RO111682B1 - Process for the preparation of some derivates of cephalosporine - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: claimed invention describes process for preparing cephem derivatives of general formula (I):wherein Ris carboxy group of protected carboxy group which may form salt -COOMwith alkali metal (M), such as sodium, ion and may form -COOwhen Rhas substituent with positive electric charge such as pyridinium, pyrimidinium or thiazolium; Ris hydrogen, acyloxymethyl, heterocyclic methyl or heterocyclic thiomethyl, each of which may be substituted with suitable substituents; Ris hydrogen or amino protecting group; Ris hydrogen, C-C-alkyl or -C(R)(R)CORwherein Rand Rin -C(R)(R)CORas Rare identical or differ from each other and are hydrogen or C-C-alkyl, or Rand Rtogether with carbon atom to which they are attached may form C-C-cycloalkyl, and Ris hydrogen or carboxy protecting group, and Q is N or CH characterized in that reactive thiophosphate derivative of thia(dia)zoleacetic acid of general formula (II):wherein R, Rand Q are as defined above and Ris C-C-alkyl or phenyl or together with the oxygen or phosphorus atom to which it is attached may form 5- or 6-member heterocyclic ring, is acylated with 7-ACA of general formula (III):wherein Rand Rare as defined above, in the presence of solvent and base, and also novel reactive thiophosphate derivative of thia(dia)zoleacetic acid of formula (II) as defined above, which is used as starting material for preparing cephem derivative of formula (I), and process for preparation thereof. EFFECT: more efficient preparation process.

Description

The present invention relates to a process for the preparation of cephalosporin derivatives of general structural formula I:

OR ⁵ /

wherein R ¹ represents a carboxyl group d) or a protected carboxyl group, which may form the salt -COO ^H M ^{1 +)} with an alkali metal ion M ^{t + 1} or may represent -COO ^H , when R ² has a substituent having a positive electrical charge, R ² represents a hydrogen atom, an acyloxymethyl radical, a methyl linked to a heterocycle, or a thiomethyl radical linked to a heterocycle, each of which may be substituted with suitable substituents, R ³ represents a hydrogen atom or a protecting group for the amino group, R ⁵ represents a hydrogen atom, a C 1 -C 4 alkyl radical or -C (R ^a J (R ^b ) COOR ^C wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C 1 -C 2 alkyl radical or R ^a and R ^b together with the carbon atom 30 to which they are linked may form a C ₃ -C ₇ cycloalkyl group, and R ^c is a hydrogen atom or a carboxyl radical protecting group and Q represents N or CH, compounds which are Use as antibiotics.

Numerous processes are known for preparing β-lactam antibiotics from both specialized publications and patent descriptions. In general, they consist of the introduction of substituents or the substitution of substitutes with others on the basic nucleus of cephalosporins. The most common way of preparing cephalosporins is acylation of the amino group of 7-ACA with acids, salts thereof, or reactive derivatives thereof.

Thus, in US 4,971,962 there is presented a process for the preparation of some cephalosporins very similar to those of general formula I above, in which R ¹ and R ³ have the same meanings, R ² being an acetoxymethyl, 1-pyridiniumethyl group. , 1-methyl-1H-tetrazole-5-ylthiomethyl, signi fi cant existing between those of R ² above, Q has only CH significance, and R ⁵ is a furfuryl group. The process consists of acylation of the 7-amino group of cephalosporin having the substituents R ² and R ³ with a salt, for example sodium, of a 2- (2-aminothiazol-4-yl) -2- (furfuryloxyimino-acetic acid).

Another known process for acylation of the 7-amino group is presented in patent application EP 400.805 on the preparation of antibiotic thiadiazolylthiomethylcephalosporins. A 7-amino-3- (1,2,3-thiadiazol-5-yl) -thiomethyl-3-cefem-4-carboxylic acid ester is treated with a 2- (2-aminothiazol-4-yl) derivative. ) -2 (Z) -benzyloxyimino-acetic acid, suitably substituted, in the presence of pyridine and phosphorus oxychloride, in an organic solvent medium, for example dichloromethane, under stirring and cooling to 0 ° ... 5 ° C.

As reactive derivatives of the 2 (2-aminothiazol-4-yl] -2-imino substituted-acetic acid required for the preparation of compounds of general formula I, known are, from the methods described so far, acid chlorides, reactive esters, reactive amides, anhydrides However, reactive derivatives in the form of acid chloride or mixed acid anhydride are prepared under strict reaction conditions and are still unstable, so they should be used in situ for the acylation reaction, without being isolated. Reactive esters and reactive amides also have disadvantages in that they are prepared in low yields, their reactivity is low and therefore requires long reaction time, and the reaction co-products, for example, a hydroxy derivative such as is 2-mercaptobenzthiazole, is hardly removed.

Thus, it is noted the need to find a process that can solve the problems related to the known reactive derivatives that have been presented above. It is therefore necessary to increase the reactivity and stability of the reactive compound to be acylated by the 7-amino group of 7-ACA.

The process according to the invention con

RO 111682 Bl states that a thiophosphate reactive derivative of thia (dia) zolacetic acid of general formula II:

OR ⁵ r ³ hn

(II) wherein R ³ , R ⁵ and Q have the meanings above and R ⁴ represents a CȚ-C / or phenyl alkyl radical, or together with the oxygen or phosphorus atom to which it is attached may form a heterocyclic ring with 5 or 6 members, is subjected to 15 acylation reaction with a 7-ACA derivative having

wherein R ¹ and R 2 ^t have the above meanings, in the presence of a solvent and a base, at a temperature of 0 ° to 3 ° C.

Thus, the process according to the present invention consists in the preparation of derivatives according to the general formula I above, which consists in that a thiophosphate reactive derivative of thia (dia) zolacetic acid of the general formula II is acylated with a 7-ACA derivative of the general formula III in the presence of a solvent and a base, according to the following reaction scheme:

general structural formula III:

In (i)

Solvent

The base

In the term acyloxymethyl used in the description of the present invention, the definition "acyl" means any acyl group commonly known in the field of betalactam such as carbamoyl, aliphatic acyl groups, acyl groups having aromatic rings or heterocycles, etc. Preferred examples of acyl groups may be 0-4 alkanoyl groups such as formyl, acetyl, propionyl, butyryl, etc. In particular C 1-6 alkanoyl in terms of methyl linked to a heterocycle and thiomethyl linked to a heterocycle, the definition of heterocycle may represent a saturated or unsaturated 3 to 7 membered monocycle containing at least one heteroatom selected from nitrogen atoms, oxygen and sulfur in the cycle, or a polycycle that is formed by the fusion of two or more cycles as defined above. Typical examples for these heterocycles are pyrrolidinyl, imidazolinyl, piperidino, piperazinyl, morpholino, thiazolidinyl, pyrrolyl, pyrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,4, etc.4 ), oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, etc.], thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl), thienyl, indolyl, isoindolyl, indolinyl, benzotriazolyl,

RO 111682 Tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazolyl, benzothiazolyl, etc. substituents which may have a positive charge in the cycle, if possible, as in pyridinium, pyrimidinium, thiazole, etc., and may be substituted 5 with 1 ... 4 suitable substituents. In this case, preferred examples of suitable substituents may include C _r C ₄ alkyl (e.g. methyl, ethyl, propyl, isopropyl, t-butyl, etc.), C ₂ -C ₄ alkenyl (e.g. io ethenyl, 1-propenyl, allyl, 1,3-butadienyl etc.), C ₂ -C ₄ alkynyl (e.g. ethynyl, Isau 2-propynyl etc.), C ₃ -Cg cycloalkyl (e.g. cyclopropyl, cyclopentyl etc.), halogen (e.g. chlorine , fluorine, iodine etc.), substituted or unsubstituted amino (eg amino, methylamino, ethylamino, Ν, Ν-dimethylamino, Ν, Ν-diethylamino etc.), phenyl which is unsubstituted or substituted with hydroxy, etc. 20

The process according to the present invention, as shown in the reaction scheme above, is characterized by using the reactive thiophosphate derivative of general formula II which has the corresponding reactivity and stability for a reactive organic acid derivative and, therefore, may be widely applied to the synthesis of cephalosporin compounds currently known which have a 2- (amino-thia (dia) -zolyl) -2-methoxyiminoacetamido group at position 7 of the cefem nucleus.

In the reaction according to the process of the present invention, the thiophosphate derivative of reactive organic acid of general formula II is advantageously used in a slightly excess amount with respect to the compound of general formula III to complete the reaction. In general, thiophosphate derivative of reactive organic acid of general formula II can be used in an amount of 1.0 to 1.5 equivalents in weight relative to the compound of general formula III. However, if both the termination of the reaction and the economy are taken into account, the reactive thiophosphate derivative of general formula II is preferably used in an amount of 1.0 to 1.2 weight equivalents to the corn with general formula III.

As a base in the reaction of the process according to the invention, both an inorganic base and an organic base may preferably be used. For this purpose, the inorganic base which can be used may be carbonates and bicarbonates of an alkaline earth metal such as sodium acid carbonate, sodium carbonate, potassium acid carbonate, potassium carbonate, etc. As an organic base a tertiary amine such as triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, etc. can be used. The most preferred of these bases may be sodium carbonate, triethylamine, tri-n-butylamine and others.

Although the base amount used may vary depending on the nature of the R ² substituent, the base is generally used in an amount of 1.5 to

3.5 weight equivalents, preferably 2.0 to 3.0 weight equivalents in comparison to the compound of general formula III.

As a solvent in the reaction of the present invention, any polar or nonpolar solvent such as dichloromethane, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, Ν, Ν may be used individually. -dimethylformamide, N, N-dimethylacetamide, alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, water, etc. However, a mixed solvent composed of two or more solvents selected from the above mentioned ones, for example a mixture of alcohol-water solvents, in particular the mixture of ethyl alcohol-water, can be efficiently used to optimize the reactivity and separation of the product. reaction.

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

The reaction temperature in the process of the present invention should not be restricted, unless the chosen temperature adversely affects

The reaction according to the invention. However, in general, the reaction may be completed within 2 to 6 hours, at a temperature of 0 to 3 ° C, in particular in the range of room temperature of 20 to 25 ° C, to the preparation of the desired compound is completed.

In the above reaction scheme, when R ³ represents a protecting group of the amino group, if desired, the resulting acyl moiety may be subjected to the deprotection reaction to remove the protecting group and obtain the desired compound of the formula Wherein R ³ represents hydrogen. 15

As characteristic examples of compounds which can be prepared according to the process of the present invention may be the following: acid / 3-acetoxymethyl-7- / 2- (2-amino-4-20 thiazolyl) -2-methoxyimino / -acetamido-3-cefem- 4-carboxylic acid (cefotaxim); 7 - {[2 (2-amino-4-thiazolyl) -2- (Z) -methoxyimino / acetamido} -3- / 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2 acid 4-Triaxη-3-ylthiomethyl-3-3-2 cefem-4-carboxylic acid (ceftriaxone); 7 {[a- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino / acetamido} -3 acid - / (1-methyl-1H-tetrazol-5-yl) -thiomethyl / -phenem-4-carboxylic acid (cefmenoxime); 7- / 2-methoxyimino-30 acid

2- (2-amino-1,3-thiazol-4-yl] acetamido / -3cephem-4-carboxylic acid (ceftizoxime); 7 - {[2- (2ajT) ino-4-thiazolyl] -2- (Z) -methoxyimino / acetamido) -3- (2,3-dicyclopentenpyridiniumethyl) -3-cefem-4-carboxylate 35 (cefpirome); 7 - {[2- (2-amino-4-thiazolyl) -2-methoxyimino / acetamido} -3- (1-methylpyrrolidiniumethyl] -3-cefem-4-carboxylate (cefepime);

7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxy-40 imino] acetamido} -3- (4,6-diamino-1,1-dimethylpyrimidinium-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-45 1-methylpyrimidinium-2-yl ) thiomethyl-3-cephem-4-carboxylate; 7 - {[(Z) -2- (2-amino-1,2,4-thiazole

3-yl) -2-methoxyimino] acetamido} -3- (4,6-diamino-1-ethylpyrimidinium-2-yl) thiomethyl-3-cyphem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4- 50 thiazolyl) -2-methoxyimino / -acetamido} -3 (1,4,6-triaminopyrimidinium-2-yl) thiomethyl-3-cefem-4 carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (4,6-diamino-1,5-dimetilpirimidiniu-2-yl) thiomethyl

3-cefem-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-etilpirimidiniu-4-yl) thiomethyl-3-cephem-4-carboxylate ; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (2,6-diamino-3-metilpirimidiniu-

4-yl) thiomethyl-3-cefem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (4,5,6-triamino-1-metilpirimidiniu-2-yl) thiomethyl-3-cephem -4-carboxylate;

7 - {[(Z] -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- [4-amino-1-metilpirimidiniu-2-yl) thiomethyl-3-cephem-4- carboxylate;

7 - {[(Z) -2- (2-amino-4-thiazolyl) -2metoxiimino] acetamido} -3- (4-amino-1metilpirimidiniu-2-yl) thiomethyl-3-cephem-4-carboxylate;

7 - {[(Z) -2- (2-amino-4-thiazolyl) -2metoxiimino] acetamido} -3- (4-amino-1carboximetilpirimidiniu-2-yl) thiomethyl-3-cephem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (4 amino-1-aminopirimidiniu-2-il) thiomethyl-3-cephem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (1,4,5-triaminopirimidiniu-2-yl) thiomethyl-3-cephem-4-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) -2metoxiimino] acetamido} -3- (1,4,5,6tetraaminopirimidiniu-2-yl) thiomethyl-3-cephem-4-carboxylate;

7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminojacetamide o} -3- (1,4-diamino-5-methylpyrimidinium-2-yl) thiomethyl-3-cefem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl) -2metoxiimino] acetamido} -3- (1,4-diamino-

5-ethylpyrimidinium-2-yl) lthiomethyl-3-cefem-4-carboxylate;

7 - {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminojacetamidq} - 3 - (1,4-diamino-6- (NRO 111682 Bl-methyl) aminopyrimidinium-2-yl) thiomethyl- 3cefem-4-carboxylate; 7 - {[(Z) -2- (2-amino-4-thiazolyl] -2-methoxyimino) acetamido} -3- (1,4diamino-5-methyl-6- (N-methyl) aminopirimidiniu-2-yl) thiomethyl -3-cefem-4-5 carboxylate; 7 - {[(Z) -2- (2-amino-4-tiazolkl) -2metoxiimino] acetamido} -3- (3,4-diamino3,5,6,7-tetrahidrociclopentapirimidiniu-2-yl) thiomethyl-3-cephem 4-carboxylate; 7 - {[(Z) -2 (2-amino-4-thiazolyl) -2-methoxyimino] acyl tamido} -3- (2-amino-1-methyl-1,5,6, 7tetrahidrociclopentapirimidiniu-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- 15 tetra pyrimidine hydrocyclopenta pyrimide) 4-yl) thiomethyl-3-cephem-4-carboxylate; 7 - {[(Z) -2 (2-amino-4-thiazolyl) -2-amino-4-thiazolyl) -2-methoxyimino] acetamido) -3- (7-amino-1-methyl [1,2,4] triazolo [ 1,5-c] pyrimidinium-5-2-yl) thiomethyl-3-cefem-4-carboxyl; t or 7 {[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido} - 3- (1-Methyl, 3] imidazo [1,2-c] pyrimidinium-5yl) thiomethyl-3-cefem-4-carboxylate. 25

The thiophosphate derivative of the reactive organic acid of general formula II has good solubility in a polar or nonpolar organic solvent and also has a good stability so that it cannot be decomposed into organic acid IV even when the thiophosphate derivative of the acid The organic reagent dissolved in such a solvent is washed with acidic, basic or neutral water. Furthermore, 35, when the thiophosphate reactive derivative of organic acid of general formula II is used in the acylation reaction with the amino group of the βlactamic nucleus, this reaction can be effected easily even under mild conditions and the thiophosphoric acid derivative obtained as a co-product, it is present in the aqueous layer in the dissolved state and therefore can be easily removed. 45

Also, in the reaction according to the process of the present invention, although the compound of general formula II may be subjected to the acylation reaction after the R ³ group is protected with a protecting amino group 50, however the acylation reaction may also be carried out with the compound of the general formula II. which has no protected amino group without any restriction. Therefore, when the process according to the present invention is applied to the preparation of compounds of general formula I on an industrial scale, there is a great advantage that the final β-lactam antibiotics can be easily synthesized with high yield and high purity.

The present invention has the advantage of obtaining an antibiotic of increased purity, with an increased yield.

The following are examples of embodiments of the invention.

Example 1. Synthesis of 3acetoxymethyl-7- [2- [2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid (cefotaxime).

In a 1 L round flask, over 200 ml of distilled water and 200 ml of tetrahydrofuran, 54.46 g of 7-aminocephalosporanic acid and 77.74 g (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate are added successively. of diethylthiophosphoryl under stirring. After the addition of 74.15 g of tri-n-butylamine the reaction mixture is stirred for 3 hours, maintaining the temperature at 20 to 25 ° C, and then extracting with 453 g of 12% aqueous sodium carbonate and extracting. with 100 ml of ethyl acetate to remove the organic layer. The separated aqueous layer was extracted again with 100 ml of ethyl acetate (10D ml) to remove the organic layer. Then the aqueous layer is neutralized with 20% aqueous sulfuric acid to pH = 6. To the neutralized aqueous solution, 10 g of activated carbon is added and then the mixture is stirred for 30 minutes and filtered. The filtrate is saturated with sodium chloride. The saturated aqueous solution is brought to pH = 4 by the addition of 20% aqueous sulfuric acid. After the small amount of the title compound is added, the mixture is brought to pH = 2.5 by adding a further 20% aqueous sulfuric acid. The crystals are precipitated entirely, filtered, washed with water and then dried to obtain 83.8 g (92% yield) of the title compound as a pale yellow solid.

RO 111682 Bl

Purity determined by HPLC:

98.5%

Example 2. Synthesis of 3-acetoxymethyl-7- [2- [2-amino-4-thiazolyl] -2-methoxyimino] acetamido-3-cefem-4-carboxylic acid [cefotaxime] in a 1 L round flask was introduced 2OO ml of distilled water 54, 46 g of 7-aminocephalosporanic acid and 33.6 g of sodium hydrogen carbonate and then allowed to completely dissolve by stirring at room temperature. To this reaction solution was added 200 ml of tetrahydrofuran and 77.74 g (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate of diethylthiophosphoryl and the mixture was stirred for 5 h at 20 to 25 ° C. The reaction solution was extracted with 100 ml of ethyl acetate to remove the organic layer and the separated aqueous layer was extracted with 100 ml of ethyl acetate again and then neutralized to pH = 6 by adding 20% aqueous sulfuric acid. To the neutralized aqueous solution, 10 g of activated carbon is added and then the mixture is stirred for 30 minutes and filtered. The filtrate is saturated with sodium chloride. This saturated solution is brought to pH = 4 by the addition of 20% aqueous sulfuric acid. After the small amount of the title compound was added, the mixture was again brought to pH = 2.5 with an additional 20% aqueous sulfuric acid addition. After the crystals precipitate completely, they are filtered, washed with water and then dried to obtain 81.07 g (89% yield) of the title compound as a pale yellow solid.

Purity by HPLC: 98.6%.

Example 3. Synthesis of 3-acetoxymethyl-7- [2- [2-amino-4-thiazolyl] -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid [cefotaxime].

Working according to the procedure of Example 2, but except that 40.48 g triethylamine is used instead of sodium acid carbonate, 77.43 g (85% yield) of the title compound is obtained.

Purity by HPLC: 98.4%.

Example 4. Synthesis of 312 acetoxymethyl-7- [2- [2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid (cefotaxime)

Working according to the procedure of Example 1, except that 100 ml of N, N-dimethylacetamide and 400 ml of dichloromethane are used instead of distilled water and tetrahydrofuran and 100 ml of dichloromethane instead of ethyl acetate as the extraction solvent, 82 , 0% yield 90%), composed of the title. Purity by HPLC: 98.6%.

Example 5. Synthesis of 3acetoxymethyl-7- [2- [2-amino-4-thiazolyl] -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid [cefotaxime].

To 400 ml of 95% ethyl alcohol, in a 1 L round flask, add 54.46 g of 7-aminocephalosporanic acid and 77.74 g (Z) - (2-aminothiazole-) successively.

Diethylthiophosphoryl 4-yl) -methoxyiminoacetate under stirring. After addition of 40.48 g of triethylamine, the reaction mixture was stirred for 3 h, maintaining the temperature at 20 to 25 ° C during this time, and then 31.25 g of concentrated hydrochloric acid diluted with 200 ml of alcohol was added. ethyl 95%. The mixture is stirred vigorously for about one hour to completely precipitate the crystals. The precipitated crystals were filtered, washed with water and then dried to give 83.8 g (92% yield) of the title compound as a white solid.

Purity by HPLC: 98.6%.

Example 6. Synthesis of 3-Acetoxymethyl-7- [2- [2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefem-4-carboxylic acid [cefotamix]

Working the same as in the procedure in Example 5, but except that 100 ml of distilled water and 400 ml of isopropyl alcohol (400 ml) is used instead of ethyl alcohol, 82.0 g (90% yield) of the title compound are obtained. .

Purity by HPLC: 98.4%.

Example 7. Synthesis of Acid 7 {[2- (2-Amino-4-thiazolyl] -2- [Z} -methoxyiminoJacetamido} ~ 3 - [[2,5-dihydro-6-hydroxy-2metH-5-οχο-1 , 2,4-triazin-3-yl) -thiomethyl] -3cephem-4-carboxylic acid [ceftriaxone]

RO 111682 Bl

To 2OO ml of distilled water and 200 ml of tetrahydrofuran in a 1 L round flask is successively added 37.1 g of 7 amino 3 - [(2,5-dihydro-6-hydroxy-2-methyl-5oxo-1,2) acid , 4-triazin-3-yl) -thiomethyl] -3-cefem-4-carboxylic acid 38.8g, (Z) - (2-aminothiazol-4-yl) diethylthiophosphoryl methoxyiminoacetate and

55.7 g of tri-n-butylamine under stirring. This reaction solution was stirred for 3 h while maintaining the temperature at 20 to 25 ° C and then 200 ml of toluene was added to remove the organic layer. The aqueous layer is brought to pH = 3 with 20% aqueous sulfuric acid. The solution containing the precipitated product is stirred vigorously for one hour under ice-cooling. The obtained product is filtered, washed with water and then dried to obtain 50.7 g (91.5% yield) of the title compound. HPLC purity: 99.3%.

Example 8. Synthesis of 7 {[2- (2-amincb4-thiazolyl) -2 (Z] -methoxyimino] acetamido} -3- [2,5-dihydro-6-hydroxy-2-methyl-5-οχο-1,2 acid , 4-triazin-3-yl) -thiomethyl] -3-2 cefem-4-carboxylic acid (ceftriaxone).

In a 1 L round flask, over 400 ml of 95% ethyl alcohol, 37.1 g of 7-amino-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1) is added successively. 2,4- 30 triazin-3-yl) -thiomethyl] -3-cefem-4-carboxylic acid, 38.8g (Z] - (2-aminothiazol-4-yl) diethylthiophosphoryl methoxyquinino acetate and 30.36 g triethylamine under stirring This reaction solution is stirred for 3 35 h while maintaining the temperature at 20 to 25 ° C and then 26.04 g concentrated hydrochloric acid diluted with 200 ml of 95% ethyl alcohol is added. The solution containing the precipitated product stir vigorously for one hour under ice-cooling, the resulting product is filtered, washed with water and then dried to give 50.7 g (91.5% yield) of the title compound.

Purity by HPLC: 99.3%.

Example 9. Synthesis of 7 {[2- (2-amino-4-thiazolyl] -2- [Z) -methoxyimino] acetamido} -3 - [(1-methyl-1H-tetrazol-5-ylmethomethyl] -3-cefem acid -4-carboxylic 50 (cefmenoxime).

In a 1 L round flask add 32.8 g of 7-amino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl) -3-cefem-4- to 100 ml of distilled water. carboxylic acid and 16.8 g sodium acid carbonate and the mixture is allowed to completely dissolve under stirring at room temperature. Then it is added

38.8 g (Z) - (2-aminothiazol-4-yl) - diethylthiophosphoryl methoxyiminoacetate dissolved in 100 ml tetrahydrofuran and the reaction mixture was stirred at 20 to 25 ° C for 5 hours. To the reaction solution is added ethyl acetate (2 x 100 ml) to separate the organic layer. Then the aqueous layer was brought to pH = 3.1 with 2N aqueous hydrochloric acid solution and stirred for one hour under ice-cooling. The resulting precipitate was filtered, washed with water and then dried to give 46.3 g (90.6% yield) of the title compound. Purity by HPLC: 99.4%.

Example 10. Synthesis of 7 {(2- [2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido} -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] acid -3-cefem-4-carboxylic acid (cefmenoxime).

To 400 ml of 95% ethyl alcohol in a 1 L round flask was added successively 32.8 g of 7-amino-3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -3-cefem -4-carboxylic acid, 38.8 g (Z] -2- (2-aminothiazole-4-yl) -methoxyiminoacetate of diethylthiophosphoryl and 20.24 g of triethylamine under stirring.The reaction mixture is then stirred at 20 to 25 ° C for 5 h. and to this is added 15.63 g concentrated hydrochloric acid diluted with 200 ml of 95% ethyl alcohol. The reaction mixture is stirred for one hour under ice-cooling. The resulting precipitate is filtered, washed with water and then dried to dry. obtain 46.3 g (90.6% yield) of the title compound.

Purity by HPLC: 99.4%.

Example 11. Synthesis of 7 {[(2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl)) -acetamido) -3-cefem-4-carboxylic acid (ceftisoxime).

To a 1 L round flask add 100 ml of distilled water, 20 g of 7-amino-3-cefem-4-carboxylic acid and

16.8 g of sodium hydrogen carbonate and the mixture is allowed to completely dissolve below

RO 111682 Bl stir at room temperature. Then 38.8 g (Z) -2- (2-aminothiazol-4-yl) -methoxyiminoacetate of diethylthiophosphoryl dissolved in 1OO ml of tetrahydrofuran are added and the reaction mixture is stirred at 20 to 25 ° C for 5h. To the reaction solution is added ethyl acetate (2 x 100 ml) to separate the organic layer. Then the aqueous layer was brought to pH = 3 with 2N aqueous hydrochloric acid solution and stirred for one hour under ice-cooling. The resulting precipitate was filtered, washed with water and then dried to obtain 35.8 g (93.4% yield) of the title compound. Purity by HPLC: 98.4%.

Example 12. Synthesis of 7 {[(2-methoxyimino-2- [2-amino-1,3-thiazol-4-yl]] - acetamido} -3-cefem-4-carboxylic acid (ceftisoxime) in a 1-round flask I, to 400 ml of 95% ethyl alcohol is added successively 20 g of 7-amino-3-cefem-4-carboxylic acid, 38.8 g (Z) -2- (2-aminothiazole-4-yl) -methoxyiminoacetate of diethylthiophosphoryl and 20.24 The reaction mixture is then stirred at 20 to 25 ° C for 5 h and 15.63 g concentrated hydrochloric acid diluted with 200 ml of 95% ethyl alcohol is added thereto. The reaction mixture is stirred for one hour. hours under ice-cooling. The resulting precipitate was filtered, washed with water and then dried to give 35.8 g (93.4% yield) of the title compound.

Purity by HPLC: 98.45%.

Example 13. Synthesis of 7 - {[2- (2-amino-4-thioazolyl) -2- [Z} -methoxyimino] -acetamido} -3- (2,3cyclopentenopyridiniumethyl) -3-cefem-4caboxylatfcephyrome} sulfate a 1 l round flask, to 100 ml distilled water and 100 ml tetrahydrofuran, is added successively 45.9 g, 7-amino-3- (2,3-cyclopentenopyridiniumethyl) -3-cefem-4-carboxylate iodide

38.8 g (Z) - (2-aminothiazol-4-yl) -methoxyiminoacetate diethylthiophosphoryl g) and 37.2 g tr / n-butylamine under stirring. This reaction solution is stirred for 3 hours, during which time the temperature is maintained at 20 to 25 ° C and then ethyl acetate (2 x 100 ml) is added to the solution to remove the organic layer. The aqueous layer is brought to pH = 1.2 with 20% aqueous sulfuric acid. To this solution 300 ml of ethyl alcohol is slowly added while maintaining the temperature at 0 to 5 ° C and then the mixture is stirred vigorously for one hour. The resulting precipitate was filtered, washed with water and then dried to obtain 47.1 g (76.9% yield) of the title compound.

Purity by HPLC: 98.1%

Example 14. Synthesis of 7 - {[2- [2-amino-4-thiazolyl) -2- [Z) -methoxyimino] -acetamido} -3- (2,3-cyclopentenopyridiniumethyl) -3-cefem-4- sulfate carboxylatfcefpiroma] in a 1 L round flask, to 45 ml 95% ethyl alcohol 45.9 g, 7-amino-3- (2,3-cyclopentenopyridiniumethyl) -3-cefem-4-carboxylate iodide 38.8 g is added successively. (Z) - (2 aminothiazole-4-yl) -methoxyiminoacetate of diethylthiophosphoryl and 20.2 g of triethylamine under stirring. This reaction solution is stirred for 3 hours during which the temperature is maintained at 20 to 25 ° C and 12.25 g of concentrated sulfuric acid diluted with 300 ml of 95% ethyl alcohol are then added. The mixture is stirred for one hour, during which the temperature is maintained at 0 to 5 ° C. The resulting precipitate was filtered, washed with water and then dried to obtain 47.1 g (76.9% yield) of the title compound.

Purity by HPLC: 98.1%

Example 15. Synthesis of 7 - {[2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido} -3- [1-methylpyrrolidiniumethyl] sulfate

3-cefem-4-carboxylate (cefepime).

To 100 ml of distilled water and 100 tetrahydrofuran, in a 1 L round flask, add 43.4 g of 7-amino

3- (1-methylpyrrolidiniumethyl) -3-cefem-4-carboxylate iodide 38.8 g (Z) -2-aminothiazol-4-yl) -methoxyminoacetate of diethylthiophosphoryl and 20.2 g of triethylamine under stirring. This reaction solution is stirred for 4 hours, during which time

Maintain the temperature at 20 to 25 ° C and then add ethyl acetate (2 x 100 ml) to remove the organic layer. To the aqueous layer is added 5 g of activated carbon and the mixture is stirred for 5 30 minutes and then filtered. The filtrate was brought to pH = 1.2 with 20% aqueous sulfuric acid and then slowly added 400 ml of acetone. The mixture is stirred for one hour. The resulting precipitate was filtered, washed with water and then dried to obtain 45.1 g (78% yield) of the title compound.

Purity by HPLC: 97.1%. 15

Example 16. Synthesis of 7 - ([2- [2-amino-4-thiazolyl) -2-methoxyimino] acetamido} -3- (1-methylpyrrolidiniumethyl] - sulphate

3-cephem-4-carboxylate [cefepime)

To 400 ml of 95% ethyl alcohol in a 1 L round flask, 43.4 g of 7-amino-3- (1-methylpyrrolidiniumethyl) -3-cefem-4-carboxylate iodide, 38.8 g, was added successively. Z) - (2-Aminothiazol-4-yl) -methoxyiminoacetate diethylthiophosphoryl and 20.2 25 g triethylamine (20.2 g) with stirring. This reaction solution is stirred for 4 hours, during which time the temperature is maintained at 20 to 25 ° C and then 5 g of activated carbon is added. After that, the mixture is stirred for 30 minutes and then filtered. To the filtrate was added 12.25 concentrated sulfuric acid diluted with 400 ml of 95% ethyl alcohol and the mixture was stirred for one hour, while the temperature was maintained at 0 to 5 ° C. The resulting precipitate was filtered, washed with water and then dried to obtain 45.1 g (78% yield) of the title compound. 40 Purity by HPLC: 97.1%.

Claims (4)

1. Process for the preparation of 45 cephalosporin derivatives, having the general structural formula I: wherein R ¹ represents a carboxyl group or a protected carboxyl group, which may form the -COCTM ⁺ salt with an alkali metal ion M ⁺ , or may represent C00 'when R ² has a substituent having a positive electrical charge, R ² represents a hydrogen atom, an acyloxymethyl radical, methyl linked to a heterocycle, or a thiomethyl radical linked to a heterocycle, each of which may be substituted with suitable substituents, R ³ represents a hydrogen atom or a protecting group for the amino group, R ⁵ represents a hydrogen atom, a C 1-4 alkyl radical or C (R ^a ) (R ^b JCOOR ^c , wherein R ^a and R ^b are the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl radical or R ^a and R ^b together with the carbon atom to which they are linked may form a C 3 -C ₇ cycloalkyl group, and R ^c is a hydrogen atom or a protecting group for the carboxyl radical and Q represents N or CH, characterized in that a derivative of thiophosphorus t reagent of thia (dia) zolacetic acid of general structural formula II: (ii) wherein R ³ , R ⁵ and Q have the above meanings and R ⁴ represents an alkyl or phenyl radical, or together with the oxygen or phosphorus atom to which it is attached may form a 5- or 6-membered heterocyclic ring , is subjected to the acylation reaction with a 7-ACA derivative having general structural formula III: RO 111682 Bl a Solvent The base S c - c— o— p (oa ⁴ ) -> ii ^z o (ii) wherein R ¹ and R ² have the above meanings, in the presence of a solvent and a base, at a temperature of 0 ° ... 30 ° C. Process according to claim 1, characterized in that the solvent is selected from dichloromethane, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethijfocmamide, Ν, Ν-dimethylacetamide, al- cool it with water, or it is a mixture of two or more solvents chosen from them. Process according to claims 1 and 2, characterized in that the solvent is an alcohol selected from methyl alcohol, ethyl alcohol or isopropyl alcohol, or a mixed alcohol alcohol solvent. Process according to claim 1, characterized in that the base is selected from sodium carbonate, sodium acid carbonate, potassium carbonate, potassium carbonate, triethylamine, & nbutylamine and diisopropylethylamine.