JPH0215090A - Novel cephem compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is (protected) amino; Z is N or CH; R<2> is organic group; R<3> and R<4> are lower alkyl; R<5> and R<6> are (protected) OH; A is lower alkyl; X is NH or O; Q is N or CH] and a salt thereof. EXAMPLE:7beta-[2-(5-Amino-1,2,4-thiodiazol-3-yl)-2-allyloxyiminoacetam ido]-3-[N,N- dimethyl-N-[2-{(4,5-dihydroxy-2-pyridyl)corboxylamino} ethyl]aminomethyl]-3- cephem-4-carboxylate(sym isomer). USE:An antibiotic active against gram positive bacteria, gram negative bacteria, etc. PREPARATION:A compound (salt) of formula II is reacted with a compound (salt) of formula III preferably is an inactive solvent (e.g., acetone or chloroform).

Description

Detailed Description of the Invention "Industrial Application Field" The cephem compound of the present invention represented by the following general formula (1) and a pharmaceutically acceptable salt thereof have antibacterial activity,
It is useful as a medicine.

1 Conventional technology.

Although many cephem compounds are known, the cephem compound represented by the following general formula (I) of the present invention is not known.

"Problems to be Solved by the Invention" Many cephem compounds that have antibacterial effects and are useful as medicines are known, but this invention was made with the intention of developing even better medicines.

"Means to solve problems" This invention relates to novel cephem compounds and salts thereof.

More specifically, the present invention relates to novel cephem compounds and their salts having antibacterial activity, their production methods, and their raw material compounds.

The target cephem compound is new and has the following general formula (
1,).

(wherein R1 is an amino group or a protected amino group, Z is N or CH.

R2 is an organic group, R and R4 are each a lower alkyl group, R and R6
are each a hydroxy group or a protected hydroxy group, A is a lower alkylene group, X is NH or Ol, and Q is N or CH).

The cephem compound of this invention can be produced by the production method explained in the following reaction formula.

Production method 1 (II) or its salt, or its salt (Ia) or its salt (Ib), or its salt, or its salt, or its salt production method 4 (Ie) or its salt (If ') or a salt thereof (wherein R1, R2, R3, R4, R5, R6A, X,
Q and 2 each have the same meaning as before, Y is an acid residue, R1 is a protected amino group, R2 is a protected carboxy (lower) alkyl group, R6
means a carboxy (lower) alkyl group, and R6 means a protected hydroxy group).

The starting compound (III) is new and can be produced by the production method described in the following reaction formula.

Production method B (IIIa) or a salt thereof (II[b) or a salt thereof (in the formula , R3, R4, R5, R6, R6, A, X and Q each have the same meaning as before).

For compounds (I), (Ia)-(!f) and (II), it is understood that these compounds include syn-isomers, anti-isomers and mixtures thereof.

For example, regarding the target compound (1), the syn isomer means one geometric isomer having a partial structure represented by the following formula (wherein R1, R2 and Z each have the same meaning as before)
Anti-isomer means another geometric isomer having a partial structure represented by the following formula (wherein R1, R2 and Z each have the same meaning as before)
All such geometric isomers and mixtures thereof are included within the scope of this invention.

In this specification, the partial structures of these geometric isomers and mixtures thereof will be shown by the following formulas for convenience.

(In the formula, R1, R2 and Z each have the same meaning as before)
.

Compounds (1), (Ia)-(If), (I[[)
, (■a), (I[[b) and (V), it is understood that these compounds include tautomers. , when the group represented by the following formula of compound (1) means a pyridyl group represented by the formula: (wherein R6 has the same meaning as before), the pyridyl group also has a tautomeric form. and such tautomeric equilibrium can be represented by the formula below.

(A) Both of the above tautomers are included within the scope of this invention. In this specification, compounds containing such tautomeric groups will be designated for convenience by one representation of the pinodyl group of formula (A>).

In the foregoing and following description of this specification, preferred examples and explanations of the various definitions falling within the scope of this specification are set forth in detail below.

"Lower shall mean 1 to 6 carbon atoms, unless otherwise specified.

Suitable "protected amine groups" include amino groups protected with conventional protecting groups such as acylamino groups or al(lower) alkyl groups which may have suitable substituents such as benzyl, trityl, etc. Examples include groups.

Preferred acyl moieties of the acylamino group include
Examples include carbamoyl groups, aliphatic acyl groups, and acyl groups containing aromatic or heterocycles. Suitable examples of the acyl group include lower alkanoyl groups such as formyl, acetyl, propionyl, isobutyl As, valeryl, invaleryl, oxalyl, scunnin, and pivaloyl; for example, methoxycarbonyl, ethoxycarbonyl, propoquine carbonyl, Lower alkoxycarbonyl groups such as inbroboxycarbonyl butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; Lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.: For example, Al, -nesulfonyl groups such as benzenesulfonyl and tosyl; Aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl; Al(lower)alkanoyl groups such as phenylacetyl and phenylpropionyl; For example, benzyl Examples include alkoxycarbonyl groups such as oxycarbonyl and phenethyloxycarbonyl.

The above acyl moieties may have suitable substituents such as halogens such as chlorine, bromine, iodine or fluorine.

Suitable organic groups include, for example, lower alkyl groups such as methinoethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., such as chloromethyl, dichloromethyl, Mono (or di or tri) halo (lower) alkyl groups such as trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc., such as vinyl, 1-propenyl, allyl, 1-methylallyl, 1- or 2- or 3-butenyl, 1- or 2- or 3- or 4-pentenyl, 1- or 2
- or lower alkenyl groups such as 3- or 4- or 5-hexynyl, e.g. ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1- or 2-
or 3-butynyl, 1- or 2- or 3- or 4-pentynyl, 1- or 2- or 3- or 4-
or lower alkynyl groups such as 5-hexynyl, aryl groups such as phenyl, naphthyl, phenyl groups such as hahenzyl, phenethyl, phenylpropyl,
(lower) alkyl groups such as lower)alkyl groups, carboxyne (lower)alkyl groups where the lower alkyl moiety is as exemplified above, and where the lower alkyl moiety is as exemplified above and where the protected carboxy moiety is The following examples include protected carboxy (lower) alkyl groups.

Suitable examples of the "unprotected carboxy moiety" of the "protected carboxy (lower) alkyl group" include esterified carboxy groups.

Suitable examples of the above ester include lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, and hexyl ester. ; For example, lower alkenyl esters such as vinyl esters and allyl esters; For example, lower alkynyl esters such as ethynyl ester and propynyl ester; For example, methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 51-ethoxyethyl ester, etc. lower alkoxyalkyl esters; for example, lower alkylthioalkyl esters such as methylthiomethyl ester, methylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester; for example, 2-iodoethyl ester, 2,2.2-trichloroethyl ester, etc. Mono (or di or tri) halo lower alkyl esters of: e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
and valeryloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-
Lower alkanoyloxy (lower) alkyl esters such as propionyloxyethyl ester - lower alkanesulfonyl (lower) alkyl esters such as mesyl methyl ester, 2-mesylethyl ester; Al (lower) alkyl esters, such as pen Zyl esteno 14-methoxybenzyl ester, 4
- Nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl) mefL ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Phenyl (lower) alkyl esters that may have one or more substituents, such as phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, cumenyl esters, 4-chlorophenyl esters, - Good aryl esters with one or more suitable substituents such as substituted or unsubstituted phenyl esters such as methoxy phenyl esters; lower alkyl thio esters such as methyl thio esters and ethyl thio esters; can be mentioned.

For suitable "lower alkyl groups," those exemplified above may be referred to.

Suitable "lower alkylene groups" include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and the like.

Suitable "protecting groups" for the "protected hydroxy group" include the above-mentioned acyl group, tetrahydropyranyl group, benzyl group, and the like.

Examples of suitable monoacid residues include halogens such as chlorine, bromine, and iodine.

Suitable pharmaceutically acceptable salts of the target compound (I) are commonly used non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, and alkaline metal salts such as chlorine salts and magnesium salts. organic base salts such as formate, acetate, trifluoroacetate, etc. , organic acid salts such as maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., I1m-free salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc., e.g. arginine salt, aspartate,
Examples include salts with amino acids such as glutamate.

Preferred embodiments of compound (I) are as follows.

R1 is an amine group or an acylamino group (more preferably a lower alkanoylamino group), and 2 is N or CI.

R2 is a lower alkyl group, a lower alkenyl group, a carboxy (lower) alkyl group, or a protected carboxy (lower) alkyl group [more preferably an esterified carboxy (lower) alkyl group, most preferably a lower alkyl dicarbonyl group] R3 is a lower alkyl group, R4 is a lower alkyl group, R5 is a hydroxy group or an acyloxy group (more preferably a lower alkanoyloxy group), R6 is a hydroxy group or an acyloxy group (more preferably a lower alkanoyl group) oxy group), A is a lower alkylene group, X is NH or Ol, and Q is N or CM.

The method for producing the object compound of the present invention will be explained in detail below.

Preparation 1 Compound (I) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.

For suitable salts of compounds (U) and (III), refer to those exemplified for compound (I).

This reaction uses acetone, chloroform, acetonitrile,
Methylene chloride, ethylene chloride, formamide, N, N-
The reaction may be carried out in a solvent such as dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, or dimethyl sulfoxide, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

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

Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to an amine protecting group elimination reaction.

For suitable salts of compounds (Ia) and (Ib), refer to those exemplified for compound (1).

This reaction is carried out according to conventional methods such as hydrolysis and reduction.

Hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, trialkyls such as trimethylamine salts and triethylamine salts. Amine, picoline, 1.5-
Diazabicyclo[4,3,0]non-5-ene, 1.4
-Inorganic and organic bases such as diazabicyclo[2,2,2 cooctane, 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.

Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger such as anisole, phenol, etc.

The reaction is usually carried out in water, an alcohol such as methanol or ethanol, a solvent such as methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. It can be carried out. Liquid bases or acids can also be used as solvents.

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

Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Commonly used copper catalysts include reduced copper, Raney copper, Ullmann steel, etc.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. Furthermore, when the above-mentioned acid that can be used for chemical reduction is a liquid, it can also be used as a solvent. Furthermore, suitable solvents for use in catalytic reduction include the above-mentioned solvents and others such as diethyl ether, dioxane, etc. , tetrahydrofuran, alcohols such as methanol, ethanol, etc., or mixtures thereof.

The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

The compound (Id) or a salt thereof can be produced by subjecting the compound (Ic) or a salt thereof to an elimination reaction of the carboxy protecting group.

For suitable salts of compounds (Ic) and (Id), refer to those exemplified for compound (I).

This elimination reaction can be carried out in the same manner as in Production Method 2, and therefore, the explanation of Production Method 2 may be referred to for the reagents used and reaction conditions such as solvent and reaction temperature.

Production method 4 Compound (If) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to an elimination reaction of a hydroxy protecting group.

For suitable salts of compounds (Is) and (If), refer to those exemplified for compound (I>).

This elimination reaction can be carried out in the same manner as when tm=-, and therefore, the explanation of Production Method 2 can be referred to for the reagents used and reaction conditions such as solvent and reaction temperature.

The method for producing the raw material compound of this invention will be explained below.

Production method Δ Compound <I) or a salt thereof can be produced by reacting compound (N) or a salt thereof with compound (V) or a reactive derivative thereof at a carboxy group or a salt thereof.

Suitable reactive derivatives of the carboxy group of compound (V) include acid halides, acid anhydrides, activated amides,
Examples include activated esters.

The reaction is usually carried out in the presence or absence of conventional solvents such as chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, but they may adversely affect the reaction. The reaction can be carried out in any other solvent as long as it does not affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of from cooling to heating.

1 菫迭1 Compound (I[[b) or a salt thereof is the compound (I[[a
) or a salt thereof can be produced by subjecting it to an elimination reaction of the hydroxy protecting group.

The elimination reaction can be carried out in the same manner as in Production Method 2, and therefore, for the reagents to be used and reaction conditions such as solvent and reaction temperature, please refer to the explanation in "Washi J1 Report".

The objective compound (I) and its pharmaceutically acceptable salts are novel, exhibit strong antibacterial activity and inhibit the growth of a wide range of pathogenic bacteria, including plum-positive and plum-negative bacteria;
Useful as an antibacterial agent.

In order to demonstrate the usefulness of the target compound (1), test results regarding MIC (minimum inhibitory concentration) of representative compounds of this invention are shown below.

Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below.

The test bacterial strain was cultured overnight in soy broth, and one platinum loop (108 viable bacteria/l) was added to heart infusion agar (I) containing the test compound at each concentration level.
After inoculating on I agar) and culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was expressed as (/R).

Test compound (1) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-3-[N,N-
Dimethyl-N-(2-(3,4-dihydroxybenzoylokidi)ethyl)ammoniomethylcou 3-cephem-4-carboxylade (syn isomer).

Test result: MIC+1/Who) For treatment, the object compounds of this invention (I> and pharmaceutically acceptable salts thereof) may be prepared in organic or inorganic solid or liquid excipients suitable for oral, parenteral and topical administration. in admixture with a pharmaceutically acceptable carrier such as
It is used in the form of conventional pharmaceutical preparations containing said compounds as active ingredients. Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

If necessary, auxiliary agents, stabilizers, wetting agents, and others such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, Commonly used additives such as olive oil, cocoa butter, ethylene glycol, etc. may also be included.

The dosage of compound (I) varies depending on the patient's age, condition, type of disease, type of compound (1) to be applied, etc.

In general, between 1 g of lff and about 4000 mg or more per day of the compound of interest of this invention may be administered to a patient (with an average single dose of about 50+ ng,
100 mg, 250 mg, 500 mg, or 1000 mg may be administered to treat pathogenic bacterial infections.

The present invention will be explained in more detail below according to the manufacturing method and examples.

Production Example 1 Chloride 3.4-; acetoxybenzoyl (u, 36 g
) in tetrahydrofuran (t2ornQ) solution, 2
-(dimethylamino)ethanol (4 mQ) under stirring
Add at °C. Stirring is continued for 1.5 hours at room temperature.

The precipitate was collected by filtration and mixed with ethyl acetate (1oomQ) and cold water (15
0 mQ ) and the mixture is adjusted to p) 17.0 with saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give N,N-dimethyl-2-(3,4
-diacetoxybenzoyloxy)ethylamine (12
, 5g).

IR (Suji A-1T,)' 1770. 171
5. 1605. 1495 cm-INMR (DM
SO-d6. δ): 2.30 (6H, s), 2
．． 38 (6H.

s), 2.68 (2H, tJ=6Hz), 4.3
0 (2H, t.

J=6Hz), 7.40-7.68 (IH), 7
．． 7-8.08 To a solution of IL-based 3.4-diacetoxybenzoyl chloride (10 g) in dichloromethane (200111Q) was added N,N-dimethylethylenediamine (6.9 g) in dichloromethane (2H).
20ml1l) il! Solution F was added dropwise at 10° C. over 5 minutes while stirring. After stirring at the same temperature for 15 minutes and at room temperature for 1.5 hours, the reaction mixture was added to brine (100 mQ). The organic layer was separated and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give N,N-dimethyl-2-(3,4
-Diacetoxybenzoylamino)ethylamine (9,
5g).

NMR (DMSO-d6.δ): 2.15 (6H
,s), 2.31 (2H,t.

J=6Hz), 3.24 (2H,t, J=6Hz)
, 6.35 (LH, d.

J=8Hz), 6.98 (LH, d, J=8Hz>
, 7.03 (IH, s) 1 N,N-dimethyl-2-(3,4-diacetoxybenzoylamino)ethylamine (5 g) in water < 32.4 f
To the suspension in fl11), IN aqueous sodium hydroxide solution (32.4 mfi) is added at 10"C with stirring. The mixture is stirred at the same temperature for 50 minutes and at room temperature for 1.5 hours. The reaction mixture is lyophilized and , N,N-dimethyl-2-(3,
4-dihydroxybenzoylamino)ethylamine (6
, 3g).

IR (Streak 1-L): 1770. 1650.
1635. 1580゜1540 cm-1 NMR (D5O-d6.S): 2.20 (6H
7s>, 2.30 (6)1゜s), 2.46 (
2H, d, J=6Hz), 3.33 (2H, d.

J=6Hz), 7.35 (LH,d, J=8Hz
), 7.78 (IH, d.

J=8Hz), 7.75 (IH,s) Production Example 4 2-Methoxycarbonyl-hensyloxypyridine (t2.2g) was added to N,N-dimethylethylenediamine (20.73g) under stirring for 90 minutes.
The resulting reddish-brown solution was added at the same temperature for 15 min.
Stir for minutes and cool to 0°C. Add this to salt water (13
After adding 5 mfl), the mixture is cooled and adjusted to pH 7.8 with 3N hydrochloric acid. After stirring the mixture at O'C for 30 minutes, the precipitate is filtered off, washed with cold brine and dried under vacuum.

The crude product (20.44g) was dissolved in a mixture of isopropyl alcohol (245mA) and water (61ml) for 6 hours.
Dissolve at 0°C and filter off insoluble matter. The filtrate was gradually cooled to 0°C to collect the crystals, washed with cold isopropyl alcohol and diisopropyl ether, and then dissolved in N,N
-dimethyl-2-[(4-hydroxy-5-benzyloxy-2-pyridyl)carbonylaminoconitylamine (10,88 g) is obtained.

mp: 83-86°C IR (Xdia-L>: 1675. 1610.
1555 cm-1BMR (D20.8)'
2.90 (6H9s), 3.33 (2H1t.

J=7Hz>, 3.76 (2H, t, J near Hz)
, 5.06 (2H,s).

7.01 <18. s), 7.42 (5H, rn)
, 7.68 (LH,s) 1 production 1 N,N-dimethyl-2-[(4-hydroxy-5-benzyloxy-2-pyridyl)carbonylaminoconitylamine (10.0 g) in methanol (80 10% palladium-
Carbon (2 g) was added in a nitrogen stream and the mixture was heated under atmospheric pressure for 3
．． Hydrogenate for 5 hours. The palladium-carbon is filtered off, and the filtrate's solvent is distilled off under reduced pressure. The residue was crystallized from methanol, the crystals were collected by filtration and washed with methanol and diisopropyl ether to give N,N-dimethyl-2-[
(4,5-dihydroquine-2-pyridyl)carbonylaminoconitylamine (5,11 g) is obtained.

mp: 256-258℃ IR (Sujoor): 3300. 3180.
3050. 1670. 1605°1565, 15
40 cm"" NMR (D20.l; )' 3.00 (6H9s
), 3-46 (2H1t.

J=7Hz), 3.85 (2H, tJ=7Hz>,
7.06 (IH,s).

7.73 (IH,s)
-pyridyl) carbonylaminoconitylamine (790
Sodium 2-ethylhexanoate (870 mg) was added to a suspension of +++ g) in dimethyl sulfoxide (8111Q).
and then convert this solution into 7β-[2-(5-amino-
1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamide]-3-chloromethyl-3-
Add dropwise to a dimethyl sulfoxide (7 precepts) solution of cephem-4-carboxylic acid trifluoroacetate (syn isomer) (Ig) at room temperature. After stirring for 4 hours, the mixture is triturated with ethyl acetate (200 mM) and the precipitate is collected by filtration. The precipitate was dissolved in water and then adjusted to pH 3 with saturated aqueous sodium bicarbonate solution.
, set to 0. The solution was subjected to column chromatography using a Diaion HP-20J, eluted with a 15% aqueous isopropyl alcohol solution, and both fractions were lyophilized to obtain 7β-[2-(5-amino-1,2,4 -thiadiazol-3-yl)-2-allyloxyiminoacetamidoco-3-[N,N-dimethyl-N-[2-(4,5
-dihydroxy-2-pyridyl)carbonylamino)ethylcoammoniomethylco-3-cephem-4-carboxylade (syn isomer) (515 mg) is obtained.

IR (Streak 9-L): 1770. 1650.
1610. 1520 am-INMR (DMSO
-da, 8): 3.05 (6H, s), 3.2
0-4.15 (6H), 4.65 (2H, d, J=
5Hz>, 4.83-5.48 (2B +2H, m)
, 5.20 (IH, d, J=5Hz), 5.70
(IH, dd, J: 5Hz, 8Hz), 5.80-
6.20 (IH, m).

7.43 (LH, s), 7.93 (IH, s),
8.79 (IH, brs), 9.48 (IH,
d, J = 8Hz) 7β-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carvone N,N-dimethyl-2-(3,4-diacetoxybenzoyloxy)ethylamine (3°4g) was stirred into a solution of acid (syn isomer) (1.5g) in N,N-dimethylformamide (15mIi). The mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into ethyl acetate, and the resulting precipitate was collected by filtration to give 7β-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamide]-3-[N
, N-dimethyl-N-(2-(3,4-diacetoxybenzoyloxy)ethyl)ammoniomethylcoke-cephem-4-carboxilade hydrochloride (syn isomer)
(2.65 g) is obtained.

NMR (DMSO-d6.δ): 1.43 (9H
,s), 2.30 (6H.

s), 3.13 (6H, br s), 3.
43-3.90 <2H, m).

4.35-4.85 (4H), 5.03 (2H
, br s), 5.18 (LH, d, J=5Hz)
, 5.70 (IH, dd, J=5Hz, 8H
z).

7.40 (IH,s), 7.36-8.03 (
3H, m), 8.20 (LH, s), 9.53
(LH, d, J: 8 Hz) East J11 near β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide two 3-chloromethyl-3
-Cephem-4-carphonic acid trifluoroacetate (syn isomer) (1.0 g) in N,N-dimethylformamide (10 mQ) was added N,N-dimethyl-2-(3,
4-dihydroxybenzoylamino)ethylamine (2
, 5 g) was added at 10° C. with stirring, and the mixture was stirred at the same temperature for 3 hours.

The reaction mixture was poured into ethyl acetate, the resulting precipitate was collected by filtration, the resulting powder was added to water (50ml), and the mixture was poured into I
Adjust the pH to 4.5 with N-hydrochloric acid. This solution was subjected to column chromatography using Diaion HP-20, eluted with a 15% isopropyl alcohol aqueous solution, and both fractions were lyophilized and 7β-[2-(5-amino-1
,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]
-3-[N,N-dimethyl-N-(2-(3,4-dihydroxybenzoylamino)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer) (150 mg) is obtained.

IR (Sujimeal): 1770. 1660.
1600. 1510 crn-INMR (D 0
-NaHCO3,f; )' L57 (6H,s)
, 3-13(6)1. brs), 2.85-4.
20 (6H), 5.35 (LH, d.

J=5Hz), 5.83 (LH, d, J=5Hz)
, 6.70-6.98 (LH, m), 7.03-
7.43 (2H, m) 衷厘week 1 The following compound is obtained in the same manner as in Example 1-3.

(1) 7β-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[N,N-dimethyl-N-[2-(4, 5
-dihydroxy-2-pyridyl)carbonylamino)ethylcoammoniomethylco3-cephem-4-carboxylade (syn isomer).

IR (Streak 3-L): 3300. 1770.
1660. 1610 cm-1HMR (D O
+NaHCO3,S): 1.33 (3
)1. t, J=7)1z).

3.13 (68,s), 4.33 (2H,q,J
near Hz), 5.35 (LH, d, J=5Hz),
5.85 (IH, dJ=5Hz), 7.08 (LH
,s), 7.63 (LH,5)(2)7β-[2-
(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-3-[N,N-dimedel-N-[2
-((4,5-dihydroxy-2-pyridyl)carbonylamino)ethyl]ammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Streak 9-L): 3300. 1770.
1680. 1600°1530 am-1 NMR (DzO9S) =1.57 (6H1s), 3
．． 15 (6H1s).

5.35 (1M, d, J=5Hz), 5.87 (
IH, d, J = 5Hz).

7.07 (LH,s), 7.18 (LH,s>(
3) 7β-[2-(2-formamidothiazole-4-
yl)-2-tert-butoxycarbonylmethoxyimino)acetamitoco-3-[N,N-dimethyl-N-(2
-(3,4-dihydroxybenzoylamino)ethyl)
[ammoniomethyl]-3-cephem-4-carboxylade hydrochloride (syn isomer).

NMR (DMSO-d6.δ): 1.40 (9H
,s), 2.85-4.20(6H), 3.13
(6)1. br s), 4.55 (2H, s),
5.20 (LH, d, J: 5) 1z), 5.73 (
LH, dd, J = 5Hz, 8Hz).

7.38 (IH,s), 7.30-7.53 (L
H, m), 7.80-8.06 (2H, m),
8.50 (IH,s), 9.53 (LH
,d.

J=8Hz) (4) 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamitoco-3-[N,N
-dimethyl-N-[2-((4,5-dihydroxy-2
-pyridyl)carbonylamino)ethyl]ammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Sujimeal): 1765. 1660.
1600. 1525 cm-1(5)7β-[2
-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[N,N-tumethyl-N-+
2-(3,4-dihydroxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Sujoor): 1770. 1690.
1660. 1600°1510 am-' (6)7β-[2-(2-aminodeazol-4-yl)-2-tert-butoxycarbonylmethoxyimino)acetamide]-3-[N,N-dimethyl-N- (2-(
3,4-dihydroxybenzoylamino)ethyl)ammoniomethyl]-3-cephem-4-carboxilade dihydrochloride (syn isomer).

NMR (DMSO-da.S): 1.40 (9
H, s), 3.15 (6) 1°br s), 3.
00-3.85 (6H), 4.58 (2H,s)
.

5.35 (LH, d, J=5Hz), 5.86 (
II (, dd, J=5Hz.

8Hz), 6.68-7.20 (3H, m), 7
．． 30 (LH,s).

9.75 (LH, d, J=7Hz) (7)7β-[
2-(2-aminothiazol-4-yl)-2-tert-butoxylponylmethoxyiminoacetamidoco-3
-[N,N-dimethyl-N-+ 2-(3,4-diacetoxybenzoyloxy)ethyl)ammoniomethyl-3-cephem-4-carboxylate dihydrochloride (syn isomer).

NMR (DMSO-da, S)' 1.41 (9
H, s), 2-16-2.36 (6H, m), 3
．． 00-3.33 (6H, br s), 3.
35-4.40 (4H), 4.40-4.85 (2
H, m), 5.35 (LH, d.

5Hz>, 5.83 (IH, dd, J=8Hz,
5) (z), 6.88 (IH, s), 6.88-
7.80 (3H), 9.73 (LH, d.

J=88Z) (8) 7β-[2-(2-aminoguazol-4-yl)-2-carboxymethoxyiminoacetamitoco-3
-[N,N-dimethyl-N-(2-(3,4-dihydroxybenzoylamino)ethyl)ammoniomethyl]-
3-cephem-4-carboxylate (syn isomer).

IR (Stripe 3-L)' 1770. 1600.
1510 am-1(9)7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamitoco-3-[N,N-dimethyl-N-(
2-(3,4-dihydroxybenzoyloxy)ethyl)ammoniomedel]-3-cephem-4-carboxylate (syn isomer).

IR (Stripe 1-R'): 1770. 1700
．． 1660. 1600゜1520 am-' isomer) (
N,N-dimethyl-2-[4,5-dihydroxy-
2-pyridyl)carbonylamino]ethylamine (90
1 mg) and sodium 2-ethylhexanoate (99
7 mg) in dimethyl sulfoxide (20 mQ) is added and the mixture is stirred at room temperature for 20 hours. The mixture was triturated with ethyl acetate (960 mQ), the powder was collected by filtration, washed with ethyl acetate and diisopropyl ether, and dried in vacuo to give 7β-[2-(2-formamidothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
[N,N-dimethyl-N-[2-(4゜5-dihydroxy-2-pyridyl)carbonylamino)ethyl]ammoniomethyl]-3-cephem-4-carboxilade.
The hydrochloride salt (syn isomer) is obtained.

This compound is suspended in methanol (5mM) and concentrated hydrochloric acid (i4mp, ) is added to it. After stirring at room temperature for 3.5 hours, the suspended solution A was poured into ice water (somu) and adjusted to pH 6 with a saturated aqueous solution of sodium bicarbonate. The mixture is concentrated under reduced pressure to recover methanol, and insoluble matter is filtered off. The filtrate is subjected to chromatography using 1 Diaion HP-20J (No. 60) and eluted with a 10% aqueous isopropyl alcohol solution. The eluate was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-
2-methoxyiminoacetamide]-3-[N,N-dimethyl-N-[2-((4,S-*hydroxy-2-pyridyl)carbonylamino)ethyl]ammoniomethylco-3-cephem-4-carboxilade ( Syn isomer) (187 mg) was obtained.

IR (suji a4)' 1765. 1660.
1600. 1525 cm-'NMR (DMSO-
d6. S; ): 3.02 (6)1. br s
), 3.3-3.8 (6H, m), 3.81 (3
H,s), 4.1 and 5.0(2)1. m), 5
．． 10 (IH, d, J=5Hz), 5.60 (1
8, dd.

J=8 and 51(z), 6.68 (LH,s),
7.11 (2H, br s), 7.38 (LH,
s), 7.88 (LH, s).

8.75 (LH, br), 9.44 (IH, d,
J=8Hz) Example 6 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-3chloromethyl-3 −
Cephem-4-carboxylic acid trifluoroacetate (syn isomer) (15 g) in N,N-dimedelformamide (
N,N-dimethyl-2-(3,4-
Diacetoxybenzoyloxy)ethylamine (3g)
is added under stirring at 5° C. and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is poured into diisopropyl ether. The formed precipitate was collected by filtration and 7β-[2-(5-amino-1,
2,4-thiadiazol-3-yl)-2(1-carboxy-1-methylethoximi2))acetamide]-
3-[N,N-dimethyl-N-(2-(3,4-';
Acetoxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxilade hydrochloride (
syn isomer). Add this compound to water (80ml)
and the mixture is adjusted to pH 8.0 with saturated aqueous sodium bicarbonate solution at room temperature under stirring. The mixture was stirred at the same temperature for 2 hours while maintaining the pH at 8.0 with a 10% aqueous solution of sodium hydrogen carbonate.The reaction mixture was diluted to pH 3.0 with IN hydrochloric acid.
0, and subjected to column chromatography using Diaion 1P20J (Shanghai, manufactured by Mitsubishi Chemical Corporation) and eluted with 15% isopropyl alcohol. The fractions were lyophilized to yield 7β-[2-(5amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1
-methylethoxyimino)acetamide]-3-[N,
N-dimethyl-N-(2-(3,4-diacetoxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer) (250 m
g) is obtained.

IR (Streak 1-L): 1770. 1690.
1660. 16001510 cm-1 NMR (DMSO-d6.δ): 1.48 (6H
, s), 3.10 (68°br s), 4.43
-4.80 (2H, m), 5.15 (11(, d
.

J=5Hz), 5.73 (LH, dd, C3Hz,
8Hz>, 6.70-6.93 (LH), 7.
18-7.53 (2H), 8.15 (2) 1゜b
r s), 9.65 (IH, d, J = 8 Hz) Example 7 7β-[2-(2-formamidothiazol-4-yl)-2-tert-butoxylponylmethoxyiminoacetamidoco-3 -[N,N-dimethyl-N-(2-(3
,4-dihydroxybenzoylamino)ethyl)ammoniomethyl]-3-cephem-4-carboxilade.
hydrochloride (syn isomer) (2.8 g) in methanol (25
To the solution, monohydrochloric acid (2,2111ρ) is added under stirring and the mixture is stirred at 30°C for 2 hours. Filter the reaction mixture.

Pour the filtrate into ethyl acetate, collect the resulting precipitate by filtration,
7β-[2-(2-aminothiazol-4-yl)-2
-tert-butoxylponylmethoxyiminoacetamidoco-3-[N,N-dimethyl-N-(2-(3,4-
Dihydroxybenzoylamino)ethyl)ammoniomethylco-3-cephem-4-carboxylade dihydrochloride (syn isomer) (1.5 g) is obtained.

NMR (DMSO-d6-8)' 14o (9H
,s), 3.15 (6H1br s), 3.00
-3.85 (68), 4.58 (2H, s).

5.35 (IH, d, J=5)1z), 5.86
(LH, ddJ=5Hz.

8Hz), 6.68-7.20 (38,m), 7
．． 30 (IH, s).

9.75 (LH, d, J=7Hz) Example 8 The following compound is obtained in the same manner as in Example 7.

1) 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxylponylmethoxyiminoacetamidoco-3-[N,N-dimethyl-N-(2-(3
,4-diacetoxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-lyl poxylate.
Dihydrochloride (syn isomer).

NMR (DMSO-9, S): 1.41 (9H
,s), 2.16-2.36(6H,m), 3.0
0-3.33 (6)1. brs), 3.35-4
．． 40 (48), 4.40-4.85 (2H, m)
, 5.35 (IH, d.

J=5Hz), 5.83 (LH, ddJ=8Hz,
5Hz), 6.88 (11,s), 6.88-7
．． 80 (3H), 9.73 (LH, d.

J:8H2) (2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamide] -3-[N,N-dimethyl-N-[ 2-((
4,5-dihydroxy-2-pyridyl)carbonylaminotyl]-3-cephem-4-carboxilade (syn isomer).

IR (Sujimeal): 1770. 16
50, 1610. 1520 am-' (3)
7β-[2-(5-amino-1.2.4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-3-[N,N-dimethyl-N-( 2-(3.4-Dihydroxyhensyylamino)ethyl)ammoniomethyl]-3-cephem-4-carboxylade (syn isomer).

IR (Stripe 3-L)' 1770. 16
60, 1600. 1510 cm-'(4)
7β-[2-(5-amino-1,2.4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-
3-[N. N-dimethyl-N-[2-((4.5
-dihydroxy-2-pyridyl)carbonylamino)ethylcoammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Sugitar): 3300, 17
70, 1660. 1610 am-1 (5)
7β-[2-(5-amino-1.2.4-deadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[N,N-dimethyl-N- [2-((4.5-dihydroxy-2-pyridyl)carbonylamino=4-carboxylade (syn isomer).

IR (nuji seal): 3300. 17
70. 1680. 1600.

1530 cm' (6) 7β-[2-(5-amino-1.2.4-thiadiazol-3-yl)-2-(1-carboxy-1-
methylethoxyimino)acetamide]-3-[
N,N-dimethyl-N-(2-(3,4-dihydroxybenzoyloxy)ethyl)ammoniomethylco-3-cephem-4-carboxilade (syn isomer).

IR (Suji Co., Ltd.): '770, 16
90, 1660. 1600.

1510 am' (7) 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamidoco-3
-[N. N-dimethyl-N-(2-(3.4-dihydroxybenzoylamino)ethylcoammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Sugitar): 1770, 16
00. 1510 an-1(8)7β-[2-(
2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-[N. N-dimethyl-N-(2-(3.4-dihydroxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-
4-Rupoxylate (syn isomer).

LR (Sujoor): 1770. 170
0, 1660, 1600.

1520 cm-1 11M main 7β-[2-(2-aminothiazol-4-yl)-2
= tert-butoxylponylmethoxyiminoacetamidoco-3-[N. N-dimethyl-N- ( 2-( 3
,4-dihydroxybenzoylamino)ethyl)ammoniomethyl-3-cephem-4-carboxilade.
Dihydrochloride (syn isomer) (1.4 g) in dichloromethane (5.6111 m) and anisole (1.4 ml)
Add trifluoroacetic acid (5.611111) to the medium suspension.
Add dropwise at 5℃. Stirring is continued for 3 hours at the same temperature. The reaction mixture is poured into diisopropyl ether, the resulting precipitate is collected by filtration, the resulting powder is added to water, and the pH is adjusted to 4.0 with an aqueous sodium bicarbonate solution. This solution was subjected to column chromatography using 1Diaion HP 20J, eluted with a 10% aqueous solution of isopropyl alcohol, and the fractions were lyophilized to produce 7β-[2-(2-aminothiazol-4-yl). -2-carboxymethoxyiminoacetamide]-3-[N,N-dimethyl-N-(2-(
3,4-Dihydroxybenzoylamino)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer) (130 mg) is obtained.

IR (Streak 9-L): 1770. 1600.
1510 am-1HMR(D20.δ)' 3
．． 13 (6H, br s), 2.85-4.20 (
6H), 4.56 (2H,s), 5.31 (I
H, d, J = 5Hz).

5.83 (LH, dJ=5Hz), 6.93 (L
H, s), 6.73-6.98 (LH, m>, 7
．． 06-7.30 (2H, m>5Mdan) The following compound is obtained in the same manner as in Example 9.

(1) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboquine-1-methylethoxyimino)acetamide-3-[N,N-dimethyl- N-(2-(3,4-dihydroxybenzoylamino)ethyl)ammoniomethyl]-3-cephem-
4-carboxilade (syn isomer).

IR (Streak 3-L): 1770. 1660.
1600. 1510 am'(2)7β-[2-
(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[N,N-dimethyl-N-[2
-((4,5=dihydroquine-2-pyridyl)carbonylamino-4-carboxilade (syn isomer).

IR (Streak 3-L): 3300, 17
70. 1680. 1600.

1530 crn-' (3)7β-[2-(5-amino-1,2.4-thiadiazol-3-yl)-2-(1-carboxy-1-
methylethoxyimino)acetamitoco-3-[N,N
-dimethyl-N-(2-(3,4-dihydroxybenzoyloxy)ethyl)ammoniomedelco-3-cephem-4-carboxilade (syn isomer).

IR (Streak 3-L): 1770, 16
90. 1660. 1600.

1510 am-' (4)7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3
-[N. N-dimethyl-N-(2-(3.4-dihydroxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer).

IR (Stripe Tool): 1770, 17
00, 1660. 1600.

1520 cm-' 7β-C2-C2-aminothiazol-4-yl)-2
-tertiary butoxycarbonylmethoxyiminoacetamide]-3-[N. N-dimethyl-N-(2-(3.4-
diacetoxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxylade dihydrochloride (syn isomer) (2.6 g), dichloromethane (1
Trifluoroacetic acid (8111Q) is added dropwise to a suspension of 0ffll+) and anisole (2ml) at 25°C. Continue stirring at the same temperature for 3 hours. Pour the reaction mixture into diisopropyl ether, and filter the resulting precipitate. Dissolve the precipitate in water and adjust the pH to 8.0 with saturated aqueous sodium bicarbonate solution at room temperature while stirring. Stirring is continued under the same conditions for 2 hours. The reaction mixture was adjusted to pH 3.0 with IN hydrochloric acid.
After adjusting to 0, mix the mixture with “Diaion HP-20
, for column chromatography using
Elutes with % isopropyl alcohol. The fractions were lyophilized to give 7β-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamide]
-3- [N. N-dimethyl-N-(2-(3.4
-dihydroxybenzoyloxy)ethyl)ammoniomethyl]-3-cephem-4-carboxilade (syn isomer) (180 mg) is obtained.

IR (Sujimeal): 1770. 17
00. 1660, 1600.

1520 am-' NMR (D20+NaHCO3.l; ): 3
．． 16 (61(, br s).

3.38-4.2 (6H), 4.58 (2H,
s), 5.33 (LH, d.

J=5Hz), 5.83 (LH, dJ=5Hz)
, 6.73-7.03(1)1. m), 6.9
5 (LH,s), 7.20-7.50 (1B,
m) Example 12 The following compound is obtained in the same manner as in Example 5.

7β-[2-(2-aminothiazol-4-yl)-2
-tertiary butoxylponylmethoxyiminoacetamidoco-3-[N,N-dimethyl-N-[2-((4,5
-dihydroxy-2-pyridyl)carbonylamino)ethylcoammoniomedel]-3-cephem-4-carboxylad (syn isomer) IR (Sujol): 1770 cm-1HMR (
D20"DCl, 8)' 1.27 (9H1s)
, 3.0-5.4 (16H, m), 5.5 (LH,
d, J=5Hz), 5.8 (IH, d.

J=5Hz), 7.3 (IH,s), 7.87
(IH,s), 8.27(IH,s) Example 13 The following compound is obtained in the same manner as in Example 9.

7β-[2-(2-aminethiazol-4-yl)-2
-carboxilard niiminoacetamide]-3-(
N,N-dimethyl-N-[2-((4,5-dihydroquine-2-pyridyl)carbonylamino)ether]ammoniomethylco-3-cephem-4-carboxilade (
Shin isomer) IR (striped seal) ' 1770 cm-1H
MR(D O+NaHCO3,8)' 3.15 (
6H, s), 3.2-5.2 (IOH, m>, 5.
3 (LH, d, J=5Hz), 5.8 (LH, d
.

J=5Hz), 6.95 (IH,s), 7.03
(11,s), 7.65(IH,s) Acetamide]-3-chloromethyl-3
-Cephem-4-carboxylic acid (syn isomer) (5 g) in a solution of N,N-dimethylformamide (50 mA),
Add N,N-dimethyl-2-(3,4-diacetoxybenzoyloxy)ethylamine (7,89 g),
Stir at 5°C for 5 hours, add tetrahydrofuran (30mQ
) is added. Add the mixture to diisopropyl ether (2 parts)
The resulting powder is collected by filtration and dried under reduced pressure.

This powder (7.7 g) was dissolved in a mixture of methanol (ts4mu) and 36% hydrochloric acid (8.86ml),
Stir at room temperature for 5 hours and add water (160ml).

Adjust the mixture to pH 4 with 20% potassium carbonate aqueous solution! 11, methanol is distilled off, and then cooled.

The resulting precipitate is collected by filtration and dried under reduced pressure.

This precipitate (3,71 g) was mixed with trifluoro vinegar @ (3,7
1) and anisole (11, 11). The solution was stirred at room temperature for 1 hour and then poured into diisopropyl ether (150 mQ), and the resulting precipitate was collected by filtration and dried under reduced pressure. The obtained powder (3.79 g) was mixed with water (3.79 g).
5 mQ) and p
The mixture was adjusted to pH 8 and stirred at room temperature for 3.5 hours while maintaining the pH at 8 with IN aqueous sodium hydroxide solution.

Adjust the solution to pH 5.8 with diluted hydrochloric acid and add “Diaion H”.
Column chromatography using P 20 J (100 mn) and elution with 40% aqueous isopropyl alcohol. Isopropyl alcohol was distilled off from the eluate and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(1-hydroxy-1-methylethquinimino)acetamitoco-3-[ N, N-
Dimethyl-N-(2-(3,4-dihydroxybenzoyloxy)ethyl)ammoniomethylco-3-cephem-4-carboquinrad (syn isomer) (0,90 g)
get.

IR (line 9-l): 1770 cm-1H
MR (D20.δ): 1.76 (6H, s),
3.27 (3H,s).

3.32 (3H, s), 3.2-5.2 (8H,
m), 5.45 (IHd, J: 5Hz), 5.8
3 (IH, d, J=5)1z), 6.9 (LH,
d.

Claims (1)

[Claims] General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an amino group or a protected amino group, Z is N or CH, R^2 is an organic group, R ^3 and R^4 are each a lower alkyl group, R^5
and R^6 are each a hydroxy group or a protected hydroxy group, A is a lower alkylene group, X is NH or O, and Q is N or CH) and pharmaceutically acceptable salts thereof.