WO2004101572A1

WO2004101572A1 - 7-glutaryl imide cephalosporanic acid derivatives and process for preparing it

Info

Publication number: WO2004101572A1
Application number: PCT/KR2004/001165
Authority: WO
Inventors: Tae Won Kang; Kwan Jun Jeon; Won Kyu Choi; Hyun Nam Song; Yong Kyu Park
Original assignee: Ckd Bio Corporation
Priority date: 2003-05-16
Filing date: 2004-05-17
Publication date: 2004-11-25
Also published as: KR20040098915A; KR100643148B1

Abstract

The present invention relates to a novel 7-glutaryl imido cephalosporanic acid derivative and used in the synthesis of cephalosporinic antibiotics and a method of its preparation.

Description

7-Glutaryl i ide cephalosporanic acid derivatives and process for preparing it

Technical Field

The present invention relates to 7-glutaryl imido cephalosporanic acid derivatives with a novel structure represented by the following formula 1, which is used in the synthesis of cephalosporinc antibiotics, and a method of its preparation.

Background Art

[ ]

In the above formula 1,

R represents a halogen atom; a hydroxy group; a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a linear or branched C1-C4 alkoxy group, unsubstituted or substituted by at least a phenyl group; a benzyloxy group substituted by a linear or branched C1-C4 alkyl or an alkoxy group or a nitro group; a silyloxy substituted by at least a linear or branched, unsubstituted or substituted C1-C4 alkyl group; OM(M is an alkali metal atom);

A represents a hydrogen atom; OH; Cl; CH₂; CH2R¹; CH2SR²; CH₂R³; or a vinyl group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; R¹ represents a hydrogen atom; a halogen atom; a hydroxy group; -

OC(0)CH₃; -OC(0)NH₂; or a linear or branched C1-C4 alkoxy group;

R² represents a heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group;

R³ represents a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a cycloaliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; n is 0 or 1; and . '—' represents a single or a double bond; with the proviso that when R is a hydroxy group and n is 0, A is not - CH₂OC(0)CH₃.

It is well known that cephalosporin compounds are obtained by acylation of the amino group at C-7 position and by introduction of the acetoxy group at C-3 position of 7-aminocephalosporanic acid. However, 7-aminocephalosporanic acid cannot be used directly for the syntheses of cephalosporin derivatives, such as 3- alkenyl compounds (e.g., CefproziL Cefdinir, etc.) or 3-ammonium methyl compounds (e.g., Cefepime, Ceftazidime, etc.) but it must first go through with protection reactions of the amino group as well as the carboxyl group.

That is, the amino group at C-7 position should be acylated or modified into a Schiffs base and the carboxyl group at C-3 position should be esterified, respectively.

In addition, 7-aminocephalosporanic acid is too expensive to economically produce special cephalosporin derivatives such as compounds substituted with 3- cephem-3-halo (e.g., Cefaclor), unsubstituted compounds (e.g., Ceftizoxime, Ceftibuten, etc.). Numerous studies were done on the syntheses of cephalosporin derivatives using glutaryl 7-aminocephalosporanic acid. It is shown that glutaryl 7- aminocephalosporanic acid, its amino group being protected by a glutaryl group, has several adventages from their chemical reactivities and economical aspects as compared to that of 7-aminocephalosporanic acid. However, it has also a few disadvantages that a side reaction may occur due to the presence of a functional group of glutaric acid and a poor solubility due to the presence of two acids as a compound.

Therefore, several attempts have been made to improve solubility and reduce side reactions of glutaryl 7-aminocephalosporanic acid by esterification of the carboxyl group with a methyl, ethyl, propyl, t-butyl, 2,2,2-trichloroethyl, diphenylmethyl, 4-nitroebnzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, trimethylsilyl or triethylsilyl group, etc (U.S. Pat. Nos. 6,005,101 5,847,116 and 5,660,711). However, esterification of the carboxyl group of glutaryl 7- aminocephalosporanic acid also shown some disadvantages that it makes the manufacturing process rather complex and also increases net cost due to the simultaneous esterification of two carboxyl groups.

Considering that the glutaryl 7-aminocephalosporanic acid is more useful than 7-aminocephalosporanic acid in the syntheses of cephalosporin derivatives, the inventors of the present invention made various efforts to synthesize a glutaryl 7- aminocephalosporanic acid having a novel structure which can solve the aforementioned drawbacks of low solubility and the occurrences of side reactions by two carboxyl groups.

As a result, the inventors were able to synthesize 3-acetoxymethyl 7-glutaryl imido cephalosporanic acid represented by the following general formula 2 via an intramolecular cyclization by activation of glutaric acid using a halogenated compound without going through an additional step of protecting a glutaric acid group of glutaryl 7-aminocephalosporanic acid. Using the synthesized compounds, 7-glutarylimido cephalosporanic acid derivative with a novel structure having various substitutes at C-3 position were synthesized

cyclization

( 2 )

Therefore, an object of the present invention is to provide 7-glutarylimido cephalosporanic acid derivatives represented by the following formula 1 which is useful in synthesizing cephalosporinic antibiotics and a method of preparing the same.

Disclosure The present invention relates to a novel 7-glutarylimido cephalosporanic acid derivatives represented by the following formula 1.

In the above formula 1, R represents a halogen atom; a hydroxy group; a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched O-C4 alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a linear or branched C1-C4 alkoxy group, unsubstituted or substituted by at least a phenyl group; a benzyloxy group substituted by a linear or branched C1-C4 alkyl or an alkoxy group or a nitro group; a silyloxy substituted by at least a linear or branched, unsubstituted or substituted C1-C4 alkyl group; OM(M is an alkali metal atom);

A represents a hydrogen atom; OH; Cl; CH₂; CH2R¹; CH2SR²; CH2R³; or a vinyl group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; R¹ represents a hydrogen atom; a halogen atom; a hydroxy group; - OC(0)CH₃; -OC(0)NH₂; or a linear or branched C1-C4 alkoxy group;

R² represents a heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; R³ represents a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched C1-C alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a cycloaliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; n is 0 or 1; and zz i represents a single or a double bond; with the proviso that when R is a hydroxy group and n is 0, A is not - CH₂OC(0)CHB.

The present invention can be described in more detail as set forth hereunder.

In the compound represented by the following formula 1 of the present invention, it is preferable that R is a compound selected from the group consisting of a hydroxy group, a pyridine group with a substituted or unsubstituted linear or branched C1-C4 alkyl group, a pyrrolidine group or an imidazole group, a C1-C4 alkyl group, a 2,2,2-trichloroethoxy group; a 4-methoxybenzyloxy group, a 4- nitrobenzyloxy group, a diphenylmethoxy group, a 3,4-dimethoxybenzyloxy group, a trimethylsilyloxy group, a triethylsilyloxy group, t-butyldimethylsilyloxy group, and OM, wherein M is Na or K. In the compound represented by the following formula 1 of the present invention, it is preferable that A is and -CH2R¹, R¹ is a halogen atom, a hydroxyl group or -OC(0)CH3.

In the compound represented by the following formula 1 of the present invention, it is preferable that A is -CH₂SR²; and R²is a heterocyclic group selected from the group consisting of a thienyl group, a diazolyl group, a triazolyl group, a tetrazolyl group, a thiazolyl group, a thiadiazolyl group, a thiazolyl group, a thiatriazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidinyl group, a pyridyl group, a benzothiazolyl group, a benzothiazolyl group, a benzoimidazolyl group, and a benzooxazolyl group, wherein the heterocyclic group can be substituted with a linear or branched C1-C4 alkyl group at a position where a hetero ring structure is allowed.

In the compound represented by the following formula 1 of the present invention, wherein A is -CH2SR², it is more preferable that A is selected from the group consisting of l-(2-dimethylamino-ethyl)-lH-tetrazol-5-ylthiomethyl group, a lH-l,2,3-triazol-4- ylthiomethyl group, a l,3,4-thiadiazol-5-ylthiomethyl group, a 5- methyl-l,3,4-thiadiazol-2-ylthiomethyl group, a lH-l-methyl-l,2,3,4-tetrazol-5- ylthiomethyl group, a l-phenyl-l,2,3,4-tetrazol-5-ylthiomethyl group, a 1- sulfomethyltetrazol-5-ylthiomethyl group, a l-carboxymethyltetrazol-5- ylthiomethyl group, a l-(2-aminoethyl)-l,2,3,4-tetrazol-5-ylthiomethyl group, a 1- methylcarbamoyl-l,2,3,4-tetrazol-5-ylthiomethyl group, a 5-methyl-l,3,4-oxadizaol- 2-ylthiomethyl group, l-(2-hydroxyethyl)tetrazol-5-ylthiomethyl group, 3-methyl- l,3,4-triazine-5,6-dion-2-thiomethyl group, and a benzothiazol-2-thiomethyl group. In the compound represented by the following formula 1 of the present invention, it is preferable that A is -CH2R³, and R³ is a tertiary amine heterocyclic group or an aliphatic or a cycloaliphatic amine group.

In the compound represented by the following formula 1 of the present invention, wherein A is -CH2R³, it is more preferable that A is selected from the group consisting of a pyridinium methyl group, an aminopyridinium methyl group, a 6,7-dihydro-5H-[l] pyridinium methyl group, 5,6, 7,8-tetrahydro-l- quinolmiummethyl group, a 6,7-dihydro-5H-[2] pyridinium methyl group, 5,6,7,8- tetrahydro-2-isoquinoliniummethyl group; or an N-methyl-bis(2- hydroxyethyl) aminomethyl group, a 3,4-trans-dihydroxy-l-methylpyrrolidylmethyl group, a 1-methyl-l- pyrrolidinium methyl group, and a tropyl methyl group.

Further the present invention also relates to a method of manufacturing 7- glutarylimido cephalosporanic acid derivatives represented by the above formula 1.

The method of the present invention is characterized in that 3-acetoxymethyl 7- glutarylimido cephalosporin compound represented by the above formula 2 is used as a starting material.

Of the 3-acetoxymethyl 7-glutarylimido cephalosporin compounds represented by the above formula 2 of the present invention, 3-acetoxymethyl 7- glutarylimido cephalosporanic acid is disclosed in Japanese Patent Publication Sho 60-57837. The Japanese Patent Publication S60-57837 discloses a method for synthesis of glutaryl 7-aminocephalosporanic acid from cephalosporin C, and describes that a little amount of 3-acetoxymethyl 7-glutarylimido cephalosporanic acid is produced as an impurity. In the present invention, to provide 7-glutarylimido cephalosporanic acid as a main synthesized product, glutaryl 7- aminocephalosporanic acid was reacted with a halogenated compound and was cyclized by intramolecular cyclization.

The 3-acetoxymethyl 7-glutarylimido cephalosporanic acid represented by the above formula 2 is produced by converting glutaric acid into glutarylimido via an intramolecular cyclization, which does not require an additional step to introduce a protecting group for a carboxyl group. Therefore, it is more advantageous in cost-effectiveness than the method which uses glutaryl 7-aminocephalosporanic acid as a starting material, and is also advantageous in that it can be used via a simple chemical reaction to more readily produce 7-glutarylimido cephalosporanic acid derivatives with various substituted groups aimed by the present invention.

The following reaction scheme 1 shows a reaction to produce 3- acetoxymethyl 7-glutarylimido cephalosporin compound represented by the above formula 2, which is used as a starting material in the present invention, from a glutaryl 7-aminocephalosporanic acid compound represented by the following formula 3. In this reaction scheme 1, a cyclization appears to be performed as nitrogen atom attack carbon atom of chlorocarbonyl after an amide at C-7 position is formed into an imine of villsmeier type.

Scheme 1

In the above reaction scheme 1, R and n are same as defined in the above. In the above reaction scheme 1, the intramolecular cyclization of glutaryl 7- aminocephalosporanic acid compounds represented by the following formula 3 is conducted using a halogenating agent such as trichloro phosphoric acid, trichloro phosphin, and pentachloro phosphin in the presence of N, N-dimethylformamide, N,N-dimethylacetamide or N-methylformamide.

Examples of organic solvents to be used in the above reaction are ethyl acetate, methylene chloride, chloroform, 1,4-dioxan, tetrohydrofuran and a mixture of these solvents.

Halogenating agents are preferably used in the amount of 1-7 equivalents, more preferably 2-5 equivalents.

N, N-dimethylformamide, N,N-dimethylacetamide or N-methylformamide are used in the amount of 1-5 equivalents, more preferably 2-3 equivalents. The above reaction is to be performed at 0 - 80 ^°C, preferably for 5-24 hr at 15

- 30 ^°C, more preferably for 10-12 hr at 15 - 30 ^°C, which enables to synthesize a product represented by the above formula 2 with high yield and purity.

Further, if it is intended to separate glutaryl 7-arnino cephalosporin dichlorocarbonyl compound represented by the above formula 4 which is produced as an intermediate in the above cyclization, such halogen agents as oxalyl chloride, thionyl chloride or cyanuric chloride can be used to separate the above intermediate which is not cyclized.

The production of the above intermediate can be confirmed by observing the production of glutaryl 7-amino cephalosporin dimethylester after stirring in methanol for 10 min by NMR.

Further, a compound represented by the formula 2 can be obtained from the above intermediate represented by the above formula 4 via a cyclization induced by forming an imine when the above intermediate is placed in the presence of a halogenating agent such as trichloro phosphoric acid, trichloro phosphin, and pentachloro phosphin; and a compound selected from the group consisting of N, N- dimethylformamide, N,N-dimethylacetamide and N-methylformamide.

The following reaction scheme 2 shows a method to obtain a 7-glutarylimido cephalosporanic acid derivatives represented by the above formula 1, a target compound of the present invention, by using 3-acetoxymethyl 7-glutaryl imido cephalosporin compound as a starting material represented by the above formula 2, wherein an acetoxymethyl group undergoes a substitute reaction, a halogenation and a chemical reduction. Scheme 2

In the above reaction scheme 2, R, R¹, R², R³ and n are same as defined above.

The compound represented by the above formula la can be synthesized by hydrolyzing a compound represented by the above formula 2 followed by an esterification or halogenation thereby introducing a -CH2R¹ substitution group at C- 3 position.

1. hydrolysis

2. ester ification or halogenat ion

In the above reaction, R, R¹ and n are same as defined above.

The above hydrolysis is performed by using 1-10 equivalents of sodium bicarbonate with respect to the compound represented by the above formula 2, preferably 2.2-3 equivalents of sodium bicarbonate, and stirring for 2-4 hr at 25- 100 ^°C, more preferably for 2-4 hr at from 50 to 70 °C, thereby the acetoxy methyl group at C-3 position is hydrolyzed and substituted with 3-hydroxymethyl group.

Thus obtained product is then reacted with a compound having various substitute groups represented by R¹ and produces the compound represented by the above formula la.

In case when an esterification is performed, the reaction is performed at pH 1-5, preferably at pH 1.5-2.5, at from -25 to 30 ^°C, more preferably at from -10 to 15 °C, by stirring for 4-8 hr. In case when a compound represented by the above formula la where R¹ is a halogen atom, 3-halogenated methyl compound can be obtained from a 3- hydroxymethyl compound via a halogenation reaction using a halogenating agent.

Examples of halogenation agent to be used are trichloro phosphoric acid, trichloro phosphin, pentachloro phosphin, cyanuric chloride, etc. The reaction using pentachloro phosphin is performed same as in the conventional method. The reaction using cyanuric chloride is performed by using a general organic solvent except alcohols, and uses 0.5-3 equivalents of cyanuric chloride, preferably 0.7-1.2 equivalents. N, N-dimethylformamide or N,N-dimethylacetamide are used in the amount of 10-30 equivalents, preferably 15-20 equivalents at from -10 to 30 ^°C, more preferably at 0-15 ^°C by stirring for 3 hr.

Thus produced compound represented by the above formula la is very useful as an intermediate for synthesizing Cefixime, Cefuroxime and Cefcapene. The compound represented by the above formula lb can be synthesized by performing a nucleophilic substitution reaction between the compound represented by the above formula 2 and a thiol compound having SR² and then introducing a substitution group CH2SR² at C-3 position.

In the above reaction, R, R² and n are same as mentioned above. The above reaction is performed by using water or a mixed solvent of acetone, methanol, ethanol and a base at 30-100 ^°C, preferably at 70-90 ^°C, for 1-5 hr, more preferably for 1.5-2.5 hr by reacting with various thiol compounds.

As a base for the above reaction, sodium carbonate or sodium bicarbonate can be used in the amount of 2-5 equivalents with respect to the compound represented by the above formula 2, preferably 2.2-2.4 equivalents. Thiol compounds are used in the amount of 1-3 equivalents, preferably 1-1.4 equivalents. Once the reaction with a thiol compound is completed, the pH of the reactant is maintained at 0-5, preferably at 0-1, to extract using an organic solvent and then crystallized and then finally the target product represented by the above formula lb is obtained. As an organic solvent for extraction, it is preferable to use ethyl acetate, and as a crystallization solvent it is preferable to use ethyl acetate, hexane or pentane.

Thus manufactured compound represented by the above formula lb is very useful as an intermediate for synthesis of cephalosporinic antibiotics, especially Ceftriaxone, Cefotiam, Cefpiramide, Cefamandole, Cefoperazone, etc.

As for the method of manufacturing a compound represented by the above formula lc, the compound represented by the above formula 2 is iodized and then introduced with a substitution group at C-3 position thereby synthesizing the target compound represented by the formula lc.

In the above reaction, R, R³ and n are same as mentioned above.

Because the iodination agent used in the above iodination has a relatively high reactivity with water the iodination is performed in anhydrous condition, and thus the solvent used in the reaction was dried prior to use.

Examples of the reaction solvents are chlorinated solvents such as chloroform, methylene chloride, 1,2-dichloroethane, ,1,2-trichloroethane, and tetrachloroethane, or solvents such as acetonitrile, propionitrile, nitroalkane, sulforan, 1,4-dioxane, tetrahydrofuran, etc. Examples of iodination agents include iodotrimethylsilane, iodotrimethylsilane pyridium salt, sodium iodide, and potassium iodide, more preferably iodo trimethylsilane, iodo trimethylsilane pyridium salt.

An iodination agent can be used in the amount of 1-5 equivalents, preferably 1.1-2 equivalents, at a reaction temperature of from 0 to 100 ^°C, preferably from 15 to 80 ^°C , for 1-5 hr, more preferably 2-3 hr.

The nucleophilic substitution reaction is performed at 0 to 80 ^°C, preferably from 0 to 40 ^°C . Amine compounds used as a nucleophile is used in the amount of 1-5 equivalents, preferably 1.1-2 equivalents, and reacted for l-12hr, more preferably 3-5 hr.

The compound represented by the above formula lc produced as a result of the nucleophilic substitution reaction can be easily collected by crystallization using acetone. The compound represented by the above formula lc produced by the above-mentioned method is very useful as an intermediate to synthesize cephalosporinic antibiotics, especially Ceftazidime, Cefepime, etc.

^■ Further, the target compound of the present invention represented by the above formula Id can be synthesized by reacting the compound represented by the above formula 2 in the presence of zinc and an acid thereby introducing an exomethylene group at C-3 position.

In the above reaction, R and n are same as mentioned above. The introduction of an exomethylene group is performed according to the technology in the art. It is preferable to use 4-10 equivalents of zinc, more preferably 6-8 equivalents and it is preferable to use 2-6 equivalents of ammonium chloride, more preferably 4-5 equivalents by reacting with hydrochloric acid.

As the reaction temperature increases it is more likely that there occurs a side reaction, it is preferable to maintain the reaction temperature below 0 ^°C, more preferably in the range of from -20 to 0 ^°C . The compound represented by the above formula Id produced by the above-mentioned method is very useful as an intermediate to synthesize cephalosporinic antibiotics, especially Cefaclor, Cefbuperazone, Ceftibuten, etc.

The glutarylimido group of a 7-glutarylimido cephalosporanic acid derivative, a target compound of the present invention represented by the above formula 1, easily undergoes decyclization under an acidic or a basic condition.

Therefore, various cephalosporins can be manufactured via decyclization under an acidic or a basic condition.

Acidic condition (deprotection)

Referring to the reaction of the compound represented by the above formula 1 under a basic condition, the compound represented by the above formula 1 is dissolved in the presence of a single solvent or a mixed solvent selected from the group consisting of water, alcohol, methyl alcohol, ethyl alcohol, 2-propanol, N,N- dimethylformamide, N,N,-dimethylaceamide, and then stirred along with the bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, etc., for 30 - 100 min thereby producing glutaric acid.

Decyclized glutaric acid compounds can be easily converted into a cephlosporin compound represented by the above formula 5 at pH 7.0 - 8.5 by using glutaryl amidase.

Referring to the reaction of the compound represented by the above formula 1 under an acidic condition, the compound represented by the above formula 1 is dissolved in the presence of a single solvent or a mixed solvent selected from the group consisting of water, tetrahydrofuran, methylene chloride, 1,4-dioxane, chloroform, acetone, methyl alcohol, ethyl alcohol, 2-propanol; refluxed at a temperature of from 50 to 100 ^°C along with acids such as hydrochloric acid, iodic acid, fluoric acid, bromic acid, sulfuric acid, nitric acid, etc.; and then stirred for 3-5 hr thereby inducing decyclization, wherein glutaric acid at C-7 position is decomposed as time passes thus finally producing the cephalosprin compound represented by the above formula 5.

Best Mode

This invention is explained in more detail based on the following Examples and Test Examples but they should not be construed as limiting the scope of this invention.

Example 1 : Synthesis of 7-glutarylimido cephalosporanic acid

To 70 mL of methylene chloride was added 14.5 mL (3eq.) of trichloro phosphoric acid N,N-dimethylformamide and stirred for 30 min at 0 °C . After increasing the temperature to room temperature, the mixture was added with 20g of 3-acetoxymethyl 7-glutaryl imido cephalosporin compound and stirred until all the starting material is depleted.

Upon completion of the reaction, extraction was performed using 100 mL of water and 200 mL of ethyl acetate, and then washed the organic solvent with 100 mL of saturated NaCl solution. The organic solvent was dried with magnesium sulfate and then vacuum dried. It was then recrystallized with ethyl acetate and hexane and obtained 17.1 g of the target compound (90%). Ή NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin diphenylmethylester

1 g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in 10 mL of methanol. 8.5 mL (1.6 eq) of diphenyldiazomethan hexane solution was dropwisely added to the above mixture and stirred for 3 hr. Then, there forms diphenylmethyl ester and crystal is precipitated. Upon confirmation of depletion of all starting materials via HPLC, the solids generated thereof are filtered, washed with a mixed solvent of cyclohexane and isopropyl ether, dried and finally obtained 1.32 g of the target compound with high purity (95%). Η NMR(CDC1₃, 400MHz) 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); ¹³C NMR δ(ppm) 172, 170, 162, 61, 139, 138, 128, 127, 62, 61, 58, 32, 20; Mass(FAB) m/z 534

Example 3 : Synthesis of 7-glutarylimido cephalosporanic acid sulf oxide

Under the ambient nitrogen atmosphere, lg of the 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in 30 mL of anhydrous methylene chloride and dropwisely added with 5mL of 32% peracetic acid. In 2 hr, as the reaction is completed in HPLC, the solvent is distilled and crystallized with 30 mL Of ethyl acetate and then obtained lg of the target compound. Η NMR(DMSO-d₆, 400MHz) 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(2H)

Example 4 : Synthesis of 7-glutarylimido cephalosporin pyridium salt

To 100 mL of methylene chloride was added 7.36 g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 and then stirred for 10 min, and added again with 2.53 mL(0.6 eq) of 1,1,3,3-hexamethyldisilazane and refluxed.

Upon completion, the reaction mixture was allowed to cool down to room temperature and dropwisely added with 3.4 mL (1.2 eq) of iodotrimethylsilan and then stirred for 1.5 hr. The reaction mixture was cooled down to 0 °C and then dropwisely added with 1.8 mL (1.1 eq) of pyridine. After stirring for 4 hr at room temperature, the mixture was added with a little amount of 2N HCl and then stirred again for 30 min. After vacuum drying the organic solvent, the target compound in solid was obtained by using acetone. NMR(DMSO-d₆, 400MHz) 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(1H), 2.69(4H), 1.86(2H); ⁱ³C NMR δ(ppm) 172, 163, 161, 145, 130, 127, 118, 61, 59, 34, 25, 16

Example 5 : Synthesis of glutaryl 7-aminocephalosporin pyridium salt: acidic condition

0.3 g of 7-glutarylimido cephalosporin pyridium salt synthesized in Example

4 was dissolved in 3 mL of water and 1 mL of tetrahydrofuran and then added with 0.25 mL of cone, nitric acid. After refluxing the above reaction mixture for 3 hr, the organic solvent was dried. The target compound in light brown solid was obtained by adding acetone to the reaction mixture. Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of glutaryl 7-aminocephalosporin pyridium salt: basic condition 0.5 mg of NaOH was dissolved in 10 ML of water and 10 mL of methanol and then dropwisely added with lg of 7-glutarylimido cephalosporin pyridium salt synthesized in Example 4 at -30 "C . Upon completion of the reaction after stirring for 30 min, glutaryl-7-amino cephalosporin pyridium salt was obtained.

Example : Synthesis of 7-aminocephalosporin pyridium salt in solid

1 g of solid glutaryl-7-aminocephalosporin pyridium salt synthesized in Example 5 was added to 15 mL of water and adjusted its pH to 8. The mixture was stirred until it was dissolved. Then, 0.5 g of glutaryl imidase was added to the mixture and stirred until the reaction was complete while maintaining its pH at 8 with 2N NaOH. The glutaryl imidase was filtered and 0.92 g of the target compound in solid was obtained using acetone.

Η NMR(D₂0, 400MHz) 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 : Synthesis of 7-aminocephalosporin pyridium salt in liquid

Liquid glutaryl-7-aminocephalosporin pyridium salt synthesized in Example 5 was not crystallized but its pH was increased to 8 and 5.74 g of the target compound was obtained using the method as in Example 7.

Example 9 : Synthesis of 7-glutarylimido cephalosporin pyrrolidiniummethyl salt

2.2 g of the target compound was obtained from 3g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 using 1,1,3,3-hexamethyldisilazan (0.6 eq) and 1-methylpyrrolidine using the same method in Example 4 Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(l-methyl-lH-tetrazol- sulfanylmethyi)

1 g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 and 0.45 g of NaHC0₃ (2eq) was dissolved in 40 mL of water. The mixture was added with 0.47 g of l-methyl-lH-tetrazol-5-thiol (1.5 eq) and stirred for 2 hr under reflux to deplete the starting material. Then, the mixture was adjusted to have a pH 1 with cone. HCl and then extracted twice with 50 mL of ethyl acetate. The resulting organic phase was washed with 100 mL of saturated NaCl solution. The organic solvent was dried and then recrystallized with ethyl acetate and hexane and 1.05 g of the target compound with 92% purity was obtained.

Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutaι limido cephalosporin-3~(l-methyl-lH-tetrazol - sulfanylmethyl) diphenylmethylester

1 g of 7-glutarylimido cephalosporin-3-(l-methyl-lH-tetrazol- sulfanylmethyl) synthesized in Example 10 was dissolved in 10 mL of methyl alcohol and then dropwisely added with 7.5 mL of diphenyl diazomethane hexane. The mixture was stirred for 5 hr to deplete the starting material. All the solid compounds produced during the reaction were filtered, washed with cyclohexane, dried and obtained 1.3 g of the pure target compound (94%).

Η NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(2-methyl-5,6-dioxo- l,2,5,6-tetrahydro-[l,2,4]triazine-3- ylsulf anylmethyl)

1 g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in a mixture of 40 mL water and NaHC0₃ (2 eq). The mixture was the added with 2-methyl-5,6-dioxo-l,2,5,6-tetrahydro-[l,2_/4]triazine-3-yl-thio (1,5 eq) and 1.18 g of the target compound (93%) via the method used in Example 10.

Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7- glutarylimido cephalosporin-3-(2-methyl-5,6-dioxo- 1,2,5,6-tetr ahy dro-[l,2,4]triazine-3-y lsulf any lmethyl) diphenylmethylester

1 g of the product synthesized in Example 12 was dissolved in 10 mL of methyl alcohol and obtained 1.4 g (96%) of the target compound using diphenyldiazomethane hexane solution (2eq) via the method used in Example 11. iH NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(5-methyl-l,3,4- thiadiazol-2-ylsulfanylmethyl)

1 g of the 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in a mixture of 40 mL water and NaHC0₃ (2 eq). Then the mixture was added with 5-methyl-l,3,4-thiadiazol-2ylthio (1.5 eq) and the target compound was obtained via the method used in Example 10.

Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(5-methyl-l,3,4- thiadiazol-2-ylsulfanylmethyl)diphenylmethylester

1 g of the product synthesized in Example 14 was dissolved in 10 mL of methyl alcohol and 1.29 g (94%) of the target compound was obtained using diphenyldiazomethane hexane solution (2eq) via the method used in Example 11. Η NMR(CDC1₃, 400MHZ) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(l,3,4-thiadiazol-5- ylsulfanylmethyl)

1 g of the 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in a mixture of 40 mL water and NaHC0₃ (2 eq). Then the mixture was added with l,3,4-thiadiazol-2ylthio (1.5 eq) and the target compound was obtained via the method used in Example 10. NMR(DMSO-d₆, 400MHz) 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(2H)

Example 17 : Synthesis of 7-glutarylimido cephalosporin-3-(l,3,4-thiadiazol-5- ylsulfanylmethyl)diphenylmethylester

1 g of the product synthesized in Example 17 was dissolved in 10 mL of methyl alcohol and 1.32 g (95%) of the target compound was obtained using diphenyldiazomethane hexane solution (2eq) via the method used in Example 11. NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(l-(2-dimethylamino- ethyl)-lH-tetrazol-5- ylsulfanylmethyl)

1 g of the 7-glutarylimido cephalosporanic acid synthesized in Example 1 was dissolved in a mixture of 40 mL water and NaHC0₃ (2 eq). Then the mixture was added with l-(2-dimethylamino-ethyl)-lH-tetrazol-5-ylthio (1.5 eq) and the target compound was obtained via the method used in Example 10. Ή NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutarylimido cephalosporin-3-(l-(2-dimethylamino- ethyl)-lH-tetrazol-5-ylsulfanylmethyl)diphenylmethylester

1 g of the product synthesized in Example 18 was dissolved in 10 mL of methyl alcohol and 1.32 g (95%) of the target compound was obtained using diphenyldiazomethane hexane solution (2eq) via the method used in Example 11. Η NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutarylimido-3-exomethylene cepham

1 g of the 7-glutarylimido cephalosporanic acid synthesized in Example 1 was stirred at 0 ^°C along with 5 mL of tetrahydrofuran and 10 mL of water and then added with 1.4 g (8 eq) of zinc and 0.58 g (4 eq) of ammonium chloride. Then the mixture was slowly added dropwisely with 3.5 mL of cone. HCl. The reaction mixture was stirred for 2 hr at 0 °C. Upon depletion of the starting material, zinc was removed and then extracted the resulting mixture twice with 50 mL of ethyl acetate at pH 1. The organic solvent was dried with magnesium sulfate, vacuum dried and then crystallized using ethyl acetate and hexane and the target compound was finally obtained.

Η NMR(DMSO-d₆, 400MHz) 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 : Synthesis of 7-glutarylimido-3-exomethylene cepham diphenylmethylester

1 g of the product synthesized in Example 20 was dissolved in 10 mL of methyl alcohol and the target compound was obtained using diphenyldiazomethane hexane solution (2eq) via the method used in Example 11. NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutarylimido-3-hydroxylmethyl cephalosporin diphenylmethylester

0.3 g of NaOH (3 eq) was dissolved in a mixture of 10 mL of methyl alcohol and 2 mL of water and then added with 1.5 mL of boric acid (pH 8.) and then cooled down to -25 ^°C. The mixture was then added with 1 g of 7-glutarylimido cephalosporanic acid synthesized in Example 1 and stirred for 2 hr to deplete the starting material. The reaction mixture was adjusted to a pH 2 at -15 °C and dropwisely added with 8.5 mL of diphenyldiazomethane hexane solution (1.6 eq) and then stirred for 5 hr. The resulting mixture was extracted twice with 50 mL of ethyl acetate. The organic solvent was dried using magnesium sulfate, vacuum dried, recrystallized using isopropylether and cyclohexane and 1.06 g of the target compound (80%) was finally obtained. NMR(CDC1₃, 400MHz) 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 : Synthesis of 7-glutaqryIimido-3-chloromethyl-cephalosporin diphenylmethylester

3 g of the product synthesized in Example 22 was dissolved in a mixed solvent of 5 mL of methylene chloride and 5 mL of 2V,IV-dimethylformamide, and added with 0.58 g (0.7 eq) of cyanuric chloride under nitrogen atmosphere at 0 °C . The mixture was stirred at the same temperature for 1 hr and then slowly added dropwisely to 30 mL of ice water. The yellow solid obtained from this was filtered and vacuum dried and finally obtained 2.9 g of the target compound (96%). Η NMR(CDC1₃, 400MHz) 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 2 : Synthesis of glutaryl 7-amino cephalosporin dichlorocarbonyl

2 g of glutaryl 7-aminocephalosporanic acid was added to 6 mL of tetrahydrofuran and slowly added dropwisely with 3.88 mL of oxalylchloride at 0 °C .

The mixture was stirred for 10 min and added with a catalytic amount of N,N- dimethylformamide. The turbid reaction mixture was increased to room temperature and stirred until the reaction mixture becomes clear. Upon completion, the solvent was dried and recrystallized with dichloromethane and hexane and produced light yellow compound of glutaryl 7-amino cephalosporin dichlorocarbonyl. The production of the target compound was confirmed by dissolving a little amount of the above obtained product in 10 mL methanol, stirring it for 10 min and observing via NMR thereby confirming the production of the glutaryl 7-amino cephalosporin dimethylester.

Industrial Applicability

The present invention enables to manufacture a variety of glutaryl 7- aminocephalosporanic acid derivatives represented by the above formula 1 in a cost- effective manner using 3-acetoxymethyl 7-glutarylimido cephalosporin compound represented by the above formula 2 as a starting material, which is produced by an intramolecular cyclization of a glutaric acid functional group of the glutaryl 7- aminocephalosporanic acid. Further, the glutaryl imido group of the compound represented by the above formula 1, the target compound of the present invention, is easily decyclized under a basic or an acidic condition and thus it can be used to manufacture a variety of important cephalosporinic antibiotics.

Claims

Claims We claimed :

1. 7-glutaryl imido cephalosporanic acid derivatives represented by the following formula 1,

[1] wherein

R represents a halogen atom; a hydroxy group; a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched O-C4 alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a linear or branched C1-C4 alkoxy group, unsubstituted or substituted by at least a phenyl group; a benzyloxy group substituted by a linear or branched C1-C4 alkyl or an alkoxy group or a nitro group; a silyloxy substituted by at least a linear or branched, unsubstituted or substituted C1-C4 alkyl group; OM(M is an alkali metal atom);

A represents a hydrogen atom; OH; Cl; CH2; CH2R¹; CH2SR²; CH2R³; or a vinyl group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; R¹ represents a hydrogen atom; a halogen atom; a hydroxy group; - OC(0)CH₃; -OC(0)NH₂; or a linear or branched C1-C4 alkoxy group;

R² represents a heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; R³ represents a tertiary amine heterocyclic group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a tertiary aliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; a cycloaliphatic amine group, unsubstituted or substituted by a linear or branched C1-C4 alkyl group; n is 0 or 1; and i ^-ii represents a single or a double bond; with the proviso that when R is a hydroxy group and n is 0, A is not -

2. In claim 1, said R is a compound selected from the group consisting of a hydroxy group, a pyridine group with a substituted or unsubstituted linear or branched C1-C4 alkyl group, a pyrrolidine group or an imidazole group, a C1-C4 alkyl group, a 2,2,2-trichloroethoxy group; a 4-methoxybenzyloxy group, a 4- nitrobenzyloxy group, a diphenylmethoxy group, a 3,4-dimethoxybenzyloxy group, a trimethylsilyloxy group, a triethylsilyloxy group, t-butyldimethylsilyloxy group, and OM, wherein M is Na or K.

3. In claim 1, said A is -CH₂SR²; and R² is a heterocyclic group selected from the group consisting of a thienyl group, a diazolyl group, a triazolyl group, a tetrazolyl group, a thiazolyl group, a thiadiazolyl group, a thiazolyl group, a thiatriazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidinyl group, a pyridyl group, a benzothiazolyl group, a benzothiazolyl group, a benzoimidazolyl group, and a benzooxazolyl group, wherein said heterocyclic group can be substituted with a linear or branched C1-C4 alkyl group at a position where a hetero ring structure is allowed.

4. In claim 3, said A is selected from the group consisting of l-(2- dimethylamino-ethyl)-lH-tetrazol-5- ylthiomethyl group, a lH-l,2,3-triazol-4- ylthiomethyl group, a l,3,4-thiadiazol-5-ylthiomethyl group, a 5-methyl-l,3,4- thiadiazol-2-ylthiomethyl group, a lH~l-methyl-l,2,3,4-tetrazol~5- ylthiomethyl group, a l-phenyl-l,2,3,4-tetrazol-5-ylthiomethyl group, a l-sulfomefhyltetrazol-5- ylthiomethyl group, a l-carboxymethyltetrazol-5- ylthiomethyl group, a l-(2- aminoethyl)-l,2,3,4-tetrazol-5-ylthiomethyl group, a 1- methylcarbamoyl-1,2,3,4- tetrazol-5-ylthiomethyl group, a 5-methyl-l,3,4-oxadizaol-2-ylthiomethyl group, 1- (2-hydroxyethyl)tetrazol-5-ylthiomethyl group, 3-methyl-l,3,4-triazine-5,6~dion-2- thiomethyl group, and a benzothiazoI-2-thiomethyl group.

5. In claim 1, said A is -CH2R³, and R³ is a tertiary amine heterocyclic group or an aliphatic or a cycloaliphatic amine group.

6. In claim 5, said A is selected from the group consisting of a pyridinium methyl group, an aminopyridinium methyl group, a 6,7-dihydro-5H-[l] pyridinium methyl group, 5,6,7,8-tetrahydro-l-quinoliniummethyl group, a 6,7-dihydro-5H-[2] pyridinium methyl group, 5,6,7,8-tetrahydro-2-isoquinoliniummethyl group; or an N-methyl-bis(2-hydroxyethyl)aminomethyl group, a 3,4-trans-dihydroxy-l - methylpyrrolidylmethyl group, a 1-methyl-l- pyrrolidinium methyl group, and a tropyl methyl group.

7. In claim 1, a compound represented by the following formula la,

wherein n is 0 or 1; R is -OH, -ONa, -OK, -OCH(C₆H5)2 or -OSi(CH₃)₃; R^s a halogen atom, -OH or -OC(0)CH₃, with the proviso that when R=OH and n=0 A is not -CH₂OC(0)CH3.

8. In claim 1, a compound represented by the following formula lb,

wherein n is 0 or 1; R is -OH or OCH(C₆H₅)₂; SR² is

9. In claim 1, a compound represented by the following formula lc,

wherein n is 0 or 1; R is -OH, OCH(C₆H5)2 or OSi(CH3)s; R³ is

10. In claim 1, a compound represented by the following formula Id,

wherein n is 0 or 1; R is -OH or OCH(C₆H5)2.

11. A method of preparing the compound represented by the following formula la, wherein the compound represented by the following formula 2 is hydrolysed and then introduced with a -CH2R¹ group at C-3 position via esterification or halogenation,

wherein said R, R¹ and n are same as defined in claim 1.

12. A method of preparing the compound represented by the following formula lb, wherein the compound represented by the following formula 2 is introduced with a -CH2SR² group at C-3 position via a nucleophilic substitution reaction with a thiol compounds(HSR²)

wherein said R, R² and n are same as defined in claim 1.

13. A method of preparing the compound represented by the following formula lc, wherein the compound represented by the following formula 2 undergoes an iodination and then introduced with a -CH2R³ group at C-3 position via a nucleophilic substitution reaction with an amine compound having a R³ group,

nucleophilic iodination substitution

wherein said R, R³ and n are same as defined in claim 1.

14. A method of preparing the compound represented by the following formula Id, wherein the following formula 2 undergoes a chemical reduction under an acidic condition in the presence of zinc and ammonium chloride, and then introduced with an exomethylene group at C-3 position,

wherein said R and n are same as defined in claim 1.

15. A method of preparing 3-acetoxymethyl 7-glutaryl imido cephalosporin compound represented by the following formula 2, which is characterized in that glutaryl 7-aminocephaolosporanic acid represented by the following formula 3 undergoes a cyclization in the presence of a halogenating agent selected from the group consisting of trichloro phosphoric acid, trichloro phosphin, and pentachloro phosphin; and a compound selected from the group consisting of N, N- dimethylformamide, N,N-dimethylacetamide or N-methylformamide,

wherein said R and n are same as defined in claim 1.

16. A method of preparing glutaryl 7-amino cephalosporin dichlorocarbonyl compound represented by the following formula 4, which is characterized in that glutaryl 7-aminocephaolosporanic acid represented by the following formula 3 undergoes a halogenation reaction in the presence of a halogenating agent selected from the group consisting of cyanuric chloride, thionyl chloride, and oxalyl chloride; and a compound selected from the group consisting of N, N-dimethylformamide, N,N-dimethylacetamide or -methylformamide,

wherein said n is 0 or 1.

17. A glutaryl 7-aminocephaolosporanic acid compound represented by the following formula 3

wherein said n is 0 or 1.

18. A method of preparing a cepha compound represented by the following formula 5 by reacting 7-glutarylimido cephaolosporanic acid derivatives represented by the following formula in the presence of an acid or a base,

herein said R, A and n are same as defined in claim 1.

19. A method of preparing a cephalosporin according to claim 18, wherein said reaction under an acidic condition is characterized by 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 together with an acid selected from the group consisting of hydrochloric acid, nitric acid, iodic acid, fluoric acid, bromic acid, sulfuric acid, and nitric acid,

wherein said R, A and n are same as defined in claim 1.

20. A method of preparing a cepha compound according to claim 18, comprising (a) manufacturing a glutaryl 7-amino cephalosporin derivative, wherein said reaction under a basic condition is characterized by using a single solvent or a mixed solvent selected from the group consisting of water, tetrahydrofuran, acetone, 1,4-dioxane, methanol, ethanol, N, N-dimethylformamide, and N,N- dimethylacetamide together with a base selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, and

(b) reacting said glutaryl 7-amino cephalosporin derivative with a glutaryl amidase,

wherein said R, A and n are same as defined in claim 1.