DD157802A5 - PROCESS FOR PREPARING NEW CEPHEM COMPOUNDS - Google Patents

Abstract

A process for the preparation of novel cephem compounds of the general formula I, wherein: R 1 is an amino or protected amino group; R 2 is hydrogen, lower alkyl which may be substituted by one or more suitable substituents, lower alkenyl, lower alkynyl, cyclo (lower) alkyl, cyclo (lower) alkenyl or a 0-containing 5-membered heterocyclic group represented by one or more substituents substituted several oxo groups; R 3 is a group of formula II wherein X is hydrogen or carbamoyl; and R high 4 -COO high -; or R "tall" 3 "2" lower-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; and R "" 4 "" carboxy or protected carboxy, and their salts, especially their pharmaceutically-acceptable salts, antimicrobial Have activities and can be used in pharmaceutical agents for the therapeutic treatment of infectious diseases in humans and animals.

Description

T.52 608

Title dex; Invention:

Process for the preparation of cephemic compounds

Field of application of the invention:

The invention relates to novel processes for the preparation of new cephem compounds and salts, in particular pharmaceutically acceptable salts thereof, which have antimicrobial activities and can be used in pharmaceutical agents for the therapeutic treatment of infectious diseases in humans and animals.

Object of the invention:

The object of the present invention is to produce new cephem compounds and salts, in particular pharmaceutically acceptable salts thereof, which are opposite to one another

r 2 -

22 811 2

Series of pathogenic microorganisms are active or effective. The aim of the invention is in particular to provide novel processes for the preparation of these novel cephem compounds and their salts, in particular their pharmaceutically acceptable salts. ,

Presentation of the essence of the invention:

The invention has for its object to produce new cephem compounds, which have the properties mentioned and are suitable for the said treatment.

The invention relates to the following Ver drive 1 to 4 for the preparation of new Cephenr compounds of the general formula

(I)

in which mean:

R is an amino or protected amino group;

R is hydrogen, lower alkyl, which is replaced by one or more

suitable substituents may be substituted, lower alkenyl, lower alkynyl, cyclo (lower) alkyl, cyclo (lower) alkenyl or a 0-containing 5'-membered heterocyclic group which is substituted by one or more oxo groups; ·.

-R. a group of the formula ~~

  - 3 -

wherein X represents hydrogen or carbamoyl; and

R - COO "; or

R 2 "" lower ~ 5 ~ oxo-6-hydroxy ^ ~ _2/5 ~ dihydro-l _{/ 2/4} ~

4 triazinylthio and R carboxy or protected carboxy,

and their salts _7, in particular their pharmaceutically acceptable salts,

Method T

(Π)

or a reactive derivative on the amino group or a salt thereof

i fl

i-C-COOH (HI)

"A,

or a reactive derivative on the carboxy group or a salt thereof

or a salt of it

Method 2

(D

or a salt of it

Method 3

S π K

5

OR &

5b

(XIII)

or a salt thereof (IV)

or a reactive derivative thereof

· -J? -Vc-CQNH N OR ^a

I '

(I b)

or a salt thereof eliminating the Cärb oxy protective group

- · 5

No

(Ic) or a salt thereof

Method 4

³ ^ -CH:> ti

? e

Elimination of the hydroxy- protecting group _s

(Id)

...... or a salt of it

OH

(Ie)

or a salt of it

228112!

12 3 4

wherein R, R, R and R are each as defined above; ·

R is a group that is represented by a group of the formula

3 3

R may be substituted, wherein R is the above

Has meanings;

R is a compound of formula ^N \ _ /

wherein X has the meanings given above, and

4a R is carboxy; or

OL O_

R is a compound of the formula R -H, wherein 3c

R. 2 ~N.drigalkyl-5-oxo-6-hydroxy-2 _/ 5-dihydro-1 _/ 2 _/ 4-

4a; triazinylthio represents and R is carboxy or protected

Carboxy;

R is a protected carboxy (lower) alkyl;

R is a carboxy (ni, edrig) alkyl; and

R is a hydroxy protecting group.

Among the starting compounds, some of the compounds of formula (Ia) are novel and can be prepared by the following methods:

OE ²

3d --->

(πι) (ν)

or a reactive derivative or a reactive derivative. «

at the carboxy group or a salt derivative at the amino group or

of it a salt of it

(VI) or a salt thereof

3d

Second

Elimination of carboxy-protecting group

(VII) or a salt thereof

(VIII) or a salt thereof

1 "? 9n 9 h

where R, R, R and R are each the above indicated

OJ

have lower alkyl alkanoyl (lower) alkanoyloxy

4b and R carboxy or protected carboxy are _e

In addition, some oer compounds (II) can be prepared by the following methods: ..

M (j n

(IX)

or a salt of it

»

Elimination of the Amino «

(XI)

or a salt of it

COO

(AI)

or a salt of it

wherein X has the meanings given above and R is a group which may be substituted by a group of formula ij / ^% --- "^

Among these compounds, the compound (XI) is new.

It goes without saying that, in addition to the compounds (I) ₇ (Ib), (Ic), (Id) and (Ie) and the starting compound, the invention also provides

compounds (III), (VI), (VII), (VIII) and (xIiL) uinfaßt also the tautomeric isomers _e That is, when in the molecules of the compounds and starting compounds, the group of the formula N-

(where R has the meanings given above), this group of the formula can alternatively also be represented by its tautomeric formula:

(where R is an imino or protected imino group). That is, these two groups are in equilibrium with each other, and this tautomerism can be represented by the following equilibrium:

N.

Il - * \

in which R and R each have the meanings given above,

These types of tautomerism between the amirolino compound and the corresponding imino compound ₇ as indicated above are known per se in the literature and it will be readily apparent to one skilled in the art that both tautomeric isomers are readily interconvertible and, therefore, are also useful in the art Compounds per se included

228112 1

Accordingly, the two tautomeric forms of the abovementioned compounds according to the invention and of the abovementioned starting compounds are within the scope of the present invention. Here, the compounds according to the invention and starting compounds which contain the group with these tautomeric isomers are represented by one of the two possible expressions, ie through the formula

IJ

With respect to the compounds (I), (Ib), (Ic), (Id) and (Ie) and the starting compounds (III), (VI), (VII), (VIII) and (XIIl) of the present invention, it is clear that the Compounds according to the invention and the starting compounds also include the syn isomers, anti isomers and mixtures thereof. For example, in relation to the compound (i) according to the invention, the syn isomer is to be understood as a geometric isomer having the partial structure represented by the following formula:

C-CO-

1 o . (wherein R and R each have the meanings given above) and the anti-isomer is to be understood as meaning the other geometric isomer having the partial structure represented by the following formula:

R ² -0-N

<- 11

(wherein R and R "each have the meanings given above)»,

With respect to the other compounds of the present invention and starting compounds as mentioned above, the syn isomers and anti isomers can also be represented by the same geometric isomers as explained above for compound (I) ©

Suitable salts, especially suitable pharmaceutically acceptable salts of the compounds (i) include conventional Not ^ t-toxic salts, such as _e, metal salts ^ such as an alkali metal salt (e.g. "B". A sodium, potassium salt and the like ") and a alkaline earth metal salt (e.g. _o B, a calcium, magnesium salt and the like.) (, an ammonium salt, a salt of an organic base such as, _e B "a Trimethylamine-, triethylamine," pyridine, picoline, dicyclohexylamines Ν, Ν'-Dibenzyläthylen · »diamine. and the like *), a salt of an organic acid (e.g. _e B _e is an acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate _ff toluenesulfonate and the like"), a salt of an inorganic acid (such as _ζ β Β β a Hydrochloride, hydrobromide, hydroiodide, thiocyanate, sulfate, phosphate and the like _e ) or a salt with an amino acid (such as arginine, aspartic acid, glutamic acid and the like) and the like.

For the radicals indicated above and below, some suitable examples are given below and the various definitions are explained in more detail below.

22 8 112

The term "lower" or "lower" denotes a radical which, unless stated otherwise, contains 1 to 6 carbon atoms.

The "protected amino group" indicated for R may be, for example, an acylamino or amino group which is substituted by a conventional protecting group such as an acylamino or amino group. Ar (lower) alkyl which may have at least one suitable substituent (such as ζ <* Β · benzyl, trityl and the like), or the like.

The acyl radical in the term "acylamino" may be, for example, a carbamoyl group, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of the acyl group may be lower alkanoyl (such as formyl, acetyl, propionyl, Butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like); lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, T, cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert -butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like); lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl- _7- isopropanesulfonyl, butanesulfonyl and the like); Arenesulfonyl (such as benzenesulfonyl, tosyl and the like); Aroyl (such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indanecarbonyl and the like); ,

Ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl and the like); Ar (lower) alkoxycarbonyl (such as bejizyloxycarbonyl, phenethyl)

~ 13 -

oxycarbonyl and the like) and the like

The above-mentioned acyl group may have mindestens'einen suitable substituents, such as _e B, halogen (such as chlorine, bromine, fluorine and iodine), lower alkanoyl as mentioned above, or the like "

A suitable "lower alkyl group" for R is one having 1 to 6 carbon atoms and which may include methyl, ethyl ^ propyl, Is-opropyl, butyl, iso ~ butyl, shouldered ^ Butylj pentyl, tert _e -pentyl, Hexyl and the like ", preferably a radical having 1 to 4 carbon atoms",

Examples of a suitable "lower alkyl" containing the

substituents on 1,2,4-triazinylthio for R, and lower alkyl groups "in the printings" protected carboxy (lower) alkyl "and" carboxy (lower) alkyl "are those as exemplified above _e

The "lower alkyl" for R "may be substituted by 1 to 3 suitable substituents, such as _e halogen (such as chlorine, bromine, fluorine or iodine); carboxy; protected carboxy as mentioned below; lower alkylthio (such as methylthio, Ethylthio, propylthio, butylthio and the like;); aryl (such as phenyl, tolyl, xylyl, mesityl, cumenyl and the like) or the like,

Suitable examples of lower alkenyl may be vinyl, allyl, isopropenyl, Ί-propenyl, 2'-butenyl _/ 3-s ^D entenyl, and the like ", preferably one having 2 to 4 carbon atoms.

228.11 2

Examples of suitable lower alkynyl may be one having 2 to 6 carbon atoms _/ such as ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3 ~ hexynyl or the like. _F preferably one having 2 to 4 carbon atoms.

Examples of suitable cyclo (lower) alkyls may be those having 3 to 6 carbon atoms, such as z * B. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, preferably one with 4 to 6 carbon atoms.

Examples of a suitable cyclo (lower) alkenyl may be one having 3 to 6 carbon atoms, e.g. Cyclopentene, cyclohexenyl or the like, preferably one with 5 or 6 carbon atoms,

Examples of a suitable 5-membered heterocyclic group containing 0 may be a saturated or unsaturated group, e.g. Dihydrofuryl, tetrahydrofuryl or the like, which is substituted by one or two oxo groups.

Examples of protected carboxy and a protected carboxy radical in the term "protected carboxyC-lower alkyl" may be esterified carboxy, which may be the ester, e.g. a lower alkyl ester (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropyl ethyl ester and the like), wherein the lower alkyl radical. preferably, it may be one having Ί to 4 carbon atoms; a lower alkenyl ester (such as vinyl, allyl ester and the like); a low al

cynyl esters (such as ethynyl-1-propynyl ester and the like); a mono - "(or di or tri) halo (lower) aikyiester (such as 2-JOdOtHyI-, 2,2,2 ~ trichloroethyl and the like _e);

a lower alkanoyloxy (lower) alkyl ester (such as acetoxymethyl-f propionyloxymethyl, 1-acetoxypropyl ,. valeryloxymethyl, pivaloyloxymethyl-y-j Hexanoyloxymethyl-, 1-acetoxyethyl · - "2-Propionyloxycithyl-, 1 ~ Isobutyryloxyäthylester and the like _e); a lower alkanesulfonyl (lower) alkyl ester (such as mesyl-IHOtIIyI, 2-mesylol ester and the like); an ar (lower) alkyl ester / _e B _e such a phenyl (lower) - "alkyl ester which may be substituted by one or more suitable substituents (such as" B _o benzyl '4-methoxybenzyl'

f. * ·

4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, bis (methoxyphenyl) methyl _, 3,4-dimethoxybenzyl, 4-hydroxy, 3 _, 5-di-tert-butylbenzyl ester, and the like); a lower alkoxycarbonyloxy (lower) alkyl ester (such as _{meth-; i} ^ oxycarbonyloxymethy, A'thoxycarbonyloxymethyl-, A'thoxycarbonyl · - oxyäthylester * and the like), which may be substituted with azido; a heterocyclic ester, preferably a benzotetrahydrofuryl ester, which may be substituted by an oxo group, preferably a phthalidyl ester; an aroyloxy (lower) alkyl ester (such as a benzoyloxymethyl, benzoyloxyethyl) toluoyloxyethyl ester and the like); an aryl ester which may have one or more suitable substituent (such as a phenyl, "ToIyI-, shouldered-butylphenyl," XyIyI-, mesityl, and the like Cumenylester _e), and the like "

Preferred examples of protected carboxy may be lower alkoxycarbonyl (such as methoxycarbony 1, a'thoxycarbonyl, propoxycarbonyl, β-butoxycarbonyl, t -butoxycarbonyl, t 1 -pentyl)

2 0 11 ^ ο I f 2

oxycarbonyl, hexyloxycarbonyl and the like) of 2 to 7 carbon atoms, preferably of 2 to 5 carbon atoms, and phenyl (lower) alkoxycarbonyl which may be substituted by nitro (such as 4-nitrobenzyloxycarbonyl, benzyloxycarbonyl, 4-nitrophenethyloxycarbonyl and the like). ) ο

Preferred examples of R and R may include acyloxy, halo, azido, and the like, wherein the acyl radical in the term "acyloxy" and halo may be those as exemplified above. "

Suitable hydroxy-protecting groups may include the above-mentioned acyl, Ar (lower) alkyl (such as benzyl, trityl, and the like), and the like.

Suitable examples of lower alkanoyl (low) alka ~ can noyloxy include acetoacetoxy, Propionylacetoxy, acetonitrile = propionyloxy, etc. ·}

In the following, preferred compounds of the formula (i) are explained in more detail.

R is preferably amino;

R is preferably hydrogen, lower alkyl, ar (lower) alkyl [more preferably triphenyl (lower) alkyl], lower alkylthio (lower) alkyl, halo (lower) alkyl, most preferably trihalo (lower) alkyl], carboxy (lower) alkylj. esterified carboxy (lower) alkyl [more preferably lower alkoxycarbonyl (lower) alkyl or

Phen, yl (lower) alkoxycarbonyl (lower) alkyl], lower alkenyl, lower alkynyl; Cyclo (lower) alkyl _/ cyclo (lower) alkenyl or tetrahydrofuryl substituted by an oxo group; R is preferably a group of formula v

4 wherein X represents hydrogen or carbamoyl, and R preferably represents COO; or

R is preferably 2-lower-alkyl-5-oxo-6-hydroxy

4 _2/5 ~ dihydro-1 _/ 2.4 ~ triazinylthio and R preferably represents carboxy "

In the following, the various processes for the preparation of the inventive cephem compounds will be explained in more detail

Method 1

The compound (i) can be prepared by reacting the compound (II) or a reactive derivative at the amino group or a salt thereof with the compound (III) or a reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivatives at the amino group of the compound (II) may include conventional reactive derivatives as used in the amidation ₇ such as Z ₀ Bo a ship-type ~ imine derivative or its tautomeric enamine-type isomer is formed by reacting the compound (II) with a carbonyl compound; a silyl derivative which is formed by reacting the compound (II) with a silyl compound _/ as Bis (tri-)

 - "-. '.22 8 t 1-2 1

methylsilyl) acetamide, tri-methylsilyl-α-ce-ta-mid or the like; a derivative formed by reacting the compound (II) with phosphorus trichloride or phosgene, and the like.

Suitable salts of compound (II) may include an acid addition salt, e.g. a salt of an organic acid (such as an acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate and the like) or a salt of an inorganic acid (such as a hydrochloride, hydrobromide, sulfate, phosphate and the like); a metal salt (such as a sodium, potassium, calcium, magnesium salt and the like), an ammonium salt, a salt of an organic amine (such as a triethylamine, dicyclohexylamine salt and the like) and the like.

Suitable reactive derivatives at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester and the like. Suitable examples may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (such as dialkylphosphoric acid, Phenylphosphorsaure, diphenylphosphoric ₇ dibenzyl "phosphoric acid, haiogenierter phosphoric acid and the like"), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic, an aliphatic carboxylic acid (such as pivalic acid, pentanoic acid , Isopentanoic acid, 2-ethylbutyric acid, acetic acid or trichloroacetic acid and the like), or an aromatic carboxylic acid (such as benzoic acid and the like); a symmetrical acid anhydride; an activated amide with imidazole, dimethylpyrazole, triazole or tetrazole;

or an activated ester (for example, _o .a cyano ο methyl, "methoxymethyl-H dimethyliminomethyl [(CH _{3) 2} N SCH-O-, vinyl," propargyl ~ / p-nitrophenyl, 2,4 ~ Dinitropheny.l ~, Trichlorophenyl, pentachlorophenyl, mesylphenyl "^ phenylazophenyl, phenylthio, p-nitrophenylthio ™, p-cresylthio, carboxymethylthio, pyranyl ·, pyridyl», piperidyl, 8 "-> quinolylthioester or an ester with Ν, Ν-dimethylhydroxylamine, 1 ~ hydroxy ~ 2 ~ (iH) pyridone _/ N-hydroxysuccinimide, N'-hydroxyphthalimide or 1-hydroxy-6'-chloro-1H-benzotriazole and dglo These reactive derivatives may be selected in any manner from the above-mentioned. depending on the type of compound used (III).

It may the salts of the compound (III) be salts with an inorganic base, such as _o Alkaliinetallsalze (such as a sodium or potassium salt) or alkaline earth metal salts (such as _e a calcium or Magnesiunisalz), a salt with an organic base such as trimethylamine, triethylamine, pyridine, a salt with an acid (such as hydrochloric or hydrobromic acid) or the like,

The reaction is typically carried out in a conventional solvent Z _n Be in water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, -diethylnamide, pyridine or any other organic solvent containing the Reaction not adversely affected. Among these solvents, the hydrophilic solvents can be used mixed with water. _E

«20

-228112

When the compound (HI) is used in the form of the free acid or its salt in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexylcarboximide;N-cyclohexyl-N'-morpholinoäthylcarbodiimid; N-cyclohexyl-N ^l '(4 "diäthylaminocyclohexyl) carbodiimide; N, N-Diäthylcarbodiimid; N, ^{N-diisopropylcarbodiimide;!} N-ethyl" N "(3' dimethylaminopropyl) carbodiimide, N, N ~ carbonylbis (2 ~ methylimidazole); Pentamethylene-ketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Athoxyacetylen; Athylpolyphosphat; Isopropyl polyphosphate; Diäthylphosphorchloridat; phosphorus oxychloride; phosphorus; Phosphorus pentachloride; thionyl chloride; oxalyl chloride; triphenylphosphine; N-ethyl-7-hydroxybenzisoxazoliumfluorborat; N-ethyl-5 phenylisoxazolium ~ ~ 3 ^f sulfonate; 1 «(p ~ chlorobenzenesulfonyloxy) '- 6« chloro-1H-benzotriazole; the so-called Vilsmeier reagent such as (chloromethylene) dimethyl ammonium chloride prepared by reacting dimethylformamide with thionyl chloride or phosgene, a compound formed by reacting dimethylformamide with phosphorus oxychloride and the like; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, a tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N _f N -di (lower ) alkylbenzylamine, N _y N -di (lower) alkylaniline, such as. -explained, for example, explained in more detail below, or the like. If the base or the condensing agent is liquid, it can

, ~ 21 -

(it) can also be used as a solvent "The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

In the reaction of the invention, a syn isomer of the compound (I) can be obtained by preferably carrying out the reaction of the compound (II) with a symi isomer of the starting compound (III).

Method 2

The compound (i) or a salt thereof can be prepared by reacting the compound (XIIl) or a salt thereof with the compound (IV) or a reactive derivative thereof.

Examples of suitable salts of the compound (XIIl) are those as indicated above for the compound (II),

(IV) Suitable reactive derivatives of the compound include a metal salt such _e B "is an alkali metal salt (zeb '' is a sodium, potassium salt and the like"), or the like "

The reaction according to the invention can be carried out in a solvent, e.g. in water, a phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol. Ethanol, ether, tetrahydrofuran, di-methyl sulfoxide or any other organic solvent.

agent which does not adversely affect the reaction,

~ 22 -

228.1 1.2. i

preferably in one with strong polarities. Among the solvents, the hydrophilic solvents may be used in admixture with water. The reaction is preferably carried out in an approximately neutral medium. When the compound (XIII) or the compound (IV) is used in its free form, the reaction is preferably in the presence of a base, ζζΒ. an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate _{7 of} an organic base such as a trialkylamine and the like. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, with heating or with gentle heating.

The reaction of the invention also includes the case where a protected carboxy group is converted to the free carboxy group during the course of the reaction _e ,

Method 3

The compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to an elimination reaction to remove the carboxy-protecting group. "

Suitable salts of the compound (Ib) include those as given above as examples of the compound (II).

The reaction according to the invention is carried out using a

· - 23 -

conventional method such as hydrolysis, reduction or the like _{O /} performed

When the protecting group is an ester, the protecting group may be eliminated by hydrolysis. "" The hydrolysis is preferably carried out in the presence of a base or acid. "Suitable bases may include an inorganic base and an organic base such as an alkali metal (such as sodium, -potassium and the like _o), an alkaline earth metal (such as magnesium, calcium and the like *), the hydroxides or carbonates or bicarbonates thereof, a trialkylamine (such as Trimethylarain, triethylamine and the like _e), picoline, 1,5 ~ Diazabiayclo -C4 _e 3 _e 03non-5-ene, l _/ 4-diazabicyclo [2 _e 2 _e 23octani 1,8-diazabicyclo [5 _e 4 "0] undecene-7 or the like" Suitable acids may include an organic acid ( such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like ") and an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like _e) e

The reaction is usually in a solvent, for _e B "in water, an alcohol (such as methanol, ethanol and the like"), a mixture thereof or any other solvent which does not affect adversely on the reaction performed. As a solvent, a liquid base or acid can be used, "The reaction temperature is not critical and the reaction is usually carried out with cooling to heating". · ..- '

For the elimination of the protecting group, e.g. a 4-nitrobenzyl

2281121

2-iodoethyl, 2,2,2-trichloroethyl or the like, _t may preferably be applied to the reduction. Reduction methods that can be used to carry out the elimination reaction may include, for example, reduction using a combination of a metal (such as zinc, zinc amalgam and the like) or a salt of a chromium compound (such as chromium (II) chloride, chromium (II ) acetate and the like) and an organic or inorganic acid (such as acetic acid, propionic acid, hydrochloric acid and the like); and the conventional catalytic reduction in the presence of a conventional metal catalyst (such as palladium-carbon and the like).

Method 4

The compound (Ie) or a salt thereof can be prepared by subjecting the compound (Id) or a salt thereof to elimination reaction to remove the hydroxy-protecting group

Examples of suitable salts of the compound (Id) are those as exemplified above for the compound (II).

The elimination reaction according to the invention can be carried out in substantially the same way as the acid hydrolysis in the process 3,

The preparation of the starting compounds will be explained in more detail below.

~ 25 -

Manufacture 1

The compound (VI) or a salt thereof can be prepared by reacting the compound (III) or a reactive derivative at the carboxy group or a salt thereof with the compound (V) or a reactive derivative at the amino group or a salt thereof ©

Examples of suitable reactive derivatives and salts of the compound (V) are those as exemplified above for the compound (II),

The reaction according to the invention can be carried out in virtually the same way as stated in process 1 »

Production 2

The compound (VIII ') or a salt thereof can be prepared by subjecting the compound (VIl) or a salt thereof to elimination reaction to remove the carboxy-protecting group

Examples of suitable salts of the compound (VII) are those as have been given above by way of example for the compound (II) _e

The reaction according to the invention can be essentially the same. As indicated in method 3 ",

~ 26 -

22 8112 1

production 3

The compound (XI) or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound (X).

Examples of suitable salts of. Connection (i.X). are those as exemplified above for the compound (il) «

The reaction according to the invention can be carried out in substantially the same way as indicated in process 2,

Production 4 ·

The compound (XIII) or a salt thereof can be prepared by subjecting the compound (XI). Or a salt thereof to an elimination reaction to remove the amino-protecting group in the 7-position.

The elimination reaction of the present invention is carried out by reacting the compound (XI) or a salt thereof with an imino-halogenating agent and then with an imino-ether-releasing agent, and if necessary, subjecting the resulting compound to hydrolysis. "

The reaction according to the invention is carried out using a conventional method. «

In the above-mentioned reactions of the present invention and / or post-treatment of the reactions of the present invention, occasionally the above-mentioned geometric isomer and / or tautomeric isomer may be converted to the other geometric isomer and / or tautomeric isomer, and these cases are also within the scope of the present invention.

When the compound (I) has a free carboxy group and / or a free amino group, it can be _/ as indicated above, by a conventional method in their _x Saiz particular its pharmaceutically acceptable salt, transferred v / ground "

The compound (I) prepared according to the present invention has a high antimicrobial activity and "inhibits" the growth of a number of microorganisms including the pathogenic Gram-positive and Gram-negative bacteria.

For therapeutic administration, the 'cephalosporin compounds according to the invention in the form of a pharma * are - ceutical preparation used, the B containing these compounds in admixture with one or more pharmaceutically acceptable carriers, such as _{e e} an organic or inorganic solid or liquid excipient which for oral, parenteral or external administration is suitable · _o the pharmaceutical preparations may be in solid form, for example in the form of capsules, tablets, dragees, ointments or suppositories, or in liquid form, z'.B. in the form of

~ 28 -

2 2 811 5 f

"'vent ^ S' B ^ v · B

Solutions, suspensions or emulsions are present in the above-mentioned preparations, auxiliary substances, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives may also be present.

Although the dosage of the compounds may vary widely and also depends on the age and condition of the patient, an average single dose of about 50 mg, 100 mg, 250 mg and 500 mg of the compounds has been shown to be effective in the treatment of infectious diseases. which are caused by a number of pathogenic bacteria. "Generally, amounts in a daily dose may be administered between 1 mg and about 1000 mg per patient or even higher doses."

The usefulness of the compounds (i) is demonstrated below on the basis of experimental results for the determination of the antimicrobial activity of some representative compounds.

Test method ·

An eyelet filling of a overnight culture of each test strain

in trypticase soy broth (10 viable cells per ml) was streaked on a cardiac infusion agar (HI agar) containing graded concentrations of antibiotics and the minimum inhibitory concentration (MIC) expressed in μ9 / ηι1 _/ ηαο [Ί Incubated for 20 hours at 37 ° C. ·

~ 29 ~

Tested binding.

(1) 7 "[2-A ^ hoxyimino ~ 2 ~ (5-amino-l, 2 _/ 4-thiadiazol-3-yl) -acetamido] -3- (i-pyridiniomethyl) -3-cephem-4 ~ carboxylate (syn isomer),

(2) 7-C2-Allyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) -acetamido 3 ~ 3 "" (1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer)

(3) 7 "[2- (2-Propynyloxyimino) -2- (5-amino-1,2 _/ 4-thiadia2: o1-3-yl) -acetamido] -3- (i -pyridinium-diethyl) -3-cephem -4 ~ carboxylate (syn-isomer),

(4) 7- [2-Cyclopentyloxyimino-2- (5'-amino- "" 1 _/ 2,4-thiadiazol-3-yl) acetamido] -3 "- (1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer),

(5) 7 "- [2- (2-Cyclopentene-1-yloxyimino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3- (i-pyridiniomethyl)" 3-cephem-4-carboxylate (syn isomer),

(6) 7- [2-Methoxyimino ~ 2 ~ (5 "amino ~ 1 _/ 2 _/ 4-thiadiazol-3-yl) -acetamido]" -3 "(i-pyridiniomethyl HyI) -S-CePHeITi ^ -COr boxylate (syn-isomer),.

(7) 7- [2 ~ ~ Isopropoxyimino 2- (5 ~ amino ~ _{1/2/4-thiadiazol-3-yl)} asetamido] ~ 3- (2 ~ methyl ~ 5-oxo'-o'-hydroxy-2 _/ 5-dihydrol _/ 2 _/ 4-triazine-3-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer),. ,

(8) 7 ~ [2-AtHoxyimino ~ 2 - "(5-amino-l _/ 2 _/ 4-thiadiazol-3-yl) -acetamido] -3- (4 -carbamoyl-1-pyridiniomethyl) -3-cepHem "4-carboxylate (syn-isonieres) e

 2.2.8 1.12

Test results '

c. ''.

Test bacteria tested compound MIC (pg / ml)

(D) (2) (3) (4) (5) (6) (7) (8)

E. coli NIHJ JC-2 0.10 O ₇ IO 0.20 0.78 1.56 0.39 0.39 0.05

Kl. Pneumoniae 12 0.10 0.78 0.39 1.56 1.56 0.20 0.39 0.20

Pr. Vulgaris 2 0.10 0.39 0.20 3.13 3.13 0.20 <0.025 0.20

Ps. Aeruginosa NCTC

10490 1.56 1.56 1.56 6.25 6.25 1.56 1.56 3.13

B. subtilis ATCC 6633 0.78 0.78 0.78 0.20 0.39 0.78 3.13 0.78

With regard to the nomenclature of the compounds prepared according to the invention (3-pyridiniummethyl compounds), it should be noted that there are a number of different nomenclatures. Thus, for example, the compound (a) given below is substituted as 7- (2-methoxy-imino-2- (5-amino) l, 2,4-thiadiazol-3-yl) -acetanido] -3- (1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer) or as N-L7 ~ 2-methoxyimino-2- (5 amino "l, 2,4-thiadiazol-3" yl) acetamido5-3-cephem "3-ylmethyl] pyridinium" 4 "carboxylate (syn isomer). The hydrochloride salt of the compound (β) is prepared as 1-C (7-amino-4-carboxy-3-cephem "3" yl) methyl] pyridinium chloride or N- [7-amino-.3-cephem-3-ylmethyl-3-pyridinium-4 -carboxylate hydrochloride "

COO U) (B)

The other compounds prepared according to the invention can be correspondingly referred to and are all within the scope of the present invention.

The invention is explained in more detail by the following preparation examples and examples, but without being limited thereto

Ausführungsbei sp i ele '.

Production Example 1 ·

Preparation of Methyl ~ 5-Amino-1'-Thiadiazole S-Carboxylate To a solution of 16 ", 6 g of 1-ethoxycarbonylformamidine hydrobromide in 84 ml of absolute methanol was added a solution of 1.93 g of sodium in 42 ml of absolute methanol at 0 C. To the mixture was alternately added 12.8 g of bromine and a solution of 1.93 g of sodium in 42 ml of absolute methanol at 0 C and then to the suspension was added 8.1 g of potassium thiocyanate in 100 ml of absolute methanol The reaction mixture was stirred for 1 hour at 0 C and for additional 6 hours at ambient temperature The mixture was filtered through cellulose powder and the filtrate was evaporated to dryness The residue was dissolved in a mixture of ethyl acetate and water and then the ethyl acetate layer The solvent was evaporated and the residue was triturated with diethyl ether to give 9.0 g of the title compound, mp 202 to 205 ° C.

I.R. (Nujol): 3400, 3250, 3100, 1710,

161O ₇ 1540 cm "" ¹ '

N.M.R. (D, DMSO)

*. O-

S: 3.85 (3H, "s), 8.25 (2H> s)

Production Example 2

Preparation of methyl 5-formamido ~ 1 ^^ - thiadi

oxylate _; _ _ · _ '

To a mixture of 33 g of formic acid and 22 g of acetic acid

Anhydride was added to 6.2 g of methyl 5-amino-1,4-thiadiazole-3-carboxylate and then the mixture was allowed to stand for 2 hours. stirred at ambient temperature for a long time «. The reaction mixture was concentrated under reduced pressure and the residue was triturated with a mixture of diethyl ether and η-hexane to give 7.2 g of the title compound, m.p.

I "R _e (Nujol): 3100, 1720, 1680 cm"" ¹ N ₆ M ₀ R ₀ (D ₆ -DMSO)

δ; 3.90 (3H, s), 8.85 (IH, s).

Example 3 : Example 3.

Preparation of 5-formamido-3 - (2-methylthio-2-methylsulfinylacetyl) - J,

To a mixture of 9.2 g of Msthyl-5-formamido-l _/ 2,4-thiadiazole-3-carboxylate and 6.1 g of methylmethylthomethylsulfoxide in 100 ml of N, N-dimetylformamide were added 7 _f, 1 under cooling in an ice-bath The mixture was stirred at ambient temperature for 1 hour and then at 40 C for an additional hour. After cooling to ambient temperature, 300 ml of methylene chloride was added to the reaction mixture and the resulting precipitates were collected by filtration and washed with methylene chloride. »The precipitates were added to a stirred mixture of 14.7 ml of hydrochloric acid, 200 ml of ice water and 200 ml of methylene chloride. An insoluble material was filtered off and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate , evaporated and the residue was triturated with diethyl ether,

obtaining 4/5 g of the title compound

IR · (Nujol): 3100, 1680, 1670 cm ^-1 NMR (d ₆ -DMS0)

6: 2.22

, 2s)

2.68 /

⁽ ' ^2s)

5.70

8,86 (1H, s) ·. · ... '

Production Example 4 "'

Preparation of S-methyl- (5-formamido-1 _/ 2,4-thiadiazol <-3-yl) ~

thioglyoxylate [ _____

A mixture of 0.85 g of 5-formamido-3- (2-methylthio-2-methyl-sulfinylacetyl), 2,4-thiadiazole and 0.2 g of sodium periodate in 10 ml of glacial acetic acid was stirred at 70 ° C for 45 minutes , The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 7 with an aqueous sodium bicarbonate solution and treated with an aqueous sodium thiosulfate solution. The organic layer was separated / dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and petroleum ether to give 280 mg of the title compound, mp 186-187C

IcR * (Nujol): '3100, 1680, .1660 cm "" ¹

N.M.R. (d, -DMSO) ο

6: 2.55 (3H ₇ S), 8.95 (IH ₇ s)

Production Example 5 .

Preparation of 2 ~ methoxyimino "2 ~ (5" formamido ~ 1,2 _/ 4 '"thia-

diazole «-3 ~ yl) essigsQU-re (syn isomer);

A mixture of 231 mg of S ~ methyl (5-formamido ~ 1,2,4-thiadiazol ~ 3 ~ yl) thioglyoxylate in 2 ml of methanol and 3.5 ml of a Ί η aqueous potassium hydroxide solution was stirred for 1 hour at ambient temperature. The mixture was adjusted to pH 7.6 with 1N hydrochloric acid, then 90 mg of O.sub.3 methylhydroxylamine hydrochloride was added and stirred at ambient temperature for 30 minutes. The reaction 'mixture was neutralized with an aqueous sodium bicarbonate solution and concentrated to remove the methanol _e The concentrated aqueous solution was adjusted with Chiorwasserstoffsäure to pH 4 and washed with ethyl acetate »The aqueous layer was adjusted to pH 1 with hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate the extracted extract was evaporated to dryness and the residue was triturated with diethyl ether, collected by filtration and then dried to obtain 80 mg of the title compound, mp 185-186 ⁰ C ₆

IR (Nujol): 3150, 1720, 1690 cm " ¹ .

NMR ₉ (d ₆ -DMSO) .δ: 3.98 (3H, s), 8.84 (1H, s) ν

"- * - 22811

Preparation Example 6 Preparation of ^ -azol-3-yl) acetic acid (syn-I some res)

A mixture of 3.2 g of 5-formamido-3- (2-methylthio-2-methyl-sulfinylacetyl) -1,2,4-thiadiazole and 0.8 g of sodium periodate in 32 ml of glacial acetic acid was stirred at 70 ° C for 45 minutes , The resulting mixture was evaporated and the residue was washed with n-hexane and then 20 ml of methanol and 40 ml of a 1N aqueous potassium hydroxide solution were added. The solution was stirred for 1 hour at ambient temperature. The reaction mixture was adjusted to pH 8 with 1 N hydrochloric acid, then 0.96 g of O-methylhydrochloride hydrochloride was added and stirred for one hour at ambient temperature. The reaction mixture was neutralized with an aqueous sodium bicarbonate solution and concentrated to remove the methanol. The resulting aqueous solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated and the residue was triturated with diisopropyl ether to give 1.02 g of the title compound, mp 185-186 ° C.

Production Example 7 ; r '

Preparation of 2-methoxyimino-2- (5-amino-l _/ 2 _/ 4-thiadiazole)

3-yl) acetic acid (syn isomer) ^:

A solution of 1.4 g of 2-methoxyimino-2- (5-formamido-l, 2 _J 4-thiadiazol-3-yl) acetic acid (syn isomer) in 19.1 ml of a 1 η aqueous sodium hydroxide solution for 1 hour on

, - 37 -

50 to 55 C'erhitzt. To the solution was added 1.9 ml of concentrated hydrochloric acid under cooling in an ice bath. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give O ₁ 9 g of the title compound, mp 180-182 ° C (dec.) ·

I _e R. (Nuj oil): 3450, 3250, 3100, 1715, 1610, 1530 cm " ¹

N ₉ MR (d ₆ ~ DM $ 0)

: 3.90 (3H, 's), 8.10 (3H, broad s) Manufacturing Example 8 ".'

A mixture of 10 g of 5-formamido-3 ~ (2-methylthio-2-methylsulfinylacetyl) -1 _x 2,4-thiadiazole and 2.0 g of sodium periodate in 50 ml of glacial acetic acid was stirred at 70 ° C for 50 minutes. The solution was evaporated and the residue was washed with h-hexane. To the residue was added 160 ml of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added 3.5 g of O-ethylhydroxylamine hydrochloride and the solution was adjusted to pH 3 to 10 with 10 % hydrochloric acid 4 and then stirred for 1 hour at ambient temperature. After an insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was

· "38 ·»

dried sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and diisopropyl ether to give 4.5 g of 2-Xthoxyimino-2- (5-formamido-1 _/ 2 _/ 4-thiadiazol-3-yl) acetic acid (syn isomer), F _e 165 to 168 ° C (Zers.) *

IR '(NuJoI): 3450, 3170, 3050, 1730, 1690, 1595, 1565 cm " ¹

NMR (d ₆ b : 1.30 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 8.87 (IH, s)

Production Example 9 .

In a similar manner as in Preparation Example 8, the following compounds were prepared:

(1) 2-Propoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) -acetic acid (syn- * isomer), m.p. 168-170 ° C (dec.).

LR. (Nujoi): 3250, 3140, 1720, 1690, f

1590, 1530 cm ^-1 NMR (d ₆ -DMS0)

h : 0.90 (3H, t, J = 6Hz), 1 \ 4-1.9 (2H, _m ), 4.17 (2H, t, J = OHz), 8.85 (IH, s)

(2) 2-Isopropoxyimino-2- (5-formamido-1 _/ 2,4-thiadiazol-3-yl) -acetic acid (syn-isomer), m.p. 180 ° -182 ° C (Zers).

IR (Nuj oil): 3230, 1720, 1690, 1590, 1530 cm ^-1 NMR Cd ₆ -DMSO)

δ: 1.25 (6H, d, J = 6Hz), 4.2-4.7 (IH, m), 8.85 (1H, s). - '_;

Manufacture 10

A mixture of 4.4 g of 2-ethoxyimino-2- (5'-formamido-1 _/ 2 _/ 4-thiadiazol-3-yl) acetic acid (syn isomer) and 54 ml of a 1 N aqueous sodium hydroxide solution was heated at 50 for 2 hours to 55 C stirred The mixture was cooled in an ice bath ₇ acidified with 5.4 ml of hydrochloric acid and with ethyl acetate extracted, the extract was dried over magnesium sulfate and evaporated to dryness The residue was triturated with Diäthylather to give 2.92 g of 2 ~ Äthoxyimino ~ 2- (5 ~ amino ~ 1 ^ 2 _J 4 ^ thiadia2ol ~ 3-yl) acetic acid (syn ^ isomer), mp 168 ~ 17O ⁰ C (Zers.) _O

I _e Re (Nu j oil): 3450, 3370, 3250, 315O _x 1665, 1610, 1530 cm ^"1

NMR (d ₆ -DMSO)

&: 1,22 (3H, t, J = 7Hz), 4,17 (2H, q, J =: 7Hz) ₇ 8,17 (2H, wide s)

Production Example 11

The following compounds were prepared in a manner similar to that described in Preparative Example 10: 2 ~ propoxyimino ~ 2 ~ (5-amino-1 _f 2,4-thiadiazol-3-yl) -acetic acid (syn-isomer), F " , 100 ~ 103 ° C {Zers _e ) _e 1.R ₆ (Nu j oil): 3620, 3520 _f 3350, 3120 _f 2600,

2500, 1720, 1620, 1550 cm ^-1 N.MoR (d ₀ -DMSO)

S i 1, OO (3H, t, J = OHz), 1.3-2.0 (2H, m),

4.13 (2H, t, J = OHz), 8.17 (2H _f wide, s)

22 81 12

(2) 2-Isopropoxyimino-2- (5-amino-1, 2,4-thiadiazo 1 · 33-νΐ) -acetic acid (syn-isomer), mp 152-155 ° C (dec.). I.R. (Nujol): 3450, 3300, 3200, - 1730,:

1620, 1530 cm " ¹ .NMR Od ₆ -DMSO)

6 : 1,22 (6H, d, J = OHz), 4,1-4,6 (IH, m),

8,20 (2H, wide s).

Construction Example 12

1) A mixture of 8.15 g of N-hydroxyphthalimide, 5 ₇ 05 g of triethylamine, 60 ml of N, N-dimethylformamide and 8.05 gl was bromo-2 ~ cyclohexen at room temperature The reaction mixture gerührti 3 ₇ 5 hours poured into 300 ml of water. The precipitated crystals were collected by filtration, washed successively with water and n ~ hexane and then dried ^ wherein one 9.8 g of N received "(2-cyclohexen» -l-yloxy) phthalimide, mp 87 ⁰ C.

IR (Nuiol): 1770, 1720, 1610 cm " ¹ r

NMR Xd ₆ -DMSO ^): 1.50-2.17 (6H, m), 4.60-4.77 (IH, m), 5.73-6.27 (2H, m), 7.90 (4H, s)

2.) A mixture of 58.2 g of N-hydroxyphthalimide, 36.9 g of 1-chlorocyclopejite and 53.9 g of triethylamine in 370 ml of acetonitrile was treated in a manner similar to that described in Section (1) above, wherein 56.5 g of N- (2-cyclopenten-1-yloxyphthalimide were obtained.

I _e R _e (Nujol): 1780, 1730, 1610 cm " ¹

NMR Cd ₆ -DMSO ₇ S): 7.92 (4H, s), 6.28 (1H, m),

~ 6.00 (IH, m), 5.42 (IH, m), 2.9-1.98 m)

Hers tellun gs example 13 .

1 ") A mixture of 22.9 g of N- (2-cyclopentene-M'-yloxy) phthalene. The reaction mixture was filtered. The filtrate, which contained (2-cyclopentene-1-yl) oxyamine, became a solution of 22, 4 g of sodium (5 »form'-amido-1 _/ 2 _/ 4-thiadiazole-3-yl) glyoxylate in water were added. The mixture was adjusted to pH 2 with 10 % hydrochloric acid, stirred for 2 hours and The concentrate was adjusted to pH 1 with 10% hydrochloric acid and the precipitates were collected by filtration and dried, yielding 20.0 g of 2- (2-cyclopentene-1-yl) oxyimino-2 ( 5-formamido-1,2,4-thiadiazole ~ "3" yl) acetic acid (syn isomer ~) received, F, 150 C (dec _e).

I _e R _e (Nu j oil): 3400, 3100, 1720, 1690, 1540 cm * " ¹ N _e M _e R _o (d ₆ -DMS0, S): -1.80 to 2.50 (4H, m , 5.30-5.50 ClH ₇ m), 5.83-6.30 (2H, m), 8.90 (IH, s)

2 ") A mixture of 7.29 g of N 2 (2-cyclohexene-1-yloxy) phthalimide and 1.5 g of hydrazine hydrate in 40 ml of ethanol was allowed to react for 5 minutes

- «· '-

The reaction mixture was cooled and filtered to give the filtrate which was (2-

V 42 «

228112 1

Cyclohexene-1-yl) oxyamine (filtrate A).

On the other hand, a mixture of 6.93 g of S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate in 90 ml of a 1N aqueous sodium hydroxide solution was stirred for 30 minutes at room temperature. The reaction mixture, containing sodium 2- (5-formamido-l, 2,4-thiadiazol-3-yl) glyoxyate, was adjusted to pH 7 with 10% hydrochloric acid and the filtrate A was added and then the pH became Value is adjusted to 3 with 10% hydrochloric acid. The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated and to the concentrate was added ethyl acetate. The mixture was adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by FII-trate to give 2.5 g of 2- (2-cyclohexen-1-yl) oxyimino ~ 2- (5-formamido-l, _{2/4-thiadiazol-3-yl)} acetic acid (syn Isomer). On the other hand, the ethyl acetate layer was separated from the filtrate and evaporated. The residue was triturated with diethyl ether to give 1.5 g of the same desired compound, total yield 4.0 g, mp 190 192 ° C (dec.).

I.R. (Nujol): 3550, 3400, 3200, 2500, 1690,

1590, 1540 cm ^-1 NMR Cd ₆ -DMSO) ₇ S): 1.5-2.3 (6H, m), 4.73-5.0.

(Him),. 5.76-6.23 (2H, m), 8.97 (IH, s), 13.60 (IH, broad s)

3.) To a solution of 11.2 g of sodium hydroxide in 140 ml of water was added 27 g of S ~ methyl ~ 2- (5-formamido-l _/ 2,4-thiadiazol ~ 3-yl) · -. thioglyoxylate at .10 C was added and the mixture was stirred for 30 minutes.

The reaction mixture, containing sodium 2 ~ (5-formamido-1, 2,4-thiadiazol-3-yl) glyoxylate, was cooled, adjusted to pH 7 with 10% hydrochloric acid, and there was added a solution of 15.3 g Cyclopentyloxyamin in 150 ml ethanol added, the · mixture was acid with 10 / Siger hydrogen chloride adjusted to pH 3 and stirred for I ₇ 5 hours "The Reaktionimischung was adjusted to pH 7 with an aqueous sodium bicarbonate" solution and then evaporated to remove the ethanol. The residue was washed with ethyl acetate. Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration to give 3.99 g of 2-cyclopentyloxyimino "2" - (5-formamido-1 _J .2 _/ 4 - thiadiazol ~ 3 'yl) acetic acid (syn isomer) received "the Fil ~ appeared was extracted with ethyl acetate and the extract was dried over magnesium sulfate and then concentrated the Never" · Dersch would were collected by filtration and washed with diethyl "- washed ether to give 8.1 g of the same desired compound, total yield 12.09 g, F" 180-185 C (dec _{e) E} R (Nu j oil). 3130, 3040, 2680 , 2610, 2520,

1720, 1690, 1660, 1600, 1550 cm ^-1 NMR Cd ₆ -DMSO, S): 1.33-2.10- (8H, m), 4.67-5.0 (IH, m), 8, 88 (IH, s), 13.50 (1H, s) _;

Production Example 14

A mixture of 20.0 g of 2 ~ (2-cyclopentene-1-yl) oxyiniino-2- (5-amidormamido-1,2 _/ 4-thiadiazol-3-yl) acetic acid (syn isomer) and

· .- 44 -

200 ml of a 1N aqueous sodium hydroxide solution was stirred at 50 to 55 C for 1 hour. The reaction mixture was cooled, adjusted to pH 7 with 10% hydrochloric acid and ethyl acetate added. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated. The residue was triturated with diisopropyl ether to give the 2- (2-cyclopenten-1-yl) oxy-imino-2- ( 5-amino "1 _/ 2.4"'thiadia2ol-3-yl) acetic acid (syn isomer) .erhielt, F _e 150 ° C (dec.).

IR, (Nuj oil): 3300, 3150, 1710, 1620, 1520 cm ^-1 NM _C R Cd ₆ -DMSO, 6): 1.80-2.50 (4H, -m); 5.50 (IH, m), 5.83-6.30 (2H, m), 3.20 <2H, s)

Manufacturing example 15

The following compounds were prepared in a manner similar to that described in Preparative Example 14: 0) 2- (2-Cyclohexen-1-yl) oxyimino-2- (5-amino-1,2 _/ 4-thiadiazol-3-yl ) -acetic acid (syn "isomer"), F "173 ° C. IAR. (Nu oil): 3400, 3300, 3200, 1720, 1620, 1600, 1520 cm " ¹

NMR (d, DMSO): 1.50-2.17 (6H, m); 4 _# 53-4.83 (IH, m), 5.57-6.13 (2H, m), 8, 18

(2H, s);

(2) 2-cyclopentyloxyimino ~ 2- (5-amino-1,2,4-thiadiazole)

3-yl) essigsäur.e (syn "isomer), mp 160-165 ° C (dec _e). •. -IR (Nujol): 3470/3290, 3200, 2400, 1715 ,. , , 161-5, 1600, 1520 cm " ¹

.- 45 -

NMR-Cd ₆ -DMSO ₁ S): 1.17-2.10 (8H ₇ m), 4.60-4.97 CiH, m), 8.22 (2H, s)

Production example 16.

A mixture of 10 g of 5-forhiamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole and 2.0 g of sodium periodate in 50 ml of glacial acetic acid was stirred at 70 ° C for 50 minutes To the residue was added 160 ml of a 1N aqueous sodium hydroxide solution and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added 4.31 g of O-allylhydroxylamine hydrochloride and the solution was adjusted to pH 3 to 4 with 10% hydrogen chloride hydrochloric acid and then stirred for 1 hour at ambient temperature. After filtering off an insoluble material, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was washed with a mixture of diethyl ether and diisopropyl ether to give 5.6 g of 2 ~ allyloxyimino "2" (5 ~ formamido-T, 2,4-thiadiazo1 3-yl) acetic acid (syn isomer), mp 169-172 ° C (ZersJ ,

I.Re (Nujol): 3130, 2500, 1720, 1690, 1590, 1550 cm " ¹

.NMR (d ₆ ~ DMS0),

S: 4 ", 79 ₍₇ 2H d, J = OHN), 5, l-5, 6 (2H, m), 5.8 to 6.4 (IH, m), 8.88 (IH /. s)

28112 ί

j-jetting example 17

The following compounds were prepared in a manner similar to that given in Preparation Example 16

2 "(24 ropinyloxyimino ^J) '2 ~ (5-" formamido-1,2 _/ 4-thiadiazol 3 "yl) acetic acid (syn isomer), mp 150-155 C (Zer.s") I _e R _e (Nuj oil); 3570, 3360/3260, 3120/1720,

167O ₇ 1550, 1530 cm "* ¹ N.MoRo (d ^ -DMSO)

hi 3.55 (IH, t, J = 2Hz) / _{4/88 (7} 2H d, J = 2Hz), 8.85 (IH ₇ s)

(2) 2-Hydroxyimino-2 ~ 5 ~ formamido-1 _/ 2 _/ 4-thiadiazol-3-yl) acetic acid (syn-isomer), F 240-224 C (Zers _e ). IR (Nujol): 3550, 3460, 1665, 1635 ₇ 1560 cm " ¹

Production Example 18

A solution of 6.64 g of S-methyl- (5-formamido-1-yl-2,4-thiadiazol-3-yl) thioglyoxylate in 80 ml of a 1 N aqueous sodium hydroxide solution was adjusted to pH 8.5 with 10% hydrochloric acid, and 30 minutes stirred at ambient temperature for _e other hand, a mixture of 8.78 g of N '- _(2/2/2 ~ trifluoro "ethoxy) phthalimide and 1.7 g Hydra zi η t hydra heated in 40 ml of ethanol for 5 minutes under reflux and then cooled in an ice-bath. The resulting precipitates were filtered off and washed with ethanol. The filtrate and washings were combined and the combined solution

0- (2,2,2-trifluorothyl) hydroxylamine was added to the above aqueous solution. The mixture was adjusted to pH 3-4 with 10% hydrochloric acid and stirred at ambient temperature for 1.5 hours The solution was neutralized with an aqueous solution of sodium bicarbonate, concentrated in vacuo to half of its volume and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness, and the residue became triturated with diisopropyl ether ver "to give 2.46 g of 2- (2,2 ₇ 2-Trifluoräthoxyimino) -2- (5 ~ formamido-1 _/ 2.4" thiadiazol ~ 3-yl) acetic acid (syn isomer) · received _e F 180-185 ° C (dec.) ·

NMRo (d ₆ ~ DMSO).

S: 4.80 and 5.07 (2H ₇ ABq, J = 9Hz), 8.85 (IH, s)

19

The specified hereinafter indicated compound was prepared in a similar manner as in Preparation Example 18: 2-Methylthiomethoxyimino ~ 2- (5-formamido "l, _2/4« thiadiazol-3-yl) acetic acid (syn isomer), mp 146 - 148 ° C (Zers _e )

IR (Nujpl): 3300, 2600, 2550, 1730, 1705, •. 1680, 1600, 1530 cm * " ¹

NMR (d ₆ ~ DMS0)

6: 2.23 (3H, s), 5.40 (2H, s), 8.87 (IH ₇ 's)

Production Example 20 _. '

A mixture of 6 g of S ~ methyl (5-formamido-l _/ 2 _/ 4-thiadiazol-3-yl) thioglyoxylate and 50 ml of an aqueous solution of 4.2 g of sodium hydroxide was stirred at 50-55 ° C for 1 hour. The mixture was cooled to ambient temperature and adjusted to pH 7 with 10% hydrochloric acid. On the other hand, a mixture of 12.9 g of N- (Athoxycarbonylmeth ~ oxy) phthalimide and 2 _r 08 g of hydrazine hydrate in 60 ml of ethanol was heated for 5 minutes under reflux and cooled in an ice bath. A resulting precipitate was filtered off and washed with ethanol. The filtrate and washings were combined together and the combined solution containing O.sub.10 (ethoxycarbonylmethyl) hydroxylamine was added to the above aqueous solution. The mixture was adjusted to pH 3-4 with 10% hydrochloric acid and stirred at ambient temperature for 1.5 hours. The solution was neutralized with an aqueous solution of sodium bicarbonate, concentrated to half of its volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness, and the residue was triturated with diisopropyl ether to give 1.8 g of 2-ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn -Isomeres), mp 135-140 ° C (Zers.). IR (Nuj oil): 3500, 3330, 3210, 2670, 2550, 1740,

1610 _f 1540 -cm " ¹ NMR (cL ~ DMS0) '

, - §: 1.24 (3H ₇ t, J = 7Hz), 4.14 (2H ₇ q, J = 7Hz),

4.80 (2H, s), 8.15 (2H, wide s)

Production Example 21

The following compound was prepared in a manner similar to that given in Preparative Example 20:

2 ~ (l ~ ethoxycarbonyi-1-methylethoxyimino) ~ 2 ~ (5-amino-1j2 _/ 4 · thiadiazol-3-yl) acetic acid (syn-isomeres) _? F «165-168 C

IR (Nujol): 3450, 3350, 3240, 1750, 173O ₇ 1630, 1530 N.Me'Rc (d 1 -DMSO)

S: 1,1.8 (3H, t, J = 7Hz), 1,50 (6H, s), 4,15 (2H, q, J = 7Hz), 8,23 (2H, wide s)

Production Example 22

The following compounds were prepared in a manner similar to that given in Preparation Example 14:

(1) 2-Allyloxyimino-2 ~ (5-amino-l _/ 2,4-thiadiazol-3-yl ') acetic acid (syn isomer), m.p. 93-95 C (dec.). IoR _e (Nujol): 3430, 3100, 1710, 1615, 1525 cm * " ¹ NMR (d ₆ -DMS0)

5: 4.72 (2H, d ₇ J = OHz), 5.1-5.5 (2H, m), 5.7-6.3 (IH, m), 8.17 (IH, broad s)

(2) 2- (2'-Propinyloxyimino) ~ 2 ~ (5-amino-1, 2 _# 4-thiadiazole, 3'-yl) -. acetic acid (syn-isomer) ,. F «155 - 157 C (Zers *)

22 8112 t

IR (Nujol): 3500, 3310, 3160, 260O ₇ 2480,

1745, 1610, 1535 cm ^-1 NMR Cd ₆ -DMSO)

6: 3.53 (IH, t, J = 2Hz), 4.87 (2HZd, J = 2 Hz), 8 ^ 23 (2H ₁ broad s).

(3) 2- (2,2,2 "trifluoroethoxyimino) r2- (5-qmino-1,2,4-thiadiazol-3-yl) acetic acid (syn-isomer), m.p. 140-143 C (Zers,) , IR (Nuj oil): 3450, 3350, 3260, 1745, 167O ₁

1645, 1615, 1515 cm " ¹ N ₉ M _e R (d ₆ -DMS0)

5: 4.72 and 4.95 (2H, ABq, J = 9Hz), 8.25 (2H, broad s).

(4) 2-Methylthiomethoxyimino-2- (5-amino-1 _/ 2 _/ 4-thiadiazol-3-yl) acetic acid (syn ^ isomeris), F, 140-143 C (dec.). IR (Nujol): 3500, 3300, 3150, 2670, 2580,

1740, 1615, 1605, 1530 cm " ¹

NMR (d ₆ "DMS0)> *

S-. 2.22 (3H, s), 5.33 (2H, s), 8.20 (2H, broad s)

(5) 2-trityloxyimino-2- (5 'amino-1,2,4-thiadiazol ~ 3-yl) -essigsöure (syn isomer), F, 173 - (174 C (dec _{e) ö} IR Nu j oil ): 3450, 1735, 1620, 1540 cm ^-1 NMR (d ₀ -DMS0)

S: 7.35 (15H, s), 8.22 (2H, sj ·

Production Example 23

To a mixture of 9.5 g of 2'-hydroxyimino-2 * - (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) and 80 ml

Dimethylformamide was added with stirring at ambient temperature 22.8 g of trityl chloride and after stirring for 3 minutes, 4.1 g of triethylamine were added portionwise. The resulting mixture was stirred for 10 minutes and 250 ml of ethyl acetate were added. The mixture was washed 3 times with water and washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. To the residue were added 50 ml of an aqueous sodium bicarbonate solution and 100 ml of diisopropyl ether. The precipitates were collected by filtration and the aqueous layer in the filtrate was separated. The collected precipitates were suspended in the separated aqueous layer and ethyl acetate was added. The mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was washed with hexane to give 17.1 g of 2-trityloxyimino-2- (5-formamido-1 _/ 2 _/ 4-thiadiazol-3-yl) acetic acid (syn isomer), F 175-176 C (Zers).

IR (Nuj oil): 3180, 3070, 1700, 1600, 1540 cm ^-1 NMR .Cd ₆ -DMSO)

δ: 7.35 (15H, s), 8.83 (lH, s), 13.52 (1H, broad s)

Production Example 24

The following compounds were prepared in a manner similar to that given in Preparative Example 12 (1):

- «- 22 81 12

N- (i '-t-Butoxycarbonylb'thoxy) phthalimicl, F "80-82 C. NMR; Cd ₆ -DMSO, (S): 1.42 (9H, s).

1.48 (3H, d, J = 7Hz), 4.72 (IH, q, J = 7Hz),

7.86 (4H, s)

(2) N- (lt-butoxycarbonyl * 1-methylethoxy) phthalimide ₇ F. 96-100 ° C.

NMR Cd ₆ -DMSO ₇ ^): 1.42 (9H, s), 1.48 (6H, s), '

7.87 (4H, s)

(3) N- (1-benzyloxycarbonylethoxy) phthalimide _/ F. 65-68 C

I.R. (Nujol): 1790, 1740, 1450, 1210, 1190,

1110, 1080, 980, 880, 735, 700 cm " ¹

(4) N- (2-oxo-3-tetrahydrofuryloxy) phthalimide _/ m.p. 140 ~ 142 ° C.

IR (Nujol): 1785, 1760, 1720, 1605, 1215, 1185, 870, 695 cm ^-1

Production Example 25

The following compounds were prepared in a similar manner to that given in Preparative Example 20:

2- (t-Butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer), F "150-155 ° C (dec.)

IR (Nujol): 3420, 3230, 3100, 1725, 1610, 1530 cm ^"1 NMR _e (DMSO ^ _d6, 6): 1.45 (9H, s), 4.70 (2H, s), 8, 12 (2H, wide s)

(2) 2- (it-butoxycarbonylethoxyimino) -2- (5 »<3mino-l _/ 2,4-thiadiazol ^ 3- = yl) -acetic acid (syn-isomer), F, 155-156 ° C (dec.)

.- 53 -

I, R. (Nujol): 3400, 3300, 3200, 1720, 1710,

1620 _f 1520 cm " ¹ '

NMR (D ₆ -DMSO, 5): 1.2-1.7 (12H, m), 4.72 (IH, q, J = 7Hz), 8 ₇ 2 (2H, broad s)

(3) 2 (5-Amino-1,2,4-thiadiazol-3-yl) acetic acid (syn-isomer) (m.p.-butoxycarbonyl-1-methylethoxyimino), m.p. 180-181 ° C (decomp ). "

I .R. (Muj oil): 3400, 3300, 3200, 1745, 1715,

1630> 1530 cm * " ¹ NcM.Ro (d ₆ ~ DMS0, £): 1.38 (9H, s), 1.43 (6H, s),

8,15 (2H, broad s). '

(4) 2, - (i-Berizyloxycarbonyläthoxyimino) ~ 2- (5-amino-1 _/ 2,4 'thiadiazol-3-yl) acetic acid (syn "isomer), F _e 129-133 C

IR, (NuJoI) ι 3300, 3200, 1720, 1620, 1530 cm ^-1 . NMR (DMSO ~ d ₆ , S): 1.45 (3H, d, J = OHz), 4.97> (IH ₁ q , J = OHz), 5.18 (2H, s), 7.31 (5H, s),

8,17 (2H, broad s) _; ;

Production Example 26

64.8 g of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) -thioglyoxylate and 1-carboxy-3-hydroxypropoxyamine which had been prepared by refluxing a mixture of 65.0 g N ~ (2-0xo "3-tetrahydrofuryloxy) phthalimide _/ 50 ml of concentrated hydrochloric acid and 200 ml of water for a period of 1 hour were treated in a similar manner as described in Preparation 20, whereby 33.2 g of 2 ~ ( i-carboxy ~ 3 ~ hydroxypropoxyimino) ~ 2 ~ (5 ~ amino "1,2 _/ 4-

L 54 -

thiadiazol-3-yl) acetic acid (syn isomer), m.p. 186 188 ° C (dec.).

IR "(Nyj oil): 3400, 3250, 310O ₇ 1710, 1620,

1540 cm * " ¹ NMR (DMSO-Cl ₆ , S): 1.73-2.10 (2H, m), 3.50 (2H ₇

t, J = OHz), 4.73 (IH, t, J = 6Hz), 8.13 (2H, s)

Manufacturing Example 27 . .. - .. · ..

To a solution of 33.0 g of 2- (i-carboxy-3-hydroxypropoxyimino) ~. 2- (5-amino-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) in 2.8 To 1 methanol was added 120 g of anhydrous magnesium sulfate and 60 g of acetic anhydride. The mixture was stirred at ambient temperature for 30 minutes, filtered and the filtrate was evaporated to dryness. The residue was triturated in 200 ml of acetone and 1 liter of ethyl acetate added. The mixture was stirred for 1 hour at ambient temperature and the precipitates were collected by filtration and washed with ethyl acetate »

The precipitates were dissolved in 200 ml of water, and then 500 ml of ethyl acetate, 200 ml of acetone and 40 ml of 6N hydrochloric acid were added. An organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether, filtered and washed with diisopropyl ether to give 26.5 g of 2 ~ (2'-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1, 2,4-thiadiazol)

3-yl) acetic acids (syn isomer), F ₆ 185-187 C (dec.) _E IR (nujol): 340Oj 330O ₇ 3200, 1775, 173O ₇

1640, 1605, 1535 cm * " ¹

NMR * (Cl ₆ -D ₁ MSO ₇ Γ): 2.27-2.70 (2H, m), "4.17-4.50 (2H, m), 5.27 (IH, t, J = 8Hz) / 8,22 (2H, s)

Production Example 28

The following compound was prepared in a similar manner to that given in Production Example 20;

2-Metoxy carbo ylmet hoxyi mi no-2- (5-a mi no-1, 2 _S 4-t hia dia zo 1 ~ 3-yl) acetic acid (syn isomer), F, 190-193 C (Zers ·) «! Rc (Nujol): 338Ö, 3280, 3180, 1750, 1710,

1610, 1510, 1260, 1230 cm "" ¹

NMR (DMSO-Cl ₆ , S): 3.73 (3H, s), 4.87 (2H ₇ s), 8.2 (2H, bs)

jferste lunqsbeispiel 29

The following compound was prepared in a manner similar to Preparation Example 30:

7 ~ [2- (Cyclopentyloxyimino-2- (5-amino-1,2,4-tiiiadia2ol-3-yl) -acetamido-dcephalosporanic acid (syn-isomer), F, 140-145 C (dec.).

I. Ro (Nujol): 3480, 3370, 3250, 1785;

1730, 1680, 1630, 1530 cm ^-1 NcMeR. (Ci ₆ -DMSO, · δ) i 1.33-2.17 (8H, m), • 2.03 (3H, s), 3.57 ( 2H, wide s), \

4.60-4.90 (Ik, m), 4.73 and 4.97 (2H, ABq, J = ISHz), 5.15 (1H, d, J = 5Hz), 5.80 (IH, dd , J = 5 and 8Hz), 8.10 (2H, broad s), 9.47 (IH, d, J = 8Hz).

Production Example 30

To a cold solution of 10.4. g of phosphorus pentachloride in 250 ml of methylene chloride, 12.8 g of 2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) was added at -18 ° C. and the mixture became On the other hand, a mixture of 15.7 g of 7-amino-3-a'cetoacetoxymethyl-3-cephem-4-carboxylic acid and 50 g of trimethylsilylacetamide in 250 ml of methylene chloride was heated to obtain a clear Solution and cooled to -10 C. The cold solution was added to the above activated mixture and the mixture was stirred at -10 ° C for 25 minutes. The reaction mixture was poured into 500 ml of an aqueous solution of 29.5 g of sodium bicarbonate and stirred for 15 minutes at room temperature. The aqueous layer was separated, adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give 13.5 g of 7- [2-cyclopentyloxyimino-2 - (5-amino-1,2,4-thiadiazol-3-yl) -acetamido3-3-acetoacetoxy-methyl-3-cephem ~ 4-carboxylic acid (syn isomer) in the form of a powder, m.p. 130-135 ° C (Ze _r s ").

, ~ 57 -

"I" R _e (Nujol): 3300, 178O ₇ 172O ₇ .1680, 162O ₇

-. 1525 cm " ¹

_E N MR (DMSO ^ _d6, S): 1.3-2.0 (8H, m), 2.15 (3H ₇ s), 3.52 (2H, bs), 3.60 (2H, s ), 4.5-4 _f 7 (IH, m), 4.77, 5.00 (2H ₇ ABq, J = UHz), 5.13 (1H, d, J = 4Hz), 5.80 (IH , 2d, J = 4 and 8Hz), 8,10 (2H, s), 9,50 (IH, d, J = 8Hz)

Production Example 31

To a solution of 5.6 g of 7'-r2- (i-t-butoxycarbonylethoxyimino) -2- (5-amino-1,2 _/ 4-thiadiazol-3-yl) acetamido] -3-acetoacetoxy-methyl 3 ml of cephenylcarboxylic acid (syn isomer) in 50 ml of anisilicic acid was added 1.7 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and the residue was washed with water The powder was dissolved in a mixture of ethyl acetate and water and adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution with stirring. The aqueous layer was separated and ethyl acetate was added was adjusted to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate The extract was dried over anhydrous magnesium sulfate and evaporated to dryness powdered with diethyl ether, collected by filtration, washed with the same solvent and dried over anhydrous phosphorus pentoxide to give 3.7 g of 7 "[2- (i-carboxyethoxyimino) -2 (5" -amino-1,2, 4-thiadiazol-3-yl) acetamido] "3-acetoacetoxy ~

*. 58 -

methyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a brownish powder, mp 95-100 ° C (dec.). IR (Nuj oil): 3450, 3350, 3230, 1780, 172O ₇

1630 ,. 1525 cm " ¹ N _e MR, (DMS0 ~ d ₆ , S ): 1.45 (3H ₇ d ₇ J = ₇ Hz) ₇ 2.20

(3H, s), 3.58 (2H ₇ broad s) ₇ 3.67 (2H, s), 4.65-5.30 (3H ₇ m), 5.22 (1H, d, J = 0Hz) , 5.77-6.10 (IH / in), 8.23 (2H, broad s), 9.40-9.68 (IH, m).

Production Example 32

The following compounds were prepared in the same manner as given in Preparation Examples 30 and 31:

7- [2- (2-cyclopenten-1 ~ yloxyimino) -2 ~ (5-araino-1,2 ₇ 4-t hia diazo l ~ 3-yl) .a ce ta mi do] -3-a cet oa cet oxy-met hy 1-3-. cephem-4-carboxylic acid (syn isomer), mp 135 - 14O ⁰ C (dec.)

 ..IJ *. (Nu j oil): 3400, 3300, 3200, 1775, 1735,

1710, 1675, 1620, 1525 ctrT ¹ NMR (DMSO-d _{6 /} ^): '1.93-2.47 (4H, ra), 2.18 3H, s), 3.55 (2H, bs) , 3.65 (2H, s), 4.80, 5.07 (2H ABq _{7 7} J = I3Hz), 5.13 (1H, d, J = SHA), 5.23 to 5.53 (IH ₇ m), 5.70-6.23 (3H, m), 8.12 (2H, bs), 9.50 (IH, d, J = 8Hz)

(2) 7 ~ [2-Carboxyniethoxyimino ~ 2 ~ (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid

• - 59 -

(syn isomer), F "95-100 ° C (Zers").

I _e R _e (Nujol): 3400, 3290, 3190, 1770, 1720,

1615, 1520 cm "" ¹

N _e MR (DMSO-Cl ₆ , S): 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.67 (2H, s), 4, 80, 5.07 (2H, ABq, J = ISHz), 5.15 (IH, d, J = 5Hz), 5.87, (IH, 2d, J = 5 and 8Hz), 8.15 (2H, bs), 9.53 (IH, d, J = 8Hz)

(3) 7- [2 ~ t-Butoxycarbonylmethoxy-2-amino (5-amino-1,2,4-thiadiazol-3-yl) -acetamidol-S-acetoaceioxy-methyl-3-cephem-4-carboxylic acid (syn ), F * 105-110 C

IR (Nujol): 3350 ,. 3250, 1780, 1720, 1620, 1525 cm ^-1 NMR (DMSO ^ d ₆ , S): 1.43 (9H, s), '2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, _S ), 4.63 (2H, s), 4.82, 5.05 (2H, ABq, J = I 3Hz), 5.15 (TH, d, • J = 5Hz) , 5.85 (IH, 2d, * J = 5 and 8Hz), 8.15

(2H, bs), 9.53 (IH, d, J = 8Hz)

(4) 7-C2- (lt-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn- Isomer), brownish powder, mp 110-115 ° C (Zers _e )

I _e R _e (Nujol): 3400, 3300, 3200, 1780, 1720,

1620, 1525 cm- " ¹

NeM.R. (DMS0-d ₆ , i): 1.40 (3H> d, J = 7Hz), 1.42 (9H, s), 2.17 (3H, s), 3.57 (2H, bs), 3 , 63 (2H, s), 4.58-5.22 (3H,! M), 5.17 (IH, d, J = SHz), 5.73-5.97 (ΊΗ, -m), 8 , 10 (2H, "bs), 9,33-9,57 (IH, m)

(5) 7- [2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2 _/ 4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4- carboxylic acid (syn isomer), mp 180-185 C (dec.).

IR / (Nujol): 3350/3250, 178O ₇ 1720, 1625, 1525 cm "" ¹

NMR (DMSO-d ₆ , S): 1.47 (6H, s), 2.17 (3H, s), 3.55 (2H, bs), 3.62 (2H, s), 4.80, 5.03 (2H, ABq, J = UHz), 5.17 (lH, d, J = 4Hz), 5.87 (IH, 2d, J = 4 and 8Hz), 8.13 (2H, s) 9.47 (IH, d, J = 8Hz)

(6) 7-C2- (i -methyl-1-t-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3 (-yl) -acetamido] -3 "

, acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), F · 140-145 ⁰ C (dec.).

IR (Nujol): 335O ₇ 3250, 1785, 1720, 1620, 1530 cm ^-1 NMR (DMSO-d ^, S): 1.47 (6H, s), .1, 50 (9H, s), 2, 17 (3H, s), 3.57 (2H, bs), 3.63 (2H, s), 4.80, 5.07 (2H, ABq, J = 14Hz), 5.17 (IH, d, J = 4Hz), 5.86 (IH, 2d, J = 4 and 8Hz), 8.13 (2H, s), 9.43 (IH, d, J = SHz)

(7) Sodium 7 ~ [2'-ethoxyimino ~ 2- (5-amino-l _/ 2,4-thiadiazol-3-yl) acetamido] -3 ~ acetoacetoxymethyl'-3-cephem-4-carboxy-lat ( syn isomer), m.p. 175-180 C (Zers.) _e

IR (Nujol): 3450, 3300, 3100, 1790, 1720 /. 1670, 1640, 1610, 1550 cm "" ¹

NMR _e (D ₂ O, δ): 1.38 (3H, t, J = 6Hz), 2.34 (3H, s), 3.44, 3.66 (2H, ABq, J = 18Hz), 4 , 40 (2H, q, J = 6Hz), 5.05, '5.86 (2H, ABq, J = 12Hz); 5.26 (iH, d, J = 4Hz), 5.90 (IH, d, J = 4Hz)

(8) 7- [2 ~ methoxyimino ~ 2 ~ (5-amino-1,2,4-thiadiazol-3-yl) aceto-amido] ~ 3 ~ a cetoacetoxymethyl-3-cephem-4-carboxylic acid ( syn isomer), mp 120-125 ° C (dec.).

IR (NuJoI): 3350, 3250, 1780, 1710, 1680, 1630, 1530 cm * " ¹

NMR, (D ₂ O ₂ -NaHCO ₃₇ S): 2.32 (3H, s), 3.40, 3.62

(2H, ABq, J = 1.8Hz), 4.10 (3H, s), 4.84, 5.04 (2H, ABq, J = HHz), 5.22 (IH, d, J = 4Hz), 5.86 (1Ή, d, J = 4Hz)

(9) 7- [2-Propoxyimino-2 "(5-amino-1,2,4'-thiadiazol-3-yl) -acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer ), F. 125 - 130 C (Zers «) ·

I ₀ R ₉ (Nujol): 3350, 3250, 1780, 1710, 1680, 1620, 1530 cm " ¹

NMR (D ₂ O + NaHCO ₃ , S): 0.94 (3H, t, J = OHz), 1.5-1.9

m), 2.30 (3H, s), 3.40, 3.62 (2H _# "ABq, J = I 8Hz), 4.26 (2H, t, J = 6Hz), 4.84, 5, 04 (2H, ABq, J = I2Hz), 5.22 (IH, d, J = 4Hz), 5.86 (IH, d, J = 4Hz)

7 "[2- Isopropoxyim5.no ~ 2" (5-amino-l _/ 2,4 "thiadiazol-3-yl) a cetamldo] - 3 ~ a cetoacetoxy-methyl-3-cephem-4-carboxylic acid (syti "Isomeres), F. 95 - 100 C (Zers") · .1.R. (Nyjol): 3400, 3300, 3200, 1775Z 1740, '

171 In 1670, 1620, 1525 cm * " ¹

NMR (DMSO-d ₆ , S "): 1.28 (6H, d, J = OHz), 2.18 (3H, s), 3 _Λ 48, 3.60 (2H, ABq, J = 18Hz), 3.62 (2H, s), 4.24-4.54 (IH, m), 4.78, 5.02 (2H ₇ ABq ₇ J = 13Hz), 5.14 (IH, d, J = 5Hz ), 5.80 (IH, dd, J = 5 and 8Hz), 8.06 (2H, broad s), 9.44 (IH ₇ d, J = 8Hz)

- ⁶² - 228112 f

(11) Sodium 7- ~ [2 ~ allyloxyimino-2- (5-arnino ~ l, 2 ₇ 4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl "3-cephem-4" carboxylate (syn-isomer) , F _e ΊόΟ - 170 C (Zers _e ). IR (Nujol): 3450, 3300, 310O ₇ 179O ₇ 172O ₇ 167O ₇ 1550 cm " ¹

NMR (D ₂ O ₇ <5): 2.31 (3H _7s ) ₇ 3.33, 3.64 (2H ₇ ABq ₇ J = 18Hz), - 4.6-5.1 (4H _7m ) ₇ 5.1-5.5 (2H, m), 5.20 (IH, d, J = 5Hz), 5.8-6.3 (IH, m), 5.84 (IH, d, J = 5Hz)

(12) Sodium 7- [2- (2 ₇ 2 ₇ 2-trifluoroäthoxyimino) -2- (5- "amino ~ 1 ₇ 2,4-thiadiazol-3-yl) acetamido3 ~ 3-acetoacetoxymethyl-3-cephem- 4-carboxylate (syn isomer), m.p. 128-132 C (Zers) IR (Nujol): 3300, 1780, 1710, 1670, 1600, 1530 cm ^-1 N _e MR (D ₂ O, δ) : 2.32 (3H, s), 3.50, 3.63 (2H ₇ ABq, J = 17Hz), 4.60 to 5.07 (4H, m) ₇ 5.23 (IH, d, J = 4Hz), 5.87 (IH ₇ d, J = 4Hz)

(13) Sodium 7- [2-methylthiomethoxyimino-2- _(5-amino-1? 2.4 "thiadiazol-3-yl) acetamido3-3-acetoacetoxy-methyl -3- ⁱ 'cephem-4-carboxylate (syn Isomer), F, 180-190 C (dec.) "1, R. (Nujol): 3500-3200, 1770, ₇ 167O 1620, 1530cm ^"1 NoM.R. _(DMS0-d6, £): 2 ₇ 18 (3H, s), 2.20 (3H, s), 3, 16, 3.48 (2H ₇ ABq, J = I8Hz), 3.58 (2H, s), 4.84, 5.08 (2H, ABq, J = 12Hz), 4.98 (iH, d, J = 5Hz), 5.22 (2H, s), 5.62 (IH, dd, J = 5 and 8Hz), 8.14 (2H, broad s), 9.48 (IH ₇ d ₇ J = 8Hz )

(14) 7- [2 ~ ^(2-i> ropinyloxyimino) -2 -. (5-amino-1,2-thiadiazol-4 ₇ "3-yl) acetamido] '- 3''acetoacetoxymet hy ^ lS-cephem -carboxylic acid (syn ~ isomer) ₇ F. 90 - 95 C '(Zers _e )

IR (Nujol): 3400, 3280, 3200, 2100, 1770, 1740, 1710, 1670, 1620 cm " ¹

NM _e R _e (DMSO-Cl ₆ , S): 2.18 (3H ₇ s), 3.46 (1H, t,

> J = 2Hz), 3.46, 3.58 (2H, ABq, J = 18Hz), 3.62 (2H _7s ) ₇ 4.76 (2H ₇ d ₇ J = 2Hz), 4.78, 5 , 02 (2H, ABq, J = HHz) ₇ 5,12 (IH, d, J = 5Hz), 5,80 (1H ₇ dd, J = 5 and 8Hz) ₇ 8,10 (2.H, broad s ), 9.60 (IH ₇ d ₇ J = 8Hz).

Production Example 33.

To a mixture of 80 g of sodium iodide and 11.36 g of pyridine in 40 ml of water were added 40 g of sodium 7- [D ~ 5 ~ carboxy-5- (3-phenyl'M ₁ reido) valeramido] cephalosporanate with stirring at 50 ° C delivered. The reaction was continued for 4.5 hours at 60 ° C. The warm reaction mixture was diluted with 80 ml of water, adjusted to pH 3.5 with 6N hydrochloric acid, and subjected to column chromatography on a nonionic adsorption resin "Diaion HP-20" (trademark for product of Mitsubishi Chemical Industries) (600 ml). After the column was washed with 2.4 l of water, elution was carried out with 35% aqueous isopropyl alcohol before use was heated to 45 ° C. To the eluate (il) was added "100 ml of N, N-dimethylformamide and the mixture was concentrated under reduced pressure to 120 ml." To the residue was added 1 liter of isopropyl alcohol with stirring, then stirring was continued for 1 hour The resulting precipitates were collected by filtration, washed with isopropyl alcohol, and dried to give 22.0 g of 7-D-5-carboxy-5-β- (3-phenylureido) valeramido! -3- (i-pyridinomethyl) - 3 «-cephem-4-carboxylate

received, F. 180 to 185 ° C (Zers.).

I.R. (Nujol): 3300, 1780, 1720, 1680, 1610,

1540, 1500 cm " ¹ ·

. N..MR - (DMS0-d ₆ + D0, S): 1.4-1.8 (4H, m),

2.0-2.3 (2H ₇ », 3.14 ₇ 3.54 (2H, ABq, J = 17Hz), 4.0-4.2 (IH, m), 5.04 (1H, d, J = 4Hz), 5.24, 5.62 (2H, ABq, J = 14Hz), 5.60 (1H, d, J = 4Hz), 6.7-7.5 (5H, m), 8, 0-8.2 (2H, m), 8.45-8.70 (IH, m), 9.28-9.42 (2H, m).

Production Example 34

• -

To a mixture of 2.77 g of 7- [D-5-carboxy-5 "- (3-phenylureido) -valeramido] -3- (i-pyridinomethyl) -3-cephem-4-carboxylate and 4.2 g of Ν , Ν-Dimethylaniline in 30 ml of methylene chloride were added dropwise while stirring at ambient temperature 3.3 g of trimethylsilyl chloride and stirring was continued for 30 minutes. The mixture was cooled to -30 ° C and 2.1 g of phosphorus pentachloride was added with stirring, then stirring was continued at -30 to -25 ° C for 1 hour. The reaction mixture was added to a solution of 4.5 g of 1,3-butanediol in 30 ml of methylene chloride with stirring at -20 ° C, then stirring was continued for 1.5 hours at ambient temperature. The resulting precipitates were collected by filtration, washed with methylene chloride and dried to give 2.1 g of 1 - [(7-amino-4-carboxy-3-cephem-3-yl) methyl] -pyridinium chloride hydrochloride dihydrate as the crude product the crude product was 8 ml of 1 η

228112

Hydrochloric acid was added and the mixture was stirred for 30 minutes at ambient temperature. An insoluble material was filtered off and the filtrate was cooled in an ice bath, then 20 ml of isopropyl alcohol were added with stirring. To the mixture was added 25 ml of isopropyl alcohol and the resulting precipitates were filtered off, washed with the same solvent and acetone and dried to obtain 1.15 g of a pure product, mp 140-145 ° C (dec.).

N.Mo'R. (D ₂ O ₁ S): 3.53 / 3.80 (2H, ABq, J = 18Hz), 5.30 (IH, d, J = 4Hz), 5.45 (IH, d, J = 4Hz) , 5.53, 5.83 (2H, ABq, J = HHz), 8.00 ^ 8.33 (2H, m), 8.50-8.33 (IH, m) ,. 8.90-9.13 (2H, m)

Production Example 35

The following compound was prepared in a manner similar to that given in Preparation Example 30:

Sodium 7 .- [2-äthoxyimino "2- (5-amino." - l _i 2,4-tbiadiazol-3 'yl) acetamido] -cephalosporanat (syn isomer), mp 180 "185 ° C ( dec.).

I.R. (Nu j oil): 3480, 3430, 3250, 1780, 1730, 1665, 1635,

1610, 1540, 1515, 1400, 1280, 1240, 1040 cm " ¹

 - * -

example

'HCJl

CJF

  "coo"

To a cold solution of 2.64 g of phosphorus pentachloride in 25 ml of methylene chloride was added 2.48 g of 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). at ~ 20 ° C and the mixture was stirred at -20 to 14 ° C for 35 minutes. 75 ml of cold diisopropyl ether were added to the mixture with stirring below -10 ° C., then stirring was continued until the mixture reached room temperature. The resulting precipitates were collected by filtration, washed with diisopropyl ether and then immersed for several minutes in a desiccator , On the other hand, a mixture of 3.27 g of gl ^ [(7-amino-4-carboxy-3-cephem-3-yl) methyl] pyridinium chloride hydrochloride dihydrate and 16 g of trimethylsilylaceiamide in 50 ml of methylene chloride was heated to 35 ° C to prepare a solution was cooled to -20 C _e to the cold solution, the precipitates obtained above were added and the mixture was minutes at "-18 to -12 ° C and stirred at -12 to -3 C for a further 20 minutes. A solution of 4 g of sodium bicarbonate in 30 ml of water was added to the reaction mixture and

22 81 12

the aqueous layer was separated, adjusted to pH 1 with 6N hydrochloric acid, washed with ethyl acetate and then adjusted to pH 4 again with an aqueous sodium bicarbonate solution. The aqueous solution was passed through a column filled with 16 g of alumina and then subjected to column chromatography on a nonionic adsorption resin Diaion HP-2O (trademark for a product of Mitsubishi Chemical Industries) (100 ml). After washing the column with water, elution was carried out with 20% aqueous methanol. The eluates containing a compound of the invention were collected / evaporated to remove the methanol under reduced pressure and lyophilized to give 2.39 g of 7- [2 -Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido3-3- (^ -pyridininiomethyl) -3-cephem-4-carboxylate (syn isomer) in the form of a received white powder, F. 155 - 165 C (Zers.). IR '(Nujol): 3400-3150, 1770, 1660, 1610, 1530 cm ^"1 NMR' _(DMS0-d6, S): 1.21 (3H, t, J = 7Hz), 2.9 to 3, 7 (2H, m), 4.12 (2H ₇ q, J = 7Hz), 5.05 (lH, d J = ₇ 5Hz), 5.19, 5.68 (2H, ABq, J = I4Hz) 5.7 (IH, m), 8.1 (4H, m), 8.6 (IH, m), 9.4 (3H ₇ m)

Example 2

To a cold solution of 1.25 g of phosphorus pentachloride in 30 mL of methylene chloride was added 1.5 g of 2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-l, 2,4-thiadicizol-3-yl). acetic acid (syn isomer) at -15 ° C and the mixture was stirred at -13 to -10 ° C for 30 minutes. On the other hand, a mixture of 1.82 g of N- [7 "amino-3-cephem-3-ylmethyl] -

⁶⁸ "2281 12

pyridinium ^ -carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in 50 ml of methylene chloride are stirred for 10 minutes at room temperature and cooled to <10 ° C. The cooled solution was added to the above activated mixture and the mixture was allowed to stand for 15 minutes. The reaction mixture was poured into 100 ml of an aqueous solution of 3.6 g of sodium bicarbonate and stirred for 15 minutes at room temperature. The aqueous layer was separated, adjusted to pH 2 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a nonionic adsorption resin Diaion IP-20 (trademark for a product of Mitsubishi Chemical Industries) (100 ml). After washing the column with water, elution was carried out with 40% aqueous methanol. The eluates containing a compound of the present invention were collected, evaporated under reduced pressure to remove the methanol, and lyophilized to give 1.5 g of N- [7]. | 2 - (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1 _/ 2,4-thiadiazol-3-yl) -acetamido-3-cephem-3-ylmethyl-3-pyridinium-4-carboxylate (syn Isomer) in the form of a white powder, mp 190-195 ° C (dec.). .

IR (Nujol): 335O ₇ 320O ₇ 1780, 1660, 1620,

1530 cm ^-1 NMR (D ₂ 0 + NaHC0 ₃ , S): 1.9-2.5 (4H, m), 3.23

3,60 (2H ₇ ABq, J = IoHz), 5,2-6,1 (7H, m), 7 ₇ 9-9 ₇ l (5H ₇ m)

2281 1 2

Example 3

To a cold solution of 1.46 g of phosphorus pentachloride in 30 ml of methylene chloride were W I ₃ g of 2- (l-methyl-l-äthoxycarbonyläthoxyimino) -2- (5-amino-l, _{2/4-thiadiazol-3} 'yl) acetic acid (syn isomer) at -18 C was added and the mixture was stirred at -14 to -11 C for 30 minutes. To the reaction mixture was added 90 ml of dry η-hexane below "TO" C and the mixture was stirred for several minutes and the solvent was removed by decantation. The residue was triturated with η-hexane and collected by filtration to give a powder of the activated acid. On the other hand, a mixture of 2 g of N- [Zr'Amino-S-cephem-S-ylmethyl-pyridinium] -carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in methylene chloride was stirred for 10 minutes at room temperature and cooled to -18 ° C. To the cold solution, the powder obtained above was added and the mixture was stirred at -13 to -10 ° C for 30 minutes and at -5 to 0 ° C for 30 minutes. The reaction mixture was poured into 100 ml of an aqueous solution of 3.6 g of sodium bicarbonate and stirred for 15 minutes at room temperature and then adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate.

22 8 11 2

After washing the columns sequentially with water, with 5% aqueous ethanol and 10% aqueous ethanol, the elution was washed with 20% aqueous ethanol The eluates containing a compound of the invention were collected, evaporated under reduced pressure to remove the ethanol, and lyophilized to give 1.30 g of N-C7- [2 "(1-methyl-1-ethoxycarbonylethoxyimino) -2 (5 '<imino-l _/ 2 _/ 4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer) in the form of a white powder, mp 164-168 ° C (Zers.).

• I.R. (Nujol): 3350-3150, 1770, 1720, 1670,

1620, 1520 cm * " ¹

NMR (DMSO ^ d ₆ , S): 1.15 (3H ₇ t, J = 7Hz), 1.45 (6H, s), 3.03 and 3.55 (2H, ABq, J = 18Hz), 4 , 10 (2H, --- q, J = 7Hz), 5.11 (IH, d, J = 5Hz), 5.20 and 5.67 (2H, ABq, J = 13Hz), 5.75 ? (1H, 2d, J = 5 and 8Hz), 8.20 (4H, m), 8.57 (IH, m), 9.47 (3H, m).

example A

The following compounds were prepared in a manner similar to that given in Examples 1 to 3:

(1) 7 "[2-Propoxyimino-2- (5-amino-1,4-thiadiazol-3-yl) * -acetamido-S-ii-pyridiniomethyl-S-cephem-1-carboxylate (syn- isomer), mp 230 -240 ⁰ C (dec.).

228112

(Nujol): 3400-3200, 1770, 1670-1600, 1530 cm "

N «MR (DMSO- (J ₆ , S): 0.85 (3H ₁ t, J = 7Hz), 1.6 (2H, m), .3.06, 3.55 (2H, ABq, J = I8Hz), 4.04 (2H, t, J = OHN) ₁ 5.06 (IH, d, J = 5Hz), 5.18, 5.70 '(2H ₇ ABq, J = UHZ), 5.74 (IH, dd, J = 5 and 8Hz), 8.2 (41Vm) ₁ 8.6 (IH, m), 9.5 (3H, m)

(2) 7- [2-Methoxy-1-yl-2- (5-amino-1,2 _/ 4-thiadiazol-3-yr) -acetanudoj-3- (1-pyridiniomethyl) -s-cephem-4-carboxylate

(syn isomer), m.p. 250 ~ 260 C (dec.) · IR (Nujol): 3400-3100, 1770, 1650, 1610, 1520 cm ^-1 . -NXr. (DMS0-d ₆ , S): 3 , 07, 3,57 (2H ₁ ABq, J = IeHz), 3,86 (3H, s), 5,06 (IH ₁ d, J = .5Hz), 5,19, '5,69 ( 2H, ABq, J = KHz), 5.73 (1H, dd, J = 5.8Hz), 8.0-8.3 (4H, m), 8.4-8.7 (IH, m), 9.3-9.6 (3H, m).

(3) 7-E2-isopropoxyimino-2- (5-amino-l _/ 2,4 "thiadiazol-3-yl) -acetamido3-3- (i-pyridiniomethyl) -3" cephem-4-carboxylate (syn ^ Isomeres), F * 160 «165 C (Zers ·)« f

IAR. (Nujol): 3270, 3180, 1770, 1660, 1610, 1525 cm ^-1 NMR (DMSO-d ₆ + D ₂ 0.5): 1.22 (6H, d, J = OHz) ₁ 3.15, 3 , 57 (2H, ABq, J = I 8Hz), 4.17-4.60 (IH, m), 5.12 (IH, d, J = 5Hz), 5.33, 5.70 (2H, ABq , J = UHz, 5.78 (IH, d, J = 5Hz), 8.0-8.4 (2H, m), 8.47-8.85 (IH, m), 9.33-9, 67 (2H, m)

(4) N-E7-i, 2- (t-Butoxycarbonylmethoxyimino) -2- (5-amino, 2,4-thiadiazol-3-yl) acetamido] -S-cephem-S-ylmethyl] pyridinium-4-carboxylate (syn isomer), mp 150-155 ° C (dec.).

- ⁷² ~ 22 811 2

IR (Nujol): 330O ₇ 320O 177O _{7 7} 1680/1620/1530 cm-, ^"1

(5) N- [7- (2-forboxymethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn- Isomer), m.p. 150-155 C (Zers.). IR / - (NuJqI): 23350, 3200, 1780, 1680, 1530 cm ^-1

(6) N - * [7 - (2-Cyclopentyloxyimino-2 '- (5-amino-l _/ 2,4-thiadiazol-3-yl) acetamido] -3-cephem-3'-ylmethyl-pyridinium-4-carboxylate ( syn-Isorneres), F. 180 "185 C (Zers.) ·

IR (Nujol): 3300, 3200, 1780, 167Ö, 162O ₇ 1530 cm "* ¹ • (7) N- [7- | | _2- (l" carboxyethoxyimino) -2> - (5-amirio "1, 2 ₇ 4-thia "diazole-3 ~ yl) acetamido |." 3-cephem-3 'ylmethyl-4 -carbamoylpyridinium ^{l-4-carboxylate} (syn isomer), mp 170 175 ° C (dec).

IR (Nujol): 330O ₇ 3160, 1770, 1680, 1610,

1560, 1520 cm " ¹ (8) N-C7" (2 "(it-butoxycarbonylethoxyimino) -2- (5-amino)

pyridinium * 4'-carboxylate (syn isomer), m.p. 160. · -. 165 C (decomp.) Β

IR (Nujol); 329O ₇ 3160, 1770, 1725, 1670, 162O ₇ 1525 cm " ¹

NMR '(CD ₃ OD 1 -D ₂ O, &): 1.2-1.6. (l2H, 'm), 3,20 and

3.67 (2H, ABq ₇ J = 18Hz). 4.40-4.90 (lH, m), 5.20 (IH, d, J = 5Hz), 5.33-5.80 (2H, m), 5.92 (IH ₇ d, J = 5Hz , 7.9-9.4; (5H, m).

(9) N-C7- ^ 2 ~ (1-car- boxyathoxyimino) -2- (5-amino-1,2,4-thia-diazol-S-yl-acetamido-S-cephem-S; ylmethyllpyridinium "4-carboxylate (syn isomer), m.p. 175" 180 ° C (dec.).

⁷³ '2281 12 1

IeRc (Nujol): 3300, 320O ₇ 1775, 1670, 1620, 1520 cm " ¹ (ΙΟ) N- [7 ~ ^ 2 <- (i-benzyloxycarbonylethoxyimino)" 2 "(5'-anino-1 _/ 2 _/ 4-thiadiazol-3-yl) acetamidoj-3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer), m.p. 178-182 C (dec.).

IR (Nujol): 3250, 3150, 1770, 1670, 162O ₇ 1520 cm ^-1 NMR (DMS0-d ₆ + D ₂ 0 / £): 1.45 (3H ₇ d ₇ J = 7Hz) ₇

3 ₇ 10 and 3 ₇ 60 (2H, ABq ₇ J = IoHz), 4.87 (IH, q, J = 7Hz), 5.20 (2H, s), 4.97-5.10 (2H, m ), 5.25 (IH, d, J = 5Hz), 5.83 (IH, d, J = 5Hz) ₇ 7.43 (5H _7s ) ₇ 8.27 (2H, m), 8.63 ( IH, m), 9.38 (2H, m) (Π) of N- [7 '(2-Äthoxycarbonylmethoxyimino'-2 "(5-amino ™ ₇ l _{2/4-thiadiazol} ~ 3 ~ yl) acetamido -3- -cephem-3-ylmethyl] pyridinium 4-carboxylate (syn ^ isomer), m.p. 184-188 C (Zers)

IR (Nujol): 3400-3100, 1770, 1670, 1610, 1520 cm ^-1 NMR (DMS0-d ₆ , 6): 1.17 (3H ₇ t, J = 7Hz), 3.05-

and 3.53 (2H ₇ ABq ₇ J = I 8Hz), 4 ₇ 13 (2H ₁ q, J = 7Hz) ₇ 4.70 (2H, s), 5.08 (IH ₇ d / J = OHz) ₁ 5,17 and 5,70 (2H, 'ABq, J = 13Hz), 5/72 (IH, dd, J = 5 and 8Hz), 8,16 (4H, m), 8,62 (IH _7m ) , 9.50 (3H, m) (12) N- [7 - '[2- (2-cyclohexen-1-yloxyimino) -2- (5-amino-1, 2,4-thiadiazole-S] ylJacetamidoj-S-cephem ^ sylmethyllpyridinium-4 "carboxylate (syn isomer),

Fo 150 ~ 155 ° C (decomp.). ..

IR (Nujol): 3300, 3200, .1775, 1660, 1610, 1520 cm ^-1

22 8 112

NMR (pMS0-d _{6 #} €): 1.5-2.0 (6H, m), 3.13, 3.57 (2H, ABq, J = 7Hz) ₇ 4.6-4.7 (IH, m), 5.07 (IH, d, J = 4Hz), 5.27, 5.60 (2H ₇ ABq, J = UHz), 5.80 (IH, 2d, J = 4 and 8Hz), 5, 77-6.0 (2H, m), 8.17 (2H, s), 8.0-8.4 (2H, m),. 8.43-8.80 (IH,: m), 9.4-9.5 (2H, m), 9.55 (IH, d, J = 8Hz)

N- [7 - {- 2-Carboxymethoxyimino-2- (5-amino-1 _/ 2 _, 4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl] -4'-carbamoylpyridinium '4 «Carboxylate (syn-isomer),

F. 175 - 18O ⁰ C (Zers.) ·

IR (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm ^-1

(14) N- [7- | 2-methoxycarbonylmethoxyimino-2- (5-amino-1, 2,4-

thiadiazol-3-yl) -acetamido-3-cephem-3-ylmethyl-pyridinium-4-carboxylate (syn isomer),

F. 165 - 17O ⁰ C (Zers.).

I.Ro (Nujol): 3300-3150, 1760, 1670, 1620, 1520 dm " ¹ NMR, (D ₂ O ₁ S): 3.17, 3.70 (2H, ABq, J = ISHz),

3.80 (3H, s), 4.93 (2H / s), 5.30 (TH / "d, J = 5Hz), 5.44, 5.73 (2H, ABq, J = MHz), 5 , 93 (IH, d, J = 5Hz), 8/10 (2H, m), 8.60 (IH, m), 8.98 (2H / m)

(15) N- [7- ^ 2- (1-Methy 1-1-CaXbOXyOtHoXyImInO) ^ - (S-QmInO-l, 2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl ] -pyridinium-4-carboxylate (syn isomer), white powder, m.p. 176-180 ° C (ze _r s _e ).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm " ¹

(16) N- [7- | 2- (1-methyl-1-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-cephem-S] ylmethyllpyridinium '- cai-boxylate (syn isomer),

228112 1

F. 176-180 ° C (decomp.)

'I.RV (Nujol): 3300, 320O ₇ 1780, 1730, 168O ₇

162O ₇ 1520 cm " ¹

NMR (DMSO ^ d ₆ -D ₂ O, S ): 1.40 (15H ₁ bs), 3.08, 3.42 (2H ₇ ABq, J = 18Hz), 5.13 (IH ₇ d, J = OHz) ₇ 5.40 (2H, m), 5.80 (IH, d, J = 5Hz), 8.17 (2H, m), 8.65 (IH, m), 9.37 (2H ₇ m)

(17) N- [7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl] -4'-carbamoylpyridinium 4-carboxylate (syn isomer). F, 230-235 C (Zers _e ).

IR · (Nujol): 3300, 3200, 1770, 1680, 161O ₇ . 1560, 1520, 1510 cm " ¹

(18) N «(7" -. (2 "(2 ~ cyclopenten-1-yl-oxyimino) -2" - (5-amino- ₇

2, 4 ** thia dia ZoI-S ^ yI) O ce tamido) -3 ~ cephe! I'-3-ylmet hyl) - ~ 4 ^T carbamoylpyridinium monocarboxylate (syn-isomer) F , 155 "160 ° C (Zers.)

IR (Nu) ol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 cm ^-1 NMR (DMS0~d ₆ , S): 2.0-2.4 (4H, m), 3.17- 3.67 (2H, m),

5.08 (IH, d, J = 5Hz), 5.23-6.30 (6H, m), 8.27 (2H _x wide s) _x 8.57 (2H, d ₇ J = 7Hz), 9 _ff 53 (IH, d, J = 8Hz), 9,70 (2H, d, J = 7Hz)

(19) N- (7- (2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino, 2,4-thiadiazol-3-yl) -acetamido) -3-cephem-3-yl-methyl) -4 ^t -carbamoylpyridinium-4-ca "rboxylate (syn isomer),

F. 180 - 185 ° C (decomp.)

IR (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm ^-1 NMR (DMSp-d ₆ , S ): 1.40 (6H, s), 3.0-3.6 (2H, m) , 5.10 (IH, d, J = 4Hz), 5.3-5.7 (2H ₇ Pi), 5.80 (IH, dd, -J = 4 and x 8Hz), 9.18 (2H , d _r J = 7Hz), 9 ₇ 50 (IH, d, J = 8Hz), 9.63 (2M, d, J = 7Hz).

r. 76 -

228112 1

(20) 7- [2-Allyloxyimino-2- (5-amino-1 _/ 2,4-thiadiazol-3-yl) -acetqmido] -3- (1-pyridininiomethyl) -3-cephem-4-carboxylate (syn Isomer), m.p. 160-165 C (dec.). IR (Nujol): 3290, 3180, 1770, 1660/1610, 1525 cm ^"1 NMR (DMS0" d ₆ + D ₂ 0, ξ): 3.12, 3.50 (2H, ABq, J = 18Hz) , 4.44-4.76 (2H, m), 5.10 (IH, d, J = 5Hz), 5.0-6.1 (6H, m), 8.0-8.4 (2H, m), 8.44-8.76 (lH, m), 9 ₇ 32-9.68 (2H, m)

(21) 7- [2- (2-Propinyloxyimino) -2- (5-amino-1 _i 2,4-thiadiazol-3 "yl) acetamido] -3- (l-pyridiniomethyl)" 3-cephem-4- carboxylate (syn-isonieres), F, 145-150 C (dec.).

IR (Nujol): 3250, .210O, 1770, 1660, 1630, 1610, 1525 cm " ¹

NMR (DMSO-d ₆ , S): 3.10, 3.55

3.47 (TH, t, J = 2Hz), 4.73 (2H, d, J = 2Hz), 5.08 (IH, d, J = 5Hz), 5.25, 5.65 (2K ₁ - ABq, J = 14Hz), 5.60-5.93 (IH, m), 8.0-8.4 (4H, m), 8.4-8.8 (IH, m), 9.3 -9 _ff 7 (3H, m)

(22) 7- [2-hydroxyimino "2- (5 ~ amino ~ 1.2 ₁ 4-thiadiazol-3-yl) -aceΐamido] ~ 3 ~ (^ - pyridiniomethyl) -3-cephem-4 ~ carboxyla ^ ( syn isomer), F _e 170-175 C (dec) ·.

IR (Nu) oil): 3350, 3200, 1780, 1620, 1530, 1490 cm ^-1

(23) 7-E2-methylthiomethoxyimino-2- (5-amino-r, 2,4-thiadiazol-3-yl) acetamido3-3- (i-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer) , Mp 195-205 ° C (dec.). IR (Nujol): 3350-3150, 1770, 1670, 1620,

1520, 1150 cm ^-1 NMR (DMSO-d ₆ + D ₂ 0, S): 2.17 (3H, s) _f

22 81 12

3.00, 3.62 '''(2H _x ABq,' J = I8Hz) _x 5 _x 10 (IH _x d, J = SHA) _x 5.22 (2H, s), 5.73 (IH, d , J = OHN) _x 5.00 to 5.83 (2H ₇ m) _x 8.13 (2H ₇ m) _x 8 _x 53 (IH _x m), 9 _x 33 (2H ₇ m)

(24) 7-t2-trityloxyimino-2 - (5-amino-1 _/ 2 _/ 4-thiadia7: ol-3-yl) -acetamido] -3- (1-pyridininiomethyl) -3-cepherri-4-carboxylate ( syn-isomer), m.p. 165-170 C (dec.). IR (Nujol): 3450, '1780, 167O ₇ 1620, 1530, 1490 cm * " ¹

NMR (DMSO-Cl _6x S) ^ _x 3.64 (2H _x ABq, J = 18Hz),

5.18 (d IH _{7 7} J = 5Hz) _{5.34, 5.74 (ABq 2H _{x 7} 'VV J = 12Hz), 5.92 (IH ₇ dd, J = 5 and 8Hz), 7.28

(15H, s), 7.94 to 8.30 (4H _x m), 8.42 to 8.66 (lH, m), 9.22 to 9.54 (2H, m), 9 _X 78 (IH _x d _x J = SHz)

(25) 7-C2- (2, 2, 2 "trifluoroethoxyimino)" 2 "(5-amino'-1,2,4-thiadiazol-3-yl) acetamido! I ~ 3 ~ (i-pyridinioniethyl) - ' 3 "cephem" 4-carboxylate (syn isomer), mp 150-155 ° C (dec.).

IR (Nujol): 3300, 1780, 1675, 1630, 1530 cm " ¹ NoM ₀ R ₀ (DMS0" d ₆ + D ₂ 0, 8): 3.23, 3.50 (2H, ABq ₇

J = ISHz) _x 4.63, 4.93 (2H _x ABq, J = 9Hz) _x , 5.17 (IH, d, J = 5Hz), 5.37, 5.73 (2H ₇ ABq, J = I4Hz), 5.83 (IH, d, J = 5Hz), 8.1-8.4 (2H, in), 8 ₇ 5 ~ 8 ₇ 8 (IH, m), 9.3-9.6 " (2H, m)

(26) 7- [2-Ethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) -acetanido-3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem-4 carboxy-ide (syn isomer), F ₄ , 160-165 ° C (dec.), IR (nujol): 330Q, 3200, 178 _× 1680, 1620,

1570, 1530 cm " ¹

(27) 7 ~ [2 ~ (2 ~ 0xotetrahydrofuran-4 ~ yloxyimino ~ 2- (5 ~ amino ~

'l _/ 2 _/ 4-thiadiazol-3-yl) -acetamido] -3- (1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), mp 140-145 ° C

IR (Nujol): 3350, 1780, 1670, 1620, 1530, 1490 cm " ¹ N ₀ M ₀ R. (DMS0" d ₆ + D ₂ 0, β): 2.43-2.83 (2H, m) , Z, 27,: ^;

3.63 (2H, ABq, J = ISHz), 4.23-4.67 (2H, m), 5.17-5.37 (IH, m), 5.20 (IH, d, J = 5Hz ), 5.38, 5.73 (2H, ABq J = ₇ I3Hz), 5.87 (1H, d, J = 5Hz), 8.07 to 8.43 (2 H, m), 8,53- 8.80 (lH / .m), 9.23-9.50 (2H, m)

(28) 7- [2-Methoxyimino-2 ~ (5-amino-1,2,4, -HiQdiaZoI-S -) '!) - acetamido3-3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem "4'-carboxylate (syn-isomer), m.p. 165 * * 170 C (Zers _e ). IR (Nuj-ol): 3350, -3200, 1780/1690 _# 1610

1570, 1530 cm " ¹

(29) 7-E2-Propoxyimino-2- (5-amino-1- _i- 2,4-thiadiazol-3-yl) -acetamido! -3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem-4 Carboxylate (syn isomer), m.p. 170-175 C (dec.). IR (nujol): 3350, 3200, 1780, 1690, 1610; ^?

1570, 1530 cm " ¹

(30) 7-L2-isopropoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) -acetamido] -3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem-4 carboxylate (syn isomer), F, 155-160 C (dec.). I. Ro (Nujol): 3350, 3220, 1780, 1680, 1615 /

1570, 1530 cm " ¹

(31) 7- [2-allyloxyimino-2- _{(5-amino-1/2/4-thiadiazol-3-yl)} -acetamido3-3 '- (. 4 <-carbamoyl-1 pyridinioinethyl.) - 3- cephem-4-carboxylate (syn isomer), F. 161-165 C (dec.) IR (Nujol): 3400-3150, 1770, 1670, 1610,

1560, 1520 cm " ¹

" ⁷⁹ ~ 228112

(32) 7- [2- (2 _/ 2,2-trifluorophenyliniino) -2- (5-amino-1, 2,4-thiadiazol-3-yl) -acetamido] -3- (4-carbamoyl-1-pyridinio ~ methyl) -3-cephem-4 ~ carboxylate (syn isomer), mp 160 165 ° C (dec.).

IR - (Nujol): 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm " ¹

(33) 7-t2-Methylthiomethoxyimino-2 - (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (4-carbamoyl-1-pyrida-niomethyl) -3-cephem-4 carboxylate (syn isomer), F, 160-165 C (IR (Nujol): 3300, 3150, 1770, 1680, 1610,

1560, 1520 cm " ¹

(34) 7 "r2" (2-f ^" ropinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido3-3- (4-carbamoyl-1-pyridiniomethyl) -3 -cephem-4-carboxylate (syn-isomer), F. 155-160 C (Zers.).

IR (Nujol): 3400, 3250, 3150, 2120, 1770, 1685, 1610, 1560, 1525 cm ^-1

(35) Natriuni'-7-C2-cyclopentyloxyimino-2- (5-amino-1,2,4-th5a-diazol-3-yl) acetamido3-3- (2-methyl-5-oxo-6-yl) hydroxy-2,5-dihydro-i _/ 2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer), m.p. 169-174 C (dec.). IR (Nujol): 3600-3100, 1760, 1690, 1665,

1640, 1610, 1520, 1005 cm " ¹

(36) Disodium 7- [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-oxido-2 , 5-dihydro-1,2 _/ 4 «triazin-3-yl) thiomethyl-3-cephem-4" carboxylate (syn isomer), F _e 220-225 ° C (dec.).

IR (Nujol): 3400-3150, 1760, 1660, 1640-1560, 1520, 1040 cm ^-1

(37) Disodium 7- [2-ethoxyimino-2- (5-amino'-1 _/ 2,4-thiadiazole]

2 2 811 2

(syn isomer), m.p. 255-265 C (dec.) © IR (Nujol): 3400-315O ₇ 1760, 1660, 160O ₇ 1500, 1400, 1030 cm ^-1

(38) 7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4 "thiadiazol-3-yl) -acetamido] -3- (2-methyl-5") Oxo-6'-hydroxy-2, S-dihydro-1'-triaziri-S-yl-thiomethyl-S-cephem-1-carboxylic acid (s yn-1 sorrier), F x 158-164 C (dec.).

IR (Nujol): 3450-3150, 1770, 1680/1630, 1510, 1260, 1180, 1100, 1030 / 1010.cm " ¹

NMR (DMSO-d ₆ , 6): 2.0-2.6 (4H, m), 3.2-4.0 (2H, m), 3.62 (3H ₇ s), 4.13, 4 , 45 (2H, ABq ₇ J = 13Hz) ₇ 5 _V 13 (1H> d, J = 5Hz), 5.2-5.5 (IH, m), 5.7-6.0 (2H, m) , 6.0-6.2 (lH, m), 8.20 (2H, broad s), 9.50 (IH, d, J = 8Hz) j

(39) 7 - [2-isopropoxyimino-2- (5-amino-1, 2,4-thibdiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-hydroxy-2, 5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 160-167 C (dec.) _E IR (nujol): 3400, 3280 , 3180, 1780, 1770,

1630, 1515, 1410, 1240, 1009 cm ^-1 NMR (DMSO-d ₆ + D ₂ 0 ₇ S): 1.27 (6H, d, J = OHz),

3.62 (3H, s), 3.5-3.9 (2H, m), 4.13, 4.41. (2H, ABq, J = 14Hz), 4.40 (IH, t, J = OHz), 5.17 (IH, d, J = SHz), - 5.83 (IH, d, J = 5Hz)

22 8 11 2

(40) 7 "[2- (2-Propinyloxyiniino) -2- (5-amino-1 _/ 2 _/ 4-thia]

diazole ~ 3 ~ yl) acetamido] ~ 3 ~ (2 ~ methyl-5 ~ oxo ~ 6-hydroxy ~ ''' .

_2/5 "dihydro" 1.2 _/ 4-triazin-3 "yl)" thiomethyl "3-cephem"

4-carboxylic acid (syn-Isorneres), F. 161-166 C (dec.). I.R. (Nujol): 3260, 3180, 1770, 1670, 1620, 1520,

1335 cm * " ¹ NMR (DMSO ~ dgD ₂ 0, S): '3.48 (IH, s), 3.61 (3H,

.s), 3.3-3.9 (2H, m), 4.10, 4.38 (2H _x ABq ₇ J = UHz), 4.77 (2H, s), 5.12 (IH, d , J = 5Hz), 5.78 (IH, d, J = 5Hz) ·

(41) 7 ~ [2-Allyloxyimino-2 ~ (5-amino-1,2,4-thiadiazol-3-yl) acetamido] - '3- (2-methyl-5-oxo-6-hydroxy "2 , 5-di "'-hydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn ^ isomer), m.p. 169-173 C (Zers).

IR (Nujol): 3360, 3210, 1775, 1670, 1625, 1560, 1520, 1250, 1175, 1100, 1020 cm ^-1

NMR (DM50 ~ d _6,?): 3.3-4.0 (2H, m), 3.58 (3H, s), 4.0-4.6 (2H, m), 4,5 4.8 (2H ₇ m), 5.13 (IH, d, J = 5Hz), 5.0-5.6 (3H ₇ m), 5.81 (IH ₇ dd, J = 5 and 9 Hz), 8.18 (2H, broad s), 9.53 (IH, d, J = 9Hz)

Example 5

A mixture of 5.1 g of 7- [2-cyclopentyloxyimino-2- (5-aminol / 2,4-thiadiazol-3-yl) acetamido] cephalosporanic acid (syn isomer), 840 mg of sodium bicarbonate, 50 ml of water, 24 , 3 g of potassium thiocyanate and 1.83 g of isohicotinamide was stirred for 22 hours at 50 to 55 C. The reaction mixture became

22811 2

cooled and added to ethyl acetate. The mixture was adjusted to pH 2 with 10% hydrochloric acid and filtered. The aqueous layer was separated from the filtrate, washed with ethyl acetate and evaporated. The residue was subjected to column chromatography (Diaion HP 2O ₇ nonionic adsorption resin manufactured by Mitsubishi Chemical Industries), and the column was washed with water (0 ₇ 7 1) then eluted with 0.7 1 30, % i like aqueous methanol. The eluates containing the compound of the invention were collected / washed with ethyl acetate and then evaporated. The residue was lyophilized to give T ₇ O g N- [7- £ 2-cyclopentyloxyimino-2- (5-amino-1,2,4 thiadiazol-3-yl) acetamido-3-rcephem-3-ylmethyl] -4 ^l -carbamoylpyridinium-4-carboxylate (syn isomer), F, 230-235C (dec.). IR (Nujol): 3300, 3200, 1770, 1680, 1610,

1560, 1520, 1510 cm "" ¹ NMR Cd ₆ -DMSO ₇ S): 1.30-1.95 (8H, m), 3.15 and 3.50 (2H, ABq, J = 18Hz), 5, 60-5.75 _; (IH, m), 5.06 (IH, d, J = 4Hz), 5.30 and

5,65 (2H, ABq, J = 14Hz), 5,70 (IH, dd, 'J = 4 and 8Hz), 8,12 (2H, s), 8,45 (2H, Cl ₇ J = OHz) , 9.42 (2H, d, J = 6Hz), 9.50

(IH, d, J = 8Hz)

Example 6

Xn

-sä- 228 1 1 2

A mixture of 2.8 g of 7- [2-cyclopentyloxyimino-2- (5-amino-1 _/ 2 _, 4-thiadiazol-3-yl) -acetamide-3-yl-3-acetoacetoxyniethyl-3-ce'-phen-4-carboxylic acid (syn-isomeric), 420 mg of sodium bicarbonate ^ 28 g of potassium iodide and 590 mg of pyridine in 28 ml of water were stirred at 55 ° C. for 1 hour. After cooling, 20 ml of ethyl acetate, 5.5 ml of 1 N hydrochloric acid and 10 ml of acetone The aqueous layer was separated, washed with ethyl acetate and concentrated under reduced pressure to 30 ml. An insoluble substance was filtered off and the filtrate was subjected to column chromatography on a nonionic adsorption resin Diaion HP20 (100 ml). After washing the column with 500 ml of water, elution was carried out with 30% aqueous methanol. The eluates containing a compound of the invention were collected, evaporated under reduced pressure to remove the methanol, and lyophilized 620 mg of N ~ [7-2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamidoj-3-cephem-4-ylmethyl] pyridinium-4-carboxylate ( syn isomer) in the form of a white powder, mp 180 185 ° C (dec.).

I.R. (Nu oil): 3300, 3200, 1780, 1670, 1620 ^

1530 cm ^-1 NMR (DMSO-d ₆ , - &): 1.4-2.0 (8H, m), 3.17

3.53 (2H ₁ ABq, J = I 8Hz), 4.60-4.83 (IH _1m ), 5.10 (IH, d, J ^ 4Hz), 5.30, 5.83 (2H ₁ ABq, J = HHZ), 5.87 (IH, 2d, J = 4 and 8Hz) / 8.17 "* (2H, s), 9.50 (IH ₁ d, J = 8Hz), 8,0- 9.7

(5H, m)

22 8112 ί

Example 7

The following compounds were prepared in a manner similar to that given in Examples 5 and 6:

(1) N- [7- | 2- (2-cyclopentene-1-yloxyimino) -2- (5-amino)

'-.V, 24, -thiadiazol-3'-yl) acetamidol-3-cep-hem-3-ylmethyl] -pyridinium ~ 4'-carboxylate (syn-isomer), F _e 190-195 C (dec.).

IR (Nu j oil) :. 3350, 3200, '17 .80, 1660, 1620, 1530 cm ' ¹

(2) N- [7- {2- (t-butoxycarbonylmethoxyimino) -2- (5 amino)

1,2,4-thiadiazol-3-yl) acetamido} -S-cephem-S-ylmethyl] pyridinium-4-carboxylate (syn isomer), mp 150-155 ° C (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 cm * " ¹

(3) N ~ 7 - {_ 2 carboxymethoxyimino-2- (5-amino-1, 2,4-thipdiazole)

3-yl) acetamido] -3-ceρhem-3-ylmethyl] -pyridinyl ammonium (syn isomer), m.p. 150-155 C (dec.). IR * (NUiOl) TSSSO ₇ 3200, 1780, T680, 1530 cm " ¹

(4) N-E7-2-cyclopentyloxyimino-2- (5-amino-1, 2,4-thiadi

azol-3-yl) acetamidoj-3-cephem-3-ylmethyl3-pyridinium

4-carboxylate (syn isomer), F _e 180-185 ° C (dec.).

IR (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm * " ¹

NMR (DMSO-d ₆ , S): 1.4-2.0 (8H, m), 3.17,

3.53 (2H, ABq, J = I 8Hz), 4.60-4.83 (IH, m), 5.10 (IH, d, J ^ 4Hz), 5.30 and 5.83 (2H,

228112 t

ABq, J = UHz), 5.87 (IH ₇ dd, J = 4 and 8Hz), 8.17 (2H, -s), 9.50 (IH, d, J = 8Hz), 8.0-9 , 7 (5H, m>

(5) N- [7- [2- (i-carboxyethoxyimino) -2- (5-amino-1 _/ 2 _, 4-thiadiazol-3'-yl) acetamido] -3-cephem-3-ylmethyl] "4 ^f -carbamoylpyridiniunwl-carboxylate (syn isomer), F · 170- 175 C (dec.).

IR (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm ^-1

NMR _(DMS0-d6, £): 1.38 (3H, d, J = 7Hz), 3.10-3.60 (2H, m), 4.40 to 4.83 (IH, m), 5 , 10 ₍₇ IH d, J = 5Hz), 5.28 to 6.00 (3H, m), 8.22 (2H, broad s), 8.48 (2H, d, J = 6Hz), 9, 48 (2H, d, J = 6Hz), 9.32-9.65 (IH, m)

(6) N-C7- [2- (i-t-butoxycarbonylethoxyimino) -2- (5-amino-)

l, 2,4-thiadiazol-3 = -yl) acetamidoj-3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer), m.p. 160-165 ° C dec.). ..._

IR (Nujol): 3290, 3160, 1770, 1725, 1670,. 1620, 1525 cm " ¹ "

(7) N- [7- [2- (1-carboxyethoxyimino) -2- (5-amino-1, 2,4-

thiadiazol-3-yl) acetamido ^ «3-cephem-3-ceρhem-3 ^ ylmethyllpyridinium - ^ - carboxylate (syn isomer), mp 175 -. 180 ⁰ C (dec)

 IiR · (Nujol): 3300, 3200, 1775, 1670, 1.620,

1520 cm "" ¹

N- [7- | _% 2- (1-Benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamidoj-3-cephem-3-ylmethyl-3-pyridinium-4-carboxylate (syn isomer), F 178 ~ 182 ° C (Zers.).

~ 86 -

228112

I / R. (Nujol): 3250, 3150, 1770, 1670, 1620,

1520 cm " ¹

(9) N-C7- ^ 2-Xthoxycarbonylmethoxyimino-2- (5-amino-1,2 _/ 4 * '

thiadiazol-3 "yl) acetamido-3-cephem-3-ylmethyl] pyridinedinium-4-carboxylate (syn isomer), F, 184-188C

IR (Nujol): 3400-3100, 1770, 1670, 1610, 1520 cm "" ¹ (10) N- [7- | _- 2- (2-cyclohexen-1-yloxyimino) -2- _(? 5-omino-1 _{2/4-thiadiazol-3} 'yl) ocetamidoj "3-cephem <-3-ylmothyl] pyridinium" 4-carboxylate (syn isomer), mp 150-155 C (dec ·) · IR (Nujol): 330O ₇ 3200, 1775, 1660, 1610, 1520 cm ^"1 • (Π) of N- [7 - [2 ~ carboxymethoxyimino-2 - (5-amino-1 _/ 2,4-thiadiazol-3-yl) -acetamido} -3-cephem-3-ylmethyl] -4 ^l -ca-ramoamoyl-pyridinium-4-C-carboxylate (syn- isomer.es)) F · 175-180 ° C) · IR (Nujol): 3350, 3200, 1775, 1680, 1615,

1565, 1525 cm ^-1 NMR (DMSO-d _6- D ₂ O, £): 3.23, 3.55 (2H, ABq ₇

J = 18Hz), 4.67 (2H, s), 5.10 (1H, d, ^f

J = 5Hz), 5.35, 5.72 (2H, ABq ₇ J = ISHz), 5.80 (1Ή, d, J = 5Hz), 8.43 (2H, d, J = OHz), 9, 38 (2H, d, J = 6Hz)

(12) N- [7- [2-Methoxycarbonylmethoxyimino-2- (4-amino-1, 2,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl] pyridinium-4'-carboxylate (syn- Isomeres), F «, 165" 170 C (Zers,).

I, R. (Nujol): 3300-3150, 1760, 1670, 1620, 1520 cm " ¹

(13) N- [7-i, 2 ~ (1-ethyl-1-carboxyethoxyimino) -2- (5-amino-

1 _# 2,4-thiadiazol-3-yl) acetamido]; S-cephem-S-ylmethyl] -pyridinium-4-carboxylate (syn isomer), white powder, mp 176-180 ° C ( dec.) c

22 8 t 1 2 ί

IR (Nu j oil): 3400-3150, 177O ₇ 1670, 1620, 1520 cm ** ¹ N- [7 '- _{> 2- (l ~ methyl-l-Uthoxycarbonyläthoxyimino) -' * 2- (5-amino -l _{/ 2/4-thiadiazol} "3-yl) acetamido ^ - 3-cephem-3-ylmethyl] pyridiniuin-4" carboxylate (syn isomer), 'white powder, F. Ί64 - 168 ⁰ C (dec. ). IR (Nujol): 3350-3150, 1770, 1720, 1670 /

1620, 1520 cm * " ¹

(15) 'N ~ [7- ^ 2- (i ~ methyl ~ 1 ~ t'-butoxycarbonylethoxyimino) -2 ~ (5-amino-l, 2,4 ~ thΪ-gadiazol ~ 3 ~ yl) acetamiclo · 3 · · cephem * - 3'-ylnethyl-3-pyridinium-4-carboxylate (syn isomer), F. ' 176 - 180 ° C (decomp.).

-1.R-. (Nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm " ¹

(16) N »- (7- (2» (2'-cyclopentene-1-yl-oxyimino) ~ 2- (5-amino-1-2 _# 4-thiadiazol-3-yl) -acetamido) - 3 '-' Cepheffl "3 ~ ylmethyl)" - 4 ^l carbamoyl-pyridinium ^ -carboxylate (syrt "" isomer).

F. 155 - 16O ⁰ C (Zers.).

WR. '(Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 cm ^-1 NMR (DMS0-d ₆ , 6): 2.0-2.4 (4H, m), 3 ^ 17-3, 67 (2H, m), 5.08 (IH, d, J = 5Hz), 5.23-6.30 (6H, m), 8.27 (2H, broad s), 8.57 (2H, d , J = 7Hz), 9.35, (lH, d, J = 8Hz), 9.70 (2.H, d, J = 7Hz)

(17) N "(7" (2 "(1-methyl" 1 "carboxyethoxyimino) ~ 2 - '(5" amino-

1 _f 2,4-thiadiazole "3" yl) acetamido) "3" cephem "3" ylmethyl) -4- ^t -carbamoyl-pyridinium "-4-carboxylate (syn ^ isomer), mp 180-185 ° C ( Zers.) IR (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm ^-1

(18) 7 ~ [2-Ethoxyimino ~ 2- (5-amino-1,2,4-thiadiazol-3-yl) '- acetamido] -3- (i-pyridiniomethyl) -3-cephem ~ 4-carb "

oxylate (syn isomer), F "155-165 C (dec.).

UR. (Nujol): 3400-3150 ,. 1770, 1660, 1610, 1530 cm " ¹ .

(19) 7- [2-Propoxyimino-2- (5-amino-1,2,4-thiadia: zol-3-yl) -α-acetamido] -3- (i-pyridiniomethyl) -3-cephem-4 -carboxylate (syn-isomer), F. 230-240 C (dec.) ·

IR (NuJoI): 3400-320O ₇ 1770, 1670-1600, 1530 cm " ¹

(20) 7- [2 "methoxyimino-2 ~ _{(5-amino-1/2/4-thiadiazol-3-yl)} ~ acetamido] -3- (l ~ pyridiniomethyl) -3-cephem-4-carboxylate (syn Isomer), mp 250-260 ° C (dec.).

IR (Nujol): 3400-3100, 1770, 1650, 1610, 1520 cm " ¹

(21) 7-E2 ~ isopropoxyimino-2 ~ (5-amino-1,2 _/ 4-thiadiazol-.3'-yl) a cetamino] -3- (1-pyridininiotyl) ~ 3-ce ρ hemo- 4'-carboxylate (syn-isomer), mp 160-165 ° C (dec.). IR (nujol): 3270, 3180, 1770, 1660, 1610, 1525 cm ^-1 .

(22) 7-C2-Allyloxyimino-2- (5-amino-1 _/ 2,4-thiadiazol-3-yl) -a CGtORiIdO] -S- (I-pyridininiomethyl) -3-cephem-4 " car boxy la t (syn-isomer), F, 160-165 C (dec.) ·

IR (Nujol): 3290, 3180, 1770, 1660, 1610, 1525 cm " ¹ .

(23) 7- [2- (2-Propinyloxyimino) -2- (5-amino-l, _{2/4-thiadiazol-3-yl)} acetamido] -3 (i-pyridiniomethyl) -3-cephem-4- carboxylate (syn-isomer), F, 145 150 150 C (dec.). IR (Nujol): 3250, 2100, 1770, 1660, 1630,

1610, 1525 em " ^1. "

(24) 7- [2 ~ .Hydroxyimino-2- (5-amino-l, _{2/4-thxadiazol} ~ 3-yl) -acetqmido3 '' 3- (l-pyridiniomethyl) -3-cephem-4-carboxylate ( syn isomer), m.p. 170-175 C (Zers _e ).

IR (Nujol): 3350, 3200, 1780/1620, 1530, 1490 cm " ¹ ,

(25) 7-L2 <~ methylthioxyethoxy-2-ylio (5-amino-1,2,4-thiadi)

, azol-3-yl) acetamido] -3- (l-pyridiriiomethyl) -3-cephem "-4 ~

22811 2

carboxylate (syn-isomer) ,. F, 195-205 C (dec.) _O IR (Nujol): 3350-3150, 1770, 167O ₇ 1620, 1520, 1150 cm ^-1

(26) 7 "[2-trityloxyimino ~ 2 ~ (5-amino"'l, 2,4-thiadiazol-3-yl) -acetamido] -3- (0-pyridiniomethyl) -3-cephem-4-carboxylate (syn- Isomeres), m.p. 165-170 C (Zers "). IR (Nujol): 345O ₇ 1780, 1670, 1620, 1530,

1490 cm " ¹

(27) 7-L2 ~ (2 _/ 2,2-trifluoroethoxyimino) -2 - (5-amino-1,2,4-thiadiazol-3-yl) -3-cetamidoiI-3 - (i'-pyridiniomethyl) ~ 3-Cephem-4-carboxylate (syn isomer), F _# 150-155 C (Zers *).

\ I _e R. (Nujol): 330O ₇ 1780 1675/1630, 1530cm "" ¹

(28) 7- [2 ~ ethoxyimino ~ 2 ~ (5'-amino-1,2,4-hexadiazol-3-yl) -acetamido3- (4-carbamoyl-1-pyridininiomethyl) -3-cephem ~ 4 -carboxylot (syn isomer), mp 160-165 ° C (dec.).

I. Ro (Nujol): 3300, 3200, 1780, 1-680, 1620,

1570, 1530 cm " ¹

, N _e MR (DMSO-d ₆ + D ₂ 0, δ): 1.33 (3H, t, J = 7Hz), 3.33, 3.67 (2H, ABq, J = ISHz), 4.35 ( 2H, q, J = 7Hz), 5.30 (IH, d, J = 4Hz), 5.47, 5.67 (2H, ABq, J = UHz), 5.90 (IH, d, J = 4Hz ), 8.40 (2H, d, J = 7Hz), 9 ^ 17 (2H, d, J = 7Hz)

(29) 7 ~ [2 ~ (2 ~ 0xotetrahydrofuran ~ 3 ~ ylpxyimino.) ~ 2 ~ (5-amino-1,2,4-thiadiazol-3 "yl) acetamido! 3-3- (1-pyridiniomethyl) ~ 3 cephem ~ 4-carboxylate (syn-

, Isomer), m.p. 140-145 C (dec.) C

IR (Nujol): 3350, 1780, 1670, 1620, 1530, 1490 cm "" ¹

2281 1 2

(30) 7- [2 ~ methoxyimino "2- (5-amino ~ 1,2 ~ ₇ 4 thiac iazol-3-yl!) · - · aceta mi do] -3 '(4 ~ carbamoyl ~ 1" ρ yridiniomet HyI) -S-CePHeItI "4-carboxylate (syn isomer), F, 165" - 170 C (dec.). IR (Nujol): 335O ₇ 320O ₇ 1780, 169O ₇ 1610,

1570, 1530 cm "" ¹

NMR (D ₂ O ₇ S): 3 ₇ 33, 3 ₇ 67 (2Η, ABq, J = 18 Hz), 4.07 (3H ₇ s), 5 ₇ 30 (IH ₇ d, J = 4 Hz), 5, 47, 5.67 (2H, ABq, J = UHz), 5.90 (1H, d ₇ J = 4Hz) ₇ 8 ₇ 40 (2H ₇ d, J = 7Hz) ₇ 9 ₇ 17 (2H ₇ dl, J = 7Hz)

(31) 7-C2-propoxyimino-2- (5-amino-l, 2 ₇ 4-thiadiazol-3-yl) acetamido] "3" (4 "carbamoyl" l "pyridiniomethyl) -3" cephem "4- carboxylate (syn-isomer) ₇ F. 170 "175X (Zers"). IR (Nujol): 3350, 3200, 178O ₇ 1690, "1610,

157O ₇ 1530 cm "" ¹ NMR (D ₂ 0 _f S): 0.95 (3H ₇ t, J = 7Hz) _/ 1.5-2.0

(2H, m), 3.33 ₇ 3.68 (2H ₇ ABq, J = I7Hz), 4.28 (2H, t, J = 7Hz), 5.33 (IH, d / .J = 4Hz) _{7 7} 5.47 5.70 (2H ₇ ABq, J = HHZ), 5.92 (IH, 'd, J = 4Hz), 8.42 (2H, d, J = 7Hz), 9.17 (2H, d, J = 7Hz); ,

(32) 7 «[2-Isopropoxyimino-2- (5-amino-1 ₇ 2 ₇ 4-thiadiazol" 3 ~ yl) acetamido] .- 3 '- (4-carbamoyl-1' pyridiniomethyl) -. S-cephem'vi-carboxylate (syn isomer) ₇ F. 155-160 ° C (Zers) *

IR (Nujol): 3350, 3220, 1780, 1680, 1615, 1570, 1530 cm ^-1

N.MeR. (DM $ 0 ~ d ₆ + D ₂ 0, h) : 1,22 (6H, d, J = 6Hz), 3,17, 3,48 (2H, ABq, J = 18Hz), 4,1-4, 6 (IH, m), '5.03 (IH ₇ d, J = 5Hz), 5.25, 5.63 (2H, ABq, J = UHZ), 5.70 (1H, d, J = 5Hz) , 8.40 (2H, d, J = OHz), 9.45 (2H, d, J = 6Hz)

228112 1

(33) 7- [2-Allyloxyimino-2- (5-aminob-1, 2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem-4 carboxylate (syn isomer), m.p. 161-165 C (dec.).

I _e Rc (Nujol): 3400-3150, 1770, 167O ₁ . 1610, 1560, 1520 cm " ¹

NMR (DMSO-d ₆ + D ₂ 0, S): 3.09, 3.50 (2H, ABq ₇

J = ISHz), 4.5-4.7 (2H, m), 4 / 9-5.4 (4H, m), 5.06 (IH, d, J = 5Hz), 5.6-6, 1 (IH, m), 5.71 (IH, d, J = 5Hz), 8.43 (2H, d, J = OHN), 9.50 (2H, d, J = OHN) (34 ^s) 7 - [2 ", (2,2,2-trifluoroethoxyimino) -2- (5-amino-1 _/ 2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinio) methyl) -3-cephem-4-carboxylate (syn isomer), F 160> 165 ° C (dec.).

IR (Nujol): 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm ^-1

NXR. (D ₂ O, S): 3.30, 3.67 (2H, ABq, J = ^17Hz); 4.73, 4.97 (2H, ABq, J = SHz), 5.30 (IH, d, J = 4Hz), 5.47, 5.67 (2H, ABq, J = HHz), 5.92 (IH, d, J = 4Hz), 8.40 (2H, d, J = 7Hz), 9.20 (2H, d, J = 7Hz) (35) 7- [2-Methylthiornethoxyimino-2 "(5- amino-1, 2,4-thiadiazol-3-yl) acetamido] -3 "(4-carbamoyl-1-pyridinio-methyl) -3-cephem-4" carboxylate (syn isomer), m.p.

160 ~ 165 ⁰ C (Zers.).

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1560, 1520 cnT ¹

NMR (DMSO-d ₆ + D ₂ 0, -S): 2.23 (3H, s), 3.15,

3.67 (2H, ABq, J = ISHz), 5.17 (IH, d, J =

228112 1

5.32 (2H, s), 5.00-5.57. (2H, m), 5.80 - (IH, d, J = 5Hz), 8.68 (2H, d, J = OHz),

9.50 (2H / d, J = OHz) '

(36) 7 ~ [2 «(24> ropinyloxyimino)« 2 ~ (5-amino-1 _/ 2 _/ 4-thia-diazo-1,3-yl) -acetamido 3 ~ 3 (4-carbamoyl-1-pyridiniomethyl) - 3 ~ cephem-4-carboxylate (syn isomer), F _# 155 »16O ⁰ C (dec.).

ICR. (Nujol): 3400, 3250, 3150, 2120, Ί770, 1685, 1610/1560, 1525 cm "" ¹ . NMR (DMSO-d ^ D ^ S): 3.23, 3.58 (2HZABq, J = 18Hz), 3.45 (IH, t, J = 2Hz), 4.80 (2H, d / J = 2Hz ), 5.13 (IH ₇ d, J = 5Hz), 5.35, 5.72 (2H, ABq, J = UHZ), 5.78 (IH, d, J = 5Hz), 8.47 (2H , d, J = 7Hz), 9.50 (2H, d, J = 7Hz).

Example 8

7-E2-cyclopentyl Io xyimino-2 ~ (S ^ amino '!, 2 ₇ 4 "thiadia zo l-r3 ~ yl) ~ acetamido] -3-acetoacetoxymethyl-3' ceρhem-4-carboxylic acid (syn" isomer) was in a similar manner as in the examples and 6 indicated with 2 ~ methyl .5-oxo <- "6-hydroxy-2,5" dihydro-l _/ 2 _i , 4-triazine-S-thiol reacted with sodium - ^ - E2r, cyclopen- <tyloxyimino-2- (5-amino-l, 2 _/ 4-thiadiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-hydroxy- * 2 _/ 5 "dihydro- <1,2,4 ^ triazin-3-yl) t hi omet hy 1-3-ce ρ hem-4-car boxy t (s yn- * I somer es), mp 169 ~ 174 ° C (Zers.), Received.

I.R. (Nujol): 3600-3100, 1760, 1690, 1665,

1640, 1610, 1520, 1005 cm " ¹

NMR (D ₂ O ₊ NaHCO _3, δ): T, 3 to 2.1 (8H, m), 3.63 (3H, s), 3.4 ^ 3.9 (2H _r m), 4.08 , 4.40 (2H, ABQ, J = HHz), 4.7 ^ 5.1 (HV m), 5/22 '. (IH, d, J = 5Hz), 5.80 (IH, d, J = 5Hz)

-. 93 -

228112 t

Example 9

The following compounds were prepared in a manner similar to Examples 5, 6 and 8: 1) disodium 7- [2-methoxyimino-2- (5-amino-1 _/ 2,4-thiadiazol-3-yl ) acetamido] -3- (2-methyl-5-oxo ~ 6-oxido-2 ₇ 5-dihydrol, _2/4 "triazine" 3 ~ yl) thiomethyl "3 ~ cephem '~ 4-carboxylaf (syn-isomer) ₇ F. 220-225 ° C (dec.). , IR (Nuj oil): 3400-3150, 1760, 1660, 1640-156O ₇

1520, 1040 cm " ¹

IWLR. (D ₂ O ₇ S): 3.64 (3H ₇ s), 3 ₇ 48, 3.78 (2H, * ABq, J = 18Hz), 4.08 (3H ₇ s) ₇ 4.00-4, 56

(2H ₇ m), 5.20 (IH ₇ d, J = 5Hz) ₇ 5.82 (IH, d, J = SHz)

(2) Disodium 7- [2-ethoxyimino '- 2- (5 "-amino ~ 1 ₇ 2 _/ 4-thiadiazol-3-yl) -acetamidol-3" (2-methyl-5-oxo-6-oxido) 2 ₇ 5-dihydro-1,2 _t 4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer), mp 255-265 C (dec). j.

IR (Nuj oil): 3400-3150, 1760, 1660, 1600 _f 150O ₇ 140O ₇ 1030 cm " ¹

NMR (D ₂ O ₇ S): 1.35 (3H, t, J = 7Hz) _7, 3.42, 3.80

(2H ₇ ABq, J = 18Hz) ₇ 3 ₇ 65 (3H _7s ), 4 ₇ 07 ₇ 4 ₇ 43 (2H, ABq, J = I 3Hz), 4.38 (2H ₇ q, J = 7Hz) ₇ 5.22 (IH ₇ d, J = 5Hz) ₇ 5 ₇ 83 (IH ₇ d, J = 5Hz)

(3) 7- [2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1 ₇ 2,4 ~ thiadiazol-3-yl) acetamido] -3- (2-methyl-S-oxo -o-hydroxy-2 ₇ 5 _7-dihydro-1, 2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ₇ 158 F. "164 C (dec.).

2.28M 2

LR. (Nujol): 3450-3150, -1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 1010 cm ^-1

(4) 7 ~ [2 ~ isopropoxyiminor ~ ~ (5-amino-1,2 _/ 4-thiadiazol-3-yl) acetamido] ~ 3 ~ (2-methyl-5-oxo-6-hydroxy-2,5- dihydro-1,2,4-triazin-3-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), F 160-167 C (-Zers.).

I _e R · (Nujol): 3400, 3280/3180, 1780, 1770,

1630, 1515/1410, 1240, 1009 cm " ¹

(5) 7-.t2- (2-Propynyloxy-imino) -2- (5-amirol-1,2,4-thiadiazol-3-yl) -acetamido3-3 (2-methyl-5-oxo-6-yl hydroxy '- 2, 5-dihydro-1,2,4-triazine-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer),' F, 161-166C ( dec.) ·

IR (Nuiol): 3260, 3180, 1770, 1670, 1620, 1520, 1335 cm ^-1

(6) 7- [2-Allyloxyimino-2 ~ (5-amino-1,2,4-thiadiazol-3-yl) "acetamido3-3" (2-methyl-5-oxo "6-hydroxy-" 2 _/ 5 "dihydro" 1 _/ 2,4-triazine "3-yl) thiomethyl" 3-cephem-4-carboxylic acid (syn isomer), m.p. 169 "173 C (dec.). IR (nujol). : 336O ₇ 3210, 1775, 1670, 1625,

1560, 1520, 1250, 1715, 1100, 1020 cm " ¹ .

Example IQ ₁

To a solution of 1.8 g of N ~ [7 ~ j _< 2-t'-butoxycarbonylmethoxy-imino-2'- (S-amino-1,2,4-thiadiazol-3-yl) -acetamido-3-cephem 3 "ylmethyl] pyridinium-4-carboxylate (syn isomer) in 18 ml of formic acid were added 0.5 ml of concentrated hydrogen chloride

- «- 228112 1

The solvent was distilled off under reduced pressure and the residue was triturated with acetone, collected by filtration, washed with acetone and diisopropyl ether to give a powder Dissolved 5 ml of water and subjected to column chromatography on a non-ionic adsorption resin Diaion HP-2O ('trademark for a product of Mitsubishi Chemical Industries) (50 ml). After the column was washed with 500 ml of water, elution was carried out with 40% aqueous methanol. The eluates containing a compound of the invention were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 800 mg of N - [7 - (2-carboxymethylethoxyimino) 2- (5-amino-1,2,4-thiadiazole-3-yl) -acetamido-3-cephem-3-ylmethyl-3-pyridiniun-4 ~ carboxylate (syn isomer) in the form of a white powder, mp 150-155 ° C (dec.).

IR (Nujol): 3350, 3200, 1780, 1680, 1530 cm ^-1 R N, M _e R (D ₉ 0 + NaHC0, S): 3.27 and 3.63 (2H, ABq,

/ L

J = 18Hz), 4.70 (2H, s), 5.30 (IH, d, J = 4Hz), 5.40 and 5.60 (2H, ABq, J = T4Hz), 5.93 (IH, d, J = 4Hz), 8.0-9.1 (5H, m)

Example 11

I O-C-COOH

ι.

~ 96 -

228112 t

To a cold mixture of 22 ml of trifluoroacetic acid and 4.4 ml of anisole was added 3.18 g of N- [7- ^ 2- (i-methyl-1-t-butoxycarbonylethoxyimino) -2 -. (5 'mino-1, _r 2 , 4-thiadiazol-3-yl) acetamido} -3-cephem-S-ylmethyldpyridinium ^ -carboxylate and the mixture was stirred for 40 minutes at room temperature. The mixture was evaporated to remove the trifluoroacetic acid, and the residue was triturated with isopropyl ether to give a yellowish powder. The powder was dissolved in an aqueous bicarbonate solution, adjusted to pH 1 with 6 η hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a nonionic adsorption resin Diaion H20 (140 ml). After the column was washed with water, elution was carried out with 5-tiger and 10-t aqueous isopropyl alcohol. The eluates containing a compound of the invention were collected, evaporated under reduced pressure to remove the isopropyl alcohol, and lyophilized to give 2.20 g of N- [7- {2- (i ~ methyl-1-carboxyethoxyimino) -2 '(5- <Jniino-1 _/ 2 ₇ 4 "thiadiazol-3-yl) acetamido-3-cephem * 3" ylmethyl] "pyridinium-4-carboxylate (syn isomer) in the form of a white powder, F, 176 ~ 180 ° C (Zers,).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm " ¹

N _e MR (DMSO-d ₆ + D ₂ 0, δ): 1.48 (6H, s), 3.10, 3.62 (2H, ABq ₇ J = '8Hz), 5.12 (IH, d , J = 5Hz), 5.45 (2H, m), 5.78 (IH, d, J = 5Hz), 8.13 (2H, m), 8.58 (IH, m), 9.38 ( 2H, m)

22 8112 1

Example 12

The following compounds were prepared in a manner similar to that given in Examples 10 and 1.1:

(1) N- [7 ~ {2- (l-Carboxyäthoxyimino) -2- (5-amino-l, 2,4-thiadiazol-3-yl) acetamidoj-3-cephem-3-ylmethyl3-4 ^l ~ carbamoylpyridinium -4-carboxylate (syn isomer), mp 170 175 ⁰ C (dec.).

IR (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm ^-1

(2) N- [7- ^ 2-0-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetmido-3-cephem-3-ylmethyl-3-pyridinium-4-coreboxylate ( syn isomer), m.p. 175-180 C (Zers.) "IR (Nujol): 3300, 3200, 1775, 1670, 1620,

1520 cm ^-1 NMR (D _o 0 + NaHC0 _ox 6): 1.50 (3H _× d, J = 7 Hz), 3.25 and 3.67 (2H, ABq, J = ISHz) _x 4.40- '"4.90 (IH, m), 5.32 (IH, d _x J = 5Hz), 5.42 and 5.60 (2H _x ABq, J = I 5Hz), 5.83-6.00 ( IH, m), 7,9-9,1 (5H _x m)

(3) N- [7- {2-Carboxymethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamido] -3-ce ρ hem-3-ylmethyl] -4 ^s -carbamoylpyridini um-4-carboxylate (syn isomer), m.p. 175-180 C (Zers *).

IR (Nujol): 3350, 3200, 1775, 168O _x 1615, 1565, 1525 cnT ¹

(4) N-C7- [2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino, 2- _i- 4-thiadiazol-3-yl) acetamido5-3-cephem-3'-ylmethyl] -4 'carbamoylpyridinium ~ 4-carboxylate (syn isomer) _x

F. 180-185 ° C (dec.).

^9S - 2281 12 t

IR '(NuJoI); 3300, 1770, 1680/1620/1560, 1520 cm " ¹

Example 13 .

A mixture of 5.55 g of 7 - [2-trityloxyimino-2- (5'-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (1'-pyridinioniethyl) -3-cepheni "4-Carboxylate (syn isomer) and 2.3 ml of concentrated hydrochloric acid in 60 ml of formic acid was stirred for 2 hours at ambient temperature. After an insoluble material was filtered off, the filtrate was evaporated to dryness and the residue was triturated with acetone and collected by filtration. The powder was dissolved in 13 ml of water and subjected to column chromatography on a nonionic adsorption resin Diaion HP-20 (Trade Mark for a product of Mitsubishi Chemical Industries) (100 ml) using water as eluent. The eluates containing a compound of the invention were collected and lyophilized to give 675 mg of 7-hydroxy-2-hydroxyimino-2- (5'-amino). l, 2,4-thiadiazole "3" -yl) acetamido] "- 3" -pyridiniummethyl) -3-cephem-4-carboxylate (syn isomer) in the form of a yellowish white powder, mp 170-175 ° C (Zers ») IR, (Nujol): 3350, 3200, 1780, 1620, 1530,.

1490 cm ^-1 NMR (DMS 0 ~ d ₆ + D ₂ 0, S): 3.14, 3.54 (2H, ABq, J = 18 Hz), 5.08 (IH, d, J = 5 Hz), 5 ^ 28 / 5.62 (2H, ABq ₇ J = I 2Hz), 5.86 (1H, d, J = 5Hz), 7.96-8.24 (2H, ra), 8.40-8.68 ( IH, m), 9.16 ^ 9.42 (2H, m)

2281 1 2

Example Ij.

HCl

COOH

COOH

To a cold solution of 20.8 g of phosphorus pentachloride in ml of methylene chloride was added 25.4 g of 2- (2-cyclo-5-heten-1-yloxy-imino) -2- (5-amino-1 _/ 2 _/ 4 -thiadiazol-3-yl) acetic acid (syn-isomers) at -18 ° C and the mixture was stirred at 12 to 10 ° C for 40 minutes. 1.2 liters of diisopropyl ether were added to the reaction mixture below -10 ° C. with stirring, then stirring was continued until the mixture had warmed to ambient temperature. The resulting precipitates were collected by filtration / washed with diisopropyl ether and then several minutes On the other hand, a mixture of 30.77 g of 1 - [(7-amino-4-carboxy-3-cephem ~ 3-yl) -lithium] -pyridiniumchlori'dhydrochloride dihydrate and 154 _r 5 g of trimethylsilylacetamide in 800 Methylene chloride heated to 35 C to prepare a solution, which was then cooled to -1.8 G. To the cold solution was added the precipitate prepared above and the mixture was stirred at -12 to -10 C for 30 minutes. It became a solution of 26 g Na. triumbicarbonate in 400 ml of water to the reaction mixture

28112

was added and the aqueous layer was separated, adjusted to pH'1.5 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 4 with an aqueous sodium bicarbonate solution and passed through a column filled with 117 g of acidic alumina. To the eluate (1.2 L) was added 56.2 g of potassium thiocyanate and 171.5 g of sodium chloride, and then the mixture was adjusted to pH 2.6 with 1N hydrochloric acid while cooling in an ice bath. After filtering off an insoluble matter, 171.5 g of sodium chloride were added to the filtrate and the solution was adjusted to pH 1.6 with 1N hydrochloric acid while stirring and cooling in an ice bath. The precipitates were filtered off, washed with twice 150 ml of cold water and dried to give 28.1 g of 1 "[7- | 2 ~ (2-cyclopentene-1-yloxyimino) -2-. (5-W 3 -mino-1,2,4-thia-diazol-3-yl) acetamidoj. "4-carboxy" -3 "cephem" 3-yl] methyl! Pyridinium thiocyanate (syn isomer), F, 151-156 ° C (dec.).

IR (Nujol): 2050, 1780, 1670, 1630, 1610 / r 1530 cm * " ¹

_E N MR (DMS0-d ₆ + D ₂ 0, S): 1.6-2.7 (4H, m), 3.33, 3.66, (2H, ABq, J = I 8 Hz), 5, 20 (IH, d, J = 5Hz), 4.9-6.3 (5H, m), 5.86 (1H, d, J = 5Hz), 8.2 (2H, m), 8.7 ( IH, m), 9,15 (2H,>)

Example 15

1-EC7 "2- (2" cyclopenten-1-yioxyimino) -2 "(5" -amino-1, 2,4-thiadiazol-3 "yl) acetamido-4-carboxy-3-cephem-.3 -yl] methyl] py "ridinium iodide (syn isomer) was prepared in a similar manner as in

22 81 1 2

Example 14 prepared using sodium iodide instead of potassium thiocyanate. I.R. (Nujol): 3400-31DO, 1775, 1670, 1620,

1520 cm * " ¹ N.MoR. (DMS0" d ₆ + D ₂ 0; S): 1,6-2,8 '(4H, m), 3,35,

3.80 (2H, ABq, J = 19Hzj, 5.31 (IH, d, J = 5Hz), 5.93 (IH, d, J = 5Hz), 5.0-6.4 (5H _1m ) , 8.28 (2H, m), 8.74 (IH ₁ -m), 9.15 (2H, m).

Example 16

To einqr solution of 11.7 g of 1 'C [7- ^ 2 ~ (2-cyclopenten "1" ~ yl oxyimino) "2- (5-ainirio-1,2 _J .4-thiadiazol"3'- yl) acetamido-4-carboxy-3-cephem-3-yl! methyl! pyridinium. thiocyanate (syn isomer) in 30 ml of dimethylformamide was added a solution of 1.7 g of lithium chloride in 20 ml of methanol with stirring, then became An insoluble material was filtered off, washed with 6 ml of dimethylformamide, and then the filtrate and washings were combined together, the combined solution was added to 300 ml of acetone with stirring, then stirring was continued for 5 minutes continued at ambient temperature. The precipitates were filtered off, washed with 3 times 40 ml of acetone and dried in vacuo to give 11.0 g of 1 '[[7- {2 ~ (2-cyclopenten-1-yloxyimino) -2] (5-Amino-1,2,4-thiadiazol-3-yl) acetamido} - ^ -carboxy-S-cephem-S-yl-methylpyridinium chloride (syn-isomer) »

-V02- 2281Ί2 1

IR, (Nujol); 3400-3100, 1780, 1660, 1630/1530 cm " ¹

NMR (DMS0-.d _6/5): 1.6-2.6 (4H, m), 3.39, 3, ₇ 61 (2H, ABq, J = 18Hz), 5.19 (IH, d, J = 5Hz), 4.9-5.6 (2H, m), 5.64 (1H, broad s), 5.81 (IH, όά, J = 5 and 8Hz), 5.7-6.2 ( 2H, m), 8.20 (2H, m), 8.64 (IH, m), 9.22 (2H, m), 9.48 (IH, d, J = 8Hz). -

Example 17

To a solution of 10 g of sodium iodide and 1.28 3 pyridine in 8 ml of formamide was added 4.0 g sodium ~ 7-r.2-äthGxyimino-2- (5-amino-1,2,4-thiadiazol-3 ~ yl acetamidocephalosporanate (syn isomer) was added with stirring at 75 ° C, then stirring was continued at 80-85 ° C for 1.5 hours. The mixture was cooled to ambient temperature and poured into 100 ml of ethanol. A resulting precipitate was collected by filtration and a further precipitate was obtained by adding 100 ml of diisopropyl ether to the filtrate. These precipitates were dissolved in 50 ml of water, and the solution was adjusted to pH 3 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a nonionic adsorption resin Diaion HP-20 (trademark for a product of Mitsubishi Chemical Industries) (160 ml). After the column was washed with water, the elutriqn was carried out with 30% aqueous methanol. The eluates containing a compound according to the invention were collected together to remove the methanol under reduced pressure.

- ¹⁰³ - 2281 12 1

evaporated and lyophilized to give 1.52 g of 7 ~ [2-ethoxyimino-2- (5 ~ aniino «1 _/ 2 _/ 4-.thiadiazol-3-yl) acetamido] -3- (i pyridiniummethy.l ) "3 ~ cephem" 4 "carboxylate (syn ^ isomeres) in the form of a white powder, F, 155 - 165 C (Zers.). : IR, (Nujol): 3400-3150, 1770, 1660, "1610, 1530 cm".

Example 18 (Purification of the compound of the invention)

0.2 g of a powder of 7- [2 ~ ethoxyimine Q ~ 2 ~ (5-amino-1,2,4-thiadiazol-3-yl) acetamido 3'-3 '' (1-pyridiniurane {ethyl) 3. cephem-4-carboxylate (syn isomer) were dissolved in 0.8 ml of water and 1.6 ml of acetone was added dropwise with stirring at room temperature. After a few minutes, the stirring was stopped and the solution was allowed to stand for 1.5 hours The colorless needles obtained were filtered off and washed with 2 × 1 ml of 90% aqueous acetone and 3 × 1 ml of acetone and dried under reduced pressure for 9 hours, yielding 120 mg of 7 ~ [2 "ethoxyimino". 2- (5-amino-1, 2,4-thiadiazol-3-yl) acetamidoj-3- (1-pyridiniomethyl) -3 "cephem-4-carboxylate-acetone adduct monohydrate (syn isomer) in the form of colorless needles , * 155 ° C (dec.).

I, R. (Nujol): 3430-3120, 1760, 1700, 1680, 1615,.

1530 cm " ¹ .

NMR (D ₂ O ₇ S): 1/32 (3H, t, J = 7Hz), '2.26 (6H, s), 3.20 and 3.72 (2H, ABq, J = 17Kz), 4 , 37 (2H, q, J = 7Hz), 5.30 (IH, d, J = 5Hz), 5.35 and 5.66. (2H, ABq, J = HH ₂ ), 5.91 (IH, d, J = 5Hz), 8.12 (2H, -tn), 8.61 (IH, m), 8.98 (2H, m ) Analysis for C ^^^^^^^^ ⁰ ^ ^ ⁰

228112

calc .: C 46.72 H 4.81 N 17.34 ^ 0.31 Found: 46.79 4.79 · 16.72 3.24 %

Example 19 (Purification of the compound of the invention)

11.4 g of 2-A ^ hoxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) and 24 g of l - [(7-amino-4-carboxy) 3-cephem-3-yl) methyl] pyridinium chloride hydrochloride dihydrate were reacted together in a manner similar to Example 1. To the reaction mixture was added 300 ml of water, and the mixture was adjusted to pH 1.5 with an aqueous sodium hydroxide solution and subjected to column chromatography on a nonionic adsorption resin Diaion hP-20 (960 ml). After washing the column with 3.6 liters of water, it was eluted with 1.26 liters of aqueous methanol. The eluates were collected and concentrated under reduced pressure to a volume of 110 ml. The solution was subjected to column chromatography on 120 g of acidic alumina and eluted with water. The eluates containing 7 - [2-A'thoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido3-3 (1-pyridiniummethyl) -3-cephem-4-carboxylate ( syn isomer) (310 ml) were collected and 1/11 acetone added with stirring at ambient temperature for 5 minutes. The mixture was stirred under ice-cooling for 1.5 hours, and the precipitates formed were collected by filtration, washed successively with 80 ml of a 90% aqueous acetone solution and 240 ml of acetone, and then dried under reduced pressure to obtain 20 g of crystals of 7- [2-Ethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) a CCtOmIdO ^ S (1-pyridiniummethyl) - "3-cephem-4-carboxylate-acetone adduct ( syn-isomer) The crystals

2281 12-1

were dissolved in 40 ml of water and the solution was passed through a column filled with 40 g of acidic alumina. Elution was performed with water and the eluates (140 ml) were collected. To the solution was added 300 ml of acetone at ambient temperature with stirring, then stirring was stopped within one minute. The mixture was allowed to stand in a refrigerator for 20 minutes at ambient temperature and for 1.5 hours. The colorless needles thus obtained were filtered off / washed with 3 times 25 ml of 90% aqueous acetone and 3 times 25 ml of acetone and dried under reduced pressure for 3.5 hours to give 14.3 g of 7 ~ [2-ethoxy-imino] 2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (pyridiniummethyl) -3-cephem-4-carboxylate acetone adduct (syn isomer) in the form of pure colorless needles, mp > 157 ^° C.

Example 20 (Purification of the compound of the invention)

A solution of 1.0 g of 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido3-3 (i-pyridiniomethyl) -3-cephem "4-carboxylate Acetone adduct (syn isomer) in 1 ml of water was allowed to stand for 5 days in a freezer at -20 ° C. A mixture of ice and precipitates was allowed to stand at ambient temperature until the ice had melted and the resulting precipitates became by filtration, collected, washed with 0.3 ml of water and dried in vacuo to give 0.52 g of 7- [2-ethyl} imino-2- (5 "-amino-1,2,4-thiadiazole-3 -yl) acetamido] -3 ~ (i-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer) in the form of colorless needles, m.p. 165-17O ⁰ C (Zers.) «

I.R. (Nu j oil): 3450-3200, 3070, 1765, 1665, 1630,

160O ₇ 153O ₇ 1485 em * ¹

NMR (D ₂ O, 6): 1.32 (3H ₇ t, J = 7Hz), - 3,2Ö and 3,72 (2H ₇ ABq, J = 7Hz) ₇ 4,33 (2H, q, J = 7Hz) ₇ 5 ₇ 27 (IH _{7 7} d J = 5Hz), 5.34 and 5 ₇ 65 (2H ABq _{7 7} 'J = HHZ) ₇ 5.89 (IH ₇ d, J = 5Hz), 8.10 (2H, m),

8.60 (IH ₇ m) ₇ 8 ₇ 97 (2H ₇ m)

Example 21 (Purification of the compound of the invention)

To a solution of 40 g of 7 ~ [2-ethoxyimino-2- (5-amino-1, 2,4-thiadiazol-3-yl) ocetamido] 3 (1-pyridiniomethyl) -3-cephem «4 ~ carboxylate-acetone adduct ± (syn isomer) in 50 ml of water was a small amount of colorless _r needles of 7 ~ [2 ~ Ä * thoxyimino-2- (5-amino-1 _/ 2 ₇ 4-thiadiazol-3-yl). acetamidoIl'-3 '' (i-pyridiniomethyl) '' - '' cephem-4-carboxylate (syn isomer) was added, and the mixture was stirred in an ice bath for 1 hour, and the resulting precipitates were collected by filtration. washed with 33 ml of cold water and dried in vacuo for 10 hours, to give 24.7 g of 7 "[2-Xthoxyimino" 2- (5-amino <-l ₇ 2 ₇ 4-thiadiazol-3-yl) acetamido3-3 "(1-pyridiniomethyl) -3-cephem-4-carboxylate dihydrate (syn ^ isomer) in the form of colorless needles, mp 170 ~ 175 ° C (dec.).

Water content (K.F. method) exceeds 6.72 %

, found: 6.20 %

Example 22 (Purification of the compound of the invention)

7.7 g of a powder of 7-E2-Methoxyimino-2 "(5 <-amino« l _/ 2 ₇ 4-thiddiazol "3-'yl) acetamidoIi cephen-3- (l-pyridiniometSiiyl) -3!" -

228112

4-Carboxylate (syn isomer) was dissolved in 15.4 ml of water and the solution was left standing in a refrigerator for over 10 minutes. The precipitated precipitates were filtered off and washed successively with 5 ml of 80% isopropyl alcohol and 5 ml of isopropyl alcohol, dried in air for 1 hour and then dried in vacuo for 2 hours to give 4.2 g of colorless needles of 7- [2~ Methoxyi ^: mino ~ 2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (i-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), F, 165 "C (Zers.). IR (Nuj oil): 3300/3200, 1765, 167O ₇ 1630/1605,

1550-1520 cm ^-1. , NMR (D ₂ O ₁ S): 3.24, 3.70 (2H, ABq, J = 18 Hz).

4.06 (3H, s), 5.28 (IH, d, J = 5Hz), 5.36, 5.60 (2H, ABq, J = HHz), 5.87 (IH, d, J = 5Hz ) / 8.06 (2H ₇ m), 8.54 (IH, m), 8.95 (2H, m)

Claims (2)

fe »W. i burn invention claim Process for the preparation of cephemes = compounds of the general formula: in which mean: R is an amino or protected amino group; R is hydrogen, lower alkyl which may be substituted by one or more suitable substituents, lower alkenyl, lower alkynyl, cyclo (lower) alkyl, cyclo- (lower) alkenyl, or an O-containing 5-membered heterocyclic group represented by one or more Substituted oxo groups; R is a group of the formula ~ ^ wherein X represents hydrogen or carbamoyl; and R-COO; or 4
azinylthio and R carboxy or protected carboxy, ~ 109 - or the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a) a compound of the general formula (Π) wherein R and R are each as defined above, or their reactive derivative at the amino group or a salt thereof with a compound of the general formula : -cooh · "' I du) ; ° - ^r2 , ι. , , wherein R and R are each as defined above, or their reactive derivative is reacted on the carboxy group or a salt thereof, or that b) a compound of the general formula (XIII) 1 2 wherein R and R are each as defined above, R ^{a represents} a group represented by a group of the formula 3 3 R may be substituted, wherein R has the meanings given above, and R is carboxy, when R is a compound of formula where X is as defined above, Ao ' or R is carboxy or protected carboxy, when R is a compound of the formula R "H, wherein R 2-lower alkyl "5-oxo-6-hydroxy-2 _(r 5" dihydro-1 _{f represents} 2,4-triazinyl-thio,. or a salt thereof with a compound of the general formula R, wherein R has the meanings given above, or its reactive derivative is reacted. 2. The method of item 1 for the preparation of a compound of the general formula. in which mean: R is an amino or protected amino group; R is a group of the formula - wherein X represents hydrogen or carbamoyl; and 4 - '·. . ' : -. ' R ~ C00; or ' R. 2 ~ lower alkyl ~ 5 ^ oxo ~ 6 ~ hydroxy ~ 2 _i 5 «dihydro-V _/ 2 _J 4 <- tri ** 4
azinylthio and R carboxy or protected carboxy, or the salts, in particular the pharmaceutically acceptable Salts thereof / -. ' " characterized in that a compound of general formula (Id) wherein R, R and R are each as defined above .2c and R represents a hydroxy-protecting group or a salt thereof is subjected to an elimination reaction to remove the hydroxy-protecting group _o '. ·