LT3870B - Diastereomers of 3-cefem-4-carboxylic acid 1-(isopropoxy-carbonyloxy)ethyl ester, process for preparingthereof, antibacteric preparations based on same and process for preparation thereof - Google Patents

Abstract

The described diastereoisomers, i.e. I formula (6R, 7R)-7-[2-(2-aminotiazole-4-il)-2-(Z) - methoxyimino) acetamide]-3-(methoxymethyl)-3-cephem-4-carboxylic acid diastereoisomers, are resorbed in the intestines<IMAGE>(I) and their physiologically proper salts and the diastereomerically pure salts of the compounds of the II formula<IMAGE>(II) where HX is monobasic or a multi-basic acid and X is an inorganic or organic physiologically proper anion. The production method of these compounds differs only by the fact that pouring the solution of 1 is equivalent of the formula I mix of diastereoisomers with a HY acid 0.2-2 equivalent in the beginning a less soluble formula IV diastereoisomer is precipitated and filtered and then a more soluble formula IV diastereoisomer is precipitated from a filtrate. Besides that, the HY acid in consecutive stages may be uniform or different and various HY acids may be added in any order. The produced salts in case of need are cleaned additionally by crystallisation.

Description

The present invention relates to intestinal resorbable (6R, 7R) -7- [2-aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3- (methoxymethyl) -3-cephem-4-carboxylic acid 1- (isopropoxycarbonylhydroxy) ethyl ester. for diastereomers (formula I)

II II

N

C-CONH

CO ₂ CHOCOC (CH ₃ ) ₂ (I)

H ₃ C oh their physiologically active salts and the manner in which they are obtained.

U.S. Pat. No. 4,486,425 describes esters of (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3- (methoxymethyl) -3-cephem-4-carboxylic acid. Particularly interesting is the Formula I ester because it is well absorbed by the gut of various animals and humans and is rapidly and completely degraded by the enzymes of the body after resorption.

Concomitant formation of antibiotically active cephalosporin with free carboxyl groups. This compound is known by the name cefpodoxymproxetil (Drugs of the Future 14, 73 (1989)).

The ester of formula I has 2 asymmetric carbon atoms of the (R) -configuration at the 6 and 7 positions of the cephem configuration and an asymmetric carbon atom at the 1 -O-CH- (CH ₃ ) -O- position of the ethyl oxyester group.

The compounds described in U.S. Patent 4,486,425 are obtained in the form of mixtures of diastereomers with 1-ethyloxyester group.

-O-CH- (CH ₃ ) -O- with respect to the asymmetric carbon atom.

Analogous diastereomeric mixtures are, for example, cefotiam-heksetilo (Drugs of the Future 13, 230 (1988)), cefuroxime-axetil (Drugs of the Future 10, 112 (1985)) bakcefuzonamo (NA Kuck et al. Proc 14 ^th Int Congr. Chemother 2, 1137 (1985)) and BMU 28271 (The Journal of Antibiotics 4 3, 1564 (1990)).

According to the current understanding of the mechanism of resorption of cephem derivatives of this kind, the configuration of the -OCH (CH ₃ ) O-group in the 1-position of the ethyl ester does not influence the amount of compound absorbed in the intestine. This has been experimentally proven in the case of cefotiam-hexethyl diastereomers (T. Nighimura et al., The Journal of Antibiotics 40, 81-90 (1987)).

In the case of cefothiam-hexethyl, the two stereoisomers are separated by chromatography. However, the use of this method is very detrimental and therefore not always acceptable since both diastereomers, such as cefpodoxymproxetil, are very close in physical properties and difficult to separate by chromatography. In addition, both stereoisomers or a mixture thereof may be cleaved by column chromatography.

Therefore, individual diastereomers of cefpodoxymproxetil have not yet been described. There are also no preparative methods for the purposeful preparation of individual diastereomers of the cephalosporin ester class of prodrugs in the 1-ethyloxyester -O-CH / CH ₃ -alkyl derivative, such as cephaphodoxymproxetil.

As a result, it has been unexpectedly found that individual diastereomers of Formula 1 show marked differences in their intestinal absorption, with better resorbable diastereomers being more bioactive than cefpodoxymproxetil in a mixture of diastereomers.

Thus, the present invention relates to diastereomerically pure compounds of formula I wherein the = N-OCH ₃ group is in the syn position. Of the two diastereomers, the more polar, biologically more active diastereomer is preferred.

The present invention also relates to diastereomerically pure salts of the general formula II

N-C — CONH to i u l

HZV <Z x ^2OCH3

HX

CO CHOCOC (CH ₃ ) ₂

H ₃ C oh or polybasic acid, and X nowhere HX is a single-base organic or organic physiologically acceptable anion.

In the case of inorganic acid, HX is, for example, the stoichiometric amount of HCl, HBr, HJ, HBF ₄ , HNO ₃ , HCl ₄ , H ₂ SO ₄ or H ₃ PO ₄ . In the case of organic acid, HX is an aliphatic or aromatic acid. Preferred are inorganic acids HCl, HBr, and H ₂ SO ₄ , as well as organic: methanesulfo-, ethanesulfo-, benzenesulfo-, p-toluenesulfo- and

4-Ethylene-benzenesulfonic acid.

The present invention also relates to a process for the preparation of diastereomerically pure compounds of formula I, characterized in that it provides a compound of formula III

H _a N-x'-CH.OCH_

Z ^{2 3}

CO ₂ CHOCOC (CH ₃ ) ₂ [III]

H ₃ C oh or an intermediate of formula IV h ₂ n / ^s x

I-n J-CHpOCH VX ² CO_CHOCOC (CHQ) ² | II

HgC O H

HY t IV] in the form of pure diastereomers, converting them into pure diastereomers of formula I or II.

The pure diastereomers of formula I thus obtained are converted into the salts of formula II by known methods for the preparation of analogous compounds.

The compound of formula I or salts of formula IV thereof are prepared by known methods, such as those described in Japanese Patent Application 60,004,190A. The method described in this application provides a mixture of diastereoisomers.

The resulting diastereoisomers are separated by crystallization of the salts of formula IV by fractional crystallization. In formula IV, HY represents a monobasic or polybasic acid, wherein Y is an inorganic or organic anion.

In the case of an inorganic acid, HY is e.g. HCl, HBr, HJ, HF, HNO ₃ , HClO ₄ , HSCN, H ₂ SO ₄ or H ₃ PO ₄ . In the case of organic acid, HY is an aliphatic or aromatic sulfuric acid, a carboxy and a phosphonic acid. For example, the following organic acids may be used: benzenesulfo-, ptoluenesulfo-, 4-ethylbenzenesulfo-, 4-chlorobenzenesulfo-,

4-bromobenzenesulfo, 2-mesitylenesulfo-, 4-diphenylsulfonaphthalene-1,5-disulfo-, methanesulfo-, ethanesulfo-, dodecylsulfo-, camphorsulfonic acid, and oxalic acid.

Most preferred are HCl, HBr, benzenesulfonic, p-toluenesulfonic, 4-ethylbenzenesulfonic and 4-diphenylsulfonic acid.

The salts of formula IV are obtained by mixing solutions of diastereoisomers of formula III and HY acid. Organic solvents used are esters and ethers, alcohols, ketones, nitriles, chlorinated hydrocarbons, hydrocarbons and mixtures thereof. Preferred solvents are benzene, toluene, ethyl acetate, butyl acetate, methanol, ethanol, n-propanol, isopropanol, tert-butanol, diisopropyl ether, acetone, acetonitrile and dichloromethane, and mixtures thereof.

In the case of inorganic acids, if the organic solvent is soluble in water, the solvent is also water. HCl and HBr solutions in organic solvents are obtained by passing gaseous hydrogen chloride or hydrogen bromide. HCl and HBr solutions in organic solvents are also obtained from acetyl halides, phosphorus halides and phosphorus oxyhalides and alcohol (halogen = Cl, Br).

The ratio of the base to the acidic component of the formula I is very important for the separation of the diastereoisomers. Preferably, the equivalent of the mixture of diastereoisomers of formula III is 0.2 to 2.0, most preferably 0.4 to 1.5 equivalents of the acidic component.

In the proposed process, it is important that the pure diastereoisomers of formula IV are precipitated in two successive steps. For example, by mixing a solution of a mixture of diastereoisomers of formula I with a solution of the acidic HY component, the less soluble diastereoisomer of formula IV is initially precipitated and filtered, and the more soluble diastereoisomer of formula IV is precipitated from the filtrate. In successive partial steps, the acidic component HY may be the same or different, and the different acidic HY components may be added in any order. For example, when the acidic HY component is correctly selected, the more polar less soluble diastereoisomer of Formula IV is initially precipitated or, conversely, the initially less polar diastereoisomer.

When the acidic component is selected, both diastereoisomers of formula IV are obtained in pure form. For example, using hydrochloric acid or hydrogen bromide initially yields a more polar diastereoisomer, whereas the use of benzenesulfonic, 4-ethylbenzenesulfonic, diphenylsulfonic or p-toluenesulphonic acid results in less polar diastereoisomers.

After filtration, the salts obtained are crystallized, if necessary, using the solvents and mixtures thereof mentioned above. The optimum solvent is selected depending on the acidic component used. For example, methanol, ethanol, n-propanol, isopropanol, acetonitrile, ethyl acetate, and dichloromethane are preferred solvents for the p-toluenesulphonic acid and hydrochloride salt.

The acidic component is added at -10 to + 50 ° C, preferably + 10 to + 30 ° C. Depending on the acidic component used and the type of solvent used, the mixture is further stirred for 10 hours until complete dissolution. In some cases, the mixture is cooled to -70 ° C to achieve complete precipitation.

In another embodiment, mixtures of diastereoisomers of Formula I may be prepared from compounds of Formula V

CO ₂ CHOCOC (CH ₃ ) ₂

H ₃ C oh

[V]

II

In this formula, the R ¹ group is an amino protecting group common in peptide chemistry, such as formyl, tert-butoxycarbonyl, chloroacetyl, phenoxyacetyl, phenylacetyl, allyloxycarbonyl, benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

The cleavage of the protecting group is carried out in known ways. For example, the formyl and tert-butoxycarbonyl groups are cleaved by acid. The phenoxyacetyl and phenylacetyl groups are cleaved by phosphorus pentachloride or penicillinase enzyme. The allyloxycarbonyl group can be cleaved by Pd [P (C ₆ H ₅ ) ₃ ] ₄ . Benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups are hydrolytically removed.

Cleavage of the phenoxyacetyl or phenylacetyl group with the aid of phosphorus pentachloride without addition of hydrogen chloride gives more polar diastereoisomers. The source of hydrochloric acid is the slow release of phosphoric acid esters, chlorine anhydrides, which are not eliminated during processing.

Using the starting compounds of Formula V, the diastereoisomerically pure compounds of Formulas I or IV may be obtained by first separating the diastereoisomers, followed by cleavage of the protecting group and an excess of the HY acidic component to precipitate the mixture of diastereoisomers of Formula IV. The diastereoisomers of formula V can be separated by crystallization or chromatography, and conditions are selected depending on the protecting group R ¹ . For example, when R ¹ is a phenoxyacetyl group, the diastereoisomers are separated by chromatography on silica gel using a mixture of organic solvents as eluents.

The diastereoisomerically pure salts of formula IV are known to yield the diastereomerically pure 3870 B nos bases of formula II, which are converted into the pure diastereoisomers of formula I as described, for example, in Japanese Patent Application No. 60,004,189A.

For this purpose, diastereoisomerically pure compounds of formula I may be exposed, for example, to compounds of formula VI

N-C-COZ

I I 1

R ¹ ™ / ν ' ^{N OCH} 3 wherein R ¹ is a hydrogen atom or as defined in the compounds of formula V and Z is a conventional activating group in beta-cyano-chemistry, e.g., chloride, p-toluenesulfonyl, 1-benzotriazololyloxy or mercaptobenzothiazolyl.

An unexpected positive effect of the present invention is the increased intestinal resorption of the more polar diastereoisomer of Formula I as illustrated in Table 1.

Table I

Type of diastereoisomer The amount of diastereoisomer found in the analysis

Diastereoisomer A (Example 7) 25%

Diastereoisomer B (Example 8) 45% of Table 6 contains (6R, 7R) -7- [2-aminothiazol-4-yl) -2 (Z) - (methoxyimino) acetamide] -3- (methoxymethyl) -3-cephem-4-carboxylic acid amount found in the urine of dogs from 0 to 24 hours following oral administration of the diastereoisomeric proLT 3870 B pharmaceutical formulation (dose: 10 mg / kg converted to a biologically active substance).

The compounds of the formula I according to the present invention are administered orally in the form of conventional pharmaceutical preparations such as capsules, tablets, powders, syrups or suspensions. The dose depends on the age, symptoms and weight of the patient as well as the duration of treatment.

However, as a rule, it amounts to about 0.2 g to

5 g, appropriate about 0.5-3 g per day. It is best to administer the compounds in divided doses, e.g., 2-4 times per day, so that a single dose may contain, for example, 50-500 mg of the biologically active substance.

Oral compositions may contain conventional carriers and / or diluents. For example, binders such as gelatin, sorbitol, polyvinylpyrrolidone or carboxymethylcellulose, diluents such as lactose, sugar, starch, calcium phosphate, or polyethylene glycol, lubricating agents such as stearate or sodium may be used in capsules or tablets. Liquid compositions such as aqueous or oily suspensions are suitable for syrups or other similar forms.

The following examples illustrate the preparation of diastereomerically pure compounds of formulas I and II according to the present invention, but are not intended to limit the scope thereof.

io

The experimental part

Example (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester p-toluenesulfonate (mixture of diastereoisomers)

1.23 g (5 mmol) of (6R7R) -7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid are suspended in 15 ml of dichloromethane under argon and completely dissolved by adding 0.75 ml (5 mmol) of DBU *. To the resulting solution at 0 ° C was added 1.3 g (5.5 mmol) of 1-iodoethoxy / isopropoxycarbonyl ester (The Journal of Antibiotics, 40, 370, (1987)), and the mixture was stirred for 40 min at 0 ° C and 30 min. Dilute to 50 ml with ethyl acetate at 20 ° C and continue working. The mixture was washed with a saturated aqueous solution of NaHCO ₃ and NaCl, dried over MgSO ₄ , and the organic solvent was evaporated in vacuo. The crude product was dissolved in 5 mL of ethyl acetate and 1.6 g (5.3 mmol) of p-toluenesulfonic acid monohydrate solution was added to the resulting solution at 20 ° C.

5 ml of ethyl acetate. After addition of 10 ml of diisopropyl ether, the mixture is cooled to 0 ° C and the product precipitate is filtered off.

Yield: 1.23 g (71% of theory).

¹ H-NMR (DMSO-d ₆ , 270 MHz): d = 1.25 (m, 6H, C (CH ₃ ) ₂ ), 1.50 (d, 3H, CH-CH ₃ ), 2.30 (s. 3H, aryl-CH ₃ ), 3.23 (s. 3H, CH ₂ OCH ₃ ), 3.70 (2H, m. S-CH ₂ ), 4.21 (m. CH ₂ O). OCH ₃ ), 4.81 (m, 1H, O-CH (CH ₃ ) ₂ , 5.25 (m, 2H, H-6, and H-7), 6.81 and 6.85 (2xkv ., 1H, O-CH (CH ₃ ) -O), 7.11 and

7.48 (2xquart., 4H, aryl-H), 9.05 (pi.s., 2H, NH ₂ ).

TLC (toluene: ethyl acetate = 1: 1).

R _f = 0.34 (diastereomer A) and 0.26 (diastereomer B).

High pressure liquid chromatography nukleozilas 7 pm C18, water (+ 0.1% NH ₄ OAc) + (methanol: water = 80:20) + 0.1% NH ₄ 0Ac) (45:55, 1 ml / min = 10.8 min (diastereoisomer A), 9.1 min (diastereoisomer B).

* 1,5 - Diazabicyclo [5.4.0 Jundek-5-ene.

Example (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (mixture of diastereoisomers).

According to the procedure described in Example 1, a mixture of 2.53 g (4.8 mmol) of diastereoisomers is dissolved in 5% aqueous NaHCO ₃ in ethyl acetate and stirred for 5 min. The layers are separated, the organic solvent layer is washed with saturated aqueous NaCl solution, dried over MgSO ₄ and evaporated in vacuo.

Yield: 1.74 g (100% of theory).

An example

I. (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester p-toluenesulfonate (Diastereoisomer A)

According to the procedure described in Example 2, 1.74 g (4.63 mmol) of the mixture of diastereoisomers are dissolved in 4 ml of ethyl acetate LT7070B and 0.44 g (2.3 mmol) of p-toluenesulphonic acid monohydrate in 3 ml of ethyl acetate are added. . 3 ml of diisopropyl ether are added to the mixture and the crystallized product is filtered off. The filtrate is treated according to method II described below in this example.

Yield: 0.904 g (36% of theory) of diastereoisomer A p-toluenesulfonate.

¹ H-NMR (DMSO - d ₆ , 270 MHz): d = 1.25 (mm, 6H (C (CH ₃ ) ₂ )),

1.50 (d, 3H, CH-CH ₃ ), 2.30 (s, 3H, aryl-CH ₃ ), 3.23 (s., 3H, CH ₂ OCH ₃ ), 3.69 (2H, AB quartet, S-CH ₂ ), 4.21 (m, CH ₂ OCH ₃ ), 4.79 (m., 1H, O-CH (CH ₃ ) ₂ ), 5.25 (m, 2H, H-6, and H-7), 6.81 (sq. 1H, O-CH (CH ₃ ) -O), 7.11 and 7.48

(2xd., 4H, aryl-H), 8.9 (pi s, 2H, NH ₂ ).

TLC (toluene: ethyl acetate = 1: 1).

R _f = 0.34.

High pressure liquid chromatography nukleozilas 7 pm C18, water (+ 0.1% NH ₄ OAc) + (methanol: water = 80:20) + 0, 1% NH ₄ 0Ac) (45:55, lml / min = 10 , 8 min (diastereoisomer A).

II. (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester p-toluenesulfonate (diastereoisomer B).

The filtrate obtained according to method I of this example is mixed with 0.44 g (2.32 mmol) of a solution of p-toluenesulfonic acid monohydrate in 3 ml of ethyl acetate and the precipitate formed is filtered off.

Yield: 0.534 g (21% of theory) of diastereoisomer B p-toluenesulfonate.

¹ H-NMR (DMSO - 270 MHz): d = 1.25 (m, 6H, C (CH ₃ ) ₂ ), 1.50 (d, 3H, CH-CH ₃ ), 2.30 (s, 3H) , aryl-CH ₃ ), 3.23 (s., 3H, CH ₂ OCH ₃ ), 3, 69 (2H, m. S-CH ₂ ), 4.21 (m, CH ₂ OCH ₃ ), 4.79 (m, 1H, O-CH (CH ₃ ) ₂ ), 5.25 (m, 2H, H-6, and H-7), 6.84 (sq • r 1H, O-CH (CH ₃ ) -O), 7.11 and 7.48

(2d, 4H, aryl-H), 89 (p. S, 2H, NH ₂ ).

Thin layer chromatography (toluene: ethyl acetate 1: 1).

R _f = 0.26.

High performance liquid chromatography, 7 µm water + (0.1% NH ₄ OAc) + (methanol: water = 80:20) + 0.1% NH ₄ OAc) (45:55, 1 mL / min = 9.1 min (diastereoisomer B).

Example (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyl) ethyl ester hydrochloride (diastereoisomer B)

According to the method described in Example 2, 1.71 g (4.57 mmol) of the mixture of diastereoisomers are dissolved in 4 ml of ethyl acetate and 0.914 ml (2.28 mmol) of 2.45 ml of isopropanolic hydrochloric acid solution are added to the resulting solution. The precipitate is filtered off and the filtrate is used for further work according to Method II of this Example.

Yield: 0.628 g (41% of theory) of diastereoisomeric hydrochloride B.

¹ H-NMR (DMSO-d ₆ , 270 MHz): d = 1.25 (m, 6H, C (CH ₃ ) ₂ ), 1.48 (d, 3H, CH-CH ₃ ), 3, 23 (s., 3H, CH ₂ OCH ₃ ), 3.68 (2H,

m. S-CH ₂ ), 4.21 (s., CH ₂ OCH ₃ ), 4.81 (m, 1H, O-CH (CH ₃ ) ₂ ),

5.21 (sq., 2H, H-6 and H-7), 6.85 (sq., 1H, O-CH (CH ₃ ) -O),

9.2 (pi s, 2H, NH ₂ ).

TLC (toluene: ethyl acetate = 1: 1).

R _f = 0.26.

High pressure liquid chromatography nukleozilas 7 pm C18, water (+ 0.1% NH ₄ OAc) + (methanol: water = 80:20) + 0.1% NH ₄ OAc) (45:55, 1 ml / min = 9.1 min (diastereoisomer B).

II. (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyl) ethyl ester p-toluenesulfonate (Diastereoisomer A)

In the example obtained, the filtrate obtained according to method I is mixed with 0.573 g (3.0 mmol) of a solution of p-toluenesulfonic acid monohydrate in 3 ml of ethyl acetate and the precipitate formed is filtered off.

Yield: 0.902 (36% of theory)

Diastereoisomer A, p-toluenesulfonate, identical to Example 3, Method I product.

Example (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (diastereoisomer A)

According to Example 4, Method II, 4.33 g (8.8 mmol) of the diastereoisomer is dissolved in 80 mL of ethyl acetate and 155 mL of water, 0.96 g (11.45 mmol) of NaHCO _{3 is added} and stirred for 5 min. The layers are separated, the organic solvent is washed with saturated NaCl solution, dried over MgSO _4, and concentrated in vacuo.

Yield: 3.29 g (100% of theory).

Example (6R, 7R) -7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (diastereoisomer B).

In Example 4, Method I, 4.99 g (12.0 mmol) of diastereoisomer B is dissolved in 110 mL of ethyl acetate and 219 mL of water by adding 1.36 g (16.28 mmol) of NaCO ₃ and the solution is stirred for 5 min. The layers are separated, the organic solvent is washed with saturated NaCl solution, dried over MgSO ₄ and concentrated in vacuo.

Yield: 4.49 g (100% of theory).

Example (6R, 7R) -7- [2- (2-Aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (Diastereoisomer A)

According to Example 5, 3.29 g (8.8 mmol) of diastereoisomer A are dissolved in 22 ml of dry dichloromethane under argon and 3.19 g (9.11 mmol) are added to the resulting solution.

2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) mercaptobenzothiazolyl acetate. The suspension is stirred for 1 h at 20 ° C, diluted with 200 mL of ethyl acetate, extracted twice with water, dried over MgSO ₄ , and the solvent is evaporated off under vacuum. The resulting residue was purified by chromatography on a SiO ₂ column eluting with toluene / ethyl acetate.

Yield: 1.1 g (22% of theory) of diastereoisomer A.

¹ H NMR (DMSO - d ₆ , 270 MHz): d = 1.23 (dd, 6H (C (CH ₃ ) ₂ )),

1.49 (d., 3H, CH-CH _3), 3.21 (s., 3H, CH ₂ OCH _3), 3.48 (2H, AB q., S-CH _2), 3.83 ( s., 3H, N-OCH ₃ ), 4.14 (s.

CH ₂ OCH ₃ ), 4.80 (m, O-CH (CH ₃ ) ₂ ), 5.21 (d, 1H, H-6), 5.82 (dd, 1H, H- 7), 6.72 (s., 1H, thiazole-H), 6.80 (sq., 1H, O-CH (CH ₃ ) -O), 7.2 (pi., 2H, NH _2). ), 9.59 (d, 1H, CONH.

High Pressure Liquid Chromatography, 7 mu m C18 nukleozilas water + 1,2 dimethoxyethane (+ EDTA 10 mg / 1, + 0.2% N-methylmorpholine + HC1O _4, pH 3.34) 68: 32,

1.5 mL / min, 12.6 min (diastereoisomer A).

Example (6R, 7R) -7- [2- (2-Aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (Diastereoisomer B)

According to Example 6, 4.59 g (12.0 mmol) of the diastereoisomer is dissolved in 30 ml of dry dichloromethane under argon and 4.39 g (12.42 mmol) is added to the resulting solution.

2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) mercaptobenzothiazolyl acetate. The suspension is stirred for 1 hour. At 20 ° C, dilute to 200 ml with ethyl acetate, extract twice with water, dry over MgSO ₄ and evaporate the solvent in vacuo. The residue is purified by chromatography on a SiO ₂ column eluting with toluene / ethyl acetate.

Yield: 4.6 g (69% of theory) of diastereoisomer B.

1 H-NMR (DMSO - d ₆ , 270 MHz): d = 1.25 (dd, 6H,

C (CH ₃ ) ₂ ), 1.50 (d, 3H, CH-CH ₃ ), 3.21 (s, 3H, CH ₂ OCH ₃ ), 3.53 (2H, AB quartz, S- CH ₂ ), 3.85 (s, 3H, N-OCH ₃ ), 4.14 (s, CH ₂ OCH ₃ ), 4.81 (m, 1H, O-CH (CH ₃ ) ₂ ). , 5.19 (d, 1H,

H-6), 5.81 (dd, 1H, H-7), 6.72 (s, 1H, thiazoleH), 6.83 (sq., 1H, O-CH (CH ₃ ) - 0), 7.2 (pi s, 2H, NH ₂ ),

9.59 (d, 1H, CONH).

High Pressure Liquid Chromatography, 7 mu m C18 nukleozilas water + 1,2 dimethoxyethane (+ EDTA 10 mg / 1, + 0.2% N-methylmorpholine + HC1O _4, pH 3.34) 68:32,

1.5 mL / min, 9.7 min (diastereoisomer B).

Example (6R, 7R) -7- [2-) _2- Aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy) ethyl ester (mixture of diastereoisomers, cefpodoxymproxetil)

4.26 g (17.5 mmol) of (6R, 7R) -7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid are suspended in 40 ml of dichloromethane under argon and completely dissolved by adding 2.65 g (17 , 5 mmol) DBU. To the resulting solution at 0 ° C was added 4.96 g (19.2 mmol) of 1-iodoethyloxyisopropoxycarbonyl ester (The Journal of Antibiotics 40, 370 (1987)) and the mixture was stirred for 60 min at 0 ° C and 20 min at 20 ° C. at temperature. 6.4 g (18.3 mmol) of 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) mercaptobenzolyl acetate are added, the suspension is stirred at 2 or 20 ° C, diluted with 200 ml of ethyl acetate, Extract several times with water, dry and evaporate the solvent in vacuo. The residue was purified by chromatography on a column of chromatoLT 3870 B eluting with toluene / ethyl acetate.

Yield: 3.42 g (35% of theory) of 5 A + BC diastereoisomer mixtures.

¹ H-NMR (DMSO - d ₆ , 270 MHz): d = 1.25 (m, 6H, C (CH ₃ ) ₂ ),

1.49 (m., 3H, CH-CH _3), 3.21 (s., 3H, CH ₂ OCH _3), 3.54 (2H, AB q., S-CH _2), 3.85 ( s., 3H, N-OCH ₃ ), 4.14 (s.

CH ₂ OCH ₃ ), 4.80 (m, 1H, O-CH (CH ₃ ) ₂ ), 5.21 (m, 1H, H-6),

5, 82 (m., 1H, H-7), 6.72 (s, 1H, thiazole-H), 6, 80 and 6, 83 (double sq. , 1H, O-CH (CH ₃ ) -O), 7.2 (pi., 2H NH ₂ ), 9, 60 (m., 1H, CONH).

High Pressure Liquid Chromatography, 7 mu m C18 nukleozilas water + 1,2 dimethoxyethane (+ EDTA 10 mg / 1, + 0.2% N-methylmorpholine + HC1O _4, pH 3.34) 68:32,

1.5 mL / min, 12.6 min (diastereoisomer A), 9.7 min (diastereoisomer B).

Claims (8)

DEFINITION OF INVENTION (6R, 7R) -7- [2- (2-Aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamide] -3- (methoxymethyl) -3-cephem-4-carboxylic acid 1- ( isopropoxycarbonyloxy) diastereoisomers of the ethyl ester of formula I N II II CO ₂ CHOCOC (CH ₃ ) ₂ [I] H ₃ C oh and their physiologically acceptable salts. 2. Diastereomerically pure salts of the compounds of the formula II S N-C-CONH -, - / \ II II II COgCHOCOC (CH ₃ ) ₂ I II I HX [II] H ₃ C oh where HX is a monobasic or polybasic acid and X is an inorganic or organic physiologically acceptable anion. 3. Diastereomerically pure salts of the compounds of the formula II according to claim 2, characterized in that HX is HCl, HBr, H ₂ SO ₄ , methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic and 4-ethylbenzenesulfonic acid. 4. A process for the preparation of diastereomerically pure compounds of formula I or II according to claims 1-3, wherein the diastereomerically pure form of the intermediate of formula III is π ₂ ν10 '-χ'-CiT OCH ₀ ^{2 3} CO CHOCOC (CH _O ) _ I II I. H ₃ C oh [III] or an intermediate of formula IV H _a N20 I — N J-CH, OCH </ VX ^{2 3} CO ₂ CHOCOC (CH ₃ ) ₂ HY [IV], H ₃ C oh (where HY is a single or polybasic acid and Y is a non-25 organic or organic anion) converts to I or Pure diastereoisomers of formula II. 5. A process for the preparation of diastereomerically pure compounds of formula I or II according to claim 4, wherein the addition of 1 equivalent of a mixture of diastereoisomers of formula I to 0.2 to 2 equivalents of a HY acid solution first precipitates and filters the less soluble diastereoisomer of formula IV. followed by precipitation from the filtrate of the more soluble diatereo35 isomer of Formula IV, furthermore, during said sequential separation steps, the HY acid may be the same or different, and the various HY acids may be added in any order and the resulting salts may be further purified by crystallization. 6. Antibacterial pharmaceuticals containing 5 inert carriers and active ingredients, characterized in that the active ingredients are used. An effective amount of a diastereomerically pure compound of formula I or II according to claims 1-3. 10th 7. A process for the preparation of an antibacterial pharmaceutical preparation which comprises converting a diastereomerically pure compound of formula I or II according to claims 1-3 in combination with pharmaceutically acceptable carriers and / or diluents into a suitable dosage form. Diastereomerically pure compounds of formulas I and II according to claims 1-3 for use in combating bacterial infections.