out the method of the present invention, a compound having the general formula (2) is reacted with an alkanesulfonic anhydride, an arylsulfonic anhydride, a dialkylphosphoryl halide, or a diarylphosphoryl halide to form a compound having the general formula (3).
), and then the obtained compound (3
) is reacted with the mercaptan compound having the general formula (4) to produce the compound having the general formula (5), which is preferably carried out in an inert solvent in the presence of a base. The alkanesulfonic anhydride used in the reaction to obtain the compound (3) from the compound (2) is sulfone 5.
Examples of the alkylphosphoryl halide include dimethylphosphoryl chloride, diethylphosphoryl chloride, diphenylphosphoryl chloride, diphenylphosphoryl bromide, etc. Among these reagents, especially anhydrous Toluenesulfonic acid or diphenylphosphoryl chloride is preferred. The solvent used is not particularly limited as long as it does not participate in this reaction, and examples include halogenated carbons such as methylene, 1,2-dichloroethane, and chloroform, nitriles such as acetonitrile, or N,N-dimethyl. Formamide, N, N
- Amides such as dimethylacetamide. The base to be used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring, but preferably organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine are used. Examples include bases.

Although there is no limit to the reaction temperature, it is preferable to conduct the reaction at a relatively low temperature in order to suppress side reactions, and it is usually carried out at a temperature of about 120°C to 40°C. The reaction time varies mainly depending on the reaction temperature and monomer type of the reaction reagent, but is from 10 minutes to 5 hours.

The obtained compound (3) can be treated without isolation by treating the reaction mixture with the mercaptan having the formula (4) in the presence of a base.

Examples of the base used in this step include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate.

There is no particular limitation on the reaction temperature, but it is usually II'1-20°C.
It is carried out at room temperature. Reaction time f'i 30 minutes to 8
It's time.

After the reaction is completed, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture can be obtained by distilling off the reaction mixture, adding an organic solvent that is immiscible with water to the residue, washing with water, and then distilling off the solvent.

The obtained target compound may be processed by conventional methods, such as recrystallization, if necessary.
Further purification can be carried out by reprecipitation or chromatography.

Next, the obtained compound (5) can be converted into a carboxylic acid derivative by carrying out a treatment for removing the carboxyl group protecting group R 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 carried out using substituent R10 in the compound having the general formula (5).
This is achieved by contacting a compound in which is a protective group such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group that can be removed by reduction treatment with a reducing agent. When the reducing agent used in this reaction (~) is a halogenoalkyl group such as 2.2-dibromoethyl or 2.2.2-trichloroethyl, the protective group for the carboxyl group is zinc-acetic acid. Suitably, the protecting group is, for example, benzyl,
Aralkyl groups such as p-nitrobenzyl or ItHf
In the case of benzhydryl groups, hydrogen and catalytic reduction catalysts such as palladium-carbon or alkali metal sulfides such as sodium or potassium sulfide are suitable. 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,
Ether deposits such as tetrahydrofuran, dioxane,
Preferred are fatty acids such as acetic acid and mixed solvents of these organic solvents and water. The reaction temperature is usually around 0° C. to room temperature, and the reaction time is usually 5 minutes to 12 hours, although it varies depending on the raw material compound and the type of reducing agent.

After completion of the reaction, 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 in an oven, 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.

In addition, when the substituent R in compound (5) has an acyloxy group, an aralkyloxycarbonyloxy group, a trialkylsilyloxy group, an acylamino group, an aralkylamino group, or an aralkyloxycarbonylamino group, it is included in the substituent R9. When the nitrogen atom has a protecting group such as an aralkyl group, an aralgyloxycarbonyl group, or an acyl group, if desired, each protecting group is removed according to a conventional method as described below to form a corresponding hydroxyl group or amino group. The compound thus obtained can be further subjected to the above-mentioned reaction for removing the carboxyl group protecting group R10. That is, the reaction for producing a compound having a hydroxyl group as a substituent R of a compound having a general formula (1a) from a compound having a general formula (5) is a reaction in which R of the compound having a general formula (5) is an acyloxy group. This is achieved by removing the acyl, aralkyloxycarbonyl or trialkylsilyl holding group of the hydroxyl group from a compound having an aralkyloxycarbonyloxy group, an aralkyloxycarbonyloxy group or a trialkylsilyloxy group. When R has a lower aliphatic acyloxy group such as acetoxy, the reaction can be carried out by treating the corresponding compound (5) 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 or water and alcohols such as methanol, ethanol, n7' lobanol, or ethers such as tetrahydrofuran and dioxane are used. A mixed solvent with an organic solvent such as 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 term, 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 and reaction temperature, but it is usually 1.
hours to 6 hours.

Furthermore, when the above substituent R8 has an aralkyloxycarbonyloxy group such as penzyloxycarbonyloxy or p-nitrobenzyloxycarbonyloxy, the reaction (contacting the corresponding compound (5) with a reducing agent) The type of reducing agent used in this reaction and the reaction conditions are the same as those for removing the aralkyl group, which is the protecting group R of the carboxyl group, as described above. R can also be removed at the same time.In addition, by this reduction reaction, the substituent R in the compound having the general formula (5) can be removed.
and a compound in which R is a protecting group for amine 7 and has an aralkyloxycarbonyl group such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, or an aralkyl group such as diphenylmethyl, by removing these protecting groups. It can be converted into an amino compound.

In addition, when the above substituent R has a tri-1 class alkylsilyl oxene group such as tert-butyldimethylsilyloxy, the reaction can be carried out by treating the corresponding compound (5) with tetrabutylammonium fluoride. It can be implemented by 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.

In addition, if the substituent R and/or R in the compound having the general formula (5) has a halogenoacetyl group such as trifluoroacetyl or trichloroacetyl, which is a protecting group for an amino group, the removal The reaction can be carried out by treating the corresponding compound (5) with a base in the presence of an aqueous solvent. The type of base and reaction conditions used in this reaction are the same as those for removing the lower aliphatic acyl protecting group of the hydroxyl group in the substituent R8 described above.

In addition, when the substituent R in the compound having the general formula (5) has an acylthio group, the reaction occurs in the same manner as in the case of removing the lower aliphatic acyl protecting group of the hydroxyl group in R8, and the mercapto group can be restored.

Of these, the reaction for producing an An compound using Yoshikazuho N-4M (Aya 1 and R1, 6 have the same meanings as those described above) is a compound having the general formula (1a) obtained by the above-mentioned reaction ( R is a cycloaliphatic amine residue and has an NH group) with the general formula % (wherein R and R have the same meaning as above, R
represents a primary alkyl group such as methyl, ethyl, n-propyl or isopropyl. ) with an imide ester. The solvent used in the reaction is not particularly limited, but it is preferable to use a phosphate buffer whose pH is maintained around 8. Reaction temperature V
A relatively low temperature of about iO<0>C to room temperature is preferable, and the reaction time is usually 10 minutes to 2 hours.

After carrying out the above various reactions, the target compound of each reaction is collected from the reaction mixture according to a conventional method, and if necessary, a conventional method such as recrystallization method, preparative thin layer chromatography, column chromatography, column chromatography is performed. It can be further purified by

Among the novel compounds (]) according to the present invention, the compound (1b) in which X is a thio group can be produced by the method shown below.

(1b) of 00R10 tl In the above formula, R, R, R, R, R and R10 have the same meanings as described in 11. R8' is a hydrogen atom, an alkyl group, an alkoxy group, or an R111A- group ( In the formula R11
' represents an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy7 group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, an acylamino group, an aralkylamino group, or an aralkyloxycarbonylamine/group; Indicates an alkylene group which may be substituted with a fluoromethyl group or a phenyl group. ), Q represents an acyloxy group such as acetoxy, propionyloxy, benzoyloxy, an alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, or an arylsulfonyl group such as pencenesulfonyl or p-toluenesulfonyl, and M indicates an alkali metal atom such as sodium or potassium,
Y represents a halogen atom such as chlorine, bromine, or iodine,
Ze゛ is a tri-lower alkylphosphonio group such as tri-n-butylphosphonio or a trisubstituted phosphonio group such as triarylphosphonio such as triphenylphosphonio, or a diethylphosphonio group with a lithium or sodium ion. Indicates a diesterized phosphono group containing a cation.

The first step is a step of producing a compound having the general formula (9), and is a step of reacting a compound having the general formula ((1)) with a trithiocarbonate alkali metal salt having the general formula (8).

In carrying out the reaction of this step, the trithiocarbonate alkali gold salt having the general formula (8) used as the c1 raw material is prepared according to a conventional method. mercaptan compound having carbon disulfide and an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium ethoxide. be able to.

The reaction is achieved by contacting the compound having the general formula (7) 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-7' lobanol, acetone, ketones 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 preferably carried out at -20' 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 (9) of this step is collected from the reaction mixture according to a conventional method. For example, adding a water-immiscible organic solvent such as ethyl acetate and water to the reaction mixture;
It can be obtained by separating the organic solvent layer, washing it with water, drying it with a desiccant, and then distilling off the solvent from the organic 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 second step is a step of producing a compound having the general formula all, and is a step of subjecting the compound having the general formula (9) to an addition reaction with the glyoxylic acid ester derivative having the general formula H.

In carrying out the reaction of this step, the reaction is carried out by adding a compound having the general formula (9) to the compound having the general formula (I) in the presence of a solvent.
This is achieved by contacting the compound with n. The solvent used in the reaction is not particularly limited as long as it is not involved in this reaction, but examples include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, 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, and the bases used for this purpose include, for example, organic bases such as triethylamine, diisopropylethylamine, and pyridine, or sodium aluminum silicate molecular sieves. I can give it to you.

The reaction temperature is not particularly limited and is usually between room temperature and around 100°C, but when the above base is used, it is around room temperature.
If not used, it is preferable to heat the solvent to around its reflux temperature, and if necessary, it can be carried out in an atmosphere of an inert gas such as phoneme. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 1 hour to 20 hours.

After the reaction is completed, the target compound fill of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by separating the reaction mixture to remove insoluble matter if necessary, washing with water, drying, and distilling off the solvent and excess reagent.

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 the general formula (I2), and is a step of halogenating the compound having the general formula 〇〇.

In carrying out the reaction of this step, the reaction is achieved by bringing the compound having the general formula αυ 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 chloride,
Thionyl halides such as thionyl bromide, phosphorus oxyhalides such as phosphorus oxychloride, phosphorus halides such as phosphorus pentachloride, phosphorus pentabromide, or oxalyl chlorides such as oxalyl chloride are preferred. I can give it to you. 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 to 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 it ranges from about 10 minutes to 30 minutes.
It is a minute.

After the reaction is completed, the target compound Qz 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 reagents from the reaction mixture, but usually the reaction solution is used as it is for the next 4th step reaction without isolating the product. Ru.

In addition, in the target compound (Iz) obtained in this way, the halogen atom represented by the substituent Y can be converted into another halogen atom by a known method. For example, the corresponding chlorine compound can be converted into an organic solvent such as ether. It 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 a medium.

The fourth step is a step of producing a compound having the general formula 〇,
This is a step of converting a compound having the general formula 0z 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 02) 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 alkyl phosphine such as tri-n-butylphosphine or triarylphosphine such as triphenylphosphine, and examples of the phosphite compound include triethyl phosphite. Suitable reagents include phosphorous acid tri-lower alkyl esters such as phosphorous acid tri-lower alkyl esters or phosphorous acid di-lower alkyl ester alkali metal salts such as phosphorous acid dimethyl ester sodium salts. When using a phosphine compound, the base used is triethylamine, diisopropylethylamine, pyridine,
An organic base such as 2.6-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. be. 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, dimethylformamide,
Dialkyl fatty acid amides such as dimethylacetamide are preferred. The reaction temperature is not particularly limited, but is usually 3.
It is preferable to carry out the reaction at a temperature of 0°C to 100°C, and if necessary, it can be carried out in an atmosphere of an inert gas such as 9-Element. The time required for the reaction varies mainly depending on the type of raw material compound, the reaction degree, etc., but is approximately 1 hour to 50 hours.

After the reaction is completed, the target compound of this step is collected from the reaction mixture according to Method 4. For example, an 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. You can get it by doing this.

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 pene-mu-3-carboxylic acid derivative having general formula I, and is a step of heating and ring-closing a compound having general formula a9. This is achieved by heating the compound having the general formula 0.1 in the presence or absence of a solvent. The solvent used in the reaction is not particularly limited, but ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene are suitable. There is no particular limitation on the heating reaction temperature, but it is usually 100°C.
The reaction is preferably carried out at a temperature between 200° C. and 200° C., in an atmosphere of an inert gas such as nitrogen or argon in the presence of a solvent, if necessary, or in a reaction vessel under reduced pressure in the absence of a solvent. I can do it. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 5 to 15 hours. During the reaction, it is desirable to have hydroquinone present in the apparatus to suppress decomposition of the product.

After completion of the reaction, the target compound 64) of this step is collected from the 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, separating the precipitates, and distilling off the solvent from the p solution.

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

The sixth step is a benem-3-carboxylic acid derivative (1
In the step of producing b), if desired, a compound having the general formula 0 is removed from the carboxyl group by a reaction to remove the protecting group R, and the corresponding protecting groups contained in R and R are removed to form a hydroxyl group or an amino group. The current amino group and mercapto group are subjected to a reaction to restore them, and the cyclic amino group at the 2-position of the resulting compound is converted into a -N-0-NR group (wherein R and R are as defined above). ) consists of a process in which reactions for K conversion are carried out in appropriate combinations.

This step can be carried out in the same manner as the step of obtaining compound [1a] from compound (5) in the method for producing carbapenem derivative (1a).

After carrying out the various reactions described above, the target compound for each reaction is collected from the reaction mixture according to conventional methods, and if necessary, further purified by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. can do.

When producing the compound (1) of the present invention, one of the mercapto compounds (4) used is a novel compound, for example, produced by the following method.

In compound (4), R is of the formula (wherein R represents an aralkyloxycarbonyl group, m
digit indicates an integer from 2 to 5. ] Compound (4a) can be produced according to the method shown below.

O Cod (lη (I咎翰 (4) t22 (4a) In the above formula, R,
R, M and m have the same meanings as described above, R represents an alkanesulfonyl group or an arylsulfonyl group, R16 represents an acyl group, L/l, and n represents an integer of 3 to 6.

The first step is to produce a compound having the general formula Compound Q7) obtained in this step is obtained as a mixture of diastereomers, but it can be separated into two types by column chromatography.

The second step is to produce a compound having the general formula Ql, and is carried out by reacting compound (1?) with a reducing agent such as lithium aluminum hydride.

The third step is a step of converting the protecting group of the amino group in the compound (I barrel) from a benzyl group to an aralkyloxycarbonyl group, and after protecting the hydroxyl group of compound 08 with an acyl group such as acetyl, the obtained compound is This is achieved by reaction with an aralkyloxycarbonyl halide and finally removal of the acyl group under conventional transesterification conditions.

The fourth step is a step of producing a compound having the general formula,
This is achieved by reacting a compound alpha-nullified with an alkanesulfonyl halide or an arylsulfonyl halide in accordance with conventional methods.

The fifth step is a step of producing a compound having the general formula (c), and is achieved by reacting the compound with a compound having the general formula (21).

The sixth step is a step for producing a compound having the general formula (4a), and is achieved by reacting the compound (2) under normal transesterification conditions to remove the acyl group.

In compound (4), R is a methyl group, h, "1.4 (wherein, R and m have the same meanings as described above, and B
Vi represents an oxygen atom or a sulfur atom. ) is a compound (
4b) can be produced according to the method shown below.

(23a) (24a) (25&)
(26a) (2γa)
(29a) (3oa)
ula)1 (32a) R1515 (331)) c(31 et al. 41 G!9 (361C
37) (4b) In the above formula, R, R, R, B and Y have the same meanings as described above, and R represents a tetrahydropyranyl group.

The first step is to produce a compound having the general formula (24a), in which the compound (73a: D-threonine) is oxidized with nitrite in the presence of an acid such as sulfuric acid, a nitrite such as IJium, and bromide. This is accomplished by reacting with alkali metal halides such as sodium, sodium iodide, potassium chloride, potassium bromide, and potassium iodide.

The second step is to preserve the hydroxyl groups of the compound (24),
This is achieved by reacting compound (241) with dihydropyran according to conventional methods.

The third step is to prepare a compound yal- having the general formula (26a).
In the production step, compound (25a) is reacted with a base such as triethylamino, a lower alkyl halogenocarbonate such as ethyl chlorocarbonate, isobutyl chlorocarbonate, isobutyl bromocarbonate, and a mixed acid anhydride derivative is produced. is achieved by then reacting the resulting compound with a reducing agent such as sodium borohydride.

The fourth step is a step of producing a compound having general formula (27a), and is achieved by treating compound (26a) with a base such as sodium hydride.

The fifth step is a step of producing a compound having the general formula (29), which is achieved by heating with a compound having the general formula f28.

The 6th step, the 7th step, and steps # and 8 are the steps of alkanesulfonylating or arylsulfonylating one NI group or hydroxyl group contained in the compound (29a) to an alkanesulfonyl halide or an aryl group. This is achieved by reacting the sulfonyl halide with the presence of tsumego.In Honsanko, the raw materials for each step are the equivalent -r alkanesulfonyl halide or arylsulfonyl halide, and the use and secondary By introducing the hydroxyl group [R group, compound (3Qa), (3
1a) and (32a) can be #formed. That is, in the 6th step, triethylamine is used as salt and a halogenated hydrocarbon such as methylene chloride or chloroform is used as a bath agent, and in the 7th and 8th steps, excess pyridine is used as a base and a solvent. can be used to achieve the objective.

The ninth step is a step of producing a compound having general formula (33a), and is achieved by treating compound (31a) with a base such as sodium hydride.

The 10th step is a step for producing a compound having the general formula (331)) i, in which the compound (32a) is converted into sodium sulfide, potassium sulfide, i: alkali metal hydrosulfide, sodium sulfide, potassium sulfide, etc. f) by reacting with an alkali metal sulfide.

In the above steps, Step 1.1, Step 4, and Step 1.
Since the reaction in step 0 proceeds stereoselectively, L-allothreonine (231) can be converted into compounds (33 and (331)) having the following stereochemistry by the same process as above.
1) can be obtained.

(231)) (33Q) (
33d) In the above formula, R, R and m have the same meanings as described above.

Therefore, in compound (c), a compound having a desired coordination with respect to the asymmetric carbon to which an oxygen atom or a sulfur atom is bonded can be selectively obtained.

The 11th step is a step for producing a compound having the general formula (2), in which compound C33 is treated with a metal hydride reducing reagent such as sodium aluminum hydride to form a cyclic amide and thus this Such a combination! The proboscis is useful as an antibacterial agent to treat bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration in the form of tablets, capsules, granules, formulations, syrups, etc., and parenteral administration in the form of intravenous injections, intramuscular injections, etc. The dosage varies depending on age, body weight, symptoms, etc., as well as the form of administration and the number of administrations, but the usual dosage for adults is approximately 200 to 3,000 doses per day. will be explained more specifically.

Reference example 1゜H2Ph diinpropylamine 23.1 ? (0,229mo
le) in 288 g of tetrahydrofuran, cooled to -78'C under a nitrogen stream, and dissolved in 15% butyllithium-
Add 1213 ml (0.21 mole) of hexane solution.

After 20 minutes, 1-benzylpyrrolidone 201 (0,114
Dissolve one mole of tetrahydrofuran in 56 ml of tetrahydrofurine and add the solution. Toyoshi punching at the same temperature for 10 minutes, acetaldehyde? 0f (0,227 mole) was slowly added dropwise, and the mixture was stirred for another 30 minutes.

After dropping 15 f (0.25 mol) of acetic acid, the acetic acid was distilled off, and the resulting oil was subjected to column chromatography using 400 f of silica gel, followed by a benzene-ethyl acetate [1:1 to 1:2] mixture. Renal form A that elutes with solvent and elutes first 8.07? (Yield: 32%) and the later eluting isomer B S, 259 (Yield: 21%) were obtained as oils.

Isomer A; Engineering R7, Vector ν”1qm'23420,1860
ax nmr spectrum (OD OZ 3) δppm
:t 18 (3H, d.

J-BN2), 15-2.7 (3H, m), 3
．． 05-3.4 (2H, m), 3.87iH, aq, J
-8,5°614z), 4.45 (2H,s), 5.1
(1B,'br,).

T, 2SC5H, B).

Isomer B: R spectrum vLiqCm': 3420, 1
660ax nmr spectrum (ODOZs) δppm
' L 20 (3H, a +J-GHz), 1
．． 7-2.2 (2H, m), 2.8 (IH.

m), 3.2? (2H, t, y-7H2), 3.75(
tH, br, ), 4.33 (IH, (1 (1, J-6° 3.5H2), 4.45 (2H, 6), Otsu 2!1 (5H
, e) Reference Example 2 Ac Isomer A of 1-benzyl-3-C1-hydroxyethyl)-2-pyrrolidone obtained in Reference Example 1 8.90 t tl
In a solution dissolved in 18 rJml of tetrahydrofuran,
Lithicum aluminum hydride 1.8 in nitrogen stream over water cooling
51F and then heated to reflux for 2 hours. After the reaction is completed, the reaction solution is cooled with ice, and 90 g of methanol is added dropwise, followed by 4.1 mnl of water and stirred for about 15 minutes. Insoluble using celite. The solvent was distilled off to give 6.2F crude 1-penzyl-3-(1-hydroxyethyl)hylolysine.

was obtained as an oil.

nmr spectrum (C!DC43) δppm'
t 1o (3H, a.

J-6,5Hz), 1.4-2.9 (5H, m)
, 3.43 (IH, br, 8), 3.55 (2H28
), 3.7 (IH.

m), 7.27 (5H, s).

Use the substance obtained above as is\methylene chloride 90mA! Triethylamine 9301 and acetic anhydride 9.3 were dissolved in water and cooled with water.
After adding 9 F, cover the container for several hours at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 5% sodium bicarbonate solution, and saturated brine in this order, and after drying, the solvent was distilled off. The residue was subjected to column chromatography using 60v of silica gel and chloroform-ethyl acetate-ethanol (
γ:5:1) to elute 1-benzyl-3- of 5T02.
(1-acetoxyethyl)pyrrolidine was obtained as an oil.

5.70 f of the above-mentioned 1-benzyl-3-(1-acetoxyethyl)pyrrolidine was dissolved in 100 ml of methylene chloride in 1 VC, and 7.45 f of p-nitrobenzyloxycarbonyl chloride was added while stirring under water cooling, followed by stirring at the same temperature for 1 hour. After the reaction is completed, the mixture is washed with water and saturated brine, dried, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel 100F, and benzene-ethyl acetate (3
:1) Elute with mixed solvent, title target compound 5.70
f (yield 42% from isomer A obtained in Reference Example 1) was obtained as an oil.

nmr spectrum (ODC45) δppm: 1.2
5 (3H, d.

J-7Hz), 2.03 (3H, e), 1.5-2.8
(3H.

m), 2.8-3.9 (4H, m), 4.8 ('H
r m) +5.15 (2H, day), 7.47 (2H, d
), 8.15 (2H, d).

Reference example 3 ■ C! 0OPNB In Reference Example 2, 5.40 r of 'hfc1-(p-nitrobenzyloxycarbonyl)-3-(1-acetoxyethyl)pyrrolidine was dissolved in 50 ml of tetrahydrofuran,
A solution of 400m9 of sodium dissolved in 50H of methanol is added to this, and the mixture is left at room temperature for 1 hour. After the reaction is complete,
The mixture is diluted with ethyl acetate, washed with saturated brine, dried, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel 1001 and eluted with a benzene-ethyl acetate (C2:1) mixed solvent to obtain 4.20 r (yield: 89 h) of the target compound as an oil.

nmr spectrum (ODO43) δppm=1°2
2 (3H, d.

J-6,5Hz), 1.5-2.7 (3H, rn
), 2.35 (IH, br, ), 2.9-4.0 (
5Hjm), 5.20 (2H1θ), 7.48 (2H,
(1), 8.18 (2H, a).

Reference Example 4 Pyrrolidine 1-(p-nitrobenzyloxycarbonyl)-3-(1-hydroxyethyl)pyrrolidine obtained in Reference Example 34.
20r was dissolved in 50ml of methylene chloride, 1.73F of triethylamine and 1.8Of of methanesulfonyl chloride were added under water cooling, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, the reaction mixture was washed with saturated brine, dried, and the solvent was distilled off to obtain the target compound 530V (yield: 100%) as an oil.

nmr spectrum (a:ooz,) δppm = 1.
47 (3H, a.

:J-6,5H2), 1.5~2.8 (3H, m
), 3.02 (3H, s), 3.0-3.9 (4H
, m), 4.76 (IH.

quintet, T-11, 5H2), 5.20
(zH, m) jγ, 46 (2H, d), 8.16 (
2H, cl).

Reference Example 5゜1-(acetylthio)ethyl]pyrrolidine C! 0OPN
B 55 Sodium hydride 1252 was washed with hexane, 20 ml of dimethylformamide was added, and the mixture was heated in a nitrogen stream.
Slowly add 3.26 g of thioacetic acid at ℃. After stirring for 15 minutes, the A obtained in Reference Example 4 was dissolved in 30 ml of dimethylformamide. Add the dissolved solution and 60℃
Heat for 5 hours. After the reaction is completed, the reaction solution is diluted with ethyl acetate, washed with water and saturated brine, dried, and the solvent is distilled off.

The residue was subjected to column chromatography using 100ml of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (C5:1) to obtain the target compound 2.86f (yield 57%) as an oil.

nmr spectrum (CDC63) δppm: 1.34 (
3H, a.

J-TH2), 1.5-2.7 (3H, m),
2.8-4.0 (5H1m), 5.20 (2H, s)
, 7.48 (2H.

d), 8. t9(2a,a).

Reference Example 6 -3-(1-mercaptoethyl]pyrrolidine R 1-(p-nitrobenzyloxy)-3 obtained in Reference Example 5
-[1-(acetylthio)ethyl]pyrrolidine 565m
g was dissolved in 7 ml of tetrahydrofuran, and a solution of 50 m9 of sodium dissolved in 7 ml of methanol was added thereto at -10°C under a nitrogen stream, and the mixture was stirred at the same temperature for 10 minutes.

Neutralize by adding diluted hydrochloric acid, dilute with ethyl acetate, and wash with water and saturated brine. After drying, the solvent was distilled off to obtain the target compound 4.
73■ (yield 95%) is obtained as a solid. Ethyl acetate
Recrystallization from hexane was performed to obtain a pure product having a melting point of 73-74°C.

IR spectrum 2m1ILxc1n:2550,1
700nmr spectrum (CD0t3) δppm:L
39 (3H, d.

J-7Hz), 1°50 (IH, d,, T-7H2).

15-4.0 (8H, m), 5.21 (2H, s), 7
．． 5fl(2H,d), 8.1! 1 (2H, a)
Reference example B Reference example? The title compound is obtained by the same procedure as that for 1-benzyl-3-(1-h) obtained in .

Recrystallized from ethyl acetate-hexane, melting point II
A pure product with a temperature of 3=94°C was obtained.

KBr -1 Engineering R spectrum νmaXcm: 2550,169
Bnmr7. Vector (CDC1,) δ :1
．． 39 (3H, d.

s ppm J-7Hz), 1.50 (IHja, J-7Hz).

1.7-4.0 (8H1m), 5.21 (2H,s
).

7.50 (2H, a), 8.19 (2H, d) Reference Example 8 23m9 of ruforin sodium was dissolved in 5 ml of methanol, and while stirring at FO℃ (RJ-4-(Ill
-nitrobenzyloxycarbonyl)-2-C(5)-
A solution of 1-[acetylthio)ethyl 3morpholine 282~ dissolved in 2 ml of tetrahydrofuran is added.

After 5 minutes, dilute hydrochloric acid is added to make it weakly acidic, ethyl acetate is added, and the mixture is washed with water and saturated brine.

After drying, the solvent was distilled off to obtain 233 mg of the crystalline target product (93 g). Recrystallization was performed from ethyl acetate-hexane to obtain a product with a melting point of 85-88°C.

nujol -1゜Engine R spectrum ν mouth, 2560.1695
ax Specific rotation [α] D-19,11@(C-0,57, OH
O13) nmr spectrum (CDCl2) δppm
' 1.36 (3H.

a, J-7HZ), L8B (IH
, d , J = 8 H2) a2.111~4.4 (8
H, m), 5.22 (2H, s).

7.49 (2H, (1), 8.22 (2H, d).

Reference Example 9゜Ruforine 00PNB In the same manner as described in Reference Example 8, (S) -4-(p-
nitrobenzyloxycarbonyl)-2-[(5)-1
- [Acetylthio]ethyl]morpholine is deacetylated to obtain a crystalline target compound in a yield of 95%. Recrystallization from benzene-hexane resulted in a melting point of 103.
A pure product with a temperature of 5-1065°C was obtained.

nujol -1 Engineering R spectrum ν σ :25B0.1702ax Specific optical rotation [α] +52° (C-0,60, cucz,)
nmr spectrum (CDC45) δppm: 1.
34 (3Hjd.

J-7Hz), 1.65 (IH, d, J-7H2).

2.6-4.4 (8H, m), 5.22 (2H, e).

Example 1 A solution of (5R,6S)-6-[(R1-1-hydroxyethyl]-2-oxocarhahenam-3-carboxylic acid p-nitrobenzyl ester (155μ) in acetonitrile (3rn1.) was cooled with water. , ♀ Add diisopropylethylamine (63■) and diphenylphosphoryl chloride (126■) under a stream of plain air. After stirring at the same temperature for 30 minutes,
diisopropylethylamine (63) and 7'j 1-(p-nitrobenzyloxycarbonyl)-3-(1-mercaptoethyl)pyrrolidine (152) obtained in Reference Example 6.
Add Tn9)Y and stir for ≥45 hours.

After diluting the reaction solution with ethyl acetate, add saturated saline.

Wash sequentially with 5 qb sodium bicarbonate solution and saturated brine, and dry with sodium sulfate. The oil obtained by distilling off the solvent was purified by preparative thin layer chromatography (developing medium: to% ethanol-ethyl acetate) to give 1341Q (yield: 4
The desired product (7) was obtained as an oily substance.

Engineering R spectrum/l, νCHC'5, . 4:34
00(br,).

ax 17TO, 1690 (br,) NMR spectrum (ODC/S) δ'ppm '1.3
2 (3H, cl, J=6Hz), 1.40 (3H, d.

J=6Hz), 1.6-2.7 (4H, m),
2.8-3.9 (8H, m), 3.9-4.4 (2H
, m), 5.16 (2H.

6), 5.13 (IH, d, J = 14H2), 5.45
(IH.

d, J=14'H7), 7.43(2H,d),
7.58 (2H.

cl), 8.16 (4H, d) Example 2 Roxyethyl]carbapenem 3-carboxylic acid 000H (5R,BS)-2-[1-[1-(p
-nitrobenzyloxycarbonyl)pyrrolidine-3-
yl]ethelthyl, t]-S-[(8)-1-hydroxyethyl]carbapenem-3-carboxylic acid p-nitropendyl ester (134■)x tetrahydrofuran4.
5 Al-based 0.1M phosphate buffer (pH 7.1)
4. Dissolve in sml.

Add platinum oxide No. 421 and stir with atmospheric pressure hydrogen for 4 hours.

After removing the catalyst YP', wash with ethyl acetate containing F solution. Concentrate the aqueous layer to about half under reduced pressure and use Diaion HP20AG.
Subjected to column chromatography using IS m1y7, both fractions eluted with 1 thiacetone and water were collected and lyophilized to obtain the target compound in powder form, yield: 22
%) was obtained.

KBr -1° engineering R spectrum ν 圀, 3400, 176
5°ax N, MR spectrum (100MHy, D20) δp
pm130 (3H, d, J = 6.5Hx), 1.38 (
3H, d.

J=T H2), 1.6-2.8 (3H, m)
, 2.9-3.8 (8H, m), 4.1-4.4 (2
H, m) Example 3 p-nitrobenzyl ester Co2PNB 002PNB In the same manner as in Example 1, (5R,6B)-6-[(8)
-1-Hydroxyethercose-oxocarbapenam-
3-carboxylic acid p-nitrobenzyl ester IT2m
9 and 1-(p-nitrobenzyloxycarbonyl)-3-<1-mercaptoethyl]pyrrolidine (1s91v) obtained in Reference Example 1, the desired carbapenemnis f
199 Jn9 (yield, 10%) was obtained as an oil.

Engineering R spectrum CHC13cm-': 3400
, 1770°ax 69O NMR spectrum b (cDct3) δppm: 1-32
(3HId, J” 6.5 H2) 11.
4 2 (31 (* d - J = 6.5) lz
), 1.1i-2.9 (4H, m), 2.9-3.
9 (8H, m), 3.9-4.5 (2H, m) Examples
4 (5R,6s)-2-[1-[1-(p
-nitrobenzyloxycarbonyl)pyrrolidine-3-
ilconitylthio]-6-[(8)-1-hydroxyethyl]carbapenem-3-carboxylic acid p-nitropendyl ester 1991Qi Tetrahydrofuran 51n1
and 0.1M phosphate buffer (pH 7,14) 5 rtr
Add 62 ml of platinum oxide, and add 2.5 ml of platinum oxide under normal pressure hydrogen.
Stir for an hour. After removing the catalyst, wash the F solution with ethyl acetate.

The aqueous layer was concentrated under reduced pressure to a concentration of about 3%, and Diaion HP20A (
) Subjected to column chromatography using 15 ml'f, fractions eluted with 1.5% acetone-water were collected and lyophilized to obtain powdered target compound No. 42.67 (yield, 42
%)! Obtained.

IR SCHECK) RUvKBrcm': 3400.
1765°ax 59O NMR spectrum” (10oME(z,D20)δp
pm: L30 (3H, d, J-T Hz), 1
．． 38 (3H*d-:J=7H2), 1.6~
2.8 (3H, m), 2.9-3.8 (8H,
m), 4.0-4.4 (2H, m) Example 5 (p-nitrobenzyloxycarbonyl]morpholine-
2-yl”ethelthio]-6-[(8)-(SR, 6S
)-s-[(t)-1-hydroxyethyl]-2-ochynecarbabenam-3-carboxylic acid p-nitrobenzyl ester 202~(0,58 mmo], e)Y Dissolved in 4 ml of acetonitrile and cooled with nitrogen Diimpropylethylamine 821ψ (0.64 mmole) under air flow
) and diphenylphosphoryl chloride 164 ml (0
,61mmo'le) Please add. After stirring for 10 minutes at the same temperature, add 82 ml of diisopropylamine (0.6
4 mmole) and (9)-4-(p-
nitrobenzyloxycarbonyl)-2-[(8)-1
-mercaptoethyl 1 morpholine 2213 ml (0
,6! l mmole) 'l and leave at 0°C overnight.

The reaction solution was diluted with ethyl acetate, and after 7'j, diluted with saturated brine.

The solution is washed successively with a 5-width sodium bicarbonate solution and a saturated saline solution, dried, and then the solvent is distilled off. The residue was purified by preparative thin layer chromatography (developing solvent: 8% ethanol-ethyl acetate) to give 272
(2) The desired compound (yield, 71%) was obtained as oily substance 1.

I only spectrum νCH"5cm-' + 3450.
1778°ax T0O NMR spectrum (CjDC13) δppm: 1.3
5 (3H, d, , T=7Hz), 1.40 (3H, d.

J=7Hz), 2.5-4.5 (13H, m), 5.2
3 (2H.

e), 5.20 (1H, d, J=14H2), 5.51
(IH+d, J"14H2), 7.48 (2H+d),
7.63 (2H.

d),, 8.21 (4H, cl) Example 6 Rubonic acid (s R, 5s)-z-[(m-1-[(m-4-(p
-Nitrobenzyloxycarbonyl)morpholine-2-
yl]ethylthio]-6-[(9)-1-hydroxyethyl]carbapenem-3-carboxylic acid p-nitrobenzyl ester 261 tons dissolved in 90% of tetrahydrofuran and 0.1M phosphate buffer (pH 7.1) , 80 g of platinum oxide were added, and the mixture was stirred for 2.5 hours under normal pressure of hydrogen.

After removing the catalyst YJ', the F solution was washed with ethyl acetate. Water layer concentrated to about 1/2 under reduced pressure Diamond Ion HP20AG
Subjected to column chromatography using 15 mly, 1
The fraction eluted with the acetone-water mixture was frozen to obtain the target compound in the form of a powder with a yield of 34m9C (Section 25).

KBr’: 3380.176B.

Engineering R spectrum νrnaXcrn 58T NMR spectrum 000 MH7, D20 ) δppm
'1.30(3I(,cl,,T=7H2),1.3
8 (3H, d.

J=TH2), 3.0 to 4.5 (13H, m) Example
T In exactly the same manner as in Example 5, (5R,6B)-e-[(
g)-1-hydroxyethylcose-oxocarbabenam-3-carboxylic acid p-nitrobenzyl ester IS
o ml (0.43 mmole) and reference example s
The desired title compound 204 (yield, 72%) was obtained from 166 ml (0.47 mmole) of (et -x -(p-nitrobenzyloxycarbonyl)-z-[(m-1-mercaptoethyl)morpholine). Obtained as an oil.

1T0O NMR spectrum (CDC15) δppm: 1.33
(3H, d, J=6H2), 1.40 (3H, d.

J=6H2), 2.6-4.5 (13H, m), 5.
23 (2H.

e), 5.20 (IH, cl,, J=14H2), 5.
52 (IH.

a,,T=14H? ), 7.51 (2H, d, ), 7
．． 66 (2H.

d, ), 8.22 (2H, d), 8.24 (21 (, d
) Example 8 Rubonic acid Similarly to Example 6, (5R,6B)-2-[(8)
-1-[(SJ-4-(p-nitrobenzyloxycarbonyl)morpholin-2-yl]ethylthio]-6-[
f, R1-1-hydroxyethyl]carbapenem-3-
185 mg of carboxylic acid p-nitrobenzyl ester was subjected to a reduction reaction for 2 hours using 1 platinum oxide 3 (NQ'11) and post-processed to obtain 36.6Tn9 (yield: 38%) of the target compound in the form of a powder.

IR Spec) Le vKBrcm-': 3400.1
770.

ax 590 nmr spectrum (100MH2, D2o) δppm
'L 31 (3H, d, :f-13-5H2) -
1,35 (3H+ d IJ = T H2) -2-9
~38 (8H*m), 3-7~4.4 (SH,
m) UV smoothing torque λWAC
300 nm (e, 7800) Example 9 Metallic sodium 7,4 m9 (0,32 mmole)
Y Methano-A, solution dissolved in 2.5 mA (0 °C
), Reference Example 8-c4rc<R1-4-<p-nitrobenzyloxycarbonyl)-2-[(9)-1-mercaptoethyl 1 morpholine 111 In9 (0,34
mmole) ”;T Dissolve in 1 ml of tetrahydrofuran, add and press with your finger for 5 minutes, and then remove carbon disulfide 261 at 0°C.
Add 0.34 mmole.

! After 0 minutes, the solution was cooled to 15°C and (3R,4R)-
4-acetoxy 3-[(8)-1tert-butyldimethylsilyloxyethypre]azetidin-2-one 92
Add In9 (0.32 mmole) Y and stir at the same temperature for 30 minutes. Add one drop of acetic acid, dilute with ethyl acetate, wash with saturated brine, dry, and evaporate the solvent.

The residue was purified by Silikage A thin layer chromatography [developing solvent: chloroform-ethyl acetate (9:1)],
A yellow-yellow target product (142 cm) (yield: 10 cm) was obtained.

IR spectrum VC""5cm-': 342
0. ITTB.

ax 101 03n spectrum (CDClρδppm: 0.08
(6H,s), 0.8r(9H,m), 1.20(3
H, d, J=6.5H2), 1.4B(3HI+1.J
=7H2), 3.20(IH, dd, J=4.2.5H
z).

2.6-4.6 (9H, m), 5.22 (2H, e),
5.66 (IH, d, , T = 2.5H2), 6.63 (
IH, br, s).

7.51 (2H, cl), 8.26 (2H, d) Example 10 C02PNB (3s, 4R)-3-[(,R1-y-tert-butyldimethylsilyloxyethyl]~4-[[( R1-1
-[(9)-4-(p-nitrobenzyloxi7carbonyl)morpholin-2-yl]ethylthio]thiocarbonyl]thioazetidin-2-one T40 In9 (1,
17 mmole), p-nitrobenzylglyoxylate hydrate 398 mq (1,75 mmole)
The mixture was heated under reflux for 26 hours in a 12°C of benzene. After the reaction was completed, the solvent was distilled off and the residue was subjected to column chromatography using silica gel 20I, and acetone-hexane (
1:3) mixed solvent, 915 mg (yield,
93%) Y as a yellow oil.

In spectrum ν heat range","cm-': 340
0.17B0゜1750(sh,'), 1700 Example 71 as Otsu02PNB (38,4R)-3-[(JU-1-tert-butyldimethylsilyloxyether]-4-[[(8)-1 −
[(2)-4-(p-nitrobenzyloxycarbonyl9morpholin-2-yl]ethelthio]thiocarbonylcoteohl-[hydroxy(p-nitrobenzyloxycarbonyl)methyl]azetidin-2-one 948 r
Dissolve n,ti (1,13 mmole) in 15 rnl of tetrahydrofuran, add 133 mq (1,24 mmole) of 2,6-lutidine at -108C, then add 148 mq (1,24 mm0) of thionyl chloride and stir at the same temperature for 15 minutes. 2,6-lutidine 24
2 mg (2,26 mmole) and triphenylphosphine T4omy (2,82 mmole) Y
The mixture was then stirred at 70°C for 45 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 20.9 liters of silica gel.
It was subjected to column chromatography and eluted with 15-20 ethyl acetate-benzene to give a yield of 8131ψ (yield,
The desired compound (66%) was obtained as a yellow oil.

In spectrum νCH0'cm-': 1755
．． 1700.

ax 625 Example 12 1-tert-Butyldimethylsilyloxyethyl]SterCo2PNB Co2PNB (3s, 4R)-3-[([-1-tert-Butyldimethylsilyloxyethyl]-4-[[(5)-1
-[(8)-4-(p-nitrobenzyloxycarbonyl)morpholin-2-yl]ethylthio]thiocarbonyl]thio-1-[1-(p-nitrobenzyloxycarbonyl)triphenylphosphoranyritenemethyl]azetidine -2-one 805■, hydroquinone 60-t in 8Qml of xylene, under nitrogen stream, bath temperature 125-128℃
Heat for 19.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel 259, eluting with a 2-5% acetic acid ether-benzene mixed solvent to obtain the desired cyclized product (5, A mixture of about 3.5:i of the (6-) lance isomer) and its (5-h)-isomer (5,6-lance isomer) was obtained at a ratio of about 5001ψ. This mixture was separated by liquid chromatography using a Kerober Lamb B (Merck) flame [solvent: ethyl acetate-benzene (1:4)] to give a trans isomer of 3401 da (yield).

58%) and cis form 1001Q (yield, 17%)'Fa
l' were each obtained as an oil.

R spectrum of trans form CHCl3. ．． ．． -1
:ax IT90. 1700 nmr spectrum of trans isomer (cDa15) δppm
'0.04 (3H, θ), [1,07 (3T (, day)
, 0.83 (9H.

day), 1.23 (3H, d, J=6.5Hg), 14B
(3H.

a, J=6.5Hz), 3.69(1H, da, J=4
．． 5゜1.5HJ, 2.6-4.5 (9H, rn), 5
．． 21 (2H.

s), 5,13 (1H, d, J=13H2), 5.39
(IH.

d,, J=13Hg), 7.46 (2H, d), 7.5
7 (2H.

a), 8.16 (2H, d), 8.1'9 (2H, d)
Example 13 Acid p-nitrobenzyl ester tsR,as)-z-[(5)-1-[(8)-4-(
p-nitrobenzyloxycarbonyl)morpholine-2
-yl]ethelthio]-6-[(8)-1-tert-
butyldimethylsilyloxyethyl]benem-3-carboxylic acid p-nitrobenzyl ester 441 (0
, 56 mmole) in tetrahydrofuran 18WLt
Dissolved in acetic acid 335 In9 (5,6 mmole)
and tetra(n-butyl)ammonium fluoride 440
(1.68 mmole) was added and left at room temperature for 60 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and the solvent was distilled off.

The residual oil was subjected to column chromatography using 15.9'lff of silica gel and ethyl acetate-benzene (1
:1) Elution with a mixed solvent gave 309m9 (yield, 82%) of the target compound as an oil.

0) To/-1° engineering R spectrum ν 5cm, 3370.17
85°ax 698 nmr spectrum CCDCt,)δppm1.35(
3H, d, J=6.5H7), L46 (3H, d.

J=6.5H2), 2.14 (I H, br,)
, 2.6-45 (10H, m), 5.22 (2H,
e), 5.16 (1H.

d, J=14Hz), 5.46(114,a, J=14
1(z).

5.64 (IH, d, J = 1.5H7), 7.47 (2
H, d).

7.58 (2H, d, ), 8.18 (2H, d), 8.
20(2H,a) Example 14 1-Hydroxyethylcopenemu-3-carvone (SR,
6 days)-z-[(RI-1-[(m-4-(p-
nitrobenzyloxycarbonyl)morpholin-2-yl]ethylthio]-6-[(8)-1-hydroxyethylcobenem 3-carboxylic acid p-nitrobenzyl ester (305 ml) was dissolved in 30 ml of tetrahydrofuran, and 0. IM-sodium phosphate buffer (pH 7,1) 3
0 mAy! 'Additionally, 10 tipalladium-carbon 800 I
Stir with n9 under normal pressure hydrogen for 5.5 hours. After completion of the reaction, remove the catalyst YF using Cerai Y and wash the residue with ethyl acetate. Concentrate the water layer under reduced pressure at about 1000 t and warm AG
Subjected to column chromatography using 15 ml of
The fuctions eluted with 10 thiacetone and water were collected and freeze-dried 7 times to obtain the target compound in powder form 119~ (yield,
I got 73 chin.

KBr　　　-1゜ Engineering R spectrum ν α, 3400.177G.

aX 1585 nmr spectrum 000 MHz ID 20 ) δpp
m'1.32 (3H, d-', T=6.5H2),
144 (3H, d.

, T=7H2), 3.92(tu, aa, J=s, 1
．． 5Hz).

2.9-4.2 (8H, m), 4.27 (1) (, r[
, 5.72 (IH, d, J = 1.5 Hz) Example 15 (SR, 68)-2-[(R1-1-[(shun-morpholin-2-yl]ethyl-y-o]-6- [(9)-1
-Hydroxyethyl]penemu-3-carboxylic acid 57.
5 Tnq (13,1jOmmole) Y O,
IM sodium phosphate buffer (pH 7.1) 28m
Pongee was dissolved in A and 2 drops of 2N sodium hydroxide solution was added thereto while stirring under water cooling to adjust the pH to 8.5. Etheracetimitate hydrochloride 150 Tnq (1,21 mmole) Y Add in small portions over 92 to 3 minutes. While simultaneously adding 7 drops of 2N sodium hydroxide solution, the reaction solution was maintained at pH 8.5.

After stirring for 15 minutes, 2N hydrochloric acid was added to adjust the pH to 7.0, and this solution was mixed with Diaion HP20AG (15ml).
The sample is subjected to column chromatography using a column chromatography.

After eluting the inorganic salt with water, the fraction eluted with 4-6% acetone-water was lyophilized and the starting compound 241~
(43%) Not recovered. Further, 8 to 10 fractions eluted with thiacetone-water were collected and freeze-dried to obtain the target compound 18 (yield: 28%) as a colorless powder.

KBr -1.

Engineering R spectrum ν t:m −3400(br,
).

ax 1765, 1675. 1620. 1580 specific optical rotation [α. +119° (a=o, 5o, H2o)n
mr spectrum (D2o) δppm '1.32 (3H
, d, J=6.5H2), 146(3H, d.

J = 7H2), 2.35 (3H, s), 3.90 (IH
.

dd-, J=6.1.5H7), 30-4.5 (9N1
m)+5.65 (I H, d, J=1.5H2)
Applicant: Sankyo Co., Ltd. Agent: Patent Attorney Shoji Kashiyama Page 1 - Continued 0 Inventor: Masayuki Iwata 1-2-58 Hiromachi, Tokyo Parts Ward, Sankyo Co., Ltd. Biological Laboratory

Claims (1)

[Claims] 1. General formula [wherein R1 is a hydrogen atom, an alkyl group, an alkoxy group, or an R5A- group (wherein R5 is a hydroxyl group, an alkoxy group,
Acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, trialkylsilyloxy group,
It represents a mercapto group, an alkylthio group, an amiZ group, or an acylamino group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group. ], R2 represents a lower alkyl group, R3 represents a 4- to 8-membered ring aliphatic amine residue which may contain an oxygen atom or a sulfur atom in the ring, and the ya atoms therein are 6 -[J,,=N-R' group (in the formula, R and R are the same or different and represent a hydrogen atom or a lower alkyl group. R4 is a hydrogen atom or a protecting group for a carboxyl group) and ζX represents a methylene group or a thio group. Carbapenem-3-carboxylic acid derivatives and penem-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof. 2. General formula [wherein R8 is a hydrogen atom, an alkyl group, an alkoxy group or an RA- group (in the formula 1, R is a hydroxyl group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy/group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, represents an acylamine group, an aralkylamine group, or an aralkyloxy7carbonylamino group, and A represents an alkylene group optionally substituted with a trifluoromethyl group or a phenyl group.
R represents a carboxyl group protecting group. ] in the presence of a base with alkanesulfonic anhydride, arylsulfonic anhydride, dialkylphosphoryl halide, or diarylphosphoryl halide to form a compound having the general formula (wherein R and RFi have the same meanings as above,
R represents an alkanesulfonyl group, an arylsulfonyl group, a dialkylphosphoryl group, or a diarylphosphoryl group. ), and then a compound having the general formula % (in the formula, R2 represents a lower alkyl group, and R9 is a 4- to 8-membered cyclic aliphatic amine residue which may contain an oxygen atom or a sulfur atom in the ring). (indicates a group in which the nitrogen atom has a protecting group) is reacted with a mercaptan in the presence of a base to form the general formula (wherein R, R, R and R have the same meanings as above). ), and then, if desired, the obtained compound is subjected to a reaction for removing the protecting group R of the carboxyl group, and the corresponding protecting groups contained in R and R9 are removed to form a hydroxyl group, an amino group, a cyclic group, etc. The resulting compound is subjected to a reaction to restore the amino group or mercapto group, and the cyclic amine 7 group moiety at the 2-position of the obtained compound is converted into a 6-formula -LA-N-R' group (wherein R6 and R7 are the same or different). [In the formula, R1 is a hydrogen atom, an alkyl group, an alkoxy group or an R5A- group (wherein R5 is hydroxyl group, alkoxy group,
Acyloxy group, alkylsulfonyl subgroup 7, arylsulfonyloxy group, trialkylsilyloxy group,
It represents a mercapto group, an alkylthio group, an ami7 group, or an acyl ami/group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group. ], R2 has the same meaning as defined above, and R3 is a 4- to 8-membered cycloaliphatic-0-NR group (in the formula, R and R
indicates the same meaning as above. ], and R4 represents a hydrogen atom or a protecting group for a carboxyl group. ] A method for producing a carbapenem-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof. 3 General formula [wherein R is a hydrogen atom, an alkyl group, an alkoxy group, or an RA- group (in the formula, R11° is an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy7 group, a It represents an alkylsilyloxy group, an acylthio group, an alkylthio group, an acylamino group, an aralkylami/group, or an aralkyloxycarbonylami/group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group.] In the formula, R2 represents a lower alkyl group, R is a 4-membered to 8-negative ring cycloaliphatic amine residue that may contain an oxygen atom or a sulfur atom, and the nitrogen atom (
R represents a protecting group for a carboxyl group, and Ze represents 3if, a substituted phosphonio group, or a diesterified phosphono group with a cation. )
A phosphorus-ylide compound having the formula % is heated to form a compound having the general formula % (wherein R, R, R and B have the same meanings as described above), and then the desired t The carboxyl group of the thus obtained compound was protected by 71I￥F.
(removal reaction and reaction of removing the respective 1.6-pair protecting groups contained in RBL and R to restore the hydroxyl group, amine 7 group, cyclic amine/group or mercapto group,
Furthermore, the cyclic amine 7 group moiety at the 2-position of the obtained compound has the following formula: -C hydrogen atom or 7 H represents a lower alkyl group. ) A general formula characterized by being applied in appropriate combinations to the K conversion reaction [wherein R is a hydrogen atom, an alkyl group, an alkoxy group or an RA- group (wherein R5 is a hydroxyl group, an alkoxy group, an acyloxy group, Indicates an alkylsulfonyloxy group, -arylsulfonyloxy group, trialkylsilyloxy group, mercapto group, alkylthio group, ami/group or acylami/group, A is alkylene optionally substituted with trifluoromethyl & or phenyl group. ) 2 Representation R2 has the same meaning as above, and R5 is a 4-membered group that may contain an oxygen atom or a sulfur atom in the ring.
A membered ring cycloaliphatic amine residue, even if the nitrogen atom therein is substituted with an N-N-R group (in the formula, R and R have the same meanings as above). Well, R4
represents a protecting group for a hydrogen atom or a carboxyl group. ] A method for producing a penem-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.