KR19980013613A - Ammonia-Off-Phenyl Cephalosporin Compounds and Their Preparation Method - Google Patents

Abstract

The present invention relates to a novel ammonia off-phenylsepalosporin compound and a process for its preparation. More specifically, it is an antibiotic having a broad antibacterial range and excellent antimicrobial activity by reacting a compound represented by the general formula (II) with a tertiary amine compound P represented by the general formula (III) after removing the amine protecting group and the carboxy protecting group.

In the general formula (I), P is an acyclic amine or heterocyclic amine having one nitrogen atom and one or two hydroxyl groups, and meso-3,4-dihydroxy-1-methylpyrrolidine , (3S, 4R) -4,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) 1-methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4- 1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine or tropine. Q represents CH Or N. In addition,

Lt; RTI ID = 0.0 > pharmaceutically < / RTI >

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

In the general formula (III), P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy- , 4-cydo-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, -1-methylpiperidine or tropin.

Description

Ammonia-Off-Phenyl Cephalosporin Compounds and Their Preparation Method

The present invention relates to a novel ammonia off-phenylsepalosporin compound and a process for its preparation. More specifically, the compound represented by the general formula (II) is reacted with the tertiary amine compound P represented by the general formula (III), and then the amine protecting group and the carboxy protecting group are removed, thereby being useful as an antibiotic having a broad antibacterial range and excellent antibacterial activity The present invention relates to novel ammonia-off-phenyl-cephalosporin compounds represented by the general formula (I) and a process for their preparation.

(One)

In the general formula (I), P is an acyclic amine or heterocyclic amine having one nitrogen atom and one or two hydroxyl groups, and meso-3,4-dihydroxy-1-methylpyrrolidine , (3S, 4R) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) Methyl-2-pyrrolidone, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy- Methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine or tropine. Q is CII or N;

In addition, pharmaceutically acceptable salts of these cephalosporin compounds, such as, for example, alkali salts such as sodium or potassium salts, tetraethylammonium salts, betaine salts, alkaline earth metal salts such as calcium salts or magnesium salts, hydrochloric acid salts such as hydrochloric acid salts, Organic sulfonates such as inorganic salts, carbonates, bicarbonates, methanesulfonates, benzenesulfonates, taurines and toluenesulfonates, organic acid carboxylates such as acetate, maleate, lactate and tartrate, arginine salts, , Amino salts such as serine salts, aspartates and glutarates, amine salts such as triethylamine, pyridine, dicyclohexylamine, N, N-dibenzylethyleneamine salts, triethanes, salts of tris Methylamino) methane salt, phenethylbenzylamine salt, and the like.

US Pat. No. 4,327,210 discloses a known data related to the present invention, which discloses that a ceftazidime (hereinafter referred to as "ceftazidime") in which a methyl group containing a quaternary ammonium salt, ie, a pyridinium methyl group, ). ≪ / RTI > (Z) -2- (aminodiazol-4-yl) -2- (2-carboxy-4-carboxylic acid) was added to the 7-position of 7-ACA (3-acetoxymethyl- -2-propoxyimino) acetyl group. Subsequently, the acetoxymethyl group at the 3-position was converted to the pyridinium methyl group by reaction with sodium iodide and pyridine to prepare ceftazidime. Although ceftazidime prepared at this time shows a high range of antimicrobial activity against Gram-negative bacteria such as Pseudomonas aeruginosa (Pseudomonas aeruginosa), it exhibits relatively weak antibacterial activity against Staphylococcus (Staphylococcus) It has relatively low antibacterial activity against Gram-negative bacteria such as Ake P99.

The present inventors have been intensively studying to develop cephalosporin antibiotics having not only a broad antibacterial action against Gram-negative bacteria but also a strong antibacterial activity against Gram-positive bacteria, And thus the novel cephalosporin compound thus synthesized has excellent antimicrobial activity against Gram-negative bacteria including Pseudomonas sp. And Enterobacter cloacae P99, as well as Gram-positive bacteria But also showed a strong antibacterial activity against.

Accordingly, first, the present invention provides a novel ammonia-offphenylsephalosporin compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof, which can be usefully used as an antibiotic having a broad antibacterial range and excellent antibacterial activity .

Hereinafter, the present invention will be described in detail.

The method of producing the phenylsacetaphosphorine compound and the pharmacologically acceptable salts thereof according to the present invention is characterized in that the compound represented by formula (II) and the compound represented by formula (III) Amine compound P, followed by removing the amine protecting group and the carboxy protecting group.

(II)

In the general formula (II), Q is CH or N, R ₁ is triphenylmethyl or hydrogen, R2 is p-methoxybenzyl or diphenylmethyl, and X is iodine as a halogen compound.

P (III)

In the general formula (III), P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy- Cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy- 1 -methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl- l-methylpiperidine or tropin.

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

Secondly, another object of the present invention is to provide a novel ammonia-offphenylsephalosporin compound of the above general formula (I) and a process for their preparation.

The process for the preparation of the novel ammonia-off phenylsphalosporin compounds represented by the general formula (I) of the present invention can be carried out differently depending on the case where Q is CII and the case where Q is N. [

When Q is CH, the novel ammonia-off phenyl cephemosporin compound represented by the general formula (I) and pharmaceutically acceptable salts thereof can be produced through the following production process.

[Reaction path 1]: Q = CH

In the general formula (I), P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- , 4R) -3,4-dihydroxy-1-methylpyrrolidine and (2S, 4R) -4-hydroxy- 1 -methyl-2-pyrrolidine methane were reacted with 3,4- 1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine or tropine, and Q is CII.

In the general formula (II), R ₁ is triphenylmethyl, X is iodine, R ₂ is p-methoxybenzyl or diphenylmethyl, and Q is CII.

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

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

In the first step, the derivatives of general formula (IV) were prepared in the same manner as in the known method [Journal of Antibiotics, 43 (5), 533-543 (l990)]. However, in most cases, the tertiary amine compound P of the general formula (III) is not well dissolved in the toluene described as a reaction solvent in the above literature, so that the reaction can not proceed smoothly. When the reaction time is prolonged, ² - isomer, which is a byproduct of the displaced cephalosporin compound. Therefore, in the present invention, 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 have found that if the compound P is silylated using 1 to 5 equivalents, preferably 3 equivalents, of a silylating agent of a tertiary amine compound P of the general formula (III), the compound P is sufficiently dissolved in a reaction solvent such as toluene, (BSTFA), hexamethyldisilazane (HMDS), hexamethyldisilazane (HMDS), and N-methyltrimethylsilyltrifluoroacetamide (MSTFA) Other silylating agents such as N, O-bistrimethylsilyl acetamide (BSA), bistrimethylsilyl urea and N-methyltrimethylsilyl acetamide can also be used. The silylation reaction is carried out by suspending a tertiary amine compound P represented by the general formula (III) in a reaction solvent and then adding a silylating agent at -20 to 0 ° C, preferably -10 ° C, And the amine compound is dissolved in the reaction solvent. Examples of the reaction solvent used in this case include hydrocarbons such as acetone, acetonitrile, dimetal sulfoxide, dichloromethane, chloroform and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatics such as benzene, toluene and xylene Compounds, or mixtures thereof, and toluene is the preferred solvent.

The novel ammonia-off-cephalosporin compounds of the present invention represented by the general formula (I) can be prepared by reacting 1 to 5 equivalents of a tertiary amine compound of the general formula (III), preferably 2 equivalents Is added dropwise to the reaction solution of the compound represented by the general formula (II) at a temperature of -20 to 0 占 폚, preferably -10 占 폚, and the compound represented by the general formula (IV) And is precipitated as a solid in toluene which is a reaction solvent used. Therefore, since the compound of the general formula (IV) precipitates as a solid in the reaction, the reaction product of the? ² -isomer, which is a byproduct formed by the reaction with the tertiary amine compound P represented by the general formula (III) Generation can be suppressed. The solvent used when the silylated amine solution is reacted with the compound represented by the formula (II) is preferably the same as the solvent used for the silylation reaction of the tertiary amine compound P represented by the formula (III) Solvent. More specifically, the compound represented by the general formula (11) is dissolved in a solvent used for the silylation reaction such as toluene or benzene, and the silylated tertiary compound P represented by the general formula (111) is added to the above- To thereby effectively prepare a compound of general formula (1V).

The novel ammonia-offphenylsephalosporin compound represented by the general formula (I) can be produced by reacting the compound represented by the general formula (IV) with a trityl group which is an amine protecting group, p-methoxybenzyl which is a carboxy protecting group Removal of the diphenylmethyl group with trifluoroacetic acid and anisole is easy to obtain

The removal of the trityl group as the amine protecting group and the p-methoxybenzyl or diphenylmethyl group as the carboxy protecting group in the general formula (IV) can be carried out in the same manner as in the known art [Journal of the American Chemical Society, 91, 567 (1969) , The target compound of formula (I) can be easily obtained by neutralization with sodium bicarbonate solution and then purification through tube chromatography.

On the other hand, when Q is N, the novel ammonia-off phenylsphalosporin compounds of the general formula (I) and pharmaceutically acceptable salts thereof can be prepared by reacting a compound represented by the general formula (II) with a compound represented by the general formula Can be prepared by reacting the indicated tertiary amine compound P to obtain an intermediate represented by the general formula (IV), and then removing the carboxy protecting group through the following production route.

[Reaction path 2]: Q = N

In the general formula (I), P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy- 1- methyl- 2- pyrrolidinemethanol, N-methyl- Amine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy- Or tropine, and Q is N.

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

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

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

Since the compound of formula (II), which is a starting material in the above process, does not dissolve in toluene, ethyl acetate is preferably used as a reaction solvent. In this solvent condition, in most cases, the tertiary amine compound P of the general formula (III) is dissolved well, so that the step of silylating the amine compound as described above can be omitted. The novel ammonio-substituted phenyl cephalosporin compound represented by the general formula (I) is obtained by reacting a tertiary amine solution represented by the general formula (III) in an amount of 1 to 5 equivalents, preferably 2 equivalents, at a temperature of -20 to 0 캜 Is added dropwise to the reaction solution of the compound represented by the general formula (II) at a temperature of -10 deg. C, preferably -10 deg. C, and the compound represented by the general formula (IV) is formed into a salt form, ≪ / RTI > At this time, since the compound of formula (IV) precipitates as a solid, it is also possible to obtain a reaction product of the? ² -isomer, which is a byproduct formed by the reaction with the tertiary amine compound P represented by the general formula (III) Generation can be suppressed.

The novel ammonia-offphenylsephalosporin compound represented by the general formula (I) can be prepared by reacting a p-methoxybenzyl or diphenylmethyl group as a carboxy protecting group in the compound represented by the general formula (IV) with trifluoroacetic acid and anisole Can be obtained by removing it using.

Removal of the carboxy protecting group p-methoxybenzyl or diphenylmethyl group in the general formula (IV) can be carried out by removing trifluoroacetic acid and anisole, which are well known in the art, and neutralizing with sodium bicarbonate solution, , An ammonio propenyl cephalosporin compound as a target compound of the general formula (I) can be easily obtained.

The cephalosporin compounds prepared according to the present invention show high antibacterial activity against a wide range of strains including Gram-positive and Gram-negative bacteria. To determine the pharmacological properties of the target compounds, ceftazidime, a known compound, was evaluated as a comparative substance by examining the Minimum Inhibitory Concentration. The minimum inhibitory concentration was determined by agar dilution method in Mueller-Hinton Agar and cultured at 37 ° C for 24 hours at 5 × 10 ⁴ cfu on a culture dish. The results are shown in the table .

Control Compound:

Ceftazidime structure

The 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 strains described above. The results are shown in Tables 1 and 2, respectively.

As shown in Table 1 and Table 2, all of the ceparoscopic compounds of the present invention are broad and exhibit excellent antibacterial activity. Particularly, the minimum inhibitory concentration of ceftazidime, which is a broad-spectrum antibiotic, is more than 100 μg / ml against Enterobacter cloacae P99, a strain resistant to cephalosporin antibiotics, while the compound of the present invention Showed a minimum inhibitory concentration of 1.56 to 12.5 μg / ml, showing superior antibacterial activity of 16 times or more than ceftazidime, and showing excellent antibacterial activity against standard strains other than Pseudomonas aeruginosa (Pseudomonas aeruginosa). In addition, almost all Gram-positive bacteria including Staphylococcus (Staphylococcus) have superior antibacterial activity than ceftazidime. In the case of ceftazidime, while the antimicrobial activity against Staphylococcus aureus (Staphylococcus aureus) ranged from 3.13 to 12.5 μg / ml, the compounds of the present invention showed a minimum inhibitory concentration of 0.2-1.56 μg / ml, It is 30 times more effective than dim. This suggests that the compounds of the present invention are more extensive and useful than ceftazidime used as a reference.

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

Example l

3 - [(E) -3- (meso-3, 4-dihydroxybenzoyl) amide] 1-methyl-l-pyrrolidino) -l-propen-1-yl] -3-cephem-4-carboxylate (Ia)

-3 - [(Z) -3-chloro-1 - [(Z) -2- (2-tritylaminothiazin-4-yl) -2-methoxyiminoacetamido] Carboxylate (300 mg, 0.47 mmol) in acetone (15 ml) was added all at once Nal (165 mg, 1.10 mmol) Lt; / RTI > The reaction mixture was concentrated, diluted with ethyl acetate, washed with 10% aqueous NaSO 3 solution and brine successively, dried and evaporated. After dissolving the resulting residue in toluene (5 ml), meso-3,4-dihydroxy-1-methylpyrrolidine (86 mg, 0.73 mmol) was suspended in toluene (1 ml) A solution obtained by adding trimethylsilylacetamide (436 mg, 2.19 mmol) at -10 째 C was added, and the mixture was left in a refrigerator (about -10 째 C) for 12 hours. The resulting solid was filtered through 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 stirred for 2 hours at 15-25 ° C. The reaction mixture was concentrated, Was added thereto to obtain a solid material. The solid was washed several times with isopropyl ether, neutralized with a sodium bicarbonate solution and purified by silica gel column chromatography (CHCN / HO = 4: `~ 2: 1) to give the title compound (74 mg, yield: 38% And confirmed as follows by the following analysis.

Example 2

7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(E) -3- (3S, Methyl-1-pyrrolidino) -1-propen-1-yl] -3-cephem-4-carboxylate (Ib)

(Yield: 25%) was obtained in the same manner as in Example 1, from (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, .

IR (KBr): 3400, 1766, 1606, 1534 cm < ^{-1 &} gt ;;

Example 3

3 - [(E) -3- (4R-hydroxy-2S-hydroxy-2S- Preparation of (2S, 4R) -4-hydroxy-l-methyl-l-methyl-l-pyrrolidino) The title compound (yield: 28%) was obtained in the same manner as in Example 1, using 1-methyl-2-pyrrolidinemethanol.

Example 4

7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [ Preparation of p-methoxybenzyl 7 β - [(Z) -2- (2-tri (meth) acryloyloxy) 3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate (457 mg, 0.56 mmol) in acetone (15 ml): NaI (252 mg, 1.68 mmol) was added all at once and stirred at 15-25 ° C for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 10% Na ₂ S ₂ O ₃ aqueous solution and brine in that order, dried and evaporated. A solution of N-methyl-diethanolamine (131 mg, 1.0 mmol) suspended in toluene (1 ml) was added to this solution, and the resulting residue was dissolved in a refrigerator (about -10 ° C) Lt; / RTI > The resulting solid was filtered through several times with ether to obtain a white solid. This solid was added to dichloromethane (0.5 ml), trifluoroacetic acid (1 ml) and anisole (0.5 ml), followed by stirring at 15 to 25 ° C for 2 hours. After the reaction mixture was concentrated, isopropyl ether (20 ml) was added to obtain a solid material. The solid was filtered and washed several times with isopropyl ether, neutralized with sodium bicarbonate solution, and then purified by silica gel column chromatography (CH ₃ CN ₁ H ₂ O = 4: 1 to 2: 1) to obtain the title compound (78 mg, : 26%). As a result of confirmation and analysis as follows, the title compound was obtained.

Example 5

7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [ Preparation of dihydroxy-1-methyl-1-piperidino) -1-propen-1-yl] -3-cephem- -Methylpiperidine, the title compound (yield: 26%) was obtained in the same manner as in Example 1, and the title compound was identified by the following analysis.

Example 6

7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(E) -3- (3,4- Methyl-1-piperidino) -1-propen-1-yl] -3-cephem-4- carboxylate (If) 3,4- The title compound (yield: 49%) was obtained in the same manner as in Example 4, using methylpiperidine, and found to be the title compound as a result of analysis as follows.

Example 7

3 - [(E) -3 - (4-hydroxy-1-methyl-1 H -imidazolyl) -1-propen-1-yl] -3-cephem-4-carboxylate (Ig) Using 3,4-trans-dihydroxy-1-methylpiperidinol The title compound (yield: 40%) was obtained in the same manner as in Example 1, and the title compound was identified and identified as follows.

Example 8

3 - [(E) -3- (2-hydroxymethyl-1 (S) -2- Piperidinio) -1-propen-1-yl] -3-cephem-4-carboxylate (Ih) Using 2-hydroxymethyl-1-methylpiperidine The title compound (yield: 28%) was obtained in the same manner as in Example 1, and the title compound was identified and identified as follows.

Example 9

3 - [(E) -3-tropinio-1-propen-1-yl] -2-methoxyiminoacetamido] Carboxylate (Ii) The title compound (Yield: 61%) was obtained in the same manner as in Example 1, using tropin. The following compounds were identified and analyzed to give the title compound It was proven.

Example 10

7 - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] -3 - [(E) Methyl-1-pyrrolidino) -1-propen-1-yl] -3-cephem-4-carboxylate (II- Methoxybenzyl 7? - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] -3- [ (108 mg) was added to a solution of (Z) -3-chloro-1-propen-1-yl] -3-cephem- The mixture was stirred at 25 DEG C for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 10% Na ₂ S ₂ O ₃ aqueous solution and brine, dried, and evaporated. The resulting residue was dissolved in ethyl acetate (1 ml). To this solution was added a solution of meso-3,4-dihydroxy-1-methylpyrrolidine (56 mg) in ethyl acetate (1 ml) -10 < 0 > C) for 24 hours. Isopropyl ether was added to the resulting suspension, and the resulting solid was filtered. The resulting solid was added to dichloromethane (0.5 ml), trifluoroacetic acid (1 ml) and anisole ((), and the mixture was stirred at 15 to 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 ether, neutralized with a sodium bicarbonate solution and then purified by silica gel column chromatography (CH ₃ CN / H ₂ O = 4: 1 to 2: 1) to give the title compound (10 mg, yield: %) Was obtained. As a result of confirming and analyzing as follows, it was proved to be the title compound.

EXAMPLES l1

3 - [(E) -3- (2-methoxy-2-methylthiazol- 3-cephem-4-carboxylate (II-b]) was prepared in the same manner as described in Example 1, except that 1 g of 3S, 4S-3,4-dihydroxy-1-methyl-1-pyrrolidino) The title compound (yield: 24%) was obtained in the same manner as in Example 10 using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, Title compound. ≪ / RTI >

Example 12

3 - [(E) -3- (2-methoxy-2-methylthiazol- Preparation of 4R-hydroxy-2S-hydroxymethyl-1-methyl-1-pyrrolidino) -1-propen-1-yl] -3- The title compound (yield: 54%) was obtained in the same manner as in Example 10, using (2S, IR) -4-hydroxy-1-methyl- One resulted in the title compound.

Example l3

7 - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] -3 - [ Preparation of bis (2-hydroxyethyl) methylammonio) -1-propen-1-yl] -3-cephem-1-carboxylate (II-d) N-methyl-diethanolamine (Yield: 16%)) was obtained in the same manner as in Example 10, and the following compound was identified and analyzed as the title compound.

Example 14

7 - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] -3 - [ (II-c) < RTI ID = 0.0 > (3-Cyclohexyl-1-methyl- The title compound (yield: 16%) was obtained in the same manner as in Example 10, using 3,4-cis-dihydroxy-1-methylpiperidine. The following compounds were identified and analyzed to give the title compound Proved.

Example 15

7 - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] -3 - [ Preparation of (3,4-trans-dihydroxy-1-methyl-1-piperidino) The title compound (yield: 10%) was obtained by the same procedure as in Example 10 using 4-trances-dihydroxy-1-methylpiperidine, and the following identified and analyzed Title compound. ≪ / RTI >

Example 16

7 - [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamido] 3-cephem-4-carboxylate (II-g) The title compound (yield: 24%) was prepared by the same procedure for Example 10 while using tropin The result was confirmed as follows.

Claims (5)

A novel ammonia offropeone semarhosporin compound represented by the general formula (I). In the general formula (I), P is an acyclic amine or heterocyclic amine having one nitrogen atom and one or two hydroxyl groups, and meso-3,4-dihydroxy-1-methylpyrrolidine , (3S, 4R) -3,4-dihydroxy-1-methylpyrrolidine, (3S, 4R) -3,4-dihydroxy-1-methylpyrrolidine, Methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4- Trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-l-methylpiperidine, tropin or a pharmaceutically acceptable salt thereof . Q is CII or. A novel ammonia off-solution represented by the general formula (I), characterized by reacting a tertiary amine compound P represented by the general formula (III) with a compound represented by the general formula (II) in the presence of 2 to 5 equivalents of a silylating agent ≪ / RTI > In the general formula (I), P is an acyclic amine or heterocyclic amine having one nitrogen atom and one or two hydroxyl groups, and meso-3,4-dihydroxy-1-methylpyrrolidine , (3S, 4R) -4,4-dihydroxy-4-methylpyrrolidine, (3R, 4R) Methyl-2-pyrrolidinemethanol, N-methyldiethanolamine, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy- Methylpyrrolidine, 4-hydroxy-1-methylpiperidine, 2-hydroxymethyl-1-methylpiperidine, tropin, or a pharmaceutically acceptable salt thereof. Q is CH or N; In the general formula (II), R1 is triphenylmethyl. R ₂ is p-methoxybenzyl or diphenylmethyl. X is iodine. And Q represents CH. In the general formula (III), P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- , 4R) -3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy- 1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpyrrolidine, / 1-hydroxy-1-methylpiperidine or tropine. In the general formula (IV), R ₁ is triphenylmethyl. R ₂ is P-methoxybenzyl or diphenylmethyl. P is at least one selected from the group consisting of meso-3,4-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy- 1 -methylpyrrolidine, (3R, 4R) Dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1 -methyl-2-pyrrolidinemethanol, 3,4-cis-dihydroxy- L, 4-trans-dihydroxy-1-methylpyrrolidine, 4-hydroxy-l-methylpiperidine or tropine. Q represents CH. The method according to claim 2, wherein the silylating agent used in silylating the tertiary amine compound P of formula (II) is N-methyl trimethylsilyl trifluoroacetamide (MSTFA) Aminonaphlorophenyl cephalosporin compounds and WH methods thereof. More specifically, the compound represented by the general formula (II) is reacted with the tertiary amine compound P represented by the general formula (III), and then the amine protecting group and the carboxy protecting group are removed, thereby being useful as an antibiotic having a broad antibacterial range and excellent antibacterial activity The present invention relates to novel ammonia-off-phenyl-cephalosporin compounds represented by the general formula (I) and a process for their preparation. The process according to claim 2, wherein the silylation reaction temperature is maintained in the range of -20 to 0 占 폚. The method according to claim 2, wherein the solvent used in the silylation is acetone, acetonitrile, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, (I), characterized in that the compound of formula (I) is a compound of formula (I).