KR820000905B1 - Process for preparing cephem and cepham compounds - Google Patents

Abstract

Title compds (Ih; R1a = thiazolyl, thiadiazolyl; R2 = H, halogen, aliph. hydrocarbon residue, optionally substituted by (esterified) carboxy; R5 = carboxy or functionally-modified carboxy) were prepd. by treating Ig (R7a = acyl) with a base. Thus, 2.6 g 7-≮2-(2-amino-4-thiazolyl)-2-methoxyaminoacetamido≉-3-cephem-4- carboxylic hydrochloride was treated 1.04 g sodium bicarbonate at room temp to give 7-≮2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido≉-3-cephem-4-carboxylate.

Description

Process for preparing novel cefem and sefam compounds

The present invention relates to a process for producing novel cefem and cefem compound. In particular, the present invention relates to a novel 7-substituted-3-cepem (or sefam) -4-carboxylic acid having antibacterial activity, a pharmaceutically acceptable salt thereof and a method for preparing a pharmaceutically acceptable biological precursor of the compound. will be.

Accordingly, it is an object of the present invention, a novel 7-substituted-3-cepem (or sefam) -4-carboxylic acid, which exhibits excellent antimicrobial activity against various types of pathogenic microorganisms, including gram negative and gram positive bacteria, and pharmaceutical To provide an acceptable salt and a method for preparing a pharmaceutically acceptable biological precursor of the compound.

The cefem compound provided in the present invention may be represented by the following structural formula (Ih).

의 티아졸릴 또는 티아디아 졸릴이고 R²는 수소 혹은 할로겐, 카르복시 혹은 에스테르화 된 카르복시로 치환될 수 있는 지방족 탄화수소기이며 R⁵는 카르복시 혹은 기능적으로 조절된 카르복시이다.Wherein R ¹ _a is _a structural formula wherein R ⁶ is amino or protective amino

Is thiazolyl or thiadiazolyl, R ² is hydrogen or an aliphatic hydrocarbon group which may be substituted with halogen, carboxy or esterified carboxy and R ⁵ is carboxy or functionally controlled carboxy.

The terms and definitions described in the specification and claims are described below.

a) Substructure of the following structural formula means the following two geometric structures.

The geometric isomer of formula (S) means syn and the other formula (A) represents anti.

Thus, one isomer of a compound having a partial structure represented by the above formula (S) relates to the "neoisomer" and another isomer of one of the compounds represented by the formula (A) relates to the "new isomer". .

From the correlation of structural activity, the new isomers of the compounds of formula (Ih) tend to have a much higher antimicrobial activity than those of the corresponding anti isomers, so in terms of prophylactic and therapeutic value the new isomers of compounds (Ih) It is a much preferred antimicrobial agent than isomers.

의 티아졸릴 그룹은 R^6′가 이미노 혹은 보호이미노기인 구조식

의 티아졸리닐 그룹과 호변이성(互變異性) 관계에 있는 것으로 이미 공지되어 있다.b) a structural formula in which R ⁶ is as defined above

The thiazolyl group of is a structural formula in which R ^{6 ′} is an imino or a protective imino group

It is already known to be in a tautomeric relationship with the thiazolinyl group of.

Tautomerism between the thiazolyl and thiazolinyl groups can be represented in the following equilibrium.

Where R ⁶ and R ⁶ ′ are as defined above.

(R⁶는 상기 정의대로임)로 표시된다.Thus, the two groups are substantially the same, and tautomers which form such a group are considered to be the same compound, especially in the field of manufacturing chemistry. Therefore, two tautomers of a compound having such a group in its molecule are included in the scope of the present invention and referred to as the generic expression “thiazolyl”, but for convenience the structural formulas in the present specification and claims

(R ⁶ is as defined above).

In the foregoing and following description of the specification, appropriate descriptions and examples of the various definitions that the present invention intends to include within its scope are described in detail below.

The term "lower" means a group having 1-6 carbon atoms, unless otherwise specified,

“Tiadiazolyl” of R ¹ is 1,2,3-thiadiazolyl (eg 1,2,3-thiadiazol-4-yl, or 1,2,3-thiadiazol-5-yl), 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl, preferably 1,2,3-thiadiazolyl and more preferably 1,2,3-thiadiazol-4-yl Say

The “aliphatic hydrocarbon residues of R ² may include saturated or unsaturated monovalent groups and straight, branched or cyclic aliphatic hydrocarbons, in particular alkyl, alkenyl, alkynyl, cycloalkyl, etc., which are described in more detail below. It is.

"Alkyl" is a straight chain having 1-12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, or the like The residues of the side chain alkanes may preferably comprise lower alkyl, more preferably lower alkyl having 1-4 carbon atoms.

"Alkenyl" is a residue of a straight or branched chain alkene having up to 12 carbon atoms, preferably lower, such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, etc. Alkenyl, more preferably lower alkenyl having up to 4 carbon atoms, and the like.

"Alkenyl" is a residue of a straight or branched chain alkyne having up to 12 carbon atoms, preferably ethynyl, propargyl, 1-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3 Lower alkynyl such as -pentynyl, 2-pentynyl, 1-pentynyl, 5-hexynyl and the like, more preferably lower alkynyl having up to 4 carbon atoms.

“Cycloalkyl” may include residues of cycloalkanes having up to eight carbon atoms, preferably lower cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably cyclohexyl.

The aliphatic hydrocarbon residue may be substituted with halogen atoms (carboxy or esterified carboxy groups. Thus, "aliphatic hydrocarbon residues substituted with halogen atoms, carboxy or esterified carboxy groups" are also referred to as "halogen-substituted aliphatic hydrocarbon residues". , “Carboxy-substituted aliphatic hydrocarbon residues” and “esterified carboxy-substituted aliphatic hydrocarbon residues”, which are more particularly halo-alkyl, alkenyl, alkynyl and cycloalkyl, carboxy-alkyl, alkenyl , Alkynyl and cycloalkyl and esterified carboxy-alkyl, alkenyl, alkynyl and cycloalkyl, respectively.

Suitable examples of "halogens" include chlorine, bromine, iodine and fluorine, and suitable examples of esterified carboxys include alkoxycarbonyl and the like, "alkyl", "alkenyl", "alkynyl" Preferred examples of alkyl moieties of “cycloalkyl” and “alkoxy-carbonyl” are the corresponding lower alkyls mentioned above.

Preferred examples of “halo-alkyl, alkenyl, alkynyl and cycloalkyl” include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 1,2 -Dichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-iodobutyl, 5-fluoropentyl, 6-bromohexyl, 3-fluoroallyl, 3-chloropropargyl And 4 one fluorocyclohexyl.

Preferred examples of “carboxy-alkyl, alkenyl, alkynyl and cycloalkyl” include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl , 6-carboxyhexyl, 1-carboxyisopropyl, 1-ethyl-1-carboxyethyl, 2-methyl-2-carboxypropyl, 3-carboxyallyl, 3-carboxy-propargyl, 4-carboxycyclohexyl and the like have.

Preferred examples of “esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl” include lower alkoxy carbonyl (lower) alkyl (eg methoxy carbonyl methyl, methoxycarbonylmethyl, propoxycarbonylmethyl, t -Butoxycarbonylmethyl, 2-ethoxycarbonyl, 2-ethylethoxycarbonyl, 4-propylethoxycarbonylbutyl, 1-t-butoxycarbonylisopropyl, 1-t-butoxycarbonyl -1-methyl-propyl, 4-t-butoxycarbonylbutyl, 5-t-butoxycarbonylpentyl, 6-butoxycarbonylhexyl, etc., lower alkoxycarbonyl (lower) -alkenyl (e.g., 3-methoxy carbonylallyl, etc. Lower alkoxycarbonyl (lower) alkynyl (eg, 3-methoxy carbonylpropargyl, etc.) Lower alkoxycarbonyl (lower) -cycloalkyl (eg, 4-methoxy Carbonyl cyclohexyl, etc.), and more preferred examples thereof include lower alkoxycarbonylmethyl.

The “acyl” of R _a ⁷ is lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, etc.), aroyl (eg, benzoyl, etc.) Phonyl (eg, mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propanesulfonyl, butanesulfonyl, etc.), arysulfonyl (eg, benzenesulfonyl, tosyl, etc.).

The "protecting group" in the "protecting amino" group of R ⁶ is substituted or unsubstituted ar (lower) alkyl (eg benzyl, benzyl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, etc.), halo (Lower) alkyl (e.g., trichloromethyl, trichloroethyl, trifluoromethyl, etc.), tetrahydroparanyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloalkylidene, acyl, etc. N-protection group.

Suitable acyl of the protecting group are substituted or unsubstituted lower alkanoyls (e.g. formyl, acetyl, chloroacetyl, trifluoroacetyl, etc.), substituted or unsubstituted lower alkoxycarbonyls (e.g. methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxyca Phenyl, trichloroethoxycarbonyl, 2-pyridylmethoxycarbonyl, etc.), substituted or unsubstituted ar (lower) -alkoxycarbonyl (e.g. benzyloxycarbonyl, benzyl oxycarbonyl, 4-nitrobenzyl Oxycarbonyl and the like), lower cycloalkoxycarbonyl (eg, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like), 8-quinolyloxycarbonyl, succinyl, phthaloyl and the like.

In addition, phosphorus compounds having a reaction product of silane, boron, aluminum or amino groups may also be included in the protecting group. Suitable examples of such compounds include trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, dibutoxyboron chloride, aluminum trichloride, diethoxy chloride, phosphorus dibromide, phenylphosphoric dibromide and the like.

“Functionally controlled carboxy” of R ⁵ means esters, amides and the like.

Suitable examples of esters include alkyl esters (eg, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, t-pentyl esters, hexyl esters, heptyl esters, octyl Esters, 1-cyclopropylethyl esters, etc.), alkenyl esters (eg, vinyl esters, allyl esters, etc.), alkynyl esters (eg, ethynyl esters, propynyl esters, etc.), alkoxy alkyl esters (eg, methoxymethyl Esters, ethoxymethyl esters, isopropoxymethyl esters, 1-methoxyethyl esters, 1-ethoxyethyl esters and the like), alkylthioalkyl esters (e.g., methylthiomethyl esters, ethylthio methyl esters, ethylthioethyl esters) , Isopropylthiomethyl ester, etc.), haloalkyl esters (eg 2-iodoethyl ester, 2,2,2-tri Chloro esters, etc.), alkanoyloxyalkyl esters (e.g. acetoxymethyl ester, propionyl oxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxy methyl ester, hexanoyloxymethyl ester, 2 Substituted or unsubstituted aralkyl esters such as acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ester, and the like, alkanesulfonylalkyl esters such as mesylmethyl ester, 2-mesylethyl-ester, E.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4- Hydroxy-3,5-di-t-butylbenzyl esters, etc.), substituted or unsubstituted aryl esters (e.g., phenyl esters, tolyl esters, t-butylphenyl esters, xyls) Esters having silyl compounds, such as trialkyl silyl esters (e.g., aryl esters, mesityl esters, cumenyl esters, salicylic esters, etc.), trialkylsilyl compounds, dialkylalkoxysilyl compounds, or trialkoxysilyl compounds , Trimethylsilyl ester, triethylsilyl ester, etc.), dialkylalkoxysilyl ester (e.g., dimethylmethoxysilyl ester, dimethylethoxysilyl ester, diethylmethoxy silyl ester, etc.) or trialkoxysilyl ester (e.g., trimeth) Oxysilyl ester, triethoxysilyl ester, and the like).

In the "protecting amino" of R ⁶ and "functionally regulated carboxy" of R ⁵ , the above groups should be understood to mean the physiological and pharmaceutical properties of the target compound as well as the preparation of the target compound by chemical methods.

In other words, in the synthesis process, the free amino group of R ⁶ or the carboxy group of R ⁵ may be used to prevent undesired reactions from occurring, as described above before entering the synthesis process, as described above. Functionally regulated carboxy "and the" protective amino "and / or" functionally regulated carboxy "groups of the resulting compound may be translocated to free amino and / or carboxy groups after the reaction has proceeded.

Such facts will become more apparent in the process described below.

On the other hand, in the sense of the physiological and pharmaceutical properties of the target compound, the compounds having “protective amino” and / or “functionally regulated carboxy” groups are the solubility of particularly active target compounds having free amino and / or carboxy groups. It is optionally used to improve properties such as stability, absorbency and toxicity.

There are non-toxic salts known as suitable “pharmaceutically acceptable salts” of the subject compounds (Ih), for example alkali metal salts (eg sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg calcium salts, magnesium salts). Inorganic bases or inorganic acid salts, including metal salts such as metal salts, ammonium salts, and inorganic acid salts (e.g. hydrochloride, embrittlement hydrochloride, sulfates, phosphates, carbonates, bicarbonates, etc.), for example, amine salts (e.g., triethylamine Salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, Tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt, etc.), organic carboxyl or sulfonate (e.g. acetate, malate, lactate, tartrate, mesylate, benzenesulfonate, rosylate), basic And acidic amino acid salts (eg argi) Organic base salts such as nin salts, aspartic acid salts, glutamate salts, lysine salts, serine salts, and the like.

If the active agent has undesirable physiological or pharmaceutical properties in terms of solubility, stability, and absorbency, the drug is translocated into a controlled derivative to improve such undesirable properties, and thus the derivative is delivered to the patient. When given, it is known that it can be translocated into the parent drug in the patient's body and have an active effect.

In the above meaning, the term "pharmaceutically acceptable bioprecursor" in the present specification and claims, when administered while having a different structure from the active compound of the present invention, refers to the active compound of the present invention in the body. It refers to a controlled derivative that is translocated, and also refers to a derivative that is physiologically derived from the compound of the present invention in the body and exhibits an antibacterial effect.

The method of this invention can be represented by the following process.

3-cefem formation

Wherein R ¹ _a , R ² and R ⁵ are as defined above and R ⁷ _a is acyl, respectively.

The process will be described in detail below.

The formation of 3-cefem

Compound (Ih) or its salt can be manufactured by treating compound (Ig) or its salt with a base.

Preferred bases include inorganic bases such as metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, etc.), metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), 3 Organic bases such as grades (eg, trimethylamine, trimethylamine, pyridine, etc.), alkali metal alkoxides (eg, sodium mexoxide, sodium alkoxide, etc.).

The reaction proceeds in known solvents such as alcohols, dimethylformamide, chloroform, methylene chloride or solvents that do not adversely affect the reaction and in cooling or ambient or higher temperatures.

Compounds obtained according to the processes described above can be isolated and purified by known methods.

When the desired compound (Ih) has a free carboxy of R ⁵ and / or a free amino of R ⁶ , it can be transformed into a pharmaceutically acceptable salt form by known methods.

The target compound (Ih), its pharmaceutically acceptable salts and biological precursors exhibit high antimicrobial activity that inhibits the growth of pathogenic microorganisms, including Gram-positive and Gram-negative bacteria, and are useful as antimicrobial agents.

According to the above-mentioned process, the following compounds can be prepared.

Functionally regulated derivatives are as follows.

Substitute salts are as follows.

Experimental data of representative compound (Ih) are shown below to show the effectiveness of the active compound (I ′).

1. Antimicrobial Activity in Test Tubes

(1) Experiment Method

Antimicrobial activity in vitro is determined by the double structure agar-plate dilution method.

100-fold dilution of each 100-fold dilution of each experimental strain cultured in trypticase-peanut juice was lined on a heart infusion agar-HI (agar) containing different concentrations of the test compound. Heat to 37 ° C. for 20 hours. The minimum inhibitory concentration (MIC) is expressed in ug / ml.

(2) experimental compound

number

(3) experimental results

2. Protective effect against rat disease

(1) Experimental method

Four-week-old male ICR strains of 18.5-21.5 g each were used in a group of 10 mice. Experimental bacteria are incubated overnight at 37 ° C. on tryticase-whey agar and suspended in 5% mucin to obtain a suspension against each challenge cell. 0.5 ml suspension is injected intraperitoneally of the mouse, and after 1 hour, the solution containing the test compound is subcutaneously injected into the rat in various amounts. After 4 days of observation, the ED ₅₀ value is calculated as the number of mice surviving each sheep.

(2) experimental compound

number

(3) experimental results

^* 1: overnight culture

^* 2: 100-fold dilution of overnight incubation

^* 3: Treated in two different amounts after 1 and 3 hours after transmission

3. Acute Toxicity

(1) Experimental Method:

Ten female and 10 male rats 6 months old (JCL-SD week) are used in the group. Experimental compounds dissolved in distilled water are injected subcutaneously and intraperitoneally in rats. Observation was made for 7 days after administration. LD ₅₀ values are calculated from the number of dead animals by the Litchfield-Wilcoxon method.

(2) Experimental compound:

(3) experimental results

4. Absorbency

(1) Experimental Method:

The test compound was orally administered to a group of five fat rats (JCL-SD week, 6 week old male), and the bail and trauma samples were collected 0-6 and 6-24 hours. The concentration of the experimental compound in the sample was determined by a biopsy (disk method) using Bacillus subtilis ATCC-6633 as the experimental organism, and the yield of bile and urine was calculated.

(2) Experimental compound:

(3) experimental results:

Total recovery in bile and urine is 22.8% over 24 hours.

In prophylactic and curative administration, the active compound (Ih) of the present invention is used as an active ingredient with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, injectable or other dosage forms. It is used in the form of a conventional medicine containing in a mixed form of. The agents may be in solid form such as capsules, tablets, dragee ointments or suppositories or in liquid form such as solutions, suspensions, emulsions. If necessary, the preparation may also include auxiliaries, stabilizers, humectants or emulsions, buffers and other commonly used additives.

The amount of compound varies in many ways and depends on the age and condition of the patient, the type and extent of the disease, and the type of active compound (Ih) used. In general, when 50mg, 100mg, 250mg and 500mg of the active compound (Ih) is used in an average dose, the infectious disease caused by pathogenic bacteria can be sufficiently treated. The active compound (Ih) may be administered in an amount of 1 mg / kg to 100 mg / kg, preferably in an amount of 100 mg / kg to 5 mg / kg.

Starting compound (III) can be prepared as follows.

Process A: Reduction of 3-hydroxy Sepam

Process B: O-Acylation

Wherein R ¹ _a , R ² and R ⁵ are each as defined above and R ⁷ _a is acyl. The following examples are given to further illustrate the present invention.

Example 1

(1) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-sefe-4-car contained 1.04 g of sodium bicarbonate in 100 ml of water under ice cooling. To 2.6 g of acid hydrochloride (new isomer) solution is added and stirred to room temperature. The solution is lyophilised to give sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyaminoacetamido] -3- cefe-4-carboxylate (new isomer).

(2) 5 g of 7-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cef-4-carboxylic acid (new isomer) at 35-40 ° C. To 30 ml of an aqueous solution of 1.04 g of sodium was added and stirred at 50 to 53 ° C for 30 minutes. Insoluble materials are removed, the filtrate is treated with 0.3 g of activated carbon and then filtered. The filtrate was lyophilised to give 4.2 g of sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer) .

(3) 1.15 g of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cef-4-carboxylic acid (new isomer) in 100 ml of water To 0.111 g of aqueous calcium hydroxide solution was added, the solution was stirred for 10 minutes at room temperature. The solution was filtered and the filtrate was lyophilised to yield calcium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate ( New isomer) 1.2 g.

(4) 1.15 g of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cef-4-carboxylic acid (new isomer) in 100 ml of water To 0.088 g of magnesium hydroxide contained was added and the mixture was stirred at 70 ° C. for 30 minutes to form a solution. The final solution was filtered and the filtrate was lyophilised to give magnesium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate 1.1 g of (new isomer) is obtained.

(5) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid (new isomer (1.15 g in 50 ml of water) Add 0.523 g of arginine solution and stir the solution for 10 min with Ceylon The final solution is filtered and the filtrate is lyophilised to give 7- [2-2-aminothiazol-4-yl) -2-meth 1.35 g of oxyiminoacetamido] -3-cepem-4-carboxylic acid arginine salt (new isomer) is obtained.

(6) 12 ml of 1.21 g of sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer) Was added to a solution of 0.55 g of lysine hydrochloride in lysine, and the solution was lysed to give 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-sefem. 1.6 g of 4-carboxylic acid lysine salts (new isomers) are obtained.

(7) Sodium hydroxide 20% aqueous solution of 7- [2-aminothiazol-4-yl) -2-methoxyaminoacetamido] -3-sefem- at room temperature contained in a mixture of 8 ml ethanol and 8 ml water. To a suspension of 15 g of 4-carboxylic acid (new isomer) is made a solution of pH 7.5. Filtrate, wash, mix the filtrate and wash solution (containing 18.3 ml of water), add 46 ml of ethanol at 20-25 ° C., stir dropwise, and stir at the same temperature for 30 minutes. 28 ml of ethanol was added dropwise to the mixture for 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with 20 ml of ethanol and dried in vacuo at room temperature to give sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cefem. 13.5 g of a plate (new isomer) of 4-carboxylate dihydrate are obtained. Melting Point 260 ° C (dec.)

(8) 15 g of sodium 7- [2- (2-sodiumaminothiazol-4-yl) -2-methoxyiminoacetamido) -3-cepem-4-carboxylate) (new isomer) 35 It is dissolved in 13 ml of water at ˜45 ° C. with stirring. 52 ml of heated ethanol (30 ° C.) was added to the stirred solution, followed by stirring at the same temperature for 5 minutes, followed by stirring at room temperature for 2 hours. The precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem- 13.45 g of a plate (new isomer) of 4-carboxylate dihydrate are obtained.

(9) Sodium hydroxide 4N aqueous solution 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-sefem- contained in 10 ml of water at 5 DEG C or lower. Carefully add to a stirred suspension of 52 g of 4-carboxylic acid (new isomer) to form a solution of pH 7.0-7.5. Filtration, washing, and 200 ml of the filtrate and washing solution were mixed and added dropwise to 2 L of ethanol for 30 minutes, and then stirred at room temperature for 15 minutes and then stirred at 5 to 10 ° C. for 1 hour. The precipitates were collected by filtration, washed with 200 ml of ethanol and dried in vacuo at 30 ° C. to give amorphous sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] 46.3 g of 3-cefem-4-carboxylate (new isomer) are obtained.

(10) 10 g of sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido] -3-cepem-4-carboxylate (new isomer) in 250 ml of methanol The suspension is treated with an ultrasonic device to make a clean solution. The solution is left at room temperature and then stirred at the same temperature for 3 hours. The precipitate was collected by filtration, washed with methanol and washed with amorphous sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acamido] -3-cepem-4-carboxylate ( Neoisomers).

(11) The crystals obtained in the above examples were dried on P ₂ O ₅ of Becuo at room temperature for one day to form nattium 7- [2- (2-aminothiazole) -2-methoxyimino acetamido] -3. Obtain a plate (new isomer) of cefem-4-carboxylate.

Example 2

(1) 4-nitrobenzyl 7- (2-phenylacetamido) -3-hydroxy-3-cepem- containing 2.12 g of triethylamine and 7.12 g of dimethylaniline and 3.93 g of trimethylsilyl chloride in 200 ml of methyl chloride. To the stirred suspension of 10 g of 4-carboxylate is added and the solution is stirred for 1 hour to room temperature. 4.88 g of pentachloride arsenic acid is added to the solution at -30 to -25 ° C and stirred at -25 to -20 ° C for 3 hours. 42 ml of methanol is added to the solution at -25 to -20 ° C, stirred for 1 hour, and then 35 ml of water at -25 to -20 ° C, and stirred to room temperature.

The precipitate was collected by filtration, washed with methylene chloride and diethyl ether, followed by drying to find 4-nitrobenzyl 7-amino-3-hydroxy-3-cepem-4-carboxylate 5.2 at a melting point of 148 ° C. (dec.) 5.2. get g

(2) 2.87 g of phosphoryl chloride was added dropwise to a solution of 1.37 g of N, N-dimethyl formamide in 10 ml of ethyl acetate at 5-10 ° C., 40 ml of ethyl acetate was added, followed by stirring for 40 minutes under ice cooling. To the solution is added 3.58 g of 2- (2-formamido-4-thiazolyl) -2-methoxyamino acetic acid (new isomer) and the solution is stirred at 0-5 ° C. for 40 minutes. The solution was added 5 g of 4-nitrobenzyl 7-amino-3-hydroxy-3-cefe-4-carboxylate, 50 ml of ethyl acetate, 14.3 g of trimethylsilylacetamide and bis (trimethylsilyl) acetamide at -15 ° C. Add to the mixture of g all at once and stir for 1 hour and 12 minutes at -20 ~ -15 ℃. Add 50 ml of water to the solution at -25--20 ° C and stir until the temperature rises to 5 ° C. The aqueous layer is separated and extracted with ethyl acetate. Ethyl acetate and extracts are mixed and washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solution was concentrated to a volume of 50 ml under reduced pressure and the precipitate was collected by filtration and then washed with ethyl acetate to give 4-nitrobenzyl 7-2- (2-formamido-4-thiazolyl) -2-methoxyiminoacet. 3.5 g of amido-3-hydroxy-3-cepem-4-carboxylate (new isomer) are obtained. Melting Point 163 ° C (dec.)

Example 3

(1) 160 mg of borane sodium is 4-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyimine contained in 10 ml of tetrahydrofuran, 3 ml of acetic acid and 1 ml of water at 0 ° C. It is suspended in a suspension of 1 g of noacetamido] -3-hydroxy-3-cefe-4-carboxylate (new isomer) for 10 minutes and stirred at 0-3 ° C. for 55 minutes, and then water is added and ethyl acetate Extract the solution with. The extract was washed with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, the solution was concentrated under reduced pressure, and the residue was triturated with diethyl ether to give 4-nitrobenzyl 7-. 0.77 g of [2- (2-formamido-4-thiazolyl) -2-methoxyimino acetamido] -3-hydroxy cefe-4-carboxylate (new isomer) is obtained. Melting point: 172-175 ° C.

(2) 0.406 g of mesyl chloride was added with 4-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-hydroxy at 0-5 ° C. To a stirring mixture of 10 g N, N-dimethylformamide 1 g N, N-dimethylformamide and 0.732 g of potassium carbonate was added dropwise for 2 minutes, stirred at room temperature for 2 hours and 30 minutes, ethyl acetate and water were added thereto. Extract with ethyl acetate. The remaining aqueous layer is extracted again with ethyl acetate and the ethyl acetate extract solution is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure, and the residue is column chromatographed on 30 g of silica gel to elute with a mixture of chloroform and ethyl acetate. . The eluate was concentrated under reduced pressure to obtain 4-nitrobenzyl 7- (2- (2-formamido-4-thiazolyl) -2-methoxyimino acetamido] -3-cepem-4-carboxylate (new isomer). ) 0.12 g Melting point: 224 ° C.

Example 4

704 mg of phosphoryl chloride was added dropwise to 336 mg of N, N-dimethylformamide in 8 ml of ethyl acetate at a temperature of 5 ° C. or lower, and stirred at this temperature for 30 minutes, followed by 2- (2-formamidothiazol-4-yl 1 g of) -2-methoxyiminoacetic acid (new isomer) is added and stirred at 5-10 ° C. for 1 hour. The solution was added dropwise to a solution of 872 mg of 7-amino-3-hydroxy cefe-4-carboxylic acid and 1.05 g of trimethylsilyl acetamide in 20 ml of ethyl acetate at -20 DEG C for 5 minutes, and then to -20 DEG C to -25 DEG C. After stirring for 1 hour, 50 ml of water is added and the pH is adjusted to 7.0 by adding sodium bicarbonate. The aqueous layer is separated, the ethyl acetate layer is extracted again with 10 ml of water, and the aqueous extract is mixed to adjust to pH 6 and absorbed on a porous nonionic absorbent diion Hp-20 (trademark: 50 ml manufactured by Mitsubishi Chemical Corporation). The column was washed with 50 ml of water, eluted with 30% aqueous isopropyl alcohol, the eluate containing the target compound was adjusted to pH 6.5 and concentrated under reduced pressure, and the electrons were lyophilised to give sodium 7- [2- (2-form 1.1 g of amido thiazol-4-yl) -2-methoxyimino acetamido] -3-hydroxy cefe-4-carboxylate (new isomer) are obtained.

Example 5 (Preparation step of lysification for inoculation)

Sodium salt of Hwasaeng A (20 g, potency) is dissolved in 200 ml of water, and 5 ml of the solution is filled in 10 ml vials, and the bottle is cooled and dried in vacuum (lyophilization).

Example 6 (suspension desired for inoculation)

Distilled water for injection is added to make 100 ml.

The aqueous suspension is suitable for intramuscular injection.

Example 7 Tablets Administered Orally

The mixture produces tablets that are used orally for the treatment of infectious diseases by pathogenic bacteria.

Example 8 (Capsules for Oral Administration)

The mixture produces a capsule that is used orally for the treatment of infectious diseases caused by virulent bacteria.

Example 9

The following compounds were obtained by methods analogous to those of the above examples.

(1) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid hydrochloride (new isomer)

(2) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid (isomer)

(3) 7- [2- (9-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cefe-4-carboxylic acid sodium (new isomer)

(4) 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid (new isomer)

(5) n-hexanoyloxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer)

(6) p-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetacedo] -3-cepem-4-carboxylate (new isomer)

Claims (1)

A process for preparing a compound of formula (III) and salts thereof by treating a compound of formula (Ig) or a salt thereof with a base.

In the above formula, R ¹ _a is _a structure wherein R ⁶ is amino or protective amino

Is thiazolyl thiadiazolyl and R ² is hydrogen or an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy, R ⁵ is carboxy or functionally regulated carboxy and R ⁷ _a is acyl.