HU193347B - Process for producing /6r,7r/-7-(/z/-2-/2-amino-thiazol-4-yl/-2-/oxy-imino/-acet-amido)-3-cepheme-4-carboxylic acid derivatives - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an antibacterial agent, by a novel process, by condensing a novel substituted hydroxyiminoacetic acid compound with an amino cephem carboxylic acid compound. CONSTITUTION:The objective compound of formula IV can be prepared by condensing (Z)-2-aminothiazolyl-2-substituted-hydroxyiminoacetic acid compound of formula I (R<1> is H or lower alkyl; n is 2 or 3) or its reactive derivative with (6R, 7R)-7-amino-3-cephem-4-carboxylic acid compound (salt) of formula II [when R<2> is acetoxy, etc., R<4> is (protected) carboxy, and when R<2> is group of formula III (Y is H or hydroxymethyl), R<4> is -COO<->], and when R<4> is protected carboxyl, removing the protecting group. The starting compound of formula I is novel, and can be produced e.g. by reacting the butyric acid derivative of formula V (R<6> is H, etc.; X is halogen) with thiourea.

Description

The present invention relates to the preparation of (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (oxyimino) acetamido] -3-cephem-4-carboxylic acid derivatives. applies to a suitable new process.

The cephalosporin derivatives obtainable by the process of the present invention have the general formula (I). In this formula

R ^{1 is} hydrogen or lower alkyl,

R ^{2 is} acetoxy or (1-methyl-1H-tetrazol-5-yl) -thio; and

R ^{3 is} carboxy; obsession

R ² is a group of formula (a), and

R ^{3 is} -COO ', while

Y is hydrogen, hydroxymethyl or carbamoyl, and n is 2 or 3.

The process also includes the preparation of pharmaceutically acceptable salts of these compounds.

The cephalosporin derivatives of formula (I) and their pharmaceutically acceptable salts, which are obtainable by the process of the present invention, exhibit favorable antibacterial activity against a wide range of microorganisms, including both Gram-positive and Gram-negative bacteria, and are thus useful as active ingredients in antibacterial agents. for the treatment of patients suffering from infections caused by Gram-positive and Gram-negative bacteria, such as cephalosporin derivatives of the formula (I) and their pharmaceutically acceptable salts having excellent anti-bacterial activity Against bacteria belonging to the species Staphylococcus, Enterobacteriaceae and Pseudomonas. For example, (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) - oxyimino] -acetamidooj-3- (1-pyridinomethyl) -3-cephem-4-carboxylate against such organisms.

According to the invention, the eephalosporin derivatives of the formula I and their salts are prepared according to the following process steps:

a (Z) -2-amino-thiazolyl-2- (substituted-oxyimino) -acetic acid of formula (II) wherein R ¹ is as defined above and n is as defined above or a reactive derivative thereof, as defined in formula (III); with (6R, 7R) -aminocephem-4-carboxylic acid of the formula wherein R ^{4 is a} carboxy group or a protected carboxy group when R ^{2 is} an acetoxy group or a (1-methyl-1 H -tetrazol-5-yl) thio group; or R ⁴ represents a -COO ^- group, when R ² is (a) a group of formula, and Y has the meaning given above, or the compound of formula (II) to reaction with a salt of the compound of formula (III), then in in the case where R ^{4 is a} protected carboxy 2 group, the protecting group is removed from the resulting product and optionally converted to a pharmaceutically acceptable salt thereof.

Examples of starting materials of formula (II) for use in the process of the invention include those of formula (II) wherein R ^{1 is} hydrogen or lower alkyl such as methyl, ethyl or propyl; and n is 2 or 3. When a compound of formula (III) wherein R ^{4 is} a protected carboxy group is used, this protecting group is preferably one that is readily removed by conventional methods such as hydrolysis, solvolysis, acid treatment or reduction. Examples of such protecting groups include lower alkyl groups such as tert-butyl; substituted or unsubstituted phenyl (lower) alkyl groups such as benzyl, p-methoxybenzyl or p-nitrobenzyl; the benzhydryl group; tri- (lower alkyl) silibyl groups such as trimethylsilyl and the like. In the case where R ^{4 is a} carboxy group, the compound of formula (III) is preferably converted to a salt before the condensation reaction. Suitable salts of the compounds of formula (III) include, for example, inorganic salts, such as sodium or potassium salts, and organic salts, such as trimethylamine or triethylamine salts. The compounds of formula (II) exist in two optical isomeric forms due to the asymmetric carbon atom represented by an asterisk in formula (b). In this formula, R ¹ and n have the same meanings as defined. The condensation reaction of a compound of formula (II) or a reactive derivative thereof with a compound of formula (III) or a salt thereof can be carried out by conventional methods. For example, compound (II) is condensed in free form with compound (III) in the presence of four dehydrating agents in a solvent. Suitable dehydrating agents include dicyclohexylcarbodiimide, N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine and the like. Vilsmeier reagents made from dimethylformamide and phosphorus oxychloride, dimethylformamide and oxalyl chloride, dimethylformamide and phosgene or dimethylformamide and thionyl chloride may also be used as dehydrating agents. Dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, N, N-dimethylacetamide, ethyl acetate, pyridine and water are also suitable solvents. Preferably, the reaction is carried out at a temperature of -50 ° C to 50 ° C, in particular -30 ° C to 20 ° C.

Alternatively, the reactive derivative of the compound of formula (II) in a solvent in the presence of an acid acceptor or

-2193347 without being condensed with the compound of formula (III) or a salt thereof. Suitable reactive derivatives of the compound of formula (II) include, for example, the corresponding acid halide (e.g., acid chloride or bromide), a mixed anhydride (e.g., mixed anhydride of (II) with alkyl carbonate), an active ester (e.g., p-nitrophenyl ester). , 2,4-dinitrophenyl ester, succinimide ester, phthalimide ester, benzotriazole ester, 2-pyrrolidon-1-yl ester), acid azide and an acid amide (e.g. imidazolamide, 4-substituted-imidazolamide, triazole) -amide). Dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, Ν, Ν-dimethylacetamide, ethyl acetate, pyridine, acetone and water are suitable solvents. Suitable acid scavengers are, for example, alkali metal hydroxides (e.g., potassium hydroxide, sodium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydrogencarbonates, trialkylamines (e.g. amine, triethylamine), Ν, Ν-dialkylanilines (e.g., N, N-dimethylaniline, Ν, Ν-diethylaniline), pyridine and N-alkylmorpholines (e.g., N-methylmorpholine). ). The reaction is preferably carried out at a temperature of from -50 ° C to 50 ° C, in particular from -30 ° C to 20 ° C.

In the case where R ^{4 in} the resulting compound is a protected carboxy group, the deprotection may be carried out by conventional methods such as hydrolysis, solvolysis, acid treatment or reduction, such as when the protecting group on the carboxy group is tert-butyl or benzhydryl, then these groups can be removed by acid treatment. Suitable acids for this purpose include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid and mixtures thereof. This reaction is carried out with or without a solvent. Suitable solvents are, for example, water, methanol, ethanol, acetic acid or dioxane. The reaction is preferably carried out at a temperature of -30 ° C to 70 ° C, in particular 0 ° C to 30 ° C. In addition, when trifluoroacetic acid is used as the acid, it is preferably used in the presence of anisole.

In the case where the protecting group on the carboxy group is benzyl, p-methoxybenzyl or p-nitrobenzyl, these protecting groups are removed by catalytic hydrogenation of the compound in hydrogen in the presence of a catalyst. Suitable catalysts include palladium-BaCO3, palladium-on-charcoal and palladium-carbon black. This catalytic hydrogenation is preferably carried out in a solvent at atmospheric pressure or above atmospheric pressure in a temperature range of 0 ° C to 100 ° C, preferably 10 ° C to 40 ° C. Methanol, ethanol, tetrahydrofuran and water are suitable solvents for this purpose.

The cephalosporin derivatives of formula (I) may be used in pharmaceutical form in free form or in the form of their salts. Pharmaceutically acceptable salts of the compounds of formula I include, for example, non-toxic metal salts such as sodium, potassium, calcium or aluminum; salts with non-toxic amines such as trialkylamines such as phenylethylbenzylamine; salts with inorganic acids such as hydrochloric acid or hydrobromic acid; salts with organic acids such as tartaric acid and other salts. These salts are readily prepared by treating the compounds of formula (I) with a stoichiometric equivalent of the appropriate alkaline agent or acid. The treatment is carried out at ambient temperature in an aqueous solvent.

The starting compounds of formula (II) are new and can be prepared by reacting a butyric acid derivative of formula (IV) in which -COOR® is a carboxy group or a protected carboxy group, X is a halogen atom, and R ¹ and n are as defined above, with thiourea in the presence of an agent (such as an organic tertiary amine such as N, N-dimethylaniline, triethylamine or pyridine) at a temperature of about 10 ° C to 80 ° C in a solvent (e.g. water or a mixture of water and lower alkanol); COOR® protected carboxy group, the protecting group is removed from the resulting product.

The term "lower alkyl" as used herein and in the claims refers to C 1-4 alkyl.

Experiment I (Antimicrobial activity in vitro)

The minimum inhibitory concentration of the test compound was determined by the MIC (pg / ml) standard agar plate dilution method (according to the method of the Japanese Chemotherapeutic Society). For these experiments Mueller-Hinton agar was used as medium (MHA; Nissui).

The results are shown in Table 1.

-3193347. Spreadsheet

examined micro-organism M.i.c. (Pg / ml) The Cefmenoxime compound of the invention is represented by (1) to (2) Note Ceftazidime (3) Staphylococcus aureus Teraj takes Staphylococcus aureus 0.78 1.56 12.5 252R 25 > 100 > 100 Streptococcus Faecalis CN-478 12.5 > 100 > 100 Bacillus subtilis ATCC 6633 0.2 1, 56 3.13 Klebsiella pneumoniae 5038 0.05 0.1 0.1 Enterobacter cloacae TU-680 £ 0.05 0.1 0.2 Serratia marcescens 7006 <0.05 0.2 0.2 Pseudomonas aeruginosa 4096 0.39 6.25 0.78 Pseudomonas putida 1, 56 100 12.5

ATCC 12633

Note)

1) (6R, 7R) -7 - {(Z) -2- (2-Aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) oxyimino] -acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate

2) Chemical Name - (6R, 7R) -7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyimino) acetamido] -3 - [(1- methyl-1H-tetrazol-5-yl) -1-thiomethyl] -3-cephem-4-carboxylic acid

3) Chemical Name = (6R, 7R) -7 - {(Z) -2- (2-Aminothiazol-4-yl) -2 - [(2-carboxyprop-2-yl) oxyimino ] -acetamido) -3- (1-pyridinylmethyl) -3-cephem-4-carboxylate

10-10 male mice weighing 20 ± 1g each were used for each dose level. The mice were infected with as many bacteria as were sufficient to kill untreated animals within 24 hours. Infection was performed intraperitoneally. All bacteria were suspended in 6% mucin. The test compounds were administered intramuscularly to the animals one hour after infection. Survival rates were determined 7 days after infection. The median effective dose (ED _50> mg / kg) of test compounds was determined by probit analysis.

The results are shown in Table 2

II. Experiment

(Protection against bacterial infection which the experiment described in Experiment I Mice) don. Table 2 ⁴ examined micro-organism ED 5u (mg / kg) Invention cefmenoxime ceftazidime of compound (1) inch (2) inch Note 3 Staphylococcus aureus 1.71 5.32 7.85 Smith (1.56) (1.56) (12.5) Escherichia coli 0.5 0.16 0.08 KC-14 (0.05) (0.025) (0.05) Serratia marcescens 0.14 0.88 0.54 7006 (0.05) (0.2) (0.2)

-4193347

2 _l Table * (cont.)

examined micro-organism ed ₅₀ (Mg / kg) Invention cefmenoxime ceftazidime of compound (1) inch (2) inch Note 3 Citrobacter freundii 0.06 0.19 0.15 916 (0.1) (0.05) (0.39) Enterobacter aerogenes 1.37 23.85 26.38 816 (0.39) (1.56) (6.25)

Note *: Numeric values in parentheses represent the minimum inhibitory concentration of each test compound (M.I.C.)

1) -3): corresponds to the compounds given in the footnote in Table 1.

Example 1 (1) 13.12 g of (6R, 7R) -7-amino-3- (1-pyridinylmethyl) -3-cephem-4-carboxylate. HJ.H ₂ O is suspended in 150 ml of chloroform and 28.5 ml of trimethylchlorosilane, 17.8 ml of pyridine and 3.1 g of triethylamine are added at -10 ° C to 0 ° C. The mixture was then stirred at -5 ° C to 0 ° C for 2 hours.

(2) 6.75 g of (Z) -2- (2-aminothiazol-4-yl) -2 - {[(3S) -2-pyrrolidon-3-yl] oxyimino} acetic acid in 200 ml Suspended in Ν, Ν-dimethylacetamide. Was added 2.6 g of ³⁵ triethylamine to the suspension and the whole was heated until 65-70 ° C until a clear solution was obtained. The solution was cooled and chloroform (50 mL) was added. The mixture is then cooled to -20 ° C to -25 ° C and 3.84 g of phosphorus oxychloride are added dropwise at the same temperature. The resulting mixture is added dropwise to the solution obtained in 1) at -15 ° C to -20 ° C. ⁴⁵ The mixture was stirred at the same temperature for 15 minutes and then added to 200 ml of an aqueous sodium chloride solution was 15%.

The mixture was stirred at 0-15 ° C for 20 minutes.

The aqueous layer was collected, washed with chloroform and concentrated under reduced pressure to remove chloroform. The resulting aqueous layer was passed through a 700 mL column packed with a nonionic diaion HP-20 ion exchange resin. The column is washed with about 6 L to about ⁵⁵ volumes of water and then the desired product is eluted with 20% methanol. The eluate was concentrated to about 400 ml under reduced pressure and lyophilized. 9.7 g of (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) ^-60

-2-] ((3S) -2-pyrrolidon-3-yl) oxyimino] acetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate is obtained in the form of a pale yellow powder. Yield 70%.

NMR (D ₂ O) δ: 2.2-2.7 (2H, m), 3.1-3.8 (4H, 65)

m), 5.05 (1H, t, J = 7Hz),

5.28 (1H, d, J = 5Hz), 5.36 (1H, d, J = 14Hz), 5.63 (1H, d, J = 14Hz), 5.87 (1H, d, J = 5Hz), 6.98 (1H, s), 8.10 (2H, t, J = 7.5Hz), 8.57 (1H, t, J = 7.5Hz), 8, 98 (2H, d, J = 7.5 Hz) [α] ²⁰ = -38.0 ° C (C = 1, H ₂ O)

2-8. example

The following compounds were prepared as described in Example 1.

2. (6R, 7R) -7 - {(Z) -2- (2-Aminothiazol-4-yl) -2 - {((3R) -2-pyrrolidin-3-yl) oxyimino ] -acetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate

NMR (D ₂ O) δ: 2.1-2.7 (2H, m), 3.1-3.7 (4H, m), 4.9-5.5 (4H, m), 5.79 (1H, d, J = 5Hz), 6.92 (1H, s), 7,89,1 (5H, m) [<* te ⁰ = + 45.7 ° (C = l, H ₂ O)

3. (6R, 7R) -7 - ((Z) -2- (2-Aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] -acetamide ) -3- (4-Carbamoyl-1-pyridinylmethyl) -3-cephem-4-carboxylate

163-166 ° C (dec.).

NMR (CF ₃ CO ₂ D 16: 2.5-3.0 (2H, m), 3.5-4.0 (4H, m), 5.2-5.5 (3H, m), 5-5.8 (1H, m), 5.9-6.2 (1H, m), 7.35 (1H, s), 8.4-8.7 (2H, m), 9.1-. 9.4 (2 H, m)

4. (6R, 7R) -7- (Z) -2- (2-Aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] -acetamide } -3- (4-hydroxymethyl-1-pyridinylmethyl) -3-cephem-4-carboxylate

162-184 ° C (dec.)

NMR (D ₂ O) δ: 2.3-2.7 (2H, m), 3.1-3.7 (4H, m), 4.8-5.0 (2H, m), 5.03 (2H, s), 5.24 (1H, d, J = 5Hz), 5.3 -5.6 (1H, m), 5.83 (1H, d, J = 5Hz), 6, 81 (1H, s), 7.8-8.2 (2H, m), 8.6-9.0 (2H, m)

5. (6R, 7R) -7- (Z) -2- (2-Aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetamide ) -5193347

-3- (3-Hydroxymethyl-1-pyridinylmethyl) -3-cephem-4-carboxylate

128-135 ° C (dec.)

NMR (D ₂ O) δ: 2.1-2.8 (2H, m), 3.1-3.8 (4H, m), 4.86 (2H, s), 4.9-5.1 (2H, m), 5.27 (1H, d, J = 5Hz), 5.3-5.6 (1H, m), 5.83 (1H, d, J = 5Hz), 6.96 (1H, s), 7.7-8.2 (1H, m), 8.3-8.6 (1H, m), 8.6-9.1 (2H, m)

6. Sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [(2-piperidin-3-yl) oxyimino] ] -acetamido} -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate

NMR (D ₂ O) δ: 1.5-2.3 (4H, m), 3.0-3.4 (2H, m), 3.4-3.6 (2H, m), 3.90 (3H, m), 4.0-4.2 (2H, m), 5.03 (1H, d, J = 5Hz), 5.63 (1H, d, J = 5Hz), 5, 85 (1H, s)

7. Sodium (6R, 7R) -7 - {(Z) -2- (2-amino-thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oxyimino] -acetate amido [-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate

NMR _(DMSO-d6) δ: 2.1-2.5 (2H, m), 3.1-3.5 (2H, m), 3.94 (3H, s);

4.2-4.5 (2H, m), 4.6-4.8 (1H, m), 5.03 (1H, d, J = 5Hz), 5.5-5.8 (1H, m) , 6.76 (1H, s), 7.3 (2H, broad s), 8.00 (1H, s), 9.55 (1H, broad s)

8. Sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [(1-methyl-2-pyrrolidon-3-yl) - oxyimino] -acetamido} -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate

NMR (D ₂ O) δ: 2.1-2.7 (2H, m), 2.89 (3H, s),

3.2-3.8 (4H, m), 4.05 (3H, s), 4.05-4.3 (2H, m), 4.9-5.3 (2H, m), 5.73 ( 1H, d, J = 5Hz), 7.00 (1H, s)

Example 9 (1) 3.0 g of 7-aminocephalosporanic acid are suspended in 30 ml of Ν, Ν-dimethylacetamide and 9 g of trimethylchlorosilane are added, followed by 6.6 ml of pyridine. The mixture is stirred at 5-15 ° C until a clear solution is obtained and then cooled to -25 ° C to -20 ° C.

(2) 2.7 g of (Z) -2- (2-aminothiazol-4-yl) -2 - {[(3S) -2-pyrrolidon-3-yl] oxyimino) acetic acid are suspended in 80 ml of Ν, Ν-dimethylacetamide, and

1.1 g of triethylamine are added to the suspension. The suspension is stirred at 65-70 ° C until a clear solution is obtained, and the solution is cooled to room temperature. Chloroform (20 ml) was then added and 1.65 g of phosphorus oxychloride was added dropwise with stirring at -30 ° C to -20 ° C. The mixture is stirred at the same temperature for 10 minutes and added dropwise to the solution obtained in 1) at a temperature ranging from -25 ° C to -15 ° C. The mixture was stirred at the same temperature for ¹ min, then water (100 mL) and ethyl acetate (200 mL) were added and the mixture was stirred at 0-10 ° C for 30 min. The organic layer was collected, washed with water and then extracted with 5% aqueous sodium bicarbonate. The extract was applied to a 400 mL Diaion-ΗΡ-20 column, eluting with water. The eluate was evaporated to dryness under reduced pressure. Acetone was added to the residue and the precipitate was collected by filtration. Thus 2.9 g of sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) _: 2 - [((3S) -2-pyrrolidon-3-yl) are obtained. ) - oxyimino] -acetamidido-cephalosporanate is obtained.

NMR (D ₂ O) δ: 2.12 (3H, s), 2.3-2.6 (2H, m),

3.2-3.9 (4H, m), 4.75 (1H, d, J = 13Hz), 4.95 (1H, d, J = 13Hz), 5.10 (1H, t, J = 7Hz), 5.25 (1H, d, J = 5Hz), 5.85 (1H, d, J = 5Hz), 7.08 (1H, s)

Example 10

1.35 g of (Z) -2- (2-aminothiazol-4-yl) -2 - [beta] - [(3S) -2-Pyrrolidon-3-yl] oxyimino] acetic acid is added to 40 ml of a mixture of Ν, il-dimethylacetamide and 1.85 g of tributylamine and the whole is heated to 60-70. At 0 ° C until a clear solution is obtained. The solution is then cooled to room temperature and 20 ml of a methylene chloride solution containing 1.65 g of tert-butyl (6R, 7R) -aminocephalosporan are added. Subsequently, 0.88 g of 1-hydroxybenzotriazole and 1.35 g of N, N'-dicyclohexylcarbodiimide are added at 0-5 ° C and the mixture is stirred at the same temperature for 5 hours. Water (50 mL) and ethyl acetate (100 mL) were added and the mixture was stirred. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated, dried and concentrated under reduced pressure. Trifluoroacetic acid (30 mL) and anisole (1 mL) were added to the residue, and the mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. Water (15 mL) was added to the residue and the mixture was made slightly basic with sodium bicarbonate. Insoluble materials were removed by filtration and the filtrate was applied to a 150 mL diaion-20-20 column. The desired product is eluted with water and the eluate is evaporated to dryness under reduced pressure. 1.2 g of sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) are thus obtained. ) -oximino] -acetamido-cephalosporanate is obtained.

The physico-chemical properties of this product are the same as those of the product prepared in Example 9.

Example 11 (1) 2.5 g of benzhydryl (6R, 7R) -7-amino-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate are dissolved in 30 ml of tetrahydrofuran,

-6193347 and cooling the solution to -20 ° C to -15 ° C.

(2) 2.0 g of (Z) -2- (2-aminothiazol-4-yl) -2 - {((3S) -2-pyrrolidone-3'-yl) oxyimino} acetic acid are added. of dimethylacetamide (0.8 g) and triethylamine (0.8 g) and heated at 65-75 ° C until a clear solution is obtained. The solution was cooled to -20 ° C to -15 ° C and 1.1 g of isobutyl chlorocarbonate was added dropwise at a temperature of -20 ° C to -15 ° C. The mixture was stirred at the same temperature for 30 minutes. The mixture is then added at -20 ° C to -15 ° C to the solution obtained in 1) and stirred at this temperature for 2 hours and at -5 ° C to 0 ° C for an additional 1 hour. To the reaction mixture was added cold water (50 mL) and ethyl acetate (100 mL), and the mixture was stirred. The organic layer was separated and washed with water and then evaporated to dryness under reduced pressure. To the residue was added 1 g of anisole and 30 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated to dryness under reduced pressure and water (20 mL) was added to the residue. The aqueous mixture was made slightly basic with sodium bicarbonate and applied to a 300 mL Diaion HP-20 column. The column was washed with water and the desired product was eluted with 10% aqueous methanol. The eluate was evaporated to dryness under reduced pressure. Acetone was added to the residue and the resulting precipitate was collected by filtration. This way

1.1 g of sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyridin-3-yl) ) oxyimino] acetamido} -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

NMR _(DMSO-d6) δ: 2.0-2.5 (2H, m), 3.1-3.5 (2H, m), 3.93 (3H, m), 4.1 to 4, Δ (2H, m), 4.6-4.8 (1H, m), 5.04 (1H, d, J = 5Hz), 5.5-5.7 (1H, m), 6.76 (1H, s), 7.3 (2H, broad s), 7.98 (1H, s), 9.57 (1H, broad)

Example 12 (1) 1.65 g of (6R, 7R) -7-amino-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid in 15 ml Ν, Ν suspended in a mixture of 5-dimethylacetamide and 5 ml of chloroform and 3.0 g of Ν, Ο-bis (trimethylsilyl) acetamide are added to the suspension. The mixture is stirred at 10 to 20 ° C until a clear solution is obtained. The solution was cooled to -30 ° C to -20 ° C.

(2) Dissolve 440 mg of dimethylformamide in 10 ml of chloroform and add 820 mg of oxalyl chloride dropwise at 0-5 ° C. The mixture was stirred at the same temperature for 30 minutes and then cooled to -30 ° C to -25 ° C.

(3) 1.35 g of (Z) -2- (2-aminothiazol-4-yl) -2 - {((3S) -2-pyrrolidon-3-yl) oxyimino acetic acid are suspended in 40 ml. ml of N, N-dimethylacetamide and then 0.55 g of triethylamine are added to the suspension. The mixture is heated at 65-70 ° C until a clear solution is obtained and the solution is cooled to room temperature. Chloroform (10 ml) was added and the mixture was cooled to -30 ° C to -20 ° C. The solution obtained in 2) is added dropwise with stirring at a temperature of -30 ° C to -20 ° C and stirring is continued for 15 minutes at this temperature. The reaction mixture is added dropwise at -25 ° C to -15 ° C to the solution of 1) and the mixture is stirred at this temperature for 30 minutes. Water (50 ml) and chloroform (150 ml) were then added and the mixture was made slightly basic with sodium bicarbonate. The aqueous layer was separated and the chloroform was removed under reduced pressure. The residue was applied to a 300 ml Diaion-ΗΡ-20 column. The column was washed with water and the desired product was eluted with 10% aqueous methanol. The eluate was evaporated to dryness under reduced pressure. Acetone was added to the residue and the resulting precipitate was collected by filtration. 1.8 g of sodium (6R, 7R) -7 - {(Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) are thus obtained. ) (oxyimino] -acetamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate.

The product obtained in this way has the same chemical-physical properties as the product obtained in Example 11.

Preparation of starting compounds

Preparation 1 (1) 31.8 g of ethyl 2-hydroxyimino-3-oxo-n-butyrate are dissolved in 150 ml of acetone and 83 g of anhydrous potassium carbonate are added. Thereafter, 33 g of 3-bromo-2-pyrrolidone were added with stirring at 20-25 ° C, and the mixture was stirred at the same temperature for 1 hour. Then 1 liter of ice water was added and the mixture was extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to remove the solvent. The residue was crystallized with diisopropyl ether and the crystals were collected by filtration and then recrystallized from ethyl acetate. This gave 32 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-n-butyrate as colorless needle crystals.

92-92 ° C.

(2) 14.5 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-n-butyrate are dissolved in 60 ml of methylene chloride and 9.6 g. sulfuryl chloride is added to the solution. The gas mixture was stirred at 15-20 ° C for 40 hours and then concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water

-7193347 turns The chloroform solution was dried and evaporated to dryness under reduced pressure. The residue was crystallized from ether and the crystals were collected by filtration. The crystalline material was recrystallized from ethyl acetate. 6.5 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-4-chloro-n-butyrate are thus obtained.

102-103 ° C.

(3) 27.7 g of ethyl (Z) -2 - [(2-pyrrolidon-3-yl) oxyimino] -3-oxo-4-chloro-n-butyrate and 7.6 g of thiourea are added to of ethanol and 20 g of Ν, Ν-dimethylaniline are added. The mixture was stirred at 20-25 ° C for 2 hours and then concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water and then with aqueous sodium bicarbonate. The chloroform solution was dried and the solvent removed under reduced pressure. The residue was crystallized from isopropanol and the crystals were collected by filtration. 17.5 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetate are obtained. 156-158 ° C.

(4) 3.0 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetate is suspended in 60 ml of methanol. , and 10 ml of 2N sodium hydroxide solution are added to the suspension. The mixture was heated at reflux for 30 minutes. After cooling, the mixture was neutralized with 20 ml of 1 N hydrochloric acid and evaporated to dryness under reduced pressure. The residue was crystallized from 10 ml of ice water, the crystals were collected by filtration and dried under reduced pressure at 70 ° C. 2.2 g of (Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oxyimino] acetic acid are thus obtained in the form of colorless prisms.

Mp 158-159 ° C (dec.).

PREPARATION 2 (1) 2 g of (R) -3-hydroxy-2-pyrrolidone (Tetrahedron Letters, 2617 (1971)) are suspended in 30 ml of acetone and 15 ml of 2N aqueous sodium hydroxide solution are added at room temperature. to obtain a clear solution. The solution was cooled to -3 ° C to 5 ° C and p-toluenesulfonyl chloride (5.7 g) was added. The mixture was stirred at the same temperature for 1 hour and at 10-15 ° C overnight. The mixture was adjusted to pH 2 with about 10 mL of 2N HCl and concentrated under reduced pressure to remove acetone. The resulting mixture was extracted with chloroform and the extract was washed with saturated sodium chloride solution. The chloroform solution was dried and the solvent removed under reduced pressure. The residue was crystallized from ether and the crystalline material was recrystallized from ethyl acetate. 3.5 g of (R) -3- (p-tosyloxy) -2-pyrrolidone are thus obtained.

Mp 148-149 ° C.

[α] D = + 17.7 ° (C = 1, MeOH) (2) 1.07 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) ) -acetate was dissolved in 5 ml of dimethyl sulfoxide and 1.53 g of (R) -3- (p-tosyloxy) -2-pyrrolidone and 1 g of potassium carbonate were added. The mixture was stirred overnight at room temperature and water was added to the reaction mixture. The mixture was extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and the crystalline material was recrystallized from aqueous methanol. 0.86 g of ethyl (Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -2-pyrrolidon-3-yl) oxyimino] acetate is obtained. .

160-163 ° C [α] D = -15.9 ° (C = 1, MeOH).

(3) Dissolve 0.27 g of sodium hydroxide in a mixture of 3 ml of methanol and 1 ml of water and add 1 g of the ester prepared in 2). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was then adjusted to pH 5 with 10% hydrochloric acid and then concentrated under reduced pressure to remove methanol. The remaining pH was adjusted to 3 with 10% hydrochloric acid and the mixture was cooled with ice. The precipitated crystals were collected by filtration, washed with methanol and dried. In this way, 730 mg of (Z) -2- (2-aminothiazol-4-yl) -2

- [((3S) -2-pyrrolidon-3-yl) oxyimino] acetic acid is obtained.

M.p. 199-200 ° C (dec.) [Α] D = -50.8 ° (C = 1, H ₂ O)

Preparation 3 (S) -3-Hydroxy-2-pyrrolidone is treated as described in Preparation 2 to give (Z) -2- (2-aminothiazol-4-yl) -2 - [((3R) -) 2-pyrrolidon-3-yl) oxyimino] acetic acid is obtained.

Mp. 198-200 ° C (decomposed) [a] ^{2 5 * *} p = + 50.5 ° (C = l, H ₂ O)

4. Production method

Sodium iodide (250 g) and pyridine (32.5 g) were dissolved in water (85 ml) and the solution was heated to 70 ° C. 50 g of 7-formamidocephalosporanic acid are then added and the mixture is heated at 70 ° C for 1 hour. The mixture was cooled and methanol (250 mL) was added. Subsequently, 250 ml of 22% methanolic hydrogen chloride solution are added dropwise at 18-20 ° C. The mixture was stirred at the same temperature for 1.5 hours. The precipitated sodium chloride was collected by filtration and 80 ml of water were added to the filtrate. The filtrate was then adjusted to pH 3.5-3.7 with pyridine. The precipitated crystals were collected by filtration, washed with water and methanol and dried. Thus 33 g of (6R, 7R) -7-amino-3- (l-pyridiniomethyl) -3-cephem-4-karboxilát.HJ.H ₂ O product.

160-163 ° C (dec.).

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Claims (3)

A process for the preparation of (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (oxyimino) acetamido] -3- cephem-4-carboxylic acid derivatives or pharmaceutically acceptable salts thereof R * is hydrogen or lower alkyl, R _{2 is} acetoxy or (1-methyl-1H-tetrazol-5-yl) thio and R ^{3 is} carboxy; obsession R ^{2 is} a group of formula (a) and R ^{3 is} -COO ', while Y is a hydrogen atom, a hydroxymethyl group or a carbamoyl group, and n is a number 2 or 3, characterized in that one of the (Z) -2-aminothiazolyl-2 compounds of formula II - (substituted-oxyimino) -acetic acid, wherein R ¹ and n are as defined above, or a reactive derivative thereof, by condensation with (6R, 7R) -7-amino-3-cephem-4-carboxylic acid of formula (III), wherein R ^{4 is a} carboxy group or a protected carboxy group when R ^{2 is an} acetoxy group or (1-methyl-1 H -tetrazol-5-yl) thio; or R ⁴ is -COO when R ^{2 is} a group of formula (a) and Y is as defined above, then when R ^{4 is a} protected carboxy group, the protecting group is removed from the resulting product and desired converting the product into a pharmaceutically acceptable ⁵ salt thereof. Process according to Claim 1, characterized in that a free form of (Z) -2-amino-thiazole- ^10- zol-2-substituted-oxyimino-acetic acid has the general formula (III). (6R, 7R) -7-amino-3-cephem-4-carboxylic acid or a salt thereof in the presence of a dehydrating agent in a solvent at -30 ° C to 20 ° C And the condensation reaction of the reactive derivative of the compound (II) with the compound (III) or a salt thereof, in the presence or absence of an acid acceptor, at a temperature of -30 to 20 ° C in a solvent. The process according to claim 1, which is (6R, 7R) -7-1 (Z) -2- (2-aminothiazol-4-yl) -2 - [((3S) -225-pyrrolidon-3-yl). ) -oximino-N-acetamido} -3- (1-pyridinomethyl) -3-cephem-4-carboxylate or a pharmaceutically acceptable salt thereof, characterized in that starting materials are used wherein R ^{1 is} hydrogen and n is R ^{2 is} pyridino and R ^{4 is} carboxyl, respectively. 1 page drawing with formulas