JPS63152388A - Novel cephem compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {RA is formula II or III [R<a> is protected amino; R<b> is protected carboxy; R<2> is (protected)amino; R<3> is (substitute)lower alkyl], R<4>-CH=N- (R<4> is aryl); RB is -CH2-XL, formula IV (R<5> is aryl; X<1> and X<2> are halogen) or -CH=P(R<5>)3; R1 is (protected)carboxy}. EXAMPLE:[7-(5-Benzamido-5-benzhydryloxycarbonylpentanamide)-4-benzhydrylo xycarbonyl-3-cephem-3-yl]methyltriphenylphosphonium iodide. USE:An intermediate for producing antimicrobial agents for oral administration. PREPARATION:A compound expressed by formula V or salts thereof are reacted with a halogenating agent, e.g. phosphorus trichloride, etc. The reaction is preferably carried out normally in an inert solvent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel cephem compounds and salts thereof.

More specifically, the present invention relates to novel cephem compounds and salts thereof which are intermediates for producing novel 7-acylamino-3-vinylcephalosporanic acid derivatives and salts thereof having antibacterial activity.

Accordingly, the object of the present invention is to provide novel 7-acylamino-3-vinylcephalosporanic acid derivatives that exhibit excellent antibacterial activity against a large number of pathogenic microorganisms and are useful as antibacterial agents, especially orally administered agents. An object of the present invention is to provide novel cephem compounds and salts thereof, which are intermediates for producing pharmaceutically acceptable salts.

Cephem compound (I), which is the object of this invention, is a new compound and can be represented by the following general formula.

[Wherein, RA represents the formula R'-CH=N- (wherein, R8 is a protected amine group, Rb is a protected carboxy group, R2 is an amine group or a protected amine group, and R3 is a lower alkyl group or lower alkyl group substituted with carboxy or protected carboxy, R4
means an aryl group), RB is a group represented by the formula % (in the formula, R is an aryl group, and X and X2 each represent a halogen), R1 is a carboxy group or a protected means a carboxy group] The target compound (I) and the corresponding raw material compound (I[>, (IV), (V), (VI) in the following methods 1 to 5)
In and (■), one or more pairs of stereoisomers such as optical isomers and geometric isomers may exist based on the asymmetric carbon atoms and double bonds in these compounds, but these All isomers are intended to be included in this invention.

Suitable salts of the target compound (1) include pharmaceutically acceptable salts, especially the customary non-toxic salts, salts with bases and acid addition salts, i.e. salts with inorganic bases, such as sodium salts, Alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, salts with organic bases such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexyl Amine salts, organic amine salts such as N,N'-dibenzylethylenediamine salts, inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates, formates, acetates, trifluoroacetates , organic carboxylic or sulfonic acid addition salts such as maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. Contains salts, etc.

In the description above and below, suitable examples included in the various definitions will be explained in detail as follows.

The term lower is used to include groups having 1 to 7 carbon atoms, unless otherwise specified.

Suitable lower alkyls include straight chain or branched groups,
Examples thereof include methinoethyl, propyl, isopropyl, butynoisobutyl, pentinoisopentyl, neopentyl, hexyl, etc. Among them, alkyl having 1 to 4 carbon atoms is preferred.

Suitable protected amines include the conventional amino protecting groups used in penicillin and cephalosporin compounds;
1
- Contains amine groups substituted with lower alkoxycarbonyl (lower) alkylidene such as methoxycarbonyl-1-propen-2-yl or its enamine tautomer, di(lower) alkylamino methylene such as dimethylamino methylene, etc. .

Suitable acyls include aliphatic acyl, aromatic acyl,
Included are heterocyclic acyls and aliphatic acyls substituted with aromatic or heterocyclic groups.

Aliphatic acyls include those saturated or unsaturated, acyclic or cyclic, such as formyl, acetyl, pro-onyl, butyryl, isobutyryl, valeryl,
Lower alkanoyl such as isovaleryl, pivaloyl, hexanoyl, i-class alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, acryloyl, methacryloyl,
Included are lower alkenoyl such as crotonoyl, 03-07 cycloalkane carbonyl such as cyclohexanecarbonyl, amidino, and the like.

Examples of the aromatic acyl include aroyl such as benzoyl, toluoyl and xyloyl, and arenesulfonyl such as benzenesulfonyl and tosyl.

Examples of the heterocyclic acyl include furoyl, thenoyl,
Included are heterocyclic carbonyls such as nicotinoyl, isonicotinoyl, thiazolylcarbonyl, and tetrazolylcarbonyl.

Examples of aliphatic acyl substituted with an aromatic group include alkanoyl (lower) alkanoyl such as phenyl (lower) alkanoyl such as phenylacetyl, phenylpropionyl, and phenylhexanoyl, alkoxycarbonyl (lower) alkoxycarbonyl such as benzyloxycarbonyl, Includes phenoxy (lower) alkanoyl such as phenoxyacetyl and phenoxyprobionyl.

Aliphatic acyl substituted with a heterocyclic group includes chenyl acetyl, imidazolylacetyl, furylacetyl,
Includes tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thenylpropionyl, thiadiazolylpropionyl, and the like.

These acyl groups may be further substituted with one or more suitable groups. Suitable substituents include:
Lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogen such as chlorine, bromine, iodine, fluorine, lower alkoxy such as methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy, hexyloxy, Methylthio, ethylthio, propylthio, isopropylthio, butylthio,
These include lower alkylthio such as pentylthio and hexylthio, nitro, etc. Suitable acyl having such a substituent -8= include mono(or di- or trifluoroacetyl) such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. ) halo(lower) alkanoyl, chloromethoxycarbonyl, mono(or di or tri)halo(lower) alkoxycarbonyl such as 2,2-trichloroethoxycarbonyl, nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, nitro(or Includes halo or lower alkoxy) phenyl ((ffi) alkoxycarbonyl stop).

Suitable protected carboxys include those commonly esterified at the 3- or 4-position of penicillin or cephalosporin compounds.

Suitable ester moieties in esterified carboxy include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester,
Lower alkyl esters such as isobutyl esters, tertiary phtyl esters, pentyl esters, tertiary pentyl esters, hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkynyl esters such as ethynyl esters and propynyl esters, methoxymethyl Lower alkoxy (such as ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester)
lower) alkyl ester, methylthiomethyl ester,
Lower alkylthio((ffi) alkyl esters, 2-amino-2-
Amines and carboxy-substituted lower alkyl esters such as carboxyethyl ester, 3-amino-3-carboxypropyl ester, 2-tertiary butoxycarbonylamino-2-benzhydryloxycarbonylethyl ester, 3-tertiary butoxycarbonylamino - protected amines and protected carboxy-substituted lower alkyl esters such as lower alkoxycarbonylamino and mono(or di- or tri)phenyl(lower)alkoxycarbonyl-substituted lower alkyl esters such as cyclocarbonylpropyl ester, 2-iodoethyl; Esther, 2.

Mono (or cy or tri) halo (lower) alkyl esters such as 2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isobutyryloxymethyl ester, valeryloxymethyl ester ,
pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-
Lower alkanoyloxy (lower) alkyl esters such as propionyloxyethyl ester and 1-acetoxypropyl ester, lower alkanesulfonyl (lower) alkyl esters such as mesylmethyl ester and 2-mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3.4-
Dimethoxybenzyl ester, 4-hydroxy-3.5
- one or more mono(or di- or tri)phenyl (lower) alkyl esters which may have one or more suitable substituents such as di-tertiary butyl benzyl esters; Al (lower) alkyl ester, phenyl ester, which may have a substituent of
tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester,
Included are aryl esters which may have one or more suitable substituents, such as salicyl esters, and heterocyclic esters, such as phthalidyl esters.

Suitable halogens include chloro, bromo, iodo, and the like.

Suitable aryls include phenyl, tolyl, xylyl, naphthyl, and the like.

The group represented by R3 is preferably carboxy(lower)alkyl such as carboxydimethyl, 1-carboxyethylethylx-1-methylethyl, esterified carboxy(lower)alkyl (preferably methoxycarbonylmethyl, Ethoxycarbonylmethyl, tertiary butoxycarbonylmethyl, 1
-Lower alkoxycarbonyl (lower) alkyl such as tertiary-butoxycarbonyl ethyl, 3-tertiary butoxycarbonyl probyl, and 1-tertiary butoxycarbonyl-1-methylethyl.

The object compound (I) of the present invention and its salts are produced by the method shown in the following reaction formula.

Method 1 Method 2 Method 3 Method 4 (I-d) or its salts 15-1 Method 5 [In the formula, RA, RB, R, R, R, R.

R5, x 1 and X2 each have the same meaning as before. ] Processes 5 to 5 in the production of the target compound (I) will be explained in detail as follows.

Method 1 Compound (I-a) or a salt thereof is produced by reacting compound (I[) or a salt thereof with a halogenating agent.

Suitable salts of compound (I) include salts with the same bases as exemplified for compound (I).

Suitable halogenating agents used in this reaction include phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, and phosphorus pentabromide, thionyl halides such as thionyl chloride, and phosgene. Those conventionally used for converting hydroxy groups into halogens are used.

This reaction is performed using alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide, alkali metal alkanoates such as sodium acetate, trialkylamines such as triethylamine,
Preferably, the reaction is carried out in the presence of a base such as a pyridine compound such as pyridine, lutidine or picoline, or an organic base such as quinoline.

This reaction usually involves methylene chloride, chloroform,
It is carried out in conventional solvents which do not adversely affect the reaction, such as ethylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, or mixtures thereof.

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

Method 2 Compound (I-b) or a salt thereof is compound (I-a)
Or, it is produced by reacting a salt thereof with a trisubstituted phosphine represented by the formula P(R5)3 (wherein R5 has the same meaning as above).

This reaction is preferably carried out in the presence of a metal halide such as an alkali metal halide such as sodium iodide, potassium iodide, sodium bromide, etc. In this case, the halogen of Xl in compound <1-a) is Compound (I
In -b), the halogen of the above metal halide may be substituted.

This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate, or a mixture thereof.

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

Method 3 Compound (I-c) or its salt is compound (I-b)
Alternatively, it can be produced by reacting its salts with a base.

This reaction can be carried out using organic bases such as those exemplified in Method 1, or alkali metals such as lithium, sodium, and potassium.
Alkaline earth metals such as calcium, alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, etc. The reaction is preferably carried out in the presence of an inorganic base such as an alkali metal hydrogen carbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate.

This reaction is usually carried out in a conventional solvent such as acetone, tetrahydrofuran, water, etc. which does not adversely affect the reaction.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at a temperature that is slightly warmed.

Method 4 Compound (I-d) or its salt is compound (It/)
or a reactive derivative thereof at the amino group or a salt thereof, and a compound (V>) or a reactive derivative thereof at the carboxy group or a salt thereof.

Suitable salts for compound (IV) include the same salts as those exemplified for compound (I).

Suitable reactive derivatives of the amine group of compound (IV) include those commonly used, such as silyl derivatives obtained by reaction with silyl compounds such as bis(trimethylsilyl)acetamide and trimethylsilylacetamide, isocyanates, isothiocyanates, Amino groups and aldehyde compounds such as acetaldehyde, isobentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, thiophenecarbaldehyde, acetone, methyl ethyl ketone, Methyl isobutyl ketone, acetylacetone,
Included are Schiff bases obtained by reaction with carbonyl compounds such as ketone compounds such as ethyl acetoacetate, or tautomers thereof.

Suitable reactive derivatives at the carboxy group of compound (V) include acid halides, acid anhydrides, active amides, active esters, etc., among which preferred ones include:
Acid chloride, acid bromide, substituted phosphoric acid (e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid) mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride, thiosulfuric acid mixed anhydride,
Sulfuric acid mixed anhydrides, alkyl carbonates (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.) mixed anhydrides, aliphatic carboxylic acids (e.g. bivaric acid, pentanoic acid, isopentanoic acid,
2-ethylbutanoic acid, trichloroacetic acid, etc.) mixed anhydrides,
Mixed acid anhydrides such as aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole,
Active amides with imino group-containing heterocyclic compounds such as tetrazole, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester &,
Phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester ester, piperidyl ester, 8-quinolylthioester, N-hydroxy compounds (e.g. N.

N-dimethylhydroxylamine, 1-hydroxy-2
(IH)-pyridone, N-hydroxyphthalimide, N
-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.).

Suitable reactive derivatives are actually used compound (IV),
It is selected as appropriate depending on the type of (V).

This reaction is carried out in the presence of an organic or inorganic base as exemplified in Method 3.

In this reaction, when compound (V) is used in the form of a free acid or a salt thereof, for example, N. N'-dicyclohexylcarbodiimidoxyl-N'-(4-diethylaminocyclohexyl)
carbodiimide, N. Carbodiimide compounds such as N'-diethylcarbodiimidodomonopropyl) carbodiimide, ketene imines such as N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc. compounds, olefin or acetylene ether compounds such as ethoxyacetylene and β-chlorovinylethyl ether, N-hydroxybenzotriazole compounds such as 1-(4-chlorohenzenesulfonyloxy)-6-chloro-IH-benzotriazole sulfonic acid esters , trialkyl phosphites are also included, combinations of triphenylphosphine and carbon tetrachloride, disulfides or diazenedicarboxylates (e.g. diazenedicarboxylic acid diethyl ester), ethyl polyphosphates, isopropyl polyphosphates, phosphoryl chloride, phosphorus trichloride. phosphorus compounds such as thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonic acid, dimethylformamide, etc. N-di(lower)alkylformamide, N
- It is preferable to carry out the reaction in the presence of a condensing agent such as the so-called Vilsmeier reagent obtained by the reaction of an amide compound such as methylformamide with a halogen compound such as thionyl chloride, phosphoryl chloride, or phosgene.

This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N
, N-dimethylformamide, pyridine, hexamethylphosphoramide, etc., or mixtures thereof, which do not adversely affect the reaction. Among these solvents, hydrophilic solvents can be used in combination with water.

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

In this reaction, when carried out in the presence of the above-mentioned Vilsmeier reagent, the amino group at R2 of the starting compound is converted into N. Compounds modified to N-di(lower)alkylaminomethylene)amine groups may be obtained, but these cases are also included in the present invention.

Method 5 Compound (1-e) or its salts can be obtained by reacting compound (Vl) or its salts with a compound (■) represented by the formula R'-CHO (wherein R4 has the same meaning as before). It is done.

This reaction is preferably carried out in the presence of a dehydrating agent such as molecular sheep.

This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as N,N-dimethylformamide.

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

In the above method steps to 5 and post-treatment of the reaction mixture, if the starting compound or the target compound contains an optical or geometric isomer, it may be converted to another optical or geometric isomer; shall be included in the invention.

The compound (I>) of the present invention is useful as an intermediate for the synthesis of 7-acylamino-3-vinylcephalosporanic acid, which is useful as an antibacterial agent. Produced from compound (I) of the invention by the method described in the Examples.

In order to demonstrate the usefulness of the target compound (I), 7 produced using the target compound (I> of the present invention as a raw material compound)
The results of measuring the antibacterial activity of representative -acylamino-3-vinylcephalosporanic acids are shown below.

(1) Test 1: In vitro antibacterial activity [Test compound No. 1 7-[2-(3-methanesulfonamidophenyl)-D-glycineamito-3-vinyl-3-
Cephem-4-carboxylic acid (compound A) No, 2 7- [2-('2-aminothiazol-4-yl)-2-methoxyiminoacetamitoco-3-
Vinyl-3-cephem-4-carboxylic acid (syn isomer)
(Compound B) No, 3 7-[2(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamitoco-
3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (compound C) No, 4 7- [2(2-aminothiazole-4-
yl)-2-(3-carboxypropoxyimino)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (Compound D) [Test method: In vitro by the following agar plate multiple dilution method. Antibacterial activity was measured.

Trypticase Soy Pross (bacterial count 108/mQ)
One loopful of the test strain cultured overnight in Heart Infusion Agar (HI) containing each concentration of test compound
After inoculation on agar) and incubation at 37 °C for 20 h, the minimum inhibitory concentration (MIC) was determined in z/mQ.

[Test result 1 MMC (pg/mu) [Test result 2 MIC (Pt, /mQ) [Test result 3 MIC (pg/mQ) (2) Test 2; Serum level after oral administration of antibiotics to rats Measurement of [Test Compound] Compound A [Test Animal] 6-week old male rats, SD strain, body weight each 160 to 2
30g [Test method] Test compound A (1100In
/kg) was administered orally. At specified time intervals, rats were anesthetized with chloroform and blood samples were collected from the heart. Antibiotic levels in each serum sample were determined by the disk method using standard solutions made with rat serum.

[Test Results] (3) Test 3: Protective effect against experimental mouse infection [Test Compound A [Test Animals] 4-week old male mice, ICR strain, body weight 20.0±1 each
．． 5g [Test method] Pathogenic microorganisms (1.3 x 10') suspended in 25% mucin were injected intraperitoneally. One hour after injection, Compound A was administered orally. This mouse was determined to be alive or dead after 4 days.
ED5o values were calculated.

[Test Results] When administering 7-acylamino-3-vinyl-cephalosporanic acid obtained from the object compound (1) of the present invention for therapeutic purposes, it contains the above compound as a main component and contains a pharmaceutically acceptable compound. carriers, such as oral, parenteral,
Alternatively, they can be administered in the form of conventional preparations with organic or inorganic, solid or liquid excipients suitable for external use. Such formulations include solids such as tablets, granules, powders, and capsules, and liquids such as solutions, suspensions, syrups, emulsions, and lemonades.

Furthermore, if necessary, adjuvants, stabilizers,
Wetting agent, other lactose, magnesium stearate, clay, sucrose, cornstarch, talc, stearic acid,
gelatin, agar, pectin, peanut oil, olive oil,
Commonly used additives such as cocoa butter and ethylene glycol can be included.

The dosage of 7-acylamino-3-vinyl-cephalosporanic acid varies depending on the patient's age, condition, type of disease, and type of compound administered, but generally ranges from 1 mg to about 4000 mg or more per day. can be administered to the patient. The average dose for one time is 50mg, 100mg, 250mg of the above compound.
, 500mg, 1000mg, 2000mg can be used to treat diseases caused by pathogenic microorganisms.

Next, the present invention will be explained in detail using examples.

Production of raw material compound Production Example 1 7-(5-amino-5-carboxypentanamide)-
Benzoyl chloride (42.1 g) was added to a solution of sodium 3-hydroxymethyl-3-cephem-4-carboxylate (118.6 g) in water (1000 mQ) and acetone (600 m11) at 10°C under stirring under water cooling.
Then, the reaction mixture was adjusted to pH 6 with 20% aqueous sodium carbonate solution.
, 5 to 7.5.

After continuing to stir at the same temperature for 1 hour, the reaction mixture was adjusted to pH 6.0 with concentrated hydrochloric acid, acetone was distilled off, and ethyl acetate (
Wash with 5oomQ). Ethyl acetate (300
mQ ) is added, a solution of diphenyldiazomethane and ethyl acetate is added until the starting compound disappears on thin layer chromatography, and the pH is adjusted to 30 with concentrated hydrochloric acid. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in acetone (400 mQ) and the solution is added dropwise to diisopropyl ether (4000 mQ). When the precipitated crystals are collected by filtration and dried, the mp 100-110"C is 7.
-(5-Benzamido-5-benzhydryloxycarbonylpentanamide-cephem-4-carribonic acid benz'hydryl ester (224.8 g) was obtained.

IR (Z';a-ru): 3270, 1
770, 1730, 1660.

1640 cm-' NMR &ppm (DMSO-d6): 1.3-2
．． 7 (6H, m), 3.38 (LH, s), 3.
63 (2)1, m), 4.27 (2H, dJ='
5) 1z).

4,67 (IH,rn), 5.15 (LH,d,
J=5Hz>, 5.77 (LH.dd, J=5Hz,
8Hz>, 6.87 (1)1,s),
6.95 (LH.s), 7.43 (25H.m),
7.97 (1) 1,m), 8.87 (IH.m) Production Example 2 Phosphorus pentachloride (27.Og) and methylene chloride (200
Pyridine (10.3 g) was added to the stent solution of mA).
Add dropwise and stir at 5°C for 20 minutes.
(Add 5-benzamido-5-benzhydryloxycarbonylpentanamidotyl-3-cephem-4-carribonic acid benz'hydryl ester (21.0 g) at -40°C all at once, -
Stirring is continued for 1 hour at 30°C and an additional hour at -10°C. The reaction mixture was added with methanol (10
0 mQ) was added all at once at -40°C, and -10°(,C'
Stir for 1 hour. The solvent was distilled off, methylene chloride (100 mQ), water (30 mQ) and diisofurobyl ether (100 mQ) were added to the residue, and the mixture was stirred briefly under water cooling. The precipitated crystals were collected by filtration, suspended in ethyl acetate (300 mQ), and adjusted to pH 8.0 with an aqueous sodium hydrogen carbonate solution. Adjust to 0. The organic layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. When the solvent is distilled off, mp 135-14
7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (2.
8g) is obtained.

IR (Nujol): 3400, 17
60, 1725. 1650 cm-”NMR
&ppm (DMSO-d6): 3.60 (2H
,q. J=17Hz>.

4,38 <28,s>, 4.85 (IH,
d. J=5Hz>, 5.05(LH.d, J=5H
z), 6.95 (LH,s), 7.4 (IOH
, m).

8,8 (2H, m) Production Example 3 To a solution of N-hydroxyphthalimide (70.08 g) in acetonitrile (300 ml), triethylamine (48 g) and tertiary butyl 4-bromocrotonic acid ester (96.0 g) were added. ) is added under stirring and the mixture is heated to reflux for 1.5 hours. The reaction mixture was diluted with water (6
ooma) and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated to dryness under reduced pressure, and the residue is triturated with n-hexane. The resulting material was subjected to column chromatography on silica gel and mixed with a mixture of n-hexane, ethyl acetate and diisopropyl ether (volume ratio 5:0.
5:4,5)-1? i and collect the fractions containing the target compound. The solvent was distilled off, and the residue was powdered with n-hexane and collected by filtration to give 4-phthalimidoxycrotonic acid tertiary butyl ester (41.7 g) 'H! Ru.

NMR l; ppm (DMSO da)
: 1.45 (9H, s), 4.90
(2H.

m), 6.09 (IH, m), 6.66-7
, 19 (IH.m), 7.86 (4H,s) Production Example 4 4-phthalimidooxydicrotonic acid tertiary butyl ester (20.0g) was mixed with methylene chloride (140mQ
), add hydrazine monohydrate (5.0 g) to the solution dissolved in
A solution prepared by dissolving the above in methanol (toma) is added under stirring, and stirring is continued for 15 minutes at room temperature.

Insoluble matter is filtered and washed with methylene chloride. The washing liquid and filtrate are combined and extracted three times with 5% hydrochloric acid. Combine the extracts, wash with diethyl ether, add methylene chloride, and add 28% ammonium hydroxide aqueous solution p) 17.
Adjust to 5. The methylene chloride solution is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off to obtain oily 4-aminooxycrotonic acid tertiary butyl ester (11.03 g).

IR (liquid film): 3340.3250.2980.2
940.1720°1660 cm-' NMRSppm (DMSO-ds): 1.43 (
9H, i), 4.18 (2) 1゜m), 5.8
5 (IH, m), 6.14 (2H, broad S).

=39-6.52-7.06 (LH,m> Production Example 5 4-aminooxycrotonic acid tertiary butyl ester (1
Ethanol (150 mQ) and water (15 ml) are added to the solution (2-formamidothiazol-4-yl) glyoxylic acid (11,0 g) is added to the mixture under stirring. During the addition, the pH of the mixture is adjusted to 5-55 with 10% aqueous sodium hydroxide solution and stirring is continued for 2 hours at room temperature. Ethanol was distilled off, ethyl acetate was added to the remaining aqueous solution, and the mixture was diluted with 10% sodium hydroxide aqueous solution.
Adjust to H7.5. Separate the aqueous layer and wash with ethyl acetate. Add ethyl acetate to this, add 10% hydrochloric acid to pH 2,
Adjust to 0. The organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was pulverized with n-hexane and tetrahydrofuran and collected by filtration. Ethanol (50 mQ) and water (30 mQ) are added to this, and the pH is adjusted to 7.5 with a 10% aqueous sodium hydroxide solution. The precipitate is collected by filtration, washed with a mixture of water and ethanol (volume ratio 1:1), water and ethyl acetate are added, and the pH is adjusted to 2.0 with 10% hydrochloric acid.

The organic layer was separated, washed with saturated aqueous sodium chloride solution,
Dry with magnesium sulfate. When the solvent was distilled off and the residue was powdered with n-hexane and tetrahydrofuran, 2
-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazole-4
-yl)acetic acid (syn isomer) (12,01 g) is obtained.

IR: 3150. 1720.
1650 cm-'NMRE ppm (DMSO-
d6) ' 1.47 (9H,s>, 4.89 (
2H.

m), 5.96 (LH, m), 6.69-7.1
6 (IH, m>, 7.60 (LH, s), 8.
57 (LH,s), 12.72 (LH, Broad S) Production Example 6 2-(trans-3-tertiary-butoxycarbonylallyloxyimino)-2-(2-formamidothiazole-
A solution of 4-yl) acetic acid (syn isomer) (8.0 g) dissolved in ethyl acetate (6 Q ml ) and ethanol (6 om was added in a nitrogen stream and catalytically reduced at 1 atm for 4 hours. The catalyst was filtered off and the filtrate was concentrated. Water and ethyl acetate were added to the residue, and the pH was adjusted to 7.5 with saturated aqueous sodium hydrogen carbonate solution.
Adjust to. The aqueous layer is separated, washed with ethyl acetate, further ethyl acetate is added, and the pH is adjusted to 2.0 with 10% hydrochloric acid. The organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed by filtration, and the residue was crystallized from n-hexane and collected by filtration.
(2-)-2-(2-
Formamidothiazol-4-yl)acetic acid (syn isomer) (1,80 g) is obtained.

NMRδppm (DMSO-d6)' 1.44 (
9H,s), 1.93 <2)1゜m), 2.33
(2H, t, J=6.0Hz), 4.20 (2H
,t.

J=6.0Hz), 7.61 (LH,s), 8.
61 (LH,s).

12.63 (LH, Broad S> 1 color Kaoru Kaoru Goho 1 Example 1 7-(5-benzamide-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3
-cephem-4-carboxylic acid benzhydryl ester (
Phosphorus pentachloride (25.6 g) was added to a solution of 100 g) dissolved in methylene chloride (600+nσ) at -30°C.
and pyridine (98 g) was added dropwise at the same temperature. The reaction mixture is stirred for 1 hour at -20°C and poured into a mixture of methylene chloride (500 ml!) and water (300 ml). The organic layer was separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness.
-benzamide-5-benzhydryloxycarbonylpentanamido-3-10-methyl-3-cephem-
4-Carboxylic acid benzhydryl ester (114.5
g) Obtain wo.

IR (Nujol): 1780, 17
25. 1640 cm-1HMR 8 ppm (
DMSO-d6) ' 1.3-2.5 (6) 1, m
>, 3.67 (2H, m>, 4.43 (2M, m
>, 4.67 (IH.m), 5.22 (1) 1,
d, J=5Hz>, 5.83 (IH, m), 6.
83 (1) 1, s>.

7,00 (LH.s), 7.4 (25H,m>,
7.92' (IH, m).

8,90 (IH,m> Example 2 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (10
Triphenylphosphine (48.5 g) was dissolved in N,N-dimethylformamide lsomQ).
) and sodium iodide (18.4 g) are added and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture was added dropwise to isopropyl alcohol (5000 ml), and the precipitate was collected by filtration and washed with diisopropyl ether.
p [7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-4-benzhydryloxycarbonyl-em- at 165-175°C (decomposition)
3-yl]methyltriphenylphosphonium iodite (123.5 g) is obtained.

IR (Nujol)' 1780. 17
30, 1710. 1650 am-'NMR
δppm(DMSO-d6): 1.3-2.6 (
6H, m), 4.33 (2) 1, m), 4.67
(2H.m), 5.13 (18,m>, 5.33
(LH, d, J=5Hz), 5.75 (IH, m)
, 6.33 (IH, s).

-4.5- 6, 83 (LH.s), , 7.0-8.3 (41
H, m), 8.92 (LH, m) Example 3 7-Amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester g) in N,N-dimethylformamide (40 mQ) Molecular sheep (Log) and benzaldehyde (
2. tg) and stirred at 40°C for 40 minutes. To this were added sodium iodide (2.9 g) and triphenylphosphine (10.1 g), and the mixture was stirred at 40°C for 1 hour. The reaction mixture was dissolved in diisopropyl ether (200 m
Q) and ethyl acetate (100 mfl), and the precipitated crystals were filtered and dried, mp 150
[4-Benzhydryloxycarbonyl-7-penzylideneamino-3-cephem-3 at 158°C (decomposition)
-Ilcomethyl-triphenylphosphonium iodite (16.9 g) is obtained.

IR '1780, 17
05. 1635 cm-”NMRδppm (DM
SO-d6) ' 3.67 <2H, m>, 5.2
(2H.

m), 5.58 (IH.d.J=5Hz),
5.82 (1) 1, d.

J=5Hz), 6.30 (IH.s), 7.
2-8.3 (30H, m).

8, 70 (IH.s) Example 4 Phosphorus oxychloride (18
．． 5 g) at −5 to 0° C. and the mixture is stirred briefly. Add 2-(2-formamidothiazole-
4-yl)-2-methoxyiminoacetic acid (syn isomer)
(25.2 g) was added at 3°C and stirred at the same temperature for 40 minutes to obtain a fully activated acid solution.

On the other hand, 7-amino-3-chloromethyl-3-cephem-
4-Carboxylic acid benzhydryl ester hydrochloride (45.
1g), trimethylsilylacetamide (104.8
g) and ethyl acetate (40011111) (
7) Stir the mixture for 20 minutes at room temperature. Add the above activated acid solution to this solution with stirring at -40°C,
Stirring is continued for 1.8 hours at -10°C. Water (200
After adding mQ), separate the organic layer. The remaining aqueous layer is extracted with ethyl acetate, and the extracts are combined with the organic layer, washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After concentration, the precipitate was collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-
3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (45.2g)
get. The filtrate is concentrated to dryness and the residue is washed with diethyl ether to recover the same material (7.9 g). Total yield 53,1 g.

IR (Nujol) j 3250. 3160.
3110. 1780. 1720°1690, 1
660,1630,1565゜1540 cm-' NMRSppm (DMSO-d6) ' 3.70
(28, Broad S).

3.93 (3H, s), 4.47 (2H,
Broad s), 5.30 (LH, d, J=5Hz
), 6.03 (IH, dd, J=5Hz, 8)+
z＞.

7.03 (IH,s), 7.17-7.73
(IIH, m>, 8.62(1)1.s), 9
．． 90 (LH, d, J = 8 Hz) Example 5 7-[2-(2-formamidothiazol-4-yl)
-2-Methoxyiminoacetamitoco-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (25.0 g) was added to ethyl acetate (3
Triphenylphosphine (21.0g) was dissolved in tetrahydrofuran (170ml) in a solution dissolved in
Add the dissolved solution and heat the mixture to reflux for 10 hours. When the precipitate was collected by filtration, [7-(2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide)-4-benzhydryloxycarbonyl-em-3-ylcomethyl-triphenylphosphonium chloride ( Syn isomer) (17.7 g) is obtained. The remaining filtrate is heated to reflux for 10 hours. Similarly, the precipitate is collected by filtration to recover the same substance (9.75 g). This operation is further repeated once to collect the same substance (3.3 g). Total yield 30.75g.

IR (Nujol): 1780. 17
20. 16B0, 1590.

1540 cm-' Example 6 (7-(2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide)=4-benzhydryloxycarbonyl-3-cephem-3-ylcomethyl-triphenylphosphonium chloride (syn isomer) (5.33 g) was dissolved in a mixture of acetone (60 ml) and water (tomQ), the solution was adjusted to pH 11 with 2N aqueous sodium hydroxide solution, and ethyl acetate (
Extract 3 times with 1ooma).

The extract was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness to give a residue, which was triturated with diethyl ether to give 7-[2-(2-formamidothiazol-4-yl). -2-Methoxyiminoacetamitoco-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (3.7 g) is obtained.

IR (Nugijir): 3300-3170
．． 1730, 1670, 1580.

1540 cm-1 48 Example 7 Phosphorus oxychloride (H.8 g), N,N-dimethylformamide (7.07 g) and ethyl acetate (501 [IQ
) to make Vilsmeier reagent by a conventional method. 2-(
tertiary-butoxycarbonylmethoxyimino)-2-(formamidothiazol-4-yl)acetic acid (syn isomer)
(29 g) were mixed with the above Vilsmeier reagent and ethyl acetate (
Add to 250ml of kentaku liquid while stirring with water cooling,
Stir at the same temperature for 30 minutes to obtain an activated acid solution.

On the other hand, 7-amino-3-chloromethyl-3-cephem-
4-Carboxylic acid benzhydryl ester monohydrochloride (3
6.1g) to trimethylsilylacetamide (63g)
and ethyl acetate (4 oomn). To this solution is added the above activated acid solution at -12°C and the mixture is stirred at -20 to 0°C for 1 hour. Add water to the reaction mixture at 0°C. The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution. The solution is dried over fermented magnesium sulfate and concentrated under reduced pressure.

Trituration of the residue with diethyl ether gives 7-[2-
tertiary butoxycarbonylmethoxyimino-2-(2-
Formamidothiazol-4-yl)acetamitoco-
3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (49.7g)
get.

IR (Nujol): 3200. 1780.
1720. 1680°1540 cm-1 NMRδppm (DMSO-da) ' 1.42 (
9H9s), 3.66 (2H1q,,Cl8Hz>,
4.43 (2H, s), 4.64 (2B, s)
.

5.27 (ILd, J=5)1z), 5.98 (
1)1. dd, J=5Hz.

8Hz>, 6.96 (LH,s), 7.00-7
．． 60 (IIH, m).

8.50 (LH, s), 9.64 (IH, d, J
=8Hz), 12.58 (IHl Broad S) Example 8 7-[2-Tertiary Butoxycarbonylmethoxyimino-
Sodium iodide ( 4.5 g) are added and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is poured into a mixture of ethyl acetate (zoomn) and aqueous sodium chloride (1oomQ), and the organic layer is separated and washed with 10% aqueous sodium thiosulfate and aqueous sodium chloride. The solution is dried over magnesium sulfate and concentrated to give a residue. This residue and triphenylphosphine (5.2 g) are dissolved in ethyl acetate (100 mA) and stirred for 1 hour. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give [4-benzhydryloxycarbonyl-(7-(2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)]. Acetamido)-3-cephem-3-ylmethylcotriphenylphosphonium iodide (65 g) is obtained.

IR (Nujol): 1785. 1710.
1680. 1530 cm-'Reference example 1 of manufacturing an antibacterial agent using the target compound as a raw material 7-[2-(2-formamidothiazol-4-yl)
-2-Methoxyiminoacetamide-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (2,2
g), 36% formaldehyde aqueous solution (20mQ
) and tetrahydrofuran (60 ma) are stirred at room temperature for 12.5 h. Ethyl acetate (roomx) is added to the reaction mixture, and the organic layer is separated, washed with 10% hydrochloric acid and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue is triturated with diethyl ether and chromatographed on silica gel, eluting with chloroform and then with a mixture of chloroform and acetone (19:1 and 9:1 by volume). What happens when fractions containing the target compound are collected and concentrated? −
[2-(2-formamidothiazol-4-yl)-2
-Methoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (0.25 g) is obtained.

IR (Nujol): 3250. 1780.
1710. 1700. 1660°1540cm
-1 Reference example 2 7-[2-(2-formamidothiazol-4-yl)
-2-methoxyiminoacetamido-3-vinyl-3
-cephem-4-carboxylic acid benzhydryl ester (
syn isomer) (2,3 g) and methylene chloride (40
Anisole (3.3 g) and trifluoroacetic acid (8.7 g) are added to the suspension solution of 1119) while stirring under water cooling, and stirring is continued for 75 minutes at room temperature. Concentrate the reaction mixture;
Water and ethyl acetate are added to the residue, and the pH is adjusted to 7 with saturated aqueous sodium bicarbonate solution. Separate the aqueous layer, add ethyl acetate, and adjust the pH to 2 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated to dryness, and the residue was washed with diethyl ether to give 7-[2-(2-formamidothiazol-4-yl). )-2-methoxyiminoacetamitoco-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g) is obtained.

IR (Nujol): 3250. 1770.
1690. 1650°1540 cm-' NMRδppm (DMSO-9)' 3.70 (2
H, q, J = 17Hz>.

3.88 (3H, s), 5.20 (LH, d
, J=5Hz>, 5.30(LH,d, J=11H
z>, 5.55 (IH, d, J=18Hz>,
5.82 (LH, dd, J: 5Hz, 8Hz),
6.93 (IH, dd, J=11Hz.

1B) 1z), 7.45 (IH,s), 8.
52 (LH, s), 9.73 (IH, d, J-8
Hz) Reference Example 3 7-[2-(2-formamidothiazol-4-yl)
-2-methoxyiminoacetamide]-3-vinyl-3
-cephem-4-carboxylic acid (syn isomer) (1,4g
) in methanol (30 mQ) and tetrahydrofuran (2 om) was added concentrated hydrochloric acid (1, om).
a) is added and the mixture is stirred at room temperature for 2.7 hours. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran to give 7-[2-(2-amitthiazol-4-yl)
-2-methoxyiminoacetamitoco-3-vinyl-3
-cephem-4-carboxylic hydrochloride (syn isomer) (1
, 2g).

IR (Nujol): 3260. 1775.
1720. 1660. 1645°1600, 15
50 cm-1 NMR8ppm (DMSO-9) = 3°75 (2H,
Q, J=18H2).

4.00 (3H, s), 5.25 (IH, d,
, C3Hz), 5.35 (IH, d, J=11Hz
>, 5.60 (LH, d, J=18Hz),
5.80 (IH, dd, J=5Hz, 8Hz),
6.98 (LH, dd, J=11Hz, 18Hz)
, 7.02 (LH,s), 9.87 (LH
, d, J4) 1z) Reference Example 4 [4-Benzhydryloxycarbonyl-7=benzylideneamino-3-cephem-3-ylcomethyl-triphenylphosphonium iodite (16.9 g) was dissolved in methylene chloride (200 m11) and water. (100mA
), add 36% formaldehyde aqueous solution (48 mfl), and p) with sodium carbonate 19.
Adjust to 0. After stirring the mixture at room temperature for 1 hour, the organic layer is separated, washed with aqueous sodium chloride solution, and dried over magnesium sulfate. When the solvent is distilled off, mp 124-1
7-penzylideneamino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (8,
6g) is obtained.

IR (Nujol)' 1770. 1710.
1630 am-1HMRδppm (DhSo-9): 3.75 (2H,q, J=18Hz).

5.1-5.8 (4H, m), 6.75 (LH
, dd, J=10Hz.

18Hz>, 6.93 (IH,s), 7.1
-8.0 (15H, m>.

8.58 (LH,s) Reference Example 5 7-penzylideneamino-3-vinyl-3-cephem-
4-Carboxylic acid benzhydryl ester (8.6g
) and Ar=7al (10+nQ) ty) trifluoroacetic acid (10m-Q) was added to the suspension at -20°C.
The reaction mixture was brought to room temperature under stirring with a stopper and stirred at room temperature for half an hour. The reaction mixture was diluted with ethyl acetate (100 mQ
) and saturated aqueous sodium bicarbonate solution (100 mQ
), and the pH was adjusted to 7.5 with a 20% aqueous sodium hypochlorite solution. Separate the aqueous layer and ethyl acetate (
100mA) and pH 7.0 with concentrated hydrochloric acid. 2 and subjected to column chromatography using alumina (1 omrL). Elute with 15% aqueous sodium chloride solution,
Collect the fractions containing the target compound and adjust the pH to 3 with concentrated hydrochloric acid.
．． Adjust to 3. The precipitated crystals are collected by filtration, washed with acetone and dried to give 7-amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) with mp 200-230°C (decomposed).

T[(Xjia-L): 1800, 16
05 0m-'NMR &ppm(D20+NaHC
O3): 3.67 (2H, s), 4.8-5,
8 (5H.m), 6.88 (LH, dd, J=1
2Hz, 18Hz) Reference Example 6 2-(3-methanesulfonamidophenyl)-D-glycine (2.44g) and methylene chloride (25mA
) Hydrogen chloride gas is added to the solution at 5 to 10°C.
Infuse for 5 minutes. Phosphorus pentoxide (3.1 g) is added and the mixture is stirred at 0-10°C for 5 hours. The precipitated solid is collected by filtration, washed with methylene chloride (5 mQ), and dried to obtain a residue (section 2.7). This residue was converted into 7-
Amino-3-vinyl-3-cephem-4-carboxylic acid (
1.8g) and trimethylsilylacetamide (6.3g
) in methylene chloride (30 mQ) at -15°C with stirring, and stirring was continued at -5 to 0°C for 3 hours. Add water (30 mA) to the reaction mixture and shake briefly. The aqueous layer was separated, adjusted to pH 5 with a 20% aqueous sodium carbonate solution, and concentrated to dryness under reduced pressure.
-204 (120 mA). After washing with water, elution is performed with 30% isopropyl alcohol, and fractions containing the target compound are collected and concentrated under reduced pressure. Lyophilization of the residue gives 7-['2-(3-methanesulfonamidophenyl)-D-glycinamide 1-3-vinyl-3-cephem-4-carboxylic acid (0.47 g).

IR (Nujol): 3300-3150.
1760. 1685°1605 cm-' Reference Example 7 [4-Benzhydryloxycarbonyl-7-(2-tertiary-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamide)-3
-Cephem-3-ylcomethyltriphenylphosphonium iodite (syn isomer) (0.59g) was dissolved in a mixture of methylene chloride (20mQ), water (1omQ) and 36% formaldehyde aqueous solution (1mQ), and 20% carbonic acid Adjust the pH to 8.0 with an aqueous sodium solution. After stirring for 3 hours at 30-35°C, the reaction mixture was reduced to 10%
Adjust the pH to 2.0 with hydrochloric acid and extract with methylene chloride. The extract is washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Residue (0,46g)
Chromatography on silica gel and elution with a mixture of benzene and ethyl acetate (2:1 by volume) yielded 7-
[2-tertiary butoxycarbonylmethoxyimino-2-
(2-formamidothiazol-4-yl)acetamitoco-3-vinyl-3-cephem-4-carboxylic acid benzhydryl esterone isomer) (0.14 g) is obtained.

IR (Sujoor): 3250. 17
80, 1720. 1680.

1540 cm' Reference Example 8 7-[2-tertiary butoxycarbonylmethoxyimino)
-2-(2-formamidothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (2 g) and anisole (g. 1)-Toluenesulfonic acid (2.2g) was added to a solution dissolved in butyl alcohol (8.omQ), and the mixture was heated at 60°
Stir at C for 5 hours. Ethyl acetate and water are added to the reaction mixture, and the pH is adjusted to 7.5 with saturated aqueous sodium hydrogen carbonate solution.

The aqueous layer is separated, washed with ethyl acetate, ethyl acetate and tetrahydrofuran are added, and the pH is adjusted to 2.2 with 10% hydrochloric acid. The aqueous layer is saturated with sodium chloride, and the organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off, the residue is washed with diisopropyl ether and filtered. Add water to this and adjust the pH to 5 with 2N* sodium oxide aqueous solution. Adjust to 5. The aqueous layer was treated with a nonionic adsorption resin “Diaion IP-20J”.
Column chromatography (20 mA) and elution with water (4 ml). Ethyl acetate and tetrahydrofuran were added to the eluent, and the pH was adjusted to 2.0 with 10% hydrochloric acid.
Adjust to 2. The aqueous layer is saturated with sodium chloride, and the organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off and the residue was powdered with diisopropyl ether and collected by filtration to give 7-[2-(
2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamitoco-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.31 g) is obtained.

IR (Nujol): 3350, 17
70. 1680. 1640 cm-'NMR
8 ppm (DMSO-d6)' 3.70 (2
H, q, J48Hz).

4,62 (2H,s), 5.21 (IH,d,J
=5Hz), 5.82(LH, dd, J=5Hz,
8Hz), 5-6 (2H, m>, 6.82 (LH
,s), 7.22 (2)1, Broad s
), 6.5-7.5 (LH.

m>, 9.5 (1) 1, d, J = 8 Hz) Reference Example 9 [7-(5-benzamido-5-benzhydryloxycarbonylpentanamidezhydryloxycarbonyl-3-cephem-3-ylcomethyl -triphenylphosphonium iodite (12
3.5g) dissolved in methylene chloride (1000mQ), 36% formaldehyde aqueous solution (3.5g) was dissolved in methylene chloride (1000mQ).
00mQ) and adjust the pH to 9.0 with 20% rehydrated aqueous sodium hydrogen oxide solution. After stirring the mixture at 25° C. for 2 hours, the pH was adjusted to 5.0 with concentrated hydrochloric acid. Separate the organic layer,
Concentrate and add ethyl acetate to the concentrate.

When the precipitated crystals are filtered and dried, mp 180 18
7-(5-benzamide 5-benzhydryloxycarbonylpentanamide 3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (63.5 g) of 4'c (decomposition) is obtained.

IR (Nujol) 7 3300. 17
7 (L 1730, 1710.

1650 cm-' NMR δppm (DMSO-d6): 1.3-2.
6 (6H, m), 3.72 (2) 1. m>, 4.
67 (LH, m), 5.1-5.6 (2) 1, m
).

5, 7-5.9 (2H, m), 6.83 (LH,
dd, J = 12Hz.

18) 1z), 6.86 (LH,s), 7.0
(LH, s), 7.42 (25M, m), 7.98
(1) 1, m), 8.92 (IH.m>Reference example 1
0 5 Phosphorus chloride (15.5g) and methylene chloride (200g)
Pyridine (5.9 g) is added dropwise to the suspension of mQ) at 5 to 10°C while stirring, and stirring is continued at 5°C for 20 minutes. This was added to 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide-vinyl-3-
Cephem-4-carboxylic acid benzhydryl ester (2
0 g) in one portion at 5° C. and the mixture is stirred at the same temperature for 2 hours. -4 methanol (120 mQ) to the reaction mixture
Add gradually at 0°C and stir at -20 to -10°C for 1 hour. The solvent was distilled off, and the residue was diluted with ethyl acetate (300
mQ) and water (50 ml) are added. The mixture was stirred for a while while cooling with water, and the precipitated crystals were collected by filtration and washed with isopropyl alcohol.MP 180-195
7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (8.
4g) is obtained.

IR (X-i-R): 1760, 170
5. 1580 cm-1HMR Sppm (DM
SO-d6): 3.88 (2H, q.J=18H
z).

5, 1-5.4 (2H.m), 5.58 (LH,
d, J=6Hz), 5.93(1)1,m), 6.
97 (LH, s), 7.0 (IH, dd, J=1
2) 1z.

18Hz>, 7.42 (IOH, m), 9.17
(2H, m) Reference Example 11 7-Amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (2.3 g) was mixed with dry ethyl acetate (50i1Q) and trimethylacetamide (4.9 g') Melt at 40℃.

Meanwhile, dry N,N-dimethylformamide (0.5 g)
, phosphorous oxychloride (Llg) and ethyl acetate (1.om
Tetrahydrofuran (2QmQ) and 2-(3-tertiary
(2-)-2-(2-
Add formamidothiazol-4-yl)acetic acid (syn isomer) (2.1 g) and stir briefly at -3 to 3°C to obtain a fully activated acid solution.

This solution is added to the above ethyl acetate solution under stirring at -10°C, and stirring is continued for half an hour at -10 to -15°C. Water is added to the reaction mixture, and the separated organic layer is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with diisopropyl ether to give 7-[2
-(3-tertiary ptoxycarbonylbroboximino)
3.63 g
).

IR (Nujol): 3280. 3150
, 1780. 1720.

1660 cm-1 NMR Sppm ('DMSO-d6): 1.43
(9H,s), 1.97 (2H.

m>, 2.38 (2H, t, J=6.0Hz),
3.79 (2) 1,q.

J=18.0)Iz), 4.18 (28,t,J=
6.0Hz), 5.33 (18, d, J=11.0)
lz), 5.34 (IH, d, J=5.0Hz).

5, 67 (LH, d, J=17.0Hz), 5.9
7 (LH, dd.

J=5.0)lz, 8.0Hz), 6.82 (I
H. dd, J = 11.0Hz.

17,0Hz), 7.00 (IH,s), 7.1
9-7.73 (IIH.

m), 8.57 (1)1,s), 9.77
(IH, d, J = 8.0 Hz) Reference Example 12 7-[2-(3-tertiary butoxylponylbroboximino)-2-(2-formamidothiazol-4-yl)acetamitoco-3- Vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester (syn isomer) was treated in the same manner as in Reference Example 8 to obtain 7-[2-(2-aminothiazol-4-yl)-2-(3-carboxypropoxyimino)acetamide]-3- vinyl roux 3-cephem-4
- obtain carboxylic acid (syn isomer).

Claims (1)

[Claims] Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_A is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Syn type), or R^4-CH=N- (wherein, R^a is a protected amino group, R^b is a protected carboxy group, R^2 is an amino group or a protected amino group, and R^3 is a lower an alkyl group or a lower alkyl group substituted with carboxy or protected carboxy, R^4 means an aryl group, respectively), R_B is a group represented by the formula -CH_2-X^1, -CH_2P^■ (R^ 5)_3
・X^2^■ or -CH=P(R^5)_3 (in the formula, R^5 is an aryl group, and X^1 and X^2 each mean a halogen), R^1 means a carboxy group or a protected carboxy group] A compound or a salt thereof.