KR100449775B1 - New Cephalosporin Derivatives and Intermediates - Google Patents

Abstract

The present invention provides cefem compounds represented by the following structural formula (I ^a ) and pharmaceutically acceptable salts or esters thereof, and also the present invention provides compounds of the following structural formulas (II) and (III) useful as intermediates for their preparation do.

Wherein R is a hydrogen atom or a protecting group, R ¹ is a carboxyl or protected carboxyl group, R ² is lower fluoroalkyl, Z is CH or N and Het is a group of the formula

[Meal, Is or to be.]

The compounds of the present invention have a wide range of antimicrobial activities against Gram-positive bacteria and Gram-negative bacteria, and have little toxicity, and thus are expected to be used as new antimicrobial agents.

Description

Novel cephalosporin derivatives and their intermediates

The present invention relates to a novel cephalosporin derivative and a novel cellulosporin derivative represented by the following general formula (I ^a ) and pharmaceutically acceptable salts, hydrates, organic solvents, and esters readily hydrolyzed in the body of these compounds It is about.

Wherein R is a hydrogen atom, a protecting group, R ¹ is a carboxyl group or a protected carboxyl group, R ² is a methyl or lower monofluoroalkyl group, Z is CH or N, and Het is a group of the formula

Wherein R is a hydrogen atom, a protecting group, R ¹ is a carboxyl group or a protected carboxyl group, R ² is a methyl or lower monofluoroalkyl group, Z is CH or N and Het is a group of the formula

Food, Is or to be.

An object of the present invention is to provide an antimicrobial agent that has a wide range of antimicrobial activities, including Gram-positive bacteria, negative bacteria and durable.

Cephaloridine (Fr 1,384,197), Sephazoline (USP 3,516,997), Sephamandol (USP 3,641,021), Cythiam (Ger. P. 2,607,064), and Cepu, which are classified into first and second generations of conventional cephalosporin antibiotics. Roxime (USP 1,384,197) mainly shows antimicrobial activity centered on Gram-positive bacteria, but its antimicrobial activity against Gram-negative bacteria including Pseudomonas aeruginosa is very weak, and it is known to be unstable against beta lactamase.要 賢, 日本 藥業 時 報社, 1992). The third generation of cephalosporin antibiotics, such as Celltaxim (USP4,098,888), Ceftazidime (Ger. P. 2,921,316) and Ceftriaxone (GB 2,022,090), developed from the late 1970s to the 1980s Compared to second-generation cephalosporin antibiotics, the stability of beta lactamase and antimicrobial activity against gram-negative bacteria were significantly improved, but the antimicrobial activity against gram-positive bacteria was very weak. Palosporin antibiotics have the drawback that they do not show antimicrobial activity against Pseudomonas aeruginosa (American Journal of Medicine, 79 (Suppl. 2A): 14 20, 1985). Also, clinically, antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa is Increasing infections caused by these resistant strains caused by the abuse of this weak third-generation cephalosporin antibiotic have become a serious social problem. In addition, third-generation cephalosporin antibiotics generally have a short blood half-life and therefore have excellent antibacterial activity against pathogens. It does not have the expected therapeutic effect, and in order to maintain the blood concentration that can have a therapeutic effect, several injections per day are inevitable, resulting in patient pain and an increase in medical expenses (Clinical Pharmacokinetics, 10: 101-143, 1985). Some third-generation cephalosporin antibiotics, such as ceftriaxone, have long blood half-lives, but also have a weak antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa (Clinical Pharmacy, 3: 351-373, 1984). .

Therefore, the present inventors show a wide range of strong antimicrobial activity against Gram-positive bacteria including Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa, and at the same time have long blood half-lives and high blood concentrations, which are expected to provide excellent therapeutic effects. The pyrazolopyrimidine and triazolopyrimidine were substituted at the C-3 position of the parent nucleus, and the C-7 position was (Z) -2- (5-amino-1,2,4-thiadiazole. Wide range of antimicrobial activity by substitution with a -4-yl) -2- (fluoroalkoxyimino) acetyl group or a (Z) -2- (2-aminothiazol-4-yl) -2- (fluoroalkoxyimino) acetyl group A new cephalosporin antibiotic of general formula (I ^a ) was prepared, showing strong yet strong pharmacokinetic properties.

Accordingly, an object of the present invention is a novel cephalosporin derivative of general formula (I ^a ) having a strong antibacterial spectrum against Gram-positive bacteria and a negative bacterium, high blood half-life, high AUC, and excellent therapeutic effect, and a pharmaceutically acceptable salt thereof. And hydrates, organic solvents, and esters that are readily hydrolyzed in the body.

The present inventors synthesized a number of new cephalosporin-based derivatives, general formula (I ^b ) to solve the above problems.

Wherein R ³ is a lower alkyl group or lower fluoroalkyl group which may have a substituent, Z is CH or N, and Het 'is a group of the following structural formula.

In the above formula, R ⁴ , R ⁵ , R ⁶ may be a hydrogen atom or lower alkyl, and R ⁴ and R ⁵ may be linked to form a pentagonal ring hexagonal ring. And, Is or to be.

The present inventors carried out antimicrobial activity according to the correlation of R ³ , R ⁴ , R ⁵ , R ⁶ of the compound of general formula (I ^b ), infection treatment effect and pharmacokinetic test with animal to find a compound with excellent therapeutic effect. . As a result, the new cephalosporin-based antibiotic represented by the general formula (I ^a ) has ^a broad and strong antimicrobial spectrum against Gram-positive and negative bacteria, has a long half-life and high AUC, and has excellent therapeutic effect. It confirmed to have and came to complete this invention.

The object of the present invention therefore relates to novel cephalosporin derivatives of the general formula (I ^a ), pharmaceutically acceptable salts, hydrates, organic solvates and esters thereof.

Wherein R, R ¹ , R ² , Het and Z are as described above.

The present invention also provides compounds of formulas (II) and (III) below which are useful intermediates for the preparation of compounds of formula (I ^a ).

Wherein R ¹ , Het and Y are as described above.

As a representative example compound of the cephalosporin derivative according to the present invention, a novel cytosporin derivative represented by the general formula (I ^c ) is synthesized by the method shown below.

<Method 1>

<Method 2>

<Method 3>

<Method 4>

<Method 5>

<Method 6>

<Method 7>

Detailed description of the methods shown above is as follows.

Method 1)

In the case of compound (III ^a) or amino cephalosporin acid (7-ACA) can be obtained by reacting at pH 7~8 of 7-ACA and the compound (II ^a) to a mixed solution of water or a water organic solvent. Obtained compound (IV) can be refine | purified by a conventional method. For example, adsorption, isolation, and purification are performed using a nonionic adsorptive resin (Mitsubishi Chemical Co., Ltd .: Diaion HP20, etc.) as an aqueous solution of sodium salt with sodium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. A halogen such as chloro compound in the X of (III ^a), in this case a protected carboxy group R ¹ is the compound (III ^a) and compound (II ^a) may be reacted in a dimethyl sulfoxide or dimethyl formamide solvent. Reaction conditions are 30 minutes-2 hours at 0-30 degreeC. Compound (IV) can be obtained with high purity. The compound (IV) obtained by the above operation is acylated by the compound (V). The operation of acylation can be performed according to a conventionally known method or the same.

When compound (V) is used as it is, condensing agents, such as Vilsmeier reagent, dicyclohexyl carbodiimide, and carbonyldiimidazole, are used. Moreover, it is also possible to make it react with the reactive derivative of compound (V). For example, an acyl halide, an acid anhydride, mixed acid anhydride, active ester, active thioester, etc. are used. These reactions were performed at -10-50 degreeC in the normal organic solvent. After the reaction, it is isolated or deprotected by a conventional method and, if necessary, is adsorbed, isolated and purified using a nonionic adsorptive resin (Mitsubishi Chemical Co., Ltd .: Dion HP-20, etc.) as an aqueous solution of sodium salt in a conventional manner as necessary. .

Method 2)

Compound (V) is a known compound already described in many literatures. Compounds (VI ^a ) and (II ^a ) synthesized using this are reacted in water, water-organic or organic solvents by adjusting the pH or in the presence of a base. When making it react in water or a water organic solvent, it is preferable to carry out by adjusting to pH 7-8. After the reaction, it is isolated or deprotected by a conventional method and, if necessary, is adsorbed, isolated and purified using a nonionic adsorptive resin (such as Mitsubishi Chemical Corporation Dion HP 20) as an aqueous solution of sodium salt. .

Method 3)

Monofluoromethoxyamine is reacted after compound (IV) is made into compound (VII) according to a conventional method. Usually, the reaction is carried out in water, but may be reacted in an organic solvent such as dimethylformamide and dimethylacetamide. After reaction, it isolates by normal method. Alternatively, the deprotection treatment is carried out by adsorption, isolation and purification using a nonionic adsorptive resin (Mitsubishi Chemical Co., Ltd .: DIION HP 20, etc.) as an aqueous solution of sodium salt in a conventional manner as necessary.

Method 4)

(IX) can be obtained by reacting compound (III ^b ) and compound (VIII) in a dimethyl sulfoxide or dimethylformamide solvent. Compound (V) can be obtained by making compound (V) react here according to a conventional method. If necessary, after purification by silica gel chromatography, hydroxylamine is reacted. Vilsmeier reagent, dicyclohexylcarbodiimide, carbonyldiimidazole and the like are used as condensing agents, or reactive derivatives of compound (X), for example, acyl halides, active esters, active thioesters, mixed acid anhydrides. After making the hydroxylamine is reacted. These reactions react at room temperature in organic solvents. After reaction, it isolates, deprotects, and refine | purifies by the method normally performed.

Method 5)

This method is particularly good for preventing Δ ² -femization.

Known compound (VI ^b ) is oxidized with 3-chloroperbenzoic acid (m-CPBA) or the like to form (XI). This compound (XI) and compound (VIII) are reacted in the presence of a tertiary amine in an organic solvent. Tertiary amines include triethylamine, diisopropylethylamine, dimethylaniline, N methylmorpholine, pyridine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), and the like. Examples of the organic solvent include methanol, ethanol, isopropanol, dioxane, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like. Although reaction temperature and time are not specifically limited, The reaction completion point is confirmed by thin layer chromatography in 30 minutes-5 hours at 10-50 degreeC.

Next, the compound (XII) obtained by the above reaction is reacted with the protected hydroxylamine (XI) in the presence of a condensing agent in an organic solvent. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, and Vilsmeier reagent. Examples of the organic solvent include tetrahydrofuran, dimethylformamide, dimethylacetamide dioxane, ethyl acetate, methylene chloride, chloroform and the like. After the reaction, the residue is purified by column chromatography, if necessary, followed by reduction with phosphorus trichloride to obtain a compound (XIV). The reduction reaction with phosphorus acid chloride is carried out in accordance with known techniques. For example, it is performed at -10--20 degreeC in organic solvents, such as dimethylformamide and acetonitrile. The obtained compound (XIV) is purified by column chromatography as needed and then deprotected by conventional methods. For example, trichloroacetic acid-anisole, aluminum chloride, or the like is used. The deprotected compound (I) is neutralized with sodium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, and is adsorbed, isolated, and purified using an aqueous solution of sodium salt, using a nonionic adsorptive resin (Mitsubishi Chemical Co., Ltd .: Dion HP 20, etc.). Is done.

Method 6)

Known compound (VI ^b ) is reacted with compound (VIII) in a dimethylsulfoxide or dimethylformamide solvent. The reaction temperature is reacted at 20 to 50 ° C. until the raw material disappears by thin layer chromatography or the like. Compound (XV) obtained in the reaction is reacted with hydroxylamine. In this case, condensing agents such as Vilsmeier reagent, dicyclohexylcarbodiimide and carbonyldiimidazole are used, or reactive derivatives of compound (XV) such as acyl halides, active esters and active thioesters are used. These reactions are performed at room temperature in an organic solvent. After the reaction, isolation, deprotection and purification are carried out by conventional methods.

Method 7)

Compound (XVI) is reacted with glyoxylic acid in a conventional manner to synthesize compound (XVI), to which fluoromethoxyamine is reacted. In this case, the compound (XVI) is reacted in a mixture of water or an organic solvent mixed with water and water as an alkali salt, or at 20 to 50 ° C. in dimethylformamide and dimethylformacetamide. The reaction completion point is determined by the identification of thin layer chromatography. After the reaction, the compound (XVI) can be obtained according to the usual operation. If necessary, after purification by nonionic adsorption resin or silica gel column chromatography, hydroxylamine is reacted. As a condensing agent, Vilsmeier reagent, dicyclohexylcarbodiimide, carbonyldiimidazole, etc. are used, or the reactive derivative of a compound (XVI). For example, the hydroxylamine is reacted after being made of acyl halide, active ester, active thioester and mixed acid anhydride.

These reactions are organic solvents such as dioxane, acetone, acetonitrile, tetrahydrofuran, methylene chloride, dimethylformamide, dimethyl sulfoxide and the like. Reaction temperature is 0-30 degreeC, and reaction time is complete | finished in 30 minutes-5 hours. After reaction, it isolates, deprotects, and refine | purifies by a conventional method.

Synthesis of esters that hydrolyze easily in the body

The sodium salt of the compound (I ^a ) according to the present invention is a halogen compound, specifically iodine methyl pivalate, 1-iodine ethyl pivalate, iodomethylcyclopentanecarboxylate, 1-iodine ethylcyclopentanecarboxylate, 1-iodoethylethylcarbonate, 1-iodoethylisopropylcarbonate, 1-iodoethylcyclopentylcarbonate, 1-iodoethylcyclohexylcarbonate, 4-bromomethyl-5-methyl-1,3-di Oxolan and the like are reacted in organic solvents such as dimethylformamide, dimethylacetamide, acetone, tetrahydrofuran and the like. Reaction temperature is performed at 5-50 degreeC. Since the reaction time varies greatly depending on the type of halogen compound, it is determined by thin layer chromatography. After the reaction, it is usually purified by column chromatography or the like to obtain each ester of the target compound.

The compound (I ^a ) obtained by the present invention is appropriately selected depending on the pharmaceutically acceptable salt, hydrate, organic solvent, method of administration, and type of drug. For example, salts for amino groups include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, naphthalenesulfonic acid, citric acid, succinic acid, fumaric acid, malic acid and acetic acid. Lactic acid, ascorbic acid, gluconic acid, and the like. Examples of salts for carboxyl groups include sodium, potassium, calcium, magnesium, lysine, arginine, monoethanolamine, piperazine, morpholine, triethylamine, and the like. Examples of the organic solvents include ethanol and propylene glycol.

Preferred compounds according to the present invention include, for example, the following compounds.

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3- (3-N-hydroxycarbamoyl-s-pyrazolo [1.5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid,

Fibaroyloxymethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3- (2-N-hydroxycarbamoyl -s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylate,

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3- (3-N-hydrate Oxycarbamoyl-s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3cepem-4carboxylic acid,

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoroethoxyimino) acetamido] -3- (3-N- Hydroxycarbamoyl-s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylic acid,

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3- (2-N-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid,

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3- (2-N-hydrate Oxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylic acid.

Next, although an Example and an experimental example demonstrate this invention, this invention is demonstrated in detail, and this invention is not limited to these Examples.

Experimental Example 1. Measurement of antimicrobial activity.

The antimicrobial activity of the derivatives of the present invention was measured as follows with reference to the Minimal Growth Inhibition Concentration (MIC) assay (Japanese Chemical Society, 29 (1): 76-79, 1981). (CAZ), ceftriaxone (CTRX), and ceftrum (CPR) were used as comparative materials.

10 ml of Mueller Hinton broth or 5% horse serum-containing Mueller Hinton broth were dispensed into sterile test tubes, and each strain was inoculated with one platinum solution and then cultured at 37 ° C. for 18 hours. Each antibiotic was weighed about 10mg, dissolved in distilled water to make 1mg / ml, and then diluted twice in sterile test tubes to 0.25mg / ml in order to prepare an antibiotic solution. Dispense 1 ml of antibiotic solution into a Petri dish, sterilize, and cool to 50 ℃, add 9 ml of Mueller Hinton agar medium or 5% horse blood containing Müller Hinton agar medium, and harden to measure minimum growth concentration. Plates were prepared. Take 0.11ml of the above culture solution, mix it into a sterile test tube containing 10ml gelatin-containing saline solution (BSG), prepare the inoculation bacteria solution, and inoculate the plate containing antibiotics using an inoculator. The growth of the bacteria was visually observed by incubating at 18 ° C. for 18 to 48 hours, and the minimum concentration of antibiotics in which the growth of bacteria was suppressed was determined as the minimum growth inhibition concentration.

Table 1. Minimum growth inhibitory concentrations (MIC, ㎍ / ml)

On the other hand, in Table 1, the original representation of each strain is as follows.

Staphylococcus aureus SG511

Staphylococcus aureus 209P

Staphylococcus aureus smith

Streptococcus pneumoniae 1

Streptococcus pyogenes 3

Escherichia coli DCO

Klebsiella pneumoniae ATCC10031

Proteus mirabilis ATCC14273

Proteus vulgaris 5

Pseudomonas aeruginosa 1592E

Pseudomonas aeruginosa 1771

Pseudomonas aeruginosa 93

Experimental Example 2. Pharmacokinetic Test.

The pharmacokinetic test of the derivatives according to the present invention was carried out as follows, Ceftazidim (CAZ), Ceftriaxone (CTX) and Cefpirm (CPR) was used as a comparative. 30 mg of each antibiotic is dissolved in sterile saline solution to prepare an antibiotic solution to 20 mg / ml, and then the antibiotic solution is administered to the rat tail vein once at 250 ± 30 g of male SI to make a dose of 20 mg / kg. After bleeding at the appropriate time, blood concentration was measured, and then pharmacokinetic constants such as half-life and area under the curve (AUC) were obtained.

Table 2. Pharmacokinetics

Compounds according to the present invention shown in Tables 1 and 2 is Staphylococcus (Staphylococcus), A Streptococcus (Streptococcus) in such gram-positive bacteria and Escherichia coli (Escherichia coli), A keulrep when Ella (Klebsiella) genus Proteus (Proteus) Gram-negative bacteria such as genus Pseudomonas and Pseudomonas showed much broader and stronger antimicrobial activity than ceftazidime and ceftriaxone used as comparative substances. Because of its pharmacokinetic properties with a much longer blood half-life than comparable drugs, the compounds of the present invention are known as oral, parenteral, or other known methods of administration for excipients used alone or in pharmaceutical preparations in humans or animals. Tablets, mixed with conventional auxiliaries such as solvents, suspending agents, lubricants, dissolution aids, stabilizers, antioxidants, and It can be used in the form of general pharmaceutical compositions such as lip, capsule, powder, syrup, ointment, suppositories and subcutaneous, muscle, intravenous or injectable drops.

The daily dosage of a compound of the present invention may vary depending on the type of human or animal, age, weight and patient's condition, but usually 1 to 1000 mg, preferably 10 to 800 mg per 1 kg body weight, usually 1 day It may be administered once or in divided doses.

Experimental Example 3. Toxicity Test.

No single death was observed even at a dose of 3000 mg / kg when a single dose of the compounds according to the present invention was administered to a tail vein of 20 ± 2 g in weight and 4-5 weeks of age in an ICR mouse, and the results are shown in Table 3 below.

Table 3. Half dose (LD ₅₀ , mg / kg)

The novel cephalosporin derivatives indicated in the present invention have strong antibacterial activity against gram positive and negative bacteria producing β lactamase, have a long half-life in blood, and can be administered orally or parenterally. Accordingly, the compounds of the present invention can be effectively used for the prevention or treatment of diseases caused by pathogens as described above for humans or animals.

Example 1

Preparation example of 2-hydroxycarbamoyl-7-mercapto-s-triazolo [1,5-a] pyrimidine

To a solution of 17.6 g of sodium hydroxide and 15.3 g of hydroxyamine hydrochloride in 50 ml of water, 24 g of 2-methoxycarbonyl-7-mercapto-s-triazolo [1,5-a] pyrimidine was added and 12 hours at room temperature. Stir. The precipitate was adjusted to pH 2 with 2N hydrochloric acid, filtered, washed and dried to obtain 19.3 g of the target product.

NMR (DMSO-d ₆ ) δ: 6.93 (1H, d, J = 7 Hz), 7.99 (1H, d, J = 7 Hz)

Example 2)

Preparation Example of 3-hydroxycarbamoyl-7-mercapto-s-pyrazolo [1,5-a] pyrimidine

11.5 g of dicyclohexylcarbodiide was added to a 300 ml solution of dimethylformamide of 8.2 g of 3-carboxy-7-mercapto-s-pyrazolo [1,5-a] pyrimidine and 7.7 g of N-hydroxybenzotriazole. Add under ice cooling. It is filtered after stirring for 12 hours at room temperature. 4.7 g of hydroxylamine hydrochloride and 9.4 ml of triethylamine were added to the filtrate, followed by stirring for 5 hours. After concentration under reduced pressure, the residue was added dropwise to 100 ml of ethyl ether. To the resulting viscous material is added a small amount of methanol to obtain 2.9 g of the desired product.

NMR (DMSO-d ₆ ) δ: 6.85 (1H, d, J = 6.8 Hz), 7.68 (1H, d, J = 6.8 Hz), 8.44 (1H, brs) 9.08 (1H, brs), 11.07 (1H, brs)

Example 3

Preparation Example of p-methoxybenzyloxyamine

(a) p-methoxybenzyloxyphthalimide

After adding 62 g of potassium carbonate to an 800 ml solution of 36.4 g of N-hydroxyphthalimide, 62 g of potassium carbonate was cooled with ice, and 30 ml of p-methoxybenzyl chloride was added dropwise for 10 minutes and stirred at 50 ° C for 2 hours. 1.5 L of ethyl acetate was added to the reaction solution, and the solvent was removed after washing with water. N-hexane was added to the crystallized residue, followed by stirring. The crystals were filtered and dried to obtain 51.2 g of the target substance.

NMR (CDCl ₃ ) δ: 3.32 (3H, s), 5.08 (2H, s), 6.82 (2H, d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz), 7.68 (4H, s)

(b) p-methoxybenzyloxyamine

To a 500 ml solution of 51.2 g of p-methoxybenzyloxyphthalimide, a 100 ml solution of methanol of 5 ml of hydrazine hydrate was added for 5 minutes. After 30 minutes, 300 ml of 5 M aqueous sodium hydroxide solution was added to the mixture, followed by stirring. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed to obtain 27.0 g of the target substance.

NMR (CDCl ₃ ) δ: 3.82 (3H, s), 4.49 (2H, s), 5.28 (2H, s), 6.8 (2H, d, J = 8 Hz), 7.22 (2H, d, J = 8 Hz)

Example 4

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-[(2-hydroxycarbamoyl Preparation of) -s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

(Example 4-1)

35 g of p-methoxybenzyl 7-amino-3-chloromethyl3-cepem-4-carboxylate, (Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxy 43.7 g of mino) acetic acid and 14.5 g of 1-hydroxybenzotriazole are dissolved in 200 ml of dimethylformamide. After cooling the reaction solution to 0 ° C, 23.7 g of dicyclohexylcarbodiimide was dissolved in 50 ml of dimethylformamide, added dropwise for 30 minutes, and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was added to 1 L of ethyl acetate and washed with water and brine. The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido ] -3-chloromethyl-3-cepem-4-carboxylate can be obtained.

NMR (CDCl ₃ ) δ: 3.66 (2H, brs), 3.72 (3H, s), 4.46 (2H, brs), 5.1 to 5.42 (4H, m), 6.02 to 6.30 (2H, m), 6.93 (1N, s). 6.70Z ~ 7.82 (19H, m)

(Example 4-2)

The above material was dissolved in 200 ml of chloroform, and a solution of m CPBA 20 g dissolved in 300 ml of chloroform was added dropwise for 2 hours and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, added dropwise to 2.5 L of isopropyl ether, and the precipitate was filtered and washed with isopropyl ether. Purified by silica gel column chromatography, p-methoxybenzyl- (6R, 7R) -7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino 57.2 g of acetamido] -3chloromethyl-3-cepem-4-carboxylate-1-oxide can be obtained.

NMR (DMSO d ₆ ) δ: 3.22, 3.72 (2H, ABq, J = 18 Hz), 3.69 (s, 3H), 4.15, 4.72 (2H, ABq, J = 12 Hz), 4.51 (1H, d, J = 5 Hz ), 5.12, 5.38 (3H, m), 5.98-6.17 (2H, m), 6.88 (1H, s), 6.72-7.78 (19H, m),

(Example 4-3)

p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-chloromethylcepem-4-car 16.6 g of cyclate-1-oxide is dissolved in 100 ml of dimethylformamide. After dissolving 5.5 g of 7-mercapto-s-triazolo [1,5a] pyrimidine-2-carboxylic acid and 4.2 ml of DBU in 200 ml of dimethylformamide, the solution was added dropwise for 10 minutes under ice-cooling, and then cooled at room temperature for 4 hours. Stir. The reaction solution was added dropwise to 2.6 L of diisopropyl ether, and the precipitate was filtered off, washed with isopropyl ether, and dried to give p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl ) -2- (fluoromethoxyamino) acetamido] -3-[(2-carboxy-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4 25.8 g of -carboxylate-1-oxide are obtained.

25.8 g of this compound, 6.13 g of p-methoxybenzyloxyamine, and 6.13 g of 1-hydroxybenzotriazole are dissolved in 50 ml of dimethylformamide. To this solution, 8.25 g of dicyclohexylcarbodiimide is dissolved in 30 ml of dimethylformamide and added dropwise. The reaction solution is stirred at room temperature for 4 hours, filtered and the filtrate is added dropwise to 3.6 L of water. The precipitate was filtered, dissolved in 700 ml of chloroform, dried over anhydrous magnesium sulfate, and the filtrate was added dropwise to 2.6 L of isopropyl ether to obtain 24.1 g of crystals. Purified by silica gel column chromatography to obtain p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3- [(2-p-methoxybenzyloxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylate-1-oxide 11.3 get g 11.3 g of this material is dissolved in 60 ml of dimethylformamide and cooled to 0 ° C. 2 ml of phosphorus trichloride was added dropwise to this solution, and after stirring for 30 minutes, the reaction solution was added to 400 ml of ice water, and the solid was filtered. The solid was dissolved in 200 ml of chloroform, dried over anhydrous magnesium sulfate, and the filtrate was added dropwise to 400 ml of isopropyl ether to obtain 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (flo Romethoxyimino) acetamido] -3-[(2-p-methoxybenzyloxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefem 7.85 g of 4-carboxylate are obtained. 7.85 g of this material is dissolved in 25 ml of dichloromethane and 25 ml of anisole and then cooled to 0 ° C. 50 ml of trifluoroacetic acid is added dropwise, followed by stirring at room temperature for 4 hours. The reaction solution was added dropwise to 700 ml of ethyl ether to precipitate 5 g of solid. After dissolving the above crystals in 30 ml of dimethylformamide, a solution was dissolved in 50 ml of methanol of 5.32 g of sodium-2-ethylhexanoate. This solution is added dropwise to 1 L of ether, and the precipitate is filtered off and washed with ether. 5.7 g of the pale white powder obtained was purified by Diaion HP 20 column chromatography, and 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] 1.8 g of 3-[(2-hydroxycarbamoyl) -s-triazolo [1.5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid as a light white powder are obtained .

NMR (DMSO-d ₆ ) δ: 3.37, 3.56 (2H, ABq, J = 18 Hz), 4.54, 4.63 (2H, ABq, J = 18 Hz), 4.99 (1H, d. J = 4.6 Hz), 5.55 (3H , m), 5.83 (1H. brs), 6.87 (1H, s), 7.23 (2H, brs), 7.95 (1H, d, J = 4.6 Hz), 8.64 (1H, d, J = 4.6 Hz), 9.52 (1H, d, J = 8.6 Hz)

Example 5

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-[(3-hydroxycarbamoyl Preparation of) -s-pyrazolo [1,5-a] -pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

P-methoxybenzyl (6R, 7R) -7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino obtained in Example (4-1) 10.4 g of acetamido] -3-chloromethyl-3-cepem-4-carboxylate-1-oxide are dissolved in 50 ml of dimethylformamide. In this solution, 3.51 g of 3-carboxy-7-mercapto-s-pyrazolo [1.5-a] -pyrimidine and 3.0 ml of DBU were dissolved in 30 ml of dimethylformadi. The solution was then lowered for 10 minutes under ice-cooling and 3 hours at room temperature. Stir. The reaction solution was added dropwise to 1.6 L of diisopropyl ether, and the precipitate was filtered off, washed with isopropyl ether, and dried to give p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl ) -2- (fluoromethoxyamino) acetamido] -3-[(3-carboxy-s-pyrazolo [1.5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-car 20.2 g of carboxylate-1-oxide are obtained. 20.2 g of this substance, 3.83 g of p-methoxybenzyloxyamine, and 3.83 g of 1-hydroxybenzotriazole are dissolved in 50 ml of dimethylformamide. 5.16 g of dicyclohexylcarbodiimide is dissolved and added dropwise to 20 ml of dimethylformamide. The reaction solution is stirred at room temperature for 4 hours, filtered and the filtrate is added dropwise to 2.6 L of water. The precipitate was filtered, dissolved in 500 ml of chloroform, dried over anhydrous magnesium sulfate, and the filtrate was added dropwise to 1.8 L of isopropyl ether to obtain 24.1 g of crystals. Purified by silica gel column chromatography to obtain p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3- [(3-p-methoxybenzyloxycarbamoyl) -s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylate-1-oxide Get 6.0 g.

Thereafter, a target product is obtained in the same manner as in Example (4).

NMR (DMSO-d ₆ + D ₂ O) δ: 3.62 (2H, brs), 4.50 (2H, brs), 5.20 (1H, d, J = 5 Hz), 5.39 (1H, s). 5.79 (1H.d, J = 5Hz), 6.33 (1H, s), 7.06 (1H, s), 7.52 (1H, d, J = 5Hz), 8.58 (1H, d, J = 5Hz), 8.63 (1H , s)

Example 6

(6R.7R) -7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3- Preparation of [(2-hydroxycarbamoyl-s-triazolo [1.5-a] -pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

(Example 6-1)

20.3 g (Z) -2- (5-tritylamino-1,2,4-thiadiazole-4- p-methoxybenzyl 7-amino-3-chloromethyl-3-cepem-4-carboxylate Dissolve 39.55 g of 1) -2- (fluoromethoxyimino) acetic acid and 8.4 g of 1-hydroxybenzotriazole in 100 ml of dimethylformamide. After cooling the reaction solution to 0 ° C, 11.9 g of dicyclohexylcarbodiimide was dissolved in 30 ml of dimethylformamide, added dropwise for 30 minutes, and stirred at room temperature for 2.5 hours. The reaction solution was filtered, and the filtrate was added to 500 mL of ethyl acetate and washed with water and brine. The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-4-yl) -2- ( 60 g of fluoromethoxyimino) acetamido] -3-chloromethyl-3-cepem-4-carboxylate can be obtained.

NMR (DMSO-d ₆ ) δ: 3.53, 3.74 (2H, ABq, J = 18 Hz), 3.73 (3H, s), 4.46, 4.93 (2H, ABq, J = 18 Hz), 5.74 (1H, d, J = 55 Hz), 5.82 (1H.dd, J = 5, 8.5 Hz), 6.92 (2H, d, J = 6.7 Hz), 7.25-7.39 (17H.m), 9.74 (1H, d, J = 8.6 Hz), 10.1 (1H, s)

(Example 6-2)

The solution obtained in Example 6-1 was dissolved in 100 ml of chloroform and 10.35 g of m CPBA in 150 ml of chloroform was added dropwise for 1.5 hours and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, added dropwise to 2 L of isopropyl ether, and the precipitate was filtered off and washed with isopropyl ether. Purified by silica gel column chromatography, p-methoxybenzyl (6R, 7R) -7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) 28.5 g of acetamido] -3-chloromethyl-3-cepem-4-carboxylate-1-oxide can be obtained.

NMR (DMSO-d ₆ ) δ: 3.25, 3.70 (2H, ABq, J = 18 Hz), 3.69 (3H, s), 4.12, 4.69 (2H, ABq, J = 12 Hz), 4.48 (1H, d, J = 5 Hz), 5.04 to 5.35 (3H, m), 5.95 to 6.18 (2H, m), 6.88 to 7.77 (19H, m),

(Example 6-3)

p-methoxybenzyl (6R, 7R) -7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-chloro 12.44 g of methyl-3-cepem-4-carboxylate-1-oxide is dissolved in 100 ml of dimethylformamide. After dissolving 4.12 g of 2-carboxy-7-mercapto-s-triazolo [1,5-a] pyrimidine and 3.14 ml of DBU in 40 ml of dimethylformamide, this solution was added dropwise for 10 minutes under ice-cooling, and then cooled at room temperature for 4 hours. Stir. The reaction solution was added dropwise to 3.5 L of diisopropyl ether, and the precipitate was filtered, washed with isopropyl ether, and dried to give p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1,2,4 -Thiadiazol-4-yl) -2- (fluoromethoxyamino) acetamido] -3-[(2-carboxy-s-triazolo [1,5-a] pyrimidin-7-yl) thio 20.1 g of methyl] -3-cepem-4-carboxylate-1-oxide is obtained. After dissolving the material in 50 ml of dimethylformamide, 4.6 g of p-methoxybenzyloxyamine and 4.6 g of 1-hydroxybenzotriazole are dissolved in 50 ml of dimethylformamide. 6.2 g of dicyclohexylcarbodiimide is dissolved in this solution and added dropwise into 20 ml of dimethylformamide. The reaction solution is stirred at room temperature for 4 hours. The precipitate was filtered, dissolved in 500 ml of chloroform, dried over anhydrous magnesium sulfate, and the filtrate was added dropwise to 2.6 L of isopropyl ether to obtain 21.8 g of crystals. Purification by silica gel column chromatography on p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-4-yl) -2- (fluoromethoxyimino ) Acetamido] -3-[(2-p-methoxybenzyloxycarbamoyl) -s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4- 7.2 g of carboxylate-1-oxide are obtained. Thereafter, the target product was obtained in the same manner as in Example (4).

NMR (DMSO-d ₆ + D ₂ O) δ: 3.56 (2H, s), 4.44 to 4.68 (2H, m), 5.08 (1H, d. J = 5 Hz), 5.37 (1H, s). 5.72 (1H, d.J = 5 Hz), 6.27 (1H, s), 7.64 (1H, d, J = 5 Hz), 8.67 (1H, d. J = 5 Hz)

Example 7

(6R, 7R) -7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3- Preparation of [(3-hydroxycarbamoyl) -s-pyrazolo [1,5-a] pyrimidin-7-yl)] thiomethyl-3-cepem-4-carboxylic acid sodium salt

P-methoxybenzyl (6R, 7R) -7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino obtained in (Example 6-2) 12.44 g of acetamido] -3-chloromethyl-3-cepem-4-carboxylate-1-oxide and 2-carboxy-7-mercapto-s-triazolo [1,5-a] pyrimidine Instead, 4.1 g of 3-carboxy-7-mercapto pyrazolo [1,5-a] pyrimidine was used in the same manner as in Example (6) to obtain 10.2 g of the target compound.

NMR (DMSO d ₆ + D ₂ O) δ: 3.58 (2H, s) 4.55 (2H, brs), 5.14 (1H, d, J = 5 Hz), 5.40 (1H, s), 5.77 (1H, d, J = 5 Hz), 6.29 (1H, s), 7.55 (1H, d, J = 5 Hz), 8.53 (1H, d, J = 5 Hz), 8.65 (1H, s)

Example 8

(6R, 7R) -7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3- Preparation of [(2-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

(Example 8-1)

After dissolving 3 g of 2- (5-tritylamino-1.2.4-thiadiazol-3-yl)-(Z) -2- (fluoromethoxyimino) acetic acid in 30 ml of dichloromethane, under 0 ° C Add 3.2 ml of N, N-dimethylaniline and 2.6 g of p-methoxybenzyl 7-amino-3-chloromethyl-3-cepem-4-carboxylate. To the reaction mixture is slowly added 0.7 ml of phosphoryl chloride diluted with 10 ml of dichloromethane for 30 minutes. After stirring for 1.5 hours, water was poured, followed by extraction with chloroform. The extract was washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl). 4.8 g (92%) of 2- (fluoromethoxyimino) acetamido] -3-chloromethyl-3-cepem-4-carboxylate are obtained.

NMR (DMSO d ₆ ) δ: 3.53, 3.74 (2H, ABq, J = 18 Hz), 3.73 (3H.s), 4.46, 4.93 (2H, ABq, J = 18 Hz), 5.74 (1H, d, J = 55 Hz ), 5.82 (1H, dd, J = 5, 8.5 Hz), 6.92 (2H.d, J = 6.7 Hz), 7.25-7.39 (17H, m), 9.74 (1H, d, J = 8.6 Hz), 10.1 (1H, s)

(Example 8-2)

p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2- (fluoromethoxyimino) acetamido] -3 2.7 g of potassium iodide is added to a 35 ml solution of 9 g of acetone 35 g of chloromethyl-3-cefe-4-carboxylate, followed by stirring at room temperature for 3 hours, followed by pouring water and extracting with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl). 9 g (90%) of 2- (fluoromethoxyimino) acetamido] -3-iodinemethyl-3-cepem-4-carboxylate are obtained.

NMR (DMSO-d ₆ ) δ: 3.50, 3.74 (2H, ABq, J = 17.8 Hz), 3.74 (3H, s), 4,33, 4.37 (2H, ABq, J = 15.5 Hz), 5.17 (3H, m), 5.75 (1H, dd, J = 4.8, 8.4 Hz), 5.76 (2H, d, J = 54.9 Hz), 6.92 (2H, d, J = 8.6 Hz), 7.33 (17H, m), 9.73 ( 1J, d, J = 8.4 Hz), 10.1 (1H, s)

(Example 8-3)

After dissolving 5.6 g of this substance in 20 ml of dimethylformamide, 1.2 g of 2 hydroxycarbamoyl-7-mercapto-s-triazolo [1,5-a] pyrimidine under 0 ° C., DBU 0.84 ml, N 20 ml mixture of N-dimethylformamide is added. After stirring for 3 hours at the same temperature, it was added dropwise to ethyl ether, and the solid was filtered to give p-methoxybenzyl 7-[(Z) -2- (5-tritylamino-1.2.4-thiadiazol-3-yl ) -2- (fluoromethoxyimino) acetamido] -3-[(2-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3- 4.05 g of cefem-4-carboxylate is obtained.

NMR (DMsO-d ₆ ) δ: 3.58, 3.79 (2H, ABq, J = 20 Hz), 3.67 (3H, s), 4.34 (2H, Brs), 5.17 (3H, m), 5.75 (2H, d, J = 55Hz), 5.80 (1H, dd, J = 4.9, 10Hz), 6.78 (2H, d, J = 8.5Hz), 7.32 (18H, m), 8.68 (1H, d, J = 6Hz), 9.38 (1H , brs), 9.74 (1H, d, J = 10 Hz), 10.1 (1H.s), 11.7 (1H, s)

(Example 8-4)

After dissolving 5.1 g of this substance in 1 ml of dichloromethane, 20 ml of trifluoroacetic acid and 10 ml of anisole were added at 0 ° C., stirred at the same temperature for 2 hours, and added dropwise to diisopropyl ether, and the solid was filtered. After drying, the powder was suspended in 5 ml of water, adjusted to pH 6.8 with 5% sodium hydrogen carbonate solution, and purified by diion HP-20 column chromatography to obtain the same 7- (Z) -2- (5) as in Example 6. -Amino-1,2,4-thiadiazol-3-yl) -2-fluoroethoxyiminoacetamido] -3-[(2-N-hydroxycarbamoyl-s-triazolo [1 , 5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt 1.82 g is obtained.

Example 9

(6R, 7R) -7β-[(Z) -2- (5-amino-1,2.4-thiadiazol-3-yl) -2- (fluoroethoxyimino) acetamido] -3- [ Preparation of (3-hydroxycarbamoyl-s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

The target product was obtained in the same manner as in Example 8.

NMR (DMSO-d ₆ ) δ: 3.56 (2H, m), 4.26 (1H, m), 4.39 (1H, m), 4.38 (3H, m), 4.73 (1H, m), 4.97 (1H, d, J = 5Hz), 5.58 (1H, dd, J = 8.6, 5Hz), 7.71 (1H, d, J = 5Hz), 8.09 (1H, brs), 8.49 (1H, d, J = 5Hz), 8.54 (1H , s), 9.21 (1H, brs), 9.50 (1H, d, J = 8.6 Hz), 10.2 (1H, brs)

Example 10)

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(2-hydroxycarbamoyl- Preparation of s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

The target product was obtained in the same manner as in Example 8.

NMR (DMSO-d ₆ ) δ: 3.38, 3.60 (2H, ABq, J = 18 Hz), 3.78 (3H, s), 4.45, 4.71 (2H, ABq, J = 18 Hz), 4.96 (1H, d, J = 4.7 Hz), 5.53 (1H, dd, J = 4.7, 8.3 Hz), 6.87 (1H, s), 7.26 (2H, brs), 7.96 (1H, d, J = 5.2 Hz), 8.64 (1H, d, J = 5.2 Hz), 9,20 (1H, brs), 9.53 (1H, d, J = 8.3 Hz), 10.1 (1H, brs)

Example 11

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(3-hydroxycarbamoyl- s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

The target product was obtained in the same manner as in Example 8.

NMR (DMSO-d ₆ ) δ: 3.35, 3.55 (2H, ABq, J = 17 Hz), 3.80 (3H, s), 4.52 (2H, m), 4.99 (1H, d, J = 4.6 Hz), 5.54 ( 1H, dd, J = 4.6, 8.2 Hz), 6.71 (1H, s), 7.17 (2H, brs), 7.79 (1H, d, J = 5 Hz), 8.49 (1H, d, J = 5 Hz), 8.55 ( 1H, s), 9.18 (1H, brs), 9.49 (1H, d, J = 8.2 Hz), 10.2 (1H, brs)

Example 12)

(6R, 7R) -7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- [ Preparation of (3-hydroxycarbamoyl-s-pyrazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylic acid sodium salt

The target product was obtained in the same manner as in Example 8.

NMR (DMSO-d ₆ ) δ: 3.36, 3.57 (2H, ABq, J = 17.2 Hz), 3.81 (3H, s), 4.45 (2H, m), 4.99 (1H, d, J = 4.8 Hz), 5.60 (1H, dd, J = 4.8, 8.6Hz), 7.72 (1H, d, J = 4.6Hz), 8.09 (2H, brs), 8.50 (1H, d, J = 4.6Hz), 8.55 (1H, s) , 9.20 (1H, brs), 9.47 (1H, d, J = 8.6 Hz), 10.2 (1H, brs)

Example 13

(6R, 7R) -7β-[(Z) -2- (5-amino-1,2.4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(2 Preparation of -hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxylic acid sodium salt

The target product was obtained in the same manner as in Example 8.

NMR (DMSO-d ₆ ) δ: 3.32, 3.58 (2H, ABq, J = 18 Hz), 3.75 (3H, s), 4.49, 4.63 (2H, ABq, J = 18 Hz), 4.98 (1H, d, J = 4.9 Hz), 5.59 (1H, dd, J = 4.9, 8.1 Hz), 7.97 (1H, d, J = 5.2 Hz), 8.12 (2H, brs), 8.65 (1H, d, J = 5.2 Hz), 9.40 (1H, brs), 9.65 (1H, d, J = 8.1 Hz), 10.6 (1H, brs)

Example 14

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-[(2-hydroxycarbamoyl Preparation of -s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cephem-4-carboxylic acid nattium salt and pivaloyloxymethyl ester

(Example 14-1)

Into a 200 ml solution of 28.57 g of p-methoxybenzyl 7-amino-3-chloromethyl-3-cepem-4-carboxylate dimethylformamide 2-hydroxycarbamoyl-7-mercapto-s-triazolo [1 , 5-a] pyrimidine and 10.9 ml of DBU are added and stirred at room temperature for 2 hours. The reaction solution was added dropwise to water, adjusted to pH 5.5 with 5% sodium bicarbonate solution, and the precipitate was filtered off, washed with water, methanol and ether and dried to give p-methoxybenzyl 7-amino-3-[(2-hydrate). 29.5 g of oxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cefe-4-carboxylate are obtained.

NMR (DMSO-d ₆ ) δ: 3.7 (5H, brs), 4.3 (2H, brs), 4.8 (2H, m), 5.1 (2H, s), 7.4-8.6 (5H, m), 8.5 (1H, brs)

(Example 14-2)

p-methoxybenzyl 7-amino-3-[(2-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4-carboxyl 150 ml of dimethylformamide (35.5 g, 27.4 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetic acid and 11.2 g of 1-hydroxybenzotriazole) Dissolve in. After cooling the reaction solution to 0 ° C, 16.4 g of dicyclohexylcarbodiimide was dissolved in 100 ml of dimethylformamide, added dropwise thereto for 30 minutes, and stirred at room temperature for 1 hour. The reaction solution is filtered, and the filtrate is added to 2 L of isopropane ether and filtered. After dissolving this solid in a small amount of dichloromethane, it was added dropwise to 2 L of ether, and the precipitate was filtered and dried to obtain p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl)- 2- (fluoromethoxyimino) acetamide] -3-[(2-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl) thiomethyl] -3-cepem-4 -60 g of carboxylate are obtained.

NMR (DMSO-d ₆ ) δ: 3.5 (5H, brs), 4.3 (2H, brs), 4.9-5.4 (5H, m), 6.0 (1H, brs), 6.8-7.2 (21H, m), 8.5 ( 1H, brs)

(Example 14-3)

7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido-3-[(2-hydroxycarbamoyl-s-triazolo 30 g of [1,5-a] pyrimidin-7-yl) -thiomethyl-3-cepem-4-carboxylate is dissolved in 100 ml of dichloromethane and 50 ml of anisole and cooled to 0 ° C. 100 ml of trifluoroacetic acid is added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was added dropwise to 1 L of ethyl ether. The precipitate was filtered and washed with ethyl ether to give (6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxy). Mino) acetamido] -3-[(2-hydroxycarbamoyl-s-triazolo [1,5-a] pyrimidin-7-yl)] thiomethyl-3-cepem-4-carboxylic acid trifluoro 23 g of roacetate is obtained.

NMR (DMSO-d ₆ ) δ: 3.5 (2H, brs), 4.5 (2H, brs), 5.0 to 6.2 (4H, m) 6.8 (1H, brs), 7.2 (1H, brs), 8.5 (1H, brs ), 9.3 (1H, brs)

(Example 14-4)

(6R, 7R) -7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-[(2-hydroxycarbamoyl ) -s-triazolo [1.5-a] pyrimidin-7-yl)] thiomethyl-3-cepem-4-carboxylic acid trifluoroacetate 23 g was dissolved in 200 ml of dimethylformamide, followed by sodium-2-ethylhexa A solution dissolved in 200 ml of 12.4 g of noate is added for 15 minutes. This solution was added dropwise to 5 L of ether, and the precipitate was filtered off and washed with ether to give 22.5 g of sodium salt. 1.5 g of this substance was dissolved in 30 ml of dimethylformamide, 0.4 ml of iodomethylpivalate was added thereto, stirred at room temperature for 30 minutes, and then added dropwise to water to obtain a precipitate. Z) -2- (2-aminothiazol-4-yl) -2- (fluoromethoxyimino) acetamido] -3-[(2-hydroxycarbamoyl-s-triazolo [1,5- a] pyrimidin-7-yl)] thiomethyl-3-cepem-4-carboxylic acid pivaloyloxymethyl ester 0.8g is obtained.

NMR (DMSO-d ₆ ) δ: 1.7 (9H, s), 3.7 (2H, brs), 4.4 (2H, brs), 5.0 to 6.2 (6H, m), 6.8 to 7.3 (2H, m), 8.5 ( 1H, brs), 9.5 (1H, brs)

Claims (3)

A cefem compound represented by the following structural formula (I ^a ), and a pharmaceutically acceptable salt or ester thereof. Wherein R is a hydrogen atom or a protecting group, R ¹ is a carboxyl group or a protected carboxyl group, R ² is a lower fluoroalkyl having 1-4 carbon atoms, Z is CH or N, and Het is a group of the formula [In the meal, Is or to be.] The compounds of formula (III) below and pharmaceutically acceptable salts or esters thereof. R ¹ is a carboxyl group or a protected carboxyl group and Het is a group of the formula [In the meal, Is or to be.] A compound of formula (II) [In the meal, Is or to be.]