CS217960B2 - Method of preparation of 7-substituted 3-cefem-4-carboxyl acids - Google Patents

Description

The preparation of 7-substituted-3-cephem-4-carboxylic acids proceeds according to the invention by treating a compound of formula Ig

wherein R _and ^{x are} thiadiazolyl, or thiazolyl,

R ² is hydrogen, alkyl, or substituted alkyl, cycloalkyl, alkenyl or alkynyl,

R ⁵ is a carboxy group or a pharmaceutically acceptable ester group, and

_And R ⁷ is an acyl group, or a salt thereof with an inorganic or organic base, optionally followed by further processing.

The compounds prepared by the process of the present invention exhibit excellent antimicrobial activity against a variety of pathogenic microorganisms including gram-negative and gram-positive bacterial species.

218 9 6 0

The invention relates to a process for the preparation of novel cephem compounds, in particular novel 7-substituted-3-cephem-4-carboxylic acids and pharmaceutically acceptable salts thereof. These compounds exert an antimicrobial effect.

It is an object of the present invention to provide a novel process for the preparation of these novel 7-substituted-3-cephem-4-carboxylic acids and pharmaceutically acceptable salts thereof which exhibit excellent antimicrobial activity against various species of pathogenic microorganisms including gram-negative and gram-positive bacterial species.

New compounds, i. The 7-substituted-3-cephem-4-carboxylic acids prepared by the process of the invention can be represented by the following general formula Ih

(Ih.) In which Ra ^{1 represents a} thiadiazolyl group, a thiazolyl group of the general formula:

in which it means

R ^{6 is} amino, trihalo (C 2 -C 6) -alkanamide or C 1 -C 6 alkanamide,

R ² is hydrogen, alkyl containing 1 to 12 carbon atoms which may be substituted by halogen, carboxyl or alkoxycarbonyl of 2 to 7 carbon atoms, a cycloalkyl group having 5-7 carbon atoms, alkenyl of 2-6 carbon atoms or (C 2 -C 6) alkynyl, and

R ⁵ is a carboxy group or a pharmaceutically acceptable ester group, preferably a (C 1 -C 6) alkanoyloxy (C 1 -C 6) alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl group, the invention also relates to the preparation of pharmaceutically acceptable salts thereof .

The process according to the invention is characterized in that a compound of the general formula (Ig) is treated

in which they have substituents

Ra ¹ , R ² and R ⁵ are as defined above, and

_And R ⁷ is an acyl group, preferably an alkanesulfonyl group having 1 to 6 carbon atoms or alkanoyl having 1 to 6 carbon atoms, or a salt thereof with an inorganic or organic base, optionally followed by:

Reacting the resulting compound wherein R ² is a hydrogen atom with an etherifying agent to give the resulting compound wherein R ² is a C 1 -C 12 alkyl group which may be substituted by a halogen, carboxy or 1-alkoxycarbonyl group up to 6 carbon atoms in the alkyl moiety, a cycloalkyl group containing 5 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an alkynyl group having 2 to 6 carbon atoms, or - the resulting compound in which R ^{6 is} trihaloCa -Cejalkanamidová group or a (Cl-C6) alkaneamide group, to an elimination reaction to afford the title compound in which the substituent R ⁶ is an amino group, or - the resulting compound in which the substituent R ⁵ is carboxy, or a reactive derivative thereof, is reacted with a reagent capable of forming a pharmaceutical, e.g. an acceptable ester, preferably a (C 1 -C 6) alkanoyloxy (C 1 -C 6) alkoxycarbonyl group or a nitrophenyl (C 1 -C 6) alkoxycarbonyl group, to give the title compound wherein R ^{5 is} (C 1 -C 6 alkanoyloxy (C 1 -C 6 alkoxycarbonyl), or a nitrophenyl (C 1 -C 6) alkoxycarbonyl group, or - converting an ester of the resulting compound wherein R ^{5 is a} pharmaceutically acceptable ester group, preferably a (C 1 -C 6) alkanoyloxy (C 1 -C 6 alkoxycarbonyl group or nitrophenyl (C 1 -C 6) alkoxycarbonyl, to carboxy, to give the title compound, wherein R ^{5 is} carboxy.

The advantage of the process according to the invention is its simplicity and ease of feasibility both on a laboratory and industrial scale, thereby producing novel compounds which exhibit excellent antimicrobial effects against various types of pathogenic microorganisms including gram-negative and gram-positive bacterial species.

In a preferred embodiment of the process of the invention, the compound of the above-mentioned general formula (Ig) is treated in which it is

R @ ² is hydrogen, C1 -C6 alkyl, C2 -C6 alkenyl, carboxy C1 -C6 alkyl or (C3 -C7) alkoxycarbonyl (C1 -C6) alkyl,

R e is amino, trihalogen (C 1 -C 6 alkanamide or (C 1 -C 6 alkanamide), and

R ^1, R ⁵ and R ⁷ are subistituenty _and with the same meaning as hereinbefore, or a salt thereof, with an organic or inorganic basic compound.

According to another preferred embodiment of the process for preparing the compounds of the invention by reacting the compound of formula Ig in which R ¹ represents a thiazolyl group of formula:

in which

R ⁶ represents an amino group, a trihalogen (C 2 -C 6) alkanamide group or a (C 1 -C 6 alkanamide group),

R ² is an alkyl group containing 1 to 6 carbon atoms,

R ⁵ is a carboxy group or nitrophenyl (C 1 -C 6 alkoxycarbonyl group, and

_And R ⁷ is (C Cejalkansulfonylová group, or a salt thereof with an organic or inorganic basic compound.

According to a further preferred embodiment of the process of the invention, a compound of the general formula (Ig) is treated in which it is

R ^{2 is} C 5 -C 7 cycloalkyl or C 2 -C 6 alkynyl, and

R ^1, R ^5, R ⁶ and R 7 _and have the same meaning as in 1, or a salt thereof with an organic or inorganic basic compounds herein.

Preferably, 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is a syn isomer or a pharmaceutically acceptable salt thereof. performed by treating 7- [2- (2-aminothiazol-4-yl -) - 2-methoxyiminoacetamido] -3-acyl- [preferably (C 1 -C 6) alkanesulfonyl or (C 1 -C 6) alkanoyl] - an oxy-cepham-4-carboxylic acid or a salt thereof with an organic or inorganic basic compound.

In an alternative embodiment of the process of the invention, the compounds represented by the general formula (I) can be prepared

in which it means

R ^{1 is a} thiadiazolyl group or a thiazolyl group of the general formula:

in which it means

^R6 amino or protected amino,

A is a group of the formula:

-O or an aliphatic hydrocarbon radical which may be substituted by halogen, carboxy or esterified carboxy, and

R ⁵ is a carboxy group or a functionally modified carboxy group.

The individual terms and definitions used to characterize the substituents of the compounds prepared according to an alternative embodiment of the process of the invention will be explained in more detail in the following:

(a) Partial structure of the general formula:

/? - C-CO '

II

N

O ~ R ^Z in the above text means both geometric forms, that is:

R1-C-CO

II

N-O-R ² (S) and

R ¹ —C — CO

II

R ² -O-N

The structure of the general formula (Sj means "syn" arrangement) and the structure of the general formula (A) means "anti" arrangement.

Accordingly, the isomer of a compound containing a partial structure designated by the symbol (S) is called the "syn" isomer and a second isomer of a compound containing an alternative structure designated as (A) in the above is called the "anti" isomer.

In terms of structure-activity relationship, it should be noted that the syn isomer of the compound of formula I has a much higher antimicrobial activity than the corresponding anti isomer, and for this reason the syn isomer of the compound of formula I is a much more preferred antimicrobial agent than the corresponding anti isomer prophylactic and therapeutic values.

bj As regards the thiazolyl group of the general formula:

Where R ⁶ is as defined above, it is well known that it becomes a tautomeric form with a thiazolinyl group of the formula:

in which it means

^R 'is imino or a protected imino group.

The tautomerism between said thiazolyl and thiazolinyl groups can be represented by the following equilibrium:

wherein in the formulas R ⁶ and R ⁶ 'are as previously defined.

Accordingly, it is clear that the two groups are substantially the same, and the two tautomeric forms formed by these groups are considered to be the same compounds, especially with respect to industrial chemical production. For this reason, both tautomeric forms of the compounds containing the above groups in their molecule are included within the scope of the present invention, both forms being referred to by only one term "thiazolyl" and represented by the general formula:

AA

R wherein R ⁶ is as defined above. This has been done only to simplify the description and definition of the invention.

In the foregoing, a variety of terms and definitions have been used to specify compounds in alternative embodiments of the preparation process, and practical examples of the meanings of each term will be given to illustrate, and the terms will be discussed in detail below.

The term "lower" as used herein refers to a group containing 1 to 6 carbon atoms, unless otherwise indicated in a particular case.

The term "thiadiazolyl" for R ¹ in an alternative embodiment of the process of the present invention may be 1,2,3-thiadiazolyl (i.e., 1,2,3-thiadizol-4-yl or 1,2,3-thiadiazole- 5-yl), furthermore 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl, preferably 1,2,3-thiadiazolyl, and most preferably 1,2,3-thiadiazolyl- 4-yl.

The "aliphatic hydrocarbon radical" for the substituent R ² in an alternative embodiment of the process of the invention may be a monovalent radical of a saturated or unsaturated, straight or branched, optionally cyclic aliphatic hydrocarbon, and in particular may be an alkyl group, an alkenyl group , alkynyl, cycloalkyl, and the like, the terms of which are discussed in detail below.

"Alkyl" means a straight or branched alkane radical containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl , hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, preferably a lower alkyl group, and more preferably a C 1 -C 4 alkyl group .

The term "alkenyl" means a straight or branched alkene radical containing up to 12 carbon atoms, preferably a lower alkenyl such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobuteriyl, pentenyl, hexenyl and the like, and more preferably an alkenyl group containing up to 4 carbon atoms is used,

The term "alkynyl" refers to a straight or branched alkyne radical containing up to 12 carbon atoms, and preferably a lower alkynyl such as ethynyl, propargil, 1-propynyl, 3-butynil, 2-butynil,

4-pentynyl, 3-pentynyl, 2-pentynyl, 1-pentynyl,

5-hexinyl and the like, and more preferably an alkynyl group containing up to 4 carbon atoms is used.

The term "cycloalkyl" refers to a cycloalkane radical having a maximum of 8 carbon atoms, and is preferably a lower cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and more preferably cyclohexyl.

The above aliphatic hydrocarbon radicals may be substituted by a halogen atom or atoms, a carboxy group or an esterified carboxy group or groups. Accordingly, the "aliphatic hydrocarbon radical substituted with a halogen atom or halogen atoms, carboxy or esterified carboxy group (s)" may also be alternatively referred to as "halogen substituted aliphatic hydrocarbon radical", "carboxy substituted aliphatic hydrocarbon radical" and "esterified carboxy" aliphatic hydrocarbon radicals, which may in particular be, for example, haloalkyl, alkenyl, alkynyl and cycloalkyl, carboxyalkyl, alkenyl, alkynyl, and cycloalkyl, and further esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl; cycloalkyl.

Suitable examples of "halogen" include chlorine, bromine, iodine and fluorine, suitable examples of "esterified carboxy" include alkoxycarbonyl or the like, and preferred alkyl, alkenyl, alkynyl, cycloalkyl and alkyl moieties of the above alkoxycarbonyl group are the corresponding "lower" groups, as mentioned above.

Preferred examples of "haloalkyl, alkenyl, alkynyl and cycloalkyl" include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl,

2-chloroethyl, 1,2-dichloroethyl, 2,2,2-trifluoroethyl,

3-chloropropyl, 4-iodobutyl, 5-fluoropentyl, 6-bromohexyl, 3-fluoroallyl,

3-chloropropargyl, 4-fluorocyclohexyl or the like.

Preferred examples of "carboxyalkyl, alkenyl, alkynyl, and cycloalkyl" include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5- carboxypentyl, 6-carboxyhexyl, 1-carboxyisopropyl, 1-ethyl-1-carboxyethyl, 2-methyl-2-carboxypropyl, 3-carboxyallyl, 3-carboxypropargyl, 4-carboxycyclohexyl or the like.

Preferred examples of "esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl" include lower alkoxycarbonyl (lower) alkyl, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, t-butoxycarbonylmethyl, 2-ethoxy a 4-ethoxycarbonylbutyl group, a 1-t-butoxycarbonylisopropyl group. a group, 1-t-butoxycarbonyl-1-methylpropyl, 4-t-butoxycarbonylbutyl, 5-t-butoxycarbonylpentyl,

6-butoxycarbonylhexyl, etc., further lower alkoxycarbonyl (lower Jalkenyl, such as 3-methoxycarbonylallyl, etc.), further lower alkoxycarbonyl (lower jalinyl, such as 3-methoxycarbonylpropargyl, etc.), further lower an alkoxycarbonyl (lower) cycloalkyl group such as a 4-methoxycarbonylcyclohexyl group, etc., or the like, and most preferably a lower alkoxycarbonylmethyl group exemplified earlier.

The term "acyl" means, alternatively, a lower alkanoyl group such as a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, isovaleryl group, pivaloyl group 217960 na, etc., an aroyl group such as benzoyl group a group, etc., a lower alkanesulfonyl group such as mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propensulfonyl, butanesulfonyl, etc., an arensulfonyl group such as benzenesulfonyl, tosyl, etc., or the like groups.

The term "protecting group" in the case of the term "protected amino" of the substituent R ⁶ in an alternative embodiment of the process of the invention means a commonly used N-protecting group such as a substituted or unsubstituted ar (lower jalkyl group such as benzyl, benzhydryl) , trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, etc., and halo (lower) alkyl such as trichloromethyl, trichloroethyl, trifluoromethyl, etc., tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloalkylidene, acyl or the like.

The above-mentioned suitable acyl group in the case of a protecting group may be a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, chloroacetyl, trifluoroacetyl, etc., further substituted or unsubstituted lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, pyridyl, 2-trichloroethoxy. (lower jalkoxycarbonyl, such as benzyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc., lower cycloalkoxy xycarbonyl, such as cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc., 8-quinolyloxycarbonyl, succinyl, phthaloyl, or the like.

Further, the reaction product of silane, boron, aluminum or phosphorus compounds can be included in the protecting groups. Suitable examples of such compounds include trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, butoxybordichloride, aluminum chloride, diethoxyaluminium chloride, phosphorus tribromide, phenylphosphoribromide, or the like.

The term "functionally modified carboxy" in the case of the substituent R ⁵ in an alternative embodiment of the process of the invention means an ester group, an amide group or the like.

Suitable examples of ester groups include:

An alkyl ester group such as a methyl ester, an ethyl ester, a propyl ester, an isopropyl ester, a butyl ester, an isobutyl ester, a t-butyl ester, a pentyl ester, a t-pentyl ester, a hexyl ester, a heptyl ester, an octyl ester, an octyl ester a group, etc., an alkenyl ester group such as a vinyl ester group, an allyl ester group, etc., an alkynyl ester group such as an ethynyl ester group, a propynyl ester group, etc., an alkoxyalkyl ester group such as a methoxymethyl ester group, an ethoxymethyl ester group, isopropoxymethyl ester, tert-methoxyethyl ester, 1-ethoxyethyl ester, etc., - alkylthioalkyl ester group such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylth iomethyl ester group, etc., - haloalkyl ester group such as 2-iodoethyl group, 2,2,2-trichloroethyl ester group, etc., - alkanoyloxyalkyl ester group such as acetoxymethyl ester group, propionyloxymethyl ester group, butyryloxymethylmethyl ester group, valeryloxymethyl ester group, valeryloxymethyl ester group, valeryloxymethyl ester group, valeryloxymethyl ester group a group, hexanoyloxymethyl ester, a 2-acetoxyethyl ester group, a 2-propionyloxyethyl ester group, a palmitoyloxymethyl ester group, etc., an alkanesulfonylalkyl ester group such as a mesylmethyl ester group, a 2-mesylethyl ester group, etc., substituted or unsubstituted benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4 a hydroxy-3,5-di-t-butylbenzyl ester group, etc., a substituted or unsubstituted aryl ester group such as; is, for example, a phenyl ester, a tolyl ester, a t-butylphenyl ester, a xylyl ester, a mesityl ester, a cumenyl ester, a salicylester, etc., an ester of a silyl compound such as a trialkylsilyl compound, a dialkyl217960 alkoxysilyl compound or a trialkoxysilyl such as trimethylsilyl ester, triethylsilyl ester, etc., further a dialkylalkoxysilyl ester such as dimethylmethoxysilyl ester, dimethylethoxysilyl ester, diethylmethoxysilyl ester, etc., or a trialkoxysilyl ester like triethoxysilyl ester, such as trimethoxysilyl ester, etc. other groups.

With respect to the "protected amino" of R ⁶ and the "functional modified carboxy" of R ⁵ in an alternative embodiment of the process of the invention, it is noted that these groups are of great importance not only in the synthetic preparation of the compounds of the invention by however, they also affect the physiological and pharmaceutical properties of the compounds of the present invention.

That is, in the synthetic preparation of the compounds of the invention, the free amino group for R ⁶ and / or the free carboxy group for R ⁵ in an alternative embodiment of the process of the invention can be converted to "protected amino" and / or "functionally modified carboxy""As mentioned above, before carrying out the preparation process itself, to avoid any possible side reactions or reaction, wherein the" protected amino "and / or" functionally modified carboxy "in the resulting compound can be converted to the free amino and / or carboxy group after the reaction is complete. This measure will be apparent from the description of the reaction according to the invention.

On the other hand, regarding the physiological and pharmacological properties of the compounds of the invention, it should be noted that compounds containing an "protected amino" and / or "functionally modified carboxy" group can be used to improve properties such as solubility, stability , absorbency, toxicity, of the partially active compounds of the present invention containing a free amino and / or carboxy group.

A suitable "pharmaceutically acceptable salt" of the compounds of formula (I) in the alternative, or Ih in the basic embodiment, may be a conventional nontoxic salt, including inorganic basic compounds or acids, e.g. mention a metal salt such as an alkali metal salt such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt, magnesium salt, etc., an ammonium salt, an inorganic acid salt such as e.g. chloride, bromide, sulfate, phosphate, carbonate, hydrogen carbonate, etc., and a salt with an organic basic compound or acid, for example an amine salt such as trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methyl 1 N, N'-dibenzylethylenediamine salt, diethanolamine salt, triethanolamine salt, trisjhydroxymethylaminoiodomethane salt, phenethylbenzylamine salt, etc., as well as a salt with an organic carboxylic acid or with a sulfonic acid such as acetate, maleate, lactate, tartrate, mesylate, mesylate tosylate, etc., a salt with a basic or acidic amino acid such as an arginine salt, an aspartic acid salt, a glutamic acid salt, a lysine salt, a serine salt, etc., and the like.

Furthermore, from a pharmaceutical standpoint, it is well known that active drugs, when they possess certain undesirable physiological or pharmaceutical properties, such as solubility, stability, absorbency, are converted into modified derivatives of these compounds to improve these compounds. wherein said derivatives, when administered to a patient, are converted to their original form in the body while exhibiting their original activity. As used herein, the term " pharmaceutically acceptable biopursor " as used herein means essentially all modified derivatives having a structural formula different from that of the active compound prepared by the process of the present invention but converted to the active form in the patient. after administration of a medicament to form a compound of the present invention, and also refers to derivatives, which in some cases are physiologically derived from the compounds of the present invention, that are produced in the patient and exhibit antimicrobial activity.

Processes for preparing compounds according to the basic process and alternative embodiments of the process of the invention may be illustrated by the following schemes:

Procedure A: etherification

Procedure B: elimination of the amino protecting group

Procedure D: esterification

(tk) wherein in the above schemes means:

R _{and a} ² aliphatic hydrocarbon radical which may be substituted by halogen, carboxy or esterified carboxy,

_And R ⁵ is esterified carboxy,

R _b ⁵ is a functionally modified carboxy group,

R _and ⁶ are protected amino,

_And R ⁷ is an acyl group, and

R ¹ , R g ¹ , R ² , R ⁵ and A are as defined above.

The above stages of preparation of the compounds of the invention will be explained in more detail in the following.

Procedure A: etherification

In one embodiment, the compound of formula (Ic) and a salt thereof can be prepared by reacting a compound of formula (V) or a salt thereof with an etherifying agent.

The starting compound of formula (V) corresponds to a compound of formula (I) in which substituent A is an n-hydroxyiminomethylene group.

Suitable examples of the etherifying agent include a conventional alkylating agent such as dialkyl sulfate (e.g. dimethyl sulfate, diethyl sulfate, etc.), diazoalkane (such as diazomethane, diazoethane, etc.), and an alkyl halide (such as methyl iodide, ethyl iodide, ethyl bromide, etc.J, alkyl sulfonate (such as methyl tosylate, etc.), the corresponding alkenylating, alkynylating or cycloalkylating agent wherein the aliphatic hydrocarbon moiety is optionally substituted with a halogen atom, a carboxy group or an esterified carboxy group such as an alkenyl halide (e.g. allyl iodide) , etc., an alkynyl halide (such as propargyl bromide, etc.), a cycloalkyl halide (such as cyclohexyl bromide, etc.), a lower alkoxycarbonylalkyl halide (such as ethoxycarbonylmethyl iodide, etc.), and the like.

When diazolaalkane is used as an etherification agent in the above reaction, the reaction is typically carried out in a solvent such as diethyl ether, dioxane, or any other solvent that does not adversely affect the above reaction at a temperature in the range from cooling temperature to ambient temperature.

When other other etherification agents are used, the above reaction is usually carried out in the presence of a solvent such as water, acetone, ethanol, diethyl ether, dimethylformamide or another other solvent that does not adversely affect the above reaction, at temperatures ranging from a cooling temperature to a heating temperature, and preferably a process of the invention in the presence of a basic compound such as an inorganic or organic basic compound, suitable examples of which have already been mentioned and will be given for basic hydrolysis for the process referred to as process B below .

Some of the compounds of Formula Ic and the salts of the compounds can be used as antimicrobial agents and some of these compounds, and in particular compounds in which R ¹ represents a haloacetyl group, may be used for other methods of preparing similar compounds.

The above process is an alternative process for the preparation of a compound of formula (Ic) wherein R ¹ is a haloacetyl group and is also particularly preferred and suitable for the preparation of a compound of formula (Ic) wherein R ^{1 is a} haloacetyl group and R ² is substituted or unsubstituted. lower alkyl, lower alkenyl or lower alkynyl, with lower alkyl being most preferred.

Procedure B: elimination of the amino protecting group

The compound of formula (Ie) and a salt of the compound of formula (Ie) may be prepared by a process of elimination of a compound of formula (VIII) or a salt thereof by removal of the amino protecting group of substituents R _and ⁶ .

The starting compound of formula (VIII) corresponds to a compound of formula (I) wherein R ^{1 is a} thiazolyl group of formula

in which it means

R _and ^{6 are} protected amino, and A is a group of the formula:

-cII

Wherein R ² is as defined above and may be prepared, for example, as described above.

The above elimination reaction can be carried out by a conventional method, such as hydrolysis, reduction or the like. The method of carrying out this reduction is selected according to the type of protecting group to be eliminated.

The above hydrolysis may be carried out by a process using an acid (acid hydrolysis), a basic compound (basic hydrolysis) or hydrazine, and the like.

Particular mention should be made of hydrolysis using an acid which is one of the most widely used and preferred methods for deprotecting, which may be, for example, an acyl group such as a substituted or not, substituted lower alkanoyl group, substituted or unsubstituted ar a (lower) alkoxycarbonyl group, a lower cycloalkoxycarbonyl group, a substituted phenylthio group, a substituted alkylidene group, a substituted aralkylidene group, a substituted cycloalkylidene group or the like, and especially those already mentioned in connection with the N-protecting group.

Examples of suitable acids for carrying out the above acid hydrolysis include inorganic or organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, cation exchange resin and the like . In a preferred embodiment of the process of the present invention, an acid is used which can be readily separated from the reaction product by a conventional method, such as neutralization or distillation under reduced pressure, such acids being, for example, formic acid, trifluoroacetic acid, hydrochloric acid. or similar other compounds. The choice of the acid most preferred for carrying out the above hydrolysis is made according to the chemical properties of the starting compound and the product, and also with respect to the type of protecting group to be eliminated. The acid hydrolysis may be performed in the presence. or in the absence of a solvent. A suitable solvent may be a conventional organic solvent, water, or a mixture of these, which does not adversely affect the above reaction. In particular, it should be noted that when hydrolysis is carried out with trifluoroacetic acid, the reaction can be accelerated by the addition of anisole.

Hydrolysis using a basic compound may be used to eliminate a protecting group, such as an acyl group, and preferably a haloalkanoyl group (such as a trifluoroacetyl group, etc.) and the like other other groups. As an example of a suitable basic compound, for example, an inorganic basic compound such as an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (such as magnesium hydroxide, calcium hydroxide, etc.) may be mentioned. , an alkali metal carbonate (such as sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (such as magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate, etc.) alkaline earth phosphate (such as magnesium phosphate, calcium phosphate, etc.), an alkali metal phosphate in the form of hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc., or the like, and other other compounds) and organic basic Compounds such as alkali metal acetate (such as sodium acetate, potassium acetate, etc.), and trialkylamine (such as triinethylamine, triethylamine, etc.), picoline, N-methyl-pyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [5.4.0] -7-undecene, anion exchange resin, or similar other compounds. The hydrolysis performed with the basic compound is often carried out in water or in a conventional organic solvent or mixture thereof.

Hydrolysis using hydrazine can be applied in cases of deprotection, such as a dibasic acyl group, for example a succinyl group, a phthaloyl group, or similar other compounds.

Hydrolysis carried out using a reduction may be applied in cases of elimination of such a protecting group such as, for example, an acyl group, for example halogen, (lower jalkoxycarbonyl group (such as trichloroethoxycarbonyl, etc.) substituted or unsubstituted ar (lower jalkoxycarbonyl group) (such as benzyloxycarbonyl, p-nitroben, zyloxycarbonyl, etc., 2-pyridylmethoxycarbonyl, etc., and aralkyl (such as benzyl, bishydryl, trityl, etc.) and the like In a suitable embodiment of the process according to the invention, the abovementioned reduction is carried out using, for example, an alkali metal borohydride (such as sodium borohydride, etc.), conventional catalytic hydrogenolysis, and the like.

It should further be noted that protecting groups such as halogen (lower jalkoxycarbonyl or 8-quinolyloxycarbonyl) can be eliminated by treatment with heavy metals such as copper, zinc or the like other metals.

The reaction temperature is not critical in this case and can be selected according to the chemical properties of the starting compound and the reaction product, as well as the nature of the N-protecting group and the manner in which the hydrolysis is carried out. the reaction is carried out under mild conditions, such as under cooling, at ambient temperature or at a slightly elevated temperature.

The process herein also includes, where the functionally modified carboxy is present, the group for the substituent R ^{5 is} simultaneously converted to the free carboxy group during the above reaction or during post-reaction processing.

In this step, it is clear that the aim of this phase is to prepare a more generally active compound of formula I wherein R _and ^{1 are} aminothiazolyl, eliminating the protecting group from the protected amino group of the compound of formula , the procedures described above and the procedures that will be discussed below.

Procedure C: formation of the 3-cephem compound

The process of this embodiment is a process for preparing a compound of Formula Ih or a salt thereof, which may be prepared by treating compound Ig or a salt thereof with a basic compound.

An example of a suitable basic compound is an inorganic basic compound such as an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide, etc.), a metal carbonate (such as sodium carbonate, potassium carbonate, magnesium carbonate, etc.). , a metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate, etc.), an organic basic compound such as a tertiary amine compound (such as trimethylamine, triethylamine, pyridine, etc.), and an alkali metal alkoxide (such as such as sodium methoxide, sodium ethoxide, etc.) and the like of other other compounds.

The above reaction is generally carried out in the presence of a conventional solvent, such as an alcohol, dimethylformamide, chloroform, methylene chloride or any other solvent that does not adversely affect the reaction, at temperatures ranging from cooling to ambient temperature, or at somewhat elevated temperatures.

Procedure D: esterification

According to this embodiment, an ester compound of formula Ij and a salt thereof is prepared, improving the chemical, physiological and / or pharmaceutical properties of the corresponding compound of formula XII with a free carboxy group corresponding to the 3-cephem compound of formula I wherein R ⁵ carboxy, or salts thereof.

The esterification according to this embodiment is carried out by reacting a compound with a free carboxy group of formula (XII), a reactive derivative thereof at the carboxy group or a salt thereof with an esterification agent.

Preferably, the carboxy-reactive derivative of the compound of formula (XII) is a derivative already exemplified in relation to the compound of formula (III).

In the above embodiment, the esterifying agent may be, for example, a hydroxy compound and a reaction equivalent thereof.

A suitable example of a hydroxy compound is a lower substituted unsubstituted alcohol such as an alkanol, aipalkanol, arenol or the like, especially a substituted alcohol, such as an alkanoyloxy (lower) alkanol (such as acetoxymethanol). propionyloxymethanol, butyryloxymethanol, pentanoyloxymethanol, hexanoyloxymethanol, acetoxyethanol, propionyloxyethanol, butyryloxyethanol, pentanoyloxyethanol, hexanoyloxyethanol, acetoxypropanol, propionyloxypropanol, hexanoyloxypropanol, hexanoyloxyhexanol (lower, mono, ethoxy, ethanol, palmitoyloxymethanol, lower, etc.); -, chloroethanol, etc., - lower cycloalkyl (lower) alkanol, such as 1-cyclopropylethanol, etc., - substituted ar (lower) alkanol, such as 4-nitrobenzyl alcohol, 4-chlorobenzyl alcohol, 4- methoxybenzyl alcohol, 3,5-di-tert-butyl-4-hydroxybenzyl alcohol, bis ( methoxyphenyl) methanol, etc., substituted arenol (such as 4-methoxyphenol, etc.), the corresponding unsubstituted alcohols or the like.

A suitable reactive equivalent of a hydroxy compound is a conventional compound, such as a halide, alkanesulfonate, airenesulfonate or salt of the hydroxy compound, diazoalkane, diazoaralkane and other compounds.

The preferred halide of said hydroxy compound may be chloride, bromide or iodide.

A preferred alkanesulfonate or arenesulfonate of said hydroxy compound may be, for example, methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate or the like.

A preferred salt of said hydroxy compound may be, for example, an alkali metal salt such as a lithium salt, a sodium salt, a potassium salt or other similar compounds.

Preferred diazoalkane and diazoaralkane may be, for example, diazomethane, dialzoethane, diazopropane, diphenyldiazomethane or the like.

The above reaction may be carried out in the presence or absence of a solvent, and suitable solvents include N, N-dimethylformamide, dimethylsulfoxide, or any other solvent that does not adversely affect the above reaction, and is carried out at temperatures ranging with the cd cooling temperature to the heating temperature. In the above reaction, liquid hydroxy compounds may also be used as the solvent.

The reaction is preferably carried out in the presence of an inorganic or organic basic compound, exemplified in connection with Process B.

In the case of the preparation of a substituted or unsubstituted aryl ester compound of formula (Ij), and in particular in the case of the preparation of a substituted or unsubstituted phenyl ester compound, this reaction is carried out by reaction of:

(a) a compound of the formula (XII) or a salt thereof with phenol or a phenol salt in the presence of a condensing agent, exemplified in the above processes; or

b) a reactive derivative of a compound of formula XII, preferably a mixed acid anhydride of a compound of formula XII, with a phenol or a salt thereof in the presence of a basic compound.

In the case where a compound of the formula XII in which A is a group of the formula:

~ CII y i

O-Rve, which is a R ² aliphatic hydrocarbon radical substituted with a carboxy group, is used as the starting compound in this reaction, then the carboxy group can also be esterified depending on the reagent and reaction conditions, and this embodiment is within the scope of the invention.

Further, when a 2-cephem compound corresponding to the compound of formula (Ij) is prepared, then said 2-cephem compound may be converted to the 3-cephem compound of formula (Ij) by oxidation and then reduction of the resulting oxide compound in a conventional manner. This embodiment is also within the scope of the invention.

Procedure E: formation of the carboxy compound

According to this embodiment, a compound with a free carboxy group of the formula Ik or a salt thereof, and in particular a compound of the formula Ik, in which:

R ¹ thiadiazolyl sky thiazolyl group of formula

wherein R ⁶ is as defined above, and

A is a group of the formula:

-cII

N wherein R ² is as defined above, which generally exhibits greater antimicrobial activity as compared to the corresponding functionally modified carboxy compound of formula (XIII).

In view of the above, it will be appreciated that the function of the functionally modified carboxy group in the compound of formula (XIII) will be particularly evident in the synthetic preparation of the chemical processes described above.

The above procedure is carried out by converting the functionally modified carboxy group of the starting compound of formula XIII to the free carboxy group, in the preferred embodiment of the invention is the functionally modified carboxyl, in the case of R _b ⁵ in the compound XIII of the esterified carboxy group which has been exemplified in relation with a R ⁵ substituent on a compound of formula I.

The method for carrying out this procedure includes commonly known procedures, such as hydrolysis, reduction and the like.

The hydrolysis process may be carried out in a conventional manner using an acid, a basic compound, an enzyme or an enzyme preparation, and the like.

Examples of suitable acids and basic compounds include those exemplified in Process B above, wherein the acid hydrolysis or hydrolysis with a basic compound may be performed in a manner similar to that described for the procedure described as the safety procedure. B.

Examples of suitable enzymes are esterase and esterase preparations which exhibit esterase activity, such as a culture medium of a microorganism or a processed biomass of a microorganism, animal or plant tissue preparations, or the like, preferably a culture medium of the microorganism. or processed biomass of the microorganism.

The above esterase, which is used for enzymatic hydrolysis, can be used not only in the pure state but also in the crude state.

This esterase is commonly found, for example, in various types of microorganisms, and can be very easily isolated from soil and other sources and other sources by conventional means, and can be further isolated from stored cultures, which are kept at the disposal of an unlimited circle of people. collections of microorganisms such as:

ATCC (American Type Culture Oollection)

Maryland, USA]

IFC (Insute For Ferment-ation, Osaka, Japan),

IID (The Institute for Infectious DiseaSes)

University of Tokyo, Japan)

CBB (Centraalbureau voor Schimmelcultuires, Bearn, The Netherlands),

FERM (Fermentation Research Institute)

Agency (Industrial Science and Technology, Chiha, Japan), and

NRRL (Northern Utilization Research &

Development Dlvision, US Department of Agriculture, Illinois, USA), and similar institutions.

For microorganisms exhibiting esterase activity, for example, microorganisms belonging to the genus Bacillus, Coryneobactertum, Micrococcus, Flavobacterium, Salmonella, Staphylococcus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azotobacter, Alcaligenes, Rhiz. Kluyvera, Proteus, Sarcina, Pseudomonas, Xanthomonas, Protaminohacter, Comamonus and others.

Examples of microorganisms mentioned above are:

Bacillus subtilis IAM-1069, IAM-1107, IAM-1214

Bacillus sphaericus IAM-1286

Corynebacterium equi IAM-1308

Micrococcus varians IAM-1314

Flavobacterium rigeus IAM-1238

Salmonella typhimurium IAM-1406, Staphylococcus epidermidis IAM-1296, Microbacterium flavum IAM-1642, Alcaligenes faecalis ATCC-8750,

Arthrobacter simplex ATCC-6946

Azobacter vinelandii IAM-1087

Escherichia salts IAM-1101,

Rhizobium japonicum IAM-0001

Vibrio Metchnikovii IAM-1039

Brevibacterium helvolum IAM-1637, Protaminoibacter alboflavum IAM-1040, Comamonas terrigena IFC-12 685,

Sarcina lutea IAM-1099

Pseudomonas schuylki liensis IAM-1055, Xanthomonas trifolii ATCC-12 287, or the like of other microorganisms.

In carrying out enzymatic hydrolysis, the above-mentioned esterase may advantageously be used in the form of a culture medium obtained by culturing microorganisms having esterase activity, in any suitable manner, or in the form of processed biomass.

Cultivation of the microorganisms can generally be carried out in any suitable manner. In this cultivation, a culture medium should be used, and a culture medium containing sources of assimilable carbon and nitrogen and inorganic salts can be used. Preferred carbon sources include glucose, sucrose, lactose, sugars, glycerin and starch. Preferred nitrogen sources are, for example, meat extract, peptone, gluten meal, corn meal, cottonseed meal, soybean meal, corn steep liquor, yeast extracts, casein hydrolyzate and amino acids, as well as inorganic and organic nitrogen compounds such as for example, ammonium salts (such as ammonium sulfate, ammonium nitrate, ammonium phosphate, etc.), sodium nitrite or the like other compounds. Other mineral salts such as calcium carbonate, sodium or potassium phosphate, magnesium and copper salts, and various vitamins may also be used where necessary.

The appropriate pH of the culture medium, the appropriate culture temperature and the appropriate culture time vary with the type of microorganism used. The desired pH of the culture medium is usually in the range of pH 5 to pH 8. The temperature used is usually in the range of about 20 to about 35 ° C. The cultivation time usually ranges from 20 to 120 hours.

The culture medium thus obtained and its processed biomass can be used for the enzymatic hydrolysis of the present invention as they are. By " processed biomass " of a culture medium is meant any preparation that exhibits esterase activity that is processed in a conventional manner to enhance its esterase activity.

The esterase activity of the culture medium is concentrated in cells (intracellularly) and / or outside the cells (extracellularly).

When the activity is mainly concentrated in cells, the following preparations can be used, for example, as processed biomass of the culture medium:

1. raw cells: separated from the culture medium by conventional means, such as filtration or centrifugation,

2. dry state cells: obtained by drying said raw material containing cells in a conventional manner, such as lyophilization and vacuum drying;

3. cell-free extract: obtained by disrupting said raw or dried cells by conventional means (such as grinding the cells with alumina, sea sand, etc., or by ultrasonic treatment of the cells); or

4. enzyme solution: obtained by purifying ne217960 or partially purifying said cell-free extract in a conventional manner.

When the activity is concentrated mainly outside the cells, the following preparations can be used as processed biomass:

1. supernatant or filtrate: recovered from the culture medium by conventional means; or

2. Enzyme solution: obtained by purifying or partially purifying said supernatant or filtrate by conventional means.

Said enzymatic hydrolysis is carried out by contacting a compound of formula XIII with a microorganism culture medium or a processed biomass thereof in an aqueous medium such as water or a buffer (such as a phosphate buffer, etc.), and preferably carrying out the process of the present invention in the presence of a conventional surfactant. That is, the above reaction is usually carried out by adding a compound of formula (XIII) to the culture medium of the microorganism or to its liquid processed biomass (such as supernatant, filtrate, enzyme solution, etc.), or to the culture medium solution or suspension, or into its processed biomaisy in an aqueous medium. In some cases, it is preferable to stir said reaction mixture.

The preferred pH of the reaction mixture, substrate concentration, reaction time and reaction temperature may vary with the characteristics of its processed biomass to be used in the present case or with the characteristics and properties of the compound of Formula XIII to be used in the present case. However, preferred reaction conditions in a preferred embodiment of the process of the invention are as follows: the pH ranges from 20 to 50 ° C, and even more preferably from 25 to 35 ° C, and the reaction time is from 1 to 100 hours. The concentration of the starting compound of formula (XIII), which in this case is used as a substrate in the reaction mixture, may be in the range of 0.1 to 100 milligrams per milliliter, and preferably in the range of 1 to 20 milligrams per milliliter. milliliters.

The reduction in the case of the process according to the invention can be carried out in a manner similar to that described in process B above.

The process of the present invention also includes those cases where the protecting group in the protected amino group for the substituent R ⁶ which is a substituent on the thiazolyl group for the substituent R ¹ is eliminated and / or an esterified carboxy group which is an optional substituent in the hydrocarbon aliphatic radical, where the substituent R ^2, relating to the A group is converted into free karlboxyskupinu in the course of the reaction or after the reaction.

The compounds obtained as described above can be isolated and purified by conventional methods.

In cases where the present compound of formula (I) contains a free carboxy group for R ⁵ and / or a free amino group for R ⁶ , it can be converted to a pharmaceutically acceptable salt thereof by conventional means.

The compounds of the present invention of formula (I), the pharmaceutically acceptable salts thereof, and the bireicursors of said compounds exhibit high antimicrobial activity in inhibiting the growth of various species of pathogenic microorganisms, including gram-positive and gram-negative bacteria. preferably used as antimicrtibal agents.

In particular, the following compounds can be prepared by the process of the invention:

7- [2- [1,2,3-thiazol-4-yl] -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido) -5-cephem-a-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer],

7- (2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-isobutyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-n-butoxyiminoacetamide) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-n-hexyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-cyclohexyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-allyloxyiminoacetamido] ^{-3-cephem-4-ka;} ťboxylová acid (syn isomer),

7- [2- (2-amino-4-thiaznlyl) -2-propargyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-Amino-4-, thiazolyl) -2-ethoxycarbonylmethoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- [2- (2-amino-4-thiazolyl) -2-carboxymethoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-n-pentyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thlazolyl) -2- (2,2,2-trifluoroethoxyimino) acetamido) -3-cephem-4-carboxylic acid (syn Isomer),

7- (2- (2-amino-4-thiazolyl) -2- (2-chloroethoxylamino) acetamido] -3-cephem-4-carboxylic acid (syn isomer),

7 - ((2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid (anti feomer),

7- (2- (2-amino-4-thiazolyl) -2-n-octyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2- (2,3,3-trifluoro-2-propenyloxyimino) acetamido] -3-cephem-4-ka'r ^| tricarboxylic acid (syn isomer )

7- [2- (2-amino-4-thiazolyl-2-n-pentyl) 7- (2- (2-amino-4-thiazolyl) -2-lauroyloxymethoxyiminoacetamido) -3-cephem-4-cariboxyl acid (syn isomer),

7- (2- (1,2,3-thiadlazol-4-yl) -2-n-hexyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-trifluoromethoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer), further corresponding functionally modified derivatives such as the following compounds:

hexanoyloxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer), pivaloyloxymethyl-7- [2- (2-amino-4-thiazolyl)] -2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer),

4-nitro-benzyl-7- [2- (2-amino-4-thiazolyl) -2-methioxyimino, acetamido] -3-cephem-4-carboxylate (syn isomer), and the corresponding salts thereof, such as are for example:

Sodium 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carbaxylate (syn isomer),

Calcium 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylate magnesium (syn isomer), arginine salt 7- (2- (2-amino-4-thiazolyl)) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid lysine salt acid ( ¹ syn isomer), 7- [2- (2-amino-4-thiazophyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer).

The usefulness of the compounds of the invention of formula I and their activity will be shown in the following tests and results, carried out with several representative compounds of formula Γ:

1. Antibacterial activity in vitro:

(1) Test method:

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

An eye with a 100-fold overnight culture of each cultivated species in tripticase-soybean medium was plated on cardiac vinegar infusion agar (HI-agar) containing increasing concentrations of test compounds and incubated at 37 ° C. ° C for 20 hours. The minimum inhibitory concentration (MIC) was expressed in µg / ml.

(2) Test compounds:

C.

... 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer],

... 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-n-propoxyiminoacetamido] -3-oephem-4-cadboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-n-butoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2 ^! - (2-amino-4-thiazothyl) -2-allyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-priopargyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-n-hexyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer),

... 7- [2- (2-amino-4-thiazolyl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer), 11 ... 7- [2- (2- amino-4-thiazolyl) -2- (2-chloroethoxyimino Jacetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- [2- (2-amino-4-thiazollyl) -2- (2,2,2-trifluoroethoxyimino) acetamido) -3-cephem-4-carboxylic acid (syn isomer).

oxyiminoacetamido] -3-cep-4-carboxylic acid (syn isomer), (3) Test results:

Tested species

MIC (µg / ml)

1 2 3 4 5 6

Staphylococcus aureus 209P.JC-1 6.25 0.39 3.13 1.56 0.78 1.56 Escherichla coli NIHJ JC-2 with 0.025 0.1 0.05 0.2 0.39 0.1 Proteus vulgaris IAM-1025 <0.025 0.1 Ě 0,025 á 0.025 0.05 w 0.025 Klebsiella pneumoniae 20 May g 0.025 x 0.025 š 0,026 š 0,026 0.2 w 0.025 Proteus mirabilis 18 á 0.025 á 0.025 á 0.025 0.1 0.2 Ě 0,025 Pseudomonus aeruginosa NCTC-10 490 0.39 6.25 š 1.56 š 1.56 š 1.56 S, 1.56 Serratia marcescens 1.56 12.5 0.78 3.13 6.25 1.56

(3) Test results - continued:

Tested species 7 9 Compound No. 10 11 12 13 Staphylococcus aureus 1.56 0.39 1.56 0.39 1.56 1.56 209P JC-1 Escherichia coli 0.1 3.13 1.56 3.13 0.1 0.2 NIHJ JC-2 Proteus vulgaris w 0.025 0.39 0.2 0.78 w 0.025 á 0.025 IAM-1025 Klebsiella pneumoniae w 0.025 0.2 0.05 0.39 0.1 0.05 20 May Proteus mirabilis w 0.025 1.56 0.78 1.56 0.2 0.2 18 Pseudomonus aeruginosa š 1.56 3.13 1.56 1.56 1.56 1.56 NCTC-10 490 Serratia marcescens 3.13 3.13 12.5 12.5 12.5 6.25

2. Protective effect against experimental infection in mice (1) Test method:

at different doses one hour after cell separation. ED 50 values were determined based on the number of mice that survived for each dose after four days of observation.

Male ICR mice, 4 weeks old, each subject weighing from 18.5 to 21.5 g, were concentrated into a group of 10 individuals. Test bacteria were grown overnight at 37 ° C in tripticase-soy agar and then suspended in 5% mucin to obtain a suspension. The above mice were dosed intraperitoneally with 0.5 ml of the above suspension. The solution containing the test compound was administered subcutaneously by the above we (2) Test compounds:

C.

... 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer), ... 7- [2- (2-amino) -4-thiazolyl) -2-methoxyiminoacetamido] cep alospolanic acid (syn isomer i.

(3) Test results:

Testing bacteria Apliko- vané cells/ /mouse ED 50 (s.c.) (mg / kg) Test compounds 1 control MIC (µg / ml) Amount inocula Test compounds 1 control Escherichia ooli 54 1.1 χ 10 ⁷ 0.95 2.8 10 ° 0.78 3.13 10-2 * 2 0.05 0.1 Klebsiella pneumoniae 8 x 10 ^sec 0.98 0.995 10 ° 0.39 3.13 10 “ ^{1 2} <0.025 0.05 Próteus rettgeri 25 9.9 x 106 0.39 1.171 10 ° 1.56 50 10- ² w 0.025 0.1 Serratia marcescens 1.2 χ 10 ⁷ 3.562 * ³ 31.427 * ³ 10 ° 25 50 10 ² 0.39 1.56 * 1: overnight culture dissolved in distilled water and then they were

* 2: 100-fold diluted overnight culture; * 3: treatment with two separate doses at 1 hour and 3 hours after infection.

administered subcutaneously and intravenously to said subjects. The animals were observed for 7 days after dosing. LD 50 values were determined based on the number of animals killed by the Litchfield-Wllsoxon method.

3. Acute toxicity (1) Test method:

Ten male and ten female rats, 6 weeks of age (JCL-SDj species were grouped together. Test compounds were (3) Test results:

Test animals Male female sex

4. Absorption capacity (lj Test method:

Test compounds were administered orally to a group of 5 rats (jCL-SD species, 6 weeks old, male) that had previously been fasted. After about 0-6 hours and 6-24 hours, bile and urine samples were collected from these animals. The concentration of these test compounds was determined in the samples by bioassay (disk method), and as test organism (2) Test compounds were:

7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer i.

LD 50 (mg / kg)

s.

8000 about 8000

8000 8000 mu using Bacillus subtilis ATCC-6633, and then recovery in bile and urine samples was determined.

(2) Test compounds:

7- (2- (2-amino-4-thiazolyl) -2-n-pentyloxyiminoacetamido) -3-cephem-4-carboxylic acid (syn isomer).

(3) Test results:

The total recoverability in urine and bile after 24 hours was 22.8%.

In the case of prophylactic and / or therapeutic administration of the active compounds according to the invention of formula (I), it should be noted that they can be administered in the form of conventional pharmaceutical preparations containing said compounds as active ingredient, further in admixture with pharmaceutically acceptable carriers such as organic or inorganic solids or liquids which are suitable for oral, parenteral or enteral administration. The pharmaceutical preparations may be in solid form such as capsules, tablets, dragees, ointments or suppositories, or in liquid form such as solutions, suspensions or emulsions. If necessary, various additives, stabilizing agents, wetting agents or emulsifying agents, buffering agents and other commonly known additives can be added to the above compositions.

The amount of compounds to be administered can vary within wide limits, depending on the age and condition of the patient, the type of disease and the degree of infection, as well as the type of active compound of formula I to be used, etc., wherein: on average, single doses of about 50 ml, 100 ml, 250 ml and 500 ml are sufficient to treat patients with infectious diseases caused by pathogenic bacteria. In general, the active compounds of formula I may be administered in an amount ranging between 1 mg / kg and 100 mg / kg, and preferably from 5 mg / kg to 50 mg / kg.

The following examples illustrate the invention in further detail without restricting it in any way.

Example 1

1. In this embodiment, pnitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate is dissolved in the form of the syn isomer in an amount of 0.8 g in a mixed solution of methanol (30 ml) and tetrahydrofuran (60 ml). To this solution was added 10% palladium on carbon at a rate of 0.4 g, and the mixture was subjected to catalytic reduction at ambient temperature and atmospheric pressure. The above catalyst is then filtered off and the filtrate is concentrated under reduced pressure. Water (30 ml) was added to the residue, and the mixture was adjusted to pH 7.5 with aqueous sodium bicarbonate. After insoluble matter was removed by filtration, the filtrate was washed with 50 ml of ethyl acetate. 70 ml of ethyl acetate were added to the obtained solution, and the pH of the mixture was adjusted to 1.5 with 10% hydrochloric acid, and the mixture was shaken well. After removal of the ethyl acetate layer, the aqueous layer was subjected to extraction with ethyl acetate (30 ml) twice. The ethyl acetate layer and extracts were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to give 7- [2- (2) -acetic acid as the final product. (formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 0.48 g. The melting point of the product thus obtained ranges from 165 to 174. ^C (dec.).

Product characteristics:

IR at _max (nujolj:

3250, 1780, 1730, 1690, 1660, 1550 cm -1.

NMR .delta. _Ppm (DMSO-d6):

3.57 (2H, btSj,

3.91 (3H, s,

5.30 (1H, d, J = 5Hz),

5.88 (1H, dd, J = 5.8 Hz),

7.44 (1H, sj,

8.52 (1 H, s),

9.78 (1H, d, J = 8Hz),

12.60 (1H, s).

According to this embodiment, 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer and in an amount of

0.4 g was suspended in methanol (15 ml). Concentrated hydrochloric acid (0.16 g) was added to the suspension, and the mixture was stirred at ambient temperature for 2.5 hours. From the resulting mixture, methanol was distilled off under reduced pressure to give a residue which was dissolved in 15 ml of water. The resulting solution was then washed with ethyl acetate (30 ml) and dichloromethane (30 ml). Nitrogen was then introduced into the aqueous layer to remove residual organic solvent and the solution was lyophilized to give 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro acid hydrochloride. -3-cis-4-carboxylic acid in the form of the syn isomer and in a yield of 0.35 g. The melting point of the product thus prepared is from 170 to 180 ° C (with decomposition).

Product characteristics:

I. R. Pmax (nujolj.

3300, 1780, 1730, 1670, 1630, 1545 ^cm-first

NMR% _Dm (DMSO- _d 6):

3.88 (2H, AB-q, J = 17Hz).

3.94 (3 H, s),

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

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

6.92 (1 H, s),

9.88 (1 H, d, J = 8 Hz).

3. According to this embodiment, 7- [2- (2-amino-4-thiaeolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid hydrochloride is in the form of the syn isomer in an amount of 1 0.5 g of sodium hydrogen carbonate was dissolved in 50 ml of water at ambient temperature with stirring and then lyophilized. To this product, obtained as described above, was added dropwise a solution jodmethylhexanoátu 0.93 g of dimethylformamide in an amount of 5 ml, the addition is performed dropwise to a solution of the above product in dimethylformamide 15 ml at a temperature of -5 C ^Q and the solution is stirred at the same temperature for 30 minutes.

To the resulting solution was added ethyl acetate (50 mL) and water (100 mL), and the resulting ethyl acetate layer was separated. The aqueous layer obtained above was extracted twice with ethyl acetate (50 ml). The extracts were combined with the ethyl acetate layer, washed with a saturated aqueous sodium bicarbonate solution for a total of three times, dried over magnesium sulfate, treated with charcoal and finally concentrated under reduced pressure. The concentrate thus obtained was washed with n-hexane (50 ml) and n-hexane (50 ml) and diethyl ether (25 ml) were added to the residue and the solution was allowed to stand overnight in the refrigerator. The above precipitated powder was collected by filtration, then washed with n-hexane and dried to give a mixture of n-hexanoyloxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3 chloro-3-cephem-4-carboxylate in the form of the syn isomer and n-hexanoyloxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-2-cephem-4-carboxylate in the form of the syn isomer, the yield of this mixture being 1.0 g.

Example 2

According to this embodiment, 7- (2- (2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido} -2,3-dimethyl-3-cephem-4-carboxylic acid) in the form of the syn isomer and 0.86 g in a 9 ml aqueous solution containing 2.3 g of sodium acetate trihydrate and stirred at ambient temperature for 19 hours. The resulting filtrate was adjusted to an ipH value of 2.5 using a 10% hydrochloric acid solution while cooling in an ice bath. The precipitate is collected by filtration, then washed with water and dried to give 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2,3-dimethyl-3-cephem- 4-carboxylic acid in the form of the syn isomer 0.16 g.

Product characteristics:

IR at _max (nujol):

3320, 3200, 1770 (range), 1670,

1630 cm ^-1 .

NMR _{? PPm} (DMSO- _{d 6):?}

1.44 (3H, d, J = 7 Hz), 1.98 (3H, 3), 3.57 (1H, q, I = 7 Hz), 3.82 (3H, 3), 5.18 (1H, d, J = 5 Hz), 5.73 (1H, dd, J = = 5.8 Hz), 6.76 (1H, with), 9.63 (1H, d, J = 8 Hz). Ex and d 3

According to this embodiment, a solution consisting of 7- {2- [2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido} -3-methoxy-3-eephem-4-carboxylic acid is in the form of syn isomer 0.55 g, sodium acetate trihydrate 1.76 g, 3 ml ethyl acetate, 3 ml tetrahydrofuran and 5.5 ml water, stirred at ambient temperature overnight The aqueous layer was separated from the resulting mixture, washed with dichloromethane, then evaporated under reduced pressure to remove the organic solvent, and the pH of the aqueous solution was adjusted to 4.2 with cooling in a water bath. and the solution is then purified in a 15 ml diaion HP-20 resin chromatography column (commercially available from Mitsubishi Chemical Industries, Ltd.) after washing the column with water. and eluted with 20% aqueous isopropanol. The eluate is then concentrated under reduced pressure and the residue is lyophilized to give 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) acid. -3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 0.4 g. Melting point: 185-190 ° C (dec.).

{217960

Product characteristics:

IR at _max (nujol):

3300, 1770, 1660, 1630, 1540 cm ¹ .

NMR <5 _ppm (DMSO-d6):

3.60 (2H, s-band),

3.75 (3 H, s),

3.83 (3 H, s),

5.12 (1 H, d, J = 4 Hz),

5.55 (1H, dd, J = 4.8Hz),

6.82 (1 H, s),

9.52 (1H, d, J = 8Hz).

He attaches

1. According to this embodiment, to a solution consisting of p-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer and 1.25 g in methanol (40 ml) and tetrahydrofuran (50 ml), 10% palladium on carbon (0.65 g) are added, and the mixture thus obtained is subjected to catalytic reduction at ambient temperature and atmospheric pressure which takes place for 3.5 hours. The catalyst was then removed from the resulting reaction mixture, and the filtrate was concentrated under reduced pressure. A residue was prepared to which 80 ml of water was added and the mixture was adjusted to pH 7.5 with aqueous sodium bicarbonate. After this procedure, insoluble materials are formed which are filtered off. The resulting filtrate was washed with ethyl acetate (50 ml) and 100 ml of ethyl acetate were added. The pH of the solution was then adjusted to 1.5 with 10% hydrochloric acid, and the resulting ethyl acetate layer was separated. After this separation, the aqueous phase remains, which is subjected to extraction with ethyl acetate (80 ml), the extraction is carried out twice in total, and the extracts are combined with the ethyl acetate layer obtained as above. The solution was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The above product gave 7- (2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid as the final product, yielding: 0.60 g. Melting point: 176-183 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3250, 1780, 1690, 1660, 1550 cm ^-1 .

NMR δ _ppm (DMSO-d 6):

3.63 (2H, d, J = 4Hz);

3.93 (3 H, s),

5.10 (1 H, d, J = 5 Hz),

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

6.53 (1 H, t, J = 4 Hz),

7.47 (1 H, s),

8.57 (1 H, s),

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

12.63 (1 H, s).

2. In this embodiment, 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is synthesized in the form of the syn isomer in an amount of 95 mg. is suspended in 4 ml of methanol. Concentrated hydrochloric acid (110 mg) was added to the suspension, and the solution was stirred at ambient temperature for 4 hours. The methanol is then removed from the solution by distillation under reduced pressure. The residue was dissolved in water (30 ml) and washed with ethyl acetate (10 ml) and dichloromethane (15 ml). Nitrogen is then introduced into the aqueous solution to remove the last residual organic solvent, and the aqueous solution is then lyophilized to give 7- [2- (2-amino-4-thiazolyl) -2-] hydrochloride. methoxyiminoacetamido) -3-cep-4-carboxylic acid in the form of the syn isomer in a yield of 83 mg. Melting point: 180-190 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3300, 1770, 1710, 1660, 1630 cm @ -1.

NMR .delta. _Ppm (DMSO-d6):

3.64 (2H, s-band),

3.95 (3 H, s),

5.14 (1H, d, J = 5Hz),

5.82 (1 H, t, J = 4 Hz),

6.95 (1 H, s),

9.80 (1 H, d, J = 8 Hz).

3. A solution consisting of 7- (2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer and 10.8 g of concentrated hydrochloric acid (11 g) and methanol (350 ml) was stirred at ambient temperature for 4 hours, then the resulting solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The pH of the above solution was adjusted to 8.0 with saturated aqueous sodium bicarbonate solution, and the aqueous layer was separated and washed with diethyl ether, and nitrogen was bubbled into the aqueous solution and bubbled through the aqueous solution. aqueous solution, the pH of the aqueous solution being adjusted to 4.0 using a 10% hydrochloric acid solution. A precipitate is formed which is collected by filtration and then washed with water afterwards. The resulting product of the present invention is 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, yielding 8, 2 g. The melting point of this product is greater than 290 ° C.

Product features:

IR in _max (nujol j:

3470, 3280, 3200, 1780, 1695, 1655,

1622 cm ^-1 .

NMR 5 _{p. M} (DMSO-d):

3.60 (2H, s-band),

3.84 .3H, sj,

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

5.84 (1 H, dd, J = 8 Hz),

6.52 (1H, band t),

6.76 (1H, sj,

7.26 (2H, sj band,

9.65 (1H, d, J = 8Hz).

4. Add 1.04 g of sodium bicarbonate to a solution of 7- [2- (2-amino-4-thiazclyl) -2-methoxyiminoacetamido] -3-cephem- 4-carboxylate in the form of the syn isomer and 2.6 g in 100 ml of water, stirred and added at room temperature to an ice bath solution, and the resulting solution was lyophilized to give the final product is sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer.

Product characteristics:

IR in _lliax (nujolj:

3100, 1760, 1650, 1590, 1530 cm ^-1 .

N. M, R, (.delta. (D2 O, ppm):

3.60 (2H, qj band,

4.00 (3H, sj,

5.22 (1 H, d),

5.88 (1 H, d),

6.35 (1 H, q),

7.03 (1H, sj,

5. The product obtained above was dissolved in dry N, N-dimethylformamide in an amount of 20 ml. To this solution is then added dropwise a solution of iodomethyl n-hexanoate in an amount

1.33 g and dry Ν, Ν-dimethylformamide (5 ml) were added at -40 ° C over 5 minutes. The solution was stirred at the same temperature above for 40 minutes and then for 45 minutes while cooling in an ice bath. The solution thus prepared is then added to a stirred solution consisting of 60 ml of ethyl acetate and 125 ml of water. This procedure creates an ethyl acetate layer which is separated, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. Drying is then carried out with magnesium sulphate and finally this solution is treated with activated carbon. After removal of ethyl acetate from the solution, the residue obtained is triturated with diethyl ether. The end product of this process is n-hexanoyloxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer, yield 750 mg. .

Product characteristics:

IR in _m x (nujol):

3170, 1780, 1750 (range),

1670, 1630, 1530 cm ^-1

N. M. R. $ (CDCl3, ppm):

0.68-1.84 (9H, m),

2.20 - 2.48 (2H, i.e.

3.20-3.80 (2H, m)

4.02 (3 H, s),

5.04 (1 H, d),

5.60 - 6.20 (3H, m),

6.62 (1 H, q),

6.80 (1 H, 3),

7.72 (1 H, d).

6. In this embodiment, pn: trobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer and in an amount of 1 1 gram was suspended in a mixture of ethanol (10 ml) and water (15 ml). To the suspension was added dropwise 1 N aqueous potassium hydroxide (6 mL) at a temperature ranging from 5 to 7 ° C over 10 minutes, and then stirred with the mixture for a period of 10 minutes. 10 minutes. The pH of the resulting solution is then adjusted to pH

7.5 using a 10% hydrochloric acid solution, followed by washing with ethyl acetate and finally adjusting the pH to 2.5 again with a 10% hydrochloric acid solution. Crystals precipitate which are collected by filtration to give 7- [2- (2-formamido-4-thiazolyl) -2-methoxyminoacetamido] -3-cephem-4-carboxylic acid as a syn. of isomer in an amount of 0.32 g and 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cep-4-carboxylic acid in the form of the syn isomer, which compound is present in an amount of 0.035 g.

7. In this embodiment, 7- [2- (2-amino-4-carboxylic acid)] in the form of the syn isomer and 5 g is added sequentially to an aqueous solution of a total volume of 30 ml of sodium bicarbonate in an amount of 1 g. The addition is carried out at a temperature in the range of from 35 to 40 [deg.] C. The solution is then stirred at a temperature in the range of from 50 to 53 [deg.] C. for 30 minutes. insoluble material, which was removed from the resulting solution by filtration, and the filtrate was treated with activated charcoal (0.3 g) and finally filtered, and the filtrate was lyophilized and the final product of the process of the present invention. Sodium 7- [2- (2-amino-4-4hiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer, yield 4.2 g.

Product characteristics:,

IR at _max (nujolj:

3300-3100, 1760, 1670, 1595,

1530 cm ¹

NMR. _{PB PBm} (DMSO-de j:

3.50 (2H, s-band),

3.83 (3 H, s),

5.00 (1 H, d, J = 5 Hz),

5.68 (1H, dd, I = 5Hz),

6.13 (1H, s-band),

6.73 (1 H, s),

7.3 (2H, s-band),

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

8. In this embodiment, 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 1.15 g is added to an aqueous solution of calcium hydroxide containing 0.111 g in 100 ml of water, the resulting solution is stirred at ambient temperature for 10 minutes, filtered and the filtrate lyophilized, the final product of this embodiment. According to the process of the invention, the calcium (7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylate) is in the form of the syn isomer in a yield of 1.2 g.

Product characteristics:

IR at _max (nujol):

3350, 1760, 1670, 1590,

1535, 1465 cm ¹

N. M. R. δ (D0, ppmj:

3.51 (1 H, d, J = 5 Hz),

3.59 (1H, d, J = 3Hz),

3.97 (3 H, s),

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

5.82 (1H, d, J = 5Hz),

6.33 (1H, dd, J = 5Hz, 3Hz),

6.95 (1 H, s).

9. 7- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1.15 g, to a suspension of magnesium hydroxide in an amount of 0.088 g in 100 ml of water. The mixture was stirred at 70 ° C for 30 minutes to prepare a solution. After this procedure, the resulting solution is filtered and the filtrate is lyophilized, the final product of which is 7- [2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate magnesium. , in the form of the syn isomer and in a yield of 1.1 g.

Product characteristics:

I.R. Vmax (nujol):

3350 1760 1660 1610

1530, 1460 cm ¹

N.M.R. (D2O, ppm):

3.53 (1 H, d, J = 5 Hz),

3.59 (1H, d, J = 3Hz);

3.96 (3H, s,

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

5.84 (1H, d, J = 5Hz);

6.32 (1H, dd, J = 5Hz, 3Hz),

7.98 (1 H, s).

10. 7- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1.15 g was added to a solution of 0.523 g of arginine in 50 ml of water, and the solution was stirred at ambient temperature for 10 minutes.

The mixture is filtered and the filtrate is lyophilized to give 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cef arginine salt. 4-carboxylic acid in the form of the syn isomer in an amount of 1.35 g.

Product characteristics:

IR p _max (nujol):

3350, 3150, 1770, 1650 (band),

1580, 1530, 1460 Crrl · ⁴

NMR δ [D ₂ O, ppm]:

I, 4-2.1 (4H, m),

3.22 (2H, t, J = 6Hz),

3.55 (1 H, d, J = 6 Hz),

3.65 (1 H, d, J = 3 Hz),

3.82 (1 H, d, J = 6 Hz),

3.97 (3 H, s),

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

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

6.33 (1H, dd, J = 6Hz, 3Hz),

7.00 (1 H, s).

II. According to this embodiment is performed so that 7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] ^{-3-cephem-4-l} ka'r bcxylát syn isomer,

1.21 g is added to a solution of lysine hydrochloride 0.55 g in 12 ml water. The solution thus obtained is freeze-dried and the final product of this embodiment of the process of the invention is 7- [2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-cepheremic acid lysine salt. -4-carboxylic acid as the syn isomer, yield 1.6 g.

Product characteristics:

IR at _max (nujol):

3350, 3150, 1770, 1600 (band),

1530, 1460 cm ¹

NMR δ (D ₂ O, ppm):

1.3-2.1 (6H, m),

3.03 (2H, t, J = 7Hz),

3.54 (1 H, d, J = 5 Hz),

- 3.64 (1H, d, J = 3Hz),

3.80 (1 H, d, J = 6 Hz),

3.97 (3 H, s),

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

5.84 (1 H, d, J = 5 Hz),

6.32 (1H, dd, J = 5Hz, 3Hz),

6.99 (1 H, s).

12. A 20% solution of sodium hydroxide in water is added to a suspension of 7- [2- (2-aminothiazol-4-yl) -2-mothoxyiminoacetamide] -3-cephem-4-carboxylic acid in the form of syn isomer and 15 g, in a mixture of 8 ml of ethanol and 8 ml of water at ambient temperature, to prepare a solution having a pH of 7.5. The solution was filtered and washed, and the filtrate and washings were combined (18.3 mL water) and added dropwise to 46 mL ethanol at a temperature ranging from 20 ° C to 20 ° C. to 25 ° C, while stirring the mixture and further mixing at the same temperature for 30 minutes. To the above mixture was then added dropwise ethanol in an amount of 28 ml over a period of 30 minutes. The mixture was stirred at the same temperature for 2 hours. The solids are collected by filtration, washed with 20 ml of ethanol and dried under vacuum at ambient temperature to give 7- (2- (2-aminothiazole-4) dihydrate). sodium yl-2-methoxyminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer, and in a yield of 13.5 g. The melting point of the product thus obtained is 260 ° C (dec.).

Product characteristics:

IR in _nM (nujol):

3430, 3260, 1760 (range), 1745, 1650,

1630 (range), 1590, 1540 cm ^-1

13. Sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in an amount of 15 g, Dissolve in 13 ml of water at a temperature ranging from 35 to 45 ° C, said addition being carried out with stirring. Thereafter, 52 ml of warm ethanol was added dropwise to the stirred solution at 30 ° C, and stirring was continued at the same temperature for 5 minutes and then at ambient temperature for 2 hours. A precipitate is precipitated, which is collected by filtration, then washed with ethanol and finally dried under reduced pressure, the final product of this process being 7- [2- (2-aminothiazol-4-yl) -2- sodium methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 13.45 g.

14. Carry out a 4N aqueous sodium hydroxide solution carefully by dropwise addition to a stirred suspension consisting of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 -cephem-4-carboxylic acid, in the form of the syn isomer, in an amount of 52 g in 100 ml of water, operating at a temperature below 5 ° C to prepare a pH of 7.0 to 7, 5. The solids are precipitated, filtered and washed, and the combined filtrate and washings are added and the mixture (200 ml) is added dropwise to ethanol (2 liters) with stirring over a period of time. 30 minutes, and stirring is then continued at ambient temperature for 15 minutes and then at a temperature in the range

217980 from 5 to 10 ° C for one hour. The material precipitates by filtration, then washed with 200 ml of ethanol and finally dried under vacuum at 30 ° C to give amorphous 7- [2- (2-aminothiazole- 4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate sodium is the syn isomer, yielding 46.3 g.

Product characteristics:

IR at _max (nujol):

3400, 3300, 3170, 1750, 1650,

1580 cm ¹

15. Sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in an amount of 10 grams, 250 ml of methanol are treated in an ultrasonic apparatus to purify the above solution. This solution is then allowed to stand at ambient temperature and then stirred at the same temperature for 3 hours. A precipitate is formed in the solution which is collected by filtration and washed with methanol to give amorphous 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- cef em-4-carboxylate sodium in the form of syn-sorter.

16. The crystals obtained in Example 4- (12) above are dried over phosphorus pentoxide under vacuum for one day at ambient temperature to provide 7- [2-]. Sodium 2- (2-aminothiazol-4-yl) -2-methoxyimmaacetamido] -3-cephem-4-carboxylate as the syn isomer. Example 5

1. Add 0.6% of 10% palladium on carbon to a solution of p-nitrobenzyl-7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] Of 3-chloro-3-cephem-4-carboxylate in the form of an anti-isomer, 1.16 g in 20 ml of methanol and 40 ml of tetrahydrofuran, and then subjected to catalytic reduction at ambient and atmospheric temperature The reaction mixture is stripped of catalyst and the filtrate is concentrated under reduced pressure, water (30 ml) and ethyl acetate (60 ml) are added to the residue. the pH of the resulting mixture is adjusted to 7.5 with aqueous sodium bicarbonate, and then shaken well to form an aqueous layer which is separated. and then 90 ml of ethyl acetate were added to the aqueous solution. The pH of the above aqueous layer is then adjusted to pH

2.5 using a 10% hydrochloric acid solution, with stirring and cooling on a water bath, forming an ethyl acetate layer which separated. The aqueous layer remains, which is subjected to extraction with ethyl acetate 30 ml to give an extract which is combined with the above ethyl acetate layer, washed with aqueous sodium chloride solution, dried and finally concentrated. under reduced pressure. The residue is washed with diisopropyl ether to give 7- [2- (2-farmamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid as The title compound was colored at 210 ° C and decomposed above 250 ° C.

Product characteristics:

IR at _max (nujol):

3250, 1780, 1720 (band),

1670 to 1690 cm ^-1

NMR .delta. _Ppm (DMSO-d6):

3.8 (2H, AB-q, J = 17Hz)

4.0 (3H, s);

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

5.83 (1H, dd, J = 5.8Hz),

8.05 (1 H, s),

8.47 (1 H, s),

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

12.55 (1H, s band).

2. In this embodiment, 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of an anti isomer in an amount of 0.4 g, suspended in 15 ml of methanol. Concentrated hydrochloric acid (0.16 g) was added to the suspension, and the mixture was stirred at ambient temperature for 5 hours. The above precipitate is collected by filtration, then washed with a 1: 1 mixture of methanol and diethyl ether, and dried to give 7- (2- (2- (2- amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of an anti isomer and in yield

0.31 g. The melting point of the compound thus prepared is higher than 250 ° C.

Product characteristics:

IR v, _nax (nujol):

3250, 3200, 1788, 1720, 1680,

1640 cm ¹

NMR _{δ ppm} (DMSO-d 6):

3.81 (2H, AB-q, J = 17Hz);

4.08 (3 H, s),

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

5.7 (1H, dd, J = 5.8Hz),

7.59 (1 H, s),

9.5 (1 H, d, J = 8 Hz).

Example 6

10% palladium (0.85 g) on activated carbon is added to a solution of p-nitro-benzyl-7- [2- (1,2,3-thiadiazol-4-yl)]. -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer and in an amount of

1.65 g, in methanol (70 ml) and tetrahydrofuran (90 ml), and the above mixture was subjected to a catalytic reduction at ambient temperature and atmospheric pressure for 3.5 hours. After this reaction, the catalyst is removed from the reaction mixture by filtration, and the filtrate is concentrated under reduced pressure. A residue is obtained to which water is added and the mixture is adjusted to a pH value of 7 to 8 with sodium bicarbonate, followed by washing of the solution with ethyl acetate, and again adjusting the pH to 1.5 with 10% hydrochloric acid, and finally extracting the resulting solution with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to give a residue which was triturated with diethyl ether. The precipitated mass is collected by filtration and then dried to give 7- [2- (1,2,3-thiadiazol-4-yl) -2-methoxyiminoacetamldo] -3-cephem acid. -4-carboxylic acid in the form of a yellow powder and in the form of the syn isomer in a yield of 0.3 g.

Product characteristics:

IR p _max (nujol):

3250, 2550-2600, 1785, 1715,

1655, 1630, 1600 cm ^"1 NMR £ _ppm (DMSO-d):

3.58 (2H, AB-q, J = 14Hz);

4.00 (3 H, s),

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

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

6.52 (1 H, t, J = 5 Hz),

9.38 (1 H, s),

9.84 (1 H, d, J = 8 Hz).

Example 7

2. In this embodiment, the p-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate is in the form of the syn isomer in an amount of 7 8 g, suspended in a mixture of 60 ml of ethanol and 60 ml of water. To the above suspension was added a 1N aqueous potassium hydroxide solution (45 ml) dropwise with stirring while cooling in an ice bath over a period of 10 minutes, and stirring was continued at this temperature. 5 ° C for 15 minutes. The resulting solution was adjusted to pH 7.0 with concentrated hydrochloric acid, washed with ethyl acetate, and then concentrated under reduced pressure to half its initial volume. The concentrated solution thus obtained is adjusted to a pH of 5.0 and then subjected to a chromatography column packed with macroporous, non-ionic adsorption resin material "Diaion HP-20" (a trade name of a product manufactured by Mitsubishi Chemical Industries Ltd.) in an amount of 80 ml, using 5% aqueous isopiroipyl alcohol as eluent. The fractions containing the subject compound of the invention were combined and then adjusted to pH 3.2 with a 10% hydrochloric acid solution. Crystals are formed in this way, which are collected by filtration and dried, and the final product of the process of the invention is 7- [2- (2-amino-4-thiazolyl) -2-methoxyminoacetamido] -3-cephem-4-carboxylic acid in the form of syn isomer and in a yield of 2.3 g.

Example 8

In this embodiment, crayfish is added to add 1.0 g of palladium on charcoal, moistened with 3 ml of water, to a solution of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2] ethoxyiminoacetamido-3-cephem-4-carboxylate in the form of the syn isomer (2.3 g) in a mixture of tetrahydrofuran (30 ml) and methanol (15 ml) and acetic acid (0.3 ml), and the suspension thus prepared is subjected to catalytic reduction at ambient temperature and under normal pressure for 2 hours. After the reduction, the catalyst is removed from the above reaction mixture by filtration and the filtrate thus obtained is concentrated under reduced pressure. Ethyl acetate was added to the residue, and the pH was adjusted to 7.5 with aqueous sodium bicarbonate. An insoluble material is formed, which is collected by filtration, the aqueous solution is separated, washed with ethyl acetate, adjusted to pH 5.5, and then treated with activated carbon. After this step, the aqueous solution is adjusted to pH 3.2 to precipitate a mass which is collected by filtration and then dried, the final product of this embodiment being 7- [2- (2-amino-4) acid. (thiazolyl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 0.6 g.

Product characteristics:

IR at _max (nujol):

3500, 3300, 3200, 1785

1625, 1600 cm ¹

Ν. MR <5 _ppm (DMSO-d 6):

1.20 (3H, t, J = 7Hz);

3.57 (2 H, m),

4.08 (2H, q, I = 7Hz),

5.08 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 8Hz),

6.47 (1 H, m),

6.73 (1 H, s),

7.20 (2 H, m),

9.58 (1 H, d, j = 8 Hz).

Example 9

A solution of 1 g of 15 ml of methanol, 5 ml of tetrahydrofuran and 0.72 g of concentrated hydrochloric acid was stirred at room temperature for 1 h. one hour. To the resulting solution was then added diethyl ether in an amount of 100 ml and then triturated. Crystals precipitate from the solution, which are collected by filtration and the final product of this embodiment of the invention is 4-nitrobenzyl-7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- liydroxy-3-cephem-4-carboxylate in the form of the hydrochloride and in the form of the syn isomer, the yield of which is 0.65 g.

C har player of product:

IR at _max (nujol):

3180, 1780, 1680, 1670, 1640 cm ¹

3.2-4.0 (2H, m),

3.97 (3 H, s),

5.27 (1H, d, J = 4Hz),

5.41 (2 H, s),

5.60 (1H, dd, J = 4Hz, 8Hz),

7.10 (1 H, s),

7.66 (2H, d, J = 9Hz);

8.25 (2H, d, I = 9Hz)

9.73 (1 H, d, J = 8 Hz).

Example 10

A suspension of 0.8 g of palladium on charcoal in 5 ml of water is added to 4-nitrobenzyl 1-7- (2- (2-amino-4-thiazolyl) - 2-ethoxyiminoacetamido] -3-chloro-S-cephem-a-carboxylate in the form of the syn isomer in 2.0 g, acetic acid in 0.6 ml and tetrahydrofuran in 60 ml and the suspension thus obtained is subjected to catalytic reduction The reaction is carried out at ambient pressure and at ambient temperature for 3 hours After the reduction, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give a residue which is then treated with ethyl acetate (50 ml). The pH of the solution thus obtained is adjusted to 7.4 with an aqueous sodium bicarbonate solution, thereby forming an insoluble material which is separated by filtration. The pH was adjusted to 6.0 using a 10% hydrochloric acid solution, after which the organic solvent was removed under reduced pressure. The aqueous solution thus obtained is subjected to a chromatography column which is filled with macroporous material "Diaion HP-20" (trade name of Mitsubishi Chemical Industries Ltd.) in an amount of 30 ml. The column was then washed with water and eluted with 5% aqueous isopropyl alcohol. The eluate obtained is lyophilized, the end product thus obtained being sodium Ί- (2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido) -3-chloro-3-cephem-4-carboxylate in sodium in the form of the syn isomer and in a yield of 0.3 g.

Product characteristics:

IR _inax (nujol):

3350, 3200, 1770, 1675, 1620 cm ¹

Ν. MR 5 _ppm (D 2 O):

1.33 (3H, t, J = 7Hz);

3.76 (2H, q, J = 18Hz, 30Hz),

4.30 (2H, q, J = 7Hz);

5.33 (1 H, d, J = 5 Hz),

5.83 (1 H, d, J = 5 Hz),

7.06 (1 H, s).

Ν. MR 5 _ppm (DMSO-d 6):

Example 11

To this was added 1 ml of acetic acid, and a 10% palladium on carbon suspension of 2.0 g in 8 ml of water, to the solution of 4-nitro-benzyl-7- [2- ( 2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer (5.0 g) in tetrahydrofuran (150 ml), and the suspension thus obtained is subjected to catalytic reduction. the reduction is carried out at ambient temperature and under normal pressure. After reduction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added 80 ml of ethyl acetate, and then the pH was adjusted to 7.5 with aqueous sodium bicarbonate. In this way, an organic layer is formed, which is separated and then subjected to extraction with aqueous sodium bicarbonate solution. After this extraction, an extract is obtained which is combined with the aqueous layer obtained as described above, then the pH of this solution is adjusted to 3.0 with concentrated hydrochloric acid and then extracted with tetrahydrofuran. The extract thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and finally concentrated under reduced pressure.

Crystals precipitated from the above process, which are collected by filtration and then dried, and the final product of this embodiment of the process of the invention is 7- [2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido | -3-cep-4-carboxylic acid in the form of the syn isomer in an amount of 0.8 g.

C har act e r is t i k a of birth k here:

IR at _max (nujol):

3320, 1780, 1670, 1635 cm ¹

NMR <5 _ppm (DMSO-d6):

1.20 (6H, d, J 6 Hz),

3.55 (2 H, m),

4.30 (1 H, q, J = 6 Hz),

5.08 (1 H, d, J = 5 Hz),

5.82 (1H, dd, J = 5Hz, 8Hz),

6.45 (1 H, m),

6.68 (1 H, m),

7.10 (2 H, m),

10.08 (1 H, d, J = 8 Hz).

Example 1 a d 12

According to this embodiment, 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer was treated with a similar amount of 5.0 g in a similar manner. by the method of Example 11 to give 7- (2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer and the yield of this product is 0.9 g.

Product characteristics:

IR at _max (nujol):

3250, 1770, 1650, 1660, 1620 ^cm-1

NMR _{δ ppm} (DMSO-d 6):

0.93 (3H, t, J = 7Hz),

1.67 (2H, sextet, J = 7Hz),

3.60 (2 H, m),

4.03 (2H, t, J = 7Hz),

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

5.83 (1H, dd, J = 5Hz, 8Hz),

6.48 (2H, t, J = 4Hz);

6.70 (1 H, s),

7.18 (2 H, m),

9.53 (1H, d, I = 8Hz).

Example 13

1. A mixture of 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-n-butoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer and 34.5 g, tetrahydrofuran 345 ml, 10% palladium on carbon, 14 g, methanol 140 ml, acetic acid 2.5 ml and water 50 ml, catalytic reduction The reduction is carried out at normal pressure and at ambient temperature for a total of 3 hours. The resulting mixture is filtered, and then washed with tetrahydrofuran. The filtrate is concentrated in vacuo and the residue is dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate. In this way an insoluble material is formed which is collected by filtration. Then, the ethyl acetate layer was separated and subjected to extraction with aqueous sodium bicarbonate solution, the aqueous layer and the aqueous extract combined. The aqueous solution was washed with ethyl acetate and then with diethyl ether, the solution was adjusted to pH 2.0 with 10% hydrochloric acid, and then stirred for 30 minutes. The precipitated mass is collected by filtration, washed with water and finally dried over magnesium sulphate to give the final product 7- (2- (2-formamidothiazol-4-yl) - 2- ¹ butoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 18.3 g.

217360

Product characteristics:

IR in _innx (nujol):

3330, 3040, 1780, 1725, 1695,

1655 cm ” ¹

N.M.R. (DMSO-d6, ppm):

0.90 (3H, t, I = 7Hz),

1.1-1.9 (4H, m),

3.58 (2H, d, J = 5Hz),

4.12 (2H, t, J = 7Hz)

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

5.86 (1H, dd, J = 5Hz, 8Hz),

6.46 (1 H, t, J = 4 Hz),

7.40 (1 H, s),

8.50 (1 H, s),

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

12.57 (1H, s band).

2. In this embodiment, the mixture of 7- [2- (2-formamidothiazol-4-yl) -2-n-butoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount 12.7 g, followed by concentrated hydrochloric acid (9.6 ml), methanol (9.5 ml) and tetrahydrofuran (9.5 ml) were stirred at ambient temperature for 3 hours. The resulting solution was concentrated in vacuo and the residue suspended in water. The pH of the suspension is then adjusted to 3.5 with sodium bicarbonate and cooled in an ice bath, and then stirred at the same temperature for 30 minutes. The insoluble material is precipitated by filtration and dried over magnesium sulphate to give a powder of 10 g. The powder thus obtained is suspended in 300 ml of water and then adjusted to pH 7.0 with bicarbonate. sodium. The pH of the solution is then adjusted to 6.0 with a 10% hydrochloric acid solution and then subjected to chromatography in a column packed with "Diaion HP-20", a trade name of Mitsubishi Chemical Industries Ltd. 300 ml, and a 10% solution of isopropyl alcohol in water was used as eluent. The eluate obtained is adjusted to pH 3.5 with 10% hydrochloric acid solution while cooling in an ice bath to give a precipitate which is then collected by filtration, washed with water and dried to give the final product, which is of this embodiment 7- (2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer, yield 7.2 g.

Char.akte.ris.tlka product:

IR at _max (nujol):

3320, 1775, 1660 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

0.88 (3H, t, J = 7Hz),

1.1-1.9 (4H, m),

3.58 (2H, s-band),

4.05 (2H, t, J = 7Hz);

5.08 (1 H, d, J = 5 Hz),

5.80 (1H, dd, j = 5Hz, 8Hz),

6.44 (1H, s-band),

7.18 (2 H, s),

9.51 (1H, d, J = 8Hz).

Example 14

1. The method comprises 4-nitrobenzyl-7- [2- (2-phirmamidothiazol-4-yl) -2-isobutoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer of 14, 2 g, 10% palladium on charcoal 5.7 grams, 57 milliliters methanol, 142 mL tetrahydrofuran, 1 mL acetic acid and 10 mL water are treated in a similar manner to Example 13- (1), which provides 7- (2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetamido) -3-cephem-4-carboxylic acid. in the form of the syn isomer and in a yield of 4.24 g.

Product characteristics:

IR at _max (nujol):

3260, 1790, 1725, 1670 cm!

N.M.R. '(DMSO-d6, ppm):

0.92 (6H, d, J = 6Hz),

1.6-2.3 (1H, m),

3.61 (2H, d, J '= 4 Hz),

3.91 (2H, d, J = 6Hz),

5.14 (1H, d, J = 5Hz),

5.88 (1H, dd, J = 5Hz, 8Hz),

6.50 (1 H, t, J = 5 Hz),

7.40 (1 H, m),

8.56 (1 H, s),

9.64 (1 H, d, J = 8 Hz).

2. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -2-iso-butoxyiminoacetamido] -3-cephem-4-carboxylic acid is in the form of the syn isomer and in an amount of 4, 1 g, and then concentrated hydrochloric acid (3.65 g) and methanol (61.5 ml) were treated in a similar manner to Example 13- (2) to prepare 7- [2- (2- aminothiazol-4-yl) -2-iso-butoxyiminoacetamido] -3-cephem. -4-cariboxyl in the form of the syn isomer in a yield of 2.4 g.

Product characteristics:

IR at _max (nujol):

3330, 1780, 1665, 1630, 1545 cm ^-1

N.M.R. δ (DMSO-d6, ppm):

0.89 (6H, d, J = 7Hz),

1.6-2.2 (1H, m);

3.58 (2H, s-band),

3.84 (2H, d, J = 7Hz),

5.10 (1H, d, J = 5Hz),

5.82 (1H, dd, J = 5Hz, 9Hz),

6.46 (1H, s-band),

6.68 (1 H, s),

7.20 (2 H, s),

9.53 (1H, d, J = 9Hz).

Example 15

1. In this embodiment, 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylate is present in the form of the syn isomer and in an amount of 2 0 g, and 10% palladium on carbon at 0.8 g, methanol at 8 ml, tetrahydrofuran at 20 ml, acetic acid at 0.14 ml and water at 1.4 ml. following the procedure of Example 13- (1), to give 7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylic acid. boxyl in the form of the syn isomer and in yield

0.77 g.

Product characteristics:

IR ( _max ):

3275, 3070, 1780, 1675 cm -1.

N.M.R. δ (DMSO-d 6, ppm):

0.8-2.2 (10 H, m),

3.62 (2H, s-band),

4.12 (1 H, m),

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

5.87 (1H, dd, J = 5Hz, 9Hz),

6.47 (1H, s-band),

7.37 (1 H, s),

8.50 (1 H, s),

9.58 (1H, d, J = 9Hz);

12.61 (1H, s band).

2. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylic acid is the syn isomer in an amount of 0.72 g, 10.8 ml of methanol, and 0.61 g of concentrated hydrochloric acid are treated in a similar manner to that described in Example 13- (2), the final product of this process being acid 7. - [2- (2-Aminothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, yield 0.28 g.

Ch-ar and Rte r i product line:

IR at _max (nujol):

3350, 1775, 1665, 1620, 1540 cm -1.

N.M.R. δ (DMSO-d6, ppm):

0.8-2.2 (10 H, m),

3.60 (2H, s-band),

4.04 (1 H, m),

5.09 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 9Hz),

6.45 (1 H, t, J = 4 Hz),

6.67 (1 H, s),

7.19 (2 H, s),

9.48 (1H, d, J = 9Hz).

Example 16

1. A suspension of 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of an anti-isomer and in an amount 4.2 g, followed by 10% palladium on carbon at 1.7 g, 0.63 ml of acetic acid, 6.3 ml of water, 42 ml of methanol and 84 ml of tetrahydrofuran, subjected to catalytic reduction under a hydrogen atmosphere, which is carried out at ambient temperature for 2 hours. After reduction, the catalyst was removed by filtration, and the filtrate was concentrated to a volume of about 15 ml using reduced pressure. Water (30 ml) and ethyl acetate (50 ml) were added to the concentrated solution, and the pH of the solution was adjusted to 8.0 with sodium bicarbonate while stirring. An insoluble material was formed, which was removed by filtration, and the resulting aqueous layer was separated and washed with 50 ml of ethyl acetate. The solution is treated with charcoal and the pH is adjusted to 2.2 with 10% hydrochloric acid while cooling in an ice bath. A precipitate is formed, which is removed by filtration and then washed with water, the final product of the process of the invention being 7- [2- (2-formamldothiazol-4-yl) -2-methoximeiminoacetamido] -3-cephem. -4-carboxylic acid in the form of an anti isomer, yielding 2.52 g.

Product characteristics:

IR _max (nujc-L):

3300 (band), 1780, 1680, 1670, 1550 ^cm-first

AND

N.M.R. δ (DMSO-d 6, ppm):

3.63 (2H, s-band),

4.08 (3 H, s),

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

5.87 (1H, dd, J = 5Hz, 8Hz);

6.55 (1H, t, J = 4Hz),

8.09 (1 H, s),

8.52 [1H, s]

9.46 (1H, d, J = 8Hz).

2. A suspension of 7- [2- (2-formamidothiazol-4-yl) -2-methoxyimino [eta] &lt; 8 &gt; -acetamido] -3-cephem-4-carboxylic acid in the form of an anti-isomer and amount of 2.5 g, followed by hydrochloric acid concentrated

2.5 ml and methanol (38 ml) were stirred at ambient temperature for two hours. The solution thus obtained is treated with activated carbon and the residue is crystallized in diisopropyl ether (100 ml) and the resulting mass is collected by filtration and washed with diisopropyl ether (30 ml) to give 7- [7-] hydrochloride at this stage. 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of an anti-isomer in an amount of 2.1 g. The crystals thus obtained are then added to 20 ml of water. pH of the resulting solution was adjusted to 6.0 with sodium bicarbonate. the solution was then subjected to column chromatography, which is filled with an absorbent non-ionic, resinous material "Diaion ^HP-2! 0" (which is trade mark of Mitsubishi Chemical Industries Ltd., in an amount of 75 ml, eluting with 10% diisopropyl ether. the eluate is adjusted to pH 3.5 with 10% hydrochloric acid and the precipitated mass is then collected by filtration and dried, the final product of this embodiment being 7- (2- (2-aminothiazole- 4-yl] -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of an anti-isomer in a yield of 0.7 g.

Product characteristics:

IR> _inilx (nujolj:

3400—3200 (band), 1770, 1680, 1640,

1520 cm ^-1 .

N.M.R. δ (DMSO-d6, ppm):

3.60 (2H, d, J = 5Hz);

4.00 (3 H, s),

5.10 (1H, d, J = 5Hz),

5.82 (1H, dd, J = 5Hz, 8Hzj,

6.48 (1H, t, J = 4Hz);

7.13 (2H, band),

7.47 (1H, s),

9.42 (1H, d).

Example 17

1. In this embodiment, a suspension of 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-n-propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate in the form of the syn isomer and 2.4 g, 10% palladium on charcoal 1.0 g, 24 ml methanol, 3.6 ml water, and 48 ml tetrahydrofuran and catalytic reduction After the reduction, the insoluble material is removed by filtration and the filtrate is concentrated in vacuo, and the residue is treated with water and acetic acid methyl ester, the pH of the solution thus obtained being added. The reaction mixture was adjusted to 8 with a saturated aqueous sodium bicarbonate solution to give an insoluble material which was removed by filtration and the aqueous layer was separated. The pH of this solution was adjusted to 2.0 with hydrochloric acid, followed by extraction with ethyl acetate. The obtained ethyl acetate solution and the extract were combined, then washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solution is concentrated in vacuo and the residue is triturated with diethyl ether and the solid collected by filtration to give 7- [2- (2-formamidothiazol-4-yl) -2- (2-formamidothiazol-4-yl) -2- n-prapoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 1.6 g.

Product characteristics:

IR at _max (nujolj:

3300 - 3150, 1780, 1720, 1685, 1650,

1540 cm ^1st

N.M.R. δ (DMSO-d 6, ppm):

0.93 (3H, t, J = 7Hz),

1.72 (lH, m),

3.88 (2H, q, J = 18Hz),

4.08 (2H, q, I = 7Hz),

5.33 (1H, d, J = 5Hz),

5.92 (1H, dd, J = 5Hz, 8Hz),

7.43 (1H, s),

8.57 (1H, s),

9.73 (1H, d, J = 8Hz).

According to this embodiment, the suspension of 7- [2- (2-formamidothiazol-4-yl) -2n-propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 1.5 g, followed by concentrated hydrochloric acid (0.7 ml) and methanol (30 ml) were stirred at ambient temperature for 1.5 hours. Methanol was removed from the resulting solution under vacuum and water (30 ml) was added to the residue. The pH of the solution was then adjusted to 7.5 with saturated aqueous sodium bicarbonate solution to give an insoluble material which was removed by filtration. The pH of the filtrate thus obtained is adjusted to 3 with a 10% hydrochloric acid solution. In this way a precipitate is formed which is collected by filtration, then dried with phosphorus pentoxide to give the final product, which is 7- [2- (2-amino-thiazol-4-yl) -2-n] -propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 0.6 g.

Product characteristics:

IR at _max (nujol):

3300, 1780, 1670, 1630, 1530 cm ¹ .

N.M.R. S (DMSO-d 6, ppm):

0.92 (3H, t, J = 7 Hz),

1.67 (1 H, m),

3.70 (2H, q, J = 18Hz);

4.00 (2H, q, J = 7 Hz),

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

5.83 (1H, dd, J = 5Hz, 8Hz),

6.75 (1 H, s),

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

Example 18

1. The process is carried out with 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-pentyloxyiminoacetamidio] -3-cephem-4-carboxylate in the form of the syn isomer in an amount of 8 g. and 10% palladium on charcoal 3.6 g, 36 ml methanol, 90 ml tetrahydrofuran, acetic acid

0.63 g and water, 6.3 ml, were treated in a similar manner to that described in Example 13- (1j) to prepare 7- (2- (2-phenoxy) -butyric acid. aminamidothiazol-4-yl) -2-pentyloxyiminoacetamido) -3-cephem-4-carboxylic acid as the syn isomer in 3.4 g.

Product characteristics:

IR ( _max ):

3275, 3075, 1795, 1700, 1660, 1630 cmM

N.M.R. S (DMSO-d 6, ppm):

0.6-2.0 (9H, m),

3.60 (2H, d, J = 4Hz);

4.12 (2H, t, J = 6 Hz),

5.14 (1H, d, J = 5 Hz),

5.87 (1H, dd, J = 5Hz, 9Hz),

6 _; 49 (1 H, t, 1 = 3 Hz),

7.40 (1 H, s),

8.53 (1 H, s),

9.64 (1H, d, J = 9Hz),

12.68 (1 H, s).

2. In this embodiment, 7- [2- (2-fluoramidothiazol-4-yl) -2-pentyloxy-fluoro-acetamido] -3-cephem-4-carboxylic acid in the form of syn isomer62 is added in an amount of 3.3 g, and concentrated hydrochloric acid (2.80 g), tetrahydrofuran (20 ml) and methanol (50 ml) were treated in a similar manner to that described in Example 13- (2). of the invention, the final product is 7- [2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 2.3 g.

Product characteristics:

IR> _max (nujol):

3300-1775, 1650, 1540 ^cm-first

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.0 (9H, m),

3.56 (2H, d, J = 2Hz),

4.03 (2Ή, t, 1 = 6 Hz),

5.08 (1H, d, J = 5 Hz),

5.81 (1H, dd, J = 5 Hz, 8 Hz),

6.46 (1 H, t, J = 4 Hz),

6.69 (1 H, s),

7.20 (2 H, s),

9.15 (1H, d, J = 8Hz).

Example 19

According to this first embodiment is performed so that 4-nitrobenzyl 7- [2- ^(2-FO rmamidothiazol-4-y1) -2-ethoxycarbonyl bonylmethoxyiminoacetamido) -3-cephem-4-carboxylate syn isomer and at 2.52 g, and at 1.3 g, ethanol at 13 ml, tetrahydrofuran at 25 ml, acetic acid at 0.22 ml, and water at 2.2 ml, are treated in a similar manner as as described in Example 13- (1), wherein the final product of the process is 7- (2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetamido) -3-cef em-4-carboxylic acid in the form of the syn isomer and in yield

0.4 g.

Product characteristics:

IR at _max (nujol):

3250, 3060, 1780, 1750, 1690, 1660 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

1.23 (3H, t, J = 7 Hz),

3.61 (2H, s-band),

4.15. (2H, q, J = 7Hz);

4.73 (2 H, s),

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

5.87 (1H, dd, J = 5 Hz, 9 Hz),

6.48 (1H, s-band),

7.43 (1 H, s),

8.50 (1 H, s),

9.62 (1 H, d, J = 9 Hz),

12.58 (1 H, s).

2. A solution of 7- [2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer is added in an amount of 0, 35 g, and concentrated hydrochloric acid 0.39 g, in ethanol

5.3 ml and tetrahydrofuran (8 ml) were stirred at ambient temperature for 4.5 hours. The resulting solution was concentrated in vacuo, and the residue was dissolved in aqueous sodium bicarbonate, and the solution was treated with charcoal and filtered. The filtrate thus obtained is adjusted to pH 3.5 with a 10% hydrochloric acid solution while cooling in an ice bath. A precipitate is formed, which is collected by filtration, then washed with water and dried to give the final product, which is 7- [2- (2-aminothiazol-4-yl) -2- ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, yield 0.1 g.

Product characteristics:

IR at _max (nujolj:

3250, 3050, 1775, 1720, 1660, 1630,

1550 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

1.21 (3H, t, J = 7Hz),

3.59 (2 H, s),

4.14 (2H, q, J = 7Hz);

4.66 (2 H, s),

5.10 (1H, d, J = 5Hz),

5.83 (1H, dd, J = 5Hz, 8Hz),

6.47 (1H, sj band,

6.87 (1H, sj,

7.23 (2 H, s),

9.52 (1H, d, J = 8Hz).

Example 20

In this embodiment, the suspension of 7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamido] -3-cephem-4-carboxylic acid is in the form of syn isomer and 1.5 g, concentrated hydrochloric acid 1.3 ml, 10 ml tetrahydrofuran and 30 ml methanol in a similar manner to that described in Example 17- (2), the final product of this embodiment of the process of the invention is 7- [2- (2-aminothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamido] -3-cephem-4-carboxylic acid in the form of syn isomer, yield 1.1 g.

Product characteristics:

IR in _lllax (nujolj:

3450, 3300, 1780, 1660, 1625, 1590,

1550 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

3.60 (2H, s-band),

4.70 (2H, q, J = 8.5Hz),

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

5.87 (1H, dd, J = 5Hz, 8Hz),

6.52 (1 H, t, J = 4 Hz),

6.87 (1 H, s),

9.80 (1H, d, J = 8Hz).

Example 21

According to this embodiment the procedure is such that a 7- [2- (2-formamidoth ⁱ 'azole-4-y1) -2- (2-chloro j ethoxyimino acetamido] -3-cephem-4-carboxylic acid syn isomer and 1.8 g, and concentrated hydrochloric acid 1.6 g, methanol 27 ml and tetrahydrofuran 40 ml are treated in a similar manner to that described in Example 13- (2), the final product of the process of the invention is 7- (2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) acetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer and yield 1.4 g.

Product characteristics:

IR at _max (nujolj:

3440, 3300, 3070, 1780, 1660, 1625,

1555 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

3.60 (2 H, s),

3.80 (2H, t, J = 6Hz);

4.30 (2H, t, J = 6Hz);

5.10 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 9Hz),

6.47 (1 H, s),

6.78 (1 H, s),

7.24 (2 H, s),

9.58 (1H, d, J = 9Hz).

Example 22

According to this embodiment, the mixture of 7- [2- (2-formaidothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 1.35 g. and further concentrated hydrochloric acid (3.926 g), methanol (20 ml) and water (10 ml) and tetrahydrofuran (40 ml) were stirred at 30 ° C for 6 hours. The resulting solution was concentrated under vacuum to remove methanol, and the aqueous solution was adjusted to pH 4.2 with 10% aqueous sodium hydroxide. The solution was adjusted to pH 3.0 with 10% hydrochloric acid. In this way, a precipitate is formed which is collected by filtration and dried to give the final product, which according to this embodiment of the process of the invention is 7- (2- (2217960) acid.

(aminothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 0.8 g.

Product characteristics:

IR at _max (nujol):

3300 (band), 3200 (band), 1775, 1670,

1635 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

3.64 (2H, s,

4.64 (2 H, s),

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

5.86 (1 H, dd, J = 5 Hz, 7 Hz),

6.49 (1 H, t, J = 4 Hz),

6.82 (1 H, s),

7.33 (2H, sj,

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

Example 23

1. The suspension is 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamido] -3-chloro-3. -cephem-4-carboxylate in the form of the syn isomer in an amount of 1.8 g, and further treated with 10% palladium on carbon in an amount of 0.9 g in 20 ml of methanol and 20 ml of tetrahydrofuran, in a similar manner to this is the case of Example 17- (1), wherein the final product of this embodiment of the process of the invention is 7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino acid) Acetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1.0 g.

Product characteristics:

IR at _max (nujolj:

3250, 1780, 1690, 1655, 1530 ^cm-first

N.M.R. δ (DMSO-d6, ppm):

3.86 (2H, q, J = 17Hz).

4.80 (2H, q, J = 8.5Hz),

5.35 (1 H, d, J = 5 Hz),

5.92 (1H, dd, J = 5Hz, 8Hz),

7.53 (1H, s,

8.53 (1H, s,

9.93 (1 H, d, J = 8 Hz),

12.70 (1H, band ²⁾

2. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamido] -3-chloro-3-cephem- 4-carboxylic acid in the form of the syn isomer at 0.7 g, and then concentrated hydrochloric acid at 0.43 ml and methanol at 16 ml were treated in a similar manner to that described in Example 17 - ( 2), wherein the final product of this embodiment of the process of the invention is 7- [2- (2-aminothiazoleES)

-4-yl) -2- (2,2,2-trifluoroethoxyimino Jacetamido] -3-chloro-3-ene-4-carboxylic acid as the syn isomer in a yield of 0.65 g.

Product characteristics:

IR (i) _max (nujol):

3320, 3150, 1775, 1720, 1660, 1645, 1600

1345 cm ^1st

N.M.R. δ (DMSO-d 6, ppm):

3.87 (2H, q, J = 18Hz).

4.80 (2H, q, J = 8.5Hz),

5.30 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 8Hz),

7.05 (1 H, s),

10.00 (1H, d, J = 8Hz).

Example 24

1. A mixture of 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate in the form of syn isomer and in an amount of 2.7 g, and 10% palladium deposited on carbon in an amount

1.3 g, 4 ml of water, 0.4 ml of acetic acid, 27 ml of methanol and 54 ml of tetrahydrofuran were treated in a similar manner to that described in Example 17- (1j), according to this embodiment of the process of the invention, the final product is 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, the yield is 1.4 g and the product is a yellow powder.

Product characteristics:

IR in _max (nujo-1j):

3250, 2400—2600, 1780, 1700, 1690, 1650

1610 cm ^-1 .

N.M.R. δ (DMSO-d6, ppm):

0.90 (3 H, m),

1.2 - 1.70 (4H, m),

3.88 (2H, AB-q, J = 19Hz).

4.0—4.25 (2Ή, ia,

5.32 (1 H, d, I = 5 Hz),

5.90 (1H, dd, J = 5Hz, 9Hz),

7.42 (1 H, s),

8.50 (1 H, s),

9.73 (1 H, d, J = 8 Hz),

12.60 (1 H, s).

2. In this embodiment, the mixture of 7- (2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido) -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer and 1.3 g, and concentrated hydrochloric acid (1.3 ml) and methanol (20 ml) were treated in a similar manner to that described in the Example.

17- (2), wherein the final product of this embodiment of the process of the invention is 7- (2- (2-aminothiazol-4-yl) -2-butoxyiminoacetamido) -3-chloro-3-cephem-4-carboxylic acid in the form of syn isomer, the yield of which is 1.2 g and the product is in the form of a pale yellow powder.

Product characteristics:

IR at _max (nujol):

3300, 2500—2600, 1785, 1730, 1665,

1630 cm ^1st

N.M.R. δ (DMSO-d 6, ppm):

0.90 (3 H, m),

1.2-1.75 (4H, m),

3.88 (2H, AB-q, J = 19Hz),

5.17 (2 H, m),

5.33 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 8Hz),

6.93 (1 H, s),

9.50 (2I-I, s-band)

9.85 (1 H, d, J = 8 Hz).

Example 25

1. A mixture of 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylate in in the form of the syn isomer and 1.7 g, and 10% palladium on charcoal in 1 g, water in 3 ml, acetic acid in 0.3 ml, methanol in 20 ml and tetrahydrofran in 35 ml are treated in a similar manner to that described in Example 13- (1), wherein the final product of this invention is 7- (2- (2-formamidothlazol-4-yl) -2-butoxyiminoacetamido) - 3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1 g, which is a yellow powder.

Product characteristics:

IR _m , _x (nujol):

3200—3250, 2600, 1775, 1700, 1690,

1650 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

1.0 (3H, m);

1.2-1.75 (4H, m),

3.67 (2H, s-band),

3.86 (3 H, s),

4.0-4.3 (2 H, m),

5.23 (1 H, d, J = 4 Hz),

5.68 (lH, dd, J = 4Hz, 8Hz),

7.50 (1 H, s),

8.58 (1 H, s),

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

2. In this embodiment, a mixture of 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] 63 is added.

-3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer and 0.9 g, concentrated hydrochloric acid 0.8 ml and 13.5 ml methanol in a similar manner as described above in the case of Example 13- (2), wherein the final product of this embodiment of the process of the invention is 7- [2- (2-aminothiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem- 4-carboxylic acid in the form of the syn isomer in a yield of 0.4 g, the resulting product being a yellowish-white powder.

Product characteristics:

IR in _{in (1x} (nujol)):

3200—3300, 2600, 1770, 1705, 1670

1620 cm ^1st

N.M.R. δ (DMSO-d 6, ppm):

0.90 (3 H, m),

1.2 - 1.65 (4H, m)

3.60 (2 H, s),

3.96 (3 H, s),

4.0-4.16 (2 H, m),

5.12 (1 H, d, J = 4 Hz),

5.55 (1H, d, d, J = 4Hz, 8Hz),

6.80 (1 H, s),

7.2-7.6 (2H, s-band),

9.50 (1 H, d, J = 8 Hz).

Example 26

A solution of diazomethane in diethyl ether is added in small portions to a solution of 4-nitrobenzyl 7- [2- (2-bromoacetyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylate in an amount of 0 9 g in tetrahydrofuran (30 ml) was carried out with ice-cooling until the reaction was complete and acetic acid was added to the resulting solution to quench excess diazomethane. The resulting solution is concentrated under reduced pressure to give the final product in the form of a foam, which is 4-nitrobenzyl-7- [2- (2-bromoacetyl) -2- methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer and in a yield of 0.9 g.

Example 27

10% palladium on charcoal 0.35 g was added to a solution of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3- cef em-4-carboxylate in the form of the syn isomer and 0.7 g in 70 ml of methanol, and the mixture thus obtained is subjected to a catalytic reduction at ambient temperature and atmospheric pressure for 1.5 hours . This gives a final mixture which is filtered and the filtrate is concentrated in vacuo. reduced pressure. The residue is added to an aqueous solution of sodium bicarbonate to give an insoluble material which is filtered off. The filtrate thus obtained is washed with ethyl acetate and methylene chloride, then purged with nitrogen and then lyophilized. The residue is dissolved in 30 ml of water and the pH of the solution is adjusted to 3.8 with 10% hydrochloric acid. This solution is then subjected to a chromatography column packed with 20 ml of macroporous, non-ionic adsorption resin material "Diaion HP-20" (trade name of Mitsubishi Chemical Industries, Ltd.), followed by washing with water and then washing with water. eluting with 40% aqueous acetone, removing the acetone from the eluate under reduced pressure and lyophilizing to give the final product, which is 7- [2- (2-amino-4-) - thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid as the syn isomer, yield 0.25 g.

..... ~ · ^ »Ρϊπ

Product characteristics:

IR at _max (nujolj:

3350 to 3200, 1770, 1670, 1630 cm ^-1 .

NMR δ _ppm (DMSO-d 6):

3.60 (2H, s-band),

5.10 (1 H, d, J = 5 Hz),

5.83 (1H, dd, J = 5Hz, 8Hz),

6.47 (1 H, t, J = 4 Hz),

6.67 (1 H, s),

9.47 (1H, d, J = 8Hz).

Example 28

A solution of diazomethane in diethyl ether is added portionwise to a solution of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4- of carboxylate as the syn isomer and 0.3 g in 30 ml of methanol until the reaction is complete The resulting solution is then concentrated under reduced pressure to give a residue which is triturated with diethyl ether and the precipitated fraction is collected by filtration and dried to give the final product of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -6-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer, and the yield of this product is

This product was identified by comparison with the same sample.

Example 29

Following the procedure of Example 28, the following compounds of the invention were prepared:

1.

4-nitrobenzyl 7- [2- [2-aminothiazol-4-yl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer,

2.

4-nitroibenzyl 7- [2- (2-aminothiazol-4-yl) -2-propoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer,

3.

4-Nitro-benzyl 7 - [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer.

Example 30

1. Add 160 mg sodium horohydride to a suspension of 4-nitrobenzyl-7- [2- (2-fluoramido-4-thiazolyl) -2-methoxyiminoacetamido] -3-hydroxy -3-cep-4-carboxylate in the form of the syn isomer and 1 g in tetrahydrofuran in 10 ml, acetic acid in 3 ml and water in 1 ml at 0 ° C for 10 minutes . The solution is stirred at a temperature ranging from 0 to 3 ° C for 55 minutes. Water was added to the treated solution, and the solution was subjected to extraction with ethyl acetate. The extract obtained is washed with a saturated aqueous solution of sodium chloride, then with a saturated aqueous solution of sodium bicarbonate and finally with a saturated aqueous solution of sodium chloride, and then drying with magnesium sulphate. The solution is then concentrated under reduced pressure to give a residue which is triturated with diethyl ether to give the final product of this embodiment of the invention, 4-nitrobenzyl-7- [2- (2-foramido-4-) thiazolyl) -2-methoxyminoacetamido] -3-hydroxycephem-4-carboxylate in the form of the syn isomer, yield 0.77 g. Melting point: 172-175 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3250, 1775, 1745, 1660 cm ¹ .

NMR < $ _ppm (DMSO-d6):

2.76 (1H, dd, J = 14Hz, 3Hz),

3.17 (1H, dd, J = 14Hz, 13Hz),

3.92 (3H, sj,

4.03 (1 H, m),

4.72 (1H, d, J = 6Hz);

5.24 (1 H, d, J = 4 Hz),

5.37 (2 H, s),

5.56 (1H, dd, J = 9Hz, 4Hz),

6.07 (1 H, d, J = 4 Hz),

7.44 (1 H, s),

7.72 (2H, d, J = 8Hz);

8.27 (2H, d, J = 8Hz),

8.54 (1 H, s),

9.67 (1 H, d, J = 9 Hz).

2. Add 0.406 g of mesyl chloride to the stirred mixture of 4-nitrobenzyl-7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-hydroxycepham dropwise. 4-carboxylate in the form of the syn isomer at 1 g, and N, N-dimethylformamide at 10 ml and potassium carbonate at 0.732 g at a temperature ranging from 0 to 5 ° C. within 2 minutes, and the solution thus obtained is stirred at ambient temperature for 2.5 hours. Ethyl acetate and water were added to the solution, and the solution was subjected to extraction with ethyl acetate. The remaining aqueous solution is then subjected to extraction again with ethyl acetate. The ethyl acetate extract thus obtained is then washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. This gives a residue which is subjected to a chromatography column which is not loaded with silica gel (30 g) and is eluted with a mixture of chloroform and ethyl acetate. The eluate thus obtained is concentrated under reduced pressure to give the final product, which is 4-nitrobenzyl-7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3- cefem-4-carboxylate in the form of the syn isomer, yielding 0.12 g. Melting point: 224 DEG C. (dec.).

Example 31

704 mg of phosphorus oxychloride is added dropwise to a solution of 336 mg of N, N-dimethylformamide in 8 ml of ethyl acetate, at a temperature below 50 ml. 5 ° C and this solution is then stirred at the same temperature above for 30 minutes. 2- (2-Formamidothiazol-4-yl) -2-methoxyiminoacetic acid, as the syn isomer, is added to the solution in an amount of 1 g and stirred at a temperature ranging from 5 to 10 °. C for one hour. The solution thus prepared was then added dropwise to a solution of 772-amino-3-hydroxycepham-4-carboxylic acid in an amount of 872 g and trimethylsilyl acetamide in an amount of 1.05 g in 20 ml of ethyl acetate, at -20. The solution was stirred at -20 ° C to -25 ° C for 1 hour. Water (50 ml) was added to the resulting solution, and the pH was adjusted to 7.0 with sodium bicarbonate. An aqueous layer was formed, which was separated, and the ethyl acetate layer was then subjected to extraction with water (10 ml). The aqueous extracts were combined, adjusted to pH 6 and then adsorbed onto a macroporous, non-ionic adsorbent material such as 50 ml of "Diaion HP-20" resin (a trade name of Mitsubishi Chem'cal Industries). Ltd.). The chromatography column was then washed with water (50 ml) and eluted with 30% aqueous isopropyl alcohol. The eluate thus obtained containing the subject compound of the invention is adjusted to pH 6.5 and then concentrated under reduced pressure. The residue is lyophilized to give the final product, 7- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-hydroxycephene-4-carboxylate in the form of the syn isomer, yield 1.1 g.

Product characteristics:

N. M. R. δ (D2O, ppm):

2.72-3.18 (2H, m),

4.02 (3 H, s),

4.02-4.28 (1 H, m),

4.54 (1 H, d, J = 4 Hz),

5.28 (1 H, d, I = 4 Hz),

5.53 (1 H, d, J = 4 Hz),

7.50 (1 H, s),

8.53 (1 H, s).

Example 32

Fermentation:

Inoculation medium: tripticase-soybean (BBL).

Culture environment:

glycerin 3 g peptone 1 g corn extract 1 g dry yeast 2 ^! g sodium carbonate 0,1 g

KH2PO1. 12 H 2 O 2.15 g (The above components were dissolved in water, the total volume was adjusted to 100 ml, and the pH of this medium was adjusted to 7.2.

The culture medium was placed in an amount of 100 ml in a 500 ml Sakaguchi flask and sterilized at 120 ° C for 20 minutes. The above medium was then inoculated with 1 ml of each of the microorganisms listed below, grown at 30 ° C for 18 hours in an inoculation medium, and shaken at 30 ° C for 18 hours. for 48 hours.

Reaction:

To the above 1 ml culture medium, a substrate of 0.1 g, the characteristics of which are given below, suspended in 0.1 M phosphate buffer at pH 7.2 and 1 ml, is then added and the mixture is shaken. at 30 ° C for 48 hours.

Identification and examination:

After the reaction was carried out in order to identify the product in the reaction mixture obtained as described above, the mixture was subjected to chromatography in an Eastman cellulose-based 6065 chromatogram at ambient temperature. In this case:

A. Upper layers of 4: 1: 5 (v / v) n-butanol / ethanol / water, and

B. 7: 3 n-propanol / water.

_Rf value was determined by an index of antimicrobial activity against sensitive species Escherichia coli EC 111, and as a result was observed in only one spot, showing Product I and II, 6065 to Eastman chromatogram based on cellulose was observed without any stain the substrate I and II. R _f values are given in the following table.

TABLE

Reaction mixture (Product I)

Control (Substrate I)

Reaction mixture (Product II)

Control (Substrate II)

Note:

Substrate I:

4-nitrobenisyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer,

Product I:

7- (2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephemarboxylic acid in the form of the syn isomer,

Substrate II:

4-nitro-benzyl-7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer.

Developing agent A B

0.85 0.90 0.39 0.60 0.90 0.92 0.36 0.54

Product II:

7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid as the syn isomer.

The product formed in the above mixture, which was formed after the above procedure, was detected by the paper disc method using simultaneously sensitive species of microorganisms Escherichia coli ES 111 grown at 37 ° C for 16 hours, whereby the yield of the process was determined. The results are shown in the following table.

7S

TABLE

Microorganisms used for enzymatic hydrolysis

Bacillus subtilis IAM 1069

Bacillus sphaeiricus IAM 1286

Bacillus subtilis IAM 1107

Bacillus subtilis IAM 1214

Corynebacterium equi IAM 1038

Micrococcus varians IAM 1313

Flavobaeterium rigens IAM 1238

Salmonella typhimurium IAM 1406 Staphylococcus epidermidis IAM 1296 Microbacterium flavum IAM 1642

The following are examples of pharmaceutical compositions prepared according to the process of the present invention, which contain 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamide-0] -3-carboxylic acid-4-carboxylic acid in the form of syn isomer (compound A) as the active ingredient.

Example 33

Lyophilization product for injection

According to this embodiment, the sodium salt of Compound A (20 g potency) was dissolved in 200 ml of water and the 5 ml solution was filled into 10 ml tubes. These tubes were frozen and then vacuum dried (lyophilized).

Example 34

Suspension for injection:

Compound A 25 g methylcellulose 0.5 g

Methyl 4-oxobenzoate 0.1 g

Polysolvate 80 0.1 g

Lidocaine hydrochloride 0.5 g

For these injections make up to 100 ml with water.

This aqueous suspension is suitable for intra-

muscular injection. Example 35 Tablets for oral use Compound A 500 mg lactose 375.5 mg hydroxypropylcellulose 2 mg magnesium stearate 22.5 mg This mixture is suitable for preparation tablet

for oral use in the treatment of infectious diseases caused by pathogenic bacteria.

Yield (%)

Product I Product II

75 60 75 20 May 75 95 85 20 May 95 95 70 20 May 85 90 90 20 May 90 95 90 95

Example 36

Capsules for oral use

Compound A 500 mg magnesium stearate 10 mg

This composition is suitable for the preparation of capsules for oral use in the treatment of infectious diseases caused by pathogenic bacteria.

Example 37

According to this embodiment, a mixture of 4-nitrobenisyl-7- [2- (2-formamidothiazol-4-yl) -2-n-hexyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate as the syn isomer and 5.6 g, and acetic acid 0.4 ml, 10% palladium on charcoal 2.24 g, water 4 ml, methanol 23 ml, and tetrahydrofuran 56 ml are treated in a similar manner to that described in Example 17- (1), the final product of this embodiment being 7- [2- (2-formamidothiazol-4-yl) -2- n-hexyloxy iminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 2.5 g.

Product characteristics:

I * R- (nU 10).

3225, 1785, 1690, 1650 cm ¹

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.0 (11H, m),

3.86 (2H, q, J = 18Hz),

4.13 (2H, t, J = 6Hz);

5.30 (1 H, d, J = 5 Hz),

5.88 (1H, dd, J = 5Hz, 8Hz),

7.41 (1 H, s),

8.54 (1 H, s),

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

12.68 (1 H, s).

2. According to this embodiment, the mixture of 7- [2- (2-fluoramido-thiazol-4-yl) -2-n-hexyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 2, 4 g, followed by concentrated hydrochloric acid (1.84 g), methanol (36 ml) and tetrahydrofuran (30 ml) were stirred at 30 DEG C. for 2 hours and the resulting solution was concentrated in vacuo. a residue is added to which 60 ml of water is added and as a result a solid precipitates which is collected by filtration, washed with water and dried with phosphorus pentoxide to give the final product, which is 7- (2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetamido) -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 1.86 g.

Product characteristics:

IR at _max (nujolj:

3300, 1780, 1665, 1535 cm ^-1

N.M.R. δ (DMSO-d6, ppm):

0.6-2.0 (11H, m),

3.84 (2H, q, J = 18 Hz),

4.08 (2H, t, J = 7Hz),

5.28 (1 H, d, I = 5 Hz),

5.82 (1H, dd, J = 5Hz, 8Hz),

6.77 (1 H, s),

9.66 (1H, d, J = 8 Hz),

6.0 - 8.0 (2IT, s band).

Example 38

According to this embodiment, the mixture of 7- (2- (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetamide) -3-methoxy-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 0.9 g, followed by concentrated hydrochloric acid (0.9 ml) and methanol (13.5 ml), stirred at ambient temperature for 4 hours, then concentrated in vacuo at 35 ° C to give a residue which was Dissolve in water and wash with ethyl acetate, adjust the pH of the aqueous solution to 7.0 with sodium bicarbonate, and then wash with ethyl acetate and diethyl ether to form a solution from which removes the solvent by bubbling with nitrogen, and the resulting solution is adjusted to pH 3.0 with a 10% hydrochloric acid solution and then stirred while cooling in an ice bath. The resulting solid precipitates, which is collected by filtration, then washed with water and dried to give the final product, 7- (2- (2-aminothiazol-4-yl)). -2-propargyloxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer, yielding 0.25 g of the product as a whitish yellow powder.

Product characteristics:

IR at _max (nujol):

3300, 2500 - 2600, 2120, 1775

1710, 1670, 1620 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

3.52 (1 H, m),

3.82 (3 H, s),

4.77 (2H, d, J = 2Hz);

5.17 (1H, d, J = 4Hz);

5.58 (1H, dd, J = 4Hz, 8Hz),

6.93 (1 H, s),

7.1 - 7.3 (2H, s-band),

9.67 (1 H, d, J = 8 Hz).

Example 39

In this embodiment, the mixture of 7- [2- (2-formamidothiazol-4-yl) -2-proparoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer and amount of 1.4 g, followed by concentrated hydrochloric acid (1.4 ml) and methanol (20 ml) were treated in a similar manner to that described in Example 37- (1), the end product of of the invention is 7- [2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yielding 0.7 grams of product form of yellowish white powder.

Product characteristics:

IR at _max (nujol):

3350, 2500 - 2600, 2130, 1775

1710, 1670, 1630 cm ¹

N.M.R. δ (DMSO-d 6, ppm):

4.38 (1 H, m),

4.48 (2H, AB-q, J = 19Hz);

4.72 (2H, d, I = 2Hz);

5.28 (1 H, d, J = 4 Hz),

5.80 (1H, dd, J = 4Hz, 8Hz),

6.78 (1 H, s),

9.73 (1 H, d, J = 8 Hz).

Example 40

4-Nitrobenzyl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate as the syn isomer and 5.0 g, and 10% palladium on carbon at 3.0 g, methanol at 100 ml, water at 21 7 9 60 ml and tetrahydrofuran at 150 ml, were treated in a similar manner to Example 27, wherein the final product of this embodiment is 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide O] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, and the yield of the product thus obtained is

1.28 g.

Product characteristics:

IR at _max (nujol):

3330, 1775, 1675, 1630 cm ¹

Ν. M. R. δ (DMSO-d 6, ppm):

3.72 (2 H, m),

5.24 (1 H, d, J = 5 Hz),

5.80 (1H, dd, J = 5.0Hz, 8.2Hz),

6.66 (1 H, s),

9.50 (1 H, d).

Example 41

7- [2- (2-Formamidothiazol-4-yl) -4-n-octyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 8 0.02 g, 6.23 g concentrated hydrochloric acid, 15 ml tetrahydrofuran and 120 ml methanol, were treated in a similar manner to that described in Example 17- (2), with the end product of this embodiment of the process of the invention is 7- [2- (2-aminothiazol-4-yl) -2-n-octyloxy-aminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, and the yield of this product is 6.95 g.

Product characteristics:

IR v, _nax (nujol):

3320 [band s], 1785, 1660,

1630, 1535 ^cm-1

Ν. M. R. (DMSO-d6, ppm):

0.6-2.0 (15H, m),

3.62 (2H, s-band),

4.07 (2H, t, J = 6Hz),

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

5.83 (1H, dd, I = 5Hz, 9Hz),

6.48 (1 H, s),

6.72 (1 H, s),

7.22 (2 H, s),

9.53 (1H, d, J = 9Hz).

Claims (5)

SUBJECT A process for the preparation of 7-substituted-3-cephem-4-carboxylic acids of the formula Ih having 5 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, and R ⁵ is a carboxy group or a pharmaceutically acceptable ester group, preferably (C 1 -C 6 alkanoyloxy) C 1 -C 6 alkoxycarbonyl or nitrophenyl (C 1 -C 6 alkoxycarbonyl), and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (Ig) in which R 1 is a thiadiazolyl group, a thiazolyl group of the general formula KJ in which he is R ^{6 is} amino, trihalogeno (C 2 -C 6) alkanamide or C 1 -C 6 alkanamide, R ² is hydrogen; (C 1 -C 12) alkyl group which may be substituted by halogen, carboxy or (C 1 -C 6) alkoxycarbonyl; further obsave cycloalkyl group having substituents R ^1, R ² and R ⁵ are as defined above, and R _and R ⁷ is an acyl group, preferably a (C-C6) alkanesulfonyl group, or alkanoyl group having 1 to 6 carbon atoms, or a salt said compound with an inorganic or organic basic compound, optionally followed by reacting the resulting compound wherein R ² is a hydrogen atom with an etherifying agent to form the resulting compound wherein R ² is a C 1 -C 12 alkyl group, which may be substituted by halogen, carboxy or C 1 -C 6 alkoxycarbonyl, furthermore C 5 -C 7 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, or the resulting compound in which the substituent ^R trihalogenfCz- C6) alkaneamide group or a (C C6j-alkaneamide group, an elimination reaction, to give the title compound in which R is substituted ^with amino, or • the resulting compound in which the substituent R ⁵ is carboxy, or a reactive derivative thereof The compound is reacted with a reagent capable of forming a pharmaceutically acceptable ester, preferably a (C 1 -C 6) alkanoyloxy (C 1 -C 6) alkanoyloxy (C 1 -C 6) alkoxycarbonyl group or a nitrophenyl (C 1 -C 6) alkoxycarbonyl group, to give the resulting compound in R ⁵ (C 1 -C 6) alkanoyloxy (C 1 -C 6) alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl, or converting an ester of the resulting compound wherein R ^{5 is a} pharmaceutically acceptable ester group, preferably (C 1 -C 6) ) alkanoyloxy (C 1 -C 6) alkoxycarbonyl or nitro phenyl · (C 1 -C 6) alkoxycarbonyl, per carboxy group, to give the resulting a compound wherein R ^{5 is} carboxy. 2. The process of claim 1 wherein the compound of formula (1g) is treated R ² is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, carboxy (C 1 -C 6) alkyl or (C 1 -C 6) alkoxycarbonyl (C 1 -C 6) alkyl, R ⁶ is amino, trihalogen (C 2 -C 6) alkanamide or (C 1 -C 6) alkanamide, and R ^1, R ⁵ and R ⁷ _and the substituents are the same meaning as in paragraph 1 or a salt thereof, with an organic or inorganic basic compound. 3. A process according to claim 1 wherein the compound of formula (1g) is treated R ¹ a thiazolyl group of formula .dp Wherein R ⁶ is amino, trihalogen (C 2 -C 6) alkanamide or (C 1 -C 6) alkanamide, R ² is an alkyl group containing 1 to 6 carbon atoms, ·, R ⁵ is carboxy or nitrophenyl (C 1 -C 6) alkoxy, rbonyl, and _And R ⁷ is [Cl-C6) alkanesulfonyl group, or a salt thereof with an organic or inorganic basic compound. 4. The process of claim 1 wherein the compound of formula (1g) is treated R ^{2 is} C 5 -C 7 cycloalkyl or C 2 -C 6 alkynyl, and substituents R ^1, R ^5, R ⁶ and R ⁷ _and have the same meaning as in 1, or a salt thereof with an organic or inorganic basic compound. A process for the preparation of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer or a pharmaceutically acceptable salt thereof, which comprises: treated with 7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] ^{-3-a'cyl-carbonyloxy-ce!} FAM-4-carboxylic acid, where the acyl is suitably (Ci-C6) alkanesulfonyl or (C 1 -C 6) alkanoyl, or a salt thereof with an organic or inorganic basic compound.