KR19980076908A - Cephalosporin compound and preparation method thereof - Google Patents

Abstract

The present invention is a cephalosporin compound represented by formula (I), which is a new compound, and a pharmacological agent thereof by reacting a carboxy compound represented by formula (II) or a salt thereof with a hetero compound represented by formula (III). It relates to acceptable salts and methods for their preparation.

The compound of general formula (I) exhibits a broad antimicrobial activity against gram negative bacteria and gram positive bacteria and a strong antimicrobial activity against various resistant bacteria.

In formulas (I) to (III), A represents CH, R 1 represents a methyl group, R 2 represents a cyano group, t-1-1 group (X represents oxygen, hydroxyl amine, Y represents hydroxy, An alkyloxy, amino group having 1 to 5 carbon atoms, a primary hydroxyalkylamino having 1 to 5 carbon atoms, formyl hydrazino or a hydrazino group protected with an acyl group, or a heterocycle of the following structural formula (R3 represents hydrogen or a methyl group A2 and A3 are nitrogen or oxygen, and A4 represents nitrogen, respectively, and Z is an iodine, bromine or acetoxy group.

Description

Cephalosporin compound and preparation method thereof

The present invention relates to a cephalosporin compound, a pharmaceutically acceptable salt, a preparation method thereof, and an intermediate compound used for the preparation thereof, which exhibit a broad antimicrobial activity against gram negative bacteria and gram positive bacteria and a strong antibacterial activity against various resistant bacteria.

Up to now, it has been proposed as an antimicrobial substance of a number of cephalosporin compounds having a structure of general formula (A) as a basic skeleton and having a 2-aminothiazolyl acetamino group substituted with α-alkoxyimino at the 7 position. These compounds are known to exhibit excellent antimicrobial activity against various Gram-negative bacteria and Gram-positive bacteria and to be effective in treating various infectious diseases. In particular, the pyridine-based compound having a 3 'position substituted with a quaternary aromatic ammonium salt shows excellent antimicrobial activity. Representative compounds include ceftazidime (US Pat. No. 4,258,041) and DQ-2556 (JP-A). 86007280) is known. They show excellent antimicrobial activity against enterobacteriaceae, but ceftazidime is known to show relatively low antimicrobial activity against staphylococcus aureus and relatively high antimicrobial activity against Pseudomonas aeruginosa compared to DQ-2556. Compared to these, cepipirome (European Patent Application No. 64740) shows an improved antimicrobial activity against Gram-negative and Gram-positive bacteria, but antimicrobial activity against Pseudomonas aeruginosa is known to be inferior to ceftazidime. .

Accordingly, it is an object of the present invention to provide a new cephalosporin compound that exhibits high anti-pneumococcal activity but also has improved anti-Staphylococcus activity.

Another object of the present invention is to provide a method for preparing a new cephalosporin compound and an intermediate compound used therein.

In order to achieve the above object, the present invention is to provide a cephalosporin compound represented by the general formula (I) and pharmacologically acceptable salts thereof.

In the general formula (I), A is CH or N, R1 is hydrogen, an alkyl group having 1 to 3 carbon atoms, a halogenated alkyl group having 1 to 3 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or a straight chain having 1 to 5 carbon atoms Or a side chain carboxyl group. R2 represents cyano group: T-4 group (X represents oxygen, hydroxyl amine, Y represents hydroxy, alkyloxy of 1 to 5 carbon atoms, amino group, primary alkyl amino group of 1 to 5 carbon atoms, 1 to 5 carbon atoms) Phosphorus hydroxy alkyl amino group, formyl amino group, aryl, hydrazino, formyl hydrazino, or hydrazino group protected with an acyl group) or a heterocycle of the following structural formula.

Here, R3 means hydrogen or methyl group, A2 and A3 are nitrogen or oxygen, respectively, and A4 means nitrogen.

The compounds of the general formula (I) are mostly syn isomers ((Z) -isomers) and the partial structural formula of the C-7 position is And the corresponding anti isomer [(E) -isomer] is It can be represented as. The present invention also provides a method for preparing a compound of formula (I) and a pharmacologically acceptable salt thereof.

The cephalosporin compound of formula (I) and pharmacologically useful salts thereof are physiologically acceptable compounds obtained by substitution of the carboxy compound of formula (II) or a salt thereof with a hetero compound of formula (III). It can be prepared by converting into an acid addition salt.

In the carboxy compound of the general formula (II) and the hetero compound of the general formula (III), A, R 1 and R 2 are the same as those of the general formula (I) defined above. In the general formula (II), Z is a halogen or an acetoxy group, and iodine or bromine is particularly preferable among the halogen atoms.

In order to obtain the cephalosporin compound of the general formula (I) by the substitution reaction of the carboxy compound of the general formula (II) and the general formula (III), the carboxy of the general formula (II) wherein Z is acetoxy Compounds or salts thereof, such as sodium or potassium salts, are used as starting materials. The reaction solvent can be advanced even in aqueous solution or anhydrous conditions. When proceeding in an aqueous solution, it is carried out in water or an organic solvent which is easily mixed with water such as acetone, acetonitrile, dimethylformamide, dioxane, dimethyl sulfoxide, ethanol or methanol, or two or more mixed solvents. The reaction temperature is in the range of 20 ~ 80 ℃, the pH of the solution during the reaction to maintain a neutral but preferably at pH 5 ~ 8. The amount of the hetero compound represented by the general formula (III) is used in an animal amount to less than 5 times the molar amount. The reaction can be promoted by adding 5-20 equivalents of sodium iodide to the reaction solution. In the anhydrous reaction, the reaction is carried out at a temperature ranging from -30 ° C to 50 ° C and the reaction time is completed in about 30 minutes to 10 hours. Suitable organic solvents for use as reaction solvents include nitrided solvents such as acetonitrile, propionitrile, or benzonitrile, halogenated alkyl solvents such as carbon tetrachloride, chloroform, or dichloromethane, ether solvents such as tetrahydrofuran or dioxane, Amides such as N, N-dimethylformamide, esters such as ethyl acetate, methyl acetate or t-butyl acetate, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, aromatic hydrocarbons such as benzene or toluene and these It is possible to use a mixed solvent of. In this case, a silylation reagent may be used to increase the solubility of the carboxy compound of formula (II) and to protect the amine group and the carboxyl group. As the silylating agent, N, O-bis (trimethylsilyl) acetamide or N- Preference is given to using methyl-N-trimethylsilyl-trifluoroacetamide and the like.

The hetero compounds of the general formula (III) substituted in the 3 'position of the cephalosporin in the reaction are mostly new materials, but 2,3-cyclohexeno-4-hydrazinocarbonylpyridine and 2,3-cyclohexeno The 4-ethoxycarbonylpyridine compound is a known compound and these are known methods [Helv. Chim. Acta, 38, 1033 (1995) and Synthetic Communication, 19 (17), 3027 (1989)]. For example, 2,3-cyclohexeno-4-carboethoxypyridine derived by esterifying 2,3-cyclohexeno-4-carboxypyridine obtained by reacting cyclohexanone and cyano acetoamide New materials can be prepared.

As a general method for preparing a pharmacologically useful salt in the present invention, a crystalline salt corresponding to the cephalosporin compound represented by the general formula (I) is obtained.

Pharmacologically acceptable salts of the cephalosporin compound represented by general formula (I) include pharmaceutically acceptable salts, especially non-toxic salts in general. Such salts include, for example, alkali salt metal salts such as sodium salts or potassium salts as inorganic salts, metal salts such as alkaline earth metal salts such as calcium salts or magnesium salts, and the like. Ethylamine salt, pyridine salt, procaine salt, dicyclohexylamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, phenylethylbenzylamine salt, or dibenzylethylenediamine salt, and the like. Carboxylates include acetates, maleates, tartarates, fumarates, citrates, succinates, lactates, or oxalates, and sulfonates include methanesulfonates, benzenesulfonates, p-toluenes, or p Toluene sulfonate, etc., and basic and acidic amino acid salts include arginine salt, asparagine salt, glutamate salt, or lysine salt, and inorganic salts include hydrochloride salt, bromate salt, and urine salt. DE volcano include salts, phosphates, sulfates or the like.

The cephalosporin compound and salts thereof represented by the general formula (I) of the present invention are novel cephalosporin-based compounds, as in the examples, against a wide range of pathogenic microorganisms including Gram-positive bacteria and Gram-negative bacteria, in particular Staphylococcus and Pseudomonas aeruginosa High antimicrobial activity.

The present invention also provides an antimicrobial agent containing the cephalosporin compound of formula (I) according to the present invention.

The antimicrobial agent of the present invention generally consists of the cephalosporin compound represented by the general formula (I) of the present invention, salts thereof, and solid or liquid excipients. Such antimicrobial agents may be solid preparations such as tablets, capsules or powders, liquid solutions such as injectable solutions or suspensions (intravenous or intramuscular injections), oral solutions, suspensions or syrups. Solid or liquid excipients herein means known ones commonly used in the art.

EXAMPLE

Antimicrobial Activity Test of Compounds of the Invention

In order to show the pharmacological usefulness of the cephalosporin compound represented by the general formula (I), the antimicrobial activity of the representative compound was tested by in vitro antimicrobial activity assay on standard strains, and cepirom was used as a comparative substance. In vitro antibacterial activity was measured by the Agar-dilution method.

That is, the antimicrobial activity test compound was diluted in two-fold steps at a concentration of 1,000 µg / ml and put into 1.5 ml of test tubes, and 13.5 ml of Hinton agar was added to prepare 100 to 0.02 µg / ml and then sterilized Petri. Pour into dish to solidify flat. Herein, the test cell culture stock was adjusted to 107 CFU / ml and inoculated using an inoculator. After 18 hours of incubation at 37 ° C., the minimum concentration of the antimicrobial substance capable of inhibiting the growth of test bacteria was determined as the minimum growth inhibition concentration (MIC).

20 standard test strains used in the present invention mostly used β-lactamase producing bacteria as a causative agent for causing urinary tract infections, respiratory infections, skin tissue infections, plasma infections, gastrointestinal infections, central nervous system infections, and the like. Is shown below.

MIC results for standard strains of representative compounds of the present invention are shown in Table 1.

Table 1. Minimum Growth Inhibitory Concentration (MIC) μg / ml]

Preparation Example 1

Preparation of 2,3-cyclohexeno-4-carbamoylpyridine (General formula (III)

2,3-cyclohexano-4-ethoxycarbonylpyridine 19.10 g (93.03 mmol) dissolved in 100 ml of methanol was added to a solution of 2.14 g (93.03 mmol) of sodium dissolved in 100 ml of methanol. Stir for 20 minutes. After injecting ammonia gas at 0 ° C. for 1 hour, stirring at 15 ° C. for 2 days to remove the methanol solvent under reduced pressure, adding 80 ml of water, extracting with chloroform (200 ml × 3), drying with anhydrous Na 2 SO 4, and filtration. After distillation under reduced pressure, the target compound in the form of a yellow solid having a mass spectrum of m / z = 176 was obtained (9.78 g, yield: 60%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.84 (t, 2H, J = 5.7 Hz), 1.89 (t, 2H, J = 5.7HZ), 2.99 (m, 4H), 5.75 (brs, 2H), 7.11 (d , 1H, J = 4.8 Hz), 8.42 (d, 1H, J = 4.8 Hz)

IR (KBr, cm-1): 3286 (N-H), 2938 (cyclohexene, C-H), 1678 (C = 0)

Mass: m / z (%): 176 (M +, 100), 159 (57), 130 (87), 117 (39), 103 (25), 77 (53), 63 (37)

Melting Point: 186 ~ 187 ℃

Preparation Example 2

Preparation of 2,3-cyclohexeno-4- (N-2-hydroxyethylcarbamoyl) pyridine (General formula (III)

1.00 g (4.87 mmol) of 2,3-cyclohexano-4-ethoxycarbonylpyridine was dissolved in 8 mL of methanol, and 0.43 mL (7.87 mmol) of 2-hydroxyethylamine was added thereto, followed by reflux for 24 hours. The solvent was evaporated with a rotary evaporator, neutralized with 2.0 M hydrochloric acid solution, and extracted with ethyl acetate (30 mL x 3). Drying with anhydrous Na 2 SO 4, filtration, and distillation under reduced pressure yielded a colorless solid as the target compound (0.56 g, yield: 52%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.80 to 1.88 (m, 4H), 2.83 (t, 2H, J = 6.2 Hz), 2.93 (t, 2H, J = 6.2HZ), 3.59 (q, 4H), 3.83 (t, 2H, J = 2.7 Hz), 6.47 (brs, 1H), 7.03 (d, 1H, J = 4.8 Hz), 8.35 (d, 1H, J = 4.8 Hz)

Mass: m / z (%): 193 (M +, 23), 206 (14), 205 (100), 177 (10), 145 (14), 115 (16), 91 (16), 77 (10)

Preparation Example 3

Preparation of 2,3-cyclohexeno-4-N-formylhydrazinocarbonylpyridine (General Formula III)

0.87 g (4.54 mmol) of 2,3-cyclohexeno-4-hydrazinocarbonylpyridine was dissolved in 3 ml of ethanol, refluxed with addition of 8.0 ml of formic acid for 2 hours, and evaporated using a rotary evaporator. 15 ml of water was added thereto, extracted with chloroform (20 ml × 3), dried over anhydrous Na 2 SO 4, and distilled under reduced pressure to obtain the target compound having a mass spectrum of m / z = 219 (0.60 g, yield: 61%).

1 H NMR (DMSO-d6, 300 MHz) δ: 1.73 (m, 2H), 1.80 (m, 2H), 2.78 to 2.83 (m, 4H), 7.09 (d, 1H, J = 4.4 Hz), 8.10 (d, 1H), 8.38 (d, 1H, J = 4.4 Hz), 10.08 (brs, 1H), 10.28 (brs, 1H)

IR (KBr, cm-1): 3280 (N-H), 3206 (N-H), 2954 (cyclohexene C-H), 2867, 1715 (C = 0), 1676 (C = 0)

Mass: m / z (%): 219 (M +, 6), 201 (7), 161 (9), 160 (100), 159 (67), 132 (48), 131 (15), 130 (23) , 117 (12), 102 (7), 77 (14)

Preparation Example 4

Preparation of 2,3-cyclohexeno-4-N-acetylhydrazinocarbonylpyridine (General Formula III)

0.19 g (0.99 mmol) of 2,3-cyclohexano-4-hydrazinocarbonylpyridine was dissolved in 7.0 ml of ethanol, and 0.21 ml (1.53 mmol) of triethylamine and 0.14 ml (1.48 mmol) of acetic anhydride were added. It was then refluxed for 1.5 hours. The reaction solution was cooled to room temperature and filtered to remove white solid. The filtrate was evaporated. Acetone and dichloromethane (3: 1, v / v) were purified by column chromatography on silica gel (230-400 mesh) as eluent. The desired compound with a spectrum of m / z = 233 was obtained as a yellow solid (0.11 g, yield: 45%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.69-1.79 (m, 4H), 1.99 (S, 3H), 2.75 (t, 2H, J = 6.0 Hz), 2.83 (t, 2H, J = 6.0 Hz), 7.02 (d, 1H, J = 4.9 Hz), 8.26 (d, 1H, J = 4.9 Hz), 9.80 (brs, 2H)

IR (KBr, cm-1): 3445 (N-H), 3246 (N-H), 2947 (cyclohexene C-H), 1650 (C-N of amide), 1710 (C = 0)

Mass: m / z (%): 233 (M +, 24), 215 (25), 160 (100), 132 (87), 77 (74), 63 (50)

Melting Point: 59 ~ 60 ℃

Preparation Example 5

Preparation of 2,3-cyclohexeno-4-N-hydroxycarboxamidylpyridine (General formula (III)

2.93 g (13.97 mmol) of anhydrous trifluoroacetic acid was added to a 40 mL solution of CH2Cl2 containing 1.23 g (6.99 mmol) of 2,3-cyclohexe-4-carbamoylpyridine and 1.41 g (13.97 mmol) of triethylamine. After slowly adding at room temperature, the mixture was stirred for 20 minutes. The solution was washed with water (30 mL x 3) and saturated brine (30 mL x 3), dried over anhydrous Na 2 SO 4, filtered, and distilled under reduced pressure to yield a yellow liquid compound which was dissolved in 15 mL of ethanol and hydroxylated thereto. 0.60 g (8.29 mmol) of amine hydrochloride and 0.47 g (8.29 mmol) of KOH were added and refluxed for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with chloroform (10 mL x 3), filtered and dried under reduced pressure to obtain the target compound as a pale yellow solid (0.52 g, yield: 42%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.71 to 2.01 (m, 4H), 2.91 (t, 2H, J = 6.3 Hz), 2.99 (t, 2H, J = 6.3 Hz), 4.82 (brs, 2H), 5.85 (brs, 1H), 6.00 (brs, 1H), 7.16 (d, 1H, J = 5.1 Hz), 8.42 (d, 1H, J = 5.1 Hz)

IR (KBr, cm-1): 3320 (O-H), 3485 (N-H), 1650 (C = N), 1596

Mass: m / z (%): 176 (M +, 89), 159 (54), 130 (100), 77 (49), 63 (46), 51 (51)

Preparation Example 6

Preparation of 2,3-cyclohexeno-4- (1,3,4-oxadiazol-2-yl) pyridine (General Formula III)

0.28 g (1.47 mmol) of 2.3-cyclohexeno-4-hydrazinocarbonylpyridine was dissolved in 3.0 ml of triethylorthoformate and refluxed at 120 ° C for 30 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was distilled under reduced pressure, and the residue was purified by column chromatography using silica gel using a mixture of diethyl ether and hexane (3: 1, v / v) as eluent. The desired compound with / z = 201 was obtained as a yellow solid (0.12 g, yield: 40%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.93 (dd, 4H), 3.05 (t, 2H, J = 6.2 Hz), 7.62 (d, 1H, J = 4.8 Hz), 8.54 (d, 1H, J = 4.8 Hz )

IR (KBr, cm-1): 3122, 2928 (cyclohexene C-H), 1564 (C = N), 1426 (C = N), 1110 (C-O)

Mass: m / z (%): 201 (M +, 100), 186 (24), 157 (29), 130 (69), 119 (23), 77 (31), 63 (32)

Melting Point: 99 ~ 101 ℃

Preparation Example 7

Preparation of 2,3-cyclohexeno-4- (5-methyl-1,3,4-oxadiazol-2-yl) pyridine (General Formula III)

0.70 g (3.00 mmol) of 2.3-cyclohexeno-4-N-acetylhydrazinocarbonylpyridine obtained in Preparation Example 4 was added to 7 g of polyphosphoric acid and refluxed at 130 ° C. for 3 hours, and then the reaction solution was cooled to room temperature. 30 mL of ice water was added thereto, followed by neutralization with saturated aqueous Na 2 CO 3 solution. Extracted with chloroform (25ml x 3), dried over anhydrous Na2SO4, filtered and distilled under reduced pressure to obtain the target compound as a yellow solid with a mass spectrum of m / z = 215 (0.40g, yield: 61%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.91 (dd, 4H), 2.65 (s, 3H), 3.04 (t, 2H, J = 5.9 Hz), 3.21 (t, 2H, J = 5.9 Hz), 7.59 (d , 1H, J = 5.0 Hz), 8.52 (d, 1H, J = 5.0 Hz)

IR (KBr, cm-1): 3422, 3236, 2938, 2877, 1656, 1580, 1424 (C = N), 1400 (C = N), 1252

Mass: m / z (%): 215 (M +, 100), 214 (34), 173 (15), 148 (28), 131 (43), 130 (71), 119 (34), 118 (24) , 103 (21), 77 (34), 51 (28)

Preparation Example 8

Preparation of 2,3-cyclohexeno-4- (3-methyl-1,2,4-oxadiazol-5-yl) pyridine (General Formula III)

1.21 g (6.85 mmol) of 2.3-cyclohexeno-4-carbamoylpyridine was mixed with 3.05 g (20.56 mmol) of N and N-dimethylacetaminodimethylacetal and stirred at 100 ° C. for 2 hours, and the N, N- was reduced under reduced pressure. Dimethylacetamidodimethylacetal was removed. 8 ml of 1,4-dioxane and 8 ml of glacial acetic acid were added to the residue, followed by 0.73 g of hydroxylamine hydrochloride (10.68 mmol) and 3.42 ml of a 2M NaOH aqueous solution, followed by refluxing at 90 ° C for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 35 ml of chloroform, washed with water (30 ml x 3), dried over anhydrous Na 2 SO 4, filtered, and distilled under reduced pressure to obtain a target compound having a mass spectrum of m / z = 215. Obtained as a yellow solid (1.12 g, yield: 76%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.88-1.92 (m, 4H), 2.51 (s, 3H), 3.05 (t, 2H, J = 6.2 Hz), 3.18 (t, 2H, J = 6.2 Hz), 7.71 (d, 1H, J = 5.1 Hz), 8.55 (d, 1H, J = 5.1 Hz)

IR (KBr, cm-1): 3176, 3036, 2932 (cyclohexene C-H), 2757, 2558, 1558 (C = N), 1442, 1406

Mass: m / z (%): 215 (M +, 11), 214 (100), 199 (28), 155 (14), 144 (18), 63 (19)

Melting Point: 185 ~ 187 ℃

Preparation Example 9

Preparation of 2,3-cyclohexeno-4- (3-methyl-1,2,4-triazol-5-yl) pyridine (General Formula III)

0.99 g (5.60 mmol) of 2.3-cyclohexeno-4-carbamoylpyridine was mixed with 2.49 g (16.82 mmol) of N and N-dimethylacetamidodimethylacetal, and stirred at 100 ° C. for 2 hours, and N, N under reduced pressure. Dimethylacetamidodimethylacetal was removed. 15 ml of glacial acetic acid and 0.84 g (16.77 mmol) of hydrazine monohydrate were added to the residue, followed by stirring at 90 ° C. for 2.5 hours. After the reaction was cooled to room temperature, 50 ml of water was added. Neutralized with saturated aqueous Na2CO3 solution, extracted with chloroform (40ml x 3), dried over anhydrous Na2SO4, filtered and distilled under reduced pressure to obtain the target compound as a brown solid (m / z = 214) as a brown solid (0.74 g, yield: 62%).

1 H NMR (CDCl 3, 300 MHz) δ: 1.82-1.92 (m, 4H), 3.03 (t, 2H, J = 6.2 Hz), 3.12 (t, 2H, J = 6.2 Hz), 7.62 (d, 1H, J = 5.1 Hz), 8.43 (d, 1H, J = 5.1 Hz)

IR (KBr, cm-1): 3500 (N-H), 2948 (cyclohexene C-H), 2872 (CH3, C-H), 1574 (C = N), 1548 (C = N)

Mass: m / z (%): 214 (M +, 10), 215 (M + 1, 13), 174 (35), 145 (30), 130 (73), 119 (100), 103 (23), 77 (33)

Example 1

7-β-[(Z) -2 (2-aminothiazol-4-yl) 2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-ethoxycarbonyl -1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R1 = CH3)

Suspension 0.465 g (1.00 mmol) was suspended in 10 mL of anhydrous methylene chloride under nitrogen atmosphere, 0.7 mL (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide were added, and the temperature was adjusted to 40 ± 5 ° C. The solution was stirred and stirred until it became clear. After cooling this solution to 20 +/- 5 degreeC, 0.4 ml (2.8 mmol) of iodine trimethylsilane were added, and it stirred for 30 more minutes. The reaction solvent was removed with a rotary evaporator, and 1.5 ml of anhydrous acetonitrile was added to the residue, followed by addition of 0.37 ml (4.5 mmol) of tetrahydrofuran to remove excess iodine trimethylsilane. 0.205 g (1.00 mmol) of 2,3-cyclohexe-4-ethoxycarbonylpyridine silylated with 0.3 ml (1.6 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide was dissolved in this solution. 4.0 ml of acetonitrile were added and stirred at 20 ± 5 ° C. for 4 hours. The reaction solution was added to acetone-methanol (95: 5, v / v) mixed solution (50 mL) to deprotect it to precipitate an off-white solid, which was filtered and dried to convert 0.332 g of iodine salt into a pale yellow solid. Obtained. This salt was dissolved in 2 ml of 5% sodium bicarbonate, and acetonitrile-water (5: 1, v / v) was used as an elution solution. The column was chromatographed with silica gel (230-400 mesh) and lyophilized to give a target compound. Obtained as a solid (0.065 g, yield: 11%).

Melting Point: Decomposition from 196 ℃

1 H NMR (D 2 O, 300 MHz) δ: 1.41 (t, 3H), 2.02 (m, 2H), 2.14 (s, 3H), 3.20 (m, 2H), 3.41 (ABq, 1H), 3.61 (ABq, 1H) , 5.23 (ABq, 1H), 5.60 (ABq, 1H), 5.92 (d, 1H), 7.05 (s, 1H), 8.08 (d, 1H, J = 6.5 Hz), 8.79 (d, 1H, J = 6.5 Hz)

Example 2

7-β-[(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-carbamoyl- 1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R 1 = CH 3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. To this was added 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran, to which 4.0 ml of acetonitrile containing 0.176 (1.00 mmol) of silylated 2,3-cyclohexeno-4-carbamoylpyridine dissolved was added. The reaction was carried out for 4 hours, and then deprotected by the method described above to obtain 0.402 g of iodide as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, acetonitrile-water (5: 1, v / v) was used as an eluent, and column chromatography was performed on silica gel (230-400 mesh). Obtained as a solid (0.211 g, yield: 37%).

Melting Point: Decomposition from 176 ℃

1 H NMR (DMSO-d6, 300 MHz) δ: 1.75 to 1.95 (m, 4H), 2.50 (s, 3H), 3.82 (s, 3H), 5.04 (d, 3H), 5.38 (ABq, 2H), 5.65 ( dd, 2H), 6.71 (s, 1H), 7.19 (brs, 2H), 7.91 (d, 1H, J = 6.2 Hz), 9.33 (d, 1h, J = 6.2 Hz), 9.55 (d, 1 Hz)

Example 3

7-β-[(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (N- 2-hydroxyethylcarbamoyl) -1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R1 = CH3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. To the solution dissolved by adding 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran was dissolved 2,3-cyclohexeno-4- (N-2-hydroxyethylcarbamoyl) pyridine 0.220 (1.00 mmol). 4.0 ml of dissolved acetonitrile was added and reacted for 4 hours, followed by deprotection by the method described above to obtain 0.419 g of iodide as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography was performed on silica gel (230-400 mesh) using acetonitrile-water (5: 1, v / v) as an eluent, and then lyophilized. Obtained as a solid (0.072 g, yield: 12%).

Melting Point: Decomposition from 280 ℃

1 H NMR (D2O, 300 MHz) δ: 1.90 (m, 2H), 2.05 (m, 2H), 3.01 (m, 2H), 3.34 (m, 2H), 3.63 (t, 2H), 3.84 (t, 2H) , 4.04 (s, 3H), 5.01 (d, 1H), 5.38 (ABq, 1H), 5.54 (ABq, 1H), 5.91 (d, 1H), 7.04 (s, 1H), 7.96 (d, 1H, J = 6.6 Hz), 8.78 (d, 1H, J = 6.6 Hz)

Example 4

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Formylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R1 = CH3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.0 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. Aceto in which silylated 2,3-cyclohexeno-4-N-formylhydrazinocarbonylpyridine 0.219 (1.00 mmol) is dissolved in a solution obtained by adding 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran. 4.0 ml of nitrile was added for reaction for 4 hours, and then deprotected by the method described above to obtain 0.421 g of an iodide salt as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography was performed on silica gel (230-400 mesh) using acetonitrile-water (5: 1, v / v) as eluent, and then lyophilized. Obtained as a solid (0.063 g, yield: 10%).

Melting Point: Decomposition from 197 ℃

1 H NMR (D2O, 300 MHz) δ: 1.90 (m, 2H), 2.05 (m, 2H), 3.06 (m, 2H), 3.20 (m, 2H), 3.63 (ABq, 1H), 4.04 (s, 3H) , 5.02 (d, 1H), 5.39 (ABq, 1H), 5.61 (ABq, 1H), 5.93 (d, 1H), 7.05 (s, 1H), 7.95 (d, 1H, J = 6.2 Hz), 8.79 ( d, 1H, J = 6.2 Hz)

Example 5

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Acetylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R1 = CH3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. Aceto in which silylated 2,3-cyclohexeno-4-N-acethydrazinocarbonylpyridine 0.233 (1.00 mmol) is dissolved in a solution obtained by adding 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran. After reacting for 4 hours by adding 4.0 ml of nitrile, it was deprotected by the method described above to obtain 0.582 g of an iodide salt as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography with silica gel (230-400 mesh) using acetonitrile-water (5: 1, v / v) as eluent and lyophilized to give an off-white solid. Compound was obtained (0.054 g, yield: 9%).

Melting Point: Decomposition from 185 ℃

1 H NMR (D2O, 300 MHz) δ: 1.91 (m, 2H), 2.05 (m, 2H), 2.18 (s, 3H), 3.59 (ABq, 1H), 5.03 (d, 1H), 5.40 (ABq, 1H) , 5.60 (ABq, 1H), 5.93 (d, 1H), 7.06 (s, 1H), 7.99 (d, 1H, J = 6.2 Hz), 8.79 (d, 1H, J = 6.2 Hz)

Example 6

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Acetylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepem-4-carboxyl sulfate (General Formula I, A = CH, R1 = CH3)

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohex) prepared in Example 5 Ceno-4-N-acetylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepem-4-carboxylate 0.540 g (0.86 mmol) was dissolved in 4 ml of water and cooled to 0-5 캜. Then adjusted to pH 1 ~ 1.5 with 3 N sulfuric acid solution and stirred for 1 hour at the same temperature. 10 ml of ethanol was added to the solution, stirred at the same temperature for 2 hours, and the resulting solid was filtered, washed with ethanol and diethyl ether, and dried to give an off-white solid target compound (0.510 g, yield: 82). %)

Melting Point: Decomposition from 166 ℃

1 H NMR (D 2 O, 300 MHz) δ: 1.88 (m, 2H), 2.05 (m, 2H), 2.18 (s, 3H), 3.05 (m, 2H), 3.20 (m, 2H), 3.39, 3.70 (ABq, J = 17.8 Hz), 4.11 (s, 3H), 5.36 (ABq, 1H), 5.55 (ABq, 1H), 5.93 (d, 1H), 7.18 (s, 1H), 8.01 (d, 1H, J = 6.2 Hz), 8.80 (d, 1H, J = 6.2 Hz)

Example 5

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (N -Hydroxycarboxamidyl-1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R1 = CH3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. Acetonitrile 1.591 and tetrahydrofuran 0.37 ml were dissolved in aceto-silylated 2,3-cyclohexeno-4-N-hydroxycarboxamimidylpyridine 0.191 (1.00 mmol) After reacting for 4 hours by adding 4.0 ml of nitrile, it was deprotected by the method described above to obtain 0.356 g of an iodic salt as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography with silica gel (230-400 mesh) using acetonitrile-water (5: 1, v / v) as eluent and lyophilized to give an off-white solid. Compound was obtained (0.143 g, yield: 24%).

Melting Point: Decomposition from 260 ℃

1 H NMR (D2O, 300 MHz) δ: 1.89 (m, 2H), 2.05 (m, 2H), 3.02 (m, 2H), 3.07 (m, 1H), 3.33 (m, 2H), 4.04 (s, 3H) , 5.0 (d, 1H), 5.34 (ABq, 1H), 5.59 (ABq, 1H), 5.93 (d, 1H), 7.06 (s, 1H), 7.88 (d, 1H, J = 6.1Hz), 8.75 ( d, 1H, J = 6.1 Hz)

Example 8

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (1 , 3,4-oxadiazol-2-yl) -1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R 1 = CH 3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. 2,3-cyclohexeno-4- (1,3,4-oxadiazol-2-yl) pyridine 0.201 (silylated in a solution dissolved by adding 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran thereto. 1.00 mmol) was dissolved in 4.0 ml of acetonitrile and reacted for 4 hours, followed by deprotection by the method described above to obtain 0.573 g of iodine salt as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography with silica gel (230-400 mesh) using acetonitrile-water (5: 1, v / v) as eluent and lyophilized to give an off-white solid. Compound was obtained (0.042 g, yield: 7%).

Melting Point: Decomposition from 165 ℃

1 H NMR (D2O, 300 MHz) δ: 1.98 (m, 2H), 2.09 (m, 2H), 3.30 (m, 2H), 3.41 (m, 2H), 3.67 (ABq, 1H), 4.05 (s, 3H) , 5.03 (d, 1H), 5.34 (ABq, 1H), 5.63 (ABq, 1H), 5.94 (d, 1H), 7.04 (s, 1H), 8.45 (d, 1H, J = 6 Hz), 8.92 (d , 1H, J = 6Hz)

Example 9

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (5 -Methyl-1,3,4-oxadiazol-2-yl) -1-pyridinium) methyl] -3-cepem-4-carboxylate (formula I, A = CH, R 1 = CH 3)

0.456 g (1.00 mmol) of Celltaxim was suspended in 10 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 0.7 ml (3.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 was used. It was concentrated by reacting with 0.4 ml (2.8 mmol) of trimethylsilane. 2,3-cyclohexeno-4- (5-methyl-1,3,4-oxadiazol-2-yl silylated in a solution in which 1.5 ml of acetonitrile and 0.37 ml of tetrahydrofuran were added thereto and dissolved. 4.0 ml of acetonitrile containing 0.215 g (1.00 mmol) of pyridine was added and reacted for 4 hours, followed by deprotection by the method described above to obtain 0.516 g of iodine salt as a pale yellow solid. This salt was dissolved in 2 ml of 5% sodium bicarbonate, column chromatography was performed on silica gel (230-400 mesh) with acetonitrile-water (5: 1 v / v) as eluent, and then lyophilized to give an off-white solid. Obtained (0.81 g, yield: 13%).

Melting Point: Decomposition from 215 ℃

1 H NMR (D2O, 300 MHz) δ: 1.94 (m, 2H), 2.05 (m, 2H), 2.76 (s, 3H), 3.27 (m, 2H), 3.33 (m, 2H), 3.63 (ABq, 1H) , 4.02 (s, 3H), 5.01 (d, 1H), 5.38 (ABq, 1H), 5.61 (ABq, 1H), 5.90 (d, 1H), 7.00 (s, 1H), 8.37 (d, 1H, J = 6.6 Hz), 8.86 (d, 1H, J = 6.6 Hz)

Example 10

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (3 -Methyl-1,2,4-oxadiazol-5-yl) -1-pyridinium) methyl] -3-cepem-4-carboxyl sulfate (formula I, A = CH, R 1 = CH 3)

0.820 g (1.80 mmol) of Celltaxim was suspended in 18 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 1.3 ml (6.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 The reaction was concentrated with 0.7 ml (3.8 mmol) of trimethylsilane. 2,3-cyclohexeno-silylated with N-methyl-N- (trimethylsilyltrifluoroacetamide 0.5 ml (3.1 mmol) in a solution dissolved by adding 2.7 ml of acetonitrile and 0.67 ml of tetrahydrofuran. 7.2 ml of acetonitrile in which 0.410 g (1.91 mmol) of 4- (3-methyl-1,2,4-oxadiazol-5-yl) pyridine was dissolved was added and reacted for 4 hours, followed by deprotection using the method described above. 0.988 g of iodic salt was obtained as a pale yellow solid, which was dissolved in 4 ml of 5% sodium bicarbonate, and purified by silica gel (230-400 mesh) using acetonitrile-water (5: 1 v / v) as eluent. After column chromatography with lyophilized to give an off-white solid, dissolved in 6 ml of water, cooled to 0 ~ 5 ℃ and adjusted to pH 1 ~ 1.5 with 3 N sulfuric acid solution and stirred for 1 hour at the same temperature 15 ml of ethanol was added to the solution, stirred at the same temperature for 2 hours, and the resulting solid was filtered out. The dried product was washed with ethanol and diethyl ether to give the target compound as a off-white solid (0.074g, yield: 5%).

Melting Point: Decomposition from 175 ℃

1 H NMR (DMSO-d6, 300 MHz) δ: 1.83 (m, 4H), 2.53 (s, 3H), 3.09 (m, 2H), 3.26 (m, 2H), 3.43 (ABq, 1H), 3.83 (s, 3H), 5.21 (d, 1H), 5.61 (ABq, 1H), 5.78 (ABq, 1H), 5.88 (dd, 1H), 6.76 (s, 1H), 7.4 (brs, 2H), 8.52 (d, 1H , J = 6.5Hz), 8.96 (d, 1H, J = 6.5Hz), 9.68 (d, 1H)

Example 11

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (3 -Methyl-1,2,4-oxadiazol-5-yl) -1-pyridinium) methyl] -3-cepem-4-carboxysulphate (formula I, A = CH, R 1 = CH 3)

0.820 g (1.80 mmol) of Celltaxim was suspended in 18 ml of anhydrous methylene chloride under a nitrogen atmosphere, and 1.3 ml (6.8 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in the same manner as in Example 1 It was concentrated by reaction with 0.7 ml (5.0 mmol) of trimethylsilane. 2,3-cyclohexenosilylated with 0.6 ml (3.2 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in a solution dissolved by adding 0.67 ml of acetonitrile 2.7 ml tetrahydrofuran. 7.2 ml of acetonitrile in which 0.428 g (2.00 mmol) of -4- (3-methyl-1,2,4-triazol-5-yl) pyridine was dissolved was added and reacted for 4 hours. To give 0.982 g of the iodide salt as a pale yellow solid. This salt was dissolved in 4 ml of 5% sodium bicarbonate, and acetonitrile-water (5: 1 v / v) was used as an eluent. The column was chromatographed with silica gel (230-400 mesh) and then lyophilized to be an off-white solid. Obtained (0.164 g, yield: 15%).

Melting Point: Decomposition from 165 ℃

1 H NMR (DMSO-d6, 300 MHz) δ: 1.83 (m, 4H), 2.53 (S, 3H), 3.08 (m, 4H), 3.42 (ABq, 1H), 3.82 (s, 3H), 5.19 (d, 1H), 5.41 (ABq, 1H), 5.70 (ABq, 1H), 5.88 (dd, 1H), 6.72 (s, 1H), 7.2 (s, 2H), 8.46 (d, 1H, J = 6.5 Hz), 8.83 (d, 1H, J = 6.5 Hz), 9.61 (d, 1H)

Claims (12)

A cephalosporin compound represented by general formula (I) and its pharmacologically acceptable salt; In general formula (I), A is CH, R1 represents a methyl group, R2 represents a cyano group, t-30 group (X represents oxygen, hydroxyl amine, Y represents hydroxy, C1-C5) Phosphorus alkyloxy, amino group, primary hydroxyalkylamino having 1 to 5 carbon atoms, formyl hydrazino or hydrazino group protected with an acyl group). Or a hetero ring of the following structural formula (R 3 represents hydrogen or a methyl group, A 2 and A 3 represent nitrogen or oxygen, and A 4 represents nitrogen). The cephalosporin compound of claim 1, wherein the compound is any one of the following and a pharmacologically acceptable salt thereof: 7-β-[(Z) -2 (2-aminothiazol-4-yl) 2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-ethoxycarbonyl -1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4carbamoyl- 1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (N- 2-hydroxyethylcarbamoyl) -1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Formylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepm-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Acetylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4-N- Acetylhydrazinocarbonyl-1-pyridinium) methyl] -3-cepm-4-carboxyl sulfate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (N -Hydroxycarboxamidyl-1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (1 , 3,4-oxadiazol-2-yl) -1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (5 -Methyl-1,3,4-oxadiazol-2-yl) -1-pyridinium) methyl] -3-cepem-4-carboxylate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (3 -Methyl-1,2,4-oxadiazol-5-yl) -1-pyridinium) methyl] -3-cepm-4-carboxyl sulfate; 7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(2,3-cyclohexeno-4- (3 -Methyl-1,2,4-triazol-5-yl) -1-pyridinium) methyl] -3-cepem-4-carboxylate. The cephalosporin compound of formula (I) according to claim 1 or 2, wherein the pharmacologically acceptable salt is a sulfate. A method for producing a cephalosporin compound represented by formula (I), characterized by reacting a carboxy compound represented by formula (II) or a salt thereof with a hetero compound represented by formula (III) in the presence of a solvent. In general formula (I), A is CH, R1 represents a methyl group, R2 represents a cyano group, t-33 group (X represents oxygen, hydroxyl amine, Y represents hydroxy, C1-C5) Phosphorus alkyloxy, amino group, primary hydroxyalkylamino having 1 to 5 carbon atoms, formyl hydrazino or hydrazino group protected with an acyl group, or a heterocycle of the following structural formula (R3 represents hydrogen or a methyl group, A2 And A3 are nitrogen or oxygen, respectively, and A4 represents nitrogen.) In General Formula (II), A is CH, R1 represents a methyl group, R2 represents a cyano group, t-33- (1) group (X represents oxygen, hydroxyl amine, Y represents hydroxy, Alkyloxy, amino group having 1 to 5 carbon atoms, primary hydroxyalkylamino having 1 to 5 carbon atoms, formyl hydrazino or hydrazino group protected with an acyl group, or a heterocycle of the following structural formula (R3 means hydrogen or methyl group) And A2 and A3 are nitrogen or oxygen, and A4 means nitrogen, respectively, and Z is an iodine, bromine or acetoxy group, In formula (III), R2 represents a cyano group, t-34 group (X represents oxygen, hydroxyl amine, Y represents hydroxy, alkyloxy having 1 to 5 carbon atoms, amino group, 1 having 1 to 5 carbon atoms. A hydroxyalkylamino, formyl hydrazino, or hydrazino group protected with an acyl group, or a heterocycle of the following structural formula (R3 means hydrogen or methyl group, A2 and A3 are nitrogen or oxygen, respectively, and A4 is nitrogen Mean). The method for producing a cephalosporin compound according to claim 4, wherein the reaction solvent selects an aqueous solution or an organic solvent. 6. The general formula (I) according to claim 5, wherein the aqueous solution selects one or more solvents from the group consisting of water or acetone, acetonitrile, dimethylformamide, dioxane, dimethylsulfoxide, ethanol and methanol. Method for producing the cephalosporin compound represented. The method of claim 5, wherein the organic solvent is acetonitrile, propionitrile, benzonitrile, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, dioxane, N, N-dimethylformamide, ethyl acetate, methyl acetate, t-butyl A method for producing a cephalosporin compound represented by the general formula (I), characterized by using one or more solvents from the group consisting of acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, benzene, and toluene. The method for producing a cephalosporin compound represented by the general formula (I) according to claim 6, wherein the reaction temperature is performed at 20 to 80 ° C. The method for producing a cephalosporin compound according to claim 6, wherein the pH of the reaction solution is 5 to 8. The method for producing a cephalosporin compound according to claim 7, wherein the reaction temperature is -30 to 50 ° C. The method for producing a cephalosporin compound according to claim 4, wherein the reaction time is 30 minutes to 10 hours. 5. The silylation reagent according to claim 4, wherein the silylation reagent uses N, O-bis (trimethylsilyl) acetamide or N-methyl-N-trimethylsilyl-trifluoroacetamide to protect the amine group and the carboxyl group. The manufacturing method of a cephalosporin compound represented by general formula (I).