RU2097385C1 - Method of synthesis of cephem derivatives, reactive thiophosphate derivatives of thia- (or dia)zole acetic acid and a method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: cephem derivatives of the general formula (I):

where: R¹ means carboxy-group or protected carboxy-group that can form salt -COO^-M⁺ with alkaline metal ion ((M⁺)), for example, with sodium ion or can mean -COO^-, when R² has substituent with positive electric charge, for example, pyridinium, pyrimidinium or thiazolium; R² means hydrogen, acylhydroxymethyl, heterocyclic methyl or heterocyclic thiomethyl each of that can be substituted with the corresponding substituents; R³ means hydrogen or amino-protected group; R⁵ means hydrogen, C_1-4-alkyl or -C(R^a)(R^b)CO₂R^c, where R^a and R^b in the group -C(R^a)(R^b)CO₂R^c as R⁵ are similar or distinct each of other and mean H or C₁-C₄-alkyl, or together with carbon atom with which they were bound form C₃-C₇-cycloalkyl group; R^c - hydrogen or carboxy-protecting group; Q - nitrogen atom or CH. EFFECT: improved method of synthesis. 15 cl

Description

в котором R¹ представляет карбоксигруппу или защищенную карбоксигруппу, которая может образовывать соль -COO^-M⁺ с ионом щелочного металла (M⁺), такого, как натрий, или может представлять -COO^-, когда R² имеет заместитель с положительным электрическим зарядом, такой как пиридиний, пиримидиний или тиазолий;
R² представляет водород, ацилоксиметил, гетероциклический метил или гетероциклический тиометил, каждый из которых может быть замещен надлежащими заместителями;
R³ представляет водород или аминозащищающую группу;
R⁴ представляет C₁-C₄-алкил или фенил, или вместе с атомом кислорода или фосфора, к которому он присоединен, может образовывать 5- или 6-членное гетероциклическое кольцо;
R⁵ представляет водород, C₁-C₄-алкил или -C(R^a)(R^b)CO₂R^c, где R^a и R^b в группе -C(R^a)(R^b)CO₂R^c для R⁵ идентичны или отличаются друг от друга и представляют водород или C₁-C₄-алкил, или R^a и R^b вместе с атомом углерода, с которым они связаны, могут образовывать C₃-C₇-циклоалкильную группу, и R^c
водород или карбоксизащищающая группа;
Q представляет N или CH.The invention relates to a new method for producing cephalosporin compounds that can be used as antibiotics. More specifically, the invention relates to a new process for the preparation of cephem derivatives represented by the following general formula (I), which have a 2- [aminothia (dia) zolyl] -2-methoxyiminoacetamide group at the 7th position of the cepheme nucleus, characterized in that the reactive thiophosphate derivative thia (dia) zolacetic acid with the following general formula (II) is acylated with a 7-ACA derivative (7-aminocephalosporanic acid)

in which R ¹ represents a carboxy group or a protected carboxy group, which can form a -COO ^- M ⁺ salt with an alkali metal ion (M ⁺ ), such as sodium, or can represent -COO ^- when R ² has a substituent with a positive electric charge, such as pyridinium, pyrimidinium or thiazolium;
R ² represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with appropriate substituents;
R ³ represents hydrogen or an amino protecting group;
R ⁴ represents C ₁ -C ₄ alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached, may form a 5- or 6-membered heterocyclic ring;
R ⁵ represents hydrogen, C ₁ -C ₄ -alkyl or -C (R ^a ) (R ^b ) CO ₂ R ^c , where R ^a and R ^b in the group -C (R ^a ) (R ^b ) CO ₂ R ^c for R ^{5 are} identical or different from each other and represent hydrogen or C ₁ -C ₄ alkyl, or R ^a and R ^b together with the carbon atom to which they are attached can form a C ₃ -C ₇ cycloalkyl group, and R ^c
hydrogen or a carboxy protecting group;
Q represents N or CH.

 In addition, the invention relates to a new reactive thiophosphate derivative of thia (dia) zolacetic acid with the formula (II), as defined above, which can be used as starting material in the method for producing cephalosporin compounds with the formula (I), and to a method for its preparation.

где R³, R⁵ и Q определены так, как было описано ранее.Mostly in previous publications and patent descriptions, many methods for producing β-lactam antibiotics are described. In such previous methods, compounds of β-lactam antibiotics are usually prepared based on an organic acid represented by the following general formula (IV), which is converted to its reactive compound, and then subjected to an acylation reaction on the amino group of the β-lactam core:

where R ³ , R ⁵ and Q are defined as described previously.

 Reactive derivatives of the compounds of formula (IV) that are known from the foregoing methods include acid chloride, reactive ester, reactive amide, mixed acid anhydride and the like. However, a reactive derivative in the form of an acid chloride or mixed anhydride is obtained under severe reaction conditions and, moreover, it is unstable, so that it can be used for the in-situ acylation reaction without isolation. This may be the main reason for the formation of by-products. In addition, the reactive ester and the reactive amide of the compound of formula (IV) also have disadvantages in that they are obtained in a low yield, their reactivity is very low, which requires a long reaction time, and, in addition, by-products reactions such as a hydroxy derivative such as 1-hydroxybenzotriazole and a thiol derivative such as 2-mercaptobenzothiazole are difficult to remove.

В вышеприведенной формуле (А) R³, R⁴, R⁵ и Q определены так, как было описано выше.In addition, Japanese Patent Publication N (sho) 25-175196, which is published for reference, describes a compound of formula (A), which can be obtained from an organic acid with formula (IV) and a chlorophosphate derivative

In the above formula (A), R ³ , R ⁴ , R ⁵ and Q are defined as described above.

 However, the compound with formula (A) is an unstable reactive mixed acid anhydride which cannot be isolated, and therefore it can adversely affect the reaction in the next step.

 Thus, the inventors constantly conducted research in order to find a way that can solve the problems associated with the known reactive derivatives described previously. As a result, using a convenient method from an organic acid with formula (IV) and a chlorothiophosphate derivative, we were able, with high yield and high purity, to obtain a new reactive thiophosphate derivative of thia (dia) zolacetic acid with the formula (II) as defined above, which has a suitable reaction ability and stability.

 We also found that a cephalosporin derivative of formula (I), useful as an antibiotic, can be more economically prepared from the indicated new reactive thiophosphate derivative of thia (dia) zolacetic acid and then completed the invention.

 The purpose of the invention is to propose a new method for the preparation of cephem derivatives represented by the general formula (I) as defined above, characterized in that the new reactive thiophosphate derivative of thia (dia) zolacetic acid with the formula (II) as defined above, is acylated with a 7-ACC derivative with the formula ( Iii) as defined above in the presence of a solvent and a base.

 Another objective of the invention was to propose a new reactive thiophosphate derivative of thia (dia) zolacetic acid with the general formula (II) as defined above, which can be used as starting material for the preparation of a cephem derivative with the formula (I) as defined above.

 Another objective of the invention was to propose a method for producing a new reactive thiophosphate derivative of thia (dia) zolacetic acid with the formula (II) as defined above.

 The foregoing material outlined some of the most relevant objectives of the invention. These objectives should be construed as merely illustrating some of the more suitable features and uses of the invention. Many other useful results can be obtained by applying the invention in a different form or by modifying the invention within the scope of the disclosure of its essence. Accordingly, other objectives and a more detailed understanding of the invention can be understood when referring to the disclosure of the invention in addition to its scope defined by the claims.

In one of its aspects, the invention relates to a new process for the preparation of cephemic derivatives represented by the following general formula (I), characterized in that the reactive thiophosphate derivative of thia (dia) -acetic acid with formula (II) is acylated with a 7-ACC derivative with the formula (III) in the presence of a solvent and a base in accordance with the following reaction scheme 1:
In the above reaction scheme
R ¹ represents a carboxy group or a protected carboxy group that can form a —COO ^- M ⁺ salt with an alkali metal ion (M ⁺ ), such as sodium, or can represent —COO ^- when R ² has a positive electric charge substituent, such as pyridinium pyrimidinium or thiazolium;
R ² represents hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with appropriate substituents;
R ³ represents hydrogen or an amino protecting group;
R ⁴ represents C ₁ -C ₄ alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached, may form a 5- or 6-membered heterocyclic ring;
R ⁵ represents hydrogen, C ₁ -C ₄ -alkyl or -C (R ^a ) (R ^b ) CO ₂ R ^c , where R ^a and R ^b in the group -C (R ^a ) (R ^b ) CO ₂ R ^c as R ^{5 are} identical or different from each other and represent hydrogen or C ₁ -C ₄ alkyl, or R ^a and R ^b together with the carbon atom to which they are bonded, can form a C ₃ -C ₇ cycloalkyl group and R ^c hydrogen or a carboxy protecting group;
Q represents N or CH.

In the term “acyloxymethyl” used in the description of the invention, the definition of “acyl” includes any acyl group commonly known in the field of beta-lactams, such as carbamoyl, aliphatic acyl groups, acyl groups with an aromatic or heterocyclic ring, etc. A preferred example of an acyl group may include a C ₁ -C ₄ alkanoyl such as formyl, acetyl, propionyl, butyryl, etc. in particular C ₁ -C ₂ alkanoyl.

In the terms “heterocyclic methyl” and “heterocyclic thiomethyl”, the definition of “heterocyclic” may include a saturated or unsaturated 3-7 membered monocycle containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms in the ring, or a polycycle, formed by the condensation of two or more of the monocycles defined above. A typical example of said heterocycle is pyrrolidinyl, imidazolinyl, piperidino, piperazinyl, morpholinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thiazolyl, e.g. .), oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, etc.), thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl), thienyl, indolyl, isoindolyl, indolinyl, benzotriazolyl, tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazolyl, benzothiazolyl, etc. which may and optionally, bear a positive charge on the ring in the case of pyridine, pyrimidine, thiazole, etc. and may also be substituted by 1 to 4 suitable substituents. In this case, a preferred example of suitable substituents may include C ₁ -C ₄ alkyl (e.g. methyl, ethyl, propyl, isopropyl, tert-butyl, etc.), C ₂ -C ₄ alkenyl (e.g. ethenyl, 1 propenyl, allyl, 1,3-butadienyl, etc.), C ₂ -C ₄ alkynyl (e.g. ethynyl, 1- or 2-propynyl, etc.), C ₃ -C ₆ cycloalkyl (e.g. cyclopropyl, cyclopentyl, etc.), halogen (e.g. chlorine, fluorine, iodine, etc.), a substituted or unsubstituted amino group (e.g. amino, methylamino, ethylamino, N, N-dimethylamino (N, N-diethylamino group, etc.), phenyl which is substituted or unsubstituted with hydroxy group, etc.

 The method according to the invention, shown in reaction scheme 1, is characterized by the use of a reactive thiophosphate derivative with the formula (II) with suitable reactivity and stability as a reactive derivative of an organic acid and therefore can be widely used for the synthesis of currently known cephalosporin compounds containing 2- [amino-thia (dia) zolyl] -2-methoxyiminoacetamide group at position 7 of the cephem nucleus.

 In the reaction of the method according to the invention, the reactive thiophosphate derivative of the organic acid with the formula (II) is advantageously used in a slightly excessive amount with respect to the compound with the formula (III) in order to bring to the end, as a rule, the reactive thiophosphate derivative of the organic acid with the formula (II) can be used in an amount of 1.0 to 1.5 equivalent weights with respect to the compound of formula (III). However, from the point of view of completing the reaction and saving, it is preferable to use a reactive thiosphate derivative with the formula (II) in an amount of 1.0 to 1.2 equivalent weights with respect to the compound with the formula (III).

 As the base in the reaction according to the invention, both an inorganic base and an organic base can preferably be used. An inorganic base that can be used for this purpose may include alkaline earth metal carbonates and bicarbonates, as well as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, etc. As an organic base, a tertiary amine such as triethylamine, three n-butylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, etc. Of these bases, sodium bicarbonate, triethylamine, tri-n-butylamine and the like can most preferably be used.

Although the amount of base used may vary depending on the type of substituent R ² , usually the base is used in an amount of from 1.5 to 3.5 equivalent weights, preferably from 2.0 to 3.0 equivalent weights with respect to the compound with formula (III) .

 As the solvent in the reaction according to the invention, any polar or nonpolar solvent can be separately used, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N dimethylacetamide, alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, water, etc. However, in order to optimize the reactivity and isolate the reaction product, it is also possible to efficiently use a mixed solvent of two or more selected from among the aforementioned solvents, for example, an alcohol-water mixed solvent, in particular ethyl alcohol-water mixed solvent.

 Although the amount of solvent used is not critical, usually the solvent is used in an amount of from 8 to 50 ml, preferably from 10 to 30 ml, relative to 10 mmol of the starting material.

The reaction temperature of the invention should not be limited if the selected temperature does not adversely affect the reaction of the invention. However, in order to quickly obtain the desired compound, usually the reaction can be completed within 2-6 hours at 0-30 ^o C, in particular, even in the range of room temperature from 20 to 25 ^o C.

When R ³ is an amino protecting group, if desired, in the above Reaction Scheme 1, the resulting acyl compound can be deprotected to remove the protecting group and obtain the desired compound of formula (1), where R ³ is hydrogen.

,
где R³ представляет водород или аминозащищающую группу;
R⁴ представляет C₁-C₄-алкил или фенил, или вместе с атомом кислорода или фосфора, к которому он присоединен, может образовывать 5- или 6-членное генероциклическое кольцо;
R⁵ представляет водород, C₁-C₄-алкил или -C(R^a)(R^b)CO₂R^c, где R^a и R^b в группе -C(R^a)(R^b)CO₂R^c в качестве R⁵ идентичны или отличаются друг от друга и представляют водород или C₁-C₄-алкил, или R^a и R^b вместе с атомом углерода, с которым они связаны, могут образовывать C₃-C₇-циклоалкильную группу, а R^c водород или карбоксизащищающая группа;
Q представляет N или CH.A typical example of a compound that can be obtained in accordance with the method according to the invention may include the following:
3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid (cefotaxime);
7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1 2,4-triazin-3-yl) thiomethyl] -3-cefem-4-carboxylic acid (ceftriaxone);
7 - [[L- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -cefem-4 -carboxylic acid (cefmenoxime);
7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-cefem-4-carboxylic acid (ceftisoxime);
7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2,3-dicyclopentenopyridiniummethyl) -3-cefem-4-carboxylate (cefpirome);
7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidiniummethyl) -3-cefem-4-carboxylate (cefepime);
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4,6-diamino-1,1-dimethylpyrimidinium-2-yl) thiomethyl-3- cefem-4-carboxylate;
7 - [[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino] acetamido [-3- (4,6-diamino-1-methylpyrimidinium-2 -yl) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino] acetamido [-3- (4,6-diamino-1-ethylpyrimidinium-2 -yl) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,6-triaminopyrimidin-2-yl) thiomethyl-3-cefem-4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4,6-diamino-1,5-dimethylpyrimidinium-2-yl) thiomethyl-3 cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (2,6-diamino-1-methylpyrimidinium-4-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (2,6-diamino-1-ethylpyrimidinium-4-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3- (2,6-diamino-3-ethylpyrimidinium-4-yl) thiomethyl-3-cefem - 4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (2,6-diamino-3-methylpyrimidinium-4-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4,5,6-triamino-1-methylpyrimidinium-2-yl) thiomethyl-3 cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4-amino-1-methylpyrimidinium-2-yl) thiomethyl-3-cefem -4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4-amino-1-methylpyrimidinium-2-yl) thiomethyl-3-cefem -4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4-amino-1-carboxymethylpyrimidinium-2-yl) thiomethyl-3-cefem -4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4-amino-1-aminopyridinium-2-yl) thiomethyl-3-cefem -4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4,5-triaminopyrimidin-2-yl) thiomethyl-3-cefem -4 β-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (4-amino-1-methyl-6- (N, N-dimethyl) aminopyrimidinium 2-yl) thiomethyl-3-cephem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4,5,6-tetraaminopyrimidinium-2-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4-diamino-5-methylpyrimidinium-2-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4-diamino-5-ethylpyrimidinium-2-yl) thiomethyl-3-cefem -4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4-diamino-6- (N-methyl) aminopyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,4-diamino-5-methyl-6- (N-methyl) aminopyrimidinium 2-yl) thiomethyl-3-cefem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (3,4-diamino-3,5,6,7-tetrahydrocyclopentapyrimidinium-2-yl ) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (2-amino-1-methyl-1,5,6,7-tetrahydrocyclopentapyrimidinium-4 -yl) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1,2-diamino-1,5,6,7-tetrahydrocyclopentapyrimidinium-4-yl ) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (7-amino-1-methyl [1,2,4] triazolo or [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cephem-4-carboxylate;
7 - [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methyl [1,3] imidazo [1,2-c] pyrimidnium-5 -yl) thiomethyl-3-cephem-4-carboxylate;
In accordance with the second objective of the invention, it also proposed a new reactive thiophosphate derivative of thia (dia) zolacetic acid, represented by the following general formula (II), which is used as a starting material in a new process for the preparation of cephema derivatives with the above formula (I):

,
where R ³ represents hydrogen or an amino protecting group;
R ⁴ represents C ₁ -C ₄ alkyl or phenyl, or together with the oxygen or phosphorus atom to which it is attached, may form a 5- or 6-membered heterocyclic ring;
R ⁵ represents hydrogen, C ₁ -C ₄ -alkyl or -C (R ^a ) (R ^b ) CO ₂ R ^c , where R ^a and R ^b in the group -C (R ^a ) (R ^b ) CO ₂ R ^c as R ^{5 are} identical or different from each other and represent hydrogen or C ₁ -C ₄ alkyl, or R ^a and R ^b together with the carbon atom to which they are bonded, can form a C ₃ -C ₇ cycloalkyl group, and R ^{c is} hydrogen or a carboxy protecting group;
Q represents N or CH.

,
где R³, R⁴, R⁵ и Q определены так, как было описано ранее, отличающийся тем, что органическую кислоту со следующей общей формулой (IV):

,
где R³, R⁵ и Q определены так, как было описано ранее, вводят в реакцию с хлортиофосфатным производным со следующей общей формулой (V):

,
где R⁴ определен так, как было описано ранее, в растворителе в присутствии основания и катализатора.According to a third aspect of the invention, it provides a method for producing a new reactive thiophosphate derivative represented by the following general formula (II):

,
where R ³ , R ⁴ , R ⁵ and Q are defined as described previously, characterized in that the organic acid with the following General formula (IV):

,
where R ³ , R ⁵ and Q are defined as described previously, are reacted with a chlorothiophosphate derivative with the following general formula (V):

,
where R ^{4 is} defined as described previously, in a solvent in the presence of a base and a catalyst.

In connection with the formula (II) of the invention, preferably R ³ is hydrogen or triphenylmethyl, R ⁴ is methyl, ethyl or phenyl, and R ⁵ is hydrogen, methyl, ethyl or tert-butoxycarbonylisopropyl.

 More preferred compounds of formula (II) of the invention are: diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate; diethylthiophosphoryl- (Z) -2-triphenylmethylaminothiazol-4-yl) methoxyiminoacetate; diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) -2- (tert-butoxycarbonyl) -isopropoxyiminoacetate; diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) ethoxyiminoacetate; diethylthiophosphoryl- (Z) - (2-triphenylmethylaminothiazol-4-yl) ethoxyiminoacetate; diethylthiophosphoryl- (Z) - (2-triphenylmethylaminothiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacetate or diethylthiophosphoryl- (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate.

A method of obtaining a reactive thiophosphate derivative of an organic acid with the formula (II) according to the invention can be represented by the following reaction scheme II:
where R ³ , R ⁴ , R ⁵ and Q are defined as described previously.

In the above reaction scheme, an amino protecting group as R ³ is a conventional amino protecting group such as substituted or unsubstituted acyl, substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halogen (lower) alkyl (e.g. trichloromethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio group, substituted alkylidene, substituted arylalkylidene, substituted cycloalkylidene, etc. Suitable acyl as an amino protecting group may be aliphatic I acyl group or an acyl group with an aromatic or heterocyclic moiety. Such an acyl group includes, for example, lower alkanoyl with 1-6 carbon atoms (e.g. formyl, acetyl, etc.), alkoxycarbonyl with 2-6 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), lower alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or aryl (lower) -alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.) and the like. The aforementioned acyl group may contain from one to three suitable substituents selected from halogen, hydroxy, cyano, nitro groups and the like. In addition, the product of the reaction of an amino group with a silane, borane, phosphorus compound, and the like can act as an amino protecting group.

When in the group —C (R ^a ) (R ^b ) CO ₂ (R ^c ), as R ⁵ and R ^c is a carboxyl protecting group, suitable examples of the carboxyl protecting group include a (lower) alkyl ester (e.g. methyl ester, tert -butyl ester, etc.), (lower) alkenyl ester (e.g. vinyl ester, allyl ester, etc.), (lower) alkoxy (lower) alkyl ester (e.g. methoxymethyl ester etc.), (lower) -alkylthio (lower) alkyl ester (e.g. methylthiomethyl ester, etc.), halogen (bottom ) alkyl ester (e.g., 2,2,2-trichloroethyl ester, etc.), substituted or unsubstituted arylalkyl ester (e.g., benzyl ester, para-nitrobenzyl ester, etc.) or silyl ester, etc.

 In the preparation of a reactive thiophosphate derivative of formula (II) according to the method of the invention depicted in the above reaction scheme (II), a compound with formula (V) is usually used in an amount of from 0.5 to 2.0 equivalent weights, preferably from 1, 0 to 1.3 equivalent weights with respect to the organic acid of formula (IV). In addition, the reaction can be carried out in the absence of any catalyst. However, the reaction in the absence of a catalyst requires a long lead time and can lead to some by-products. Conversely, when the reaction is carried out in the presence of a suitable catalyst, the reaction is completed in a short reaction time, under mild conditions and without the formation of by-products.

Although a suitable catalyst that can be used in the reaction according to reaction scheme (II) includes tertiary amines, quaternary ammonium or phosphonium compounds and the like. in any case, it is necessary to choose a catalyst with optimal properties, since the reaction rate may vary depending on the used organic acid with the formula (IV), the type and amount of catalyst, etc. Examples of a tertiary amine catalyst may include 2,4-dimethyl-2,4-diazapentane, 2,5-dimethyl-2,5-diaghexane, N, N-N ', N'-tetramethyl-1,2-diaminocyclohexane, 1, 4-dimethyl-1,4-diazacyclohexane, 2,7-dimethyl-2,7-diaza-4-octane, 1,4-diazabicyclo [2.2.2] octane, 2,6-dimethyl-2,6- diazageptan, 2,9-dimethyl-2,9-diazadecane, 2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane and the like. A suitable example of a quaternary ammonium compound may include tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, cetyltrimethylammonium bromide, tetra-n-butylammonium iodide, methyl tri (C ₈ -C ₁₀ ) alkyl ammonium chloride, methyl tri-2-methylphenyl. in addition, tetra-n-butylphosphonium bromide is preferably used as the phosphonium compound. Typically, the catalyst is used in a ratio of from 0.1 to 50%, preferably from 0.5 to 5%, based on the molar amount with respect to the organic acid of formula (IV).

 In the reaction according to reaction scheme II of the invention, a polar or non-polar organic solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide can be used as a solvent. , N, N-dimethylacetamide and the like. However, in order to ensure optimal reactivity and the highest yield of the reaction product, you can also use a mixed solvent of two or more selected above solvents.

 A suitable base that can be used in Reaction Scheme II includes an inorganic base, for example, alkaline earth metal carbonates or hydrogen carbonates, such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, and the like. and an organic base, for example a tertiary amine, such as triethylenediamine, tri-n-butylamine, diisopropylethylamine; pyridine, N, N-dimethylaniline, etc. Most preferably diisopropylethylamine or tri-n-butylamine is used.

In the reaction in accordance with reaction scheme II, the temperature can vary from -40 to 60 ^° C, preferably from -15 to 25 ^° C. In particular, when the reaction temperature is controlled from 0 to 20 ^° C, the reaction can be completed in 1- 3 hours and it is easy to obtain the desired compound with formula (II) under mild conditions.

 The reactive thiophosphate derivative of an organic acid of the formula (II) obtained in accordance with the method of the invention has a unique physicochemical property. More specifically, the reactive thiophosphate derivative of an organic acid with the formula (II) has good solubility in a polar or non-polar organic solvent, and also has good stability, so that it cannot be decomposed to form organic acid (IV) even when the reactive thiophosphate derivative of an organic acid, dissolved in such a solvent, washed with acidic, alkaline or neutral water. In addition, when a reactive thiophosphate derivative of an organic acid of formula (II) is used in an acylation reaction with an amino group of a β-lactam nucleus, this reaction can be easily carried out even under mild conditions, and the thiophosphoric acid derivative formed as a by-product is present in the aqueous layer in dissolved state and therefore can be easily removed.

Furthermore, in the reaction of the invention, although the compound with formula (II) can be introduced into the acylation reaction after protecting the R ³ group with an amino protecting group, the acylation can also be carried out with the compound with formula (II) without an amino protecting group without any restrictions. Accordingly, when the method of the invention is applied to the production of a compound of formula (I) on an industrial scale, there is a great advantage in that the final b-lactam antibiotics can be easily synthesized in high yield and in high purity.

 The invention will now be more specifically explained based on the following examples. However, since the main distinguishing feature of the invention is contained in the reactive thiophosphate derivative of an organic acid of formula (II) and its use to obtain the desired compound described above, the technical scope of the invention should not be limited by the following examples, unless this composition of the differences of the invention is changed.

Example 1. Synthesis of diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) - methoxyiminoacetate
(Z) - (2-aminothiazol-4-yl) -matoxyiminoacetic acid (20.1 g), tri-n-butylamine (24.10 g) and 1,4-diazabicyclo [2.2.2] octane (0 , 11 g) were suspended in dry dichloromethane (200 ml), and then diethyl chlorothiophosphate (24.52 g) was added dropwise thereto over a period of 20 minutes while the mixture was kept at 0-5 ^° C in a chilled bath under nitrogen atmosphere. The reaction mixture was stirred for an additional 2 hours. After completion of the reaction, distilled water (300 ml) was added to the reaction solution, after which the mixture was stirred for 5 minutes. The organic layer was separated, washed successively with 5% aqueous sodium bicarbonate solution (300 ml) and 300 ml saturated brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Normal hexane (400 ml) was added to the concentrated solution to solidify the product, which was then filtered off, washed with normal hexane (100 ml) and dried; 33.2 g (yield 94.0%) of the title compound are obtained as a pale yellow solid.

Melting point: 87-88 ^o C.

NMR (V, CDCI ₃ ): 1.38 (t, 6H), 4.05 (s, 3H), 4.31 (m, 4H), 5.49 (br s, 2H), 6.87 (s, 1H).

Example 2. Synthesis of diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacetate
(Z) - (2-aminothiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacetic acid (32.9 g), tri-n-butylamine (22.25 g) and 1,4-diazabicyclo [2, 2,2] octane (0.11 g) was dissolved in dry N, N-dimethylacetamide (100 ml), and then diethyl chlorothiophosphate (22.63 g) was added dropwise over 20 minutes at a content of the reaction solution at 0-5 ^° C in the cooling bath. The reaction mixture was further stirred for 2 hours. Ethyl acetate (300 ml) and distilled water (300 ml) were added to the reaction solution, after which the mixture was stirred for 5 minutes. The organic layer was separated, washed sequentially with 5% aqueous sodium bicarbonate solution (300 ml) and brine (300 ml), dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Cyclohexane (100 ml) was added to the concentrated solution to solidify the product, which was then filtered off, washed with cyclohexane (50 ml) and dried; 44.26 g (yield 92%) of the title compound were obtained as a pale white substance.

Melting point: 114-115 ^o C.

NMR (V, CDCI ₃ ): 1.39 (t, 6H), 1.46 (s, 9H), 1.50 (s, 6H), 4.32 (m, 4H), 6.74 (s, 1H), 6.79 (br s, 2H).

Example 3. Synthesis of diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) - ethoxyiminoacetate
Starting from (Z) - (2-aminothiazol-4-yl) -ethoxyiminoacetic acid (21.5 g), 33.04 g (90% yield) of the title compound were obtained in accordance with a procedure analogous to Example 2.

Melting point: 118-119 ^o C.

NMR (V, CDCI ₃ ): 1.35 (m, 9H), 4.32 (m, 6H), 5.67 (br, 2H), 6.82 (s, 1H).

Example 4. Synthesis of diethylthiophosphoryl- (Z) - (2-triphenylmethylaminothiazol-4-yl) ethoxyiminoacetate
Starting from (Z) - (2-triphenylmethylaminothiazol-4-yl) ethoxyiminoacetic acid (45.7 g), 57.2 g of the title compound was obtained according to a procedure analogous to Example 1.

Melting point: 98-99 ^o C.

NMR (V, CDCI ₃ ): 1.35 (m, 9H), 4.32 (m, 6H), 6.62 (s, 1H), 7.02 (br, 2H), 7.32 (m, 15H).

Example 5. Synthesis of diethylthiophosphoryl- (Z) - (2-triphenylmethylamino-thiazol-4-yl) methoxyiminoacetate
Starting from (Z) - (2-triphenylmethylaminothiazol-4-yl) methoxyiminoacetic acid (44.3 g), 57.4 g of the title compound were obtained in accordance with a procedure analogous to Example 1.

Melting point: 101-103 ^o C.

NMR (V, CDCI ₃ ): 1.32 (m, 6H), 4.02 (s, 3H), 4.28 (m, 4H), 6.62 (s, 1H), 7.00 (br, 1H), 7.28 (m, 15H).

Example 6. Synthesis of diethylthiophosphoryl- (Z) - (2-triphenylmethylamino-thiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacetate
Starting from (Z) - (2-triphenylmethylaminothiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacetic acid (57.1 g), 68.46 g of the title compound was obtained according to a procedure analogous to Example 1.

Melting point: 101-103 ^o C.

NMR (V, CDCI ₃ ): 1.33 (t, 6H), 1.41 (s, 9H), 1.52 (s, 6H), 4.30 (m, 4H), 6.63 (s, 1H), 6.80 (br, 1H), 7.25 (m, 15H).

Example 7. Synthesis of diethylthiophosphoryl- (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetate
Starting from (Z) - (3-amino-1,2,4-thiadiazol-5-yl) ethoxyiminoacetic acid (21.6 g), 33 g of the title compound were obtained in accordance with a procedure analogous to Example 1.

Melting point: 132-133 ^o C.

NMR (V, CDCI ₃ ): 1.37 (m, 9H), 4.36 (m, 6H), 6.49 (br, 2H).

Example 8. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid (cefotaxime)
To distilled water (200 ml) and tetrahydrofuran (200 ml) and a one-liter round-bottom flask, 7-aminocephalosporanic acid (54.46 g) and diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate (consecutively) were successively added with stirring. 77.74 g). After adding tri-n-butylamine (74.15 g), the reaction mixture was stirred for 3 hours while maintaining the temperature at 20 to 25 ^° C, after which extraction was carried out with 12% aqueous sodium bicarbonate (453 g) and ethyl acetate (100 m) to remove the organic layer. The separated aqueous layer was again extracted with ethyl acetate (100 ml) to remove the organic layer. After that, the aqueous layer was neutralized to pH 6 with a 20% aqueous solution of sulfuric acid. Active carbon (10 g) was added to the neutralized aqueous solution, and then the mixture was stirred for 30 minutes and filtered. The filtrate was saturated with sodium chloride. The pH of the saturated aqueous solution was adjusted to 4 by adding a 20% aqueous solution of sulfuric acid. After adding a small amount of the title compound, the pH of the mixture was adjusted to 2.5 by the further addition of a 20% aqueous sulfuric acid solution. The crystal was carefully precipitated, filtered off, washed with water, and then dried; 83.3 g (yield 92%) of the title compound were obtained as a pale yellow solid.

HPLC purity: 98.5%
Example 9. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid (cefotaxime)
Distilled water (200 ml), 7-aminocephalosporanic acid (54.46 g) and sodium bicarbonate (33.6 g) were placed in a one-liter round-bottom flask and left under stirring at room temperature until completely dissolved. To this reaction solution were added tetrahydrofuran (200 ml) and diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate (77.74 g), and the mixture was stirred for 5 hours at a temperature of from 20 to 25 ^° C. The reaction solution extracted with ethyl acetate (100 ml) to remove the organic layer, and the separated aqueous layer was again extracted with ethyl acetate (100 ml) and then neutralized to pH 6 by adding a 20% aqueous solution of sulfuric acid. Active carbon (10 g) was added to the neutralized aqueous solution, and then the mixture was stirred for 30 minutes and filtered. The filtrate was saturated with sodium chloride. The pH of the saturated aqueous solution was adjusted to 4 by adding a 20% aqueous solution of sulfuric acid. After adding a small amount of the title compound, the mixture was again brought to a pH of 2.5 by the further addition of a 20% aqueous solution of sulfuric acid. After the crystal was carefully precipitated, it was filtered, washed with water and then dried; 81.07 g (89% yield) of the title compound were obtained as a pale yellow solid.

HPLC purity: 98.6%
Example 10. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid (cefotaxime)
77.43 g (85% yield) of the title compound was obtained by the same procedure as in Example 9, except that triethylamine (40.48 g) was used instead of sodium bicarbonate.

HPLC purity: 98.4%
Example 11. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid (cefotaxime)
82.0 g (90% yield) of the title compound was obtained by the same procedure as in Example 8, except that instead of distilled water and tetrahydrofuran, N, N-dimethylacetamide (100 ml) and dichloromethane (400 ml) were used. ), and instead of ethyl acetate, dichloromethane (100 ml) was used as an extraction solvent.

HPLC purity: 98.6%
Example 12. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid (cefotaxime)
To a 95% ethyl alcohol (400 ml) in a one-liter round-bottom flask, 7-aminocephalosporanic acid (54.46 g) and diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (77.74) were successively added with stirring. d). After adding triethylamino (40.48 g), the reaction mixture was stirred for 3 hours while maintaining the temperature at 20 to 25 ^° C. and then concentrated hydrochloric acid (31.25 g) diluted with 95% ethyl alcohol (200 ml) was added thereto. In order to carefully precipitate the crystals, the mixture was vigorously stirred for about 1 hour. The precipitated crystals were filtered off, washed with water and then dried; 83.8 g (yield 92%) of the title compound are obtained as a white solid.

HPLC purity: 98.6%
Example 13. Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cephem-4-carboxylic acid (cefotaxime)
82.0 g (90% yield) of the title compound was obtained by the same procedure as in Example 12, except that distilled water (100 ml) and isopropyl alcohol (400 ml) were used in place of ethyl alcohol.

HPLC purity: 98.4%
Example 14. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] -acetamido] -3 - [(2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cefem-4-carboxylic acid (ceftriaxone)
To distilled water (200 ml) and tetrahydrofuran (200 ml) in a 1 liter round-bottom flask, 7-amino-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2 , 4-triazin-3-yl) -thiomethyl] -3-cephem-4-carboxylic acid (37.1 g), diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and tri-n-butylamine (55.7 g). This reaction solution was stirred for 3 hours while maintaining a temperature of 20 to 25 ^° C., after which toluene (200 ml) was added to remove the organic layer. The aqueous layer was adjusted to pH 3 with a 20% aqueous solution of sulfuric acid. The solution containing the precipitated product was thoroughly mixed for one hour while cooling with ice. The resulting product was filtered off, washed with water and then dried; 50.7 g (yield 91.5%) of the title compound are obtained.

HPLC purity: 99.3%
Example 15. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] -acetamido] -3 - [(2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cefem-4-carboxylic acid (ceftriaxone)
To a 95% ethyl alcohol (400 ml) in a 1 liter round bottom flask, 7-amino-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4 -triazin-3-yl) thiomethyl] -3-cefem-4-carboxylic acid (37.1 g), diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine ( 30.36 g). This reaction solution was stirred for 3 hours while maintaining the temperature at 20 to 25 ^° C., and then concentrated hydrochloric acid (26.04 g) diluted with 95% ethyl alcohol (200 ml) was added thereto. The solution containing the precipitated product was thoroughly mixed for one hour while cooling with ice. The resulting product was filtered off, washed with water and dried; 50.7 g (yield 91.5%) of the title compound are obtained.

HPLC purity: 99.3%
Example 16. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] -acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefem-4-carboxylic acid (cefmenoxime)
Distilled water (100 ml), 7-amino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefem-4-carboxylic acid (32.8 g) was added to a one-liter round-bottom flask. and sodium bicarbonate (16.8 g), and the mixture was allowed to mix at room temperature until completely dissolved. Then diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) dissolved in tetrahydrofuran (100 ml) was added thereto, and the reaction mixture was stirred for 5 hours at 20-25 ^° C. ethyl acetate (2 x 100 ml) was added to the solution to separate an organic layer. Then the aqueous layer was adjusted to pH 3.1 with 2 N. aqueous hydrochloric acid and stirred for one hour while cooling with ice. The resulting precipitate was filtered off, washed with water and dried; 46.3 g (yield 90.6%) of the title compound are obtained.

HPLC purity: 99.4%
Example 17. Synthesis of 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] -acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefem-4-carboxylic acid (cefmenoxime)
To a 95% ethyl alcohol (400 ml) in a one liter round bottom flask, 7-amino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefem-4-carboxylic acid was successively added while stirring (32.8 g), diethylthiophosphoryl- (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.24 g). The mixture was then stirred for 5 hours at 20-25 ^° C. and concentrated hydrochloric acid (15.63 g) diluted with 95% ethyl alcohol (200 ml) was added thereto. The reaction mixture was stirred for one hour while cooling with ice. The resulting precipitate was filtered off, washed with water and then dried; 46.3 g (yield 90.6%) of the title compound are obtained.

HPLC purity: 99.4%
Example 18. Synthesis of 7 - [[2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl)] acetamido] -3-cefem-4-carboxylic acid (ceftisoxime)
Distilled water (100 ml), 7-amino-3-Cephem-4-carboxylic acid (20 g) and sodium bicarbonate (16.8 g) were added to a one-liter round-bottom flask, and the mixture was allowed to stir at room temperature until completely dissolved. Then diethylthiophosphoryl- (Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) dissolved in tetrahydrofuran (100 ml) was added to it, and the reaction mixture was stirred at 20-25 ^° C for 5 h. Ethyl acetate (2 x 100 ml) was added to the reaction solution to separate an organic layer. Then the aqueous layer was adjusted to pH 3 using 2 N. aqueous hydrochloric acid and stirred for one hour while cooling with ice. The resulting precipitate was filtered off, washed with water and then dried; 35.8 g (yield 93.4%) of the title compound are obtained.

HPLC purity: 98.4%
Example 19. Synthesis of 7 - [[2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl)] acetamido] -3-cefem-4-carboxylic acid (ceftisoxime)
To a 95% ethyl alcohol (400 ml) in a one-liter round-bottom flask, 7-amino-3-Cephem-4-carboxylic acid (20 g), diethylthiophosphoryl- (Z) -2- (2-aminothiazole-4) was successively added with stirring -yl) methoxyiminoacetate (38.8 g) and triethylamine (20.24 g). Then the reaction mixture was stirred at 20-25 ^° C for 5 hours and concentrated hydrochloric acid (15.63 g) diluted with 95% ethanol (200 ml) was added to it. The reaction mixture was stirred for one hour while cooling with ice. The resulting precipitate was filtered off, washed with water and then dried; 35.8 g (yield 93.4%) of the title compound are obtained.

HPLC purity: 98.4%
Example 20. Synthesis of salt 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyiminoacetamido] -3- (2,3-cyclopentenopyridiniummethyl) -3-cefem-4-carboxylate (cefpirome) with sulfuric acid
To distilled water (100 ml) and tetrahydrofuran (100 ml) in a one-liter round-bottom flask, 7-amino-3- (2,3-cyclopentenopyridinomethyl) -3-cefem-4-carboxylate hydroiodide (45.9 g) was successively added with stirring. diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and tri-n-butylamine (37.2 g). This reaction solution was stirred for 3 hours while maintaining the temperature at 20 to 25 ^° C. and then ethyl acetate (2 x 100 ml) was added thereto to remove the organic layer. The aqueous layer was adjusted to pH 1.2 with a 20% sulfuric acid solution. Ethyl alcohol (300 ml) was slowly added to this solution, maintaining the temperature from 0 to 5 ^° C and then the mixture was thoroughly stirred for 1 hour. The resulting precipitate was filtered off, washed with water and then dried; 47.1 g (yield 76.9%) of the title compound are obtained.

HPLC purity: 98.1%
Example 21. Synthesis of salt 7 - [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2,3-cyclopentenopyridiniummethyl) -3-cefem-4-carboxylate ( cefpirome) with sulfuric acid
To a 95% ethyl alcohol (400 ml) in a one-liter round-bottom flask, 7-amino-3- (2,3-cyclopentenopyridiniummethyl) -3-cefem-4-carboxylate (45.9 g) diethylthiophosphoryl- was subsequently added with stirring. (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.2 g). The reaction solution was stirred for 3 hours while maintaining the temperature at 20 to 25 ^° C. and then concentrated sulfuric acid (12.25 g) diluted with 95% ethanol (300 ml) was added thereto. The mixture was stirred for one hour, maintaining the temperature from 0 to 5 ^o C. The resulting precipitate was filtered off, washed with water and then dried; 47.1 g obtained (76.9% yield of the title compound.

HPLC purity: 98.1%
Example 22. Synthesis of the salt of 7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidinium methyl) -3-cephem carboxylate (cefepime) with sulfuric acid
To distilled water (100 ml) and tetrahydrofuran 100 in a one-liter round-bottom flask, 7-amino-3- (1-methylpyrrolidiniummethyl) -3-cefem-4-carboxylate hydroiodide (43.4 g), diethylthiophosphoryl- (Z) was successively added with stirring - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.2 g). This reaction solution was stirred for 4 hours while maintaining the temperature at 20 to 25 ^° C. and then ethyl acetate (2 x 100 ml) was added thereto to remove the organic layer. Activated carbon (5 g) was added to the aqueous layer and the mixture was stirred for 30 minutes and then filtered. The filtrate was adjusted to pH 1.2 with a 20% aqueous solution of sulfuric acid, and then acetone (400 ml) was slowly added to it. The mixture was stirred for one hour. The resulting precipitate was filtered off, washed with water and then dried; 45.1 g (78% yield) of the title compound are obtained.

HPLC purity: 97.1%
Example 23. Synthesis of the salt of 7 - [[2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido] -3- (1-methylpyrrolidiniummethyl) -3-cefem-4-carboxylate (cefepime) with sulfuric acid
To a 95% ethyl alcohol (400 ml) in a one-liter round-bottom flask, 7-amino-3- (1-methylpyrrolidiniummethyl) -3-cefem-4-carboxylate (43.4 g) diethylthiophosphoryl- (Z ) - (2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (20.2 g). The reaction solution was stirred for 4 hours while maintaining the temperature at 20 to 25 ^° C. and then activated carbon (5 g) was added thereto. After that, the mixture was stirred for 30 minutes and then filtered. Concentrated sulfuric acid (12.25 g) diluted with 95% ethanol (400 ml) was added to the filtrate, and the mixture was stirred for one hour while maintaining the temperature from 0 to 5 ^° C. The resulting precipitate was filtered off, washed with water and then dried; 45.1 g (78% yield) of the title compound are obtained.

HPLC purity: 97.1%
Although the invention has been described in its preferred form with a certain degree of specificity, it will be understood by those skilled in the art that the description of the preferred form has been made by way of example only and that various changes can be made to the details of the structure, combination and arrangement of its parts without departing from the spirit and scope of the invention.

Claims (15)

1. The method of obtaining derivatives of Cephem of General formula I

where R ^{1 is a} carboxy group or a protected carboxy group that can form a COO ^- M ⁺ salt with an alkali metal ion (M ⁺ ), or can represent -COO ^- when R ² has a substituent with a positive electric charge;
R ^{2 is} a hydrogen atom, C ₁ -C ₄ alkanoyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, wherein said heterocyclic radical is selected from the group consisting of pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, thiazolidinyl, pyrrolyl pyrrolidinyl pyrinyl pyrinyl pyrrolidinyl , pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, isoxazolyl, oxydiazolyl, thiazolinyl, thiadiazolyl, thienyl, indolyl, isoindolyl, indolinyl, benzotriazolyl, tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazol 2,3-dicyclopentenopyridinyl, 3,5,6,7-tetrahydrocyclopentapyrimidinyl, 1,5,6,7-tetrahydrocyclopentapyrimidinyl and 1,2,4-triazolo- (1,5-c) pyrimidinyl, which may be substituted if necessary from 1 to 4 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₂ C ₄ alkenyl, C ₃ C ₆ cycloalkyl, a halogen atom, an amino group substituted or unsubstituted by an alkyl radical, and phenyl which may be substituted by a hydroxy group ;
R ^{3 is} hydrogen or an amino protecting group;
R ⁵ C ₁ C ₄ -alkyl or a group
-C (R ^a ) (R ^b ) CO ₂ R ^c ,
where R ^a and R ^b in the group C (R ^a ) (R ^b ) CO ₂ R ^{c are} identical or different from each other, a hydrogen atom or C ₁ C ₄ -alkyl;
R ^{c is} hydrogen or a carboxy protecting group;
QN or CH,
characterized in that the reactive thiophosphate derivative of thia- (or dia-) zolacetic acid of the general formula II

where R ³ , R ⁵ and Q have the indicated meanings;
R ⁴ C ₁ C ₄ -alkyl,
Derivatives of 7-aminocephalosporanic acid of general formula III

where R ¹ and R ² have the indicated meanings,
in the presence of a solvent and a base.  2. The method according to p. 1, characterized in that a solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N- dimethylacetamide, alcohols and water, or a mixture of two or more solvents selected from among them.  3. The method according to p. 2, characterized in that they use an alcohol solvent or a mixed alcohol-water solvent.  4. The method according to p. 3, characterized in that the alcohol used is methyl alcohol, ethyl alcohol or isopropyl alcohol.  5. The method according to p. 1, characterized in that the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, tri-n-butylamine and diisopropylethylamine. 6. The method according to any one of paragraphs. 1 5, characterized in that the reaction temperature is 0 30 ^o C. 7. Reactive thiophosphate derivatives of thia- (or dia) zolacetic acid of general formula II

where R ^{3 is} hydrogen or an amino protecting group;
R ⁴ C ₁ C ₄ -alkyl;
R ⁵ C ₁ C ₄ -alkyl or a group
—C (R ^a ) (R ^b ) —CO ₂ R ^c ,
where R ^a and R ^b in the group —C (R ^a ) (R ^b ) CO ₂ R ^{c are} identical or different from each other, hydrogen or C ₁ C ₄ alkyl;
R ^{c is} hydrogen or a carboxy protecting group;
QN or CH. 8. The compound of formula II according to claim 7, characterized in that R ³ is hydrogen or triphenylmethyl, R ^{4 is} methyl or ethyl, and R ^{5 is} methyl, ethyl or tert-butoxycarbonylisopropyl.  9. The compound of formula II according to claim 8, characterized in that it is selected from the group consisting of diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) methoxyiminoacetate, diethylthiophosphoryl- (Z) - (2-triphenylmethylaminothiazole-4 -yl) methoxyiminoacetate, diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) -2-tert-butoxycarbonyl) isopropoxyiminoacetate, diethylthiophosphoryl- (Z) - (2-aminothiazol-4-yl) ethoxyiminoacetate, diethylthiothiophosphoryl ) - (2-triphenylmethylaminothiazol-4-yl) ethoxyiminoacetate, diethylthiophosphoryl- (Z) - (2-triphenylmethylaminothiazol-4-yl) -2- (tert-butoxycarbonyl) isopropoxyiminoacet tata and diethylthiophosphoryl - (Z) -3-amino-1,2,4-thiazol-5-yl) ethoxyimino acetate. 10. A method of obtaining compounds of General formula II, characterized in p. 7, characterized in that the organic acid of General formula IV

where R ³ , R ⁵ and Q have the indicated meanings,
react with a chlorothiophosphate derivative of the general formula V

where R ⁴ has the indicated meaning,
in a solvent in the presence of a base and a catalyst selected from the group consisting of tertiary amines, quaternary ammonium or phosphonium compounds.  11. The method according to p. 10, characterized in that they use a single solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide and N, N dimethylacetamide, or a mixture consisting of two or more solvents selected from among them.  12. The method according to p. 10, characterized in that the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, tri-n-butylamine and diisopropylethylamine.  13. The method according to p. 10, characterized in that they use 1,4-diazobicyclo [2.2.2] octane, tetra-n-butylammonium bromide or tetra-n-butylphosphonium bromide as a catalyst.  14. The method according to PP. 10, 12 or 13, characterized in that the catalyst is used in an amount of from 0.1 to 50% based on a molar calculation with respect to the organic acid of formula IV. 15. The method according to p. 10, characterized in that the reaction temperature is from -40 to 60 ^o C.

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