KR20040098915A - 7-Glutaryl imide cephalosporanic acid derivatives and process for preparing it - Google Patents

Abstract

PURPOSE: 7-Glutaryl imide cephalosporanic acid derivatives and a process for preparing the same derivatives are provided, thereby cheaply preparing several cephalosporin-based antibiotics because the glutaryl imide group of the derivatives can be easily subjected to decyclization under base or acid condition. CONSTITUTION: The 7-glutaryl imide cephalosporanic acid derivatives represented by formula (1) are provided, wherein R is halogen atom, hydroxy, linear or branched chain C1-C4 alkyl optionally substituted tertiary nitrogen heterocycle, linear or branched chain C1-C4 alkyl optionally substituted tertiary aliphatic amine, phenyl optionally substituted linear or branched chain C1-C4 alkoxy, benzyloxy which is optionally substituted with alkoxy, nitro or linear or branched chain C1-C4 alkyl, linear or branched chain C1-C4 alkyl optionally substituted silyloxy, or OM wherein M is alkali metal atom; A is hydrogen, OH, Cl, CH2, CH2R1, CH2SR2, CH2R3 or linear or branched chain C1-C4 alkyl optionally substituted vinyl; R1 is hydrogen, halogen, hydroxy, -OC(O)CH3, -OC(O)NH2 or linear or branched chain C1-C4 alkoxy; R2 is linear or branched chain C1-C4 alkyl optionally substituted heterocycle; R3 is linear or branched chain C1-C4 alkyl optionally substituted tertiary nitrogen heterocycle, linear or branched chain C1-C4 alkyl optionally substituted tertiary aliphatic amine, or linear or branched chain C1-C4 alkyl optionally substituted cyclo aliphatic amine; and n is 0 or 1, provided that a case that A is -CH2OC(O)CH3 when R is hydroxy and n is 0 is excluded.

Description

7-Glutaryl imide cephalosporanic acid derivatives and process for preparing it}

The present invention relates to a 7-glutarilimide cephalosporan acid derivative represented by the following formula (1) of the novel structure used for synthesizing a cepha antibiotic and a preparation method thereof.

[Formula 1]

In Chemical Formula 1,

R is a halogen atom; Hydroxyl group; Tertiary nitrogen heterocycle groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Linear or branched C ₁ -C ₄ alkoxy groups unsubstituted or substituted with one or more phenyl; An alkoxy, nitro group or benzyloxy group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Silyloxy groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; OM, where M is an alkali metal atom,

A is a hydrogen atom; OH; Cl; CH ₂ ; CH ₂ R ¹ ; CH ₂ SR ² ; CH ₂ R ³ ; Or a vinyl group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted,

R ¹ is a hydrogen atom; Halogen atom; Hydroxyl group; -OC (O) CH ₃ ; -OC (O) NH ₂ ; Or a linear or branched C ₁ -C ₄ alkoxy group,

R ² represents a heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted,

R ³ is a tertiary nitrogen heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; A linear or branched C ₁ -C ₄ alkyl group represents a substituted or unsubstituted cycloaliphatic amine group,

n is 0 or 1,

Means a single or double bond,

However, R is a hydroxyl group, except when A is -CH ₂ OC (O) CH ₃ when n = 0.

Generally, cephalosporin-based compounds are synthesized by acylating the amino group at the C-7 position of 7-aminocephalosporane acid or introducing the acetoxy group at the C-3 position by nucleophilic substitution. ought.

However, in synthesizing 3-alkenyl compounds (e.g., ceprozil, ceftinir, etc.) or 3-ammonium methyl compounds (e.g., cefepime, ceftazidime, etc.) as cephalosporin derivatives, 7-amino Cephalosporranic acid cannot be used on its own and can only be synthesized through a multistage chemical reaction. That is, a complex series of chemical reactions such as acylating the amino group at the C-7 position of 7-aminocephalosporranic acid, changing to a Schiff's base, or esterifying a carboxyl group at the C-4 position Must go through.

In addition, in synthesizing special cephalosporin derivatives such as 3-sefem-3-halo-substituted compounds (e.g., Sephacller) and unsubstituted cephalosporin compounds (e.g., Ceftizosim, Ceftibutene, etc.) In addition, 7-aminocephalosporranic acid is too expensive and uneconomical and difficult to use.

On the other hand, various studies have been conducted regarding the synthesis of cephalosporin-based derivatives using glutaryl 7-aminocephalosporan acid. Although glutaryl 7-aminocephalosporranic acid may be easier to chemically synthesize than 7-aminocephalosporranic acid because the glutaryl group at the C-7 position protects the amino group, In addition to the possibility of side reactions due to the presence of functional groups, it has been pointed out that there are problems of poor solubility in organic solvents with the two acid compounds. Thus, in order to increase the solubility of glutaryl 7-aminocephalosporranic acid and reduce side reactions, the carboxyl group is methyl, ethyl, propyl, t-butyl, 2,2,2-trichloroethyl, diphenylmethyl, 4-nitro Examples thereof include esterification with benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, trimethylsilyl or triethylsilyl groups and the like (US Pat. No. 6,005,101, US Pat. No. 5,847,116, US Pat. No. 5,660,711). This esterification reaction has the disadvantage of not only increasing the production cost but also complicating the production process because it esterifies two carboxyl groups at the same time.

Thus, the inventors of the present invention may be more useful in the synthesis of various cephalosporin-based derivatives than glutaryl 7-aminocephalosporanic acid as compared to 7-aminocephalosporonic acid, Efforts have been made to synthesize glutaryl 7-aminocephalosporanic acid derivatives with a novel structure that can solve the problem of side reactions caused by dog carboxyl groups and lowering solubility in organic solvents.

As a result, an intramolecular cyclization reaction was carried out by activating glutaric acid using a halogenated compound without going through the cumbersome process of protecting the glutaric acid group of glutaryl 7-aminocephalosporanic acid with another protecting group. 3-acetoxymethyl 7-glutaryl imide cephalosporin compound represented by 2 was synthesized, and from this compound, a novel structure of 7-glutarilimide three having various substituents introduced at the C-3 position The present invention has been completed by synthesizing a palosporranic acid derivative.

Accordingly, an object of the present invention is to provide a 7-glutarilimide cephalosporan acid derivative represented by Formula 1 and a method for preparing the same useful for synthesizing a cepha antibiotic.

The present invention is characterized by the novel 7-glutarilimide cephalosporan acid derivative represented by the following formula (1).

[Formula 1]

In Chemical Formula 1,

R is a halogen atom; Hydroxyl group; Tertiary nitrogen heterocycle groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Linear or branched C ₁ -C ₄ alkoxy groups unsubstituted or substituted with one or more phenyl; An alkoxy, nitro group or benzyloxy group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Silyloxy groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; OM, where M is an alkali metal atom,

A is a hydrogen atom; OH; Cl; CH ₂ ; CH ₂ R ¹ ; CH ₂ SR ² ; CH ₂ R ³ ; Or a vinyl group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted,

R ¹ is a hydrogen atom; Halogen atom; Hydroxyl group; -OC (O) CH ₃ ; -OC (O) NH ₂ ; Or a linear or branched C ₁ -C ₄ alkoxy group,

R ² represents a heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted,

R ³ is a tertiary nitrogen heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; A linear or branched C ₁ -C ₄ alkyl group represents a substituted or unsubstituted cycloaliphatic amine group,

n is 0 or 1,

Means a single or double bond,

However, R is a hydroxyl group, except when A is -CH ₂ OC (O) CH ₃ when n = 0.

Referring to the present invention in more detail as follows.

In the compound represented by Formula 1 according to the present invention, Preferably R is a hydroxy group; A pyridine group, a pyrrolidine group or an imidazole group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; C ₁ -C ₄ alkoxy group; 2,2,2-trichloroethoxy group; 4-methoxybenzyloxy group; 4-nitrobenzyloxy group; Diphenylmethoxy group; 3,4-dimethoxybenzyloxy group; Trimethylsilyloxy group; Triethylsilyloxy group; t-butyldimethylsilyloxy group; OM, where M is Na or K.

In the compound represented by Chemical Formula 1 according to the present invention, A is preferably -CH ₂ R ^1, wherein R ¹ may be a halogen atom, a hydroxyl group, or -OC (O) CH ₃ .

In the compound represented by Chemical Formula 1 according to the present invention, A is preferably -CH ₂ SR ^2, wherein R ² is thienyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thia It is a heterocycle group selected from a diazolyl group, a thiazozolyl group, an oxazolyl group, an oxdiazolyl group, a pyridyl group, a pyrimidinyl group, a benzothiazolyl group, a benzimidazolyl group, and a benzoxazolyl group, Heterocycle groups may be substituted with linear or branched C ₁ -C ₄ alkyl groups at possible positions of the heterocyclic structure. In the case where A is -CH ₂ SR ² , more preferably a 1- (2-dimethylamino-ethyl) -1H-tetrazol-5-ylthiomethyl group, 1H-1,2,3-triazole-4- Ylthiomethyl group, 1,3,4-thiadiazole-5-ylthiomethyl group, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl group, 1H-1-methyl-1,2, 3,4-tetrazol-5-ylthiomethyl group, 1-phenyl-1,2,3,4-tetrazol-5-ylthiomethyl group, 1-sulfomethyltetrazol-5-ylthiomethyl group, 1-carboxy Methyltetrazol-5-ylthiomethyl group, 1- (2-aminoethyl) -1,2,3,4-tetrazol-5-ylthiomethyl group, 1-methylcarbamoyl-1,2,3,4, -Tetrazol-5-ylthiomethyl group, 5-methyl-1,3,4-oxadiazol-2-ylthiomethyl group, 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl group, 3- A methyl-1,3,4-triazine-5,6-dione-2-thiomethyl group, a benzothiazole-2-thiomethyl group, etc. are mentioned.

In the compound represented by Chemical Formula 1 according to the present invention, A is preferably -CH ₂ R ^3, wherein R ³ is a tertiary nitrogen heterocycle group, tertiary aliphatic or cycloaliphatic amine group. In the case where A is -CH ₂ R ³ , more preferably, pyridiniummethyl group, aminopyridiniummethyl group, 6,7-dihydro-5H- [1] pyridiniummethyl group, 5,6,7,8-tetra Hydro-1-quinolinium methyl group, 6,7-dihydro-5H- [2] pyridiniummethyl group, 5,6,7,8, -tetrahydro-2-isoquinoliniummethyl group; Or an N-methyl-bis (2-hydroxyethyl) aminomethyl group, a 3,4-trans-dihydroxy-1-methylpyrrolidylmethyl group, a 1-methyl-1-pyrrolidiniummethyl group, or a trophyllmethyl group.

On the other hand, the present invention includes a method for producing a 7- glutaryl imide cephalosporan acid derivative represented by the formula (1), in the production method according to the invention 3-acetoxymethyl represented by the formula (2) It is characterized in that 7-glutaryl imide cephalosporin compound is used as a starting material.

3-acetoxymethyl 7-glutaryl imide cephalo of 3-acetoxymethyl 7-glutaryl imide cephalosporin compound represented by Formula 2 used as a starting material in the preparation method according to the present invention Sporanic acid is known from Japanese Patent Laid-Open No. 60-57837. Japanese Patent Application Laid-Open No. 60-57837 discloses an example of synthesizing glutaryl 7-aminocephalosporranic acid from cephalosporin C by the enzyme method, wherein 3-acetoxymethyl 7- writing as one of the impurities. It is supposed that a small amount of rutaryl imide cephalosporan acid is obtained. In the present invention, however, glutaryl 7-aminocephalosporranic acid compound was reacted with a halogenated compound to activate glutaric acid and intramolecular cyclization, thereby synthesizing as a main product.

3-acetoxymethyl 7-glutaryl imide cephalosporin compound represented by Chemical Formula 2 is a compound produced by converting glutaric acid into glutarylimide by intramolecular cyclization reaction, and protecting group of carboxyl group Since no additional process is required for introduction, it is advantageous in terms of cost compared to the method of using glutaryl-7-aminocephalosporanic acid as a starting material and has various substituents aimed at by the present invention by a simple chemical reaction. It has the advantage of easily synthesizing 7-glutarilimide cephalosporan acid derivatives.

The following scheme 1 is a 3-acetoxymethyl 7-glutaryl imide represented by the formula (2) used by the present invention as a starting material from the glutaryl 7-aminocephalosporanic acid compound represented by the following formula (3) The reaction for synthesizing the cephalosporin compound is shown, and the cyclization reaction appears to occur when the amide at the C-7 position is formed of a bismeyer type imine and nitrogen attacks the carbon of chlorocarbonyl.

In Scheme 1, R and n are the same as mentioned above, respectively.

Intramolecular cyclization of the glutaryl 7-aminocephalosporanic acid compound represented by the following Formula 3 according to Scheme 1 is N, N-dimethylformamide, N, N-dimethylacetamide or N-methylform In the presence of an amide using a halogenating reagent trichloro phosphoric acid, trichlorophosphine or pentachlorophosphine. The organic solvent used in the reaction may be ethyl acetate, methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran and a mixed solvent thereof as general organic solvents except alcohols. The halogenating agent is used in the range of 1 to 7 equivalents, more preferably 2 to 5 equivalents. N, N-dimethylformamide, N, N-dimethylacetamide or N-methylformamide is used in the amount of 1 to 5 equivalents, more preferably 2 to 3 equivalents. When the reaction temperature is stirred for 5 to 24 hours, more preferably 10 to 12 hours at a reaction temperature of 0 to 80 ° C, more preferably 15 to 30 ° C, the compound represented by Formula 2 is synthesized in high yield and high purity. It is done.

In addition, in order to separate the glutaryl 7-amino cephalosporin dichlorocarbonyl compound represented by Formula 4 synthesized from the above-mentioned cyclization intermediate, oxalyl chloride, thionyl chloride or cyanuric among halogenating agents Reaction with chloride may separate the intermediate compound which is not cyclized. Confirmation of the formation of the intermediate compound can be seen by confirming that glutaryl 7-amino cephalosporin dimethyl ester is formed through a nuclear magnetic resonance apparatus after stirring for 10 minutes in methanol. In addition, the intermediate compound represented by Formula 4 is a halogenating agent selected from trichlorophosphoric acid, trichlorophosphine and pentachlorophosphine and N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl By forming an imine using formamide, a cyclization reaction is performed to obtain a compound represented by Chemical Formula 2.

Meanwhile, in Reaction Scheme 2, the acetoxymethyl group substitution reaction, halogenation reaction, chemical reduction reaction, etc. are performed using 3-acetoxymethyl 7-glutaryl imide cephalosporin compound represented by Chemical Formula 2 as a starting material. By simply showing the method for producing a 7- glutarylimide cephalosporan acid derivative represented by the formula (1) for the purpose of the present invention.

In Scheme 2, R, R ¹ , R ² , R ³ and n are as defined above, respectively.

The compound represented by Chemical Formula 1a may be synthesized by hydrolyzing the compound represented by Chemical Formula 2, followed by esterification or halogenation to introduce a -CH ₂ R ¹ substituent at the C-3 position.

In the above scheme, R, R ¹ and n are the same as mentioned above, respectively.

In the hydrolysis reaction, 1 to 10 equivalents, more preferably 2.2 to 3 equivalents, of sodium bicarbonate are added to the compound represented by the above formula (2), and 2 to 4 hours at 25 to 100 ° C, more preferably 50 to 70 ° C. It proceeds by stirring for a while, and as a result, the acetoxymethyl group in the C-3 position is hydrolyzed and substituted with 3-hydroxymethyl group.

Then, by reacting with a compound having a variety of substituents represented by R ¹ to synthesize the desired compound represented by the formula (1a). In the case of esterification reaction, it is performed at pH 1-5, more preferably 1.5-2.5, and it is performed by stirring for 4-8 hours at reaction temperature -25-30 degreeC more preferably -10-15 degreeC. In order to synthesize the compound represented by Chemical Formula 1a wherein R ¹ = halogen, the 3-hydroxymethyl compound may be halogenated with various halogenating agents to obtain a 3-halogenated methyl compound. As the halogenating agent, trichlorophosphoric acid, trichlorophosphine, pentachlorophosphine, cyanuric chloride and the like can be used. The reaction using pentachlorophosphine as the halogenating agent is carried out in the same manner as conventional methods. The reaction using the cyanuric chloride as the halogenating agent uses a general organic solvent except for alcohols, and the reaction conditions are 0.5 to 3 equivalents of cyanuric chloride, preferably 0.7 to 1.2 equivalents, and N, N-dimethylformamide. Alternatively, N, N-dimethylacetamide is carried out by stirring at a temperature of 0 to 15 ° C., more preferably at 10 to 30 ° C., more preferably at 10 to 30 equivalents, preferably at 15 to 20 equivalents. The compound represented by Chemical Formula 1a prepared by the above method is very useful as an intermediate for synthesizing Sepiksim, Sepuroxime, Cefcapen, etc. among the Sepha antibiotics.

Further, the compound represented by Formula 1b can be synthesized by introducing a substituent to -CH ₂ SR ^2-thiol compound and the nucleophilic substitution reaction of the C-3 position of the compound represented by the general formula (2) include SR ² .

In the above scheme, R, R ² and n are the same as mentioned above.

The reaction is performed using various thiol compounds for 1 to 5 hours, more preferably 1.5 to 2.5 hours, at a temperature of 30 to 100 ° C., more preferably 70 to 90 ° C., using a mixed solvent of water or acetone, methanol, and ethanol. React with As the base, a conventional substance such as sodium carbonate or sodium bicarbonate is used in the range of 2 to 5 equivalents, more preferably 2.2 to 2.4 equivalents, based on the compound represented by the formula (2). The thiol compound is used in the amount of 1 to 3 equivalents, more preferably 1 to 1.4 equivalents. When the reaction with the thiol compound is completed, the pH of the reactant is maintained at 0 to 5, more preferably at pH 0 to 1, extracted with an organic solvent, and then crystallized to recover the compound represented by Chemical Formula 1b. Ethyl acetate is particularly preferably used as the extraction solvent, and ethyl acetate, hexane, and pentane are preferably used as the crystallization solvent. The compound represented by the formula (1b) prepared by the above method is very useful as an intermediate for synthesizing ceftriaxone, ceftriam, ceftyramide, sephamandol, and ceperazone among the sepha antibiotics.

In addition, the method for preparing the compound represented by Chemical Formula 1c will be described first, after the iodide reaction of the compound represented by Chemical Formula 2, followed by nucleophilic substitution reaction with an amine compound including R ³ at the position C-3; By introducing a CH ₂ R ³ substituent, the desired compound represented by the formula (1c) is synthesized.

In the above scheme, R, R ³ and n are the same as mentioned above, respectively.

Since the iodide reaction used in the iodide reaction is highly reactive with water, the iodide reaction is carried out under anhydrous conditions, and the solvent used in the reaction is dried before use. Reaction solvents include a hydrogen chloride solvent such as chloroform, methylene chloride, 1,2-dichloroethane, 1,1,2-trichloroethane, tetrachloroethane, acetonitrile, propionitrile, nitroalkane, sulfolane, 1, 4-dioxane, tetrahydrofuran and the like can be used. As the iodide agent, triiodyl iodine, ioditrimethylsilanepyridium salt, sodium iodide, potassium iodide and the like can be used, and more preferably, iodide trimethylsilane or ioditrimethylsilanepyridium salt is used. The iodide agent was used in 1 to 5 equivalents, more preferably in the range of 1.1 to 2 equivalents. Reaction conditions are 0-100 degreeC More preferably, it reacts at 15-80 degreeC for 1 to 5 hours, Preferably it is 2-3 hours.

The nucleophilic substitution reaction is carried out at 0 to 80 ° C, more preferably at 15 to 40 ° C. The amine compound used as the nucleophile is used in the range of 1 to 5 equivalents, more preferably 1.1 to 2 equivalents, and the reaction is carried out for 1 to 12 hours, more preferably 3 to 5 hours. The compound represented by Chemical Formula 1c resulting from the nucleophilic substitution reaction can be easily recovered by crystallization with acetone after completion of the reaction. The compound represented by Chemical Formula 1c prepared by the above method is very useful as an intermediate for synthesizing ceftazidime, cefepime and the like among cepha antibiotics.

In addition, the compound represented by Chemical Formula 1d synthesizes the compound represented by Chemical Formula 1d by reacting the compound represented by Chemical Formula 2 with zinc in an acid present condition to introduce an exo methylene group at the C-3 position.

In the above scheme, R and n are the same as those mentioned above, respectively.

The introduction reaction of the exo methylene group is carried out according to the generalized prior art, and more preferably 4 to 10 equivalents of zinc and 6 to 4 equivalents of ammonium chloride and preferably 4 to 5 equivalents of hydrochloric acid are reacted with hydrochloric acid. Do it. As the reaction temperature is higher, a side reaction is generated, so that the reaction temperature is maintained at -20 to 0 ° C, more preferably at 0 ° C or less. The compound represented by the formula (1d) prepared by the above method is very useful as an intermediate for synthesizing sephacller, cefebuferazone, ceftutibutene and the like among the sepha antibiotics.

On the other hand, the glutaryl imide group of the 7- glutaryl imide cephalosporanic acid derivative represented by the formula (1) for the purpose of the present invention is easily de-cyclized to acid under acid or base conditions, the formula (1) Decyclization of the compound represented by the acid or base conditions can be prepared a variety of important cepha compounds.

In the above schemes, R, A and n are each as mentioned above.

For example, when describing the reaction under the basic conditions of the compound represented by the formula (1), the compound represented by the formula (1) is water, methyl alcohol, ethyl alcohol, 2-propanol, N, N- dimethylformamide, N, N After dissolving in single and mixed solvents of -dimethylacetamide, glutaric acid is easily prepared by stirring with a base agent such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and the like at -10 to -40 ° C. can do. The decyclized glutaric acid compound may be easily prepared as a cepha compound represented by Chemical Formula 5 by a glutaryl amidase enzyme at pH 7.0 to 8.5.

In addition, when the reaction of the compound represented by the formula (1) is described under acidic conditions, the compound represented by the formula (1) is water, tetrahydrofuran, methylene chloride, 1,4-dioxane, chloroform, acetone, methyl alcohol, ethyl After dissolving in single solvent and mixed solvent of alcohol and 2-propanol, it is refluxed at 50 ~ 100 ℃ with acid such as hydrochloric acid, iodic acid, fluoric acid, bromic acid, sulfuric acid, nitric acid, and stirred for 3 ~ 5 hours. The reaction is made, the glutaric acid of the C-7 position is broken over time to finally produce a cepha compound represented by the formula (5).

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1.Preparation of 7-glutarilimide cephalosporan acid

14.5 mL (3 equivalents) of trichlorophosphoric acid and N, N-dimethylformamide were added to 70 mL of methylene chloride, and the mixture was stirred at 0 ° C. for 20 minutes. After raising to room temperature, 20 g of 3-acetoxymethyl 7-glutaryl imide cephalosporin compound was added and the stirring was continued until all starting materials disappeared. After completion of the reaction, the mixture was extracted with 100 mL of water and 200 mL of ethyl acetate, and the organic solvent was washed with 100 mL of saturated aqueous NaCl solution. The organic solvent was dried over magnesium sulfate and then vacuum dried. Recrystallization with ethyl acetate and hexane gave 17.1 g (90%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.82 (1H), 5.05 (1H), 4.91 (1H), 4.62 (1H), 3.41 (1H), 3.21 (1H), 2.60 (4H), 2.01 (3H), 1.82 (2H); Mass (FAB) m / z 368

Example 2. Preparation of 7-glutarilimide cephalosporin diphenylmethyl ester

1 g of 7-glutarilimide cephalosporan acid synthesized in Example 1 was dissolved in 10 mL of methanol. 8.5 mL (1.6 equiv) of diphenyldiazomethane hexane solution was added dropwise and stirred for 3 hours. Crystals formed as diphenylmethyl ester was formed and all starting materials disappeared. After confirming HPLC, the resulting solid was filtered, washed with a mixed solvent of cyclohexane and isopropyl ether, and dried to obtain 1.32 g of a high-purity target compound. 95%).

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.41 (10H), 6.92 (1H), 5.98 (1H), 5.21 (1H), 5.01 (1H), 4.96 (1H), 3.53 (1H), 3.27 ( 1H), 2.77 (4H), 2.04 (3H), 2.00 (2H); ¹³ C NMR δ (ppm) 172, 170, 162, 161, 139, 138, 128, 127, 62, 61, 58, 32, 20; Mass (FAB) m / z 534

Example 3. Preparation of 7-glutarilimide cephalosporanic acid sulfoxide

Under normal temperature nitrogen, 1 g of 7-glutarilimide cephalosporranic acid synthesized in Example 1 was dissolved in 30 mL of anhydrous methylene chloride, and 5 mL of 32% peracetic acid was slowly added dropwise thereto. After completion of the reaction on HPLC after 2 hours, the solvent was distilled off and crystals were formed with 30 mL of ethyl acetate to obtain 1 g of the target compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 6.16 (1H), 5.24 (1H), 4.92 (1H), 4.82 (1H), 4.14 (2H), 2.69 (4H), 2.03 (3H), 1.82 (2 H)

Example 4. Preparation of 7-glutarilimide cephalosporin pyridium salt

Into 100 mL of methylene chloride, 7.36 g of 7-glutarilimide cephalosporan acid synthesized in Example 1 was stirred for 10 minutes, and then 2.53 mL of 1,1,3,3-hexamethyldisilazane (0.6 equiv. ) And refluxed for about 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, and 3.4 mL (1.2 equivalents) of iodotrimethylsilane was slowly added dropwise thereto, followed by stirring for 1 hour and a half. After cooling the reaction mixture to 0 ° C., 1.8 mL (1.1 equiv) of pyridine was slowly added dropwise. After stirring for 4 hours at room temperature, a small amount of 2N hydrochloric acid was added, followed by further stirring for 30 minutes. After drying the organic solvent in vacuo, acetone was used to obtain 7 g of the target compound as a solid.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 9.07 (2H), 8.76 (1H), 8.25 (2H), 6.03 (1H), 5.50 (2H), 5.05 (1H), 3.42 (1H), 3.32 (1 H), 2.69 (4 H), 1.86 (2 H); ¹³ C NMR δ (ppm) 172, 163, 161, 145, 130, 127, 118, 61, 59, 34, 25, 16

Example 5. Preparation of glutaryl-7-aminocephalosporin pyridium salt; Acid condition

0.3 g of 7-glutarilimide cephalosporin pyridium salt prepared in Example 4 was dissolved in 3 mL of water and 1 mL of tetrahydrofuran, and 0.25 mL of concentrated hydrochloric acid was added thereto. After refluxing the reaction mixture for 3 hours, the organic solvent was dried. Acetone was added to the reaction mixture to obtain a target compound as a light brown solid.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 9.03 (1H), 8.85 (2H), 8.5 (1H), 8.1 (2H), 5.73 (1H), 5.57 (1H), 5.50 (1H), 5.12 (1H), 3.5 (1H), 3.4 (1H), 2.20 (4H), 1.70 (2H)

Example 6. Preparation of glutaryl-7-aminocephalosporin pyridium salt; Base condition

After dissolving 0.5 mg of NaOH in 10 mL of water and 10 mL of methanol, 1 g of 7-glutarilimide cephalosporin pyridium salt prepared in Example 4 was added dropwise at -30 ° C. When the reaction was terminated by stirring for 30 minutes, acetone was used to obtain a glutaryl-7-aminocephalosporin pyridium salt.

Example 7. Preparation of 7-aminocephalosporin pyridium salt; Solid state

After adding 1 g of the 7-aminocephalosporin pyridium salt in the solid state prepared in Example 5 to 15 mL of water, the pH was raised to 8 and stirred until it dissolved. 0.5 g of glutaryl diamidase enzyme was added thereto and stirred until the reaction was completed while maintaining pH 8 in 2N NaOH solution. After filtering the enzyme, acetone was used to obtain 0.92 g of the target compound as a solid.

¹ H NMR (D ₂ O, 400 MHz) δ (ppm) 8.97 (2H), 8.62 (1H), 8.12 (2H), 5.67 (1H), 5.39 (1H), 5.20 (1H), 4.95 (1H), 3.36 (1H), 3.32 (1H)

Example 8. Preparation of 7-aminocephalosporin pyridium salt; Liquid state

In Example 5, after the completion of the reaction, the resulting liquid 7-aminocephalosporin pyridium salt was immediately raised to pH 8 without crystallization, and was carried out in the same manner as in Example 7 to obtain 5.74 g of the target compound.

Example 9. Preparation of 7-glutarilimide cephalosporin pyrrolidiniummethyl salt

3 g of 7-glutarilimide cephalosporranic acid synthesized in Example 1 was added 1,1,3,3-hexamethyldisilazane (0.6 equiv), iodotrimethylsilane (1.2 equiv), 1 2.2 g of the target compound were obtained in the same manner as in Example 4 using -methyl pyrrolidine (1.1 equivalent).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.85 (1H), 5.10 (1H), 4.73 (1H), 4.11 (1H), 3.96 (1H), 3.67 (1H), 3.54 (4H), 3.10 (3H), 2.71 (4H), 2.22 (4H), 1.80 (2H)

Example 10 Preparation of 7-glutarilimide Cephalosporin-3- (1-methyl-1H-tetrazol-sulfanylmethyl)

1 g of 7-glutarilimide cephalosporranic acid synthesized in Example 1 was added to 40 mL of H ₂ O and dissolved in 0.45 g (2 equivalents) of NaHCO ₃ . After adding 0.47 g (1.5 equivalents) of 1-methyl-1H-tetrazol-5-thiol, the mixture was stirred under reflux for 2 hours, and when the starting material was completely removed, the pH was adjusted to 1 with concentrated hydrochloric acid. Extracted twice. The organic layer was washed with 100 mL of saturated NaCl aqueous solution, and the organic solvent was dried and recrystallized with ethyl acetate and hexane solution to obtain 1.05 g (92%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.89 (1H), 5.08 (1H), 4.48 (1H), 4.19 (1H), 3.95 (3H), 3.64 (1H), 3.39 (1H), 2.72 (4H), 1.88 (2H)

Example 11. Preparation of 7-glutarilimide cephalosporin-3- (1-methyl-1H-tetrazol-sulfanylmethyl) diphenylmethylester

1 g of 7-glutarilimide cephalosporin-3- (1-methyl-1H-tetrazol-sulfanylmethyl) prepared in Example 10 was dissolved in 10 mL of methyl alcohol and diphenyldiazomethane hexane. 7.5 mL (1.6 equiv) of the solution was added dropwise. Stir for 5 hours until all starting material is gone. The solid compound produced during the reaction was filtered, washed with cyclohexane and dried to obtain 1.3 g (94%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.51 (10H), 6.88 (1H), 5.89 (1H), 5.31 (1H), 5.01 (1H), 4.88 (1H), 3.87 (3H), 3.54 ( 1H), 3.26 (1H), 2.82 (4H), 1.98 (2H)

Example 12. 7-Glutaryllimide Cephalosporin-3- (2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- [1,2,4] triazine- Preparation of 3-ylsulfanylmethyl)

1 g of _7- glutarilimide cephalosporranic acid synthesized in Example 1 was dissolved in 40 mL of H ₂ O and NaHCO ₃ (2 equivalents). After adding 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- [1,2,4] triazine-3-ylthio (1.5 equiv), The reaction was carried out in the same manner to obtain 1.18 g (93%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.89 (1H), 5.18 (1H), 4.40 (1H), 4.15 (1H), 3.55 (3H), 3.45 (1H), 3.39 (1H), 2.67 (4H), 1.85 (2H)

Example 13. 7-glutarilimide cephalosporin-3- (2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- [1,2,4] triazine- Preparation of 3-ylsulfanylmethyl) diphenylmethyl ester

1 g of the compound synthesized in Example 12 was dissolved in 10 mL of methyl alcohol, and reacted in the same manner as in Example 11 using diphenyldiazomethane hexane solution (2 equivalents) to obtain 1.4 g (96%) of the target compound. Got

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.51 (10H), 6.93 (1H), 5.91 (1H), 5.00 (1H), 4.55 (1H), 4.32 (1H), 3.52 (3H), 3.54 ( 1H), 3.26 (1H), 2.82 (4H), 1.98 (2H)

Example 14 Preparation of 7-Glutaryllimide Cephalosporin-3- (5-methyl-1,3,4-thiadiazol-2-ylsulfanylmethyl)

1 g of _7- glutarilimide cephalosporranic acid synthesized in Example 1 was dissolved in 40 mL of H ₂ O and NaHCO ₃ (2 equivalents). After adding 5-methyl-1,3,4-thiadiazol-2-ylthio (1.5 equivalents), the reaction was carried out in the same manner as in Example 10 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.45 (1H), 5.15 (1H), 4.10 (1H), 3.85 (1H), 3.25 (1H), 3.14 (1H), 2.43 (3H), 2.23 (4H), 1.75 (2H)

Example 15 Preparation of 7-Glutaryllimide Cephalosporin-3- (5-methyl-1,3,4-thiadiazol-2-ylsulfanylmethyl) diphenylmethyl ester

1 g of the compound synthesized in Example 14 was dissolved in 10 mL of methyl alcohol and reacted in the same manner as in Example 11, using a diphenyl diazomethane hexane solution (2 equivalents) to obtain 1.29 g (94%) of the target compound. Got

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.49 (10H), 6.96 (1H), 5.91 (1H), 5.00 (1H), 4.58 (1H), 4.22 (1H), 3.24 (1H), 3.09 ( 1H), 2.91 (3H), 2.54 (4H), 1.88 (2H)

Example 16 Preparation of 7-Glutaryllimide Cephalosporin-3- (1,3,4-thiadiazol-5-ylsulfanylmethyl)

1 g of _7- glutarilimide cephalosporranic acid synthesized in Example 1 was dissolved in 40 mL of H ₂ O and NaHCO ₃ (2 equivalents). 1,3,4-thiadiazol-2-ylthio (1.5 equivalents) was added and the reaction was carried out in the same manner as in Example 10 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.89 (1H), 5.05 (1H), 4.72 (1H), 4.31 (1H), 3.35 (1H), 3.14 (1H), 2.45 (4H), 1.85 (2 H)

Example 17 Preparation of 7-glutarilimide cephalosporin-3- (1,3,4-thiadiazol-5-ylsulfanylmethyl) diphenylmethyl ester

1 g of the compound prepared in Example 17 was dissolved in 10 mL of methyl alcohol, and reacted in the same manner as in Example 11 using diphenyldiazomethane hexane solution (2 equivalents) to yield 1.32 g (95%) of the target compound. Got

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.65 (10H), 6.91 (1H), 5.96 (1H), 5.25 (1H), 4.62 (1H), 4.25 (1H), 3.34 (1H), 3.11 ( 1H), 2.55 (4H), 1.95 (2H)

Example 18. Preparation of 7-glutarilimide cephalosporin-3- (1- (2-dimethylamino-ethyl) -1H-tetrazol-5-ylsulfanylmethyl)

1 g of _7- glutarilimide cephalosporranic acid synthesized in Example 1 was dissolved in 40 mL of H ₂ O and NaHCO ₃ (2 equivalents). 1- (2-dimethylamino-ethyl) -1H-tetrazol-5-ylthio (1.5 equiv) was added and the reaction was carried out in the same manner as in Example 10 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.61 (1H), 5.05 (1H), 4.72 (2H), 4.31 (1H), 3.91 (1H), 3.35 (1H), 3.14 (1H), 3.02 (2H), 2.85 (6H), 2.25 (4H), 1.85 (2H)

Example 19. Preparation of 7-Glutaryllimide Cephalosporin-3- (1- (2-dimethylamino-ethyl) -1 H-tetrazol-5-ylsulfanylmethyl) diphenylmethylester

1 g of the compound prepared in Example 18 was dissolved in 10 mL of methyl alcohol and reacted in the same manner as in Example 11, using a diphenyl diazomethane hexane solution (2 equivalents), to give 1.25 g (93%) of the target compound. Got.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.65 (10H), 6.91 (1H), 5.96 (1H), 5.25 (1H), 4.62 (2H), 4.25 (1H), 4.02 (1H), 3.34 ( 1H), 3.11 (1H), 3.01 (2H), 2.90 (6H), 2.35 (4H), 1.95 (2H)

Example 20. Preparation of 7-glutarilimide-3-exomethylenecepam

1 g of 7-glutarilimide cephalosporranic acid synthesized in Example 1 was added to 5 mL of tetrahydrofuran and 10 mL of H ₂ O at 0 ° C., and then stirred, 1.4 g (8 equivalents) of zinc, and ammonium 0.58 g (4 equiv) of chloride was added. Then 3.5 mL concentrated hydrochloric acid was slowly added dropwise. The reaction mixture was stirred at 0 ° C. for 2 hours, and when all the starting materials were gone, zinc was removed and extracted twice with 50 mL of ethyl acetate at pH 1. The organic solvent was dried over magnesium sulfate, dried in vacuo, and crystallized with ethyl acetate and hexane to obtain the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 5.25 (1H), 5.17 (1H), 5.11 (1H), 5.01 (1H), 4.86 (1H), 3.14 (1H), 3.01 (1H), 2.45 (4H), 1.78 (2H)

Example 21. Preparation of 7-Glutarylimide-3-exomethylenecepam diphenylmethyl ester

1 g of the compound prepared in Example 20 was dissolved in 10 mL of methyl alcohol and reacted in the same manner as in Example 11, using a diphenyl diazomethane hexane solution (2 equivalents) to obtain a target compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.23 (10H), 6.89 (1H), 5.37 (1H), 5.17 (1H), 5.09 (1H), 4.98 (1H), 4.77 (1H), 3.35 ( 1H), 3.21 (1H), 2.65 (4H), 1.85 (2H)

Example 22 Preparation of 7-Glutarylimide-3-hydroxymethyl Cephalosporin Diphenylmethyl Ester

0.3 g (3 equivalents) of NaOH was added to 10 mL of methyl alcohol and ₂ mL of H ₂ O, dissolved, 1.5 mL of boric acid (pH 8.0) was added, and the mixture was cooled to −25 ° C., which was synthesized in Example 1, 7-gluta 1 g of rilimide cephalosporan acid was added. Stir at −25 ° C. for 2 hours until all starting material is gone. The reaction mixture was adjusted to pH 2 at −15 ° C. and 8.5 mL (1.6 equiv) of diphenyldiazomethane hexane solution was added dropwise and stirred for 5 h. Extract twice with 50 mL of ethyl acetate, dry the organic solvent with magnesium sulfate, and dry under vacuum to recrystallize with isopropyl ether and cyclohexane to obtain 1.06 g (80%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.19 (10H), 6.72 (1H), 5.45 (1H), 5.14 (1H), 4.45 (1H), 4.20 (1H), 3.18 (1H), 3.02 ( 1H), 2.48 (4H), 1.81 (2H)

Example 23. Preparation of 7-glutarilimide-3-chloromethyl-cephalosporin diphenylmethyl ester

3 g of the compound prepared in Example 22 was dissolved in a mixed solvent of 5 mL of methylene chloride and 5 mL of N, N-dimethylformamide, and 0.58 g (0.7 equivalents) of cyanuric chloride was added under nitrogen at 0 ° C. After stirring for 1 hour at the same temperature, it was slowly added dropwise to 30 mL of ice water. The resulting yellow solid was filtered and dried in vacuo to give 2.9 g (96%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 7.34 (10H), 6.96 (1H), 5.79 (1H), 5.17 (1H), 4.40 (2H), 3.71 (1H), 3.52 (1H), 2.54 ( 4H), 1.76 (2H)

Example 24 Preparation of Glutaryl 7-Amino Cephalosporin Dichlorocarbonyl

2 g of glutaryl 7-aminocephalosporranic acid was added to 6 mL of tetrahydrofuran, and 3.88 mL of oxalyl chloride was slowly added dropwise at 0 ° C. After stirring for 10 minutes, catalytic amount of N, N-dimethylformamide was added, the turbid reaction mixture was raised to room temperature, and stirred until the reaction mixture became clear. Upon completion of the reaction, the solvent was dried and then recrystallized from dichloromethane and hexane to obtain a pale yellow glutaryl 7-amino cephalosporin dichlorocarbonyl compound. In addition, in order to confirm the formation of the target compound, a small amount of the obtained compound was dissolved in methanol and stirred for 10 minutes, and it was confirmed that glutaryl 7-amino cephalosporin dimethyl ester was produced using NMR.

In the present invention, 3-acetoxymethyl 7- represented by the formula (2) prepared by intra-molecular cyclization of glutaryl acid functional group of glutaryl-7-aminocephalosporanic acid to form glutarylimide By using a glutaryl imide cephalosporin compound as a starting material, the 7-glutarilimide cephalosporan acid derivative represented by Chemical Formula 1 of the novel structure can be prepared in a more economical manner.

In addition, since the glutarylimide group of the compound represented by Chemical Formula 1 synthesized as an object of the present invention is easily decyclized to an acid under a base or acid condition, various important cepha antibiotics can be prepared using the same. have.

Claims (20)

7-glutarylimide cephalosporan acid derivative represented by the following Chemical Formula 1: [Formula 1] In Chemical Formula 1, R is a halogen atom; Hydroxyl group; Tertiary nitrogen heterocycle groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Linear or branched C ₁ -C ₄ alkoxy groups unsubstituted or substituted with one or more phenyl; An alkoxy, nitro group or benzyloxy group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Silyloxy groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; OM, where M is an alkali metal atom, A is a hydrogen atom; OH; Cl; CH ₂ ; CH ₂ R ¹ ; CH ₂ SR ² ; CH ₂ R ³ ; Or a vinyl group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted, R ¹ is a hydrogen atom; Halogen atom; Hydroxyl group; -OC (O) CH ₃ ; -OC (O) NH ₂ ; Or a linear or branched C ₁ -C ₄ alkoxy group, R ² represents a heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted, R ³ is a tertiary nitrogen heterocycle group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; Tertiary aliphatic amine groups in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; A linear or branched C ₁ -C ₄ alkyl group represents a substituted or unsubstituted cycloaliphatic amine group, n is 0 or 1, Means a single or double bond, However, R is a hydroxyl group, except when A is -CH ₂ OC (O) CH ₃ when n = 0. According to claim 1, wherein R is a hydroxyl group; A pyridine group, a pyrrolidine group or an imidazole group in which a linear or branched C ₁ -C ₄ alkyl group is substituted or unsubstituted; C ₁ -C ₄ alkoxy group; 2,2,2-trichloroethoxy group; 4-methoxybenzyloxy group; 4-nitrobenzyloxy group; Diphenylmethoxy group; 3,4-dimethoxybenzyloxy group; Trimethylsilyloxy group; Triethylsilyloxy group; t-butyldimethylsilyloxy group; And OM, wherein M is Na or K. The compound according to claim 1, wherein A is -CH ₂ SR ² , wherein R ² is thienyl group, diazolyl group, triazolyl group, tetrazolyl group, thiazolyl group, thiadiazolyl group, tithiazolyl group, oxa Is a heterocycl group selected from a zolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidinyl group, a benzothiazolyl group, a benzimidazolyl group, and a benzoxazolyl group, and the heterocycle group is located at a possible position of the heterocyclic structure. Compounds which can be substituted with linear or branched C ₁ -C ₄ alkyl groups. The method according to claim 3, wherein A is a 1- (2-dimethylamino-ethyl) -1H-tetrazol-5-ylthiomethyl group, 1H-1,2,3-triazol-4-ylthiomethyl group, 1, 3,4-thiadiazole-5-ylthiomethyl group, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl group, 1H-1-methyl-1,2,3,4-tetrazole -5-ylthiomethyl group, 1-phenyl-1,2,3,4-tetrazol-5-ylthiomethyl group, 1-sulfomethyltetrazol-5-ylthiomethyl group, 1-carboxymethyltetrazol-5- Ylthiomethyl group, 1- (2-aminoethyl) -1,2,3,4-tetrazol-5-ylthiomethyl group, 1-methylcarbamoyl-1,2,3,4, -tetrazol-5- Ylthiomethyl group, 5-methyl-1,3,4-oxadiazol-2-ylthiomethyl group, 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl group, 3-methyl-1,3, A compound selected from 4-triazine-5,6-dione-2-thiomethyl group and benzothiazole-2-thiomethyl group. A compound according to claim 1, wherein A is -CH ₂ R ³ , wherein R ³ is a tertiary nitrogen heterocycle group, tertiary aliphatic or cycloaliphatic amine group. 6. A compound according to claim 5, wherein A is a pyridiniummethyl group, an aminopyridiniummethyl group, 6,7-dihydro-5H- [1] pyridiniummethyl group, 5,6,7,8-tetrahydro-1-quinolinium Methyl group, 6,7-dihydro-5H- [2] pyridiniummethyl group, 5,6,7,8, -tetrahydro-2-isoquinoliniummethyl group; Or N-methyl-bis (2-hydroxyethyl) aminomethyl group, 3,4-trans-dihydroxy-1-methylpyrrolidylmethyl group, 1-methyl-1-pyrrolidiniummethyl group, trophyllmethyl group Compound made into. A compound according to claim 1, represented by the following general formula (1a): In Formula 1a, n is 0 or 1; R is -OH, -ONa, -OK, -OCH (C ₆ H ₅ ) ₂ or -OSi (CH ₃ ) ₃ ; R ¹ is a halogen atom, —OH or —OC (O) CH ₃ , except when A is —CH ₂ OC (O) CH ₃ when R = OH and n = 0. The compound of claim 1, wherein the compound is represented by the following Chemical Formula 1b: In Formula 1b, n is 0 or 1; R is a hydroxy group or OCH (C ₆ H ₅ ) ₂ ; SR ² , , , or to be. A compound according to claim 1, represented by the following general formula (1c): In Formula 1c, n is 0 or 1; R is a hydroxy group, OCH (C ₆ H ₅ ) ₂ or OSi (CH ₃ ) ₃ ; R ³ is or to be. A compound according to claim 1, represented by the following formula (1d): In Formula 1d, n is 0 or 1; R is a hydroxy group or OCH (C ₆ H ₅ ) ₂ . After the hydrolysis of the compound represented by the formula (2), the esterification or halogenation reaction to produce a compound represented by the formula (1a) characterized in that the preparation by introducing a -CH ₂ R ¹ substituent in the C-3 position: In the above scheme, R, R ¹ and n are each as defined in claim 1 above. Next, the compound represented by Chemical Formula 1b is prepared by introducing a -CH ₂ SR ² substituent into the C-3 position by nucleophilic substitution reaction of the compound represented by Chemical Formula 2 with a thiol-based compound (HSR ² ). Way : In the above scheme, R, R ² and n are each as defined in claim 1 above. After the iodide reaction of the compound represented by the following formula (2), the nucleophilic substitution reaction with the amine compound containing R ³ and the -CH ₂ R ³ substituent to the C-3 position to be prepared by the following formula 1c Method for preparing a compound represented by: In the above scheme, R, R ³ and n are each as defined in claim 1 above. A method for preparing a compound represented by Chemical Formula 1d, wherein the compound represented by Chemical Formula 2 is chemically reduced under acidic conditions in the presence of zinc and ammonium chloride to introduce an exo methylene group to the C-3 position; In the above scheme, R and n are as defined in claim 1, respectively. N-N-dimethylformamide with a halogenating agent selected from the group consisting of trichlorophosphoric acid, trichlorophosphine and pentachlorophosphine , 3-acetoxymethyl 7-glutaryl imide cephalosporin represented by the following Chemical Formula 2, characterized in that it is prepared by a cyclization reaction under conditions using N, N-dimethylacetamide or N-methylformamide Preparation of Compounds: In the above scheme, R and n are as defined in claim 1, respectively. The glutaryl 7-aminocephalosporranic acid compound represented by the following formula (3) is a halogenating agent selected from the group consisting of cyanuric chloride, thionyl chloride and oxalyl chloride, and N, N-dimethylformamide, N, N A process for producing a glutaryl 7-amino cephalosporin dichlorocarbonyl compound represented by the following formula (4), which is prepared by halogenation under conditions using dimethylacetamide or N-methylformamide. In the above scheme, n is 0 or 1. Glutaryl 7-aminocephalosporanic acid compound represented by the following formula (3): In Formula 3, n is 0 or 1. A method for preparing a cepha compound represented by the following Chemical Formula 5, characterized in that the 7-glutarilimide cephalosporranic acid derivative represented by the following Chemical Formula 1 is reacted under conditions using an acid or a base: In the above scheme, R, A and n are each as defined in claim 1 above. 19. The method of claim 18, wherein the reaction under acidic conditions is performed using a single solvent or a mixed solvent selected from the group consisting of water, tetrahydrofuran, acetone, 1,4-dioxane, methanol, ethanol and 2-propanol, hydrochloric acid and iodine. A process for producing a cepha compound, characterized in that it is carried out under conditions using an acid selected from the group consisting of acid, fluoric acid, bromic acid, sulfuric acid and nitric acid. In the above scheme, R, A and n are each as defined in claim 1 above. 19. The reaction according to claim 18, wherein the reaction under basic conditions is water, tetrahydrofuran, acetone, 1,4-dioxane, methanol, ethanol, 2-propanol, N, N-dimethylformamide and N, N-dimethylacetamide A glutaryl 7-amino cephalosporin derivative was prepared by reacting a single solvent and a mixed solvent selected from the group consisting of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate. And a step of reacting the prepared glutaryl 7-amino cephalosporin derivative with an enzyme of gluglutaryl amidase. In the above scheme, R, A and n are each as defined in claim 1 above.