JPH0347186A - Cephalosporin-based compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X and Y are H or halogen; Z is H, halogen, CH=CH2, CH=CH-CH2, OR<1>, SR<2> (R<1> and R<2> are lower alkyl) or CH2W (W is H or nucleophilic residue)]. EXAMPLE:Sodium 7-[2-(2-aminothizol-4-yl)-2(Z)-2,5-dichloro-3,4- dihydroxybenzyloxyiminoacetamido]-3-(1,2,3-thiadiazol-5-yl)thiomethyl- 3-cephem-4- carboxylate expressed by formula II. USE:An antimicrobial agent. PREPARATION:A compound (reactive derivative) expressed by formula III (R1 is H or carboxyl-protecting group) is reacted with a compound (reactive derivative) expressed by formula IV (R2 is H or amino-protecting group; R3 is H or OH-protecting group).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel cephalosporin compounds having antibacterial activity, pharmaceutically acceptable salts thereof, antibacterial agents containing them, and methods for producing the same.

Problems to be Solved by the Prior Art and the Invention Cephalosporin antibiotics exhibit a wide range of antibacterial activity against Durham-positive and Durham-negative bacteria, and various semi-synthetic cephalosporin compounds are already commercially available, and It is used clinically as a therapeutic agent for sexually transmitted diseases. However, among these compounds, there are only a few therapeutic agents that exhibit antibacterial activity against Pseudomonas aeruginosa and Proteus. Furthermore, many of these compounds are unstable against β-lactamase produced by resistant bacteria, and have drawbacks such as low antibacterial activity against Pseudomonas aeruginosa, which is currently a clinical problem (W, ε).

Buy, “Cephalosporins
and Pencillins.

Chemistry and Biology, E
, ■, edited by Flynn.

^cadeaic Press, New Work,
N, Y,, f972. Chapter 11).

A compound having the formula is known as a substituent at the 7-position of the cephem ring (Japanese Patent Application Laid-Open No. 62-2705
No. 89, see No. 63-99,077).

Means for Solving the Problems The present invention et al.
As a result of extensive research on the structure-activity relationship of the substituents at the positions of the formula (I
The cephalosporin compound shown in The present invention was completed based on the discovery that the compound has low toxicity and is well absorbed.

Therefore, the present invention provides a general formula ([
) [In the formula, X and Y may be the same or different, and each represents a hydrogen atom or a halogen atom, and Z is a hydrogen atom, a halogen atom, CH=CH,, CH=CtoC1+,, OR
', SR''(R' and R1 represent a lower alkyl group) or CH, W (W represents a hydrogen atom or a nucleophilic residue)] and pharmacologically acceptable salts thereof. It is something to do.

The pharmacologically acceptable salts of the compound represented by the formula (R) of the present invention include conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as carunium salts and magnesium salts. Salts, ammonium salts, salts with organic bases, for example organic amine salts such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and amino acid salts such as lysine and arginine.

In the above-mentioned formula (r), the halogen atoms in X and Y include a chlorine atom, a bromine atom, a fluoro atom, and the like. Preferably it is a chlorine atom or a fluoro atom. More preferred is a chlorine atom. X,! 1.
It is preferable that both Y's are a hydrogen atom, a chlorine atom or a fluoro atom, or one of them is a chloro atom or a fluoro atom and the other is a hydrogen atom.

The lower alkyl group in the groups OR' and SR'' means a straight or branched alkyl group containing 1 to 4 M carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, Mention may be made of butyl or isobutyl groups.

The nucleophilic residue in W of the group CHJ includes a halogen atom,
Any 2! an optionally substituted aromatic heterocyclic thio group, a lower alkylthio group, a lower alkoxy group, a primary, secondary or tertiary amino group, or a methylene group containing at least one nitrogen atom and connected via the nitrogen atom. Contains a tow ring group attached to. Examples of the halogen atom include those similar to the halogen atoms in X and Y. The aromatic ring ring in the aromatic ring ring thio group, which may be optionally substituted, is
A 5-membered ring or a 6-membered ring containing at least one heteroatom of a nitrogen atom, a sulfur atom, and an oxygen atom is included. More specifically, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, oxazole, imidazole, pyrazole, oxadiazole, isoxazole, pyridazine, triazine and the like are included. Examples of substituents on these aromatic hydrocarbon rings include lower alkyl groups such as methyl, ethyl, and propyl, halogen atoms such as chloro, bromo, and fluoro, amino groups, and cyano groups. Lower alkylthio groups include methylthio, propylthio, and the like. Lower alkoxy groups include methoxy, ethoxy, propoxy and the like. Tertiary amino groups, which are primary and secondary, include amine groups substituted with 1 to 34 acyl groups such as benzyl, which are lower alkyl groups, such as methylamino, ethylamino, trimethylamino, triethylamino, and methylbenzyl. Contains amino acids.

Examples of the tow ring group containing at least one nitrogen atom and bonding to a methylene group via the nitrogen atom include the nitrogen-containing groups listed above as examples of the aromatic tow ring. These search ring groups may be substituted with lower alkyl groups such as methyl and ethyl, halogen atoms such as chloro, bromine, and fluoro, amino groups, cyano groups, and the like.

Preferred nucleophilic residues are (I,2,3-deadiazol-5-yl)thio, (N-methylpyridin-4-yl)
Examples include thio, (5-methyl-2-tetrazol-2-yl)thio, and the like. Particularly preferred is (I,2,3-thiadiazol-5-yl)thio.

The compound ([) of the present invention can be produced by the method shown below. That is, the following formula ([I) [where 2 is the formula (
Same meaning as in I), R1 represents a hydrogen atom or a protecting group for a carboxyl group. The compound represented by or a reactive derivative thereof at the amino group or a salt thereof has the following formula ([) [wherein X and Y have the same meaning as in formula (I), R8
represents a hydrogen atom or an amino group-protecting group, and R5 represents a hydrogen atom or a hydroxyl group-protecting group. ] Compounds represented by these can be produced by reacting reactive derivatives or salts thereof at the carboxyl group.

Suitable examples of reactive derivatives at the amino group of compound (II) include Schiff base-type iminos produced by the reaction of compound (1) with carbonyl compounds such as aldehydes, ketones, etc., or their tautomers. Certain enamine-type isomers: compound (fI) and bis(trimethylsilyl)
Silyl derivatives formed with acetamide etc.: Compounds (
Examples include derivatives produced by the reaction of n) with phosphorus trichloride or phosgene.

Suitable salts of compounds (■) and (DI) include salts with eic acid (for example, acetic acid, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or salts with inorganic acids ( Acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; alkali metal salts or alkaline earth metal salts (e.g. sodium, potassium, calcium, magnesium salts, etc.); Examples include metal salts, ammonium salts, and organic amine salts (eg, triethylamine salt, dicyclohexylamine salt, etc.).

Suitable examples of reactive derivatives at the carboxyl group of compound (III) include acid halides, acid azides, acid anhydrides, active amides, active esters, and more specifically acid chlorides, acid bromides, etc. Substituted phosphoric acids (e.g. dialkyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfite, thiosulfate, sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, etc.), fatty carboxylic acids (e.g. mixed acid anhydrides with acids such as pivalic acid, valeric acid, isovaleric acid, 2-ethyl acetic acid, trichloroacetic acid, etc.) or aromatic carboxylic acids (such as benzoic acid); with imidazole, dimethylpyrazole, triazole or tetrazole; active amide: or active ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(
CHs)tN=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 24
- dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, menulfenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester,
pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-hydroxy compounds (e.g., N,N-tumethylhydroxyamine, 1-hydroquine-2-(IH)-pyridone, N-hydroxyphthalimide, Examples include esters with N-hydroxyphthalimide, l-hydroxy-6-chloro-IH-benzotriazole, etc.). These reactive derivatives are the reactant compounds to be used (
It is selected as appropriate depending on the type of [).

The reaction between compound (n) and ([[I) is usually carried out using water,
Acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N
, N-dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction. These solvents may be used in combination with water.

In this reaction, when compound ([II) is used in the form of a free acid or a salt, it is preferably carried out in the presence of a condensing agent. Examples of the condensing agent include N,N'-nocyclohexylcarbodiimide, N-chlorohexyl-No-morpholinoethylcarbodiimide, N-cyclohexyl-N'
-(4-diethylaminocyclohexyl)carbodiimide, N, N'-noethylcarbodiimide, N,
N'-diisopropylcarbodiimide, N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide, N.

No-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene, N-cyclohexylimine, ethoxyacetylene, ■-alkoxy■-chloroethylene, trialkyl phosphite, ethyl polyphosphate, polyphosphorus Isopropyl acid, phosphorus oxychloride, phosphorus acid chloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)-isoxa Zolium hydroxide inner salt, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-11(-benzotriazole, so-called Wilsmeier obtained by reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.) Examples include reagents.

This reaction may also be carried out in the presence of an inorganic or aorganic base, examples of such bases include alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal carbonates. (e.g. calcium carbonate), tri(lower)alkylamines (e.g. triethylamine, trimethylamine, etc.), pyridine, N-(lower)-alkylmorpholine, N,N-di(
(lower)-alkylbenzylamine and the like.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Or general formula (■°) [wherein A is an acetoxy group or a halogen atom, X, Y
lR, , R1 and R1 have the same meanings as above. ] It is also possible to produce the compound of general formula (I) by reacting a nucleophilic compound with the compound represented by formula (I).

Examples of the nucleophilic compound here include tow ring thiols containing S and LO which may have substituents, lower alkylthiols or lower alkanols, tertiary amines such as primary and secondary amines, and a tow ring compound containing a nitrogen atom.

The products obtained by these methods are the target compound (I) of the present invention, or are protected forms of the amino group, carboxyl group, and phenolic hydroxyl group of the target compound (I). Therefore, in the case of a protected form, the protecting group is removed according to a conventional method, if necessary. The method for removing the carboxyl group-protecting group and the amino group-protecting group should be appropriately selected depending on the number of protecting groups to be removed. Methods for removing the protecting group from the amino group include hydrolysis and reduction. Furthermore, for compounds in which the protecting group for the amino group is an acyl group, conventional methods such as a method of reacting with an iminohalogenating agent, then an iminoetherifying agent, and then hydrolyzing as necessary can be applied. For hydrolysis, filtration using an acid is one of the common methods, and is applied, for example, to eliminate alkoxycarbonyl groups, formyl groups, trityl groups, etc. Further, as the filter acid used, formic acid, trifluoroacetic acid, hydrochloric acid, etc. are appropriately selected depending on the type of protecting group for the amino group. The reaction can be carried out either in the absence of a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. On the other hand, any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of the protecting group of the carboxyl group. Hydrolysis using an acid is one of the common methods and is applied, for example, to eliminate silyl groups, p-methoxybenzyl groups, diphenylmethyl groups, etc. Any commonly used methods such as hydrolysis and reduction can also be applied to the elimination reaction of the protecting group of the phenolic hydroxyl group. Hydrolysis using acids or bases is one of the common methods.
For example, an acid is used to eliminate a p-methoxybenzyl group or a diphenylmethyl group, and a base is used to eliminate an acyl group such as an acetyl group or a benzoyl group.

The compound of general formula (I) obtained as described above is separated and purified from the reaction mixture by a conventional method.

For example, Amberlite XAD-2 (manufactured by Rohm and Haasha), Diaion IP-20 or Sepabeads 5.
This can be achieved by appropriately combining purification with adsorbent resin such as P207 (manufactured by Mitsubishi Kasei (Aji)), precipitation method, crystallization method, etc.

Incidentally, when the compound of formula () is obtained in the form of a free acid, it can be converted into a corresponding salt by a conventional method.

Antibacterial agents containing the compound represented by general formula (I) or a salt thereof as an active ingredient are mainly injections such as intravenous and intramuscular injections, oral preparations such as capsules, tablets, and powders, rectal preparations, and oils and fats. It is used in various dosage forms such as sex suppositories and water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, and preservatives. It can be manufactured by a conventional method using a flavoring agent, a soothing agent, etc.

Dosage should be determined by considering symptoms, age, gender, administration route, etc.
The decision shall be made as appropriate depending on the circumstances of each side. In the case of parenteral administration, the usual dose for adults is 25G-30001119 per day, which is divided into t-4 doses per day.

Good luck! The object compound (I) of the present invention or its salts is a new compound and exhibits high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms, including Durham-positive and -negative bacteria. In order to demonstrate the usefulness of the target compound (I), the compound (I) of this invention
Table 1 shows the antibacterial activity measured by the agar selection method.

[Examples] The present invention will be further explained in detail in the following Examples, but these do not limit the present invention, and various changes and modifications can be made without departing from the scope of the present invention. Needless to say.

Note that the NMR data in the examples are 90M unless otherwise specified.
Hz, and in the case of heavy water, the peak of water is δ614
．． The δ value is shown when it is set to 82, and in the case of pond heavy solvent,
The δ value is shown based on TMS.

Reference Example 1 i) Synthesis of 2,5-dichloro-3,4-dihydroxybenzoic acid 3,4-dihydroquine benzoic acid (protocatechuic acid)
50g, sulfuryl chloride lG5.19 to acetic acid 20g
Add to 0xQ and stir at 50°C for 10 hours. After the reaction is completed, the solution is cooled and crystallized to obtain blocked crystals.

This is recrystallized from ethyl acetate and n-hexane to obtain the title compound 359.

mp 230°C 1i) Synthesis of 2.5-dichloro-3,4-di-p-methoxybennoloxybenzoic acid p-methoxybenzyl ester 2.5-fuchloro-3,4-dihydroquine bene, folic acid 1
09 is dissolved in dimethylformamide (DMF) 50zQ. Add p-methoxybenzyl chloride 289 and potassium carbonate 339, and stir toqM at 70 to 80°C. After the reaction is completed, ethyl acetate 2003112 is added, insoluble materials are removed, and the solvent and DMF are distilled off from the filtrate under reduced pressure.

Add ethyl acetate and brine to the residue, and separate the evening layer.

After washing with water, it is dried over anhydrous Mg5Oa, and the solvent is distilled off under reduced pressure. The residue was transferred to a silica gel column (Wako Gel C-200, 70
09, developing solvent (ethyl benzenediacetate (20:l))
Purification to give the title compound 189.

1ii) Synthesis of 2,5-dichloro-3,4-di-p-methoxybenzyloxybenzyl alcohol LiAIH,
2,79 was suspended in 100×Q of anhydrous tetrahydrofuran and cooled with water. To this, add 2,5-dichloro-3,4-no-p-methoxybenzyloxy, p-methoxybenzyl ester 109 in anhydrous tetrahydrofuran LOR.
Add the solution dissolved in Q dropwise. Stir at the post-drop temperature for 6 hours. After the reaction is complete, ethyl acetate *ORQ is added and stirred for 30 minutes, and the pH is adjusted to 2.0 with 20% citric acid under water cooling. Insoluble materials (on alumina) are removed, and the r liquid is poured into ethyl acetate 30ON+2 and washed with water. After drying with anhydrous Mg5O4, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (Wako Gel C-2001009, developing solvent: benzene:
Purification with ethyl acetate (20:1) gives 7 g of the title compound.

NMR, (CDCI23.6 value ppm) 3.85 (
6H, s ), 4.55 (2H, b s ).

4.70 (2H, bs), 5.0G (2H, s).

6.85-6.90 (4H, d).

7.20-7.35 (5H, m) iv) 2-(2-)ditylaminothiazol-4-yl)-2(Z)-(2,5-dichloro-3,4-di-p
-Methoxybenzyloxybenzyloxyimino) Synthesis of allyl acetate 2. 5-Dichloro-3,4-di-p-methoxybenzyloxybenzyl alcohol 29 was mixed with methylene chloride 20z&
and cooled to -10°C. 2,6-lutidine 57
3x9 was added, and methylene chloride 5112 containing thionyl chloride 632z9 was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 1 hour after the dropwise addition. After the reaction is completed, wash with water and remove anhydrous Mg5O*
Dry with. The solvent is distilled off under reduced pressure. Apart from this, 2-
(2-tritylaminothiazol-4-yl)-2(
Z)-hydroxyimisoacetic acid allyl ester 29 to D
Dissolve in M F IQi (7), add K, CO319 and the reaction product obtained above, and stir at room temperature for 20 hours. After the reaction is complete, pour into ethyl acetate (m2) and wash with water. Dry over anhydrous Mg5Oa. Thereafter, the solvent is distilled off, and the residue is purified by silica gel chromatography (Wako Gel C-200309, developing solvent: benzene:ethyl acetate = 20:1) to obtain 3.2 g of the title compound.

[R (Nugijir) 3300-3200.1720c
m-'NMR (CDC1, δ value ppm) 3.11
(3H, s), 3.81 (3H, s).

5.0 (2H, s), 5.05 (2H, s).

5.1 (2H, s), 5.8 (2H, d).

6.1 (lH, m), 6.7-6.9 (7H,
m) 7.3(I9H, m) V) 2- (2-) dithylaminothiazol-4-yl)-2(Z)-(2,5-dichloro-3,4-di-p-
Synthesis of methoxybenzyloxybenzyloxyimino)acetic acid 2-(2-tritylaminothiazol-4-yl)-2
(Z)-(2,5-di-p-methquinbenzyloxybenzyloxyimino)acetic acid allyl ester 90G+11
9 was dissolved in 20 g of methylene chloride and cooled with water. 2-
Sodium ethylhexanoate teaiy and tetrakistriphenylphosphine-palladium complex compound 50R9
and stirred at the same temperature for 1 hour. After the reaction is complete, cool with water.
Adjust H to 2.0 and wash with water. Dry over anhydrous Mg5O+ and evaporate the solvent under reduced pressure to obtain the title compound 620x9.

NMR (CDC1*, δ value pps) 3.75 (
3H,s), 3.80(3H,s).

5.0 (2H, s), 5.05 (2H, s).

5.06.5.10 (2H, ABq, J=12Hz).

6.75-6.90 (7H, m), 7.25-7.3
5(I9H, m) Reference Example 2 i) 2-(2-tritylaminothiazol-4-yl)
Synthesis of -2(Z) -(3,4-di-p-methquinbenoloxybenzyloxyimino)acetic acid allyl ester 2- (2-tritylaminothiazol-4-yl)-
2(Z)-Hydroxyiminoacetic acid allyl ester 410
Dissolve xg in DMF5xI2 and cool with water. Add 201 mg of calcium carbonate, further add 500 m9 of 3,4-di-p-methoxybenzyloxybenzyl chloride,
Stir at room temperature for 20 hours. After the reaction is complete, add ethyl acetate 6Ox
Pour into Q and rinse with water. It was dried over anhydrous MgSO4, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (Wako Gel C-20020y, developing solvent benzene: ethyl acetate=
20:1) to obtain 450 mg of the title compound.

IR (Nugizil) 1720cm-' NMR (CDCIs, δ value ppa+) 3.75 (3H
, s), 3.80 (3H, s).

4.95 (2H, s), 5.00 (2H, s).

5.05 (2H, bs), 5.80 (2H, b, d).

8.00 (IH, m), 6.70-6.95 (
9H, m).

7.30-7.50((9H)m) ii) 2-(2-)Ritylaminothiazol-4-yl)-2(Z)-3,4-di-p-methoxybenzyloxybenzyloxyiminoacetic acid Synthesis of 2-(2-tritylaminothiazol-4-yl)-2(Z)-3,4-
Di-p-methoxybenzyloxybenzyloxyiminoacetic acid allyl ester 78019 in methylene chloride 20xQ
Dissolve in water and cool in water. Sodium 2-ethylhexanoate 190JI9 and tetrakistriphenylphosphine-
Palladium complex compound 501t9 (Pd(P-Phs)4
) and stirred at the same temperature for 1 hour.

After the reaction is complete, pour into water and adjust the pH to 2.0.

The organic layer is separated, washed with water, dried over anhydrous Mg5Oi, and the solvent is distilled off under reduced pressure. The residue is washed with isopropyl ether and dried to give the title compound 610xy.

IR (methanol) 1600cm” NMR (CDCIs, δ value, ppm) 3.75 (9H, s), 3.80 (3H, s).

4.95 (2H, s), 5.00 (2H, s).

5.06. 5.10 (2H, AB q J =
(2Hz).

6.75-8.90 (9H, m).

7.25-7.35 (9H, m) Reference Example 3 1) Synthesis of 5-chloro-3,4-dihydroxybenzoic acid methyl ester 5-chloro-3,4-dihydroxybenzoic acid 59 was dissolved in anhydrous methanol 40'xQ and cooled to -20 to -10°C. Saturate with dry hydrochloric acid gas at the same temperature and seal for 20 minutes.
Leave at room temperature for an hour. A small amount of benzene was added to the reaction solution, and the reaction solvent was concentrated to about ⅓ volume and cooled with water. The precipitated crystals were collected and washed with a mixture of n-hexane and methanol.
Obtain the title crystal. Further, the mother liquor is treated in the same manner to obtain a second crystal. Total yield 4.99 (92%), mp202-20
3°C (methanol).

1i) Synthesis of 5-chloro-3,4-di-p-methoxybenzyloxybenzoic acid methyl ester (D i )
Dissolve 4.489 of 5-chloro-3,4-dihydroxybenzoic acid methyl ester obtained in DMF 16i12, add 7 g of potassium carbonate, and dropwise add 9.59 of p-methoxybenzoic acid chloride at room temperature. , and stirred for 20 hours.

After the reaction was completed, 30 ml of ethyl acetate was added to remove insoluble materials. Add 30xQ of ethyl acetate and 20xQ of water to the filtrate, and adjust the pH to 7.3 with 7% sodium bicarbonate water while stirring under water cooling.
Adjusted to. The organic layer was separated, the aqueous layer was extracted several times with ethyl acetate, the organic layers were collected, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was diluted with ethyl acetate-n-
It was crystallized from a mixture of hexane. 8.959 (91%) of the title compound was obtained as colorless crystals. m p 122-12
3°C (methanol).

1ii) Synthesis of 5-chloro-(3,4-di-p-methoxybenzyloxy)benzyl alcohol The methyl ester compound 6.429 obtained in ii) above was dissolved in 401 (!) of tetrahydrofuran (THF') and cooled with water. I did.LiAl
Add H4t and 4y little by little at the same temperature, and after adding
Stirred at 5°C for 1.5-2 hours. After the reaction was completed, a small amount of ethyl acetate was carefully added dropwise to inactivate excess LiAIH. Further, 50xQ of ethyl acetate was added, and a water-cooled aqueous solution 50J112 containing 59% of tartaric acid was added, and the saline was saturated with stirring. The organic layer was separated, and the aqueous layer was extracted several times with ethyl acetate. The organic layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate-benzene) to obtain 5.589 (94%) of the title compound as a powder. mp 107℃.

1v) Synthesis of 2-(2-tritylaminothiazol-4-yl)-2(Z)-(5-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid allyl ester M F 0 Methylene chloride 40txQ containing .55g
The solution was cooled to -15°C, and a methylene chloride solution containing 0.659% of trichloromethylchloroformate was added.
was dripped. After dropping, gradually raise the temperature to 20-30℃ for 30 minutes.
After stirring for several minutes, the reaction solution was further cooled to ~20°C. Add 5-chloro-3,4-di-p obtained in iii) above to this solution.
-methoxybenzyloxybenzyl alcohol 2.65
9 was added, and the mixture was stirred at -20 to -1O<0>C for 40 minutes. The reaction solution was added to ice water 2OxQ, and the solution was stirred and analyzed. The aqueous layer was extracted several times with methylene chloride, and the organic layers were collected, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure.

The residue was dissolved in a mixture of DMF4j112 and DMSO6ZQ, and 2-(2-tritylaminothiazol-4-yl)
-2-hydroxyiminoacetic acid allyl ester (mp18
7-189°C) and potassium carbonate (1.49°C) were added, and the mixture was stirred at room temperature for 20 hours. After the reaction was completed, 30 ml of ethyl acetate was added to remove insoluble materials. Add 30 mQ of ethyl acetate and 20 ml of water to the filtrate, and add 7% ethyl acetate while stirring under water cooling.
The pH was adjusted to 7.3 with sodium bicarbonate water. The organic layer was separated, the aqueous layer was extracted several times with ethyl acetate, the organic layers were collected, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate-benzene) to obtain the title compound 4.1.
69 (74%) was obtained as a powder.

! ') Synthesis of 2-(2-tritylaminothiazol-4-yl)-2(Z)-(5-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid obtained in iv) above. 2-(2-)cutylaminothiazol-4-yl)-2(Z)-(5-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)
3 g of allyl acetate was dissolved in 20 ml of methylene chloride. Add 1.0% potassium 2-ethylhexanoate to this solution.
Add a solution of 59 dissolved in ethyl acetate 8112, add N,
Stir in an air stream and add triphenylphosphine 90M
9 and tetrakistriphenylphosphine-palladium complex 50R9 were added. After stirring at room temperature for 3 hours, crystals precipitated. Add isopropyl ether 503112,
After further stirring for 1 hour, the mixture was cooled with water. The crystals were collected and washed with a mixture of ethyl acetate and isopropyl ether to obtain the potassium salt of the title compound. The resulting salt was dissolved in methylene chloride 30x
It was added to a mixed solution of i2 and water 10*12 times, and the pH was adjusted to 2.5 with citric acid while stirring under water cooling.

The organic layer was separated, the aqueous layer was extracted several times with ethyl acetate, the organic layers were collected, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was crystallized from n-hexane. The title compound 2.29 (77%) was obtained as colorless crystals. mp
122-126°C.

(Left below) Example! A, 7-1:2~(2-tritylaminothiazole-4
-yl) -2(Z)-(2,5-dichloro-3,4-
Synthesis of p-methoxybenzyl di-p-methoxybenzyloxybenzyloxyimino)-3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid ester C! [In the formula, PMB represents a p-methoxybenzyl group, Ph and C represent a trityl group] 2-(2-tritylaminothiazol-4-yl)-2
(Z)-(2,5-dichloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid 8603
450 u of 19 and 7-amino-3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p~methoxybenzyl ester are dissolved in 20zQ of methylene chloride and cooled to -20°C. . Pyridine 3
20ml of methylene chloride was added thereto, and methylene chloride 511e containing phosphorus oxychloride 22Qzy was added dropwise over about 5 to 10 minutes. After the addition, the reaction solution is stirred at 0 to 5°C for 1 hour.

After the reaction was completed, the reaction solution was poured into ice water and diluted with 7% NaHCOs.
Adjust pH to 7.0 with water. Stir at 5°C for 30 minutes,
Wash the organic layer with water. Dry over anhydrous Mg5Oa and remove the solvent under reduced pressure. The residue was transferred to a silica gel column (Wako Gel C-
200309, developing solvent, benzene:ethyl acetate lO:
1) to obtain 150 mg of the title compound.

IR (Nugetar> 3200.1780, 1720
．． 16801620cm-' NMR (CDCS, δ value ppm) 3.30. :(
, 51 (2H, AB q, J = 18Hz).

3.80 (3H,s, 0CRs), 3.82
(6H,s).

3.93.4.13 (2H, ABQ, J=13Hz).

4.95-4.98 (8H, m).

5.18 (LH, d, J=4.8Hz).

5.36 (2H%bI).

5.86 (LH, d, d, J=5Hz and 10H
z).

6.75-7.10 (9H, m).

7.25-7.40 (2LH, m), 8.40 (
IH, s).

8,7-(2-(2-aminothiazol-4-yl)
-2(Z)-2,5-dichloro-3,4-dihydroxybenzyloxyiminoacetamide) -3-(I,2
,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt synthesis 1 7-(2-(2-tritylaminothiazol-4-yl)-2(Z)-2,5- Dichloro-3,4-di-p-
Methoxybenzyloxyiminoacetamide]-3-(
I,2,3-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid p-methoxybenzyl ester 200R9 is dissolved in anisole 0.5xQ and cooled with water. Add 2xQ of trifluoroacetic acid and stir at the same temperature for 1 hour. After the reaction is complete, add isobutyl ether 5 to the reaction solution.
The trifluoroacetate of the title compound precipitated from Of12te7X+ is filtered and dried. The suspension was suspended in 1×Q water and adjusted to pH=7.2 with 7% NaHCO while cooling with water to form a solution. Diaion HP ~ Expanded during 2020xQ, 5%
Elute with aqueous acetone, concentrate the eluent to remove acetone, and lyophilize to give the title compound 40R9.

IR (Nugetar) 3400-3200.1760
．． 16501600cm-' NMR (DMSO-da, 6m ppm) 3.60
(2H,s), 4.40 (2H,s).

4.98 (IH, d, J=5Hz).

5.05 (2H, b, s).

5.56 (IH, d, d, J=5Hz and 1O
Hz) 6.74 (IH, s), 8.88 (LH,
s).

7.20 (2H, b s ), 9.04 (IH, S
).

9.60 (LH, d, J = lGHz) Example 2 A, 7- (2-(2-tritylaminothiazole-4
-yl) -2(Z)-(2-chloro-3,4-zip
-methoxybenzyloxybenzyloxyimino)acetamide) -3-(I,2,3-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid p
-Synthesis of methoxybenzyl ester 2- (2-)Dithylaminothiazol-4-yl)-2(Z)-(2-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid 82511+9 and 7 -Amino-
The product was treated in the same manner as in Example 1 using 3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 450119 to obtain the title compound 680xy.

IR (Nujol) 3200.178G, 1710
．． 168f) 1610cs+-' NMR (CDC15, δfii ppm) 3.2
3,3.46 (2H, ABQ, J=18Hz).

3.79 (3H, s), 3.80 (6H, s).

4.06.4.12 (2H, AB q , J = 14H
z).

4.91 (IH, d, J = 5Hz).

5.12 (4H, m), 5.25 (2H, b s
).

5.81 (IHdd, J-5Hz and 9Hz).

6.74~6.98 (9H, m), 7.25~
7.35 (22H, m).

8.44(IH,s) 8.7- (2-(2-aminothiazol-4-yl)
-2(Z)-(2-chloro-3,4-dihydroxybenzyloxyimino)acetamide] -3-(I,2,
Synthesis of 3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt 7-(2-
(2-tritylaminothiazol-4-yl)-2(Z
)-(2-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetamide) -3-
Treatment in the same manner as in Example I using (I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 150Q gave the title compound 32R9.

IR (Nujol> 34130~3200.178
0.16801610cm-' NMR (DMSO-db, δ value ppm) 3.73
(2H, s), 4.41 (2H, s).

4, H (IH, d, J = 5Hz), 5.03
(2H,s).

5.54 (IHd, d, J=4.8Hz and 8
．． 2Hz).

6.70 (LH, s), 6.87 (LH, d, Jx8.
6Hz).

7.17 (2H, b s), 7.30 (IH, d,
J = 8.6Hz).

9.06 (IH,s), 9.55 (LH,d
, J -8,6Hz) Performed PI3 A,7- (2-(2-tritylaminothiazole-4
-yl) -2(Z)-(2,5-dichloro-3,4-
Di-p-methoxybenzyloxybenzyloxyimino)acetamide di-3-chloromethyl-3-cephem-
Synthesis of 4-carboxylic acid p-methoxybenzyl ester 2-(2-)ditylaminothiazol-4-yl)-
2(Z)-2,5-dichloro-3,4-di-p-methquine benzyloxybenzyloxyiminoacetic acid 860zy
, and 7-acyno-3-chloromethyl-3-cephem-
4-Carboxylic acid p-methoxybenzyl ester 370x
The title compound 85 was obtained in the same manner as in Example 1 using
Obtained 0 prisoners and 9 prisoners.

IR (Nuzijiru) 3300.1780,1680
, 1610ca+-'NMR (CDCI, δ value pp
m) 3.36.3.58 (2H, ABq, J=18Hz).

3.79 (3H,s), 3.82 (6H,s
).

4.32.4.53 (2H, ABq, J = 12Hz
).

5.92-5.00 (6H, m).

5.18 (LH, d, J = 4JHz).

5.37 (2H, bs).

5.91 (lH, d , d J =4.8Hz
and 9Hz).

6.75-6.90 (9H, m).

7.30-7.40 (2LH, m).

B, 7-(2-(2-tritylaminothiazole-4
Synthesis of p-methoxybenzyloxybenzyloxyimino)acetamide)-3-(N-methylpyridinio-4-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester, iodide 150 mg of p-methoxybenzyl ester was added to 5xQ of tetrahydrofuran.
Dissolve in water and cool. Sodium iodide 20R9 and N-
Add 20 days of methyl-4-pyridothione, and stir for 4 hours under nitrogen purging and cooling with water. After the reaction is completed, the reaction solution is poured into 50zQ of methylene chloride and washed with water. The mixture is anhydrous Mg5O
*, and the solvent was distilled off under reduced pressure. The residue was washed successively with isopropyl ether and ethyl acetate to obtain the title compound.
Get 50319.

IR (nuzijiru) 1760cm-'C, 7-(2-
(2-aminothiazol-4-yl)-2(Z)-(2
,5-dichloro-3,4-hydroxybenzyloxyimino)acetamido)-3-(N-methylpyridinio-
Synthesis of 4-yl)thiomethyl-3-cephem-4-carboxylic acid 7-[2-(2-tritylaminothiazol-4-yl)-2(Z)-2,5-dichloro obtained in step A above −
3,4-di-p-methoxybenzyloxybenzyloxyiminoacedeamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybe obtained in the above step B? -(2-(2-tritylaminothiazol-4-yl) -2(Z)-(2,5-dichloro-3,4-di-
p-methoxybenzyloxybenzylbenzyloxyimino)acetamide]3-(N-methylpyridinio-4
-yl)thiomethyl-3-cephem-4-carboxylic acid p
-Methoxybenzyl ester iodide salt 150B
was suspended in anisole 0.2112 and cooled with water. Add 2Ra of trifluoroacetic acid and stir at the same temperature for 1 hour. After the reaction is completed, isopropyl ether 50xQ is added to the reaction solution to obtain the trifluoroacetate of the title compound as a powder.

After washing with isopropyl ether, dry. Suspend in 5xQ of water and adjust p)l to 7.2 with 7% NaHCOs to make a solution. Developed in DIAION-HP-2020xQ and eluted with 20% acetone water, concentrated the eluate under reduced pressure to remove acetone, and lyophilized to obtain the title compound 2219.
I got it.

IR (Nujigor) 3300-3200.1760
,1680°1620cm-'NMR' (DMSO-da, δ value pp■)3
．． 73 (2H, b s), 4.10 (3H, s).

4.40, 4.56 (2H, ABq, J=14Hz).

4.95 (IH, b s ), 5.03 (IH, d
, J = 4.8Hz).

5.29 (IHd, d, J=4.8Hz and 9
Hz).

6.63 (IH, s), 6.74 (LH, s).

8.2g, 8.58 (4H, ABq, J = 7Hz)
9.58 (IH, d, J = 9Hz) Example 4 A, 7- (2-(2-tritylaminothiazole-4
-yl) -2(Z)-(2-chloro-3,4-di-p
-Methoxybenzyloxybenzyloxyimino)acetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester synthesis 2- (2-tritylaminothiazol-4-yl)-
2(Z)-(2-chloro-3,4-di p-methoxybenzyloxybenzyloxyimino)acetic acid 82519 and 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 310 mg was treated in the same manner as in Example 1 to obtain the title compound 920m9
I got it.

IR (Nujol) 3300.1770, 1720.1680.1610c
m-'NMR (CDC1, δ value pp gu) 3.25
．． 3.52 (2H, ABq, J=I8Hz).

3.80 (9H, s), 4.40.4.50 (
2H, AB q.

J = 12Hz), 4.93(l H,d, J
=5. Hz).

5.2-5.25 (8H, m), 5.84 (LH
,d,d.

J-5Hz and 9Hz), 6.70-6.
90 (9H, m).

7.25-7.35 (21H, m) Example 5 A, 7- (2-(2-tritylaminothiazole-4
-yl) -2(Z)-(3,4-di-p-methquinbenzyloxybenzyloxyimino)acetamide]-
Synthesis of 3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 2-(2-)dithylaminothiazol-4-yl)-
2(Z)-(3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid 800m? and 440 x g of 7-amino-3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester are dissolved in 20 x methylene chloride (2) at -20°C. Cool, add pyridine 320xy, and add methylene chloride 5 containing phosphorus oxychloride 24019.
Dripping down the mountain pass. The mixture was stirred for 1 hour under water cooling, and after the reaction was completed, the mixture was poured into ice water and the pH was adjusted to 7.0. After washing with water, anhydrous Mg5
Dry over Oa, remove the solvent under reduced pressure, and purify with silica gel chromatography (Wakogel C-200309, developing solvent: benzene-ethyl acetate = 20:l) to obtain the title compound 92.
Get 019.

IR (Nujol) 3300-3200.1760.1720,1680.
1610co+-'NMR (CDC13, δ value ppm
) 3.15, 3.42 (2H, ABq, J = 18
Hz).

3.82 (6H,s), 3.86.4.18 (2
H,AB qJ=14Hz), 4.90(LH,d,J
=5Hz).

5.10 (2H, b s ), 5.05 (2H,
bs).

5.25 (2H, b s ), 5.85 (LH,
d, d.

J = 5Hz and 9Hz), 6.78-7.
05 (9H, m).

7.30-7.45 (I9H, m), 8.40
(IH,s)8,7-(2-(2-aminothiazol-4-yl)-'2(Z)-(3,4-dihydroxybenzyloximino)acetamide)-3-(I
,2,3-thiadiazol-5-yl)thiomethyl-3
Synthesis of -cephem-4-carboxylic acid sodium salt 7-C2-(2-)ditylaminothiazol-4-yl)-2(Z)-3,4-di-p- obtained in the above step A
methoxybenzyloxybenzyloxyiminoacetamide) -3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 150t9 with anisole 2xQ
Dissolve in water and cool. Add 2*(l) of trifluoroacetic acid,
Stir at ℃ for 1 hour. Isopropyl ether 50i+i
2 was added, and the trifluoroacetate of the title compound was collected by filtration. Suspended in water Lx (7% NaHCO).

Adjust the pH to 7.2 with water to form a solution. Diaion H
P-20LQzQ is developed and the eluate is eluted with 10% aqueous acetone. The eluate is concentrated under reduced pressure to remove acetone and lyophilized to obtain the title compound 4219.

IR (Nuzir) 3300~3200.1760cm-'N M R (D
! O, δ value ppm) 3.25, 3.65 (2H, ABQ, J=18Hz)
.

4.10.4.35 (2H, AB q , J = 14
Hz).

5.05 (LH, d, J = 5Hz), 5.15
(2H,s).

5.72 (LH, d, J = 5Hz), 5.
85-7.05 (3H, m), 8.70 (IH, s) Example 6? -(2-(2-aminothiazol-4-yl)-2(
Z)-(a,4-dihydroxybenzyloxyimino)
Synthesis of acetamide)-3-(5-methyl-2H-tetrazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt Dyloxyimino)acetic acid 200 shoulders 9 and 7-amino-3
The title compound 18R9 was obtained according to Example 5 from -(5-methyl-2H-tetrazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 12Qxy.

IR (Nujol) 3300-3200.1770
cm-'NMR (D, O, δ value ppm) 2.4 (3H, s), 3.4 (2H, by, s), 5.
0 (IH, d, J = 5Hz), 5.1 (2H
,s).

5.6 (IH, d, J = 5Hz), 5.8
(2H, AB q).

5.9-7.05 (3H, m) 2-(2-)ditylaminothiazol-4-yl)-
2(Z)-(3,4-dimethoxybenzyloxybene Example 7 A,7-(2-(2-tritylaminothiazole-4
-yl) -2-(Z)-(5-chloro-3,4-di-
p-methoxybenzyloxybenzyloxyimino)acetamide] -3-(I,2,3-thiadiazole-
Synthesis of p-methoxybenzyl 5-yl)thiomethyl-3-cephem-4-carboxylic acid ester I 2-(2-tritylaminothiazol-4-yl)-
2(Z)-(5-chloro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid 466R9 and 7-amino-3-(I,2,3-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid p
-Methoxybenzyl ester 260u methylene chloride 3
Pyridine 18
G319 was added, and 2xf2 of a methylene chloride solution containing 100a+y of phosphorus oxychloride was added dropwise at the same temperature.

After stirring at 20°C for 30 minutes and at -10°C for 30 minutes, pour into 20ml of ice water. While stirring, adjust p to 7.3 with 7% sodium bicarbonate water. Wash the methylene chloride layer with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.The residue was purified by column chromatography (Wakogel-C-20
0.509, developing solvent: benzene-ethyl acetate) to obtain the title compound 631Q (91%) as a powder.

MS m/z: t25+3(M+H)”IR
(Nuji-dai-ru): 3400.1786.1719.1
684°1586cm-' NMR (CDC13) δ: 3.25, 3.50 (2
H, ABq, J=L8Hz, 2-H), 3.76
(8H, bs, OcH3xa).

3.95.4.15 (2H, A b q , J = 1
3Hz, 3'-H).

4.85 (IH, d, J = 5 Hz, 6-H)
, 4.95 (2H.

s, OCH,), 5.05-5.20 (6H,
m, OCH*X3), 5.82 (LH, dd, J=5
Hz, J=8 Hz.

7-H), 8.75-7.40 (32H, m, aromatic, NHX2°thiazole 5-H), 8.35 (I
H,s, thiadiazole 4-H).

8.7-(2-(2-aminothiazol-4-yl)
-2-(Z)-(5-chloro-3,4-dihydroxybennol)oxyimino)acetamitoco-3-(I゜2
．． Synthesis of 3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt CI! 7-[2-(2-tritylaminothiazol-4-yl)-2(Z)-(5-chloro-3,4-di-p-methoxybenzyloxyimino)acetamitoco-3-(I
,2,3-thiadiazol-5-yl)thiomethyl-3
-Cephem-4-carboxylic acid p-methoxybenzyl ester 61019 was dissolved in Anisole 2RI2 and cooled with water. Four liters of trifluoroacetic acid was added and stirred at 0 to 5°C for 2 hours. Add 50 iQ of isopropyl ether, centrifuge the precipitate, and wash with isopropyl ether. Dissolved in water 5R12 containing LLOmg of sodium bicarbonate,
Furthermore, the pH was adjusted to 7.5 to 7.8 with 0.1N hydrochloric acid. The obtained solution was diluted with Diaion HP-20,6 (lJF
It was developed on an I2 column, washed with water, and eluted with 20% acetone water. Acetone was removed from the eluate under reduced pressure and the residue was lyophilized to give the sodium salt of the title compound 231x9 (
71%).

IR (Nujol) +3400-3800.1762.
1718°1670cm-' NMR(DMSO-da)δ: 3.25.3.4
0 (2H, A B q.

J -18Hz, 2-H), 4.40 (2H,b
s, 3-H).

4.90 (2H,s,0CR1), 4.95
(IH, d, J = 5HZ, 6-H), 5.5
5 CIHld d , J = 5Hz.

J = 8Hz, 7-)(), 6.65-6.75
(2H, m, aroma).

6.70 (IH, s, thiazole 5-H), 9.05 (
IH.

S, thiadiazole 4-H), 9.50 (IH, d,
J=llIHz, C0NH).

Example 8 7-(2-(2-aminothiazol-°4-yl)-
2(Z)-(2,5-difluoro-3,4-dihydroxybenzyloxyimino)acetamide] -3-(I,
2゜3-thiadiazol-5-yl)thiomethyl-3-
Synthesis Example 1 of Cephem-4-carboxylic acid sodium salt
-A using the same method as 7-(2-(2-tritylaminothiazol-4-yl)-2(Z) to (2,5-difluoro-3,4-di-p-methoxybenzyloxybenzyloxy) imino)acetamide]-3-(I,2,3
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester,
7-amino-3-(L, 2,3-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid p-
Produced from methoxybenzyl ester and 2-(2-)ditylaminothiazol-4-yl)-2(Z)-(2,5-difluoro-3,4-di-p-methoxybenzyloxybenzyloxyiminoacetic acid (Note that the oxyiminoacetic acid is 2,5-difluoro-3-methoxy-4=hydroxybenzaldehyde (J, Org, C
hew 46 (I981), 203) to 2,5-difluoro-3,4-di-p-methoxybenzyloxybenzyl chloride through four steps, and this was converted into 2-(2
-tritylaminothiazol-4-yl)-2(Z)-
It was made by reacting with hydroxyiminoacetic acid allyl ester. ) The above p-methoxybenzyl ester compound was treated in the same manner as in Example 1% Jl-8 to obtain the title compound.

IR (Nujol)::440Q~3200.1760
．． 1650°1600c+s-' NMR(DMSO-d,)δ: 3.6G (2H
, s), 4.40 (2H.

s), 4.98 (lH, d, J=5Hz), 5.05 (
2H, b, s).

5.56 (LH, d, d, J=5Hz and IOHz)
, 6.74 (IH, s), 6.88 (LH, s)
, 7.20 (2H, b, s).

9.04 (IH, s ), 9.60 (IH, d , J
=10Hz).

Example 9? -(2-(2-aminothiazol-4-yl)-2(
Z)-(5-fluoro-3,4-dihydroquinebenzyloxyimino)acetamide] -3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-
Synthesis of 4-carboxylic acid sodium salt By the same method as in Example 1-A, 7-amino-3-(I,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4
-carboxylic acid p-methoxybenzyl ester and 2-(2
-tritylaminothiazol-4-yl)-2(Z)-
(5-fluoro-3,4-di-p-methoxybenzyloxybenzyloxyimino)acetic acid. (The oxyiminoacetic acid is 3-methoxy-4-hydroxy-5-fluorobenzaldehyde (J, Org.

Chew, 51 (I986), 4073). ) The above p-methoxybenzyl ester compound was treated in the same manner as in Example 1-B to obtain the compounds listed below.

IR (nujigor): 3400-3800.176
2.1718°1670co+-'NMR(DMSO-da)δ: 3.25. 3.
40 (2H, ABq, J=18H, 2-H),
4.40 (2H, bs, 3-H), 4.90 (2H.

s, 0CHt), 4.95 (IH, d, J =
5Hz, 6-H).

5.55 (IH, dd, J = 5Hz, 8Hz
, 7-H).

6.85-6.75 (2H, m, aroma), 8.70 (
I1-1, s, thiazole 5-H), 9.05 (LH
, s, thiadiazole 4-)I).

9.50 (LH, d, J=8Hz, CONH).

Next, the minimum inhibitory concentration of the representative compound of this invention against Durum-positive bacteria and Gram-negative bacteria was measured (agar dilution method).
The results are shown in Table 1.

(Margin below)

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X and Y may be the same or different, and each represents a hydrogen atom or a halogen atom. , Z is a hydrogen atom, a halogen atom, CH=CH_2, CH=CH-CH_3,
Cephalosporin compounds represented by OR^1, SR^2 (R^1 and R^2 represent a lower alkyl group) or CH_2W (W represents a hydrogen atom or a nucleophilic residue); and its pharmacologically acceptable salts; 2. An antibacterial agent containing the compound according to claim 1 as an active ingredient.