KR0176333B1 - Ammonioprophenylcephalosporin compounds and method of preparation for the same - Google Patents

Abstract

The present invention relates to a novel amono-offrophenyl cephalosporin compound and a preparation method thereof. More specifically, it is an antibiotic having a broad antimicrobial range and excellent antimicrobial activity by reacting a compound represented by formula (II) with a tertiary amine compound P represented by formula (III) and then removing an amine protecting group and a carboxy protecting group.

(I)

In general formula (I), P is meso-3,4-dihydroxy-1-methylpyrroli as acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups. Dean, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4, -dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy -1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine or tropin. Q is CII or N. Also included are pharmaceutically acceptable salts of these cephalosporin compounds.

In formula (II), Q is CII or N, R ₁ is triphenylmethyl or hydrogen, R ₂ is p-methoxybenzyl or diphenylmethyl and X represents iodine as halogen compound.

In General Formula (III), P is meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3, 4-cis-dihydroxy-1-methylpyridine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl- Denotes 1-methylpiperidine or tropin.

Description

Ammoniophenphenylcephalosporin Compounds and Their Manufacturing Methods

The present invention relates to a novel amono-offrophenyl cephalosporin compound and a preparation method thereof. More specifically, by reacting the compound represented by the formula (II) with the tertiary amine compound P represented by the formula (III) and then removing the amine protecting group and the carboxy protecting group, it is useful as an antibiotic having a broad antibacterial range and excellent antimicrobial activity. The present invention relates to a novel amonooff phenyl cephalosporin compound represented by general formula (I) and a method for producing the same.

(I)

In general formula (I), P is meso-3,4-dihydroxy-1-methylpyrroli as acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups. Dean, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2R, 4R)- 4-hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy- 1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine or tropin are indicated. Q is CII or N.

In addition, pharmaceutically acceptable compounds of these cefephalosporin compounds, such as alkali salts such as sodium salts and potassium salts, tetraethylammonium salts, betaine salts, alkaline earth metal salts such as calcium salts and magnesium salts, hydrochloride salts, bromate salts and sulfate salts Inorganic salts, carbonates, bicarbonates, methanesulfonates, benzenesulfonates, taurines, organic sulfonates such as toluenesulfonates, organic acid carboxylates such as acetates, maleates, lactates, tartarates, arginine salts, lysine salts Amino acid salts such as serine salt, aspartate, glutarmate, triethylamine, pyridine, dicyclohexylamine and amine salt, N, N-dibenzylethyleneamine salt, triethanol salt, tris (hydroxymethylamino) It is a state of nontoxic phosphorus salts, such as methane salt and phenethylbenzylamine salt.

Regarding the present invention, a similar notice is known from US Pat. No. 4,327,210, which includes a ceftazidime in which a methyl group including a quaternary ammonium salt at the 3-position of cephalosporin, that is, a pyridinyl group, is introduced. It relates to the manufacture of. In this case, (Z) -2- (aminodiazol-4-yl) -2- (2-carboxy at 7 position of 7-ACA (3-acetoxymethyl-7-amino-3-cefe-4-carboxylic acid) A 2-propoxyimino) acetyl group was introduced. Thereafter, the acetoxymethyl group in the 3-position was converted to a pyridiniomethyl group by reaction with sodium iodine and pyridine to prepare ceftazidime. The ceftazidime prepared at this time exhibits a high range of antimicrobial activity against Gram-negative bacteria such as Pseudomonas bacteria (Pseudomonas aeruginosa), but a relatively weak antimicrobial activity against Staphylococcus aureus (E. coli). Gram-negative bacteria, such as Ake P99, also show relatively low antibacterial activity.

The present inventors have been steadily researching to develop cephalosporin-based antibiotics having not only a wide range of antimicrobial effects on Gram-negative bacteria but also strong antimicrobial activity against Gram-positive bacteria, and are represented by the general formula (I) shown above. We succeeded in producing novel cephalosporin compounds of the ammoniaoprophenyl series, and the novel cephalosporin compounds thus synthesized not only show excellent antimicrobial activity against Gram-negative bacteria, including Pseudomonas strains and Enterobacter cloac P99, -They found that they show strong antibacterial activity against benign bacteria.

Therefore, firstly, the present invention provides a novel amnonnioprophenylcephalosporin compound represented by formula (I) which can be usefully used as an antibiotic having a broad antimicrobial range and excellent antimicrobial activity, and a pharmaceutically acceptable salt thereof. To provide.

Hereinafter, the present invention will be described in detail.

Ammonoprophenyl cepanosporin compounds of the general formula (I) of the present invention and pharmaceutically acceptable methods for producing these salts are compounds represented by the general formula (II) and tertiary represented by the general formula (III) It can be prepared by reacting the amine compound P and then removing the amine protecting group and the carboxy protecting group.

In Formula (II), Q is CH or N, R ₁ is triphenylmethyl or hydrogen, R ₂ is p-methoxybenzyl or diphenylmethyl, and X represents iodine as a halogen compound.

In formula (III), P is meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3, 4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl- 1-methylpiperidine or tropin is indicated.

The compound of formula (II), which is used as a starting material of the present invention, is described in detail in the preparation method thereof as in the known materials [Journal of Antibiotics, 43 (5), 533-543 (1990)]. The inventors also produced and used according to this method.

Secondly, another object of the present invention is to provide a novel ammonium phenyl cephalosporin compound of the general formula (I) and a method for preparing the same.

The manufacturing method of the novel amnoniprophenyl cefephalosporin compound represented by general formula (I) of this invention can be made into the manufacturing method according to the case where Q is CII and Q is N.

When Q is CH, the novel amonooff phenyl cephalosporin compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof can be prepared through the following preparation methods.

[Reaction Path 1]: Q = CH

In Formula (I), P is meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, 3,4-cis-dihydroxy -1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine or tropin, Q is CH.

In general formula (II), R <_1> is triphenylmethyl, X is iodine, R <_2> is p-methoxybenzyl or diphenylmethyl, and Q is CH.

In General Formula (III), P is as defined in General Formula (I).

In general formula (IV), R ₁ is triphenylmethyl, R ₂ is p-methoxybenzyl or diphenylmethyl, P is as defined in general formula (III), and Q is CH.

Derivatives of the general formula (IV) in the first process was to be prepared by performing the same method as known in the Journal of Antibiotics, 43 (5), 533 ~ 543 (1990). However, in most cases, the tertiary amine compound P of general formula (III) was not solubilized in toluene as described as a reaction solvent in the literature, so that the reaction could not be progressed smoothly. Difficulties occurred in the formation of the Δ ² -isomer, a byproduct of the shifted cephalosporin compound. Accordingly, in the invention, many efforts have been made to solve these problems, and as a result, the following effective manufacturing method has been found beyond expectations.

The inventors of the present invention, when the silylated compound P using 1 to 5 equivalents, preferably 3 equivalents of silylating agent of the general formula (III), are dissolved in a reaction solvent such as toluene so that the reaction proceeds well. Preferred silylating agents are N-methyltrimethylsilyltrifluoroacetamide (MSTFA), N, O-bistrimethylsilyltrifluoroacetamide (BSTFA), hexamethyl disilazane (HMDS) And other silylating agents such as N, O-bistrimethylsilylacetamide (BSA), bistrimethylsilylurea, and N-methyltrimethylsilylacetamide. The silylation reaction is carried out by suspending the tertiary amine compound P represented by the general formula (III) in the reaction solvent, and then adding a silylating agent at -20 ° C to 0 ° C, preferably at -10 ° C, and stirring, and then silylation reaction. This progresses and the amine compound dissolves in the reaction solvent. The reaction solvent used at this time may be acetone, acetonitrile, dimethyl sulfoxide, dichloromethane, chloroform, hydrocarbons such as carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane, aromatic compounds such as benzene, toluene, and xylene Or mixtures thereof, and toluene is the preferred solvent.

The novel ammonium opiophenyl cephalosporin compound of the present invention represented by general formula (I) is 1 to 5 equivalents, preferably 2 equivalents of silylated tertiary amine compound of general formula (III) as described above. When the amine solution is added dropwise to the reaction solution of the compound represented by the formula (II) at a temperature of -20 ° C to 0 ° C, preferably at -10 ° C, the compound represented by the general formula (IV) It forms as a salt and precipitates as a solid in toluene, a reaction solvent used. Therefore, the compound of general formula (IV) precipitates as a solid during the reaction, so that the by-product of the Δ ² -isomer formed by reaction with the tertiary amine compound P represented by the general formula (III) present in excess in the reaction solution. Production can be suppressed. The solvent used in the reaction of the silylated amine solution with the compound represented by the general formula (III) is preferably the same as the solvent used in the silylation reaction of the tertiary amine compound P represented by the general formula (III). Solvent. In more detail, the temperature condition stated in the solution which dissolves the compound represented by general formula (II) in the solvent used for the silylation reaction of toluene, benzene, etc., and the silylation of the tertiary compound P represented by general formula (III) It is added dropwise at to effectively prepare the compound of formula (IV).

The novel ammonium-offrophenyl cephalosporin compound represented by general formula (I) is the triamine group and the carboxy protecting group p-methoxybenzyl in the compound represented by general formula (IV) as in the second bone tablet. Alternatively, diphenylmethyl group can be easily obtained by using trifluoroacetic acid and anisole.

Removal of trityl, an amine protecting group, and p-methoxybenzyl or diphenylmethyl group, in general formula (IV) is shown in the Journal of the American Chemical Society, 91, 5674 (1969). It is easily removed using trifluorohydroacetic acid and anisole well known in the art, neutralized with sodium bicarbonate solution, and purified through tube chromatography to easily obtain the target compound of formula (I).

On the other hand, when Q is N, the novel amono-offrophenyl cephalosporin compounds of formula (I) and the salts thereof applied pharmaceutically are represented by the compounds represented by formula (II) and formula (III). After reacting the tertiary amine compound P represented to obtain an intermediate represented by the general formula (IV), it can be prepared through the following production route to remove the carboxy protecting group.

[Reaction Path 2]: Q = N

In formula (I), P is meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4, -dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyl-diethanolamine, 3 , 4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine or tropin, Q is N.

In formula (II), R ₁ is hydrogen, X is iodine, R ₂ is p-methoxybenzyl or diphenylmethyl, and Q is N.

In general formula (III), P is the same as P defined by general formula (I).

R ₁ in formula (IV) is hydrogen, R ₂ is p-methoxybenzyl or diphenylmethyl, P is as defined in formula (III), and Q is N.

Since the compound of the general formula (II) which is a starting material in the process is insoluble in toluene, it is preferable to use ethyl acetate as the reaction solvent. Under these solvent conditions, in most cases, the tertiary amine compound P of the general formula (III) dissolves well, so that the process of silylating the amine compound as described above can be omitted. The novel ammonium-offrophenylpallosporin compound represented by the general formula (I) is a mixture of 1 to 5 equivalents, preferably 2 equivalents of the tertiary amine solution represented by the general formula (III) at a temperature of -20 to 0 ° C. When the reaction mixture is added dropwise to the reaction solution of the compound represented by the formula (II) at a temperature of -10 ° C, the compound represented by the formula (IV) is formed in the form of a salt in ethyl acetate, a reaction solvent used. Precipitates as a solid. At this time, the compound of general formula (IV) precipitates as a solid, so that by-product of Δ ² -isomer formed by reaction with the tertiary amine compound P represented by general formula (III) present in excess in the anticorrosive solution Production can be suppressed.

The carboxy protecting group p-methoxybenzyl or diphenylmethyl group in the compound represented by the general formula (IV) of the novel amonooffphenyl cephalosporin compound represented by the general formula (I) You can get it by using the brush.

Removal of the carboxy protecting group p-methoxybenzyl or diphenylmethyl group in general formula (IV) using trifluoroacetic acid and anisole well known in the art, neutralized with sodium bicarbonate solution, and then Purification via a compound easily yields an ammonium phenyl cephalosporin compound as a target compound of formula (I).

Separosporin compounds prepared in the present invention show high antimicrobial activity against a wide range of strains including Gram-positive bacteria and Gram-negative bacteria. In order to show the pharmacological usefulness of the target compounds, ceftazidime, a known compound, was evaluated by investigating the minimum inhibitory concentration (Minimum Inhibitory Concentration). The minimum inhibitory concentration was investigated by the agar dilution method in Mueller-Hinton Agar. The strains of 5 × 10 ⁴ cfu were incubated at 37 ° C. for 24 hours, and the results are shown in the table.

Control Compound:

Standard test strains used in the present invention are as follows.

The antibacterial activity of the novel cephalosporin compound prepared in the present invention was measured using the standard test strain described above, and the results are shown in Table 1 and Table 2, respectively.

As shown in Table 1 and Table 2, the cephalosporin combinations of the present invention are both broad and excellent antibacterial activity. In particular, while the minimum inhibitory concentration of ceftazidime, a widely known antibiotic for enterobacter cloacae P99, a strain resistant to cephalosporin antibiotics, is 100 μg / ml or more, the compounds of the present invention It exhibited a minimum inhibitory concentration of 1.56 to 12.5 µg / ml, showing superior antibacterial activity more than 16 times that of ceftazidime, and excellent antibacterial activity against other standard strains including Pseudomonas aeruginosa (Pseudomonas). In addition, almost all Gram-positive bacteria, including Staphylococcus aureus, have superior antimicrobial activity to ceftazidime. In the case of ceftazidime, the antimicrobial activity against Staphylococcus aureus (Staphylococcus aureus) is 3.13 to 12.5 μg / ml, whereas the compounds of the present invention exhibit a minimum inhibitory concentration of 0.2 to 1.56 μg / ml. 30 times more excellent antibacterial activity. This suggests that the compounds of the present invention are more extensive and useful than ceftazidime used as a control agent.

The following examples will illustrate the invention in more detail and do not limit the scope of the invention.

Example 1

7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(E) -3 (meso-3,4-dihydroxy -1-methyl-1-pyrrolidinio) -1-propen-1-yl] -3-cefe-4-carboxylate (Ia)

p-methoxybenzyl 7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(Z) -3-chloro- To a solution of 1-propen-1-yl] 3-sefe-4-carboxylate (300 mg, 0.47 mmol) in acetone (15 ml) was added NaI (165 mg, 1.10 mmol) all at once and then Stir for hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 10% aqueous NaSO solution and brine, dried and evaporated. The residue obtained at this time was dissolved in toluene (5 ml), and then meso-3,4-dihydroxy-1-methylpyrrolidine (86 mg, 0.73 mmol) was suspended in toluene (1 ml) in this solution, and N-methyltrimethyl. The solution obtained by adding silylacetamide (436 mg, 2.19 mmol) at −10 ° C. was added and then left in a refrigerator (about −10 ° C.) for 12 hours. The solid produced at this time was filtered and washed several times with ether to obtain about 290 mg of a white solid. This solid was added to dichloromethane (0.5 ml), trifluoroacetic acid (1 ml) and anisole (0.5 ml) and then stirred at 15-25 ° C. for 2 hours. The reaction mixture was concentrated and isopropyl ether (20 ml) was added to obtain a solid substance. The solid was washed several times with isopropyl ether, neutralized with sodium bicarbonate solution and purified by silica gel column chromatography (CHCN / HO = 4: 1 ~ 2: 1) to give the title compound (74mg, yield: 38%). As a result of identification and analysis, the title compound was identified.

Example 2

Using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, the title compound (yield 25%) was obtained in the same manner as in Example 1, and the title compound was identified and analyzed as follows. It turned out to be.

Example 3

Using (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, the title compound (yield 28%) was obtained in the same manner as in Example 1, and the result was confirmed and analyzed as follows. It turned out to be a compound.

Example 4

p-methoxybenzyl7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(Z) -3-chloro- NaI (252 mg, 1.68 mmol) was added to a solution of 1-propen-1-yl] -3 cefe-4-carboxylate (457 mg, 0.56 mmol) in acetone (15 ml) at once and then Stir for hours. The reaction mixture was concentrated and diluted with ethyl acetate, washed sequentially with 10% Na ₂ S ₂ O ₃ aqueous solution and brine, dried and evaporated. The residue obtained at this time was dissolved in toluene (5 ml), and a solution of N-methyl-diethanolamine (131 mg, 1.0 mmol) suspended in toluene (1 ml) was added to this solution, followed by 12 minutes in a refrigerator (about -10 ° C). It was left for hours. The solid produced at this time was filtered off and washed several times with ether to obtain a white solid. This solid was added to dichloromethine (0.5 ml), trifluoroacetic acid (1 ml) and anisole (0.5 ml), and the mixture was stirred at 15 to 25 DEG C for 2 hours. The reaction mixture was concentrated and then isopropyl ether (20 ml) was added to obtain a solid phase. The solid was filtered, washed several times with isopropyl ether, neutralized with sodium bicarbonate solution and purified by silica gel column chromatography (CH ₂ CN / H ₂ O = 4: 1 ~ 2: 1) to give the title compound (78mg, yield: 26 %) Was identified and identified as the title compound by the following results.

Example 5

Using 3,4-cis-dihydroxy-1-methylpiperidine, the title compound (yield: 26%) was obtained in the same manner as in Example 1, and was identified as the title compound by the following procedure. .

Example 6

Using 3,4-trans-dihydroxy-1-methylpiperidine, the title compound (yield: 49%) was obtained in the same manner as in Example 4, and was identified and identified as the title compound as follows. .

Example 7

Using 3,4-trans-dihydroxy-1-methylpiperidine, the title compound (yield: 40%) was obtained in the same manner as in Example 1, and was identified and identified as the title compound as follows. .

Example 8

The title compound (yield: 28%) was obtained by the same method as Example 1 using 2-hydroxymethyl-1-methylpiperidine, and the result was confirmed to be the title compound by the following analysis.

Example 9

Using the pin, the title compound (yield: 61%) was obtained in the same manner as in Example 1, and was identified and identified as the title compound as follows.

Example 10

p-methoxybenzyl 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(Z ) -3-Chloro-1-propen-1-yl] -3-cefe-4-carboxylate (139 mg) was added to NaI (108 mg) all at once in a solution of acetone (15 ml). Stir for 2 hours. The reaction mixture was concentrated and diluted with ethyl acetate, washed sequentially with 10% Na ₂ S ₂ O ₃ aqueous solution and brine, dried and evaporated. The residue obtained at this time was dissolved in ethyl acetate (1 ml), and a solution of meso-3,4, -dihydroxy-1-methylpyrrolidine (56 mg) in ethyl acetate (1 ml) was added to the solution, followed by a refrigerator (about -10 ° C) for 24 hours. Isopropyl ether was added to the suspension obtained at this time, and the solid obtained was filtered. The solid obtained at this time was added to dichloromethane (0.5 ml), trifluoroacetic acid (1 ml) and anisole (0.5 ml) and then stirred at 15-25 ° C. for 2 hours. The reaction mixture was concentrated and isopropyl ether (20 ml) was added to give a solid material. The solid was washed several times with isopropyl ethyr and neutralized with sodium bicarbonate solution, followed by silica gel column chromatography (CH ₃ CN / H ₂ O = 4). : 1 ~ 2: 1) to obtain the title compound (10mg, yield: 8%) was identified as the title compound as confirmed and analyzed as follows.

Example 11

Using (3S, 4S) -3,4, dihydroxy-1-methylpyrrolidine to give the title compound (aqueous: 24%) in the same manner as in Example 10. The title was confirmed and analyzed as follows. It turned out to be a compound.

Example 12

Using (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, the title compound (yield: 54%) was obtained in the same manner as in Example 10. The result was confirmed and analyzed as follows. It turned out to be the title compound.

Example 13

The title compound (yield: 16%) was obtained in the same manner as in Example 10 using N-methyl-diethanolamine, and the result was confirmed to be the title compound by the following analysis.

Example 14

Using 3,4-cis-dihydroxy-1-methylpiperidine, the title compound (yield: 16%) was obtained in the same manner as in Example 10. The result was confirmed and analyzed as follows. .

Example 15

Using 3,4-trans-dihydroxy-1-methylpiperidine, the title compound (yield: 10%) was obtained in the same manner as in Example 10. The result was confirmed and analyzed to be the title compound. .

Example 16

Using the pin, the title compound (yield: 24%) was obtained in the same manner as in Example 10. The result was confirmed and analyzed to find the title compound.

Claims (5)

Novel amono-offphenyl cephalosporin compound, indicated by formula (I). In general formula (I), P is meso-3,4-dihydroxy-1-methylpyrroli as acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups. Dean, (3S, 4S) -3,4-dihydroxy-1-methyl-2-pyrrolidineethanol, N-dimethyldiethanolamine, 4-hydroxy-methylrrolidine, (3R, 4R)- 3,4, -dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine, tropin or These pharmaceutically acceptable salts are indicated. Q is N. A novel ammonium off compound represented by formula (I) characterized by reacting a tertiary amine compound P represented by formula (III) with a compound of formula (II) in the presence of 2 to 5 equivalents of silylating agent. Method for preparing a phenyl cephalosporin compound. In general formula (I), P is meso-3,4-dihydroxy-1-methylpyrroli as acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups. Dine, (3S, 4S) -3,4, -dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4-dihydroxy-1-methylpyridine, (2S, 4R) -4 -Hydroxy-1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine, tropin or The salts acceptable for their pharmaceuticals are indicated. Q is N. In formula (II), R ₁ is hydrogen, X is iodine, R ₂ is p-methoxybenzyl or diphenylmethyl, and Q is N. In formula (III), P is meso-3,4-dihydroxy-1-methylpyrrolodine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolodine, (3R, 4R ) -3,4, -dihydroxy-1-methylpyrrolodine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, 3,4-cis-dihydroxy-1 -Methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine or tropin. N-methyltrimethylsilyltrifluoroacetamide (MSTFA), N, O- and bistrimethylsilylacetamide as silylating agents used in silylating tertiary amine compound P of general formula (II) (BSA), bistrimethylsilylurea, N-methyltrimethylsilylacetamide. A process for producing a novel ammonium orthophenylcephalosporin compound represented by the general formula (I). The method for producing a novel ammonioprophenyl cephalosporin compound according to claim 2, wherein the silylation reaction temperature is maintained in the range of -20 to 0 ° C. The method of claim 2, wherein the solvent used for silylation is acetone, acetonitrile, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, or a mixture thereof. A method for producing a novel amono-offphenyl cepilosporin compound represented by the general formula (I), which is selected.