JP2522671B2 - Crystalline carbapenem compound, method for producing the same and injectable antibacterial agent containing the compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (4R, 5S, 6S, 8R, 2'S, 4'S) -3 of crystalline form represented by
-[4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl)
-1-Azabicyclo [3.2.0] hept-2-ene-7-
The present invention relates to a trihydrate of on-2-carboxylic acid (hereinafter abbreviated as compound A), a method for producing the same, and an injectable composition containing compound A and a nontoxic carbonate.

Compound A is a compound belonging to the carbapenems, has a broad antibacterial spectrum and a strong antibacterial activity, and is a useful compound as a drug. The amorphous state of this product is described in JP-A-60-104088 (EP126587A), and its production method and use as an antibacterial agent are also described.

The present inventors produced Compound A in crystalline form, that is, the trihydrate of Compound A. Compound A in crystalline form is more stable than that in amorphous form (solid obtained by freeze-drying). The crystalline compound A is extremely stable and can be obtained as high-purity crystals, so that not only is it excellent in storage stability, but it can be used for the purification of compound A.

The crystalline compound of the present invention can be administered as an injectable antibacterial agent. For administration by injection, the crystalline compound may be mixed with a nontoxic carbonate and dissolved in a solution such as distilled water or physiological saline before use. That is, since the compound A is quickly dissolved by adding the solution to the mixture of the crystalline compound A and the non-toxic carbonate, the solution for injection can be easily obtained. The crystalline compound of the present invention is stable even when blended with a non-toxic carbonate, and is suitable for storage.

When the compound A in the crystalline form of the present invention is produced, the aqueous solution of the crude mixture containing the compound A without isolation is optionally concentrated and then cooled, or an organic solvent compatible with water is used. It can be prepared by dilution or by a combination of both cooling and dilution.

Further, it can be produced by dissolving the isolated amorphous compound A in water or a water-containing organic solvent and cooling it, or diluting it with an organic solvent compatible with water, or by combining both. it can.

In this way, the crystalline compound A can be obtained as a trihydrate, which normally contains about 12% by weight of water.

Examples of the organic solvent compatible with water include ethanol,
Isopropyl alcohol, acetone, tetrahydrofuran, dioxane, acetonitrile and a mixed solvent thereof can be used.

The water-containing organic solvent refers to an organic solvent that is compatible with water and contains water at an arbitrary ratio.

The organic solvent, methanol, ethanol, lower alcohols such as propyl alcohol, acetone, ketones such as methyl ethyl ketone, methyl acetate, carboxylic acid esters such as ethyl acetate, dichloromethane, halogenated hydrocarbons such as dichloroethane, heptane, Hydrocarbons such as hexane, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and dioxane,
Usual organic solvents such as amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile and propionitrile, and mixed solvent systems thereof can be used. Preferably, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane,
Acetonitrile and mixed solvent systems thereof are used.

Crystalline compound A is produced by concentrating an aqueous solution of a crude mixture containing compound A, if necessary, and then cooling it, or by adding an organic solvent compatible with water,
Alternatively, the compound A is brought into a supersaturated state by combining the two, or the compound A in the amorphous state is dissolved in water or a water-containing organic solvent and cooled, or the compound A is added by adding an organic solvent. This is done by precipitating crystals by leading to supersaturation and then isolating and drying the product.

When the non-crystalline compound A is used, it is preferable to prepare an aqueous solution, cool it, dilute it with an organic solvent, or combine them.

In this case, the concentration of the compound A in the aqueous solution of the compound A or the solution of the water-containing organic solvent is preferably a concentration necessary for crystallization, and preferably 0.5 to 20% with respect to water.
It is desirable that the concentration range is

A supersaturated solution is a saturated solution of Compound A that is free of any crystallizing species or is nearly saturated, eg, about 20-50.
The solution at a temperature of ° C is added until supersaturation occurs, for example about 0
It can be obtained by cooling to 20 ° C., adding an organic solvent, or combining cooling and addition of an organic solvent. The cooling operation is preferably carried out at a slow speed with stirring.

Crystal formation can occur spontaneously, for example at the surface of the reactor or stirrer, but can be initiated by seeding, ie by introducing seed crystals, to further promote crystallization.

The crystalline form of Compound A formed may be isolated and collected by any available method for separating solid / liquid systems, such as by filtration, pressurization, vacuum suction, centrifugation or decantation. You can

Drying at room temperature or slightly elevated temperature, for example about 15
To about 50 ℃, preferably about 20 to 30 ℃ (room temperature)
And continue until the weight is almost constant. It is also possible to carry out the operation under reduced pressure in order to accelerate the drying.

As a method of concentration, a normal concentration method such as a method of evaporating water by applying heat under normal pressure or reduced pressure using an evaporator and a method of concentrating water only by power using a membrane such as a reverse osmosis membrane are available. Can be used. Of the usual concentration methods, the concentration using a reverse osmosis membrane is preferable in that it can be concentrated at a low temperature without decomposing the compound A. Examples of the type of reverse osmosis membrane that can be used include polyacrylonitrile-based membranes (Sumitomo Chemical Co., Ltd., Solrox (registered trademark) SC-0500, SC-
1000), polyvinyl alcohol film (Nitto Denko, NTR-7
250, NTR-7197), polyamide-based membrane (Organo Corporation,
Generally used membranes such as JO-0162) and cellulose acetate membranes can be selected.

The crystalline compound of the present invention is improved in that it is more stable and has a longer shelf life than the amorphous compound.

That is, the crystalline compound A (trihydrate) of the present invention and the non-crystalline compound A (solid obtained by freeze-drying) were sealed at 50 ° C. and stored, and the stability (residual rate) As shown in the following table, no degradation deterioration was observed in the crystalline compound of the present invention for 6 months, whereas in the amorphous compound, the residual rate after 7 days was 51.8%.
It was.

Specific examples of the non-toxic carbonate used in the composition containing the compound A include alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and the like. Can be given. The ratio of compound A and non-toxic carbonate is
The amount ratio of the compound A to the non-toxic carbonate is usually about 1: 0.5 to 2.5 equivalents, more preferably about 1: 1 to 2 equivalents. Therefore, a monoacid base such as sodium hydrogencarbonate is preferably used in an amount of about 1 to 2 mol, and a diacid base such as sodium carbonate is used in an amount of about 0.5 to 1 mol, per 1 mol of the compound.

The composition of the compound A and the non-toxic carbonate is produced by mixing the above-mentioned quantitative ratio by a means known per se.
At this time, known pharmaceutical additives such as local anesthetics such as lidocaine hydrochloride and mebivacaine hydrochloride may be further added.

The composition thus produced is aseptically filled into vials. If necessary, it is also possible to vacuum seal after filling. The degree of vacuum at the time of vacuum sealing is usually about 0 to 4 × 10 ⁴ P
is a.

The amorphous compound A, which is a starting material, can be produced as follows.

(Wherein R ₁ is an amino-protecting group and R ₂ is a carboxyl-protecting group) (hereinafter referred to as compound B), the amino-protecting group R ₁ and carboxyl Group protecting group
R ₂ is removed stepwise or simultaneously. In this case, an embodiment in which two protecting groups are simultaneously removed in one step is preferable.

The amino group-protecting group R ₁ is, for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, or the like, which is optionally substituted with a nitro group, such as allyloxycarbonyl or 2-chloro. allyloxycarbonyl such as chlorine, a halogen is substituted by connexion optionally atoms (C ₃ ~C ₇₎ a lower alkenyloxycarbonyl group such as bromine, for example trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, etc., tri (C ₁ To C ₄ ) lower alkylsilyl group and the like, and a carboxyl group protecting group R
₂ is a benzyl group optionally substituted with a nitro group such as benzyl, p-nitrobenzyl, o-nitrobenzyl, etc., such as allyl, 2-chloroallyl, etc., and a halogen atom such as chlorine, bromine, etc. A (C ₃ -C ₇ ) lower alkenyl group substituted by, eg, an ethyl group substituted at the 2-position by a tri (C ₁ -C ₄ ) lower alkylsilyl such as 2-trimethylsilylethyl, eg trimethylsilyl, Examples thereof include tri (C ₁ -C ₄ ) lower alkylsilyl groups such as triethylsilyl and t-butyldimethylsilyl.

The protecting group can be removed by a generally known method, for example, the following removing method.

For example, when R ₁ and R ₂ are tri (C ₁ -C ₄ ) lower alkylsilyl groups, or R ₂ is an ethyl group substituted at the 2-position by tri (C ₁ -C ₄ ) lower alkylsilyl, For example, a salt of hydrofluoric acid that produces a fluorine anion in the presence of a macrocyclic polyether (crown ether), that is, a treatment with an alkali metal fluoride such as sodium fluoride or potassium fluoride, an organic quaternary base. Fluoride,
For example, tetraethylammonium fluoride, tetra-
Tetra- (C ₁ ~ such as n-butylammonium fluoride
C ₄ ) treatment with lower alkyl ammonium fluoride, or inorganic acids such as phosphoric acid, acetic acid, citric acid,
Alternatively, it can be removed by treatment with an acidic buffer solution containing an organic acid.

For example, R ₁ is a benzyloxycarbonyl group optionally substituted with a nitro group, R ₂ is a benzyl group optionally substituted with a nitro group is reduced, for example, in the presence of a suitable hydrogenation catalyst such as palladium or platinum. It can be removed by carrying out a catalytic hydrogenation reaction with hydrogen. Further, R ₁ is o-nitrobenzyloxycarbonyl, R ₂ is o
When it is -nitrobenzyl, it can be removed not only by a catalytic hydrogenation reaction but also by a photochemical reaction.

For example, R ₁ is a lower alkenyloxycarbonyl group optionally substituted with a halogen atom (C ₃ -C ₇ ), R ₂ is optionally substituted with a halogen atom (C ₃ -C ₇ ).
The lower alkenyl group is in the presence of a lower alkenyl acceptor,
It can be removed by reaction with a catalytic amount of an organic soluble palladium complex having a coordinating phosphine ligand such as tetrakistriphenylphosphine palladium.

In a preferred embodiment of the present invention, the combination R ₁ is a benzyl group R ₂ in a benzyloxycarbonyl group which is substituted by connexion phenyl optionally substituted by nitro group is substituted by connexion optionally a nitro group, especially R ₁ Is a p-nitrobenzyloxycarbonyl group and R ₂ is a p-nitrobenzyl group, or R ₁ is a lower alkenyloxycarbonyl group and R ₂ is a lower alkenyl group, and especially R ₁ is an allyloxycarbonyl group. By selecting a combination in which R ₂ is an allyl group, the two protecting groups can be simultaneously removed in one step.

a) a combination of a benzyloxycarbonyl group optionally substituted with a nitro group and a benzyl group optionally substituted with a nitro group (especially p-nitrobenzyloxycarbonyl group and p-nitrobenzyl group) Is characterized in that the protecting group is removed by a reduction reaction, for example, a catalytic hydrogenation reaction with hydrogen in the presence of a suitable hydrogenation catalyst.

Examples of the hydrogenation catalyst used in this reaction include palladium-carbon, palladium hydroxide-carbon, and palladium-carbon.
Palladium-based catalysts such as calcium carbonate, palladium-barium sulfate, and palladium-aluminum, for example, platinum-based catalysts such as platinum oxide and platinum-carbon can be mentioned.
Preference is given to palladium-carbon, palladium hydroxide-carbon and platinum oxide.

The reaction is carried out in an inert solvent, and examples of the solvent to be used include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid, or an organic solvent and water thereof, Alternatively, a mixed solvent with a buffer solution such as phosphoric acid or morpholinopropanesulfonic acid can be used. Preferred is a mixed solvent of tetrahydrofuran and water or a morpholinopropane sulfonate buffer solution.

The reaction temperature is 0 to 100 ° C, preferably 0 to 50 ° C.

The hydrogen pressure can be atmospheric pressure or under pressure,
Preferably, the range of atmospheric pressure to 100 kg / cm ² can be mentioned.

The reaction solution containing the compound A obtained by this method, after removing the catalyst, the organic solvent is distilled off, or if necessary, desalting with an adsorption resin such as HP-20P (manufactured by Mitsubishi Kasei) gel. The compound A in a non-crystalline state can be obtained by subjecting to a freeze-drying process.

When this reaction is carried out in a water-containing organic solvent, the catalyst is removed from the reaction solution containing the compound A, the organic solvent is distilled off, the resulting aqueous solution is concentrated if necessary, and a direct crystallization operation is carried out. By carrying out, the crystalline compound A can be obtained without isolating and purifying the amorphous compound A by, for example, column chromatography or freeze-drying.

In order to efficiently obtain the crystalline form of Compound A, the amorphous form has a problem in storage stability as described above. Therefore, the amorphous form of Compound A is directly extracted from the reaction solution without isolation and purification. Method is preferred.

b) In the combination of a (C ₃ -C ₇ ) lower alkenyloxycarbonyl group and a (C ₃ -C ₇ ) lower alkenyl group (in particular, an allyloxycarbonyl group and an allyl group), a catalytic amount is present in the presence of a lower alkenyl group acceptor. The protecting group is removed by the reaction of with tetrakistriphenylphosphine palladium.

Suitable acceptors for lower alkenyl groups (especially allyl groups) include, for example, sterically hindered amines such as t-butylamine, for example tri (C ₁ -C ₄ ) lower alkylamines such as triethylamine, diisopropylethylamine, for example pyrrolidine, piperidine, Cyclic amines such as morpholine or thiomorpholine, aromatic amines such as aniline, N-methylaniline, such as acetylacetone,
Aliphatic or cycloaliphatic β-dicarbonyl compounds such as ethyl acetoacetate, 1,3-dichlorohexanedione or dimedone, and (C ₂ -C ₉ ) lower such as acetic acid, propionic acid or 2-ethylhexanoic acid Mention may be made of alkanecarboxylic acids and their alkali metal salts (for example sodium or potassium salts etc.) or mixtures thereof. Preferred acceptors include alicyclic β-dicarbonyl compounds such as 1,3-cyclohexanedione and dimedone, and aromatic amines such as aniline and N-methylaniline.

The reaction is carried out in the presence of 1.5 to 10 molar equivalents of the lower alkenyl group acceptor relative to compound B, using 2 to 20 mol% of tetrakistriphenylphosphine palladium catalyst, in an inert solvent.

Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, acetic acid esters such as ethyl acetate and isopropyl acetate, such as methylene chloride, chloroform and 1, Examples thereof include halogenated hydrocarbons such as 2-dichloroethane, such as acetonitrile or a mixed solvent thereof. Preferable examples include acetic acid esters, tetrahydrofuran and methylene chloride or a mixed solvent thereof.

The reaction temperature is room temperature, or a slightly high or low temperature, for example, in the range of about 0 to 70 ° C., preferably
A range of 10 to 50 ° C can be mentioned. Further, if necessary, the reaction can be carried out in an atmosphere of an inert gas such as nitrogen or argon.

In this method, after the completion of the reaction, an appropriate amount of water is added to the reaction solution to separate the organic solvent, and impurities soluble in the organic solvent are removed by repeating washing with the organic solvent to remove the amorphous state. Compound A can be subjected to a crystallization process without isolation.

It can be said that this method is more advantageous than the deprotection method by the catalytic hydrogenation reaction because the amount of solvent used and the amount of transition metal in the catalyst are small.

The starting compound, Compound B, can be prepared by a method known per se, for example, JP-A-60-104088 (EP126587A) and EP188816A.
It can be manufactured according to the method described in the specification. Although not necessarily limited to those shown below,
An example of a method for producing the 1β-methylcarbapenem compound B will be shown.

[In the formula, X represents a protected hydroxyl group, and COY represents a carboxyl group.
Active ester of sil group, or active acid anhydride, thio-
Thiolcarbo protected with a protecting group for the carboxyl group
A xyl group, a substituted aryloxycarbonyl group, or
Represents a teloaryloxycarbonyl group, B is an alkali
Represents a metal atom, RA is an alkylating agent or an acyl
Represents an agent, L represents water an active ester group of a hydroxyl group,
R₁And R₂Has the same meaning as described above. ] Inactivate the β-lactam compound represented by the general formula (I)
Compound (IV) by treatment with a base in a neutral solvent [(i)
However, without removing this compound, the activity in the reaction solution
Residue of ester or activated acid anhydride, substituted aryl group
Xycarbonyl group or heteroaryloxycarbo
Residue of nyl group or protected thiol carboxyl
Group thiol residue (Y ) For iodomethane, iodopro
Bread, allyl bromide, benzyl bromide, p-toluenesulfo
Alkylating agent such as methyl ester of acid, p-toluene
Reedyl chloride, methanesulfonyl chloride, and other reeds
Of the hydroxyl group after being captured by a oxidant (step (ii))
Represented by the formula (V) by treatment with a reactive esterifying agent.
Can be induced to 1β-methylcarbapenem compounds
[Step (iii)]. If necessary, this compound (V)
You can take it out or do not take it out.
Kumercaptan compound (II)(Where R₁Has the same meaning as described above. ) And optionally a base to treat the formula
To 1β-methylcarbapenem compound represented by (IV)
Derivatization [(iv) step], and then removing the protective group for the hydroxyl group
Compound (B) can be obtained by subjecting to [(v) step]
You.

The compound (I), which is a starting material compound, will be described below. The protective group for the hydroxyl group in X is not particularly limited as long as it is a commonly used protective group, and examples thereof include t-butoxycarbonyl and 2-ethyloxycarbonyl iodide. ,
Chlorine such as 2,2,2-trichloroethyloxycarbonyl,
(C ₁ -C ₄ ) lower alkoxycarbonyl group optionally substituted by a halogen atom such as bromine or iodine, for example, chlorine atom such as allyloxycarbonyl or 2-chloroallyloxycarbonyl, or halogen atom such as bromine. Optionally substituted (C ₃ -C ₇ ) lower alkenyloxycarbonyl groups, such as nitro groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like. , A benzyloxycarbonyl group optionally substituted with a methoxy group or the like, for example, trimethylsilyl,
Examples thereof include tri (C ₁ -C ₄ ) lower alkylsilyl groups such as triethylsilyl and t-butyldimethylsilyl, substituted methyl such as methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, etc., and tetrahydropyranyl group. it can.

When COY is an active ester of a carboxyl group or an active acid anhydride, examples of the Y group include chlorine, bromine,
Halogen atom such as iodine, for example, (C ₁ -C ₅ ) lower alkoxycarbonyloxy group such as ethoxycarbonyloxy, isopropyloxycarbonyloxy, sec-butoxycarbonyloxy, etc. (C ₁ -C ₄ ) lower such as methanesulfonyloxy Alkanesulfonyloxy group, for example, arylsulfonyloxy group such as p-toluenesulfonyloxy, for example, di (C ₁ -C ₄ ) lower alkylphosphoryloxy group, for example, dimethylphosphoryloxy, diethylphosphoryloxy, etc., for example, di (phenyl) phosphoryloxy, etc. Diarylphosphoryloxy groups, for example, cyclic imidooxy groups such as N-succinimidooxy and N-phthalimidoxy, heteroaryl groups such as imidazole and triazole, for example, heteth such as 3- (2-thioxo) -thiazolidinyl. And a cycloalkyl group. Further, as the protective group for the thiol carboxyl group used when COY is a protected thiol carboxyl group, those generally used can be used, but preferably, for example, methyl, ethyl, isopropyl, t-butyl, 2-ethyl iodide, 2,2,2-chlorine-trichloroethyl, etc., bromine, optionally substituted with halogen atoms such as iodine (C ₁ ~C ₄₎ a lower alkyl group, such as allyl, 2-
Chlorine such as methylallyl or 2-chloroallyl, halogen atom such as bromine, or (C ₃ -C ₇ ) lower alkenyl group optionally substituted with lower alkyl group such as methyl or ethyl, such as phenyl, p-chlorophenyl, 2 Phenyl group optionally substituted with chlorine atom such as 1,4,6-trichlorophenyl, p-nitrophenyl, o-nitrophenyl and p-methoxyphenyl, halogen atom such as bromine, nitro group and methoxy group, for example, 2- Pyridyl, 3-pyridyl, 4
-Pyridyl, 2-pyrimidyl, 2- (4,6-dimethyl)
Examples thereof include a heteroaryl group such as pyrimidyl.

Suitable bases that can be used in the step (i) include alkali metal hydrides such as sodium hydride and potassium hydride such as sodium methylsulfinylmethide such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and the like. Mention may be made of metal salts of amines such as sodium amide. In addition, suitable examples of the inert solvent used at the same time include ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like and mixtures thereof. A solvent may be mentioned.

Suitable hydroxyl group active esterifying agents that can be used in the step (iii) include, for example, diphenylphosphoryl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, and the like, and a base that can be used in the step (iv). Examples of the compound include, in addition to those used in the step (i), for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU), 1, 5-diazabicyclo (4.3.0)
-Nona-5-ene (DBN), 1,4-diazabicyclo (2.2.
2) Organic bases such as octane (DABCO) can be mentioned. In this case, another inert solvent may be added as necessary to accelerate the reaction, and as such solvent, acetonitrile, dimethylformamide, dimethylsulfoxide and the like can be preferably mentioned.

The amount of each reagent used in steps (i) to (iv), including the mercaptan compound (II), must be such that the reaction proceeds sufficiently, and a suitable amount is the amount used in step (i). It is desirable to use 2 to 4 equivalents for the base used and 1 to 1.5 equivalents for the other reagents. The reaction temperature may be in the range of -78 ° C to 60 ° C, but is preferably in the range of -40 ° C to 10 ° C.

The method of removing the hydroxyl-protecting group in the step (v) varies depending on the kind of the protecting group, but is a general method known per se, such as the above-mentioned amino-protecting group (R ₁ ) and carboxyl-protecting group ( It can be carried out by hydrolysis, catalytic reduction method, treatment with acid or base, or reduction method, including the same method as the method for removing R ₂ ). It is also possible to remove the above-mentioned amino-group protecting group (R ₁ ) and carboxyl-group protecting group (R ₂ ) at the same time when removing the hydroxyl-group protecting group.

The compound A in the crystalline form in the present invention, the composition of the compound A and the non-toxic carbonate, and the method for producing them will be described in detail with reference to the following examples and reference examples, but the scope of the present invention is not limited thereto. Not something.

 The meanings of the abbreviations are as follows.

Ph; Phenyl group Me; Methyl group AOC: Allyloxycarbonyl group t-Bu; tert-Butyl group TBDMS; t-Butyldimethylsilyl group Example 1 Freeze-vacuum dried (4R, 5S, 6S, 8R, 2'S, 4 '
S) -3- [4- (2-Dimethyl-aminocarbonyl)
Pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-
En-7-one-2-carboxylic acid (5.0 g) in water (50 ml)
And melted at a temperature of 30 ° C. When this solution was cooled in a water bath, precipitation of a small amount of crystals was observed. Acetone (250 ml) was added, the mixture was stirred for 1 hour, crystals were collected, washed with acetone (90 ml), and dried at room temperature for 2 hours under reduced pressure to give 4.7 g.
(4R, 5S, 6S, 8R, 2'S, 4'S) -3- [4-
(2-dimethylaminocarbonyl) pyrrolidinylthio]
-4-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
A carboxylic acid trihydrate was obtained.

Elemental analysis (as C ₁₇ H ₂₅ N ₃ O ₅ S.3H ₂ O) Calculated value C 46.67; H 7.14; N 9.60; S 7.33 Measured value C 46.32; H 7.41; N 9.71; S 7.24 The crystalline compound A thus produced exhibited a powder X-ray pattern as shown in the following table.

It should be noted that I / I ₁ represents the relative intensity when the maximum diffraction intensity is 100.

Example 2 (4R, 5S, 6S, 8R, 2 ′S, 4 ′ of the crystalline form obtained in Example 1
S) -3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one -2-carboxylic acid 568mg and sodium carbonate 1
Fill 03 mg and stopper tightly to prepare a soluble injection before use.

Example 3 (4R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-
3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl) pyrrolidinylthio]
-4-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (content 78%, 3.0 g) was dissolved in tetrahydrofuran (177 g), water (240 g) and 10% palladium carbon (6.0 g) were added, and hydrogenation was carried out at room temperature for 5 hours under a hydrogen pressure of 5 Kg / cm ² . After the catalyst was washed with water and washed with water, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, and the organic solvent was distilled off under reduced pressure again to obtain an aqueous solution (472 g) of the crude mixture. 50 Kg / c of this aqueous solution (230 g)
The solution was concentrated with a flat membrane type reverse osmosis concentrator under m ² G pressure to obtain a concentrate (7.7 g). The concentrated solution was cooled to 5 ° C, tetrahydrofuran (7.7 ml) was added, and the mixture was stirred for 1 hour. Further, tetrahydrofuran (30.8 ml) was added and stirred for 1 hour, crystals were collected, washed with tetrahydrofuran (15 ml), and room temperature. After drying under reduced pressure for 2 hours, 390 mg of crystalline (4R, 5S, 6
S, 8R, 2'S, 4'S) -3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6-
(1-Hydroxyethyl) -1-azabicyclo [3.2.
0] Hept-2-en-7-one-2-carboxylic acid.3
A hydrate was obtained.

Example 4 By the same operation as in Example 1, using tetrahydrofuran instead of acetone and freeze-drying vacuum-dried amorphous compound A 200 mg, crystalline compound A trihydrate 152 mg
I got

Example 5 In the same manner as in Example 1, isopropyl alcohol was used in place of acetone, and 200 mg of the non-crystalline compound A that had been freeze-vacuum dried to the crystalline compound A trihydrate 14
0 mg was obtained.

Example 6 (4R, 5S, 6S, 8R, 2'S, 4'S) -allyl-3- [4-
(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1
-Hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (content 67%, 1.033 g) was dissolved in 20.7 ml of ethyl acetate, 0.85 g of dimedone was added, and argon was added. Blow gas for 5 minutes and then 30
Warmed to ° C. Tetrakistriphenylphosphine palladium (155 mg) was dissolved in methylene chloride (5 ml) and added dropwise at 30 ° C., and the reaction mixture was stirred under a nitrogen stream at 30 ° C. for 3 hours. Water 10.3 ml was added to the reaction solution with stirring, the aqueous layer was separated, washed twice with 10 ml of ethyl acetate, and poured into 20 ml of ice-cooled tetrahydrofuran little by little. After stirring for 30 minutes under ice cooling (4R, 5S, 6S, 8R, 2'S, 4'S) -3- [4- (2-
Dimethylaminocarbonyl) pyrrolidinylthio] -4-
About 1 mg of crystals of methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid trihydrate was added, and 30 ml of tetrahydrofuran was added little by little. In addition, stirring was continued for 2 hours under ice cooling. The precipitated crystals were collected and tetrahydrofuran (10
(4R, 5S, 6S, 8R, 2 ′S, 4 ′S) -3- [4- (2- (2-
Dimethylaminocarbonyl) pyrrolidinylthio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid trihydrate was obtained.

Example 7 149 mg of aniline was dissolved in 4 ml of isopropyl acetate, refluxed for 20 minutes, and then cooled to 30 ° C. Then (4R, 5S, 6S, 8R,
2'S, 4'S) -Allyl-3- [4- (1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-hydroxyethyl) -1- Azabicyclo [3.2.0] hept-2-ene-
7-one-2-carboxylate (102 mg) and tetrakistriphenylphosphine palladium 46 mg 30
C., and the mixture was stirred under a stream of nitrogen at 30.degree. C. for 3 hours.
Thereafter, the reaction solution was treated in the same manner as in Example 6 to give crystalline (4R, 5S, 6S, 8R, 2'S, 4'S) -3- [4- (2-dimethylaminocarbonyl) pyrrolidinini. Luthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid trihydrate was obtained.

Example 8 N-methylaniline 129 mg, isopropyl acetate 4 ml,
(4R, 5S, 6S, 8R, 2'S, 4'S) -allyl-3- [4- (1
-Allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] -hept-2-en-7-one-carboxy The crystalline form of (4R, 5S, 6S, 8) was prepared from 102 mg of the rate and 46 mg of tetrakistriphenylphosphine palladium by the same method as in Example 7.
R, 2'S, 4'S) -3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-
Hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid trihydrate was obtained.

Reference example 1 (3S, 4S) -3-[(1R) -1-hydroxyethyl]
-4-[(1R) -1-phenylthiocarbonylethyl]
-1-carboxymethyl-2-azetidinone (content 92.8
%, 13.15 g) was dissolved in 14.4 ml of allyl alcohol, chlorotrimethylsilane (10.8 ml) was added at room temperature, and after stirring for about 1.5 hours, 50 ml of toluene was added and the reaction mixture was concentrated as it was under reduced pressure. The obtained residue was purified by silica gel column chromatography, (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-allyloxycarbonylmethyl-2-azetidinone (13.4 g yield 98.2%)
I got

NMR δ (CDCl ₃ ): 1.33 (3H, d, J = 6.2Hz), 1.34 (3H, d,
J = 6.9Hz), 3.16 (2H, m), 3.88 (1H, ABd, J = 18.1H
z), 4.17 (1H, dd, J = 2.3Hz and 4.3Hz), 4.23 (1H, quint
et, J = 6.2Hz), 4.34 (1H, ABd, J = 18.1Hz), 4.62 (2H,
d, J = 5.9Hz), 5.25 (1H, d, J = 10.2Hz), 5.32 (1H, d, J
= 17.2 Hz), 5.88 (1H, m), 7.42 (5H).

Reference example 2 (3S, 4S) -3-[(1R) -1-hydroxyethyl]
-4-[(1R) -1-phenylthiocarbonylethyl]
Dissolve -1-allyloxycarbonylmethyl-2-azetidinone (content 90.6%, 14.7 g) in dry toluene 60 ml,
Chlorotrimethylsilane (7.8 g) and then triethylamine (7.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was diluted with 300 ml of toluene, washed with 300 ml of 2% sodium bicarbonate solution, further washed twice with 300 ml of brine and dried over magnesium sulfate, and then (3S, 4S) -3-[(1R) -1-trimethylsilyloxyethyl ] -4-[(1R) -1-Phenylthiocarbonylethyl] -1-allyloxycarbonylmethyl-
2-azetidinone (content 90%, 16.35 g) was obtained.

NMR δ (CDCl ₃ ): 0.15 (9H, s), 1.29 (6H, d, J = 6.9H
z), 3.08 (1H, dd, J = 2.3 and 7.6Hz), 3.15 (1H, dq, J =
3.3 and 6.9 Hz), 3.85 (1H, ABd, J = 17.2 Hz), 4.1 to 4.2
(2H, m), 4.33 (1H, ABd, J = 17.2Hz), 4.60 (2H, d, J =
5.6Hz), 5.2-5.3 (2H, m), 5.8-5.92 (1H, m), 7.41
(5H, m).

Reference example 3 (3S, 4S) -3-[(1R) -1-Trimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-allyloxycarbonylmethyl-2
-Azetidinone (content 90%, 1.0 g) was dissolved in 5.5 ml of a dry mixed solvent of toluene-tetrahydrofuran (4: 1), sodium hydride (60% oily) (200 mg, 5 mM), benzyl bromide (410 mg, 2.4 mM) ), Trimethylsilanol (2.7m
g) and a suspension of toluene-tetrahydrofuran (4: 1) in a dry mixed solvent (8.5 ml) at -15 to -10 ° C, and the mixture was stirred for 2 hours and then diphenylchlorophosphate (59
A solution of 0 mg, 2.2 mM) in toluene (1 ml) was added dropwise. After stirring for a further 4 hours, [2S, 4S] -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (670 mg, 2.6 mM) in tetrahydrofuran (1 ml)
Inject solution, then add 1,8-diazabicyclo [5.4.0] undec-7-ene (426 mg, 2.8 mM), -15 to -10
Stirred at 0 ° C. overnight. To the reaction mixture, 10 ml of 0.1 M potassium dihydrogen phosphate aqueous solution was added for liquid separation, and the aqueous layer was mixed with 5 ml of toluene.
Extracted twice with, and the organic layers were combined, washed with 0.1 M pH 7.0 phosphate buffer, and then with saturated saline, and then magnesium sulfate-
After drying over potassium carbonate (1: 1), the solvent was evaporated under reduced pressure. The residue is purified by silica gel chromatography,
(4R, 5S, 6S, 8R, 2'S, 4'S) -allyl-3- [4- (1
-Allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (0.90 g) was obtained.

Reference example 4 (4R, 5S, 6S, 8R, 2'S, 4'S) -allyl-3- [4-
(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1
-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (600 mg, 1.04 mM) was dissolved in 6 ml of tetrahydrofuran, and 3 ml of citrate buffer solution of pH 3 was added, Stir vigorously at room temperature for 1.5 hours, dilute with 30 ml of ethyl acetate, wash with brine, dry over magnesium sulfate-potassium carbonate (1: 1), and evaporate the solvent under reduced pressure (4R, 5S, 6S, 8R). , 2'S, 4'S)-
Allyl-3- [4- (1-allyloxycarbonyl-2
-Dimethylaminocarbonylpyrrolidinyl) thio] -4
-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate was obtained.

NMR δ (CDCl ₃ ): 1.26 (3H), 1.36 (3H), 1.94 (1H,
m), 2.67 (1H, m), 2.97,2.99,3.063.11 (total 6H, ea
ch singlet), 3.2 to 3.7 (4H, m), 4.25 (2H, m), 4.47
~ 4.87 (5H, m), 5.15 ~ 5.5 (4H, m), 5.94 (2H, m).

Reference example 5 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2 -Azetidinone 1.0 g was dissolved in dry methylene chloride 10 ml, anisole 497 mg and boron trifluoride diethyl ether complex 1.04 g were added, and the mixture was stirred at 38 to 42 ° C for 3 hours. The organic layer was washed with water and NaHCO ₃ water, and the organic layer and the aqueous layer were separated. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. 1 ml of ethyl acetate was added to the residue, the temperature was kept at 50 ° C., 5 ml of toluene was added dropwise, and the mixture was stirred for 30 minutes and returned to room temperature. The precipitated crystals were taken and dried to obtain (3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1- (1 -Carboxymethyl) -2-azetidinone was obtained.

mp: 81-83 ° C; NMR δ (CDCl ₃ ): 1.29 (3H, d), 1.31 (3H, d), 3.16
(2H, m), 4.08 (2H, ABq, J = 18.1Hz), 4.22 (1H, dd, J
= 2.3Hz and 4.3Hz), 4.27 (1H, m), 7.35 (1H, ABq, J = 8.
6Hz).

Reference example 6 (3S, 4S) -3-[(1R) -1-hydroxyethyl]
-4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1- (1-carboxymethyl) -2-azetidinone (371 mg) was dissolved in aryl alcohol (0.4 ml), trimethylchlorosilane (0.3 ml) was added, and the mixture was stirred at room temperature for 1 hour. It was stirred. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (3S, 4S) -3-[(1R)
-1-Hydroxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1- (1-aryloxycarbonylmethyl) -2-azetidinone was obtained.

NMR δ (CDCl ₃ ): 1.32 (3H, d, J = 6.6Hz), 1.33 (3H, d, J
J = 6.9Hz), 2.36 (1H, brs), 3.15 (2H, m), 4.10 (2
H, ABq, J = 18.1Hz), 4.17 (1H, dd, J = 2.3Hz and 4.3Hz),
4.22 (1H, m), 4.62 (2H, d, J = 5.9Hz), 5.28 (2H,
m), 5.87 (1H, m), 7.35 (4H, ABq, J = 8.6 Hz).

Reference example 7 (3S, 4S) -3-[(1R) -1-hydroxyethyl]
-4-[(1R) -p-chlorophenylthiocarbonylethyl] -1- (1-aryloxycarbonylmethyl)
2-Azetidinone (305 mg) was dissolved in dry toluene (1.5 ml), and chlorotrimethylsilane (145 mg) and triethylamine (1) were dissolved.
50 mg was sequentially added and stirred at room temperature for 1 hour. 2% organic layer
After washing once with NaHCO ₃ water and once with saturated saline solution, drying with sodium sulfate, and distilling off the solvent under reduced pressure, (3S, 4S) -3-[(1R)
-1-Trimethylsilyloxyethyl] -4-[(1R)
-P-chlorophenylthiocarbonylethyl] -1-
(1-Allyloxycarbonylmethyl) -2-acetidinone was obtained.

NMR δ (CDCl ₃ ): 0.14 (9H, s), 1.30 (3H, d, J = 6.9H
z), 1.30 (3H, d, J = 6.6Hz), 3.07 (1H, m), 3.14 (1
H, dq, J = 3.3 and 6.9Hz), 4.08 (2H, ABq, J = 17.8Hz), 4.
10 (1H, m), 4.16 (1H, m), 4.60 (2H, dt, J = 1.3 and 5.6H
z), 5.27 (2H, m), 5.88 (1H, m), 7.35 (4H, ABq, J =
8.6Hz).

Reference example 8 (3S, 4S) -3-[(1R) -1-Trimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-allyloxycarbonylmethyl-2
-Azetidinone (308 mg) was dissolved in 2 ml of a dry mixed solvent of toluene-tetrahydrofuran (4: 1), sodium hydride (60% oily) (89.2 mg, 2.23 mM), allyl bromide (77.
4mg, 0.64mM), trimethylsilal (0.864mg), toluene-tetrahydrofuran (4: 1) dry mixed solvent (2.5
ml) and added dropwise at −15 ° C. to the suspension at −10 ° C. to −15 ° C.
After stirring for an hour, a solution of diphenylchlorophosphate (207 mg, 0.77 mM) in toluene (0.5 ml) was added dropwise at the same temperature. After further stirring for 2 hours, a solution of [2S, 4S] -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (165 mg, 0.64 mM) in THF (1 ml) was added dropwise at -5 to 0 ° C. Stir for 1 hour. To the reaction mixture was added 0.1M-potassium dihydrogenphosphate aqueous solution (5 ml), the layers were separated, the aqueous layer was extracted with 5 ml of ethyl acetate, the organic layers were combined and washed with brine, and then magnesium sulfate-potassium carbonate (1:
After drying in 1), the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3- [4- (1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl)
Thio] -4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] -hept-2
-En-7-one-2-carboxylate was obtained. This product had the same IR spectrum as that obtained in Reference Example 3.

Reference example 9 (3S, 4S) -3-[(1R) -1-Trimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-allyloxycarbonylmethyl-2
-Azetidinone (content 90%, 15g) was dissolved in a dry mixed solvent of toluene-tetrahydrofuran (4: 1) 65ml, sodium hydride (60% oily) (4.2g, 105mM), allyl bromide (4.0g, 33mM) 115 ml of a dry mixed solvent of trimethylsilanol (28 mg) and toluene-tetrahydrofuran (4: 1)
Was added dropwise to the suspension of and at −15 to −10 ° C., stirred for 3 hours, and then diphenylchlorophosphate (9.67 g, 36 mM) at the same temperature.
Toluene-tetrahydrofuran (4: 1) in a dry mixed solvent (15 ml) was added dropwise at -15 to -10 ° C, and the mixture was stirred at the same temperature for 4 hours, then 0.1M phosphate buffer (pH 7.0) was added. The reaction was stopped by the addition of drops. The same phosphate buffer (150 ml) was added, and the mixture was extracted with ethyl acetate (150 ml). The aqueous layer was extracted again with 100 ml of ethyl acetate, combined with the above organic layer, washed with saturated saline, dried over magnesium sulfate-potassium carbonate (1: 1), and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with toluene-ethyl acetate (95: 5 to 90:10) were collected and concentrated to give (4R, 5R, 6S, 8R) -allyl-3.
-(Diphenylphosphoryloxy) -4-methyl-6-
(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate was obtained.

NMR δ (CDCl ₃ ): 0.11 (9H, s), 1.19 (3H, d, J = 7.3H
z), 1.25 (3H, d, J = 6.3Hz), 3.24 (1H, dd, J = 3.0 and 6.6Hz), 3.46 (1H, m), 4.11 (1H, dd, J = 3.0 and 1)
0.6Hz), 4.18 (1H, m), 4.66 (2H, d, J = 5.61Hz), 5.2
0 (1H, d, J = 10.6Hz), 5.37 (1H, d, J = 17.2Hz), 5.86
(1H, m), 7.21 to 7.41 (10H, m).

Reference example 10 (4R, 5R, 6S, 8R) -Allyl-3- (diphenylphosphoryloxy) -4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-ene-7- 290 mg of on-2-carboxylate was dissolved in 1.5 ml of dry acetonitrile, then [2S, 4S]-
After adding 142 mg of 1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine and cooling the mixture to -15 ° C, diisopropylethylamine 7
7.5 mg of dry acetonitrile solution (about 0.2 ml) was added dropwise,
After stirring at -15 to -10 ° C for 5 hours, 10 ml of 0.1 M potassium dihydrogen phosphate aqueous solution and 10 ml of ethyl acetate were added to the reaction mixture,
After liquid separation, the organic layer is again added with 0.1 M potassium dihydrogen phosphate aqueous solution.
After washing with 10 ml and confirming that the pH of the aqueous layer was 4 to 5, the organic layer was stirred as it was at room temperature for 5 to 15 hours. Thin layer chromatography- [benzene-ethyl acetate (1: 1)]
After confirming that the trimethylsilyl group was removed by washing with saturated saline and drying with magnesium sulfate-potassium carbonate (1: 1), the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, (4R, 5S, 6S, 8
R, 2'S, 4'S) -Allyl-3- [4- (1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-hydroxyethyl)- 1-azabicyclo [3.2.0] hept-2-ene-
7-on-2-carboxylate was obtained.

This product is the compound obtained in Reference Example 4 and UV, IR and NMR.
Matched.

Reference example 11 By the method described in Reference Example 9, (4R, 5R, 6S, 8R) -allyl-
3- (diphenylphosphoryloxy) -4-methyl-6
-(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate was prepared and used as a crude product without purification by column chromatography as a reference example. By subjecting it to the reaction described in 10, (4R, 5S, 6S, 8R, 2'S, 4'S) -allyl-3- [4- (1-allyloxycarbonyl-2-
Dimethylaminocarbonylpyrrolidinyl) thio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate could be obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Haruki Matsumura 3-98 Kasugadinaka, Konohana-ku, Osaka City, Osaka Prefecture, Sumitomo Pharmaceutical Co., Ltd. (72) Inventor, Fifty-five Jo, Kuragakiuchi, Ibaraki City, Osaka Prefecture No. 45 Sumitomo Pharmaceuticals Co., Ltd. (72) Inventor Tetsuo Noguchi 1-345 Kuragakiuchi, Ibaraki City, Osaka Prefecture No. 45 Sumitomo Pharmaceuticals Co., Ltd. No. 3-45 Sumitomo Pharmaceutical Co., Ltd. (56) References JP-A-60-104088 (JP, A)

Claims (6)

(57) [Claims] 1. A formula Of the crystalline state represented by (4R, 5S, 6S, 8R, 2 ′S, 4 ′
S) -3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one -2-carboxylic acid trihydrate. 2. Amorphous (4R, 5S, 6S, 8R, 2'S, 4'S)-
3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-ene-
Crystals are prepared by dissolving 7-one-2-carboxylic acid in water or a water-containing organic solvent and cooling, or diluting by adding an organic solvent compatible with water, or by combining both cooling and dilution. (4R, 5S, 6S, 8R, 2'S, 4'S) -3- [4- (2-dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6 in crystalline form characterized by A method for producing-(1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid trihydrate. 3. An organic solvent compatible with water is added at the same time as cooling to dilute and crystallize.
The manufacturing method according to the item. 4. The organic solvent is ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dioxane,
The method according to claim 2 or 3, which is selected from acetonitrile and a mixed solvent thereof. 5. A formula Of the crystalline state represented by (4R, 5S, 6S, 8R, 2 ′S, 4 ′
S) -3- [4- (2-Dimethylaminocarbonyl) pyrrolidinylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one Antibacterial agent for injection of 2-carboxylic acid trihydrate. 6. The antibacterial agent for injection according to claim 5, which contains a non-toxic carbonate.