CS217959B2 - Method of preparation of the syn isomere of the 7-substituted-3-cefem or cefam-4-carboxyl acids - Google Patents

Abstract

The present invention relates to a process for preparing a syn isomer 7-substituted-3-cephem or cefam-4-carboxylic acid acids by reaction with 7-amino-3-cephem or a cefam compound with a carboxylic acid acid. The resulting products by of the invention exhibit excellent antimicro- biological effects against different pathogenic species microorganisms, including Gram-positive and gram negative bacteria.

Description

The invention relates to a process for preparing the syn isomer of 7-substituted-3-cep or cefam-4-carboxylic acids which exhibit an antimicrobial effect.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel process for the preparation of novel 7-substituted-3-cephem or cefam-4-carboxylic acids, pharmaceutically acceptable salts thereof and pharmaceutically acceptable bioprecursors thereof. species of pathogenic micro-organisms, including Gram-positive and Gram-negative bacteria.

The prepared isomeric 7-substituted-3-cephem or cefam-4-carboxylic acids according to the process of the invention may be represented by the following general formula (I):

in which

R ¹ represents a thiadlazole group, a thiazolyl group of the general formula

wherein R ⁶ is amino, trihaloC 1 -C 6 alkanamide, C 1 -C 6 alkanamide, or haloacetyl,

A is methylene or -C-

II

N - OR ² wherein R ² represents a hydrogen atom; (C 1 -C 12) alkyl group which may be substituted by halogen, carboxy or C 1 -C 6 alkoxycarbonyl, C 5 -C 7 cycloalkyl; (C 2 -C 6) alkenyl or (C 2 -C 6) alkynyl,

R ³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ⁴ is hydrogen, halogen, C 1 -C 6 alkyl or -O-R ⁷ wherein R ⁷ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanesulfonyl carbon, an arensulfonyl group having 6 to 10 carbon atoms or an alkanoyl group having 1 to 6 carbon atoms,

R ⁵ is a carboxy group or a pharmaceutically acceptable ester, preferably a (C 1 -C 6 -alkanoyloxy (C 1 -C 6) alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl group, and the dotted line indicates an optional double bond between the 3 and 4 position, with the proviso that:

R ⁴ is a hydrogen atom or a group of the formula -O-R ⁷ wherein R ⁷ is as defined above when R ³ is hydrogen;

R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ³ is an alkyl group having 1 to 6 carbon atoms;

- A is a group of formula —C—

N-O-R ² wherein R ² is as defined above when R ¹ is a thiadiazolyl group or a thiazolyl group of the general formula

Wherein R ⁶ is as defined above; a .....

- the dotted line represents a double bond between position 3 and position 4 and R ⁴ is a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms or a group -O-R ⁷ wherein R ⁷ is an alkyl group having 1 to 6 carbon atoms 6 carbon atoms, when R ¹ is haloacetyl, and - R ² is not hydrogen or C 1 -C 6 alkyl, when R ⁴ is halogen or a group of the formula -O-R ⁷ wherein R is ⁷ is an alkyl group having 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof are also prepared according to the process of the invention.

The process according to the invention for the preparation of the syn isomers of the 7-substituted-3-cephem or cefam-4-carboxylic acids of the formula I according to the invention consists in reacting the 7-amino-3-cephem or cepham compound of the general formula. formula li,

wherein R ³ , R ⁴ and R ^{5 are} as previously defined, a reactive amino derivative of the compound or a carboxylic acid salt of the compound of formula III,

R ¹ -A-COOH (III), wherein R ¹ and A are as defined above, with a reactive derivative at the carboxy group of the compound or a salt thereof, optionally followed by:

Reacting the resulting compound wherein R ² is hydrogen with an etherifying agent to give the resulting compound wherein R ² is C 1 -C 12 alkyl, which may be substituted by halogen, carboxy or alkoxycarbonyl C 1 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, or - the resulting compound wherein R ⁶ is trihaloalkanamide containing 2 to 6 carbon atoms; to 6 carbon atoms or alkaneamide group having 1 to 6 carbon atoms, to an elimination reaction trihalogenalkanoylové groups containing 2-6 carbon atoms or alkanoyl groups having 1 to 6 carbon atoms, to give the title compound in which R ⁶ represents an amino group nu, or - reacting the resulting compound wherein R ⁵ is carboxy, or a pharmaceutically acceptable ester, with an esterifying agent, to give the resulting compound wherein R ⁵ is (C 1 -C 6 alkanoyloxy (C 1 -C 6)) an alkoxycarbonyl group or nitrophenyl group (C 1 -C 6 alkoxycarbonyl group), or - converting an ester of the resulting compound wherein R ^{5 is a} pharmaceutically acceptable ester, preferably (C 1 -C 6 alkanoyloxy (C 1 -C 6) alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl, to carboxy to give the title compound, wherein R ⁵ is carboxy.

In a preferred embodiment of the process of the invention, the compound of formula II is reacted in which

R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and

R ³ and R ⁵ have the same meaning as in 1 and the dotted line represents a double bond between the 3 and 4 position, or a reactive derivative of this compound at the amino group, or a salt of this compound with a compound of formula III, wherein

R ¹ represents a thiadiazolyl group or a thiazolyl group of the general formula

wherein R ⁶ is amino, trlhalogenalkanamidová group containing 2-6 carbon atoms or alkanamidoyá group having 1 to 6 carbon atoms, and

A is a group of the formula -ΟΝ-O-R ² wherein R ² represents an alkyl group containing 1-6 carbon atoms, alkenyl radicals containing 2 to 6 carbon atoms, a carboxyalkyl group having 1 to 6 carbon atoms or (C Cejálkoxykarbónyl (C - a C 6 alkyl group or a reactive derivative thereof on the carboxy group or a salt thereof, provided that - R ⁴ is hydrogen, halogen or C 1 -C 6 alkoxy when R ³ is hydrogen, R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ^{3 is an} alkyl group having 1 to 6 carbon atoms, R ² is not an alkyl group having 1 to 6 carbon atoms when R ⁴ is halogen or alkoxy having 1 to 6 carbon atoms.

According to a further preferred embodiment of the process according to the invention, the reaction is reacted

217939 the compound of formula (II) in which they are

R ³ , R ¹ and R ^{5 have the} same substituents as above and the dotted line has the same meaning as above, or a reactive derivative at the amino group of the compound or a salt thereof, with a compound of formula ΙΠ, in which

R ¹ represents a thiazolyl group of the general formula

wherein R ⁶ has already been defined in the preferred embodiment above,

A is a group of formula

-CN-O-R 2 in which R ² is a C 1 -C 6 alkyl group or a reactive derivative thereof on the carboxy group or a salt thereof, provided that - R ⁴ is hydrogen, halogen or alkoxy containing 1 to uhlíku carbon atoms when R ^{3 is} hydrogen, - substituent R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ³ is an alkyl group having 1 to Θ carbon atoms, and - substituent R? is not an alkyl group having 1 to e carbon atoms when R ⁴ is halogen or an alkoxy group having 1 to 0 carbon atoms,

According to a further preferred embodiment of the process of the invention, the compound of formula II is reacted in which:

R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 0 carbon atoms or an alkoxy group having 1 to 6 'carbon atoms,

R ³ and R ⁵ have the same meanings as given in the Summary of the Invention, and the dotted line represents a double bond between the 3rd and 4th positions, or a reactive derivative at the amino group of the compound or a salt thereof with a compound of formula III

R ¹ is a haloacetyl group, and

A is a methylene group, or a reactive derivative thereof on the carboxy group or a salt thereof, provided that: - R ⁴ is hydrogen, halogen or C 1 -C 0 alkoxy when R ³ is an atom and - R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ^{3 is an} alkyl group having 1 to Θ carbon atoms.

According to another preferred embodiment of the process of the invention, the compound of formula II is reacted in which:

R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula -O-R ⁷ wherein R ⁷ is a hydrogen atom or an alkyl group having 1 to 0 carbon atoms,

R ³ and R ⁵ have the same meaning as stated in the Summary of the Invention, and the dotted line represents a double bond between the 3 and 4 position, or a reactive derivative of this compound at the amino group or a salt thereof with a compound of formula III

A represents a group of the general formula

-CN-OR ² wherein R ² is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, carboxy (C 1 -C 6) alkyl or (C 1 -C 6) alkoxycarbonylf C 1 -C 6 an alkyl group, and

R 1 is a thiadiazolyl group or a group of the formula

wherein R ⁶ has the same meaning as in Part 1, or with a reactive derivative thereof on the carboxy group or a salt thereof, provided that - R ⁴ is hydrogen, halogen or a group of the formula -O-R ⁷ .

wherein R ⁷ is hydrogen or C 1 -C 6 alkyl when R ³ is hydrogen, R ⁴ is C 1 -C 6 alkyl when R ³ is C 1 -C 6 alkyl; - R ⁴ is -O-R ⁷ .

in which R ⁷ is hydrogen, in the case where the proviso that both R ² is an alkyl group containing 1-6 carbon atoms, alkenyl of 1-6 carbon atoms ^-1, carboxy (Ci-- Cejalkylová group or a (Ci-Ce alkoxycarbonyl, j (C 1 -C 6 alkyl, and - R ² is not hydrogen when R ⁴ is halo or skuphia of the formula:

—O — R ⁷ wherein R ⁷ is an alkyl group having 1 to 6 carbon atoms.

According to a further preferred embodiment of the process according to the invention, the compound of formula II is reacted in which:

R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula -O-R ⁷ wherein R ⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ³ and R ⁵ have the same meaning as described in the Summary of the Invention, and the dotted line represents a double bond between the 3 and 4 position, or a reactive derivative of this compound at the amino group or a salt thereof, with a compound of formula III, in which

R ¹ represents a thiadiazolyl or thiazolyl group of the general formula:

—O — R ⁷ in which, represents R ⁷ . a hydrogen atom or an alkyl group having 1 to 6 carbon atoms when R ³ is a hydrogen atom;

R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ³ is an alkyl group having 1 to 6 carbon atoms.

According to another preferred embodiment of the process of the invention, the reaction is reacted with 7-amino-3-cephem-4-carboxylic acid, an amino-reactive derivative thereof, or a salt thereof with 2- (2-aminothiazol-4-yl) -2-acid. -.methoxyimi-. non-acetic acid in the form of the syn isomer, with a reactive derivative thereof or a salt thereof, to give 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of syn an isomer or a pharmaceutically acceptable salt thereof ^;

The novel cephem and cepham compounds of formula (I) prepared by the above process of the invention, as well as preferred embodiments of the process, can be used as antimicrobial agents as well as compounds which are intermediate products in the process of preparing other antimicrobial agents, will be shown - below.

The compounds of the present invention which can be used as antimicrobial agents can be represented by the following general formula:

wherein R ^{6 has the} same meaning as essentially described herein; and

A is a group of formula —C—

II

N-O-R ² wherein R ² is a cycloalkyl group containing 5-7 carbon atoms or alkynyl having 2 to 6 carbon atoms, or a reactive derivative thereof at the carboxy group or a salt thereof, with the proviso that: - R R ⁴ is hydrogen, halogen, or a group of the formula wherein:

_And R ⁴ represents a thiazolyl or thiadiazolyl structure of Formula

wherein R ⁶ 'is amino or protected amino or haloacetyl,

R ² 'represents a hydrogen atom or an aliphatic hydrocarbon radical which may be substituted by halogen, carboxy or esterified carboxy,

217

R ³ 'is hydrogen or lower alkyl,

R ⁴ 'is hydrogen, halogen, lower alkyl or a group of the formula:

-O-R ⁷ 'in which

R ⁷ 'represents hydrogen, or a lower alkyl group or an acyl group,

R ⁵ 'is a carboxy group or a functionally modified carboxy group, and the dashed line represents the 3-cephem or cepham core.

The compounds which can be used as intermediates for the preparation of the abovementioned compounds of the general formula (mohou) can be represented by the following general formula (I ');

in which

R _c ^x represents a thiadiazolyl or thiazolyl group of the general formula

in which

R ⁴ _b represents a haloacetyl group,

_And R ⁴ is hydrogen, halogen, lower alkyl or a group of the formula

O-R ⁷ "wherein R ⁷ " represents a lower alkyl group, and

R ³ , R ⁵ and A are substituents as defined above.

Furthermore, it should be noted that compounds of formula Γ in which R _and ⁴ represent the thlazolyl structure of formula

R in which

R ⁶ 'is a protected amino group,

R ⁴ 'is a group of the formula -O-R ⁷ wherein R ⁷ ' is hydrogen or acyl, and / or

R ⁵ 'is a functionally modified carboxy group, and is also a useful product for the preparation of a more active compound of the invention, as discussed below.

The most advantageous product

R ^2, R ³ and R ^₄ are substituents as previously defined.

the particular terms and definitions of the substituents that have been used to characterize compounds according to alternative embodiments of the process of the invention will be further specified in the following:

a) Partial structure of the general formula R ¹ —C — CO—

N

O-R ² herein denotes both the geometric forms, namely:

Ri — C — CO—

N-O-R ² (S) and

R1-C-COR2-O-N (Aj

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

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

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

bj As regards the thiazolyl group of the formula

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

in terms of simplification of the description and definition of the invention.

c) It is also known that a 3-hydroxy-3-cephem compound having a partial structure represented by the general formula

becomes the tautomeric form, i.e., to the 3-oxocepham compound of formula:

wherein R ⁶ 'is imino or protected imino.

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

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

Accordingly, it is apparent 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 as regards 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 invention, both forms being referred to by only one term "thiazolyl group" and represented by the general formula

wherein R ⁶ is as defined above. referred to as the enol- or keto-tautomer, and the enol-tautomer is usually a more stable form.

In view of the above, it should be noted that both compounds containing the aforementioned tautomeric structures are within the scope of the present invention and are included in a single structure, indicating that, for simplicity, the structure and nomenclature of these tautomers are expressed. with only one term, i.e., a stable enol tautomer, i.e., a 3-hydroxy-3-cep compound, as used throughout the specification and in the definition of the subject matter.

Numerous terms and definitions are set forth above and the following description, illustrative of which will give practical examples of terms for each of the alternative embodiments of the preparation process of the invention and 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" in the case of R ¹ may be 1,2,3-thiadiazolyl (i.e. 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazol-5-yl), further 1,3 4-thiadiazolyl or 1,2,4-thiadiazolyl, preferably 1,2,3-thiadiazolyl, and most preferably 1,2,3-thiadiazol-4-yl.

The 'aliphatic hydrocarbon residue' referred to in the alternative

217939 for R ² , the monovalent substituent of a saturated or unsaturated and straight, branched or cyclic aliphatic hydrocarbon may be alkyl, alkenyl, alkynyl, cycloalkyl, and optionally, detailed terms discussed in the following.

By "alkyl" is meant, in alternative embodiments of the invention, a straight or branched alkane radical containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isoproipyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyloxy, decyl, undecyl, dodecyl, and the like, preferably a lower alkyl group and more preferably a C 1 -C 4 alkyl group.

The term "alkenyl" as used herein refers to a straight or branched alkene radical containing up to 12 carbon atoms, preferably a lower alkenyl such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, 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 having a maximum of 12 carbon atoms, and preferably a lower alkynyl such as ethnyl, propargyl, 1-propynyl, 3-butynyl, 2-butynyl, 4 pentinyl, 3-pentynyl, 2-pentynyl, 1-pentynyl, 5-hexynyl and the like, more preferably an alkynyl group containing up to 4 carbon atoms is used according to the invention.

The term "cycloalkyl" refers to a cycloialcan 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, "an aliphatic hydrocarbon radical substituted by a halogen atom or halogen atoms, a carboxy group or an esterification by a carboxy group or groups" may also be alternatively referred to as a "halogen substituted aliphatic hydrocarbon radical", "a carboxy substituted aliphatic hydrocarbon radical"

And " esterified carboxy substituted aliphatic hydrocarbon radical " which may be, for example, haloalkyl, alkenyl, alkynyl and cycloalkyl, cartooxyalkyl, alkenyl, alkynyl and cycloalkyl, and esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl.

Suitable examples of "halogen" include chlorine, bromine, iodine and fluorine, suitable examples of "esterified carboxy" include alkoxycarbtanyl 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-trifluoromethyl; uoroethyl, 3-chloropropyl, 4-iodobutyl, 5-fluorarpentyl, 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, tert-butoxycarbonylmethyl, 2-ethoxycarbonylmethyl, 2-ethoxycarbonylmethyl, 2-ethoxycarbonylmethyl, 2-ethoxycarbonylmethyl) ethoxycarbonylbutyl, 1-tert-butoxycarbonylisopropyl, 1-tert-butoxycarbonyl-1-methylpropyl, 4-t-butoxycarbonylbutyl, 5-tert-butoxycarbonylpentyl, 6-butoxycarbonylhexyl, etc., further lower alkoxy (e.g. methoxycarbonylallyl, etc., a lower alkoxycarbonyl (lower) alkynyl group (such as a 3-methoxycarbonylpropargyl group, etc.), a lower alkoxycarbonyl (lower) cycloalkyl group (such as a 4-methoxycarbonylcyclohexyloxy group, etc.) or the like The lower alkoxycarbonylmethyl group is exemplified above.

The term "lower alkyl" in the case of R ³ , R ⁴ and R ⁷ for an alternative embodiment of the preparation process of the present invention refers to the group already exemplified in connection with the term aliphatic hydrocarbon radical in the case of R ² for alternative and is preferably an alkyl group containing up to 4 carbon atoms per molecule, and most preferably a methyl group.

The term "halogen" in the case of the substituent R ⁴ means chlorine, bromine, iodine or fluorine, preferably halogen is chlorine or bromine.

The term " acyl group " in the case of R < ⁷ > for an alternative embodiment of the present invention refers to a lower alkanoyl group (such as formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl etc.); a group etc., a lower alkanesulfonyl group (such as mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propanesulfonyl, butanesulfonyl, etc.), an arensulfonyl group (such as benzenesulfonyl, tosyl, etc.), or the like.

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 alkyl group such as benzyl, benzhydryl, trityl, 4-inethoxybenzyl, 3,4-dimethoxybenzyl, etc., halogen (lower (alkyl, such as trichloromethyl, trichloroethyl, trifluoromethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidenoic, substituted aralkylidene substituted cycloalkylidene, acyl or the like.

The aforementioned suitable acyl group for a protecting group in an alternative embodiment of the process of the invention 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, l-cyklopropylethoxykarbonylová, isopropoxycarbonyl, butoxycarbonyl, terc.butoxykarboinylová, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxykarbonylqvá, trichloroethoxycarbonyl, 2-pyridylmethoxycarbonyl atd.j further substituted or unsubstituted ar (lower jalkoxykarbonylová group (e.g. a group banzyloxykarbonylová , berizhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc., and a lower cycloalkoxycarbonyl group (such as a cyclopentyl group) oxycarbonyl, cyclohexyloxycarbonyl, succimyl, phthaloyl or the like).

Further, the reaction product of a silane, boron, aluminum or phosphorus compound may 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, phenylphosphorus bromide, or the like.

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

Suitable examples of ester groups include:

An alkyl ester group such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, heptyl ester, octyl ester, 1-cyclopropyl ether;

An alkenyl ester group such as a vinyl ester group, an allyl ester group etc .;

An alkynyl ester group such as ethinyl ester, propynyl ester etc .;

An alkoxyalkyl ester group such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester etc .;

An alkylthioalkyl ester group such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester etc .;

A haloigenalkyl ester group such as 2-iodoethyl, 2,2,2-trichloroethyl ester, etc .;

An alkanoyloxyalkyl ester group, such as, for example, the acetoxymelthyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl estero217959

1Sa, pivaloyloxymethyl ester, hexanoyloxymethyl ether, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ethyl ester etc .;

An alkanesulfonylalkyl ester group such as mesylmethyl ester, 2-mexyl ethyl ester, etc .;

A substituted or unsubstituted aralkyl ester group such as, for example, benzyl, 4-methoxybenzyl, 4-nitroibenzyl, phenethyl, trityl, benzhydryl ester, bisi (methoxyphenyl methyl ether, 3,4-dimethoxybenzyl ester, 3,4-dimethoxybenzyl ester). butylbenzyl ester etc .;

A substituted or unsubstituted aryl ester group such as phenyl, tolylester, tert-butylphenyl, xylyl, mesitylester, cumenyl, salicylester, etc .;

An ester of a silyl compound such as a trialkylsilyl compound, a di-alkylalkoxysilyl or a trialkoxyslyl group, for example a trialkylsilyl ester group (such as a trimethylsilyl ester, triethylsilyl ester etc.), a dialkylalkoxysilyl ester group, a dimethylethoxysilyl esterlyilyl ester group, diethylmethoxyl ester; , trietboxysilyl ester, etc.) or similar other groups.

With respect to the "protected amino group" for the substituent R ⁶ and the "functional modified carboxy" for the substituent R ⁵ 'for an alternative embodiment of the process of the invention, it should be noted that these groups are of great importance not only in the synthetic however, they also affect the physiological and pharmaceutical properties of the compounds of the 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 this process can be converted to a "protected amino group" and / neibo to a "functionally modified carboxy group""As mentioned above, before carrying out the preparation itself, to avoid any possible side reactions of the netoo 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, as regards the physiological and pharmacological properties of the compounds of the invention, it should be noted that compounds containing an "protected amino group" can be used to improve properties such as solubility, stability, absorbency, toxicity, partially active of the compounds of the invention which contain a free amino and / or carboxy group.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be a conventional non-toxic salt, including inorganic basic compounds or acids such as a metal salt such as an alkali metal salt (e.g., sodium salt). , potassium salt, etc.), and alkaline earth metal salts (such as calcium salt, magnesium salt, etc.), ammonium salt, inorganic acid salt (such as chloride, bromide, sulfate, phosphate, carbonate, bicarbonate, etc.) a salt with an organic basic compound or acid, for example, an amine salt (such as trimethylamine, triethylamine, pyridine, procaine, picoline, dicyclohexylamine, N, N'-dibemzylethylenedlamine, N-methylglucamine, diethanolamine, triethanolamine, tris (hydroxymethylamino) meithane, phenethylbenzylamine, etc.); 1 with an organic carboxylic acid, or with a sulfonic acid (such as acetate, maleate, lactate, tartrate, mesylate, benzenesulfonate, tosylate, etc.), a salt with a basic or acidic amino acid (such as arginine salt, aspartic acid salt, with glutamic acid, lysic acid, serine, 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. In this context, the term "pharmaceutically acceptable biopresursor" as used herein refers essentially to all modified derivatives having a structural formula different from that of the active compound of the invention, but converted to the active form in the patient's body after drug administration. to form a compound of the invention, and also refers to derivatives, which in some cases are physiologically derived from the compounds of the invention, to be produced in the body of the patient and exhibit an antimicrobial effect.

The process for the preparation of the compounds of the invention may be illustrated by the following schemes:

Procedure C: elimination of the amino protecting group

wherein in the above schemes it means:

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

R _b ⁴ is a halogen atom,

_And R ⁵ is carboxy esterifikovainá,

R _b ⁵ is a functionally modified keto group,

R _and ⁶ are protected amino,

_And R ⁷ is an acyl group,

Ri, Ra ^1, Rb ^1, R 2, R ^3, R ^4, R ⁴ _and R ⁵ and A have meaning as previously uveidený.

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

Procedure A: N-acylation

In this embodiment, a compound of formula I and a salt thereof may be prepared by reacting a 7-amino-3-cephem (or cefam) compound of formula II, a reactive amino derivative thereof, or a carboxylic acid salt of the compound of formula III with a reactive derivative thereof. at the carboxyl group or salts thereof, the reaction being carried out in a conventional manner, by the so-called amidation reaction, which is commonly known in the chemistry of β-lactamous compounds.

The starting compounds of the formula (III) are both known and novel compounds, and the novel compounds of formula (III) can be prepared by a process which will be described in more detail below.

A suitable reactive derivative of a compound of formula II on an amiradium group may be a conventional reactive derivative that is commonly used in various kinds of amidation reactions, such as an isocyanate derivative, an isothiocyanate derivative, a derivative prepared by reacting a compound of formula II with a silyl compound (e.g. trimethylsilylacetamide). , bis (trimethylsilyl / acetamide, etc.), with an aldehyde compound (such as acetaldehyde, isopenltaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobeinzlaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, corresponding to hydroxynaphthaldehyde, furfuralthaldehyde, furfuralthaldehyde, furfuralthaldehyde, furfuralthaldehyde, furfuralthaldehyde, furfuralthaldehyde). hydrates, acetals, hemiacetates or enolates thereof, with a ketone compound (such as acetone, methyl ethyl ketone, methyl isobutyrketone, acetylacetoin, ethyl acetoacetate, etc., or the corresponding ketal, hemiketal, or enolate thereof enyne) with a phosphorus compound (e.g. phosphorus oxychloride, phosphorus trichloride etc.) or with a sulfur compound (e.g. thionyl chloride, etc.), or other similar compound.

A suitable salt of the compound of formula II may be a salt exemplified by the compound of formula I.

A suitable reactive derivative on the carboxy group of a compound of formula (III) may be, for example, an acid halide, acid anhydride, activated amide, active ester, and the like, with an acid halide such as acid chloride, acid bromide, it may be a mixed acid anhydride such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphoric acid, sulfuric, sulfuric, thiosulphic, alkylcarboxylic, such as aliphatic carboxylic acid pivalic acid, valeric acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acids (such as benzoic acid, etc.), furthermore it may be symmetrical acid anhydride, active amide acids with imidazole, 4-suibstituted imidazole, dlmethylpyrazole, triazole or tetrazole, further may be an active ester [such as cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, frichlorophenyl ester, pentachlorophenyl ester, , phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolylthioester, ester with N-hydroxy compound such as N, N-dimethylhydroxylamine, 1-hydroxy-2- (1) -hydroxy-2- (1) hydroxy-2- (1) pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.] and the like.

In particular, a suitable reactive derivative of the compounds of formulas II and III may be selected from the above compounds according to the kind of compound of formulas II and III practically used and the reaction conditions.

A suitable salt of the compound of formula (III) may be a salt with an inorganic basic compound such as an alkali metal salt (such as sodium, potassium, etc.) and an alkaline earth metal salt (such as calcium, magnesium, etc.); with an organic basic compound such as a tertiary amine (such as, for example, trimethylamine salt, triethylamine, Ν, Ν-dimethylaniline, pyridine, etc.), an inorganic acid salt (such as hydrochloric acid, hydrobromic acid, etc.) and the like .

The above reaction of the invention is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other solvent, which do not adversely affect the reaction, or optionally a mixture of said solvents.

When the acylating agent of formula III is used in the free acid or salt form of the reaction, the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound [e.g., N, N'-dicyclohexylcarbodiimide, N- cyclohexyl-N-morpholinoeithylcarbodiimide, N-cyclohexyl-N'- (4-diethylaminocytoclohexyl) carbodiimide, N, N'-diethylcarhodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N- (3-dimethylaminopropyljcarbodiimide etc.), furthermore in the presence of a bisimidazolide compound [such as N, N-carbonylbis (2-methylimidazole) etc.], further in the presence of an imine compound (such as pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine etc.), further in the presence of olefinic or an acetylenic ether (such as ethoxyacetylene, β-chloro vinylethylether, etc.), further in the presence of 1- (4-chlorobenzenesulfonyl) -6-chloro-1H-benzotriazole, N-ethylbenzisoxa zoliové salts, ^{N-sthyl-5-phenylisoxazolium-3!} sulfonyl] benzene sulfonate, a phosphorus compound (e.g. polyphosphoric acid, trialkyl phosphite, ethylpolyfosforečnan, isopropylpolyfosfoírečnan ^OX: phosphorus pentachloride, phosphorus trichloride, diethylchlorfosforitan, orthofenylenchlorfosfcritan etc.), in the presence of thionyl chloride, oxalyl chloride, a Vilsmeier reagent, which is prepared by reacting dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene or the like.

Regarding the geometry of the compounds of formula I, wherein substituent A is a group of formula

-C ~

II

N (referred to herein as the " oxyimine compound " of formula (I)) prepared by the process of the invention should be noted that there is stereoselectivity between the syn and the anti isomer as described below.

When the reaction according to the invention is carried out with a compound of the formula II or a reactive derivative thereof at the amino group or a salt thereof and with a compound of the formula III, in which A represents a group of the formula:

-CII

N (referred to herein as the "oxyimine acylating agent of formula III) in the presence of a condensing agent such as phosphorus pentachloride, thionyl chloride, etc., then predominantly forms the main product of the anti-isomer of the oxyimine compound of formula I in the above reaction; the corresponding syn isomer of this compound is very difficult to isolate from the reaction product, even though the syn isomer of the oxyimine acylation reagent of formula III was used. It will be appreciated that the tendency to said isomerization in the reaction carried out in the above manner occurs therefore; The less stable syn isomer tends to isomerize partially or completely to the corresponding more stable anti isomer during the above reaction, for example during the so-called activation phase of the oxime acylating agent of formula III, resulting in the more stable isomer being isolated from the reaction product. i.e., the anti-isomer of the oximine compound of formula (I) as the final product.

In view of the above, and in an effort to obtain the syn isomer of the oximine compound of formula I in a selective manner and in high yield, preferably the syn isomer of the oximine acylating agent of formula III is used and the reaction is carried out from and under predetermined conditions. . This means that the syn isomer of the oximine compound of formula (I) can be obtained in a selective manner and in high yield by reacting a compound of formula (II) with the syn isomer of the oximine acylating agent III, for example in the presence of a Vilsmeier reagent. under approximately neutral conditions.

The compound of formula (I) and the salt thereof can be used as an antimicrobial agent, and some of these compounds can also be used as starting materials in the subsequent stages of the process.

Procedure B: etherification

The compound of formula (Ic) and a salt thereof may be prepared by reacting a compound of formula (V) or a salt thereof with an etherification agent.

The starting compound of formula (V) corresponds to a compound of formula (I) in which A is a n-hydroxyiminomethylene group, which compound may be prepared as described above for phases A and B and may also be prepared according to hereafter referred to as phase D.

suitable examples of an etherifying agent include conventional alkylating agents such as dialkyl sulfide (e.g., dimethyl sulfate, diethylsulfate, etc.), a diazoalkane (e.g., diazomethane, diazoethane, etc.), an alkyl halide (e.g., methyl iodide, ethyl iodide, ethyl bromide, etc.). alkyl sulfonate (such as methyl tosylate, etc.), and the corresponding alkenylating, alkynylating or cycloalkylating agents in which 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.), (such as propargylbnomide, etc.), a cycloalkyl halide (such as cyclohexylbromide, etc.), a lower alkoxycarbonylalkyl halide (such as ethoxycarbonylmethyl iodide, etc.) and the like.

When diazoalkane is used as an etherification agent in the above reaction, the reaction is generally 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 of from cooling to ambient temperature.

In the case where 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 which does not adversely affect the above reaction at temperatures ranging from a cooling temperature to a heating temperature, and preferably a process according to 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 procedure indicated below.

Some of the compounds of formula (Ic) and salts thereof may be used as antimicrobial agents, see below.

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

Procedure C

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 the formula:

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

cO-R ^z in which the substituent R ² has already been defined above, which compound can be prepared, for example, by the aforementioned procedure referred to as phase A.

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

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

Particular attention should be paid to hydrolysis using an acid, which is one of the most widely used and preferred methods for deprotection, which may be, for example, an acyl group such as a substituted or unsubstituted lower alkanoyl group, substituted or unsubstituted lower group. alkoxycarbonyl, substituted or unsubstituted ar (lower jalkoxycarbonyl, lower cycloalkoxycarbonyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloalkylidene or the like, and especially those already mentioned in connection with N -protecting group.

Examples of suitable acids for carrying out the above acid hydrolysis include inorganic or organic acids such as formic, trifluoroacetic, benzenesulfonic, p-toluenesulfonic, hydrochloric, cation exchange resins and the like. In a preferred embodiment of the process of the 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 trifluoroacetic acid, hydrochloric acid or the like. 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 carried out in the presence or absence of a solvent. A suitable solvent for carrying out this reaction may be a conventional organic solvent, water or a mixture thereof which does not adversely affect the above reaction. In particular, it should be noted that when the hydrolysis is carried out with trifluoroacetic acid, the reaction can be accelerated by the addition of anisole.

Hydrolysis using a basic compound can 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 (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkaline carbonate, etc. a metal (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.), an alkaline metal phosphate soils (such as magnesium phosphate, calcium phosphate, etc.), alkali metal phosphate in the form of hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc.), or the like, and other organic compounds such as for example an alkali metal acetate (such as sodium acetate, potassium acetate, etc.), a trialkylamine (such as trimethylamide, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3, O] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [5.4.0] -7-undecene, an anion exchange resin or the like. 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 divalent acyl group, for example a succinyl group, a phthaloyl group or the like.

Hydrolysis carried out using a reduction may be applied in cases of elimination of such a protecting group such as an acyl group, for example halogen (lower alkoxycarbonyl group (such as trichloroethoxycarbonyl, etc.), substituted or unsubstituted arj lower alkoxycarbonyl group (such as benzyloxycarbonyl) , p-nitrobenzyloxycarbonyl, etc.], 2-pyridylmethoxycarbonyl, etc., an aralkyl group (such as, for example, benzyl, benzhydryl, trityl, etc.), and the like. for example using an alkali metal borohydride (such as sodium borohydride, etc.), followed by conventional catalytic hydrogenolysis and the like.

It should further be noted that such protecting groups, such as, for example, halogeno-lower alkoxycarbonyl or 8-quinolyloxycarbonyl, can be eliminated by treatment with heavy metals such as copper, zinc or the like other metals.

217939

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 encompasses cases where a functionally modified carboxy group in the case of the substituent R ^{5 is} simultaneously converted to a free carboxy group during the above reaction or during post-reaction processing.

Regarding this step, it is evident that the aim of this phase is to prepare a universally active compound of formula I in which represents ^Rg1 amlnothlazolyloVou group, which in this procedure eliminates the protective group from a protected amino compound of formula VIII, which are prepared by procedures mentioned above and at the same time the procedures which will be described below.

Procedure D: esterification

An ester compound of formula (Ij) and a salt thereof are prepared, improving the chemical, physiological and / or pharmaceutical properties of the corresponding compound of formula (XII) with a free carboxy group corresponding to a 3-cephem compound of formula (I) wherein R is 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 eaterifying agent.

Preferably, the carboxy-reactive derivative of the compound of formula (XII) is a derivative already exemplified in connection with the compound of formula (III) in the process designated A.

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

A suitable example of a hydroxy compound is a substituted or unsubstituted alcohol, such as an alkanol, aralkanol, arenol or the like, especially a substituted alcohol, such as an alkanoyloxy-lower-alkanol (such as acetoxymethanol, propionyloxymethanol, butyryloxymethanol). pentanoyloxymethanol, hexanoyloxymethanol, acetoxymethanol, propionyloxyethanol, butyryloxyethanol, pentanoyloxyethanol, hexanoyloxyethanol, acetoxypropanol, propionyloxypropanol, hexanoyloxypropanol, hexanoyloxyhexanol, palmitoyloxymethanol, etc.), for example, halogen (lower) monochloroethanol, such as di-trichloroethanol; 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, arenesulfonate, or hydroxy salt, diazoalkane, diazoaralkane, and other compounds.

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

A preferred alkane sulfonate 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, sodium, potassium salt or the like.

Preferred diazoalkane and diazoaralkane may be, for example, diazomethane, diazoethane, diazopropane, diphenyldiazo, methane 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, at temperatures varying from the cooling temperature to the heating temperature. Liquid hydroxy compounds can also be used as solvents in the above reaction.

The above reaction is preferably carried out in the presence of an inorganic or organic basic compound, an example of which is given in connection with the process referred to as process C.

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

(a) a compound of formula (XII) or a salt thereof with a phenol or a phenol salt in the presence. a condensing agent, exemplified in the above procedures, for example in Process A, 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 of a compound of formula XII in which A is a group of the formula:

_ _C in which R ² represents an aliphatic hydrocarbon residue substituted by carboxy is used as starting compound of .the given reaction, then moížno said esterified carboxy group also depending on the reagent and reaction conditions, and in this embodiment also falls within the scope of the invention.

Further, when a 2-cephem compound corresponding to a compound of formula I is prepared, said 2-cephem compound may be converted to a 3-cephem compound of formula I by oxidation and then reduction of the resulting S-oxide compound. in the usual way. This embodiment is also within the scope of the invention.

Procedure E: formation of the carboxy compound

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

wherein R ^{1 is a} thidiazolyl group of the general formula

where R ⁶ is as defined the above, and A is a group of the formula

-cII

OR ² 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) is particularly evident in the synthetic preparation of the chemical processes described above.

The above process is accomplished by converting a functionally modified carboxy group in the starting compound of formula (XIII) to a free carboxy group, preferably the functionally modified carboxy group for Rb ⁵ in compound XIII is an esterified carboxy group exemplified. 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 the above process, designated C, wherein the acid hydrolysis or hydrolysis with the basic compound may be carried out in a manner similar to that described in Procedure C.

Examples of suitable enzymes are esterase and esterase preparations which exhibit esterase activity, such as a culture medium of a microorganism or 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 kinds of microorganisms, and can be isolated very easily from a sample of soil and other sources and other sources by conventional means, and can also be isolated from stored cultures which are available to an unlimited circle of people in collections. microorganisms such as:

ATCC (American Type Culture Colectlon)

Maryland, USA)

IAM (Institute of Applied Microbiology,

University of Tokyo, Japan),

IFO (Institute for Fermeritation, Osaka,

Japan),

IID (The Institute for Infectious Diseases,

University of Tokyo, Tokyo, Japan), CBS (CentraaTbureau voor Schimmelcultures, Bearn, The Netherlands),

FERM (Fermentation Research Institute)

Agency of Industrial Science and Technology, Chiba, Japan);

NRRL (Northern Utilization Research &

Development Division, U.S. Department of Agriculture, Illinois, USA) and the like.

For microorganisms exhibiting esterase activity, for example, microorganisms belonging to the genera Bacillus, Corynebacterium, Micrococcus, Flavobacterium, Salmonella, Staphylococcus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azobacter, Alcaligenes, Rhizobium, Rhizobium, Rhizobium, Proteus, Sarcina, Pseudomonas, Xanthomonas, Protaminobacter, Comamonus and the like.

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

Azotobacter vinelandii IAM-1078

Escherichia coti IAM-1101

Rhizobium japonicum IAM-0001

Vibrio metchnikovii IAM-1039

Brevibacterium helvolum IAM-1637, Protaminobacter alboflavum IAM-1040, Cotnamorias terrigena IFO-12 685,

Sarcina lutea IAM-1099

Pseudomonas schuylkilliensis IAM-1055, Xarithomonas trifolii ATCC-12 287, and the like.

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, where 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 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 microorganisms 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 which exhibits an esterase activity that is processed in a conventional manner in order to increase its esterase activity.

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

In the case where the activity is mainly concentrated in the cells, then, for example, the following preparations may be used 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 material containing the raw cells in a conventional manner, such as lyophilization and vacuum drying;

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

4. enzyme solution: obtained by purifying ne217959 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 purification or partial purification of 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 solution (such as a phosphate buffer, etc.), and preferably This means that 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 (e.g., supernatant, filtrate, enzyme solution, etc.). or into a solution or suspension of the culture medium or its processed biomass in an aqueous medium.

The preferred pH of the reaction mixture, concentration of substrate, reaction time and reaction temperature may vary with the characteristics of the culture medium with the characteristics or its processed material to be used in a given case, ^or! with the characteristics and properties of the compound of formula (XIII) to be used in the present case. However, the following preferred reaction conditions are preferred: pH is 6 to 8, temperature is 20 to 50 ° C, and more preferably 25 to 35 ° C C, and the reaction time ranges 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 of the process according to the invention can be carried out in a manner similar to that described in process C above.

The process of the invention also encompasses those cases where the protecting group in the protected amino group for the substituent R ⁶ , which is a substituent on the thliiazolyl group for the substituent R ¹ , is eliminated and / or esterified with a C ^1-6 carboxy group. The residue of the substituent R ² relating to group A is converted to the free carboxy group during 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.

Among the present compounds of formula (I), mention may be made in particular of a compound of formula (I '), a pharmaceutically acceptable salt thereof and a precursor thereof, which exhibit high antimicrobial activity in inhibiting growth of various species of pathogenic microorganisms including Gram positive and Gram negative bacteria. these compounds may be advantageously used as antimicrobial agents.

Further, the compounds of formula (T) and salts thereof are novel and preferred intermediate products for the preparation of active compounds of formula (Γ), pharmaceutically acceptable salts of the compounds or bioprecursors thereof.

In particular, the following compounds can be prepared according to the above procedures:

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

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

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

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) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-methoxyimmoacetamido) -3-methoxyloxy-3-eephem-4-carboxylic acid (syn isomer),

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

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

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

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

7- (2- (2-amino-4-thiazolyl) -2-propoxyimino217959 acetamido) -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-butoxyiminoacetamido] -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-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiaisolyl) -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-carbexymethoxyiminoacetamido) -3-eephem-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-thiazolyl) -2- (2,2,2-trifluoroethoxyimino) acetamido) -3-cephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2- (2-trifluoromethylimino) acetamide) -3-eephem-4-carboxylic acid (syn isomer),

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

7- (2- (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 (aka Isomer),

7- (2- (2-amino-4-thiazolyl) -2-n-octyloxyiminoacetamido) -3-cephem-4-carbaxyl acid,

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

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

7- (2- (1,2,3-thiadiazol-4-yl) -2-n-hexyloxyiminoacetamide) -3-methyl-4-carboxylic acid (syn isomer),

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

7- (2- (2-amino-4-thiazolyl) -2-n-butoxyiminoacetamido) -3-methoxy-3-eephem-4-carboxylic acid (syn isomer),

7- (2- (2-amino-4-thiazolyl) -2-propargyloxylminoacetamido) -3-methoxy-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-nitrobenzyl 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylate (syn isomer),

4-nitrobenzyl 7- (2- (2-amino-4-thiazolyl) -2-methoxyimineacetamido) -3-hydroxy-3-cephem-4-carboxylate (syn isomer),

4-nitro-benzyl 7- (2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido) -3-hydroxy-3-eephem-4-carboxylate (syn isbmer),

4-nitrobenzyl 7- (2- (2-amino-4-thiazolyl) -2-n-propoxyiminoacetamido) -3-hydroxy-3-cephem-4-carboxylate (syn isomer),

4-nitrobenzyl 7- (2- (2-amino-4-thiazolyl) -2-isobutoxyiminoacetaniido) -3-hydroxy-3-cephem-4-carbexylate (syn isomer), and the corresponding salts thereof, such as for example:

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

Calcium 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-catboxylate (syn isomer),

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

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

217953

1. In vitro antibacterial activity (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-soy medium was plated on cardiac muscle infusion agar (Hi-agar) containing increasing concentrations of test compounds and incubated at 37 ° C. for 20 hours. The minimum inhibitory concentration (MIC) was expressed in µg / ml.

(2) Test compounds

C.

C.

1 ... 7- [2- (2-amino-4-thiazolyl) -2-methoxyamino-naphthamido] -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-ethoxyiminoacetamldo] -3-cephem-4-carboxylic acid (syn isomer),

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

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

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

... 7- [2- (2-amino-4-thiazolyl) -2-propargyloxyiminoacetamido] -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-thiazolyl) -2m < 7 & gt _; y.

- hexyloxyiminoacotamido] -3-cephem-4-carboxylic acid (syn isomer);

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

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

what you want

Φ> u tí

O ω

CU>.

C th c-1

Ό>.

«3

Q3 'f cfl>>

β ca>

o <4 = *

W ω

And in 10 ó co cm cm cm in cm «o <o o rd © © co

VII VII VII co 05 in

WHAT O CM CM © * o o * * * in CD CM CM o o cm o o o * o * CT O "

VII VII ©

ιό CM 05 CM rH 10 CO <3 t O O CM * O O O ** VII

10 10 CO 10 CM CM CM th o o co o o o o o o o o o 03 03

VII VII in the US CM CM CM CM CM CO (© <3 co C) ´ Cj ^ 0 CO

Vij vil Vil Vil © CO in © rd rd

VII © m in cm rd ©

VII what about 10 rH rd CO

Vil co o in co eo> i-To *

VII m in CO rd

CO co uo O * rd * in co CM VO lO ^ CM ^ O CD CM rd * O © O * O *

VII

VO © CM © rd O rd CM r-Γ © * O * © O *

VII © CO 00 © © CO rH 'co in d o * o r-T © 10 UO ^ CM rd © ©

rd CM *

VII rd ©

CMό 'rd CM

VII rd ca a

0)> o β

about what

© © © © © Ó CM ^ L · ^ r-Γ rd * O * O * O * © CO © ©

CO rd CO OJ ^ IO * CO O * © rd *

CMό Ιό Ιό CM CM CM CM U0 ~ rH θ 'O_ θ' rd * O * © * o * o *

VII VII VII

0m ©

O

CM cn β

ω (-1 β

ca ω

β ο

ο ο

ο ο

ΛΟ CO · ->

CM

Λ $

Η—> ’'

Ε 4 ► — I <

^Μ I — I

0 ° 0 § ’- <

Ε ω © ©

U0 10 ^ rd * CM *

VII rH

CO CO rd 'oo CO * © CO ICH rd * CO *

VII β

% of those οο β

Š β

. & 0 β β β β-H Qj f- <

sgca-g

β.2 Φ w β

Ο Φ--i ιό ω

β φ

ο

Μ φ

ω ρ ~

5 Ο S -f the third S-ι

O ® Z ρ f-ι tfl Φ CO W Λ M Ph fL CZ5 .2. Protective effect against experimental infection in mice (1) Test method

Male ICR mice, 4 weeks old, each subject weighing between 18.5 and 21.5 g, were concentrated into groups of 10 individuals. Test bacteria were grown overnight at 37 ° C in trypticase-soy agar and then suspended in 5% nucin 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 to the aforementioned mice at various doses, one hour after cell separation. ED 50 values were determined based on the number of surviving mice observed for each dose after four days.

(2) Test compounds

C.

1- ... 7- [2- (2-amino-4-thiazolyl) -2-methoxy-aminoacetamido] -3-cephem-4-carboxylic acid (syn isomer), control ...... 7- [2 - (2-Amino-4-thiazolyl) -2-methoxyiminoacetamide Ocephalosporanic acid (syn isomer).

(3) Test results

Tested bacteria Applied cells / mouse ED50 (p. C.) (Mg / kg) Test compounds 1 control Escherichia co li 54 Klebsiella ΙΟ, ΙχΙΟ ⁶ 0.95 2.8 pneumoniae Proteus 8x10® 0.98 0.995 rettgeri 24 Serratia 9,9x10® 0.39 1,171 marcescens 58 1.2 χ 10 ⁷ 3,562+ ^{3 *} 31,427+ ³

MIC (, «g. Nil)

Inoculum 1 Control Compound Quantity

10 ° + ¹ 0.78 3.13 ² + ² 0.05 0.1

10 ° 0.39 3.13

IO ^'2 š0,025 0.05

10 ° 1.56 50 ~

IO ² SO, O25 0.1

10 ° 25

10-2 o, 39 1.56 + ¹ : overnight culture, + ² : 100-fold overnight culture, ⁺³ : treatment with two separate doses at 1 hour and 3 hours after infection.

3. Acute toxicity (1) Test method

Ten male and ten female rats, 6 weeks old (JCL-SD species), were grouped. Test compounds were dissolved in distilled water and then administered subcutaneously and intravenously to the indicated 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-Wilcoxon method.

(2j Test compounds

7- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetumido) -3-cephem-4-carboxylic acid (syn isomer).

(3) Test results

Test animals sex

LD 50 (mg / kg)

s.

male rats> 8000> 8000 about 8000> 8000

4. Absorbency (1) 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 in the samples was determined by bioassay (disk method) using Batillus subtilis ATCC-6633 as the test organism, and then the recovery in the bile and urine samples was determined.

(2) Test compounds

7- (2- (2-amino-4-thiazole) -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 the general formula Γ, 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 external 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, stabilizers, wetting 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 the formula to be used, etc. on average, single doses of about 50, 100, 250 and 500 mg 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 from 1 mg / kg to 100 mg / kg, and preferably from 5 mg / kg to 50 mg / kg.

The starting compound of formula III can be prepared as follows:

^ ch ^ c-cooz _(III ^

OH x-ch ₂ co-c-cooz (IIIb) o

JU y

/?, - C-NH ₂ ^(VII-a COOZ

rc-nh ₂ ^and II ^{2 s} (VU &) c-cooz

II N!

OH (III c)

O-R / (lld)

/? fONH ₂

ÍXfVJ

C-COOH

II

O (lk) (AVI)

NNH-Y

(Ulj) wherein in the above procedures means:

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

R _and ⁶ are protected amino,

X is a halogen atom,

Y is a lower alkoxycarbonyl group, and

Z is a lower alkyl group. ........ _ i.

Each of the above phases will be explained in more detail below.

Phase 1: Etherification

In this embodiment, the compound of formula IHb and IIId may be prepared by reacting a compound of formula IIIa or IIIc with an etherification agent.

This reaction can be carried out in essentially the same manner as described in Process B. &lt; tb &gt;

Phase 2: Thiazine ring formation

The compounds of formula IIIc and IIId may be prepared by reacting a compound of formula IIIa or IIIb with a thiourea compound of formula VIIa, and further, a compound of formula IIIb may be prepared by reacting a compound of formula IIIb and thiomolecin.

Phase 3: Elimination of the amino protecting group

Compounds of formulas IIIe and IIIg may be prepared by subjecting compounds of formula IIId or III to an amino-protected amino protecting group for substituents R _and ⁶ .

This reaction can be carried out essentially as described above, see Procedure C.

Stage 4: Carboxy compound formation

Compounds of formulas IIIf, IIIg and IIIj may be prepared by converting the esterified carboxy groups in the compounds of formula IIId, IIIe or IIIa into free carboxy groups.

This reaction can be carried out in essentially the same manner as described in Procedure E.

Stage 5: Oximation

The compound of formula (IIh) may also be prepared by reacting a compound of formula (IIIh) with a hydroxylamine derivative of formula (XIV) or a salt thereof.

The aforementioned hydroxylamine derivative of formula (XIV) may be a hydroxylamine substituted with an aliphatic hydrocarbon radical which may be substituted with a halogen, carboxy or esterified carboxy group, in particular the compounds already exemplified above. A suitable salt of said hydroxylamine derivative of formula (XIV) is hydrochloride, hydrobromide, sulfate or the like.

The reaction is usually carried out in conventional solvents such as water, alcohol, tetrahydrofuran, acetonitrile, dimethylsulfoxide, pyridine or any other solvent which does not adversely affect the reaction or mixture thereof, the reaction temperature being not critical.

When a salt of a hydroxylamine derivative is used as the reagent, the above reaction is preferably carried out in the presence of a conventional basic compound.

Stage 6: Thiadiazole ring formation

The compound of formula III may be prepared by reacting a compound of formula XV with a hydrazine derivative of formula XVI and then reacting the resulting compound of formula XVII with a sulfur trioxide of formula XVIII.

Among the starting compounds of the formula III, there is a compound of the formula ni ‘,

R _and -C-COOR ^&

OK (ΙΙΠ in which Ra ^{1 represents a} thiadiazolyl or thiazolyl group of the general formula

R * in which R ⁶ 'is amino or protected amino,

R _and ² 'are an alkyl, alkenyl or alkynyl group containing more than one carbon atom or a cycloalkyl group which may be substituted by halogen, carboxy or esterified carboxy, and

R ® is a hydrogen atom or a lower alkyl group, with the proviso that R ⁶ 'is an amino group which may be protected by a formyl group and R ® is a hydrogen atom when R _a ² ' is an ethyl group, an isopropyl group or an allyl group , a novel compound which can be used as the starting compound in the above process, referred to as process A.

The above terms and definitions of each term have been explained in more detail above.

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

Preparation of starting compounds:

Example A

According to this embodiment, a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomer in an amount of 34.6 g and t-butoxycarbonylhydrazine in an amount of

26.4 g in 200 ml of ethanol are stirred for 7.5 hours at ambient temperature and then left to stand overnight, whereupon crystals precipitate. The crystals thus obtained are collected by filtration, washed with ethanol and finally dried to give ethyl 2-methoxyimino-3-tert-butoxycarbonylhydrazonobutyrate (syn and anti isomers) in an amount of 41.7 g, m.p. 144-145 ° C.

Product characteristics:

IR at _max (nujolj.

3200, 1750, 1705, 1520 cm ¹

NMR No _ppm (CDCLs):

8.52 (1H, sj band,

4.35 (2H, q, J = 7Hz);

4.10 (3H, s,

2.00 (3 H, s),

1.50 (9H, sj,

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

2. According to this embodiment, sulfur trichloride (15.9 ml) is added with stirring at ambient temperature to a solution of ethyl 2-methoxyimino-3-tert-butoxycarbonylhydrazonohydrate (a mixture of syn and anti isomer) of 14.36 g in methylene chloride (150 ml) and the resulting mixture was stirred for 1 hour at ambient temperature. 300 ml of ice-water are added to the reaction mixture, and the methylene chloride layer is washed with water, then with a saturated aqueous sodium bicarbonate solution and finally with a saturated aqueous sodium chloride solution and finally dried over magnesium sulfate. The solvent was distilled off to give an oily matter. The oil was purified by column chromatography using silica gel and benzene / n-hexane (19: 1) as eluent to give 2-methoxyimino-2- (1,2,3-thiadiazole) first. 4-yl) acetate as the syn isomer in an amount of 1.8 g, the melting point of the product thus obtained being in the range of 77 to 79 ° C.

Product characteristics:

IR at _max (nujolj:

1720, 1595 ^cm-1

NMR and _ppm (CDCL3):

8.92 (1 H, s),

4.46 (2H, q, J = 7Hz),

4.06 (3 H, s),

1.38 (3H, t, J = 7Hz).

The following fractions gave ethyl 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetate as the anti-isomer, 0.7 g, the title product being an oil.

Product characteristics:

-IR in _max (film):.

. 1730, 1590 cm ¹

NMR _{δ ppm} (CDCl ₃ ):

9.38 (1 H, s),

4.47 (2H, q, J = 7Hz).

4.20 (3H, s),

1.40 (3H, t, J = 7Hz).

3. According to this embodiment, 1N aqueous sodium hydroxide solution is added in an amount

6.7 ml to a solution of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) ethyl acetate as the syn isomer in an amount of 1.2 g in methanol in an amount of 10 ml, and the mixture thus obtained is stirred for 1.5 hours at ambient temperature. Methanol is distilled off from this reaction mixture and water is added to the residue. The mixture was washed with ether, the pH was adjusted to 1 with 10% hydrochloric acid, and finally extracted with ethyl acetate. The extract obtained is washed with a saturated aqueous solution of sodium chloride and finally dried over magnesium sulphate. The solvent was distilled off to give the prism of 2-methoxyimino-2- (1,2,3-thiadiaisol-4-yl) acetic acid as syn isomer in an amount of

0.7 g. Melting point: 110-113 ° C.

. Product characteristics:

IR at _max (nujol):

2750 - 2150, 1730, 1595 cm ¹ ·

NMR δ _ppm (d 6 -DMSO): _δ .

9.47 (1.13, s),

4.01 (311, s),

Example 1 a d B

1. According to this embodiment, 160 g of ground potassium carbonate is added to a solution of ethyl 2-hydroxyiminoacetoacetate in the form of a mixture of syn and anti isomers of 152 g in 500 ml of acetone. Dimethyl sulfate (130 g) was added dropwise to the mixture while stirring for 1 hour at 45-50 ° C, followed by stirring for a further 2 hours. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material is dissolved in 500 ml of water and the solution is added to the residue above. The mixture is then extracted twice with 300 ml of ethyl acetate. The extract was washed twice with 200 ml of water and 200 ml of a saturated aqueous sodium chloride solution, and then dried over magnesium sulphate. The solvent was then distilled off under reduced pressure to give a colorless oily substance, ethyl 2-methoxyiminoacetoacetate, as a mixture of syn and anti isomer, 145.3 g. The melting point of this product was 55-64 °. C / 65.5 Pa.

Product characteristics:

IR in _max (film):

1745, 1695, 1600 cm ¹

NMR .delta. _Ppm (CDCL3):

4.33 (4H, q, J = 8Hz);

4.08 (3 H, s),

3.95 (3 H, s),

2.40 (3 H, s),

1.63 (3 H, s),

1.33 (6H, t, J = 8 Hz).

2. In this embodiment, 235 ml of sulfuryl chloride is added dropwise over 20 minutes with stirring and cooling in an ice bath to a solution of ethyl 2-methoxylminoacetoacetate as a syn isomer of 500 g in 500 ml of acetic acid, and the resulting mixture is then stirred overnight with water cooling. Nitrogen was then added to the reaction mixture for ♦ 2 hours and the mixture was poured into 2.5 L of water. This mixture was then subjected to extraction with 500 mL methylene chloride and then 200 mL methylene chloride again, and the combined extracts were combined. . The combined extracts were then washed with saturated aqueous sodium chloride solution and the pH was adjusted to 6.5 by addition of 800 ml of water and sodium bicarbonate. The methylene chloride layer was separated, washed with brine and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate as the syn isomer in 559 g.

Product characteristics:

IR in _m ax (film):

1735, 1705 cm ¹

3. According to this embodiment, ethyl 2-methoxyimino-4-chloroacetoacetate is added as the syn isomer in an amount of 50 g over 3 min. with stirring at ambient temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium ethane in a mixture of 250 ml of methanol and 250 ml of water. The mixture is stirred for 35 minutes at a temperature between 40 and 45 ° C and the reaction mixture is cooled with ice and the pH is adjusted to 6.3 with a saturated solution of sodium bicarbonate in water. This mixture was further stirred for 30 min. at the same temperature above, the precipitate was collected by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether, and finally dried to give colorless crystals of 2-methoxyimino-2- (2-amino-l, 3-thiaisol-4-yl) ethyl acetate in the form of the syn isomer in an amount of 37.8 g. The melting point of the product thus prepared is between 161 and 162 ° C.

Characteristics of the product:

IR at _max (nujol):

3400, 3300, 3150, 1725, 1630,

1559 cm ^-1

NMR δ _PDm ( _CDCL3 ):

6.72 (1 H, s),

5.91 (2H, s-band),

4.38 (2H, q, I = 7Hz)

4.03 (3 H, s),

1.38 (3H, t, J = 7Hz).

4. Ethanol (10 ml) is added to a suspension of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) ethyl acetate as a syn isomer in an amount of 2.2 g in 1N aqueous solution. Sodium hydroxide (12 ml) was added and the mixture was stirred at ambient temperature for 15 hours. The pH of the reaction mixture was adjusted to 7.0 with 10% hydrochloric acid and ethanol and then distilled off under reduced pressure. After this step, an aqueous solution is obtained, which is washed with ethyl acetate, and the pH is then adjusted to pH 5

2.8 with a 10% hydrochloric acid solution and the mixture was stirred under ice-cooling, whereupon crystals precipitated. The crystals thus separated are filtered off, washed with acetone and finally recrystallized from ethanol to give 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid needles as the syn isomer and yield 1.1 g.

Product characteristics:

IR at _max (nujol):

3150, 1670, 1610, 1585 cm -1

NMR _{δ ppm} (de-DMSO):

7.20 (2H, s-band),

6.85 (1 H, s),

3.83 (3 H, s).

Example C

1. According to this embodiment, sulfuryl chloride is added in an amount of 35.2 g as a single addition to the stirred solution

Ethyl 2-ethoxyimino-3-oxobutyrate as syn Isomer 48.9 g in 49 ml acetic acid at ambient temperature, and the solution was stirred at the same temperature for four hours. After this operation, the above solution was added to 200 ml of water and the final solution was extracted with methylene chloride. The extract obtained is washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and finally washed with water. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate as the syn isomer 53.8 g as a light yellow oil. .

2. According to this embodiment, the mixture consisting of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate in the form of the syn isomer in an amount of 38.7 g, the amount of thiourea in an amount of

13.2 g, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water were stirred at 48 ° C for 40 min. After adjusting the pH of this solution to 6.5 with aqueous sodium bicarbonate, a precipitated mass appears, which is collected by filtration and then washed with diisopropyl ether to give 2- (2-amino-4-thiazolyl). Ethyl 2-ethoxyiminoacetate as the syn isomer in an amount of 14.7 g. The melting point of this product ranges from 130 to 131 ° C.

Product line characteristics:

IR in _nux (nujol):

3450, 3275, 3125, 1716,

1620 cm ¹

3. According to this embodiment, ethyl 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetate in the form of the syn isomer is added in an amount of 5 g to a mixture of 1N sodium hydroxide (45.9 ml) and ethanol (30 ml). the mixture is then stirred at ambient temperature for a further 5 hours. After removal of the solvent, i.e. ethanol, from the resulting solution under reduced pressure, the residue is dissolved in 60 ml of water and the pH is adjusted to 2.0 with 10% hydrochloric acid. The solution thus obtained is subjected to salting-out and the resulting precipitated mass is collected by filtration and finally dried to give 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetic acid as the syn isomer, 2.9 g.

Product characteristics:

IR ( _lililx (nujol)):

3625, 3225 (band), 3100, 1650,

1615 cm -1

NMR% _pm (DMSO-d 6):

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

4.09 (2H, q, J = 7Hz),

6.82 (1 H, s),

7.24 (2H, s).

4. According to this embodiment, the mixture consisting of 2- ^(2-i aminoth azole-4-yl) -2-ethoxyiminooctové syn isomer, 100 g of formic acid in an amount of 85.5 g of acetic anhydride 190.1 g, treated in the same manner as in Example F- (5) to give 2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetic acid in the form of the syn isomer 99.1 G.

Product characteristics:

IR at _max (nujol):

3200, 3140, 3050, 1700 cm ' ¹

NMR <5p _pm (DMSO-d):

1.18 (3H, t, J = 6Hz),

4.22 (2H, q, J = 6Hz),

7.56 (1 H, s),

8.56 (1 H, s),

12.62 (1H, s band).

Example D

1. According to this embodiment, take to a suspension

Ethyl 2-hydroxyimino-3-oxobutyrate as the syn isomer of 15 g, and potassium carbonate of 19.8 g in 75 ml of acetone are added dropwise propyl iodide (16.2 g) with stirring, the resulting mixture further Stir at ambient temperature for 1.5 hours. After this procedure, insoluble materials were separated, which were removed by filtration and washed with acetone. The combined washings and filtrate were combined and evaporated to dryness under reduced pressure. This gives a residue to which water is added and the aqueous solution obtained is extracted twice with chloroform. The extract thus obtained is washed with an aqueous sodium chloride solution, dried over magnesium sulphate and then evaporated to dryness under reduced pressure to give

Ethyl 3-oxo-2-propoxyiminobutyrate in the form of the syn isomer in an amount of 15.4 g. The resulting mass is of an oily nature.

2. According to this embodiment, 3-oxo-2-propoxyiminobutyrate in the form of the syn isomer in an amount of 15.4 g and sulfuryl chloride in an amount of 10.6 g are dissolved in 15.4 ml of acetic acid, heated to a temperature in the range of from 35 to 40 ° C and then heated at this temperature for 10 minutes with stirring and finally stirred at ambient temperature for a further 6 hours. The reaction mixture was then poured into 200 ml of ice-water and the mixture was subjected to extraction with chloroform twice. The extiract obtained above was washed with aqueous sodium chloride solution, then twice with saturated aqueous sodium bicarbonate solution and finally once with water, then dried over magnesium sulphate and finally evaporated to dryness under reduced pressure to give 4-chloro-3-oxo. Ethyl-2-propoxyiminobutyrate in the form of syn Isomer in an amount of 15.4 g. The resulting product is in the form of an oily matter.

Product characteristics:

IR in _raax (movie :):

1740, 1710, 1605, 1455 cm ¹

3. According to this embodiment, ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate in the form of the syn isomer in an amount of 15.4 g, the thiourea in an amount of 4.97 g and sodium acetate hydrate in an amount of 8.89 g are dissolved in a mixture of water. 40 ml of ethanol and 50 ml of ethanol are added and the mixture is stirred at 40 DEG C. for 1 hour. The pH of the reaction mixture was then adjusted to 6.5 with saturated aqueous potassium carbonate solution under cooling, and the mixture was stirred at the same temperature for half an hour. Crystals precipitated as described above, which were collected by filtration, washed with water and diisopropyl ether, and then dried, yielding crystalline ethyl 2- (2-amino-4-thiazolyl) -2-propoxyiminoacetate as the syn isomer in 10.55 g. The melting point of the product thus prepared is from 142 to 144 ° C.

Product characteristics:

IR at _max (nujol):

3460, 3220, 1720, 1620,

1540 cm ^-1

NMR δ _pm (de-DMSO):

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

1.27 (3 H, t, J = 6 Hz),

1.60 (2H, sextet, J = 7Hz),

4.04 (2H, t, I = 7Hz),

4.28 (2H, q, J = 6Hz).

6.86 (1 H, s),

7.23 (2 H, s).

4. According to this embodiment, a solution of ethyl 2- (2-amino-4-thiazolyl) -2-propoxyiminoacetate in the form of the syn isomer in an amount of 10 g is mixed with 39 ml of tetrahydrofuran, 39 ml of methanol and 1N sodium hydroxide solution. in an amount

75.8 mL, stirred at 35-40 ° C for 5 hours.

After the resulting solution was concentrated under reduced pressure, the pH of the resulting aqueous solution as a residue was adjusted to 2.5 with a 10% hydrochloric acid solution. After this procedure, a precipitate was formed which was collected by filtration and dried to give 2- (2-amino-4-hiazolyl) -2-propoxyiminoacetic acid as the syn isomer at 6.2 g. of the prepared product is 161 ° C (dec.).

Product features:

IR in _max (nujol j:

3380, 3120 (band), 1630,

1610, 1460 cm @ -1

NMR .delta. _Ppm (DMSO-d6):

0.89 (3H, t, J = 7Hz),

1.63 (2H, sextet, J = 7Hz),

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

6.83 (1 H, s),

6.9 - 8.8 (3H, band).

According to this embodiment, 2- (2-aminothiazol-4-yl) -2-n-propoxyminoacetic acid is in the form of the syn isomer in an amount of

21.8 g, acetic anhydride in an amount

38.8 g and 17.5 g of formic acid are treated in the same manner as in Example F- (5), and the oily matter thus obtained is triturated with diisopropyl ether to give 2- (2-formamidothiazole-4-) acid. yl) -2-n-propoxyiminoacetic acid in the form of the syn isomer in an amount of 19.2 g. The melting point of the product thus obtained is 164 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3200, 3120, 3050, 1700, 1550 cm -1 NMR δ _ppm (DMSO-d 6):

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

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

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

7.53 (1Ή, s)

8.54 (1H, s).

Example E

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer in 30 g, isopropyl iodide in 32.5 g, potassium carbonate in 39.5 g and acetone in a volume of 150 ml are treated in the same way as This is shown in Example D- (1), whereby ethyl 2-isopropoxyimino-3-oxobutyrate is obtained in the form of syn Isomer in an amount of

35.4 g. The resulting product is an oil-yellow mass.

Product characteristics:

I R. Vmax (film):

1745, 1690, 1600 cm ^-1

N.M.R. δ (CCI, ppm):

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

1.35 (6H, d, J = 6Hz),

2.32 (3 H, s),

4.1 ~ 4.7 (3H, inter alia.

2. According to this embodiment, ethyl 2-isopropoxyimino-3-oxohutyrate in the form of the syn isomer in the amount of 35.4 g, sulfuryl chloride in the amount of 24.5 g and acetic acid in a volume of 35.4 ml are treated in a similar manner as in the example D- (2), thereby obtaining ethyl 4-chloro-3-oxo-2-isopropoxyiminobutyrate as the syn isomer in an amount of 41.5 grams. The resulting product is an oily matter.

Product characteristics:

IR in _max (film):

1745, 1715, 1375 cm ¹

3. According to this embodiment, ethyl 4-chloro-3-oxo-2-isopropoxyiminobutyrate in the form of the syn isomer is 41.5 g, thiourea is 13.4 g, sodium acetate is 14.4 g, water of 110 ml and ethanol (110 ml) were treated in a similar manner to Example D- (3j) to give ethyl 2- (2-amino-thiazol-4-yl) -2-isopropyloxyiminoacetate as the syn isomer in an amount of The melting point of the product thus obtained is in the range of from 162 to 164 ° C.

Product characteristics:

IR at _max (nujolj:

3460, 3430, 3260, 3150, 1735,

1615, 1540 cm -1

N.M.R. δ (DMSO-d 6, ppm):

1.17 (6H, d, J = 6Hz),

1.24 (3H, t, J = 7Hz), ~ 4.7 (3H, m),

6.86 (1 H, s),

7.24 (2H, sj.

4. According to this embodiment, ethyl 2- (2-amino-thiazol-4-yl) -2-isopropoxyiminoacetate as the syn isomer in an amount of 26.8 grams, 1N aqueous sodium hydroxide solution (156 ml), methanol 156 ml and tetrahydrofuran (100 ml) were treated in a similar manner to Example D- (4) to give 2- (2-aminothiaeol-4-yl) -2-isopropoxyiminoacetic acid as the syn isomer. The melting point of this product is 151 ° C (dec.).

Product characteristics:

AND

IR in _inax (nujolj:

3610, 3580, 3080, 1650,

1610 cmn ¹

N.M.R. δ (DMSO-d6, ppm):

1.22 (6H, d, J = 6Hz).

4.33 (1H, quintet, j = 6 Hz),

6.80 (1H, sj,

7.22 (2H, sj.

According to this embodiment, 2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetic acid in the form of the syn isomer in an amount of 4 g, acetic anhydride in an amount of

7.6 g and formic acid (3.4 g) were treated in a similar manner to Example F- (5j) to give 2- (2-formamidothiazol-4-yl) -2-isopropoxyiminoacetic acid as syn isomer, 3.75 g. Melting point: 168-169 ° C (dec.).

Product characteristics:

IR at _max (nujolj:

3200, 3130, 1710, 1600

1560 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

1.26 (6H, dj,

4.4 (1 H, m),

7.54 (1H, sj,

8.52 (1 H, s),

12.56 (1H, sj band).

Example F

1. According to this embodiment, n-butyl iodide in an amount of 46.9 g is added dropwise to a stirred suspension consisting of ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer in an amount of 40 g, potassium carbonate in an amount of 52.7 g and acetone. in an amount of 200 ml while cooling in an ice bath and this step takes 5 min. and the mixture is then stirred at ambient temperature for a further 4 hours. The resulting solution was filtered and washed with acetone. The filtrate and wash solution thus obtained were combined and concentrated in vacuo. 300 ml of water was added to the residue, which was then extracted three times with methylene chloride. The solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-n-butoxyimino-3-oxebutyrate as the syn isomer at 48.8 g. oily nature.

Product characteristics:

IR in _max (film).

1750, 1700, 1470, 1370, 1320 cm ^-1

S 5 a

2. According to this embodiment, a solution consisting of ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer) in an amount of 48.8 g, sulfuryl chloride in an amount of 31.5 g and acetic acid in an amount of 48.8 ml is stirred at at 40 ° C for 10 minutes and then further stirred at ambient temperature for 5.5 hours. 300 ml of water were added to the resulting solution while cooling in an ice bath, and the solution was then subjected to extraction with methylene chloride three times. The extract was washed with water, aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution, and the resulting solution was dried over magnesium sulfate. The solution was concentrated in vacuo to give ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate as the syn isomer in an amount of 52.1 g. The product was obtained as an oil.

Product characteristics:

I. R. »max (film):

1740, 1710, 1470, 1370 cm ^-1

3. According to this embodiment, a solution consisting of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate in the form of the syn isomer in an amount of 52.1 g, thiourea in an amount of

15.9 g, 28.4 g of sodium acetate trihydrate, 130 ml of water and 180 ml of ethanol are stirred at 40 DEG C. for 1.25 hours. The resulting solution, which is adjusted to pH 6.5 with aqueous sodium carbonate solution while cooling in an ice bath, is stirred for 20 minutes while cooling in an ice bath. The above precipitate was collected by filtration and washed with water and diisopropyl ether to give the final ethyl 2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetate as the syn isomer, and yield. The melting point of the product thus prepared is from 126 to 128 ° C.

Product characteristics:

IR at _max (nujol):

3460, 3370, 3230, 1720,

1620, 1550 ^cm-1

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

0.6-2.0 (6H, m),

1.28 (3H, t, J = 7Hz),

4.12 (3 H, t, J = 6 Hz),

4.31 (2H, q, J = 7Hz),

6.89 (1 H, s),

7.24 (2 H, s).

starting from ethyl 2- (2-aminothiazol-4-yl) -2'-n-butoxyiminioacetate in the form of the syn isomer in 36.0 g, methanol in 133 ml, tetrahydrofuran in 133 ml and 2 N aqueous hydroxide solution Sodium (133 mL) was stirred at 30 ° C for 5 hours. The solution was concentrated in vacuo and the residue was dissolved in water. The pH of the product thus obtained is then adjusted to 7 with 10% hydrochloric acid and finally treated with activated carbon. The pH of the solution was then adjusted to 2.0 with 10% hydrochloric acid, and the solution was stirred for 20 minutes while cooling in an ice bath. The precipitate was collected by filtration, washed with water and acetone, and dried to give 2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetic acid as the syn isomer in amount of 25.4 grams.

Product features:

R. Vmax (nujol):

3325, 3190, 1660, 1620 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

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

1.0 - 1.9 (4H, m),

4.06 (2Ή, t, J = 7Hz),

6.81 (1 H, s),

7.21 (2H, s).

5. Add 18.95 g of formic acid dropwise to 42.0 g of acetic anhydride with stirring at ambient temperature for 5 minutes and then stir at 50 ° C for 1 hour . 2- (2-Aminothiazol-4-yl) -2-n-butoxyiminoacetic acid (25 g) is then added to the solution, while cooling in an ice bath, and then stirred at ambient temperature. for 3 hours and then at 30 ° C for another one hour. The solution is concentrated in vacuo and the loss is dissolved in diethyl ether. The solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The oily matter thus obtained was triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part), and then the solid was collected by filtration to give 2- (2-formamidothiazol-4-yl). -2-n-butoxyiminoacetic acid in the form of the syn isomer in an amount of 20.1 g.

4. According to this embodiment, the solution is glassed at 17959

Product characteristics;

IR at _max (nujol):

3350, 3160, 3050, 1700, 1680,

1570 cm @ -1

N.M.R. δ (DMSO-d 6, ppm):

0.91 (3 H, t, J = 6 Hz),

1.0-2.2 (4H, m),

4.18 (2H, t, J = 6Hz);

7.57 (1 H, 3),

8.59 (1 H, 3),

12.66 (1H, s band).

Example G

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxo-3-butyrate is in the form of the syn isomer and 40 g, N, N-dimethylformamide 200 ml, potassium carbonate 52.7 g and isobutyl bromide 34.94 g. The reaction was carried out in a similar manner to that described in Example F- (1) to give ethyl 2-isobutoxyimino-3-oxo-butyrate as the syn isomer in 42 g.

Product characteristics:

IR at _max (nujol):

1740, 1670 (band) cnr ¹

2. According to this embodiment, ethyl 2-iso-butoxyimino-3-oxobutyrate in the form of the syn isomer in 42 g, acetic acid in 42 ml and sulfuryf chloride in 27.1 g are treated in a similar manner to that described in the procedure Example F- (2) to give ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate as the syn isomer, 31.9 g.

Product characteristics:

IR Vj | _13x (film).

1750, 1720, 1680 cm ¹

3. According to this embodiment, ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate is in the form of the syn isomer in an amount of 31.9 g, further thiourea in an amount of 9.72 g, sodium acetate in an amount of 17.4 g in ethyl acetate. in the form of the trihydrate, 120 ml of ethanol and 80 ml of water were treated in a similar manner to that described in Example F- (3) to give 2- (2-aminothiazol-4-yl) -2-isobutoxyiminoacetate ethyl acetate in the form of the syn isomer in an amount of 17.6 g, the temperature of the product being in the range of 122 to 124 ° C.

Product characteristics:

IR at _max (nujol):

3470, 3260, 3120, 1730, 1620, 1545 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

0.86 (6H, d, J = 7Hz),

1.28 (3H, t, J = 7Hz);

1.6-2.2 (1 H, m),

3.86 (2H, d, J = 7Hz);

4.28 (2H, q, J = 7Hz);

6.86 (1H, s).

7.22 (2 H, s).

4. According to this embodiment, ethyl 2- (2-aminothiazol-4-yl) -2-isobutoxyiminoacetate in the form of the syn isomer is added in an amount of 19.6 grams, followed by a 2 N aqueous solution of sodium hydroxide 72.2 ml, methanol 72.2 ml and 72.2 ml tetrahydrofuran were treated in a similar manner to that described in Example F- (4) to give 2- (2-aminothiazol-4-yl) acid. -2-isobutoxyiminoacetic acid in the form of the syn isomer. Yield 16.1 g, m.p. 180 DEG C. (dec.).

Product characteristics:

IR at _max (nujol):

3375, 3300, 3130, 3050, 1640 cm ^-1 .

N.M.R. δ (DMSO-d6, ppm):

0.91 (6H, d, J = 7Hz),

1.5-2.3 (1H, m),

3.90 (2H, d, J = 7Hz),

6.87 (1 H, s),

7.26 (2H, s).

5. According to this embodiment, 2- (2-amino-thiazol-4-yl-2-isobutoxyiminoacetic acid) is in the form of the syn isomer and in an amount of

19.3 g and acetic acid (8.7 g) were treated in a similar manner to that described in Example F- (5) to give 2- (2-formimidothiazol-4-yl) -2-acid. The isobuthoxyiminoacetate in the form of the syn isomer in an amount of 11.15 g. The melting point of this product is 163 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3175, 3110, 3050, 1695, 1550 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

0.91 (6H, d, J = 7Hz),

1.7-2.3 (1 H, m),

3.92 (2H, d, J = 7Hz),

7.52 (1 H, s),

8.52 (1 H, s),

12.58 (1H, s band).

Example H

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer and in an amount of 30 g, further N, N-dimethylformamide in an amount of 100 ml, carbonate

B5, 217959 potassium (39.5 g) and cyclohexyl bromide (31.1 g) were treated in a similar manner to that described in Example F- (1) to give ethyl 2-cyclohexyloxyimino-3-oxobutyrate as syn isomer in an amount of 41.8 g. This product is in the form of an oil.

Product features:

IR in _max (film).

1740, 1680 cm ^-1 .

2. According to this embodiment, ethyl 2-cyclohexyllmino-3-oxobutyrate in the form of the syn isomer in 41.3 g, acetic acid in 41.3 ml and sulfuryl chloride in 23.8 g are treated in a similar manner as described above. Example F- (2) to give ethyl 4-chloro-2-cyclohexylimino-3-oxobutyrate as the syn isomer, 27.8 g, as an oil.

Product features:

I R. Pmax (film).

1745, 1715, 1680 and ¹ .

3. According to this embodiment, ethyl 4-chloro-2-cyclohexylimino-3-oxobutyrate is in the form of the syn isomer in an amount of 27.8 g, further thiourea in an amount of 7.7 g, sodium acetate in the form of a trihydrate in an amount of 13.7 g and 70 mL of water with 140 mL of ethanol were treated in a similar manner to Example F- (3) to give ethyl 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetate as described above. syn isomer, 3.6 g. Melting point of the obtained product ranges from 125 to 126 ^C C.

Product characteristics:

IR at _max (nujolj:

3430, 3250, 3160, 3130, 1715, 1635 cm @ ^-1 .

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

1.28 (3H, t, J = 7Hz),

1.0-2.2 (10H, m);

4.22 (1 H, m),

4.32 (2H, q, J = 7Hz),

6.88 (1H, sj,

7.24 (2H, sj band).

4. According to this embodiment, ethyl ethyl 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetate is in the form of syn Isomer and 3.5 g of 2 N aqueous sodium hydroxide in 11.8 ml, methanol in 11.8 ml and tetrahydrofurian in an amount of 11.8 ml are treated in a similar manner to that described in the embodiment

BB of Example F- (4) to give 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid as the syn isomer in an amount of 2.1 g. Melting point: 148 ° C (with decomposition).

Product characteristics:

IR> _mass (nujolj:

3110, 1630, 1450 ^cm-first

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

0.8-2.3 (10H, mj,

4.14 (1 H, m),

6.86 (1 H, s),

7.5 (2H, ss.

5. According to this embodiment, 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid in the form of the syn isomer and 1.5 g, further acetic anhydride 2.27 g and formic acid 1, 03 g were treated in a similar manner to that described in Example F- (5) to give an oily matter, which was then suspended in aqueous sodium bicarbonate, and the resulting suspension was adjusted to pH 3.5 with 10% hydrochloric acid solution. This procedure yielded a precipitate which was collected by filtration, then washed with water and dried to give 2- (2-formamidothiazol-4-yl) -2-cyklobexyloxyim ^s nooctová syn isomer and in an amount of 1.0 g. The melting point of this product is higher than 230 ° C.

Product characteristics:

IR at _max (nujolj:

3175, 3100, 3060, 1680 cm ^-1 .

Example I

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer and 56.7 g, further N, N-dimethylformamide in 280 ml, potassium carbonate in 72.3 g and propargyl bromide in 43 g were processed in a similar manner to that described in Example F- (1), and prepared

Ethyl 2-propyrgyloxyimino-3-oxobutyrate as the syn isomer in an amount of 71.2 g.

Product characteristics:

IR in _max (film):

3280, 3220, 2120, 1735, 1670 cm ^-1 .

2. According to this embodiment, ethyl 2-propargyloxyimino-3-oxobutyrate is in the form of the syn isomer at 71.2 g, acetic acid at 81 ml and sulfurylchlo217959

507 g of G7 are treated in a similar manner to Example F- (2) to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate as the syn isomer in an amount of 50.2 g. 61.6 g. The resulting product is in the form of an oil.

Product characteristics:

IR in _max (film):

3300, 2130, 1745, 1720, 1675 ^cm-first

N.M.R., δ (CCl 4, ppm):

1.39 (3H, t, J = 7Hz),

2.57 (1 H, t, J = 2 Hz),

4.36 (2H, q, J = 7Hz),

4.56 (2 H, s),

4.86 (2H, d, J = 2Hz).

3. According to this embodiment, ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate is in the form of the syn isomer at 61 g, furthermore thiourea at 20 g, sodium acetate trihydrate at 35.8 g, water at 150 ml and ethanol (180 ml) were treated in a similar manner to that described in Example F- (3) to give ethyl 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetate as the syn isomer in an amount of 35,6 g.

Product characteristics:

IR V _m ax (nujolj.

3290, 2220, 1729 cm ^-1 .

N.M.R. δ (DMSO-d6, ppm):

1.28 (3H, t, J = 7 Hz),

3.49 (1H, t, J = 3Hz);

4.31 (2H, q, J = 7Hz),

4.76 (2H, d, J = 3Hz),

6.95 (1 H, s),

7.29 (2 H, s).

4. According to this embodiment, ethyl 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetate is in the form of the syn isomer at 2.8 g, followed by methanol at 23 ml, tetriahydrofuran at 20 inl and 1 N aqueous sodium hydroxide solution in an amount of 22.17 ml. by treatment in a similar manner to that described in F- (4) to give 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetic acid as the syn isomer in an amount of 1.924 g.

Product characteristics:

Mr R. Vmax (nujolj:

2190, 1740 ^cm-first

N.M.R. δ (DMSO-d 6, ppm):

3.47 (1H, t, J = 5Hz), 4.74 (2H, d, J = 1.5Hz),

6.90 (1 H, s).

Example J

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer and at 40 g and further N, N-dimethylformamide at 200 ml, potassium carbonate at 52 g and n-hexylbiromide at 41.4 g are processed. in a similar manner to that described in Example F- (1), whereby ethyl 2-n-hexyloxyimino-3-oxobutyrate was prepared in the form of the syn isomer. Yield: 60.7 g, oil.

Product characteristics:

IR at _max (film).

1740, 1705, 1700 ^cm-first

N.M.R. δ (CC14, ppm):

0.6-2.1 (14H, m),

2.37 (3 H, s),

4.1-4.6 (4 H, m).

2. According to this embodiment, ethyl 2-n-hexyloxyimino-3-oxobutyrate in the form of the syn isomer at 60.7 g and further acetic acid at 61 ml and sulfuryl chloride at 34.7 g are treated in a similar manner as described in Embodiment according to Example F- (2) to prepare ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate as the syn isomer. The yield of this product is

55,6 g.

Product characteristics:

IR in _max (film):

1740, 1720, 1470 ^cm-first

N.M.R. δ (CC14, ppm):

0.6-2.2 (14H, m),

4.1-4.6 (4 H, m),

4.47 (2 H, s).

3. According to this embodiment, ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate is in the form of the syn isomer and in the amount of 55.6 g and further thiourea in the amount of 27.2 g, ethanol in the amount of 280 ml and water in the amount of 140 ml were treated in a similar manner to that described in Example F- (3) to give ethyl 2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetate as an isomer. Yield 29.3 g, m.p. 77-78 ° C.

Product characteristics:

IR at _max (nujolj:

cm- ¹ .

3460, 3250, 3140, 1720, 1535

N.M.R. δ (DMSO-d 6, ppm):

0.85 (3H, t, J = 6Hz)

1.0-1.9 (11 H, m),

2.07 (2H, t, J = 6Hz),

2.26 (2H, q, J = 7Hz),

6.85 (1 H, s),

7.22 (2 H, s).

4. According to this embodiment, 2- (2-amino-thiazol-4-yl) -2-n-hexyloxyiminoacetate of ethynyl in the form of the syn isomer in an amount of 29.1 grams, followed by methanol in an amount of 97.2 ml, 2 N aqueous sodium hydroxide solution 97.2 ml and tetrahydrofuran 50 ml were treated in a similar manner to that described in Example F- (14) to give 2- (2-aminothiazol-4-yl) -2- n-hexyloxyiminoacetic acid in the form of the syn isomer and in an amount of 24.0 g. Melting point: 174 DEG C. (dec.).

Product characteristics:

IR at _max (nujol):

1660, 1625, 1425 cm -1.

N.M.R. (DMSO-de, pp, m):

0.6-2.1 (11 H, m),

4.07 (2H, J = 6Hz),

6.83 (1 H, s),

7.19 (2 H, s).

Example K

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer and 40 g and N, N-dimethylformamide in 200 ml, potassium carbonate in 52 g and pentyl bromide in 37.9 g are treated in a similar manner as in Example F- (1) to give ethyl 2-pentyloxyimino-3-oxobutyrate as the syn isomer in an amount of 57.5 g. The resulting product is an oil.

Product characteristics:

I R. Vmax (film):

1745, 1680, 1470 om-1.

N.M.R. S (CC14, ppm):

0.7-2.2 (12H, m);

2.36 (3 H, s),

4.1-4.6 (4 H, m).

2. According to this embodiment, ethyl 2-pentyloxyimino-3-oxobutyrate in the form of the syn isomer at 57.5 g and acetic acid at 58.5 ml and sulfuryl chloride at 20.9 ml are treated in a similar manner as EXAMPLE F- (2) to give ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate as the syn isomer in an amount of 51.1 g. The resulting product is an oily matter.

Product characteristics:

IR in _max (film):

1750, 1715, 1470 cm -1.

N.M.R. δ (CC14, ppm):

0.7-2.1 (11 H, m),

4.1-4.6 (4 H, m),

4.48 (2 H, s).

3. According to this embodiment, ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate is present in the form of the syn isomer and in an amount of 51.1 g and thiourea in an amount of 14.7 g, sodium acetate trihydrate in an amount of 26.4 g; 175 ml and 125 ml water were treated in a similar manner to Example F- (3) to produce ethyl 2- (2-aminothlazol-4-yl) -2-pentyloxyiminoacetate in the form of the syn isomer in an amount of 28.7 g. The melting point of this product is from 86 to 88 ° C.

Product characteristics:

1. R. for _max (nujol):

3450, 3250, 3130, 1715, 1535 cm -1

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.0 (12 H, m),

4.11 (2H, t, J = 6Hz),

4.32 (2H, q, J = 7 Hz),

6.90 (1 H, s),

7.25 (2 H, s).

4. According to this embodiment, ethyl 2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetate is in the form of the syn isomer and in an amount of

28.6 g and 100.2 ml of 2 N aqueous sodium hydroxide solution, 100 ml of methanol and 100 ml of tetrahydrofuran are treated in a similar manner to that described in Example F- (4), wherein: 2- (2-Aminothiazol-4-yl) -2-pentyloxyiminooctoic acid was obtained in the above manner as a syn isomer in yield

22.4 g. Melting point: 176 DEG C. (dec.).

Product characteristics:

IR at _max (nujol):

3160, 1655, 1620, 1460 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.2 (9H, s),

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

6.82 (1 H, s),

7.20 (2 H, s).

5. According to this embodiment, 2- (2-aminothiazol-4-yl) -2-pentyloxy-amino-acetoic acid is synthesized in the form of the syn isomer and in the amount of g and acetic anhydride in the amount of 23.8 g and formic acid in the amount of 10.7 g. by the method of Embodiment F- (5) to give 2- (2-formamidothiazol-4-yl) -2-pentyloxyiminoacetic acid as the syn isomer in 14.7 g. mp 125 ° C (dec.).

What the product is like:

IR in _lliax (nujol):

3200, 3140, 1700, 1565 cm @ -1.

N. M. R. <5 (DMSO-d 6, ppm):

0.6-2.0 (9H, m),

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

7.53 (1 H, s),

7.54 (1 H, s),

12.66 (1 H, s).

Example L

1. According to this embodiment, allyl bromide in an amount of 2.91 g is added dropwise to a stirred suspension consisting of ethyl 2- (2-tritylaanin-3'-thi-aza-4-yl) -2-hydroxyiminoacetate in the form of syn. of isomer and 10 g, followed by ml, Ν-dimethylformamide in 100 ml and potassium carbonate in 4.54 g while cooling in an ice bath and the addition is carried out in 5 minutes. The mixture was stirred at the same temperature for 4 hours. Then 200 ml of water was added to the mixture and the resulting solution was then extracted twice with diethyl ether. The extract thus obtained was washed with a saturated aqueous solution of sodium chloride and then dried with magnesium sulfate. This solution is then concentrated under vacuum and the residue is then triturated with a solution of n-hexane and diethyl ether. The precipitate was collected by filtration to give ethyl 2- (2-tritylaminothiazol-4-yl) -2-aliyloxyiminoacetate as the syn isomer in a yield of 9.4 g. ranging from 130 to 132 ° C.

Product characteristics:

IR at _max (nujol):

3380, 1735, 1520, 1500 cm long

N.M.R. δ (DMSO-d 6, ppm):

1.08 (3H, t, J = 7Hz);

3.96 (2H, q, J = 7Hz),

4.54 (2H, band d, J = 5Hz),

5.0-5.5 (2 H, m),

5.6-6.3 (1 H, m),

6.90 (15H, s-band),

7.74 (1 H, S).

2. According to this embodiment, solution 2- (272

ethyl triethylaminothiazol-4-yl) -2-allyloxyiminoacetate in the form of the syn isomer and 8.7 g, 50% formic acid (42.5 ml) and tetrahydrofuran (42.5 ml) are stirred at 60 ^° C for for 40 minutes. After concentrating the resulting solution under vacuum, the residue obtained is dissolved in ethyl acetate, then washed with aqueous sodium bicarbonate solution to saturated aqueous sodium chloride solution, and finally dried over magnesium sulfate. The resulting solution was concentrated in vacuo and chromatographed on silica gel, eluting with benzene and ethyl acetate to give 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetate as described above. ethyl acetate in the form of the syn isomer and in a yield of 3.7 g, m.p. 102-104 ° C.

Product features:

IR at _max (nujol):

3460, 3260, 3130, 1725, 1620, 1540

1460 cm ¹ .

N. M. R. <5 (DMSO-d 6, ppm):

1.25 (3H, t, J = 7Hz),

4.30 (2Ή, q, J = 7Hz)

4.61 (2H, dd, J = 5Hz, 1Hz),

5.0-5.5 (2 H, m),

5.6-6.5 (1 H, m),

6.95 (1 H, s),

7.28 (2 H, s).

3. According to this embodiment, a solution consisting of ethyl 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetate in the form of the syn isomer and in an amount of 3.6 g, further a 2 N aqueous sodium hydroxide solution in an amount of 14, 1 ml, tetrahydrofuran (14.1 ml) and methanol (15 ml) were stirred at 40 ° C for 1.5 hours. The resulting solution was concentrated in vacuo and the residue was dissolved in water. The pH is then adjusted to 2.8 with a 10% hydrochloric acid solution while cooling in an ice bath, whereupon a precipitate is collected which is collected by filtration, then washed with water and acetone and dried. The resulting product is 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetic acid as the syn isomer. Yield: 1.91 g, m.p. 187 DEG C. (dec.).

Product characteristics:

IR in ', _ax (nujol):

3350, 1630, 1580, 1460 ^cm-first

N.M.R. δ (DMSO-d 6, ppm):

4.61 (2H, d, J = 6Hz),

Ď17953

5.1-5.5 (2 H, m),

5.7-6.2 (1 H, m),

6.84 (1 H, s),

7.25 (2H, s).

Example M

1. According to this embodiment, propargyl bromide in an amount of 4.16 g is added to the suspension

Ethyl 2- (2-trityl-aminothiazol-4-yl) -2-hydroxyiminoacetate in the form of a syn isorner at 10 g, potassium carbonate at 4.84 g and N, N-dimethylformaimide at 22 ml under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 100 minutes. This measure separates the insoluble matter, which is separated by filtration, and then washes the precipitate with a small amount of dimethylformamide. Thereafter, the wash solution and the filtrate were combined and 400 ml of water were added. Thereafter, the suspension is subjected to extraction with 400 ml of ethyl acetate, the extract is washed with a saturated aqueous solution of sodium chloride and then dried with magnesium sulfate. After the solution was treated with activated carbon, the solution was concentrated in vacuo. The residue is triturated with diisopropyl ether. The resulting precipitate was collected by filtration, washed with diisopropyl ether to give

Ethyl 2- (2-tritylaminothiazol-4-yl) -2-propargyloxyiminoacetate as the syn isomer in an amount of 8.34 g.

Product characteristics:

W IR _max (nujol):

3290, 2225, 1735 cm -1.

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

1.12 (3H, t, J = 7Hz),

3.47 (1 H, t, J = 3 Hz),

3.97 (2H, q, J = 7Hz),

4.67 (2H, d, J = 3Hz);

6.95 (1 H, s),

7.28 (1 H, s),

8.77 (1 H, s).

2. According to this embodiment, 50% formic acid of 41 ml is added to a solution of ethyl 2- (2-tritylaminothiazol-4-yl) -2-propargyloxyiminoacetate as the syn isomer of 8.2 g and tetrahydrofuran of 41 ml and the mixture was stirred at 60 ° C for one hour. The resulting solution was concentrated to half its original volume under reduced pressure and the resulting precipitated mass was collected by filtration and then washed with diisopropylether. The filtrate and wash solution were combined and then concentrated in vacuo. The residue is added to 200 ml of ethyl acetate with stirring. The resulting insoluble materials were collected by filtration and washed with diethyl ether to yield

2- (2-Amino-thiazol-4-yl) -2-propargyloxyiminoacetate in the form of the syn isomer in an amount of 0.3 g. The filtrate and ethyl acetate of acetic acid used as the wash solution were combined, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solution twice and then this mixture is dried over magnesium sulfate. The solution was treated with charcoal and concentrated in vacuo. The residue is dried under vacuum after the addition of benzene. The residue is subjected to chromatography on a silica gel column using benzene and ethyl acetate as the eluent. The eluate is concentrated under vacuum and the residue is triturated with diisopropyl ether. A solid is precipitated by filtration and washed with diisopropyl ether to give the same compound as above as the syn isomer. Yield 2.658 g.

Product characteristics: The I.R. spectrum and the N.M. R. spectrum are the same as the compound obtained according to the procedure of embodiment (3) in Example I.

Example 1 a d N

Sodium bicarbonate (0.84 g) was added to a suspension of 2- (2-formamidothiazol-4-yl) oxalic acid (2 g) in water (120 ml) to prepare a solution. Ethyl 2-aminooxyacetate hydrochloride (4.56 g) was added to the solution, which was stirred at ambient temperature for 3 hours while adjusting the pH to 6 by adding sodium bicarbonate. The mixture is adjusted to 1.5 with hydrochloric acid, the solution is salted out and extracted with ethyl acetate for a total of three times. The extract obtained was further dried over magnesium sulphate and then concentrated in vacuo. The residue is triturated with diethyl ether and the precipitated mass is collected by filtration and dried to give 2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetic acid as the syn isomer, yielding:

1.44 g. Melting point: 112 DEG C. (dec.).

Nature of product illusion:

IR at _max (nujol):

3150, 1740, 1670, 1550 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

1.23 (3H, t, J = 7Hz). 4.16 (2H, q, J = 7Hz);

4.77 (2 H, s),

7.56 (1 H, s),

8.54 (1 H, s).

Example O

According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer in an amount of 60 g and further 1-bromo-2-chloroethane in an amount of 54.1 g, potassium carbonate in an amount of 78 g and N, N-dimethylformamide 200 ml were treated in a similar manner to Example F- (1) to give ethyl 2- (2-chloroethoxyimino) -3-oxobutyrate as the syn isomer, yield 83%. 6 g, the product being in oil form.

Product characteristics:

IR in, _nax (film):

1740, 1680, 1430 ^cm-first

N.M.R. δ (CC14, ppm):

1.34 (3H, t, J = 7Hz);

2.34 (3 H, s),

3.72 (2H, t, J = 6Hz),

4.28 (2H, q, J = 7Hz);

4.46 (2H, t, J = 6Hz).

2. According to this embodiment, ethyl ethyl 2- (2-chloroethoxyimino) -5-oxobutyrate in the form of the syn isomer and in the amount of 83.6 g and further sulfuryl chloride in the amount of 52.4 g and acetic acid in the amount of 83.6 ml are treated in a similar way as indicated in the embodiment of Example F- (2) to give the above process was prepared 2- (2-chloroethoxyimino) ^-3-oxo-4-c; hlorbutyrát syn isomer, wherein the product is an oily substance. Yield 68 g.

Product characteristics:

IR i> _max (film):

1740, 1720 cm ^-1

N.M.R. δ (CC14, ppm):

1.32 (3H, t, J = 7Hz),

3.70 (2H, t, J = 6Hz),

4.29 (2H, q, I = 7Hz),

4.47 (2 H, s),

4.48 (2H, t, J = 6Hz).

3. According to this embodiment, ethyl ethyl 2- (2-chloroethoxyimino) -3-oxo-4-chlorobutyrate is in the form of the syn isomer at 68 g, followed by thiourea at 20.2 g, sodium acetate trihydrate at 36.2 g, ethanol (270 ml) and water (170 ml) were treated in a similar manner to that described in Example F- (3) to give 2- (2-aminothiazole-4-) as described above. yl) -2- (2-chloroethoxyimino ethyl acetate) in the form of the syn isomer, the yield of this product being

33.7 g. The melting point of this product is 126 to 128 ° C.

Product characteristics:,

IR at _max (nujolj:

3440, 3260, 3140, 1725,

1620, 1540 cm ¹

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

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

3.78 (2H, t, J = 6Hz),

4.1 - 4.6 (4H, m),

6.96 (1H, sj,

7.27 (2H, sj.

4. According to this embodiment, 2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) ethyl acetate in the form of the syn isomer in an amount of 30.5 g, followed by 1N aqueous sodium hydroxide solution in an amount of 220 ml , methanol (110 ml) and tetrahydrofuran (140 ml) were treated in a similar manner to that described in Example F- (4) to give 2- (2-aminothiazol-4-yl) acid. 1- (2-Chloroethoxyimino) acetic acid as the isomer, yield 23.4 g, m.p. 201 DEG C. (dec.).

Product characteristics:

IR at _max (nujolj:

3210, 3100, 1640, 1620, 1580 cm ¹

N.M.R. δ (DMSO-d 6, ppm):

3.83 (2H, t, J = 6Hz),

4.36 (2H, t, J = 6Hz),

6.92 (1H, sj,

7.30 (2 H, s).

5. According to this embodiment, 2- (2-amino-thiazol-4-yl) -2- (2-chloroethoxyimino) -acetic acid is in the form of the syn isomer and in an amount of 15 g and acetic anhydride in an amount of 24.5 g; of 11.0 g and tetrahydrofuran in 50 ml were treated in a similar manner to that of Example F- (5) to give 2- (2-formamidothiazole-4-). 2-chloro-2-chloroethoxyimino) acetic acid in the form of the syn isomer and the yield of product is 13.4 g. M.p. 155 ^DEG C. (dec.).

Product characteristics:

IR at _max (nujol):

3100, 1740, 1690, 1660 cm ^{-1 1} 17959

N. M R δ (DMSO-d 6, ppm):

3.87 (2H, t, J = 6Hz),

4.40 (2H, t, J = 6Hz);

7.60 (1 H, s),

8.56 (1 H, s),

12.62 (1H, s band).

Example P

A suspension of 2- (2-formamidothiazol-4-yl) oxalic acid (3.0 g) in methanol (60 ml) and water (60 ml) was prepared and the pH of the suspension adjusted to 8 with 1N aqueous sodium hydroxide solution while stirring. 2,2,2-Trifluoroethoxyamine hydrochloride (2.24 g) was added to the treated solution and the pH of the resulting solution was adjusted to 2.5-3 with 1N aqueous sodium hydroxide. The solution was stirred at ambient temperature for 1.5 hours and methanol was removed from the resulting solution under reduced pressure. This gives a concentrated solution, the pH of which is adjusted to 7 with 1N aqueous sodium hydroxide solution, and the solution is further washed with ethyl acetate. Additional ethyl acetate was added to the obtained aqueous solution, and the pH was adjusted to 1.5 with 10% hydrochloric acid, then extracted with ethyl acetate. The resulting aqueous layer was then re-extracted with ethyl acetate. The extracts thus obtained were combined, washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. This solution was then concentrated in vacuo to give 2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetic acid as the syn isomer, yield 2.4 g. The melting point of the product thus prepared is from 162 to 163 ° C (with decomposition).

Product characteristics:

IR at _max (nujol):

3200, 1700, 1600, 1560 ^cm-1

N.M.R. 8 (DMSO-d6, ppm):

4.83 (2H, q, I = 8.5Hz),

7.65 (1 H, s),

8.58 (1 H, s),

12.60 (1H, s band).

Example Q

Following the procedure of this example, the acid was formed

2- (2-formamidothiazol-4-yl) oxal in an amount of 10 g, followed by sodium bicarbonate in an amount of 4.2 g and a tert. Butyl 2-aminopoxyacetate (8.1 g) was treated in a similar manner to that described in Example N to give an oily matter. The oily substance was then triturated with n-hexane and the precipitated mass collected by filtration and dried to give 2- (2-formamidothiazol-4-yl) -2-tert-butoxycarbonylmethoxyiminoacetic acid as the syn isomer, yield

11.3 g. Melting point: 117 DEG C. (dec.).

C harak t er Product Name:

IR at _max (nujol):

3180, 3140, 1750, 1690, 1630 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

1.46 (9H, s);

4.66 (2 H, s),

7.56 (1 H, s),

8.56 (1 H, s),

12.67 (1H, s-band).

Example R

1. According to this embodiment, ethyl 2-hydroxyimino-3-oxobutyrate in the form of the syn isomer at 100 grams and further N, N-dimethylformamide at 300 ml, potassium carbonate at 130 g and tricalcium at 121 g are treated in a similar manner, as in Example F- (1), wherein the final product of this embodiment of the invention is ethyl 2-n-octyloxyimino-3-oxobutyrate in the form of the syn isomer at 165.5 g, and the product it takes the form of oil.

Product characteristics:

IR in _max (film):

1745, 1695, 1470 cm ¹

N.M.R. δ (CC14, ppm):

0.6-2.1 (18H, m),

2.35 (3 H, s),

4.0-4.6 (4H, m).

2. According to this embodiment, ethyl 2-n-octyloxyimino-3-oxobutyrate in the form of the syn isomer at 165.5 g, and sulfuryl chloride at 84.7 g and acetic acid at 165 ml are treated in a similar manner to reported in Example F- (2), wherein the end product of this embodiment of the present invention is ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate as the syn isomer in an amount of 169.6 g. oils.

Product characteristics:

I. R. Vmax (phi).

1745, 1710, 1465 cnv ¹

217939

N.M.R. δ (CC14, ppm):

0.6-2.1 (18H, m),

4.0 - 4.6 (4H, m),

4.48 (2 H, s).

3. According to this embodiment, ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate is in the form of the syn isomer and in an amount of 169.6 g and further thiourea in an amount of 42.3 g, sodium acetate trihydrate in an amount of 75.5 g, water of 420 ml and ethanol of 1020 ml are treated in a similar manner to that described in Example F- (3), the final product of this embodiment of the process being 2- (2-aminothiazol-4-yl) Ethyl 2-n-octyloxyiminoacetate in the form of the syn isomer at 65 g and the melting point of the product thus prepared is in the range of 77 to 78 ° C.

Product characteristics:

IR y _max

3470, 3250, 3125, 1735, 1545, 1465 cm ^-1

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

0.81 (3H, t, J = 6Hz),

0.6 - 1.9 (15H, ia,

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

4.28 (2H, q, J = 7Hz),

6.86 (1H, sj,

7.02 (2H, s-band).

4. According to this embodiment, ethyl ethyl 2- (2-aminothiazol-4-yl) -2-n-octyloxyiminoacetate is in the form of the syn isomer and 64 g and a 2N aqueous sodium hydroxide solution of 196 ml, methanol of 196 ml and 300 ml of tetrahydrofuran were treated in a similar manner to that described in Example F- (4), the end product of this process being 2- (2-aminothiazol-4-yl) -2- n-octyloxyiminoacetic acid in the form of the syn isomer in a yield of 52.5 g and the melting point of this product is 146 ° C (dec.).

Product characteristics:

IR in _nx (nujol):

3170, 1635, 1565, 1460 cni ' ¹

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

0.86 (3H, t, J = 6Hz),

0.6-1.9 (12H, m),

4.06 (2H, t, J = 6Hz),

6.81 (1H, sj,

7.22 (2 H, s).

5. According to this embodiment, 2- (2-aminathiazol-4-yl) -2-n-octyloxyiminoacetic acid is in the form of the syn isomer and in an amount of 20 g and acetic anhydride in an amount of 27.3 g and formic acid in an amount of 12.3 g were treated in a similar manner to that described in Example F- (5), the final product of this embodiment being 2- (2-formamidothiazol-4-yl) -2-n-octyloxyiminoacetic acid. in the form of the syn isomer and the yield of this product is 21.3 g.

Product characteristics:

IR P ' _13X (nujol):

3350, 3150, 3050, 1700, 1675, 1560 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.0 (15H, m),

4.16 (2H, t, J = 6Hz);

7.56 (1 H, s),

8.57 (1H, s,

12.67 (1 H, s).

Example 1

1. N, N-dimethylformamide (0.16 g) and phosphorus oxychloride (0.34 g) are mixed to prepare a Vilsmeier reagent in a conventional manner, and the resulting Vilsmeier reagent is suspended in dry ethyl ester. of acetic acid. To this suspension was then added 2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetic acid in the form of the syn isomer in an amount of 0.46 g while stirring and the mixture was cooled in an ice bath, then this solution was Stir at the same temperature for 30 minutes to prepare an active acid solution. P-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (2.10 g) was dissolved in ethyl acetate (200 mL). To this solution is then added an activated acid solution obtained as described above, at a temperature of -20 ° C, with the solution stirred at a temperature ranging from -20 to -5 ° C for 1.5 hours. clock. Water and ethyl acetate (100 mL) were added to the resulting solution at -20 ° C to give an insoluble product which was collected by filtration, washed with water and acetone, and then dried to give p-nitrobenzyl 7- [2- (2-formamido-α-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate in the form of the syn isomer in 0.6 g. The filtrate obtained above is then removed. ethyl acetate and the resulting aqueous layer was extracted twice with ethyl acetate (50 ml). The resulting ethyl acetate layer and the extract were combined, washed with a 10% aqueous solution of hydrochloric acid, then with a saturated solution of sodium bicarbonate in water and with a saturated aqueous solution of sodium chloride, and then dried with magnesium sulfate. After ethyl acetate was removed from the solution, diethyl ether was added to the resulting residue. This results in an insoluble product which is collected by filtration to give the same compound of the invention in an amount of 0.25 g. The melting point of the product thus prepared is from 226 to 228 ° C (with decomposition). The total yield is thus 0.85 g.

Product characteristics:

IR ( _max ):

3250, 1780, 1720, 1685, 1645,

1605, 1550, 1520 ^cm-1

NMR <5 _ppm (DMSO-dd:

3.45 (2H, s-band),

3.93 (3H, sj,

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

5.50 (2 H, s),

5.95 (1H, dd, J = 5.8 Hz),

7.43 (1H, sj,

7.72 (2H, d, J = 9Hz),

8.28 (2H, d, J = 9 Hz),

8.55 (1 H, s),

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

2. According to this embodiment, p-nitrobenzyl 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 0.4 g, and the mixture was subjected to a 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 removal of insoluble materials, the resulting filtrate is 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 vigorously. 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 sulphate and then concentrated under reduced pressure to give 7- [2- (2-) 2- 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 ( decomposition).

Product characteristics:

IR at _max (nujol):

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

NMR <5 _ppm (DMSO-d 6):

3.57 (2H, s-band),

3.91 (3 H, s),

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

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

7.44 (1 H, s),

8.52 (1H, sj,

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

12.60 (1 H, s).

3. According to this embodiment, 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-oephem-4-carboxylic acid is in the form of the syn isomer in an amount of 0.4 g is suspended in methanol in an amount of 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-3-cephem-4-carboxylic acid in the form of the syn isomer 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:

IR in _niax (nujol):

3300, 1780, 1730, 1670, 1630, 1545'cm ^-1 .

NMR .delta. _Ppm (DMSO-d6):

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 = 5.8 Hz);

6.92 (1 H, s),

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

4. In this embodiment, the hydrochloride of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoiacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 1, 5 g of 0.56 g of sodium bicarbonate are dissolved in 50 ml of water at ambient temperature with stirring, and then freeze-dried. To this product obtained above was added dropwise a solution of 0.93 g of iodomethyl hexanoate in dimethylformamide (5 ml) dropwise to a solution of the above product in dimethylformamide (15 ml) at a temperature of -5 ° C. 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 thus obtained was extracted with ethyl ester. of acetic acid in an amount of 50 ml, said extraction being performed twice in total. 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 then concentrated under reduced pressure. The concentrate thus obtained was washed with n-hexane (50 ml) and n-hexane (50 ml) and diethyl ester (25 ml) were added to the residue, and the solution was allowed to stand in a refrigerator overnight. 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-cartoxylate in the form of the syn isomer, the yield of this mixture being 1.0 g.

Example 2

1. 2- [2- (2,2,2-Trifluoroacetamido] -4-thiazolyl] -2-methoxyiminoacetic acid in the form of the syn isomer is added in an amount of 0.65 g at temperature 0 ° C to a Vilsmeier reagent, previously prepared from dimethylformamide and phosphorus oxychloride, in 10 ml of ethyl acetate, and stirred at the same temperature for 40 minutes to prepare activated acidic solution. This activated acid solution was then added dropwise to a solution of ^{7-amino-2,3-dimethyl-l-ethyl-3-cephem-4-carboxylate} 0.5 g of trimethylsilylacetamide 1.73 g in ethyl acetate 30 ml at -20 [deg.] C., and the mixture is stirred at the same temperature for 40 minutes, to which 10 ml of water is added and the resulting ethyl acetate layer is stirred for 30 minutes. The mixture was separated and washed with water, 30 ml of water was added and the pH of the mixture was adjusted to 7.5 with sodium bicarbonate while cooling in an ice bath. The mixture was then shaken vigorously, and the resulting aqueous layer was separated. 50 ml of ethyl acetate were added to the aqueous solution, the pH of the mixture was adjusted to 2 with dilute hydrochloric acid while stirring the mixture, and the resulting ethyl acetate layer was separated, then washed with water and a saturated aqueous solution. sodium chloride, treated with activated carbon, dried over magnesium sulphate and then concentrated under reduced pressure. The residue thus obtained is triturated with diisopropyl ether to give 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 in a yield of 0.9 g.

Product characteristics:

IR at _max (nujof):

3250, 1780, 1725, 1680, 1650 cm ¹ .

NMR and _p - _jm (DMSO-d):

1.43 (3H, d, J = 8Hz);

1.92 (1 H, s),

3.82 (3 H, s),

3.98 (1H, q, J = 8Hz),

5.18 (1 H, d, J = 6 Hz),

5.73 (1H, AB-q, J = 6Hz);

7.43 (1 H, s),

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

According to this embodiment, 7- {2- [2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido} -2,3-dimethyl-3-cephem-4-carboxylic acid form of the syn isomer and 0.86 g in an aqueous solution of 9 ml containing sodium acetate trihydrate

2.3 g, and this solution was then stirred at ambient temperature for 19 hours. The insoluble material was removed by filtration, and the filtrate was adjusted to pH 2.5 with 10% hydrochloric acid, while cooling in an ice bath. The above precipitate is collected by filtration, washed with water and dried to give 7- (2- (2-amino-4-thiazotyl) -2-methoxyimino-17959-noacetamido) -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 band), 1670, 1630 ^cm-first

NMR δ _ppm (DMSO-d 6):

1.44 (3H, d, J = 7Hz),

1.98 (3 H, s),

3.57 (1H, q, J = 7Hz);

3.82 (3 H, s),

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

5.73 (1H, dd, J = 5.8 Hz),

6.76 (1 H, s),

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

Example 3

According to this embodiment, the mixture consisting of 2- [2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetic acid in the form of the syn isomer and in an amount of 0.8 g, dimethylformamide in an amount of 0, 20 g of phosphorus oxychloride in 0.41 g ethyl acetate 10 ml was stirred for 30 minutes while cooling in an ice bath to prepare an activated acid solution ^1, wherein the process takes place in a similar manner as indicated in the procedure according to Example 2- (1). In parallel, a solution consisting of 7-amino, -3-methoxy-3-cephem-4-carboxylic acid in the form of hydro-chloride in an amount of 0.6 g and trimethylsilylacetamide in an amount of 3 g in ethyl acetate of 15 ml is separately prepared. Stir at 40 ° C for 3 hours. To the thus prepared solution is then added dropwise an activated acid solution at a temperature ranging from -10 ° C to -20 ° C for 2 minutes, and the mixture is then stirred at the same temperature for 1.5 hours. Water (10 ml) was then added to the resulting solution to visualize the ethyl acetate layer, which was separated and allowed to stand. In this way, a precipitate is formed which is collected by filtration to give the final product, 7 {2- [2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido) -3-methoxy -3-cephem-4-carboxylic acid in the form of the syn isomer, yielding 0.3 g. Next, the aqueous layer which is separated from the ethyl acetate layer is treated with ethyl acetate and the extract is combined with the mother liquor. , obtained as described above. The ethyl acetate solution obtained is then washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and then filtered. The filtrate is concentrated under reduced pressure and the residue is washed with diethyl ether to give the same compound as above in 0.25 g. The total yield is 0.55 g.

Product characteristics:

IR at _max (nujol):

3230, 1770, 1715, 1650, 1580 ^cm-first

NMR < $ _ppm (DMSO-d6):

3.62 (2H, AB-q, J = 16Hz),

3.78 (3 H, 3 H, s),

3.93 (3 H, s),

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

5.54 (1H, dd, J = 8.4Hz),

7.60 (1 H, s),

9.69 (1 H, d, J = 8 Hz).

2. According to this embodiment, a solution consisting of 7- {2- [2- (2,2,2-trifluoroacetamido) -4-thiazolyl] -2-methoxyiminoacetamido-3-methoxy-3-cephem-4 carboxylic acids in the form of the syn isomer and in an amount

0.55 g and sodium acetate as the trihydrate (1.76 g), ethyl acetate (3 ml), tetrahydrofuran (3 ml) and water (5.5 ml) were stirred at room temperature overnight. The resulting aqueous layer was separated from the resulting mixture, washed with dichloromethane and then evaporated under reduced pressure to remove the organic solvent. The pH of the aqueous solution was then adjusted to 4.2 ' while cooling in a water bath, and the solution was then purified in a chromatography column packed with Diaion HP-20 (a trade name of the product manufactured by Mitsubishi Chemical Industries Ltd.). amount 15 ml. After washing the column with water, the title compound is eluted with a 20% aqueous solution of isopropyl alcohol. The eluate is then concentrated under reduced pressure and the residue is lyophilized to give 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-methoxy-3-methoxy-3- fem-4-carboxylic acid in the form of the syn isomer, and the yield of this product is 0.4 g. Melting point: 185-190 ° C (dec.).

Product characteristics:

IR at _max (nujol J:

3300, 1770, 1660, 1630, 1540 cm ¹ .

NMR d _ppm (DMSO-d 6):

3.60 (2H, s-band),

3.75 (3 H, s),

3.83 (3 H, s),

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

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

6.82 (1 H, s),

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

Example 4

1. In this embodiment, a suspension of p-nitrohenzyl 7-phenylacetamido-3-cephem-4-carboxylic acid is obtained ^. boxylate in amount

10.50 g in dry dichloromethane (100 ml) dry dry pyridine (2.14 g) was added in dry dichloromethane (100 ml). Phosphorus pentachloride (5.50 g) was added to the solution thus prepared at - 10 ° C, and the mixture is stirred at -5 ° C for 45 minutes and then at 10 ° C for 1 hour. To the resulting mixture was further added 520 g of methanol, and the mixture was then stirred at -20 ° C for 1.5 hours. The above precipitates are collected by filtration, washed with dichloromethane (120 ml) and finally with diethyl ether (130 ml), then dried to give p-nitrobenzyl-7-amino-3. -cephem-4-carboxylate in 7.90 g. m.p. 182 DEG C. (dec.).

Product characteristics:

IR D _max (nujol):

1790, 1730, 1638, 1600 cm ¹ .

NMR δ _ppm (DMSO-d 6):

3.78 (2H, d, J = 4Hz);

5.27 (2H, dd, J = 5Hz),

5.44 (2 H, s),

6.87 (1H, t, J = 4Hz),

7.72 (2H, d, J = 9Hz),

8.26 (2H, d, J = 9Hz).

2. According to this embodiment, a Vilsmeier reagent prepared from dimethylformamide in an amount of 0.43 g and phosphorus oxychloride in an amount of 0.92 g is suspended in dry ethyl acetate in an amount of 10 ml. To this suspension was then added 2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetic acid as the syn isomer in an amount of 1.15 g while cooling in an ice bath while stirring. Stirring is then continued for 30 minutes at the same temperature to prepare the activated acid solution. Simultaneously, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate as hydrochloride and 1.79g and trimethylsilylacetamide (5.0g) were dissolved in ethyl acetate (40ml). To the thus prepared solution is then added an activated acid solution at -20 ° C, all at once, and the mixture is stirred at the same temperature for 2.5 hours. 60 ml of water and 200 ml of ethyl acetate were added to the resulting solution, and the ethyl acetate layer was separated and then washed with a 10% solution of 60 ml of hydrochloric acid, further saturated with aqueous sodium bicarbonate solution. 60 ml and finally 50 ml of aqueous sodium chloride solution. The solution is then dried with magnesium sulfate, treated with activated carbon and finally concentrated under reduced pressure. This yields a residue to which diethyl ether is added and the resulting precipitate is collected by filtration. The above procedure afforded p-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer in a yield of 1.30 g. Melting point: 210 ° C to 212 ^° C (dec.).

Product characteristics:

IR at _max (nujol):

3240, 1780, 1730, 1690, 1655, 1605, 1550,

1520 cm ” ¹ .

N.M.R., DMSO-de:

3.65 (2H, s-band),

3.90 (3 H, s),

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

5.43 (2 H, s),

5.95 (1H, q, J = 5.8Hz),

6.68 (1 H, t, J = 4 Hz),

7.42 (1 H, s),

7.72 (2H, d, J = 9Hz);

8.28 (2H, d, J = 9Hz)

8.46 (1 H, s),

9.72 (1 H, d, J = 8 Hz).

3. 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 in amount of 1.25 g in methanol (40 ml) and tetrahydrofuran (50 ml), 10% palladium on carbon (0.65 g) are added and the mixture is subjected to catalytic reduction at ambient temperature and atmospheric pressure for 3 hours, 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 solution 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. 7- [2- (2-Formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is obtained in the form of the syn isomer, yielding 0 60 g. The melting point of this product is from 176 to 183 ° C (dec.).

Product characteristics:

IR at _max (nujol):

3250, 1780, 1690, 1660, 1550 tin ¹ .

NMR .delta. _Ppm (DMSO-d6):

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, I = 8Hz),

12.63 (1 H, s).

4. 7- [2- (2-Formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 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 the aqueous solution was washed with ethyl acetate (10 ml) and dichloromethane (15 ml). Nitrogen is then introduced into the aqueous solution to remove the last organic solvent residue and the aqueous solution is lyophilized to give 7- (2- (2-amino-4-thiazolyl) -2-methoxyoxyiminoacetamido) hydrochloride. 3-Cephem-4-carboxylic acid in the form of the syn isomer in a yield of 83 mg, m.p. 180 DEG-190 DEG C. (dec.).

Product characteristics:

IR _inax (nujol):

3300, 1770, 1710, 1660, 1630 cmd.

NMR δ _ppm (DMSO-d 6):

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).

5. According to this embodiment, the solution consisting of 7- (2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer in 10.8 g of concentrated hydrochloric acid, 11 g of methanol and 350 ml of methanol are stirred at ambient temperature for 4 hours, then the solution is concentrated under reduced pressure and ethyl acetate is added. The pH of the above solution was adjusted to 8.0 with a saturated aqueous sodium bicarbonate solution, and the aqueous layer was separated and washed with diethyl ether. aqueous solution, the pH of the aqueous solution being adjusted to 4.0 using a 10% hydrochloric acid solution. The precipitates are collected by filtration and then the precipitates are washed with water. The product of this embodiment of the present invention is 7- (2- (2-amino-4-thihiazolyl) -2-methoxyiminoacetamido) -3-o-em-4-carboxylic acid in the form of the syn isomer, yield 8.2. g. The melting point of this product is greater than 290 ° C.

Product characteristics:

IR _{ν ηΐί) χ} (neat)

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

1622 tin ¹ .

NMR δ _ppm (DMSO-d 6):.

3.60 (2H, s-band),

3.84 (3 H, s),

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

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

6.52 (1H, band t),

6.76 (1 H, s),

7.26 (2H, s-band),

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

6. Add 1.04 g sodium hydrogen carbonate to a solution of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephalic acid hydrochloride. The 4-carboxylic acid isomer of the isomer, 2.6 g, in 100 ml of water, stirred and added at room temperature to the ice bath solution. The resulting solution is lyophilized to give the final product, sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer.

Product characteristics:

IR at _max (nujo.1):

3100, 1760, 1650, 1590, 1530 cm ¹ .

N. M. R. δ (0- /.), Ppmj:

3.60 (2H, q-band),

4.00 (3H, sj,

5.22 (1 H, d),

5.88 (1 H, d),

6.35 (1 H, q),

7.03 (1H, sj.

7. 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) 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 is triturated with diethyl ether. The end product of this invention is n-hexanoyloxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer, yielding 750 mg.

Product characteristics:

IR at _max (nujol):

3170, 1780, 1750 (range), 1670, 1630,

1530 cm ¹ .

N.M.R. δ (CDCl 3, ppm):

0.68-1.84 (9H, ia,

2.20-2.48 (2H, t),

3.20-3.80 (2H, m),

4.02 (3 H, s),

5.04 (1 H, dj,

5.60-6.20 (3H, ia,

6.62 (1 H, q),

6.80 (1H, sj,

7.72 (1 H, dj,

8. In this embodiment, the p-nitrobenzyl 7- [2- (2-formido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate is in the form of the syn isomer and an amount of 1.1 g is suspended in a mixture of 10 ml of ethanol and 15 ml of water, and a 1 N aqueous solution of potassium hydroxide (6 ml) is added dropwise to the suspension thus obtained at a temperature of about 5 ml. from 5 to 7 ² C over 10 minutes, then agitation is carried out with this mixture for 10 minutes. the pH of the resulting solution was adjusted to pH 7.5 with 10% hydrochloric acid, with the further steps washing with ethyl acetate and finally adjusting the pH to 2.5 again with 10% hydrochloric acid to precipitate crystals, which are separated by filtration, resulting The dilution is a mixture of 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of

0.32 g and 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, which compound is present in an amount of 0.035 g.

9. 7- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 5 g. gradually added to an aqueous solution of 30 ml total sodium bicarbonate in an amount of 1.04 g, the addition being carried out at a temperature ranging from 35 to 40 ° C. The solution is then stirred at a temperature ranging from 50 to 53 ° C for 30 minutes. Insoluble matter was formed by this procedure, which was removed from the resulting solution by filtration, and the filtrate was treated with activated charcoal (0.3 g) and finally filtered. Thereafter, the filtrate is lyophilized and the final product of this embodiment is sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer. The product is 4.2 g.

Product characteristics:

IR at _max (nujol):

3300-3100, 1760, 1670, 1585, 1530 cm -1.

NMR .delta. _Ppm (DMSO-d6):

3.50 (2H, s-band),

3.83 (3 H, s),

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

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

6.13 (1H, s-band),

6.73 (1 H, s),

7.3 (2H, s-band),

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

10. 7- [2- (2-Amino-thiazol-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 an aqueous solution of calcium hydroxide, which contained 0.111 g in 100 ml of water, and the resulting solution was stirred at ambient temperature for 10 minutes. The solution is then filtered and the filtrate is lyophilized, the final product of this embodiment of the present invention being 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in calcium. in the form of the syn isomer and in a yield of 1.2 g.

Product characteristics:

W IR _max (nujol):

3350, 1760, 1670, 1590, 1535, 1465 ^cm-first

N. M. R. δ (D2O, ppm):

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

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

3.97 (3 H, s),

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

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

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

6.95 (1 H, s).

11. 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 suspension of magnesium hydroxide in an amount of 0.088 g in 100 ml water. the mixture is stirred at 70 ^o C for a time of 30 minutes to prepare the solution. after this · surgery resulting solution was filtered and the filtrate lyophilized, the final product of this embodiment of the invention being 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate magnesium, in the form of the syn isomer and in yield 1.1 g.

Product characteristics:

IR in _inax (nujolj:

3350, 1760, 1660, 1610, 1530, 1460 ^cm-first

N. M. R. δ (D2O, ppm):

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

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

3.96 (3 H, s),

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

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

6.32 (lH, dd, J = 5Hz, 3Hz),

7.98 (1 H, s).

12. 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.

This procedure will form a mixture which was filtered, and the filtrate lyophilized to give the final product according to this embodiment of the invention the arginine salt of 7- [2- ^(2-i aminoth azole-4-yl j -2-methoxyiminoacetamido] -3-cep-4-carboxylic acid in the form of the syn isomer in an amount of 1.35 g.

Product characteristics:

IR in _nlax (nujol):

3350, 3150, 1770, 1650 (band), 1580, 1530,

1460 cm ¹ .

N. M. R. δ (D2O, ppm):

1.4-2.1 (4 H, 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 (1 H, dd, J = 6 Hz, 3 Hz),

7.00 (1 H, s).

13. In this embodiment, 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate is in the form of the syn isomer in an amount of 1.21 g, added to the lysine solution in the form of the hydrochloride and in an amount

0.55 g in 12 ml water. The resulting solution is lyophilized and the final product of this embodiment of the invention is 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid lysine salt. the syn isomer, yielding 1.6 g.

Product characteristics:

IR at _max (nujol):

3350, 3150, 1770, 1600 (band), 1530,

1460 cm ¹ .

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

1.3-2.1 (6H, m);

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

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

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

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

3.97 (2 H, s),

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

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

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

6.99 (1 H, s).

14. A 20% solution of sodium hydroxide in water is added to a suspension of 7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-cephem-4-one. -carboxylic acid in the form of the syn isomer and in an amount of 15 g, in a mixture of ethanol in an amount of 8 ml and water in an amount of 8 ml, at ambient temperature to prepare a solution of pH 7.5. The filtrate and washings were combined (18.3 ml water) and then added dropwise to 46 ml ethanol at 20-25 ^° C with stirring. The mixture was then stirred at the same temperature for 30 minutes, and then 28 ml of ethanol was added dropwise over 30 minutes, followed by stirring at the same temperature for 30 minutes. 2 hours solids are collected by filtration, washed with 20 ml of ethanol and dried under vacuum at ambient temperature to give 7- [2- (2-aminothiazole-) dihydrate. Sodium 4-yl) -2-methoxyiminoacetaniido] -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 at _max (nujol):

3430, 3250, 1760 (range), 1745, 1650,

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

15. Sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer is dissolved in an amount of 15 g. in water of 13 ml at a temperature ranging from 35 to 45 ° C, said addition being carried out with stirring. Thereafter, 52 ml of warm ethanol at 30 ° C was added dropwise to the stirred solution, 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 end product of the process of the invention being 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido dihydrate. Sodium] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 13.45 g.

16. In this embodiment, a 4 N aqueous sodium hydroxide solution is carefully added dropwise to a stirred suspension consisting of 7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) - 3-cep-4-carboxylic acid in the form of the syn isomer and 52 g in 100 ml of water 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 is added dropwise to 2 L of ethanol with stirring during stirring. 30 minutes, and stirring is then continued at ambient temperature for 15 minutes and then at a temperature ranging 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 in the form of the syn isomer in a yield of 46.3 g.

Product characteristics:

IR> _max (nujo-1):

3400, 3300, 3170, 1750, 1650, 1580 ^cm-first

17. 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 g, 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-cephem Sodium -4-carboxylate in the form of the syn isomer.

18. The crystals obtained in Example 4- (14) above are dried over phosphorus pentoxide under vacuum for one day at ambient temperature to give 7- [2]. Sodium (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer.

Example 5

1. The Vilsmeier reagent, previously prepared from 0.22 g of dimethylformamide and 0.46 g of phosphorus oxychloride, is suspended in dry 20 ml of ethyl acetate. To this suspension is added 2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetic acid in the form of an anti-isomer in an amount of 0.62 g while cooling in an ice bath and The mixture was stirred at the same temperature for 30 minutes to prepare an active acid solution, and then added as a one-time addition to the p-nitrobenzyl-7-amino-3-chloro solution. Of 3-cefem-4-carboxylate weighing 1 g and trimethylsilylacetamide (2.58 g) in 20 ml of ethyl acetate at -20 ° C with stirring, and the solution is stirred at a temperature in the range of - 10 to - 20 ° C for a period

1.5 hours. Water (20 ml) was added to the resulting solution and finally stirred at -20 ° C. The above procedure gave an ethyl acetate layer, which was separated, and the remaining aqueous layer was subjected to extraction with ethyl acetate (20 mL). The ethyl acetate layer and the extract were combined, washed with 10% hydrochloric acid (20 ml) twice in total, then with 20 ml water once, with 5% sodium bicarbonate in water. in an amount of 20 ml a total of three times, and finally an aqueous solution of sodium chloride in an amount of 20 ml once. The solution is then dried and further concentrated under reduced pressure. The above measure yields a residue which is washed with diethyl ether (50 ml), resulting in p-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] - 3-chloro-3-cephem-4-carboxylate in the form of an anti-isomer in a yield of 1.27 g. The melting point of the product thus prepared is in the range of 135-145 ° C (dec.

Product characteristics:

I, R. in _max (nujolj:

3150 to 3300 (band), 1780, 1730, 1670 to

1690 (band) cm ^-1 .

NMR and _ppin (DMSO- _dd :

3.83 (2H, AB-q, J = 17Hz),

3.97 (3 H, s),

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

5.41 (2H, s,

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

7.62 (2H, d, J = 8Hz),

8.0 (1 H, s),

8.2 (2H, d, J = 8Hz)

8.42 (1 H, s),

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

12.43 (1 H, s).

2. According to this embodiment, 10% palladium on carbon is used

0.6 g was added to the solution of p-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate as an anti isomer and 1.16 g in 20 ml of methanol and 40 ml of tetrahydrofuran, and the mixture is subjected to a catalytic reduction at ambient temperature and atmospheric pressure for 5 hours. After this reduction, the catalyst was removed from the reaction mixture and the filtrate was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (60 ml) were added to the residue, and the pH of the resulting mixture was adjusted to

7.5 with the aid of an aqueous solution of sodium bicarbonate, and then shake well. After this work-up, an aqueous layer was formed which was separated and 90 ml of ethyl acetate were added to the aqueous solution. The pH of the above aqueous layer is then adjusted to 2.5% with a 10% hydrochloric acid solution, with stirring and cooling on a water bath; an ethyl acetate layer is formed and separated. An 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 brine, dried and then concentrated. under reduced pressure. The residue is washed with diisopropyl ether to give 7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid as The title compound was colored at 210 ° C and decomposed at a temperature greater than 250 ° C.

Product characteristics:

IR at _max (nujolj:

3250, 1780, 1720 (band), 1670 to 1690 cm ^-1 .

100 ALIGN!

Ν. Μ. R. _ppm (DMSO-d):

3.8 (2Η, AB-q, J = 17Hz)

4.0 (3H, S);

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

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

8.05 (1 H, s),

8.47 (1 H, s),

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

12.55 (1H, s band).

3. 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 is added in an amount of 0 4 g is 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-amino-2-amino) -acetic acid hydrochloride as the final product). 4-thiazolyl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of an anti-isomer and in a yield of 0.31 g. The melting point of the product thus obtained is higher than 250 ° C.

Product characteristics:

IR at _max (nujol):

3250, 3200, 1788, 1720, 1680, 1640 cm -1

N. M, R. <J _ppm (DMSO-d 6):

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

4.08 (3 H, s),

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

5.7 (1H, dd, J = 8.8 Hz),

7.59 (1H, sj,

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

Example 6

1. In this embodiment, a Vilsmeier reagent is first prepared from dry dimethylformamide (0.39 g), dry ethyl acetate (1.2 ml) and phosphorus oxychloride (0.84 g) in a conventional manner. To this solution was then added a solution of 2- (1,2,3-thiadiazol-4-yl) -2-methoxyiminoacetic acid in the form of the syn isomer at 0.93 g in 10 ml of ethyl acetate at -15 ° C. ° C to prepare an active acid solution. Simultaneously and separately, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate in an amount of 1.5 g, trimethylsilylacetamide in an amount of 4.6 g and bis (trimethylsilyl jacetamide in an amount of 1 ml Y dry ethyl acetate of 50 ml) Stir at 45 ° C for 5 hours to prepare a solution.

To the above solution is then added in the form of a single addition of the active acid solution obtained as described above, at a temperature of -10 ° C and with stirring. The solution was then stirred at -5 ° C for 1.5 hours. Water was added to the reaction mixture to give insoluble materials which were collected by filtration, then washed with ethyl acetate and finally with water and dried. The resulting product of this embodiment of the process of the invention is p-nitrobenzyl 7- [2- (1,2,3-th ^; adiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as a pale yellow powder and in the form of the syn isomer, yield 1.9 g. The melting point of the above product is 243 ^DEG- 245 ^DEG C. (dec.).

Product characteristics:

IR at _max (nujol):

3250, 1782, 1725, 1655, 1630,

1600, 1520, 1345 cm ^-1

NMR and _ppra (DMSO- _d 6):

3.69 (2H, AB-q, J = 14Hz);

4.00 (3H, sj,

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

5.46 (2 H, s),

6.00 (1H, dd, J = 5.8Hz),

6.68 (1H, t, J = 4Hz),

7.7 - 8.4 (4H, m),

9.44 (1H, sj,

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

2. According to this. Carry out the procedure by adding 10% palladium on activated carbon in an amount of 0.85 g to a solution of p-nitrobenzyl 7- [2- (1,2,3-thiadiazol-4-yl) -2-methoximinoacetamido] - 3-cef-4-carboxylate in the form of the syn isomer at 1.65 g, in methanol (70 ml) and tetrahydrofuran (90 ml), and the mixture is then subjected to catalytic reduction at ambient temperature. and at atmospheric pressure for 3.5 hours. After the reaction, the catalyst is removed from the reaction mixture by filtration and the filtrate is concentrated under reduced pressure. The residue is diluted with water and the mixture is adjusted to a pH of 7 to 8 with sodium bicarbonate, followed by washing with ethyl acetate, and again with ethyl acetate. adjusting the pH to 1.5 with 10% hydrochloric acid and finally extracting the resulting solution with ethyl acetate. The above procedure yields

101

The extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then 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, resulting in 7- [2- (1,2,3-thiadiazol-4-yl) -2-methoxyiminoacetamido] -3- cefem-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. The melting point of this product ranges from 200 to 210 ° C (with decomposition).

Product characteristics:

IR in _niax (nujol):

3250, 2550-2600, 1785, 1715,

1655, 1630, 1600 cm ¹ ,

NMR δ _ppm (DMSO-d 6):

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

7-amino-3-cephem-4-carboxylic acid (1.7 g) and sodium bicarbonate (2.84 g) were dissolved in a mixture of water (35 ml) and acetone (35 ml). Simultaneously, phosphorus oxychloride is added dropwise separately in an amount

1.95 ml to the 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid suspension in the form of the syn isomer and in an amount of

3.42 g, in 34 ml of dry ethyl acetate, added over 10 minutes at 0 to 6 ° C, then stirred at the same temperature for 30 minutes. minutes. The solution thus obtained was further treated dropwise with a solution of 2.39 g of trimeithylsilyilacetamide in 5 ml of ethyl acetate, at a temperature ranging from 0 to 6 ° C for 20 minutes. minutes, and the mixture is then stirred for 20 minutes. To this mixture was added phosphorous oxychloride (1.95 ml) dropwise at the above temperature for 10 minutes, and the mixture was stirred for 30 minutes. Dimethylformamide (1.29 ml) was added dropwise to the above mixture over 10 minutes at the same temperature, and the resulting mixture was stirred for one hour to prepare a clear solution. The above solution is then added dropwise to a solution of 7-amino-3-cephem-4-carboxylic acid at a temperature ranging from -5 to 5 ° C over a period of 30 minutes at a pH of The reaction mixture is stirred for one hour at the same temperature as above. 200 ml of ethyl acetate were added to the resulting solution, and the aqueous layer was separated, washed with methylene chloride, then purged with nitrogen and finally adjusted to pH uprav with acetic acid. This solution is then subjected to a chromatographic column packed with macroporous, non-ionic adsorption resin material "Diaion HP-20" (Trade name of Mitsubishi Chemical Industries Ltd.), eluting with a 20% aqueous solution. isopropyl alcohol. The eluate is concentrated under reduced pressure and then lyophilized to give 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid in the final product. in the form of the syn isomer and in a yield of 2.0 g. This product was identified by the same sample by IR and NMR spectra.

Example 8

1. An amount of 1.2 g of phosphorus oxychloride is added as a single addition to a suspension of 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid in the form of the syn isomer and in an amount of 1 g. 23 g in 12 ml of ethyl acetate are added at 5 DEG C. and the solution is then stirred at 4 DEG to 6 DEG C. for 30 minutes. To this solution is again added phosphorus oxychloride in an amount of 1.2 g and then stirring is carried out for 15 minutes. Next, 0.5 g of dimethylformamide is added to the above solution, in the form of a single addition, and then stirred for 40 minutes to prepare a clear solution. In addition, separation of para-nitrobenzyl ^and benzyl-7-amino-3-cephem-4-carboxylate hydrochloride in an amount of 1.9 g was added to THF 30 ml acetone at 10 ml and then to this mixture was added an aqueous solution with a total volume of 20 ml of sodium bicarbonate in an amount of 0.6 g. To this prepared solution

103

104, the solution prepared above was added dropwise at a temperature ranging from 0 to 5 ° C and at a pH of 8.0. Thereafter, the mixture was stirred at a temperature in the range of -2 to 2 ° C and at a pH of 8.0 for 30 minutes to form an insoluble material which was removed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. In this way a residue is obtained which is triturated with diisopropyl ether. The final product of this embodiment of the invention is p-nitrohenzyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 1.6 g.

Product characteristics:

IR at _max (nujol):

3300, 1780, 1730, 1670, 1520 ^cm-1

NMR 6 _pprn (DMSO- _d 6):

3.60 (2 H, m),

3.81 (3 H, s),

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

5.85 (1H, dd, J = 5Hz, 10Hz),

6.64 (1 H, m),

6.70 (1 H, s),

7.20 (2 H, s),

7.65 (2H, d, I = 10Hz);

8.19 (2H, d, J = 10Hz);

9.60 (1 H, d, J = 10 Hz). ²

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 are 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 for 10 minutes and then stirring was continued at 5 ^° C for 15 minutes. The 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 Mistubishi Chemical Industries Ltd.) in an amount of 80 ml, in this case a 5% aqueous solution of isopropyl alcohol is used as eluent. The fractions containing the present 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 separated by filtration and dried, and the final product of the process according to the invention is 7- (2- (2-amino-4-thiazolyl-2-meithoxyiminoacetamido) -3-cephem-4-carboxylic acid as syn). isomer and in a yield of 2.3 g.

Example 9

P-nitrohenzyl-7-amino-3-cephem-4-carboxylate (3.4 g) was suspended in tetrahydrofuran (60 ml) and an aqueous solution of sodium bicarbonate in water was added to the suspension. amount of 1.2 g with a total volume of 20 ml. To the above solution was added a 1N aqueous solution of sodium hydroxide in a total volume of 30 ml, dropwise at a temperature ranging from 3 to 4 ° C, and then stirred for 20 minutes. The resulting solution was adjusted to pH 7.0 with a 10% hydrochloric acid solution and then concentrated under reduced pressure. The insoluble material is separated by filtration and the filtrate is washed with ethyl acetate. Acetone (30 ml) was added to the filtrate and the mixture was cooled to -5 ° C. Separately, a solution of phosphorus oxychloride, dimethylformamide, trimethylsilylacetamide and 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid was prepared in the form of the syn isomer in an amount of 2.2 g, the same as described above. The solution was then added to the above solution at a temperature in the range of -5 to 0 ° C and a pH in the range of 7.5 to 8.5. The mixture is stirred at a temperature in the range of 3 to 7 ° C and at said pH in the range of 7.5 to 8.5 for 2 hours. This procedure forms an insoluble material which is collected by filtration. The resulting aqueous layer was separated from the filtrate, then washed with ethyl acetate and adjusted to pH 3.0. The final product of this process of the invention is 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 1.1 g.

105

Example 10

1. An amount of 1.646 g of phosphorus oxychloride is added to a suspension of 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetic acid in the form of the syn isomer and 1.0 g of tetrahydrofuran in tetrahydrofuran. 10 ml at a temperature of less than 5 ° C and stirred at the same temperature for 20 minutes, then trimethylsilylacetamide (0.4 g) is added, 0.4 g of Ν-dimethylformamide is stirred for 40 minutes at a temperature below 5 DEG C. This solution is designated A. In addition, 3.5 g of trimethylsilylacetamide is added separately to a suspension consisting of 4 g. nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.5 g) in tetrahydrofuran (15 ml), and the mixture was stirred at ambient temperature for 1.5 hours. after according to this example, the above solution, referred to as solution A, is added in the form of a one-time addition at a temperature of -20 ° C, and the resulting solution is then stirred at a temperature ranging from -5 to 0 ° C for one hour. To the resulting solution was added water 20 ml, and this addition is carried out at a temperature of --20 ⁼ C. The pH of the solution is adjusted to 7.5 with aqueous sodium bicarbonate. 70 ml of tetrahydrofuran and 50 ml of saturated aqueous sodium chloride solution are then added to the solution, which is then shaken vigorously. This procedure creates an aqueous layer which is separated and then subjected to extraction with tetrahydrofuran. In this way, a tetrahydrofuran layer was formed, which was combined with the extract and then washed with a saturated aqueous solution of sodium chloride. The above solution was then dried over magnesium sulfate and further concentrated under reduced pressure. The residue thus obtained is triturated with diisopropyl ether, the final product of this embodiment of the invention being 4-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylate in in the form of the syn isomer and in a yield of 2.5 g.

Product characteristics:

IR at _max (nujol):

3330 1780 1730 1680

1640, 1610 cm ^-1

Á _ppni NMR (DMSO-d):

1.17 (3H, t, J = 7Hz),

3.50 (2 H, m),

4.05 (2H, q, J = 7Hz),

108

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

5.85 (1H, dd, I = 5Hz),

6.67 (1 H, s),

7.17 (2 H, m),

7.63 (2H, d, J = 8Hz),

8.18 (2H, d, J = 8Hz);

10.13 (1H, d, J = 8Hz).

2. To this effect, add 1.0 g of palladium on carbon, moistened with 3 ml of water, to a solution of 4-nitrobenzyl 7- (2- (2-amino-4-thiazolyl) - 2-ethoxyiminoacetamido] -3-methyl-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); The catalyst is subjected to catalytic reduction at ambient temperature under normal pressure for 2 hours, after which the catalyst is removed from the above reaction mixture by filtration and the filtrate is concentrated under reduced pressure. Ethyl acetate was added and the pH was adjusted to 7.5 with aqueous sodium bicarbonate to form an insoluble material which was separated by filtration. After separating by filtration, the aqueous solution is separated, washed with ethyl acetate, the pH is adjusted to 5.5 and then treated with activated carbon. After this step, the aqueous solution is adjusted to pH 3.2 to precipitate a substance which is collected by filtration and then dried, the final product of this embodiment being 7- [2- (2-amino- 4-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

NMR d _ppin (DMSO-d ₆ ):

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

3.57 (2 H, m),

4.08 (2H, q, J = 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 11

1. According to this embodiment, triethylamine in an amount of 2.37 g, dimethylanllin in an amount of 7.12 g and trimethylsilyl chloride in an amount of 3.93 g are added to the stirred suspension of 4-ni217959

107

108

-trobenzyl-7- [2-phenylacetamido] -3-hydroxy-3-cephem-4-carboxylate (10 g) in methylene chloride (200 ml) and the solution was stirred at ambient temperature for 1 hour. Phosphorus pentachloride (4.88 g) was added to the solution at -30 ° C to -25 ° C and stirred at a temperature between -30 ° C and -25 ° C. from -25 to -20 ° C for 3 hours. Methanol (42 ml) was added to the solution at -25 to -20 ° C and the solution was stirred for one hour. Water (35 ml) was added to the solution so prepared at a temperature ranging from -25 to -20 ° C and the solution was stirred at ambient temperature. The precipitate is separated by filtration, then washed with methylene chloride and diethyl ether and finally dried, the final product of this embodiment of the invention being 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate 5.2 g. m.p. 148 DEG C. (dec.

Product characteristics:

IR at _max (nujol):

3440, 3300, 1760, 1740 ^cm-1

NMR δ _Bpm (DMSO- _d 6):

2.8 - 3.7 (2H, mj,

4.90 (1 H, t, J = 4 Hz),

5.29 (1H, d, J = 4Hz),

5.38 (2 H, s),

7.71 (2H, d, J = 8Hz),

8.26 (2H, d, J = 8Hz). ²

2. In this embodiment, phosphorus oxychloride is added in an amount

2.87 g was added dropwise to a solution of N, N-dimethylformamide (1.37 g) in ethyl acetate (10 ml) at a temperature ranging from 5 to 10 ° C. Ethyl acetate (40 ml) was added to the solution and stirred for 40 minutes while cooling in an ice bath. 2- (2-Formamido-4-thiazolyl) -2-methoxyiminoacetic acid is then added to the solution as the syn isomer and 3.58 g is added and the solution is stirred at a temperature ranging from 0 to 5. ° C for 40 minutes. The resulting solution was then added as a single addition to a mixture of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (5 g), ethyl acetate (50 ml), trimethylsilylacetamide (14.3 ml). ga bis (trimethylsilyl) acetamide in an amount of 5.8 g at a temperature of -15 ° C and then stirred at -20 to -15 ^° C for 1.2 hours . Water (50 ml) was added to the resulting solution at a temperature ranging from -25 to -20 ° C, and the solution was stirred until the temperature rose to 5 ° C. . The aqueous layer thus obtained was separated and subjected to extraction with ethyl acetate. The ethyl acetate layer and extract are combined, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure to a volume of 50 mL to give a precipitate which was collected by filtration and then washed with ethyl acetate, the final product of this embodiment being 4-nitrobenzyl-7- [2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-hydroxy-3-cephem-4-carboxylate in the form of the syn isomer in a yield of 3.5 g. Melting point: 163 ° C (with decomposition).

Product characteristics:

IR in _max (nujol j:

3210, 3160, 3050, 1780, 1685 cm ¹

NMR δ _ppm (DMSO-d 6):

3.0 - 4.2 (2H, mj,

3.95 (3H, sj,

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

5.41 (2H, sj,

5.64 (1H, dd, J = 4 Hz, 9 Hz),

7.49 (1 H, s),

7.67 (2H, d, J = 8Hz),

8.21 (2H, d, J = 8Hz),

8.50 (1 H, t, J = 9 Hz).

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

Product characteristics:

I. R, in _max (nujol):

3180, 1780, 1680, 1670, 1640 cm ¹

109

NMR ( _ppm) (DMSO-d ₆ ):

3.2-4.0 (2H, m),

3.97 [3H, sj,

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

5.41 (2H, sj,

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

7.10 (1 H, s),

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

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

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

Example 12

1. In this embodiment, phosphorus oxychloride is added in an amount

1.76 g and trimethylsilylacetamide in amounts

0.4 g was added to the stirred suspension of acid

2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetic acid in the form of the syn isomer and 1.0 g in tetrahydrofuran in 10 ml at a temperature below 5 ° C and with this mixture is then stirred at the same temperature above for 30 minutes. N, N-dimethylformamide (0.4 g) was then added to the resulting solution, and the solution was stirred at a temperature below 5 ° C for 20 minutes to give the A-labeled solution. 4.8 g was added to a stirred suspension of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (1.9 g) in tetrahydrofuran (15 ml) and the solution was stirred at ambient temperature for 15 min. for one hour. To this solution was added the above solution, labeled A, as a one-time addition at -20 ° C, and the solution was stirred at 0 ° C for one hour. Water (50 ml) was added to the solution at -20 ° C and the pH was adjusted to 8.0 with aqueous sodium bicarbonate. To the solution was added tetrahydrofuran (50 ml) and saturated aqueous sodium chloride (50 ml). In this way, an aqueous layer and an organic layer are formed, the organic layer is separated, then washed with a saturated aqueous solution of sodium chloride and finally dried over magnesium sulfate. The solution is then concentrated under reduced pressure to give a residue which is triturated with diisopropyl ether to give a precipitate which is collected by filtration, the final product of this embodiment of the invention being 4-nitrobenzyl-7- [2- (2) amino-4-thiazolyl) -2-ethoxyiminoacetamido 3-chloro-3-cephem-4-carboxylate in the form of the syn isomer, yield 2.0 g.

110

Product characteristics:

IR at _max (nujolj:

3200, 1780, 1730, 1670 cm ^-1

NMR _{δ ppm} (DMSO-dd:

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

3.96 (2Ή, s),

4.13 (2H, q, I = 7Hz),

5.31 (1H, d, J = 5Hz),

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

6.77 (1H, sj,

7.67 (2H, d, J = 8Hz),

8.25 (2H, d, J = 8Hz),

10.30 (1 H, d, J = 8 Hz).

2. In this embodiment, a suspension of palladium on activated carbon of 0.8 g in water of 5 ml is added to a mixture of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl)]. -2-ethoxyiminoacetamido] -3-chloro-3-cephem-4-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 was carried out under normal pressure and at ambient temperature for 3 hours After the reduction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue which was then treated with ethyl acetate (50 ml). The pH of the product thus obtained is adjusted to 7.4 with aqueous sodium bicarbonate solution to form an insoluble material which is collected by filtration. The layer was adjusted to pH 6.0 with a 10% hydrochloric acid solution and then the organic solvent was removed under reduced pressure. The aqueous solution thus obtained is subjected to chromatography in a column which is packed with macroporous, non-ionic adsorption resin material "Diaion HP-20" (trade name of Mitsubishi Chemical Industries Ltd.) in an amount of 30 ml. The eluate obtained is lyophilized, the end product thus obtained being 7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] -3-chloro-3. sodium cephem-4-carboxylate in the form of the syn isomer in a yield of 0.3 g.

Product characteristics:

IR at _max (nujolj:

3350, 3200, 1770, 1675, 1620 ^cm-1

NMR _{δ ppm} (D ₂ O):

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

111

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

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

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

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

7.06 (1 H, s).

Example 13

1. The process is such that phosphorus oxychloride is added in an amount

4.6 g, 0.95 g trimethylsilylacetamide and Ν, Ν-dimethylformamide

1.2 g are added to the stirred suspension of 2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetic acid in the form of the syn isomer and in an amount of

2.8 g in tetrahydrofuran (25 ml) was added at a temperature below 5 ° C for 30 minutes to give the solution labeled A. Simultaneously, trimethylsilylacetamide (10.5 g) was added to the suspension of 4-nitrohenzyl- Of 7-amino-3-cephem-4-carboxylate (3.9 g) in tetrahydrofuran (50 ml) and the solution was stirred at ambient temperature for 1.5 hours. To the solution thus prepared is added the above solution with the number A addition at -20 ° C once and the solution is stirred at a temperature ranging from -5 to 0 ° C for 40 minutes. minutes. Water (70 ml) and tetrahydrofuran (100 ml) were added to the resulting solution at -20 ° C. The pH of the solution is adjusted to 7.5 with aqueous sodium bicarbonate and stirred for one hour. A saturated aqueous sodium chloride solution (200 ml) was then added to this solution to form an organic layer, which was then separated. The remaining aqueous layer remaining after separation of the organic layer is subjected to extraction with tetrahydrofuran, the extract obtained and the above organic layer are combined, then washed with a saturated aqueous solution of sodium chloride, dried with magnesium sulfate and then finally this solution is concentrated under reduced pressure. A residue is obtained which is triturated with diisopropyl ether to give a precipitate which is then collected by filtration, the end product of the above process being

4-nitrobenzyl-7- 2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 6.0 g.

Product characteristics:

IR at _max (nujol):

3320, 3270, 1775, 1730, 1670, 1630 em ^'first

112

NMR _{δ ppm} (DMSO-d 6):

1.17 (6H, d, J = 6Hz), 3.63 (2H, m),

4.33 (1 H, q, J = 6 Hz),

5.17 (lH, d, J = 5Hz),

5.42 (2 H, s),

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

6.67 (1 H, m),

6.70 (1 H, s),

7.22 (2 H, m),

7.70 (2H, d, J = 8Hz),

8.25 (2H, d, J = 8Hz),

10.13 (1H, d, J = 8Hz).

2. Add 1 ml of acetic acid and a 10% palladium on carbon suspension of 2.0 g in 8 ml of water to a 4-nitrobenzyl-7- [2- (2) solution. amino-4-thiazolyl) -2-isopropoxyiminoacetamido-3-cephem-4-carboxylate in the form of the syn isomer and 5.0 g in 150 ml of tetrahydrofuran, and the suspension thus obtained is subjected to a 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. 80 ml of ethyl acetate were added to the residue, and the pH was adjusted to 7.5 with aqueous sodium bicarbonate. This procedure forms an organic layer, which is separated and then subjected to extraction with aqueous sodium bicarbonate. After this extraction, an extract is obtained, which is combined with the aqueous layer obtained as described above, then the pH of the solution is adjusted to 3.0 with concentrated hydrochloric acid and 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 separated by filtration and then dried, the end product thus obtained being 7- [2- (2-amino-4-thiazazolyl) -2- isopropyloxyiminoacetamido] -3-caffeine-4-carboxyl in the form of the syn isomer in an amount of 0.8 g.

Product characteristics:

IR at _max (nujol):

3320, 1780, 1635 cm ^-1 .

NMR .delta. _Ppm (DMSO-d6):

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

3.55 (211 m);

4,30 | 11), q, J = 6 Hz.),

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

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

113

114

6.45 (1 H, m),

6.68 (1 H, s),

7.10 (2 H, m),

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

Example 14

1. In this embodiment, phosphorus oxychloride is added in an amount

4.6 g, 0.95 g of trimethylsilylacetamide and N, N-dimethylformamide

1.2 g are added to the stirred suspension of acid

2- (2-amino-4-thiazolyl) -2-propoxyiminoacetic acid, in the form of the syn isomer, in an amount of 2.8 g in 25 ml of tetrahydrofuran at a temperature below 5 ° C, and this solution is then passes for 20 minutes. The solution was added dropwise to a suspension of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate (3.9 g) in a mixture of 20 ml of tetrahydrofuran, 20 ml of water and 20 ml of acetone. The addition is carried out at a temperature of -5 to 5 ° C, maintaining the pH in the range of 6.9 to 7.1 by the addition of a 20% aqueous sodium carbonate solution. The solution is stirred at -5 to 5 ° C for 30 minutes and then at 10 ° C for one hour and finally adjusted to pH 7 , 5. After tetrahydrofuran (100 ml) and saturated aqueous sodium chloride (200 ml) were added to the resulting solution, the insoluble material was collected and filtered. In this way, an organic layer is also formed which is separated from the filtrate, then washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The residue thus obtained is triturated with diisopropyl ether to give an insoluble material which is collected by filtration and the final product of this embodiment of the invention is 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido] -3-Cephem-4-carboxylate in the form of the syn isomer in a yield of 5.8 g.

Product characteristics:

IR in _nx (nujol):

3300, 1780, 1730, 1670, 1640 Cllf ¹ .

NMR δ _m (DMSO-d 6):

0.93 (3H, t, J = 6Hz),

1.70 (2 H, m),

3.70 (2 H, m),

4.08 (2H, t, J = 6Hz),

4.5 (2H, m);

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

5.50 (2 H, s),

5.97 (1H, dd, J = 5Hz, 8Hz),

6.73 (1 H, m),

6.80 (1 H, s),

7.75 (2H, d, I = 9Hz),

8.30 (2H, d, J = 9Hz);

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

2. According to this embodiment, the nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamldo] -3-cephem-4-carboxylate is in the form of the syn isomer and is treated in a similar manner in an amount of 5.0 g, as in Example 13- (2), to give 7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido] -3-cephem- 1-carboxylic acid in the form of syn isober and the yield of this product is 0.9 g.

Product characteristics:

IR v, _nil (nujol):

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

NMR δ _P (DMSO-d 6):

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

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

3.60 (2 H, m),

4.03 (2H, f, I = 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, J = 8Hz).

Example 15

1. In this embodiment, phosphorus oxychloride is added in an amount

13.2 g is added dropwise to a stirred solution of Ν, Ν-dimethylformamide in an amount

6.3 g and tetrahydrofuran (24.7 ml) were added at -5 ° C and the mixture was stirred at the same temperature for 30 minutes. 120 ml of tetrahydrofuran and 2- (2-formamidothiazol-4-yl) -2-n-butoxyiminoacetic acid in the form of the syn isomer and 19.5 g are then added to the solution thus prepared, and the addition is carried out at a temperature of -5 ° C, and this solution is then stirred at the same temperature above for 30 minutes. This solution is then added dropwise to a stirred suspension of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate (24.7 g), tetrahydrofuran (120 ml), acetone (60 ml) and water (60 ml). said addition being carried out at a temperature ranging from -5 ° C to 5 ° C over a period of 15 minutes, adjusting the pH of the solution to between 7 and 7.5 with a 20% aqueous solution of sodium carbonate, and then the solution is stirred for 30 minutes. In this way, an insoluble material is formed which is filtered off and to the filtrate thus obtained

Then, a saturated aqueous sodium chloride solution is added. The solution is then extracted twice with tetrahydrofuran. The extract obtained was washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate and finally concentrated in vacuo. The residue is triturated with diisopropyl ether to give the final product 4-nitrobenzyl-7- [2- (2-fluorophenothiazol-4-yl) -2-2-n]. butoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 34.6 g.

Product characteristics:

IR at _max (nujol):

3240, 3050, 1780, 1730, 1695, 1660 cm ^-1 .

NMR _{δ ppm} (DMSO-d 6):

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

0.8-2.2 (4H, mj,

3.67 (2'H, d, J = 4Hz),

4.16 (2H, t, J = 7Hz),

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

5.46 (2 H, s),

5.99 (1H, dd, J = 5Hz, 8Hz),

6.71 (1 H, t, J = 5 Hz),

7.43 (1 H, s),

7.76 (2H, d, J = 9Hz),

8.30 (2H, d, J = 9Hz),

8.58 (1 H, s),

9.72 (1H, d, J = 8Hz),

12.66 (1 H, s). ²

2. In this embodiment, the mixture of 4-mtrobenzyl-7- [2- (2-formamldothiazol-4-yl) -2-n-butoxyiminoacetamido] -3-cephem-4-carboxylate is syn. isomer and 34.5 g, followed by 345 ml of tetrahydrofuran, 10% palladium on carbon, 14 g, 140 ml of methanol, 2.5 ml of acetic acid, and 50 ml of water to catalyze reduction, the reduction being 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 is separated and subjected to extraction with aqueous sodium bicarbonate, 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.

116 minutes. The precipitated mass thus obtained is collected by filtration, then washed with water and finally dried over magnesium sulphate to give the final product, 7- [2- (2-formamidothiazol-4-yl) - 2-butoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 18.3 g.

Product characteristics:

IR at _max (nujol):

3330, 3040, 1780, 1725, 1695, 1655 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

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

1.1-1.9 (4H, mj,

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

12.57 (1H, s band).

3. In this embodiment, the mixture of 7- [2- (2-formamidothiazol-4-yl) -2-n-butoxyiminoacetiamido] -3-cephem-4-carboxylic acid in the form of the syn isomer is in the form of the syn isomer. 12.7 g, further concentrated hydrochloric acid 9.6 ml, methanol

9.5 ml and 9.5 ml tetrahydrofuran 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 was 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, which is collected 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 was adjusted to 6.0 with a 10% hydrochloric acid solution and then subjected to chromatography in a column packed with a nonionic adsorption resin material (Diaion HP-20, a trade name of Mitsubishi Chemical Industries). 300 ml, eluting with 10% isopropanol in water The pH of the eluate is adjusted to pH 3.5 with 10% hydrochloric acid, while cooling in an ice bath to give a precipitate, which is then from 217959

117

The mixture is separated by filtration, washed with water and dried to give the final product, which is 7- [2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetamide] -3-cephem-4-carboxylic acid. in the form of the syn isomer, yield 7.2 g.

Product characteristics:

IR in _{m; 1x} (nujolj:

3320, 1775, 1660 cm ^-1 .

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

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

1.1-1.9 (4 H, 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 (1 H, d, J = 8 Hz).

Example 16

1. 2- (2-Formamidothiazol-4-yl) -2-isobutoxyiminoacetic acid in the form of the syn isomer and in the amount of 6.48 g and further N, N-dimethylformamide in an amount of 2.10 g , phosphorus oxychloride at 4.40 g, tetrahydrofuran at 110 mL, 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate at 8.23 grams, acetone at 16 mL, and water at 16 mL were treated in a similar manner to that described in Example 15- (1), wherein 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetamido was prepared 3-tert-4-caroxylate in the form of the syn isomer, the yield of this product being

12,8 g.

Product characteristics:

IR at _max (nujol):

3240, 3050, 1780, 1720, 1700, 1655 cm ^-1 .

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

0.92 (6H, d, J = 7Hz),

1.7-2.2 (1 H, m),

3.67 (2H, s-band),

3.91 (2H, d, J = 7Hz),

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

5.95 (1H, dd, J = 5Hz, 9Hz),

6.67 (1 H, t, J = 4 Hz),

7.37 (1 H, s),

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

8.24 (2H, d, J = 8Hz),

8.52 (1 H, s),

9.68 (1H, d, J = 9Hz);

12.58 (1H, s band).

2. In this embodiment, 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetamido] -3-cephem-4-cartooxylate is the syn isomer in an amount of 14, 2 g, 10% palladium on carbon 5.7 g, 57 ml methanol, 142 ml tetrahydrofuran, 1 ml acetic acid and 10 ml water are treated in a similar manner to that described in Example 15- (2), 7- [2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetamido] -3-cephem-4-carboxylic acid as the syn isomer and in a yield of 4.24 g.

Product characteristics:

IR in _niax (nujol):

3260, 1790, 1725, 1670 cm ^-1 .

N.M.R. 5 (DMSO-d6, ppm):

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

1.6-2.3 (1 H, m),

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

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

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

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

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

7.40 (1 H, s),

8.56 (1 H, s),

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

3. 7- [2- (2-Formamidothiazol-4-yl) -2-isobutoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 4.1 g. and concentrated hydrochloric acid (3.65 g) and methanol (61.5 ml) were treated in a similar manner to Example 15- (3) to give 7- [2- (2-aminothiazole) acid. -4-yl] -2-isobutoxyiminoacetamido] -3-cep-a-carboxylic acid in the form of the syn isomer in a yield of 2.4 g.

Product characteristics:

IR in _lllax (nujol):

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

N.M.R. δ (DMSO-d 6, ppm):

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

1.6-2.2 (1 H, m),

3.58 (2H, s-band),

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

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

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

6.46 (1H, s-band),

6.68 (1H, sj,

7.20 (2 H, s),

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

Example 17

1. In this embodiment, the acid is 2- (2-formamidothiazole217959)

119

120

-4-yl) -2-cy ^l klohexyloxyiminoootová syn isomer, 0.9 g, and further Ν, Ν-dimettiylformamíd 266mg, fosofrečný oxychloride in an amount of 557 mg, tetrahydrcfuran in an amount of 20 mL, 4- 1-g-1-nitrobenzyl 7-amino-3-cephem-4-carboxylate, 3-ml acetone and 3-ml water were treated in a similar manner to that described in Example 15- (1), wherein 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylate is obtained in the form of the syn isomer, 1,69 g.

Product characteristics:

IR _inax (nujol):

3260, 3170, 3070, 1785, 1725, 1700,

1655 cm ^-1 .

N.M.R. 6 '(DMSO-d6, ppm):

0.8-2.2 (10H, m),

3.66 ί2H, sj band,

4.10 (1 H, m),

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

5.42 (2 H, s),

5.95 (1H, dd, J = 5Hz, 9Hz),

6.66 (1H, sj band,

7.37 (1 H, s),

7.70 (2H, d, J = 8Hz),

8.22 (2H, d, J = 8Hz),

8.50 (1 H, s),

9.63 (1H, d, J = 9Hz),

12.60 (1H, s band).

2. In this embodiment, the 4-nitrobenzyl 7- [2- (2-formamldothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem-4-carboxylate is in the form of the syn isomer and in an amount of 2.0 g, 0.8% palladium on charcoal, 0.8 ml methanol, 8 ml methanol, 20 ml tetrahydrofuran, 0.14 ml acetic acid and 1.4 ml water are treated in a similar manner as in Example 15- (2), wherein 7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cephem is prepared according to the present invention. -4-carboxylic acid in the form of the syn isomer in a yield of 0.77 g.

Product characteristics:

IR at _max (nujol):

3275, 3070, 1780, 1675 ^cm-first

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 (m, s),

8.50 (1 H, s),

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

12.61 (1H, s band).

3. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyoxyino-acetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 0.72 g and methanol (10.8 ml) and concentrated hydrochloric acid (0.61 g) were treated in a similar manner to that described in Example 15- (3) to prepare 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.

Product characteristics:

IR in _nlax (nujol):

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

N.M.R. 6 (DMSO-d6, ppm):

0.8-2.2 (10 H, m),

3.60 (2H, s-band),

4.04 (1 H, m),

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

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

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

6.67 (1 H, s),

7.19 (2 H, s),

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

Example 18

In this example, phosphorus oxychloride is added in an amount

0.84 g was added dropwise to a stirred suspension of 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetic acid in the form of the syn isomer at 1.0 g, tetrahydrofuran at 10 ml and water at 0.05 ml at 5 ° C and stirred at the same temperature for 20 minutes. To this solution was added trimethylsilylacetamide (0.66 g), followed by phosphorus oxychloride (0.84 g) and N, N-dimethylformamide (0.45 g), then stirred at 5 ° C for one hour. to prepare an active acid solution. On the other hand, trimethylsilylacetamide (4.0 g) was added separately to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.88 g) in tetrahydrofuran (10 ml) at 40 ° C. The solution is then stirred for 30 minutes. To this solution is added in the form of a one-shot addition of the acidic solution obtained as described above, at -20 ° C, at a temperature of -20 ° C.

121

The 122 solution was then stirred at 0 ° C for one hour. Water (20 ml) was added to the resulting solution at -20 ° C, and the pH was adjusted to 7.5 with aqueous sodium bicarbonate. Ethyl acetate was added to the solution to form an aqueous layer which was then separated. The solution thus obtained was washed with ethyl acetate and diisopropyl ether, the pH of the resulting solution was adjusted to 5.0, and this solution was treated with activated carbon. The solution is adjusted to pH 3.0, the precipitated mass is collected by filtration, then washed with water and dried over phosphorus pentoxide, the final product of this example being 7- [2- (2-amino, thiazole- 4-yl) -2-allyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, yield 0.8 g.

Product characteristics:

IR for _lliax (nujol):

3300, 1780, 1770, 1030 cm ¹ .

N.M.R. δ (DMSO-d 6, ppm):

3.67 (2H, d, I = 4Hz)

4.67 (2 H, m),

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

5.25 (1 H, m),

5.50 (1 H, m),

5.90 (1H, dd, J = 5Hz, 8Hz),

6.03 (1 H, m),

6.55 (1 H, m),

6.80 (1 H, s),

7.50 (2 H, m),

9.68 (1 H, d, J = 8 Hz).

Example 19

To this example, phosphorus oxychloride (1.4 g) is added dropwise to a suspension of 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetic acid in the form of the syn isomer and in an amount of

1.7 g in tetrahydrofuran (15 ml) was added at a temperature below 7 ° C and then stirred at the same temperature for 10 minutes. Phosphorus oxychloride (1.4 g), trimethylsilylacetamide (1.3 g) and Ν, Ν-dimethylformamide (0.76 g) were added to the solution, and the solution was stirred for 20 minutes to prepare. active acid solution. On the other hand, trimethylsilylacetamide (7.8 g) is added separately to a suspension of 7-amithio-3-cephem-4-carboxylic acid (1.5 g) in tetrahydrofuran (20 mt), and this solution is then stirred at 40 ° C for for 30 minutes. To this solution is added in the form of a single addition of the active acid solution obtained as described above at -20 ° C, and the solution is then stirred for 30 minutes at 0 ° C. Water (20 ml) was added to the resulting solution at -20 ° C and the pH of the solution was adjusted to 7.5 with aqueous sodium bicarbonate. This measure creates an aqueous layer which is separated, then washed with ethyl acetate and diisopropyl ether, followed by treatment with activated carbon at pH 5.5. The pH of the solution was adjusted to 3.0, and the precipitated mass was collected by filtration and dried over phosphorus pentoxide under reduced pressure, the final product of this example being 7- [2- (2- aminothiazol-4-yl) -2-propargyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 1.47 g.

Product color:

IR at _max (nujol):

3500, 3300, 1780, 1720, 1660, 1630 cm

N.M.R. δ (DMSO-d 6, ppm):

3.48 (1 H, m),

3.67 (2 H, m),

4.80 (2H, d, J = 2Hz);

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

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

6.55 (1 H, m),

6.85 (1 H, m),

7.33 (2 H, m),

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

Example 20

1. Add 3 drops of Ν, Ν-dimethylformamide to a suspension of 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetic acid in the form of the syn isomer in an amount of 23 g in thionyl chloride in 230 ml and the solution is stirred at 60 ° C for 5 minutes. The solution was then concentrated in vacuo and benzene was added to the residue. The precipitate was collected by filtration and then washed with benzene (30 ml) for a total of three washes, followed by diethyl ether to give 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetyl chloride. On the other hand, trimethylsilylacetamide (46 g) was added separately to a suspension of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate (16.8 g) in methylene chloride (168 ml). and the mixture is then stirred at 40 ° C for one hour. TO

123

The suspension thus obtained is then sequentially added 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetyl chloride in the form of an anti-isomer in an amount of 13.6 g at a temperature ranging from -5 to 0 ° C, and this solution is then stirred at the same temperature above for one hour. Water (150 ml) was added to the resulting solution and stirred for 15 minutes. A precipitate is formed, which is collected by filtration, then washed with water and finally dried using phosphorus pentoxide under reduced pressure, the end product of the process according to the invention being

4-nitro-benzyl-7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as an anti isomer, yield 25.7 g.

Product characteristics:

IR at _max (nujol):

3300 (band), 1780, 1730, 1680,

1520 cm ” ¹ .

NMR δ (DMSO-d 6 _; ppm):

3.70 (2H, s-band),

4.07 (3 H, s),

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

9.57 (1H, d, J = 8Hz),

6.00 (1H, dd, J = 5Hz, 8Hz),

5.30 (2 H, s),

6.70 (1 H, t, J = 4 Hz),

7.71, 8.25 (4H, A2B2, J = 9 Hz),

8.07 (1 H, s),

8.50 (1 H, s),

12.55 (1H, s band).

2. According to this embodiment, the procedure is such that a suspension of 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as an anti isomer and in an amount of 4.2 g, 10% palladium deposited on the carbon in an amount

1.7 g, 0.63 ml of acetic acid, 6.3 ml of water, 42 ml of methanol and 84 ml of tetrahydrofuran are subjected to a catalytic reduction under a hydrogen atmosphere, which is carried out at ambient temperature and 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 was treated with activated carbon and the pH was 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 present invention being 7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-cephem. -4-carboxylic acid in the form of an anti isomer, yielding 2.52 g.

Product characteristics:

IR at _max (nujol):

3300 (band), 1780, 1680, 1670, 1550 cm ” ¹ .

N.M.R. S (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, I = 5Hz, 8Hz),

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

8.09 (1 H, s),

8.52 (1 H, s),

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

3. In this embodiment, a suspension of '7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of an anti isomer and in an amount of 2.5 g followed by concentrated hydrochloric acid

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 solution is concentrated in vacuo. The residue thus obtained is crystallized in 100 ml of diisopropylether.ru and the resulting mass is collected by filtration and then washed with 30 ml of diisopropyl ether to give 7- [2- (2-aminothiazole) hydrochloride at this stage. -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 added to 28 ml of water and the pH of the solution is is made up to 6.0 with sodium bicarbonate. The solution is then subjected to a 75 ml chromatography column packed with 75 ml non-ionic adsorption resin material "Diaion HP-20" (a trade name of Mitsubishi Chemical Industries Ltd.), eluting with 10% diisopropyl ether. In this way an eluate is obtained whose pH is adjusted to

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-aminothiazol-4-yl) -2-methoxyiminoacetamido] - 3-cephem-4-carboxylic acid in the form of an anti isomer and in a yield of 0.7 g.

125

Product characteristics:

IR in _niax (nujal):

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

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

6.48 (1 H, t, I = 4 Hz),

7.13 (2H, band),

7.47 (1 H, s),

9.42 (1 H, d).

Example 21

1. According to this embodiment, a Vilsmeier reagent is first prepared from 0.4 g of N, N-dimethylformamide and 0.86 g of phosphorus oxychloride, in a conventional manner. The reagent was then suspended in ethyl acetate (10 mL) and 2- (2-formamidothiazol-4-yl) -2-n-propoxyiminoacetic acid as the syn isomer was added to the stirred slurry at 1.3 g. cooling in a water-bath with ice and stirring for 30 minutes. The solution thus obtained is then added to a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate as hydrochloride (2.0 g), trimethylsilylacetamide (5.2 g) and ethyl acetate (40 g). ml at -25 ° C and stirring at -20 to -10 ° C for 1.5 hours. Water was added to the resulting solution, and the solution was subjected to extraction with ethyl acetate (60 ml). An aqueous layer was thus obtained which was extracted with ethyl acetate (50 ml). The extracts obtained above were combined, washed with a saturated aqueous solution of sodium chloride and finally dried over magnesium sulfate. The solution thus obtained was concentrated in vacuo and the residue was triturated with diethyl ether. Thus obtained precipitates, which is collected by filtration, then washed and dried, whereby the thus obtained final product according to this embodiment of the invention is 4-nitrobenzyl 7- [2- ^{(2-formamidoth!} Triazol-4-yl j - 2-n-propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate in the form of the syn isomer in a yield of 2.55 g.

Product characteristics:

IR at _max (nujolj:

3250 - 3150, 1780, 1730, 1690

1660, 1610, 1550, 1520 cm ¹

126

N.M.R. δ (DMSO-d 6, ppm):

0.87 (3H, t, J = 7Hz) 1.64 (1H, m), 3.88 (2H, q, t = 17 Hz), 3.97 (2H, q, I = 7Hz) 5.30 (1H, d, J = 5Hz) 5.40 (2H, with), 5.92 (1H, dd, J = 5Hz, 8Hz) 7.33 (1H, with), 7.65 (2H, d, J = 9Hz) 8.20 (2H, d, J = 9Hz) 8.47 (1H, with), 9.70 (1H, d, J = 8Hz) 12.40 (1H, with).

2. In this embodiment, a suspension of 4-nitrobenzyl-7- [2- (2-formamido-thiazol-4-yl) -2-n-propoxyiminoacetamido] -3-chloro-3-carboxylic acid is obtained. 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 subjected to catalytic reduction, which is carried out under normal pressure and at ambient temperature. After the reduction, insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue, and the pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. In this way, an insoluble material is formed which is removed by filtration, and the resulting aqueous layer is separated. Ethyl acetate was added to the solution and the pH 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 a saturated aqueous solution of sodium chloride 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, the final product thus obtained being 7- [2- (2-formamidothiazel-4-yl) -2- n-propoxyiminoacetamido] -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 ¹

N.M.R. δ (DMSO-d 6, ppm):

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

1.72 (1 H, m),

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

4.08 (2H, q, J = 7Hz), > 21 79 5 9

127

128

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

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

7.43 (1H, s),

8.57 (1 H, s),

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

3. In this embodiment, the suspension of 7- [2- (2-formamidothiazol-4-yl) -2-n-propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer and in an amount of 1.5 g, then 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. A precipitate is formed, which is collected by filtration, then dried with phosphorus pentoxide to give the final product, which is 7- [2- (2-aminothiazol-4-yl) -2- n-propoxyiminoacetamido] -3-chloro-3-cephem-4-cartoxyl in the form of the syn isomer and in an amount of 0.6 ^: g.

Product characteristics:

IR p _max (nujol):

3300, 1780, 1670, 1630, 1530 cm ^-1

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

0.92 (3H, t, 1-7 Hzj,

1.67 (1 H, m),

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

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

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

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

6.75 (1 H, s),

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

Example 2 ^; 2

2- (2-Aminothiazol-4-yl) -2-n-hexyloxyiminoacetic acid in the form of the syn isomer at 3 g, water at 0.15 g, phosphorus oxychloride at 3 8 g, trimethylsilylacetamide (10.7 g), N, N-dimethylformamide (1.0 g), tetrahydrofuran (50 ml) and 7-amino-3-cephem-4-carboxylic acid (2.0 g) were treated similarly according to the procedure of Example 18, whereby 7- (2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetamido) -3-ethyl acid is obtained -4-catboxylate in the form of the syn isomer and in an amount of 1.1 g.

Product characteristics:

IR at _max (nujol):

3250, 1760, 1640, 1600 cm ^-1

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

1.88 (3 H, m),

1.1-1.9 (8H, m),

3.60 (2 H, m),

4.06 (2H, t, J = 6Hz),

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

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

6.46 (1 H, m),

6.70 (1 H, s),

7.26 (2 H, m),

9.56 (1H, d, J = 8Hz).

Example 23

2- (2-Formamidaphthiazol-4-yl) -2-propargyloxyiminoacetic acid in the form of the syn isomer and 0.506 g and N, N-dimethylformamide in an amount of 0.161 g, phosphorus oxychloride in an amount of 0.506 g. 0.337 g and 7.9 ml of ethyl acetate were treated in a similar manner to that described in Example 15- (1) to prepare an active acid solution. On the other hand, trimethylsilylacetamide in separate amounts

1.85 g and 1.60 g of bis (trimethylsilyl) acetamide are added to a suspension of 4-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate in an amount of 0.703 g in 10 ml of ethyl acetate. and this solution is then stirred at ambient temperature for one hour. To the solution thus prepared is added the active acid solution prepared as described above at -10 ° C in the form of a single addition, and the solution thus obtained is stirred at the same temperature for one hour. This gives a solution to which 20 ml of water and 20 ml of ethyl acetate are added. In this way, an organic layer is formed which is separated, washed with a saturated aqueous solution of sodium bicarbonate of 8 ml and an aqueous solution of sodium chloride of 15 ml, and finally dried over magnesium sulphate. The solution was concentrated in vacuo to give a residue which was triturated with diethyl ether and the precipitated mass collected by filtration to give 4-nitrobenzyl-7- [2- ( 2-formamidothiazol-4-yl] -2-propargyloxyiminoacetamido] -3-hydroxy-3-cephem-4-carboxylate in the form of the syn isomer in a yield of 0.71 g.

Product characteristics:

Mr R. Umax (nujol):

3270, 1770, 1740, 1670 cm ¹

129

N.M.R. 8 (DMSO-d6, ppm):

3.39 (1 H, m),

3.63 (2H, s-band),

4.90 (2H, s-band),

5.23 - 5.90 (4H, m),

7.57 (1 H, s),

7.83 (2H, d, J = 9Hz);

8.40 (2H, d, I = 9Hz)

8.67 (1 H, s),

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

12.83 (1H, s-band).

Example 24

2- (2-formamidothiazol-4-yl) propoxylminoacetic acid in the form of the syn isomer in an amount of 0.515 g, followed by N, N-dimethylformamide in an amount of 0.161 g, phosphorus oxychloride in an amount of 0.337 g Ethyl acetate (7.9 ml) was treated in a similar manner to that described in Example 15- (1j) to prepare the active acid solution. On the other hand, trimethylsilylacetamide (1.85 g) and bisftrimethylsilyl] diacetamide were separately added. an amount of 1.60 g was added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate in an amount of 0.703 g in 10 ml ethyl acetate, and this solution was then stirred at ambient temperature for one The active acid solution obtained as described above is then added to the solution thus prepared, at a temperature of -10 ° C in the form of a single dose. addition, and then the solution is stirred at the same temperature above for one hour. Water (20 ml) and ethyl acetate (20 ml) were added to the resulting solution. The organic layer was separated, washed with aqueous sodium bicarbonate (8 ml) and water (14 ml) and dried over magnesium sulfate. The solution was then concentrated in vacuo and the residue was triturated with diethyl ether, whereupon the resulting precipitate was collected by filtration. The end product of this embodiment of the invention is 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-propoxyiminoacetamido] -3-hydroxy-3-cephem-4-carboxylate as the syn isomer and in a yield of 0.75 g.

Product characteristics:

IR ( _ml) x (nujol):

3250, 1765, 1740, 1670 cm ^-1

N.M.R. 3 (DMSO-d6, ppm):

0.90 (3H, t, J = 8Hz),

1.67 (2 H, m),

3.40 (2H, AB-q, J = 20Hz)

4.08 (2H, q, J = 8Hz),

130

5.03 - 5.83 (4H, m),

7.40 (1 H, s),

7.70 (2H, d, J = 9Hz),

8.27 (2H, d, J = 9Hz)

8.53 (1 H, s),

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

12.60 (1H, s band).

Example 25

2- (2 -ormamidothiazol-4-yl) -2-isohutoxyiminoacetic acid in the form of the syn isomer in an amount of 0.54 g and further in N, N-dimethylformamide in an amount of 0.16 g, oxychloride Phosphoric acid (0.34 g) and ethyl acetate (10 mL) were treated in a similar manner to that described in Example 15- (1) to prepare an active acid solution. On the other hand, trimethylsilylacetamide in separate amounts

1.85 g and 1.62 g of bis (trimethylsilyl) acetamide are added to a suspension of 4-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate in an amount of 0.7 g in 10% ethyl acetate. ml and the solution was stirred at 40 ° C for 30 minutes. The above active acid solution is then added to the solution so prepared at a single time at -20 ° C and stirred at the same temperature for one hour. Water (10 ml) was added to the resulting solution, and the organic layer was separated, washed with water, brine and dried. The solution was concentrated in vacuo to give a residue which was triturated with diisopropyl ether. The precipitated mass thus obtained is collected by filtration, washed with diisopropyl ether and dried to give the final product, which is 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -isodium. 12-Hydroxy-3-cephem-4-carboxylate as syn isomer, yield 1.09 g.

Product characteristics:

IR in _innx (nujol):

3250, 3050, 1750, 1650, 1610 cm ¹

N.M.R. 8 (DMSO-d6, ppm):

0.97 (6H, d, J = 6Hz),

2.0 (1 H, m),

3.60 (2H, AB-q, J = 18Hz);

3.95 (2H, d, J = 6Hz);

5.1-5.8 (4H, m),

7.53 (1 H, s),

7.63 (2H, d, J = 8Hz),

8.18 (2H, d, J = 8Hz);

8.58 (1 H, s),

131

132

9.47 (1 H, d, J = 9 Hz),

12.77 (1H, sj band).

Example 26

N, N-dimethylformamide (0.114 g), phosphorus oxychloride (0.240 g) and ethyl acetate (0.5 ml) were first reacted under conventional conditions to prepare a Vilsmeier reagent. Ethyl acetic acid (5 ml) and 2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetic acid (0.35 g) are added to the reagent and added at the same rate. On the other hand, trimethylsilylacetamide (1.31 g) and bis (trimethylsilyl) acetamide (1.14 g) are added separately to the suspension of 4-nitrobenzyl-7-amino-3-hydroxy-3. of cephem-4-carboxylate (0.50 g) in ethyl acetate (7.5 ml) and the solution was stirred at ambient temperature for one hour. The active acid solution obtained as above was added to the solution in the form of a single addition at -10 ° C, and the solution was stirred at the same temperature for 30 minutes. Water (15 ml) and ethyl acetate (15 ml) were added to the resulting solution. An organic layer was formed, which was separated, then washed with saturated aqueous sodium bicarbonate (15 ml) and then concentrated in vacuo. The residue is triturated with diethyl ether and the precipitated mass is then removed by filtration to give the final product, which is 4-nitrobenzyl-7- [2- (2-formamidothiiazole). 4-yl) -2-ethoxyiminoacetamido] -3-hydroxy-3-cephem-4-carboxylate in the form of the syn isomer, yield 0.634 g.

Product characteristics:

IR at _max (nujolj:

3220, 1760, 1740, 1670 cm -1

N.M.R. δ (DMSO-d6, ppm):

1.24 (3H, t, J = 8Hz),

3.36 (2H, AB-q, J = 20Hz);

4.16 (2H, q, J = 8Hz),

5.10 - 5.60 (4H, ia,

7.37 (1 H, s),

7.65 (2H, d, J = 9Hz),

8.22 (2H, d, I = 9Hz),

8.48 (1H, s,

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

12.58 (1H, sj band).

Example 27

1. According to this embodiment, 2- (2-formamidothiazol-4-yl) -2-pentyloxyiminoacetic acid is in the form of the syn isomer and in an amount of 4.14 g and further 4-nitrobenzyl-7-amino-3-cephem. -4-carboxylate 4,5 g, Ν, Ν-dimethylformamide 1,41 g, phosphorus oxychloride 2,96 g, terahydrofuran 72 ml, acetone 15 ml and water 15 ml, were treated in a similar manner to that described in Example 15- (1), wherein the end product was 4-nitro-benzyl-7- [2- (2-formamidothiazol-4-yl) -2- pentyloxyimincucetamido] -3-cephem-4-carboxylate in the form of the syn isomer, yield 8.1 g.

Product characteristics:

IR at _max (nujolj:

3240, 3050, 1780, 1730, 1655 cm -1

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

0.6 - 2.0 (9H, mj,

3.66 (2 H, s),

4.10 (2H, t, J = 6Hz);

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

5.42 (2H, sj,

5.95 (1H, dd, J = 5Hz, 8Hzj,

6.16 (1H, s-band),

7.38 (1H, sj,

7.72 (2H, d, J = 9Hz),

8.26 (2H, d, J = 9Hz),

8.54 (1H, sj,

9.69 (1H, d, J = 8Hz),

12.69 (1H, sj band).

2. 4-Nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-pentyloxy iminoacetamido] -3-cephem-4-carboxylate as the syn isomer and in an amount of 8 g and 10% palladium on charcoal in an amount of 3.6 g, methanol in an amount of 36 ml, tetrahydrofuran in an amount of 90 ml, acetic acid in an amount

0.63 g and 6.3 ml of water are treated in a similar manner to that described in Example 15- (2), and 7- (2- (2-formamidothiiazole-) is prepared according to this embodiment. 4-yl) -2-pentyloxyiminoacetamido] -3-cephem-4-carboxylic acid as the isomer in 3.4 g.

Product characteristics:

IR at _max (nujolj:

3275, 3075, 1795, 1700, 1660,

1630 cm -1

133

134

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 = 6Hz),

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

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

6.49 (1 H, t, J = 3 Hz),

7.40 (1 H, s),

8.53 (1 H, s),

9.64 (d, J, 9 Hz),

12.68 (1 H, s).

3. In this embodiment, 7- [2- (2-form, amidothiazol-4-yl) -2-pentyloxyiminoacetamido] -3-cephem-4-carboxylic acid is present in the 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 15- (3), according to the present invention. the final product 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 at _max (nujol):

3300, 1775, 1650, 1540 cm -1

N.M.R. 5 (DMSO-d6, ppm):

0.6-2.0 (9H, m),

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

4.03 (2H, t, J = 6Hz),

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

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

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

6.69 (1 H, s),

7.20 (2 H, s),

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

Example 28

1. According to this embodiment, triethylamine in an amount of 3.41 g, Ν, Ν-dimethylphenylamine in an amount of 10.3 g and trimethylchlorosilane in an amount of 5.64 g are added to a stirred solution of 7-phenylacetamido-3-tosyloxy acid. 3-cephem-4-capboxylic acid (15 g) in methylene chloride (150 ml) was added at room temperature and the resulting solution was stirred at ambient temperature for one hour. Phosphorus oxychloride (7.03 g) is then added to the solution at a temperature of -35 ° C and the solution stirred at -25 to -20 ° C. , for 1.5 hours. To the solution was added methanol (61 ml) and stirred for 40 minutes. Water was then added to the resulting solution in an amount of 50 ml at a temperature ranging from -20 to -10 ° C. In this way, an organic layer is formed, which is separated and washed with water, washing twice in total. The aqueous layer and the washing liquid were combined and then washed twice with methylene chloride and diethyl ether. The pH of the solution was adjusted to 4.7 with 10% aqueous sodium hydroxide, cooling, to form a precipitate which was collected by filtration, washed with water, acetone and diethyl ether, and finally dried with phosphorus pentoxide, the final product thus obtained according to this embodiment of the invention being 7-amino-3-toisyloxy-3-cephem-4-carboxylic acid in a yield of 5.01 g and the melting point of the product thus obtained is 172 ^° C (with decomposition).

Product characteristics:

IR in _mnx (nujol):

3210, 1800, 1653, 1620 cm ^-1

N. M. R. δ (D2O + NaHCO3, ppm):

2.45 (3 H, s),

3.51 (2Ή, q, J = 18Hz),

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

5.51 (1 H, d, I = 5 Hz),

7.48 (2H, d, J = 9Hz);

7.84 (2H, d, J = 9Hz).

2. According to this embodiment, 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid in the form of the syn isomer in an amount of 0.76 g, further N, N-dimethylformamide in an amount of 0.33 g, phosphorous oxychloride (1.46 g), trimethylsilylacetamide (0.5 g) and ethyl acetate (10 ml) were prepared to prepare the active acid solution in a conventional manner.

On the other hand, trimethylsilylacetamide (2.7 g) was added separately to a suspension of 7-amino-3-tosyloxy-3-cephem-4-carboxylic acid (1.0 g) in ethyl acetate (15 ml) and the mixture was then stirred at ambient temperature. To this solution is added the acidic acid solution obtained as above as a single addition at -15 ° C and stirred at a temperature in the range of -5 ° C to 5 ° C. for one hour. The solution was cooled to -20 ° C and 30 ml of water was added thereto, and the pH of the solution was adjusted to 6.5 with aqueous bicarbonate.

217939

135

136 sodium. In this way an insoluble material is formed which is collected by filtration. The aqueous layer was separated and the pH was adjusted to 3.0 with hydrochloric acid. The resulting precipitates are collected by filtration and then dried, the final product of this embodiment of the invention being 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-tasyloxy-3-cephem-4. -carboxylic acid in the form of the syn isomer, the yield of which is 1.0 g.

Product characteristics:

IR in _n tax (nujol).

3350, 1780, 1670, 1630 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

2.17 (3 H, s),

3.71 (2 H, m),

3.92 (3 H, s),

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

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

6.82 (1H, s),

7.50 (2H, d, J = 8Hz);

7.92 (2H, d, J = 8Hz);

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

Example 29

1. 2- (2-Formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetic acid in the form of the syn isomer and 1.35 g, further 4-nitrobenzyl-7- amino-3-cephem-4-carboxylate at 1.54 g, Ν, Ν-dimethylformamide at 393 mg, phosphorus oxychloride at 825 mg, tetrahydrofuran at 21.2 ml, acetone at 3.9 ml, and water in the amount of 3.9 ml they are treated in a similar manner to that described in Example 15- (1), the final product of this embodiment of the process according to the invention being 4-nitrobenzyl-7- (2- (2-formamidothiazole-4)). -yl) -2-ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer in a yield of 2.52 g.

Product characteristics:

IR p _m ax (nujol).

3250, 1790, 1730, 1690, 1640 cm ^-1

N.M.R. δ (DMSO-d 6, ppm):

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

3.66 (2 H, s),

4.13 (2H, q, J = 7Hz);

4.74 (2 H, s),

5.22 (lH, d, J = 5Hz),

5.42 (2 H, s),

5.98 (1H, dd, J = 5Hz, 9Hz),

6.49 (1H, s-band),

7.43 (1 H, s),

7.71 (2H, d, J = 9Hz),

8.23 (2H, d, J = 9Hz)

8.52 (1 H, s),

9.68 (1 H, d, j = 9 Hz),

12.66 (1H, s).

2. In this embodiment, 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylate is the syn isomer and in an amount of 2.52 g, followed by 10% palladium deposited on carbon in an amount

1.3 g, ethanol 13 ml, tetrahydrofuran 25 ml, acetic acid 0.22 ml and water 2.2 ml were treated in a similar manner to that described in Example 15- (2). the final product of this embodiment of the process of the present invention is 7- (2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminolacetamido) -3-cep-4-carboxylic acid in the form of the syn isomer in a yield of 0.4 g .

Product characteristics;

IR at _max (nujol):

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

N.M.R. δ (DMSO-d6, ppm):

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

3.61 (2H, s-band),

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

4.73 (2 H, s),

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

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

6.48 (1H, s-band),

7.43 (1 H, s),

8.50 (1 H, s),

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

12.58 (1 H, s),

3. In this embodiment, the solution of 7- [2- (2-form, amidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylic acid is in the form of the syn isomer and in an amount of 0.35 g, 0.39 g of concentrated hydrochloric acid, 5.3 ml of ethanol and 8 ml of tetrahydrofuran were stirred at ambient temperature for 4.5 hours. The resulting solution is then concentrated under vacuum; the resulting residue was dissolved in aqueous sodium bicarbonate solution and then treated with charcoal and filtered. The filtrate thus obtained is adjusted to pH

3.5 using 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.

137

138

Ch-arak tari-sti ka

IR ( _max ):

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

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

6.47 (1H, s-band),

6.87 (1 H, s),

7.23 (2 H, s),

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

Example 30

1. According to this embodiment, Vil'smeier's reagent is first prepared from 0.32 g of N, N-dimethylformamide and 0.67 g of phosphorus oxychloride, in a conventional manner. The reagent was then suspended in ethyl acetate (10 ml) and 2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyiminojoic acid) was added with stirring to the solution. Acetic acid, in the form of the syn isomer, in an amount of 1.2 g, while cooling is carried out, and then, after the addition, the mixture is stirred at the same temperature as above for 30 minutes. amino-3-cephem-4-carboxylic acid (0.8 g) and trimethylsilylacetamide (4.2 g) in ethyl acetate (20 ml) at -25 ° C and stirred at -25 ° C. ranging from -20 ° C to -10 ° C for one hour, then water and ethyl acetate are added to the resulting solution, which forms an ethyl acetate layer which is separated. The aqueous layer was extracted with ethyl acetate, water was added to the combined extract, and the pH of the mixture was adjusted to

7.5 using a saturated aqueous solution of sodium bicarbonate. This produces an aqueous layer which is separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 1.5 with hydrochloric acid to form an ethyl acetate layer which was separated. Then, the aqueous layer is again subjected to extraction with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. Thereafter, the solution is concentrated under vacuum to give a residue which is triturated with diethyl ether and the precipitate is collected by filtration to give the final product, which is 7- (2- (2- Methyl-thiazol-4-yl-2- (2,2,2-trifluoroethoxyimino) -acetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 1.55 g.

Product characteristics:

IR at _max (nujo-1):

3250 1790 1690 1660 1630

1605, 1580, 1550 cm ¹

N.M.R. δ (DMSO-d6, ppm):

3.67 (2H, s-band),

4.78 (2H, q, J = 8.5Hz),

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

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

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

7.52 (1 H, s),

8.57 (1 H, s),

9.83 (1 H, d, J = 8 Hz),

12.67 (1H, s-band).

2. A suspension of 7- [2- (2 -ormamidothlazol-4-yl) -2- (2,2,2-trifluoroethoxyimino Jacetamido) -3-cephem-4-carboxylic acid is used in this embodiment. in the form of the 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 21- (3). ), wherein the final product of this embodiment of the process of the invention is 7- [2- (2-aminothiazol-4-yl) -2- (2,2,2-trifluoroethoxyiminojacetamido] -3-cephem-4-carboxylic acid in the form of syn isomer, yield 1.1 g.

Product characteristics:

IR in _max (nujo-1j):

3450, 3300, 1780, 1660, 1625,

1590, 1550 cm ¹

N.M.R. 5 (DMSO-d6, 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 (1 H, d, J = 8 Hz).

Example 31

1. A solution of 2- (2-formamidothiazol-4-yl) -2- (2-chloro ^, rethoxyimino) acetic acid in the form of the syn isomer in an amount of 3.47 gram of Ν, Ν-dimethylformamide in an amount

1.1 g and phosphorus oxychloride in an amount

2.3 g in 35 ml of ethyl acetate and 7-amino-3-ce217959

139

140-fem-4-carbonyl and bs-trimethylisilyl acetamide in an amount of 12.7 g in 25 ml of ethyl acetate were treated in a similar manner to that of Example 15- (1j), the final product of this of the invention is 7- (2- (2-formamidothiazol-4-yl) -2- (2-chloroethoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer and the yield of this product is 1.85 g.

Product characteristics:;

I. R · V max (nujolj:

3250, 3050, 1780, 1695, 1685,

1655, 1625 cm ”!

N. M. R. <5 (DMSO-d6, ppm):

3.62 (2H, d, J = 4Hz),

3.86 (2H, t, J = 6Hz),

4.37 (2H, t, J = 6Hz),

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

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

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

7.50 (1 H, s),

8.53 (1H, s,

9.68 (1 H, d, J = 9 Hz),

12.72 (1H, s band).

2. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -2- (2-chloroethoxyimino) acetamido] -3-cephem-4-carboxylic acid is the syn isomer and 1.8 g, concentrated hydrochloric acid 1.6 g, methane 27 ml and tetrahydrofuran 40 ml were treated in a similar manner to Example 15- (3), the final product of of this embodiment of the process of the invention is 7- [2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyiminoacetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 1.4 g.

Product characteristics:

IR at _max (nujolj:

3440, 3300, 3070, 1780 1660,

1625, 1555 cm ^-1

N.M.R. δ (DMSO-d6, ppm):

3.60 (2H, sj,

3.80 (2Ή, t, J = 6Hz),

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

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

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 32

1. A solution of 2- (2-formamidothiazol-4-yl) -2- (tert-butoxycarbonylmethoxyimino) acetic acid in the form of the syn isomer in an amount of 3.2 g, Ν, Ν- of dimethylformamide at 0.852 g and phosphorus oxychloride at 1.79 g in 34 ml of ethyl acetate, and a solution of 7-amino-3-cephem-4-carboxylic acid at 1.95 g and bis (trimethylsilyl) acetamide at 9.9 g in 19.5 g of ethyl acetate were treated in a similar manner to that described in Example 15- (1), the final product of this embodiment being 7- (2- (2- Formamidotrazol-a-yl) -2- (tert-butoxycarbonylmethoxyimino acetamido) -3-cephem-4-carboxylic acid in the form of the syn isomer in a yield of 2.9 g.

Product characteristics:

1. R. D _max

3280, 3180, 3060, 1785, 1730.

1690, 1640 cm ” ¹

N.M.R., δ (DMSO-d6, ppm):

1.44 (9H, s);

3.63 (2H, sj,

4.62 (2 H, s),

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

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

6.48 (1H, sj band,

7.42 (1 H, s),

8.50 (1 H, s),

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

12.62 (1H, s band).

2. In this embodiment, the mixture of 7- [2- (2-formamidothiazol-4-yl) -2- (tert-butoxycarbonylmethoxyimino) acetamido] -3-cephem-4-carboxylic acid is in the form of the syn isomer. and in amounts

2.8 g followed by 2.8 ml of anisole and 11.2 ml of trifluoroacetic acid were stirred at ambient temperature for one hour. Ethyl acetate and water were added to the resulting solution, and the pH was adjusted to 7.0 with sodium bicarbonate. In this way, an aqueous layer was formed which was separated and the ethyl acetate layer was subjected to extraction with water. The aqueous extracts were combined, washed with ethyl acetate and diethyl ether, and then the pH of the solution was adjusted to 2.0 with 10% hydrochloric acid while cooling on an ice water bath. A precipitate is formed, which is collected by filtration and then washed with water and dried to give the final product, which is 7- [2- (2-formamidothiazol-4-yl) -2- carboxymethylcellulose, thoxyimin ^| oacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1.43 g.

141

142

Product characteristics: ₍

IR (> _{11) ax} (nujol):

3270, 3120, 3070, 1760, 1720

1690, 1660, 1620 cnv ¹

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

3.60 (2 H, s),

4.63 (2 H, s),

5.11 (1 H, d, J = 5 Hz),

5.88 (1H, dd, J = 5Hz, 9Hz),

6.48 (1 H, t, I = 4 Hz),

7.44 (1 H, s),

8.52 (1 H, s),

9.59 (1 H, d, I = 9 Hz),

12.64 (1H, s band).

3. In this embodiment, a mixture of 7- [2- (2-formamidothiazol-4-yl) -2-carboxymethoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer in an amount of 1.35 g , concentrated hydrochloric acid (20 ml), 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. This gives a precipitate which is collected by filtration and dried to give the final product, which is 7- [2- (2-aminothiazazol-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: i

IR at _max (nujol):

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

1670, 1635 cnv ¹

N.M.R. δ (DMSO-d 6, ppm):

3.64 (2 H, s),

4.64 (2 H, s),

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

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

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

6.82 (1 H, s),

7.33 (2 H, s),

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

Example 33

1. In this embodiment, a solution of 2- (2-formamid'othiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetic acid in the form of the syn isomer and in an amount of

0.9 g, Ν, dl-dimethylformamide at 0.24 g and phosphorus oxychloride at 0.5 g in 10 ml of ethyl acetate and 4-nitrobenzyl-7-amino-3-chloro-3-cephem- hydrochloride solution. Of 4-carboxylate (1.23 g) and trimethylsilylacetamide (2.8 g) in ethyl acetate (20 ml) were treated in a similar manner to that described in Example 21- (1), the final product of this embodiment of the invention 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 syn isomer, yield 1.9 g.

Product Characteristics:

IR v, _llax (nujol):

3250, 1790, 1740, 1700, 1660, 1610,

1530 ^cm-1

N.M.R. δ (DMSO-d 6, ppm):

3.92 (2H, q, J = 17Hz).

4.77 (2H, q, J = 8.5Hz),

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

5.48 (2 H, s),

5.95 (1H, dd, J = 5Hz, 8Hz),

7.50 (1H, s),

7.70 (2H, d, J = 9Hz),

8.27 (2H, d, J = 9Hz)

8.53 (1 H, s),

9.92 (1 H, d, J = 8 Hz),

12.67 (1H, s-band).

2. In this embodiment, a suspension of 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino Jacetamido] -3-chloro-3 is obtained. -cephem-4-carboxylate in the form of the syn isomer, 1.8 g, and 10% palladium on carbon, 0.9 g in 20 ml of methanol, and treated with 20 ml of tetrahydrofuran in a similar manner to as described in Example 21- (2), wherein the final product of this embodiment of the invention is 7- [2- (2 -ormamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamide. 3-chloro-3-cephem-4-carboxylic acid as the syn isomer in an amount of 1.0 g.

Product characteristics:

IR v, _nax (nujol):

3250, 1780, 1690, 1655, 1530 cm ^-1

N.M.R. δ (DMSO-d 6, 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 (1 H, s),

8.53 (1 H, s),

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

12.70 (1H, s-band).

3. In this embodiment, 7- [2- (2-formamidothia) 17959 acid is added

143

144 Zol-4-yl) -2- (2,2,2-trifluoroethoxyimino] acetemido] -3-chloro-3-fluoro-4-carbhoxy] -3a in the form of the syn isomer in an amount of 0.7 g, followed by concentrated hydrochloric acid (0.43 ml) and methanol (16 ml) were treated in a similar manner to that described in Example 21- (3), the final product of this embodiment of the invention being 7- [2- (2-Aminothiazol-4-yl) -2- (2,2,2-trifluoroethoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid as the isomer in a yield of 0.65 g.

Product characteristics:

IR v, _mx (nujol):

3320, 3150, 1775, 1720, 1660,

1645, 1600, 1545 cnr ¹

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

3.87 (2H, cj, 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 (1H, sj,

10.00 (1H, d, J = 8);

Example 34

1. A solution of 2- (2-form, amidothiazol-4-yl) -2-butoxyiminoacetic acid in the form of the syn isomer in an amount of 1.5 g of N, N-dimethylformamide in an amount of 440 mg and phosphorus oxychloride (920 mg) in ethyl acetate (12 ml) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (2.03 g), trimethylsilylacetamide (7 g) his (trimethylsilyl) acetamide (2 ml) in ethyl acetate (25 ml) were treated in the same manner as in Example 21- (1), the final product of this embodiment being 4-nitrobenzyl- 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate in the form of the syn isomer, yield 2.8 g and the final product is in the form of a yellow powder.

Product characteristics:

IR v, _nax (nujol):

3200—3250, 1780, 1730, 1690, 1655, 1605,

1530, 1350 cm ^-1 .

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

0.90 (3H, ni);

1.2-1.6 (4 H, m),

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

4.0-4.2 (2H, mj,

5.32 (1H, l: J: 4);

5.44 (2H, 3).

5.92 (TH, dd, J = 4 Hz, 8 Hz),

7.36 (1 H, s),

7.68 (2H, d, J = 8Hz);

8.22 (2H, d, J = 8Hz),

8.50 (1 H, s),

9.72 (1 H, d, J = 8 Hz),

12.56 (1 H, s).

2. In this embodiment, a mixture of 4-nitro-benzyl-7- [2- (2-formamide) -thiazol-4-yl] -2-butoxyiminoacetamido] -3-chloro-3-cephem-4- of the carb isoxylate in the form of the syn isomer at 2.7 g and 10% palladium on charcoal in 4 ml, acetic acid in 0.4 ml, methanol in 27 ml and tetrahydrofuran in 54 ml. by the method of Example 21- (2), wherein 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 of which is 1.4 g and the product is in the form of a yellow powder.

Product characteristics:

I. R. (nujol):

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

1610 cnr ^first

N.M.R., δ (DMSO-d 6, ppm):

0.90 (3 H, m),

1.2 - 1.70 (4H, m),

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

4.0-4.25 (2 H, m),

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

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

7.42 (1 H, s),

8.50 (1 H, s),

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

12.60 (1H, s).

3. 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 in an amount of 1.3 g, concentrated hydrochloric acid in an amount

1.3 ml of methanol and 20 ml of methanol are treated in a similar manner to that described in Example 21- (3), the final product of this embodiment being 7- (2- (2-amino-thiazole-) 4-yl) -2-, butoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 1.2 g and the product is in the form of a pale yellow powder.

Product characteristics:

IR at, _rax (nujol):

3300, 2500—2600, 1785, 1730, 1655, 1630 cm ¹ .

145

146

Ν. Μ. R. δ (DMSO-d 6, ppm):

0.90 (3Η, m),

1.2 - 1.75 (4Η, m)

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

5.17 (2 H, m),

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

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

8.93 (1 H, s),

9.50 (2H, s-band),

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

Example 35

1. A solution of 2- (2-formamidothiazol-4-yl) -2-butoxyoxyiminoacetic acid in the form of the syn isomer in an amount of 1.09 g of N, N-dimethylformamide in an amount of 322 mg and phosphorus oxychloride 675 mg in ethyl acetate

9.2 ml and a solution of 4-nitrobenzyl 7-amino-3-methoxy-3-cepine-4-carboxylate as hydrochloride in 1.5 g, trimethylsilylacetamide 5 g and bisptrimethylsilyl acetamide 2 ml in ethyl acetate in ethyl acetate they are treated in a similar manner to that described in the example procedure

3- (1), wherein the end product of this embodiment of the process of the invention is

4-Nitrobenzyl 7- [2- (2-phthalamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylate in the form of the syn isomer, yield 1.8 g gram.

Product characteristics:

I. R. i>, nax (nujol).

3300, 3220, 1770, 1715, 1690, 1650, 1610,

1540, 1350 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

0.90 (3 H, m),

1.2-1.7 (4H, m),

3.73 (2H, s-band),

3.96 (3 H, s),

4.10 (2 H, m),

5.22 (1 H, d, J = 4 Hz),

5.32 (1H, d, d, J = 4Hz, 8Hz),

7.43 (1 H, s),

7.64 (2H, d, J = 9Hz);

8.20 (2H, d, J = 9Hz),

8.48 (1 H, s),

9.56 (1 H, d, J = 8 Hz),

12.59 (1 H, s). ²

2. In this embodiment, the mixture of 4-nitrobenzyl-7- [2- (2-formamidothiiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylate is syn. isomer and 1.7 g, 10% palladium on charcoal 1 g, 3 ml water, 0.3 ml acetic acid, 20 ml methanol and 35 ml tetrahydrofuran are treated in a similar manner as in Example 15- (2), wherein the final product of this embodiment is 7- (2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido) -3- methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer and in an amount of 1 g, which is a yellow powder.

Product characteristics:

IR v, _nax (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, d, d, J = 4Hz, 8Hz),

7.50 (1 H, s),

8.58 (1 H, s),

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

3. In this embodiment, the mixture of 7- [2- (2-formamidothiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylic acid is the syn isomer and 0.9 g, concentrated hydrochloric acid

0.8 ml of methanol and 13.5 ml of methanol are treated in a similar manner to that described in Example 15- (3), the final product of this embodiment being 7- [2- (2- aminothiazol-4-yl) -2-butoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer and yield 0.4 g, the title product being a yellowish-white powder.

Product characteristics:

IR at _max (nujol):

3200—3300, 2600, 1770, 1705, 1670

1620 cm ¹ .

N.M.R. (.delta. (DMSO-d6, 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 36

1. In this embodiment, 4-nitrobenzyl-7-amino-3-cephem217939 is used.

147

148

Dissolve 4-carboxylate (5 g) in a solution of trimethylsilylacetamide (10 ml) in dry ethyl acetate (50 ml) and stir at 45 ° C for 1.5 hours. Then, a solution of 2.88 g of bromine in 7 ml of methylene chloride was added dropwise to a 1.5 g solution of diketane in methylene chloride. 7 ml, wherein the addition is carried out at -40 ° C over 20 minutes, and the resulting solution was stirred at -30 ^C Celsius for 1 hour. The solution is then added dropwise to the above solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate under cooling to -15 ° C and then stirred at the same temperature for 30 minutes. Water (50 ml) was added to the resulting solution, followed by extraction with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oily product which was 4-nitrobenzyl-7- [2- (2- bromoacetyl) acetamido] -3-cephem-4-carboxylate and the yield of this product is 6.15 g.

Product characteristics:

I. R · (nujol):

1780, 1740, 1630 cm ¹ .

NMR čp _{pm (} DMSO-d 6):

3.62 (2H, sj band,

4.37 (2H, sj,

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

5.40 (2H, sj,

5.77—6.05 (mj,

6.67 (1 H, t, J = 5 Hz),

7.68, 8.04 (4H, m, J = 9 Hz),

9.07 (1H, d, J = 8Hz).

2. A solution of diazomethane in diethyl ether is added in small portions to a solution of 4-nitrobenzyl 7- [2- (2-bromoacetyl) -2-hydroxyiminoiacetamido] -3-cephem-4-carboxylate in an amount 0.9 g in 30 ml of tetrahydrofuran, while cooling with ice until the reaction is complete, and acetic acid is added to the resulting solution to quench excess diazomethane, and the resulting solution is concentrated under reduced pressure to give a solid. the final product in the form of a foam, and the final product obtained according to this embodiment of the process of the invention is 4-nitrobenzyl 7- [2- (2-bromoacetyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of son iSOineni and in a yield of 0.9 g,

Example 37

To this was added 10% palladium on carbon at a rate of 0.35 g to a solution of 4-nitrobenzyl-7- [2- (2-amino-4-thiazole) -2-hydroxyiminoacetamido] -3- cefem-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. clock. This gives a final mixture which is filtered and the filtrate is concentrated under reduced pressure. The residue is added to sodium bicarbonate solution to give an insoluble material which is filtered. The filtrate is washed with ethyl acetate and methylene chloride, then purged with nitrogen and then lyophilized to give a residue which is dissolved in 30 ml of water and the pH of the solution is adjusted to 3.8 ml. with a 10% hydrochloric acid solution. This solution is then subjected to a chromatography column which is packed with microporous, non-ionic adsorption resin material "Diaion HP-20" (trade name of Mitsubishi Chemical Industries Ltd.) in an amount of 20 ml, then washed with water and then eluted with 40% aqueous acetone solution, acetone is removed from the eluate under reduced pressure and the residue is lyophilized 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.

Product characteristics:

IR> _max (nujolj:

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

N.M.R. _ppm (DMSO-d6):

3.60 (2H, sj 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 (1 H, d, J = 8 Hz).

Example 38

A solution of diazomethane in diethyl ether is added portionwise to a solution of 4-nitrobenzyl-7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetiamido] -3-cephem-4-carboxylate in in the form of the syn isomer in an amount of 0.3 g in metha217959

149

150 ml of 30 ml 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 precipitate is collected by filtration and dried to give the final product, which is 4-thiitrobenzyl. 7- [2- (2-amino-4-thiiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer, yield 0.26 g. This product was identified by comparison with the same sample. .

Example 39

The procedure was followed by dissolving 2.54 g of 7-amino-3-cephem-4-carboxylic acid in 11.7 g of trimethylsilylacetamide and 15 ml of bis (trimethylsilyl) acetamide in dry ethyl ester. 50 ml of acetic acid. Subsequently, a solution of 2.43 g of bromine in dry methylene chloride (10 ml) was added dropwise to a solution of diketene of 1.28 g in dry methylene chloride (25 ml) at a temperature of - 30 ° C for 10 minutes, and then stirred at the same temperature above for 1.5 hours. This solution is then added to the above solution containing 7-amino-3-cephem-4-carboxylic acid at -15 ° C for 10 minutes, and then stirred at a temperature of about -15 ° C. in the range of -15 to -10 ° C for 1.5 hours. Water (50 ml) was added to the resulting solution. In this way, an ethyl acetate layer was formed, which was separated and then extracted with an aqueous sodium bicarbonate solution. The pH of the aqueous extract thus obtained is adjusted to 2.0 with a 10% hydrochloric acid solution and then extracted with ethyl acetate. The ethyl acetate extract thus obtained is washed with water, dried over magnesium sulphate and then concentrated under reduced pressure to give the final product, 7- (2- (2-bromoacetyl jacetamido) -3-cephem-). 4-carboxylic acid, and the yield is 2.82 g.

Product characteristics:

IR at _max (nujol):

1760, 1660 cm -1.

NMR _ppplu (DMSO- _d 6):

3.58 (2H, d, J = 4Hz),

3.65 (2 H, s),

4.40 (2 H, s),

5.06 (1H, d, J-5 1-Iz),

5.73 (1 H, dd, J = 8 Hz),

6.50 (1 H, t, J = 4 Hz),

9.08 (1H, d, J = 8Hz).

Example 40

Following a procedure similar to that of Example 38- (2), the following compounds of the invention were prepared:

1.

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

2.

4-nitrobenzyl 7- [2- (2-amino-thiazol-4-yl) -2-propoxyimimoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer,

3.

4-Nitrobenzyl 7- [2- (2-amniothiazol-4-yl) -2-isopropoxyiminoacetamido] -3-cephem-4-carboxylate as the syn isomer.

Example 41

704 mg of phosphorus oxychloride was added dropwise to a solution of 336 mg of Ν, Ν-dimethylformamide in 8 ml of ethyl acetate, at a temperature below 5 ° C. , and the solution is then stirred at the same temperature above for 30 minutes. 2- (2-Formamidothiazol-4-yl) -2-methoxyiminoacetic acid in the form of syn isomer is added to the solution so obtained in an amount of 1 g and then stirred at a temperature ranging from 5 to 10 °. C for one hour. The solution was then added dropwise to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (1.05 g) in ethyl acetate (20 ml) at -20 ° C over 5 minutes. and the solution is then stirred at a temperature ranging from -20 to -25 ° C for one hour. Water (50 ml) was added to the resulting solution and the pH of the solution 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-ionogenic adsorption resin material of Diaioin HP-20 (a trade name of Mitsubishi Chemical Industries). The chromatography column was then washed with water (50 ml) and eluted with 30% aqueous isopropyl alcohol. The eluate thus obtained, containing pre 217939

131

The compound of the invention was adjusted to a pH of 6.5 and then concentrated under reduced pressure. The residue thus obtained is lyophilized to give the final product, which is 7- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-hydroxycepham-4-carboxylate syn. isomer, yield 1.1 g.

Product characteristics:

N. M. R. δ (D2O, ppm):

2.72-3.18 (2H, m),

4.02 (3H, s,

4.02-4.28 (1 H, m),

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

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

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

7.50 (1 H, s),

8.53 (1H, sj.

Example 42

Fermentation:

Inoculation environment:

tripticaso-soy medium (BBLj.

Culture environment:

glycerin 3 g peptone 1 g corn extract 1 g dry yeast 2 g sodium carbonate 0.1 g

KHzPOá. 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 then shaken the culture at 30 ° C. C for 48 hours.

Reaction:

To the above 1 ml culture medium is added 0.1 g of substrate, the characteristics of which are given below, suspended in 0.1 M phosphate buffer at pH 7.2 and 1 ml, 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) an upper layer of a 4: 1: 5 (v / v) mixture of n-butanol, ethanol and water, and (B) a 7: 3 v / v mixture of n-propanol and water.

The Rf value was determined by the index of antimicrobial activity against susceptible species of Escherichia coli ES 111 and as a result only one spot was observed, showing Product I and II in Eastman cellulose-based chromatogram 6065 without any staining of Substrate I and II. The Rf values are given in the following table:

TABLE

Developing agent A B

Reaction mixture (Product I) 0.85 0.90 Control (Substrate I) 0.39 0.60 Reaction mixture (Product II) 0.90 0.92 Control (Substrate II) 0.36 0.54

153

154

Note:

Substrate I:

4-nitro-benzyl-7- [2- (2-formamido-α-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-cartooxylate in the form of the syn isomer,

Product I:

7- (2- (2-formamido-4-thlazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid in the syn isomer farm,

Substrate II:

4-nitrobenzyl 1-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of the syn isomer,

Product II:

7- [2- (2-amino-4-thiazolyl-2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid in the farm isomer.

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

TABLE

Microorganisms used for enzymatic hydrolysis

Bacillus subtilis IAM 1069

Bacillus sphaericus

Bacillus subtilis IAM 1107

Bacillus subtilis IAM 1214

Corynebacterium equi IAM 1038

Micro · coccus varians IAM 1314

Flavobacterium rigens IAM 1238 Salmonella typhimurium IAM 1406 Staphylococcus epidermidis IAM 1296 Micrabacterium flavum IAM 1642

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

The following are examples of pharmaceutical compositions prepared by the process of the invention which contain 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer (Compound A ) as an active ingredient.

Example 43

Lyophilization preparation for injection

According to this embodiment, the sodium salt of compound A (20 g efficacy) is dissolved in 200 ml of water and this 5 ml solution is filled into 10 ml tubes, which are frozen and then vacuum dried (lyophilized).

Example 44

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 intramuscular injection.

Example 45

Tablets for oral use

Compound A 500 mg lactose 375.5 mg hydroxypropylcellulose 2 mg magnesium stearate 22.5 mg

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

Example 46

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 47

1. A solution of 2- (2-formamidothiazol-4-yl) -2-n-hexyloxyiminoacetic acid in the form of a syn isomer in an amount of 3.24 g, N, N217959

155

156

-dimethylformamide in an amount of 0.951 g and phosphorus oxychloride in an amount of 2.00 g in ethyl acetate in an amount of 20 ml and a 4 g solution of 4-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate as hydrochloride in acetone (20 ml), water (20 ml) and tetrahydrofuran (40 ml) were treated in a similar manner to Example 21- (1), the end product of the process according to the invention being 4-nitrobenzyl-7- [2- ( 2-formamidothiazol-4-yl] -2-n-hexyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate as the syn isomer, yield 5.78 g.

Product characteristics:

IR in _mM (nujol):

3240, 3200, 3050, 1780, 1730, 1695,

1660 cm ^-1 .

N. M. R. <5 (DMSO-d 6, ppm):

0.6-2.1 (11H, mj,

3.96 (2H, q, J = 19Hz).

4.15 (2H, t, J = 6Hz);

5.37 (1 H, d, J = 5 Hz),

5.50 (2H, sj,

5.97 (1H, d, d, [= 5Hz, 8Hz],

7.42 (1 H, 3),

7.72 (2H, d, J = 9Hz),

8.28 (2H, d, J = 9Hz)

8.54 (1H, sj,

9.74 (1H, d, J = 8Hz),

12.73 (1H, sj band).

2. In this embodiment, a mixture of 4-nitrobenzyl-7- [2- (2-formamidothiazol-4-yl-2-n-hexyloxyiminoacetamido) -3-chloro-3-cep-4-carboxylate as the syn isomer and 5.6 g, acetic acid

0.4 ml, 10% palladium on charcoal (2.24 g), water (4 ml), methanol (23 ml) and tetrahydrofuran (56 ml) were treated in a similar manner to that described in Example 21- (2), wherein the final product of this embodiment of the process of the invention is 7- (2- (2-formamidothazol-4-yl) -2-n-hexyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer and the yield of this product is 2.5 g.

Product characteristics:

IR in _max (nujol j:

3225, 1785, 1690, 1650 cm ^-1 .

N.M.R. 5 (DMSO-d6, ppm):

0.6-2.0 (11H, m),

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

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

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

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

7.41 (1H, sj,

8.54 (1H, sj,

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

12.68 (1 H, s).

3. According to this embodiment, the mixture of 7- [2- (2-formamldothiazol-4-yl) -2-hexyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 2, 4 g, 1.84 g of concentrated hydrochloric acid, 36 ml of methanol and 30 ml of tetrahydrofuran were stirred at 30 DEG C. for 2 hours. The resulting solution was concentrated in vacuo. This gives a residue 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-hexyloxylminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 1.86 g .

Product characteristics:

IR at _max (nujol):

3300, 1780, 1665, 1535 cm ¹ .

N.M.R. δ (DMSO-d6, ppm):

0.6-2.0 (11 H, m),

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

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

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

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

6.77 (1 H, s),

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

6.0-8.0 (2H, s-band),

Example 48

1. 2- (2-Formamidothiazol-4-yl) -2-propargyloxyiminoacetic acid in the form of the syn isomer in an amount of 1.27 g, N, N-dimethylformamide in an amount of 402 mg, oxychloride phosphorous phosphate (843 mg) and ethyl acetate (11.2 mL) are treated in a conventional manner to prepare an active acid solution. Simultaneously, a mixture of 7-amino-3-methoxy-3-cephem-4-carboxylic acid in the form of the hydrochloride in an amount of 1.33 g, trimethylsilylacetamide in an amount of 4 g, bis (trimethylsilyl) acetamide in 2 ml and ethyl acetate in an amount of 20 ml is stirred at a temperature ranging from 40 to 45 ° C for one hour. To the solution thus prepared is added the active acid solution obtained as described above in the form of a single addition at a temperature of -15 ° C and then stirred at a temperature in the range of 179595.

157

158 limits from -5 to -10 ° C for 1.5 hours. Water (30 ml) was added to the resulting solution, the solution was filtered and the resulting organic layer was separated. The insoluble matter is filtered and dissolved in a saturated aqueous sodium bicarbonate solution, and this solution is then added to the organic layer. The pH of the solution was adjusted to 7.5 and the aqueous solution was separated and then extracted with ethyl acetate at pH 2.0.

The extract thus obtained is washed with water, then dried over magnesium sulphate and filtered. The filtrate is concentrated in vacuo to give the final product, 7- [2- (2-phthamidamido-thiazol-4-yl) -2-propargyloxyiminoacetamido] -3-methoxy- 3-cephem-4-carboxylic acid in the form of the syn isomer, the yield of which is 1.0 g and the product is in its final form a yellow powder.

Product characteristics:

IR in _niax (nujol):

3200—3300, 2500—2600, 2120, 1770, 1710,

1690, 1670 cm @ -1.

N.M.R. δ (DMSO-d 6, ppm):

3.50 (1 H, m),

3.65 (2 H, s),

3.82 (3 H, s),

4.80 (2H, d, J = 2Hz);

5.20 (1H, d, J = 4Hz);

5.62 (1H, d, d, J = 4Hz, 8Hz),

7.52 (1 H, s),

8.55 (1 H, s),

9.68 (1 H, d, J = 8 Hz),

12.65 (1H, s band).

2. In this embodiment, the mixture of 7- (2- (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetamido) -3-methoxy-3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 0.9 g of concentrated hydrochloric acid (0.9 ml) and methanol (13.5 ml) were stirred at ambient temperature for 4 hours, then the resulting solution was concentrated in vacuo at 35 ^DEG C. to give a residue which was dissolved. The aqueous solution was adjusted to pH 7.0 with sodium bicarbonate and washed with ethyl acetate and diethyl ether to form a solution from which the solvent was removed in the next step. by bubbling nitrogen, and the resulting solution was adjusted to pH 3.0 with a 10% hydrochloric acid solution and then stirred while cooling in an ice bath. step, a solid precipitates, 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-propargyloxyiminoacetamido) 3-methoxy-3-cephem-4-carboxylic acid in the form of the syn isomer, the yield of which is 0.25 g and the product is in the form of an off-yellow powder.

Product Features:

IR: _III (nujol):

3300, 2500—2600, 2120, 1775, 1710, 1670,

1620 cm ^-1 .

N.M.R. δ (DMSO-d 6, ppm):

3.52 (H-1, m),

3.82 (3 H, s),

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

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

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

6.93 (1 H, s),

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

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

Example 49

1. The process is carried out by adding 2- (2-formamidothiazol-4-yl) -2-propargyloxylminoacetic acid in the form of the syn isomer and in an amount of 1.27 g, followed by Ν, Ν-dimethylformamide in an amount of 400 mg, 850 mg phosphorus oxychloride and 11.2 ml ethyl acetate were processed in a conventional manner to prepare an active acid solution. The active acid solution is then added to a 2 g solution of 7-amino-3-chloro-3-cephem-4-carboxylic acid hydrochloride, 6 g of trimethylsilylacetamide, and 3 g of bis ^: (trimethylsilyl) acetamide 3 ml in 40 ml of ethyl acetate, added once at -15 ° C, and then stirred at a temperature ranging from -5 to -10 ° C for 1.5 hours. . 30 ml of water was added to the resulting solution, which formed an ethyl acetate layer which was separated and then subjected to extraction with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate was added to the aqueous extract, and the pH was adjusted to 2.0 with 10% hydrochloric acid. The ethyl acetate layer thus formed is separated, washed with water, dried over magnesium sulphate and finally filtered. The filtrate was concentrated in vacuo to give a residue, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether. The precipitate was collected by filtration and dried to give the final product of this embodiment

159 of the invention, which is 7- (2- (2-formamidothiazol-4-yl) -2-propargyloxyimimoacetamido) -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer; The product is 1.5 g and the product is a yellow powder.

Product characteristics:

IR _inax (nujol):

3250-3300, 2500—2600, 2120, 1780, 1725,

1690, 1670 cm -1.

N.M.R. δ (DMSO-d 6, ppm):

3.45 (1 H, m),

3.57 (2H, AB-q, J = 20Hz);

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

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

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

8.42 (1 H, s),

8.52 (1 H, s),

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

12.72 (1H, s band).

2. A mixture of 7- [2- (2-phirmamidothiazol-4-yl) -2-propargyloxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer is followed. and 1.4 g of concentrated hydrochloric acid, 1.4 ml, and 20 ml of methanol were treated in a similar manner to that described in Example 51- (2), the final product of this embodiment of the process of the invention. is 7- (2- (2-aminothiazol-4-yl) -2-propargyloxyiminoabetamido) -3-chloro-3-cephem-4-carboxylic acid in the form of the syn isomer, yield 0.7 g 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, J = 2Hz);

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

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

6.78 (1 H, s),

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

Example 50

Accordingly, the 4-nitrobenzyl-7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate is synthesized in the form of syn. isomer and 5.0 g and 10% palladium on carbon at 3.0 g, methanol at 100 ml, water at 10 ml and tetrahydrofuran at 150 ml.

160 was reported for Example 37- (2), the final product of this embodiment of the invention being 7- [2- (2-aminothlazol-4-yl) -2-hydroxyiminoacetamido] -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.

N.M.R. δ (DMSO-d6, ppm):

3.72 (2 H, m),

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

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

6.66 (1 H, s),

9.50 (1 H, d).

Example 51

1. A solution of 2- (2-formamidothlazoil-4-yl) -2-n-octyloxylminoacetic acid in the form of the syn isomer in an amount of 7.52 g of phosphorus oxychloride in an amount of 5.4 g Of g, Ν-dimethylformamide (2.58 g) in tetrahydrofuran (16 ml), prepared in a similar manner to that described in Example 30- (1), and a solution of 7-amino-4-cephem-4-carboxylic acid in 4 g in 20 ml of acetone, 20 ml of water and 20 ml of tetrahydrofuran are treated in a similar manner to that described in Example 30- (1), the end product of this process being an acid 7- [2- (2-formamidothiazoil-4-yl) -2-n-octyloxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn isomer, yield 8.1 g.

Product characteristics:

IR in _niax (nujol):

3280, 3200, 3060, 1795, 1705, 1660,

1630 cm ^1st

N.M.R. δ (DMSO-d 6, ppm):

0.6-2.1 (15 H, m),

3.62 (2H, d, J = 4Hz);

4.14 (2H, t, J = 6Hz);

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

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

6.51 (1 H, t, J = 4 Hz),

7.42 (1 H, s),

8.54 (1 H, s),

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

12.66 (1 H, s).

2. In this embodiment, 7- [2- (2-formamidothiazol-4-yl) -4-n-octyloxyiminoacetamide] -3-cephem-4-carboxylic acid is in the form of the syn isomer in an amount of 8, 0 g and further concentrated

101

102, 6.23 g of hydrochloric acid, 15 ml of tetrahydrofuran and 120 ml of methanol are treated in a similar manner to that described in Example 21- (3), the end product of the process being acid 7- (2- (2-aminothiazol-4-yl) -2-n-octyloxyiminoacetamido] -3-cephem-4-carboxylic acid as the syn isomer, yield 6.95 g.

Product characteristics:

IR in _mnx (nujol):

3320 (band), 1785, 1660, 1630,

1535 cm ^-1 .

N.M.R. δ (DMSO-d6, ppm): 0.6-2.0 (15H, m),

3.62 (2H, s-band),

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

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

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

6.48 (1H, sj band,

6.72 (1H, sj,

7.22 (2 H, s),

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

Claims (7)

A process for the preparation of the syn isomer of 7-substituted-3-cephem (or cepham-4-carboxylic acids of formula I wherein R ¹ is a thiadiazolyl group, a thiazolyl group of the formula wherein: R ⁶ is amino, trihalogen (C 2 -C 6 alkanamide, C 1 -C 6 alkanamide; or haloacetyl, A is a methylene group or a group of the formula -ΟΝ- OR ² wherein R ² represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted by halogen, carboxyl or alkoxycarbonyl having 1 to 6 carbon atoms, a cycloalkyl group (C 5 -C 7), (C 2 -C 6) alkenyl or (C 2 -C 6) alkynyl, R ³ is a hydrogen atom or an alkyl group containing 1 to Θ carbon atoms, YNÁLEZU R ⁴ is hydrogen, halogen, C 1 -C 6 alkyl or -O-R ⁷ wherein R ⁷ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanesulfonyl carbon, an arensulfonyl group having 6 to 10 carbon atoms or an alkanoyl group having 1 to 6 carbon atoms, R ⁵ is a carboxy group or a pharmaceutically acceptable ester, preferably (C 1 -C 6 alkanoyloxy (C 1 -C 6 alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl), and the dotted line indicates an optional double bond between the 3 and 4 position, with the proviso that that R ⁴ is hydrogen or -O-R ⁷ . wherein R ⁷ has the same meaning as above, when R ³ is hydrogen; - R ⁴ is an alkyl group having 1 to 6 carbon atoms, when R ³ is an alkyl group having 1 to 6 carbon atoms, - A is a group of the general formula -ΟΝ-O-R ² wherein R ² has the aforementioned meaning, in the case where R ¹ is a thiadiazolyl group or a thiazolyl group of formula 163 164 wherein R ⁶ is as previously defined, and - the dotted line indicates a double bond between the 3 and 4 position and R ⁴ is hydrogen, halogen, C 1 -C 6 lower alkyl or -O-R ⁷ . wherein R ⁷ is an alkyl group having 1 to 6 carbon atoms when R ¹ is haloacetyl, and - R ² is not hydrogen or an alkyl group having 1 to 6 carbon atoms when R ⁴ is halogen or a general group -O-R ⁷ wherein R ⁷ is an alkyl group containing 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof, characterized by reacting a 7-amittO-3-cephem (or cefamjová compound of formula (II) in which the substituents R ³ , R ⁴ and R ⁵ are as defined above, a reactive derivative at the amino group of the compound or a salt of the compound with a carboxylic acid of the formula III, Rl-A-COOH (III) in which R ¹ and A are as defined above, with a reactive derivative at the carboxy group thereof or a salt thereof, optionally followed by - reacting the resulting compound in which R ² represents hydrogen, with an etherifying agent, to give the title compound wherein R ² is C 1 -C 12 alkyl which may be substituted by halogen, carboxy or C 1 -C 6 alkoxycarbonyl, C 5 -C 6 cycloalkyl Or - the resulting compound in which R @ ⁶ represents a trihaloalkanamide group containing 2 to 6 carbon atoms or an alkane group is an amide group having from 1 to 7 carbon atoms; 6 carbon atoms, subjected to elimination Reaction of a trihaloalkanoyl group having 2 to 6 carbon atoms or an alkanoyl group having 1 to 6 carbon atoms? for vizniku resulting compound in which R ⁶ represents amino, or - reacting the resulting compound in which R ⁵ represents a carboxy, or pharmaceutically acceptable ester with esteriíikačním agent, to give the title compound in which R ⁵ represents (C, -C6) alkane Oy alkyloxy (Cl-C6) alkoxykartoonylovou group or nitrophenyl (Ci-C6 jalkoxykarbonylovou group, or - converting the ester of the title compound in which the substituent ^R5 pharmaceutically acceptable ester, preferably a (C CsjaikanoloxyjCi-6 ) alkoxycarbonyl or nitrophenyl (C 1 -C 6) alkoxycarbonyl, to a carboxy group to give the title compound wherein R ⁵ is carboxy. 2. The process of claim 1, wherein the compound of formula (II) is reacted wherein: R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and R ³ and R ⁵ have the same meaning as in 1 and the dotted line represents a double bond between the 3 and 4 position, or a reactive derivative of this compound at the amino group, or a salt of this compound with a compound of formula III, wherein R ¹ represents a thiadiazolyl group or a thiazolyl group of the general formula R in which R ⁶ is amino, trihaloalkanamide having 2 to 6 carbon atoms or alkanamide having 1 to 6 carbon atoms, and A is a group of the general formula -ΟΝ-O-R ² in which R ² represents an alkyl group containing 1-6 carbon atoms, alkenyl radicals containing 2 to ^6: carbon atoms, a carboxyalkyl group having 1 to 6 carbon atoms or (C CejalkoxykarhonyifCi- -CE) alkyl group, or a reactive derivative thereof at carboxy group or with a salt of this compound, with the proviso that - R ⁴ is hydrogen, halogen or C 1 -C 6 alkoxy, when R ³ is hydrogen, 165 166 - R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ^{3 is an} alkyl group having 1 to 6 carbon atoms, - R ² is not an alkyl group having 1 to 6 carbon atoms when R ⁴ is an halogen or alkoxy having 1 to 6 carbon atoms. 3. A process according to claim 2 wherein the compound of formula II is reacted wherein R ^{@ 3} , R ^{@ 4} and R @ ^{5 are the} same substituents as described in point 2 and the dotted line has the same meaning as in or a reactive derivative at the amino group of the compound or a salt of the compound with a compound of formula III in which: R ¹ is a thiazolyl group of the formula wherein R ⁶ is as previously defined in point 2, A is a group of formula -C- N-O-R ² in which R ^{2 is an} alkyl group having 1 to 6 carbon atoms, or with a reactive derivative thereof on the carboxy group or a salt thereof, with the proviso that - R ⁴ is hydrogen, halogen or alkoxy having 1 to 6 carbon atoms when R ³ is hydrogen, - R ⁴ is an alkyl group having 1 to 6 carbon atoms when R ³ is an alkyl group having 1 to 6 carbon atoms, and - R ² is not an alkyl group having 1 to 6 carbon atoms when R ⁴ is halogen or an alkoxy group having 1 to 6 carbon atoms. 4. The process of claim 1, wherein the compound of formula (II) is reacted R ⁴ is hydrogen, halogen, alkyl of 1-6 carbon atoms or alkoxy containing 1-6 carbon atoms; R ³ and R ⁵ have the same meaning as in 1 and the dotted line represents a double bond between the 3 and 4 position, or a reactive derivative at the amino group of the compound or a salt of this compound with a compound of Formula III, wherein R ¹ represents a haloacetyl group, and A is a methylene group, or a reactive derivative thereof on a carboxy group or a salt thereof, provided that: - R ⁴ is hydrogen, halogen or C 1 -C 6 alkoxy when R ³ is hydrogen, and - R ⁴ is C 1 -C 6 alkyl when R ³ is C 1 -C 6 alkyl. 5. The process of claim 1, wherein the compound of formula (II) is reacted wherein: R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula -O-R ⁷ in which: R ⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ³ and R ⁵ have the same meaning as in point 1 and the dotted line represents a double bond between the 3 rd and 4 th position, or a reactive derivative of this compound at the amino group or a salt thereof, with a compound of formula III A represents a group of the general formula -ΟΝ-O-R ² in which R ² is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, carboxy (C 1 -C 6) alkyl or (C 1 -C 6 alkoxycarbonyl (C 1 -C 6) alkyl), and R ¹ is a thiadiazolyl group or a group of the general formula wherein R ⁶ has the same meaning as in point 1, or with a reactive derivative of this compound on the carboxy group or a salt thereof, provided that - R ⁴ is hydrogen, halogen or a group of the formula -O-R ⁷ wherein: R ⁷ is hydrogen or C 1 -C 6 alkyl, when R ³ is hydrogen, R ⁴ is ob217359 167 having 1 to 6 carbon atoms when R ³ is an alkyl group having 1 to 6 carbon atoms, - R ⁴ is a group of the general formula -O-R ⁷ in which R ⁷ is a hydrogen atom when R is ² is an alkyl group containing 1-6 carbon atoms, alkenyl of 1-6 carbon atoms, karboxyjCi-ϋβ) alkyl or (C - C6) alkoxykařboinyl (C j -C alkyl group, and - R ² is not hydrogen in wherein R ⁴ is halogen or -O-R ⁷ wherein R ⁷ is C 1 -C 6 alkyl. 6. The process of claim 1, wherein the compound of formula (II) wherein: R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula -O-R ⁷ in which: R ( ⁷⁾ is hydrogen or (C1-C6) -alkyl, R ³ and R ⁵ have the same meaning as in point 1 and the dotted line represents a double bond between the 3 rd and 4 th position, or a reactive derivative of this compound at the amino group or a salt thereof, with a compound of formula III in which ^R1 is thiadiazolyl or thiazolyl radical of the general formula · 168 wherein R ^{6 has the} same meaning as in 1, and A is a group of formula —C— N-O-R ² wherein R ² is a cycloalkyl group containing 5-7 carbon atoms or alkynyl having 2 to 6 carbon atoms, or a reactive derivative thereof at the carboxy group or a salt thereof, with the proviso that: - R R ⁴ is hydrogen, halogen or a group of the formula -O-R ⁷ wherein R ⁷ is hydrogen or C 1 -C 8 alkyl when R ³ is hydrogen, and R ⁴ is alkyl C 1 -C 6 when R ³ is C 1 -C 6 alkyl. 7. The process of claim 1, wherein the reaction is reacted with a 7-amino-3-cephem-4-carboxylic acid, an amine reactive derivative thereof, or a 2- (2-aminothlazol-4-yl) salt thereof. ) -2-methoxyiminoacetic acid (syn isomer), with a reactive derivative of the compound or with a salt thereof, to give 7- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-cephem-4- carboxylic acids in the form of the syn isomer or a pharmaceutically acceptable salt thereof.