DE2223375A1 - Antibiotics and their method of manufacture - Google Patents

Description

GLAXO LABORATORIES LIMITED, Greenford, Middlexes, England

Antibiotics and their method of manufacture

The invention relates to antibiotics of the cephalosporin series.

The cephalosporin compounds described in this application are generally named with reference to Cepham (j.Amer.Chem.Soc. 1962, 84 3400). Of the The term "cephem" means the cepham backbone with a double bond.

It is well known that cephalosporin series antibiotics use 7β-acylamido-ceph-3-em-4-carboxylic acids and their various non-toxic derivatives, for example the salts, esters, lactones (if such can be formed), the amides, Hydrates or the corresponding sulfoxides. These antibiotics can have various substituents, especially in the 3-position such as unsubstituted methyl and methyl groups substituted by a variety of substituents are included, Such compounds are in the

2G984 & / 113S

Literature described.

The new compounds according to the invention are characterized in that that the acylamido group of the cephalosporin antibiotic is an (α-etherified oximino) acylamido group where the compounds are syn isomers or mixtures thereof, the syn isomeric form predominating.

The invention relates to 7β-acylamidoceph-3-em-4-carboxylic acids (and their non-toxic derivatives), which are characterized in that the acylamido group is the structure

R.C.CONH-

Il

^N \ a 0R ^a

has, wherein R is a hydrogen atom or an organic
Which is connected to the oxygen atom via a carbon atom group and R ^a is a monovalent organic group etherified, mean, wherein the compound is a syn isomer or is present as a mixture containing at least 75% of syn-isomer. The isomer mixture preferably contains at least 90% of the syn isomer and not more than 10% of the
anti isomers.

The compounds of the invention are named as if
they have the syn (cis) isomeric form, indicating the configuration of the
Group 0R ^a relates, based on the carboxamido group. In the present application, the cis configuration is drawn structurally as follows

R.C.CO.NH-

! I

N \

0R ^a

209848/119

and the anti configuration as follows

R.C.CO.NH-N

rV

These configurations were assigned on the basis of the work of Ahmad and Spencer (Can. J. Chem., I96I, £ 3, 1340),

The compounds of the invention can be represented by the formula

RCCO.NH
11

OR

(D

COOH

are described, wherein R and R have the meanings given above, B ^ S or ^ S - £ 0 and Z means a group in which 2 carbon atoms connect the core sulfur atom and the carbon atom which carries the carboxylic acid group, and the & -unsaturation having.

The term "non-toxic" as used for the derivatives according to the invention means those derivatives which are physiologically acceptable at the doses in which they are administered.

Salts which, when useful, can be prepared from the compounds of the invention include (a) Salts of inorganic bases such as of alkali metal, for example sodium and potassium, alkaline earth metal, for example Calcium, and organic bases, for example

209848/1 196

Procaine, phenylethylbenzylamine and dibenzylethylenediamine, salts and (b) acid addition salts, for example with hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form the resinate are present, made for example with a polystyrene resin, the amino, quaternary amino or Contains sulfonic acid groups, or with a resin that Contains carboxyl groups, for example a polyacrylic acid resin. If desired, the resin can be crosslinked, for example, it can be a copolymer of styrene and divinylbenzene which contains the appropriate groups. The derivatives can also be in the form of chelates with heavy metals such as iron or copper.

The compounds according to the invention, including their non-toxic derivatives, are highly antibacterial due to their high level of antibacterial properties Characterized activity against a range of gram-positive and gram-negative organisms, coupled with especially high stability against ß-lactamases, which are produced by various gram-negative organisms.

The stability to β-lactamases can be determined by comparing with cephaloridin, which one is any Value of 1, based on the particular organism, assigns.

The properties of the compounds according to the invention have the effect that they are useful in the treatment of a large number of diseases, caused by pathogenic bacteria in humans and animals are useful.

Preferred cephalosporin compounds according to the invention are compounds of the general formula

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R.C.CONH

(ID

COOH

wherein R, R ^a and B are as defined above and P is an organic group, and their non-toxic derivatives. In the formula (II), B is preferred

The invention also relates to cephalosporin compounds, which are not specifically encompassed by formula (II), for example 2-methyl- and 2-methylencephalosporins.

The. Group R ^a in the above formula can be any group having a carbon atom with a free valence so that the desired ether group can be formed with the adjacent oxygen atom. The group R ^a preferably contains no more than 16 carbon atoms.

R ^a can mean, for example, an alkyl group: with 1 to 16 carbon atoms, preferably a lower alkyl group with 1 to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec. -Butyl, tert-butyl, octyl or dodecyl group; an alkenyl group having 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, for example a vinyl, allyl, isopropenyl or dimethylallyl group; an alkynyl group having 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, for example a propynyl group such as a propargyl group; a cycloalkyl group having 3 to 4 carbon atoms, for example a cyclopropyl, cyclopentyl or cyclohexyl group; a cycloalkenyl group with

209848/1196

4 to 7 carbon atoms, for example a cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl group; a carboxylic aryl group such as a phenyl or naphthyl group _; ; a heterocyclic group, especially one with a 5- or 6-membered heterocyclic ring which contains at least one heteroatom such as oxygen, nitrogen and sulfur, for example a pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, thiadiazolyl, diazolyl -, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl or Puriny! Group; or a carbocyclic or heterocyclic aryl-lower alkyl group in which the lower alkyl part contains 1 to 4 carbon atoms, for example benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl such as thien-2-ylmethyl, furylmethyl such as one Furfuryl, pyridylmethyl or pyrrolylmethyl group.

In general, R ^a can be unsubstituted or contain one or more substituents, such as, for example, hydroxy; Alkoxy, for example methoxy, ethoxy, n-propoxy or isopropoxy such as in methoxymethyl or 1-ethoxyethyl; Aryloxy, e.g. phenoxy; Aralkoxy, e.g. benzyloxy; Mercapto; Alkylthio, for example methylthio or ethylthio; Arylthio; Aralkylthio; Amino such as in 2-aminoethyl; substituted amino, for example methylamines, ethylamino or dimethylamino; Halogen, for example chlorine or bromine such as in 2-bromoethyl; Nitro; Azido; Carboxy; esterified carboxy, for example lower alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl or benzyloxycarbonyl; Formyl; Acyl, for example acetyl, propionyl or benzoyl; Acyloxy, for example acetoxy, propionyloxy or pivaloyloxy; Cyano; Phthalimido; Acylamido, for example acetamido or benzamido; Alkoxycarbonylamino, for example methoxycarbonylamino or ethoxycarbonylamino; or aralkoxycarbonylamino, for example benzyloxycarbonylamino.

209848/1196

The group R in the above formulas can be selected from the following list; which is in no way exhaustive:

(i) hydrogen

(ii) R ^u _f where R ^{u is} aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or a non-aromatic or mesoionic group. Examples of this group include phenyl; Naphthyl, for example naphth-1-yl; Phenyl or naphthyl, substituted by halogen, for example chlorine or bromine as in o-chlorophenyl, hydroxy, lower-alkyl, for example methyl, nitro, amino, lower-alkylamino, for example methylamino, di-lower-alkylamino, for example dimethylamine, lower-alkanoyl , for example acetyl, lower-alkanoylamido, lower-alkoxy, for example methoxy or ethoxy, or lower-alkyl thio, for example methylthio; a 5- or 6-membered heterocyclic group which contains at least one heteroatom such as S, 'N and 0, for example thien-2-yl, thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3- yl, pyrrolyl, N-substituted pyrrolyl, for example N-methylpyrrolyl, isothiazolyl, thiadiazolyl, oxydiazolyl, 3- or 4-isoxazolyl; substituted 3- or 4-isoxazolyl, for example 3-aryl-5-methylisoxazol-4-yl, where the aryl group is for example a phenyl or halophenyl group; condensed heterocyclic groups which contain at least one heteroatom such as S, N and O, for example benzothienyl such as benzothien-3-yl, benzofuryl, indolyl; Cyclohexyl, cyclopentyl, sydnone; and cyclohexadienyl.

(iii) R ^u (CH ₂ ) _m Q _n (CH ₂ ), where R ^{u has} the definition given above and m 0 or an integer from 1 to 4, η 0 or 1, ρ an integer from 1 to 4 and Q is S, 0 or NR, where R is hydrogen or an organic group, for example an alkyl group such as a methyl or aryl group such as phenyl. Examples of these groups include

209848/1136

Methyl, ethyl or butyl, substituted by the various specific R ^u groups which were specified under (ii), for example benzyl and the correspondingly substituted benzyl groups.

(iv) C _n H _{2n + 1} , where η is an integer from 1 to 7. The group can be straight-chain or branched and, if desired, be interrupted by an oxygen or a sulfur atom or the group NR, where R is a hydrogen atom or an organic group, for example an alkyl group such as a methyl or aryl group such as phenyl or by a cyano, Carboxy, alkoxycarbonyl, hydroxy or carboxycarbonyl (HOOCCO,) group or be substituted by a halogen atom. Examples of such groups include hexyl, heptyl, butylthiomethyl, cyanomethyl or trihalomethyl.

(v) CH, where η is an integer from 2 to 7. The group can be straight-chain or branched and, if desired, through an oxygen or sulfur atom or be interrupted by the group NR, wherein R is a hydrogen or an organic group, for example a Alkyl group such as methyl or aryl group such as phenyl group means. An example of such a group is vinyl or propenyl.

(vi) CH. ,, where η represents an integer from 2 to 7. An example of such a group is ethynyl.

(vii) Various carbon-bonded organic groups including cyano, amido and lower alkoxycarbonyl .

The substituent P in the 3-position of the above compounds of Formula II can be an organic group. The feature of the invention is the nature of the 7-substituent. P can thus

209848/1 1 96

a saturated or unsaturated substituted or unsubstituted one be an organic group containing 1 to 20 carbon atoms. Preferred saturated organic Groups include methyl and ethyl. Preferred unsaturated organic groups include vinyl and substituted vinyl groups the formula

-CH = C

"= 5 4
wherein R and R, which can be the same or different, each hydrogen or a substituted or unsubstituted aliphatic group, for example alkyl, preferably C ₁ - to Cg-alkyl such as methyl, ethyl, isopropyl, n-propyl etc., Cc- to Cy cycloaliphatic (e.g. cyclopentyl or cyclohexyl), C ₇ - to CQ-araliphatic (for example benzyl or phenylethyl), Cg-C ₁ p ^"arom atic (for example, phenyl or nitrophenyl) group, nitrile or alkoxycarbonyl low mean.

When P is a substituted methyl group it can be represented by the formula

-CH ₂ Y

are represented, wherein Y represents an atom or a group, for example the remainder of a nucleophile or the derivative of a residue of a nucleophile. For example, Y can be from a wide variety of nucleophilic species Derive compounds which are characterized in that they are a nucleophilic nitrogen, carbon, sulfur or Contain oxygen atom. Such groups are in previous patents and publications dealing with deal with cephalosporin chemistry. Examples of such nucleophiles include:

209848/1196

Nitrogen nucleophiles

Examples of nitrogen nucleophiles include tertiary, aliphatic, aromatic, araliphatic ^ and cyclic amines including the trialkylamines, for example Triethylamine, pyridine bases such as pyridine and alkyl pyridines, heterocyclic amines that have more than one heteroatom, where at least one heteroatom is nitrogen such as pyrimidines, purines, pyridazines, pyrazines, pyrazoles, Imidazoles, triazoles and thiazoles.

A preferred class of nitrogen nucleophiles are compounds of the formula

where η represents 0 or an integer from 1 to 5 and R, which, when η represents 2 to 5, can be the same or different, represents an aliphatic group, for example lower-alkyl such as methyl, ethyl, n-propyl, isopropyl, etc. ., an aryl group, for example phenyl, an araliphatic group, for example phenyl-lower alkyl such as benzyl, phenethyl, etc., or an alkoxymethyl group, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, etc., or an acyloxymethyl group, for example alkanoyloxymethyl such as acetoxymethyl , a formyl, carbamoyl, acyloxy, for example alkanoyloxy group such as an acetoxy group, an esterified carboxyl group, an alkoxy, for example methoxy, ethoxy _r , n-propoxy, isopropoxy group, etc., an aryloxy, for example a phenoxy group, a Aralkoxy, for example a benzyloxy group, an alkylthio, for example a methylthio, ethylthio, arylthio, aralkylthio group, a cyano group, a hydro xy group, an N-mono-lower-alkylcarbamoyl group, for example an N-methylcarbamoyl, N-ethylcarbamoyl, etc. group, a Ν, Ν-di-lower-alkylcarbamoyl group, for example a

209848/1 13C

Ν, Ν-dimethylcarbamoyl, NjN-diethylcarbamoyl, etc. group, N- (hydroxy-lower alkyl) -carbamoyl-, for example a N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl group etc. or a carbamoyl lower alkyl, for example Carbamoylmethyl, carbamoylethyl, etc.

Another preferred class of nitrogen nucleophiles are azides, for example alkali metal azides such as sodium azide.

When the group Y is a derivative of a residue of a nucleophile it can be an amino group or an acylamido group. Compounds in which Y is an amino group, can be derived from the corresponding azides by reduction, for example by catalytic hydrogenation of the azide using noble metal catalysts such as palladium or platinum.

The amino group can be acylated, with a corresponding 3-acylaminomethyl compound is formed. The formation of such Compounds can be achieved, for example, by any method that is suitable for the acylation of Aminocephalosporin compounds is suitable, for example by reacting the 3-arainomethyl compound with an acid chloride, Acid anhydride or a mixed anhydride or an acid containing the desired acyl group and another Acid corresponds.

The 3-aminomethyl compounds can also with a substituted isocyanate or isothiocyanate are reacted, urea or thiourea derivatives being obtained.

Other compounds in which Y is a derivative of a residue or residue of a nucleophile can can be obtained by using 3-azidomethyl compounds converts a dipolarophilic compound. Preferred classes

209848/1 136

of dipolarophilic compounds include acetylene! see, Ethylenic and cyano-dipolarophilic compounds.

Acetylenic dipolarophilic compounds can have the following structure

R ¹ .CC.R ²

1 2

are represented in which R and R, which may be the same or different, represent atoms or groups.

In general, it is preferred that R and preferably

2
R also have an electronegative character. Examples of such groups include cyano, COpR, COR (where R is, for example, lower alkyl, aryl or lower aralkyl) and trihalomethyl, e.g. trifluoromethyl.

1 2

However, R, and preferably also R, can be electropositive

Be groups, for example alkoxy or alkylamino groups.

1 2

R and R can be taken together with the acetylenic group form a ring system, for example in an aryne.

1 2

If R and R are discrete atoms or groups that are identical, a single compound is obtained in the Implementation with the azidocephalosporin. If they are different, a mixture is generally obtained of positional isomers.

Ethylenic dipolarophilic compounds can be given by the following formula

. R ⁵ R ⁷

C = C
R ⁶ ' ^X R ⁸

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are represented in which R, R, R and R, which can be identical or different, mean atoms or radicals. Although R? _t R, R 'and R can all be hydrogen,

ethylene per se reacts like acetylene with the azido

5 7
groups slowly. R and R together can form a cyclic structure, for example a carbocyclic structure, with the ethylene group, so that the double bond is stretched or strained. Examples of ethylenic dipolarophilic compounds which contain strained double bonds are norbornenes, trans-cycloalkenes and acenaphthalene.

Other ethylenic dipolarophilic compounds that can be used include compounds of the formula R .R .C = CR .R, in which at least one of the radicals R, R,

7 8 5

R and R represent an electronegative group. R and R 'can thus optionally be identical electronegative groups and R and R can represent other groups, R and R can thus form a ring system. Examples of such dipolarophilic compounds include benzoquinone and nucleus substituted benzoquinones and maleimide (maleimide). Again, all of the radicals R ^, R, R 'and R ^{8 can be the} same electronegative groups. Electronegative groups that can be used include those given above under the acetylene! See dipolarophilic group section and examples of such compounds thus include dicyanoethylene and lower mono- and dialkoxycarbonylethylene.

One or more of R, R, R ', and R4 may be desired enfall be electropositive.

Cyano compounds, especially those produced by electronegative Groups activated can be called cyanodipolarophilic compounds. Examples of such dipolarophilic compounds include lower alkoxycarbonyl cyanides and dicyan.

209848/1136

Carbon nucleophiles

Examples of carbon nucleophiles include inorganic cyanides, pyrroles and substituted pyrroles, for example Indoles and compounds that give stabilized carbanions, such as acetylenes and compounds that contain ß-diketone groups, for example acetoacetic acid and malonic acid esters and cyclohexane-1,3-diones or enamines, ynamines or enols.

The carbon nucleophiles can cephalosporin compounds as shown which are characterized in that they contain a substituent in the 3-position, in which a carbonyl group is connected via two carbon atoms to the cephalosporin nucleus is ₀ Such compounds have the 3-substituent is a group of formula

-CH ₉ . CCO. R ⁴

* - ι

2 3
where R and R, which may be the same or different, are hydrogen, cyano, lower-alkyl, for example methyl or ethyl, phenyl, substituted phenyl, for example halogen, lower-alkyl, lower-alkoxy, nitro, amino or lower-alkylaminophenyl , lower-alkoxycarbonyl, mono- or diaryl-lower-alkoxycarbonyl, lower-alkylcarbonyl, aryl-lower-alkyl or C ₁ - or Cg-cycloalkyl and R denotes hydrogen, lower-alkyl, for example methyl or ethyl, phenyl, substituted phenyl , for example halogen, lower-alkyl, lower-alkoxy, nitro, amino or lower-alkylaminophenyl, aryl-lower-alkyl or C1- or C1- cycloalkyl.

Sulfur nucleophiles

Examples of "sulfur nucleophiles" include thiourea and aliphatic, aromatic, araliphatic, alicyclic

209848/1 1 96

and heterocyclic substituted thioureas, dithiocarbamates, aromatic, aliphatic and cyclic thioamides, for example thioacetamide and thiosemicarbazide, Thiosulfates, thiols, thiophenols, thio acids, for example thiobenzoic acid or thiopicolinic acid and dithio acids.

A preferred class of "sulfur nucleophiles" comprises Compounds of the formula R .S (O) H, in which R is an aliphatic group, for example a lower alkyl such as a Methyl, ethyl, n-propyl, etc., an alicyclic group Group such as a cyclohexyl, cyclopentyl group, etc., an aromatic group such as a phenyl, naphthyl group etc., represents an araliphatic group such as a benzyl group or a heterocyclic group and η means 0, 1 or 2. A particularly preferred class of nucleophiles falling under the above formula are those of the general formula R SH, where R is an aliphatic group, for example a lower alkyl, for example a methyl, ethyl, n-propyl group, etc., an araliphatic group, for example a phenyl-lower alkyl, for example benzyl, phenylethyl, etc., or a substituted phenyl-lower alkyl group, an alicyclic group, for example a cycloalkyl, for example a cyclopentyl or cyclohexyl group, an aromatic, for example a phenyl or substituted phenyl group or a 5- or 6-membered group heterocyclic group with at least one 0-j-, N- and S atom, for example thiadiazolyl, in particular 5-methyl-1,3,4-thiadiazol-2-yl, diazolyl, triazoly}., Tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl and pyrimidyl, or a substituted one means heterocyclic group including those groups substituted by divalent groups and where condensed ring systems are formed, for example benzimidazolyl, benzoxazolyl, triazolopyridyl and Purinyl.

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Oxygen nucleophiles

Examples of oxygen nucleophiles include water, Alcohols, for example alkanols such as methanol, ethanol, propanol and butanol, and lower alkane carboxylic and alkene carboxylic acids.

The term "oxygen nucleophile" thus includes compounds the following formula

R ¹ OH

wherein the group R can be: lower-alkyl (for example Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.), lower alkenyl (e.g. allyl), lower alkynyl (e.g. propynyl etc.), lower cycloalkyl (e.g. Cyclopropyl, cyclopentyl, cyclohexyl etc.) »lower-cycloalkyl-lower-alkyl (for example cyclopropylmethyl, Cyclopentylmethyl, cyclohexylethyl, etc.), aryl (for example phenyl or naphthyl), aryl-lower alkyl (e.g. benzyl), a heterocyclic group, heterocyclic lower alkyl (e.g. furfuryl), or one of the groups mentioned is substituted, for example with one or more lower alkoxy (methoxy, ethoxy, etc.), lower alkylthio (methylthio, ethylthio, etc.) groups, Halogen (chlorine, bromine, iodine or fluorine), lower alkyl (methyl, ethyl etc.), nitro, hydroxy, acyloxy, carboxy, Carbalkoxy, lower alkylcarbonyl, lower alkylsulfonyl} lower-alkoxy sulfonyl) amino-, lower-alkylamino- or acylamino groups.

In the case where water is the nucleophile, 3-hydroxymethylcephalosporin compounds are obtained.

Such compounds have the formula:

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CH ₂ OH (A)

COOH

wherein R and R ^{a are} the definitions given above. Compounds of the formula (A) and their non-toxic derivatives have antibacterial activity and it should be noted that they can be metabolites of compounds of the general formula II in which B _> S and P denote acetoxymethyl. Compounds of the formula (A) can be acylated to give derivatives which are characterized in that they represent the group

Q 1Ω

3-CH ₉ .0.CO.R ^ or 3-CH ₉ .0.CO.AR where A

Q
0, S or NH, R a methyl or an organic group

10 with an atomic weight sum of at least 16 and R

q
Signify hydrogen or R.

Q 10

The group R ¹⁷ CO- or R A.CO- can be selected from the wide variety of such groups which are described in the literature and which contain up to 20 carbon

contain atoms. The group R can thus be a hydrocarbon group or a group containing one or more substituents such as atoms or groups. The group R ^y can be selected from the following list, which is not exhaustive.

(i) ^c _n ^H 2n + 1 * ^{where n is an} integer from 1 to 7, for example 2 to 4. The group can be straight-chain or branched and, if desired, it can be interrupted by an oxygen or sulfur atom or an imino group or substituted by cyano, carboxy, alkoxycarbonyl, hydroxy, carboxycarbonyl (HOOCCO.), Halogen, for example chlorine, bromine or iodine, or amino . Examples

209848/1136

of such groups include ethyl, propyl, isopropyl, η-butyl, tert-butyl, sec-butyl and 2-chloroethyl.

(ii) C H2 _n _-i> where η is an integer from 2 to 7. The group can be straight-chain or branched and, if desired, be interrupted by an oxygen or sulfur atom or an imino group. An example of such a group is vinyl or propenyl.

(iii) R ^v where R ^{v is} an aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl and substituted cycloalkyl group. Examples of this group include phenyl, substituted phenyl, e.g. hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl; Thien-2- and -3-yl; Pyridylj cyclohexyl; Cyclopentyl; Cyclopropyl; Sydnon; Naphthyl; substituted naphthyl, for example 2-ethoxynaphthyl.

(iv) R ^v (CHp) t in which R ^{v has} the meaning given in (iii) above and m represents an integer from 1 to 4. Examples of these groups include methyl, ethyl or butyl substituted by the various specific R ^v groups indicated under (iii), for example benzyl and the correspondingly substituted benzyl groups.

An important class of cephalosporin compounds are those which have the group 3-CHpHaI, where Hai is chlorine, bromine or Means iodine. Such compounds can mainly be of value as intermediates for the preparation of active cephalosporin compounds own.

Important antibiotic compounds of the present invention because of their generally broad spectrum of antibiotic ones Properties including activity against strains

209848/1 1 0 (5

of Haemophilus influenzae associated with stability against β-lactamases produced by a variety of Gram-negative organisms are compounds the general formula

.C.CO.NH
N X N / J CH ₀ Y (B)

COOH

and their non-toxic derivatives. In formula (B), R ^u denote phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl or pyridyl or any of these groups substituted by halogen (chlorine, bromine, iodine or fluorine), hydroxy, lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkanoyl, lower-alkanoylamido, lower-alkoxy, lower-alkylthio or carbamoyl, R-lower-alkyl, cycloalkyl (C, 7) or aryl (carbocyclic or heterocyclic) -lower-alkyl or any of these groups substituted by hydroxy, carboxy, esterified carboxy, amido, cyano, alkanoyl, amino, substituted amino, halogen or lower alkoxy, and the group Y is selected from

a) acetoxy,

b) the remainder of a nitrogen nucleophile of the formula

where R and η have the definitions given above. In this case the group in the 4-position of the compound of formula (B) will be present as -CO ₂ ".

209848/1 196

c) The group -SW, in which W is thiadiazolyl, preferably 5-methyl-1,3,4-thiadiazol-2-yl, diazolyl, triazolyl, Tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridyl, Means purinyl, pyridyl or pyrimidyl.

d) lower (C ₁ -C ₄ ) alkylthio.

e) The group -O.CO.R ^, wherein R ^ is C ₂ -C ₄ -AlCyI or C ₂ -C, -alkenyl.

f) The group -O.CO.NH. (CH ₂ ) _m D, in which m is an integer from 1 to 4 and D is chlorine, bromine, iodine or fluorine, and

g) azido.

Particularly important compounds of the general formula (B) are because of their broad spectrum of antibiotic properties including high activity against strains of 'Pseudomonas pyoeyanea those of the formula

CH ₀ .O.CO.CH, (C)

i. Λ · V / * ^^ _m ^, μ. Λ. Q im -J

COOH

where R ^{x is} phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl and R ^{c is} CpC ^ -alkyl, benzyl, phenethyl, thienylmethyl or furylmethyl and their non-toxic derivatives.

Important compounds falling under the general formula (C) include the following compounds within theirs syn isomeric form:

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3-acetoxymethyl-7ß- (2-ethoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid, 3-acetoxymethyl ~ 7β- [2-tert-butoxyimino-2- (2-thienyl) acetamido ] -ceph-3-em-4-carboxylic acid, 3-acetoxymethyl-7ß- [2- (2-thienyl) -methoxyimino-2- (2-thienyl) acetamido] -ceph-3-em-4-carboxylic acid, 3-acetoxymethyl-7β- [2-tert-butoxyimino-2- (2-furyl) acetamido ] -ceph-3-eni-4-carboxylic acid, 3-acetoxymethyl-7ß- [2-benzyloxyimino-2- (2-thienyl) -acetamido] -ceph-3-em-4-carboxylic acid, 3-acetoxymethyl-7β- [2-tert-butoxyimino-2- (1-naphthyl) acetamido ] -ceph-3-em-4-carboxylic acid, and 3-acetoxymethyl-7ß- [2-n-butoxyimino-2- (2-thienyl) -acetamido] -ceph-3-em-4-carboxylic acid, especially in the form of their sodium or potassium salts.

An important group of compounds falling under the general formula (B) are because of their broad spectrum the antibiotic properties including high activity against strains of Haemophilus influenzae compounds the general formula

(D)

COOH

χ b
wherein R and R are as defined above and T is acetoxy, azido and the remainder of a nitrogen nucleophile of the formula

209848/1196

mean, in which R and η are the definitions given above

Q Q

own or the group -O.CO.R, wherein R ₂ C -C.-alkyl, C ₂ -C, alkenyl or phenyl and their

non-toxic derivatives.

Another important group of compounds of the general formula (B) is, because of their broad spectrum, the antibiotic Properties coupled with substantial absorption when administered orally, as demonstrated by animal studies has been shown compounds of the general formula

R .C.CO.NH

■ V ο

where R ^x and R

COOH

(E)

have the definitions given above and V is lower- (C. -C _Zf ) alkylthio, C 1 _{-C 4 -alkanoyloxy or CC 2} , -alkenoyloxy and their non-toxic derivatives. "

Another important group of compounds that fall under the general formula (B) and which compared to a A large number of gram-positive and gram-negative organisms have a high degree of activity, combined with a high level of activity Stability to ß-lactamases produced by a variety of organisms are general formula

CH ₂ OCOCH ₃

(F)

COOH

wherein R has the definition given above for formula (C), and their non-toxic derivatives. A particularly important one

209848/1196

Compound of formula (F) is 3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer), especially in the form of the sodium or potassium salt.

Manufacturing

The compounds of the invention can be prepared by any suitable method.

The invention also relates to a process for the preparation of a compound of the formula

RCCO.NH- • ι

(D

COOH

wherein R is a hydrogen atom or an organic group, R ^{a is} an etherified monovalent organic group which is connected to the oxygen atom via a carbon atom,

B ^ S or ^ S 0 and Z represent a group in which

2 carbon atoms, the core sulfur atom and the carbon atom bearing the carboxylic acid group, combines, and contains the £ -Unsättigung, and derivatives thereof. The inventive method is characterized in that either

(A) a compound of the formula

H ₂ N

III

—N 0

2098Λ8 / 1196

wherein B and Z have the definitions given above and

R denotes hydrogen or a carboxyl protective group,

with an acylating agent, preferably the syn isomer, according to the acid

R. C. COOH

¹¹ IV

wherein R and R ^{a have} the definitions given above, or with an acylating agent corresponding to an acid which is a precursor for the acid IV, or

(B) a compound of the formula

B O = C = N

COOR ¹⁰

10
where B, Z and R have the definitions given above,

10 with the exception that R is not hydrogen,

with an acid or a precursor of the formula IV, or

(C) where Z is the group

represents wherein Y is the residue of a nucleophile or a derivative of the residue of a nucleophile and which dashed line connecting the 2, 3 and 4 positions,

209848/1196

indicates that the compound is a Ceph-2-em or Ceph-3-em compound can be with a compound of the formula

Acyl NH

> J? ₂ ¹ VI COOR ¹⁰

R.C.CO-where acyl is the group »· or a precursor

a 10 for it, and where B, R, R and the dashed lines have the meanings given above and Y is a is a substitutable or replaceable residue of a nucleophile, reacted with a nucleophile, after which in each In the event that it is necessary or desired, any of the following reactions (D) are carried out:

(i) Conversion of a precursor for the R.C.CO group,

0R ^a

in the desired group,

(ii) Conversion of an A -isomer into the desired 4 -isomer,

(iii) removal of a carboxyl protecting group,

(iv) reduction of a compound wherein Z ) is S - ^ 0 to give the desired Z = \. To get S-connection,

(v) reduction of a compound wherein Y is an azide and wherein the 3-aminomethyl compound is obtained, and if desired Acylation of the amino group formed, the corresponding 3-acylaminomethyl compound being obtained,

(vi) reacting a compound in which Y is an azide with a dipolarophilic compound, whereby a compound

209848/1 196

is formed which contains a polyazole ring linked to the 3-methylene group,

(vii) deacylating a compound in which Y represents an acyloxy group and wherein a 3-hydroxymethyl group is obtained, and

(viii) acylation of a compound in which Y is a hydroxyl group, being a 3-acyloxymethyl or 3-carbamoyloxymethyl compound is obtained, and

(E) Obtaining the desired compound of the formula (I), if necessary after separating off the isomers.

The salts of the compounds according to the invention can be obtained in any convenient and suitable route. For example Salts with bases can be obtained by treating the cephalosporic acid with sodium or potassium 2-ethylhexanoate implements.

In practice it is useful to use an acylating agent that is acid

R.C.COOH

Il

. N

corresponds, in which R and R ^{a have} the definitions given above, with an amino compound of the formula

III

COOR ¹⁰

209848/1196

where Z and B have the definitions given above,

and R is hydrogen or a carboxyl protecting group, for example the remainder of an ester-forming alcohol (aliphatic or araliphatic), a phenol, a silanol, Stannanols or an acid, means, condensed, the condensation, if desired, in the presence of a Condensation agent is carried out. Then can

If desired, the group R can be removed.

In the case of the preparation of preferred cephalosporin compounds of the formula (II) above, the amino compound (III) may have the formula

(VIII)

COOR ¹⁰

10
where R, B and P are as defined above. It is also possible to use an amino compound derivative such as a salt, for example a tosylate.

The compounds of the formula I can be prepared by using an acid halide, in particular an acid chloride or bromide, as the acylating agent. The acylation can be carried out at temperatures of -50 to +50 ⁰ C, preferably -20 to +30 C, performed. The acylating agent can be prepared by reacting the acid VII or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride. The use of oxalyl chloride together with the sodium or potassium salt of acid (VII) is preferred since isomerization is minimal under these conditions; the acylation can be carried out in aqueous or non-aqueous medium, and suitable media

209848/1 196

include an aqueous ketone such as aqueous acetone, an ester such as ethyl acetate, or an amide, for example Dimethylacetamide, or a nitrile, for example acetonitrile or mixtures thereof.

The acylation with an acid halide can be carried out in the presence of an acid-binding agent, for example a tertiary one Amine (e.g. triethylamine or dimethylaniline), an inorganic base (e.g. calcium carbonate or sodium bicarbonate) or an oxirane, which contains the hydrogen halide released during the acylation reaction binds, to be carried out. The oxirane is preferably a lower 1,2-alkylene oxide, for example ethylene oxide or propylene oxide.

If the free acid form of a compound of formula (VII) is used, suitable condensing agents include for the preparation of the compounds according to the invention carbodiimides, for example Ν, Ν'-diethyl, dipropyl or Diisopropylcarbodiimide, NjN'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbodiimide, a suitable one Carbonyl compound, for example carbonyldiimidazole, or an isoxazolinium salt, for example N-ethyl-5-phenylisoxazolinium-3'-sulfonate and N-tert-butyl-5-methylisoxazolinium perchlorate. The condensation reaction is preferably carried out in an anhydrous reaction medium, for example in methylene chloride, Dimethylformamide or acetonitrile, carried out, because you can then regulate the reaction parameters such as temperature better and more precisely.

Alternatively, the acylation can be carried out with other amide-forming Free acid derivatives such as a symmetrical anhydride or mixed anhydride, for example with pivalic acid, or with a haloformate, for example a lower alkyl haloformate. the mixed or symmetrical anhydrides can be generated in situ

209848/1196

·? 29 -

forms are. For example, you can form a mixed anhydride by adding N-ethoxycarbonyl-2-ethoxy-i, 2-dihydroquinoline is used. Mixed anhydrides can also be used with phosphoric acids (for example with phosphoric acids or phosphorous acids), sulfuric acid or aliphatic or aromatic sulfonic acids (for example p-toluenesulfonic acid). Another useful one Acylating agent is an activated ester, for example a compound of the formula

R. C. CO. L (IX)

^ a 0R ^a

where L is, for example, an azide-j oxysuccinimide, oxybenztriazole, Means pentachlorophenoxy or p-nitrophenoxy group.

Alternatively, the compound of formula (I) can be selected from a compound the formula

O = C = N

COOR ¹⁰

10, wherein B, Z and R are those given above

Have 10 definitions, with the exception that R is not hydrogen, by reacting with an acid or precursor of the formula VII and then ^{removing the group R 10} (cf.
760 494).

10
R removed (see for example the Belgian patent

The reaction of the compound of the formula (III) or (V) can be carried out towards the end of the preparative sequence or the Step reaction can be carried out, the only one

209848/1196

additional reactions are the deprotecting reactions and the purification procedures.

If desired, one can first use a compound of the formula

R. CO.CO.NH

I I I

(X)

COOR ¹⁰

10

where R, R, B and Z have the definitions given above mean and then you can implement the

Compound of formula (X) with R ^a O.NH (where R ^{a is} the above

2 has given definition) and then

10

remove group R if necessary. The reaction product can be separated off, the desired syn isomer before or after the removal of the

10
Group R receives.

A useful precursor to the desired R.C.CO group is

It

N 0R ^a

the corresponding 2-hydroxyiminoacyl group

R ₁ , C. CO-

Il

You

since this can easily be converted into the desired group by etherification. So you can connect the Formula (i) obtained by adding a compound of the formula

2098A8 / 1 196

χι

COOR ¹⁰

10

wherein R, R, B and Z have the definitions given above ", reacted with an etherifying agent which serves to introduce the group R ^a , and then, if desired and if necessary, any of the reactions D (ii) - (viii) , which have been described above, perform and, if necessary, isolate the desired compound of the formula (I) after separation of the isomers.

The etherifying agent can, for example, be an organic one Halide or sulfate or a sulfonate such as a tosylate be. Other etherifying agents include diazoalkanes, for example diazomethane or diazoethane, alkylfluorosulfonates, for example methyl fluorosulfonate, and alkyloxonium tetrafluoroborate, for example trialkyloxonium tetrafluoroborate such as triethyloxonium tetrafluoroborate and diphenyljοdonium bromide. It may be necessary to use a fluorosulfonate in etherification reactions involving a diazo compound or a tetrafluoroborate is used to add auxiliaries such as a Lewis acid such as BF.

You can compounds of the formula (i) in which R is an activating acting group such as a cyano or 2- or 4-pyridyl group means, according to processes in which nitrosated and the resulting oxime is etherified. One can use such a compound that has an acylamido group

R.CH ₂ CONH- or R.CH.CO.NH-

COOH

209848/1196

contains, using nitrous acid (which is produced in situ by reacting an alkali metal nitrite with a weak acid, for example acetic acid, is produced) nitrosate and one can use nitrosyl chloride or a use organic nitrosating agent, for example an alkyl, cycloalkyl or aralkyl nitrite. If you have a Connection that the group

R.CH.CO.NH-COOH

contains, nitrosated, decarboxylation will occur. After the nitrosation or etherification reaction the separation of the syn and anti isomers may be required.

If desired, the replacement of one P group by another preferred P group can take place after the Acylation of the 7-amino or 7-isocyanato compound was carried out. Especially if P is the group

-CH ₂ Y

where Y has the definition given above, the group Y can according to any one described in the literature Procedures are introduced. Compounds in which Y is a halogen atom, an ether group or a thioether group can thus be used means to produce as described in Belgian patents 719 711, 719 710, 734 532 and 734 533 is. Compounds in which Y is the radical a nucleophile can be prepared by adding a 3-acetoxymethylcephalosporin compound with a nucleophile, for example, pyridine or another tertiary amine, as described in British Patent 912 is described, a sulfur-containing or sulfur-bound, nitrogen-bound or inorganic nucleophile, as described in British Patent 1,012,943, a sulfur-containing nucleophile,

209848/1 196

as described in British Patents 1,059,562, 1 101 423 and 1 206 305, or one Nitrogen-containing nucleophiles as disclosed in British Patents 1,030,630, 1,082,943 and 1,082,962 is described.

Compounds in which Y is a derivative of a residue of a nucleophile, for example in which Y is an amino or acylaraido group derived from an azido group can be prepared as described in US Pat British patents 1,057,883 and 1,211,694 is described, in these patents also the implementation of compounds in which Y is an azido group, with a dipolarophilic compound is. Compounds according to the invention in which Y is the radical of a nucleophile can also be obtained by reaction a 3-halomethylcephalosporin with any of the nucleophiles described in the above references are prepared, for example according to a method, as described in Belgian patent 719 711. When Y is a hydroxy compound, the compound can be obtained by methods such as those described in British Patent 1,121,308.

Compounds that have a vinyl or substituted 3-substituent Containing vinyl group can be prepared according to the method as described in the Belgian patent 761 897 is described.

When Y represents a halogen atom (for example chlorine, bromine or iodine), the Ceph-3-em compounds used as the starting material can be by halogenation of a 7ß-acylamido-3-methylceph-3-em-4-carboxylic acid ester-1ß-oxide, followed by reduction of the 1β-Oxyd group made later in the sequence as described in Belgian patent 755 256.

209848/1196

The corresponding Ceph-2-em compounds can according to the in the published Dutch patent application 6902013 can be obtained method, wherein one Ceph-2-em-3-methyl compounds reacted with N-bromosuccinimide and the Ceph-2-em-3-bromomethyl compound is obtained.

When Y is a hydrogen atom, the compound can obtain are according to the procedure as described in British patent specification 957 569, or one can according to the Process as described in US Pat. No. 3,275,626 and Belgian Patents Nos. 747 119 and 747 120 make a penicillin compound.

Cephalosporin compounds which contain an acyloxymethyl group as a substituent in the 3-position can be prepared by all known processes. For example, they can be prepared from cephalosporin _{compounds which contain a 3-CH 2} Y group, where Y = OH or the remainder of an acid HY, which has a pKa value of not greater than 4.0 and preferably not more than 3-5 (determined in water at 25 ° C).

The group Y can be a chlorine, a bromine or an iodine atom, a formyloxy or an acetoxy group with at least one Electron withdrawing substituents on the ct carbon atom or a nucleus-substituted benzoyloxy group, the nucleus substituent belonging to the group, the electrons peel off as described in British Patent 1 241 657, and the nucleophilic substitution reaction, in which the desired substituent is introduced in the 3-position, can be carried out as described in commonly assigned British Patent 1,241,657, previously mentioned is described.

Alternatively, when Y is a hydroxy group, the desired 3-Acyloxymethylcephalosporin can be obtained by

209848/1 1 96

acylating described in an analogous manner as described in British Patent Specification 1,141,293, wherein a process in this patent for the preparation of Δ -Cephalosporin with a 3-acyloxymethyl SubstLtuenten from the corresponding 3-hydroxymethyl analogues described, which consists in that the 4-carboxy group is aralkylated, the 3-hydroxymethyl group of the protected compound is acylated and then the aralkyl group is removed.

The acylation can be carried out by any known method using, for example, an acid chloride, Acid anhydride or a mixed acid anhydride as acylating agent, preferably in the presence of an acid-binding agent By means of, for example, an organic base such as pyridine or a lower alkylene oxide such as ethylene oxide or propylene oxide, the reaction being carried out in solution in an inert, anhydrous solvent, for example methylene chloride. Alternatively, the acylation can be carried out in aqueous acetone / sodium bicarbonate solution be performed. The preferred acylating agent is the acid chloride.

The acylation reaction should be carried out as quickly as possible because under the acylation conditions UmIa-

2
struggling of the & derivatives can occur, especially when an aroyloxy group is introduced into the exocyclic methylene group in the 3-position.

Compounds of formula III can be used as esters. Compounds of formula V are esters. You can too use the free amino acid or an acid addition salt of the free amino acid or the ester thereof. Salts, which can be used include acid addition salts, for example with hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, toluene-sulfonic acid and methanesulfonic acid.

209848/119 6

The esters can be formed with an alcohol, phenol, silanol, or stannanol having up to 20 carbon atoms land the at a later stage of the overall implementation can easily be split off.

Any esterifying group that has the 4-carboxyl group the compound of the formula (III), (V) or (X), is preferably substituted with an alcohol (aliphatic or araliphatic) , Phenol, silanol, stannanol or an acid that is easily formed at a later stage of the reaction can be split off. Suitable esters thus include compounds containing ester groups selected from the following Can be selected from a list that is not exhaustive.

(i) -COOCR ^f R ^g R ^h , in which at least one of the radicals R ^f , R ^ and R is an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy,

f e · h acetoxy or fur-2-yl. The remaining R -> R ^ and R groups can be hydrogen or organic substituent groups be. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

(ii) -COOCR ^f R ^s R. ^, in which at least one of the radicals R, R ^s and R is an electron attractive group, for example benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, Arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or cyano. The remaining R -> R ^g - and R groups can be hydrogen or organic substituent groups. Suitable esters of this type include benzoyl methoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridyl methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl.

(iii) -COOCR R% t, in which at least two of the groups R, R ^g and R are hydrocarbon radicals such as alkyl,

209848/1 1 96

for example methyl or ethyl, or aryl, for example phenyl, and the remaining R, R ^s and R groups, if present, are hydrogen. Suitable esters of this type include tert-butyloxycarbonyl, tert-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.

(iv) -COOR, where R is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahydropyran-2-yl means.

(v) Silyloxycarbonyl groups obtained by reaction a carboxyl group with a derivative of a silanol. The derivative of a silanol is conveniently a halosilane or a silazane of the formula

R ¹ ^ SiD; R ⁿ ₂ SiD ₂ ; R ¹ → Si.NR ¹¹ ; R ¹ ^ Si.NH.SiR ¹ ^; R ^U ₃ Si.NH.COR ¹¹ ; R ¹ ^ Si.NH.CO.NH.SiR ¹ ^; R ¹¹ NH.CO.NR ^U1

or R ^

11 wherein D is a halogen atom and the various groups R, which may be the same or different, are hydrogen atoms or alkyl, for example methyl, ethyl, n-propyl-j isopropyl, Aryl, for example phenyl, or aralkyl, for example benzyl groups. Preferred derivatives of silanols are silyl chlorides such as trimethylchlorosilane and dimethyldichlorosilane.

The carboxyl group can be regenerated from an ester by any of the conventional methods, for example Hydrolysis catalyzed by acids and bases is easy to carry out, just like enzymatically catalyzed hydrolysis Hydrolyses. However, aqueous mixtures can and can be poor solvents for these compounds Isomerizations, rearrangements, side reactions and general degradation cause so that specific processes' are desirable can be worth.

209848/1 196

Five suitable saponification methods or ester cleavage reactions are

(1) Reaction with Lewis acids.

Suitable Lewis acids for reaction with the esters include trifluoroacetic acid, formic acid, hydrogen chloride acid in acetic acid, zinc bromide in benzene and aqueous solutions or suspensions of mercury (II) compounds. The reaction with the Lewis acid can be facilitated by adding a nucleophile such as anisole.

(2) reduction.

Suitable systems to carry out the reduction are zinc / acetic acid, zinc / formic acid, zinc / low alcohol, Zinc / pyridine, palladium-on-charcoal and hydrogen and Sodium and liquid ammonia.

(3) attack by nucleophiles.

Suitable nucleophiles are those which contain a nucleophilic oxygen or sulfur atom, for example Alcohols, mercaptans and water.

(4) Oxidative processes, such as those using hydrogen peroxide and acetic acid.

(5) irradiation,

Where towards the end of a preparative production sequence compounds are obtained in which B ^ S - ^ 0 and if a compound is desired in which B ^ S is, the conversion into the sulfide can be done, for example, by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, this in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt is made, the reduction for example with sodium dithionite or by iodide ion in the form of a solution of potassium iodide in one with water

209848/1196

miscible solvent, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide, takes place. The reaction can be carried out at a temperature of -20 to + 5O ⁰ C.

Alternatively, the reduction of the 1-sulfinyl group by phosphorus trichloride or tribromide in a solvent such as methylene chloride, dimethylformamide or tetrahydrofuran, preferably at one
be performed.

preferably at a temperature of -20 ⁰ C to +50 ⁰ C

When the resulting compound is a Ceph-2-em-4-ester, the desired Ceph-3-em compound can be obtained by treatment of the first can be obtained with a base.

The acid IV, which corresponds to the acylating agent, can be obtained by reacting a glyoxylic acid of the formula

R.CO.COOH

wherein R has the definition given above, or an ester thereof with R ^a 0.NH ₂ can be obtained (R ^a has the definition given above).

The resulting acid or ester can then be separated into the syn and anti isomers, for example by crystallization, chromatography or distillation, and then you can optionally, if necessary, hydrolyze the ester.

In particular in the case of 2-alkoxyiminoarylacetic acid esters, for example esters of acids of the formula (IV) in which R is an aryl group (carbocyclic or heterocyclic) and R ^{a is} an alkyl group, the separation of the syn and anti isomers can be achieved by selective hydrolysis of the esters occur because the less sterically hindered anti-isomer tends to saponify more quickly and it can therefore be used as a free acid

2098Λ8 / 1196

removed, leaving the purified syn ester. The separated syn isomer can then be added as desired will be converted into the corresponding acylating agent.

The acid (IV) can also be produced by undergoing some kind of O-alkylation or O-arylation reaction on a compound of the formula

R.C.COOH Il

OH

performs, ie a 2-hydroxyimino acid or, more preferably, on an ester of such a 2-hydroxyimino acid. The desired reaction can be carried out with an organic halide, sulfate or sulfonate, for example a compound of the formula R ^a J, in which R ^{a has} the definition given above and J is a halogen, sulfate or sulfonate such as a tosylate. Alternatively, the 2-hydroxyimino acid or an ester thereof can be reacted with a diazoalkane, for example diazomethane, an alkyl fluorosulfonate, for example methyl fluorosulfonate, or an alkyloxonium tetrafluoroborate, for example a trialkyloxonium tetrafluoroborate such as trimethyloxonium tetrafluoroborate, or an ester thereof (alkoxy) or an ester thereof VI (alkoxy) desired , or with a diphenyliodonium bromide, the corresponding phenoxyimino acid (VII) being formed. In these reactions with a diazo compound, a fluorosulfonate or a tetrafluoroborate, it may be necessary to add auxiliaries, for example a Lewis acid such as BF ^.

If the acid (IV) is converted into the corresponding acylating agent, it should be noted that it is desirable that amino groups present in R or R are protected as far as possible

209848/1196

should be in order to avoid undesirable side reactions. Similar protection of amino groups is also desirable, if the acylating agent is then reacted with a compound of the formula (III) or (V).

The syn and anti isomers can be distinguished by suitable methods, for example by their ultraviolet Spectra, by thin-layer or paper chromatography or by their NMR spectra. For example show DMSO-dg solutions of compounds of the formula I the doublet for the amide NH at a lower field for the syn isomers than for the anti isomers. These factors can be used if you want to follow the implementation.

The antibacterial compounds of the invention can be formulated for administration in any suitable manner are analogous to other antibiotics and the invention therefore relates to pharmaceutical compositions which an antibacterial compound of formula I or a non-toxic derivative, for example a salt thereof (such as it previously defined), and which are suitable for use in human or veterinary medicine. Such compositions can be used in the usual manner with the aid of the necessary pharmaceutical excipients or diluents.

The antibacterial compositions of the invention can and can be formulated for injection in unit dose forms, in ampoules, or in multi-dose containers with added preservatives be. The compositions can also be in the form of suspensions, solutions, emulsions in oily or aqueous Carriers and they can be formulating agents such as suspending, stabilizing and / or dispersing agents contain. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier,

209848/1139

for example with sterile, pyrogen-free water of use.

The compositions can be in a form suitable for gastrointestinal absorption Tract. Tablets and capsules for oral administration may be in unit dose presentation forms, and they can use suitable diluents such as binders, for example syrup, gum arabic, gelatin, sorbitol, Tragacanth or polyvinyl pyrrolidone, filler, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or Glycine, lubricants or lubricants, for example magnesium stearate, talc, polyethylene glycol, silicon dioxide, Disintegration agents, for example potato starch, or suitable crosslinking agents such as sodium lauryl sulfate contain. The tablets can be coated according to known methods. Oral liquid preparations can be used in Or they may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc. be in the form of a dry product, which before use with water or other suitable carriers is reconstituted. Such liquid preparations can contain known additives such as suspending agents, for example Sorbitol syrup, methyl cellulose, glucose / sugar syrup, Gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, Aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitol monooleate or Gum arabic, non-aqueous carriers, edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoates or include sorbic acid. Suppositories can contain conventional suppository bases, for example cocoa butter or other glycerides »contain.

209848/1196

The composition can also be in forms that are suitable for absorption through the mucous membranes of the nose and throat or through the bronchial tissues and these can conveniently be in the form of powders or liquid sprays or inhalants, lozenges, means for Brushing out the throat, etc. are available. For the medication of the eyes and ears, the preparations can be used as individual Capsules, in liquid or semi-liquid form, or they can be used as drops. Topical Applications can be in hydrophobic or hydrophilic base materials as ointments, creams, lotions, brushes, Powders, etc. are present.

For example, the compositions can be used in veterinary medicine as intramammary preparations in raw materials that either work for a long time or release the active ingredient quickly, be formulated.

The compositions can be from 0.1% upwards, preferably contain from 10 to 60% of the active material, depending the method of administration. When the compositions contain unit doses, each unit dose is preferred Contains 50 to 500 mg of active ingredient. The dose required for treating adult humans is used is preferably in the range of 100 to 3000 mg / day, e.g. 1500 mg / day depending on the route and frequency of administration.

The compounds of the invention can be used together with other therapeutic agents such as antibiotics, for example with other cephalosporins, penicillins, or tetracyclines.

The following examples illustrate the invention without, however, restricting it.

209848/1196

Manufacturing process 1
2-methoxyiminophenylacetic acids (syn and anti isomers)

A solution of sodium (5 g) in dry methanol (100 ml) became a solution of Q-methylhydroxylamine hydrochloride (15 g) in dry methanol (100 ml) until phenolphthalein was neutral. The precipitated sodium chloride was removed by filtration and the filtrate was added to a solution of phenylglyoxylic acid (25 g) in given to dry methanol (100 ml). The solution was refluxed for 2 hours, cooled and evaporated, whereby an oil was obtained which was dissolved in ether (200 ml). The solution was filtered and evaporated, whereby Received 32.9 g of oil. This oil was recrystallized from petroleum ether (b.p. 60 to 80 °), giving a colorless Solid (19 | 61 g) and an oil (3.9 g) was obtained.

The solid (17.8 g) and oil (3.9 g) were combined (21.7 g) and methylated with essential diazomethane to give 24.2 g of oil. This was purified by chromatography on silica gel (600 g), using syn-methyl-2-methoxyiminophenyl acetate in the form of an oil (13> 6 g, 55%), Λ (EtOH) 259 nm (<£ 10 400) and anti- Methyl 2-methoxyiminophenyl acetate was obtained, the slower compound in the form of a solid (8.7 g, 33%), m.p. 54 °, A _mav (EtOH) 251 nm (£ 7,260).

Methyl 2-methoxyiminophenyl acetate (anti isomer) (8.7 g) was dissolved in methanol (100 ml) and 2N sodium hydroxide solution (22 ml) was added. The solution was at room temperature Stirred for 1 hour and the pH was adjusted to 7 with 2N hydrochloric acid. The methanol was removed by evaporation, water (150 ml) was added and the solution was washed with 2N hydrochloric acid acidified to a pH of 1.5. The mixture was extracted with ethyl acetate (3 × 100 ml), the organic Extracts were combined, dried and evaporated, whereby

209848/1196

a solid (6.74 g) was obtained which was recrystallized from petroleum ether (b.p. 60 to 80 °): benzene to give the anti-2-methoxyiminophenylacetic acid (4.84 g), melting point 103 to 104 °, ^Λ _max (EtOH) 248 mn (£ 7010), C (CDCl ₃ ) values include 2.64 (Ph), 5.92 (CH ₃ ).

Methyl 2-methoxyiminophenyl acetate (syn-isomeres) (1316 g) was hydrolyzed in a similar manner, except that the hydrolyzing mixture was stirred for 40 hours at room temperature. The colorless solid (11.13 g) which formed was obtained from petroleum ether (b.p. 60 to 80 °); Benzene recrystallized to give the syn-2-methoxyiminophenylacetic acid as a colorless solid (10.02 g), melting point 96 to 97 ° i A _mav (EtOH) 255 nm (£ 13,200), V (CDCl3) values 2.2 to 2.8 (Ph), 5.92 (CH ₃ ).

Manufacturing process 2

2-methoxyimino (thien-2-yl) acetic acid (syn and anti isomers)

A solution of methoxyamine hydrochloride (5.85 g) in dry methanol (60 ml) was mixed with a solution of sodium methylate in methanol (from sodium, 2.5 g, and dry Methanol, 50 ml) neutralized with respect to phenolphthalein. The precipitated sodium chloride was filtered off removed and the filtrate became a solution of thien-2-ylglyoxylic acid (10 g) in dry methanol (60 ml). The resulting solution was refluxed for 1 hour, cooled and evaporated to give an oil. Ether (100 ml) was added, the mixture was filtered and the filtrate was evaporated to an oil (13.06 g).

The oil (12.5 g) was dissolved in ether (50 ml) and an ethereal solution of diazomethane was added until permanent yellow color remained. The excess diazomethane was destroyed by leaving the solution in sunlight for 1 hour

209848/1 196

left standing. Evaporation of this solution gave 13.2 g of oil.

The oil (10.33 g) was purified by preparative layer chromatography (silica gel PF ₂ 54 + 366), eluting three times with 75% petroleum ether (b.p. 60 to 80 °) in benzene, and using a) methyl ~ 2 methoxyimino-2- (thien-2-yl) acetate (syn-Isomeres) (3.44 g, 27%), A _mov (EtOH) 290 mn "( £ 11 250), A _{inf <} 271 nm (a 5400), ^ _max (CHBr ₃ ) 1738 and 1230 cm " ¹ (CO ₂ Me)! Z values (CDCl ₃ ) include 6.06 (s, CO ₂ CH ₃ ), 5.78 (s, OCH,); and b) Methyl 2 ~ methoxyimino-2- (thien-2-yl) acetate (anti-isomer) (1.21 g, 9 _f 5%), ^ _may: (EtOH) 221 and

288 nm (£ 5 020 and 11 000), ^ _mev (CHBrJ 1732 and 1212 cm "* ¹

Iu 3. λ ^)

(CO ₂ Me), T * (CDCl ₃ ) values include 6.06 (s, CO ₂ Me), 6.00 (s, OCH ·,) and other fractions obtained that were isomeric mixtures.

2N sodium hydroxide (8.27 ml) was added to a solution of methyl ~ 2-methoxyimino-2- (thienyl-2-yl) acetate (syn-Isomeres) (3.28 g) in methanol (50 ml) and the Solution was stirred at room temperature for 18 hours. Water (20 ml) was added and the solution was evaporated to remove the methanol and then washed with ethyl acetate. The pH of the solution was changed to 2 with 2N hydrochloric acid under ethyl acetate (50 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to give a colorless solid (2.58 g). This was crystallized from cyclohexane to give the title compound (syn-isomeres) (2.23 g, 73 ^c / o), m.p. 105.5 °, λ _{m & x} (EtOH) 289 nm ( t 10 100), ⁷ ^ _1n Jf 262 and 271 nm (£ 7750 and 8150), Γ (CDCl ₃ ) values include 0.32 (OH) and 5.92 (OCH ₃ ).

A similar hydrolysis of the anti-methyl ester gave 2-methoxyimino- (thien-2-yl) -acetic acid (anti-isomer) (0.85 g), A _max (EtOH) 286-287 nm ( £ 10 200), Γ ( CDCl ₃ ) values include 1.31 (OH) and 5.73 (OCH ₃ ).

209848/1 1 96

Manufacturing process 3

syn-tert-butoxyiminothien-2-ylacetic acid

A solution of thien-2-ylglyoxylic acid (6.2 g) and sodium bicarbonate (3.36 g) in water (100 ml) was added dropwise to a stirred solution of tert-butoxyamine hydrochloride (5.65 g) and sodium bicarbonate ( 3.78 g) in water (100 ml) at 0 to 5 ° and the mixture was stirred at room temperature for 18 hours. The mixture was acidified to pH 2.0 with 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to give a solid (9.75 g). Recrystallization from petroleum ether ( Kp 60 to 80 ⁰ C) yielded 106. the title compound (4.0 g, 44%), mp. to 107 °, / V _v.

Max

(EtOH) 290 nm (£ 11,600), ^ (CDCl ₃ ) values include 2.46, 2.66, 2.98 (d doublets, thienyl protons), 8.60 [C (CH ₃ ),] .

Manufacturing process 4

2-ethoxyiminophenylacetic acids (syn and anti isomers)

Ethoxyamine hydrochloride (4.0 g) and phenylglyoxylic acid (6.0 g) were dissolved in water (50 ml) and the resulting solution was basified to an alkaline reaction corresponding to pH 4.5 and stirred at this pH for 15 hours. Acidification and extraction of the mixture gave, after evaporation of the ethyl acetate, a mixture of syn- and anti-ethoxyiminophenylacetic acids (7.4 g, 94%). Four recrystallizations from cyclohexane gave no pure syn acid. However, after evaporation of the mother liquors from the first crystallization and recrystallization of the residue from cyclohexane, anti-ethoxyiminophenylacetic acid (1.36 g, 17%), melting point 90.9 to 91.6 °, A _max (ethanol) 249 nm ( £ 7600), r (DMS0-d ₆ ) values include 2.52 (s, Ph), 5.74 (q, CH ₂ ), 8.76 (t, -CH ₃ ).

2098Λ8 / 1196

A solution of the mixed acids (4.0 g) in ether (100 ml) was treated with an ether solution of diazomethane until the yellow color no longer disappeared. Acetic acid was added to destroy excess diazomethane and the ethereal solution was washed with sodium bicarbonate solution, water and brine and then dried. Evaporation of the ether solution gave the methyl ester (4.1 g) as an orange oil. This was separated on five 40 × 20 cm preparative plates, eluting with petroleum ether (b.p. 40 to 60 °) / ether (3: 1). The slower band was eluted with chloroform and removal of the solvent gave anti-methyl-2-ethoxyiminophenyl acetate (1.45 g) as a pale yellow oil, f (CDCl ₃ ) values include 2.58 (Ph), 5.66 (q, CH ₂ ), 6.12 (s, OCH ₃ ), 8.72 (t, CH ₃ ). Similar treatment of the faster band gave syn-methyl-2-ethoxyiminophenyl acetate (2.45 g) as a pale yellow oil, £ "(CDCl,) - values range from 2.3 to 2.7 (m, Ph), 5, 72 (q, CH ₂ ), 6.06 (s, OCH ₃ ), 8.67 (t, CH ₃ ).

The above syn methyl ester (2.39 g) in methanol (60 ml) was treated with sodium hydroxide solution (2N, 12 ml) and the solution was stirred for 18 hours. The methanol was removed and, after acidification to pH 1.5, the aqueous mixture was extracted with ethyl acetate. The washed and dried extracts were evaporated to dryness and the residue was recrystallized from cyclohexane to give syn-ethoxyiminophenylacetic acid (836 g), melting point 77.9 to 79.0 °, A ^ _x (ethanol) 256.5 nm ( £ 12,800), X (DMSO-d ₆ ) values include 2.48 (m, Ph) ₁ 5.74 (q, CH ₂ ), 8.71 (t, CH ₃ ).

Manufacturing process 5 to 23

2-alkoxviminoarylacetic acids

General procedures

A mixture of substituted glyoxylic acid and an over-

209848/1136

A shot (10 "to 15%) of alkoxyamine hydrochloride was suspended in barrels or aqueous ethanol, stirred and the pH of the mixture was adjusted to between 4 and 5 (method B) with sodium hydroxide solution (n to 1On)«, By adding more sodium hydroxide solution and ethanol as required, a clear solution was maintained at a pH of 4 to 5 during the reaction adding more of the more volatile alkoxyamines) _o The progress of the reaction was followed by acidification of an aliquot, extraction with ethyl acetate and thin-layer chromatography of the extract on silica gel plates (developed with a mixture of chloroform / methanol: acetic acid, 18: 2: 1) Alkoxyiminoacetic acids were less polar than the keto acids used as starting material and reaction times were 2 hours to 2 Ta ge. Reactions carried out at pH 7-8 were designated Method A. When the reaction was complete, the mixture was adjusted to pH between 7 and 8 and the ethanol (if present) was removed by evaporation. The aqueous mixture was extracted with ether, the extract was discarded and the aqueous phase was acidified to pH ^ 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, the extract was dried and evaporated to give a crude product which was purified by one of the following methods:

(a) crystallization and recrystallization (if necessary) from a suitable solvent}

(b) the crude product, dissolved in ether, was treated with a slight excess of a solution of diazomethane in ether. The excess reagent was destroyed with acetic acid and the solution was washed with sodium bicarbonate solution and evaporated, leaving the crude methyl ester

209848/1196

Received ". The Ssxer were by preparative thin layer chromatography or column chromatography on silica gel separated and then hydrolyzed in a known manner with alkali, where the pure syn acid was obtained,

(c) The mixture of esters was prepared as in (b), and the isomers were through. Separated crystallization from a suitable solvent and hydrolyzed accordingly.

These procedures were used to prepare the intermediates (syn isomers) given in Table I,

20984a / "i 1 96

Table I.

ο co co. *> co

Manufacturing Author

No.

R '

procedure

Cleaning

Fp.

-Values

(Solvent)

Max.
nm
(EtOH)

Yield, % (before purification

Ph

Ph

Ph

^{G (CH} 3 ⁾ 3 |

GH _n Ph

CH,

^C 2 ^H 5

(a)

(a)

(a)

(a)

(a)

127-129 °

103.3 °

110-111 °

108-109 °

89.5-93.5 '

2.2 - 2.7 (DMS0-d ₆ )

2.2-2.7 (CDCl ₃ )

2.44

(DMSO-O ο

2.61-2.91 (CDCl ₃ )

2,29,2,76,2,86 (DMSO-d,)

8.62

4.67 (CH ₂ )

4.58 (CH ₂ )
2,92,2,78,2,44
(T.hien-2-yl)

257
257

13 060 15,150

5 _; 92

289

10 700

5.79 (CH ₂ )
8.72 (CH ₃ )

289.5

12 500

"00

100

91

87

--Ge -

co ■ P U O

Φ H ri Φ

CD

3 · ι. P-O co O I. • Η CD ι rl CO
OO 200
I. vO r-i in vO Φ ^ -ΰ · Η ^ DMS • Η Pj Ρ5 ρ-ι JCj CN
ι — i , Q CJ bO
CQ » U · Η ti Qi Φ P I W φ 300 σ » 1
100 CN CvJ 300 3 Φ O (D 3 Cri bO I γΗ bO J t-, CS 00
it CO CO I I CT. ω α φ-μ ρ ö) ö in O in C) CO r-l in φ pci CS CTi · »* ^ * S cn X O I Λ 00 CN <H i-l CS CS cd B ±>
BC ω φ Φ Cd / -ν. CN CS • Ρ Cu CJ vß U V ^ "Vw ' in φ ct> r ^
in r ^ in CT.
• s it I. • ^ · ^
it <r co in O co CO CTi r \ CTi OO CN co · ». - '? CTi it r ^ ^^ in r-i in , ", ^, ^ co CS r-l OJ Cn I I I O ro c-vj CN co • s Is «V CS r-lH (N. CTi pq CS Cv-I O CO (M S. O
in
, ι CM*" CO
it CTi r-l I. - \ 0 / - I.
CN (Ö) CS r-l rO r-l CD (N
r-I pq pq U < it α
CN co te co
K PU
CS α CJ CJ α ι— (. / —- \ / ^ ₁ V • (Or (Ö) ^ _, / pH r-I σ r-I r-I

209848/1136

Table I (cont.)

CO ₂ H

0R ^c

Manufacturing process no.

procedure

Cleaning

τ values

(DMSO-d

Max.
nm
(EtOH)

Yield % (before cleaning)

15 16

17 18

CH ₂ Ph CH ₀

CH ₂ Ph

AWAY

B B

(a)

(a)

(c)

85-87 °

110.5 -

104-105.5

129-130 °

1,53,1,92,2,2-2,7 '2 10, 3.18, 3.33

2.12, 3.24, 3.35 2.12, 3.19, 3.33

1.40,1,83,1.95,2 / A

(Ph)
4.64 (CH ₂ )

6.06
8.70

2.58 (Ph)
A.'75 (CH ₀

5 _; 92

294
275

275.5
277

233

284

296.5

306 '5

8 300 21,500

16 040

17 650

22,900

10 900

10,500

9. 270

86 81

95

81 99

pi

■ μ φ ω ■ Ρ

O • 22233 I. O j 3? rn pi \ 75 O co - 0 I. H
SI bO O O CN 1 0 £ $ fa 4_Ι cn vO Φ ^ RtS
, α
τη ■, C ₁ O O O 2 Φ O I.
• Η & 0 O C ro O • Η d
φ 3 O O <f cn CN cd «20 CN CO in in φ S. in r ^ * • in I Sh ri O vD ω Φ Oi CN pi r-4 ri O in cr> ro CN in CD Wi cn it CN Ρί X CNi in CN it ε CO CTv y ^ s CN ε C PS CN T'-j P <O I (Q O Cn VD 'IrIhOI O in r * ^ "^ k Φ Ö ί- • ν .Λ Ό φ -ρ 3 α vO cn <r f ... O CO in
in in
MD CN ^ CN Q J CN vO C ¹ *) ro • \ Φ η CN ■ Ρ O CN U • -i O CN Φ CN O CN τ OO · ■ » OO CN O CN ι- * a approx _ 1-4 <r in φ <r
r-i O U 1 r-H T-i ro 1 'cd k 1 CO in O r-i 'CD "ti fQ PQ P ^ ro CN SG 0 U K b 0
* ~ \ 0 r-i CN CTi r-i.

209848 / 119G

CD H H

CD

J ₁ I. CD ο I (Q Φ σ » O ο CN sr » CN 222337 ρ "· ι Ρί I iH hO I k OO <f eat cy » φ "d-H P < fi O β tiXl ο Γ- · - » <r in ύ Pooh Φ-Ρ ρ φ cd U ο r-l 00 0 0 0 Ol -U "H Ö JeJ βι η t> cn S CO CN Tt t- < 0 i) O) O Φ P ι CN 00 • Η νθ CN Ö bO γ-Ι in Φ ρ CO "-I U) UD in FtS Φ rv uxi CN PQ Q) cd r— XEO CN to G JJ B ω CD
Ρί cn in β in φ CN ö ο co vO -P Ό (N OO ο I. CTv OO U cy » O <r cn Ph r- IO ιη I. in ^ CN H Q r-) CO γΗ co * "CO Φ • «ro -P O Φ CN 0 I. CN CTi F-I CD PQ in te CN
O
I. Ci = 00 CN

209848/1196

Manufacturing process 24
2-methoxyiminopyrid-3'-ylacetic acid (syn and anti isomers)

Pyrid-3-ylglyoxylic acid (3.02 g) and methoxylamine hydrochloride (2.59 g) were heated under reflux in ethanol (50 ml and treated with a solution of sodium ethylate in ethanol, until the mixture just gave an alkaline reaction to phenophthalein. The mixture was refluxed for 1 1/2 hours, then further parts of methoxylamine hydrochloride (0.5 g) and ethanolic sodium ethylate were added and refluxed for another hour. The emerging Mixture was filtered through kieselguhr and evaporated to dryness. The residue was in a small Volume of ethanol dissolved and the remaining fine suspension was clarified by filtration through kieselguhr. Dilution of the filtrate with ethyl acetate gave a crystalline solid. . The solid was washed well with ethyl acetate and dried to give 2-methoxyiminopyrid ~ 3'-ylacetic acid as an isomeric mixture (2.72 g, 76%), Λ (pH

Max

Buffer) 250 nm ( t 6630), μ *. (NuJoI) 1610 (CO ") and

λ IJIdJS. . £

1038 cm '(= CO -), T (d ₆ DMSO) 1.21, 1.43, 2.202, 2.60 (multiplets; aromatic protons), 6.20 (s; OCH,).

Manufacturing process 25

(a) Methyl 2- (1-ethoxy) ethoxyimino-2- (thien-2-yl) acetate (syn isomer)

Phosphorus oxychloride ( 2 drops). 'After 20 minutes at 50 ° the ethyl acetate was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated to give an oil which contained 2- (1-ethoxy) ethoxyimino-2- (thien-2-yl ) acetate (syn-isomeres) gave (5.7 g, 100Ji) _t .λ. _v (EtOH) 289 nm (£ 11,700), (, "(CDCl ₃ ; 60 MHz) 2.61 (multiplet, thienyl H ₅ ),

209848/1196

2.82 to 2.97, (multiplet, thienyl H ₃ and H ₄ ), 4.64 (quartet, J5 Hz; -0-CH-), 6.06 (singlet, -COOCH,), 6.24 ( Quartet, CH ₃

J 7 Hz, OCH ₂ ), 8.56 (doublet, J 5 Hz, CH-CH ₃ ), 8 _f 79 (triplet, J 7 Hz, 0.CH ₂ CH ₃ ).

(b) 2- (1-Ethoxy) -ethoxyimino ~ 2- (thien-2-yl) -acetic acid sodium salt (syn isomer)

In sodium hydroxide (1 eq.) And sufficient methanol to form a homogeneous system, methyl 2- (1-ethoxy) ethoxyimino-2- (thien-2-yl) acetate (syn-isomer) (5 , 7 g). After 4 hours at 50 ° the methanol was evaporated and the residue was azeotropically distilled with benzene / methanol, a colorless solid, 2- (1-ethoxy) -ethoxyimino-2- (thien-2-yl) -acetic acid-sodium salt- syn ~ isomer _s obtained. (4.6 g, 78.5? 6, A _max (pH 6 buffer 287 _S 5 nm (£ 10 650), T (D ₂ O) values include 2.42 (multiplet; thienyl H ₅ ), 2, 68 to 2.84 (multiplet; thienyl H ₃ and H ^), 4.63 (quartet, J 5 Hz; -CH-), 6.21 (quartet, J 7 Hz; -CH ₂ -CH ₃ ), 8 , 57 CH ₃

(Doublet, J 5 Hz; -CH-), 8.82 (triplet, J 7 Hz, -CH ₂ -CH ₃ ).

CH ₃

Method of manufacture 26 syn-Then-2-yloxyimino - (. Thien-2-yl) acetic acid

Then-2-yloxamine hydrochloride (7.37 g) and thien-2-ylglyoxylic acid (6.24 g) were dissolved in ethanol (110 ml) and water (20 ml). The pH of the solution was adjusted to 5.0 and this solution was stirred for 22 hours. The ethanol was evaporated and the aqueous mixture was neutralized, _{washed 9} times with ether and then acidified to pH 1.5. The acidic mixture was extracted from ethyl acetate * The combined extracts were washed, dried and evaporated to dryness, leaving a yellow oil

20984i / 11iS

(9} 2 g, & 6%) which crystallized on standing. TLC showed that the solid consisted of a mixture of isomers. Recrystallization of this solid several times from cyclohexane did not allow separation of the isomers. The acid mixture (5.0 g) was esterified with diε "omathan, a mixture of the methyl esters being obtained in the form of a pale yellow oil.

2N sodium hydroxide solution (7.6 ml) was added to a solution of the mixture of the methyl esters (2.14 g) in methanol (50 ml). After this solution had been stirred for 0.5 hour: " ¹ ", the solution was neutralized. The methanol was evaporated and the aqueous residue was extracted with ethyl acetate. The extracts were washed, dried and evaporated to dryness, whereby sin yellow oil (1.0 g) This oil was dissolved in methanol (25 nil) and stirred for 13 hours with 2N sodium hydroxide solution (5 ml), methanol was removed by evaporation and the aqueous residue after washing with ethyl acetate and acidification extracted at pH 1.7 with ethyl acetate »The extracts were washed, dried and -singedampft to dryness to give. Past a substance (730 mg), two-fold recrystallization of this solid from cyclohexane afforded syn? lien-2- yloxyimino (thien-2-yl) acetic acid (359 ag), m.p. 101-102 °, Λ _{η & χ} (EtOH) 239, 289.5 mm (B 11 700}, T (DMS0-d ₆ ) value 3 4.67 (s, CH ₂ ).

Manufacturing process 27
syn ~ 2-Ben2yloxyisinoben.zo [b] -thien-3 '"! acetic acid

Benzo [b] -thieno>3'-yIglyoxylsäure (2, i7 g) and benzyloxyamine hydrochloride (1 g _9''5?) Were (ml 70) in ethanol and dissolved water (30 ml), slide ords solution to pH ainen value of 4.5 eingestelltj which comprises i-Oftige Gev / »/ 7ol, lIatriuirihydroxydlösung used and bai d.i33 3: x pH 2 3 ', - urf.den stirred _o The solution vfuria about: sloop kept un .i on a pH value of 9; -: - ^ id: Lann: old ether gsv. £ .33hön. The aqueous phase

203843/1 1S6

was acidified under ethyl acetate, and the organic layer was washed with water and saturated saline and dried. Evaporation gave a mixture of syn and anti isomers as a buff crystalline solid (314 g, 99%). The crude acid in ether was treated with excess diazomethane in ether at 0 to 5 °. The excess reagent was destroyed with acetic acid and the ether solution was washed with sodium bicarbonate and water and dried. Evaporation gave a pale brown oil (3 »34 g, 93%). The crude product in methanol (100 ml) was treated with sodium hydroxide solution (1N, 10 ml) at room temperature for 1 hour. The hydrolysis was followed by thin layer chromatography on silica gel. Hydrochloric acid (2N 5 ml) was added to stop hydrolysis and the methanol was removed by evaporation. Ethyl acetate was added and the anti-2-benzyloxyiminobenzo [b] -thiens'-acetic acid was removed by washing with sodium bicarbonate. The ethyl acetate layer was washed with water and dried and evaporated to give a pale orange oil (1.99 g, 56%). This was treated in methanol (90 ml) with sodium hydroxide (1N 10 ml) at room temperature for 7 hours. Another aliquot of the sodium hydroxide (1N 5 ml) was added and the solution was allowed to stand for 2 days until hydrolysis was complete. The methanol was removed by evaporation and the residue dissolved in ethyl acetate and water. The mixture was adjusted to pH 1.5, and the ethyl acetate layer was washed with water, saturated saline and dried. Evaporation gave yellow crystals (1.82 g, 50%). Crystallization from a mixture of benzene and cyclohexane gave the title compound as pale orange crystals (1.29 g, 36%), melting point 120.5 ° to 121 °, / \ _max (EtOH) 232, 285.5, 296.5 , 306.5 mn (<£ 22,500, 11,800, 11,500 , 10 hOO), Z values (DMSO-d ₆ ) include 1.90, 1.97, 2.3 to 2.7 (aromatic protons), 4 .64 (CH ₁ ,, singlet).

209848/1196

Manufacturing process 28
syn-2-benzyloxyiminobenzo [b] -thien-2'-ylacetic acid

Benzo [b] -thien-2-3 ^r glyoxylic acid (3 * 092 g) and benzyloxyamine hydrochloride (2.72 g) in ethanol (170 ml) and water (70 ml) were adjusted to pH with sodium hydroxide (40%) set from 4.5. The solution was stirred at this pH value at room temperature for 6 hours. Benzyloxyamine hydrochloride (500 mg) was added and the solution was stored at room temperature overnight. The solution was adjusted to pH 8 and washed with ether. The aqueous phase was acidified to pH 1.5 under ether. The ether layer was washed with water and dried. Evaporation gave an off-white solid (4.28 g, 91%) as an isomeric mixture.

The crude isomeric mixture was treated in ether with excess diazomethane in ether at 0-5 °. The excess Reagent was destroyed with acetic acid and the ether solution was washed with sodium bicarbonate and water and dried. Evaporation provided an oil (4.45 g, 91%). This was in methanol (140 ml) and treated at room temperature with sodium hydroxide solution (in, 14 ml) for 2 1/4 hours. Hydrochloric acid (2N, 7 ml) was added and the alcohol was removed by evaporation. The aqueous phase was between Sodium bicarbonate solution and ether distributed. The ether layer was washed with water and dried. Evaporation provided an oil (2.16 g, 44%). This was refluxed directly in boiling methanol (70 ml) was hydrolyzed with sodium hydroxide (1N, 7 ml) for 4 hours. The methanol was removed by evaporation removed and the residue distributed between water and a little ether. The aqueous layer was diluted with ether pH 1.5 acidified and the ethereal layer was washed with water, dried and evaporated, whereby one pale off-white solid (1.97 g, 42%). Recrystallization from a mixture of benzene and cyclohexane

209848/1196

gave the title compound in the form of a colorless crystalline solid (1.61 g, 35%), m.p. 141 to 143 ° (dec.), A _max (StOH) 230.5, 253, 297.5 nm (£ 16,400, 7,400, 24,100) _P T (öMS0-d ₆ ) values include 2.00, 2.36, 255 (aromatic protons), 4.71 (CH ₂ singlet).

Manufacturing process 29

(a) (2-tert-Butoxycarboxamido) -etho3cyimino-thien-2-> ylacetic acid (syn isomer)

N-Carbo-tert-butoxy-2-bromoethylamine (1.12 g) was added to a solution of the sodium salt of methyl-syn-hydroxyimino-thien-2-ylacetate (1.035 g) in benzene: dimethylformamide {2% 1 V / 7, 30 ml) and the mixture was stirred for 16 hours. Ethyl acetate (50 ml) was added and the mixture was washed several times with water, dried and evaporated to dryness, giving methyl-syn- (2-tertφ-butoxy »carboxamidoethoxy) -imino-thien-2-ylacetate (1.21 g, 75%), € (CDCl ₃ ) values include 2.62, 2.86, 299 (thienyl protons), 5.10 (NH), 6.06 (s, CH ₃ ), 8.58 (s, C (CH ₃ ) ₃ ).

The crude ester (1.1 g) in methanol (20 ml) was treated with 2N sodium hydroxide solution (3.4 ml) and stored for 16 hours. The methanol was distilled off and the aqueous residue, after washing with ether, was acidified to pH 2.0 and extracted with ethyl acetate. The extracts were washed (water, saturated saline), dried and evaporated to dryness. Recrystallization of the residue from cyclohexane provided the title compound (951mg, 90%), mp. 112.8 to ^114> ^ °> * _max (EtOH) 290.5 nm (£ 11,600),% (DMSO-dg) values include 2.19, 2.6-2.9 (thienyl protons), 3.14 (NH), 8.52 (s, C (CH ₃ ) ₃ ).

The alkylating agent used for the above preparation was prepared as follows?

209848/1196

A mixture of tsrt * «Bi: tylazid.c:;: ^Y crmiat (15.81 g) and triethylamine (30 ml) was - dropwise? added to a stirred suspension of 2 ~ bro? diethyIa: i: L] ihydroDr: r: ld (20.5 g) in methylene chloride (100 ml). The mixture was stirred for 3 hours and then filtered., The filirate was concentrated to a small volume, and l "r residue was partitioned between ether and water. The Xthersoh.Lcit was dried and then was distilled under vermin -: '.- extern Ι ^: Γ ^ ύΐ, the fraction _s the bsi 92 to P - * ^ / O ₃ S ~ -K e: .edete was collected . It was N-Carbo-t9rt _f -butc: cy-2 »brc :): ätIi37lamin (1.756 g).

Manufacturing process 50

Pyrid-2-ylm9thcxyimino-'thian-2-yl) acetic acid (syn-isomeres)

2-chloromethylpyridine (a 25% solution in toluene, 2.8 ml) became a solution of the sodium saline of methyl-synhydroxyimino-thien-2-ylacetate (1.035 g) in benzene dimethylformamide (30 ml, 2: 1., V / V) »The solution was 18 hours stirred, ethyl acetate (50 ml) was added and the mixture was washed several times with water, dried and brothed Evaporated dry to give a dark green oil (1.4 g). This oil was preparative on two 40 χ 20 cm chromatographed on chromatographic plates, with Chloroform eluted. The only major band was eluted from the silica gel with chloroform: ethanol (9: 1 v / v), whereby one after evaporation of the solvent methyl-pyrid-2-ylmethoxyimino- (thien-2-yl) acetate obtained (889 mg, 47%) (75% syn, 25% anti isomer). A solution of the crude ester (828 mg) in methanol (20 ml) and 2N sodium hydroxide solution (3 ml) was stored for 16 hours. Refinement of the Methanol was the aqueous mixture in the presence of methylene chloride on a pK Werx. acidified by 2.0. the Acid mixture was extracted with methylene chloride and the Extracts were washed (water, brine), dried and evaporated to dryness. Rub in the residue with Ether provided the title compound (210 mg, 27%; m.p. 152.1 bis

20984S / 1136

_- 63 152.9 °, ^A mQY (EtOH) 260 _f 5, 266, 289 nm ( £ 12,300; 12,000;

III α. λ.

11,700), tr (DMS0-d ₆ ) values include 4.66 (singlet, CH ₂ ).

Production process 31 n-butoxyimino-thien-2-ylacetic acid (syn-isomer)

1-Bromobutane (0.6 ml) was added to a solution of methyl synhydroxyimino-thien-2-ylacetate sodium salt (produced by treating methyl-syn-hydroxyimino-thien-2-ylacetate with ι Equ. -Sodium methylate) (1.0 g) in benzene: dimethylformamide (2: 1, 15 ml) and the mixture was stirred at room temperature for 17 hours and then poured into water. the aqueous solution was extracted with ethyl acetate, washed with water and dried and evaporated to give syn methyl ester (0.88 g) was obtained as a pale yellow oil.

2N sodium hydroxide (4.0 ml) was added to a solution of the syn methyl ester (0.85 g) in methanol (10 ml) and the mixture was kept at room temperature for 18 hours. The methanol was removed by evaporation, the aqueous residue was diluted with water, washed with ether and acidified to pH 2.0 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined extracts washed with water, dried and evaporated to give the title compound (0.74 g, $ 81) as a pale yellow oil, f (DMSO-dg) values include 2, 30 2.7 to 3.0 (thien-2-yl protons), 5.84 (OCH ₂ ), 9.10 (CH ₃ ).

Manufacturing process 32

2-methoxymethoxyimino (thien-2-yl) acetic acid (syn isomer)

A solution of sodium methylate in methanol (approximately 0.2m) was added to methyl 2-hydroxyimino-2- (thien-2-yl) acetate (syn-isomer) (0.5 g) and the resulting solution was evaporated, a yellow oil was obtained which was distilled azeotropically with petroleum ether (b.p. 40 to 60 °)

209848/1196

Sodium salt of methyl 2-hydroxyimino-2- (thien-2 ~ yl) acetate (syn-isomeres) (0.49 g »88%) was obtained. To a stirred solution of the sodium salt (0.49 g) in benzene / DMF (5 ml, 2: 1) was added chlorodimethyl ether (0.22 ml). After 10 minutes the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with benzene. The combined extracts were with. Washed water, dried over sodium sulfate and evaporated to give a yellow oil, methyl 2-methoxymethoxyimino (thien-2-yl) acetate (syn-isomer) (0.62 g, 100%), 7 \ _max ( EtOH) 288 nm (£ 10,300), ^ _max (CHBr ₃ ) 173O (COOCH ₃ ), 1660 cm " ¹ (-C = N-), TXCDCl ₃ ) values range from 2.61 to 2.83 (multiplet, Thien-2-yl), 4.83 (singlet, CH ₂ ), 6.06 (CO ₂ CH ₃ ) 6.56 (singlet, CH ₂ OCH ₃ ).

A solution of sodium hydroxide (4 ml, 2N) and methanol was added to the methyl ester (0.4 g). After 30 minutes the Mixture poured into water / water, washed with ethyl acetate. The aqueous layer was purified using 2N hydrochloric acid acidified to pH 1 and extracted with ethyl acetate. The ethyl acetate was dried and evaporated, a colorless oil was obtained; which was azeotroped with petroleum ether (bp 40 to 60 °), whereby one colorless solid, syn-2-methoxymethoxyimino (thien-2-yl) acetic acid (0.21 g, 55%) was obtained, mp 61.2 °, A (EtOH) 286 nm

1 max

(£ 10 400), U _m ( Nujol) 1732, 2600 cm "'(CO ₉ H), ΐ (DMSO-d, -) values include 2.26 (multiplet; thienyl H ₅ ), 2.7 to 2 , 9 (multiplet, thienyl H ₃ and H ^) 4.88 (singlet, O-CH ₂ -), 6.6 (singlet, OCH ₃ ).

Manufacturing process 33

2-tert-butoxyiminobenzo [b] -thien-2'-ylacetic acid (syn isomer)

Benzo [b] -thien-2-ylglyoxylic acid (3.09 g) and tert-butoxyamino hydrochloride (1.98 g) are dissolved in 50% aqueous ethanol (100 ml). The solution was made with sodium hydroxide solution adjusted to a pH of 4.5 and stored for 4 hours at room temperature. Thin layer chromatography showed

209848 / ' 136

only an incomplete conversion _o tert-butoxyarainohydrochloride (500 mg) was added and the solution was stored at room temperature overnight. The alcohol was removed by evaporation and the aqueous phase was adjusted to pH 8 and washed with ether. The aqueous phase was then adjusted to pH 1.5 under ether. The ether solution was washed with water and dried. Evaporation provided an off-white solid (4.05 g). Fractional crystallization from cyclohexane gave the anti-isomer of the title compound (1.6 g). The mother liquors were combined and evaporated to give an off-white solid (2.11 g) which was treated in ether with excess diazomethane in ether at 0-5 °. The excess reagent was destroyed by acetic acid and the ether solution was washed with sodium bicarbonate, water and dried. Evaporation provided an oil (1.75 g). This was dissolved in methanol (70 ml) and treated with sodium hydroxide solution (n; 7 ml) at room temperature for 3 hours. Hydrochloric acid (2N, 3 »5 ml) was added and the methanol was removed by evaporation. The aqueous residue was partitioned between ether and sodium bicarbonate solution. The ether layer was washed with water and dried. Evaporation gave an oil (0.92 g) which was dissolved in methanol (20 ml) and treated with sodium hydroxide (n, 7 ml) at reflux temperature for 3 hours. Sodium hydroxide (n, 5 ml) was added and the solution was refluxed for 6 hours. The methanol was removed by evaporation and the residue was partitioned between ether and water. The aqueous phase was acidified under ether (pH 1.5) and the ether layer was washed with water, dried and evaporated to give a pale orange-colored crystalline solid (760 mg, 18%).

Crystallization from benzene containing cyclohexane gave syn-tert-butoxyiminobenzo [b] -thien-2-ylacetic acid (430 mg), m.p. _{108-109, A max} (EtOH) 231, 253, 297 nm (£ 17 000, 7240, 24 500).

209848/1196

Manufacturing process 34

Benzo [b] -thien-2-ylglyoxyic acid and benzo [b] -thien-3-yl-glyoxylic acid

A mixture of 2- and 3-acetylbenzo [b] thiophene (about 1: 1) (11.0 g) in pyridine (50 ml) was ^{heated to 60 °} C. with vigorous stirring and selenium dioxide (9.92 g) were added in portions. The mixture was heated to 110 ⁰ C and an exothermic reaction occurred, the temperature increased to 120 °. The reaction mixture was stirred at 90 ° for 45 minutes and then allowed to cool. Water (80 ml) was added and the mixture was filtered through a bed of kieselguhr. The pyridine was removed by evaporation and the aqueous residue filtered again. The filtrate was acidified to pH 2 with 40% o-phosphoric acid (40 ml) under ether.

The aqueous phase was extracted with ether and the ether fractions were combined, washed with water and dried. Evaporation provided an orange crystalline solid (11.0 g, 86Sa) ₁ . Crystallization from benzene (100 ml) gave pale yellow crystals of benzo [b] -thien-2 ~ ylglyoxylic acid (2.3 g, 1855), melting point 175.9 °, \ _{ι & χ} (EtOH) 233, 247, "? \ _Nfl .308 nm ( L 11 400, 7200, 14 600), £ * (BMSO-dg) values include 1.83 (C-4 and C-7 protons), 1.42 (C-3 protons), 2, 40 (C-5 and C-6 protons).

The mother liquors were concentrated to give an orange oil which crystallized on standing (8 g). Recrystallization from benzene (20 ml) gave pale yellow needles from benzo [b] -thien-3-ylglyoxylic acid (1.6 g, 12.5? 0, melting point 92 to 93 °,

V (DMSO-dg) values include 0.83 (C-2 proton), 1.32 (C-4 proton), 1.79 (C-7 proton), 2.40 (C-5 and C-6 Protons), A (EtOH) 235, 310.5 nm (£ 11,200 and 7,400)

209848/1198

2-alkoxviminoyrylacetyl chlorides Manufacturing process 35

syn-2-methoxyiminophenylacetyl chloride

Phosphorus pentachloride (5 »21 g) was stirred in portions to one Suspension of syn-2-methoxyiminophenylacetic acid (4.51 g) in dry benzene (20 ml). Thionyl chloride (0.3 ml) was added added to the solution which was heated to reflux for 30 minutes. Benzene was removed by evaporation and the residue was distilled, using a mixture of syn and anti acid chlorides (approx. 1: 1) as a colorless oil (3.08 g, 62%) received, bp 74 ° (0.01 mm). A repetition of this reaction (with 5.04 mmol) at room temperature gave a mixture of the isomeric acid chlorides.

The acid chlorides were separated and prepared by preparative Purified plate chromatography, eluting three times with petroleum ether (bp 60 to 80 °) and the title compound as colorless oil (1.43 g, 24%) was obtained.

In another experiment, a mixture of the syn- and anti-2-methoxyiminophenylacetic acids (10 g, approx. 1: 1) transferred into a mixture of the acid chlorides as above and attached to silica gel (120 g, Hopkins and Williams MFC) using petroleum ether (b.p. 60 to 80 °) chromatographed, the syn -2-methoxyiminophenylacetyl chloride was obtained (4.32 g, 39%).

General procedure to convert 2-alkoxyiminoarylacetic acid into the To convert acid chloride without isomerization

A solution of the pure syn- or 2-alkoxyiminoarylacetic acid (1 eq.) In methanol (approx. 2 to 4 ml / mmol) was treated with sodium methylate (1 eq.) In methanol at 0-25 ° and the mixture was evaporated to give the sodium salt, which is dried by azeotropic distillation with a few portions of benzene and / or drying in vacuo over phosphorus pentoxide became.

209848/1196

The anhydrous sodium salt (1 eq.) Is dissolved in dry benzene (approx. 5 ml / mmol) containing a few drops of dry dimethylformamide contains, suspended and treated with freshly distilled oxalyl chloride (1 to 2.5 eq.). The mixture will be at Stirred at room temperature for 1 hour and then evaporated to remove the benzene. The resulting acid chlorides were not characterized, but dissolved in acetone or methylene chloride and used immediately to prepare the corresponding To acylate cephalosporin nucleus or the corresponding cephalosporin compound.

The following acids were converted into their acid chlorides in this way:
syn-2-ethoxyiminophenylacetic acid,
syn-2-tert-butoxyiminophenylacetic acid, syn-2-benzyloxyiminophenylacetic acid, syn-2-then-2'-yloxyiminophenylacetic acid, syn-2-methoxyimino- (thien-2-yl) -acetic acid, syn-2-ethoxyimino- (thiene -2-yl) acetic acid, syn-2-benzyloxyimino (fur-2-yl) acetic acid, syn ~ 2-n-buto} ryimino ~ (thien-2-yl) acetic acid, syn-2-tert. -Butoxyimino- (thien-2-yl) -acetic acid, syn-2- (2-bromoethoxy) -imino- (thieu-2-yl) -acetic acid, syn-2- (2-tert-butoxycarbonylaminoethoxy) -imino- (thi en-2-yl) -

acetic acid,

syn-2-Benzyloxyimino- (thien-2-yl) -acetic acid, syn-2-Then-2'-yloxyimino- (thien-2-yl) -acetic acid, syn-2- (1-ethoxy) -ethoxyimino- (thien-2-yl) -acetic acid, syn-2- (pyrid-2-ylmethyl) -oxyimino- (thien-2-yl) -acetic acid, syn-2-methoxyiminonaphth-1'-ylacetic acid, syn-2-tert-butoxyiminonaphth-1'-ylacetic acid, syn-2-benzyloxyiminonaphth-1'-ylacetic acid, syn-2-methoxyiminobenzo [b] -thien-3'-ylacetic acid, syn-2-tert-butoxyaminobenzo [b J-thien-3'-ylacetic acid, syn-2-Benzyloxyirninobenzo [b] -thien-3'-ylacetic acid, syn-2-methoxyiminobenzo [b] -thien-2'-ylacetic acid, syn-2-tert-butoxyiminobenzo [b] -thien-2'-ylacetic acid,

209848/1196

syn-2-Benzyloxyiminobenzo [b] -thien-2'-ylacetic acid, syn-2-methoxyimino (fur-2-yl) acetic acid, syn-2-tert-butoxyimino (fur-2-yl) acetic acid, syn-2-benzyloxyimino- (fur-2-yl) -acetic acid, syn-2-furfuryloxyimino- (fur-2-yl) -acetic acid, and syn-2-ethoxyimino (fur-2-yl) acetic acid.

example 1

3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

To a solution of dicyclohexylcarbodiimide (1.15 g) and tert-butyl-3-acetoxymethyl-7β-aminoceph-3-era-4-carboxylate (1.83 g) in dry methylene chloride (30 ml) is added to a solution of syn-2-methoxyiminophenylacetic acid (1 g) in dry methylene chloride (15 ml) and stir the resulting solution at room temperature for 1.5 hours. After filtration, the Filtrate with 2N hydrochloric acid, water, saturated Sodium bicarbonate solution and water washed, dried and evaporated to give an orange foam (2.60 g). A portion of this foam (0.21 g) was washed with petroleum ether (Bp. 60 to 80 °) triturated, with syn-tert-butyl-3-acetoxymethyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4- carboxylate as a solid (0.15 g). Λ (EtOH)

-ι max

258 nm (£ 17,400) O _m ^ (CHBrJ 1784 cm "'(β-lactam, T (CDCI ,,) 2.99 (doublet, J 9.0; NH), 2.2 to 2.7 (multiplets , Ph), 5.97 (singlet; OCH ₃ ), 7.93 (singlet; acetate), 8.48 (singlet tert-butyl),

The remainder of the foam (2.4 g) was stirred with trifluoroacetic acid (10 ml) at room temperature for 10 minutes and evaporated to give an oil. Ether (^ - / 80 ml) was added to give a solution from which syn-3-acetoxymethyl-7ß - ^ - methoxyimino ^ -phenylacetamido) -ceph-3-em-4-carboxylic acid precipitated as a colorless solid on standing (1.58 g, 66 ° / ₀ ), [ccjjp + 55 ° (c, 1.02 in dioxane), A ^ _x (pH 6

Phosphate buffer), 258 nm (£ 19,550), O '(NuJoI) 1782 cm " ¹

IUcLjC

IUcLjC

209848/1 196

(ß-lactam), T (DMSO-Cl ₆ ) 0.21 (doublet, J 8.0 Hz; NH), 2.3 to 2.6 (multiplet; Ph), 6.08 (singlet; OCH ₃ ) , 7.98 (singlet, acetate).

Example 2

3-crotonyloxymethyl-7ß- (S-methoxyimino ^ -phenylacetamido) ceph-3-em ^ - carboxylic acid (sjTi-IsoRieres)

A suspension of diphyriethyl-7β-amino-3-crotonoyloxymethylceph-3-em-4-carbox7late-toluene-p-sulfonate salt (1.0 g) in ethyl acetate (20 ml) was shaken with sodium bicarbonate solution. The ethyl acetate layer was washed with water and brine, dried and concentrated under reduced pressure. The residue vnirde (10 ml) and dicyclohexylcarbodiimide (O ₅ 324 g) was added in methylene chloride. The solution was treated with 2-I-ethoxyimino- ^ - phenylacetic acid (syn-isomeres) (0.281 g). After 1 hour the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with 2N hydrochloric acid, TaivriunMcarb & riatlösung, water and brine _. dried and concentrated under reduced pressure. The disfiguring foam (1.0 "g) was dissolved in anisole (2 ml) and the solution was treated with trifluoroacetic acid (8 ml). After 5 minutes at 20 ° the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and this solution was extracted several times with sodium bicarbonate solution. The combined extracts were washed with ethyl acetate and then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated under reduced pressure, and added to stirred petroleum ether , whereby the title aethoxime precipitated (0.467 g, 67/0 »[cc] _D -37.3 ° (c 0.9 in DMSO), A _max (pH 6 phosphate buffer) 258 mn (£ 17 800) O _av (Nujol) 1782 (β-lactam), 1710 (CO.-H), I68O

- 1
and 1540 (CONH) and 1660 cm (unsaturated ester)

100 MHz) 0.19 (doublet, J 8 Hz), 3.03 (multiplet; CH = CH-CH ₃ )

208848/1196

6.06 (singlet; NOCH ₃ ), 6.28 and 6.50 [2 doublets (two of a quartet), J 18 Hz; C-2 CH ₂ ], and 8.12 (double doublet, J 7 and 1.5 Hz; CH = CH-CH ₃ ).

Examples 3 "to 11

General methods for the preparation of 7ß- (2-alkoxyimino-2-subst.acetamido) -3- (subst.) Methylceph-3-em-4-carboxylic acids using dicyclohexylcarbodiimide

(i) Preparation of intermediate 4-carboxylic acid esters

Procedure A

To a solution of tert-butyl or diphenylmethyl esters of 7ß-araino-3- (sübst.) Raethylceph-3-em-4-carboxylic acid (1 eq.) and dicyclohexylcarbodiimide (1 to 1.2 eq.) in dry methylene chloride (as cosolvents were for example Dmethylformamide or dioxane used) a solution of the syn-2-alkoxyimino-substituted acetic acid (1 eq.) Was added at 0 to 20 ° in dry methylene chloride. After stirring for 45 minutes up to 3 hours at room temperature, the mixture was filtered, the filtrate was washed successively with 2N hydrogen chloride acid, saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried and evaporated to give the desired ester as an oil or foam.

Procedure B

As above, with the dimethyl ether instead of methylene chloride of diethylene glycol used.

Procedure C

Same as Method A, except that the ester is obtained by chromatography Silica gel cleaned.

Method D

Same as method A, but with the previous regeneration of the

2098Λ8 / 1136

7ß-amino ester from its p-toluenesulfonic acid salt (1 eq.) by shaking with ethyl acetate and an excess of saturated sodium carbonate solution. After washing with Water and brine, the organic layer was evaporated to dryness and redissolved in methylene chloride.

(ii) Cleavage of the protecting groups in the intermediate esters Method E

The tert-butyl or diphenylmethyl ester was dissolved in trifluoroacetic acid (5 to 10 ml / g ester) dissolved and left to stand at room temperature for 5 to 10 minutes and then under evaporated under reduced pressure. The crude product was taken up in ether or ethyl acetate, in aqueous sodium hydrogen carbonate solution extracted and washed with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid and extracted into ethyl acetate. The organic layer was washed, dried and evaporated to give the desired syn-7β- (2-alkoxyimino-2- subst.acetamido) -3- (subst.) methylceph-3-em-4-carboxylic acid received.

Method F

The ester was dissolved in anisole (1 to 5 ml / g ester) and mixed with Trifluoroacetic acid (4 to 10 ml / g ester) at room temperature for 5 to 10 minutes and then treated as in Method E described worked up.

(iii) Preparation of diphenylmethyl-7β-amino-3-cyclopropylcarbonyloxymethylceph ^ -em ^ -carboxylate-ptoluenesulfonic acid salt used as the starting material in Example 11

(a) Diphenylmethyl-3-cyclopropylcarbonyloxymethyl-7β- (thien-2-yl) -acetamidoceph-3-em-4-carboxylate

To a stirred solution of diphenylmethyl-3-hydroxymethyl-7β- (thien-2-yl) -acetamidoceph-3-em-4-carboxylate (8 g) in dry tetrahydrofuran (20 ml), the anhydrous pyridine

209848/1 1 96

(6.7 ml) was added a solution of cyclopropanecarbonyl chloride (from 6.7 g of acid and thionyl chloride at room temperature over 90 minutes) in dry tetrahydrofuran (10 ml) over a period of 10 minutes at room temperature, after stirring at room temperature for For 2 hours the mixture was evaporated to near dryness and diluted with ethyl acetate (100 ml). The mixture was washed successively with sodium hydrogen carbonate solution, 2N hydrochloric acid and water. The organic layer was stirred with activated charcoal at room temperature for 1 hour, filtered, and the filtrate was evaporated to give a foam. Trituration with petroleum ether (b.p. 60 to 80 °) gave the title ester (7.8 g, 87%), [a] _D + 28 ° (c 0.83 in dioxane) ^A _inf . (EtOH) 235, 255 nm (£ 12,800,7,700), V? _max (CHBr ₃ ) 1790 (ß-lactam), 1728 cm " ¹ (ester) T (DMSO-dg) values include 0.8 (doublet NtI),

3.02 (CHPh ₂ ), 8.4 (multiplet, -CHj), 9.0 to 9.2 (CH ₂ groups in the cyclopropane ring).

Example 3

(a) tert -Butyl 3-methyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)

was obtained as a yellow solid, melting point 66 ° (decomp.), A _n ,,, "

Iu Q Λ

(EtOH) 255 nm (£ 16,350), V _ov (CHBr,) 1785 (β-lactam), 1720

max λ j

(tert-butyl ester), 1690, 1520 cm "'(CONFl); V (CDCl ₃ ) 3.02 (doublet J 8.0 Hz; NH) 2.3 to 2.7 (multiplet, Ph), 5, 96 (singlet; OCH ₃ ), 7.89 (singlet, CH ₃ , 8.48 (singlet, t-butyl). Deprotection according to Method E gave

(b) 3-Methyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

as a cream-colored solid, (67%), m.p. 145 ° (decomp.) [a] _D ⁷ + 100 ° (c 1.32 in dioxane), ^ _max (pH 6.0 phosphate buffer) 258 to 259 nm (<£ 18 65O), p _max (Nujol) I76O (β-lactam), 1702 (CO ₂ H), 1660, 1536 (CONH), £ (DMSO-d ₆ ) 0.24 (doublet, J 8.0 Hz; NH ),

2.3 to 2.6 (multiplet »Ph), 6.05 (singlet, OCH ₃ ), 7.94

209848/1196

(Singlet; CH ₃ ). Example 4

D ld JL ti IJ J. ti X H

(a) tert-Butyl- (3-acetoxymethyl-7β- (2-benzyloxyimino-2 ~ phcnylacetamido) -c-9pli.-3-em-4-carboxylate (syn-isomer)

Mp. 123 Ms 125 °, A _Wilv (EtOH) 259 nm (£ 20,500 ), Ό (CHBr ₃ ) 1796 (ß-lactan), V 1522 cm " ¹ (COIH), T (CdQI-

1732 (acetate and ester), 1694 and.) 3.00 (doublet, J 9.0 Hz, NH), 2.38, 2.60 (HultiplsT-t, Ph), 2.60 (benzyl-aromatic protons), 4.74 (singlet, methylene group of benzyl), 7.94 (singlet, acetate), 8.48 (singlet, tert-butyl) was prepared according to method A. obtain. The protective groups were split off according to method E, and resulted in:

(b) 3-Acetoxymethyl-7β- (2-benzyloxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

as a colorless solid (5S $ 0, m.p. 167 ° (decomp.), [a] ^ ⁶ + 50.5 ° (c, 0.85 in dioxane), A _m (pH 6 ^ 0 phosphate buffer) 259 nm (i 20 700), v> _mwy . (Ν1130Ϊ) 1771 (ö-Lactara), 1735, 1252 (acetate), 165O and 1530 a " ¹ 'COIiH), Z (DMS0-d ₆ ) 0.14 (doublet, J 8, 0 Hz, NH), 2.3 to 2.7 (multiplet, aromatic protons), 4.79 (singlet, CHp of benzyl group), 7.96 (singlet, acetate).

Example 5

(a) Diphenylmethyl 7β- (2-methoxyimino-2-phenylacetamido) -3-methylth-ethyl-ethylceph-3-em-4-carboxylate (syn isomer)

^{/ V} max ^{(EtOH) 2D9 nm} (£ ^{10 55O)} '^ niax ( ^CHBr ₃ ) ¹ ^ Ö5 (β-lactam), 1722 (benzhydryl ester), 1688 and 1518 cm " ¹ (COWH); T (CDCl ₃ ) 3 .01 (doublet 7 Hz, NH), 2.32, 2.64, 2.65 (aromatic protons) 5.97 (singlet, OCH ₃ ), 8.16 (singlet, SCH ₃ ) was prepared according to method A. The subsequent splitting off of the protective groups according to process E yielded

2Q9848 / 119G

(b) 3-methylthiomethyl-7ß- (2-methoxyimino-2-phenylacetamido) ceph-3-em-4-carboxylic acid (syn-isomeres)

as a precipitated solid (51S0, [α] ^ ⁶ + 51 ° (c, 0.98 in dioxane), 7 ^ - _mQV (pH 6.0 phosphate buffer) 259 nm (£ 18,300),

l ^ _MV (Nujol) 1781 (ß-lactam), 1770 (CO ₉ Il), 1670 and 1531 cm " ¹ max <-

(COIIH), C (DMSO-dg) 0.22 (doublet J 9 Hz; NH), 6.06 (singlet, OCH ₃ ), 8.01 (singlet SCH ₃ ).

Example 6

(a) Diphenylmethyl-3-benzoyloxymethyl ~ 7β- (2-methoxyimino-2 ~ phenylacetamido) -ceph-3-em-4-car "boxylat (syn-isomeres)

was obtained as a crude orange solid (80%) by method Λ. Cleavage of the protecting groups according to method F provided

(b) 3-Benzoyloxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

as colorless powder (48%), O] _n + 46.5 ° (c 0.9 in DMSO), A (pH 6 phosphate buffer) 232.5 (£ 22 400) and 258.5 nm ( I 21 400), v> _v (Nujol) 1780 (ß-lactam), 1720 and 1265 (benzoate), 1705 (CO _? H), 1675 and 1532 cm "'" (CONH), Z (DMSO-dg, 100 MHz), 0, 16 (doublet, J 8 Hz; NH), 4.06 (double doublet, J 5 and 8 Hz; C-7H), 4.70 (doublet, J 5 Hz; C-6 H), 6.03 (singlet , NOCH ₃ ) and 6.14 and 6.44 [2 doublets (Zv / eige of a quartet), J 18 Hz; C-2 CH ₂ ].

Example 7

(a) Diphenylmethyl J-isobutyryloxymethyl ^ ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)

vnirde prepared according to method A and the protecting groups have been made cleaved without purification according to process F, wherein one

(b) 3-Isobutyryloxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomeres) (73%) received,

209848/1196

- 76 Fa] _n + 48.5 ° (c 1.0 in DMSO), λ _ην (pH 6 phosphate) 258 nm

L) ■ - ΙΩαΛ.

(18 700), y ^ rnax (Nujol) 1783 (β-lactam), 1725 (carboxylic acid ester and acid), '1670 and 1530 cm " ¹ (CONIi), ~ (DMS0-d ₆ ; 100 MHz), 0.19 (Doublet, J 8 Hz; NH) 2.2 to 2.6 (multiplet, aromatic protons), 4.09 (double doublet, J 5 and 8 Hz; C-7H), 4.76 (doublet, J 5 Hz ; C-6 H), 4.94 and 5.26 [2 doublets, (branches of a quartet), J 13 Hz; C-3 CH ₂ J, 6.04 (singlet; NOCH ₃ ), 6.28 + 6 , 50 [2 doublets (branches of a quartet), J 18 Hz, C-2 CH ₂ ], 7.40 (septet, J 7 Hz; CH (CH,) ₂ ) and 8.80 (doublet, J 7 Hz; CH (CH ₃ ) ₂ ).

Example 8

(a) tert -Butyl 3-acetoxymethyl-7β- [2-methoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylate (syn isomer)

was obtained as a solid ($ 85), A _m . (EtOH) 262 to 263 nm,

UIaLn.

(£ 14 900), A. _{inf #} 280 nm (£ 13 280), v ^ _max (CHBr ₃ ) 3400

(NH); 1780 (β-lactam), 1738, 1120 (CO ₂ R) and 1684, 1514 cm " ¹ (CONH) T (CDCl ₃ ) 2.5 to 2.7, 2.95 (Thieny! Protons), 5.97 (OMe), 7.93 (OAc), and 8.48 (tert-butyl) according to method Λ. Cleavage of the protecting groups according to method E yielded the free acid:

(b) 3-Acetoxymethyl-7β - ([2-methoxyimino-2- (thienyl-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

(56%), [a] {p + 60 ° (c, 0.8 in dioxane), / \ _{& χ} 262 nm (£ 15 700), ⁷ V- _, ___ 290 nm (£ 10 700), \? 3275 (NH), 1768 (ß-lactam),

1728 (OAc), 1700, 2600 (CO ₂ H) and 1648, 1520 cm "'(CONH), T (DMSO-d ₆ ) 2.2-2.9 (thienyl), 6.08 (OMe), 0 , 13 (NH), 4.12, 4.76 (β-lactam), 6.28, 6.52 (J 18 Hz, CH ₂ in ring), A, 94, 5.27 (J 13 Hz, CH ₂ OAc) and 7.94 (OAc).

Example 9

(a) tert-Butyl-3-acetoxymethyl-7β- (2-tert-butoxyimino-2-phenylncoi.nnidoJ-ceph-S-em-A-carboxylate (syn-Jsomeres)

became-]] θ] · ₍ ^ -π1π] It grinäß Voi'fahren] 3 and by chromatography ο

Purified on silica gel according to method C to give a pale yellow foam (43/0, which was recrystallized from isopropyl ether to give the ester, mp 150-153 °, T "(CDCl ₃ ) 2.2-2 .75 (multiplet, aromatic protons), 2.83 (doublet, NH), 8.61 (tert-butoximine), 8.46 (tert-butyl ester). Cleavage of the protective groups according to method F yielded

(b) 3-acetoxymethyl-7β- (2-tert-butoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

as a pale yellow foam, ν * (CHBr ^) 1782 (ß-lactam), λ max j

1685, 1522 cm "'(CONH) V (DMSO-dg) 2.2 to 2.75 (multiplet, aromatic protons), 0.4 (doublet, NH), 8.70 (tert-butoxime),

Example 10

(a) tert -Butyl 3-acetoxymethyl-7β- [2-methoxymethoxyimino-2- • (thien-2-yl) acetamido] ceph-3-em-4-carboxylate (syn isomer)

^K max ^{(Et0H) 26} ° ⁵ ^ ^{( ε 12 940)} »^ max ( ^CHBr ₃ ) ¹ ? 78 (ß-lactam), 1688 and 1510 cm" ¹ (CONH) ₁ T (CDCl ₃ ) 2.74 (doublet , NH), 4.76

(-OCH ₂ OCH ₃ ), 6.49 (OCH ₂ OCH ₃ ), 7.91 (OCOCH ₃ ), 8.44

was made by Method A and then by Method E.

treated with trifluoroacetic acid, whereby one

(b) 3-Acetoxymethyl-7β- [2-methoxymethoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

received, [a] "+ 51 ° (0.8, DMSO), A _mnv (pH 6 phosphate buffer) 262.5 nm (£ 16,400), \> _max (Nujol) 1778 (β-lactam), 1670, 1530 cm " ¹ (CONH), IT (DMSO-CL ₆ ) 0.11 (doublet, NH), 4.89 (OCH ₀ OCH ₇ ), 6.62 (OCH ₀ OCH-,), 7.96 (OCOCH, ,).

Example 11

(a) Diphenylmethyl-3-cyclopropylcarbonyloxymethyl-7β- (2-ethoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)

A _max (KtOH) 256.5 nm ( £ 15 800), V> _max (CHBr ₃ ) 1780 (ß-lactam),

2 09848/1196

1680, 1510 (CONH), 1720 cm " ¹ (ester), T (BMSO-dg) values include 0.19 (doublet, KH), 3.01 (CHPh ₂ ), 5.76 (CH ₂₃

8.68 (CH ₇ ), 8.35 (multiple y <3 ) _f 9.2 (CH ₂ groups in the cyclo-

propane ring) vmrde prepared according to procedure C and then were split off the protective groups according to process F, wherein one

(b) 3-Cycloi-propylcarbonyloxymethyl-7β- (2-ethoxyimino-2-phenyl ~ acetamido) -ceph-3-ent-4-carboxylic acid (syn-isomer)

received, [a] _n + 75 °, (c 0.86 dioxane), / \ _ (pH 6 phosphate- ij max j,

buffer) 257 nm (£ 16,000), \> _m _ (Nirjol) 1780 cm " ¹ (ß-lactam),

Max.

tr (DMSO-dg) fourths include 0.25 (doublet NH), 5.80 (CH 8.73 ()

Example 12

3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetainido) -ceph-3-em-4-carboxylic acid (syn isomer)

To a cold (0 to 5 °) solution of 3-acetoxymethyl-7ßaminoceph-3-em-4-carboxylic acid (0.565 g) in acetone (10 ml) and water (10 ml), the anhydrous sodium bicarbonate (0.42 g) a solution of syn-2-methoxyiminophenylacetyl chloride (0.495 g) in acetone (5 ml) was added over 5 minutes. The solution was stirred at room temperature for 30 minutes and then evaporated to remove the acetone. The solution was washed with ether (20 ml) and the aqueous phase was acidified under ethyl acetate (50 ml) to a pH of 2 with 2N hydrochloric acid. The mixture was filtered and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to give a colorless solid (0.48 g). This was triturated with ether, whereby the title compound was obtained (0.45 g, 64 $ ί), ["Jr / + 56 ° (1.04 in dioxane), Λ _ΜΤ (pH 6 phosphate buffer) 259 mn (£ 19,700 ),

^ max ( ^IIu J ^o1 ) ¹⁷⁷⁸ («-lactam), 1740, 1262 (OCOCH ₃ ) 1712 (COpII), 1660, 1534 cm" ¹ (COHH), Z (DKSO-d ^ V / erte include 0.2

209848/1 196

(Doublet, J 8.0 Hz, NH), 2.3 Ms 2.6 (multiplet; Ph), 6.05 (singlet, OCH ₃ ), 7.94 (singlet, acetate).

Example 13

3-acetoxymethyl-7β- (2-ethoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

Oxalyl chloride (0.26 ml) was added to a suspension of sodium syn-ethoxyiminophenyl acetate [prepared from the corresponding acid (300 mg) and 0.43N sodium methoxide solution (3.62 ml) and dried over phosphorus pentoxide] in dry benzene (20 ml), which contained a drop of dimethylformamide. After stirring for 1 hour, the mixture was evaporated to dryness at room temperature. The residue was dissolved in acetone (15 ml), this solution was added dropwise to an ice-cooled, stirred solution of 7β-aminocephalosporanic acid (424 mg) in water (20 ml) containing sodium bicarbonate (262 mg). The mixture was stirred for 2 hours, then the acetone was evaporated and the aqueous solution acidified to pH 1.5. The mixture was extracted with ethyl acetate, the extracts combined, washed (water, brine) and dried. Evaporation of the extracts gave the title compound (622 mg, 89? 0 as colorless foam, [a] n + 56 ° (c 1.04 dioxane), / V _mov (pH 6 phosphate buffer), 257.5 nm (S 20 200) , ν> _ν (Nujol) 1772 (.beta.-lactam), 1656 and 1518 cm ^"l ~ (COMI), Ct values (BMSO-dg) include 0.23 (doublet, J 8 Hz, NII), 2.3 to 2.6 (multiplet, aromatic protons), 5.75 (quartet, CH ₂ CH ₅ ), 8.68 (triplet, CH ₂ CH ₃ ), 7.96 (OCOCH ₃ ).

Example 14

3-acetoxymethyl-7β- (2-tert-butoxyiminothien-2'-ylacetamido) -ceph-3-em - ^ - carboxylic acid (syn isomer)

Methanolic lithium methylate (0.53N, 7.5 ml) was added dropwise to a stirred solution of syn-tert.-Butoxyimi.no-

2 0 9 8 k 8/1 Ί Ώ G

thien-2-ylacetic acid (0.9 g) in dry methanol (10 ml) at 0-5 °. The mixture was evaporated to remove the methanol and dried by azeotropic distillation with dry benzene. Oxalyl chloride (0.63 ml, 0.95 g) was added to the stirred suspension of the sodium salt and dimethylformamide (3 drops) in dry benzene (40 ml). The mixture was stirred at room temperature for 1 hour and evaporated to remove the benzene. The acid chloride in acetone (10 ml) was added dropwise to a stirred solution of 7β-aminocephalosporanic acid (1.09 g) and sodium bicarbonate (0.672 g) in acetone (20 ml) and water (20 ml) at 0-5 ° and the The mixture was stirred at room temperature for 2 hours. The resulting solution was evaporated to remove the acetone and washed with ethyl acetate. The aqueous solution was acidified to pH 1.5 with 2N hydrochloric acid in the presence of ethyl acetate and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated to give the title compound (1.15 g, 61%) as a pale yellow foam, [<x] ip + 61 ° (c 1.0, dioxane), Ä _mov (pH 6 phosphate buffer) 260 nm (£ 12 500), ι? '(NuJoI) 1780 (β-lactam) 1666 and 1520 cm

Max

(COOTi), Tars (DMSO-dg) include 0.28 (doublet, J 8 Hz, NH) 2.36 (1H) and 2.84 (2H) (dien-2-yl protons), 7.98 ( OAc), 8.68 ¹

Example 15

3-acetoxymethyl-7β- (2-tert-butoxyiminobenzo [b] -thien-3'-ylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

syn-tert-butoxyiminobenzo [b] -thien-3-ylacetic acid (0.976 g) was treated with sodium methylate solution (0.445 mm, 6.1 ml) at room temperature treated. Evaporation provided the sodium salt as a colorless powder (1.05 g). This was via phosphorus pentoxide dried over after.

209848/1196

The sodium salt (0.5 g) suspended in dry benzene (10 ml) containing dimethylformamide (1 drop) was treated with oxalyl chloride (0.4 ml) at room temperature for 1 hour. The solvent was removed by evaporation and the residue in acetone (20 ml) was added dropwise to a solution of 7β-aminocephalosporanic acid (0.49 g) and sodium bicarbonate (0.378 g) in water (30 ml) at 0-5 °. The resulting pale yellow suspension was stirred at room temperature for 2 1/2 hours. The acetone was removed by evaporation and the aqueous phase was acidified to pH 2 under ether. The ether fraction was washed with water and dried. Evaporation gave a cream colored foam which was dissolved in methylene chloride and evaporated again to give the title _{compound after drying (0.85 g, 9596), [α] β} + 61 ° (c 1 dioxane), ^ mgjs. (pH 6 buffer), 230, 297, 304 inf. nm (£ 27,600 , 11,500, 10,630), ΐ (DMSO-d ₆ ) values include 0.29 (doublet, NH), 4.04 (double doublet, 7 proton), 4.73 (doublet, 6 proton), 8.59 (Bu *).

Example 16

3-acetoxymethyl-7β- (2-tert-butoxyiminofur-2'-ylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

syn-tert-Butoxyiminofur-2-ylacetic acid (2.11 g) was used in Treated room temperature with sodium methylate (0.525 m, 19 »1 ml)". The methanol was removed by evaporation and the resulting chamois-colored powder was dried over phosphorus pentoxide dried overnight »the sodium salt (933 mg) in dry benzene (10 ml), the dimethylformamide (1 drop) was washed with oxalyl chloride (0.8 ml) at room temperature treated for 1 hour. The solvent was removed by evaporation and the residue dissolved in acetone (30 ml) dropwise to a solution of 7β-aminocephalosporanic acid (1.09 g) and sodium bicarbonate (672 mg) in water (50 ml) given at 0 to 5 °. The resulting solution was stirred at room temperature for 11/2 hours. The acetone was through

2098A8 / 1196

Evaporation was removed and the aqueous phase was adjusted to pH 8 and washed with a little ether. The aqueous layer was acidified to pH 2.0 under ether and the organic layer was washed with water, dried and evaporated to give a pale tanned foam. This was dried over silica gel and potassium hydroxide pellets, whereby the title compound was obtained as a pale yellow foam (1.6 g, 86 ^), [ ⁰ On + 62 ° (£ 1 dioxane) ^{,: λ} · _max (pH 6 phosphate buffer) 272 ^{nm (£ 18,600} ), ^ max (CHBr 3) ¹⁷⁸⁰ (ß-lactam) 1674 and 1510 cm " ¹ (CONH), T (DMSO-d ₆ ) values include 0.34 (doublet, NH), 2, 17 and 3.34 (fur-2-yl, protons), 8.71 (Bu "^.

Example 17

3 ~ Azidomethyl-7ß- (2-benzyloxyiminophenylacetamido) -ceph-3 ~ em-4-carboxylic acid (syn-isomer)

syn-Benzyloxyiminophenylacetic acid (1.28 g) was added at room temperature treated with 0.525 M sodium methylate solution (9.55 ml) in methanol. Evaporation gave the sodium salt as colorless powder.

The sodium salt was suspended in dry benzene (15 ml) containing dimethylformamide (2 drops) and treated with oxalyl chloride (0.51 ml) and stored at room temperature for 1 hour. After filtration through a dry frit, the filtrate was evaporated and the residue dissolved in dry methylene chloride (20 ml) to a solution of 7β-amino-3-azidomethylceph-3-em-4-carboxylic acid (1.27 g) and triethylamine (2 , 07 ml) in dry methylene chloride (50 ml) at 0 to 5 °. The resulting pale orange solution was stirred at room temperature for 1 1/4 hours. Evaporation gave a brown foam which was dissolved in water, washed with a little ether and acidified to pH 1.8 under ethyl acetate. The ethyl acetate provided the crude product as a yellow foam (1.9 g, IT / o). Precipitates from sodium bicarbonate

20i £ 48/1 1 96

Solution (50 ml) with dilute acid gave the title compound (1.4 g, 56%), [cc] _D + 49.5 ° (c 1 dioxane) λ _max (pH 6 phosphate buffer) 258.5 m (; 19 400 ) 1? " _V (CHBr,) 1782 (ß-lactam)

λ ^l " JHaX Q

1684 and 1512 cm (CONH), T values (DMSO-dg) include 0.07 (doublet, J 8 H7, NH), 2.58 (multiplet, aromatic protons), 4.76 (CH ₂ Ph), 4 , 05 (double doublet, C 7 proton).

Example 18

Sodium 3-azidomethyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-cartooxylate (syn isomer)

To a cold (0 to 5 °) solution of 3-azidomethyl-7ß-aminoceph-3-em-4-carboxylic acid (4.6 g) in acetone (100 ml) and water (100 ml) containing sodium bicarbonate (3.66 g) were added a solution of syn-2-methoxyiminophenylacetyl chloride dropwise over 20 minutes (4.32 g) and stir the resulting yellow solution at room temperature for 30 minutes. The acetone was removed by evaporation and the dark green solution was washed with ether. The pH of the aqueous phase was below Ethyl acetate (100 ml) reduced to 2 with 2N hydrochloric acid. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were made combined, dried and evaporated to give a pale brown foam (8.2 g) with petroleum ether (b.p. 60 to 80 °) was triturated and decolorized with activated charcoal, whereby one received a cream colored foam (7.67 g) *

This was dissolved in ethyl acetate (30 ml) and a 10 w / v. % solution of sodium 2-ethylhexanoate in n-butanol (34.8 ml) was added dropwise to the stirred solution, whereupon the title compound precipitated (4.05 g, 51%), [oc] Jp +63.5 ( c, 1.0 in V / water), Λ. _mav (pH 6.0 phosphate buffer) 258 to 259 nm (£ 18,850), v> _max (Nujol) 2102 (N ₃ ), 1756 (β-lactam), 1596 (CO ₂ "), 1682 and 1528 cm" ¹ (CONH), Z (DMSO-dg) values include 0.22 (doublet, J 8 Hz, NH), 2.3 to 2.6 (multiplet, Ph), and 6.04 (singlet, OCH ₃ ).

209848/1196

Examples 19 to 46

General processes for the preparation of 3-substituted methyl-7β- (2-substituted oxyimino-2-arylacetamido) -ceph-3-em-4-carboxylic acids

Procedure A

A solution of the appropriate syn-2-substituted oxyimino-2-arylacetyl chloride (prepared from 1 eq. of the corresponding sodium salt with oxalyl chloride) v / is dissolved in acetone and the Solution was added dropwise to a stirred ice cold (0 to 5) solution of 7 [beta] -aminocephalosporanic acid or 3-azidoraethyl-7 [beta] -amino-ceph-3-em-4-carboxylic acid (1 eq.) In water containing sodium bicarbonate (2 to 2.5 eq.) Was added. The mixture was stirred for 30 minutes to 2.5 hours while allowing the temperature to rise to room temperature. Acetone was removed by evaporation at reduced pressure, the pH was adjusted to 1.5-2.0 and the product became extracted into ethyl acetate (or occasionally ether). The extracts were washed with water or saturated saline, dried and evaporated to give a foam or solid.

Procedure B

As in Method A, but the product was purified by dissolving it in aqueous sodium bicarbonate solution and acidifying failed again.

Procedure C

As in Method A, but the sodium salt was extracted into ethyl acetate and the extract was washed successively with 2N hydrochloric acid and water, dried and evaporated to give a foam.

Method D

A solution of the appropriate acid chloride (1 eq.) Was dissolved in dry methylene chloride (ca. 5 ml / mmol) and the solution

2098Λ8 / 1 196

became a suspension or a solution of 7β-aminocephalosporanic acid or S-azidomethyl-yβ-aminoceph-J-em-4-carboxylic acid (1 eq.) And triethylamine (3 eq.) Given in methylene chloride at 0 to 5 °. After stirring at room temperature The solution was evaporated to dryness over 1 to 1.5 hours, dissolved in water and washed with ethyl acetate and the aqueous layer acidified to pH 1.5 under ethyl acetate. The ethyl acetate extract was washed with water and washed with saturated brine and evaporated to give a foam or solid.

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! -ι

O PQ co ffi r ^ CJ

O O O O CT- N Ol

ο m ν

NHN

ο <) ■ cn cn in ο ν οι cn

in

cn cn

20984871196

Table III

(x)

, CONH ^ (y)

OR

CH ₂ N ₃

co co

to cn

3sp.
No. R. R * Procedure
ren (Dioxane) pH 6
λ
Max.
ran ε ß-lactam,
ν cm.
Max.
( ^f solver) τ values for DMS0-d ι
at 100 MHz R ^a y Lusbeu-
ofce
/ 0 42 Ph C (CH ₃ ) ₃ D. + 56 ° 258 18 300 1785
(Nujol) X 8.65 4 ₅ 07 30th 43 CH ₃ D. + 53 ° 262 14,600 1780
(CHBr ₃ ) 0.38 6.10
• 4 ^ 10 55 44 C ₂ H ₅ B. + 58 ° 263 15,600 1770
(Nujol) 0.09 5.83 (CH ₉ )
8 _; '74 (CH ₃ ) 4.09 59 45 C (CH ₃ ) 3 B. + 62 ° 262
288 12 200
13> 00 1780
(Nu j 01) 0.13 8 _; 68 4 ₅ 07 50 46 CH ₂ Ph D. + 48 ° 263 15 800 0. _y 25 4.79 (CH ₂ )
2 _; 60 (Ph) 4.12 11 0.05

K) K) CO OJ

cn

LO

Example 47

7ß- (2-Benzyloxyiminothien-2 ^! -Ylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn-Isoraeres)

Oxalyl chloride (0.45 ml) was added to a stirred suspension of sodium syn-benzyloxyiminothien-2-ylacetate (0.747 g) in dry benzene (20 ml) containing dimethylformamide (1 drop). The mixture was stirred for 1 hour and then evaporated to dryness. A solution of the residue in ethyl acetate (25 ml) was added dropwise to a stirred suspension of diphenylmethyl-7β-amino-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -ceph-3-em-4 carboxylate (1.35 g) in ethyl acetate (20 ml) containing propylene oxide (1.0 ml) was added. The solid rapidly dissolved and the resulting solution was stirred for 16 hours. The solvent was distilled off and the residue was redissolved in ethyl acetate (50 ml). This solution was washed successively with 3% sodium bicarbonate solution, 2N hydrochloric acid, water and saturated brine, dried and evaporated to dryness to give the title compound as diphenylmethyl ester (2.01 g) as a pale brown foam. t fourths include (DMSO-dg) 0.03 (doublet, NH), 4.79 (CH ₂ Ph), 7.26 (CH ₃ ).

To this crude ester (1.67 g) were added anisole (0.24 g) and trifluoroacetic acid (10 ml). The resulting solution was kept at room temperature for 10 minutes. The trifluoroacetic acid was then removed by evaporation at room temperature. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was acidified to pH 1.7, then extracted three times with ethyl acetate. The combined extracts were washed ₅ to give (water, saturated brine), dried and evaporated to dryness to a red foam (1.04 g). The foam was dissolved in aqueous sodium bicarbonate solution and gut

2098 4.6 / 1196

reprecipitated by addition of 2N hydrochloric acid. This was repeated to obtain the title compound (350 mg, 28%), [cc] _D -96 ° (c 0.97 dioxane), \ _{& χ} (pH 6 buffer) 274 nm (£ _18,500 ), \> mnv (Nuiol) 1784 (ß-lactam), Γ values around-

Max

Hold (DMS0-d ₆ ) 0.07 (doublet, NH), 2.60 (Ph), 4.81 (CH ₂ Ph) and 7.32 (CH ₃ ).

Example 48

(a) tert-Butyl-3-acetoxymethyl-7ß- (2-methoxyiminopyrid-3 ^t -ylacetamido) -ceph-3-em-4-carboxylate (syn-isomer)

A suspension of 2-methoxyiminopyrid-3'-ylacetic acid (1.8 g) in dichloromethane (50 ml) was cooled to about -10 ° and with Treated phosphorus pentachloride (2.08 g). The mixture was stirred and kept at about -10 ° for 11/2 hours. to At this point, most of the suspension had dissolved. The cold mixture was made with tert-butyl 7β-amino-3-acetoxymethylceph-3-em-4-carboxylate (3.0 g) and propylene oxide (2 ml) and stirred for an additional 30 minutes. The solution was between ethyl acetate and saturated sodium bicarbonate solution distributed and extracted with ethyl acetate. The combined organic extracts were washed with water and then with Extracted 2N hydrochloric acid. Unchanged amine was removed by adding an excess of sodium nitrite to the cooled acidic extract and then after about 5 minutes washed at 0 with ethyl acetate. The resulting aqueous phase was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated-, being a mixture of the syn- and. anti isomers the title compound was obtained as a foam (1.33 g),

Chromatography on silica gel using chloroform-methanol (99r!) Gave da 3 anti isomers (394mg) and then the syn isomer as 3ch £ .um (6? 3 nig) «The syn isomer was dissolved in ethyl acetate and added to petroleum ether

(Kp. 40 Ms 60 °) precipitated. The amorphous solid was collected, washed with petroleum ether and dried to give the title ester (484 mg, 10%), [α] ^ ° + 49 ° (c 0.45, DMSO), A _max (EtOH) 255 nm ( £ 16 100), O _max (CHBr ₃ ) 3396 (NH), 1786 (ß-lactam), 1735 (OAc), 1724 (CO _£ R), 1682 and 1518 cm " ¹ (CONH), X (dg DMSO) 0.14 (d, J 8 Hz, NH), 1.26, 1.30, 203 and 2.48 (multiples; aromatic protons), 4.10 (q, J 5 and 8 Hz, C-7H), 4.74 (d, J 5 Hz, C-6H), 5.03 and 5.36 (2d, J 13 Hz, C-3 CH ₂ ), 6.03 (s, OCH ₃ ), 6.28 and 6.52 (2d, J 18 Hz, C-2 H ₂ ), 7.97 (s, OCOCH ₃ ), 8.52 (s, C (CH ₃ ) ₃ ).

(b) 3-Acetoxymethyl-7β- (2-methoxyiminopyrid-3'-ylacetamido) -ceph-3-em-4-carboxylic acid trifluoroacetic acid salt (syn isomer)

A solution of tert-butyl-3-acetoxymethyl-7ß- (2-methoxyiminopyrid-3-ylacetamido) -ceph-3-em-4-carboxylate-syn-isomer (440 mg) in trifluoroacetic acid (7 ml) was added at 20 ° Stored for 15 minutes. The solvent was removed and the residue was evaporated three times from benzene. The resulting gum was dissolved in a small amount of acetone and slowly added to an excess of stirred petroleum ether (b.p. 40 to 60 °). The solid was collected by filtration, washed well with petroleum ether and dried to give the titleyn acid salt as a solvated, pale yellow powder (561 mg), [α] 2 ° ₊ 30 ° (c 0.88, DMSO) , A ^ _x ( _pH 6 buffer) 254 nm (£. 14 300), 0 " _w (Nujol) 3250 (NH), 2600 and 1720 (CO ₂ H), 1782 (ß-lactam), 1736 (OAc), 1670 (CF ₃ CO ₂ "), 1670 and 1550 cm" ¹ (CONH), Z (d ₆ -DMSO) 0.08 (d, J 8 Hz, NH)., 1.16, 1.22, 1, 90 and 2.36 (multiples, aromatic protons), 4.06 (q, J 5 and 8 Hz, C-7H), 4.73 (d, J 5 Hz, C-6H), 4.93 and 5, 26 (2d, J 13 Hz, C-3 CH ₂ ), 5.98 (s, OCH ₃ ), 6.26 and 6.49 (2d _y J 18 Hz, C-2 H ₂ ), 7.94 ( s, OCOCH ₃ ).

Example 49

7β- (2-Methoxyimino-2-phenylacetamido) -3-pyridinium methyl ceph-3-em-4-carboxylate (syn isomer)

209848/1196

A solution of 3-acetoxymethyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomeres) (5 g) in v / water (30 ml), acetone (30 ml ) and pyridine (2.8 ml) was heated at 50 ° for 4 hours. More pyridine (2.8 ml) was added and the solution was warmed (pH ^ 5) at 50 for 16 hours. The dark brown solution was decanted from a gum and evaporated to remove the acetone and washed with methylene chloride. Excess solvent was removed by evaporation and the solution was passed over a Dowex 1 ion exchange resin column in the acetate cycle and the column was eluted with water. The eluate was freeze-dried and the solid was triturated with acetone to give the title compound as an off-white solid (0.84 g), f -6.4 ° (c, 0.94 in water), 7 ^ _v (pH 6 , 0 phosphate

buffer) 257 nm (έ 19 900), >> _mov (Nujol) 1770 (ß-lactam)

Jr

1660, 1540 (CONH) and 1604 cm " ¹ (CO ₂ "), T (D ₂ O) values include 1.03, 1.90 and 1.40 (α, ß and γ protons in the pyridium ring) , 2.2 to 2.6 (multiplet, Ph) 5.99 (singlet, OCH ₃ ), Γ (DMSO-dg) values include 0.27 (doublet, J 8 Hz, NH), 6.10 (singlet , OCH ₃ ).

Example 50

7β- (2-Methoxyimino ~ 2-phenylacetamido) -3- (4-carbamoylpyridiniummethyl) -ceph-3-em-4-carboxylate (syn isomer)

3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-Isomeres) (5 g) and isonicotinamide (4.2 g) were mixed in water (150 ml) and acetone (30 ml) and the suspension was heated at 50 ° for 20 hours. The mixture was cooled, filtered, to remove the acetone evaporated and the aqueous solution was passed through a column (3x16 cm) of Dowex 1 ion exchange resin in the acetate cycle. After washing the column with water, the eluate was freeze-dried and the resulting solid was freeze-dried triturated with acetone (250 ml) for 30 minutes and the suspension filtered to give the title compound (1.4 g)

209848/1 138

[ _α ] 23-50 ° C (c 1.06 in DMSO), A _mv (pH 6 buffer) 260 nm

20 900), ν? _v (Nojol), 1770 (β-lactam), 1675 and 1560 (CONH) and 1605 cm "'(CO ₂ "), T (DMSO-Ug) values include 0.33, 1.49 (α and β -Protons in the pyridinium ring), 1.19 and 1.74 (-CONH ₂ ), 2.4 to 2.6 (multiplet, Ph), 0.26 (J 8 Hz, NH), 6.10 (singlet, OCH ₃ ).
Example 51

Sodium 3-hydroxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)

3-Acetoxymethyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomeres) (2.0 g) was dissolved in the smallest volume of saturated sodium bicarbonate solution and the solution was washed with water (160 ml) and warmed to 37 °. Defatted wheat germ (15 g) was added and the mixture was stirred for 3 1/2 hours after which time the pH was 7.4. The mixture was then poured into acetone (200 ml) and filtered through kieselguhr. The acetone was distilled off under reduced pressure at 30 ° and the aqueous solution was covered with ethyl acetate, adjusted to pH 2.7 by adding concentrated hydrochloric acid. The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water. More water was added to the ethyl acetate solution and the pH was adjusted to 7 by careful addition of 2N sodium hydroxide solution. The organic layer was further extracted with water and the combined aqueous solution was washed with ethyl acetate and ether, degassed and lyophilized to give the title methoxime as a brown solid (1.52 g, 82%), [a ] _n + 104 ° (c 1.1, DMSO), Λ „ _v (pH 6 phosphate) 258.5 nm (£ 14 100), v? (Nujol) 1730 (β-lactam), 1570 (COO "), 1640 and 1520 cm- ¹ (CONH), T (D ₂ O; 100 MHz) 2.2 to 2.6 (multiplet; aromatic protons), 4 , 16 (doublet, J 4 Hz, C-7H), 4.79 (doublet, J 4 Hz, C-6H), 5/72

209848/1196

(Singlet, C-2 CH ₂ ), 5.97 (singlet, NOCH ₃ ), 6.32 and 6.59 [2 doublets (branches of a quartet), J 18 Hz, C-3 CH ₂ ].

Example 52

3-hydroxymethyl-7ß- (2-benzyloxyiminothien-2'-ylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomer)

Sufficient saturated sodium bicarbonate solution was added to a suspension of 3-acetoxymethyl-7ß- (2-benzyloxyiminothien-2 ^f -ylacetamido) ~ ceph-3-era-4-carboxylic acid (1.0 g) in water (50 ml) Dissolve solid and adjust the solution to a pH of 7.0. Defatted wheat germ (8.0 g) was added to the solution and the mixture was stirred for 21 hours, adjusted to pH 6.8-7.0 by adding acetic acid. After 5 hours the pH no longer changed and TLC (CiICl ₃ : MeOH: AcOH; 18: 2: 1) showed on an aliquot that the reaction was almost complete.

The mixture was filtered and the pH of the filtrate was adjusted to 4.5. Filtration through kieselguhr gave a yellow solution, the pH of which was adjusted to 2.5 under ethyl acetate. The aqueous mixture was extracted with ethyl acetate extracted and the combined extracts were washed (water, brine), dried and evaporated to dryness, a brown solid was obtained. Trituration of this solid with methylene chloride provided a colorless solid (480 mg) whose NMR spectrum was consistent with that that was expected for the hydroxymethyl compound.

A portion of the solid (366 mg) was dissolved in 5050 strength aqueous ethanol (10 ml) and washed carefully with. 0.1N Katriumhydroxydlösung (3 "02 mL were neutralized requiring ::} The ethanol v / urd & evaporated varl the aq. ¹ - ^ Miachuij / r was γ extracted three times with Α \ ~ ^Ι λ · Evaporation is aqueous.?. The solution got KatriuiL-3-lr _: 'äro :: - a ^: ah ^ I - 7ß- ^: ''2-benz \ l: ... :: yininothien-2' -

■■■ idf

ylacetamido) -ceph-3-em-4-carboxylate dihydrate (132 mg),

[oc] "+ 88 ° (c 0.89, DMSO), Ά_ _" (pH 6 phosphate buffer) 262 nm υ ~~ max

(£ 16 100), v>"(Nujol) 1744 (ß-Lactara), 1650 and 1522 (CONH), 1580 (CO ₂ ") cm, V (DMSO-dg) values include 0.13 (doublet, NH ), 2.54 (Ph), 4.76 (CH ₂ Ph), 4.26 (quartet, 7 proton).

Example 53

3- (2-chloroethylcarbamoyloxymethyl) -7ß- (2-methoxyiminophenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

A solution of 3-hydroxymethyl-7ß- (2-methoxyiminophenylacetamido) ~ ceph-3-em-4-carboxylic acid (syn-Isomeres) (0.35 g), 2-chloroethyl isocyanate (0.097 g) and triethylamine (1.79 g) in Dimethylformamide (10 ml) was stirred at room temperature for 2 hours. The reaction mixture became saturated. Sodium bicarbonate solution poured and the aqueous phase was washed with ethyl acetate, acidified and extracted with ethyl acetate. The combined extracts were dried, concentrated to ca. 5 ml and added dropwise with stirring to petroleum ether (250 ml) given. The resulting solid was filtered and dried to give the title acid (0.157 g, 35? O, λ. (PH 6 buffer) 258 nm (£ 16,800), V>

max iucLX.

(Nujol), 3250 (NH), 2600 and 1715 (CO ₂ H), 1700 and 1530 (NHCO ₂ R), 1660 and 1540 cm " ¹ (COMI), £ * (DMSO-dg) values include 0.22 (Doublet, J 9 Hz, 7B-NH), 2.3 to 2.6 (multiplet, aromatic protons), 6.05 (singlet, OCH ^), 6.40 (multiplet, C-2 CII ₂ and -CH ₂ Cl), 6.65 (multiplet, -MICH ₂ ).

Example 54

(a) tert -Butyl 3-acetoxymethyl-7β- (pyrid-4-ylacetamido) -ceph-3-em-4-carboxylate

A suspension of pyrid-4-ylacetyl chloride hydrochloride (6.0 g) in ethyl acetate (50 ml) containing propylene oxide (12 ml), was stirred, cooled in ice and added dropwise with

209848/1 196

treated with a solution of tert-butyl-3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (5.0 g) in ethyl acetate (50 ml). The mixture was stirred at 20 hours and then washed with saturated sodium bicarbonate solution and extracted with 2N hydrochloric acid. The aqueous extract was washed with ethyl acetate, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to a small amount, whereupon crystallization began. The crystalline solid was washed well with petroleum ether (bp 40 ° to 60 °) and dried, the title ester being obtained as a chamois-colored powder (5.4 g, 80/0, calculated on the amine). A portion (250 mg) was recrystallized from ethyl acetate to give colorless needles (i70 mg) [a] _D +94 ^U (c 0.9, DMSO), λ ^ (EtOH) 256.5 nm (£ 9900) ® ^rhielt '\> _mnv (CHBr _x ) 3412 (NH), 1784 (β-lactam), 1736 (OAc), 1722 (CO ₂ R), 1690 and 1512 cm " ¹ (CONH), TU ₆ -DMSO) 0.81 (d, J 8 Hz, NH), 1.47 and 2.68 (2d, J 5 Hz, aromatic protons), 4.27 (q, J 8 and 5 Hz, C-7H), 4.85 (d , J 5 Hz, C-6 H), 5.01 and 5.36 (2d, J 13 Hz, C-3CH ₂ ), 6.38 (s, CH ₂ CONH), 6.39 (s, C- 2H ₂ ), 7.96 (ε, OCOCH ₇ ) and 8.50 (s, C (CH ₃ ) -).

(b) tert-butyl 3-acetoxymethyl-7ß- ^(2-t-4 hydroxyiminopyrid -ylacetamido) ceph-3-em-4-carboxylate

A solution of tert-butyl-3-acetoxymethyl-7β-(pyrid-4-ylacetamido) -ceph-3-er-4-carboxylate (3.0 g) in acetic acid (30 ml) was stirred, chilled briefly in ice and added dropwise during 3 to ■■ -: - minutes with a solution of sodium nitrate (1.38 g) in V / water (IC ml) treated, the mixture was at 20 ° 30 minutes): stirred 'Uiiu then diluted with water and washed with ethyl acetate The organic extract was washed with saturated sodium bicarbonate solution and water and then washed over magnesium sulfate dried. Evaporation almost to dryness gave a residue which dissolved in a minimal volume of acetone and was added dropwise to stirred petroleum ether (b.p. 40 to 60 °). The resulting solid was collected with

209848/1 19G

Washed petroleum ether and dried to give the title oxime as a colorless powder (2.9 g, 91%) which, like the NMR spectrum showed was a mixture of syn and anti compounds (30:70).

The oxime mixture (2.5 g) was chromatographed on silica gel and eluted with methanol-chloroform (1:49) to give the title compound (anti-isomer).

Further elution with methanol-chloroform (1:49) yielded material which was dissolved in acetone and added to the stirred petroleum ether (b.p. 40 to 60 °), the tert-butyl-3-acetoxymethyl-7ß- (2-hydroxyiminopyrid-4'-ylacetamido) -ceph-3-em-4-carboxylate (syn isomer, 0.81 g, 32% from the mixture) obtained, [a] _n + 57 ° (c'1, 11, DMSO), TV (EtOH) 253.5 min

yy ■ "· max

(£ 17,600), \ / _nav (Nujol) 3220 (NH), 1784 (ß-lactam),

Max

1744 (OAc), 1710 (CO _£ R) 1640 and 1526 cm " ¹ (CONH), * C (dg-DMSO) -2," 26 (s, NOH), 0.27 (d, J 8 Hz, NH ), 1.33 and 2.47 (2d, aromatic protons), 4.04 (q, J 5 and 8 Hz, C-7H), 4.71 (d, J 5 Hz, C-6H), 4, 98 and 5.33 (2d, J 13 Hz, C-3 CH ₂ ), 6.20 and 6.53 (2d, J 18 Hz, C-2 H ₂ ), 7.94 (s, OCOCH ₃ ), 8.49 (s, C (CH _{3) 3).}

(c) tert-butyl-3-acetoxymethyl-7ß- (2-methoxyiminopyrid-4 ^! -ylacetamido) -ceph-3-eni-4-carboxylate (syn-isomer)

A solution of tert-butyl-3 ~ acetoxymethyl-7β- (2-hydroxyiminopyrid-4 '-ylacetamido) -ceph ^ -em ^ -carboxylate (syn-Isomeres) (50 mg) in tetrahydrofuran (10 ml) was brought to 0 ° cooled and treated with an excess of essential diazomethane. The mixture was stirred at about 5 ° for 45 minutes and then washed with water. The organic extract was dried and evaporated to give the title ester as a yellow foam (48 mg, 93%), [a] _ß + 55.5 ° (£ 0.88, DMSO),

^A max ^{(Et0H) 257} ' ^{5 nm (} £ ^{16 580)} ' ^ max ( ^CHBr ₃ ) 33.90

max ^{(EtOH) 257} ' ^{5 nm (} £ ^{16 580)} ' ^ max ( ₃ (NH) 1784 (β-lactam), 1736 (OAc), 1726 (CO ₂ R) 1684 and

1516 cm " ¹ (CONH), V (d ₆ -DMSO) 0.20 (d, J 8 Hz, NH) ₅ 1 _P 33 and

2098Λ8 / 1196

2.48 (multiplets, aromatic protons), 4.09 (q, J 5 and 8 Hz, C-7H), 4.74 (d, J 5 Hz, C-6H), 5.01 and 5.35 ( 2d, J 13 Hz, C-3CH ₂ ), 5.99 (s, NOCH ₃ ), 6.38 (broad singlet, C-ZR ₂ ), 7.96 (s, OCOCH ₃ ), 8.52 (s , C (CH ₃ ) ₃ ) o

(d) 3-Acetoxymethyl-7ß- (2-methoxyiminopyrid-4'-ylacetamido) -ceph-3-em-4-carboxylic acid, trifluoroacetic acid salt (syn isomer)

A solution of tert-butyl-3-acetoxymethyl-7β- (2-methoxyiminopyrid-4 ^l -ylacetaraido) -ceph-3-em-4-carboxylate (syn-isomeres) (0.35 g) in trifluoroacetic acid (10 ml ) was kept at 20 ° for 15 minutes. The solution was diluted with benzene and evaporated to dryness to give a gum which was triturated with ether to give the title salt as a solid (0.26 g, 67%), [α] + 42 ° (c 0.45, DMSO), A _moY (pH 6 buffer) 255 nm (£ 19,000), ^ _mQV (Nujol) 3250 (NH), 2600 and 1720 (CO ₂ H), 1778 (ß-lactam), 1734 (OAc), 1666 (CF ₃ CO ₂ "), 1670 and 1520 cm" ¹ (CONH), f (DMSO-d ₆ ) values include 0.10 (d, J 8 Hz, NH), 1.23 and 2.36 (multiplets , aromatic protons), 4.11 (q, J 5 and 8 Hz, C-7H), 4.76 (d, J 5 Hz, C-6H), 4.98 and 5.29 (2d, J 13 Hz , C-3 CH ₂ ), 5.97 (s, NOCH ₃ ), 6.29 and 6.52 (2d, J 18 Hz, C-2H ₂ ), 7.98 (s, OCOCH ₃ ).

Example 55

3-acetoxymethyl ~ 7β- [2-aminoethoxyimino (thien-2-yl) acetamido ] -ceph-3-em-4 ~ carboxylic acid, trifluoroacetate salt (syn isomer)

A solution of syn- (2-tert-butoxycarboxamido) -ethoxyiminothien-2-ylacetyl chloride (from the acid 314 mg) dissolved in acetone (10 ml) was added dropwise to an ice-cold, stirred solution of 7β-aminocephalosporanic acid (272 mg) in water (20 ml) containing sodium bicarbonate (168 mg), given. The solution was stirred for 2 hours, then the acetone was distilled off. The aqueous mixture was reduced to one pH-value of 2.0 acidified under ethyl acetate and with ethyl

208848 / 119G

acetate extracted. The combined extracts were washed (water, brine), dried and evaporated to dryness, giving 3-acetoxymethyl-7β- [2 ~ tert-butoxycarboxamidoethoxyimino (thien-2-yl) acetamido] -ceph-3-em ~ 4-carboxylic acid (540 mg, 95%) obtained, f (DMSO-dg) values include 0.27 (d, IiH), 7.96 (s, OCOCH ₃ ), 8.62 (s, CCCH ^).

This crude acid (500 mg) was dissolved in trifluoroacetic acid (5 ml) and the solution was kept at room temperature for 5 minutes and then evaporated to dryness at room temperature. Dry benzene (25 ml) was added to the residue and the mixture was evaporated to dryness again. The oily residue was triturated with ether, giving the title compound (346 mg, 64%) as a colorless solid [a] _n + 39 ° (c 0.97 dioxane), Λ (pH 6 phosphate buffer) 283 nm (£ 16,500 ), l ^ _max (Nujol) 1780 cm "', ^ (DMSO-dg) values include 0.31 (doublet, J 8 Hz, NH), 1.98 (NH ₃ ), 4.08 (C-7 Proton), 5.66 (-0CH ₂ ), 6.8 (-CH ₂ -NC) s 7.96 (OGOCH ₃ ).

Example 56

7ß- [2-tert-Butoxyimino-2- (benzo [b] -thien-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethylceph- 3-em-4-carboxylic acid (syn isomer)

A solution of 2- (tert-butoxyimino) -2- (benzo [b] -thien-3-yl) -acetic acid (1.11 g) in methylene chloride (5 ml) and dimethylformamide (1 ml) became a solution of diphenylmethyl-7β-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) »thiomethylceph-3-em-4-carboxylate (2.04 g) in methylene chloride (20 ml) . A solution of dicyclohexylcarbodiimide (0 _s 823 g) in methylene chloride (5 ml) was added to the above-stirred solution at 20 °. The mixture was stored at 5 ° for 16 hours and then filtered. The filtrate was washed with 2N hydrochloric acid, dilute sodium bicarbonate solution, water and brine, dried (MgSO ₁₁ ) and under reduced pressure

209848/1 1 96

Concentrated pressure to give the crude diphenylmethyl ester of the title compound as an orange foam (3.37 g). The foam was dissolved in anisole (6 ml) and the solution was treated with trifluoroacetic acid (25 ml). After 5 minutes at 20 ° the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was concentrated again. The residue was then partitioned between ethyl acetate and dilute sodium bicarbonate solution. The ethyl acetate layer was extracted well with dilute sodium bicarbonate solution and the combined extracts were washed with ethyl acetate and then covered with ethyl acetate and adjusted to pH 2 with concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried and concentrated under reduced pressure to a low volume. The solution was then added dropwise to stirred petroleum ether (b.p. 40 to 60 °, 400 ml) and the precipitate was filtered off and washed with petroleum ether, the title acid being obtained as a chamois-colored solid (1.0 g, 41%), [cc] _D -87 ° (c 1 in DMSO), λ _max (pH 6 phosphate buffer) 277.5 nm (£ 16,850), V? _may _ (Nujol) values include 1786 (β-lactam, 1672 and 1520 cm " ¹ (COiIH)," £ * values (DMSO-dg) include 0.27 (d, J 8 Hz, NH), 1.38 (m, H-4 benzo [b] thienyl), 1.86 (m, benzo [b] thienyl H-7), 2.15 (s, benzo [bj-thlenyl H-2), 2.44 (m, Benzo [b] - · & :. enyl H-5 and HS), 4.05 (da, J 8 and 5 Hz, H-7), 4.72 'A, J 3 Ez _t H-6 ), 5.40 + 5.74 (2d, J 13 Hz, C-3 CH ₀ ), - :. : 3 ν 6.57 (2d, J 13 Hz ₁ C-2 CH-), 7.29 (s, CH ^) and 3.5 '"is, C; -jH ^^) _r

7R [Z- ^Ä-: ho::;. / I ^ ino-2-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl _/ --thior :: c -thylceph-3-em-4-carboxylic acid (syn isomer)

v / virde prepared, v: ie it i: is a Example 56

2 U 9 a 4 3 / ■ IS 3

(Yield 6 ^%), [α] _η -86 ° (c 1.1 in DMSO), Λ. _mov (pH 6

JLJ - max

JLJ ma

Phosphate) 262.5 nm (£ 22,350), V? _max (Nujol) values

1780 (ß-lactam) and 1664 and 1520 cm " ¹ (CONH), V values. (DMSO-dg) include 0.21 (d, J-8 Hz, NH), 2.46 (m, aromatic protons) , 4.06 (dd, J 8 and 5 Hz, H-7), 4.73 (d, J 5 Hz, H-6), 5.40 + 5.72 (2d, J 14 Hz, C-3 CH ₂ ), 5.74 (q, J 7 Hz, CH ₃ CH ₂ O), 611 + 6.39 (2d, J 18 Hz, C-2 CH ₂ ), 7.27 (s, CH ₃ in thiadiazole ), 8.68 (t, J 7 Hz, CH ₅ CH ₂ O).

Example 58

7β- [2-tert-Butoxyimino-2- (thien-2-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethylceph-3-em-4 -carboxylic acid (syn isomer)

was prepared as described in Example 56, the acid being obtained (58% yield), [α] -η -76 ° (c _t 1, DMSO), H _max (pH 6 phosphate) 271 mn (£ 14 400), V> (Nujol) include 1780 (β-lactam) and 1670 and 1530 cm "^ (CONH), T ^ values (DMSO-dg) include 0.26 (d, J 8 Hz, NH), 2 , 32 + 2.80 (m, thienyl protons), 4.08 (dd, J 8 and 5 Hz, H-7), 4.73 (d, J 5 Hz, H-6), 5.38 + 5, 73 (2d, J 13 Hz, C-3 CH _£ ), 6.10 + 6.36 (2d, J 18 Hz, C-2 CH ₂ ), 7.27 (s, CH ₃ ) and 8.64 (s, C (CH ₅ ) ₃ ).

Example 59

(a) tert. -Butyl ^ -acetoxymethyl ^ β- (2-ethoxyiminopyrid-4-ylacetamido) -ceph-3-em-4-carboxylate (syn isomer)

A solution of tert-butyl 3-acetoxymethyl-7ß- (2-hydroxyiminopyrid-4-ylacetamido) -ceph-3-em-4-carboxylate (syn-Isomeres) (1.15 g) in tetrahydrofuran (20 ml) was treated with a Treated excess of diazoethane at 20 ° for 40 minutes. The mixture was diluted with ether, washed with water and extracted with 2N hydrochloric acid. The aqueous extract was saturated with sodium bicarbonate solution neutralized and extracted with ethyl acetate. Evaporation of the dried organic extract gave the title ester as

209848/1196

Foam (0.84 g, 69%), OL + 47 ° (c 0.84 DMSO), λ (EtOH)

Jj ~~ max

259 nm (£ 15 450), v> _v (Nujol) 3300 (NH), 1788 (ß-lactam), 1740 (OAc), 1724 (CO ₂ R), 1678 and 1540 cm "'(CONH), T ( dg-DMSO) -Y / erte include 0.12 (d, J 8 Hz, NH), 1.26 and 2.42 (multiplets, aromatic protons), 5.69 (q, 7 Hz, OCH ₂ CH ₃ ) , 7.93 (s, OCOCH ₃ ), 8.50 (s, (CH ₃ )) and 8.69 (t, J 7 Hz, OCH ₂ CH ₃ ).

(b) 3-Acetoxymethyl-7ß- (2-ethoxyiminopyrid-4-ylacetamido) -ceph-3-em-4-carboxylic acid trifuloroacetic acid salt (syn isomer)

tert-Butyl - ^ - acetoxymethyl ^ ß- (2-ethoxyiminopyrid-4-ylacetamido) -ceph-3-em-4-carboxylate (0.75 g) were cleaved off the protective groups with trifluoroacetic acid (10 ml) in the usual way, the title salt was obtained as a powder (0.61 g, 73%), [α] _η + 30 ° (c 0.4, DMSO), Λ _mnv (pH 6 buffer) 257 nm (P 12 800),

yy ■ "* max

^ _ffl "(Nujol) 3300 (NH), 2600 and 1720 (CO ₀ H), 1782 (ß-lactam),

ΙΉςίΛ. egg. jt

1740 (OAc), 1680 (CF ₃ CO ₂ "), 1670 and 1552 cm" ¹ (CONH), Z (% "DMSO) values include 0.06 (d, J 8 Hz, NH), 1.20 and 2.28 (multiplets, aromatic protons), 5.65 (q, J 7 Hz, OCH ₂ CH ₃ ), 7.92 (s, OCOCH ₃ ) and 8.64 (t, J 7 Hz, OCH ₂ CH ₃ ).

20S848 / 1 196

Example I.

Then-2-yloxamine hydrochloride (used as starting material in the Manufacturing process 7 used)

(a) N- (Then-2-yloxy) phthalimide

Anhydrous potassium carbonate (11.04 g) was added to a stirred suspension of N-hydroxyphthalimide (17.12 g) in dry dimethyl sulfoxide (200 ml). A brown color formed. 2-Chloromethylthiophene (28.5 g) was added dropwise and the mixture was stirred for 16 hours, during which time the color disappeared. The suspension was poured into water (800 ml) and cooled to 5 °. The white precipitate was filtered off and recrystallized from ethanol, giving colorless needles of N- (then-2-yloxy) phthalimide (23.4 g, 83%), melting point 129.7 ° to 130.9 °, T - Values (DMSO-d ₆ ) are 4.58 (CH ₂ ), 2.28, 2.68, 2.90 (thienyl protons), 2.08 (phthalimide protons).

(b) Then-2-yloxyamine hydrochloride

A mixture of N- (then-2-yloxy) phthalimide (22.4 g), 100% hydrazine hydrate (5 g) and ethanol (600 ml) was heated to reflux for 2 hours. A yellow solution initially formed but then a solid began to separate out. The mixture was cooled, acidified with concentrated hydrochloric acid (12 ml). The precipitated phthalhydrazide was filtered off and washed with ethanol (3 × 50 ml) and water (100 ml). The combined filtrates and washing water were evaporated to dryness and the residue was suspended in water and treated with 2N sodium hydroxide solution until a basic reaction was achieved The mixture was extracted with ether and the combined extracts washed (with water, saturated saline), dried and saturated with dry hydrogen chloride. The resulting precipitate was collected and washed well with ether to give then-2-yloxaraine hydrochloride (12.45 g, 8755 ) obtained, m.p. 157.1 to 157 _S 5 ° V A sample was recrystallized from ethanol / ether, mp ₀ 161.7 to

209848/1186

162.1, Γ values (DMSO-dg) include 4.69 (CH ₂ ), 2.30, 2.72, 2.90 (thienyl protons).

Example II

Furfuryloxamine hydrochloride (was used as starting material in Manufacturing process 22 used)

(a) N-furfuryloxyphthalimide

To a stirred mixture of N-hydroxyphthalimide (41 g), anhydrous potassium carbonate (26.4 g) and dry dimethyl sulfoxide (400 ml) was added 2-chloromethylfuran (freshly prepared but not distilled, from 46.2 g of furfuryl alcohol according to the method described by WR, Kirner JACS, 1928, 50, (1955) described method) o The mixture was stirred for 18 hours, then poured into water (1.5 l). The precipitated solid was filtered off, washed well with water and recrystallized from ethanol, N-furfuryloxynaphthalimide (42.8 g, 70%), melting point 145.3 ° to 146.2 °, ZT values (DMSO- dg) are 4.80 (CH ₂ ), 2.22, 3.30, 3.50 (furyl protons), 2.08 (phthalimide protons).

(b) furfuryloxyamine hydrochloride

100/0 hydrazine hydrate (20 ml) was added to a stirred solution of N-furfuryloxyphthalimide (42.0 g) in methylene chloride (600 ml). Abundant precipitate formed immediately and the mixture was stirred for 45 minutes. 5N ammonium hydroxide solution (y ", j ml) was added to dissolve the precipitate. The '':. Vi ^,:: a layers were separated and the aqueous layer WUR · ■ "- ¹ * z / ^ ':: el ηί.τ, I-Iethylencnlorid .gewaschen, The combined Met / :. v." ?, e:.:. o-.:loric extracts were washed (saturated saline solution: .. = ._ ■ ";:.:. rl, ^ u'-rockiiet. The iisthylene chloride was evaporated and the remaining liquid was in ether (250 ml). dry hydrogen chloride chloride was dissolved in this solution during 1 hour ^ 'ilzLtet * The precipitated solid was filtered off ::. Lt Ztker gsv / asclien and dried and crystallized from isopropanol

209848/1196

recrystallized to give the furfuryloxamine hydrochloride (12.89 g, 50%) , m.p. ₀ 135 Ms 136 ° (dec.), 'D values (DMSO-dg) include 4.87 (CH ₂ ), 2.20, 3.27, 3.44 (furyl protons)

Example III

According to the method as described in General Preparation Examples 5 to 23 for the preparation of 2-alkoxyiminoarylacetic acids were described, the compounds were prepared which are set out in the table below (The table can be viewed as a continuation of Table I).

209848/1196

cd pi

Wed)

Φ
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Pj bO
• Η Ö O O O O O O O pci hO O O O O <f O O co cd ω • Ο <ί OO CM CT> vD IO ω «Η U -P ω - I γ-Η CO r- cm ^ j- cm U rH r-l - I CM CM CM φ
►ρ.
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υ VD CM I. Pll CM VD Pn co CM CM co I.
rH I. CM K <* CM CM CM CM O IO H O · ♦ ο : θ IO vD
CM CM CD pq pq pq IO cn CM
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209848/1 1 96

- 111 -

Example IV

2-alkoxyiminoarylacetyl chlorides (continued)

• The following acids have been converted into their acid chlorides, using the general procedure for the conversion of 2-alkoxyiminoarylacetic acid to its acid chlorides without isomerization is described immediately after manufacturing process 35:

syn-2-butoxyiminophenylacetic acid syn-2-isopropoxyiminophenylacetic acid syn-2-propoxyiminophenylacetic acid syn-2-propoxyimino (thien-2-yl) acetic acid syn-2-ethoxyimino- (benzo [b] -fur-2-yl) -acetic acid syn-2-ethoxyimino (thien-3-yl) acetic acid.

Example V
syn-isopropoxyiminophenylacetic acid

A mixture of phenylglyoxylic acid (3 »0 g), isopropoxyamine hydrochloride (2.5 g), ethanol (100 ml) and water (50 ml) was stirred and adjusted to pH 4.5-5 with sodium hydroxide solution (2N) . The solution was stirred for 5 hours and maintained at pH 4.5-5 by further additions of sodium hydroxide solution. The ethanol was removed by evaporation, the aqueous residue was acidified and the product was collected by extraction with ethyl acetate. Evaporation of the ethyl acetate yielded a brown oil (4.2 g) which was esterified in the usual way with diazomethane, a mixture of the syn = and anti-methyl esters of the title _{compound being obtained as an oil (4 9} θ4 g).

The ester mixture (4.0 g) in methanol (60 ml) was treated with sodium hydroxide solution (2N, 19.0 ml) and added for 2 hours stored at room temperature. The methanol was evaporated and the residue was diluted with water and with Ethyl acetate extracted. Evaporation of the dried (MgSO,)

209848/1196

Ethyl acetate solution provided the crude syn methyl ester (0.82 g). The ester (0.82 g) in methanol (20 ml) was treated with sodium hydroxide solution (2N, 3.6 ml) and stored at room temperature for 31 hours. The acidic material was isolated in the usual way to give the crude syn isomer (0.706 g) which was recrystallized from cyclohexane to give the title _compound (0.358 g), m.p. 59.5 °, A msav (EtOH)

III el λ.

258 nm (£ 12,700), Z (DMSO-dg) values include 2.47 (phenyl), 5.53 (O-ChC ^), 8.71 (CH,).

Example VI syn-propoxyiminothien-2-ylacetic acid

A mixture of thien-2-ylglyoxylic acid (3 »12 g), n-propoxyamine hydrochloride (2.8 g), ethanol (75 ml) and water (75 ml) was brought to pH 4.5 with sodium hydroxide solution (2N) set to 5 and stirred at room temperature. Additional base or ethanol was added as needed to maintain a clear solution at a pH of 4.5 to 5. After 4 hours a further portion of n-propoxyamine hydrochloride (1.4 g) was added and the mixture stirred for an additional 3 hours (keeping the pH at 4.5-5) and then stored overnight. The ethanol was evaporated and the remaining solution was diluted with water, acidified, and extracted with ethyl acetate. Evaporation of the dried (MgSO ^) ethyl acetate solution gave a mixture of the syn and anti forms of the title acid as an oil (4.8 g).

The "-".:. Εchvüig of the acids was made in the usual way with diazo- 'mef ...?.' ·. ·. Y & rssteirv.j? / Obei one got a mixture of the syn- and airt: v ---: - ^: "th" _: ^r ie £ Tsr (3 _} '^ 75 :?.' -

The mixture of the esters in methanol (50 ml) was made with sodium hydroxide solution (2n, 14 ml) treated for 10 minutes at room temperature ο The methanol '- / ur-de quickly by mixing

L 0 S ο k δ / "'1 ' 3 6

Evaporation was removed and the residue was extracted into water with ethyl acetate. Evaporation of the dried (MgSO ») ethyl acetate solution gave the syn methyl ester (0.416 g). The ester was treated with sodium hydroxide solution (2N, 1.7 ml) in methanol (10 ml) and held at room temperature for 26 hours. Isolation in known manner of the acidic material provided the title compound as an oil (0.235 g), £ (DMSO-dg) values include 2.28, 2.7-2.9 (thienyl), 5.90 (O-CH ₂ ).

Example VII

The general procedures for the preparation of 3-substituted-methyl-7β- (2-substituted, oxyimino-2-arylac etamido) -ceph-3-em-4-carboxylic acids described in Examples 19-46 were followed used to make the compounds given in the following table (the table can be viewed as a continuation of table II) _o

2098Λ8 / 1 1 96

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I.
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B. r-l α-. vD O r-i CM r-l • r-l OO in
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2 O 9 8 Λ 8/1 1 G

(χ)

• CONH

(y)

H H

O ^ -N

OR "

H ₂ OAc

CO ₂ H

NJ E.g.
No. R. R ^a C ₂ H ₅ Procedure
ren [«]"
(Dioxane) pH 6
λ
Max. ε β-Ii ac camouflage
ν -1
max. cm. τ values for r DMSO-d _fi
100 MHz R ^a y the end
prey
% O nm (Solver) 5.81, 8.75 CO
CO 64 A. + 53 ° 261.5 20 300 1786 X 95 ■ **
Co
"^
._> (Dioxane) (Nujol) 0.28 5.71, 8.68 4.09 '.O
O 65 A. + 55.5 ° 237 12 900 1785 77 (Dioxane) 273 inf 15 500 (CHBr ₃ ) 0.03 303 _? 5 23 600

NJ) OJ CO

Example VIII

3- (5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-7ß- [2- (then-2-yl) -oxyimino-2 ~ (thien-2 ~ yl) -acetamido] - ceph-3-em-4-carboxylic acid (syn isomer)

A solution of syn-Then-2-yloxyiminothien ~ 2-ylacetic acid (715 mg) in methanol (20 ml) was mixed with 0.32N sodium methylate solution (8.7 ml) neutralized. The solvent was removed in vacuo and the remaining sodium salt was passed through azeotropic distillation with benzene (2 × 20 ml) dried. Oxalyl chloride (685 mg) was added to a suspension of the above salt in benzene (30 ml), the N, N-dimethylformamide (1 drop) included. The resulting solution was stirred at 20 ° for 1.5 hours and evaporated to dryness in vacuo, whereby the acid chloride was obtained.

A solution of this acid chloride in acetone (20 ml) was added dropwise to a stirred solution of 7β-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethylceph-3-em-4-carboxylic acid ~ Hydrochloride (1.00 g) in water (30 ml) containing sodium bicarbonate (660 mg) added at 0 °. The mixture was stirred for 2 hours and then warmed to room temperature. The acetone was removed in vacuo and the solution was acidified to pH 1.9. The solution was extracted with ethyl acetate (6 × 70 ml) and the combined extracts were washed with water, dried and evaporated to dryness. The crude product was washed with benzene / cyclohexane (1: 1, 2 × 20 ml) and the cyclohexane was dried and evaporated to give the title carboxylic acid (863 mg), [a] _D -61 ° (c 1.44 , DMSO), Λ _max (pH 6 buffer) 239 nm (£ 17900), 273 nm (<f 19 150), \> _max (Nujol) 1784 cm " ¹ (ß-lactam, Z (DMSO-dg) values include 0.09 (d, NH), 4.68 (s, CH ₂ -thienyl), 7.31 (s, CH ₃ ).

209ß48 / 1 196

The sodium and potassium salts of the compounds of the examples are in a conventional manner by reaction with sodium or Potassium 2-ethylhexanoate produced. To make a To explain such salt in more detail, the following is the production of sodium 3-acetoxymethyl-7β (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn-isomeres) described in detail

Syn-3-acetoxymethyl-7ß ~ (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (10.84 g) was in the minimum
Dissolved amount of ethyl acetate (280 ml) and a 1m solution of
Sodium ethylhexanoate (25 ml) was added dropwise to the stirred solution stirred for 20 minutes and was then cooled to 0 for 2 hours ₀ The precipitated salt was stirred removed by filtration and washed with ethyl acetate (100 ml) v / hile 2 hours. The solid (9.6 g) was filtered off, washed and dried. It was then triturated with ether (2 × 200 ml) at room temperature for 30 minutes, whereby the title compound (8.9 g, 78%) was obtained,

[cc] ?. ² + 60 ° (c 1.06 in water), A ( _p h 6 buffer) 258 to υ - ~ max

259 nm (£ 19,150).

209848/1 19G

The following examples illustrate the formulation of pharmaceutical preparations.

Example A. Dry powder for injection

Sterile sodium 3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn-Isomeres) is filled in powder form in glass ampoules, making the glass ampoules each contain 500 mg and 1.0 g of the antibiotic as required. The filling is carried out aseptically under a Layer of nitrogen. The ampoules are closed using rubber washers secured by aluminum seal rings be retained and avoiding a gas exchange or the entry of microorganisms. The product is for reconstitution with v / ater for injections or other suitable sterile vehicle just prior to administration certainly.

Example B

Intramammary infusion for cattle

Percentage of the composition (w / w)

Sodium 3-acetoxymethyl-7ß- (2-ethoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate

(syn-isomer) 10.00

Drug carrier to 100.00

Medicinal product: Tween 60 3.00

White beeswax 6.00

Peanut oil 91.00

The last three constituents are heated together for 1 hour at 150 ^° C. and then cooled to room temperature with stirring. The sterile antibiotic powder is aseptically added to this carrier and the product is distributed with a high speed stirrer. The preparation is aseptically packed into sterile, compressible aluminum tubes

20984-8- / 1 196

so that each tube contains 3.0 g of the preparation containing 300 mg of the cephalosporin derivative.

Example C Dry mongrel for an oral syrup

Sodium 3-acetoxymethyl-7ß- (2-methoxyimino-2-thiene-2 ^! -Ylacetamido) -ceph-3-era-4-carboxylate (syn-isomeres) 5.00 g

Sodium saccharin 0.10 g

Sodium citrate (anhydrous) 1.00 g

Citric acid (anhydrous) 0.10 g

Amaranth 0.01 g

spray-dried raspberry flavor 1.00 g

Sucrose to 75.00 g

The product is for reconstitution with sufficiently purified Determined water, making a final volume of 100 ml and with the drug within a few Days to be administered, with each 5 ml dose of syrup containing 250 mg of cephalosporin derivative, given should be.

To make the mixture, the amaranth is mixed well with some of the sodium citrate and ground. That Sodium saccharin and citric acid are then mixed together. They will be mixed well with the color mix as well then with the rest of the sodium citrate, the taste and the antibiotic powder in the order given. the Mixture was ground, mixed with the sucrose and then mixed are each 75 g in a series of 150 ml bottles filled in and these become moisture-proof with screw caps locked.

209848/1196

Example D

(a) Oral capsules

Sodium ~ 3 ~ acetoxymethyl - 7ß- (2 ~ ethoxyimino-2-phenylacetamido) ceph-3-em-4-carboxylate (syn-Isomeres) is mixed with 1% magnesium stearate and filled into hard gelatin capsules of size O, each capsule being one contains certain dose of 250 mg of the cephalosporin antibiotic. The capsules are placed in glass ampoules with plastic caps that seal against moisture.

209848/1196

Claims (1)

-'121 claims 1. 7ß-Acylamidoceph-3 ~ em-4-carboxylic acids and their non-toxic derivatives, characterized in that the acylamido group the structure R.C.CONH- N
^X 0R ^a has, where R is a hydrogen atom or an organic group and R ^{a is} an etherified, monovalent organic group which is connected to the oxygen atom via a carbon atom, and where the compound as a syn isomer or as a mixture which contains at least 75% of the syn- Contains isora, is present. 2.. A compound according to claim 1, of the formula R.C.CO.NH- (D 0OH where R is a hydrogen atom or an organic group, R ^{a is} an etherified, monovalent group which is connected to the oxygen atom via a carbon atom, B> S or]> S -> 0 and Z is a group in which 2 carbon atoms are the core sulfur atom and connect the carbon atom containing the carboxyl group _? mean, and the A unsaturation and the derivatives thereof _s where the compound is present as a syn isomer or in the form of a mixture _f which contains at least 75% of the syn isomer € 20984/1196 3.. A compound according to claim 1 of the formula (II) wherein R, R ^a and B have the meanings given in claim 2 and P represents an organic group, and the non-toxic derivatives thereof. 4. A compound according to claim 3, wherein B ^ S is. 5. A compound according to any one of claims 1 to 4, present as a mixture, which contains at least 90% of the syn isomer contains. 6. A compound according to any one of the preceding claims, wherein R is a group selected from (i) R ^u , where R ^{u is} aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or a non-aromatic or mesoionic group, (ii) R ^U (CH _O ) Q (CH ₉ ). where R ^{u has} the definition given above and m represents 0 or an integer from 1 to 4, η denotes 0 or 1 , ρ denotes an integer from 1 to 4 and QS, 0 or NR, v / whether ei RV / represents a material or an organic group, (iii) C Hp,. ,, where η is an integer from 1 to 7, where ixe group can be straight-chain or ver ^ weigtkettig and can be interrupted by an oxygen or sulfur atom or by the group NR, where R is hydrogen or 3ins the organic group consider- _s greed by a Cy a: -: = -, Carbcx ;; - ™ ^ Alkoxy ο arc or; yi, ilydrcxy or -: ■ ν A: ig tii ir Xi Carboxycarbonyl (HOOC.CO.) Group or through a halogen atom can be substituted, (iv) C _n H _2n-1 , where η is an integer from 2 to 7 and where the group can be straight-chain or branched and can be interrupted by an oxygen or sulfur atom or by the group NR, where R is water, means substance or an organic group, (v) C Hp _n _ ^ »where η is an integer from 2 to 7, and (vi), cyano, amido or lower alkoxycarbonyl. 7. A compound according to claim 6, wherein R ^{u is} phenyl, naphthyl, phenyl or naphthyl, substituted by halogen, hydroxy, lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkanoyl, lower-alkanoylamido, lower-alkoxy or lower-alkylthio, a 5- or 6-membered heterocyclic group containing at least one heteroatom such as S, N and 0, a condensed heterocyclic group containing at least one heteroatom such as S, N and 0, cyclopentyl, cyclohexyl or is cyclohexadienyl. 8. A compound according to claim 7 »wherein the heterocyclic group or condensed heterocyclic group Thien-2-yl, thien-3-yl, furyl, pyridyl, pyrrolyl, N-substituted Pyrrolyl, isothiazolyl, thiadiazolyl ^ oxadiazolyl, 3- or 4-isoxazolyl, substituted 3- or 4-isoxazolyl, Means sydnone, benzothienyl, benzofuryl or indolyl. 9. A compound according to any one of the preceding claims, wherein R ^{a is} an alkyl group having 1 to 16 carbon atoms, an alkenyl group having 2 to 16 carbon atoms;, an alkynyl group having 2 to 16 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkenyl group having 4 to 7 carbon atoms, a carbocyclic aryl group, a heterocyclic group containing at least one 209848/1196 Contains heteroatom such as oxygen, nitrogen and sulfur, a carbocyclic or heterocyclic aryl-lower-alkyl group, wherein the lower alkyl portion has 1 to 4 carbon atoms contains, or any of these groups substituted by hydroxy, alkoxy, aryloxy, aralkoxy, mercapto, alkylthio, Arylthio, aralkylthio, amino, substituted amino, halogen, nitro, azide, carboxy, esterified carboxy, formyl, Acyl, acyloxy, cyano, phthalimido, acylamido, alkoxycarbonylamino or is aralkoxycarbonylamino. 10. Compound according to claim 9, wherein R ^{a is} an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms or any of these groups substituted by hydroxy, alkoxy, aryloxy, aralkoxy, mercapto, Alkylthio, arylthio, aralkylthio, amino, substituted amino, halogen, nitro, azide, carboxy, esterified carboxy, formyl, acyl, cyano, phthalimido, acylamido, alkoxycarbonylamino or aralkoxycarbonylamino means. 11. A compound according to claim 9, wherein R ^a is methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, octyl, dodecyl, vinyl , Allyl, isopropenyl, dimethylallyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, phenyl, naphthyl, pyridyl, pyrimidyl, furyl -, thiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, triphenylmethyl Furfuryl, pyridylmethyl or pyrrolylmethyl group or any of these groups substituted by hydroxy, alkoxy, aryloxy, aralkoxy, mercapto, alkylthio, arylthio, aralkylthio, amino, substituted amino, halogen, nitro, azide, carboxy, esterified carboxy, formyl, acyl, Acyloxy, cyano, phthalimido, acylamido, alkoxycarbonylamino or aralkoxycarbonylamino. 209848/1 1 96 - ■ 125 - 12. A compound according to any one of claims 1 to 8, wherein R ^{a is} an alkyl group having 1 to 8 carbon atoms or such a group substituted by hydroxy, carboxy, esterified carboxy, amido, cyano, alkanoyl, amino or substituted amino, an aryl-lower -alkyl- or substituted aryl-lower-alkyl group, in which the alkyl part contains 1 to 8 carbon atoms, denotes an aryl or substituted aryl group or a heterocyclic group. 13. A compound according to claim 12, wherein R ^{a is} methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or any of these groups substituted by hydroxy, carboxy, esterified carboxy, amido, cyano, alkanoyl, amino or substituted amino, or benzyl, phenethyl, phenyl or naphthyl or a substituted version of such a group. 14. A compound according to any one of claims 9 to 13, wherein R ^a by methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, benzyloxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, chlorine, bromine, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, acetyl , Propionyl, benzoyl, acetamido, benzamido, methoxycarbonylamino, ethoxycarbonylamino or benzyloxycarbonylamino is substituted. 15. A compound according to any one of claims 3 to 14, wherein P is a saturated or unsaturated, substituted one or means unsubstituted organic group. 16. A compound according to claim 15, wherein P is methyl or Means ethyl. 17. A compound according to claim 15, wherein P is a group the formula 209848/1196 -CH = C 3 4 denotes in which R and R, which can be identical or different, are each hydrogen or a substituted or unsubstituted aliphatic, C ^ -Cy cycloaliphatic, Cy-C ^ ₀ araliphatic or Cr-C. ρ mean aromatic group. 18. A compound according to claim 15, wherein P is the group -CH ₂ Y means, wherein Y is the radical of a nucleophile, which is a nucleophilic carbon, nitrogen, oxygen or Contains sulfur atom, or means a derivative of such a residue of a nucleophile. 19. A compound according to claim 18, wherein Y d denotes where η is 0 or an integer from 1 to 5 and R, when η is 2 to 5, can be identical or different and is an aliphatic group, an aryl radical, an araliphatic group Group, an alkoxymethyl, acyloxymethyl, formyl, acyloxy, esterified carboxyl, alkoxy, aryloxy, aralkoxy, Alkylthio, arylthio, aralkylthio, cyano, hydroxy, carbamoyl, N-mono-lower-alkylcarbamoyl-, N, N-di-lower-alkylcarbamoyl-, N- (hydroxy-lower alkyl) carbamoyl or carbamoyl lower alkyl group means. 209848/1196 20. A compound according to claim 18, wherein Y is azido. 21. A compound according to claim 18, wherein Y is an amino or acylamido group. 22. A compound according to claim 18, wherein Y is a derivative of a residue of a nucleophile which by reaction a compound in which Y is azido with an acetylenic, ethylenic or cyano-dipolarophile Connection has been established, 23. A compound according to claim 18, wherein Y -c.co.r '* 2 "3
denotes in which R and R, which can be identical or different, are hydrogen, cyano, lower-alkyl, phenyl, substituted phenyl, lower-alkoxycarbonyl, mono- or diaryl-lower-alkoxycarbonyl, lower-alkylcarbonyl, aryl-lower-alkyl or C _r - Or Cg-Cycloalkyl and R is hydrogen, lower-alkyl, phenyl, substituted phenyl ,. Aryl-lower alkyl or C ₁ - or C / - cycloalkyl. 24. A compound according to claim 18, wherein Y -S (O) _n R ¹ means where R 'is an aliphatic, araliphatic, alicyclic, aromatic or heterocyclic group and η 0, 1 or 2 denote. 25. A compound according to claim 24, wherein the heterocyclic group is thiadiazolyl, diazolyl, triazolyl, tetrazole 209848/1 1 96 yl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, Means benzoxazolyl, triazolopyridyl, purinyl, pyridyl or pyrimidyl. 26. A compound according to claim 25, wherein the thiadiazolyl group Means 5-methyl-1,3,4-thiadiazol-2-yl. 27. A compound according to claim 18, wherein Y -OR * 4- means, in which R is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-cycloalkyl, lower-cycloalkyl-lower-alkyl, Aryl, aryl-lower-alkyl, a heterocyclic group, a heterocyclic lower-alkyl group or any of these groups substituted by one or more substituents such as lower-alkoxy, lower-alkylthio, Halogen, lower-alkyl, nitro, hydroxy, acyloxy, carboxy, carbalkoxy, lower-alkylcarbonyl, lower-alkylsulfonyl, lower-alkoxysulfonyl, amino, lower-alkylamino or acylamino groups. 28. A compound according to claim 18, wherein Y is acetoxy. 29. A compound according to claim 18, wherein Y is the group Q Q -O.COR represents, where R represents an organic group with a total atomic weight of at least 16 means. 30. The compound of claim 29 wherein R is selected is under (i) CH _2. , where η is an integer from 1 to 7 and the group can be straight-chain or branched and, if desired, can be interrupted by an oxygen atom or a sulfur atom or an imino group, or by cyano, carboxy, alkoxycarbonyl, hydroxy , Carboxycarbonyl (HOOCCOo), halogen or amino can be substituted, 2098Λ8 / 1 196 (ii) C Hp ,, where η is an integer from 2 to and the group can be straight-chain or branched and, if desired, through an oxygen or sulfur atom or an imino group can be interrupted, (iii) R ^v , where R ^{v is} aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl or substituted cycloalkyl, (iv) R ^v (CHL) _m , in which R ^{v has} the meanings given above under (iii) and m is an integer from 1 to. .10 A compound according to claim 18, wherein Y is the group -O.CO.AR represents, wherein A is an oxygen or sulfur 10
atom or the group NH and R are hydrogen, methyl or R as defined in claim 30. 32. A compound according to claim 18, wherein Y is the group -0.CO.NH (CH ₂ ) D, where D is halogen (C ^, Br, J or F) and m is an integer from 1 to 4. 33. A compound according to claim 32, wherein Y is 2-chloroethyl means. Compounds of the general formula (B) COOH where R is phenyl, naphthyl, thienyl, furyl, benzothienyl, Benzofuryl, pyridyl or any of these groups, substi- 209848/119 6 determined by halogen (chlorine, bromine, iodine or fluorine), hydroxy, lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkanoyl, lower-alkanoylamino, lower-alkoxy, lower-alkylthio or carbamoyl, R lower-alkyl, cycloalkyl, having 3 to 7 carbon atoms, carbocyclic or heterocyclic aryl-lower-alkyl or any of these groups substituted by hydroxy, carboxy, esterified carboxy, amido, cyano, alkanoyl, amino, substituted amino, halogen or lower -Alkoxy, and Y is acetoxy, a group of the formula wherein R and η have the definition given in claim 19> a group of the formula -SW, in which ¥ thiadiazolyl, diazolyl, Triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridyl, Represents purinyl, pyridyl or pyrimidyl, an alkylthio group having 1 to 4 carbon atoms, a group of the formula Q Q -O.CO.R, where R is an alkyl or alkenyl group Represents 2 to 4 carbon atoms, the group -0.CO.NH. (CHp) D, where m is an integer from 1 to 4 and D Mean chlorine, bromine, iodine or fluorine and azido means and the non-toxic derivatives thereof. 35. Compounds according to claim 34, wherein Y is a group of the formula -SW, wherein V / 5-methyl-1,3,4-thiadiazol-2-yl means. 36. Compounds of the general formula 209848/1196 R * .C.CO.NH Il - 131 - (C) O.CO.CH COOH where R is phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl and R ^{c is} an alkyl group having 2 to 4 carbon atoms, benzyl, phenethyl, thienylmethyl or furylmethyl, and their non-toxic derivatives. Compounds of the general formula R .C.CO.NH- (D) COOH wherein R ^{x has} the definition given in claim 36 and R has the definition given in claim 34 and T acetoxy, azido, a group of the formula v / orin R and η the definitions given in claim 19 q q sit and a group of the formula -O.CO.R, where R is a Represents alkyl or alkenyl group having 2 to 4 carbon atoms or phenyl, and the non-toxic derivatives of that. 209848/1196 Compounds of the general formula R ^A .C.CO.NH (E) 0OH wherein R has the definition given in claim 36 and R has the definition given in claim 34 and V denotes an alkylthio group having 1 to 4 carbon atoms or an alkanoyl oxy or alkenoyl oxy group having 2 to 4 carbon atoms, and the non-toxic ones Derivatives thereof «. Compounds of the general formula R .C.CO.NH (F) CH ₂ OCOCH ₃ 0OH wherein R is as defined in claim 36 and the non-toxic derivatives thereof. 40.3 ~ acetoxymethyl-7ß- [2-methoxyimino-2-phenylacet- amido] -ceph-3-em-4-carboxylic acid (syn-isomer). 41 3-acetoxymethyl-7ß- (2-ethoxyimino-2-phenyl-acet- amido) -ceph-3-em-4-carboxylic acid (syn-isomer). 42. 3-acetoxymethyl-7ß- (2-terto-butoxyimino-2-phenyl- acetamido) -ceph-3-em-4-carboxylic acid (syn-isomeres). 209848/1 1 96 - .133 - 43. 3-acetoxymethyl-7β- (2-l-benzyloxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 44. 3-Acetoxymethyl-7β- [2- (thien-2-ylmethoxyimino) -2-phenylacetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 45. 3-Acetoxymethyl-7β- [2-methoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer), 46. 3-Acetoxymethyl-7β- [2-ethoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-cartionic acid (syn isomer). 47. 3-Acetoxymethyl-7β- [2-n-butoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) 48 »3-acetoxymethyl-7ß- [2-tert-butoxyimino-2- (thiene- 2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) 49 · '3-Acetoxymethyl-7ß- [2-methoxymethoxyimino-2- (thiene- 2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn isomer). 50. 3-Acetoxymethyl-7β- [2- (1-ethoxyethoxyimino) -2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 51. 3-Acetoxymethyl-7β- [2-benzyloxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 52. 3-Acetoxymethyl-7β- [2- (thien-2-ylmethoxyimino) -2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) " 53. 3-Acetoxymethyl-7β- [2- (2-bromoethoxyimino) -2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) 54. 3-Acetoxymethyl-7β ~ [2- (2-aminoethoxyimino) -Z- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) and its acid addition salt with trifluoroacetic acid. 209848/1196 55. 3-Acetoxymethyl-7β- [2-benzyloxyimino-2- (thien-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 56. 3-Acetoxymethyl-7β - ([2-methoxyimino-2- (naphth-1-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 57. 3-Acetoxymethyl-7β- [2-tert-butoxyimino-2- (naphth-1-yl) acetamido] ~ ceph-3-em ~ 4-carboxylic acid (syn isomer). 58. 3-Acetoxymethyl-7β- [2-benzyloxyimino-2- (naphth-1-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 59. 3-Acetoxymethyl-7β- [2-methoxyimino-2- (pyrid-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) 60. 3-Acetoxymethyl-7β- [2-methoxyiraino-2- (benzo [b] -thien-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer), 61. 3-Azidomethyl-7β- (2-tert-butoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 62 ο 3-Azidomethyl-7β- [2-ethoxyimino-2- (thien-2-yl) acetamido J ~ ceph-3-em-4-carboxylic acid (syn-isomeres). 63. 3-Azidomethyl-7β- [2-tert-butoxyimino-2- (thien-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 64. 3-Azidomethyl-7β- [2-benzyloxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 65. 3-Azidomethyl-7β- (2-benzyloxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 66. 3-Cyclopropylcarbonyloxymethyl-7β- (2-ethoxyimino-2-phenylacetarnido) -ceph-3-em ~ 4-carboxylic acid (syn isomer). 209848/1 196 67. 3-Acetoxymethyl-7ß- [2-tert-butoxyimino - ^ - (benzo [b] thien-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) 68. 3-Acetoxymethyl-7β- [2-benzyloxyimino-2- (benzo [b] -thien-3-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer) 69. 3-Acetoxymethyl-7β- ^ -methoxyimino ^ - (f ur-2-yl) -acetamido] -ceph-3-era-4-carboxylic acid (syn-isomer), 70. 3-Acetoxymethyl-7β- [2-tert-butoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) " 71. 3-Acetoxymethyl-7ß- [2-benzyloxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer). 72. 3-Hydroxymethyl-7β- (2-methoxyimino-2- phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 73 ο '3- (pyrid-1-ylmethyl) -7ß- (2-methoxyimino-2-phenyl- acetamido) -ceph-3-em-4-carboxylate (syn-isomeres). 3-Azidomethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 75. 3-Methyl-7ß- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 76 ο 3- (4-carbamoylpyrid-1-ylmethyl) -7ß- (2-methoxyimino- 2-phenylacetamido) -ceph-3-em-4-carboxylate (syn-isomer). 77. 3-Methylthiomethyl-7ß- ^ -methoxyimino ^ -phenylacet- amido) -ceph-3-em-4-carboxylic acid (syn-isomer) ₀ 76. 3-Isobutyryloxymethyl-7β- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer). 209848/1136 79.3 ~ Benzoyloxymethyl-7ß- (2-methoxyimino ~ 2-phenylacet- amido) -ceph-3-em-4-carboxylic acid (syn-isomer). 8O ₀ 3 "(W-2-chloroethylcarbamoyloxymethyl) -7ß- (2-meth- oxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomeres) . 81 ο 3-crotonyloxymethyl ~ 7ß- (2-methoxyimino-2-phenylacet- amido) ~ ceph-3-em-4-carboxylic acid (syn-isomer). 82. 3-Azidomethyl-7β- [2-methoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-A-carboxylic acid (syn-isomer) ₀ 83. 3-Hydroxymethyl-7β- [2-benzyloxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 84. 3- (5-Methyl-1,3,4-thiadiazol-2-ylmethyl) -7β- [2-benzyloxyimino-2- (thien-2-yl) acetamido] -ceph-3-em-4- carboxylic acid (syn isomer). 85. 3 ~ Acetoxymethyl-7β- [2-tert-butoxyimino-2- (benzo [b] -thien-2-yl) -acetamido] -ceph-3-er-4-carboxylic acid (syn isomer). 86. 3-Acetoxymethyl-7β- [2-methoxyimino-2- (benzo [b] -thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 87. 3-Acetoxymethyl-7β- [2-benzyloxyimino-2- (benzo [b] -thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 88. 7β- [2-tert-Butoxyimino-2- (benzo [b] -thien-3-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) - thiomethylceph-3-em-4-carboxylic acid (syn isomer). 89. 7β- (2-Ethoxyimino-2-phenylacetamido) -3- (5-methyl-1,3 »4-thiadiazol-2-yl) -thiomethylceph-3-em-4-carboxylic acid
(syn isomer). 2098A8 / 113G - .137 - 90 · 7β- [2-tert-butoxyimino-2- (thien-2-yl) acetamido] - 3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethylceph-S-em ^ - carboxylic acid (syn isomer). 91 ♦ 3-Acetoxymethyl-y3- [2-methoxyimino-2- (pyrid-4 ~ yl) - acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) _o 92. 3-Acetoxymethyl-7ß- [2-ethoxyimino-2- (pyrid-4-yl) - acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) ₀ 93 · 3-acetoxymethyl-7ß- [2- (fur-2-ylmethoxyimino) ~ 2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) 94. 3-Acetoxymethyl-7β- [2-ethoxyimino-2- (fur-2-yl) acetamido ] -ceph-3-em-4-car "bonic acid (syn-isomeres). 95. 3-Acetoxymethyl-7β- [2-methoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer) _o 96. A non-toxic derivative of a compound according to any one of claims 40 to 95. 97. A sodium or potassium salt of a compound according to any one of claims 40 to 95. 98. A pharmaceutical composition containing a compound according to any one of claims 1 to 97 in one Form suitable for use in human or veterinary medicine. 99. Pharmaceutical composition according to claim 98, containing a compound according to one of claims 1 to 97, together with a pharmaceutical carrier or diluent. 2098Λβ / 1196 100. Pharmaceutical composition according to claims 98 and. 99, containing from 0.1% upwards one Compound according to any one of claims 1 to 97 101. Pharmaceutical composition according to claim 100, containing from 10 to 99% of a compound according to one of Claims 1 to 97. 102. Pharmaceutical composition according to one of Claims 98 to 101, in the form of dosage units. 103 · Pharmaceutical composition according to claim 102, wherein each dosage unit contains from 50 to 500 mg of a compound according to any one of claims 1 to 97. 104o pharmaceutical composition according to one of claims 98 to 103, also containing another therapeutic agent. 105. Process for the preparation of a compound of the formula R.C.CO.NH- Ii IiVz - (ι) 0OH where R is a hydrogen atom or an organic group, R ^{a is} an etherified monovalent organic group which is bonded to the oxygen atom via a carbon atom, B ^ or j> S ^ -0 and Z is a group in which 2 carbon atoms are the core atom and the Carbon atom containing the carboxyl group, and the ^ -unsaturation have, mean, and the derivatives thereof, thereby marked 209848/1 196 draws that one (A) a compound of the formula XX (III) ) COOR 10 wherein B and Z have the definitions given above and 10
R denotes hydrogen or a carboxyl protecting group, with an acylating agent corresponding to the acid R.C.COOH Il N 0R ^£ (IV) wherein R and R have the definitions given above, or with an acylating agent which corresponds to an acid, which is a precursor for the acid (IV), condenses, or (B) a compound of the formula, B O = C = N- (V) COOR .10 wherein B, Z and R ^{1W have} the definitions given above, 10 with the exception that R is not hydrogen, with an acid or a precursor of the formula (IV), or 20984871196 (C) if Z is the group means in which Y is the residue of a nucleophile or represents a derivative of the residue of a nucleophile, and the dashed lines representing the 2-, 3- and 4-positions connect, indicate that the connection can be a Ceph-2-em or Ceph-3-em connection, a connection the formula Acyl NH- (VI) COOR wherein acyl is the group RC ₀ CO- or a precursor thereof Il OR a 10
means B, R, R and the dashed lines have the definitions given above and Y 'represents a substitutable radical of a nucleophile, reacted with a nucleophile and then, if necessary or as desired in each case, carries out any of the following reactions 209848 / 11SC -Ί41 - (i) Conversion of a precursor of the desired R.C.CO group in the appropriate group, η (ii) Conversion of an A isomer into the desired Δ. ■ 'isomers, (iii) removal of any carboxyl protecting groups, (iv) reduction of a compound where Z> S ^ represents to form the desired Z => S connection, (v) reducing a compound in which Y is azide to form a 3-aminomethyl compound, and if desired Acylation of the resulting amino group to form the corresponding 3-acylaminomethyl compound, (vi) reaction of a compound in which Y is an azide with a dipolarophilic compound, where a Compound is obtained which has a polyazole ring attached contains the 3-methylene group, (vii) deacylation of a compound in which Y is an acyloxy group, being a 3-hydroxymethyl compound is formed, and (viii) acylation of a compound wherein Y Hydroxy denotes and where a 3-acyloxymethyl or 3-carbamoyloxymethyl compound is obtained, and formation of the desired compound of formula (I). 106. The method according to claim 105, characterized in that the acid of the formula (IV) is in the syn isomer form present « 209848/1196 107. The method according to claim 105 or 106, characterized in that characterized in that the compound of the formula (III) is a cephalosporin compound of the formula (VIII) COOR is wherein R and B are as defined in claim 96, P is an organic group and the dashed lines connecting the 2, 3 and 4 positions indicate that the connection is a Ceph-3-em- or Ceph-2-em compound. 108. The method according to any one of claims 105 to 107, characterized in that the acylating agent an acid chloride or an acid bromide is used. 109. The method according to claim 108, characterized in that it is carried out ^{at -50 to +50 0 C.} 110. The method according to claim 109, characterized in that it is carried out ^{at -20 to +30 0 C.} 1110 method according to claims 108 to 110, characterized in that it is in an aqueous ketone, an ester, an amide, a nitrile or in mixtures of which carried out. 112. The method according to any one of claims 108 to 111, characterized in that in Anviesenhe.it an acid-binding Means is carried out. 209848/1196 113. The method according to claim 112, characterized in that that a tertiary amine, an inorganic base or an oxirane is used as a means for binding the acid used. 114. The method according to any one of claims 108 to 113, characterized in that the acylating agent by Reaction of an acid of the general formula (IV) as defined in claim 105 or a salt thereof is made with a chlorinating or brominating agent. 115. The method according to claim 105, characterized in that that the chlorinating agent used is phosphorus pentachloride, thionyl chloride or oxalyl chloride. 116. The method according to claim 115, characterized in that that the sodium or potassium salt of an acid of the general formula (IV) is reacted with oxalyl chloride » 117. The method according to any one of claims 105 to 107, characterized in that the acylation is carried out by adding a compound of the general formula III condensed with an acid of the general formula IV in the presence of a condensation agent. 118. The method according to claim 117, characterized in that the condensing agent used is carbodiimide, a carbonyl compound or an isoxazolinium salt is used. 119. The method according to any one of claims 105 to 107, characterized in that the acylation with an amide-forming Derivative of the free acid is carried out. 120. The method according to claim 119, characterized in that that the amide-forming derivative is a symmetrical or 209848/1 1 Sii mixed anhydride, or an activated ester of the formula RCCO ₀ L (IX) Il N
0R ^a where R and R ^a are as defined in claim 105 and L is azide, oxysuccinimide, oxybenztriazole, pentachlorophenoxy or p-nitroplienoxy. 121. The method according to any one of claims 105 to 120, characterized in that a precursor acid is used formula RcCOoCOOH wherein R has the definition given in claim 105, or uses a corresponding acylating agent and the. resulting acylated compound with a compound of the formula R ^a 0.NH ₂ converts, wherein R ^{a has} the definition given in claim 105. 122. The method according to any one of claims 105 to 120, characterized in that a precursor acid is used formula R.E.COOH Avorin R is an activating group and E -CHp- or -CH- or a corresponding acylating agent is used, and the acylated compound formed is reacted with a nitrosating agent and the oxime formed is etherified to introduce the group R ^a . 209848/1 1 96 123 .. The method according to claim 122, characterized in that the nitrosating agent used is nitrous acid, Nitrosyl chloride or an organic nitrosating agent used, 124ο Process for the establishment of connections of the general formula I as defined in claim 105, characterized in that a compound of general formula R. fi. CONH- COOR ¹⁰ 10 wherein R, R, B and Z have the definitions given in claim 105, reacted with an etherifying agent in order to introduce the group R ^a and then, if necessary and desired, carrying out one of the following reactions: (i) Conversion of a ^ -isomer into the ge ■ 7.
wished Λ -isomers, (ii) removal of any carboxyl protecting group, (iii) reduction of a compound in which Z ^> S - ^ 0 and where the desired Z = y- S compound is formed, (iv) Reduction of a compound in which Y is an azide and in which a 3-aminomethyl compound is formed is, and if desired, acylation of the resulting Amino group to the corresponding 3-acylaminomethyl compound to build, 209S48 / 1196 (ν) reaction of a compound in which Y is azide, with a dipolarophile, forming a compound that has a polyazole ring attached to a 3-methylene group e, contains, (vi) deacylation of a compound in which Y is an acyloxy group and where a 3-hydroxymethyl compound is formed, and (vii) Acylation of a compound in which Y is hydroxy and where a 3 ~ acyloxymethyl or 3-carbamoyloxymethyl compound is formed and its recovery the desired compound of formula (I). 125. The method according to claim 124, characterized in that the etherifying agent is an organic Halide, sulfate or sulfonate, a diazoalkane, alkyl fluorosulfonate, Trialkyloxonium tetrafluoroborate or diphenyl iodonium bromide is used. 126. The method according to any one of claims 105 to 125, characterized in that the resulting compound of general formula I is converted into the non-toxic salt will. 127 ο method according to claim 126, characterized in that that one prepares the sodium or potassium salt. 128. Compounds produced according to a process of claims 105 to 127. 129. 3-Acetoxymethyl-7ß- (2-butoxyimino-2-phenyl-acetamido) -ceph-3-em-4-carboxylic acid (syn-isomer) " 130. 3-Acetoxymethyl-7ß- (2-isopropoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomer) _o 209848/1196 3-acetoxymethyl-7β- (2-propoxyiinino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomer) 132. 3-acetoxymethyl-7β- [2-propoxyimino-2- (thien-2-yl) acetamido] ~ ceph-3-em-4-carboxylic acid (syn-isomer). 133. 3-Acetoxymethyl-7β- [2-ethoxyimino-2- (benzo [b] -fur 2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer) <> 3-acetoxymethyl-7β- [2-ethoxyimino-2- (thien-3-yl) acetamido] -ceph-3-eni-4-carboxylic acid (syn isomer) _o 135. 3- (5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-7β- [2- (then-2-yl) -oxyimino-2- (thien-2-yl) -acetamido ] -ceph-3-em-4-carboxylic acid (syn isomer). 136. Compounds of the general formula R COOH 11 0R ^a wherein R and R ^a are as defined in claim 1, and the derivatives thereof. 20984.8 / 1196 ^ "*