JPS58986A - 7-acylamino-3-vinylcephalosporanic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R<1> is halogen, aminothiazolyl, which may be substituted; R<2> is carboxyl, protected carboxy-lower-alkyl; R<3> is carboxyl or protected carboxyl) or its salt. EXAMPLE:7-[2-( 2-Aminothiazol-4-yl )-2-benzhydriloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-car boxylic benzhydril ester. USE:Antibacterial, especially for oral administration. PREPARATION:The reaction between a compound of formula II, its derivative with an activated amino group or their salt, and a compound of formula III, its derivative with an activated carboxylic group or their salt, is carried out in the presence of an organic or inorganic base in a solvent such as acetone, preferably using a condensation reaction reagent such as Vilsmeier reagent to give the compound of formulaIor its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel syn isomer of 7-acylamino-3-vinylyafalosborane acid derivative and its pharmaceutically acceptable salt W4.

More details KFi, this invention is a new m1 with antibacterial activity
The present invention relates to syn isomers of ky-acylamino-3-vinylceph 10 spotnic acid derivatives, pharmaceutically acceptable salts thereof, methods for producing them, and pharmaceutical compositions containing them as main ingredients.

Therefore, the object of Jin's invention is to develop a novel 7-acylamino-3-vinylcephasboranic acid derivative that exhibits excellent antibacterial activity against a large number of pathogenic microorganisms and is useful as an antibacterial drug, a drug for oral administration to species. The purpose of the present invention is to provide a syn isomer of and pharmaceutically acceptable JlI classes thereof.

Another object of the present invention is to obtain the syn isomer of 7-acylamino-3-vinylceph 10-sboranic acid or its m-series! I! K-stone provided with a method of making.

Another object of the present invention is to provide an antibacterial agent containing the syn isomer of the 7-acylamino-3-vinylcephalosporan eas form and its pharmaceutically acceptable salts as active ingredients.
I have K to offer.

The syn isomer of 7-acylamino-3-vinylse-7-allosboxonic acid #I is a novel compound which is the object of this invention and can be represented by the following general formula.

(In the formula, R1 is an aminothiazolyl group that may be substituted with a halogen or a protected aminothiazolyl group that may be substituted with a halogen, R1 is a carboxy or protected nine-carboxy(lower) alkyl group, and R8 is a carboxy group or a protected aminothiazolyl group. (respectively means a carboxy group) The target compound l1kJfI obtained by the method shown below.
) and the corresponding raw material compounds (■), (to) and Both bodies are intended to be encompassed by this invention.

Suitable salts of the object compound (I) include pharmaceutically acceptable salts, especially the customary non-toxic salts, such salts with bases and acid addition salts, i.e. with inorganic bases; For example, sodium salts, alkali metal salts of Calicum Shiohata, calcicum salts, alkaline earth metal salts of Magnesicum 1141, ammonicum salts, salts with organic bases such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts. organic amine salts such as salts, dicyclohexylamine salts, M,H'-dibenzylethylenediamine salts, hydrochlorides, hydrobromides,
Inorganic acid addition salts such as sulfates and phosphates, formates, acetates, trifluoroacetic acid salts, maleates, tartrates, mecnesulfone salts, benzenesulfonates, p-)luenesulfonates, etc. Organic carboxylic acid ma9 is a sulfonic acid addition salt,
There are rumors of salts with basic or acidic amino acids such as alkaline, asparagine, and glutamic acid.

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

(1) Method 1 (I) or its salts (2) Method 2 (1-b) First its salts im+ Method 3 (4) Method 4 (1-c) or its salts (6) Method 5 (I-e ) or its salts (-) Method 6 (1-g)t or its salts (1) Method 57 (I-1) Maku is its salts In formula 1, R1, BS and R51i Same meaning as before, RA
is a protected aminothiazolyl group that may be substituted with halogen, cursor is a protected aminothiazolyl group that may be substituted with 710 gen, food is a protected carboxy (lower) alkyl group, RA is a carboxy (lower) alkyl group,
R: Fi protected 9 carboxy group, R911i protected carboxy (lower) alkoxy carbonyl group, ridge is carboxy (lower) alkoxy carbonyl group, R4 is amine 7 group or protected amino group, X"Fi/'logen, respectively meaning] FIl used in solutions 1 and 5
It contains the novel compounds No. 1), (8) and [) #-1, and is represented by the following general formula.

[In the formula, RA is the formula R' -H(CH,)@CCMH-1b RL-C-■匪-1 or garlic\(IR" BLCH=M- (wherein, BS is a substituted or unsubstituted aryl group) BS means a protected amino group, Rb means a protected nine-carboxy group, R1 and R2 have the same meanings as before), RBFi formula % formula % ((in the formula, XI and X5Vi each halogen, R'd
(means an aryl group), and has the same meaning as before R'tli, and when RA is a group represented by the formula % (in the formula, Hqd means an unsubstituted aryl group), KFi , RBFi formula % formula %) ] or its salts (2) , Rc and Rd are combined to form a protected oxo group, and “t ”r R”+ R
b and xl have the same meanings as before) means a group represented by HaF! It has the same meaning as before,
When Ro is an amine 7 group, RsFi is a carboxyl group] Maku is its salt OR: [In the formula, X4 is hydrogen or halogen, and R8 means a carboxyl group or a protected carboxy group, respectively. death
B: , HQ and Rd B each has the same meaning as above or a salt thereof [wherein R:, R4 and R@ each have the same meaning as above 1 or a salt thereof As an appropriate salt of 1IAP+ compound ■ to ■ shown in the above The same kind of compounds as those exemplified for compound <11 are given below.

The raw material compounds can be prepared, for example, by starting from a known compound and performing the fertilizing process by using a method similar to that of #i or a conventional method. be treated well.

k] (■-C) Maku is its salts in formula 1, n", 'Rg, R" OyoU: (■-f) (■-g) or its salts 1IiI or its salts (Φ-1 ) (■-h) [% in the formula ”
& e R' and zR#'i each have the same meaning as above] [In the formula H! , H3 and xlFi each have the same meaning as above] (■-1) (■-a)0O
H (■-b) or its salts In formula 1, R: , R' and R- each have the same meaning as above) Process ■-(3) R" (■-e) Maku is its salt J (■) or its salt furnace [in the formula, RJL, Rb, R"OyoOR"#i soh soh same meaning as above] process ■ (■-d) (■-C) or its salts [in the formula ''' + Rd , H: and xl have the same meanings as above, respectively.
i7h! tL Previous J Same Meaning J Below and in the following explanation, appropriate examples included in the various definitions will be explained in detail as follows.

The term lower is used to include groups having from 1 to 7 oxygen atoms, unless h specifies otherwise.

The lower alkyl moiety in the above definition is a branched group, such as methyl, ethyl, propyl, inpropyl, butyl, isobutyl, pentyl, impentyl,
Contains neopentyl, hexyl, etc., of which carbon #1
to 4 alkyl is preferred.

Suitable protected carboxylic acids include the commonly used esterified carboxylic acids at the 3rd and 4th positions of penicillin and cef10 compounds.

Suitable ester moieties in esterified carboxy include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester,
Lower alkyl esters such as isobutyl ester, 11g tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, lower alkynyl esters such as vinyl ester, lower aryl ester of allyl ester, ethynyl ester, propynyl ester,
Lower alkoxy (lower) nalkyl esters such as methoxymethyl ester, ethoxymethyl ester, impropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthio Lower alkylthio (lower) alkyl esters such as methyl esters, 2-iodoethyl esters, λ2,2-)! Mono (or di or tri) halo (lower) alkyl esters such as 7-chloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, imbutyryloxymethyl ester, valeryloxymethyl, ester, pi Baloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxymethyl ester, l-
Lower alkanoyloxy (lower) alkyl ester such as acetoxyethyl ester, mesyl methyl ester, 2
-Lower alkane-sulfonyl (ail) alkyl ester of 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,s-di1131butylbenzyl ester mono(or di- or trip)phenyl(
Lower II) Al (lower) alkyl esters optionally having two or more substituents, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityls of alkyl esters 1 such as ester, cumenyl ester, butyl ester, etc.
Aryl esters, heterocyclic esters such as phthalidyl esters, carboxymethyl esters, l or Fi2-carboxyethyl esters, l or 2 or ti3-carboxyethyl esters, which may have one or more suitable substituents.
Carboxy (lower) alkyl ester such as carboxybutyl ester, methoxycarbonyl methyl ester, ethoxy carbonyl methyl ester, tertiary ptoxycarbonyl methyl ester, l also L<1lt 2-butoxycarbonyl ethyl ester, 1 or Fi2 or 1li
Included are protected carboxy (lower) alkyl esters such as lower alkoxycarbonyl (lower) alkyl esters such as 3-113-butoxycarbonyl probyl ester.

Suitable protected aminos include the customary amino protecting groups used in penicillin and cephalosporin compounds, such as the acyls described below, such as mono(or di-tri)phenyl(lower) alkyls such as benzyl, benzhydryl, trityl, etc. Al (lower) alkyl, such as
Lower alkoxycarbonyl (lower) alkylidene such as 1-methoxycarbonyl-1-7'lopen-2-yl, its enamine tautomer, di(lower) alkylamino methylene such as dimethylamino methylene, etc. substituted with 9 amino groups is included.

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

Aliphatic acyl includes saturated or unsaturated, acyclic or cyclic, such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl,
Lower alkanoyl such as invaleryl, pino(loyl, hexanoyl, etc.), lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, quaternary butoxycarbonyl, acryloyl, methacryloyl,
These include lower alkenoyl such as crotonoyl, C5-C such as cyclohexanecarbonyl, cycloalkanecarbonyl, amidino, and the like.

Examples of the aromatic acyl include aroyl such as benzoyl, toluoyl, and xyloyl-7taroyl, arenesulfonyl such as benzenesulfonyl and tosyl, phenylcarbamoyl, tolylcarno(moyl), and arylcarno(moyl) such as naphthylcarbamoyl. It will be done.

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

The aliphatic acyl substituted with an aromatic group includes alkanoyl (lower) alkanoyl such as phenyl (lower) alkanoyl such as phenylacetyl, phenylpropionyl, 7-enylhexanoyl, benzyloxycarbonyl, 7-enethyloxycarbonyl, etc. Included are alkoxycarbonyls such as phenyl(lower)alkoxycarbonyl, and phenoxy(lower)alkanoyls such as phenoxyacetyl and phenoxypropionyl.

Aliphatic acyl substituted with a heterocyclic group includes chenyl acetyl, imidazolylacetyl, 7lylacetyl,
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, chlorine, bromine, iodine, fluorine, etc., methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy,
Lower alkoxy such as hexyloxy, lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, gutylthio, pentylthio, hexylthio,
Nitro, etc. are included, and examples of permissible acyl having such substituents include chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl◆, mono (or di or tri) halo (lower) alkanoyl, chloromethoxy carbonyl, dichloromethoxycarbonyl, 2
, 2.2-Trichloroethoxycarbonyl, mono(or di- or tri)halo(lower)alkoxycarbonyl, nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, nitro(or halomodyl or lower alkoxy) such as methoxybenzyloxycarbonyl Includes phenyl (lower) alkoxycarbonyl, etc.

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

Suitable substituted or unsubstituted aryls include phenyl, tolyl, xylyl, naphthylhydroxyphenyl, dihydroxyphenyl, and the like.

Suitable protected oxos include di(lower)alkoxy such as dimethoxy, jetoxy, dipropoxy, lower alkylenedioxy such as ethylenedioxy, trimethylenedioxy, propylenedioxy, tetramethylenedioxy, hequinamethylenedioxy, etc. Includes bis(substituted oxy) such as.

Suitable aryls include phenyl groups.

Suitable lower alkoxycarbonyl moieties include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl, and the like.

Furthermore, some preferred examples of the above definition are as follows.

Examples of "aminothiazolyl optionally substituted with [).logn" in Bl and R' include 2-1 minothiazol-4-yl and 2-amino-5-chlorothiazol-4-yl.

Examples of the "protected aminothiazolyl optionally substituted with nitrogen" in R1 and Curse include 2-acylaminothiazol-4-yl (more preferably 2-lower alkanamidothiazol-4-yl,
Most preferred is 2-formamide Vthiazole-4
-yl), 2-acylamino-5-710thiazole-
4-yl (more preferably Fi2-lower alkanamido-5-)10thiazol-4-yl, most preferably 2-formamido-5-chlorothiazol-
4-il).

Examples of "carboxy (lower) alkoxy" in R3 and R"K include carboxymethyl, carboxyethyl, carboxypropyl, 1-methyl-1-carboxyethyl, carboxyhexyl, etc., and carboxymethyl is most preferred. and t=≠≠Yuzou l-carboxyethyl.

'Protected carboxy(lower)alkyl' in R1 and R: is, for example, esterified 9-carboxy(lower)alkyl, more preferably L<Fil-18
Lower alkoxycarbonyl (lower) alkyl of the tertiary butoxycarbonylethyl group, benzyloxycarbonylmethyl, benzhydryloxycarbonylmethyl, etc., mono- or di- or a)'J phenyl <low e> alkoxycarbonyl (lower) alkyl, chloro Examples include mono-, di-, or trichloro(lower)alkoxycarbonyl(lower)alkyl such as methoxycarbonylmethyl, 2-iodoethoxycarbonylmethyl, and 2°λ2-trichloroethoxycarbonylmethyl.

[Protected 9-carboxy] in Ra and R1 includes, for example, esterified 9-carboxy,
More preferably benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl,
Mono- or di- or triphenyl (lower) alkoxycarbonyl such as P-nitrobenzyloxycarbonyl, carboxy (lower) alkoxycarbonyl such as carboxymethoxycarbonyl, carboxymethoxycarbonyl, carboxypropykoxycarbonyl, 93-butoxycarbonylmethoxycarbonyl , methoxycarbonylethoxycarbonyl, ethoxycarbonylmethoxycarbonyl, methoxycarbonylethoxycarbonyl, lower alkoxycarbonyl (lower) alkoxycarbonyl such as l- or #'12-tertiary butoxycarbonylethoxycarbonyl, etc. (lower) alkoxycarbonyl stone.

Examples of the [protected carboxy (lower) alkoxy carbonyl] in R8 include, for example, the esterified carboxy (lower) to alkoxy carbonyl specifically mentioned in the explanation of R3 and R:.

As the p3y>y stone "carboxy (lower) alkoxycarbonyl", for example, those specifically listed in the explanation of R1$P and R3 can be mentioned as they are.

Examples of the "protected amino" in '14 include acylamino, and more preferably lower alkanamides.

Examples of the "protected amino" in R1 include acylamino, and more preferably lower alkoxycarbonylamino such as methoxycarbonylamino and ethoxycarbonylamino, 7enyl uccireidofuryed, and tutarimide.

[Protected carboxy-1 in RbK includes, for example, esterified carboxy, and more preferably mono-, di-, or triphenyl (lower) alkoxycarbonyl such as benzyloxycarbonyl and benzhydryloxycarbonyl. .

Examples of He and RfK "protected carboxy" include esterified carboxy,
More preferred are lower alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, and tertiary butoxycarbonyl.

Methods 1 to 7 for producing the target compound will be explained in detail as follows.

(1) Method 1 A compound or a salt thereof is prepared by reacting compound (1) or a reactive derivative thereof at an amino group or a salt thereof with compound 1) or a reactive derivative thereof at a carboxy group or a bottle thereof. is manufactured.

Suitable salts of starting compounds 1) and 1) include those of the same type as mentioned in the compounds.

Suitable reactive derivatives of the amino group of the compound (iris) include commonly used derivatives, such as V-lyl derivatives obtained by reaction with V-lyl compounds such as bis(trimethysilyl-V)acetamide and trimethylsilylacetamide; , isoVane), inthiocyanate, amino group and aryon, toaldehyde, isobentaldehyde, benzua
Dehyde? Aldehyde compounds such as lityla V dehyde, pheny V acetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenmer dehyde, todromV naphthoa ν dehyde, furfufu V, thiophene carbaldehyde, acetone, methyl ethyl ketone, methyl isobutylene Ketone, acetyl heptane,
Included are ship bases obtained by reaction with carbonyl compounds such as ethyl acetoacetate JI/Misaki ketone compounds or tautomers thereof.

Suitable reactive derivatives in the force V poxy group of compound 1) include lamps, acid halides, l! Includes anhydrides, activated amides, active esters, etc., among which preferred are:
Acid chloride, acid bromide, f% phosphoric acid C e.g. 971
W Kir"1411!, y engineering=sy phosphoric acid, diphenylene V phosphoric acid, dibenzyl phosphoric acid, halogen north neighbor i11 mixed anhydride, shea A/kyl phosphorous acid mixed anhydride.

Sulfite mixed anhydride, Thio@! Acid mixed anhydrides, RWII mixed anhydrides, alkylblown acids (e.g. methyl #I! acid, ethyl pvp acid, propyl sub-acid, etc.) mixed anhydrides, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, isopentanoic acid,
2-ethylbutanoic acid, triclosacetic acid, etc.) mixed anhydrides,
Mixed #anhydrides such as aromatic carboxylic acids (e.g. benzoic acid) mixed anhydrides, symmetric #anhydrides, imidazo-A/%4-
Substituted imidazole, dimethyl bifuzo A/,) activated amide with an imino group-containing heterocyclic compound such as Reashi V, tetrazole, p-nitrophenyl ester A/, 2.
4-dinitrophenyl ester, trichloropheny V ester, pentachloropheny V ester Iv, medi V phenyl V ester, phenyl V azophenyl M ester, phenyl thio ester, p-nitrophenyl thio ester, p
-Cr-V ruthioester, carboxymethylthioester, pyridyl ester, piperidyl ester, 8-quinolylthioester ν, arm-hydroxy compound C e.g. Ml
M-dimethylhydroxylamine, 1-hydroxy-2
(lH)-pyridone, H-e doloki V succinimide,
Active esters such as N-hydroxyphtashiimide, esters of 1- and do-P-xybenzocyriazole, 1-hydroxy-6-chloropenzotriazo V, etc.) are included. Suitable reactive derivatives include (■
) is selected as appropriate depending on the type.

This reaction is preferably carried out using alkali metals such as lithium, sodium, and potassium, alkaline earth metals such as S/v, alkali metal hydrides such as sodium hydride, and alkaline earth metals such as calcium hydride. metals, hydroxide)
Alkali metal hydroxides such as IJium and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium hydrogen envyate and potassium hydrogen hydrogen, sodium methoxide, sodium ethoxide , potassium tertiary butoxide and other alkali metal alkoxides, sodium acetate and other alkali metals, triethylamine and other trialkylamines, pyridine, lutidine, picoline and other pyridine compounds;
It is carried out in the presence of an organic species such as quinoline and an inorganic base.

In this reaction, when compound 1) is used in the form of a free acid or a salt thereof, 1, for example, N,N-dicyclohexyl V
Carbodiimide, irises-cyclohexyl-1i-(4-diethylV-aminocyclohexyl)carbodiimide, m,
Carbodiimide compounds such as i-diethylcarbodiimide, N,II-diisopropylcarbodiimide, N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, etc.

N-carbonylbis(2-methylimidazo-v).

Ketenimine compounds such as pentamethylene ketene-N-cyclohexylimine, diphenylene V-kedene-N-cyclohexy imine, etho*s' acetylene.

Olefin or care acetylene ether compounds such as β-chlorovinylethyl ether;
1' Compound sulfonic acid ester, trialkyl phosphite or triphenylphosphine and tetrachloride, disl@/phyto or diazendica V poxylate (
For example, combinations with diazendica V (bonic acid diethyl ester), polyphosphoric acid ethyl V1 polyphosphoric acid isopropylene V, phosphorus compounds such as phosphorus chloride IJw, phosphorus pentachloride, thionyl chloride, oxali chloride V%-ethylbenzisoxazolium bottle. ,
Summer, H-di(low I
&) 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 alkylformamide or H-methylformamide with a halogen compound such as thionyl chloride, phosphoryl chloride or phosgene.

This reaction usually involves water, acetone, yt*sane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chlorophyte, detofhydrof? /, #acid-f4,
This is carried out in conventional F# ropes that do not affect N,Il-dimethylene such as formamide, pyridine, hexamethylene V phosphoramide, etc. or mixtures thereof.

During these washings, the hydrophilic solvent 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, a compound in which the amino group in R1 of the starting compound is converted to N,H-di(lower)alkyl to aminomethylene)aminobhVc,w is obtained during the reaction. Kotomeru, but
In this case, this child is included in child #4 who stutters.

(27 Method 2 Compound (J-b) or its salt is compound (1-a)
Alternatively, it can be produced by subjecting its salt IIIA to an elimination reaction of the amino protecting group at -.

This removal of #1f is carried out by conventional methods such as hydrolysis, reduction, or combination of iminohalogenation and iminoate V-formation and, if necessary, hydrolysis.

(1) Hydrolysis Hydrolysis is carried out in the presence of an acid or a base.

Suitable acids include inorganic soaps such as hydrobromic acid, sulfuric acid, etc.; *.

A cylindrical ion exchange resin or the like is used. In this reaction, when an organic phase such as trifluoroacetic acid (%p-)Benesulfonic acid is used, it is desirable to carry out the reaction in the presence of a cation scavenger such as aniso-.

As suitable bases, 11 specific examples of the bases mentioned in Method 1 can be cited.

The acid and 4m suitable for this hydrolysis are selected depending on the type of protecting group to be removed, e.g. Preference is given to applying hydrolysis to the protecting groups.

Hydrolysis is usually carried out using conventional solvents that do not adversely affect this reaction, such as water, methanol, ethanol, propano-J/, tertiary butyl alcohol, tetrahydrofuran, w, m-N methoxyformamide, dioxane, etc. It is carried out in a solvent or a mixture thereof, and can also serve as a bath when the upper limit is liquid.

The reaction temperature for hydrolysis is not particularly limited, but the reaction is usually carried out under cooling or with slight heating (acupuncture).ReductionReduction is carried out by conventional methods such as chemical reduction or catalytic reduction.

Suitable reducing agents used in the chemical reduction include metal compounds such as tin, iron, iron, chromium chloride, #acid, formic acid, acetic acid, propionic acid, trifluoroacid, etc. p
- Toluene Vhonkyo, - Meng, bromide solution ** or a combination with black acid is used.

Suitable catalysts used in the catalytic reduction include platinum catalysts such as platinum plate, sponge platinum, platinum black, colloidal platinum, saponified platinum, platinum wire, sponge puffium black, saponified padjilum, palladium footmine, colloidal puff V um, badge rum barium sulfate, palladium wrought barium, etc. Bara 99m touch rope, reduced nifkeshi, mized nifke V, lane nicke, etc.=fuke V touch, I! Cobalt catalysts such as primary cobalt and Raneycoba, iron catalysts such as reduced iron and Fune iron,
Conventional catalysts include copper catalysts such as 111 steel, Raney copper, crimped Mann copper, and the like.

The selection of the method is appropriate depending on the type of plant to be used. For example, chemical reduction 1 is used for the amino protecting group used in Ryo such as halo (low @) It is preferable that it is applicable to substituted or unsubstituted A, IW (lower), V, koxycarbon, and the like.

It is best to use catalytic reduction 1ki@.

Kangensha, water, methanol, ethanol-V, propano-V%
11. This reaction of M-dimethylformamide etc.
It is carried out in conventional # ropes, or mixtures thereof. Furthermore, if the acid used in the chemical reduction is a liquid, it may also serve as a solvent. Further, as the solvent used for the catalytic reduction, in addition to the above-mentioned solvents, conventional solvents such as diethyl V-ether, dioxane, tetrahydrofuran, etc., or mixtures thereof may be used.

The reaction temperature for reduction is not particularly limited, but il! I The reaction is carried out under normal cooling or heating.

[Phases] Iminohalogenation (first step), iminoate V conversion second step @1, and hydrolysis as necessary (
The binding method of the final step) The WJl and second steps of this method are carried out in anhydrous water. Suitable solvents in the first step (iminohalogenation) include methylene chloride, chloroform, aprotons such as dioxane, dioxane, etc.; ) is usually carried out during the first step. These two steps are usually carried out under cooling or at room temperature. These two steps and the final step (hydrolysis)
It is desirable to perform this in one batch.

Suitable iminohalogenating agents include phosphorus halogen compounds such as phosphorus trichloride, phosphorus pentachloride, phosphorus hexabromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene, and the like.

Suitable iminoetherification agents include methanol, ethanol, propano-V, isopropano-V, butano-V.
alkano-V or ti2-methokinoethano-pv, such as
2-EthoxyV ethanol, etc. to the corresponding AV koxy'1', and sodium methoxide, potassium nidoxide, magnesium ethoxide.
Included are alkoxides of metals such as alkaline earth or alkaline earth metals such as lithium methoxide.

The obtained compound is hydrolyzed by a conventional method if necessary. The hydrolysis is preferably carried out at room temperature or under cooling, the reaction mixture being simply water or hydrated methano-V,
Hydrophilicity such as Etano-V! Simply inject into the solution and add a base to the acid mixture as necessary.

Suitable acids include those mentioned in the middle hydrolysis, and suitable bases include those mentioned in Method 1.

The method described above is appropriately selected depending on the class of the S-binding group to be eliminated.

In this reaction, the protected force V in n12 and R3 may change into the free force V during the reaction, but this case is also included in this invention.

(3) Method 6 The compound (1-<1) or its salts is the compound (l-
o) or its salts tR: is produced by subjecting the Hoki V group to an elimination reaction.

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

Hydrolysis and reduction methods and reaction conditions C reaction temperature;
Since the reaction (solvent, etc.) is similar to the elimination reaction of the amino protecting group in compound (1-a) described in Method 2 and Kltli1, the above description is incorporated.

In this reaction, the protected amino in B1 and/or
In addition, the protected force in ti- may change to free amino and/or the free force to *kiV during the reaction, but this case is considered to be included in the present invention.

(4) Method 4 Compound (1-o) or a salt thereof is compound (1-a)
Alternatively, it can be produced by subjecting its salts to a reaction for introducing a Hoki V protecting group.

The power that comes out with this method is amazing! Agents for introducing IrV protecting groups include esterifying agents such as alcohols or reactive equivalents thereof such as hafides, sulfokiites, sulfonates, diazo compounds and the like.

This reaction can be carried out in the presence of a base; suitable examples of bases include those mentioned in Method 1; and this reaction can be carried out in the presence of a metal iodide, such as sodium iodide. is preferred.

This reaction is usually carried out in a conventional solvent such as N,H-dimethyV-formamide, tetrahydrofuran, dioxane, methanol, ethanol-V, etc., which does not affect the reaction temperature, or a mixture thereof.

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

When using a V-co #ie as an agent for introducing a protective group, it is desirable to carry out the reaction in the presence of the condensing agent described in Method 1.

In this reaction, compound (1-<1) 1 in 4C
The force V in 12 may change to the protected force V during the reaction, but this case is also included in this invention.

(b) Direction: 5. Add compound (1-e) and, in the same order, compound (IV) or 8mK compound (vI').
I! be done.

Appropriate salts of compound G) include salts with the same bases as exemplified in the compound.

This reaction is carried out in a conventional solvent that does not adversely affect the reaction, such as monoethyl acetate, methylene chloride, chlorofoshim, IM tetrachloride, tetrahydrofuran, dioxane, water, or a mixture thereof.

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

(6) - The compound (1-g) or the woodcutter - is the compound (1-f
) It is carried out by subjecting it to an elimination reaction of the calhoki Vα protecting group in the *@kR”.

This anti-&cA is carried out by conventional methods such as hydrolysis and #L oxidation.

How to hydrolyze and reduce? and reaction conditions (reaction temperature,
solvent, etc.) rL, compound (1-a) VC described in method 2
Substantially the same procedure as the elimination reaction of the amino protecting group in
The above description is incorporated.

In this reaction, the protected amino in E and/
Alternatively, the protected force Vboxy in R may be changed to free amino and/l or free force S/, but these cases are also included in the present invention.

(7) Method 7 Compound (J-1) or its woodcutter II4 is compound (1-
h) or its salts 1kR3 is produced by subjecting it to an elimination reaction of the protective group.

This reaction is carried out by conventional methods fk such as hydrolysis 1 and reduction.

Hydrolysis and reduction methods and reaction conditions (reaction temperature,
Solvent, etc.) Fi, the reaction is qualitatively similar to the elimination reaction of the amino protecting group in compound (1-a) described in Method 2, so the above description is incorporated.

In this Ii reaction, the tasted amino in R and/
Alternatively, the calhoquine removed from the protective field in R2 may be converted to free amino and/or free force during the reaction, but this case is also included in the present invention.

? A single #11 sample is added to the target compound obtained by the above-mentioned methods 1 to 1 by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, and chromatography.

A detailed explanation of the procedures for producing raw material compounds (methods ■ to ■) is as follows.

(1) fcsu1Sn1su [process] Compound (■-b) and its vagueness are compound (■-&)
Alternatively, it can be produced by reacting a reactive derivative at its amino group or a bottle thereof with compound 1) or a reactive derivative at its amino group.

Examples of suitable salts of compounds C■-a) and C■-b) include those of the same kind as those exemplified in the compounds ri.
It will be done.

Suitable reactive derivatives at the amino group of compound (■-a) include the same ones as exemplified for compound 1) in method 1.

In this reaction, we explained about gj1 and the actual Kfj
The reaction method, reaction conditions (reaction temperature, solvent, base, etc.) are carried out in the same manner as described above.

[Process B]

Compound (■-0) or its salt is compound (■-b)
Or is there a halogenating agent in the w4? Manufactured by reaction.

Suitable salts for compound C-0) include the same salts as those exemplified for the compound.

An unreasonable halogenating agent used in this reaction is!
Phosphorus halides such as 1 Fukuka phosphorus, 5 Moka phosphorus, Oki V Asahi Kitadori, 3 bromide phosphorus, 5 bromide phosphorus, Gonka thioni A/special halogenated thionidium, phosgene, etc. and droxy group t halogen. Those commonly used for this purpose are used.

This reaction L1 is preferably carried out in the presence of a base such as the organic base mentioned in connection with Section 1.

This reaction usually involves methylene chloride, chloroform,
It is carried out in conventional f# media which do not acutely 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.

(2) Process ■-(2) Compound (■-e) or its salt is compound C■-d)
It can also be produced by subjecting the seal to a reaction of introducing an amino protecting group and a Hoki V protecting group.

This reaction is carried out qualitatively in the same manner as described for the as/conversion reaction and the reaction for introducing a V-boxy protecting group in Methods 1 and 4, so depending on the reaction conditions (reaction temperature, solvent, etc.) , the above description is incorporated.

(3) Process ■-(3) [Step A] Compound C■-g) or a class thereof is compound (■-f)
t7'jfl is produced by reacting the compound with a compound represented by the formula R''-CEO (wherein R has the same meaning as before).

Suitable salts for compounds (■-f) and C■-g) include the same salts as exemplified for the compounds.

Kono reaction, moleki: L Fushi ++ Fuya 741-t'
Preferably, it is carried out in the presence of the listed bases.

This reaction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, dimethylformamide, and the like.

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

[Engineering IIB) ・The compound (■-h) is the compound (■-glt&kesoj11
It is produced by introducing a carboxy protecting group into

Since this reaction is carried out in substantially the same manner as explained for method fk4, the above explanation regarding the reaction conditions (reaction temperature, solvent, base, etc.) is referred to.

[Step 0] Compound (■-1) is produced by subjecting compound (■-h) to a halogenating agent.

This reaction is carried out in substantially the same manner as described for [Step B] of Process ①-(1), so the reaction conditions (reaction temperature, M strategy, halogenating agent, etc.) K are as explained in Explanation 1 above. I will use it.

(4) lヱ34東云士 Compound @) or its jj1 inclination is a compound (position) or a reactive derivative at its amino group, or a salt thereof, or a reactive derivative at its poxy group or its ms. 'i by reacting l111
m is done.

Suitable bottles for the compound include those exemplified for the compound.

Suitable reactive derivatives of compound .include the same as exemplified for compound 1) in method 1.

Since this reaction is carried out in substantially the same manner as described for Method 1, the reaction method, reaction conditions, C reaction temperature, #l
(bases, etc.), the above description is cited.

(6) Process■-(2) [Work 1! A) Compound (■-a) is compound [■-1) K formula PLR) 3
f (wherein R6 has the same meaning as before) is reacted with a tri-substituted main sphine, then the generated phosphonium compound is reacted with a base ', and the generated phosphonium compound is further reacted with foshimade Vde. Manufactured.

In this reaction, when a trisubstituted phosphine is allowed to act, it is preferably carried out in the presence of a metal halide such as alkali metal halide such as sodium iodide, potassium iodide, and sodium bromide.

Suitable bases for use in this reaction include those exemplified for Method 1.

This reaction is usually carried out using conventional materials that do not have an adverse effect on this reaction, such as M0M-dimethyl V-formamide, dimethyl V oxide, methylene chlorophyte, tetofhydrofuran, ethyl acetate, dioxane, acetic acid, tetofhydrofuran, water, etc. It is done in a solvent.

The reaction temperature is not particularly limited, but the reaction is carried out at normal cooling to slightly warm temperature.

[Work! 1B] Compound (■-b) or one of its classes, compound C■-a)
't-7 is produced by subjecting it to an elimination reaction of a amino-holding tII group and a carboxy-holding M group.

A suitable class of compounds (■-b) includes the same compounds as those exemplified in the compound.

This reaction is carried out by conventional methods such as hydrolysis.

Hydrolysis is explained for 10,000 m2 and substantial VCX
The hydrolysis method and reaction conditions (reaction temperature, solvent content) are as described above.

(6) Process ■-(3) [Step M] The compound (■-0)'f or its salts is the compound (■-6
) or its salts are reacted with a halogenating agent, and then the generated halogen compound has the formula P(B ).

(R6 in the formula c has the same meaning as before), reacting the generated phosphonium compound with a base, and further reacting the generated honupholidene compound with formaldehyde.
It is manufactured well.

This reaction is carried out in substantially the same manner as Process 1-(1) [Step B] and Process 2-(2) [Step A], so the reaction conditions are C: reaction temperature, solvent.

Regarding the base, halogenating agent, etc.), the above description is cited.

[Step B] Compound (1) or its salts are produced by subjecting it to an elimination reaction of compound C-0) or its group S/J%/.

This reaction is usually carried out by a bonding method consisting of iminohalogenation, iminoate V-formation and, if necessary, hydrolysis.

This bond (B) and reaction conditions (C, reaction temperature, melting point) are:
Since this is substantially the same as the explanation regarding the direction gt2, the above explanation will be cited.

(7) Process ■ [Step M] It is produced by reacting the compound (■-b) with the compound (■-a) or a reactive derivative thereof.

Suitable N-responsive derivatives of compound (Vl) include pallite such as chloride, bromide and B-dite.

This reaction is usually carried out in the presence of a base, and 70 cases of the bases exemplified in Method 1 are used as such bases.

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

[Process B]

Compound (■-C) is prepared from compound C■-b) [K by reacting with a halogenating agent.

Suitable examples of the halogenating agent include halogens such as chlorine and bromine, hypohalous acids such as hypochlorous acid, hypochlorous acid, 6th-butylbutylene, or its alkyl-ester V%-gromoacetamide. ON-haloamide compounds such as , I-iodoacetamide, chlorinated succinimide, chloronac imide, N-chlorophthalamide, cuprous halides such as JII copper, cuprous bromide, and Examples include Vnium hydropromide perpromide% dioxane promide.

For this reaction, the following substances are usually used: Common practice 119 that does not have a negative effect on the reaction! carried out in ropes, or mixtures thereof.

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

In this reaction, when palm is used as a solvent, Rf
In some cases, the V-retaining group is removed during the reaction, and such cases are also included in this reaction.

[Process C]

Compound t■-d) or its xmh, compound (■-o)
It is produced by subjecting the force V in kR' to an elimination reaction.

Suitable salts of compound C-6) include bottles with the same bases as exemplified in the compound.

This reaction is carried out by conventional methods such as hydrolysis, reduction, etc.

The hydrolysis and reduction methods and reaction conditions (reaction a1%, etc.) are substantially the same as those described for Method 2, so the above description is incorporated.

(8) Two otsu-m and [process m] The compound (■) or its bottle l1lil is the compound (■-
&) It is produced by reacting the salt with the compound ff)k.

Suitable salts of the compound (■-a) include salts with the same bases as exemplified for the compound.

Since this reaction is carried out essentially in the same manner as described for Method 5, the above description is incorporated into the reaction conditions (C, reaction temperature, #I strategy, etc.).

[Process B]

Compound C■) or its deposit @ can be obtained by reacting compound ■ or a salt thereof with a hydroxy V amine compound α represented by the formula R:0NH2 (wherein R: has the same meaning as before) or a salt thereof. is manufactured.

Suitable salts of the hydroxylamine compounds include the same acid addition salts exemplified for neutralizing the compound.

Suitable salts for compound (1) include the same salts as exemplified for compound (2).

When the hydroxy VIM amine compound is in the form of a salt,
The reaction described in Method 1 is suitably carried out in the presence of a crosslinking group.

This reaction is usually carried out in conventional materials which do not affect this reaction, such as methano-v, ethanol-V, or mixtures thereof.

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

The raw material compounds produced by the above method are:

It is isolated by routine refining as described for the target compound.

The above-mentioned methods 1 to 7, 1 to 2, and their optical isomers may be supported, but this invention is also included in these cases.

When the target compound (Iφ11, VboxyMit or free amino group) has at the 4th or 7th position, these groups can be converted into multiple groups by conventional methods.

The object compound of this invention, the salts of Nakazutsuta Tadaso, exhibits high antibacterial activity inhibiting the growth of a wide range of pathogenic symptoms including Ashi, Durham positive and Negative 1It-, as shown in the data below. It is useful as an antibiotic, especially for oral administration, and raw material compounds 1 to 2 are useful as synthetic intermediates for producing them.

In order to demonstrate the usefulness in target compounds, the antibacterial activity of representative compounds Φ of the present invention was measured and the results are shown below.

(1) Test 1: In vitro antibacterial activity test compound 7-(2-(2-amino-5-chlorothiazo-pv-4)
-A/)-2-(1-force VpokiyxtokiVimino)acetamido2-6-vinyA/-6-cephem-4-forceV
Test method: The in vitro antibacterial activity was determined by the agar plate multiple dilution method described below.

Trypticase Soi Pross (1611k108/
- 1 platinum loop of one plant, each containing m degrees of the test compound, grown overnight in heart infusion agar (
After inoculating onto H-technical agar) and culturing at 67°C for 20 hours,
The minimum initial concentration (MIO)' was measured in μfΔd.

In the compound of interest of this invention or its pharmaceutically acceptable composition, K is administered for the purpose of treating sr.

Containing the above compound as a main component and a pharmaceutically acceptable carrier, such as oral, parenteral, or topical JCilL,
It can be administered in the form of conventional preparations with organic or inorganic, solid or liquid excipients. Such preparations include solids such as tablets, granules, powders, and capsules, and liquids such as solutions, suspensions, syrups, emulsions, and lemonades.

Furthermore, if necessary, adjuvants, stabilizers,
Moist #M, sono lactose, magnesium stearate, white clay, soy sauce, 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 the compound depends on the patient's age, condition, type of disease,
and agm in the administered compound, but generally 1
Amounts ranging from 91 q per day to about 400 q or more can be administered to the patient. The average dose for one time is approximately 50q, 100cm, 250dah, 500dah of the target compound of this invention.
~． 1000■.

20001f't, which can be used to treat diseases caused by pathogenic microorganisms.

2-hydro diimino-3-oxobutyric acid tertiary butyl ester (5 turtle 4F) 11! Acid potassium (lL45F)
A suspension of 1 chloroacetic acid benzyl ester (61') in ethyl acetate (300 m) and N,N-dimethylformamide (60 sf) was added with 1 chloroacetic acid benzyl ester (61') and stirred at 40°C for 7 hours. The reaction mixture was poured into ice water (1 Goose), and the separated organic layer was washed twice with an aqueous solution of sodium chloride koji and dried over magnesium sulfate. The solvent was distilled off to give an oily 2-penzyloxycarponylmethoxyimide/-3-
Oxobutyric #tertiary butyl ester (9t3F) was obtained.

IR (74lA): 29g0. 1740. 18
95. 1610 (11+-1HMRlppm (CD
C/J): 1.50 (911,s), 2.28 (
31, a), 4.78 (2H, m), 5.18
(2H,!l).

7.28 (5H, s) Production Example 2 According to the method of Production #111*, 2-hydroxy 45-phenyl-3-oxobutyric acid ethyl ester (45,29)-chloroacetic acid 112.2.2-trichloroethyl ester (31
, 4f) in the presence of member acid potassium (41,5?) to produce 2-(λλ2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid ethyl ester (6-7F). friend.

IR (74 A): 1750 (P0-F), 1
610s+-1HMRJppm (CDC/s): 1
．． 33 (31,t, J-7Hz).

2-37 (3HIe)t 4.37 (2He
q −X7Hz).

4.83(2H,s), 4.93(21,s) Production Example 3 i-benzyloxycarbonylmethoxyimino-3-oxobutyric acid tertiary butyl ester (3L3y) in acetic acid (3
Bromine (16F) was gradually added to the Ls/) solution while stirring at 45-48°C, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and then washed six times with saturated aqueous sodium chloride solution. The solution was concentrated under reduced pressure to obtain 2-benzyloxycarbonylmethoxyimino-4-promo-3-oxo-11 acid (35jF
) and make friends.

Engineering R: 2950. 1740 (Broad).

1602eMA-1 MMRappm (CDC/,): 4.02 (2H,
s), 4.82 (211, s), 5.16 (2
H,! 7.32(5H,e) Production Example 4 According to the method of sI Preparation #13, 2-benzyloxycarbonylmethoxyimino-3-oxobutyric acid tertiary butyl ester (5,Oy) and sulfuryl chloride (1 ,25i
sff) in acetic acid (5m), 2
-Benzyloxycarbonylmethoxyimino-4-chloro-3-oxobutyric acid (3,8F) was produced.

IR (film): 3200. 1730 (Broad).

1610am-” NMRJppm (CDC/s): 4.03(2
H, s), 4.83 (2H, s), 5.23 (
2H,a), 7.33(5H,s) Production Example 5 To a solution of 2-benzyloxycarbonylmethoxyimino-3-oxobutyric acid tertiary butyl ester (2,0y) in dry tetrahydro-7 (20m/), Hokusan trisulfide-
Diethyl ether (3.0 m/) and bivdinicum hydropromide perpromide (3, Of) were added at normal humidity, followed by stirring for 6 hours.

The anti-N5 mixture was poured into *(501Il) and then extracted twice with ethyl acetate (70m/). The combined extracts were washed with 10-hydrochloric acid and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. Distill the solvent, 2
-benzyloxycarbonylmethoxyimino-4-promo 3-oxobutyric #(1oy>9).

Engineering R (Nujigor): 295G, 1740 (Broad).

602cs Production Example 6 A mixture of 2-(λλ2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid ethyl ester (20F) and sul7lyl chloride (7,7F) in acetic acid (20yd) was stirred at 40°C for 7 cycles. did.

The garlic mixture was mixed with water (100sf) and methylene chloride (10sf).
After stirring, the separated organic layer was washed with an aqueous solution of 50% sodium hydrogen oxide and water, and dried over magnesium sulfate*.

The residue was distilled off to obtain 2-(2,λ2-trichloroethoxycarbonylmethoxyimino)-4-I lower 3-oxobutyric acid ethyl ester (22?).

IR (74 lums): 1750 (broad), 1
610cm~1NMRJppm (CC14): 1
．． 36 (3H, t, J-7Hz).

4.32 (211,q, J=7Hz), 4.46 (
2H, e).

4.79 (2H, e), 4.90 (2H, a) Production Example 7 Vilsmeier reagent prepared from N, Fuki-dimethylformamide (0.67m) and phosphorus oxychloride (0.79wI) was dissolved in dry tetrahydrochloride. 7 runs (25d).To this, 2-benzyloxycarbonylmethoxyimino-4-promo-3-okynebutyric acid (LIJf) was added at 0°C.
and stirred at 0 to 5° C. for 1 hour to prepare an active acid solution. Add this 1'&4'I# solution to 7-amino-3
-Vinyl-3-cephem-4-carboxylic acid benzhydryl ester salt chloride (2,2f') and trimethylsilylacetamide (7,0y) chloride 1f L/
G ml ) solution at -135'C, -10~
-5℃? Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate (
200d) and water, and the separated organic solvent layer was washed with a saturated aqueous solution of IIe# sodium hydroxide and a saturated aqueous solution of sodium chloride, and then dried with magnesium sulfate. The solvent was distilled off to obtain 7-(2-benzyloxycarbonylmethoxyimino-4-promo-3-oxobutylamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester <tsy>*.

IR (X Di*-R): 3270. ．． 1773. 17
15°1ssocs+-1 NMRJppm (DMSO-d@): 3.56.
196 (2H.

ABq, J=18Hz), 4.57(21,a)
, 5.03 (2H,s), 6.23 (2Ls)
, 5.30 (IH, d.

J-5Hs)+5.55(1111,d, J=1
8Hm), 5.61 (IH, d, Js-11Hm)
, 5.90 (III, ld, J-5°8Hz)+
&83()]] Ldd, J-IL11BHz+ 7
．． 0 Production Example 8 2-(L2.2-trichloroethoxycarbonylmethoxyimino)-4-chloro-3-oxobutyric acid ethyl ester (20P), thiourea (3,9F) and #Shun natrichum (4,2F), A warm mixture of ethanol (SoWIl) and water (50 m/s) was brought to 40° C. and stirred occasionally.

After distilling off the solvent from the reaction mixture, the residue was triturated in diisopropyl ether. The precipitate was PRXed and washed with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(LL2-trichloroethoxycarbonylmethoxyimino)acetic acid ethyl ester (syn isomer) (1@, @f ) was obtained. Melting point 138-141
℃.

IR (Streak 1-L): 3400. 1750. 17
10°1620, 1540611-1 1MRJppm (DMSO-d,): 1.27
(3H, t, J-7Hz).

4.32 (FH, q, J=7Hz), 4.93 (2
B, s).

4.97 (21, s), 6.93 (IH, s),
7.27 (2H.

Production Example 9 Methanol (16d) of hydrazine hydrate (&l'-)
The solution was diluted with 2-7 talimidooxyacetic acid benzyl ester (
The mixture was stirred at room temperature for 30 minutes. Add 20-hydrochloric acid to the anti-t5 mixture under water cooling, and then add 10-hydrochloric acid to the anti-t5 mixture under water cooling, and then
Stir for a minute. Insoluble matter was removed by F to obtain a solution containing benzyl 2-aminooxyacetic acid ester. Add (2-
Formamidothiazol-4-yl) glyoxyl #(
24,7F) and pyridine (24,ilm) were added and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was triturated with 10% aqueous sodium hydroxide solution for 5 kg, and then washed with ethyl acetate. This aqueous solution was acidified with 10-hydrochloric acid to adjust the pH to 2, and then extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and then dried over magnesium sulfate.

The solvent was evaporated and the residue was triturated in diisopropyl ether to give 2-benzyloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)# acid (syn isomer) (37f). Melting point: 152℃ (
Disassembly).

IR (Streak 1-L): 3350. 1?30. 17
00e11-11MRlppm (DM80-a,)
: 4.87 (2H, ri, 5.20 (2H, g:
L 7.30 (5H, s), 7.52 (1111
,s).

8.53 (IH, s), 12.57 (IH, Broad 8) Production Example 10 Vilsmeier reagent was produced from phosphorus oxychloride (lL4y) and N,N-dimethylformamide (4,0y) by a conventional method. . 2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (] & 5p) was added to a suspension of the Vilsmeier reagent in tetrahydrofuran (100 s/) under water cooling. and stirred at the same temperature for 30 minutes to prepare an active acid solution.

On the other hand, 7-amino-3-hydroxymethyl-3-cephem-4-carbon all! (11,5P) in sodium bicarbonate (&4F) in water (50sf) and acetone (
sod) solution. 9. Add the active acid solution dropwise to this solution at 3-8°C. Add this sodium chloride acid 20-aqueous solution, maintain the pH value of the mixture at 7 to 8, and stir the mixture for 1 hour at the same temperature. The reaction mixture was then diluted with 10
Adjust the pH to 6.0KII by adding % salt, wash with ethyl acetate, and prepare 7-(2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-hydroxymethyl- 3-Sefe A-4
- An aqueous solution containing carvone 11F (syn isomer) was obtained.

To this aqueous solution was added an ethyl acetate solution of diphenyldiazomethane (1 ml/d") (100 MIl),
- Adjust pm and t5Kml with hydrochloric acid. After stirring for 2 hours at No. 11, the solution was extracted with a mixed solvent of ethyl acetate and tetrahydrochloride (1:1).

After washing the extract with a saturated aqueous solution of sodium legate and an aqueous solution of sodium chloride, 1 was dried over magnesium sulfate. The solvent was distilled off, and the residue was powdered with diethyl ether to give 7-(2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)).
Acetamide]-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (synthetic form) (1 g, 5F) was obtained.

IR: 32GG, 1785.1
720°16g01111+-” MMRappw+ (DM80-d4): 1.4
7(9H,a), 3.68(2H=s)-435
(2H-4J5Hz), 4-7 (2Hpa)y [
27 (IH, d, J=5Hz), 5.97 (11,
4d.

J=5.8Hz), 6.97(IH,s), 7
．． 2-7.77 (IIH.

m)-&5g(IH,a), 8.67(IH,d,
J=8Hz).

12.70 (IH, a) Production Example 11 7-[2-@tertiary gutoxycarponylmethoxyimino-
2-(2-formamidothiazol-4-yl)acetamido)-3-t=Droxymethyl-3-cephem-4
-Carboxylic acid benzhydryl ester (syn isomer) (
2, IP) and phosphorus pentachloride (1,1jF) in methylene chloride (20 m/), add pyridine (a, 45f) to -20
mL at 'C, and stirred at -20 to -5°C for 2 hours. The 5c reaction mixture was washed with 10-dihydrochloric acid and sodium chloride ice solution, and then dried over magnesium sulfate. The solvent was distilled off to give 7-(2-II3M butoxycarbonylmethoxyimino-2-(2-formamidothiazo-4-yl).
Acetamide]-3-chloromethyl-3-cephem-4
-Carboxylic acid benzhydryl ester (syn isomer) (
λxy> was obtained.

Engineering R: 3200. 1780. 17
20°1680, 1540 low 1 NMRJppm (DMSO-d6): 1.42 (9H
,s), 3.66 (2H, q, J=18Hz)+
4.43 (2H, a), 4.64 (2H9a),
5.27 (IHtdsJ5Hz) 15.9B (IH, d
d, J=5. 8Hz), IL96(IH,5)t
7.00-7.60 (IIH, m), &5G (IH
, s), 8.64 (IH, d, J-8Hz), 1
158 (IH, Broad S) Production Example 12 7-amino-3-hydroxymethyl-3-cephem-4
-carboxylic acid (121f) in water (200sk)
The mixture became cloudy and neutralized with dicyclohexylamine (7f) to pH 7.5. Add salicylaldehyde (!
6.42f) was added dropwise. After stirring at room temperature for 2 hours, collect the precipitate, II! 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt (17,4y) was obtained.

IR(Xa-R)=3300. 1780.164
0゜1560m-1 NMRJppm (DMSO-d,): 0.9-2
．． 2 (22H, m).

3.5 (2H, broad s) + 4.2 (2H,!
Q), 5.15 (II(t d, J-51!x)
*s, s (IHI d, J-=5Hz).

&8 7-8 (4H-m)-8,8(I He s
) Production Example 13 According to the method of Production Example 12, 7-asanino-3-human Ooxymethyl-3-cephem-4-carboxylic acid (10y) was mixed with benzaldehyde (t2p) 12 and dicyclohexylamine<7.2Sf! 7-penzylideneamino-3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt Cl5P) was obtained by reacting in water (200%).

IR (Nuji Reversal): 3300. 1780. 16
50゜1560511-1 Nan Jppm (nMso-a,): &91.
2 (22H, m) 13.5 (2H, broad s),
4.15 (2H, MUBq.

J-14Hg), 5.15 (IH, d, J-5Hz),
5.5 (IH, d, J-5Hz), 7.3-&1 (5H
, m).

8.55 (IH, s) Production Example 14 7-? lylideneamino-3-hydroxymethyl-3-
Celaem-4-carboxylic acid dicyclohexylamine salt (
3f) ethyl acetate (60+/) middle stitch 11J#K P
An ethyl acetate solution of -toluenesulfonic acid (1, IP) was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. After removing the precipitate from F, the F solution was simultaneously treated with an excess diphenyldiazomethane in ethyl acetate solution. The solvent was distilled off, the residue was powdered in diisopropyl ether, removed from F, and dried.
7-Salicylideneamino-3-hydroxymethyl-3-
Cephem-4-carboxylic acid benzhydryl ester (2
L61F) was obtained.

IR: 3470. 1760.170
0゜1620as+-1 NMRJppm (DMSO-d6): 17(2H
, s), 4.3 (2H2 mouth), Li2 (IH, broad), 3-s (IHT d.

J-511z), 5.71 (IH, d, I=5H
ys), &96 (IH.

s+), 7.0-7.7 (14H,■)I &8(
IH, a) Production Example 15 7-Salicylideneamino-3-hydroxymethyl-3-
Cephem-4-carboxylic acid benzhydryl ester (1
, 01f) was dissolved in methylene chloride (10 m/)K and cooled to -30°C. Add phosphorus pentachloride (0,4@
Add f ), then add pyridine (0°1jlsf) and make a circle. The reaction mixture was stirred at -30 to -20°C for 1 hour and then poured into ice water. The organic layer was separated, washed with water and an aqueous sodium chloride solution, and then dried over magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain 7-4j lylideneamino-3-chloroamethyl-3-cephem-4-carboxylic acid benzhydryl ester (0,9f).

IR (Stripe 1-L): 1775. 1710. 16
05゜Is 60 (s) asg-1 NIIRJppm (DMSO-d,): 3.85
(2H, MuBq.

J-18Hz), 4.55(2H,s), &4
0(IH, a).

5.50 (IH, d, J=5H!I), 5.85
(IH, d, Jm5Hz).

7.05 (IH, a), 7.2-7.8 (14H,
m).

&95(IH,s) Production Example 16 Tsusalicylidene amino-3-chloromethyl-3-cephem-4-carvone benzhydryl ester (4F)
Add dimethylformamide (10 s/c) cold 1 liquid K) Riphenylphosphine (22F) and sodium chloride under stirring. After stirring at room temperature for 2 hours, the reaction mixture was poured into isopropyl alcohol (250s/), and the precipitated solid (&7F) was collected. This solid methylene chloride (10 anti-t3 mixture) was adjusted to pH & 0 Kli'Ji with a saturated aqueous solution of sodium chloride. After stirring at room temperature for 1 hour, the separated organic layer was washed with water and an aqueous solution of sodium chloride, and then with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-salicylideneamino-3-vinyl-3-cephem-4-carboxylic benzhydryl ester (3y).

IR (Nuzir): 1770. 1710. 16
20°1580 (slam-1 MMRIpp ugly (DMSO-d,): 3.8
5(21(,AB(1°J=18Hz), 5.30
(IH, d, J-11Hz), 5.42 (IH,
d, J=ii1m), 5.65(lH,d, J=1
8Hz).

5.75 (IH, d, J=5Hz), 6.90 (
IH, dd, J=11°18Hz), 7.05(
11, a), 7.2-7.9 (14H, in).

-8,95 (IN, @) Production Example 17 7-Surithiyanamino-3-vinyl-3-cephem-
Methylene chloride of 4-carvone benzhydryl ester (1,6F)? zosz) and anisole (5ml)
Trifluoroacetic acid (6d) was added dropwise to the medium solution while stirring,
The mixture was stirred at constant temperature for 1 hour. The reaction mixture was poured into diisopropyl ether, the precipitate was taken up and suspended in water, and then the pH was adjusted to 3.5 with a saturated aqueous solution of sodium bicarbonate. The solid was collected and 7-amino-3-vinyl-3-cephem-4-carvone #(0,1') was obtained.

Engineering R (Nujol): l800. 1605 Country-1 Production Example 18 2-Hydroxyimino-3-oxobutyric acid tertiary butyl ester CaL8f> and Sumashun Kalicum (51,8F)
of ethyl acetate (70 gg) and N.

N-dimethylformamide (70 aff)
Chloro@Shun 2,2.2-trichloroethyl ester (5
&5p) and stir at 45-48°C for 15 hours. Insoluble inorganic substances were removed from F*, and water and ethyl acetate were added to F*.

The separated ethyl nine acetate solution was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and washed. The solvent was distilled off to give 2-(2°2.2-)! 7chloroethoxycarbonylmethoxyimino)-3-oxobutyric acid tertiary butyl ester (84,9y) was obtained.

Engineering R (film): 1760 (broad), 1
700°1615 country m-1 MMRappvn (coco=): 1.52 (9
H, s), 2.35 (3E, s), 4.85 (
2H2a)s 4-95 (2H2s) Production Example 1
9 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid tertiary butyl ester (
The odor @ (23,2
)) was added at 52°C and stirred at 5°C to 68°C for 15 minutes. After distilling off the acetic acid from the anti-t3 mixture under reduced pressure, the remaining sister was converted into ethyl acetate (400 sir) K#! I understand. This solution was washed with lO dihydrochloric acid (20d) and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate.

The solvent was distilled off to obtain 4-promo-2-(2,2,2-)lichloroethoxylponylmethoxyimino)-3-oxobutyric acid (30,7F).

IR (Nuji Soru): 1740 (Broad) 1 160
9(!IIll-1N Jppm (CO/4): 4
．． 27 (2H, s), 478 (2H, s), 4
9g (2H,s) Production Example 20 According to the method of Production Example 19, 2-(2,2,2-trichloroethoxylponylmethoxyimino)-3-oxoma acid tertiary butyl ester C5,0? 4-chloro-2-(λ2.2-)lichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (4,70jF) by reacting > with sulfuryl chloride (2,83wl1)
was manufactured.

Engineering R (film): 1740 (broad) t 171
0cm-”NMRJppm (CC/4): 4.
5G (211!, s) + 4.17 (2H, s),
4.93(2H,s) Production Example 21 Thiourea (3
, 9P) and an aqueous solution of sodium acetate (4゜2f>
50 Hz) and stirred at 40°C for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half its original volume, adjusted to pH 7.5 with saturated aqueous sodium hydroxide solution, and then washed with ethyl acetate.

This aqueous solution was further diluted with 10% salt and water was removed by decantation. The residue is diluted with tetrahydro7'
Dissolve in yin (200 wIl) and dry over magnesium sulfate. The oil obtained by removing the solvent was powdered in diisopropyl ether to give 2-(2-amitthiazol-4-yl)-2-(milk 2,2-trichloroethoxycarbonylmethoxyimide/) vinegar #( syn isomer) (3,51
) was obtained.

Engineering R (line 1-rule): 3200 (broad), 17
62°1610 (broad) cs+” NIIRJppm (DM80-d,): 4.88
(2H, 8), 4.96 (2n, s), 184
(IHle) + 7.2 (2H, Broad 8) Production Example 22 1 Prior to the method of Preparation Example 8, 4-bromo-2-benzyloxycarbonylmethoxyimino-3-oxo
2-(2-
aminothiazol-4-yl)-2-benzyloxycarbonylmethoxyimino vinegar # (syn isomer) (1,7y
) was manufactured.

IR (X-wheel): 1730. 1610 (broad) 1-1HMB ippm, (DM80-d6
): 478 (2H, e).

5.18 (2H, e), &86 (IH, a),
7.48 (2H.

Broad a), 7.56 (5H; 8) Preparation Example 23 Vilsmeyer reagent prepared from phosphorus oxychloride (7.1 m/) and H,M-dimethylformamide (6.0 sd) was dissolved in tetrahydrofuran (25 d) with KWA turbidity. did.

4-promo 2-(Z, 2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (25F) was added to this suspension, and the mixture was stirred at 5°C for 1 hour to produce active acid fixation. This solution was added to 7-amino-3-vinyl-3-
Cephem-4-carboxylic acid benzhydryl ester hydrochloride (1&2jF) and trimethylsilylacetamide (4
0f! ) in ethyl acetate (140 sd) solution.
The mixture was added all at once at -15 to -5°C and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. By distilling off the solvent,
7-[4-promo 2-(2, 2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyramide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (2&Op) was obtained.

rR (CHCI,): 3400 (broad),
1775°1713, 1690as+” NMRJppm (DM80-a,): 3.4g,
3.88 (2H.

ABq, J-18Hz), 4.8-5.5 (8
H, m), 5.5 (IL d-J-=18 Hz
), 5.80 (I HT d d , J =5.

8Ifz), 6.83(LH+ d4 J-11
, 18Hz).

6.85 (IH, a), 7.3 (IOH, m),
9.4 (IH, d.

J=8Hz) Production Example 24 7-(5-7 minnow 5-carboxypentanami F)-
Sodium 3-hydroxymethyl-3-cephem-4-carboxylate (10y) in water (50d) and acetone (
Ethyl chloroformate (7,142) was added to the solution in 30m) and stirred at 7-8°C for 45 minutes. The pH value was maintained at 7.8-B with this aqueous potassium chloride solution. To this solution was added diphenyldiazomethane (14.7f) dissolved in ethyl acetate (122sZ), and the mixture was stirred at room temperature for 1 hour.

During this time, the pH value was maintained at 2.5 with 6N salt. The organic layer was separated and washed with an aqueous sodium chloride solution.

The residue obtained by distilling off the solvent was dissolved in 77 tons (30 m). This a7ton solution was mixed with diisopropyl ether (30
011d), the precipitate was collected, and 7-(5
-benzhydryloxycarbonyl-5-ethoxycarbonylaminopentanami F)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (18,15y) was obtained.

IR (Streak 1-L): 3300. 1780. 17
2G.

1670α-1 NMRJppm (DM80-ds/DzO): 1
．． 15 (3H, t.

J=7Hz), 1.43-137(6H,m),
3.4-3.73 (3Hem) 14.03 (2H, q
, J=7Hz), 4-27 (3H, m), 5.
13 (IHed, J-5Hz) * 5.71 (IH, d
d, J-8,5Hz), &83. (IH,5)-
6,97 (IH, e), 7.17-7.7 (21H,
m) ta, 5s (IH, d, J=8Lz) Production Example 25 According to the method of Production Example 24, 7-(5-amino-5-carboxypentanamide)-3-hydroxymethyl-3
-Cephem-4-carboxylic sodium trichum (1(1)) is reacted with phenyl isocyanate (111y) and diphenyldiazomethane (14,7y), 7-
(5-benzhydryloxycarbonyl-5-(3-phenylfreido)pentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl (
1 elephant o@y) was manufactured.

NMRJppm (DM80-ds): 1.28-
140 (6H, +m).

3.59 (2H, s), 4.21 (2H, q, J
-14Hz).

42G-4,55 (IH, m), 5.1 (IH,
d, J=5Hz).

5.6J1 (IH, ld, J=5.8H2), 6.
61 (IH, d.

J=7Hm), 6.81 (IH, a), 8.9
0(IH,s).

7.01-7.77 (25H, m), 8.59 (I
H,5)t8,82 (IHe a-J=8Hz) Production Example 26 According to the method of Production Example 24, 7-(5-amino-5-carboxypentanamide)-3-hydroxymethyl-3
-Cephem-4-carbonyloxycarbonyl-7-(5-benzhydryloxycarbonyl- 5-7thalimidobentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (21,04P) was prepared.

Engineering R: 3350. 1780. 171
5611-1HMRlppm (DM80-d6):
1.4-2h53 (6H, m).

3.35 (IH, ba), 3. ．． 60 (2H, be
), 425 (2H9m), 4.83-5-13
(IH*m)t S-08(IH, d, J=5H
m), 5.68 (IH, dd, X-5Hz.

8Hz), 6i, 83 (IHLs), 6.90 (I
B-8) e7.07-7.67 (20H, m), 7
．． 9 (4H, s), &82 (I H= d, J-
8Hz) Production Example 27 According to the method of Production Example 24, 7-(5-amino-5-carboxypencunamido)-3-hydroxymethyl-3
7-(5
-Benzhydryloxycarbonyl-5-acetamidopentanami 1-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (3,94)
) is manufactured.

IR: 3280. 1780. 17
20°1655 (to)-1 NM Rappm (DM80-di): 1.4-13
6 (6H-!11).

1.90 (3H, s), 3.62 (2H, s),
425 (2H, s).

4.28-45! (IH, m), 5.1 (IH,
d, J=5Hz).

5.71 (11, dd, J=5.8Hz), 6.
79 (IH, a).

6.92 (IH, s), 7.0-7.74 (21H
, m), &83 (IH, d, J-8H2) Production Example 28 Prior to the method of Production Example 24, 7-(5-amino-5-carboxypentanamide)-3- and droxymethyl-3
- From K, 7-
(5-Benzhydryloxycarbonyl-5-isobutoxycarbonylaminopentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester 17.45F) was prepared.

Engineering R (nuji kitchen): 3300,1780t 17
20゜1670c11-1 NMRappvx (DMSO-d, /D, O): 0
．． 87 (6H, d.

J-6Hz) + l-33-15(6H, ma)-3
43 (1■.

m)l 3.62 (3■1m)1 3.77 (2B,
d, J-MHz).

4, 23 (3H* va), 5-12 (I H2
4J-5Hz) I5.72 (IH, d d, J=
8Hz, 5Hz), 6.82 (lB, s),
&93(IH,e), 7.12-7.83(2
1H9* )-& 83 (I H2d+ J-8Hl
) Production Example 29 7-(5-Benzhydryloxycarbonyl-5-ethoxycarbonylaminopentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (181!) of ethylene chloride (180m/
) solution contains phosphorus pentachloride (4,82y) and pyridine (1
, 83y) was added at -30 to -35°C. After stirring for 30 minutes, water (180 m/) was added and the organic layer was separated and washed with aqueous sodium chloride solution. The solvent was distilled off, and the residue was dissolved in N,N-dimethylform Ay=F(39j)K. Triphenylphosphine (&66P) and sodium iodide (3,81P) were added to this solution at room temperature. After stirring for 1 hour, the mixture was diisopropylalkonyl (lo
ses/)KG was added at ~5°C and left for 1 hour. The precipitate was collected, washed with diisopropyl alcohol, and then dissolved in ethylene chloride (160 m/k). Add water (3!3m) and formaldehyde 36-aqueous solution to the kernel solution,
The mixture was stirred at room temperature for 70 minutes. During this time, the pH value was maintained at 9.0 Km with a 40-potassium carbonate aqueous solution. The organic layer was separated, washed with aqueous sodium monochloride solution, and dried over magnesium sulfate.

The solvent was distilled off, and the remaining solution was dissolved in acetone (30 Hz). This acetoxy solution was mixed with diisopropyl ether (300
m/)K added. The deposited precipitate was collected by F, washed with diimpropyl ether, and washed with ? -(5-benzyloxycarbonyl-5-ethoxycarbonylaminopentanamide)-3-vinyl-3-cephem-4-carboxylic nicbenzhydryl ester (1,82F) was obtained.

Engineering R (Nuzir): 1780. 1715. 16
80(!II ”NMRippm (DMSO-ds
/D20): 1.17 (3H2t.

J=7IIZ)1 1.43-2.47 (611, m
), 3.4-3.1 (3■1m), 4.03 (21
! , q, J-7Hz), 5-22 (I He d,
511 z )-5,39(111,4Jl l
III v ) 15-65 (I He dv J-1
8Hz)-5-78(lllll-d d.

J=8.5Hz), 6.82(III, d d, J
-18,11Hz).

8.83 (IH, s), 7.00 (III, s)
, 7.17-7.9(21Ti, m), &90(
IH, d, J-8H2) Production Example 30 According to the method of Production Example 29, 7-[5-benzhydryloxycarbonyl-5(37z nylclide) pentanamide no 3-hydroxymethyl-3-cephem-4-
Carboxylic acid benzhydryl ester (18F), phosphorus pentachloride (4,54f), pyridine (1,72y), )riphenylphosphine (&29P), sodium iodine (3)
, 6F) and 30% formaldehyde aqueous solution (33,
By reacting with 4m/)! 7.7-[5-benzhydryloxycarbonyl-5-(3-7enylcleito)hentanamyl']-3-vinyl-3-cephem-
4-Carboxylic acid benzhydryl ester (9°34y)
was manufactured.

Engineering R (Nuji Seal) = 3330. 3250. 178
0°1725, 1700. 1650 countries - 1NIIR
lppm (DMSO-d, ): 1.36-2.5
(6H, m).

176 (2H, ABq, J=18Hs), 4.28
-4.62 (1111゜m), 5.24 (1■,
d, J=5Hz), 5.38 (IH, d.

J=lIHz)+5.55(IH,d,Jl7)1
z), &78(IH9d d, J-5Hz, 8Hz
) + 6.65 (IH, (1°J-8Hz), fL
90 (IH, dd, J-11Hz, 17Hs).

6.86 (IH, a), 7.00 (IH, s),
7.18-7.69 (2511,!Iri, &63
(IH, 8), &94 (III, d, J=8Hz)
Production Example 31 According to the method of Production Example 29, 7-(S-benzhydryloxycarbonyl-5-7talimidopentanamide)
-3-Hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (zoy)
,91'), pyridine (2,08F), triphenylphosphine (6,9F), sodium iodine (3,94F)
> and formaldehyde 30-water culture solution (36.6m)
By reacting with 7-(5-benzhydryloxycarbonyl-5-7talimidopentanamide)-
3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (13,35F) was produced.

IR (Nuji Seal): 3300. 1780. 172
0611-1FMRIppr! 1 (DM80-d@)
: 1.34-15 (6H, m).

3.62(1)1. Broad s)t 3.72(2
a, Su).

s, 0-5-24 (I L va ), L 2 (
I Hld, J-5HS) + 5.37 (III, d,
J=11Hz), L53 (1fI, d.

J=17Hz), 5.75(IH, (ld, J-
5,8Hz).

6.78 (IH, d d, J=11.17Hz),
6.87 (IH, e), 7.0 (IH, e),
7.17-7.83 (20H, m), 7-94 (4H
, e), &92 (IH, d, J=8Hs) Production example 32 Ethylene chloride (47°75) of phosphorus pentachloride (7,87F)
1) Pyridine (2,992) was added to the solution at 5-6°C. After stirring for 30 minutes, 7-(5-benzhydryloxycarbonyl-5-ethoxycarbonylaminopentanamido)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (9,75P) was added. 5～
After stirring at 6°C for 2 hours, cooled to -30 to -20°C,
The mixture was diluted with 2-methoxyethanol (7,67/) 1.
Treated for 5 hours, then treated with water (10 m/) for 1 hour.

The precipitate was collected in F, washed with ethyl acetate and diisopropyl alcohol, and 7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (1
, 99F) was obtained.

Engineering R: 1760. 1705. 15
80(!ll-1 Production Example 33 Prior to the method of Production Example 32, 7-[5-benzhydryloxycarbonyl-5(37znylclide)pencunamide]-3-vinyl-3-cephem-4-carboxylic acid Benzhydryl ester (9,25) Phosphorus pentachloride (7
,04F), by reacting with pyridine (2,77F) and 2-methoxyethanol (6,88F),
7-Asanno-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (3,45p) was prepared.

IR: 1760. 1705. 1
580 Uniform 1 Manufacturing Example 34 According to the method of Manufacturing Example 32, ? -(5-benzhydryloxycarbonyl-5-tutarimidopentanami F)
-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (113F) was combined with phosphorus pentachloride (5F), pyridine (1,96p) and 2-methoxyethanol (
9,74F), 7-amino-3
-Vinyl-3=cephem-4-carboxylic acid benzhydryl ester hydrochloride (1,2F) was produced.

IR (5L diw-le): 1760. 1705. 1
580611-1 Example 1 Phosphorus oxychloride (1,28/) and N,! -Dimethylformamide (1,06m) to tetrahydro7>(
Vilsmeier reagent was prepared by a conventional method in 35WIl). 2-Benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (synisomer) (5y) was added to this suspension under water cooling, and the mixture was stirred at the same temperature for 30 minutes. , an active acid solution was prepared. This melt is 7-amino-3-vinyl-3-cephem-
4-carvone benzhydri pancreatic stellate hydrochloride (489F
) and trimethylsilylacetamide (9,22) in ethyl acetate (40/) at -20"C, and then stirred at -20 to -10C for 1 hour in (a).

After adding water and ethyl acetate to the anti-It5 mixture, the separated organic layer was taken, washed with 5-aqueous sodium carbonate solution and aqueous sodium chloride solution, and then aW! Dried with magnesium. The solvent was distilled off to give 7-[2-penzhydryloxycarponylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamifl-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester ( syn isomer) (8,7F) was obtained.

Engineering R (Nujol): 3250. 1780. 17
20°1680, 1620. 1540 small-1HMR
Ipprn (nMso-a, ) = 3.70 (2H
, l1l).

4.95(2H, Broad”)-5-25(IH
9dm J=5Hz).

5.26 (IH, d, J = 11Hs), 5.50 (
IH, d.

J-18Hz), 5.95 (IH, dd, J=5
．． 8Hz).

6.78 (IH, dd, J=11.18Hz), 6
．． 90 (11!, @) + 6.95 (IH, s), 7
．． 2-7.7 (11Lm).

8.50 (IH, s), 9.72 (IH', d, J
-8Hz) Example 2 According to the method of Example 1, 7-amino-3-vinyl-3
-Cephem-4-carboxylic benzhydryl ester hydrochloride (4,3F) was converted into 2-benzyloxycarbonylmethoxyimino-2-(2-formamidothiazole-4
-yl) acetic acid II (syn isomer) (4,Of), by reaction with an activated acid solution prepared from phosphorus oxychloride (1,9F) and N,N-dimethylformamide (0,'l'). 7-[2-benzyloxycarbonylmethoxyimino-2-(2-formamidothiazole-4-
yl) acetamide F]-]s-vinyl-3-cephemu-4-carboxylic acid benzhydryl ester syn isomer)
(&95F) was obtained.

IR (Nuji Seal): 3250 1775. 1710
゜1680, 1610 country-1 NMRJppm (Dl[FtO-dg): 3.8
0 (2B, q, J=18Hz).

4.36 (2H, s), 5.27 (2H, s),
5.35 (IH, d.

J-111! i), 5.35 (IH, d, J=5H
z), 5.67 (lH, d, J-17H1),
6.00 (IH, dd, J=5.8Hz).

6.83 (I'll,'dd, J=11.17Hz)
, 7.00 (IH, 827, 21-7, 70 (16
H, m), &60(1)1. e).

9.80 (IH, d, J-8Hz), 12.73 (
IH9F3) Example 3 According to the method of Example 1, 7-amino-3-vinyl-3
-Cephem-4-carboxylic acid benzhydryl ester hydrochloride (1-1y) was converted into 2-(1-tert-butoxycarbonylethoxyimino)-2-(2-formamide-5-
Chlorothiazol-4-yl)acetic acid (syn isomer) (1
, IP), oxy1M phosphorus (0,53p) and plexus,
Active WIIfsff! prepared from N-dimethylformamide (0,259)! By reacting 7-(
2-(1-tertiary butoxycarbonylethoxyimino'
)-2-(2-formamide-5-chlorothiazole-
4-yl)acetami)']-3-vinyl-3-cephemu 4-carboxylic acid benzhydryl ester (syn isomer) (1,IP) was obtained.

IR (nujim-ru): 17g0. 1710. 16
80611 “NMRJppm (DMSO-d,
): 133-1.70 (12H.

m), 3.80(21111m)-468(IM,
5.18-5.19 (4H, m), 6.7
8 (IH9dd, J=11.0°17.011z),
7.00 (1111,s), 7.41 (10M,
s).

8.58 (IH, s), 9.60.173 (IH,
d, J=8.0Hz).

12.87 (IH, Broad) Example 4 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)
Acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn JIL) (&
Add 35-hydrochloric acid (2-
, 3d) was added. After stirring at 30° C. for 1 hour, the reaction mixture was poured into ice water, and the pH was adjusted to 3.5 KIN with a saturated aqueous solution of sodium bicarbonate. The precipitate was collected and dried to give 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid. Benzhydryl ester (syn isomer) (7,08
P) was obtained.

11'l (Nuji layer): 33G0. 1780.
1720゜1680, 1620511-1゛NMRlppm (DMSO-d,): , 17
2 (2H, Broad 8).

4J5 (2H, s), 5.30 (IH, d, , r
-11H2).

5.32 (IH, d, J = 5Hz), 5.56 (I
H, d, J-18Hz).

5.85 (IH, a, , T=8.5E+2),
6.82 (IH, dd.

J=111. 18Hz), &87(11,s),
&90(IH,s), 6.95(IL e)t
7.2-7.7 (1011[, Iff), 9.
8 (lull, d, J-8Hz) Example 5 According to the method of Example 4, 7-[2-benzyloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3- vinyl roux 3-
By reacting cephem-4-carboxylic acid benzhydryl ester (syn isomer) (4,9F) with No. thiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester (syn isomer) (4
, 2F) were obtained.

IR: 3300. 1780. 17
20°1680, 16205+ -1 NIIIRJppm (D1180-(1,): 3
．． 72 (2H, m).

4.83(21(,s), 5.23(!III,s
), 5.30 (ILd, J”5Hz), 5.
32 (IL d, J-1211g).

5J7 (111, d, J-18H, z), &87
(1)1. dd, J=12°18Hs'), 6.8
7 (IH, s) + 7.00 (IH, e).

7.13-'1.77 (15H,!II), 9.7
(IH, d, J-8H!) Example 6 According to the method of Example 40, 7'-[2-(1-tertiary butoxycarbonylethoxyimino)-2-(2-formamide-5-chlorothiazole 7- (
2-(1-tertiary butoxycarbonylethoxyimino)
-2-(2-amino-5-chlorothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (x,
5lP) was produced.

IR (infrared): 3420.325G, 3150
゜1770, 1715. 1670. 1620c*
-1HMRJppm (DI[8O-ds): 1.
43 (12111, s).

3.68 (2L m), 4.57 (IH, m),
5.17-5.77 (21,+m), 5.25 (14
4J-5,0Hz), 5-87(IH, d4. J-5
,0,8,OHg), &69(IH, ad.

, y-11, Ot 16.0Hz), &513(
IHle) * 7.35 (IOH, e), fj,
34.9.47(III, d, J-MHz>Example 7 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetami)']-]3- Vinyl-3-cephemu-4-carboxylic acid benzhydryl ester syn isomer) (3f)
f) Gishun (12m/)@liquid [35- Add hydrochloric acid (1wl1) at 0°C9. After stirring for 1 hour at room temperature, the mixture was poured into diisopropyl ether. The deposited precipitate was collected by F, washed with diisopropyl ether, and then washed with water (1
5d). Add this aqueous solution to 5 ml of sodium hydrogen carbonate.
The pH was adjusted to 3.5fCW4 with Kansuibyou fluid. The precipitate was collected and dried to give 7-[2-carboxymethoxyimino-2-(
2-aminothiazol-4-yl)ayatamide]-3
-Vinyl-3-cephem-4-carboxylic acid (syn isomer) (1,5P) was obtained.

Engineering R: 3200. 1770. 1
670m-1 Example 8 Trifluoro vinegar! ! (&4tI 7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(2-
Amino-5-chlorothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (1,6F) in methylene chloride (3,0 m/) and anisole ( 1,6me)
It was added to the solution under water cooling and stirred at room temperature for 1.5 hours. Add diisopropyl ether (50m/) to the reaction mixture,
Add the precipitate to a mixture of purified water and ethyl acetate. After adjusting the pH to 7.5 with a 10% aqueous solution of sodium hydroxide,
The separated aqueous layer was diluted with 10-hydrochloric acid to a pPI of 2.2 ffcl [L
, saturated with sodium chloride. This aqueous solution was extracted with a mixed solvent (1:1) of ethyl chloride, tetrahydro, and phthalate (1:1). The extract was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. Distill the solvent, 7
-(2-(1-carboxyethoxyimino)-22(2
-Amino-5-chlorothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.52p) was obtained.

IR: 330G, 3200. 177
0゜16705+1-” 5.20 (1!I, d, J-5,0Hz), 5.1
1-5.92 (3) 1. mu).

6.92 (IH, m), 9.47 (IH, simplified) Example 9 7-(2-benzyloxycarbonylmethoxyimino-
4-promo 3-oxbutyramide) = 3-vinyl-
3-cephem-4-carboxylic benzhydryl ester CLS? ) in tetrahydrofuran (25 m/), thiourea (1), 78P) and sodium acetate (0,3
A solution of 4F) in water (10 m/) was added, and the mixture was stirred at 35°C for 4 hours. The reaction mixture was extracted with ethyl acetate, and the □ extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give 7-[2-benzyloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (synisomer (LOP) was obtained.

IR (Nujol): 3300. 1780. 17
20°1680, 1620 Country-1 Example 10 7-[4-promo2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyramide]-3-vinyl-3-cephem-4- A solution of thiourea (3, IP) and sodium acetate (3,3F) in water (100 s/) was added to a solution of carboxylic acid benzhydryl ester (26,0y) in tetrahydrofuran (losw), and the mixture was stirred at 35°C for 3 hours. The reaction mixture was extracted with ethyl acetate, the extract was washed with water, and then dried over magnesium sulfate.

The solvent was distilled off to give 7-[2-(,2-aminothiazol-4-yl)-2-(2,λ2-trichloroethoxycarbonylmethoxyimino)acetamide 1-3-vinyl-3nicephem-4-carbon. Acid benzhydryl ester (syn isomer) (12,5P) was obtained.

Engineering R: 3200. 1773. 17
16°1640a+x-1 NMRappm (DM80-d@):3.51.3.
88 (2H.

AB (1, J = 18Hz), 4.83 (2L e)
, 4.95 (2H, s), 5.22 (IH, d
, J-5Hz), 5.23(I Hy d,, y=
i 0 Hz), 5.55 (ITJ-d-J-18
Hz).

5.82 (IL dd, J=5.8H2), 6.6
8 (IH, dd.

J=10.18Hz), 6.75(IH,s),
6.87 (IH.

s), 7.3 (IOH, m), 9.50 (IH
, d, J-8Hz) Example 11 2-(2-aminothiazol-4-yl)-2-(2,
To a solution of 2,2-)lichloroethoxylponylmethoxyimino) vinegar # (syn isomer) (1,13F) and phosphorous oxychloride (0,5'6 f ) in ethyl acetate (20 m/) was added trimethylsilylacetamide ( 0,30F) 4
C. and stirred at 4-6.degree. C. for 15 minutes. Phosphorus oxychloride (0°56y) was further added to the mixture, and the mixture was stirred at the same temperature for 15 minutes. This solution KM was added with H-dimethylformamide (0,269) and stirred at 4 to 6°C for 50 minutes to prepare an activated silane solution. Add this solution to 7-amino-3
-Vinyl-3-cephem-4-carboxylic acid benzhydryl ester salt 11Thl! (1,1y) and trimethylsilylacetamide (2,1F) in ethyl acetate (20
vll) solution at -20°C, and stirred at -20° to 0°C for 1 hour. After adding ethyl acetate and water, the organic layer was separated, washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in diethyl ether to give 7
-(2-(2-aminothiazol-4-yl')-2-
(2,2,2-)lichloroethoxycarbonylmethoxyimino)acetami)']-3-vinyl-3-cephemu 4-carboxylic acid benzhydryl ester (syn J1 body) (1,6y) was obtained.

IR: 32G0. 1773. 17
16°1640σ-1 Example 12 7-(2-<2-aminothiazol-4-yl)-2-
(2,2,2-)lichloroethoxylponylmethoxyimino)acetamide)-3-vinyl-3-cephem-
4-Carboxylic acid benzhydryl ester (syn isomer'
) (2,,5f>) solution of triple oroacetic acid (7,5s/) and anisole (2,5s/) was stirred at room temperature for 30 minutes.The mixture was poured into diisopropyl ether and the precipitate was collected. K was dissolved in a saturated aqueous sodium hydrocarbon solution (50 swf). This aqueous solution was washed with ethyl acetate, adjusted to pH 2 and OK with 10% chloride, and then washed with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The solvent was distilled off to give 7-r2-(2-aminothiazol-4-yl)-2-(2,λ2-trichloroethoxycarbonylmethoxyimino)acetamide]-3-vinyl-3-cephem-4-carboxylic acid ( syn isomer) (1,551F)
I got it.

Engineering R: 3270. 1760 (Broad).

1663 (broad) cm-' N lid Rappwr (D seal 80-d@) = 3.68 (2
11, m), 4.87 (2T1.8), 4.9
3 (2H,!+), 5.17 (1 ml, d.

J=5H*), 5.28(IL d, J=12Hz
), 5.53 (IH.

d, J=18Hz), 5.73 (IH, ad, J-5,
8H21).

&83(1B,s),6.87(lH,dd,,T=1
2.1811! g) 9.53 (111, d, J-8)
1m) Example 13 7-(2-(2-aminothiazol-4-yl)-2-
1! , 2-)lichloroethoxycarbonylmethoxyimino)acetamide]-3-vinyl=3-cephem-4-
Carboxylic acid (syn isomer) (0,5P)r)fto9hiF
A solution of water (4d) containing zinc dust (0,5P) and ammonium chloride (0,3F) was added at room temperature with stirring, and the mixture was stirred for 30 minutes. P zinc powder
After separating, the P solution was adjusted to pH 13 with 10-chloride solution, and after 9 hours,
Extracted with ethyl acetate. After extracting the extract with sodium chloride and Licum-hydrous solution, dry it with magnesium sulfur. The solvent was distilled off under reduced pressure, and the remaining liquid was powdered with diisopropyl ether to give 7-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamyl'
]-]3-vinyl-3-cephemu-4-carvone isomer) (0,11f) was obtained.

Engineering R: 3200. 1'170. 1
670ts-'Example 14 According to the method of Example 13, 7-(2-(2-aminothiazol-4-yl)-2-('1,2.2-trichloroethoxycarbonylmethanediimino)acetami) '
]-] 3-vinyl-3-cephemu 4-carboxylic acid isomer) (1,e,) was reacted with zinc dust (1,Oy) and potassium hydrogen phosphate lIr5 solution (10-) to form 7- (2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-
3-vinyl-3-cephem-4-carboxylic acid (synthetic form) (0,19F) was obtained.

Engineering R: 3200. 1770. 16
70511+-”Example 15 7-Amino-3-vinyl-3
-cephem-4-carboxylic acid (4,53F), 2-<
2-formamidothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetic acid (syn isomer) (lo, 5sr), phosphorus oxychloride <4.4f)
7-[2-(2-formamidothiazol-4-yl)-2-benzhydryloxycarbonyl Methoxyiminoacetamide]-3-vinyl-3-cephem-4-
Carbon II (syn isomer) (10,5P) was obtained.

Engineering R: 35GG, 3200. 177
0°1730, 1680 (II-1 1'fMR#ppm (DIISO-d, ): 3
．． 71 (2!I, m).

4.96 (2!lI, 8), 5.15 (III, d
, J=11Hg).

s, 25 (I He d,!-5Hz), & 5
7 (I H-d, Jl 7 Hv).

& 89 (1ft-dd, J-a5-BTUs)
*6.92 (I H-s)+7-00 (I
Hldd, J=11.17! [z)e 7-12-
7-68(10He m)=-&54(I H2
s)-9-75(11!-d.

J=8Hz), 11.78 (IM, broad $)
Example 16 Trifluoroacetic acid (5,75f) was converted into 7-(2-(2-
Methylene chloride of aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid piparoyloxymethyl ester (synnetic form) (3,7F) (14,8m/) and anisole (1,09P)
The mixture was added to the fs solution under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was then dissolved in diisopropyl ether (160s/)K
IH was lowered. The precipitate was collected, washed with diisopropyl ether, and then mixed with water (60m) and ethyl acetate (60m).
I added it to my axilla. The resulting mixture was adjusted to pH 7 with a sodium hydroxide saturated aqueous solution. The separated aqueous solution was further sautéed with 10 g of salt. The precipitate was collected in V, washed with water, and dried over phosphorus pentoxide under reduced pressure.
-(2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-vinyl-
3-cephem-4-carboxylic acid piparoyloxymethyl ester (syn isomer) (2,13y) was obtained.

Engineering R: 3300. 3200. 17
80°1750, 1670(!11-1 MMRJppm (DM80-ds): 1.2(9
H, a), 18 (2H, q, J-18Hz),
4.63 (2H, s), 5.26 (IH, d, J=
5Hz), 5.56 (IH, d, J=11Hz).

5.63 (IH, d, J=17Hz), 5.73-
6.14 (3H, m).

6,83(lH-s)16.87(IHldd,J
=11+17Hz).

7.27 (2H, P-i-do-), 9.55 (I
L d, J 8 Hz) Example 17 7-(2-('2-formamidothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamide]-3-vinyl-3=cephem-4- Carboxylic acid (syn isomer) (11°72) in methanol (
Concentrated hydrochloric acid (3.97 m/) was added to the 120 s/) solution at 30°C, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (150 d) and ethyl acetate (100 s/d) were added to the residual oil, and then the pH was adjusted to 7.0 with a saturated aqueous solution of sodium hydroxide. The precipitate was collected in F, washed with ethyl acetate, and dried over phosphorus pentoxide to give 7-(2-(2-
aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetami)')-3
-vinyl-3-cephem-4-carboxylic natrichum (
syn isomer) (4,14p) was obtained.

XR(9di*-#): 3450,3270. 175
0-1670all-” NMRJppm (DM80-da) = 3.4
2 (2M, broad a) + 4.82 (2H, e),
4.95 (IH, d, J=11Hz).

5.02 (IH, d, J”5Hz), 5.08 (I
H, d, J-17Hz), 5.57 (IH, d d
, J=5. 8Hz).

6.73 (IH*s), 6-83 (LH-s) -6,9
0 (IH2dd, X=11e 17Hz), 7.0
5-7.52 (]OH1m).

9,40 (IH,d, J=8Hz) Example 18 7-[2-(2-aminothiazol-4-yl)-2-
Benzhydryloxycarbonylmethoxyiminoacetamide F ]-]3-vinyl-3-cephemu 4-carboxylic acid natrichumcin (tip) II, II-
Pivaline iodine methyl (1,55y) was added to the dimethylformamide (41yLl) solution at t-0°C, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into water (15011d) and extracted with ethyl acetate (2001). The extract was washed with a saturated aqueous sodium legate solution and water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-
[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid piparoyloxymethyl ester (synnetic form) (3 ,15
f) was obtained.

IR (nuji*-ru): 3425, 3300, 1780
゜1740, 1680 (1ml-1 111RJppm (DM80-d, ): 1.17
(9H,s), 3.74(21,q, J=18H
z), 4.82 (2H, s), 5.17 (lH
+d, J=11Hz), 5.21(IH,d,J=
5Hz).

5.60 (IH, d, J=17Hz), 5.84
(IH, dd.

J=5.8Hz), 5.85(2H,s)+6
．． 76 (IH, e).

6.76 (IH, dd, J=11.17Hz), 6
．． 84 (IH, s).

7.1-7.63 (IOH, m), 9.56 (IH, d
, J=8Hz) Example 19 According to the method of Example 18, 7-(2-(2-aminothiazo-AI-4-yl)-2-penzhydryloxycarbony7remethoxyiminoacetamide F] - ] 3-vinyl-3-cephemu 4-carboxylic acid natricumcin isomer) (3,5F) to bromoacetic acid s1 tert-butyl (2,
7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamide]-3-vinyl-3=cephem-4-carboxylic acid tertiary Obtain class butoxycarbonyl methyl ester (syn isomer) (3,4F).

IR: 3450. 3330. 17
82°1740, 1661. 1602 country-1HMR
Jppm (DM80-d@): 1.44 (9H,
a), 3.56°3.88 (2H, ABq, J-
14Hz), 4.71(2H,a)-4,114(
2H, a), 5.24 (IH, d, J-5Hz)
.

5.36 (IH, d, JllHz), 5.65 (
IH, d, J-18Hz).

5.83 ('IH, dd, J=5.8H2),
8.78 (IL s).

6.87 (IH, s), 7.0 (LH, III)
, 7.42 (IOH.

9.59 (IH, d, J=8Hz) Example 20 7-12-(2-aminothiazol-4-yl)-2-
Benzhydryloxycarbonylmethoxyiminoacetamide 1″]-3-vinyl-3-cephem-4-carboxylic acid tertiary butoxycarbonyl methyl ester (synthetic form) (3, (1) triple oroacetate l11 (IM ) and anisole (5-) solution were stirred for 1 hour at 25-30°C.The reaction mixture was diluted with diisopropyl ether (150 m
/), and the precipitate was collected and dissolved in 5 liters of sodium leg hydroxide solution (Sod) K. The aqueous solution of the kernels was poured down with ethyl acetate and then adjusted to pH 13 with 10-hydrochloric acid.

The precipitated substance was collected with P and washed with water to give 7-[2-(2-aminothiazol-4,-yl)-2-carboxymethoxyiminoacetamide]-3-vinyl-3-cephem-4.
-Carboxylic acid carboxymethyl ester (syn isomer)
(1,7F) was obtained.

Engineering R (Nuzir) 7330G, 1775. 17
23゜167351-' NMRJppm (DM80 d@): 310,3
．． 97 (21'!

ABq, J=187ru 4.57 (211,s), 4
．． 75 (2HtB) * 5.27 (IHtd, J-5
1! s) + 5.38 (III, d.

Claims (1)

[Scope of Claims] (1) General formula (wherein % RIH halogen-substituted aminothiazolyl group or halogen-substituted unprotected aminothiazolyl group % R”Ficarboxy or protected Carboxy (lower) alkyl group H
(a means a carboxy group or a protected carboxy group, respectively) A syn isomer of a 7-acylamino-3-vinyl 7710 suborane derivative or its basenote. (R1 is an aminothiazolyl group or a lower alkanamidothiazolyl group, and HR is mono- or di- or R)!
j phenyl (lower) alkoxycarbonyl (lower) alkyl group or mono-, di- or ketotrihalo (low tS
>Alkoxycarbonyl<lower>alkyl group 18 is a carboxy group, mono or cyto9 4L<tJ♂enyl (lower) alkoxycarbonyl group, lower alkanoyloxy (low #) alkoxycarbonyl group, or lower alkoxycarbonyl (lower) alkoxycarbonyl group A compound according to claim (1). (117-[2-(2-1minothiazol-4-yl)
-2-benzhydryloxycarbonylmethoxyiminoacetamide] -3-vinyl-3-cephem-4-carbonylbenzhydryl ester 2-(2-aminothiazol-4-yl)
-2-Benzyloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydrocate ester. Aminothiazole-4-
The compound according to claim S (t), which is benzhydryl ester of l-(λλ2-trichloroethoxycarbonylmethoxyimino)acetamidonot-3-vinyl-3-cephem-4-carboxylic acid. (・17-[2-(2-aminothiazol-4-iA/
)-2-(Lλ2-trichloroethoxycarbonylmethoxyimino)acetamide)-3-vinyl-3-cephem-4-carboxylic acid. (te37-[2-(2-aminothiazol-4-yl)
-Penzhydryloxycarponylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid sodium compound. (1) 7-[2-(2) -Aminothiazole-4-
yl)-2-benzζdolyloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4
-carboxylic acid piparoyloxymethyl ester.
4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamide]i-vinyl-3-cephem-
The compound according to claim (!), which is a 4-carboxylic acid benzhydryl ester. (117-[2-(2-formamidothiazole-4-
(ml) 7-[ 2-(2-formamidothiazole-4~4#)-2-benzhydryloxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid Compound. -7-(2-(2-aminothiazol-4-yl)-2
-benzhydryloxycarbonylmethoxyiminoacetamide)-3-vinyl-3-se7emu-4-carboxylic acid tertiary-butoxycarbonylmethyl ester. Heavy ring R1 is aminothiazolyl group, R1 is carboxy (
(lower) alkyl group Claim No. 1, wherein Rm is a lower alkanoyloxy (lower) alkoxycarbonyl group
A compound according to item 11. 64 7-C2-<2-aminothiazol-4-yl)
-2-Carboxymethoxyiminoacetamide F)-3-
The claimed aSS compound is vinyl-13-cephem-4-carvone-piparoyloxymethyl ester. Casting 7-(2-(2-aminothiazol-4-yl)
-2-carboxymethoxyiminoacetamide F)-3
-vinyl-3-cephem-4-carboxylic acid carboxymethyl ester. Fist groaning R1 is substituted with halogen and mourning aminothiaserialkoxycarbonyl (lower) alkyl L R'' is ditu<
IJ Carboxy group 9 is mono 4 L < duck) Riphenyl (
The compound according to claim (1), which is a lower) alkoxycarbonyl group. First 7-(2-(2-amino-5-chlorothiazole-
4-yl)-2-(1-carboxyethoxyimi/)acetamido-3-vinyl-3-cephem-4-carboxylic acid. - (a) Reactivity I of the compound represented by the general formula (in the formula, HaFi carboxy group teFi means an interlocked carboxy group) or its amino group! zero body or its salts, -soft formula % (wherein R'tt halogen-substituted aminothiazolyl group or optionally halogen-substituted protected aminothiazolyl group, R1 is carboxy or protected aminothiazolyl group) (respectively meaning a carboxy (lower) alkyl group) or a reactive derivative thereof at the carboxy group is reacted with a salt thereof, and -(in the formula R1
, H snow and BaFi, respectively) to obtain its salts; refers to an aminothiazolyl group (R1 and R3 each have the same meaning as before) or a salt thereof is subjected to amino-protecting group removal reaction 115 and substituted with the general formula (in the formula, #i) ・logon 1m and Ra each have the same meanings as before) or salts thereof, or (wherein RS means a protected carboxy group, R1
and R2 are the same meanings as above) or their salts are subjected to a carboxy-protecting group elimination reaction to form a compound represented by the general formula (wherein R1 and BR are the same meanings as above) or A compound represented by the general formula (wherein R1 and R1 each have the same meanings as before) or a salt thereof is subjected to a carboxy-protecting group introduction reaction to obtain a salt thereof; R", R" and R: (each has the same meaning as before) Compounds represented by the formula (e) can be obtained from its salts, where XI means halogen, and R1 and Ra each have the same meaning as before. (same meaning as before) or its salts is reacted with a compound represented by the general formula % (in the formula, R'Fi means an amino group or a protected amino group) to form a compound represented by the general formula ( Compounds represented by the formula (R, R1 and R4 each have the same meanings as before) can be used to obtain salts thereof, or (to) a compound represented by the general formula (wherein R1 is a protected carboxy(lower) alkyl group) A compound represented by R1 and R''#'i, each with the same meaning as above) is obtained by subjecting its salts to an elimination reaction of the carboxy-protecting group to obtain the compound represented by the general formula (wherein, is carboxy (lower) means an alkyl group,
(R1 and Ba1l, each having the same meaning as above) or (g) general formula (wherein R%, ti means a protected carboxy(lower) alkoxycarbonyl group) (each has the same meaning as before) A compound represented by the formula (wherein R means a carboxy (lower) alkoxycarbonyl group) or its INs is subjected to a carboxy-protecting group elimination reaction to form a compound represented by the general formula are the same meanings as above). A method for producing a syn isomer of sporanic acid WII conductor or a salt thereof. - General formula (wherein R1 #i an aminothiazolyl group optionally substituted with halogen or a protected aminothiazolyl group optionally substituted with halogen, R"u carboxy-protected carboxy(lower) alkyl An antibacterial agent containing as an active ingredient a syn isomer of a 7-acylamino-3-vinyl heptaphalospotunic acid derivative or its salts represented by the following formula (respectively meaning a carboxyl group or a protected carboxy group). - General formula % Formula % (In the formula, R1 is a protected carboxy (lower) alkyl group, R6 and R4 #i are bonded to form a protected oxo group across the oxo group, and R@h carboxy group or protected carboxy group 14 (21(a) General formula (in the formula, %R'ii means a protected carboxy group, R'ii means a protected carboxy group, R'
Reacting a compound represented by the general formula % (where R: the same meaning as before) or a reactive derivative thereof with a compound represented by the general formula % (where R: the same meaning as before),
To obtain a compound represented by the general formula: (wherein R: #R6I R" and Rt each have the same meaning as before, or t or -) with the general formula (wherein, .R:, Rc, R" and A halogenating agent is reacted with a compound represented by the formula (wherein XI means halogen and 3 '':'R'l
(R" and Rf have the same meanings as above).
h, each having the same meaning as before) is subjected to an elimination reaction of the carboxy protecting group to form a compound represented by the general formula: (wherein R:, R'l R' and 11 each have the same meaning as before) The general formula is characterized by the following formula: (wherein 14 is hydrogen or), 14 represents a carboxy group or a protected 9-carboxy group, respectively, and Ra, R'' and R'' tj each has the same meaning as before) 9 is a method for producing its salts.