CS199273B2 - Process for preparing 7-/alpha,alpha-disubstituted-acetamido/-3-substituted-3-cephem-4-carboxylic acids - Google Patents

Description

The invention relates to a process for the preparation of novel 7- (α, α-disubstituted-acetamido) -3-substituted-3-cephem-4-carboxylic acids, their derivatives at the carboxyl group, and pharmaceutically acceptable salts of these compounds which exhibit antibacterial activity.

The aforementioned novel 7- (α, α-disubstituted-acetamido) -3-substituted-3-cephem-4-carboxylic acid prepared by the process of the invention can be illustrated by the following general formula I,

in which

R1 is hydrogen, halogen, hydroxy, nitro, (C1-C6) alkoxy or (C1-C6) alkanesulfonamido,

R ² is hydrogen, C 1 -C 6 alkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 haloalkanoyl, or C 1 -C 6 thienylalkanoyl carbon, and

R ³ is C 1 -C 6 alkanoyloxy, carbamoyloxy which may have C 2 -C 3 haloalkanoyl, tetrazoylthio which may have C 1 -C 6 alkyl, or thiadiazolylthio which may have C 1 -C 6 alkyl 6 carbon atoms.

The process for the preparation of the abovementioned compounds of the formula I, in which the substituents R ¹ , R ² and R ^{3 are} as defined above, furthermore the C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl esters of these compounds or pharmaceutically acceptable salts thereof reacting the 7-amino-3-substituted-3-cephem-4-carboxylic acid of formula II,

wherein R ³ is as defined above, or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters, or salts thereof with α, α-disubstituted acetic acid of the formula ΙΠ, wherein R ³ is as defined above, or the C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters of the compound or a salt of the compound with α, α-disubstituted acetic acid of formula III,

OR ^ (III)

wherein R ¹ and R ² are as hereinbefore defined, or with an acid halide, an acid anhydride, an activated amide or an alkanoyloxy derivative of the above-mentioned compound having 1 to 6 carbon atoms, or with a salt thereof, that means

R ² C 1 -C 6 alkanoyl, C 1 -C 6 haloalkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl, undergo an elimination reaction of: and optionally converting the resulting compound into a pharmaceutically acceptable salt.

The above prepared esters of the compounds of the invention are C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl esters.

In a preferred embodiment of the process of the invention, a compound of formula (I) is prepared,

in which

R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an alkoxy group having 1 to 6 carbon atoms or an alkanesulfonamide group having 1 to 6 carbon atoms, and I

R ³ is a tetrazolylthio group which may optionally contain an alkyl group having 1 to 6 carbon atoms, or a thiadiazolylthio group which may optionally contain an alkyl group having 1 to 6 carbon atoms, or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters thereof or a pharmaceutically acceptable salt thereof, according to the invention by reacting a 7-amino-3-substituted-3-cephem-4-carboxylic acid of formula II,

in which

R ¹ represents the same substituent as above, and

R ² is hydrogen, C 1 -C 6 alkanoyl, C 1 -C 6 haloalkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl carbon, or an acid halide, an amide-activated acid anhydride or an alkanoyloxy derivative thereof containing from 1 to 6 carbon atoms, or salts thereof, the resulting compound wherein

A R ² alkanoyl group having 1 to 6 carbon atoms, a haloalkanoyl group having 1 to 6 carbon atoms, an aroyl group having 7 to 11 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms or a thienylalkanoyl group having 1 to 6 carbon atoms is subjected to an elimination reaction of said group, and optionally converting the resulting compound to a pharmaceutically acceptable salt.

According to another preferred embodiment of the process according to the invention in which it is prepared

in which

R ¹ is hydrogen, halogen, hydroxy, nitro, alkoxy having 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms,

R ² represents a C 1 -C 6 alkanoyl group, a C 7 -C 11 aroyl group, a C 2 -C 7 alkoxycarbonyl group, or a C 1 -C 6 thienylalkanoyl group, and

R ³ is a tetrazolylthio group, which may optionally contain an alkyl group having 1 to 6 carbon atoms, or a thiadiazolylthio group, or the C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters thereof, or a pharmaceutically acceptable salt thereof, reacting the 7-amino-3-substituted-3-cephem-4-carboxylic acid of formula II,

wherein R ³ is as defined above, or C 1-6 (alkanoyloxy) -C 1 -C 6 -alkyl esters thereof, or salts thereof with α, α-disubstituted acetic acid

wherein R ¹ and R ² are as defined above, or with an acid halide, acid anhydride, amide-activated or alkanoyloxy derivative of the compound having 1 to 6 carbon atoms, or a salt thereof, and optionally converting the resulting compound to a pharmaceutically acceptable salt thereof an acceptable salt.

According to a further preferred embodiment of the process according to the invention for the preparation of a compound of the formula II ‘,

C-CONH-IOH ° ^C00H, (11), wherein means

R ¹ OH and

The R ³ alkanoyloxy group having 1 to 6 carbon atoms, or its C 1-6 (alkanoyloxy) -C 1 -C 6 -alkyl esters or pharmaceutically acceptable salts thereof, is reacted by reacting 7-amino-3-substituted- 3-Cephem-4-carboxylic acid of formula II

wherein R ³ is as defined above, or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl esters of the compound or a salt thereof, with α, α-disubstituted acetic acid of formula III ",

C-COOH

(I // ') in which

R ¹ represents the same substituent as above, and

R ² is hydrogen, C 1 -C 6 alkanoyl, C 1 -C 6 haloalkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl or an acid halide or acid anhydride, an activated amide or alkanoyloxy derivative of the compound containing from 1 to 6 carbon atoms, or a salt thereof, and the resulting compound wherein

A R ² alkanoyl group having 1 to 6 carbon atoms, a haloalkanoyl group having 1 to 6 carbon atoms, an aroyl group having 7 to 11 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms or a thienylalkanoyl group having 1 to 6 carbon atoms are subjected to elimination reacting said group and the resulting compound is optionally converted to a pharmaceutically acceptable salt thereof.

Due to the nature of the resulting compounds of the invention, it will be appreciated that the compounds of structural formula I may include the syn-isomer, the anti-isomer, and a mixture of these isomers.

In the following, the term "lower" to be used for individual residues means a structure having 1 to 6 carbon atoms, unless explicitly stated otherwise.

Furthermore, it should be noted in the present description that the syn-isomer is a geometric isomer. with a group of the following structural formula:

N-OR and anti-isomer means a second geometric isomer with a group of the following structural formula:

^HO -C-CONH

R ^l ON

Suitable halogen for the substituents in the invention is chlorine, bromine, fluorine and iodine.

Regarding the substituent R ¹ in the above compounds, the prepared according to the invention, there can be mentioned, a preferred example is an alkoxy group having 1 to 6 carbon atoms which may be branched such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert. butoxy, pentyloxy or hexyloxy, preferably is C 1 -C 4 alkoxy and most preferably C 1 -C 2 alkoxy.

Another possible group at the site of R ¹ may generally be an amino group containing an acyl group, as described below, and preferably a lower alkanesulfonamino group having 1 to 6 carbon atoms, such as mesylamino, is used. , ethanesulfonamido, propanesulfonamido, butanesulfonamido or hexanesulfonamido, and most preferably the acylamino group has 1 to 4 carbon atoms, and more preferably the acylamino group has 1 to 2 carbon atoms.

As a preferred example of an acyl group in place of R ² , the following groups may be mentioned:

lower alkanoyl having 1 to 6 carbon atoms (such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, etc.), and preferably acyl having 2 to 5 carbon atoms;

aroyl having 7 to 11 carbon atoms (such as benzoyl, toluoyl, xyloyl, naphthoyl, 4-isopropylbenzoyl etc.), preferably a 7 to 8 carbon aroyl;

lower alkoxycarbonyl having from 2 to 7 carbon atoms (such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, etc., preferably hexyloxycarbonyl, hexyloxycarbonyl, hexyloxy); 3 to 5 carbon atoms;

aryloxycarbonyl (such as phenoxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl, etc.);

lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl hexanesulfonyl etc.);

arenesulfonyl (such as benzenesufonyl, tosyl etc.);

heterocyclic oxycarbonyl (such as 8-quinolyloxycarbonyl, pyridyloxycarbonyl, etc.);

heterocyclic carbonyl (such as thenoyl, furoyl, nicotinoyl, isonicotinoyl etc.);

carbamoyl;

arylcarbamoyl (such as phenylcarbamoyl, tolylcarbamoyl etc.);

lower alkylcarbamoyl (such as methylcarbamoyl, ethylcarbamoyl etc.);

lower alkylthiocarbamoyl (such as methylthiocarbamoyl, ethylthiocarbamoyl etc.) and arylthiocarbamoyl (such as phenylthiocarbamoyl, tolylthiocarbamoyl etc.);

The above acyl groups may contain at least one substituent at selected positions such as aryl (e.g. phenyl, tolyl etc.), the aroyl, halogen, cyano, lower cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl, etc.) lower alkoxy, lower alkylthio (such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), the aforementioned lower alkoxycarbonyl, amino, hydroxy group such as lower alkanoyloxy, e.g. etc., aryloxy, (such as phenoxy, tolyloxy, xylyloxy, etc.), arylthio (such as phenylthio, tolylthio, xylylthio, etc.), heterocyclic group (such as thienyl, thiadiazolyl, pyridyl) adiazolyl, benzothiazolon-3-yl, etc., heterocyclic oxy (such as pyridyloxy, etc.), heterocyclic thio (such as thiadiazolylthio, etc.), lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, pentyl) , hexyl, etc., nitro, phenylazo, the above lower alkanesulfonyl, lower alkanesulfonamido or lower alkanoylamino (such as acetamido, propionamido, etc.);

Where the acyl group contains more than two substituents, the substituents may be the same or different.

Of the above substituents, the aryl group may be an aryl group. the aryloxy, aryl 11, and heteroeyl groups still contained one or more of the aforementioned substituents at the selected sites, such as lower alkoxy, -halo, lower alkyl or nitro.

A preferred example of an acyl group containing the above-mentioned substituents is lower mono- or lower-alkyl. a di- or trihaloalkyiroyl group containing from 1 to 6 carbon atoms (such as chloroacetyl, chloropropionyl, chlorobutyryl, dichloroacetyl, difluoroacetyl, dichlorhexanoyl, trifluoroacetyl, trichloroacetyl, etc.), or lower alkanoyl, substituted sulfur containing an unsaturated five membered heterocyclic member, as is. for example, lower alkanoyl substituted with a thienyl group (e.g., thlenylacetyl, thienylpropinylthienylhexanoyl-ntd.), and in this case a compound having a lower alkanoyl group containing 1 to 3 carbon atoms may be used.

· Go out of the substituents R ³ in the above compounds, there may be mentioned, as a preferable example alkanoyloxy, generally speaking, may be mentioned aikanoyloxyskupinu which contains 1 to. 6 - carbon atoms, such as a formyloxy group, an acetoxy group, proplonyloxy group, butyryloxy group, isobutyryloxy group, -. valeryloxy, pivaloyloxy or hexanoyloxy, and preferably is C 1 -C 4 alkanoyloxy, and even more preferably C 1 -C 2 alkanoyloxy.

as a preferred example -carbamoyloxy group, listed as one of the possible substituents of R ³ having a -lower alkyl group, mention may be made of a lower-alkylcarbamoyloxy group (containing 2 to 7 carbon atoms, such as, for example methylcarbamoyloxy, ethylcarbamoyloxy) Polylcarbamoyloxy or α-exylcarbamoyloxy, and is preferably alkylcarbamoyloxy having 2 to 4 carbon atoms.

As a preferred example of a carbamoyloxy group which contains an aryl group, an arylcarbamoyl group having 7 to 8 carbon atoms, such as a phenylcarbamoyloxy or tolylcarbamoyl group, may be mentioned.

A preferred example of an amino protecting group on a -carbamoyloxy group is. mentioning aeyl, such as lower haloalkanoyl containing 2 to 3 carbon atoms - (such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.), or the like.

As a suitable example of another group in place of substituent R ^3, heteroalkyl and thio, and in particular saturated or unsaturated monocyclic or polycyclic-heterocyclic thio, containing at least one heteroatom such as oxygen, sulfur, nitrogen and the like may be mentioned. similar to other atoms.

As preferred examples of the above toete, rocyclic thio groups may be mentioned. heterooylic groups the following: saturated. a five membered heteromonocyclic group containing a sulfur atom having 1 to 3 nitrogen atoms, for example thiazolyl, isothiazojyl,. TLI IA thiadiazolyl (e.g., 1,2,4-thiadiazolyl, _3; 4 thladiazoiyl, 1,2,5-thiadiazolyl, etc.). a saturated five membered heterocyclic group containing an oxygen atom having 1 to 3 nitrogen atoms, e.g. oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc) etc .;

an unsaturated five-membered heteromonocyclic group containing 2 to 4 nitrogen atoms, such as imidazolyl, pyrazolyl, triazolyl (such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2, 3-triazolyl etc.), tetrazolyl etc., tetrazolyl group (such as 1H-tetrazolyl group, 2Hdetrazolyl group etc.) etc.;

an unsaturated-fused heterocyclic group with s-benzene containing nitrogen, sulfur and / or oxygen, such as benzothiazolyl, benzimidazolyl or benzoxazolyl;

or an unsaturated six-membered heteromonocyclic--oxide group having 1 to 3 nitrogen atoms (such as pyridine-1-oxide, etc.).

The above heteroaryl groups may: - be optionally substituted; a lower alkyl group containing 1 to 1 ^; 6 carbon atoms (e.g., "Meth-yl, ethyl, propyl p I isopropyl, butyl, isobutyl," tert-butyl, pentyl, h exyl etc.), - and is preferably alkyl .'to Nominal ^-groups: which contains a ^1: to 4 carbon atoms and not), more preferably to> is -group, which also contains up to 2 carbon atoms.

As a preferable example of ester ¹ 'above (said compounds prepared according to the' Invention 'can - be brought - common lower-alkyl ester of ^6-1Ci! (E.g. maethyisšter, ethyl, propyl, isopropyl, butyl, isobutyl, terč.bůtyiester , target pentylester, etc.).

Suitable examples: íarmaeeůtiéky -'přijatelných salts of the compounds of the invention may be mentioned inorganic salts such as alkali-metal (e.g., sodium jako'jsou ¹ salt or drasélůá ^sulphonyl); The salts of alkaline earth metals (such as calcium salt or magnesium salt), salts therefrom with organic bases -.sloučeninami ^as: is: for example ,: · trimethylamine, triethylamine, dicyclohexylamine, arginine, and the like other compounds.

-All or some; the compounds of structural formula I, derivatives thereof; ckarboxyskupině and to pharmaceutically acceptable - salt - such slouče199273 • ^r nin of the invention may be prepared by the following preparation processes.

A: The basic process for the preparation of the compounds of the formula I according to the invention, their carboxylic acid derivatives and the pharmaceutically acceptable salts of these compounds is the process schematically represented as follows:

HIM

R * '

where

R ^1, R ² and R ³ have the meanings already given above.

The above reaction is carried out by reacting a 7-amino-3-substituted-3-cephem-4-carboxylic acid of structural formula II or a derivative thereof at the amino and / or carboxy group or a α, α-disubstituted salt thereof. acetic acid of structural formula III or a reactive derivative thereof on the carboxy group or a salt thereof, and further, if necessary, the resulting compound wherein R ² is C 1 -C 6 alkanoyl, C 1 -C 6 aroyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl and in general the acyl group is subjected to an elimination reaction of this group and optionally converted to a pharmaceutically acceptable salt in the usual way.

In the above process, α, α-disubstituted acetic acid of structural formula III is used as the starting compound, for example 2-hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetic acid (syn-isomer) can be prepared by reduction of 3- nitro-4-benzyloxyacetophenone followed by reaction of the resulting 3-amino-4-benzyloxyacetophenone with mesyl chloride to give 3-mesylamino-4-benzyloxyacetophenone, which is oxidized to 3-mesylamino-4-benzyloxyphenylglyoxylic acid, which reacts with the acid, and the resulting product, 3-mesylamino-4-hydroxyphenylglyoxylic acid, reacts with hydroxylamine, and 2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer) can be prepared by reacting 3-hydroxyphenylglyoxylic acid with hydroxylamine and the resulting product, which is

2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer), reacted with pivaloyl chloride; and the other compounds of structural formula III may be prepared in a manner similar to that described above. In the context of the preparation of these starting compounds, when the substituted glyoxylic acid is reacted with hydroxylamine, it should be noted that either the syn-isomer or the anti-isomer or a mixture of both isomers are obtained according to the reaction conditions.

Suitable amino derivatives of the compound of formula II include isocyanate, isothiocyanate, or Schiff's base, or a tautomeric enamine isomer thereof, formed by reaction of an amino group with an aldehyde compound (such as acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde). nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphtholaldehyde, furfural, etc.) or with a ketone compound (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, ethyl acetoacetate, etc.) or the like.

Suitable derivatives of the compound of formula (II) on the carboxy group may be the same as those already mentioned for the compound of formula (I).

Salts of a compound of structural formula II include salts on the carboxy group, such as salts with inorganic basic compounds such as alkali metal salts (such as sodium or potassium salts) or alkaline earth metal salts (such as calcium or magnesium) salts), further salts with organic basic compounds such as trimethylamine, triethylamine, dicyclohexylamine or the like, and finally amino salts such as salts with acids, for example with inorganic acids (for example with hydrochloric or sulfuric acid) and with organic acids) such as salts with acetic, tartaric, maleic, benzenesulfonic or toluenesulfonic acids).

The compound of structural formula III may be a syn-isomer, an anti-isomer, or a mixture thereof.

Salts of compounds of structural formula III may be salts with inorganic basic compounds such as alkali metal salts (e.g. sodium or potassium salt) or alkaline earth metal salts (e.g. calcium or magnesium salt), salts with organic basic substances such as trimethylamine , triethylamine, dicyclohexylamine or the like.

198273

Suitable reactive derivatives of compounds of structural formula III on the carboxy group may be, for example, acid halides, acid anhydrides, activated amides, activated esters, preferably acid chlorides and acid azides, mixed acid anhydrides with acids such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid , dibenzylphosphoric, halogenated phosphoric acid, dialkylphosphoric acid, sulfuric acid, thiosulphuric acid, sulfuric acid, aliphatic carboxylic acid [such as pivalic acid, valeric, isovaleric, 2-ethylbutyric, trichloroacetic acid], aromatic carboxylic acid (such as benzoic acid, etc.) or symmetrical acid anhydrides, acid amides with imidazole, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles, or esters (such as cyanomethyl, methoxymethyl, vinyl, propargyl, p-nitrophenyl,

2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester,

8-quinolylthioester, or esters with Ν, Ν-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole etc.) or the like.

A suitable reactive derivative may be selected from the abovementioned derivatives according to the type of the α, α-disubstituted acetic acid used, of the structural formula

III.

In the process of the invention, a compound of structural formula II may also be reacted with a silyl compound (such as chlorotrimethylsilane or bis (trimethylsilyl) acetamide) to form a silyl derivative of the compound of structural formula II at the carboxy or amino and carboxy groups which reacts with the structural compound. The compound of formula III or its reactive derivatives on the carboxy group or its salts are within the scope of the invention.

The above reaction is usually carried out in a cross-linking agent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction. In addition to these solvents, hydrophilic solvents may be used in admixture with water.

When α, α-disubstituted acetic acid of structural formula III in the free acid or salt form is used in the above reaction, the reaction is preferably carried out in the presence of a condensing agent such as, for example,

N, N-dicyclohexylcarboxii mid,

N-cyclohexyl-N‘-morpholinethylcarbodiimide,

N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide,

N, N‘-diethylcarbodiimide,

N, N‘-diisopropylcarbodiimide,

N-ethyl-N - (3-dimethylaminopropyl) carbodiimide,

N, N‘-carbonyldi (2-methylimidazole), pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene,

1-alkoxy-1-chlorethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine,

N-ethyl-benzisoxazolium salt,

N-ethyl-5-phenyl-isoxazolium-3‘-sulfonate,

A Vilsmeier reagent such as (chloromethylene) dimethylammonium chloride, or the like.

9 2/7 3

Also, the above reaction may be carried out in the presence of a basic compound, for example an inorganic basic compound such as an alkali metal hydroxide, an alkali metal bicarbonate or an alkali metal carbonate, or an organic basic compound such as a trialkylamine, Ν, Ν-dialkylbenzylamine, an alkali metal alkoxide, Ν, dia-dialkylaniline or pyridine. When the basic compound or condensation agent is in the form of a liquid, it can also be used as a solvent. The reaction temperature is not critical to the above reaction, and the reaction can be carried out with cooling or at ambient temperature.

When the acylation reaction is carried out in which a compound of formula III in which R ^{2 is} an acyl radical is used as the starting compound, a compound of structural formula I in which R ^{2 is an} acyl radical may be obtained under conditions; hydrogen, depending on the type of acyl group, reaction conditions, etc., and if a compound of structural formula II in which R ^{3 is a} carbamoyloxy group containing an amino-protecting group is used as the starting compound, any structural compound of of formula I wherein R ^{3 is} either a carbamoyloxy group containing an amino protecting group or a carbamoyloxy group, depending on the reaction conditions. In the case that the obtained compound of structural formula I 'wherein R ² acyl, in carrying out the above-acylation reaction, followed, if necessary, this compound may be subjected to elimination reaction of the rest of the acyl group R ² to give a compound of Structure of formula I wherein R ^{2 is} hydrogen. In this elimination reaction of the acyl group R ² , the carbamoyloxy group containing the amino protecting group can be converted to the free carbamoyloxy group.

In this acyl elimination reaction, an elimination method may be used using a basic compound, for example an inorganic basic compound, such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal bicarbonate: (such as sodium bicarbonate, hydrogen , potassium carbonate, etc.) or an alkali metal carbonate (such as, for example, sodium carbonate, potassium carbonate, etc.), and an organic basic compound such as an alkali metal alkoxide (such as, for example, sodium methoxide, sodium ethoxide, etc .; , trialkylamine: (such as ^: trimethylamine, triethylamine, etc.), triethanolamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or pyridine, or the elimination reaction can be performed using: silica gel, basic my acidic oxides aluminum, basic or acidic ion-exchange resins, thioureas, e.g. difluoroacetic acid, a mixture of trifluoroacetic acid and anisole, a mixture of copper and dimethylformamide, a mixture of zinc and dimethylformamide, a mixture of zinc and acetic acid, a mixture of zinc and formic acid, a mixture of zinc and trifluoroacetic acid, etc. a solvent or a mixture thereof. The reaction temperature is not critical to the above elimination reaction, and the reaction is preferably carried out at ambient temperature or with cooling.

In carrying out the reaction of a compound of structural formula II with a compound of structural formula III or an elimination reaction of an acyl group, the synisomer or antiisomer of the compound of structural formula III may be partially or fully isomerized depending on reaction conditions, type of acyl group, etc. the carboxyl group derivatives or salts of the compounds of structural formula II may be converted, their free form during the reaction, or the reaction.

The starting compounds of structural formulas (II), (III) and the compound of the present invention of structural formula (I), hereinafter referred to as derivatives of this compound, are:. The carboxy group and the pharmaceutically acceptable salts of this compound are all relatively unstable compounds and are readily decomposed during the reaction, and it is therefore desirable to carry out the reaction and isolate the final product under mild conditions.

E: Another ¹ typical process for the preparation of some of the compounds of structural formula I of the invention, their derivatives at the carboxy group, or the pharmaceutically acceptable salts of these compounds is a process that can be illustrated by the following scheme:

in which he is

Y group which may be substituted by a group

R ³ '—S— in which

R ³ 'is a heterocyclic group which may contain a lower alkyl group,

R ² 'is hydrogen, lower alkanoyl, cyclo (lower) alkanecarbonyl or aroyl and

R ^1, R ² and R ³ are as previously defined.

The reaction is carried out by reacting a compound of formula IV or a carboxy derivative thereof or a salt thereof with a thiol compound of formula V or a salt thereof and, if necessary, subjecting the resulting compound to an acyl elimination reaction.

The compound of structural formula IV may be a syn-isomer, an anti-isomer or a mixture of these isomers.

As a suitable example, a group which may be substituted by a group

R ³ '-S' is, for example, halogen, azido and acyloxy, wherein said halogen and acyl in the acyloxy group may be halogen and acyl as previously mentioned.

As a suitable example of a heterocyclic group, a lower alkyl group, a lower alkanoyl group, a lower cycloalkanecarbonyl group or an aroyl group, the same groups as mentioned above for the compound of structural formula I may be mentioned.

Also suitable derivatives of the compound of formula (IV) on the carboxy group may be the same derivatives as those of the compound of formula (I) and the salts of the compound of formula (IV) may be the same as those of the compound of formula (III).

As a suitable example of a salt of a compound of Formula V, an alkali metal salt (such as a sodium salt, a potassium salt, etc.) may be mentioned.

The above reaction may be carried out in the presence of a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or other organic solvents that do not adversely affect the reaction is preferably highly polar. In addition to the solvents already mentioned, hydrophilic solvents may be used in admixture with water.

The above reaction is preferably carried out in a neutral environment. When a compound of structural formula IV or a thiol compound of structural formula V is used in free form, the reaction is preferably carried out in the presence of a basic compound, for example an inorganic basic compound such as an alkali metal hydroxide, alkali metal carbonate, acidic. an alkali metal carbonate, in the presence of a basic organic compound such as a trialkylamine, or in the presence of similar compounds. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or boiling. The reaction product obtained can be isolated from the reaction mixture by a variety of suitable methods.

In connection with the above reaction, it should be noted that when compounds of structural formula IV containing an acyl group R ² are used as the starting compound, a compound of structural formula I containing a hydrogen atom such as R ² can be directly obtained Depending on the type of residue of the acyl group R ² , reaction conditions, etc. If the resulting compound contains an acyl group on the hydroxyimine group, the acyl group elimination reaction can then be carried out, if necessary.

The elimination reaction can be carried out in the same manner as described above.

In the reaction of a compound of structural formula IV with a compound of structural formula V or an elimination reaction of an acyl group, the syn-isomer or anti-isomer of a compound of structural formula IV may be partially or fully isomerized, depending on reaction conditions, type of acyl group, etc. the compounds of structural formula IV on the carboxy group or salts of the compound of structural formula IV may be converted to their free form during the reaction or during subsequent processing.

The starting compounds of structural formula IV and the compounds of the present invention of structural formula T, their carboxy derivatives and their pharmaceutically acceptable salts are all relatively unstable and readily decompose during the reaction, and it is therefore desirable to carry out the reaction and isolate the product under moderate conditions. conditions.

The starting compounds of structural formula IV are novel compounds and can be prepared according to the following procedures.

C: Another possible process for the preparation of some of the compounds of the invention, structural formula I, their carboxy derivatives or pharmaceutically acceptable salts thereof, is as follows:

in which

R ¹ and R ³ have the meanings already given above and

R ² 'is acyl.

The above reaction is carried out by reacting a compound of structural formula (I '), a carboxy derivative thereof, or a salt thereof with an acylating agent.

A suitable example of an acyl group R ² 'is the same acyl group as shown for the compound of structural formula (I).

A suitable example of a derivative of a compound of formula (I) on the carboxy group may be the same as that described for a compound of formula (I) and, for example, a salt of a compound of formula (I), III.

The compound of structural formula I 'may be in the form of a syn-isomer, an anti-isomer, or a mixture of these isomers.

Compounds such as aliphatic acid, aromatic acid and heterocyclic carboxylic acid as well as the corresponding sulfonic acid and thioacid having the above acyl groups may also be used as acylating agents for the above reaction, and finally the reactive derivatives of the above mentioned may be used. of acids. A suitable reactive derivative of the aforementioned acids may be the same derivative as that mentioned above for the compound of structural formula III.

A suitable acylating agent may also be an isocyanic acid ester (such as methyl isocyanate, phenyl isocyanate, etc.), isothiocyanate esters (such as methyl isothiocyanate, phenylisothiocyanate, etc.) and formic acid halides (such as benzyl chloroformate, etc.). In this case, if, for example, is used as acylating agent, methyl isocyanate, such as a methylcarbamoyl, an acyl group R ² ', and if it is used as the acylating agent, ethyl chloroformate, a ethoxycarbonyl group as acylating R ² ".

In carrying out the above reaction, a compound of structural formula I may also be reacted with a silyl compound (such as chlorotrimethylsilane, bis (trimethylsilyl) acetamide, etc.) to form a silyl derivative at the hydroxyimino or hydroxyimino and carboxy group of the compound of structural formula I. product with acylating agent.

The above reaction is carried out under similar reaction conditions to those described for the reaction of a compound of Formula II with a compound of Formula III.

In the reaction of a compound of Formula I "with an acylating agent, the syn-isomer or anti-isomer of a compound of Formula I" may be isomerized partially or fully, depending on reaction conditions, the second acyl group, etc., and derivatives on the carboxy group of the compound of Formula I Or the salts of this compound can be converted to their free forms during or after the reaction.

The starting compounds of structural formula (I ') and compounds of structural formula (I' '), their carboxylic acid derivatives, and pharmaceutically acceptable salts thereof are relatively unstable compounds and readily decompose22 during the course of the reaction, and it is desirable to carry out the reaction and isolate the product under mild conditions .

The starting compound of Structural Formula I 'is a novel compound and can be prepared by the methods set forth below.

D: Another alternative method for preparing compounds of the invention wherein the carboxy derivative is an ester may be illustrated by the following scheme:

C-CONH _R 1 = y il

N? _λ

OIC

CH 2 R ³

HIM

a.stfcňi.fúka. & e.

C-CONH '

O'·

of.

or ^l

COOH fl

-W

-i? 3

COOR ¹¹

CHfR in which

R ^1, R ² and R ³ are as previously defined and

R ⁴ is an ester component of an esterifiable carboxy group, represented by the formula —COOR ⁴ .

The above reaction may be carried out by subjecting a compound of Formula I or a salt thereof to esterification.

A suitable salt of a compound of Formula I may be a salt already exemplified in a compound of Formula III.

A suitable example of the radical R ⁴ may be an ester component as described above for an ester derivative on the carboxy group of a compound of structural formula I.

The esterifying agent used for the above reaction may be a compound of Formula VI,

X - - R ⁴ (Vij in which has

R ⁴ is as defined above, x is hydroxy or a reactive derivative thereof.

A suitable example of a reactive hydroxy derivative is the aforementioned halogen or the like.

The above reaction is conveniently carried out in a solvent such as dimethylformamide, pyridine, or other solvents that do not adversely affect the reaction.

When the compound of formula (I) is used in the free acid form, the reaction is carried out in the presence of a basic compound such as an inorganic basic compound such as the above-mentioned alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate, or an organic basic compound such as trialkylamine, Ν, Ν-dialkylaniline, N, N-dialkylbenzylamine or pyridine. The reaction temperature is not critical; the reaction may be carried out preferably under cooling, at ambient temperature or under boiling.

The compounds of structural formulas I, T and I 'získané thus obtained, which are the subject of the invention, are in the form of the free acids, which compounds can be converted into pharmaceutically acceptable salts of these compounds by elaboration by conventional methods.

The compounds of structural formula I of the present invention exhibit high antibacterial activity and further inhibit the growth of a large number of microorganisms, including gram-positive and gram-negative bacteria. For therapeutic administration, the cephalosporin compounds of the invention may be used in the form of pharmaceutical compositions containing the compounds in admixture with pharmaceutically acceptable carriers, such as inorganic or organic solid or liquid excipients, suitable for oral, parenteral or external administration. These pharmaceutical preparations may be in the form of a solid, such as capsules, tablets, dragees, pastes, or in the form of a liquid, such as solutions, suspensions, emulsions. If necessary, additives, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives can be added to the above compositions.

The amount of compounds to be administered may vary within wide limits depending on the age and condition of the patient, with an average single dose being 50 mg, 100 mg, 250 mg and 500 mg, which have been found to be effective in the treatment of diseases. caused by bacterial attack. In general, amounts of the compounds of the invention ranging from 1 mg to 1000 milligrams or more can be administered.

The compounds closest to the compounds of the invention are those disclosed in DOS 2,204,060.

The test results below show that the compounds of the present invention of structural formula I have unexpectedly superior properties over the compounds of the prior art. The comparative results with respect to the antimicrobial activity of the compounds of the invention and the compounds of DOS 2,204,060, which represent the prior art, are presented in the tests below.

Test 1

Test compounds

1.

Sodium 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer);

2.

Sodium 7- (2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer;

3.

7- [2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] cephalosporanate sodium (syn-isomer;

4.

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer);

5.

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer);

6.

7- [2-benzoyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-4-yl) thiomethyl-3-cep-4-carboxylic acid (syn-isomer);

7.

7- [2-ethoxycarbonyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer);

8.

7- [2- (hydroxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanic acid (syn-isomer);

9.

Sodium 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylate (syn-isomer);

10.

7- [2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer).

Compound listed in the above DOS (German Offenlegungsschrift 2 204 060):

7- (2-hydroxyimino-2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

Test method:

The antibacterial activity of the compounds was determined by a two-fold dilution method on an agar plate, in vitro, as described below.

According to this method, one full seed of overnight cultures of each of these species in trypticase and soybean solution (10 ^{7 8} viable cells per ml) were placed in heart infusion agar (HI-agar) containing increasing concentrations of antibiotics and recorded the minimum inhibitory concentration (MIC), which was expressed in µg / ml after incubation at 37 ° C for 20 hours. The table below shows the results of this test.

Test results

Test MIC (µg / ml) baTteria Test compounds co

198273

CO CO CO O)

IO CM CM tH CO CM tH what what what what what what bx IO CM o o IO Γ-f o o

CM

CO t> in θ 'r-T what what [> 10 in ιη o η η CM what co σ) what LO CM IO rH

CO O) 1Ο CO O) co O CO CM IO CO O o co T-f o o c co co CO CM LO [>. O rH o o cm o o what what what rH IO O O LO O CO tH CM

O) WHAT WHAT WHAT WHAT WHAT WHAT HAT> TH CM, WHAT WHAT WHAT WHAT WHAT

CO tx LO whatever + mo

O TH o o o what what what what bx rH LO, r — I what O what LO rH what r-T

CM

IO 10 cm LO WHAT what what O cm cm LO rH r-i

«G .23

CM 's- <.ti CD S- <thi «ti« w

J 'i xi λ co co

CM

Cx cd <ti o.

.2 'those

SbSI tí co f-ι ‘Ό π fi

BJ

Φ Pi fi 'S ns at> · CM W rj f- ¹ W Pj

From the above test results, it can be seen that compounds of the invention of structural formula I having a hydroxyl group on the benzene nucleus at position 7 exhibit stronger antimicrobial activity against various pathogenic microorganisms compared to the compound of DOS 2,204,060 which represents the prior art. techniques.

T e st 2

Test compounds:

1.

Sodium 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thlomethyl-3-cephem-4-carboxylate (syn-isomer) ;

2.

Sodium 7- [2-hydroxy-amino-2- (3-hydroxy-phenyl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate (syn-isomer);

3.

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer);

4.

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer);

5.

7- [2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer);

6.

Sodium 7- [2-hydroxyimino-2- (3-methoxy-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn- isomer);

'7.

7- [2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer );

8.

Sodium 7- [2-hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn -isomer);

9.

7- (2-hydroxyimino-2- (4-chlorophenyl) acetamido] cephalosporanic acid (syn-isomer).

The above compounds 1-8 are compounds of the invention and compound 9 is a compound of DOS 2,204,060 which represents the prior art.

In addition to DOS No. 2,204 OSO, it is noted that there is one exemplary embodiment with a compound having a phenyl substituent at the 7-position, i.e. 7- [2-hydroxy oxyimino-2- (4-chlorophenyl) acetamido] cephalosporan, syn-isomer (compound 9), which is closest to the compounds of the invention as compared to the other compounds of the above-mentioned DOS.

Test method:

The antibacterial activity of the compounds was determined by a double dilution method on an agar plate, in vitro, as described below.

According to this method, one full seed of overnight cultures of each of these species in trypticase and soybean solution (10® viable cells per ml) were placed in heart-infusion agar (Hi-agar) containing increasing concentrations of antibiotics, with minimal inhibitory concentration (MIC), which was expressed in µl / ml after incubation at 37 ° C for 20 hours. The table below shows the results of this test.

eo

O ID O O O O O CM O O. O? -? CO? -? -? RH

AND

WHAT oo what WHAT what UO Ογ U0 O* r-l rH o IO rH O what

oo what what WHAT what 00 Os_ Os it τ — 1 O; O O r ~ f what O O

tí tí

Φ> o th i o 'Φ th th §

4->

w

Φ

A & o o

what oo LO 00 what to ^ CM Os τ — 1 rH o o what O what

what what what cn LO CM ^ CM 'rH what cm τ-f o what what o o w

φ

4-J

Ί3

Φ ω

'>>

>

CM

what what oo what 00 CM LO Os O ^ r-l O O cm O O what

o what what what what what i>. r-ι iry o o to o co r-f

CM what what Os LO o r-f oo what o. O. To o o o r-f o what CO what what what C \ rH LO_ rH LO

CM t-t

Φ

4-3 cd thi 'th o

4-3

W φ

CM

Axis cB CM c CM G C • rM O n. Φ 'r <

Φ bp X Φ <4-1 tx r-1

1x .2 ^1x1 ti 03 About ti! § 2 3 2 aB t ca w cn what CL • ^l— “<f — I

W X CL

From the above results of this test, it can be seen that the compounds 1-8 of the present invention achieve much stronger antibacterial activity against various types of pathogenic microorganisms compared to compound 9, i.e., as compared to the prior art.

The following Examples illustrate the process of the present invention.

Preparation of the starting compounds

Preparing 1

1) A mixture of 3-nitro-4-benzyloxyacetophenone (40 g), 99% ethanol (800 ml) and water (300 ml) was heated at 80 ° C.

To this mixture was added sodium sulfide, nonahydrate (80 g), and the mixture was stirred for 1 hour, then refluxed with stirring for 3 hours. The resulting reaction mixture was concentrated to a volume of 300 mL at 40 ° C under reduced pressure. After this operation some of the precipitate was collected by filtration, washed with water and dried to give 25.5 g of 3-amino-4-benzyloxyacetophenone, melting at 113-114 ° C.

2) A solution of mesyl chloride (6.3 g) in dry methylene chloride (20 mL) was added dropwise over 30 minutes while stirring and cooling the reaction vessel with ice to a solution of 3-amino-4-benzyloxyacetophenone (12 g) and dry pyridine (8.0 g) in dry methylene chloride (100 mL) and the resulting mixture was stirred for 4 hours at ambient temperature. Thereafter, the reaction mixture was concentrated at 40 ° C under reduced pressure, and concentrated hydrochloric acid was added until the pH of the solution reached 1. The precipitated product was collected by filtration, washed with water and dried to give the resulting 3- mesylamino-4-benzyloxyacetophenone (15.4 g), melting at 124-127 ° C.

3) A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g), dimethylformamide (60 mL), benzyl chloride (9.35 g), potassium carbonate (14.5 g) was stirred for 1 hour at a temperature of Mp 100 ° C. The reaction mixture was then poured into water (150 mL) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After distilling off the solvent, the residue (18 g) was recrystallized from ethanol (160 ml) to give the resulting 3-chloro-4-benzyloxyacetophenone (13.2 g), melting at 110-112 ° C.

Preparation 2

1] Selenium dioxide powder (12.6 g) was added over 10 minutes to a solution of 3-chloro-4-benzyloxyacetophenone (19.7 g) in dry pyridine (100 mL) with stirring at 100 ° C and the resulting the mixture was stirred for 3 hours at the same temperature. Precipitated selenium was removed by filtration and the filtrate was concentrated. The obtained residue was dissolved in water (150 mL) and the resulting solution was washed with ether. The aqueous phase was acidified under cooling with concentrated hydrochloric acid and then extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated to give 15.9 g of the title 3-chloro-4-benzyloxyphenyl glycolic acid, mp 134-135 ° C.

(2) The following compounds were prepared according to the procedure described above under Preparation 2-1:

(1)

3-nitro-4-benzyloxyphenylglyoxalic acid, m.p. 161-164 ° C;

(2)

3-Mesylamino-4-benzyloxyphenylglyoxylic acid, m.p. 165-167 ° C (dec.).

Preparation 3

1) A mixture of 3-nitro-4-benzyloxyphenylglyoxylic acid (30 grams), concentrated hydrochloric acid (90 mL) and acetic acid (120 mL) was stirred at 100 ° C for 3 hours. To this reaction mixture was added ice water (600 mL) with cooling, and the resulting mixture was extracted with ethyl acetate. The obtained extract was washed with ice water, dried with magnesium sulfate and concentrated to dryness under reduced pressure. The resulting residue was recrystallized from a mixture of benzene, ether and petroleum ether (2: 1: 4). The crystals were collected by filtration, then washed with benzene and dried under reduced pressure to give the title 3-nitro-4-hydroxyphenylglyoxylic acid (19.0 g), mp 139-140.5 Deň: 32 ° C.

2) Following the procedure described above under Preparation 3-1, the following compounds were prepared:

(1)

3-mesylamino-4-hydroxyphenylglyoxylic acid, m.p. 163-165 ° C;

W

3-Mesylainino-4-hydroxyphenylglyoxylic acid, melting at 114-116 ° C Preparation 4

1] To a solution of sodium bicarbonate (5.56 g) in water (200 mL) was added under stirring and dissolved 3-hydroxyphenylglyoxyl (11 g) with cooling, in particular a solution of hydroxylamine hydrochloride (4.60 g) dissolved in a solution of sodium bicarbonate (5.56 grams) in water (70 ml) prepared under stirring at room temperature, the solution was added to the above solution with stirring while cooling. The reaction solution was acidified with hydrochloric acid and extracted with ethyl acetate. the crystals were collected by filtration to give the resulting 2-hydroxyimine Ino-2- (3-hydroxyphenyl) acetic acid (syn-isomer, 6 g).

IR spectrum (nujol)

3200—3350, 1700 cm ¹

2) A mixture of 3-hydroxyphenylglyoxylic acid (3.32 g) and a solution of 1N-methanol and hydroxy laminate (45 ml) was refluxed with stirring for 25 minutes. The reaction mixture was then concentrated to dryness. The residue was dissolved in aqueous 1 N sodium hydroxide (50 mL) and the solution was washed with ether, acidified with hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried and concentrated to a yellow oil. To this oily matter was added benzene and then benzene was distilled off. The residue was recrystallized with petroleum ether and the crystals were collected by filtration, washed with petroleum ether, and dried to give the title product 2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (a mixture of syn-isomer and anti-isomer, 2.9 g).

IR spectrum (nujol)

3200, 1700 cm ¹

3) In a manner similar to Preparation 4-1 above, the following compounds were prepared:

(1)

2-hydroxyimino-3- [3-methoxy-4-hydroxyphenyl) acetic acid (syn-isomer),

IR spectrum (nujol)

3250—3350, 1710 cm ¹ (3)

2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) -acetic acid (syn-isomer), melting at 170-171.5 ° C (dec.);

(3)

2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (syn-isomer), mp 162 ° C (dec.);

(4),

2-hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetic acid (syn-isomer), m.p. ranging from 94 to 95 ° C (dec.).

Preparation 5

1) Dissolve dichloroacetyl chloride (8.14 g) in methylene chloride (25 mL) and add to this solution 2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer) in an amount of 2.5 g, with stirring, and then the resulting mixture was stirred for an additional 45 minutes at room temperature. Petroleum ether was added to the resulting reaction mixture to give a precipitate which was collected by filtration and then washed thoroughly with petroleum ether to give the title product, 2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer, 3). 57 g).

IR spectrum (nujol)

3450, 1765, 1740 cm ¹

2) A mixture of 2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer, 9.06g), benzoyl chloride (32.25g) and tetrahydrofuran (50ml) was stirred for 6 hours at To the reaction mixture was added petroleum ether at 5 DEG C. A precipitate was formed which was collected by filtration, washed with petroleum ether and dried to give the title product 2-benzoyloxyimino-2- (3-hydroxyphenyl). acetic acid (syn-isomer, 11.12 g), m.p. 140-142 ° C (dec.).

3) Dissolve dichloroacetyl chloride (14.7 g) in methylene chloride (50 mL). To the thus obtained solution was added 2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (syn-isomer, 5.65 g) with stirring while cooling the reaction solution with ice. The solution was stirred for 30 minutes at room temperature and then ether (10 mL) was added to this solution. Petroleum ether was then added to the solution under ice-cooling. This gave a precipitate which was filtered off and washed thoroughly with petroleum ether to give the title product, 2-dichloroacetoxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (syn-isomer, 6.1 g), which was used as the starting compound for the following acylation reaction without further purification.

4) 2-Hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetic acid (syn-isomer, 1.37 gj and dichloroacetyl chloride (0.9 gj) was treated in the same manner as above. which were designated as Preparation 5-1 to 5-3 to give 2-dichloroacetoxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetic acid (syn-isomer, 1.9 g) which was used as the starting compound for the following acylation reaction without further purification.

5) The following compounds were prepared according to this procedure, which was similar to the above procedures designated as Preparation 5-1 to 5-4:

(1)

2-dichloroacetoxyimino-2- (4-hydroxyphenyl) acetic acid (syn-isomer);

IR spectrum (nujol)

3350, '1755, 1730 cm' ¹ (1)

2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetic acid (mixture of syn-isomer and anti-isomer);

IR spectrum (nujol)

3400, 1760, 1730 cm ^-1 (3)

2- [2- (2-thienyl jacetoxyimino) -2- (3-hydroxyphenyl) acetic acid (syn-isomer);

IR spectrum (nujol)

3400, 1730—1740 cm ^-1 (4)

2-benzoyloxyimino-2- (4-hydroxyphenyl) acetic acid (syn-isomer);

IR spectrum (nujol)

3350, 1735, 1725 cm ^-1 (5)

2-dichloroacetoxyimino-2- (3-methoxy-4-hydroxyphenyl) acetic acid (syn-isomer);

IR spectrum (nujol)

3450, 1795, 1705 cm ^-1 (6)

2-dichloroacetoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (syn-isomer);

IR spectrum (nujol)

3400, 1780, 1700 cm ¹ (7)

2-Pivaloyloxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer), m.p. 123-126 ° C (dec.).

Example 1

AND)

Thionyl chloride (1.3 g) was added to dimethylformamide (0.8 g) and the resulting mixture was stirred for 30 minutes at 40 ° C. The mixture was concentrated to dryness and the residue was dissolved in methylene chloride (15 mL). To this mixture was added 2-dichloroacetoxyimino-2- (4-hydroxyphenyl) acetic acid (syn-isomer, 1.61 g) and the resulting mixture was stirred for 30 minutes at -30 ° C. To this solution was added at one time a solution of 7-amino-3- (1-methyl-1H-terazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (1.64 g) and bis (trimethylsilyl) acetamide ( 2.1 g) in methylene chloride (30 ml), the mixture was stirred for 20 minutes at the same temperature, a small amount of water was added thereto, methylene chloride was distilled from the mixture, and ethyl acetate and water were added to the residue. After shaking the mixture, the ethyl acetate layer was separated (which was forged twice) to give an ethyl acetate layer containing 7- [2-dichloroacetoxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H). -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), washed with saturated sodium chloride solution, water was added and the resulting mixture was stirred under cooling. of a mixture of (aqueous) sodium bicarbonate in such an amount The solution was then stirred for 10 minutes at the same temperature, and 10% hydrochloric acid was added thereto with stirring and cooling in an amount to adjust the pH of the solution to 5. After stirring at room temperature, the solution was stirred at room temperature. washing with ethyl acetate, the aqueous layer was again adjusted to pH 2 with 10% hydrochloric acid. Extraction was carried out with ethyl acetate. The extract obtained was washed and dried. The solvent was distilled off. The residue was triturated with ether, separated by filtration and washed with ether to give the final product, 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido) -3- (1-methyl- 1H-Tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer, 0.46 g).

IR spectrum (nujol)

3250, 1770, 1710, 1660 cm -1 ¹ H NMR spectrum (d 6 -dimethylsulfoxide, δ ppm)

11.25 (1 H, s)

9.57 (1 H, d, J = 9 Hz)

7.43 (2H, d, J = 9Hz)

6.80 (2H, d, J = 9 Hz)

5.85 (1H, dd, J = 9Hz)

5.17 (1H, d, J = 5 Hz)

4.32 (2H, AB _q , J = 13 Hz)

3.95 (3 H, s)

3.73 (2H, AB _q , J = 18 Hz)

The thus obtained 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl- (thiomethyl-3-cephem-4-carboxylic acid) (syn-isomer) was converted by conventional to its sodium salt to give 7 - [- 2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) - (thiomethyl-3-cephem-4-carboxylate) sodium (syn-isomer j.

IR spectrum (nujol)

3250, 1770, 1710, 1660 cm -1 ¹ H NMR spectrum (D 2 O, δ ')

PPm

7.5 (2H, d, j = 9 Hz)

6.9 (2H, d, J = 9 Hz)

5.85 (1H, d, J = 5Hz)

5.16 (1H, d, J = 5 Hz)

4.2 (2H, _ΑΒ ς, J = 13Hz)

3.95 (3 H, s)

3.6 (2H, AB _q , J = 18 Hz)

(B)

A mixture of dimethylformamide (1.33 g) and phosphorus oxychloride (2.55 g) was heated at 40 ° C for 1 hour. After cooling the mixture, methylene chloride (30 mL) was added and then distilled off. To the obtained residue was added ethyl acetate (30 mL). To this mixture was added 2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer, 5.3 g) while stirring with ice-cooling. In particular, a mixture of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (4.96 g) and bis (trimethylsilyl) was then prepared. of acetamide (9.21 g), which were dissolved in ethyl acetate (50 ml), stirred under cooling, and then the mixture was added as above at a temperature ranging from -15 to -10 ° C. The resulting solution was stirred for 1 hour at the same temperature and water was added to precipitate a precipitate which was filtered off and the ethyl acetate layer in the resulting filtrate was separated. The two layers of ethyl acetate were combined to extract 7- [2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) (thiomethyl-3-cep-4-carboxylic acid (syn-isomer), water was added. An aqueous solution of sodium bicarbonate was added to the mixture in an amount to adjust the pH to 6-6.5. Then the mixture was stirred for 30 minutes and the aqueous layer was treated similarly to Example 1A to give the final product, 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer, 5.12 g).

IR spectrum (nujol)

3300, 1780, 1720, 1670 cm- ¹ NMR spectrum (d-dimethylsufoxide, δ ppm)

11.6 (1 H, s)

9.6 (1H, d, J = 9 Hz)

6.7-7.5 (4 H, m)

5.85 (1H, dd, J = 5.9Hz)

5.17 (1H, d, J = 5 Hz)

4.36 (2H, AB _q , J = 13 Hz)

3.96 (3 H, s)

3.77 (2H, AB _{C 1} , J = 18 Hz)

The thus obtained 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) was converted to its sodium salt by conventional work up to give 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem- Sodium 4-carboxylate (syn-isomer).

3200–3500, 1760, 1660, 1595 cmn ¹ NMR spectrum (D2O, δ ') ppm

6.7-7.5 (4 H, m)

5.75 (1 H, d, J = 5 Hz)

5.1 (lH, d, J = 5Hz)

4.1 (2H, AB _q , J = 13 Hz)

3.91 (3 H, s)

3.55 (2H, AB _{t |} , J = 18 Hz)

C)

Phosphorus oxychloride (1.77 g) was added to dry dimethylformamide (0.8 g) and the mixture was stirred for 30 minutes at 40 ° C. To this mixture was further added dry benzene (20 mL) and the mixture was concentrated to dryness. The residue was suspended in dry ehylesteru acetic acid (20 mL) and to the suspension was added dropwise under cooling at -20 ° C and a stirring solution of ^2-di-i chloroacetoxyimino 2- (3-chloro-4-hydroxyphenyl) acetic acid ( syn-isomer, 3.26 g) in cold dry ethyl acetate (20 mL) and the resulting mixture was stirred for 30 minutes at the same temperature. In particular, a solution was obtained which was obtained by adding bis (trimethylsilyl) acetamide (8 grams) to a mixture of 7-aminocephalosporanic acid (2.7 g) and dry ethyl acetate (30 mL), and the resulting mixture was stirred for 1 hour at ambient temperature. To the solution thus obtained, the above-mentioned ethyl acetate solution was added dropwise with cooling to -20 ° C, and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added water (10 mL) dropwise at -30 ° C. Next, a solution of ethyl acetate (100 mL) and water (80 mL) was added to the mixture, and the mixture was stirred for 30 minutes. The ethyl acetate layer was then separated. To this solution, which contained 7- [2-dichloroacetoxyimio-2- (3-chloro-4-hydroxyphenyl) acetamido] -cephalosporanic acid (syn-isomer) in addition to ethyl acetate, was added water (100 mL). To this mixture was further added sodium bicarbonate under ice-cooling to adjust the pH to 6.5 and the resulting solution was stirred for 15 minutes. The resulting aqueous layer was treated as described in Example 1A to give 7- [2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] cephalosporanic acid (syn-isomer). This compound was suspended in water (20 mL) and the suspension was treated with sodium bicarbonate to adjust the pH to 6.5 and the precipitate formed was filtered off. The resulting filtrate was lyophilized at ambient temperature to give 7- [2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] cephalosporanate sodium (syn-isomer, 1.4 g).

IR spectrum (nujol)

3400—3450, 3200, 1765, 1720, 1660, 1620

1600 cm ^-1

NMR spectrum (D 2 O, δ) ppm

7.6 (1 H, d, J = 2Hz)

7.3 (1H, dd, J = 2.8Hz)

6.85 (lH, cl, J = 8Hz)

5.85 (1 H, d, J = 6 Hz)

5.20 (1H, d, J = 6 Hz)

2.1 (3 H, s)

D)

Dimethylformamide (0.4 g), phosphorus oxychloride (0.81 g), methylene chloride (20 ml), ethyl acetate (10 ml) and 2- [2- (2-thienyl) acetoxyimino) -2- (3-hydroxyphenyl) acetic acid (syn-isomer, 1.68 g) was treated in the same manner as in Example 1B to give an ethyl acetate solution. In particular, 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (1.64 g) and bis (trimethylsilyl) acetamide (3.55 g) were dissolved in ethyl acetate (20 mL) and the mixture was stirred for a suitable time at -20 ° C, to which was finally added the above solution. The reaction mixture was then stirred for 1 hour at the same temperature. To this mixture was further added water and stirred for 10 minutes. Then she was ^; Separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate. The two ethyl acetate layers were combined. Next, the extract was washed with a saturated solution of sodium chloride in water. After drying, the solvent was distilled off. The residue was treated with a mixed solution of diisopropyl ether and ether, collected by filtration and washed to give 7 - (- 2 - [[2-thienyl (acetoxyimino) -2- (3-hydroxyphenyl) acetamido) -3- (1-methyl-1H-)]. tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer, 2.2 g).

IR spectrum (nujol)

3150—3200, 1770, 1720, 1670 cnr ¹

NMR spectrum (d -dimethylsulfoxide, δ) ppm

10.12 (1H, d, J = 9Hz)

6.8-7.6 (7 H, m)

5.94 (1H, dd, J = 9Hz)

5.26 (1H, d, J = 5Hz)

4.38 (2H, AB _q , J = 13 Hz)

4.18 (2 H, s)

3.97 (3 H, s)

3.81 (2H, AB _q , J = 1Hbz)

E)

Dimethylformamide (0.31 g) and phosphorus oxychloride (0.69 g) were heated at 40 ° C for 30 minutes. To this mixture was added benzene, which was removed. The resulting residue was suspended in ethyl acetate (7 mL), and 2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetic acid (syn-isomer) was added dropwise with stirring and cooling at -10 to -20 degrees Celsius. 1.24 gj in cold ethyl acetate (6 ml) The resulting mixture was then stirred for 30 minutes at the same temperature, especially a solution of 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid was prepared. (1.05 g) and bis (trimethylsilyl) acetamide (2.04 g) in ethyl acetate (10 mL) were stirred and cooled at a temperature ranging from -10 to -20 ° C. The above ethyl acetate solution was added dropwise over 5 minutes and the mixture was stirred for 2 hours at the same temperature, then water (10 mL) was added to the reaction mixture and the ethyl acetate layer was separated. To the acetate solution containing 7- [2-dichloroacetoxyimino-2- (3-hydroxyphenyl) acetamido] -3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer) was added water in an amount of 10 ml. The pH of the mixture was then adjusted to

7.5 by the addition of sodium bicarbonate and stirring was continued for 30 minutes at ambient temperature. The collected layer was then treated in the same manner as in Example IA to give 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3-carboyloxymethyl-3-cephem-4-carboxylic acid. acid (in the form of the syn-isomer of 600 mg). This acid was converted to its sodium salt in a manner similar to Example 1C to give 7- (2-hydroxyimino-2- (3-hydroxyphenyl) -acetamido] Sodium 3-carbamoyloxymethyl-3-cephem-4-carboxylate as the syn-isomer in an amount of 500 mg.

IR spectrum (nujol)

3200-3500, 1765, 1660, 1595 cm -1. ¹ H NMR spectrum (D 2 O, δ ppm)

7.0 - 7.25 (4H, inter alia)

5.85 (1H, d,) = 5Hz

5.20 (1H, d, J = 5Hz)

4.7 (2H, AB _q , J = 20 Hz)

3.52 (2.H, AB _q , J = 17 Hz)

F)

2-Pivaloyloxyimino-2- (3-hydroxyphenyl) acetic acid as the syn-isomer (4 g) and 7-aminocephalosporanic acid (4.08 g) were treated in the same manner as in Example 1 to give a powder of 7. - [2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanic acid in the form of the syn-isomer, which was converted to its sodium salt in a manner similar to that described in Example 1C to give a 7- [2-pivaloyloxyimino powder. -2- (3-hydroxyphenyl) acetamide or cephalosporanate in the form of the syn-isomer in an amount of 3.8 g.

Gj

In a similar manner as in Examples IA to 1F, the following compounds were prepared:

(1)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (mixture of syn-isomer and anti -isomer j,

IR spectrum (nujol)

3250, 1770, 1710, 1670 cm -1 ¹ H-NMR (d 6 -dimethylsulfoxide, δ ppm

12.0 (1 H, s)

11.5 (1 H, s)

9.6 (1H, d1) = 9Hz

9.0 (1 H, d, J = 9 Hz)

7.0 (8H, et al.)

5.8 (2H, et al.)

5.15 (2 H, m)

4.3 (4H, AB _q , J = 13 Hz)

3.92 (6H, sj

3.7 (4H, ABq, J = 18Hz)

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] 3- (5-methyl-1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid as syn -isomer,

IR spectrum (nujol)

3250, 1770, 1710, 1660 cm

NMR spectrum (d 6 -dimethylsulfoxide, sS) ppm

11.17 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

7.35 (2H, d, J = 8 Hz)

6.75 (2H, d, J = 8 Hz)

5.8 (1H, dd, J = 5.9Hz)

5.15 (1H, d, J) - 5 Hz)

4.35 (2H, AB _q , J = 13 Hz)

3.68 (2H, AB _q , J = 18 Hz)

2.67 (3H, s) [3]

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in the form of the syn-isomer,

IR spectrum (nujol)

3250, 1770, 1710, 1660 ^cm-1 NMR spectrum (de -DMSO, 5) ppm;

11.13 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

9.41 (1 H, s)

7.3 (2H, d, J = 9 Hz)

6.7 (2H, d, J = 9 Hz)

5.72 (1H, dd, J = 5.9Hz)

5.12 (1H, d, J - 5Hz)

4.38 (2H, AB _q , J = 13 Hz)

3.65 (2H, AB _q , J = 18 Hz) (4)

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in the form of the syn-isomer,

IR spectrum (nujol)

3200, 1770, 1710, 1660 cm- ¹ NMR spectrum (d6-dimethylsulfoxide, δ)

7.38 (2H, d, J = 8 Hz)

6.8 (2H, d, J = 8 Hz)

5.81 (1H, dd, J = 5.9Hz)

5.15 (1H, d, J = 5Hz)

4.30 (2H, ABq J = 13 Hz)

3.68 (2H, ABq, J = 18 Hz) (5)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thladiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in the form of syn- isomer,

IR spectrum (nujol)

3270, 1770, 1720, 1660 ^cm-1

NMR spectrum (d-dimethylsulfoxide, < 5) ppm

11.68 (1 H, s)

9.65 (1 H, d, J = 9 Hz)

6.7—7.5 (4H, m)

5.85 (1H, dd, J = 5.9Hz)

5.23 (1 H, d, J = 5 Hz)

4.4 (2H, ABq, J = 13 Hz)

3.75 (2H, _ΑΒ α, J = 18Hz)

2.75 (3H, s)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido-3- (1,3,4-thladiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200, 1770, 1710, 1660 cm ¹ NMR spectrum (d6-dimethylsulfoxide, δ) NMR spectrum (d6-dimethylsulfoxide, oxS) ppm

11.5 ohms, s)

9.57 (1 H, d, J = 9 Hz)

9.5 (1 H, s)

6.7—7.45 (4 H, m)

5.85 (1H, dd, J = 5.9Hz)

5.16 (1H, d, J = 5Hz)

4.42 (2H, ABq, J = 13 Hz)

3.7 (2H, ABq, J = 18 Hz) (7)

7- [2-benzoyloxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), ppm

11.25 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

139273

IR spectrum (nujol)

3300, 1785, 1740, 1720, 1670 cm -1 ¹ H-NMR (d 6 -dimethylsulfoxide, δ) ppm

10.15 (1 H, d, J = 9 Hz)

8.05 (2H, d, J = 8 Hz)

7.65 (5 H, m)

6.95 (2H, d, J = 8 Hz)

6.03 (1H, dd, J = 5.9Hz)

5.23 (1 H, d, J = 5 Hz)

4.35 (2H, AB ₍₁ , J = 13 Hz))

3.96 (3H, s)

3.75 (2H, AB _q , J = 18 Hz) (8)

Sodium 7- (2-hydroxyimino-2- (3-methoxy-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer )

IR spectrum (nujol)

3200-3400, 1770, 1660, 1590 cm -1. ¹ H NMR spectrum (D 2 O, SS) ppm

6.6-7.3 (3 H, m)

5.8 (1 H, d, J = 5 Hz)

5.15 (1 H, d, J = 5 Hz)

4.15 (2H, AB _q , J = 13 Hz)

3.93 (3 H, s)

3.82 (3H, s)

3.53 (2H, ABq, J = 18 Hz) (9)

7- [2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer),

IR spectrum (nujol)

3300—3400, 2300—2500, 1770—1780,

1720, 1665, 1620, 1540, 1320 ^cm-1 NMR (D2 O + NaHCO, O ')

PPm

7.96 (1 H, d, J = 2 Hz)

7.50 (1H, dd, J = 2.10Hz)

6.66 (1 H, d, J = 9 Hz)

5.79 (1 H, d, J = 4Hz)

5.15 (1 H, d, J = 5 Hz)

4.15 (2H, ABq, J = 12 Hz)

3.96 (3H, s)

3.60 (2H, ABq, J = 12 Hz) (10)

7- [2-hydroxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer),

IR spectrum (nujol)

3200–3400, 1780, 1710, 1665 cmNMR spectrum (d-dimethylsulfoxide, δ) ppm

11.46 (1H, s)

9.65 (1 H, d, J = 9 Hz)

7.45 (1 H, s)

7.4 (1 H, dd, J = 2.9 Hz)

7.0 (1H, dd, J = 2.9Hz)

5.85 (1H, dd, J = 5.9Hz)

5.20 (1H, d, J = 5Hz)

4.32 (2H, ABq, J = 14 Hz)

4.00 (3 H, s)

3.75 (2H, AB _q , J = 18 Hz) (11)

7- (2-Hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer),

IR spectrum (KBr)

3600, 3400, 3200—3300, 1920—1930

1770, 1660, 1620, 1350, 1150 cm -1 ¹ H-NMR spectrum (D 2 O, δ)

Ppm

7.5 (1 H, d, J = 2 Hz)

6.84 (1H, dd, J = 2.8Hz)

6.60 (1 H, d, J = 8Hz)

5.70 (1H, d, J = 6 Hz)

5.00 (1 H, d, J = 6Hz)

4.3 (2H, d, J = 6 Hz)

2.25 (3H, s)

7- [2-benzoyloxyimino-2- (3-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) ,

IR spectrum (nujol)

3200–3400, 1780, 1720–1760, 1670 cm- ¹ NMR spectrum (d6-dimethylsulfoxide, δ ') ppm

10.12 (1 H, d, J = 9Hz)

8.03 (2H, d, J = 8 Hz)

9 27 3

6.9-7.8 (6H, m)

6.0 (1H, dd, J = 5.9Hz)

5.22 (1 H, d, J = 5 Hz)

4.3 (2H, AB _q , J = 13 Hz)

3.8 (3H, s)

3.17 (2H, AB _C1 , J = 18 Hz) (13) [-2-pivaloyloxiinino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200—3300, 1760—1780, 1670 cm-

NMR spectrum (d 6 -dimethylsulfoxide, δ) ppm

10.0 (1 H, d, J = 9 Hz)

6.9-7.4 (4H, m)

5.9 (1 H, dd, J = 5.9 Hz)

5.18 (1 H, d, J = 5 Hz)

4.31 (2H, AB _q , J = 13 Hz)

3.95 (3 H, s)

3.75 (2H, ABq, J = 18 Hz) (14)

7- [2-ethoxycarbonyloxyimino-2- (3-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) ,

IR spectrum (nujol)

3200-3350, 1775, 1730, 1680 cm ¹ NMR spectrum (d 6 -dimethylsulfoxide, α) ppm

10.16 (1H, d, J = 8 Hz)

7.30 - 7.70 (4H, m)

5.90 (1H, dd, J = 5.8Hz)

5.21 (1H, d, J = 5 Hz)

4.04-4.58 (4H, m)

3.92 (3 H, s)

3.74 (2H, ABq, J = 17 Hz)

1.30 (3H, t, J = 7 Hz) (15)

7- (2-acetoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) ,

IR spectrum (nujol)

3250–3450, 1760–1780, 1720, 1670 cm ¹ NMR spectrum (d-dimethylsulfoxide, δ) ppm

10.0 (1 H, d, J = 9 Hz)

6.9 - 7.75 (4H, m)

5.92 (1H, dd, J = 5.9Hz)

5.25 (1 H, d, J = 5 Hz)

4.32 (2H, AB _q , J = 13 Hz)

3.96 (3H, s)

3.79 (2H, AB _q , J = 18 Hz)

2.25 (3H, s)

7- [2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3450, 3350, 3250, 2400—2600

1770, 1725, 1655, 1620, 1535,

1375 cm ¹

NMR spectrum (d 6 -dimethylsulfoxide, δ) ppm

11.72 (1 H, s)

9.63 (1 H, d, J = 8Hz)

7.96 (1 H, d, J = 2 Hz)

7.74 (1H, dd, J = 2.8Hz)

7.24 (1 H, d, J = 8Hz)

6.57 (2 H, s)

5.82 (1H, dd, J = 5.8Hz)

5.20 (1H, d, J = 5Hz)

4.74 (2H, ABq, J = 13 Hz)

3.52 (2H, ABq, J = 18 Hz) (17)

7- [2-hydroxyimino-2- (3- (chloro-4-hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3450, 3250 - 3350, 1770, 1705, 1660,

1595 cm ^-1

NMR spectrum (d 6 -dimethylsulfoxide, δ) ppm

11.56 (1 H, s)

9.60 (1 H, d, J = 8Hz)

7.46 (1 H, d, J = 2Hz)

7.36 (1H, dd, J = 2.8Hz)

7.00 (1 H, d, J = 8Hz)

6.59 (2 H, s)

5.80 (1 H, dd, J = 5.8 Hz)

5.18 (1H, d, J = 5 Hz)

4.73 (2H, AB _(l , J = 15Hz))

3.54 (2H, J = 18Hz) (18)

Pivaloyloxymethyl 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer),

IR spectrum (nujol)

3300, 1780, 1750, 1660 cm &lt; ^{1 &} gt ^; NMR spectrum (d-dimethylsulfoxide, [delta]) ppm

11.28 (1 H, s)

9.60 (1 H, d, J = 8Hz)

6.64 - 7.36 (4H, m)

5.60 - 6.0 (3H, m)

5.18 (1H, d, J = 5 Hz)

4.30 (2H, AB _q , J = 13 Hz)

3.94 (3 H, s)

3.74 (2H, AB ', J = 17 Hz)

I, 16 (9H, s)

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] cephalosporanic acid (syn-isomer),

IR spectrum (nujol)

3250, 1770, 1715, 1655 cm- ¹ NMR spectrum (d6-dimethylsulfoxide, δ) ppm

H, 76 (1H, s)

10.10 (1 H, d, = 9Hz)

7.33 (2H, d, J = 9 Hz)

6.71 (2H, d, J = 9 Hz)

5.80 (1 H, dd, J = 5.9 Hz)

5.13 (1 H, d, J = 5 Hz)

4.80 (2H, AB _q , J = 13 Hz)

3.54 (2H, width d)

2.00 (3H, s) (21)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanic acid (syn-isomer),

IR spectrum (nujol) ~ 3460, 3200, 1780, 1720, 1650 cm- ¹ NMR spectrum (d6-dimethylsulfoxide, δ)

PPm

11.65 (1 H, s)

8.6 (1H, d, J = 9 Hz)

6.7-7.4 (4 H, m)

5.85 (1H, dd, J = 5.9Hz)

5.18 (1H, d, J = 5 Hz)

4.87 (2H, AB _q , J = 13 Hz)

3.57 (2H, ABq, J = 18 Hz)

2.0 (3H, s)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate sodium (syn-isomer)

IR spectrum (nujol)

3200, 1760, 1720, 1650, 1585 cm- ¹ NMR spectrum (D2O, <S) ppm

7.45 - 6.92 (4H, m)

5.85 (1H, d, J = 5Hz)

5.18 (1H, d, J = 5 Hz)

4.77 (2H, AB _q , J = 17 Hz)

3.49 (2H, AB _q , J = 17 Hz)

2.12 (3H, s)

7- (2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid (syn-isomer), melting at 131-133 ° C (dec.) )

IR spectrum (nujol)

3300, 3200, 2300—2500, 1770, 1720,

1710, 1650, 1620, 1535, 1320 cm -1 ¹ H-NMR (d 6 -dimethylsulfoxide, δ) ppm

11.77 (1H, s)

9.70 (1H, d, J = 8 Hz)

8.00 (1 H, d, J = 2Hz)

7.78 (1 H, dd, J = 2.8 Hz)

7.23 (1 H, d, J = 8Hz)

5.90 (1 H, dd, J = 4.6 Hz)

5.22 (1 H, d, J = 6Hz)

4.90 (2H, ABq, J = 13 Hz)

3.60 (2H, ABq, J = 18 Hz)

2.02 (3H, s)

7- [2 ^J hydroxyimino-2- (3-mesylamino-4-hydroxyphenyl) acetamido] cephalosporanate sodium (syn-isomer),

IR spectrum (nujol)

3600, 3300—3400, 3200, 1765, 1720,

1660, 1600, 1320.1150 ^cm-1

NMR spectrum (D 20 O 6) ppm

7.60 (1 H, d, J = 2 Hz)

7.40 (1H, dd, J = 2.8Hz)

7.00 (1 H, d, J = 8Hz)

5.88 (1H, d, J = 6 Hz)

5.20 (1H, d, J = 6 Hz)

4.7 (2H, AB _P , J = 13 Hz)

3.57 (2H, AB _q , J = 18 Hz)

3.11 (3H, s)

2.10 (3H, s) (24) acetoxymethyl 7- [2-: hydroxyimino-2- (3'-hydroxyphenyl) acetamido] cephalosporanate [syn-isomer],

IR spectrum (nujol)

3300, 1720, 1780, 1660 cm- ¹ NMR spectrum (d-dimethylsulfoxide, <5)

PPm

11.52 (1 H, s)

9.55 (1 H, d, J = 8Hz)

6.7-7.3 (4H, m)

5.7—5 .97 (3H, m)

5.19 (1 H, d, J = 5 Hz)

4.78 (2H, AB _q , J = 13 Hz)

3.62 (2H, AB _q , J = 18 Hz)

2.11 (3h, s)

2.08 (3H, s) (25) pivaioyloxymethyl 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate (syn-isomer),

IR spectrum (nujol)

3300, 1720, 1780, 1660 cniJ NHM spectrum (d6-acetone, <S) ppm

11.26 (1 H, s)

9.60 (1 H, d, J = 8 Hz)

6.60 - 7.40 (4H, m)

5.65 - 6.00 (3H, m)

5.20 (1 H, d, J = 5 Hz)

4.76 (2H, ABq, J = 13 Hz)

3.65 (2H, width s)

2.05 (3 H, s)

1,16 (9H, s) (26) pivaioyloxymethyl 7- [2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate (syn-isomer)

IR spectrum (nujol)

3300, 1790, 1750, 1670 cm ¹ NMR spectrum (d6-acetone, α)

PPm

8.9 (1 H, d, J = 9 Hz)

6.9 - 7.42 (4H, m)

5.7-7.2 (3 H, m)

5.3 (1H, d, J = 5 Hz)

4.9 (2H, ABq, J = 20Hz)

3.69 (2H, ABq, J = 20 Hz)

2.03 (3 H, s)

1.3 (8H, s)

I.21 (9H, s)

Example 2

AND:

According to this procedure, a solution composed of 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] cephalosporanic acid (0.35 g, syn-isomer) was 1-methyl-1H-tetrazole -5-thiol (92 mg), sodium bicarbonate (203 milligrams), acetone (5 ml) and water (10 ml), stirred for 6 hours at a temperature ranging from 60 to 65 ° C, the pH of the solution being The solution was washed twice with ethyl acetate, the aqueous layer was separated and the pH was adjusted to 4.0 with 10% hydrochloric acid and then washed twice with ether. The aqueous layer was then treated to pH 2.5 and extracted twice with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. Then the solvent was distilled off and the residue, which was an amorphous substance (0.2 g), was treated with ether, collected by filtration and dried to give the final product which was 7- [2-hydroximino-2 (4-hydroxyphenyl) 1-Acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer, 90 mg), as a pale yellow powder, m.p. 152 DEG C. (dec.).

IR spectrum (nujol)

3250, 1770, 1710, 1660 cm ''

NMR Spectrum (d6-dimethylsulfoxide, δ)

PPm

H, 25 (1H, s)

9.57 (1 H, d, J = 9 Hz)

7.43 (2H, d, J = 9 Hz)

6.80 (2H, d, J = 9 Hz)

5.85 (1H, dd, J = 5.9Hz)

5.17 (1H, d, J = 5 Hz)

4.32 (2H, AB _q , J = 13 Hz)

3.95 (3 H, s)

3.73 (2H, AB _q , J = 18 Hz)

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-methyl-4-carboxylic acid (syn-isomer) thus obtained was converted to its sodium salt in a conventional manner to give 7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate sodium (syn-isomer).

IR spectrum (nujol

3250, 1770, 1710, 1660 cm &lt; ^{1 &} gt ^; NMR spectrum (D2O, [delta]) ppm

7.5 (2H, d, J = 9 Hz)

6.9 (2H, d, J = 9 Hz)

5.85 (1H, d, J = 5Hz)

5.16 (1 H, d, J = 5 Hz)

4.2 (2H, AB _q , J = 13 Hz)

3.95 (3H, s)

3.6 (2H, ABq, J = 18 Hz)

B:

Following the procedure of Example 2A, the following compounds were prepared:

(1)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol

3300, 1780, 1720, 1670 cm- ¹ NMR spectrum (d 6-dimethylsulfoxide, δ) ppm

11.6 (1H, sj

9.6 (1H, d, J = 9 Hz)

6.7-7.5 (4 H, m)

5.85 (1H, dd, J = 5.9Hz)

5.17 (1 H, d, J = 5 Hz)

4.36 (2H, ABq, J = 13 Hz)

3.96 (3H, s

3.77 (2H, ABq, J = 18 Hz) (2)

Sodium 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer),

SO

IR spectrum (nujol)

3200—3500, 1760, 1660, 1595 cm ^-1 NMR spectrum (D 2 O, δ)

PPm

6.7-7.5 (4H, rn)

5.75 (1 H, d, J = 5 Hz)

5.1 (lH, d, J = 5Hz)

4.1 (2H, _ΑΒ η, J = 13Hz)

3.92 (3H, s)

3.55 (2H, ABg, J = 18 Hz) (3)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (a mixture of syn- and anti -isomer),

IR spectrum (nujol)

3250, 1770, 1710, 1670 cm -1. ¹ H NMR spectrum (d 6 -dimethylsufoxide, d) ppm

12.0 (1 H, s)

11.4 (1H, s)

9.6 (1H, d, J = 9 Hz)

9.0 (1 H, d, J = 9 Hz)

7.0 (8H, m)

5.8 (2H, m)

5.15 (2 H, m)

4.3 (4H, ABq, J = 13 Hz)

3.91 (6H, s)

3.7 (4H, ABq, J = 18Hz)

7- (2-Hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4hiadiazol-2-yl) thlomethyl-3-cephem-4-carboxylic acid (syn-isomer )

IR spectrum (nujol)

3250, 1770, 1710, 1660 ^cm-1 NMR (dimethyl sulfoxide-d6, 5) ppm;

11.17 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

7.35 (2H, d, J = 8 Hz)

6.75 (2H, d, J = 8 Hz)

5.8 (1H, dd, J = 5.9Hz)

5.15 (1 H, d, J = 5 Hz)

4.35 (2H, ABq, J = 13 Hz)

3.68 (2H, AB _q , J = 18 Hz)

2.67 (3H, s) (4)

7- [2-hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3250, 1770, 1710, 1660 cm- ^{1 1} H NMR spectrum (d 6 -dimethylsufoxide, δ) ppm

11.13 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

9.41 (1H, s)

7.3 (2H, d, J = 9 Hz)

6.7 (2H, d, J = 9 Hz)

5.72 (1H, dd, J = 5.9Hz)

5.12 (1 H, d, J = 5 Hz)

4.38 (2H, AB _{C 1} , J = 13 Hz)

3.65 (2H, AB _q , J = 18 Hz) (6)

7- [hydroxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200, 1770, 1710, 1660 cm- ¹ NMR spectrum (de-dimethylsufoxide, <5) ppm

11.25 (1 H, s)

9.5 (1 H, d, J = 9 Hz)

7.38 (2H, d, J = 8 Hz)

6.8 (2H, d, J = 8 Hz)

5.81 (1H, dd, J = 5.9Hz)

5.15 (1 H, d, J = 5 Hz)

4.30 (2H, AB _q , J = 13 Hz)

3.68 (2H, AB ', J = 18 Hz) (7)

7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-isomer),

IR spectrum (nujol)

3270, 1770, 1720, 1660 cm- ¹ NMR spectrum (d 6 -dimethylsufoxide, δ)

Ppm

11.68 (1 H, s)

9.65 (1 H, d, J = 9 Hz)

6.7-7.5 (4 H, m)

5.85 (1H, dd, J = 5.9Hz)

5.23 (1 H, d, J = 5 Hz)

4.4 (2H, ABq, J = 13 Hz)

3.75 (2H, ABq, J = 18 Hz)

2.75 (3H, s)

- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200, 1770, 1710, 1660 cm -1. ¹ H NMR spectrum (d 6 -dimethylsufoxide, δ) ppm

11.5 (1H, width s)

9.57 (1 H, d, J = 9 Hz)

9.5 (1 H, s)

6.7 -7.45 (411m)

5.85 (1H, dd, J = 5.9Hz)

5.16 (1H, d, J = 5 Hz)

4.42 (2H, ABq, J = 13 Hz)

3.7 (2H, AB _q , J = 18 Hz)

7- [benzoyloxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3300, 1785, 1740, 1720, 1670 nmr ¹ H NMR (d 6 -dimethylsufoxide, δ) ppm

10.15 (1 H, d, J = 9 Hz)

8.05 (2H, d, J = 8 Hz)

7.65 (5 H, m)

6.95 (2H, d, J = 8 Hz)

6.03 (III, dd, J = 5.9 Hz)

5.23 (1 H, d, J = 5 Hz)

4.35 (2H, ABq, J = 13 Hz)

3.96 (3H, s)

3.75 (2H, ABq, J = 18Hz)

Sodium 7- (2-hydroxyimino-2- (3-methoxy-4-hydroxyphenyl Jacetamide) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer)

IR spectrum (nujol)

3200–3400, 1770, 1660, 1590 cm ¹

NMR spectrum (D 2 O, δ S) ppm

6.6-7.3 (3 H, m)

5.8 (1 H, d, J = 5 Hz)

5.15 (1 H, d, J = 5 Hz)

4.15 (2H, AB _{f |,} J = 13Hz)

3.93 (3 H, s)

3.82 (3H, s)

3.53 (2H, AB _q , J = 18 Hz) (11)

7- [2-hydroxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer )

IR spectrum (nujol)

3300—3400, 2300—2500, 1770—1780,

1720, 1665, 1620, 1540, 1320 cm ¹

NMR Spectrum (D2O + sodium bicarbonate, 5)

Ppm

7.96 (1 H, d, J = 2 Hz)

7.50 (1H, dd, J = 2.10Hz)

6.66 (1 H, d, J = 9 Hz)

5.79 (1 H, d, J = 4Hz)

5.15 (1 H, d, J = 5 Hz)

4.15 (2H, AB _q , J = 12 Hz)

3.96 (3H, s)

3.60 (2H, AB ₍ ") = 12Hz) (12)

7- [-2-hydroxyimino-2- (3-chloro-4-liydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer),

IR spectrum (nujol)

3200-3400, 1780, 1710, 1665 cm- ¹ NMR spectrum (d 6 -dimethylsuf oxide, δ) ppm

11.46 (1H, s)

9.65 (1 H, d, J = 9 Hz)

7.45 (1 H, s)

7.4 (1H, dd, J = 2.9Hz)

7.0 (1H, dd, J = 2.9Hz)

5.85 (1H, 'dd, J = 5.9Hz)

5.20 (1H, dd, J = 5Hz)

4.32 (1H, ABq, J = 14Hz)

4.00 (3 H, s)

3.75 (2H, AB _r 'J = 18 Hz) (13)

7- [2-Hydroxylamino-2- (3-mesylamino-4-hydroxyphenyl) acetamido] -3- (1-methyl) 154.

sodium 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer),

IR spectrum (potassium bromide)

3600, 3400, 3200—3300, 1920—1930

1770, 1660, 1620, 1350, 1150 cm -1. ¹ H NMR spectrum (D 2 O, δ) ppm

7.5 (1 H, d, J = 2Hz)

6.84 (1H, dd, J = 2.8Hz)

6.60 (1 H, d, J = 8Hz)

5.70 (1 H, d, J = 8 Hz)

5.00 (1 H, d, J = 6Hz)

4.3 (2H, d, J = 6 Hz)

2.25 (3H, s)

7- [2-benzoyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200-3400, 1780, 1720-1760, 1670 cm NMR spectrum (d6-dimethylsulfoxide, δ)

PPm

10.12 (1 H, d, J = 9Hz)

8.03 (2H, d, J = 8 Hz)

6.9-7.8 (6H, m)

6.0 (1H, dd, J = 5.9Hz)

5.22 (1 H, d, J = 5 Hz)

4.3 (2H, ABq, J = 13 Hz)

3.8 (3H, s)

3.71 (2H, ABq, J = 18Hz)

7- [2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) ,

IR spectrum (nujol)

3200–3300, 1760–1780, 1670 cm ^-1 NMR spectrum (d6-dimethylsulfoxide, <S)

PPm

10.0 (1 H, d, J = 9 Hz)

6.9-7.4 (4H, m)

5.9 (1 H, dd, J = 5.9 Hz)

5.18 (1H, d, J = 5 Hz)

4.31 (2H, ABq, J = 13 Hz)

3.95 (3 H, s)

3.75 (2H, _ΑΒ Ρ, J = 18Hz) (16)

7- [2-acetoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer),

IR spectrum (nujol)

3250—3450, 1760–1780, 1720, 1670 cm ¹ NMR spectrum (d6-dimethylsulfoxide, δ) ppm

10.0 (1 H, d, J = 9 Hz)

6.9 - 7.75 (4H, m)

5.92 (1H, dd, J = 5.9Hz)

5.25 (1 H, d, J = 5 Hz)

4.32 (2H, AB _q , J = 13 Hz)

3.95 (3 H, s)

3.79 (2H, AB _q , J = 18 Hz)

2.25 (3H, s)

Pivaloyloxymethyl 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer),

IR spectrum (nujol)

3300, 1780, 1750, 1660 cm ^-1 NMR spectrum (d 6 -dimethylsulfoxide, δ) ppm

11.28 (1 H, s)

9.60 (1 H, d, J = 8Hz)

6.64 - 7.36 (4H, m)

5.60 - 6.0 (3H, m)

5.18 (1H, d, J = 5 Hz)

4.30 (2H, AB _q , J = 13 Hz)

3.94 (3 H, s)

3.74 (2H, ABq, J = 17 Hz)

1.16 (9H, s)

Example 3

AND:

Ethyl chloroformate (10.9 g) was added dropwise with stirring and ice-cooling to a solution of 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl- Sodium 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer) in an amount of 16.3 g in a mixture of water (80 ml) and pyridine (80 ml) and the resulting mixture was stirred for for 1 hour at the same temperature. Water (200 mL) was added to the mixture and the mixture was washed with ether. Then, the aqueous layer was separated and its pH was adjusted to 2 with hydrochloric acid, followed by extraction with ethyl acetate. The extract obtained was washed with dilute hydrochloric acid solution and then with aqueous sodium chloride solution and finally dried over magnesium sulfate. Further, this extract was treated with activated charcoal, the solvent was distilled off, and the residual oil was treated with a mixture of isopropyl ether and ether. The resulting powder was collected by filtration, dried and suspended in water (150 mL), sodium bicarbonate (1.7 g) was added, the solution was adjusted to pH 6 with dilute hydrochloric acid and treated with activated charcoal. Dilute hydrochloric acid was added to the mixture while cooling and stirring, and the precipitate was collected by filtration, washed with water and dried to give the final product, which was analyzed as 7- [2-ethoxycarbonyloxyimino-2- (3-hydroxyphosphine). enyl] acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer,

9.4 gj.

IR spectrum [nujol]

3200-3350, 1775, 1730, 1680 cm -1 ¹ H-NMR (d 6 -dimethylsulfoxide, δ) ppm

10.16 (1H, d, J = 8 Hz)

7.30-7.70 (4H, et al

5.90 (1H, dd, J = 5.8Hz)

5.21 (1H, d, J = 5 Hz)

4.04-4.58 (4 H, m)

3.92 (3 H, s)

3.74 (2H, ABq, J = 17 Hz)

1.30 (3H, t, J = 7 Hz)

B:

This was a mixture of 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( The syn-isomer, 9.83 g of acetic anhydride (200 ml) was stirred for 5 hours at ambient temperature, then the reaction mixture was concentrated under reduced pressure, ether was added to the obtained residue, and the mixture was stirred overnight at ambient temperature. The resulting precipitate was collected by filtration, washed thoroughly with ether and then dried to give the final product, 7- [2-acetoxyimino-2-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer,

8.5 gj.

IR spectrum (nujol)

3250—3450, 1760—1780, 1720, 1670 cm “ ¹

NMR spectrum (d-dimethylsulfoxide, δ) ppm

10.00 (1 H, d, J = 9Hz)

6.9 - 7.75 (4H, m)

5.92 (1H, dd, J = 5.9Hz)

5.25 (1 H, d, J = 5 Hz)

4.32 (2H, AB _q , J = 13 Hz)

3.95 (3 H, s)

3.79 (2H, AB _q , J = 18 Hz)

2.24 (3H, s)

C:

In a similar manner to Examples 3A to 3B, the following compounds were prepared:

(11

7- {2- [2- (2-thienyl) acetoxyimino] -2- (3-hydroxyphenyl) acetamido} -3- (1-methyl-1H-tetrazol-5-yl) methyl-3-cephem-4- carboxylic acid (syn-isomer),

IR spectrum (nujol)

3150—3200, 1770, 1720, 1670 cm- ¹ NMR spectrum (d-dimethylsulfoxide, α)

PPm

10.12 (1 H, d, J = 9Hz)

6.8-7.6 (7 H, m)

5.94 (1 H, dd, J = 5.9 Hz)

5.26 (1 H, d, J = 5 Hz)

4.38 (2H, AB _q , J = 13 Hz)

4.18 (2 H, s)

3.97 (3 H, s)

3.81 (2H, ABq, J = 18 Hz) (2)

7- [2-benzoyloxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3300, 1785, 1740, 1720, 1670 nmr ¹ H NMR spectrum (d ⁶ -dimethylsulfoxide, δ).

PPm

10.15 (1 H, d, J = 9 Hz)

8.05 (2H, d, J = 8 Hz)

7.65 (5 H, m)

6.95 (2H, d, J = 8 Hz)

6.03 (1H, dd, J = 5.9Hz)

5.23 (1 H, d, J = 5 Hz)

4.35 (2H, AB _q , J = 13 Hz)

3.75 [2H, ABq, J = 18 Hz] (3)

7- [2-benzoyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cep-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200–3400, 1780, 1720–1760, 1670 cm- ¹ NMR spectrum (d6-dimethylsulfoxide, δ) ppm

10.12 (1 H, d, J = 9Hz)

8.03 (2H, d, J = 8 Hz)

6.9 - 7.08 (6H, m)

6.0 (1H, dd, J = 5Hz)

5.22 (1 H, d, J = 5 Hz)

4.3 (2H, AB _q , J = 13 Hz)

3.8 (3H, s)

3.71 (2H, AB _q , J = 18 Hz) (4)

7- [2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer),

IR spectrum (nujol)

3200–3300, 1760–1780, 1670 cm ¹ NMR spectrum (d6-dimethylsulfoxide, δ) ppm

10.0 (1 H, d, J = 9 Hz)

6.9 - 7.4 (4H, m)

5.9 (1 H, dd, J = 5.9 Hz)

5.18 (1H, d, J = 5 Hz)

4.31 (2H, ABq, J = 13 Hz)

3.95 (3 H, s)

3.75 (2H, ABq, J = 18 Hz) (5)

Pivaloyloxymethyl 7 - [- 2-pivaloyloxyimino -2- (3-hydroxyphenyl) acetamido] cep alosporanate (syn-isomer),

IR spectrum (nujol)

33.00, 1790, 1750, 1670 cm -1. ¹ H NMR spectrum (d 6 -acetone, δ) ppm

8.9 (1 H, d, J = 9 Hz)

6.9 - 7.42 (4H, m)

5.7-7.2 (3 H, m)

5.3 (1H, d, J = 5 Hz)

4.9 (2H, ABq, J = 14 Hz)

3.69 (2H, AB _q ,) = 20 Hz)

2.03 (3 H, s)

1.3 (9H, s)

I, 21 (9H, s)

7-12-Pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido-cephalosporanic acid (syn-isomer), in powder form, and its sodium salt (syn-isomer), also in powder form.

Example 4

AND:

A solution of sodium iodomethyl ester (0.87 g) in dimethylformamide (4 mL) was added all at once with stirring and ice-cooling to a solution of sodium 7- [2-hydroxyoxy-2- (3-liydroxyphenyl) acetamido] cephalosporanate (syn isomer, 2 g) in dimethylformamide (20 ml) and the resulting mixture was stirred for 20 minutes at the same temperature. To this mixture was added ethyl acetate (100 ml) and the resulting ethyl acetate solution was immediately washed three times with water (80 ml), twice with 5% aqueous sodium bicarbonate solution (40 ml) and finally twice with aqueous sodium chloride solution (80 ml). ). The obtained ethyl acetate solution was dried, treated with activated charcoal and concentrated. The residue was taken up in a mixture of diisopropyl ether and ether and stirred overnight at ambient temperature. The resulting precipitate was collected by filtration, then washed with diisopropyl ether and finally dried to give the final product, 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido) acetoxymethyl cephalosporanate (syn-isomer, 1.4 g).

IR spectrum, (nujol)

3300, 1720-1780, 1660 cm ^{-1 1} H NMR spectrum (d -dimethylsulfoxide, δ) ppm

H, 52 (1H, s)

9.55 (1 H, d, J = 8Hz)

6.7-7.3 (4H, m)

5.7 - 5.97 (3H, m)

5.19 (1H, d, J = 5 Hz)

4.78 (2H, AB _q , J = 13 Hz)

3.62 (2H, AB _n , J = 18 Hz)

2.11 (3H, s)

2.08 (3 H, s)

B:

Following the procedure of Example 4A, the following compounds were prepared:

(1) pivaloyloxymethyl 7- [-2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn -isomer),

IR spectrum (nujol)

NMR Spectrum (d6-dimethylsulfoxide, δ)

Ppm

11.28 (1 H, s)

9.60 (1H, d, J = 8Hz)

6.64 - 7.36 (4H, m)

5.60 - 6.0 (3H, m)

5.18 (1H, d, J = 5 Hz)

4.30 (2H, AB _q , J = 13 Hz)

3.94 (3 H, s)

3.74 (2H, ABq, J = 17 Hz)

1,16 (9H, s) (2) pivaloyloxymethyl 7- [2-hydroxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate (syn-isomer),

IR spectrum (nujol)

3300, 1780, 1745, 1660 cm- ¹ NMR spectrum (d6-diinethylsulfoxide, <5) ppm

Feb, 26 (1H, s)

9.60 (1 H, d, J = 8Hz)

6.60 - 7.40 (4H, m)

5.65 - 6.00 (3H, m)

5.20 (1H, d, J = 5Hz)

4.76 (2H, ΑΒ _α , J = 13 Hz)

3.65 (2H, width s)

2.05 (3 H, s)

1.16 (9H, s) (3) pivaloyloxymethyl 7- [2-pivaloyloxyimino-2- (3-hydroxyphenyl) acetamido] -cephalosporanate (syn-isomer).

IR spectrum (nujol)

3300, 1790, 1750, 1670 cm -1. ¹ H NMR spectrum (d 6 -acetone, δ) ppm

8.9 (1H, d, J = 9 Hz)

6.9 - 7.42 (4H, m)

5.7-7.2 (3 H, m)

5.3 (1H, d, J = 5 Hz)

4.9 (2H, AB _q, J = 14Hz), 3.69 (2H, AB _q,] = 20Hz), 2.03 (3H, s)

1.3 (8H, s)

1.21 (9H, s)

The present invention is characterized by the following definition of the invention.

Claims (6)

SUBJECT A process for the preparation of 7- (α, α-disubstituted-acetamido) -3-substituted-3-cephem-4-carboxylic acids of formula I, wherein: R ¹ represents hydrogen, halogen, hydroxy, nitro, alkoxy having 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms, R ² is hydrogen, C 1 -C 6 alkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 haloalkanoyl, or C 1 -C 6 thienylalkanoyl carbon and R ³ is C 1 -C 6 alkanoyloxy, carbamoyloxy optionally containing C 2 -C 3 haloalkanoyl, tetrazolylthio optionally containing C 1 -C 6 alkyl, or thiadiazolylthio optionally containing C 1 -C 6 alkyl Or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters of said compounds or pharmacologically acceptable salts thereof, characterized in that 7-amino-3-substituted-3-cephem-4 is reacted. a carboxylic acid of the general formula II in which it has R ³ is as defined above, or the C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl esters of this compound or a salt of this compound with α, α-disubstituted acetic acid of the general formula III, YNÁLEZU OR * ' ^(III) in which R ¹ and R ² have the meanings already given above, or with the acid halide, acid anhydride, activated amide, or alkanoyloxy derivatives of the above compound, containing 1-6 carbon atoms, or a salt thereof, wherein the obtained slounina in which R ² is alkanoyl having 1 to 6 carbon atoms, a halogen-alkanoyl group having 1 to 6 carbon atoms, aroyl of 7 to 11 carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms or thienylalkanoylovou group having 1 to 6 carbon atoms, is subjected to elimination reacting said group, and optionally converting the resulting compound into a pharmaceutically acceptable salt or C 1 -C 6 (alkanoyloxy) -C 1-6 -alkyl ester. 2. The process of item 1, wherein a compound of formula (I) is prepared, R @ ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an alkoxy group having 1 to 6 carbon atoms or an alkanesulfonamide group having 1 to 6 carbon atoms, and R ³ is a tetrazolylthio group which may optionally contain an alkyl group having 1 to 6 carbon atoms, or a thiadiazolylthio group which may optionally contain an alkyl group having 1 to 6 carbon atoms, or a C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl ester thereof or a pharmaceutically acceptable salt thereof, characterized in that the reaction is a 7-amino-3-sub-14,93273 substituted-3-cephem-4-carboxylic acid of formula II, wherein R ³ is as defined above, or A C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl ester of the compound, or a salt of the compound, with α, α-disubstituted acetic acid of formula III, wherein: R ¹ represents the same substituent as above, and R ² is hydrogen, C 1 -C 6 alkanoyl, C 1 -C 6 haloalkanoyl, C 7 -C 11 aroyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl or with an acid halide, an acid anhydride, an activated amide or an alkanoyloxy derivative of the compound having 1 to 6 carbon atoms, or with salts thereof, the resulting compound in which: R ² represents an alkanoyl group having 1 to 6 carbon atoms, a halogen-alkanoyl group having 1 to 6 carbon atoms, aroyl of 7 to 11 carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms or thienylalkanoylovou group having 1 to 6 carbon atoms, SFE subjecting the group to an elimination reaction, and optionally converting the resulting compound to a pharmaceutically acceptable salt or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl ester. 3. The process of item 1, wherein a compound of formula I is prepared wherein: R ¹ is hydrogen, halogen, hydroxy, nitro, alkoxy having 1 to 6 carbon atoms or alkansulfonamldoskupinu containing 1 to 6 carbon atoms, R ² represents a C 1 -C 6 alkanoyl group, a C 7 -C 11 aroyl group, a C 2 -C 7 alkoxycarbonyl group, or a C 1 -C 6 thienylalkanoyl group, and R ³ is a tetrazoylthio group, which may optionally contain an alkyl group having 1 to 6 carbon atoms, or a thiadiazolylthio group, or a C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl ester thereof, or a pharmaceutically acceptable salt thereof, reacted with 7-amino-3-substituted-3-cephem-4-carboxylic acid in which itia. R ³ is as defined above, or a C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl ester of the compound, or a salt of the compound with an α, α-disubstituted acetic acid of the general formula III, wherein R ¹ and R ^{2 have} or with an acid halide, acid anhydride, activated amide or alkanoyloxy derivative of this compound having 1 to 6 carbon atoms, or a salt thereof and the resulting compound optionally converted into a pharmaceutically acceptable salt or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl ester. 4. The process of item 1, wherein a compound of formula II is prepared, C- CONH II N F A STEED& COOH (I) R ¹ · in which R ¹ represents hydroxy, and R ³ is an alkanoyloxy group having from 1 to ³ carbon atoms Or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 -alkyl esters of the compound, or a pharmaceutically acceptable salt thereof, characterized in that 7-amino-3-substituted-3-cephem-4- is reacted. a carboxylic acid of formula II wherein R ³ is as defined above, or C 1 -C 6 (alkanoyloxy) -C 1 -C 6 alkyl esters of this compound, or a salt thereof, with α, α-disubstituted acetic acid of formula III *, or * lili ') in which R ¹ represents the same substituent as above and R ² represents a hydrogen atom, an alkanoyl group containing 1 to 6 carbon atoms, a halogen-alkanoyl group containing 1 to (C 6 -C 6), aryl group containing C 7 -C 11 alkoxycarbonyl, C 2 -C 7 alkoxycarbonyl or C 1 -C 6 thienylalkanoyl, or acid halide, or acid anhydride, activated amide or alkanoyloxy derivative of the C 1 -C 6 compound, or salts thereof and the resulting compound wherein R ² represents an alkanoyl group having 1 to 6 carbon atoms, a halogen-alkanoyl group having 1 to 6 carbon atoms, aroyl of 7 to ^ ll carbon atoms, alkoxycarbonyl having 2 to 7 carbon atoms or thienylalkanoylovou group having 1 to 6 carbon atoms, with subjecting the group to an elimination reaction, and optionally converting the resulting compound into a pharmaceutically acceptable salt thereof or a C 1 -C 6 (alkanoyloxy) C 1 -C 6 alkyl ester.