JP2002220395A - Phosphonocephem compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antibacterial agent with enough satisfactory quality as a medicine. SOLUTION: Cephem compounds (especially their crystals) represented by formula (1) [wherein, X shows CH3COOH, CH3CH2COOH or CH3CN, and n is 0 to 5] are useful as the antibacterial agents (especially anti-MRSA agent), and have an excellent quality with high solid stability and with capability to be stably stored for a long term.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a phosphonocephem compound having excellent antibacterial activity which is useful as a medicament (especially a crystal thereof) and a method for producing the same.

[0002]

2. Description of the Related Art A phosphonocephem compound having excellent antibacterial activity is described in JP-A-11-255772.

[0003]

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7β- [2 (Z) -ethoxyimino-2-
Freezing of (5-phosphonoamino-1,2,4-thiadiazol-3-yl) acetamido] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate Dried products are described.

[0005]

SUMMARY OF THE INVENTION Generally, as a medicine,
Those having excellent quality such as absorbability, solubility, purity, stability, storage stability, and ease of handling are preferred. Therefore, an object of the present invention is to provide an antibacterial agent (particularly an anti-MRSA agent) having a sufficiently satisfactory quality as a pharmaceutical.

[0006]

Means for Solving the Problems In view of the above problems, the present inventors have made intensive studies and as a result, have found many phosphonocephem compounds having a specific chemical structure represented by the above formula (Ia). Selected from phosphonocephem compounds, this compound, water and a specific solvent (CH ₃ COOH, CH ₃ CH
₂ COOH or CH ₃ CN) can unexpectedly yield compounds of exceptionally good antibacterial activity as pharmaceuticals (especially crystals that have been successfully crystallized). As a result, the present inventors have found that the compound has a sufficiently high quality as a drug (for example, high solid stability and high purity), and completed the present invention.

That is, the present invention provides:

[0008]

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Wherein X is CH ₃ COOH, CH ₃ CH ₂
COOH or CH ₃ CN, n represents 0 to 5]
A compound represented by the formula: (2) The compound according to (1) above in a crystalline form. (3) The compound according to the above (1), wherein n is 1. (4) The compound according to the above (1) or (2), wherein X is CH ₃ COOH. (5) X-ray powder diffraction: diffraction angles 16.32, 19.06, 19.9
The compound according to the above (4), which has a peak near 0, 20.98, 23.24 °. (6) In powder X-ray diffraction, diffraction angles 11.82, 17.16, 17.8
0, 19.32, 20.00, 21.20, 21.78, 22.94, 24.10, 27.02
° The compound according to the above (4), which has a peak near. (7) The compound according to the above (1) or (2), wherein X is CH ₃ CH ₂ COOH. (8) X-ray powder diffraction: diffraction angles 16.30, 18.84, 19.7
The compound according to the above (7), which has a peak near 0, 21.80, and 23.18 °. (9) A pharmaceutical composition comprising the compound according to (1) or (2). (10) The pharmaceutical composition according to the above (9), which is an antibacterial agent. Equation (11):

[0010]

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And a compound represented by the formula: CH ₃ COOH, C
A formula characterized by mixing, dissolving and crystallizing H ₃ CH ₂ COOH or CH ₃ CN with water:

[0012]

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[Wherein X is CH ₃ COOH, CH ₃ CH ₂
COOH or CH ₃ CN, n represents 0 to 5]
A method for producing a crystal of a compound represented by the formula: (12) CH ₃ COOH, CH ₃ CH ₂ COOH or C
The production method according to the above (11), wherein the usage ratio (volume ratio) of H ₃ CN and water is 1: 0.1 to 10. Equation (13):

[0014]

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And CH ₃ COOH, C
A crystal obtained by mixing, dissolving and crystallizing H ₃ CH ₂ COOH or CH ₃ CN with water. Equation (14):

[0016]

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A disodium salt of the compound represented by the formula: (15) The disodium salt according to the above (14), which is in a crystalline form. (16) Diffraction angles 17.02, 18.94, 2 in powder X-ray diffraction
Above (1) with peaks around 2.86, 23.36, 26.48 °
The disodium salt according to 4) or (15). Etc.

Compound (I) comprises one molecule of compound (Ia)
A compound consisting of one molecule of acetic acid, propionic acid or acetonitrile and 0 to 5 molecules of water. Compound (I)
Is a compound wherein the compound (Ia) and acetic acid or propionic acid form a solvate even if the compound (Ia) and acetic acid or propionic acid form a salt. Is also good. Further, the compound (I) may contain water, and in that case, the water may be taken in as crystallization water or may be simply attached water. Compound (I) is preferably in a crystalline form in view of purity and solid stability.

Compound (I) can be produced from compound (Ia), acetic acid, propionic acid or acetonitrile and water. The compound (Ia) includes
The freeze-dried product described in 11-255772 may be used, and the compound (Ia) obtained by adding, for example, hydrochloric acid, sulfuric acid, nitric acid, or the like to a solution containing the disodium salt, dipotassium salt, or diammonium salt of compound (Ia) May be used. The above compound (I
The solution containing the disodium salt of a) may be a reaction solution containing the disodium salt of compound (Ia) obtained as a result of various reactions for synthesizing the disodium salt of compound (Ia), or the compound (Ia) It may be one in which crystals of the disodium salt of Ia) are dissolved. Compound (I) can be produced by mixing the above and with to form a solution, and isolating from this solution using ordinary isolation means such as crystallization. , And may be in any order. For example, first, and may be mixed and then mixed with each other, and and may be mixed and then mixed with, or may be mixed with and mixed with. In order to form a solution after mixing, for example, ultrasonic treatment (ultrasonic irradiation), stirring, and the like are preferably performed. Crystals may be precipitated at the same time as the solution, but if they do not crystallize, they may be crystallized by, for example, cooling, stimulating with ultrasonic treatment or stirring, or adding seed crystals. Further, in order to control the physical properties of the precipitated crystals, the mixture may be crystallized with saccharides added.

In the case of crystallization, the mixing ratio between the solvent and water is usually from 1: 0.1 to 1 by volume.
0, preferably 1: 0.5 to 5, particularly preferably about 1: 1. The amount used for and in the case of crystallization is not particularly limited as long as it is within the range of crystallization, but is usually 2 to 100 parts by weight per 1 part by weight, preferably 3 to 5 parts by weight.
0 parts by weight, more preferably 5 to 30 parts by weight. The crystallization can be carried out by cooling the above solution, reducing the amount of the solution by reducing the pressure, or adding crystallization means such as adding seed crystals. The saccharide to be added to the mixed solution can be added up to the maximum amount that can be dissolved in the mixed solution. Usually, it is preferable to use a saccharide dissolved in water. As the saccharide, glucose, mannitol, sucrose, sorbitol, xylitol, fructose,
Maltose and the like are mentioned, and glucose and mannitol are particularly preferable.

The compound (I) thus obtained is
The solution can be separated from the solution by ordinary separation means (eg, filtration, centrifugation, etc.) and purified by ordinary purification means (eg, washing with a solvent or the like).

The compound (I) (especially a crystal thereof) thus obtained is, for example, high in purity and excellent in solid stability and the like, and thus can be used in pharmaceutical preparations.

The water content of the crystals of the compound (I) can be changed depending on the degree of drying. Those containing no water are also included in the scope of the present invention.

Compound (Ia) can be converted to a dialkaline salt such as disodium salt, dipotassium salt, diammonium salt and the like. The dialkali salt of the compound (Ia) may be, for example, a solution containing the compound (Ia) [eg, a reaction solution containing the compound (Ia) immediately after production (to which a hydrophilic solvent is added if no hydrophilic solvent is contained), a compound ( Ia) dissolved in a hydrophilic solvent, etc.], for example, sodium hydroxide, sodium carbonate, sodium acetate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate, potassium acetate, potassium hydrogen carbonate, aqueous ammonia, ammonium carbonate, ammonium acetate It can be produced by adding such as to make it alkaline. Examples of the hydrophilic solvent include organic acids such as acetic acid, propionic acid, lactic acid, and succinic acid; nitriles such as acetonitrile; ketones such as acetone; alcohols such as methanol and ethanol; dioxane; and tetrahydrofuran. And hydrophilic organic solvents such as a mixed solvent thereof, and a mixed solvent thereof with water. Among them,
Acetic acid, propionic acid, acetonitrile, methanol, ethanol, lactic acid and a mixed solvent thereof with water are preferred, and acetonitrile, methanol, ethanol, acetic acid, propionic acid, and a mixed solvent thereof with water are particularly preferred.

Crystals of the disodium salt of compound (Ia)
For example, it can be produced by crystallizing a disodium salt of compound (Ia) from a hydrophilic solvent as described above.

In the case of crystallization, the ratio of the disodium salt of compound (Ia) to the solvent is not particularly limited as long as it is within the range of crystallization. To 100 parts by weight, preferably 3 to 50 parts by weight, more preferably 5 to 30 parts by weight. The crystallization can be carried out by cooling the solution, reducing the amount of solvent and water by reducing the pressure, or adding crystallization means such as adding seed crystals.

The crystals thus crystallized are separated from the solution by ordinary separation means (eg, filtration, centrifugation, etc.), and purified by ordinary purification means (eg, washing with a solvent).
Can be purified.

The crystals of the disodium salt of compound (Ia) thus obtained have high purity and can be used for the production of compound (Ia). For example, when producing the compound (Ia), the compound (Ia) is once crystallized as its disodium salt to separate crystals, which is dissolved in the hydrophilic solvent, and hydrochloric acid, sulfuric acid, nitric acid and the like are added thereto. Compound (I
Compound (Ia) can be obtained in high purity and high yield by converting to a).

The compound (I) has excellent antibacterial activity, has a broad spectrum of antibacterial activity, and has low toxicity, so that it can be used in various mammals including humans (eg, mouse, rat,
It can be used safely for the prevention and treatment of various diseases caused by pathogenic bacteria in rabbits, dogs, cats, cattle, pigs, etc., for example, respiratory tract infections and urinary tract infections. When using compound (I) as an antibacterial agent, the target bacterium is not particularly limited as long as compound (I) exhibits antibacterial activity, and a wide range of gram-positive bacteria and gram-negative bacteria can be used. Show excellent antibacterial activity, especially against staphylococci and methicillin-resistant Staphylococcus aureus (MRSA). Compound (I) has the formula:

[0030]

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A compound represented by the following formula [hereinafter simply referred to as compound (I
I)], which is considered to exhibit antibacterial activity.

Compound (I) (especially crystals thereof) has excellent stability, and is parenterally or orally administered as injections, capsules, tablets and granules in the same manner as known penicillins and cephalosporins. It can be administered as an injection, and it is particularly preferable to administer it as an injection. When administered as an injection, the dosage is usually 0.5 to 80 mg / day, more preferably 2 to 40 mg, as compound (I) per kg of body weight of humans and animals infected with the pathogenic bacteria as described above. / Day, usually divided into 2 to 3 times a day.

When used as an injection, the compound (I) crystals and a solution (eg, distilled water, physiological saline, 5
% Glucose solution) is separately packaged and provided as an injection, and the compound (I) crystal is dissolved in a dissolving solution and administered before use. Compound (I) can also be administered after being mixed with a medical infusion such as replacement fluid. Injectables usually include pH adjusters (eg, alkali metal or alkaline earth metal carbonates, phosphates, acetates, citrates (eg, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, Carbonates such as calcium carbonate, trisodium phosphate, sodium dihydrogen phosphate,
Phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, acetates such as sodium acetate, potassium acetate, calcium acetate, and citric acid Disodium, sodium citrate, sodium dihydrogen citrate, citrates such as calcium citrate), basic amino acids (eg, L-arginine, L-lysine, etc.), N-methylglucamine and the like; Among them,
Those containing an alkali metal or alkaline earth metal carbonate and a basic amino acid) are preferred, and L-arginine is particularly preferred. These pH adjusting agents are used in such an amount that the pH of the injection solution at the time of use becomes 4 to 10,
Preferably, the amount is from 4.5 to 8.5, more preferably from 5.0 to 8.0, even more preferably from 5.0 to 7.5. L
-When arginine is used, it is generally used in an amount of 0.1 to 5.0 equivalents, preferably 2.0 to 3.5 equivalents, more preferably 2.5 to 3.2 equivalents to the main drug. These p
The H regulator is usually packaged in a state of being dissolved in a solution, but may be mixed with crystals of compound (I) and packaged, or separately from the crystals of compound (I) and the solution. It may be provided in a package, and may be used in combination of the three when used. Furthermore, the stability of the injection solution at the time of use can be enhanced by adding a solubilizing agent having a reducing property to the injection. As a solubilizing agent having a reducing property,
For example, sodium sulfite, sodium hydrosulfite, sodium bisulfite, sodium pyrosulfite,
L-cysteine and the like. These reducing agents are usually used in an amount of 0.001 to 2.0 equivalents, preferably 0.01 to 0.5 equivalents, more preferably 0.05 to 1.0 equivalents to the main drug.
0.2 equivalent is used. These dissolution aids having reducing properties are usually packaged in a state of being dissolved in a dissolution solution,
It may be mixed with crystals of compound (I) and packaged,
It may be mixed with a pH adjuster and packaged, or may be provided separately from the crystals of compound (I), the pH adjuster and the solution, and may be used by mixing them when used.

The content of crystals of compound (I) in the preparation of Injection 1 is 100 to 20 in terms of compound (Ia).
00 mg, preferably 200 to 1000 mg.

The ratio of the dissolving solution in the injection is 10 to 500, preferably 20 to 300, by weight, based on 1 crystal of compound (I). The ratio of the pH adjuster is calculated by converting the crystal of the compound (I) into the compound (Ia), and the equivalent of the pH adjuster is usually 1.0 to 3.0 equivalents per equivalent.

The pharmaceutical composition of the present invention may be compound (I) alone, and includes a carrier usually used for a drug (for example, in the case of an injection, a solution and the above-mentioned pH regulator). It may be.

Among the compounds (I), a compound wherein X is CH ₃ COOH or CH ₃ CH ₂ COOH and a crystal thereof are preferred. When X is CH ₃ COOH, the diffraction angles are 16.32, 19.06, 19.90, 20.98, 23.24 ° in powder X-ray diffraction.
Compounds with peaks in the vicinity, and diffraction angles 11.82, 1
7.16, 17.80, 19.32, 20.00, 21.20, 21.78, 22.94, 24.
Compounds having a peak near 10, 27.02 ° are particularly preferred. When X is CH ₃ CH ₂ COOH, a compound having a peak at a diffraction angle of 16.30, 18.84, 19.70, 21.80, 23.18 ° in powder X-ray diffraction is particularly preferable. “Near” in the above diffraction angle means ± 0.2 °.

Next, a method for producing the compound (Ia) used as a raw material of the present invention will be described.

[0039]

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In the formulas (III), (V) and (VII), Ph represents a phenyl group, BH represents a benzhydryl group, and a compound represented by the formula (VIII)
In the formula, BH represents a benzhydryl group, and in the formula (IV), M represents an alkali metal atom such as lithium, sodium and potassium or an alkaline earth metal atom such as magnesium, calcium and barium. I-BuOH represents isobutanol. ]

First, by reacting compound (III) with a compound represented by formula (IV) [hereinafter simply referred to as compound (IV)], the compound represented by formula (V) [hereinafter simply referred to as compound (V)] is obtained. To produce a compound. Compound (III) is a known compound, for example, The Journal of the Organic Chemistry [J. Org. Chem. 1989, 54, 4962-496].
6]. This reaction is usually performed in the presence of a solvent, for example, hydrocarbons such as toluene, esters such as ethyl acetate, ketones such as acetone, chloroform, halogenated hydrocarbons such as dichloromethane, diethyl ether, tetrahydrofuran, Ethers such as dioxane, nitriles such as acetonitrile, methanol,
It is preferably carried out in an inert solvent such as alcohols such as ethanol and n-propanol, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. And a mixture of the above solvent and water can also be used as the solvent. Among them, tetrahydrofuran, acetonitrile, methanol and the like are preferable, and tetrahydrofuran, methanol and a mixture of both are particularly preferable. The amount of compound (IV) used is
(III) The amount is usually 1 to 3 mol, preferably 1 to 2 mol, per 1 mol. Reaction temperature is -40 ° C
To 80 ° C, preferably from -20 ° C to 50 ° C. The reaction time is 5 minutes to 12 hours, preferably 30 minutes to 8 hours. In this reaction, if necessary, a base or a salt can be added, and the addition can accelerate the reaction. Such bases and salts include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, alkoxides such as sodium methoxide, potassium t-butoxide, sodium t-butoxide, and And organic amines such as trialkylamines such as triethylamine and ethyldiisopropylamine. Among them, sodium hydroxide and sodium methoxide are preferred. As the salts, quaternary ammonium salts such as tetrabutylammonium salts are used.

The compound (VI) is reacted with a quaternary ammonium-forming reagent such as iodomethane represented by the formula (VI) [hereinafter simply referred to as compound (VI)].
I) can be manufactured. This reaction is usually carried out in the presence of a solvent. Examples of the solvent include hydrocarbons such as toluene, ketones such as acetone, halogenated hydrocarbons such as chloroform and dichloromethane, diethyl ether, tetrahydrofuran and dioxane. And inert solvents such as nitriles such as acetonitrile, alcohols such as methanol, ethanol and n-propanol, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. A mixture of two or three of these solvents can be used as the solvent, and a mixture of the above solvent and water can also be used as the solvent. Among them, tetrahydrofuran, dimethylformamide, acetonitrile, and dimethyl sulfoxide are preferable, and particularly, tetrahydrofuran,
Dimethylformamide is preferred. The amount of the quaternary ammonium reagent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (V). The reaction temperature is from -5 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Reaction time is from 30 minutes to 4
8 hours, preferably 2 hours to 20 hours.

Then, the compound (VII) is subjected to an amino group deprotection reaction to produce a compound represented by the formula (VIII) [hereinafter simply referred to as compound (VIII)]. In this reaction, 1 to 10 moles, preferably 1 to 5 moles of phosphorus pentachloride and 1 to 5 moles of a tertiary amine (eg, pyridine, N, N-dimethylaniline, picoline, lutidine) are used based on compound (VII). 10 moles, preferably 1
To 5 mols of these compounds in an inert solvent, followed by reaction with 2 to 200 mols, preferably 3 to 125 mols of alcohols (eg, methanol, ethanol, isobutanol, isopropyl alcohol, etc.). Complete the reaction. Preferred tertiary amines include pyridine and N, N-dimethylaniline, with pyridine being particularly preferred. Preferred alcohols include methanol, ethanol and isobutanol, and particularly preferred are methanol and isobutanol. As the inert solvent, usually, hydrocarbons such as toluene, esters such as ethyl acetate, ketones such as acetone, chloroform, halogenated hydrocarbons such as dichloromethane, diethyl ether, tetrahydrofuran, ethers such as dioxane, Examples thereof include nitriles such as acetonitrile, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. A mixture of two to three kinds of these solvents can be used as the solvent. Among them, chloroform,
Halogenated hydrocarbons such as dichloromethane are preferred,
Particularly, dichloromethane is preferable. Reaction temperature is -40 ° C
To 80 ° C, preferably from -20 ° C to 50 ° C. The reaction time is 30 minutes to 48 hours, preferably 2 hours to 24 hours.

Next, the compound (VIII) is subjected to a deprotection reaction of a carboxyl group to produce a compound represented by the formula (IX) [hereinafter simply referred to as compound (IX)]. This reaction is usually performed using an acid in a solvent. Examples of the solvent include hydrocarbons such as toluene, ketones such as acetone, halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, and ethyl acetate. And inert solvents such as alcohols such as methanol, ethanol, and n-propanol; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Can also be used as a solvent. Among them, chloroform,
Halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, and esters such as ethyl acetate are preferred, and acetonitrile, ethyl acetate, and a mixture of both are particularly preferred. As the acid, hydrochloric acid and trifluoroacetic acid are preferable, and hydrochloric acid is particularly preferable. The amount of the acid to be used is 2 to 200 mol, preferably 3 to 50 mol, relative to compound (VIII). In this case, it is preferable to add anisole, phenol or the like as a cation scavenger in order to accelerate the reaction. Reaction temperature is -40 ° C
To 80 ° C, preferably from -20 ° C to 50 ° C. The reaction time is 30 minutes to 48 hours, preferably 2 hours to 24 hours.

Compound (IX) obtained by this production method is
It is usually obtained as a 1 to 2 acid addition salt, and can be obtained as crystals of a 1 to 2 acid addition salt from an organic solvent, water or a mixture of both. Examples of the acid of the one or two acid addition salts include mineral acids and organic acids, and among them, hydrochloric acid, sulfuric acid, and trifluoroacetic acid are preferable, and hydrochloric acid is particularly preferable. Examples of the organic solvent to be used include the above-mentioned inert solvents, among which acetonitrile, ethyl acetate,
Ethanol, dioxane and tetrahydrofuran are preferred, and acetonitrile, ethyl acetate and ethanol are particularly preferred.

Next, the compound (Ia) can be produced by reacting the compound (IX) with a compound represented by the formula (X) [hereinafter, simply referred to as compound (X)].

The compound (IX) is preferably an acid addition salt crystal. In this reaction, generally, 1 to 5 moles, preferably 1 to 2 moles of compound (X) is added to 1 mole of compound (IX) in a solvent that does not inhibit the reaction in the presence of an acid scavenger that scavenges an acid generated in the reaction. And react. As the solvent, for example, tetrahydrofuran, acetonitrile, dioxane, acetone or a mixture of these solvents and water is preferable, and particularly, acetonitrile, tetrahydrofuran or a mixture of acetonitrile and water, and a mixture of tetrahydrofuran and water are preferable. As the acid scavenger, as commonly used, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate,
Salts such as sodium phosphate, for example, tertiary amines such as triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, pyridine, lutidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine Grade amine,
For example, alkylene oxides such as propylene oxide and epichlorohydrin are exemplified, and two or three kinds of these may be used as a mixture. Among them, sodium hydrogen carbonate, sodium carbonate, sodium acetate, triethylamine or a combination of sodium acetate and triethylamine is preferable, and particularly, sodium hydrogen carbonate,
Preferred are sodium acetate, triethylamine or a combination of sodium acetate and triethylamine. In this reaction, the dichlorophosphoryl group is also sequentially hydrolyzed and converted into a phosphono group. The reaction temperature is -40
C. to 80C, preferably -20C to 50C. The reaction time is from 20 minutes to 48 hours, preferably from 30 minutes to 24 hours. Compound (X) is disclosed in
The compound can be synthesized from the corresponding compound represented by formula (XI) [hereinafter simply referred to as compound (XI)] and phosphorus pentachloride by the method described in 1-255772.

[0048]

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This reaction is generally carried out in a solvent using a compound (XI)
1 to 5 moles, preferably 1 to 5 moles of phosphorus pentachloride per mole
To 3 moles. Examples of the solvent include tetrahydrofuran, ethyl acetate, isopropyl ether,
Dioxane, toluene or a mixture thereof is preferred, and tetrahydrofuran, ethyl acetate, isopropyl ether or a mixture thereof is particularly preferred. The reaction temperature is −40 ° C. to 60 ° C., preferably −10 ° C.
To 25 ° C. The reaction time is from 10 minutes to 8 hours, preferably from 20 minutes to 4 hours. As the isolation operation after the reaction, any of a usual method by extraction with water and a method of directly adding a poor solvent or a poor solvent and water to a reaction solution to obtain a solid that precipitates can be used. As the poor solvent to be added, toluene, isopropyl ether, n-hexane, cyclohexane and a mixture thereof are preferable, and toluene, isopropyl ether, n-hexane and a mixture thereof are particularly preferable.

[0050]

The present invention will be described in more detail with reference to the following reference examples, examples and experimental examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed.

In the following Reference Examples, Examples and Experimental Examples, room temperature means 10 to 25 ° C.

The melting point was measured using Yanaco MP-J3. ^{The 1} H-NMR spectrum was determined using tetramethylsilane (CDCl ₃ , DM
SO-d ₆ ) or sodium 3- (trimethylsilyl) propionate-2,2,3,3-d ₄ (D ₂ O) as the internal standard, Varian Ge
measured using mini-200 (200MHz)
It was shown in ppm.

The ultrasonic treatment is performed by SHARP UT-204.
(Water bath type) and TAITEC VP-60 (horn type) were used.

As the silica gel for the column, Kieselgel 60 (70-230 mesh) manufactured by Merck was used. HPLC column packing material ODS is manufactured by YMC Corporation, and Diaion HP-2OSS and SP-207 are manufactured by Mitsubishi Chemical Corporation.

Elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) or HPLC.
In the TLC observation, 60F254 manufactured by Merck was used as a TLC plate, and the target compound was R
Solvents developed within the f-value range of 0.1 to 0.8 or solvents similar thereto were employed by UV detection as a detection method. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. % In the solution is 10% in the solution.
Represents the number of grams in 0 ml. The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet ABq: AB type quartet dd: double doublet m: multiplet J : Coupling constant

Example 1 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (100 mg, 0.151 mmol) in distilled water for injection (0.
(5 ml) and acetic acid (0.5 ml), and sonicated to dissolve. The solution was allowed to stand at room temperature overnight. The precipitated crystals were pulverized with a spatula and collected by filtration. Distilled water for injection
Washed with 1.2 ml. Using Molecular Sieves 3A (1/16) as a desiccant, dry under reduced pressure to constant weight,
A seed crystal was obtained. Yield 79 mg (73%) Melting point: 221-223 ° C (decomposition) 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (350 mg, 0.51 mmol) in distilled water for injection (2.3
(8ml) and acetic acid (2.38ml) and sonicated to dissolve. Seed crystals were added, and the crystals were crystallized under stirring at room temperature for 4 hours, and left still in a refrigerator overnight. 0.8 ml of a mixture of distilled water for injection / acetic acid (1: 1) was added, and the precipitated crystals were pulverized with a spatula, collected by filtration, and filtered.
The mixture was washed three times with 0.8 ml of a mixture of acetic acid (1: 1) and five times with 1.0 ml of distilled water for injection. Molecular sieves 3A (1 /
Using 16) as a drying agent, drying was performed under reduced pressure until a constant weight was obtained. Yield 260mg (68%) Melting point: 221-223 ° C (decomposition) Anal Calcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
^{4.37, P 3.88 1 H-NMR} (DMSO-d 6) δ:. 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668, 1645, 1537, 1392,
1273, 1039. FIG. 1 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in this example. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Example 2 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (60 g, 87.6 mmol) in distilled water for injection (408 m
l) and acetic acid (408 ml) were suspended and sonicated to dissolve. The seed crystal obtained in Example 1 was added, and the crystal was crystallized under stirring at room temperature for 5 hours, and left still in a refrigerator overnight. The precipitated crystals are collected by filtration, and distilled water for injection / acetic acid (1: 1).
The mixture was washed twice with 68 ml and five times with 85 ml of distilled water for injection. It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 44.5g
(68%) Melting point: 221-223 ° C (decomposition) Anal Calcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
^{4.37, P 3.88 1 H-NMR} (DMSO-d 6) δ:. 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668, 1645, 1537, 1392,
1273, 1039.

Example 3 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (58 g, 84.7 mmol) in distilled water for injection (208 m
l) and acetic acid (208 ml) were suspended and sonicated to dissolve. The seed crystal obtained in Example 1 was added and subjected to ultrasonic treatment (horn type ultrasonic device) at room temperature for 30 minutes. 108 ml of a mixture of distilled water for injection / acetic acid (1: 1) was added, and the crystals were pulverized and stirred at room temperature for 1 hour. In addition, distilled water for injection /
Add 108 ml of acetic acid (1: 1) mixture, pulverize the crystals,
Stirred at room temperature for another hour. The above operation was further repeated and left in a refrigerator overnight. The precipitated crystals were collected by filtration and washed twice with 120 ml of a mixture of distilled water for injection / acetic acid (1: 1) and five times with 120 ml of distilled water for injection. It was dried under reduced pressure to constant weight using diphosphorus pentoxide as a drying agent. Yield 4
2.6g (68%) Melting point: 221-223 ° C (decomposition) Anal Calcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
^{4.37, P 3.88 1 H-NMR} (DMSO-d 6) δ:. 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668, 1645, 1537, 1392,
1273, 1039.

Example 4 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (2.0 g, 2.92 mmol) in distilled water for injection (7.5 m
l) and acetic acid (7.5 ml) were suspended and sonicated to dissolve. The mixture was allowed to stand at room temperature for 16 hours to crystallize.
The crystals are collected by filtration and mixed with distilled water for injection / acetic acid (1: 1) 5
Washed twice with 5 ml of distilled water and 5 ml of distilled water for injection. It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 1.41 g (65%) Melting point: 221-223 ° C (decomposition) Anal Calcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
^{4.37, P 3.88 1 H-NMR} (DMSO-d 6) δ:. 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668, 1645, 1537, 1392,
1273, 1039.

Example 5 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate and propionic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (100 mg, 0.15 mmol) in distilled water for injection (0.5
ml) and propionic acid (0.5 ml), and suspended by sonication to dissolve. Crystals were crystallized under stirring at room temperature for 2.5 hours. The precipitated crystals are collected by filtration and distilled water for injection 0.5 ml
And washed. It was dried under reduced pressure to constant weight using diphosphorus pentoxide as a drying agent. Yield 97 mg (88%) Melting point: 227-230 ° C (decomposition) Anal Calcd for C ₂₅ H ₂₇ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 38.66, H
3.76, N 14.16 Found:.. C 38.51, H 3.76, N 14.16 1 H-NMR (DMSO-d 6) δ: 0.99 (3H, t, J = 7.6Hz), 1.24 (3
H, t, J = 7Hz), 2.21 (2H, q, J = 7.6Hz), 3.59, 3.95 (2H, AB
q, J = 18Hz), 4.17 (2H, q, J = 7Hz), 4.33 (3H, s), 5.31 (1
H, d, J = 5Hz), 5.91 (1H, dd, J = 5 & 8Hz), 8.52, 8.98 (each
2H, d, J = 6Hz), 9.00 (1H, s), 9.24 (1H, m), 9.68 (1H,
d, J = 8Hz). IR (KBr) cm ^-1 : 3088, 1757, 1668, 1537, 1392, 1234,
1190, 1043. FIG. 2 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in this example. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Example 6 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetonitrile 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (100 mg, 0.15 mmol) in distilled water for injection (1.2
ml) and acetonitrile (1.2 ml), and dissolved by sonication and heating to 50 ° C. The solution was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration, washed with water / acetonitrile (4: 1), and air-dried to constant weight.
Yield 63 mg (59%) Melting point: 210-215 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J = 7Hz), 2.07 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.33 (3H, s), 5.32 (1H, d, J = 5Hz), 5.91 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.34 (1H, m),
9.71 (1H, d, J = 8 Hz). FIG. 3 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in this example. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Example 7 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl ) -2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4- Carboxylate 400mg (0.834m
mol) was dissolved in 24 ml of distilled water by stirring. Under ice cooling and stirring, 4.18 ml of a 2M aqueous sodium acetate solution was added. 2- (5-
Dichlorophosphorylamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetyl chloride 294 mg (0.83
(6 mmol) was dissolved in 2 ml of acetonitrile, and added to the above reaction solution at once with ice cooling and stirring. The mixture was stirred at room temperature for 1 hour and 15 minutes.
Ethyl acetate (20 ml) was added to the reaction solution, and the mixture was separated. The aqueous layer was separated and filtered through a membrane filter (0.45 μm). The filtrate was almost dried under reduced pressure. Residual solids in distilled water
Dissolved in 4 ml. 4 ml of ethanol was added and stirred.
Crystals gradually precipitated. 4 ml of ethanol was gradually added to promote crystal growth. The mixture was allowed to stand under ice cooling for 30 minutes, and the precipitated crystals were collected by filtration. Crystals were distilled water / ethanol (1:
2) After washing sequentially with 4 ml and 4 ml of ethanol, it was air-dried on a funnel. Yield: 554 mg (91%) Melting point: 217 to 222 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ : D ₂ O = 8: 2) δ: 1.27 (3H, t, J = 7H)
z), 3.40, 3.89 (2H, ABq, J = 17Hz), 4.24 (2H, q, J = 7Hz),
4.30 (3H, s), 5.23 (1H, d, J = 5Hz), 5.79 (1H, d, J = 5H
z), 8.37, 8.77 (each 2H, d, J = 7Hz), 8.66 (1H, s) .IR (KBr) cm ^-1 : 3184, 1761, 1643, 1614, 1537, 1390,
1346, 1190, 1041. FIG. 4 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in this example. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Example 8 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl ) -2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4- 60 g of carboxylate (125 mmol)
Was dissolved in 3.6 L of distilled water by stirring. 2M under ice-cooled stirring
700 ml of aqueous sodium acetate solution was added. 2- (5-dichlorophosphorylamino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetyl chloride (52.8 g, 150 mmol) was dissolved in acetonitrile (300 ml), and the solution was added to the above reaction solution at a time with ice cooling and stirring. The solution was stirred at room temperature for 1 hour. 3 L of ethyl acetate was added to the reaction solution, and the mixture was separated. The aqueous layer was separated and filtered through a membrane filter (0.45 μm). The filtrate was concentrated under reduced pressure to 600 ml. 600 ml of ethanol were added. Crystals gradually precipitated. Ethanol (600 ml) was gradually added, and the mixture was allowed to stand under ice cooling for 30 minutes. The precipitated crystals were collected by filtration and washed successively with 450 ml of distilled water / ethanol (1: 2) and 600 ml of ethanol. After washing, it was air-dried on a funnel. Yield 128.7 g (quantitative) Melting point: 217-222 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ : D ₂ O = 8: 2) δ: 1.27 (3H, t, J = 7H)
z), 3.40, 3.89 (2H, ABq, J = 17Hz), 4.24 (2H, q, J = 7Hz),
4.30 (3H, s), 5.23 (1H, d, J = 5Hz), 5.79 (1H, d, J = 5H
z), 8.37, 8.77 (each 2H, d, J = 7Hz), 8.66 (1H, s) .IR (KBr) cm ^-1 : 3184, 1761, 1643, 1614, 1537, 1390,
1346, 1190, 1041.

Example 9 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 4.0 g (5.84 mmol) was added to distilled water for injection (12
2M aqueous sodium acetate solution (5.84 ml)
Was added and dissolved. Acetic acid (24 ml) followed by 1M sulfuric acid (5.7
8 ml), seed crystals were added, and the mixture was allowed to stand at room temperature for 24 hours. The precipitated crystals were pulverized and collected by filtration. The collected crystals were washed three times with 4 ml of a distilled water / acetic acid (1: 1) mixture for injection,
Washed 5 times with 4 ml of distilled water for injection. It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 1.48 g (38%) Melting point: 221-223 ° C (decomposition) Anal Calcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
^{4.37, P 3.88 1 H-NMR} (DMSO-d 6) δ:. 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58, 3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8
Hz), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668, 1645, 1537, 1392,
1273, 1039.

Example 10 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-Cephem-4-carboxylate and acetic acid crystals Except that distilled water for injection was changed to 5% glucose injection solution, the same operation as in Example 9 was performed. The title compound was obtained. yield
1.34 g (35%)

Example 11 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-Cephem-4-carboxylate and acetic acid crystal The same operation as in Example 9 was carried out except that distilled water for injection was changed to 20% D-mannitol injection. This gave the title compound. Yield 1.88 g (48%)

Example 12 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 4.0 g (5.84 mmol) in 5% glucose injection
(12 ml) and a 2M aqueous sodium acetate solution (5.84 m
l) was added and dissolved. Acetic acid (24 ml) was added, followed by 1M sulfuric acid (5.78 ml), and seed crystals were added, followed by stirring at room temperature for 24 hours. The precipitated crystals were collected by filtration. The crystals collected by filtration were washed three times with 4 ml of a mixture of distilled water for injection / acetic acid (1: 1) and five times with 4 ml of distilled water for injection. Molecular sieves
Using 3A (1/16) as a drying agent, drying was performed under reduced pressure until the weight became constant. Yield 2.01 g (52%) The physicochemical data was the same as in Example 1.

Example 13 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-Cephem-4-carboxylate and acetic acid crystals The same operation as in Example 12 was carried out, except that the 2M aqueous sodium acetate solution was changed to a 2M aqueous ammonium acetate solution. The compound was obtained. Yield 1.44 g (37%)

Example 14 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] crystal of -3-cephem-4-carboxylate and acetic acid The same operation as in Example 12 was performed, except that distilled water for injection was changed to 20% D-mannitol injection. This gave the title compound. Yield 2.33 g (60%)

Example 15 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 10 g (14.6 mmol) in 5% glucose injection
(30 ml) and 2M aqueous sodium acetate solution (14.6 m
l) was added and dissolved. Acetic acid (60 ml) followed by 1M sulfuric acid (1
After adding 4.46 ml), seed crystals were added, and the mixture was stirred at room temperature for 2 hours and then allowed to stand for 22 hours. The precipitated crystals were pulverized and collected by filtration. The crystals collected by filtration are mixed with distilled water / acetic acid (1: 1) for injection 10
Washed three times with 10 ml and 5 times with 10 ml of distilled water for injection.
It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 6.90 g (7
1%) The physicochemical data was the same as in Example 1.

Example 16 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (10 g, 14.6 mmol) in distilled water for injection (30
ml), and dissolved by adding 2M aqueous sodium acetate solution (14.6 ml). Acetic acid (60 ml) followed by 1M sulfuric acid (14.4
After adding 6 ml), seed crystals were added, and the mixture was stirred at room temperature for 5 hours and allowed to stand for 1 hour. The precipitated crystals were collected by filtration. The crystals collected by filtration were washed three times with 10 ml of a mixed solution of distilled water for injection / acetic acid (1: 1) and five times with 10 ml of distilled water for injection. It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 5.55 g (57%) The physicochemical data were the same as in Example 1.

Example 17 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] crystal of -3-cephem-4-carboxylate and acetic acid Except that distilled water for injection was changed to 5% glucose injection solution, the same operation as in Example 16 was performed. The title compound was obtained. yield
5.70 g (59%)

Example 18 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-Cephem-4-carboxylate and acetic acid crystals The procedure of Example 16 was repeated, except that distilled water for injection was changed to 20% D-mannitol injection. This gave the title compound. Yield 6.21 g (64%)

Example 19 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid crystals 3% in a mixture of 20% D-mannitol injection (160 ml) and 2M aqueous sodium acetate (116.8 ml). -[4- (1-methyl-4
-Pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate 8
0 g (116.8 mmol) was slowly added and dissolved. Acetic acid (400
ml) and then 1M sulfuric acid (115.7 ml), seed crystals were added, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration.
The crystals collected by filtration are mixed with distilled water / acetic acid (1: 1) for injection 8
The wells were washed three times with 0 ml and five times with 160 ml of distilled water for injection. It was dried to constant weight under reduced pressure using Molecular Sieves 3A (1/16) as a desiccant. Yield 50 g
(64%) Physicochemical data were as in Example 1.

Example 20 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 1600 g (2.34 mol) was added to sodium acetate 428.
2 g (5.14 mol), dissolved in a solution of 425.7 g (2.34 mol) of D-mannitol and distilled water for injection (6.1 L), acetic acid (8 L) and 2 M sulfuric acid
1864 ml (3.73 mol) were added. After stirring at room temperature for 30 minutes, seed crystals
16 g was added and further stirred for 2 hours. The obtained crystals were collected by filtration and washed with a mixed solution of distilled water for injection / acetic acid (1: 1) (20 L). Air drying was performed until the weight became constant. Yield 1390g
(74%)

Example 21 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 94.8 g (138 mmol) in 25% aqueous ammonia 1
0.4 g (153 mmol) and distilled water for injection (406 ml) were dissolved, and acetic acid (500 ml) and 88.3 g (90 mmol) of 10% sulfuric acid were added. 80 mg of seed crystals were added, and the mixture was stirred at room temperature for 2.5 hours. Thereafter, stirring was performed once every 30 minutes for a total of 5 hours, and the mixture was allowed to stand overnight. After adding a mixed solution of distilled water / acetic acid for injection (1: 1) (500 ml), the crystals were collected by filtration, and a mixed solution of distilled water / acetic acid for injection (1: 1) was added.
(200 ml) three times. Air drying was performed until the weight became constant. Yield: 75.5 g (71.5%) The physicochemical data was the same as in Example 1.

Example 22 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
Crystalline of -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and acetic acid 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate 10 g (14.6 mol) in 25% aqueous ammonia 2.18
g (32.1 mmol), a solution of 2.66 g (14.6 mol) of D-mannitol and distilled water for injection (38 ml) were added, and acetic acid (50 ml) and 12 ml (24.0 mol) of 2M sulfuric acid were added. After stirring at room temperature for 30 minutes, seed crystals
0.1 g was added and the mixture was further stirred for 1.5 hours. The obtained crystals were collected by filtration, and mixed with distilled water for injection / acetic acid (1: 1) (50 ml).
2 times with a mixture of distilled water for injection / acetic acid (1: 4) (50 ml)
Washed once with an ethanol / acetic acid (1: 1) mixture (50 ml). Air drying was performed until the weight became constant. Yield 6.53
g (60%) The physicochemical data was the same as in Example 1.

Example 23 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-Cephem-4-carboxylate and acetic acid crystals Disodium 3- [4- () obtained by column chromatography carried out according to the method of Reference Example 25. 1-methyl-4-
Pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonateamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate The aqueous solution was concentrated under reduced pressure, 52.2 g (content 19.2%, 13.7 mmol)
Was prepared. Acetic acid (52.2ml) and 1M sulfuric acid 27.4ml
(27.4 mmol) was added. Seed crystals were added, and the mixture was stirred at room temperature for 5 hours and left standing for 1 hour. The crystals are collected by filtration and distilled water for injection / acetic acid
(1: 1) The mixture was washed with a mixed solution (100 ml) and distilled water for injection (200 ml). Vacuum drying was performed until the weight became constant. Yield 7.02g
(68.8%)

Example 24 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate Sodium acetate 1001 g (12.2 mol) in distilled water for injection 15 L
In the solution, 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl) -2 (Z) [-Ethoxyiminoacetamide] -3-cephem-4-carboxylate (3740 g, 5.46 mol) was added and dissolved. Filter through a 0.2 μm membrane filter,
Washed with 9 L of distilled water for injection. After adding 28 L of acetic acid and then 4.35 L of 2M sulfuric acid to the mixed solution of the filtrate and the washing solution, the seed crystal was added.
3.74 g was added and the mixture was stirred at 30 ° C for 5 hours. The precipitated crystals were collected by filtration, and 75 L of a mixed solution of distilled water / acetic acid for injection (1: 1), 19 L of a mixed solution of distilled water / acetic acid for injection (1: 4), ethanol /
The mixture was washed by stirring with 19 L of a mixed solution of acetic acid (1: 1).
The crystals were dried by passing air at a dew point of -5 ° C. Yield 2011 g
(49%) FIG. 5 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in this example. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Reference Example 1 Benzhydryl 7β-amino-3- [4- (4-pyridyl) -2-thiazolylthio] -3-cephem-4-carboxylate Benzhydryl 7β-phenylacetylamino-3- [4- (4
-Pyridyl) -2-thiazolylthio] -3-cephem-4-carboxylate 4.15 g (6.0 mmol) was dissolved in dichloromethane 60 ml, pyridine 0.726 ml (9.0 mmol), phosphorus pentachloride 1.87 under ice cooling.
g (9.0 mmol) were sequentially added, and the mixture was stirred under ice cooling for 1 hour. 8.0 ml of isobutanol was added to the reaction solution at once, and the mixture was stirred at room temperature for 1 hour. After dropping 300 ml of isopropyl ether, 10
Stirred for minutes. The solvent was removed by decantation. The residual oil was suspended in 600 ml of ethyl acetate, 200 ml of a saturated aqueous solution of sodium hydrogen carbonate was added dropwise, and the mixture was stirred for 15 minutes. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. 60 ml of isopropyl ether was added to the residue, and the precipitated powder was collected by filtration, washed with 20 ml of isopropyl ether, and dried under reduced pressure. Yield 3.1
8g (95%) ¹ H-NMR (DMSO-d ₆ ) δ: 3.51, 3.77 (2H, ABq, J = 18Hz),
4.82 (1H, d, J = 5Hz), 5.02 (1H, d, J = 5Hz), 7.01 (1H, s),
7.2-7.5 (10H, m), 7.71 (1H, s), 7.73, 8.68 (each 2H,
d, J = 6Hz).

Reference Example 2 Benzhydryl 7β-t-butoxycarbonylamino-3-
[4- (4-pyridyl) -2-thiazolylthio] -3-cephem-4-carboxylate benzhydryl 7β-amino-3- [4- (4-pyridyl) -2-thiazolylthio] -3-cephem-4-carboxy Rate 3.0g
(5.37 mmol) was suspended in 40 ml of tetrahydrofuran, and 2.34 g (10.7 mmol) of dibutyl dicarbonate was added. Stir at room temperature for 18 hours and concentrate under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate and applied to a silica gel column (30 g). Fractions containing the title compound eluted with ethyl acetate were collected, and the solvent was distilled off under reduced pressure. 50 ml of isopropyl ether was added to the residue,
The precipitated powder was collected by filtration, washed with 10 ml of isopropyl ether, and dried under reduced pressure. Yield 1.4 g (40%) ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.51, 3.74 (2H, AB
q, J = 18Hz), 5.04 (1H, d, J = 5Hz), 5.40 (1H, d, J = 10Hz),
5.69 (1H, dd, J = 5 & 10Hz), 7.00 (1H, s), 7.1-7.5 (10H,
m), 7.70-7.74 (3H, m), 8.67 (2H, d, J = 6Hz).

Reference Example 3 Benzhydryl 7β-t-butoxycarbonylamino-3-
[4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide benzhydryl 7β-t-butoxycarbonylamino-3-
1.3 g (1.97 mmol) of [4- (4-pyridyl) -2-thiazolylthio] -3-cephem-4-carboxylate is dissolved in 2.6 ml of dimethylformamide, and 1.23 ml (19.7 mmol) of iodomethane is dissolved.
Was added and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, 100 ml of diethyl ether was added to the residue, and the mixture was stirred for 10 minutes. The precipitated powder was collected by filtration, washed with 20 ml of diethyl ether, and dried under reduced pressure. Yield 1.57 g (99%) ¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (9H, s), 3.68, 3.97 (2H, A
(Bq, J = 18Hz), 4.34 (3H, s), 5.29 (1H, d, J = 5Hz), 5.67
(1H, dd, J = 5 & 8.6Hz), 6.96 (1H, s), 7.1-7.5 (10H, m),
8.16 (1H, d, J = 8.6Hz), 8.53, 9.00 (each 2H, d, J = 6.6H
z), 9.02 (1H, s).

Reference Example 4 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate dihydrochloride benzhydryl 7β-t-butoxycarbonylamino -3-
1.3 g of [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide (1.62 mmo
l) was dissolved in acetonitrile (3 ml) and concentrated hydrochloric acid (3 ml) was added.
Stirred at 5-40 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and 30 ml of ethanol was added to the residue. The precipitated powder is collected by filtration,
After washing with 10 ml of ethanol, it was dried under reduced pressure. Yield 239
mg (31%) ¹ H-NMR (DMSO-d ₆ ) δ: 3.82, 3.96 (2H, ABq, J = 18Hz),
4.35 (3H, s), 5.27 (1H, d, J = 5Hz), 5.40 (1H, d, J = 5Hz),
8.61, 9.06 (each 2H, d, J = 6Hz), 9.16 (1H, s).

Reference Example 5 4- (4-pyridyl) -1,3-thiazol-2-thiol sodium salt An aqueous 8N sodium hydroxide solution (1.25 L, 10 mol) was charged with 4- (4-pyridyl) -1,3-triol. 194 g (1.0 mol) of thiazole-2-thiol was added as a powder, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with an 8N aqueous sodium hydroxide solution (0.4 L), and the obtained wet crystals were recrystallized from isopropyl alcohol (200 ml) to give the title compound 166 g (0.77 mol) as yellow crystals. Was. Yield 77%. 272 ° C (decomposition). _{Anal Calcd for C 8 H 5 N} 2 S 2 Na · 0.75H 2 O: C 41.82, H 2.8
5, N 12.19. Found: C 41.78, H 2.98, N 12.11. ¹ H-NMR (DMSO-d ₆ ) δ: 7.35 (1H, s), 7.71 (2H, d, J = 6.2H
z), 8.48 (2H, d, J = 6.2Hz).

Reference Example 6 4- (4-pyridyl) -1,3-thiazol-2-thiol sodium salt 4- (4-pyridyl) -1,3-thiazol-2-thiol 194 g (1.0 mol
l) was suspended in methanol (1 L), and a powder of 71.5 g (1.2 mol) of sodium methylate was added at 25 ° C. After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure to 50 to 60 ml and stored in a refrigerator overnight. The precipitated crystals were collected by filtration, and were added in the presence of phosphorus pentoxide.
160 g (0.74 mol) of the title compound by drying under reduced pressure at ℃
I got Yield 74%.

Reference Example 7 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[(Methylsulfonyl) oxy] -3-cephem-4-carboxylate benzhydryl 7β-[(phenylacetyl) amino] -3-
Hydroxy-3-cephem-4-carboxylate 500 g (1 mol)
Was dissolved in acetonitrile (2 L), and 183 ml (1.05 mol) of ethyldiisopropylamine was added dropwise at −40 ° C. over 10 minutes with stirring. Then 86 ml of methanesulfonyl chloride (1.1mo
l) was added dropwise over 10 minutes, and the mixture was stirred at -40 ° C for 40 minutes. The reaction solution was poured into 8 L of ice water, and the precipitate was collected by filtration. The precipitate was washed with water (2 L) and ethyl acetate (300 ml), and dried under reduced pressure to obtain 544 g (0.94 mol) of the title compound as pale yellow crystals. 94% yield. 157 ° C. Anal Calcd for C ₂₉ H ₂₆ N ₂ O ₇ S ₂ : C 60.19, H 4.53, N 4.
84, S 11.08.Found: C59.86, H 4.72, N 4.73, S 10.7
_{^{7. 1 H-NMR (CDCl 3}} ) δ: 2.79 (3H, s), 3.48-3.75 (4H, m), 5.
02 (1H, d, J = 5.2Hz), 5.90 (1H, dd, J = 5.2Hz, 8.8Hz), 6.2
4 (1H, d, J = 8.8Hz), 6.93 (1H, s), 7.24-7.41 (15H, m)

Reference Example 8 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[(Methylsulfonyl) oxy] -3-cephem-4-carboxylate benzhydryl 7β-[(phenylacetyl) amino] -3-
Hydroxy-3-cephem-4-carboxylate 500 g (1 mol)
Was dissolved in acetone (2 L) and 86 ml (1.1 mol) of methanesulfonyl chloride was added dropwise at -20 ° C over 10 minutes with stirring. Then 183 ml (1.05 mol) of ethyldiisopropylamine
Was added dropwise over 30 minutes and stirred at -20 ° C for 40 minutes.
The reaction solution was poured into 8 L of ice water, and the precipitate was collected by filtration. Then water
(2 L), washed with ethyl acetate (300 ml) and dried under reduced pressure to obtain 523 g (0.90 mol) of the title compound. 90% yield.

Reference Example 9 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[4-Pyridyl-2-thiazolylthio] -3-cephem-4-carboxylate Sodium salt of 4- (4-pyridyl) -1,3-thiazole-2-thiol 194 g (1 mol) prepared by the method of Reference Example 5. Was suspended in tetrahydrofuran (1.5 L), and cooled under ice cooling to benzhydryl.
7β-[(phenylacetyl) amino] -3-[(methylsulfonyl) oxy] -3-cephem-4-carboxylate 196 g (0.91 m
ol) in tetrahydrofuran (3.0 L) was added to 3
It was added dropwise over 0 minutes. After stirring at 0 ° C. for 2 hours, saturated saline (7 L) was added, and the mixture was extracted with ethyl acetate (5 L). The organic layer was washed with saturated saline (5 L) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the title compound as crystals. The crystals were suspended in ethyl acetate (0.5 L), collected on a glass filter, and washed with methanol (1 L × 2). Drying under reduced pressure gave 412 g (0.71 mol) of the title compound. Yield 78%. 134 ° C. Anal Calcd for C ₃₆ H ₂₈ N ₄ O ₄ S ₃・ 0.5H ₂ O: C 63.05, H 4.1
1, N 8.17, S 14.02.Found: C 63.16, H 4.15, N 8.2
^{. 7, S 13.98 1 H-} NMR (CDCl 3) δ: 3.41-3.73 (4H, m), 5.02 (1H, d, J = 4.
8Hz), 5.84 (1H, dd, J = 4.8Hz, 8.8Hz), 6.23 (1H, d, J = 8.8
Hz), 6.97 (1H, s), 7.27-7.72 (17H, m), 7.73 (1H, s),
8.67 (1H, d, J = 6.2Hz).

Reference Example 10 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[4-Pyridyl-2-thiazolylthio] -3-cephem-4-carboxylate 225 g of 4- (4-pyridyl) -1,3-thiazole-2-thiol (1.16 m
ol) is suspended in tetrahydrofuran (1.5 L) and 28% at 25 ° C.
235 g (1.22 mol) of sodium methylate-methanol solution
Was added dropwise over 10 minutes and stirred for 1 hour. The reaction solution was cooled on ice, and 479 g (0.83 mol) of benzhydryl 7β-[(phenylacetyl) amino] -3-[(methylsulfonyl) oxy] -3-cephem-4-carboxylate was added to tetrahydrofuran (3.5
What was dissolved in L) was added dropwise over 30 minutes. 1 at 0 ° C
After stirring for an hour, a mixture of acetic acid (50 mL), methanol (5 L) and water (7 L) was added dropwise over 30 minutes. Stir at 0 ° C for 2 hours,
The precipitated crystals were collected by filtration. The crystals collected by filtration are treated with methanol (1
L × 2) and dried under reduced pressure to give 438 the title compound.
g (0.63 mol) was obtained. Yield 76%.

Reference Example 11 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide benzhydryl 7β-[(phenylacetyl) amino] -3-
300 g (0.43 mol) of [4-pyridyl-2-thiazolylthio] -3-cephem-4-carboxylate in tetrahydrofuran (0.6 L)
And 324 g (2.17 mol) of methyl iodide was added at 25 ° C. After stirring for 8 hours, the reaction solution was poured into ethyl acetate (6 L), and the precipitate was collected by filtration. The precipitate collected by filtration is ethyl acetate
(0.5 L), washed with diethyl ether (1 L) and dried under reduced pressure to obtain 351 g (0.42 mol) of the title compound as a yellow powder. Yield 9
7%. ¹ H-NMR (CDCl ₃ ) δ: 3.58 (2H, dd, J = 4.8Hz, 6.6Hz), 3.74
(2H, brs), 4.35 (3H, s), 5.11 (1H, d, J = 4.8Hz), 5.89 (1
(H, d, J = 4.8Hz), 6.95 (1H, s), 7.18-7.42 (15H, m), 8.30
(2H, d, J = 6.6Hz), 8.41 (1H, s), 8.75 (2H, d, J = 6.6Hz).

Reference Example 12 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide benzhydryl 7β-[(phenylacetyl) amino] -3-
300 g (0.43 mol) of [4-pyridyl-2-thiazolylthio] -3-cephem-4-carboxylate was dissolved in N, N-dimethylformamide (0.6 L), and 648 g of methyl iodide (4.34 m
ol) was added. After stirring for 16 hours, the reaction solution was poured into ethyl acetate (6 L), and the precipitate was collected by filtration. Ethyl acetate (0.5 L),
After washing with diethyl ether (1 L) and drying under reduced pressure, 317 g (0.39 mol) of the title compound was obtained as a yellow powder. 89% yield.

Reference Example 13 Benzhydryl 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate chloride monohydrochloride Phosphorus pentachloride 312 g (1.44 g) mol) were suspended in dichloromethane (2.8 L), 115 g (1.44 mol) of pyridine was added dropwise over 10 minutes under ice cooling, and the mixture was stirred for 30 minutes. Then benzhydryl 7
400 g (0.48 mol) of β-[(phenylacetyl) amino] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide powder for 10 minutes And stirred for 1 hour. The reaction solution was cooled to −10 ° C., isobutyl alcohol (5.6 L) was added, and the mixture was stirred at 25 ° C. for 3 hours. Then, ethyl acetate (6 L) was added, and the mixture was further stirred for 3 hours. The precipitate was collected by filtration on a glass filter, washed with ethyl acetate (0.5 L) and diethyl ether (1 L), and dried under reduced pressure to obtain 270 g (0.42 mol) of the title compound as a pale yellow powder. 87% yield. ¹ H-NMR (DMSO-d ₆ ) δ: 3.94 (2H, brs), 4.35 (3H, s), 5.3
2 (1H, d, J = 5.0Hz), 5.45 (1H, d, J = 5.0Hz), 6.99 (1H, s),
7.25-7.40 (10H, m), 8.59 (2H, d, J = 7.0Hz), 9.07 (2H,
d, J = 7.0Hz), 9.19 (1H, s).

Reference Example 14 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate dihydrochloride benzhydryl 7β-amino-3- [4 430 g (0.66 mol) of-(1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate chloride monohydrochloride was suspended in acetonitrile (3.5 L), and concentrated hydrochloric acid (3.5 L) Was added and stirred for 10 minutes. Then, ethyl acetate (7 L) was added to the reaction solution, and the mixture was stirred for 5 hours. The precipitate is collected by filtration, and acetonitrile (1 L x 2)
And washed. Drying under reduced pressure gave 236 g (0.49 mol) of the title compound as pale yellow crystals. Yield 74%. Melting point 202 ° C (decomposition). Anal Calcd for C ₁₆ H ₁₄ N ₄ O ₃ S ₃・ 2HCl: C40.08, H3.36, N 1
1.69, S 20.07.Found: C 39.83, H 3.43, N 11.78, S 2
^{. 0.03 1 H-NMR (DMSO} -d 6) δ: 3.90 (2H, dd, J = 17.2Hz, 17.6Hz),
4.35 (3H, s), 5.26 (1H, d, J = 5.0Hz), 5.42 (1H, d, J = 5.0
Hz), 8.61 (2H, d, J = 7.0Hz), 9.05 (2H, d, J = 7.0Hz), 9.1
7 (1H, s).

Reference Example 15 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate dihydrochloride 31.2 g (144 mmol) of phosphorus pentachloride was added. The suspension was suspended in dichloromethane (250 ml), 11.5 g (144 mmol) of pyridine was added dropwise over 10 minutes under ice cooling, and the mixture was stirred for 30 minutes. Then benzhydryl
41.7 g (48 mmol) of powder of 7β-[(phenylacetyl) amino] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate iodide was added for 10 minutes. And stirred for 1 hour. The reaction solution was cooled to -10 ° C, isobutyl alcohol (250 ml) was added, and the mixture was stirred at 25 ° C for 3 hours. The reaction solution was concentrated to about 100 ml, and acetonitrile (250 ml) and then concentrated hydrochloric acid (250 ml) were added.
Stirred for hours. The precipitate was collected by filtration, and acetonitrile (100 ml
× 2). After drying under reduced pressure, 14.5 g of the title compound (0.30mo
l) was obtained. 63% yield.

Reference Example 16 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate monohydrochloride 7β-amino-3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate lyophilized product 5.8
g (14.3 mmol) was dissolved in 290 ml of water, and adjusted to pH 1.3 by adding 1N hydrochloric acid under ice-cooling. After the solution was concentrated under reduced pressure to about 30 ml, 70 ml of ethanol was gradually added under ice-cooling, shaken, and allowed to stand under ice-cooling for 2 hours. The precipitated crystals were collected by filtration, washed with 30 ml of ethanol / water (5: 1), and dried under reduced pressure.
Yield 4.1 g (65%) Melting point: 120-140 ° C (decomposition) Anal Calcd for C ₁₆ H ₁₅ N ₄ O ₃ S ₃ Cl ・ 3.0H ₂ O: C 38.67, H
4.26, N 11.27, Cl 8.00.Found: C 38.58, H 3.92, N 1
^{1.26, Cl 8.18 1 H-NMR} (D 2 O) δ:. 3.64, 3.99 (2H, ABq, J = 18Hz), 4.37
(3H, s), 5.23 (1H, d, J = 5Hz), 5.44 (1H, d, J = 5Hz), 8.3
1, 8.76 (each 2H, d, J = 7Hz), 8.51 (1H, s) .IR (KBr) cm ^-1 : 3400, 1800, 1770, 1640, 1530, 1405,
1330, 1190, 1020.

Reference Example 17 2- (5-dichlorophosphorylamino-1,2,4-thiadiazole
1.46 g (7.0 mmol) of phosphorus pentachloride was suspended in 4.17 ml of ethyl acetate, and the mixture was stirred under ice cooling for 5 minutes. Under ice-cooling and stirring, 600 mg (2.77 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetic acid was added at once and dissolved.
The mixture was stirred for 30 minutes under ice cooling. The reaction solution was cooled under ice cooling with toluene 1
It was diluted with 6.8 ml and dissolved. To this solution was added 11.1 ml of a saturated saline solution cooled to -5 ° C or lower, and the mixture was stirred for 5 minutes under ice-cooling. The reaction solution was transferred to a separating funnel, and the organic layer was separated without shaking. The organic layer was dried with magnesium sulfate. After filtration, the mother liquor was distilled off under reduced pressure. The mixture was allowed to stand under ice cooling for 30 minutes (crystal precipitation from the residual oil). 5.67 ml of diisopropyl ether / n-hexane (1: 1) was added, and the crystals were pulverized with a spatula. The mixture was allowed to stand under ice cooling for 15 minutes. The precipitated crystals were collected by filtration, and diisopropyl ether / n-hexane
(1: 1) After washing with 5.67 ml, it was dried under reduced pressure. yield
631mg (64%) Melting point: 116-119 ℃ Anal Calcd for C ₆ H ₆ N ₄ O ₃ SCl ₃ P: C 20.50, H 1.72, N 1
5.94, P 8.81.Found: C20.52, H 1.77, N 15.99, P 8.
_{^{90. 1 H-NMR (CDCl 3}} ) δ: 1.42 (3H, t, J = 7Hz), 4.45 (2H, q, J
= 7Hz), 8.81 (1H, br s) .IR (KBr) cm ^-1 : 3063, 2984, 1784, 1593, 1223, 1057.

Reference Example 18 2- (5-dichlorophosphorylamino-1,2,4-thiadiazole
-3-yl) -2 (Z) -ethoxyiminoacetyl chloride 78 g (375 mmol) of phosphorus pentachloride was suspended in 225 ml of ethyl acetate, and stirred under ice-cooling with stirring for 2- (5-amino-1,2,4-thiadiazole- Three
-Yl) -2 (Z) -ethoxyiminoacetic acid 32.4 g (150 mmol) was added. The mixture was stirred for 30 minutes under ice cooling. The reaction solution was diluted with 900 ml of toluene and dissolved under ice cooling. To this solution was added 600 ml of a saturated saline solution cooled to -5 ° C or lower, and the mixture was stirred under ice cooling for 10 minutes. The reaction solution was transferred to a separating funnel, and the organic layer was separated. The organic layer was dried with magnesium sulfate. After filtration, the mother liquor was distilled off under reduced pressure (crystal precipitation). The crystals were pulverized with a spatula after adding 300 ml of diisopropyl ether. After stirring for 30 minutes under ice-cooling, the mixture was allowed to stand for 30 minutes. The precipitated crystals were collected by filtration, washed with 20 ml of diisopropyl ether, and dried under reduced pressure. Yield 23.5g (45%) Melting point: 116-119 ° C Anal Calcd for C ₆ H ₆ N ₄ O ₃ SCl ₃ P: C 20.50, H 1.72, N 1
5.94, P 8.81.Found: C20.52, H 1.77, N 15.99, P 8.
_{^{90. 1 H-NMR (CDCl 3}} ) δ: 1.42 (3H, t, J = 7Hz), 4.45 (2H, q, J
= 7Hz), 8.81 (1H, br s) .IR (KBr) cm ^-1 : 3063, 2984, 1784, 1593, 1223, 1057.

Reference Example 19 2- (5-dichlorophosphorylamino-1,2,4-thiadiazole
-3-yl) -2 (Z) -ethoxyiminoacetyl chloride 1.0 kg (4.6 mol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetic acid The suspension was suspended in 2.4 L of ethyl acetate and 1.6 L of diisopropyl ether, and cooled to -1 ° C or lower while replacing with nitrogen gas. 2.0 kg (9.6 mol) of phosphorus pentachloride
The mixture was added at 5 ° C or lower and stirred for 30 minutes. 2.0 L of diisopropyl ether, 120 ml of water and 12 L of n-hexane were added at 2 ° C or less,
The mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration under a stream of nitrogen, and diisopropyl ether / n-hexane (1:
2) The column was washed with 2.0 L and 2.0 L of n-hexane, and dried under a nitrogen stream. Yield 876.0g (49.7%)

Reference Example 20 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonate Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate 1.43 g (1.96 mmol)
Was slowly dissolved in 14 ml of 1% (v / v) aqueous acetic acid at room temperature. The solution was loaded on a SP-207 column (60 ml). 2% (w / v) saline
After elution with 180 ml and 60 ml of 3% (v / v) ethanol water,
A 1500 ml fraction containing the title compound eluted with% (v / v) aqueous ethanol was collected and concentrated under reduced pressure to about 20 ml. Under ice-cooling, 6N hydrochloric acid (about 1.5 ml) was gradually added with shaking to adjust the pH to 0.5, whereby a white powder precipitated. After leaving still for 30 minutes under ice cooling, the precipitated powder was collected by filtration and distilled water 2 ml
And washed three times. The mixture was dried under reduced pressure to a constant weight using Molecular Sieves 3A (1/16) as a desiccant.
Yield 800mg (59%) Anal Calcd for C ₂₂ H ₂₁ N ₈ O ₈ S ₄ P ・ 2.0H ₂ O: C 36.66, H 3.
50, N 15.55, P 4.30.Found: C 36.94, H 3.46, N 15.
^{. 57, P 3.95 1 H-} NMR (DMSO-d 6) δ: 1.23 (3H, t, J = 7Hz), 3.58, 3.94
(2H, ABq, J = 18Hz), 4.17 (2H, q, J = 7Hz), 4.33 (3H, s),
5.32 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5 & 8Hz), 8.51 (2H,
d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m), 9.70 (1H, d, J = 8
Hz) .IR (KBr) cm ^-1 : 3055, 1778, 1682, 1643, 1520, 1385,
1190, 1038.

Reference Example 21 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonate Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate 128 g (1.96 mmol)
Was slowly dissolved in 1.28 L of 1% (v / v) aqueous acetic acid at room temperature. The solution was loaded on a SP-207 column (2.5 L). 1% (v / v) aqueous acetic acid
Fraction containing the title compound eluted with 9L and then with 0.1M sodium acetate: 0.1M acetic acid: ethanol (960: 30: 110)
32 L was collected and concentrated under reduced pressure to about 700 ml. Under ice cooling, slowly add 6N hydrochloric acid (480ml) while shaking,
When the pH was adjusted to 0.5, a white powder precipitated. 30 under ice cooling
After standing for a minute, the precipitated powder was collected by filtration and washed with 300 ml of distilled water. The mixture was dried under reduced pressure to a constant weight using Molecular Sieves 3A (1/16) as a desiccant. yield
60.9g (68%) Anal Calcd for C ₂₂ H ₂₁ N ₈ O ₈ S ₄ P ・ 2.0H ₂ O: C 36.66, H
3.50, N 15.55, P 4.30.Found: C 36.94, H 3.46, N 1
^{5.57, P 3.95 1 H-NMR} (DMSO-d 6) δ:. 1.23 (3H, t, J = 7Hz), 3.58, 3.94
(2H, ABq, J = 18Hz), 4.17 (2H, q, J = 7Hz), 4.33 (3H, s),
5.32 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5 & 8Hz), 8.51 (2H,
d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m), 9.70 (1H, d, J = 8
Hz) .IR (KBr) cm ^-1 : 3055, 1778, 1682, 1643, 1520, 1385,
1190, 1038.

Reference Example 22 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl ) -2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4- Carboxylate 1.30 kg (2.71
mol) was suspended in 7.80 L of water, and 3M sodium acetate was added under ice-cooling.
1.81 L (5.42 mol), triethylamine 2.0 L (14.4 mo
l) was added sequentially. 2- (5-dichlorophosphorylamino-1,
1143.7 g (3.25 mol) of 2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetyl chloride was dissolved in 3.1 L of tetrahydrofuran, cooled to −20 ° C. or lower, and added to the above reaction solution. The temperature was raised to 15-25 ° C, and 3.78 L of 3M sodium acetate (1
7.4 mol) and 6.50 L of ethyl acetate were sequentially added, and the layers were separated. 30 L of ethanol was added dropwise to the aqueous layer, and after cooling with ice, the precipitated powder was collected by filtration. 6.5 L of water / ethanol (1: 2), 13 L of ethanol
Washed sequentially with L. After air-drying, it was dissolved in dilute saline (19.5 L) to give a stock solution for column chromatography. Yield 2
3.3kg (content 6.61%, yield 78%)

Reference Example 23 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl ) -2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4- Carboxylate 5.0 g (10.41 m
mol) was suspended in 30 mL of water / tetrahydrofuran (5: 1), and 6.9 mL (20.8 mmol) of 3M sodium acetate was added dropwise.
Under ice-cooling, 7.2 mL (52.0 mmol) of triethylamine was added. 2- (5-dichlorophosphorylamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetyl chloride 5.
87 g (16.7 mmol) was dissolved in tetrahydrofuran 12 mL,
It was dropped into the above reaction solution. The temperature was raised to 15 to 30 ° C., and 28.4 mL (85.3 mmol) of 3M sodium acetate and 25 mL of ethyl acetate were sequentially added, followed by separation. 120 mL of ethanol is added dropwise to the aqueous layer,
After cooling on ice, the precipitated powder was collected by filtration and mixed with water / ethanol (1: 1).
2) After that, the resultant was sequentially washed with ethanol and dried by aeration. yield
7.78g (content 66.2%, yield 70%)

Reference Example 24 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl ) -2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 7β-amino-3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4- 5.00 g carboxylate (10.4 m
mol) was suspended in 33 mL of water / acetonitrile (10: 1), and a portion of 19.1 mL (70.7 mmol) of triethylamine was added under ice-cooling. Dissolve 5.87 g (16.6 mmol) of 2- (5-dichlorophosphorylamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetyl chloride in 12 mL of acetonitrile,
While the remaining amount of triethylamine was being added dropwise, the reaction solution was added dropwise. Warm to 25 ° C and add 3M sodium acetate 19.1 mL
(57.2 mmol) and 25 mL of ethyl acetate were sequentially added, and the layers were separated. 120 mL of ethanol was added dropwise to the aqueous layer, and after cooling with ice, the precipitated powder was collected by filtration. Powder was mixed with water / ethanol (1: 2) 2
The extract was washed sequentially with 5 mL and 50 mL of ethanol, and dried by aeration.
Yield 6.78g (content 73.1%, yield 68%)

Reference Example 25 Disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonatoamino-1,2,4-thiadiazol-3-yl Purification of) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- ( 5.33 kg of aqueous solution of 5-phosphonateamino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate (content 4.98%, 0.516 mol) SP- The residue was subjected to 207 column chromatography (18 L), and eluted with dilute saline and ethanol water in that order. The obtained mainstream liquid was concentrated using an evaporator. 2.16 kg recovered (content 14.4%, yield 83%)

Reference Example 26 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonate Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate aqueous solution (1.89 kg, content 16.1%, 0.419 mol) in activated carbon (15.3 g) Was added and stirred. After filtering off the activated carbon, washing with water, water was added to the filtrate and 3.
96 kg. Acetic acid (95.0 mL, 1.68 mol) was added, and ethanol (4 L) was added. After adding 154 mL (0.922 mol) of 6N hydrochloric acid, the mixture was ice-cooled, and the precipitated powder was collected by filtration. The powder was washed sequentially with 0.71 L of water / ethanol (1.0: 1.1) and 2.1 L of ethanol,
It was air dried. Yield 249.7 g (content 90.8%, yield 80%)

Reference Example 27 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonate Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate aqueous solution 57.3 g (content
8.73%, 6.86 mmol) was added to make up to 65 g. At room temperature,
Acetic acid 1.57 mL (26.2 mmol), after adding ethanol 65 mL, 10%
8.7 mL (8.88 mmol) of sulfuric acid was added dropwise. After stirring under ice cooling,
The precipitated powder was collected by filtration. Powder was mixed with water / ethanol (1: 1) 1
The mixture was sequentially washed with 0 mL and 30 mL of ethanol, and dried under reduced pressure. Yield 3.8 g (81%)

Reference Example 28 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate disodium 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonate Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate aqueous solution 664 g (content 1
2.1%, 0.114 mol) with water to make 1044 g. At 10 ° C. or lower, 56.9 mL (0.341 mol) of 6N hydrochloric acid was added dropwise, and after stirring, the precipitated powder was collected by filtration. The powder was washed with 563 mL of water and dried under reduced pressure. Yield 81.4 g (content 81.6%, yield 81%)

Reference Example 29 4- (4-pyridyl) -1,3-thiazol-2-thiol 4- (4-pyridyl) -1,3-thiazol-2-thiol / hydrobromide 89.3 g (0.32 mol) was suspended in 627 ml of water under a nitrogen stream, and dissolved by adding 110.5 g (0.69 mol) of a 25% aqueous sodium hydroxide solution. The insolubles were filtered and washed with 100 ml of water.
The filtrate was adjusted to pH 6.8 by adding 31 ml of 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with 20 ml of water and 20 ml of methanol. The obtained crystals were suspended in 627 ml of methanol, stirred for 2 hours, filtered and dried. Yield 47.6 g (75.6%)

Reference Example 30 Benzhydryl 7β-[(phenylacetyl) amino] -3-
[4- (4-pyridyl) -2-thiazolylthio] -3-cephem-4-carboxylate benzhydryl 7β-[(phenylacetyl) amino] -3-
900 g (1.56 mol) of [(methylsulfonyl) oxy] -3-cephem-4-carboxylate was dissolved in 3.6 L of tetrahydrofuran and cooled to -3 ° C. Reference Example 2 while maintaining the same temperature
A 28% sodium methylate-methanol solution 360 g (1.87 mol) of 4- (4-pyridyl) -1,3-thiazol-2-thiol 362.5 g (1.87 mol) obtained in the same manner as in Example 9, tetrahydrofuran 720 ml The solution was added and stirred for 1.5 hours. Acetic acid 1
After adding 8.7 g and stirring for 30 minutes, methanol 9 L, water 5.4 L
Was added and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with 16 L of methanol, and dried under reduced pressure. Yield 884 g (84%)

Experimental Example 1 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate and acetic acid 102.4 mg (0.131 mmol)
And 27.6 mg (0.328 mmol) of sodium bicarbonate were filled into a vial, and 0.918 ml of physiological saline was gradually added. These compounds dissolved while generating carbon dioxide gas to obtain a clear solution. Dilute this solution with physiological saline to 2.0 ml and add 5
A dosing solution having a concentration of 0 mg / ml was prepared.

Experimental Example 2 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate and propionic acid in crystals 101.9 mg (0.129
mmol) and 27.1 mg (0.322 mmol) of sodium bicarbonate were filled in a vial, and 0.902 ml of physiological saline was gradually added. These compounds dissolve while generating carbon dioxide gas,
A clear solution was obtained. Dilute this solution with physiological saline 2.0ml
Was prepared at a concentration of 50 mg / ml.

Experimental Example 3 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.7 mg (0.403 mmol) of sodium carbonate and 29.2 mg (0.168 mmol) of sodium hydrosulfite were filled in a vial, and 5 ml of physiological saline was added to obtain a clear solution.

Experimental Example 4 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.7 mg (0.403 mmol) of sodium carbonate and 21.2 mg (0.168 mmol) of sodium sulfite were charged into a vial, and 5 ml of physiological saline was added to obtain a clear solution.

Experimental Example 5 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.7 mg (0.403 mmol) of sodium carbonate and 0.42 mg (0.003 mmol) of sodium sulfite were filled in a vial, and 5 ml of physiological saline was added to obtain a clear solution.

Experimental Example 6 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.8 mg (0.403 mmol) of sodium carbonate were filled in a vial, and 5 ml of a 5% glucose solution containing 1.25 mg of sodium sulfite was added to obtain a clear solution.

Experimental Example 7 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.8 mg (0.403 mmol) of sodium carbonate was filled into a vial, and 5 ml of a 5% glucose solution containing 1.25 mg of sodium bisulfite was added to obtain a clear solution.

Experimental Example 8 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.8 mg (0.403 mmol) of sodium carbonate was filled into a vial, and 5 ml of a 5% glucose solution containing 1.25 mg of sodium pyrosulfite was added to obtain a clear solution.

Experimental Example 9 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 250 mg (0.336 mmo
l), 42.8 mg (0.403 mmol) of sodium carbonate was filled into a vial, and 5% dextrose solution containing 1.25 mg of L-cysteine 5 m
l was added to give a clear solution.

Experimental Example 10 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate.monoacetic acid solvate 567 mg (0.76 mmol),
A vial was charged with 381.6 mg (2.19 mmol) of L-arginine and 4.6 mg (0.036 mmol) of sodium sulfite, and 50 ml of physiological saline was added to obtain a clear solution.

Experimental Example 11 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate.monoacetic acid solvate 567 mg (0.76 mmol),
A vial was charged with 381.6 mg (2.19 mmol) of L-arginine and 18.4 mg (0.15 mmol) of sodium sulfite, and 50 ml of physiological saline was added to obtain a clear solution.

Experimental Example 12 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate.monoacetic acid solvate 81.4 mg (3.2 equivalents) of L-arginine and 1.8 mg of sodium sulfite in 0.13.4 mg (0.
1 equivalent), and filled into a 13P vial to prepare a preparation in which the space was replaced with low-humidity air. When the obtained preparation was dissolved in 2 mL of physiological saline, it was clear up to 24 hours. When a stability test was performed on the obtained preparation, it was stable as shown in the results of Table 1.

[0122]

[Table 1]

Experimental Example 13 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 76.35 mg (3.0 equivalents) of L-arginine and 18.4 mg of sodium sulfite in 1.135 g
(0.1 equivalent) was added, and filled into a 35K vial to prepare a preparation in which the space was replaced with low-humidity air. When the obtained preparation was dissolved in 10 mL of physiological saline, it was clear up to 24 hours.

Experimental Example 14 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -ethoxyiminoacetamide] -3-cephem-4-carboxylate monoacetic acid solvate 1.135 g was filled in a 35K vial, the space was replaced with low-humidity air, and the product was sealed with a rubber stopper. Was prepared. L-arginine 763.3mg (3.0 equivalents) and sodium sulfite 18.4mg
(0.1 equivalent) dissolved in 10 mL of distilled water, and put into an ampoule 10P.
, And the space was replaced with nitrogen and sealed. When the above preparation was dissolved using the dedicated dissolution solution, the preparation was clear until 24 hours after dissolution, and showed the same quality of the injection as that of Example 14.
Further, the content of L-arginine and the content of sodium sulfite after autoclaving the dedicated solution at 121 ° C. for 20 minutes were measured by a potentiometer and ion chromatography, respectively. As shown in Table 2, the quality of the dedicated solution did not decrease even after autoclaving.

[0125]

[Table 2]

[0126]

The compounds (especially crystals) of the present invention have high solid stability and can be used as antibacterial agents (especially anti-MRSA agents) having excellent quality such as being able to be stably stored for a long period of time. it can.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in Example 1.
The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

FIG. 2 is a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in Example 5.
The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

FIG. 3 is a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in Example 6.
The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

FIG. 4 is a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in Example 7.
The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

FIG. 5 shows the powder X of the compound obtained in Example 24.
It is a line diffraction spectrum (Cu, 40kV, 50mA). The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C086 AA01 AA04 CB26 DA38 MA04 MA52 MA55 NA03 ZB35 4H050 AA01 AA03 AB29 AC90 AD15 BC31

Claims (16)

[Claims] 1. The formula: embedded image [Wherein X represents CH ₃ COOH, CH ₃ CH ₂ COOH or CH ₃ CN, and n represents 0 to 5]. 2. The compound according to claim 1, which is in a crystalline form. 3. The compound according to claim 1, wherein n is 1. 4. The compound according to claim 1, wherein X is CH ₃ COOH. 5. A diffraction angle of 16.32, 19. in powder X-ray diffraction.
The compound according to claim 4, which has a peak near 06, 19.90, 20.98, 23.24 °. 6. X-ray powder diffraction, diffraction angles 11.82, 17.
16, 17.80, 19.32, 20.00, 21.20, 21.78, 22.94, 24.1
The compound according to claim 4, which has a peak near 0, 27.02 °. 7. The method of claim 1, wherein X is CH ₃ CH ₂ COOH.
Or the compound of 2. 8. An X-ray powder diffraction with diffraction angles of 16.30 and 18.
The compound according to claim 7, which has a peak near 84, 19.70, 21.80, 23.18 °. 9. A pharmaceutical composition comprising the compound according to claim 1 or 2. 10. The pharmaceutical composition according to claim 9, which is an antibacterial agent. 11. The formula: embedded image And CH ₃ COOH, CH ₃ CH ₂ CO
A formula characterized by mixing, dissolving and crystallizing OH or CH ₃ CN with water: [Wherein X represents CH ₃ COOH, CH ₃ CH ₂ COOH or CH ₃ CN, and n represents 0 to 5]. 12. CH ₃ COOH, CH ₃ CH ₂ COOH
Or the usage ratio (volume ratio) of CH ₃ CN and water is 1:
The method according to claim 11, wherein the ratio is 0.1 to 10. 13. The formula: embedded image And CH ₃ COOH, CH ₃ CH ₂ CO
A crystal obtained by mixing, dissolving and crystallizing OH or CH ₃ CN with water. 14. The formula: embedded image A disodium salt of the compound represented by the formula: 15. The disodium salt according to claim 14, which is in a crystalline form. 16. A diffraction angle of 17.02, 1 in powder X-ray diffraction.
The disodium salt according to claim 14 or 15, which has a peak near 8.94, 22.86, 23.36, 26.48 °.