JPS58103388A - Carbapenem derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R is H, alkyl, etc.; X is thio, sulfinyl, etc.; A is single bond or alkylene; R<2> is cyclic amine residue forming a 3--8- membered ring containing O, N, etc.; R<3> is H or a protecting group of the carboxyl group). EXAMPLE:(5R,6S)-6-[1-(R)-Hydroxyethyl]-3-[3-(S)-pyrrolidinyl]thiomethyl- 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. USE:An antimicrobial agent. PROCESS:An alpha-halogenoketone compound of formula II (R<13> is H, alkyl, etc.; R<14> is H or a protecting group of beta-lactam N atom; Y is halogen) is reacted with a thiol compound and then with a glyoxylic ester. The resultant reaction product is then halogenated and reacted with a phosphoine compound to give a phosphorus ylide compound, which is further subjected to the ring closure reaction and then catalytically reduced.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-carba-2-penem-3-carboxylic acid derivative having the general formula, a pharmacologically acceptable salt thereof, and a method for producing the same.

±dt In the formula, R is a hydrogen atom, an alkyl group, an alkoxy group, or an R'B- group. ,
It represents a mercapto group, an alkylthio group, an amino group or an acylamino group, and B represents an alkylene group in which trifulle is substituted with a romethyl group or a phenyl group. ), X represents a thio group, a sulfinyl group, or a sulfonyl group, M represents a single bond or a linear or branched alkylene group, R2 represents an oxygen atom, a nitrogen atom,
A cyclic amine residue forming a three-membered ring or a member as a whole, which may have a sulfur atom, a sulfinyl group, a sulfonyl group, or a carbonyl group, in which the 1i1 group atom may have an amino group. A good lower aliphatic acyl group, amino, mono-lower alkyl-substituted amino or di-lower alkyl-substituted aminoalkylene group, or a group of the formula -〇, NR' (wherein 15 is a hydrogen atom, 5 represents an amino group or a lower alkyl group) x6 represents a hydrogen atom or a lower alkyl group) or may be substituted with the above-mentioned amine residue (wherein R5, u4 and R7 have the same meanings as described above). R5u indicates a protecting group for a hydrogen atom or a carboxy group.

Since the discovery of the naturally occurring antibiotic chenamycin, which has extremely strong antibacterial activity (Japanese Patent Application Laid-Open No. 73191/1982), research on this family of compounds has been actively conducted. However, compounds of this type are known to be relatively stable (The Journal of Antibiotics, Vol. 32, p. 1, TSYS). Therefore, the present inventor, Go, searched for compounds that would increase the stability of chenamycins even slightly without reducing their antibacterial activity, and was able to complete the present invention.

In the general formula (11), R is preferably a hydrogen atom; methyl, ethyl, n-globil, isopropyl,
n-butyl, isobutyl, -・C-butyl, tert-
Straight-chain or branched lower alkyl groups such as butyl, n-pentyl, impentyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 5ea-butoxy, tert-butoxy. A linear or branched lower alkoxy group such as R'B group (in the formula, 14 is a hydroxyl group; for example, methoxy, ethoxy, n
- lower alkoxy groups such as propoxy, impropoxy; lower aliphatic acyloxy groups such as acetoxy, glopionyloxy, n-butyryloxy, imbutyryloxy or benzyloxycarbonyloxy p-nitrobenzyloxycarbonyloxy; Alkoxy groups such as aralkyloxycarbonyloxy groups;
Lower alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, glopanesulfonyloxy; for example benzenesulfonyloxy p
-) an arylsulfonyloxy group such as luenesulfonyloxy; e.g. trimethylsilyloxy, t.rt
- tri-lower alkylsilyloxy groups such as butyldimethylsilyl; mercapto groups; e.g. methylthio,
Lower alkylthio groups such as ethylthio, n-probylthio, ingropylthio, niamino groups or e.g. acetylamino, propionylamino, n-butyrylamino,
B represents a lower aliphatic acylamino group such as imbutyrylamino, and B is, for example, methylene, ethylene, ethylidene,
May be substituted with a trifluoromethyl group or phenyl group such as trimethylene, glopylidene, isopropylidene, tetramethylene, butylidene, pentamethylene, pentylidene, 'Lλ2-trifluoroethylidene, λ3-trifluoroglopylidene, benzylidene Indicates an alkylene group. ) is preferably a thio, sulfinyl or sulfonyl group, and is preferably a single bond, for example methylene, ethylene, ethylidene,
L D and R2 are preferably linear or branched lower alkylene groups such as trimethylene, glopylidene, isopropylidene, tetramethylene and butylidene, such as aziridine, azetidine, pyrrolidine, piperidine,
Hexahydroazepine, octahydroazocine, oxazolidine, morpholine, hexahydroxazepine, imidazolidine, piperazine, hexahydrodiazepine,
Thiazolidine, thiazolidine-1-oxide, thiazolidine-1,1-dioxide, thiomorpholine, thiomorpholine-8-oxide, thiomorpholine-8-dioxide, hexahydrothiazepine, in combination with hydrothiazepine-8-ol cid, hexahydrothiazepine-S-dioxide, azetidinone, pyrrolidone, piperidone, hexahydroazepinone, oxazolidone, oxazinone,
Bleaching agents such as hexahydroxazepine, thiazolidone, thiomorpholine, hexahydrothiazepinone, imidazolitone, piperazinone, and sahydrodiazepinone contain oxygen, nitrogen, sulfur, sulfinyl, sulfonyl, or carbonyl groups. It is a residue of a cyclic amine that forms a three-membered ring or a membered ring as a whole), and the nitrogen atom therein is, for example, acetylamino,
propionylamino, n-butyrylamino, isobutyrylamino, glycylamino, a lower aliphatic acyl group which may have an acylamino group, an amino group such as methylamino, dimethylamino, ethylamino,
diethylamino, glycylamino, inbutylamino,
Ethylene, propylene, glopylidene, isopropylidene, butylene substituted with a di- or di-lower alkyl substituted amino group such as n-butylamino, isobutylamino, t-butylamino alkylene group or formula
-(1=M R' group (in the formula, R5 is hydrogen number 5 atom, amino group or methyl, ethyl, n-propyl,
It represents a lower alkyl group such as inglovir, and represents a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-propyl, or inglovir. ) (wherein R is a hydrogen atom or lower alkyl such as methyl, ethyl, n-propyl, and inglovir R6 and R7 have the same meanings as defined above). R5 is preferably a hydrogen atom, such as a linear or branched atom such as methyl, ethyl, n-propyl, inglovir, n-butyl, isobutyl, t@rt-butyl. Lower alkyl group; e.g. 2
-iodoethyl, ``L2-dibromoether, Li2-)
Halogeno lower alkyl groups such as dichloroethyl; e.g. methoxymethyl, nidooxymethyl, n-propoquinemethyl, isobutoxymethyl, n-butoxymethyl,
Lower alkoxymethyl groups such as isobutoxymethyl;
For example, acetoxyethyl, propionyloxymethyl,
Lower aliphatic acyloxymethyl groups such as n-butyryloxymethyl, imbutyryloxymethyl, pivaloyloxymethyl: e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-
1-Lower alkodicarbonyloxyethyl groups such as propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyltoxyethyl, 1-imbutoxycarbonyloxyethyl; e.g. benzyl, p-1 toxyethyl It is an aralkyl group such as benzyl, 0-nitrobenzyl, p-nitrobenzyl, or a phthalidyl group.

Further, more preferable compounds in the general formula (1) include those in which R1 is a hydrogen atom, a hydroxymethyl group, an ethyl group, 1-hydroxyethyl, 1-acetoxyethyl, 1
-Hydroxy group at α position such as globionyloxyethyl, 1-n-butyryloxyethyl, 1-aminoethyl, 1-acetylaminoethyl, 1-propionylaminoethyl, 1-n-butyrylaminoethyl , amine 7 group, 9 ethyl group substituted with lower aliphatic acyloxy group or lower aliphatic acylamino group, 1-hydroxy-1-methylethyl, 1-acetoxy-1-methylethyl, 1-propionyloxy-1-methylethyl , 1-n-butyryloxy-1-methylethyl, 1-amino-1-methylethyl, 1-acetylamino-1-methylethyl, 1-propionylamino-1-methylethyl, 1-n-butyrylamino-1-methyl an inglovir group substituted with a hydroxyl group, an amino group, a lower aliphatic acyloxy group, or a lower aliphatic acylamino group, such as ethyl, or a methoxy group, and X is a thio group, a sulfinyl group, or a sulfonyl group), group is a single bond or methylene, ethylene,
lower alkylene groups such as ethylidene, propylene, trimethylene, glopylidene, etc., such as aziridine, azetidine, pyrrolidine, piperidine, hexahydroazepine, oxazolidine, morpholine, hexahydroxazepine, imidazolidine, piperazine, hexahydro Diazepine, thiazolidine, thiazolidine-1
-oxide, tiapridine-1. 1-dioxide, thimorpholine, thiomorpholine-S-oxide, thiomorpholine-S-dioxide, hexahydrothiazepine,
hexahydrothiazepine-8-oxyto, hexahydrothiazepine-S-dioxide, azetidinone, pyrrolidone, hexahydroazepinone, oxazolidone, oxazinone, hexahydroxazepine, thiazolidone, thiomorpholine, hexahydrothiazepinone, imidazolitone, Cyclic amines such as piperazinone and hexahydrodiazepinone that form a three- to seven-membered ring as a whole through nitrogen, sulfur, oxygen, sulfinyl, sulfonyl, or carbonyl groups in the ring ), and nitrogen atoms therein, such as acetylamino, propionylamino, n-butyrylamino, isobutyrylamino, glycylamino, alanylamino,
A lower aliphatic acyl group which may be G1 with an amide group such as β-alanyl amine/, an amino group-attached system such as ethylene, propylene substituted with a mono-lower alkyl-substituted amino group such as methylamino and ethylamino. , glopylidene, imbutylidene, butylene, isobutylene, butylidene, imbutylidene, or a lower alkali group such as -C, -MR group (wherein Rs is a hydrogen atom, an amino group, or methyl, ethyl, n-globyl, Indicates a lower alkyl group such as inglovir, R
Erosion hydrogen atom or methyl, f) V, n-globil,
Indicates a lower alkyl group such as inglovir. ) may be further substituted with (t9) the acyl group or alkyl group which is a substituent of the above-mentioned cyclic amine residue, including a lower atom such as thyl, globyl, isopropyl, R, R and Ri as mentioned above. Show the same meaning as something. ), R or hydrogen atom, λ2-dibromoethyl, methoxymethyl, acetoxymethyl, piparoyloxymethyl, 1-ethoxycarbonyloxyethyl, benzyl, p-nitrobenzyl, benzhydryl or phthalidyl Compounds that are groups can be mentioned.

Particularly preferred compounds in the general formula (1) are those in which nl is a hydrogen atom, hydroxymethyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl group, and X is a thio group, a sulfinyl group or a sulfonyl group. where M is a single bond and M is a methylene, ethylene, propylene, or trimethylene group, and R2 is an aliphatic group forming a three- to seven-membered ring such as aziridine, azetidine, pyrrolidine, piperidine, or hexahydroazepine. It is a cyclic amine residue, and the nitrogen atom therein has the formula -0.
-MR group (wherein R5 and R6 are the same or different and may be substituted with a hydrogen atom, methyl, ethyl, or n-10 biru group), R is a hydrogen atom, pivaloyloxymethyl,
Compounds which are 1-ethoxycarbonyloxyethyl, p-nitrobenzyl, benzhydryl or phthalidyl groups can be excluded.

Furthermore, the most preferred mineral compounds in general formula (1) include those in which R1 is a hydrogen atom, 1-hydroxyethyl, 1-
is a hydroxy-1-methylethyl group, X is a thio group, and M is a single bond, a methylene or ethylene group,
R2 is a four- to six-membered cyclic amine residue such as acetidine, pyrrolidine, or piperidine, and the nitrogen atom therein is a group of the formula -〇, -MR' (in the formula, R5 and R
6 is the same or different and represents a hydrogen atom, methyl or ethyl group. ) may be substituted with R5
is a hydrogen atom, pivaloyloxymethyl, 1-ethoxycarbonyloxyethyl or phthalidyl group.

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 represented by a single formula, this is not intended to limit the scope of the description of the invention. However, it is preferable to select a compound in which the carbon atom at position 3 has the same coordination as that of penicillins, that is, the R coordination.

In addition, the carboxylic acid compound in which R5 is a hydrogen atom in the general formula (2) can be made into a pharmacologically acceptable salt form if necessary. Examples of such salts include lithium, sodium, potassium, Examples include inorganic salts such as calcium and magnesium salts, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium and triethylammonium, preferably sodium salts and potassium salts.

The compound having the general formula (1) of the present invention belongs to carbapenem conductors in which the sulfur atom at the 1st position of the penicillin ring is substituted with methylene and a double bond exists between the 2nd and 3rd positions of the ring. , is a group of novel compounds that have various substituted mercapto groups at the 2-position substituent.These compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals, or are compounds that exhibit these activities. It is an important synthetic intermediate.

Examples of the compounds having the general formula (2) obtained by the present invention include the compounds shown in Table 111C.

Table 1 Exemplary Compound 0 Effect 11 H-Single Bond 8 H 21H Explanation Single Bond 8 H'n CH2Oyo28 3g CI! , -0H- 32Hτ Single bond 8 Mu R1R2mu 54am!-oH-, I) 0H2aA
R'l" A XH0
kl-OH-,! I top. Single bond βOH 1 degree Yafu 8 1120M, -0H-yoH AR'R' A
X■ Furthermore, for all of the nine carboxylic acid derivatives shown in Table 1, list their sodium salts, potassium salts, pivaloyloxymethyl esters, 1-ethoxycarbonyloxyethyl esters, or phthalidyl esters as exemplary compounds. I can do it.

In addition, as mentioned above, this exemplary compound has stereoisomers, and among these isomers, preferred are compounds having (5R#6El) coordination and (SR,IIR) coordination, and・Suishun, group, at the α position of the substituent,
Compounds having a substituent such as an acetoxy group, an amino group, or an acetamide group may have an R coordination.

The novel compound (1) according to the present invention can be produced by the method shown below.

In the above formula, R, R, R, , an acyloxy group, an aralkyloxycarbonyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, or a gas-filmed amino group, and B is a trifluoromethyl group or a phenyl group. (represents an alkylene group which may be substituted with
The sulfonyl group tz is an amine residue forming a three-membered ring or a member as a whole, which may have a carbonyl group interposed therebetween, and the 1lit chain atom in the 7 has a carrier group or a carrier amine 7 group. a lower aliphatic acyl group which may have a protected amino group, a protected nine-mono-lower alkyl tI1. ．． Indicates an amino or lower alkyl substituted amino alkylene group, R is a protecting group for a carboxy group, R
represents an alkyl group such as n-butyl or n-octyl or an aryl group such as phenyl or tolyl, and R1! is a hydrogen atom, an alkyl group, an alkoxy group ti is R15-B
group (wherein R represents an alkoxy group, an acyloxy group, an aralkyloxycarbonyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, or a gas-filmed amino group, R is water lIA atom 1 has β-
It represents a holding group for the lactam nitrogen atom, xo represents a thio group, and Y and 2 represent a halogen atom such as chlorine, bromine or iodine.

The raw material compound in the production method of the present invention is the general formula (2)
) and the epoxy compound having the general formula (4) can be synthesized by the method described in Ki6 Publication [ill (%rA@511-12237@) by the applicant of the present invention.

First construction! ii←) is a method for producing a compound having the general formula (8), and an α-halogenoketone compound having the general formula (2) is added to the α-halogenoketone compound having the general formula % formula % (wherein R, M and X are This is a process of reacting a thiol compound having the same or similar characteristics as those of the same type as those of the present invention in a base-based solvent.

Main reaction Vcl! Bases used include sodium ethoxide, sodium ethoxide, chalicum ethoxide,
Alkali lower alkoxides such as potassium t-butoxide, alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, mixtures of the above-mentioned alkali metal electrocarbonates and silver nitrate, triethylamine, pyridine, N -Methylmorpholine, N, N-
Organic bases such as dimethylaniline can be mentioned, but examples of bath agents used in the reaction, such as sodium bicarbonate and silver salts, include halogenated bases such as methylene chloride and chloroform. Examples include mixtures of these organic solvents, such as hydrocarbons, ethers such as nitrogen, tetrahydrofuran, and alcohols such as methanol, ethanol, and n-glopanol. The reaction temperature is not particularly limited (usually -10 to 1
The reaction time is 30 minutes to 30 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, the reaction mixture is diluted with a water-immiscible organic solvent such as ethyl acetate, ether, benzene, or chloroform, neutralized if necessary, washed with water, dried, the solvent is distilled off, and the residue is subjected to a recrystallization method. It can be obtained by purification by reprecipitation method or column chromatography.

In addition, the compound having general formula (8) is #1 shown below.
It can also be produced by a separate synthesis method that involves 1 m (bt) per process and 11 steps (11,).

The first step (1,) is a step of producing a compound having the general formula (5), in which an epoxide compound having the general formula (4) is mixed with the general formula % formula % (where R, M and 9 is a step in which a nucleophilic reagent having the same meaning as 1) is reacted with its reactive derivative in a solvent.

The reactive derivatives of the nucleophile used in this reaction are:
lithium, sodium, potassium or calcium,
As the solvent used in the two reactions, mention may be made of alkali metal or alkaline earth metal salts such as salts with magnesium and salts with organic bases such as triethylamine, N-methylmorpholine, tetraethylammonium hydroxide, etc. Examples of the solvent include inert solvents such as halogenated hydrocarbons such as methylene chloride and chloroform, and ethers such as ethyl ether and tetrahydrofuran. The reaction temperature is not particularly limited, and is usually -10 to too°C], and the reaction time is 1
The duration ranges from 0 minutes to 2 hours. This reaction also proceeds by allowing the nucleophile I to act in the presence of a base such as n-butyllithium or an acid such as boron trifluoride etherate.

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, the reaction mixture is diluted with a water-immiscible organic solvent such as ethyl acetate, ether, benzene, or chloroform, neutralized if necessary, washed with water, dried, the solvent is distilled off, and the residue is subjected to a recrystallization method. The reprecipitation method can be obtained by purification using column chromatography.

The first step (1)) is a step of producing a compound having general formula (3), and is a step of oxidizing a secondary alcohol compound having general formula (5) in a solvent to form a ketone compound.

The oxidizing agent used in this reaction is not limited to # as long as it converts a secondary alcohol compound into a ketone compound, but chromate, manganate, hypohalite, halogen, N Examples include -haloamide, N-haloimide, oxygen, dialkyl sulfoxide and acid anhydride.

Examples of solvents used in the reaction include halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, and esters such as methyl acetate and ethyl acetate. Various oxidizing solvents can be mentioned, such as or mixtures of these solvents. Preferably using chromic anhydride as the oxidizing agent, especially Jones's reagent (6-1 ON sulfuric acid solution of chromic anhydride) or pyridinicum chlorochromate at 0 to 10°C for 5 minutes to 2 hours in acetone or dioxane. carbodiimide and phosphoric acid, such as dimethyl sulfoxide and dicyclohexyl carbodiimide,
The reaction is carried out using an oxidizing agent (MOffatt) in combination with an acid such as acetic anhydride, trifluoroacetic acid, or dichloroacetic acid at -20 to 30°C for 1 minute to 96 hours.

After completion of the reaction, the target compound (8) of this step is collected from the reaction mixture according to a conventional method. For example, after decomposing excess oxidizing agent, the reaction mixture is mixed with water as described above, diluted with an organic solvent, washed with water, dried, the solvent is distilled off, and the residue is subjected to recrystallization, reprecipitation, or column chromatography. It can be obtained by graphic purification.

The second step is a step of producing a compound having the general formula (6), and if necessary, the protecting group R14 of the l-lactam nitrogen atom of the compound having the general formula (3) is removed, and the substituent X"(
This is a step of converting a thio group) into a sulfinyl group or a sulfonyl group.

Removal of the protecting group R is carried out according to a conventional method, but when the protecting group is a trialkylsilyl group such as t.rt-butyldimethylsilyl, hydrochloric acid, hydrobromic acid, or fluorinated acid, which generates a halogen anion, is used. 6yU in the presence of a hydrohalic acid or a salt thereof, such as hydric acid, or by treatment with an organic quaternary ammonium base such as tetraalkylammonium fluoride, where the protecting group is If it is a pyranyl group, it can be removed by treatment with an aqueous mineral acid solution such as dilute hydrochloric acid or dilute sulfuric acid.

Solvents used for this removal process include fatty acid dialkylamides such as dimethylformamide and diethylacetamide, dimethyl sulfoxide, hydrous alcohols such as hydrous methanol and hydrous ethanol, and hydrous ethers such as hydrous tetrahydrofuran and hydrous dioxane. Polar solvents such as the following are suitable. The reaction is usually carried out at -10 to 30°C for 10 minutes to 3 hours.

After the completion of the reaction, the target compound for the removal reaction of the protecting group R is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is mixed with water, diluted with an organic solvent,
After neutralization, it can be obtained by washing with water, drying, distilling off the solvent, and purifying the residue by recrystallization, reprecipitation, or column chromatography.

Further, the reaction of converting the substituent X (thio group) into a sulfinyl group or a sulfonyl group is carried out by treating a compound having a thio group with an oxidizing agent. The reaction conditions and post-reaction treatment method for this oxidation reaction are described above,
0. ).

In the process of producing a compound having the general formula ('Fl), a compound having the general formula (6) is given the general formula cino-
This is a step of reacting a hemiacetal derivative of a glyoxyl ester having aoR'' 41j (in the formula, flQ has the same meaning as the above-mentioned round one) in a solvent.

When the glyoxylic acid ester ring used in this reaction is a hemiacetal derivative, hemiacetal with a lower alkanol such as methanol or ethanol is suitable. Examples of the solvent used in the reaction include fatty acid sialamides such as dimethylformamide and dimethylacetamide, and aromatic hydrocarbons such as benzene, toluene and xylene. The reaction temperature is not particularly limited, but it is preferably 2 s°C to around the reflux temperature of the solvent used), and is usually carried out in a nitrogen or argon atmosphere to avoid side reactions. The reaction time varies depending on the reaction temperature, etc., but is approximately 2 to 1 s.

In addition, when the hydrate of silicic acid ester I in Grio is used, water may be removed by azeotropic distillation or a dehydration method using a mineral molecular sieve, if necessary.

After the reaction is completed, the target compound (7) of this manuscript is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the organic solvent (from the reaction mixture) and purifying the residue by recrystallization, reprecipitation, or column chromatography.

The fourth step is a step of producing a compound having the general formula (8), and is a step of halogenating the compound having the general formula (7) in a solvent.

The halogenating agent used in this reaction is not particularly limited as long as it is a reagent that halogenates a hydroxy compound, but phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide,
Phosphorus pentahalides such as phosphorus pentachloride and phosphorus pentabromide, phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, thionyl halides such as thionyl chloride and thionyl bromide, squizaryl chloride, oxalyl Examples include succinic acid halide such as promid.

The reaction is preferably carried out in the presence of an acid binder, but the acid binders used include triethylamine, pyridine,
Organic bases such as lutidine are preferred. Examples of the solvent used in the reaction include inert solvents such as ethers, ethers such as tetrahydrofuran and dioxane, and halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is -40 to 40°C, and the p1 reaction time is 15 minutes to S time, although it varies depending on the perhalogenating agent and reaction temperature.

After the reaction is completed, the target compound (8) of this step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an inert organic solvent, the generated hydrohalide of the organic base is separated from F, the solvent is distilled off (from the F solution), and the residue is purified by recrystallization or reprecipitation. This can be obtained by
The halogenating agent and organic solvent may be distilled off from the reaction mixture under reduced pressure, and the residue may be used in the reaction in the next step.

In the step of producing a compound having the general formula (9) in the presence of a base, the compound having the general formula (8) is added to the compound having the general formula (%) (2) (wherein R is the one described above). This is a process in which a phosphine compound having the same meaning as . is reacted in a solvent.

This reaction is a part of the so-called Wittig reaction, which produces the phosphorus-ylide compound (9), but the phosphine (2) used is most preferably triphenylphosphine. There are no particular limitations on the base used, but for example, triethylamine,
Examples include organic bases such as pyridine and soletidine, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Examples of solvents used in the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride and chloroform, dimethylformamide, and dimethyl. fatty acid dialkylamides such as acetamide,
Inert solvents such as dimethyl sulfoxide can be mentioned. The reaction temperature is not particularly limited, but -30 to 12
The temperature is 0° C., and the reaction time varies depending on the reaction temperature, etc., but is usually 0.5 to 10 hours. In this reaction, if necessary, a catalytic amount of an antioxidant such as hydroquinone can be added to prevent the oxidation reaction.

After completion of the reaction, the target compound of this step (91IIi is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an organic solvent that is miscible with water, washed with water, dried, and the solvent is distilled off to form a residue. It can be obtained by purifying by recrystallization method, reprecipitation method or column chromatography.

The #Il step is a step for producing a metal carbapenem compound having the general formula al, in which the metal compound having the general formula (9) is heated in a solvent and subjected to a ring-closing reaction.

Solvents used in the reaction include inert solvents such as ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene, toluene and xylene. Alternatively, a mixed solvent of these solvents can be used. The heating reaction temperature is 30 to 20. ．． The reaction time is usually 1 to 40 hours, although it varies depending on the reaction temperature and the like. In order to prevent side reactions caused by heating in this reaction, it is preferable to carry out the rounding in a stream of inert gas such as argon or phoneme, if necessary, and to prevent oxidation reactions, a catalytic amount of hydroquinone, etc. Antioxidants can also be added.

The main ring-closing reaction by heating may also proceed in the phosphorus-ylide synthesis reaction of the fifth step described above to generate the target compound dynamic axis of this step.

In addition, when R contains a preserved hydroxyl group, the phosphorus-ylide bond is preserved as necessary with a mineral acid such as hydrochloric acid, and the hydroxyl group is retained in the 1vI-hI removal reaction as described below. It is also possible to carry out the main reaction after carrying out this step.

After the reaction is completed, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the residue from the reaction mixture and subjecting the residue to 14M crystallization, reprecipitation, or column chromatography.

The first step is the step of achieving #I of the target compound of the present invention, a 1-calper 2-penem-3-carboxylic acid conductor having the general formula (11), which was obtained in the 6th E-Yang according to the new line. Using compound mobilization, the removal reaction of carbo-Φ Schiff v--R10 and the protective groups contained in R and R9, respectively, which are harmful to water, carboxy groups, mercapto groups, and amino groups, are removed. Mono-lower alkyl-substituted amino group, crystalline x
l> and R6 have the same meanings as described above. ) is carried out by appropriately combining reactions for converting into ().

That is, among the compounds having the general formula (R), the reaction of Mm with carboxylic acid compounds in which the substituent R is a water-bearing atom is carried out with respect to the protecting group R of the carboxy group of the compound having the general formula axis.
This is achieved by removing the .

Removal of the protective group R varies depending on the type, but is generally removed by methods known in the art.

Preferably, the reaction is carried out by contacting a compound having the general formula (IG) in which the substituent R is a protecting group that can be removed by a reduction treatment, such as halogenoalkyl, with a reducing agent. Suitable reducing agents used in this reaction include zinc and vinegar when the protecting group for the carboxy group is a halogenoalkyl group such as 2.2-dibromoethyl, 2.2.2-)lichloroethyl. When the protecting group is a benzhydryl group, such as benzyl, 9-nitrobenzyl, hydrogen and a catalytic reduction catalyst such as palladium-carbon or an alkali metal such as sodium sulfide or potassium sulfide are used. ) I4 (Ii1 compound is preferred. The reaction is carried out in the presence of a solvent, and there are no particular restrictions on the solvent used as long as it does not participate in this reaction, but alcohols such as methanol and ethanol can be used. , tetrahydrofuran, ethers such as dioxane, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water or phosphate buffer (pH 7.0) are suitable.The reaction apparatus is usually heated at #20°C to The reaction time varies depending on the raw material compound and the type of reducing agent, but is usually from a minute to 12 hours.In the reduction reaction of this step, compound 14I!Ja(I
When R9 has a hydroxyl group, an amino group, a mono-lower alkyl-substituted amino group, or a cyclic amino group protected by an aralkyloxycarbonyl group, the substituents R8 and /m9 are simultaneously substituted with those aralkyloxycarbonyl groups as described below. Protecting groups can be removed.

After completion of the reaction, the target compound of the reaction for removing the carboxyl protecting group R10 is collected from the reaction mixture according to a conventional method.

For example, after removing insoluble matter precipitated from the reaction mixture, the organic solvent layer is washed with water, dried, and the solvent is distilled off. If necessary, conventional methods such as recrystallization, preparative thin layer chromatography, and column chromatography are performed. It can be purified by etc.

In addition, if the target compound is water-soluble, remove the precipitated insoluble matter from the reaction mixture, and if necessary, concentrate the tJ5 solution under reduced pressure. It can be obtained by subjecting the compound to column chromatography using a porous adsorption resin such as those manufactured by Nippon Steel & Co., Ltd., and separating the portion in which the target compound is eluted, followed by freezing and drying.

Furthermore, among the compounds having compound (1), substituent R1
The reaction for producing a compound in which and/' or R2 is a hydroxyl group or an amino group is a reaction for producing a compound in which R2 has a general formula axis.
This is achieved by removing the protecting group for the hydroxyl group or amino group contained in 8 and /l or R9.

In the compound axis, substituents Ra and/or R9 are an acyloxy group, an aralkyloxycarbonyl group,
When it has a trialkylsilyloxy group, an acylamino group, an aralkylamide group, or an aralkyloxycarbonylamino group, if desired, each protecting group is removed according to a conventional method as described below to form a corresponding hydroxyl or amino group. The compound thus obtained is converted into a compound with the above-mentioned carboxyl group protecting group R
It can also be subjected to a removal reaction.

That is, the reaction for producing a compound in which the substituent R1 has a hydroxyl group among the compounds having the general formula (1) is an acyloxy group, aralkyloxycarbonyloxy group contained in ul of the compound having the general formula al. Alternatively, trialkylsilylsoxy group] is achieved by removing the acyl, aralkyloxycarbonyl or trialkylsilyl protecting group of the hydroxyl group. When Ra has a lower aliphatic acyl group such as acetoxy, the reaction can be carried out by treating the corresponding compound 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, n-gropanol, or tetrahydrofuran or dioxane are used. Mixed solvents with organic solvents such as ethers are suitable. Nine, the base used is other parts of the compound, especially β
- Although there are no particular limitations as long as it does not affect the lactam term, alkali metal carbonates such as sodium carbonate and potassium carbonate are preferably used. 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.

In addition, when the above substituent R has an aralkyloxycarbonyloxy group such as penzyloxycarbonyloxy or p-nitrobenzyloxycarbonyloxy, the removal reaction can be carried out by contacting the corresponding compound mobilization with a reducing agent. It can be carried out by The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group which is the protecting group R for the carboxy group described above, and therefore the protecting group R10 for the carboxy group can also be removed at the same time. . Furthermore, when the above substituent R8 has a tri-lower alkyloxy group such as t@rt-butyldimethylsilyloxy, the reaction can be carried out by treating the corresponding compound α with tetrabutylammonium fluoride. can do. There are no particular limitations on the solvent used, but tetrahydrofuran,
Ethers such as dioxane or water-methanol mixtures are preferred. The reaction is suitably carried out by heating at around room temperature for 1 to 11 hours.

Furthermore, among the compounds having the general formula (1)%-, the reaction for producing a compound in which the substituent R' and/or R1 has an amino group can be carried out using the compounds having the general formula (1o) and/or R1. ′ is a halogenoacetylamino group,
Achieved by removing the haligenoacetyl, aryl or aryloxy-substituted acetyl, aralkyloxycarbonyl or aralkyl protecting group of the amino group from an aryl or aryloxy-substituted acetylamino group, an aralkyloxycarbonyl group or an aralkylaino group. be done.

When the compound has a halogenoacetyl group such as trifluoroacetyl or trictetraacetyl, the removal reaction can be carried out by treating the corresponding compound (1G) with a base in the presence of an aqueous solvent. The type of base used in this reaction and the reaction conditions are the same as those for removing the lower aliphatic acyl protecting group of the hydroxyl group in the substituent R8 described above.

When the compound has an aryl- or aryloxy-substituted acetyl group such as phenylacetyl or phenoxyacetyl, the removal reaction can be carried out by contacting the corresponding compound (10) with acylase. This enzymatic splitting reaction is carried out by the method disclosed in N-acyl-chenamycin (Japanese Patent Application Laid-Open No. 11-4-46SS).
The acylase used is Escherichia coli (ICach).
Preferred are penicillin amidohydrolases such as those of S. srichia coxi.

When an aralkyloxycarbonyl group such as penzylodicarbonyl or p-nitrobenzyloxycarboel or an aralkyl group such as diphenylmethyl is present, the removal reaction can be carried out by contacting the corresponding compound (10) with a reducing agent. Implemented by. The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group, which is the carboxy-protecting group H1lJ described above, and therefore the carboxy-protecting group BI
This can be solved by removing O at the same time.

Among the metal compounds having the general formula (1), the reaction for producing the metal compound in which the substituent R1 has a mercapto group is performed by converting the acylthio group contained in - in the compound having the general formula (1.) into a mercapto group. The zero removal reaction achieved by removing the acyl protecting group of the group is similar to the basic hydrolysis reaction when the protected hydroxyl group in RK is a lower aliphatic acyloxy group such as acetoxy. can be implemented.

After performing the above-mentioned various protecting group removal reactions, the target compound for each reaction is collected from the reaction mixture according to a conventional method, and if necessary, a conventional method such as recrystallization, preparative thin layer atomization, columnar -f K11l can be further manufactured by K such as thornfish.

Furthermore, among the compounds having the general formula (1).

and R6 have the same meanings as described above. ) Among the compounds having the general formula (1) obtained by the removal reaction of the various protecting groups described above, the reaction for producing the compounds containing the formula (1) is carried out by converting the amino compound having the general formula (in the formula RIS, R4 and Y has the same meaning as above, R16 is methyl, ethyl, 0-propyl,
Reacts with an imide ester compound having a lower alkyl group such as isoguvir, n-butyl, isobutyl, and R1' is a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl. The reaction achieved by R''&C is preferably pH Under alkaline conditions near s to general formula (14) or (l
fi) 0 reaction which can be carried out by contacting with an ester compound having a
Alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide! #! Alkali metal carbonates such as J1 sodium carbonate and potassium carbonate are preferred.

This reaction is carried out in the presence of an aqueous solvent, and the solvents used include water, water and methanol, ethanol,
Alcohols such as n-propanol, tetrahydrofuran, dioxane f) ethers, dimethylformamide.

A mixed solvent with an organic solvent such as a fatty acid dialkylamide such as dimethylacedoide or a nitrile such as acetonitrile is suitable. The reaction temperature is preferably a relatively low temperature of about 0° C. to room temperature. The reaction time varies depending on the type of raw material compound, reaction temperature, etc., but is usually 5 minutes to 1 hour.

After the reaction is completed, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is kept near neutral and subjected to column chromatography using a porous adsorption resin such as Diaion HP 2o AG (manufactured by Mitsubishi Kasei Corporation), and the portion that elutes to the target compound is fractionated. It can be obtained by freeze-drying and, if necessary, further manufacturing by a conventional method such as a recrystallization method or a reprecipitation method.

Next, the obtained compound can be converted into a carboxylic acid derivative by removing the protecting group of the carboxy group according to the conventional method described above, if necessary.

When the substituent X in compounds (7), TI) and (10) in the above-mentioned synthetic route represents a thio group, it can be converted to a sulfinyl group or a sulfonyl group by an oxidation reaction. The reaction conditions and treatment method are the same as in the first step (11) described above.

In addition, when carrying out this oxidation reaction using a phosphorus-ylide compound (-), 1 mol or more of hydrochloric acid.

It is necessary to protect the phosphorus-ylide bond by ptonation in the presence of a mineral acid such as aqueous bromide or trifluoroacetic acid.

Carbapenem-3- having the uninvented general formula (1)
Carboxylic acid derivatives exhibit excellent antibacterial activity or are important intermediates in the synthesis of compounds exhibiting such antimicrobial activity. When the activity of the compounds exhibiting antibacterial activity was measured by the agar plate dilution method, it was found that, for example, Durham-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, as well as Escherichia coli, Shigella m, Klebsiella pneumoniae, P. aeruginosa, and Pseudomonas aeruginosa, were detected. It showed activity against a wide range of pathogenic bacteria, including Gram-negative bacteria.

Such compounds are therefore useful as antibacterial agents to treat bacterial infections caused by these diseases. Examples of dosage forms for this purpose include tablets, capsules, granules, powders, and tablets for oral administration or intravenous injection.

Examples include parenteral administration such as intramuscular injection.

The dosage varies depending on age, body weight, symptoms, etc., as well as the dosage form and number of doses, but the usual dosage for adults is approximately 2 ml per day.
Administer 50 to 500 w in one dose or in divided doses.

Let's make the present invention more concrete by giving examples to doctors! ! I will clarify.

Example 1 1-mu(N-p-nitropenzyloxycarboel-37(8
)-pyrrolidinyl]mercaptan 1.27 & to a mixture of tetrahydrofuran L6- and methanol 11.2-,
Solid sodium bicarbonate ays # is added under water cooling, and then a 40-methanol solution of silver nitrate TIs # is added dropwise. (3B, JR)-3-(1-
(R)-t-butyldimethylsilyloxy]ethyl-4
-Iodomethylcarbonylmethyl-azetidin-2-one After adding a 10-solution of 122Q in methanol.

The reaction mixture is stirred on an oil bath (40° C.) for 11 hours.

After the reaction is completed, the mixture is diluted with ethyl acetate and passed through Celite to remove insoluble portions. The organic layer obtained is washed with water and brine, and then dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (cyclohexane-ethyl acetate/1:4) to obtain the target azetidin-2-one 1192.
119 was obtained as an oil. (yield 70.3%) I
R(OHOA5): *710 (β-lactam)
, 1710 (Ketone) Bei-1 NMRδ (ODOts): lot (II H*
s, M@g81).

(L@7 (9H, a, But), 1.22
(l H,a.

J = 6 Hg, 0H1OH-081), 1
．． 5-44 (14H, m), 5.20 (2H
,8,0OOH2Fh) # it -14(15i
mbaeI-9/pmwH), 7. B(2
H* 6 s J” 9 Hg, PbMO4)
e L20 (211e (l m J =t i
t' Hvs, PhMo, )-B! 3-p-nitrobenzylglyoxylate hydrate lie@
ml was placed in 300-ml benzene with a dehydration tube to remove water, firstly the benzene was concentrated to 200-ml, and azetidin-2-one (compound of Example 1) was prepared with 10 mg of tetrahydrofuran in hot water. Add the solution and 280° of benzene, and while removing water, reflux for S hours and concentrate to 200°. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (firstly, glyoxylate F was removed with isoclobil ether-ethyl acetate 2:1, and then with cyclohexane-ethyl acetate 182). The desired product was purified by bathing out) to obtain the desired hydroxyazetidin-2-one (2). (Yield rs, y
%) IR(OHGjs): 1750 (β-lactam), 1700 (ester)! +1-0 Hydroxyazetidin-2-one (compound of Example 1-B) 841 ml was added to a solution of tetrahydrofurine-2-S at -24°C under a stream of Argosy gas.

λS-lutidine α43- and thionyl chloride Q, 21
- and stirred at -24°C for 20 minutes and then at room temperature for 20 minutes. After completion of the reaction, the mixture was diluted with benzene and passed through Celite to remove the residual portion, and the resulting organic layer was concentrated under reduced pressure. Tetrahydrofuran (2 S ms )') phenylphosphine (65 s) and 'L6-lutidine Q, 211-' were added to the obtained residue in a stream of alponic gas, and the mixture was stirred at 40°C for 4 hours. The reaction mixture was diluted with 250 ml of ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (benzene-7ton/4:1) to obtain the desired phosphoranylideneazetidin-2-one 107%■ as an amorphous substance. Obtained.

(Yield Hatake 6.4tin IR (OHGjs) + 010 (β-lactam)
, 1700 (ester) as-' -D (18e4R)-3-(1-(R)-hi)'1:14 si engineering? l-4-(II-p-nitrobenzyloxy/ylide compound (compound of Example 1-0) tO5i1m
10% hydrochloric acid water is added to a 101 m methanol solution of H under water cooling. Next, the water cooling tower was removed and 1.5
Stir for an hour to obtain a clear solution. After completion of the reaction, 21 g of IJum was added to the reaction mixture.

The mixture was slowly poured into a mixture of 203 fmt of water and 203 fmt of ethyl acetate under ice-cooling. After the mixed solution is saturated with common salt, the organic layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The obtained organic layer and ethyl acetate layer are combined, washed with an aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue obtained was subjected to silica gel column chromatography (cyclohexasoacetone/1:1).
111% of the target hydroxy compound
was obtained as an amorphous substance. (Yield III 174) Engineering R (OHOts) + 1140 (β-lactam and ester) cs "1 1-" Water was removed using a benzene 200 dVC dehydration tube.

Next, after concentrating to 100-, phosphoranilide/-azetidin-2-one (l! Compound of Example 1-D) 119
A solution of 20% of tetrahydrofuran and 200% of benzene were added, refluxed in an argon gas atmosphere for s hours, and concentrated to 100 yd. Next, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (benzene-acetone/5il) K to obtain the desired carbapenem compound 4153q. (Yield 11.Z%
)IR(011Gjm): lTl0 (β-lactam) cs-'NMRδ((3DO2&): 1.
20 (3H, d, J-6u=.

Mouth H30HO81), 1.6 - 4.5
(15H, m) Meeting 5.031 and 5.38
(2H# ABq, J=14 HIM *%0O
OH2), 5.10 (2H, B, ME(:!
0OOH,).

-～-～-+, 4＼-Kaisei 1.43 and 7.52 (4H, 2 pieces) d, J=9
Hz.

PhNO2), 8.13 (4H, d,
J = 9 Hz, PhN07) -F carbapenem compound (compound of Example 1-'R) 42s
10% haladium-carbon t2111 in tetrahydrofuran SS-solution of ■ and phosphate buffer (pH 7,
0) Add s s- and perform indirect contact light for 40 minutes at 10° C. under 40 p, a, l hydrogen pressure. After the reaction is complete,
The palladium-carbon was removed through Celite, the solution was washed three times with cold ethyl ether, and the aqueous layer was concentrated under reduced pressure.

This concentrate was applied to IP-20AG column chromatography, thoroughly washed with water, and then eluted with 2-thiacetone water to obtain 116.7 mg of the target compound.

(Yield: 442 cm) I't (KBr) 11755 (β-lactam)
Steel-1UV (11120) + λmax = 274
am (g=8270)11MRδ(D20):
1.32 (3H-6s J = 7 Hz - (3MB
-OHO), 1. @-4,4 (14H, m) Example-2 (!IR-,-,@' obtained in Example (1-1)
) -11,-C5-(R)-hydroxyethyl)-
s-(s-(S)-pyrrolidinyl]thiomethyl-T-oxo-1-azabisic tetra(1,2,0)hept-2-ene-2-carboxylic acid tss sy was dissolved in phosphate buffer (
pHT, O) 18 ydK was dissolved and adjusted to pH 15 with an IN-hydrocarbon aqueous solution under water cooling. The reaction is carried out while maintaining the reaction solution at pHILi by alternately adding methylformimidate hydrochloride sso q and an aqueous TA solution. After further stirring for 10 minutes under ice-cooling, the pH was adjusted with 1M salt.
, O, and concentrate the bath liquid to about half under reduced pressure. This concentrate was subjected to HP-20AG 2 μm chromatography, thoroughly washed with water, and then eluted with 8% acetone water to obtain the target compound 12589-#. (Yield 1i2.
21) Engineering R (KBr): '1770 cm-'
(β-lactam) 11iMRδ (D20): 1.3
m (l H, (1, J: 7 Hg.

Mouth HsO110), 190-450 (
%4 11 1 m) * 7.114 (I
H, a, -light H) Example-3 3-muCM-p-nidotetrabenzyloxycarbonyl-3-azetidinyl seamercaptan 1. ! Solid sodium bicarbonate sst w is added to a mixture of 9 N tetrahydrofuran 7.1 $ and methanol 15 m under water cooling, and then a 1.07 N methanol S solution of silver nitrate is added dropwise. The resulting ice-cold suspension solution K(Sfl, 4R)-8-(1
-(R)-t-butyldimethylsilyloxyphethyl-
4-iodomethylcarbonylmethyl-azetidine-2-
On 1.301 methanol 1! After adding the sj solution, the reaction mixture was heated on an oil bath (40°C). Stir for 4 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and passed through Celite to remove insoluble parts. The organic layer obtained was washed with water and brine, and then dried over sulfuric acid. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (Schifte hexane-ethyl acetate/l).
:4) to obtain 1411 g of the desired azetidin-2-one as an oil. (Yield 11.IS
) Engineering R (OHOj island): 17IO (β-lactam)
1-1 RMRδ (ODOts) + o, oy (・”
* s * '@t81) sQ,lls (@
H, I * But) e 1.20 (S He 1
1 e' = 7 Hz, 0HBOHO81) *
2-11-41! (12H*m), S, IS
(2H, a, 0OOOH2Ph) I #4T
(S'*ba*β-lactam MH), 1.
4G (! H*6 * J-10Hg * 'E'b
”Ox ) * &tS (2He &, J
= 10 Hsg * 'PhN0! )-B p-nitrobenzylglyoxylate hydrate ttr
The water was removed using a dehydration tube in 40 ml of benzene, and then the benzene was concentrated to 200 s.

This was added to azetidin-2-one (compound of Example 3).
A solution of 1,420 μm of tetrahydrofuran 20 and 200 μ of benzene was added, and the mixture was refluxed for 10 hours while removing water.
Concentrate to 00-. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was poured onto a fV silica gel column. Togelafii (first isoptetravir ether-ethyl acetate 2:I
After removing the glyoxylate, Schiff's hexane-ethyl acetate 1! IK′c (elute the target product) to purify the target hydro or cyazetidin-2-one 1802
I got 19. (Yield T @, 3 arrogance) Engineering R (OHOt black)
+ tyso (β-lactam) wound °1-c Hydroxyazetidin-2-one (compound of Example 3-B) 1491q was added to a 18 m solution of 2 ml of tetrahydroxide at -24°C under an argon gas flow, 2. 6-lutidine 1
■- and thionyl chloride 0.43- are added, -24C
Stir for 20 minutes at room temperature and for an additional 20 minutes at room temperature. After the reaction is complete, the mixture is diluted with benzene, passed through Celite to remove insoluble parts, and the resulting organic layer is concentrated under reduced pressure. The resulting residual ff was run 5 times in a 1K% argon gas stream.
5wt, triphenylphosphine 1012■ and z
Add 0.41 mg of l-lutidine and stir at 40°C for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with saturated brine, and dried over sulfur sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel chromatography (cyclohexane-ethyl acetate/1+2).
The target phosphoranylidene azetidine is purified by
2-one ll1IIs1■ was obtained as an amorphous product.

(Yield tar%) XR(OHOjg)! 1735 (1-ra/ /
A) cst-'$-D Ylide compound (compound of Example 3-○) 109G hydrochloric acid water @S- is added to 1810 methanol 1@○- solution under ice cooling. Then remove the ice bath and stir at room temperature for 1.5 hours to obtain a clear solution. After the reaction is completed, the reaction mixture is diluted with hydrogen carbonate (+7 um, 82.9 ml, water 305 ml!). ! and ethyl acetate 30! ! - Slowly add the mixture under water cooling. After the mixed solution is saturated with common salt, the organic layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The obtained organic layer and ethyl acetate layer are combined, washed with hydrogen carbonate solution and saturated saline solution, and dried with sulfuric acid solution. After the solvent was distilled off under reduced pressure, the residue obtained was purified by silica gel column chromatography (Schiff tetrahexane-acetone/1:2) to obtain the desired human tetraxy compound 1000M4 as an amorphous substance. (Yield 783%) IR (caoz5): 1740 (β-lactam)
Shin-1$-IC 1-(R)- and droxyethyl)-3-CM-p-nitrobenzyloxycarbonyl-3-7cetidinyl]thiomethyl-T-okino-1-azabicyclo(3,2,O)
Attach a dehydration tube to hept-2-ene-2-carboxylate benzene 400 to remove water, and then add K2
After concentrating to 00 d, phosphoranylidene-azetidin-2-one (compound of Example S-D) 1047■
of tetrahydrofuran 20-solution and benzene 200 m
l! was added and refluxed for 6 hours in an argon gas stream,
Concentrate to -. Next, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (benzene-
Separation and purification with acetone/2r1) yielded 6111 ml of the desired carbapenem compound. (Yield 8&l9G) IR(cuozs): 17・Q(β
-lactam) vice-1mMRJ (ODOjl) 114
1 (l H, +l I, T -l1ls e”1O
HO81) s 12-41 (13H, m),
all and! L47 (2H, M Bq, J ax
14Hz, ? 0OOJ,) #! LIS (
2H*s*NHC000H2) #7.4m and 7,M (4B, 2 (1,J! 9.5
H,,PbMO4), 8.17 (4H,d
, J == 8.5 g, , PhN02)
-F Carbapenem compound (compound of Example 3-m) IISm
g of tetrahydrofuran 15-solution, 10 thibaradium-carbon 1852■ and phosphate buffer (pH 7,0
) 1! I- is added and catalytic reduction of TO is carried out for minutes under hydrogen pressure of 55 p*S,i (10°C).

After the reaction was completed, Badge 2 Mu carbon was removed through Celite, and the solution was washed with cold ethyl ether three times.
Concentrate the aqueous layer to the lower half under reduced pressure.

This concentrate was applied to HP-20AG column chromatography K, thoroughly washed with water, and then eluted with S-acetone water to obtain the target compound in a concentration of 31wI.

(Yield 4S, S%) Engineering R (KBr): 1755 (β-lactam) t
s-'NMRδ(D20): 1.33(3H*e
Le J" @ HM 嘗0HsCHO) e 2
1-44 (52Hs m) Example-4 Obtained in carboxylic acid zero buying example (S-1') (lR, @8)
-@-(1-(R)-hydroxyethyl)-3-(1-
7zetidinyl)thiomethyl-1-oxo-1-azubicyclo(S,Z,O)hept-2-carboxylic acid (sLs) was dissolved in ImgK in phosphate buffer (pHT, O), and IM-K was added under water cooling. pH 1 with aqueous sodium chloride solution! Let it be I. Methylformindate hydrochloride 430■ and 1M-
Adjust the reaction solution to pH & fi by adding aqueous sodium hydroxide solution alternately.
Carry out the reaction while maintaining the After further stirring for 20 minutes under ice cooling, the pH was adjusted to 7.0 with 1N hydrochloric acid, and the solution was concentrated to about half under reduced pressure. This concentrate was subjected to HP-20AG column chromatography, thoroughly washed with water, and eluted with 3thiacetone water to obtain the target compound 4Ll'Ilf.
<Yield 4L @'74)XFL (KB
r): ITTO (β-tuctum) am-'11M
Rδ (D 0) + 1.41 (l H* (1, J
m @ Hg) Step S, O-4m (44H* m
) s T-80(S Tie a #-CH=N
H).

Applicant: Sankyo Co., Ltd. Agent Patent Attorney Izuru Kashi Procedural Amendment (spontaneous) December 13, 1980 Patent Application No. 199682, filed in 1982 2, Name of invention: carbapenem derivative 3, Relationship with the person making the amendment case Patent Applicant Address: 3-1 Nihonbashihonmachi, Chuo-ku, Tokyo 103 Name 6 (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4, Agent Residence 1-2-58 Hiromachi, Honbashiwa-ku, Tokyo 140 Sankyo Co., Ltd. 6. Subject of amendment Column 1 for detailed explanation of the invention in Specification 1,
“Example-4” from page 86 of the specification to may page
Insert the following sentence after Chapter 9.

[Example-5 (SR-,6B)-6- obtained in Example (1-F)
[1-(R)-Hydroxyethylco-3-[3-(S)
-pyrrolidinyl]thiomethyl-T-okine-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid 234.6 Q in phosphate buffer (pH 7,0)
Dissolved at 21 dK and diluted with aqueous sodium hydroxide solution under water cooling.
Let it be H8.5. Ethylacetimidate hydrochloride 121
11go and a 1N aqueous sodium hydroxide solution were added alternately under water cooling, and the reaction was carried out at the same temperature while maintaining the pH of the reaction solution at 8.5. After further stirring for 20 minutes under water cooling, the pH was adjusted to 7.9 with IN hydrochloric acid, and the solution was concentrated to about half under reduced pressure. This concentrate was applied to HP-20AG column chromatography, thoroughly washed with water, and then eluted with 5 qb acetone water to obtain 136 mg of the target compound. (Yield St
Ochi) Engineering R (KBr): 17703 (β-lactam) NMRJ (D20): 132 (3H, t
l, J-T Hz.

CHsCHO) −2,28(3Hm s −CHs”
) ・210-4.50 (14H, m). J or more

Claims (2)

[Claims] (1) General formula [wherein R1 is a hydrogen atom, an alkyl group, an alkoxy group, or an R'B- group (in the formula, x4 is a hydroxyl group, an alkoxy group,
Acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, trialkylsilyloxy group,
B represents a mercapto group, an alkylthio group, an amino group or an acylamino group, and B represents an alkylene fi optionally substituted with a trifluoromethyl group or a phenyl group. )
, X represents a thio group, sulfinyl group tII- represents a sulfonyl group, M represents a single bond or a linear or branched alkylene group, and R2 represents an oxygen atom, nitrogen atom, or sulfur atom within the ring. , a cyclic amine residue forming a three-membered ring or a three-membered ring as a whole, which may have a sulfinyl group, a sulfonyl group, or a carbonyl group, in which the nitrogen atom is a lower aliphatic residue which may have an amino group. Group acyl group, amino,
Mono-lower alkyl*-substituted amino or di-lower alkyl-substituted aminoalkylene group or formula -〇, N R'
may be substituted with a group (in the formula, R5 represents a hydrogen atom, an amino group or a lower alkyl group, and R6 represents a hydrogen atom or a lower alkyl group). , R4 and R' have the same meanings as defined above.) and - represents a hydrogen atom or a group retaining a carboxy group. ) to 1 1-calper 2-penem-
3-carboxylic acid and its pharmacologically acceptable salts. (2) General formula [wherein R-hydrogen atom, alkyl group, alkoxy group, or R-B group (wherein R12 is a hydroxyl group, an alkoxy group, an acyloxy group, an aral Φyloxycarbonyloxy group,
It represents an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group, or a substituted amino group, and B is an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group. shows. ), X represents a thio group, a sulfinyl group, or a sulfonyl group, M represents a single bond or a linear or branched alkylene group, and ?
is a cyclic amine residue forming a three-membered ring to an eight-membered ring as a whole, which may have an oxygen atom, a nitrogen atom, a sulfur atom, a sulfinyl group, and a sulfonyl group in the ring. Indicates a lower aliphatic acyl group, protected amino, protected mono-lower alkyl-substituted amino or di-lower alkyl-substituted amino alkylene group, which may have a protecting group or a protected amine group. , R represents a protecting group for a carboxy group, and R represents an alkyl group or an aryl group. ] to produce a compound having the general formula (wherein, R,!, M, R9> and R have the same meanings as those described above), and then, as desired, The resulting good compound is subjected to a reaction to remove the protective group R1G of the carboxyl group and the corresponding protective groups contained in R and R to form a hydroxyl group, a carbo or cy group, an amino group, a mono-lower alkyl substituted amino group, a cyclic amino group, etc. or a mercapto group, and R6 represents a hydrogen atom or a lower alkyl group contained in the substituent at the 2-position of the compound i'', and R6 represents a hydrogen atom or a lower alkyl group. [In the formula, X and M have the same meanings as described above.]
1 is a hydrogen atom, an alkyl group, an alkoxy group, or R'B
- group (wherein R4 represents a hydroxyl group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, a mercapto group, an alkylthio group, an amino group or an acylamino group, and B represents a trifluoromethyl or an alkylene group which may be substituted with a phenyl group), and R2
is a cyclic amine residue forming a three-membered ring or a membered ring as a whole, which may have an oxygen atom, nitrogen atom, sulfur atom, sulfinyl group, sulfonyl group, or carbonyl group in the ring, and the nitrogen atom in it is Lower aliphatic acyl group, amino, mono-lower alkyl-substituted amino or di-lower alkyl-substituted amino which may have an amino group 5 represents a hydrogen atom, an amino group or a lower alkyl group, R
ah represents a hydrogen atom or a lower alkyl group. ) represents the above-mentioned cyclic amino or lower alkyl group which may be substituted with ) indicates the same meaning as the expression. ) and RI represents a hydrogen atom or a protecting group for a carboxy group. ] A method for producing 1-carba-2-penem-3-carboxylic acid and a pharmacologically acceptable salt thereof.