JPH03236392A - 3-isooxazolidinylcepharosporin derivative for oral administration - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 is H or lower alkyl; stereochemistry of carbon of * symbol is R, S or RS; R<2> is-CHR<3>OCOR<4> (R<3> is H or lower alkyl; R<4> is lower alkyl, lower alkoxy cycloalkyloxy)]. EXAMPLE:(6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2(methoxyimino) acetoamide]-3-[(S)-2-methylisooxazolidin-5-yl]-3 cephem-4-carboxylic acid pivaloyloxymethyl ester. USE:A remedy for bacterial infection. PREPARATION:A compound expressed by formula II is used as a starting substance and a halide derivative expressed by formula III (X is halogen) is subjected to esterification reaction with an addition salt of an organic base of triethylamine, etc., at -30 deg.C to ambient temperature in a polar solvent such as dimethylformamide.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a novel cephalosporin derivative for oral administration, and more particularly, it relates to a novel cephalosporin derivative for oral administration, and more specifically, a derivative of the general formula (1) [wherein R1 represents a hydrogen atom or a lower alkyl group] , the stereochemistry of the carbon atom in this mark is mutual or R5, and R2 is 100R"
0COR' group (in the formula, R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)]
The present invention relates to novel 3-isoxazolidinyl cephalosporin compounds represented by the following formulas and pharmacologically acceptable acid addition salts thereof. Furthermore, the present invention relates to an antibacterial agent for oral administration containing the compound of general formula (1) and its pharmaceutically acceptable acid addition salt as an active ingredient, and this antibacterial agent is useful as a therapeutic agent for bacterial infections. .

[Problems to be solved by the prior art and the invention 3 Various cephalosporin antibiotics are widely used for the treatment of bacterial infections, but they have lower antibacterial activity and antibacterial spectrum compared to conventionally known cephalosporins. At the same time, it is desired to discover new cephalosporin derivatives with improved clinical therapeutic effects. Furthermore, the emergence of cephalosporin derivatives that show good in vivo absorption when administered orally,
There are great expectations in the field of chemotherapy.

The inventors previously conducted intensive research, and as a result, found that 2
Cephalosporins having a -(2-aminothiazol-4-yl)-2-(substituted or unsubstituted hydroxyimino)-acetyl group as a 7-N-acyl group, at the 3-position of the cephem ring, Durham-positive and Durham-negative bacteria by introducing isoxazolidinyl groups as an entirely new type of side chain group linked through carbon-carbon bonds to form a ring-assembly heterocyclic structure. A series of new cephalospores that have a strong antibacterial effect even against Pseudomonas aeruginosa by variously converting the side chain group at the 7-position. We succeeded in creating a phosphorus derivative. That is, the present inventors have proposed the following general formula () [wherein R1 represents a hydrogen atom or a lower alkyl group, or R1 represents the same or different two lower alkyl groups, and in formula (1) NR' shown in represents a dialkylammonium group, the stereochemistry at the carbon atom of this symbol is dominant or deaf, and R2 is substituted with a hydrogen atom, a lower alkyl group, or a carboxyl group. Does it represent a lower alkyl group, a monohalo (lower) alkyl group, a dihalo (lower) alkyl group, a l-ruboxy-1-(dihydroxyphenyl)-methyl group, a cycloalkyl group having 3 to 6 carbon atoms, or a lower alkenyl group? , or R
8 is a substituted or unsubstituted aromatic ring group or hetero group selected from a phenyl group, a furyl group, a pyridyl group, a pyridonyl group, an imidazolyl group, and a pyrimidyl group, which may have 1 to 3 substituents on the ring. represents a lower alkyl group substituted with a cyclic group] and their pharmacologically acceptable salts (Patent Application No. 1999 filed by the present applicant; Invention Name: "Novel 3-isoxazolidinyl cephalosporin derivative"
, February 7, 1990 II).

The novel cephalosporin derivative having a 3-ynoxazolidin-5-yl group, which is represented by the above general formula (A) and which was previously proposed by the present inventors, is a chemotherapeutic agent having excellent antibacterial activity. This time, the present inventors selected from compounds of the formula (A) and obtained the following general formula (I) [wherein R1 represents a hydrogen atom or a lower alkyl group and one carbon atom is where R2 represents a -CHR30COR' group (wherein R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group); The present invention was completed based on the discovery that an ester derivative at the 4-position carboxyl group of the compound represented by the following formula has particularly improved in vivo absorption upon oral administration.

[Means for solving problems]

That is, according to the first invention, the general formula (1) [wherein R1 represents a hydrogen atom or a lower alkyl group, and the stereochemistry of the carbon atoms indicated by this symbol indicates mutual or mutual, R
2 represents a -CHR''0COR' group (in the formula, R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group); Pharmaceutically acceptable acid addition salts thereof are provided.

To explain in more detail, in the compound of the present invention of general formula (I), R1 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and R2 represents It is an ester-forming group that is easily eliminated by hydrolysis to give a free carboxyl group (in the case of R''=H) when the present compound is absorbed into the body after administration or after being absorbed.For example, , in the group of the formula -CHR''0COR' representing the group R2, R
3 can be a hydrogen atom or a lower alkyl group such as methyl or ethyl. Further, when R4 is a lower alkyl group, examples thereof include an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, and tert-butyl. and when R4 is a lower alkoxy group, examples thereof include methoxy, ethoxy, 1-
It can be an alkoxy group having 1 to 4 carbon atoms such as methylethoxy, and when R4 is a cycloalkyloxy group, examples thereof include cycloalkyl having 3 to 6 carbon atoms such as cyclopentyloxy and cyclohexyloxy. Mention may be made of oxy groups.

Examples include 1-acyloxy-lower alkyl groups such as 1-acetoxyethyl group, 1-acetoxyethyl group, and 1-alkoxycarbonyloxy-lower alkyl groups such as 1-ethoxycarbonyloxyethyl group and 1-isopropoxycarbonyloxyethyl group. .

The pharmacologically acceptable acid addition salt of the compound of general formula (I) according to the present invention refers to the addition salt of the compound of general formula (I) with a known pharmacologically acceptable inorganic acid, such as hydrochloric acid, to the amino group or imino group of the compound of general formula (I). , sulfuric acid, nitric acid, phosphoric acid, etc.

Alternatively, it can be a salt added with a known organic acid such as acetic acid, propionic acid, maleic acid, malic acid, etc.

The absolute configuration of the stereochemistry at the carbon atom of the wood stamp in the general formula (1) showing the compound of the present invention can be in either of the two main forms, but the compound of the present invention may be in either one of the two forms or in the hybrid form. Includes the body.

Specific examples of the compound of general formula (1) of the present invention include, but are not limited to, the compounds shown below.

(1) (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)
acetamido)-3-((S)-2-methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (compound in Examples below).

(2) (6R,7-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((fi)-2-methylisoxazolidine -5-yl2-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (Example 2 below)
compounds).

The production of the compound of general formula (I) of the present invention is a new compound represented by the following general formula () [wherein R1 represents the same meaning as above] (
6R,7R)-7-[(Z)-2-(2-7minothiazole/I/-4-1'l)-2-(substituted or unsubstituted imino)acetamide]-3-(2-methylisoxazolidine -5-yl)-3-cephem-4-carboxylic acid as a starting compound, an addition salt of a compound of general formula (n) and an organic base such as triethylamine or a compound of general formula (1)
A salt (carboxylate) of an alkali metal such as sodium or potassium in the carboxyl group of the compound is a halide derivative represented by the general formula () [wherein, X is a halogen atom, and R2 and R4 have the same meanings as above] The esterification reaction carried out by reacting with is preferably carried out at 0 DEG C. to room temperature, and is preferably carried out in a polar solvent such as dimethylformamide or dimethyl sulfoxide, water, or a mixed solution thereof.

As mentioned above, when the ester type compound of the general formula (I) according to the present invention is orally administered, the ester group represented by R2 in the general formula (1) is detached from the compound of the formula (I) in vivo to form a free carboxyl group. The compound of formula (1), which is converted into a free carboxylic acid form, exhibits excellent antibacterial activity in vivo. The excellent biological properties of the compound of the present invention according to general formula (1) are shown below.

(1) In vivo absorption test during oral administration As a 3-isoxazolidinyl cephalosporin compound represented by general formula (I) according to the present invention, the compound of Example 1 or Example 2 described later was administered to ICR mice. (female, 4 weeks old) was orally administered (dose: 300 μ/mouse), and urine was collected from 0 to 5 hours after administration to collect Bacillus subtilis (PCI219).
The antibacterial activity of the free carboxylic acid type antibiotic (compound corresponding to the case where R2=H in general formula (I)) excreted in the urine was measured using the test bacteria, and the urinary recovery rate of this antibiotic was determined. I calculated it. The results are shown in Table 1.

(2) Antibacterial activity of the cephalosporin compound of the present invention in the free carboxylic acid form [compound where R''=H in general formula (I)] To demonstrate the antibacterial activity of the compound of the present invention of general formula (1) To,
Free carboxylic acid type derivatives derived from the compound of the present invention by removing the ester-forming group (R2), that is, the starting compounds used in Examples 1 and 2 described later, were used as test compounds, and regarding these test compounds. , Minimum Inhibitory Concentration (MI) for various bacteria evaluated by standard multiple dilution method
C, wcg/i+R) was measured.

Test Compound (a) Ni(釧)-7-[(Meng)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-((S)-2 -Methyl isoxazolidine-5
-Ilgo 3-cephem-4-carboxylic acid test compound (b): - (7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino) Acetamide)-3-((and)-2-methylisoxazolidin-5-yl]-3-cephem=4-carboxylic acid The results obtained are shown in Table 2 below.

The cephem compound of general formula (I) or its acid addition salt according to the present invention can be prepared by using it as an active ingredient and mixing it with various known pharmacologically acceptable solid or liquid carriers. It can be prepared in the form of an antibacterial composition by a method.

Therefore, according to the second invention, there is provided an orally administered antibacterial composition containing as an active ingredient the cephem compound of general formula (I) or a pharmacologically acceptable acid addition salt thereof according to the first invention. provided.

The compound of the present invention of the general formula (I) contained as an active ingredient in the second antibacterial agent of the present invention has excellent oral absorbability and antibacterial activity, so it is suitable as an orally administered bacterial infection treatment agent. The useful dosage of the compound of the present invention depends on age, body weight,
It varies depending on the symptoms, etc., but it is usually 100% per day for adults.
2 to 2 g can be administered once or in divided doses.

-An antibacterial agent containing the compound of the present invention represented by formula (1) or its acid addition salt as an active ingredient may be formulated with an appropriate liquid carrier or solid carrier, similar to conventionally known cephalosporins. According to the usual oral administration formulation, oral preparations such as capsules, powders, granules, tablets, etc., or rectal administration formulations, oily suppositories, etc. according to the intestinal administration formulation.
It is prepared in various dosage forms such as water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders,
It can be prepared by conventional methods by adding wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, etc. can.

Next, a method for preparing the above-mentioned compound of general formula (n) used as a starting compound in the production of the compound of general formula (1) according to the present invention will be explained.

- For the production of the starting compound of formula (n), first, 3-isoxane is introduced so as to be bonded to the 3-position of the cephem ring with a carbon-carbon bond to form a structure of a ring assembly heterocyclic system. It is convenient to prepare 7-protected amino-3-isoxazolidinyl-3-cephem-4-carboxylic acid compounds having a zolidinyl group. For this purpose, - formula (IV) [wherein R' means a common conventional carboxyl protecting group, for example, an ester-forming group that is easily eliminated by hydrolysis such as 4-methoxybenzyl group, and Rb means a common conventional carboxyl protecting group, 3-vinylcephem derivatives [Journal of Antibiotyphoid Fever], Vol. 38, 1738
- p. 1751, (1985)] and a bipolar nitrone derivative represented by the formula (V) with the formation of a ring, the general formula (VI) [in the formula,
-Rb, Hb and * have the same meanings as above] is produced. This addition reaction is preferably carried out near neutrality, and is preferably carried out in a polar organic solvent such as methanol, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tetrahydrofuran, water, or a mixed solution thereof. Usually, it is suitable to carry out at a temperature of room temperature to 100°C. Further, the time required for this reaction is usually 3 to 6 hours (see Reference Example 1(a) below).

The compound of general formula (Vl) obtained by this addition reaction is obtained as a mixture (stereohybrid) of one stereochemistry at the carbon atom indicated by this symbol and the substrate, but this mixture is By dissolving the soluble and insoluble products in different organic solvents, such as dichloromethane, each single stereoisomeric compound can be isolated, stereochemically pure at the carbon atom of this symbol. . Furthermore, 1-body and 1-body can be separated by silica gel column chromatography (see Reference Example 1(a) below).

In addition, the nitrone derivative of the above formula (V) has the following formula H,C
It can be prepared by reacting the hydrochloride of N-methylhydroxyamine represented by -NH-OH with formaldehyde in dioxane (see Reference Example 1(a) below).

In the compound of formula (VI), Rh is a general protecting group for an amino group, and this amino protecting group (Rh) can be removed from the amino group at the 7-position by a deprotection method commonly used for cephalosporin compounds. By this, the cephem compound represented by the general formula (■) can be obtained (see Reference Example 1(b) below), and then the cephem compound 7 of the general formula (■) can be obtained. The amino group in position is defined by the general formula (
(2) A compound represented by [wherein R1 means the same hydrogen or alkyl group as the group R1 in the compound of formula (I) above, and R' represents a hydrogen atom or an amino protecting group such as a trityl group], or The general formula (
IK) [In the formula, R1, R', R6, and the wooden seal have the same meanings as above] to obtain a compound (Reference Example 2 (described later)).
a) and Reference Example 3).

Finally, by removing the protecting groups R'' and R' from the compound of formula (IX) using known deprotection methods, a novel cephem compound of general formula (II) can be produced ( (See Reference Example 2(a) below).

The compound of general formula (n) obtained as described above can be obtained by reacting this carboxylic acid compound with an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate in an aqueous solution. Metal salts (carboxylates) of compounds of general formula (n) can be formed.

Next, the compounds of the present invention will be specifically explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

The amount of loss (6R,7 phantom-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((S)-2-methyliso Oxazolidine
Preparation of 5-yl]-3-cephemu-4-carboxylic acid pivaloyloxymethyl ester.

(6R, 7 ships)-7-((Z
)-2-(2-aminothiazol-4-yl)-2-(
methoxyimino)acetamide)-3-((S)-2-
65 μm of methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid sodium salt was dissolved in 0.4 raQ of dimethylformamide, and 40 μm of pivaloyloxymethyl iodide was added to the solution at -15°C. The mixture was stirred for 30 minutes to carry out the esterification reaction. After that,
Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 10% aqueous sodium thiosulfate solution, and saturated brine. The solvent was distilled off from the washed solution under reduced pressure, and the resulting residue was purified and isolated by preparative silica gel thin layer chromatography (developing solvent system: chloroform-methanol = 9:1) to obtain the title compound (6fi, 7R)-7-((Z)-2-(2
-7minothiazol-4-yl)-2-(methoxyimino)acetamide) -3-((S)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 5) Obtained.

FABMS: ra/z 583 (MH”) NMR (δ
, CDCl5): 1.23 (pivaloyl)t 2.7
0(NMe)t5.05(H-6), 5.26(Isoxazolidine-5).

5.85 and 5.90 (OCR, O), 6.0 ()
I-7).

Loss of ectopia (6 to 7 shaku) -7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-((R)-2- Methylisoxazolidin-5-yl]-3-cephem=4-carboxylic pivaloyloxymethylester-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-(
(R)-2-methylisoxazolidin-5-yl]-
By reacting and treating 40 μl of 3-cephemu 4-carboxylic acid sodium salt in the same manner as in Example 1, (6,7K)-7-((Z)-2-(2-aminothiazole- 4-yl)-2-(methoxyimino)acetamide)-3-((R)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid
2 wg of pivaloyloxymethyl ester was obtained.

FABMS: mHz 583 (MH”) NMR (δ,
CDCl, ): 1.23 (pivaloyl L 2,73
(NMe).

5.06 (H-6), 5.64 (Isoxazolidine-5).

5.93 (OCR, 0), 5.93 (H-7).

Reference Examples 1 to 4 below illustrate methods for preparing starting compounds of formula (II).

Vinegar (6R,7R)-7-amino-3-[value)-2-methylisoxazolidin-5-yl]-3-cephemu4-
Carvone 4-methoxybenzyl ester and (6R
, 7R) -7-amino-3-((R)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

(a) Known (6R,7R)-7-phenylacetamido-3-vinyl-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 3.72%, sodium acetate 984% and 38% formalin 1.26% 2 was suspended in 75 mfl of dioxane, and a solution of 1.0 g of N-methylhydroxylamine hydrochloride dissolved in 80% ethanol water was gradually added to the suspension.
Heat at ℃ for 3 hours. At this time, formaldehyde and N-
A nitrone derivative was produced by the reaction with methylhydroxylamine, and a further reaction occurred in which this nitrone derivative was added to the vinyl group at the 3-position of the cephem compound.

Insoluble materials were filtered from the reaction solution, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in dichloromethane, washed with an aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Concentrate. The obtained solid residue was dissolved in diethyl ether, the insoluble matter was filtered off from the solution, and the filtrate was concentrated to give (6R,7R)-7-phenylacetamide-3-((S)-2-methyliso 2.0 g of oxazolidin-5-ylgo-3-cephem-4-carboxylic acid 4-methoxybenzyl ester was obtained.The insoluble matter was further removed from chloroform-methanol (96:
4) and silica gel column chromatography (
Purification was performed using a developing solvent chloroform-methanol=96:4) to further obtain 0.5 g of the (desired)-isomer and 0.9 g of the (phantom-isomer).

(b) 1.43 g of phosphorus pentachloride and 20-20 g of dichloromethane
and then add pyridine 544■ to the suspension at 5°C.
was added and stirred for 1 hour. Add step (b) to the obtained reaction solution.
(6R,?R)-7-phenylacetamido-3-((S)-2-methylisoxazolidine-5-
Add 1.2 g of il2-3-cephem-4-carboxylic 4-methoxybenzyl ester, and heat to 1.5 g at 8-10°C.
After cooling the reaction mixture for 6 hours to -35°C, 9.2ml of methanol was added, and the mixture was cooled to -15°C.
The mixture was stirred for 1.5 hours. Ice-cooled 50% saturated salt solution
mm and dichloromethane were added to 50 recommended Q. Through these steps, the aqueous layer was separated from the 6 reaction solution in which the elimination reaction of the phenylacetyl group from the cephem compound was completed, and the aqueous layer was neutralized with an aqueous sodium hydrogen carbonate solution while cooling with water.Then, the obtained aqueous solution was extracted with dichloromethane. did. The dichloromethane extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (
6R,7R)-7-amino-3-[(S)-2-methylisoxazolidin-5-yl2-3-cephem-4
-Carboxylic acid 4-methoxybenzyl ester 811■
I got it.

FABMS: mHz 406 (MH”) NMR (δ
= CDC1a): 2,67 (NMe), 4-71 (
l(-7).

4.89 (H-6), 5.25 (isoxazolidine-5).

(c) When the phenylacetyl group is removed by the same de7-N-acylation method as in the previous section (b), the (R)-isomer obtained in the previous section (a), that is, (6, 7R) -7-phenylacetamido-3-[(R)-2-methylisoxazolidin-5-yl2-cephem-4-carboxylic acid 4-methoxybenzyl ester 398■, (6
240 ml of 4-methoxybenzyl R,7R)-7-amino-3-((R)-2-methylisoxazolidin-5-yl]-3-cephemu 4-carboxylic acid ester were obtained.

FABMS: m, /z 406 (MH”) NMR (
δ-coct, ): 2.67 (NMe), 4.67 (
l(-7).

4.90 (H-6), 5.53 (isoxazolidine-5).

Yutaka 1114 (vomit, 7-7-[惺)-2-(2-aminothiazol-4-yl]-2~(methoxyimino)acetamide)
-3-((S)-2-methylisoxazolidine-5-
Preparation of Irgo 3-cephem-4-carboxylic acid sodium salt (a) (6R,IR)-7- obtained in Reference Example 1(b)
Amino-3-((S)-2-methylisoxazolidin-5-yl)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 810■, known (Z)-2-
Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid 888. and 298 ml of hydroxybenzotriazole were dissolved in 10-dimethylformamide, and the resulting solution was cooled to 5°C. To this solution, 454 ml of dicyclohexylcarbodiimide was added as a condensing agent and reacted at 25 DEG C. for 2 hours to effect 7-N-acylation of the cephem compound. The reaction solution was concentrated under reduced pressure to remove the solvent.

Ethyl acetate was added to the residue to dissolve it, and insoluble materials were filtered from the solution. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a solid. This solid was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: chloroform) to give (6R,7 and)-7-((Z)-2-(methoxyimino)-2-(2-tritylaminothiazole). -4-yl)
1.43 g of acetamido)-3-((dan)-2-methylisoxazolidin-5-yl]-3-cephemu 4-carboxylic acid 4-methoxybenzyl ester was obtained.

(b) (6R,7fi)-7-[ obtained in the previous section (a)
(Z)-2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(
Add 0.15 mQ of anisole and 1.5 mQ of trifluoroacetic acid to 150 μm of (S)-2-methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid 4-methoxybenzyl ester at 5°C and react for a working time. Ta. Elimination reaction of the 4-methoxybenzyl group from the carboxyl group of the cephem compound occurred, and the trityl group of the amino protecting group was partially eliminated. Isopropyl ether was added to this reaction solution and concentrated under reduced pressure. Isopropyl ether was further added to the resulting candy-like residue to obtain a solid. This is 5
When it was dissolved in 0% formic acid and the solution was heated at 50° C. for 1 hour to react, the removal of the trityl group of the amino protecting group was completed. Insoluble materials were filtered off from the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting candy-like residue was powdered with chloroform.

After suspending this powder in water and adjusting the pH to 7 with an aqueous sodium hydrogen carbonate solution, Amberlite XAD-2
When purified by resin column chromatography,
sii (7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)
42 ml of sodium salt of acetamido)-3-[(S)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid was obtained.

FABMS: ta/z 491 (MH”) NMR (
δ, D, 0): 2.74 and 2.84 (NMe)
, 5.03 and 5.30 (isoxazolidine-5
).

5.26 (H-6), 5.82 and 5.83 (H-
7).

(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((R)-2-methylisoxazolidine -5-yl]-3-cephem=4-carboxylic acid sodium salt production (6R,7R)-7-amino-3-[(R)-2-methylisoxazolidine obtained in Reference Example 1(c) -5
Reference Example 2 (a ), by the step of 7-N-acylation reaction of cephem compounds,
(6, 7R)-7-((1)=2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-((R)-2-methylisoxazolidine- 382 ml of 4-methoxybenzyl 5-yl]-3-cephemu-4-carboxylic acid ester was obtained.

This product was subjected to a deprotection reaction in the same manner as in Reference Example 2(b), and further including sodium hydrogen carbonate treatment.
When processed in the same manner as the latter step of (b).

Titled (6 shaku, 7K)-7-((Meng)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-((R)-2-methylisoxazolidine 148 ml of the sodium salt of -5-yl]-3-cephemu-4-carboxylic acid was obtained.

FABMS: mHz 491 (MH”) NMR (δ
, D, O): 2.73 and 2.80 (NNe),
5.0 and 5.31 (isoxazolidine-5).

5.24 and 5.25 (H-6).

5.81 (H-7).

3-(S)-2-methylisoxazolidine −
Preparation of 5-yl]-3-cephemu 4-carboxylic acid sodium salt.

(6R,7R)-7-amino-3-((S)-2-methylisoxazolidine-5- obtained in Reference Example 1(b)
Reference Example 2 was prepared from 487 mg of 4-methoxybenzyl]-3-cephemu-4-carboxylic acid 4-methoxybenzyl ester and 805 μg of the known (Z)-2-(tritylaminothiazol-4-yl)-2-(trityloxyimino)acetic acid. (6R,7R)-3-[(S)-2-methylisoxazolidin-5-yl]-7-(( Z)-2-
(2-tritylaminothiazol-4-yl)-2-(
Trityloxyimino)acetamide]-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 92
I got 6■. 150 μ of this product was subjected to the deprotection reaction in the same manner as in Reference Example 2(b), and further treated in the same manner including sodium bicarbonate treatment, resulting in the title (6, Sen)-7.
-[(Z)-2-(2-aminothiazol-4-yl)
=2-(hydroxyimino)acetamide)-3-((
S)-2-methylisoxazolidine-5-ylgo 3
45 µm of the sodium salt of -cephem-4-carboxylic acid was obtained.

FABMS: mHz 477 (MH”) NMR (δ
, D, 0): 2.79 and 2.89 (NMa),
5.08 and 5.33 (inoxazolidine-5)
.

5.27 (H-6), 5.85 and 5.86 (H-
7).

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 represents a hydrogen atom or a lower alkyl group, and the three-dimensional shape of the carbon atom marked with * Chemistry indicates ¥R¥, ¥S¥, or ¥RS¥, where R^2 is -CHR^3OCOR^
4 groups (wherein R^3 represents a hydrogen atom or a lower alkyl group, and R^4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)] and drugs thereof Physically acceptable acid addition salts. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R^1 represents a hydrogen atom or a lower alkyl group, and the stereochemistry of the carbon atom marked with an * is ¥R¥ , ¥S¥, or ¥RS¥, and R^2 is -CHR^3OCOR^
4 groups (wherein R^3 represents a hydrogen atom or a lower alkyl group, and R^4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)] and drugs thereof An antibacterial agent for oral administration characterized by containing a physically acceptable acid addition salt as an active ingredient.