JPH0323553B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel cefem compounds and salts thereof. More specifically, this invention provides novel cefem compounds and their salts having antibacterial activity;
The present invention relates to methods for producing them and pharmaceutical compositions containing them as active ingredients. That is, one object of the present invention is to provide a new cefem compound and its salts that are effective against many pathogenic bacteria, especially for oral administration. Another object of this invention is to provide a method for producing new cefem compounds and their salts. Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned novel cefem compound and its salts as active ingredients. The cefem compound targeted by this invention is a new compound and can be represented by the following general formula (). [Wherein R ¹ is carboxy(lower) alkyl or protected carboxy(lower) alkyl,
R ² is carboxy or protected carboxy,
R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxymethyl, lower alkylthiomethyl, lower alkoxymethyl,
halogen, lower alkenyl or hydrogen respectively]. According to this invention, novel cefem compounds ()
is produced by various production methods shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as before, and R ¹ _a is a protected carboxy (lower)
alkyl, R ¹ _b is carboxy (lower) alkyl,
R ² _a is protected carboxy, R ⁵ is of the formula: −
Each refers to an esterified carboxy ester moiety represented by the group COOR ⁵ ]. The raw material compound () is a new compound and can be produced by the production method shown by the reaction formula below. [In the formula, R ¹ has the same meaning as before, R ⁶ means carboxy or protected carboxy, and R ⁷ means protected carboxy, respectively]. In this invention, for the target compounds () and (a) to (e) and other compounds (), (a), (b) and (),
All of these compounds are meant to include syn isomers, anti isomers and mixtures thereof. Furthermore, for the target compound (), its syn isomer has the formula: Means ^one geometric isomer having a group of the formula: It means other geometric isomers having the group represented by [wherein R ¹ has the same meaning as before]. Furthermore, for other compounds, their syn and anti isomers are each indicated by the same geometrical configuration as the target compound (). Suitable salts of the target compound () are:
Commonly used non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts and alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts. Examples include organic base salts such as salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and salts with amino acids such as arginine, aspartic acid, and glutamic acid. In the foregoing as well as the following description of this specification, pertinent examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below. "Lower" means 1 to 6 carbon atoms unless otherwise specified. Suitable "protected carboxy" and "protected carboxy moieties" of "protected carboxy (lower) alkyl" include esterified carboxy and the like. Suitable examples of the esterified carboxy ester moiety and the esterified carboxy ester moiety represented by the group of the formula ^-COOR5 include at least one suitable substituent. may also be used, such as methyl ester,
Ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester,
Lower alkyl esters such as hexyl ester and 1-cyclopropylethyl ester, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1 (or 2)-acetoxyethyl ester,
1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyloxyethyl ester, 1 (or 2 or 3)-
Propionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1
(or 2)-pivaloyloxyethyl ester,
1 (or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl ester Lower alkanoyloxy (lower) alkyl esters such as, for example, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, mono (or di- or tri)-halo(lower)-alkyl esters, such as methoxycarbonylmethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc. Lower alkoxycarbonyloxy (lower) alkyl ester, phthalidylidene (lower) alkyl ester, or for example (5-methyl-2-oxo-
1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1,3-dioxol- 4-
(5-lower alkyl-) such as ethyl ester
2-oxo-1,3-dioxol-4-yl)
(Lower) alkyl esters; Lower alkenyl esters such as vinyl esters and allyl esters; Lower alkynyl esters such as ethyl esters and propynyl esters; or al (lower) alkyl esters such as di- or tri) phenyl (lower) alkyl esters, such as benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters, trityl esters, benzhydryl esters, bis(methoxy phenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-
Tertiary butyl benzyl ester, etc.; at least 1
Aryl esters which may have several suitable substituents, such as phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc. Can be mentioned. Preferred examples of the above esterified carboxy include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl , lower alkoxycarbonyl such as hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, lower alkanoyloxy such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, hexanoyloxymethoxycarbonyl, 1 (or 2)-propionyloxyethoxycarbonyl (Lower)alkoxycarbonyl, such as methoxycarbonyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, 1-isopropoxycarbonyloxyethoxycarbonyl, etc. (lower)alkoxycarbonyl, such as (5-methyl-2-oxo- (5-
lower alkyl, -2-oxo-1,3-dioxol-4-yl)(lower) alkoxycarbonyl,
Al(lower)alkoxycarbonyl, which may have at least one substituent, such as mono(or di- or tri)phenyl(lower)alkoxycarbonyl, e.g. benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
Included are 4-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, benzhydryloxycarbonyl, and the like. Suitable "lower alkyl" and "lower alkyl moiety" of "carboxy(lower)alkyl", "protected carboxy(lower)alkyl" and "lower alkylthiomethyl" include methyl,
Examples include ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc., preferably alkyl having 1 to 4 carbon atoms. Suitable "lower alkoxy" and "lower alkoxy moieties" of "lower alkoxymethyl" include methoxy, ethoxy, propoxy, isopropoxy,
Examples thereof include butoxy, tertiary butoxy, pentyloxy, hexyloxy, etc., and preferably alkoxy having 1 to 4 carbon atoms. Suitable "acyl" in "acyloxymethyl" include aliphatic acyl groups and acyl groups containing aromatic rings or heterocycles. Suitable examples of said acyl are lower alkanoyl, preferably having 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl; for example methoxycarbonyl, ethoxycarbonyl, propoxy lower alkoxycarbonyl such as carbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarboninyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl; e.g. mesyl, ethanesulfonyl, propane Lower alkanesulfonyl such as sulfonyl, isopropanesulfonyl, butanesulfonyl; Allensulfonyl such as benzenesulfonyl, tosyl; Aroyl such as benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl; (Lower) alkanoyl; Examples include alkoxycarbonyl (lower) such as benzyloxycarbonyl and phenethyloxycarbonyl. Preferred examples of "acyl" include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl. Examples of suitable "halogens" are chlorine, bromine, iodine or fluorine. Suitable "lower alkenyls" include vinyl, 1-propenyl, allyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl,
Alkenyls preferably of 2 to 4 carbon atoms are included, such as 1 or 2 or 3 or 4 or 5-hexenyl. Preferred examples of the target compound () are as follows. Preferred examples of R ¹ are carboxy(lower)alkyl or esterified carboxy(lower)alkyl [more preferably lower alkoxycarbonyl(lower)alkyl, or mono(or di- or tri)phenyl(lower)alkoxycarbonyl(lower) alkyl]; Preferred examples of R ² are carboxy or esterified carboxy [more preferably mono (or di or tri) phenyl (lower) alkoxy carbonyl which may be substituted with nitro;
Lower alkanoyloxy (lower) alkoxycarbonyl, lower alkoxycarbonyloxy (lower) alkoxycarbonyl, or (5-
(lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower) alkoxycarbonyl]; Preferred examples of R ³ are hydrogen or lower alkyl (most preferably methyl); Preferred examples of R ⁴ are lower alkyl ( most preferably methyl), lower alkoxy (most preferably methoxy), lower alkanoyloxymer (most preferably acetoxymethyl), lower alkylthiomethyl (most preferably methylthiomethyl), lower alkoxymethyl (most preferably methoxymethyl), halogen (most preferably chlorine), lower alkenyl (most preferably vinyl) or hydrogen. The method for producing the object compound of the present invention will be explained in detail below. Production method 1: The target compound () or a salt thereof is produced by reacting the compound () or a reactive derivative at its amino group or a salt thereof with the compound () or a reactive derivative at its carboxyl group or a salt thereof. can be manufactured. Suitable reactive derivatives of the amino group of the compound () include a Schiff base-type imino group or its enamine-type tautomer obtained by reacting the compound () with a carbonyl compound such as an aldehyde, a ketone, etc.; Examples include silyl derivatives produced by the reaction of the compound () with silyl compounds such as bis(trimethylsilyl)acetamide, trimethylsilylamide, etc.; derivatives produced by the reaction of the compound () with phosphorus trichloride or phosgene, etc. It is mentioned as. Suitable salts of the compound () include metal salts such as alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts such as trimethylamine salts and triethylamine salts; , organic base salts such as pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates, formates, Organic acid salts such as toluenesulfonate, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, or salts with amino acids such as arginine, aspartic acid, glutamic acid, etc. is given as an example. As suitable salts for compound (), the same salts as those exemplified for compound () can be mentioned. Suitable reactive derivatives at the carboxy group of compound () include acid halides, acid anhydrides, activated amides, activated esters, and the like. Preferred examples thereof are acid chlorides; acid azides; such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Substituted phosphoric acids such as dibenzyl phosphoric acid, halogenated phosphoric acids, dialkyl phosphorous acids, sulfites, thiosulfates, sulfuric acids, alkyl carbonates such as pivalic acid,
mixed acid anhydrides with acids such as aliphatic carboxylic acids such as pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, or aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides; imidazole; activated amides with 4-substituted imidazoles, dimethylpyrazoles, triazoles, or tetrazoles; or e.g. cyanomethyl esters,
Methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N+=CH−] ester, vinyl ester,
Propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thio ester, 4
- active esters such as nitrophenyl thioester, 4-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or for example N,N-dimethylhydroxylamine, 1-hydroxy-2 These include esters with N-hydroxy compounds such as -(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-6-chloro-1H-benzotriazole. These reactive derivatives can be arbitrarily selected from among them depending on the type of compound () to be used. The reaction is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
The reaction is carried out in conventional solvents such as N,N-dimethylformamide, pyridine, but any other organic solvent can be used as long as it does not adversely affect the reaction. These customary solvents may also be used in admixture with water. When compound () is used in the reaction in the form of free acid or salt, the reaction is carried out with N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide;N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimizole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine;ethoxyacetylene;1-alkoxy-1-chloroethylene; Phosphoric acid; Ethyl polyphosphoric acid; Isopropyl polyphosphoric acid; Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine;
2-Ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)
-6-chloro-1H-benzotriazole; N,
Preferably, it is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by the reaction of N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, and the like. The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. You may do so. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. Production method 2: The target compound (b) or a salt thereof can be produced by subjecting the compound (a) or a salt thereof to an elimination reaction of the carboxy protecting group in R ¹ _a . Suitable salts for compounds (a) and (b) include the salts exemplified for compound (). This reaction can be carried out according to conventional methods such as hydrolysis and reduction. When the protecting group is an ester, it can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, or hydroxides or carbonates or hydrogen carbonates of these metals, tolualkyls such as trimethylamine, triethylamine, etc. Amine, picoline, 1,5-
diazabicyclo[4,3,0]non-5-ene,
Examples include inorganic and organic bases such as 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene-7, and the like. Suitable acids include organic acids, such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid. In the case of acid hydrolysis using trifluoroacetic acid, anisole is usually added to accelerate the reaction. The reaction is usually carried out in a solvent such as water, methylene chloride, an alcohol such as methanol, ethanol, etc., or a mixture thereof, although any other solvent can be used as long as it does not adversely affect the reaction. Liquid bases or liquid acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of cooling to heating. Reduction is preferably applied to remove protecting groups such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, and the like. Reduction is carried out by conventional methods including chemical reduction and catalytic reduction. Suitable reducing agents used in the chemical reduction are, for example, metals such as tin, zinc, iron, or metal compounds such as chromium chloride, chromium acetate, and combinations of, for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p
- A combination with an organic or inorganic acid such as 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, platinum catalysts such as palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium. , palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, etc., e.g. reduced nickel, nickel oxide,
Nickel catalysts such as Raney nickel, e.g. reduced cobalt, cobalt catalysts such as Raney cobalt, e.g. reduced iron, iron catalysts such as Raney iron, e.g. reduced copper,
Conventional catalysts such as copper catalysts such as Raney copper, Ullmann copper, etc. The reduction is usually carried out in water, alcohols such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran or mixtures thereof, but any other solvent may be used as long as it does not adversely affect the reaction. be able to. Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents. The reaction temperature of this reduction reaction is not particularly limited, and the reaction is usually carried out in a range of cooling to heating. In the present invention, cases where the protected carboxy group of R ² is converted into a free carboxy group during the reaction step or during the post-treatment step of the reaction are also included within the scope of the invention. Production Method 3 The target compound (d) or its salts can be produced by subjecting compound (c) or its salts to an elimination reaction of the carboxy protecting group of R ² _a . Suitable salts for compounds (c) and (d) include the same salts as exemplified for compound (). This elimination reaction can be carried out according to Production Method 2 above. Production Method 4 The target compound (e) or its salts can be produced by subjecting the compound (d) or its salts to an esterification reaction. Suitable salts for compound (e) include the same salts as exemplified for compound (). This reaction can be carried out by reacting compound (d) or a salt thereof with an esterifying agent. Suitable esterifying agents include ^compounds of ^the formula: . Suitable reactive derivatives of the hydroxy of X include acid residues such as the aforementioned halogens. This reaction is usually carried out in a solvent such as dimethylformamide, pyridine, hexamethylphosphoric triamide, dimethyl sulfoxide, but any other solvent can be used as long as it does not adversely affect the reaction. When compound (d) is used in the free acid form,
Preferably, the reaction is carried out in the presence of a base as described in Preparation Method 2. Although the reaction temperature is not particularly limited, it is desirable to carry out the reaction under cooling, at room temperature, or under heating. When the target compound () has a free carboxy group, it can be converted into its salts by a conventional method. The method for producing the raw material compound will be explained in detail below. Manufacturing method A Compound () or its salts are Compound ()
Alternatively, it can be produced by reacting a salt thereof with a compound () or a salt thereof. Suitable salts for compound () include the same salts as exemplified for compound (). Suitable salts for compound () include the same salts as exemplified for compound (). The reaction is usually carried out using water, alcohols such as methanol, ethanol, propanol, dioxane,
It is carried out in conventional solvents or mixtures thereof which do not adversely affect the reaction, such as tetrahydrofuran and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Production method B Compound [a] or its salts can be produced by subjecting compound [] or its salts to a deamination reaction. Suitable salts for compound [] include the same salts as exemplified for compound []. Suitable salts for compound [a] include the same salts as exemplified for compound []. This reaction is carried out by reacting the compound [ ] or its salts with an alkali metal nitrite such as sodium nitrite or potassium nitrite, or a (lower) alkyl nitrite such as tertiary butyl nitrite or isopentyl nitrite. can be done. This reaction is usually carried out using tetrahydrofuran, N,N
- carried out in customary solvents which do not adversely affect the reaction, such as dimethylformamide, etc. The reaction temperature is not particularly limited, and the reaction is carried out in the range of room temperature to heating to the boiling point of the solvent. Production method C Compound () or its salts are
b) or a salt thereof can be produced by subjecting R ⁷ to an elimination reaction of the carboxy protecting group. This reaction can be carried out according to the method of Production Method 2 above. The object compound of this invention () and its salts are novel compounds with excellent antibacterial activity,
It inhibits the growth of a wide range of pathogenic bacteria, including Gram-positive and Gram-negative bacteria, and is useful as an antibiotic, especially for oral administration. When administering the object compound () of this invention or its salts for therapeutic purposes, the above-mentioned compound is used as the main ingredient, and a pharmaceutically acceptable carrier, such as an organic compound suitable for oral, parenteral or external use, is used. Alternatively, it can be used in the form of a formulation with inorganic, solid or liquid excipients.
Such preparations include capsules, tablets, granules, ointments, suppositories, solutions, suspensions, emulsions, and the like. Furthermore, if necessary, adjuvants, stabilizers, wetting agents, emulsifiers, and other frequently used additives can be included in the preparation. The dosage of the compound varies depending on the age, condition, type of disease, and type of compound () administered.
As a single average dose, about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the object compound of the present invention can be administered for the treatment of diseases caused by pathogenic bacteria. Generally, amounts from 1 mg to about 6000 mg or more can be administered per day. The antibacterial activity, urinary excretion and biliary excretion of representative compounds of the invention are shown below to demonstrate the usefulness of the object compounds of this invention. (1) Test compound 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer) (hereinafter abbreviated as compound A○). (2) Test (A) Minimum Inhibitory Concentration Test Method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. Tributicase soy broth (bacterial count
One platinum loopful of each test strain cultured overnight in 10 ⁸ /ml) was inoculated onto heart infusion agar (HI agar) containing each concentration of representative test compound, and after culturing at 37°C for 20 hours. , minimum inhibitory concentration (MIC) in μg/
Measured in ml. Test results

[Table] (B) Urinary excretion Test method Urine from rats to which 100 mg/Kg of the test compound was orally administered was collected using a urine collector for 0 to 6 hours and 6 to 24 hours. The antibiotic concentration in the urine specimen was measured by bioassay using a standard solution prepared with M/15 phosphate buffer, and the amount recovered in the urine within 24 hours was calculated. Test results

[Table] (C) Biliary excretion Test method A rat anesthetized with bentobarbital was fixed in a supine position, and a polyethylene tube was inserted into the bile duct. 0 to 3, 3 to 6 and 6 after oral administration of 100 mg/Kg of test compound
Bile samples were collected within 24 hours. The antibiotic concentration in the bile specimen was measured by bioassay using a standard solution prepared with M/15 phosphate buffer, and the amount recovered in the bile within 24 hours was measured. Test results

[Table] The present invention will be explained below with reference to Production Examples and Examples. Production example 1 2-tertiary butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)
Acetic acid (syn isomer) (15.0 g) and concentrated hydrochloric acid (9.5
A mixture of 2.5 g) in methanol (75 ml) at room temperature
Stir for hours. Add water (100ml) to the reaction mixture,
This solution was adjusted to pH 3.0 with stirring with a 10% aqueous sodium hydroxide solution. The precipitate was collected, washed with water and diisopropyl ether, and dried to give 2-
Tertiary butoxycarbonylmethoxyimino-2-
(2-aminothiazol-4-yl)acetic acid (syn isomer) (12.7 g) was obtained. IR (nujiol): 3340, 1740, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s), 4.51
(2H, s), 6.77 (3H, s) Production example 2 2-tert-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (11.5 g) in tetrahydrofuran ( Tertiary-butyl nitrite (6.5ml)
g) in tetrahydrofuran (32.5ml) for 50~
It was added dropwise under stirring at 57°C and the mixture was stirred at 50-55°C for 20 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water, and the solution was adjusted to pH 1.0 with 10% hydrochloric acid. Water (60 ml) was added to the separated organic layer, and the mixture was adjusted to pH 6.0 with a 40% aqueous potassium carbonate solution.
The separated aqueous solution was washed with ethyl acetate, and the pH was adjusted to 2.8 with 10% hydrochloric acid. This acidic solution was extracted with ethyl acetate, the ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was triturated in diisopropyl ether to give 2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (6.1 g). Melting point 141℃
(Disassembly). IR (nujiol): 1730cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (9H, s), 4.69
(2H, s), 8.08 (1H, d, J=2.0Hz), 9.21
(1H, d, J = 2.0 Hz) Production example 3 A solution of isopentyl nitrite (5.9 ml) in tetrahydrofuran (50 ml) was mixed with 2-(2-aminothiazol-4-yl)-2-(benzhydryloxycarbonylmethoxyimino). Acetic acid (syn isomer) (10.6
g) in tetrahydrofuran (100 ml).
Add dropwise under stirring at 50-55 °C and stir the mixture at 55-60 °C.
Stir for 30 minutes. Tetrahydrofuran was distilled off under reduced pressure. Dissolve the residue in a mixture of ethyl acetate and water and PH the mixture with 20% aqueous potassium carbonate solution.
Adjusted to 7.5. The separated aqueous layer was taken, adjusted to pH 2.0 with 10% hydrochloric acid, and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent was distilled off, and 2-
(benzhydryloxycarbonylmethoxyimino)-2-(4-thiazolyl)acetic acid (syn isomer)
(4.9g) was obtained. IR (nujiol): 1735 cm ^-1 NMR (DMSO-d ₆ , δ): 4.96 (2H, s), 6.90
(1H, s), 7.18-7.58 (10H, m), 8.03 (1H,
d, J = 2.0 Hz), 9.18 (1H, d, J = 2.0 Hz) Production example 4 2-(4-thiazolyl) in methanol (23 ml)
A mixture of glyoxylic acid (2.3 g) and tertiary butyl ester of 2-aminooxyacetic acid (2.6 g) was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of ethyl acetate and water, and the pH was adjusted to 7.5 with a saturated aqueous solution of sodium hydrogen carbonate. The separated aqueous layer
The acidic mixture was adjusted to pH 2.0 with 10% hydrochloric acid and saturated with sodium chloride. The acidic mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off. 2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer)
(2.8g) was obtained. Melting point 136-139℃. IR (nujiol): 1730cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (9H, s), 4.69
(2H, s), 8.08 (1H, d, J=2.0Hz), 9.21
(1H, d, J=2.0Hz) Production example 5 (1) 2-tertiary butoxycarbonylmethoxyimino-2-(2-formamidothiazole-4-
yl) acetic acid ((syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml)
ml) solution, a solution of diphenyldiazomethane in ethyl acetate (1 mmol/ml, 200 ml) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate.
The solvent was distilled off to obtain benzhydryl ester (syn isomer) of 2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (99.3 g). 2-
Tertiary butoxycarbonylmethoxyimino-2
-(2-formamidothiazol-4-yl)
Benzhydryl ester of acetic acid (syn isomer)
(99.0 g) in methanol (500 ml) was added concentrated hydrochloric acid (41.6 g) at room temperature, and the mixture was heated at the same temperature.
Stirred for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 g);
Extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in ether to give 2-tert-butoxycarbonylmethoxyimino-2-(2
-Aminothiazol-4-yl)acetic acid benzhydryl ester (syn isomer) (72.3 g) was obtained. IR (film): 1740, 1610cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
4.18 (2H, s), 6.73 (1H, s), 6.98 (1H,
s), 7.07-7.60 (10H, m) (2) A solution of tert-butyl nitrite (1.7 g) in tetrahydrofuran (10 ml) was added to 2-tert-butoxycarbonylmethoxyimino-2-(2-aminothiazole-4 The benzhydryl ester of acetic acid (syn isomer) (5 g) was added dropwise to a solution of tetrahydrofuran (50 ml) under stirring at 50-53° C. and the mixture was stirred at the same temperature for 25 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography. The column was eluted with a mixed solvent of benzene and ethyl acetate (19:1), and the eluate containing the target compound was evaporated to dryness to obtain 2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl).
Benzhydryl ester of acetic acid (syn isomer)
(2.2g) was obtained. IR (film): 1740, 1600cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
4.68 (2H, s), 7.08 (1H, s), 7.15−7.60
(10H, m), 8.03 (1H, d, J=2Hz),
9.15 (1H, d, J = 2Hz) (3) Benzhydryl ester of 2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (2.2 g) and anisole (2.2 ml) Add trifluoroacetic acid (4 ml) to a methylene chloride (22 ml) solution at room temperature,
The mixture was stirred at the same temperature for 25 minutes. Ethyl acetate was added to the reaction mixture, and the solution was washed with water.
Water was added to the separated organic layer, and the mixture was adjusted to pH 7.5 with a 20% aqueous sodium carbonate solution. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid, this acidic solution was saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off and the residue was dissolved in diisopropyl ether and n-
Trituration in hexane gave 2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (1.07 g). Melting point: 136-139℃ IR (Nudiol): 1730 cm ^-1 Example 1 Vilsmeier reagent was mixed with phosphorus oxychloride (0.76
g) and N,N-dimethylformamide (0.36
g) in ethyl acetate (1.44 ml) using a conventional method. 2-Tertiary butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (1.2 g) was added to a suspension of Vilsmeier reagent in ethyl acetate (20 ml) with water cooling, and the mixture was kept at the same temperature. The mixture was stirred for 20 minutes to prepare an active acid solution.
Trimethylacetamide (3.5g) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.76g) in tetrahydrofuran (15ml) and the mixture was stirred at 35-40°C for 20 minutes. The active acid solution was added to this solution at −10°C, and the mixture was heated at the same temperature for 30°C.
Stir for a minute. Water was added to the reaction mixture and the separated organic layer was added to water. This mixture was adjusted to pH 7.5 with a saturated aqueous potassium carbonate solution. The separated aqueous layer
The pH was adjusted to 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3.
-Cefem-4-carboxylic acid (syn isomer) (1.4
g) was obtained. IR (Nujiyor): 3240, 1775, 1715, 1670,
1630cm ^-1 NMR (DMSO-d ₆ , δ): 1.44 (9H, s), 3.60
(2H, m), 4.61 (2H, s), 5.10 (1H, d,
J = 5.0Hz), 5.86 (1H, dd, J = 5.0Hz, 8.0
Hz), 6.43 (1H, t, J=4.0Hz), 7.88 (1H,
d, J=2.0Hz), 9.10 (1H, d, J=2.0Hz),
9.49 (1H, d, J = 8.0Hz) Example 2 Vilsmeier reagent with phosphorus oxychloride (1.3g)
and N,N-dimethylformamide (0.6g)
The mixture was prepared by a conventional method in ethyl acetate (2.4 ml). 2-Tertiary butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer)
(2.0 g) of Vilsmeier's reagent ethyl acetate (20
ml) under ice cooling, and the mixture was heated at the same temperature.
The active acid solution was prepared by stirring for 20 minutes. Trimethylsilylacetamide (5.8g) 7
-amino-3-methyl-3-cephem-4-carboxylic acid (1.4 g) in tetrahydrofuran (28 ml)
medium suspension and the mixture was stirred at 38-42°C for 20 minutes. The active acid solution was added to this solution at −10° C. and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, the separated organic layer was added to water, and the mixture was adjusted to pH 7.5 with a saturated aqueous potassium carbonate solution. The separated aqueous layer was adjusted to PH2.0 with 10% hydrochloric acid,
Extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methyl. -3-cephem-4-carboxylic acid (syn isomer) (2.25 g) was obtained. IR (Nujiyor): 1750 (Broad, 1710, 1680
cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (9H, s), 2.02
(2H, s), 3.45 (2H, q, J=18.0Hz),
4.61 (2H, s), 5.10 (1H, d, J=5.0Hz),
5.73 (1H, dd, J = 5.0Hz, 8.0Hz), 7.89 (1H,
d, J=2.0Hz), 9.10 (1H, d, J=2.0Hz),
9.47 (1H, d, J = 8.0Hz) Example 3 Bissmeyer reagent with phosphorus oxychloride (2.2g)
and N,N-dimethylformamide (1.0g)
The mixture was prepared by a conventional method in ethyl acetate (4 ml). 2-(Benzhydryloxycarbonylmethoxyimino)-2-(4-thiazolyl)acetic acid (syn isomer) (4.8 g) was added to a suspension of Vilsmeier reagent in ethyl acetate (40 ml) under ice cooling, and the mixture was mixed. was stirred at the same temperature for 30 minutes to prepare an active acid solution. Trimethylsilylacetamide (10.1g) 7
-Amino-3-cefem-4-carboxylic acid (2.2
g) in tetrahydrofuran (30ml) and the mixture was stirred at 35-40°C for 30 minutes. The active acid solution was added to this solution at −10° C. and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, the separated organic layer was added to water, and the mixture was adjusted to pH 7.5 with a 20% aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off to give 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cepheme. -4-carboxylic acid (syn isomer) (6.2 g) was obtained. IR (Nujiyor): 1775, 1720, 1675, 1630cm
^-1 NMR (DMSO-d ₆ , δ): 3.56 (2H, m), 4.93
(2H, s), 5.13 (1H, d, J=5.0Hz), 5.92
(1H, dd, J = 5.0Hz, 8.0Hz), 6.48 (1H,
m), 6.90 ((1H, s), 7.11−7.65 (10H,
s), 7.90 (1H, d, J=2.0Hz), 9.16 (1H,
d, J=2.0 Hz), 9.68 (1H, d, J=8 Hz) Example 4 According to the method of Examples 1 to 3, the following compound was obtained. (1) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 1765, 1715, 1670 cm ^-1 (2) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-2-methyl-3-cephem-4-carboxylic acid (Syn isomer). IR (Nujiyor): 1780, 1720, 1670, 1630
cm ^-1 NMR (DMSO−d ₆ , δ): 1.28−1.67 (12H,
m), 3.76 (1H, m), 4.62 (2H, s), 5.13
(1H, d, J = 5.0Hz), 5.92 ((1H, dd, J
= 5.0Hz), 8.0Hz), 6.53 (1H, d, J = 6.0
Hz), 7.90 (1H, d, J = 2.0Hz), 9.14
(1H, d, J = 2.0Hz), 9.53 (1H, d, J
=8.0Hz) (3) 7-[2-carboxymethoxyimino-2-
(4-Thiazolyl)acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1770, 1720, 1670, 1630
cm ^-1 (4) 4-nitrobenzyl ester of 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid (synisomer body). IR (Nujiyor): 3230, 1770, 1710, 1675,
1600cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
3.69 (2H, s), 3.80 (3H, s), 4.62 (2H,
s), 5.19 (1H, d, J = 4.0Hz), 5.32
(2H, s), 5.65 (1H, dd, J=4.0Hz, 8.0
Hz), 7.60 (2H, d, J = 9.0Hz), 7.94
(1H, d, J = 2.0Hz), 8.18 (2H, d, J
= 9.0Hz), 9.11 (1H, d, J = 2.0Hz), 9.49
(1H, d, J=8.0Hz) (5) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 3180, 1760, 1665 cm ^-1 (6) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid (Syn isomer). IR (Nujiyor): 1770, 1690 (Broad)
cm ⁻¹ (7) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]cephalosporanic acid (syn isomer). IR (Nujiyor): 3200, 1780, 1720, 1670
cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s),
2.01 (3H, s), 3.54 (2H, m), 4.63 (2H, s),
4.83 (2H, q, J = 13.0Hz), 5.16 (1H, dd, J =
5.0Hz), 5.83 (1H, dd, J=5.0Hz, 8.0Hz), 7.89
(1H, d, J = 2.0Hz)), 9.11 (1H, d, J = 2.0
Hz), 9.53 (1H, d, J = 8.0Hz) (8) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]cephalosporanic acid (syn isomer). IR (Nujiyor): 3200, 1780, 1723, 1675
cm ^-1 (9) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methylthiomethyl-3-cephem-
Benzhydryl ester of 4-carboxylic acid (syn isomer). IR (Nujiyor): 3270, 1770, 1720, 1660
cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s),
1.78 (3H, s), 3.42-3.73 (4H, m), 4.61
(2H, s), 5.26 (1H, d, J=4.0Hz),
5.87 (1H, dd, J=4.0Hz, 8.0Hz), 6.88
(1H, s), 7.13-7.60 (10H, m), 7.91
(1H, d, J = 2.0Hz), 9.11 (1H, d, J
= 2.0Hz), 9.56 (1H, d, J = 8.0Hz) (10) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3180, 1775, 1720, 1675
cm ^-1 (11) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methoxymethyl-3-cephem-
Benzhydryl ester of 4-carboxylic acid (syn isomer). IR (Nujiyor): 3250, 1780, 1720, 1655
cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
3.06 (3H, s), 3.56 (2H, m), 4.08 (2H,
s), 4.63 (2H, s), 5.23 (1H, d, J=
5.0Hz), 5.91 (1H, dd, J = 5.0Hz, 8.0
Hz), 6.92 (1H, s), 7.17−7.62 (10H,
m), 7.91 (1H, d, J = 2.0Hz), 9.12
(1H, d, J = 2.0Hz), 9.58 (1H, d, J
=8.0Hz) (12) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1675
cm ⁻¹ (13) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 1780, 1720, 1680 cm ^-1 (14) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-chloro-3-cefem-4-carboxylic acid 4-nitrobenzyl ester (syn isomer) of IR (Nujiyor): 1780, 1720, 1670, 1600
cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
3.88 (2H, q, J = 18.0Hz), 4.63 (2H,
s), 5.33 (1H, d, J = 5.0Hz), 5.45
(2H, s), 5.94 (1H, dd, J=5.0Hz, 8.0
Hz), 7.67 (2H, d, J = 8.0Hz), 7.91
(1H, d, J = 2.0Hz), 8.23 (2H, d, J
= 8.0Hz), 9.14 (1H, d, J = 2.0Hz), 9.67
(1H, d, J = 8.0Hz) (15) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1670
cm ^-1 (16) Benzhydryl ester of 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) . IR (Nujiyor): 3250, 1770, 1720, 1710,
1655cm ^-1 NMR (DMSO-d ₆ , δ): 1.44 (9H, s),
3.75 (2H, m), 4.64 (2H, s), 5.28 (1H,
d, J = 11.0Hz), 5.29 (1H, d, J = 5.0
Hz), 5.62 (1H, d, J = 17.0Hz), 5.93
(1H, dd, J = 5.0Hz, 8.0Hz), 6.77 (1H,
dd, J=11.0Hz, 17.0Hz), 6.93 (1H, s),
7.35 (10H, s), 7.93 (1H, d, J = 2.0
Hz), 9.14 (1H, d, J = 2.0Hz), 9.62
(1H, d, J=8.0Hz) (17) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer). IR (nujiol): 1765, 1710, 1665 cm ^-1 (18)7-[2-carboxymethoxyimino-2-
(4-thiazolyl)atomido]-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3280, 1750, 1725,
1655, 1620cm ^-1 (19) 1-Propionyloxyethyl ester of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer ). IR (Nudiyol): 1775, 1735, 1680 cm ^-1 (20) 1-ethoxy of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid Carbonyloxyethyl ester (syn isomer). IR (Nudiyol): 1780, 1750, 1680 cm ^-1 (21) Pivaloyl of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid Oxymethyl ester (syn isomer). IR (nudiol): 1780, 1740, 1680 cm ^-1 (22) 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (5- Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester (syn isomer). IR (Nujiyor): 1810, 1770, 1730, 1670
cm ^-1 (23) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-1-propionyloxyethyl ester of -3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3250, 1780, 1750, 1680
cm ^-1 (24) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-1-ethoxycarbonyloxyethyl ester of -3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1750 (Broad), 1770
cm ^-1 (25) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer). IR (Nujiyor): 1740 (broad), 1680cm
^-1 (26) 7-[2-carboxymethoxyimino-2
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester (syn isomer) of -(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid. IR (Nujiyor): 1810, 1770, 1730, 1670
cm ^-1 Example 5 Trifluoroacetic acid (5.2 ml) was added to 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-
thiazolyl)acetamide]-3-cephem-4
-carboxylic acid (syn isomer) (1.3 g) in methylene chloride (2 ml) and anisole (1.3 ml) was added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. Diisopropyl ether (40%
ml) and n-hexane (30 ml) were added with stirring. Take the precipitate and diisopropyl ether and n
- Washed with a mixed solvent with hexane (1:1).
Add this precipitate to a mixture of ethyl acetate and water,
The pH was adjusted to 7.5 with a saturated aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 4.0 with 10% hydrochloric acid, and this solution was washed with ethyl acetate. Cool this solution on ice for 10 minutes.
The pH was adjusted to 1.8 with % hydrochloric acid. The precipitate was collected, washed with cold water, dried under reduced pressure with phosphorus pentoxide,
-Carboxymethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) was obtained. IR (Nujiyor): 3280, 1750, 1725, 1655,
1620cm ^-1 NMR (DMSO-d ₆ , δ): 3.58 (2H, m), 4.67
(2H, s), 5.12 (1H, d, J=4.0Hz), 5.88
(1H, d, J = 4.0Hz, 8.0Hz), 6.45 (1H,
m), 7.93 (1H, d, J = 2.0Hz), 9.02 (1H,
d, J = 2.0 Hz), 9.52 (1H, d, J = 8.0 Hz) Example 6 Trifluoroacetic acid (8.4 ml) was added to 7-
thiazolyl)acetamide]-3-methyl-3-
Cefem-4-carboxylic acid (syn isomer) (2.1
A suspension of g) in methylene chloride (4.2ml) and anisole (2.1ml) was added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. Diisopropyl ether (50 ml) and n-hexane (30 ml) were added to this solution and stirred. Collect the precipitate and add a mixed solvent of diisopropyl ether and n-hexane (1:1).
Washed with. The precipitate was added to a mixture of ethyl acetate and water, and the mixture was brought to pH 7.0 with saturated aqueous potassium carbonate solution.
Adjusted to. The separated aqueous layer was adjusted to pH 4 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.8 with 10% hydrochloric acid to saturate it with sodium chloride.
This acidic solution was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran (1:1). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off to give 7-[2
-Carboxymethoxyimino-2-(4-thiazolyl)acetamide]-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) was obtained. IR (nujiol): 1765, 1715, 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 2.03 (3H, s), 3.47
(2H, m), 4.67 (2H, s), 5.13 (1H, d,
J = 5.0Hz), 5.78 (1H, dd, J = 5.0Hz, 8.0
Hz), 7.96 (1H, d, J = 2.0Hz), 9.15 (1H,
d, J = 2.0Hz), 9.52 (1H, d, J = 8.0Hz) Example 7 Trifluoroacetic acid (1.4ml) was converted into 7-[2-benzhydryloxycarbonylmethoxyimino-2-
A suspension of 1-propionyloxyethyl ester (syn isomer) of (4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer) (1.2 g) in methylene chloride (10 ml) and anisole (0.8 ml) was added at room temperature. and the mixture was stirred at the same temperature for 2 hours. Add diisopropyl ether (50ml) to this solution.
was added and stirred. The precipitate was collected and washed with diisopropyl ether. Add the precipitate to a mixture of ethyl acetate and water and add this mixture to 20% potassium carbonate.
The pH was adjusted to 7.5 with an aqueous solution. 10% of the separated aqueous layer
The pH was adjusted to 2.0 with hydrochloric acid and extracted with ethyl acetate.
The extract layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the solvent was distilled off.
The residue was washed with diisopropyl ether and collected to give 7-[2-carboxymethoxyimino-2-
1-propionyloxyethyl ester (syn isomer) (0.47 g) of (4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid was obtained. IR (nujiyor): 3250, 1780, 1750, 1680cm
^-1 NMR (DMSO−d ₆ , δ): 1.05 (3H, t, J=
7.0 [Hz), 1.49 (3H, d, J = 5.0Hz), 2.36
(2H, q, J=7.0Hz), 3.63 (2H, m), 4.66
(2H, s), 5.16 (1H, d, J=4.0Hz), 5.93
(1H, dd, J = 4.0Hz, 8.0Hz), 6.59 (1H,
t, J = 4.0Hz), 6.89 (1H, q, J = 5.0Hz),
7.93 (1H, d, J = 2.0Hz), 9.13 (1H, d,
J = 2.0Hz), 9.54 (1H, d, J = 8.0Hz) Example 8 Trifluoroacetic acid (11.2ml) was added to 7-[2-tert-butoxycarbonylmethoxyimino-2-(4
-thiazolyl)acetamide]-3-vinyl-3
-To a suspension of benzhydryl ester of cefem-4-carboxylic acid (syn isomer) (2.8 g) in methylene chloride (5.6 ml) and anisole (2.8 ml) was added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. did. Add diisopropyl ether (40ml) to this solution.
and n-hexane (30 ml) were added and stirred.
The precipitate was collected and washed with a mixed solvent of diisopropyl ether and n-hexane (1:1). This precipitate was added to a mixture of ethyl acetate and water, and the pH was adjusted to 7.0 with a saturated aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 4.0 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.8 with 10% hydrochloric acid and saturated with sodium chloride. This acidic solution was mixed with a mixed solvent of ethyl acetate and tetrahydrofuran (1:
1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off to give 7-[2-carboxymethoxyimino-2-(4-thiazolyl)acetamide]-3-vinyl-3- Cefem-4-carboxylic acid (syn isomer) (1.22 g) was obtained. IR (nujiol): 1765, 1710, 1665 cm ^-1 NMR (DMSO-d ₆ , δ): 3.71 (2H, m), 4.72
(2H, s), 5.26 (1H, d, J=5.0Hz), 5.37
(1H, d, J = 11.0Hz), 5.61 (1H, d, J =
17.0Hz), 5.91 (1H, dd, J=5.0Hz, 8.0Hz),
6.98 (1H, dd, J=11.0Hz, 17.0Hz), 8.02
(1H, d, J = 2.0Hz), 9.21 (1H, d, J =
2.0Hz), 9.64 (1H, d, J = 8.0Hz) Furthermore, 7-[2-carboxymethoxyimino-2-(-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (synisomer 7-[2-carboxylate methoxyimino-2-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid by reacting the compound with sodium bicarbonate in a conventional manner. The sodium salt (syn isomer) was obtained. Example 9 According to the method of Examples 5 to 8, the following compounds were obtained. (1) 7-[2-carboxymethoxyimino-2-
(4-Thiazolyl)acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1770, 1720, 1670, 1630
cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (3H, d, J
=7.0Hz), 3.72 (1H, m), 4.67 (2H, s),
5.13 (1H, d, J = 4.0Hz), 5.93 (1H, dd,
J = 4.0Hz, 8.0Hz), 6.55 (1H, d, J = 6.0
Hz), 7.92 (1H, d, J = 2.0Hz), 9.12
(1H, d, J = 2.0Hz), 9.53 (1H, d, J
=8.0Hz) (2) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). IR (nujiol): 3180, 1760, 1665 cm ^-1 NMR (DMSO-d ₆ , δ): 3.60 (2H, broad s), 3.75 (3H, s), 4.68 (2H, s),
5.18 (1H, d, J = 5.0Hz), 5.62 (1H, dd,
J = 5.0Hz, 8.0Hz), 8.02 (1H, d, J = 2.0
Hz), 9.15 (1H, d, J = 2.0Hz), 9.52
(1H, d, J=8.0Hz) (3) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]cephalosporanic acid (syn isomer). IR (Nujiyor): 3200, 1780, 1723, 1675
cm ^-1 NMR (DMSO-d ₆ , δ): 2.01 (3H, s),
3.56 (2H, m), 4.67 (2H, s), 4.83 (2H,
q, J = 14.0Hz), 5.17 (1H, d, J = 4.0
Hz), 5.85 (1H, dd, J=4.0Hz, 8.0Hz),
7.92 (1H, d, J = 2.0Hz), 9.12 (1H, d,
J = 2.0Hz), 9.54 (1H, d, J = 8.0Hz) (4) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3180, 1775, 1720, 1675
cm ^-1 NMR (DMSO-d ₆ , δ): 1.96 (3H, s),
3.47−3.76 (4H, m), 4.67 (2H, s), 5.20
(1H, d, J = 4.0Hz), 5.79 (1H, dd, J
= 4.0Hz, 8.0Hz), 7.93 (1H, d, J = 2.0
Hz), 9.12 (1H, d, J = 2.0Hz), 9.54
(1H, d, J=8.0Hz) (5) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1675
cm ^-1 NMR (DMSO-d ₆ , δ): 3.27 (3H, s),
3.52 (2H, m), 4.16 (2H, s), 4.66 (2H,
s), 5.16 (1H, d, J = 4.0Hz), 5.81
(1H, dd, J = 4.0Hz, 8.0Hz), 7.91 (1H,
d, J = 2.0Hz), 9.11 (1H, d, J = 2.0
Hz), 9.52 (1H, d, J = 8.0Hz) (6) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1670
cm ^-1 NMR (DMSO-d ₆ , δ): 3.81 (2H, q, J
= 18.0Hz), 4.66 (2H, s), 5.25 (1H, d,
J = 5.0Hz), 5.87 (1H, dd, J = 5.0Hz,
8.0Hz), 7.72 (1H, d, J = 2.0Hz), 9.10
(1H, d, J = 2.0Hz), 9.63 (1H, d, J
=8.0Hz) (7) 7-[2-carboxymethoxyimino-2-
1-Ethoxycarbonyloxyethyl ester (syn isomer) of (4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid. IR (Nujiyor): 1750 (broad), 1770cm
^-1 NMR (DMSO−d ₆ , δ): 1.09and 1.22 (overall
3H, respectively t, J = 7.0Hz), 1.50 (3H,
d, J=5.0Hz), 3.63 (2H, m), 4.16
(2H, q, J=7.0Hz), 4.66 (2H, s),
5.16 (1H, d, J = 4.0Hz), 5.93 (1H,
m), 6.62 (1H, t, J=4.0Hz), 6.77
(1H, q, J = 5.0Hz), 7.94 (1H, d, J
= 2.0Hz), 9.14 (1H, d, J = 2.0Hz), 9.56
(1H, d, J=8.0Hz) (8) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer). IR (Nujiyor): 1740 (broad), 1680cm
^-1 NMR (DMSO-d ₆ , δ): 1.14 (9H, s),
3.60 (2H, q, J = 18.0Hz), 4.63 (2H,
s), 5.13 (1H, d, J = 4.0Hz), 5.62−
6.03 (3H, m), 6.55 (1H, t, J = 4.0
Hz), 7.87 (1H, d, J = 2.0Hz), 9.06
(1H, d, J = 2.0Hz), 9.48 (1H, d, J
=8.0Hz) (9) 7-[2-carboxymethoxyimino-2-
(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (syn isomer) of (4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid. IR (Nujiyor): 1810, 1770, 1730, 1670
cm ^-1 NMR (DMSO-d ₆ , δ): 2.18 (3H, s),
3.62 (2H, m), 4.67 (2H, s), 5.15 (2H,
s), 5.16 (1H, d, J = 5.0Hz), 5.93
(1H, dd, J = 5.0Hz, 8.0Hz) 6.60 (1H,
t, J = 4.0Hz), 7.95 (1H, d, J = 2.0
Hz), 9.15 (1H, d, J = 2.0Hz), 9.56
(1H, d, J=8.0Hz) Example 10 7-[2-tertiary butoxycarbonylmethoxyimino-2-(-thiazolyl)acetamide]-3
-methoxy-3-cephem-4-carboxylic acid 4
-Nitrobenzyl ester (syn isomer) (2.9
g) was dissolved in a mixed solvent of methanol (50 ml), tetrahydrofuran (30 ml) and glacial acetic acid (0.5 ml). Add 10% palladium-carbon (1.5 g) to this solution.
was added and the mixture was subjected to catalytic reduction at room temperature and atmospheric pressure. The catalyst was separated and the liquid was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3. -Methoxy-3-cephem-4-carboxylic acid (syn isomer) (1.71 g) was obtained. IR (nujiol): 1770, 1690 (broad) cm ^-1 NMR (DMSO-d ₆ , δ): 1.44 (9H, s), 3.60
(2H, s), 3.75 (3H, s), 4.63 (2H, s),
5.16 (1H, d, J = 4.0Hz), 5.61 (1H, dd,
J = 4.0Hz, 8.0Hz), 7.96 (1H, d, J = 2.0
Hz), 9.13 (1H, d, J = 2.0Hz), 9.50 (1H,
d, J=8.0Hz) Example 11 According to the method of Example 10, the following compound was obtained. (1) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1750 (Broad), 1710,
1680cm ^-1 (2) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 1765, 1715, 1670 cm ^-1 (3) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-2-methyl-3-cephem-4-carboxylic acid (Syn isomer). IR (Nujiyor): 1780, 1720, 1670, 1630
cm ^-1 (4)7-[2-carboxymethoxyimino-2-(4
-thiazolyl)acetamide]-2-methyl-
3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1770, 1720, 1670, 1630
cm ^-1 (5) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). IR (nudiol): 3180, 1760, 1665 cm ^-1 (6) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]cephalosporanic acid (syn isomer). IR (Nujiyor): 3200, 1780, 1720, 1670
cm ^-1 (7) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]cephalosporanic acid (syn isomer). IR (Nujiyor): 3200, 1780, 1723, 1675
cm ^-1 (8) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3180, 1775, 1720, 1675
cm ^-1 (9) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1675
cm ⁻¹ (10) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). IR (nujiol): 1780, 1720, 1680cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
3.81 (2H, q, J = 18.0Hz), 4.61 (2H,
s), 5.26 (1H, d, J = 5.0Hz), 5.86
(1H, dd, J = 5.0Hz, 8.0Hz), 7.99 (1H,
d, J = 2.0Hz), 9.12 (H, d, J = 2.0
Hz), 9.64 (1H, d, J = 8Hz) (11) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 1775, 1720, 1670
cm ^-1 (12) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer). IR (nudiol): 1765, 1710, 1665 cm ^-1 (13) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer ). IR (Nujiyor): 3240, 1775, 1715, 1670,
1630cm ^-1 (14) 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetami]-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3280, 1750, 1725, 1655,
1620 cm ^-1 (15)7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 1775, 1720, 1675, 1630
cm ^-1 Example 12 1-chloroethyl ester of propionic acid (0.6 g) in dimethyl sulfoxide (13 ml)
-(2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]
-3-cefem-4-carboxylic acid (syn isomer)
The reaction mixture was added to a mixture of ice water and ethyl acetate, and the pH was adjusted to 7.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with water and dried over magnesium sulfate.
The solvent was distilled off to give 1-propionyloxyethyl ester (syn isomer) of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer). 1.3g) was obtained. IR (nujiol): 1775, 1735, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.04 (3H, t, J=
7.0Hz), 1.51 (3H, d, J = 5.0Hz), 2.38
(2H, q, J=7.0Hz), 3.602H, m),
4.94 (2H, s), 5.18 (1H, d, J = 4.0
Hz), 5.96 (1H, dd, J=4.0Hz, 8.0Hz),
6.63 (1H, t, J=4.0Hz), 6.91 (1H,
s), 6.93 (1H, q, J = 5.0Hz), 7.20−
7.59 (10H, m), 7.92 (1H, d, J = 2.0
Hz), 9.18 (1H, d, J = 2.0Hz), 9.68
(1H, d, J = 8.0 Hz) Example 13 4-bromomethyl-5-methyl-1,3-dioxol-2-one (0.5 g) was dissolved in 7-[2-benzhydryl Oxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) and potassium carbonate (0.17 g) were added to a mixture and the mixture was stirred at room temperature for 2 hours. Stirred. The reaction mixture was added to a mixture of ice water and ethyl acetate, and the mixture was adjusted to pH 7.5 with a 20% aqueous potassium carbonate solution. The separated organic layer was washed with water and dried over magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography, and ethyl acetate-n-hexane (3:
2) and purified by elution. The eluate was evaporated to dryness to give the (5-methyl-2-oxo- 1,3-dioxol-4-yl) methyl ester (syn isomer).
(0.37g) was obtained. IR (Nujiyor): 1810, 1770, 1730, 1670cm
^-1 NMR (DMSO-d ₆ , δ): 2.14 (3H, s), 3.53
(2H, m), 4.86 (2H, s), 5.09 (2H, s),
5.10 (1H, d, J = 5.0Hz), 5.88 (1H, dd,
J = 5.0Hz, 8.0Hz), 6.51 (1H, t, J = 4.0
Hz), 6.81 (1H, s), 7.09-7.50 (10H, s),
7.80 (1H, d, J = 2.0Hz), 9.06 (1H, d,
J=2.0Hz), 9.57 (1H, d, J=8.0Hz) Example 14 According to the method of Examples 12 and 13, the following compound was obtained. (1) 4-nitrobenzyl ester (syn isomer) of 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methoxy-3-cephem-4-carboxylic acid. IR (Nujiyor): 3230, 1770, 1710, 1675,
1600cm ^-1 (2) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methylthiomethyl-3-cephem-
Benzhydryl ester of 4-carboxylic acid (syn isomer). IR (Nujiyor): 3270, 1770, 1720, 1660
cm ^-1 (3) 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-methoxymethyl-3-cephem-4
- Benzhydryl esters of carboxylic acids (syn isomers). IR (Nujiyor): 3250, 1780, 1720, 1655
cm ^-1 (4) 4-nitrobenzyl ester of 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (synisomer body). IR (Nujiyor): 1780, 1720, 1670, 1600
cm ^-1 (5) Benzhydryl ester of 7-[2-tert-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) . IR (Nujiyor): 3250, 1770, 1720, 1710,
1655cm ^-1 (6) 1-ethoxycarbonyloxyethyl ester of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer) . IR (nujiol): 1780, 1750, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.09 (3H, t, J
= 7.0Hz), 1.52 (3H, d, J = 5.0Hz), 3.63
(2H, m), 4.17 (2H, q, J = 7.0Hz),
4.93 (2H, s), 5.17 (1H, d, J = 5.0
Hz), 5.97 (1H, dd, J=5.0Hz, 8.0Hz),
6.65 (1H, t, J = 4.0Hz), 6.81 (1H, q,
J=5.0Hz), 6.92 (1H, s), 7.20−7.60
(10H, m), 7.92 (1H, d, J=2.0Hz),
9.68 (1H, d, J = 8.0Hz), 9.19 (1H, d,
J=2.0Hz) (7) Pivaloyloxymethyl ester of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid (syn isomer ). IR (nujiol): 1780, 1740, 1680cm ^-1 NMR (DMSO-d ₆ , δ): 1.16 (9H, s),
3.61 (2H, m), 4.91 (2H, s), 5.16 (1H,
d, J=4.0Hz), 5.69−6.04 (3H, m),
6.59 (1H, m), 6.89 (1H, s), 7.16−7.60
(10H, m), 7.89 (1H, d, J=2.0Hz),
9.16 (1H, d, J = 2.0Hz), 9.68 (1H, d,
J=7.0Hz) (8) 7-[2-carboxymethoxyimino-2-
1-Propionyloxyethyl ester (syn isomer) of (4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid. IR (Nujiyor): 3250, 1780, 1750, 1680
cm ^-1 (9) 7-[2-carboxymethoxyimino-2-
1-Ethoxycarbonyloxyethyl ester (syn isomer) of (4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid. IR (Nujiyor): 1750 (broad), 1770cm
^-1 (10) 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamide]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer). IR (Nujiyor): 1740 (broad), 1680cm
^-1 (11) 7-[2-carboxymethoxyimino-2-
(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (syn isomer) of (4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid. IR (Nujiyor): 1810, 1770, 1730, 1670
cm ^-1

Claims (1)

[Claims] 1. General formula: [Wherein, R ¹ is carboxy (lower) alkyl or protected carboxy (lower) alkyl, R ² is carboxy or protected carboxy, R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxy methyl, lower alkylthiomethyl, lower alkoxymethyl, halogen, lower alkenyl or hydrogen, respectively] and salts thereof. 2 R ¹ is carboxy (lower) alkyl or esterified carboxy (lower) alkyl, R ² is carboxy or esterified carboxy, and R ⁴ is lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower The compound according to claim 1, which is alkylthiomethyl, lower alkoxymethyl, halogen, lower alkenyl or hydrogen. 3 Syn-isomer of the compound according to claim 2. 4 R ¹ is carboxy(lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy, R ³ is hydrogen,
4. A compound according to claim 3, wherein R ⁴ is hydrogen. 5 7-[2-carboxymethoxyimino-2-
The compound according to claim 4, which is (4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer). 6 R ¹ is carboxy (lower) alkyl or al (lower) alkoxycarbonyl (lower) alkyl, and R ² is lower alkanoyloxy (lower)
alkoxycarbonyl, lower alkoxycarbonyloxy (lower) alkoxycarbonyl or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower) alkoxycarbonyl, R ³ is hydrogen, R ⁴ The compound according to claim 3, wherein is hydrogen. 7 7-[2-carboxymethoxyimino-2-
1-propionyloxyethyl ester (syn isomer) of (4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid, 7-[2-carboxymethoxyimino-2-(4
-thiazolyl)acetamide]-3-cephem-
1-ethoxycarbonyloxyethyl ester of 4-carboxylic acid (syn isomer), 7-[2-carboxymethoxyimino-2-(4
-thiazolyl)acetamide]--3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer), and 7-[2-carboxymethoxyimino-2-(4
-thiazolyl)acetamide]-3-cephem-
4-carboxylic acid (5-methyl-2-oxo-
1,3-dioxol-4-yl) methyl ester (syn isomer). 8 R ¹ is carboxy(lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy, R ³ is hydrogen,
4. A compound according to claim 3, wherein R ⁴ is lower alkyl. 9 7-[2-carboxymethoxyimino-2-
(4-thiazolyl)acetamido]-3-methyl-
9. The compound according to claim 8, which is 3-cephem-4-carboxylic acid (syn isomer). 10 R ¹ is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy, R ³ is lower alkyl, and R ⁴ is hydrogen, according to claim 3 Compound. 11 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-2-methyl-3-cephem-4-carboxylic acid (syn isomer)
The compound according to claim 10, which is 12 R ¹ is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy or alkoxy carbonyl having a nitro group, R ³ is hydrogen, and R ⁴ is lower alkoxy The compound according to claim 3, which is 13 7-[2-carboxymethoxyimino-2
13. The compound according to claim 12, which is -(4-thiazolyl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). 14 R ¹ is carboxy(lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy, R ³ is hydrogen,
4. The compound according to claim 3, wherein R ⁴ is lower alkanoyloxymethyl. 15 7-[2-carboxymethoxyimino-2
15. The compound according to claim 14, which is -(4-thiazolyl)acetamido]cephalosporanic acid (syn isomer). 16 Patent in which R ¹ is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy or ar (lower) alkoxycarbonyl, R ³ is hydrogen, and R ⁴ is lower alkylthiomethyl A compound according to claim 3. 17 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer). 18 Patent in which R ¹ is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy or ar (lower) alkoxycarbonyl, R ³ is hydrogen, and R ⁴ is lower alkoxymethyl Claim 3
Compounds described in Section. 19 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer). 20 R ¹ is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy or alkoxy carbonyl having a nitro group, R ³ is hydrogen, and R ⁴ is halogen. A compound according to claim 3. 21 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer)
The compound according to claim 20, which is 22 Claims in which R ¹ is carboxy(lower) alkyl or lower alkoxycarbonyl (lower) alkyl, R ² is carboxy or ar(lower) alkoxycarbonyl, R ³ is hydrogen, and R ⁴ is lower alkenyl. Compound according to item 3. 23 7-[2-carboxymethoxyimino-2
-(4-thiazolyl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)
The compound according to claim 22, which is 24 General formula: [wherein R ² is carboxy or protected carboxy, R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxymethyl, lower alkylthiomethyl, lower alkoxymethyl, halogen, lower alkenyl or hydrogen, respectively] The general formula: [In the formula, R ¹ means carboxy(lower) alkyl or protected carboxy(lower) alkyl] or a reactive derivative thereof at the carboxy group or a salt thereof is reacted to form the general formula: A method for producing a novel cefem compound or a salt thereof, which comprises obtaining a compound represented by the formula [wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as above] or a salt thereof. 25 General formula: [Wherein R ² is carboxy or protected carboxy, R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxymethyl, lower alkylthiomethyl, lower alkoxymethyl, halogen, lower alkenyl or hydrogen,
R ¹ _a means a protected carboxy (lower) alkyl, respectively] or a salt thereof is subjected to an elimination reaction of the carboxy protecting group in R ¹ _a , and the general formula: [In the formula, R ² , R ³ , and R ⁴ each have the same meanings as before, and R ¹ _b means carboxy(lower) alkyl] or a salt thereof. A method for producing a compound or its salts. 26 General formula: [Wherein, R ¹ is carboxy (lower) alkyl or protected carboxy (lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxymethyl, lower alkylthiomethyl, lower alkoxymethyl, halogen, lower alkenyl or hydrogen, R ² _a means protected carboxy respectively]
The compound represented by or a salt thereof is subjected to an elimination reaction of the carboxy protecting group at R ² _a to form the general formula: [In the formula, R ¹ , R ³ , and R ⁴ have the same meanings as before]
A method for producing a novel cefem compound or a salt thereof, which is characterized by obtaining a compound or a salt thereof. 27 General formula: [Wherein, R ¹ is carboxy (lower) alkyl or protected carboxy (lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is lower alkyl, lower alkoxy, acyloxymethyl, lower alkylthiomethyl, lower alkoxymethyl, meaning halogen, lower alkenyl or hydrogen respectively] A compound represented by the following or its salts is subjected to an esterification reaction, and the general formula: [In the formula, R ¹ , R ³ , R ⁴ have the same meanings as before, and R ⁵ means the ester moiety of esterified carboxy represented by the group -COOR ⁵ ] A method for producing a novel cefem compound or a salt thereof, the method comprising obtaining the compound or a salt thereof.