CS268527B2 - Method of 7 beta-(carboxyalkenolamino)-3-cefem-4-carboxyl acids production - Google Patents

Abstract

Cephems and analogues of formula (I) are new. R = aryl or heterocyclyl; R1 = H or halogen; R2 = single bond, alkylene, oxa-alkylene or thia-alkylene- R3, R6 = H, salt-forming atom or gp. or ester-forming gp.; R4 = H or MeO; R5 = H or a 3-substituent as found in cephalosporins; X = O, S or SO. Provided that when R2 = thia-alkylene, then R1 = halogen. - Intermediates of formula (II) are new.

Description

CS 2Sfi52y β2! 1

The present invention relates to a process for the preparation of antibacterially active acids 7A - carboyalkenoylamino / 3-cephem-4-carboxylic acid of formula I

wherein R is phenyl or a 5 or 6 membered monocyclic hetero group having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted amino, optionally protected by a C 8 -C 15 arylalkyloxycarbonyl aralkyl moiety, an alkoxycarbonyl group C 2 -C 12 alkoxy, C 1 -C 8 alkanoyl, C 1 -C 8 haloalkyl, dimethyl tert-butylsilyl or p-nitrobenzal; R represents a hydrogen atom or a halogen atom, R 2 represents a single bond, an alkylene group having 1 to 3 carbon atoms which is optionally branched, or a thiomethylene group, R 3 and R 4 represent a hydrogen atom, a light metal atom, an alkyl group having 1 to 3 carbon atoms, Carbon atoms, C 2 -C 7 alkenyl optionally substituted by phenyl, C 7 -C 15 aralkyl optionally substituted by methyl, methoxy or nitro, or is alkanoyloxyalkyl of 2 to 12 carbon atoms, R 4 represents a hydrogen atom or a methoxy group, and X represents a -S-, -SO- or i-O- group, with the proviso that when R represents a thiaalkylene group, R 4 represents a halogen atom.

The individual groups present as substituents in the compound of formula (I) are now elucidated. R as a heterocyclic group is an optionally substituted five- or six-membered monocyclic ring containing 1 to 3 heterocyclic ring atoms selected from the group consisting of nitrogen, oxygen or a sulfur atom. Representative rings are pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidine, pyrazinyl, triazinyl and the like. Optional substituents are amino complexes which are optionally further substituted with an aralkyloxycarbonyl group having from 5 to 15 carbon atoms in the aralkyl moiety, an alkoxycarbonyl group having from 2 to 12 carbon atoms in the alkoxy moiety, an alkanoyl group having from 1 to 8 carbon atoms, a haloalkanoyl group from CS 268527 82 C 1 -C 8, dimethyl-tert-butylsilyl, methoxyethoxymethyl or p-nitrobenzal. Preferably, R is selected from the group consisting of phenyl, furyl, thienyl / oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thlazolyl, optionally protected aminothiazolyl, thiadlazoyl and aminothiadiazolyl. Of these, the eminothesolyl group optionally protected is most preferred. As the halogen atom is a fluorine atom, or a chlorine atom, especially a chlorine atom, is preferably a hydrogen atom. 2

The alkylene group R contains 1 to 3 hydrogen atoms and has a straight, unbranched chain. A preferred alkylene group is a methylene group.

The substituents R 5 and R 5 are in principle formed by a modified carboxy group, suitably a group forming! an ester or a salt-forming atom, as well as a carboxy-protecting group or a group forming! derivatives which are suitable for therapeutic purposes. Preferably, R 1 and R 2 represent a hydrogen atom, a light metal atom, in particular a sodium atom or a potassium atom, a C 1 -C 8 alkyl group, especially a methyl or tert-butylene group, C 2 -C 7 alkenyl which may be further substituted with phenyl, C 7 -C 15 aralkyl optionally substituted by methyl, methoxy or nitro, or C 2 -C 12 alkanoyloxyalkyl. Suitably, these substituents are benzyl, methylbenzyl, nitrobenzyl or some other group of similar nature falling within the scope of the formula I,

Protecting groups may not be present in the compounds of the invention, although this may be the case. The structure of such a group has no particular significance if the group can serve well for protection. Thus, the groups of the present invention may be present and may be a wide variety of equivalent groups.

Particularly Suitable Carboxy Derivatives Medically useful substances include light metal salts and pharmaceutically acceptable esters. Suitable lightweight metals are those which form physiologically acceptable ions and belong to Groups 1 to 3 of Periods 2 to 4 of the Periodic Table of Elements. Preferred light metals include lithium, magnesium, calcium in addition to the above-mentioned sodium and potassium. aluminum and the like. Pharmaceutically acceptable esters have an antibacterial effect on oral or parenteral administration, and include well-known alkyl esters or aralkyl esters substituted at the 1, 3 to 12 carbon atoms, such as alkanoyloxyalkyl esters, for example acetyloxyethyl esters, propionoloxy esters, acetoxymethylesters, pivoyloxymethylesters, apivaoyloxy and esters. ster.

Preferably, X represents a sulfur atom in the -S- form.

Both geometric isomers on the side chain 7-position are antibacterially effective. Among these, the antibacterials are more effective compounds having substituents R and R1 in the cis position, the other geometric Jsomer (trans) being suitable as an intermediate for the preparation of the corresponding cis isomer. The following is a summary of some representative compounds of Formula 1. However, this review is not intended to be exhaustive. 7 '- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-cephem-4-carboxylic acid, 7- [2- (2-aminothiazol-4-yl)] -4-carboxy-2-butenoylamino-3-methyl-3-cephem-4-carboxylic acid. 2- (2-Amino-thiazol-4-yl) -4-carboxy-2-butenoylamino-3-vinyl-3-cephem-4-carboxylic acid; . N - [2- (2-aminothiazol-4-yl) -4-kerboxy-2-butenoylamino] -3-trifluoropropenyl-3-cetyl-4-carbonylic acid; - [2-Aminothiazol-4-yl] -4-carboxy-2-butenoylamino] -3-acetoxymethyl-3-cephem-4-carboxylic acid, 7 - [2- / 2-8minothiazol-4 -yl] -4-kerboxy-2-butenoylemino-3- (3-carbamoyloxyinethyl-3-cephem-4-carboxylic acid) - N - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-inethoxyinethyl-3-cef - 4-carboxylic acid, 7 - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-methylthiomethyl-3-acetic acid 4-carboxylic acid, 7H-2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino} -3-cyanomethylthiomethyl-3-cephem-4-carboxylic acid, 7f-Q2 -aminothiazol-4-yl / 4-carboxy, -2-butenoylamino-3-pyridinioethyl-3-cephem-4-carboxylate, 7 ' - [2- (2-aminothoazol-4-yl) -4-carboxy-2] -butenoylamino-3-triazolylthiomethyl-3-cephem-4-carboxylic acid, 7'-2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino-7-thiadiazolylthiomethyl-3-cephem- 4-carboxylic acid, 7 N - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylaroin-3-methyltetrazolylthiomethyl-3-cephem-4-carboxylic acid, 7 - [2- (2-aminothiazol-4) -yl] -4-carboxy-2-butenoylartiino-3-methoxy-3-cephem-4-carboxylic acid; N- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-chloro-3-cephem-4-carboxylic acid; -4-yl-4-carboxy-2-butenoylamino-3- (3-fluoroethilthio-3-cephem-4-carboxylic acid) - N - [2- (2-aminothiazol-4-yl) -4-carboxy-2- butenoylainino-3-trifluoroethylthio-3-cephem-4-carboxylic acid, 7'-2- (2-aminothiazol-4-yl) -5-carboxy-2-pentenoylamino-7-cephem-4-carboxylic acid, 7 $ - 2- (2-aminothiazol-4-yl) -6-carboxy-2-hexenoylamino-3-cephem-4-carboxylic acid, 7-β- (2-aminothiazol-4-yl) -4-carboxy-2- pentenoyl nino-3-cephem-4-carboxylic acid, N-2- (2-aminothiazol-4-yl) -4-carboxy-4-methyl-2-pentenoylamino-3-cephem-4-carboxylic acid and 7- [2- (2-aminothiazol-4-yl) -4-carboxy-3-chloro-2-butenoyl-amino] -3-cephem-4-carboxylic acid. Certain compounds closely related to the compounds of the invention are disclosed in Japanese Patent Publication 10996/1967 and cocaine 57-93982 and Belgian Patents Nos. 816,408 and 888,389. These compounds do not, however, override the compound of Formula I in antibacterial, intrinsic or parenteral absorbability, you - mixing or similar characteristic properties. 4 EN 268527 82

Compounds of formula (I) are antibacterially active against aerobic Gram-positive bacteria (e.g., Bacillus cereus, Bacillus subtilis, Corynebacteruradiphtheriae, Staphyloxoccous aureus, Staphylococcus epidermidis, Streptococcus pneumonitis, Streptococcus pyogenes, Streptococcus viridans, enterococci) and gramnegativnimbacteria (e.g., Citrobacter diversus, Citrobacter) freundii, Enterobacter aerogens, Enterobacter cloacae, Escherichis coli, Haemophllus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Progeus morgani, Proteus vulgaris, Providencia rettgeri.Providencia stuartii, Pseudomonas aeruginosa, Salmonella typhi, Serratia marcescens.Shigella sonnei, Yersinia enterocolitica (including anaerobic bacteria), for example Bacteroid fragilis, Clostridium difficile, Clostridium perfringens, Eubaceterium lentum, Fusobacterium nucleatum, Propionibacterium spp, Peptostreptococci, Veillonella spp./.

Particularly high antibacterial activity against Gram-negative bacteria, high absorption, excretion, distribution and similar properties are clear. Compounds of formula (I) are administered orally, parenterally or topically at a daily dose of from 10 mg to 6 g and are desirably administered with conventional additives or coating agents, for example other antibacterial agents, as a medicament for the protection or treatment of bacterial infections. .

The compounds are useful as bactericidal, bacteriostatic, disinfectant or non-extraneous agents and are useful in the treatment or prevention of human, veterinary or poultry infections caused by sensitive Gram-positive or Gram-negative bacteria, including anaerobic bacteria. In addition, the compounds are useful as inhibitors of bacterial growth in a human, animal, plant or subject subject, growth-promoting food additive in a human or animal, or as a means for testing the susceptibility of bacteria to antibacterially active compounds of Formula I.

The protected compounds of formula (I) are also suitable as starting materials for the synthesis of other antibacterially active compounds of formula (I).

A method of treatment or protection against human or veterinary bacterial infections such as abscess, bronchitis, dermatitis, ear infections, purulent inflammation, enteritis, gastroenteritis, nasopharyngitis, ceteomyelitis, pneumonitis, pneumonia, pustula, pyelonephritis, respiratory tract infections, rhinitis, septicemia, tonsils, ulcerations, urinary tract infections, soft tissue infections caused by susceptible bacteria, by administering an effective amount of a compound of formula I at a usual daily dose of 10 mg to 1 g externally, 0.2 to 5 g intravenously or 0, 1-2 g orally at a time interval of 3 to 12 hours, depending on the infectious bacterium in the patient's condition and, if desired, treated with conventional additives.

The carboxylic acid compound (I) or its light metal salt may be administered by injection or infusion intravenously, intramuscularly or subcutaneously, for example as an injection or pellet, or orally as an oral preparation, for example a capsule, dry syrup, emulsion , granules, powder, solution, suspension, tablet or twist, and, if desired, in admixture with an adjuvant, for example, an emulsifying agent. The pharmacologically active ester may be administered intravenously, iotramuscularly, subcutaneously, orally, externally or locally, for example, as an ear, nasal or ocular drug, ointment, inhalant, injection, mash, spray or suppository. 2

When R is 2-amino-4-thiazolyl, R is methylene, X is as defined in formula I, and the other substituents are each hydrogen, the compound of formula I is absorbed orally as well as subcutaneously. Pharmaceutically acceptable esters are also absorbed by the gastrointestinal tract.

The present invention also relates to an antibacterially active pharmaceutical composition. Which comprises a compound of formula (I) in various enteral or parenteral dosage forms, alone or in admixture with carriers or coating agents. These compositions may contain from about 0.01% to about 99% of a compound of Formula I dissolved, dispersed or suspended in solid or liquid pharmaceutical carriers.

The pharmaceutical compositions may be present as solid compositions, for example, capsules, dry syrup, granules, pellets, pills, powder, lace, twists, or tablets, or liquid compositions, for example, dispersion, elixir, emulsion, inhelant, injection, ointment, suspension, syrup, solution from a vial or diol containing crystals, lyophilized material or powder. These may be flavored or colored from the capsule, the granules and tablets may be coated. These funds may be in the form of a unit dose.

The carriers must be innocuous in both the compound of formula 1 and when administered to a patient. Representative examples of such carriers are outside the scope of the present invention. for solid compositions binders such as gum arabic, carboxymethylcellulose, gelatin, glucose, polyvinylpyrrolidone, sodium alginate, sorbitol, starch, syrup or tragacanth, wetting agents such as bentonite, calcium carbonate, phosphate calcium, glycine, kaolin, lactose, polycarboxymethylene, sodium chloride, sorbol, starch, sugar or talc, diluents, for example calcium carbonate, kaolin, lactose, starch or sucrose, disintegrants such as agar, carbonates, sodium lauryl sulfate or starch, glidants for example boric acid, cocoa butter, magnesium stearate, paraffins, polyethylene glycol, silica, sodium benzoate, stearic acid or particulate and wetting agents. Such as, for example, hydroxypropylcellulose, for solvent solutions, for example, alcohol, buffer, methyl oleate, peanut oil, carbon black oil or water, emulsifying agents such as gum arabic, lethicin or sorbitan monooleate, suspending agents, for example, aluminum stearate gel, carboxymethylcellulose, gelatin , glucose, hydrogenated fats, hydroxyethylcellulose, methylcellulose, sorbitol or sugar syrup, buffers, dispersants and solubilizers, and preservatives, for example, methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate or sorbic acid, absorption promoters, for example glycine mono- or dodioctanoate, antioxidants, flavorings, analgesics, edible coloring agents, stabilizing agents and the like. All of the aforementioned pharmaceutically active compositions can be prepared by conventional methods. Some compounds of formula (I) which contain a methylene group as substituent R and other substituents of formula (I) are well absorbed by the gastrointestinal tract and are useful as oral cephalosporins. It should be noted that compounds of formula (I) which contain a single bond as substituent R, a diethylene or trimethylene group or those compounds which do not contain a 74-side chain are practically enterally non-absorbable. The amino-containing compounds R may form a salt when mixed with an acid, for example a mineral acid. Such as hydrochloric acid or carboxylic acid. As is trifluoroacetic acid.

It is therefore an object of the present invention to provide a process for the preparation of compounds of formula (I), wherein the cefem compound derivative of formula (II) (6) CS 268527 B2

wherein X, R 1, R 2, R 3, R 4, and R are as defined above and R 3 is a halogen atom or an alkanesulfonyloxy group having from 1 to 3 carbon atoms, and is optionally substituted with a 1 to 3 carbon atom and then optionally the product further deprotects the carboxyl and / or amino groups - if present - by treatment with a hydrohalic acid, trihaloacetic acid, thiourea, zinc and an acid or Lewis acid selected from the group consisting of aluminum halide, titanium halide and tin tetrachloride when needed in the presence of anisole and / or is converted to a salt by treatment with an aqueous alkali metal halide solution. In carrying out the process of the present invention, the compound of formula (II) is typically reduced with iododide in an inert solvent at a temperature between 0 and 80 ° C for 0.1 to 10 hours, to the corresponding cefem compound of formula (I).

C 1 -C 3 metal and alkanoic acid reduction may be carried out at room temperature, but generally also at a temperature ranging from -60 to +120 ° C, for 10 minutes to 10 hours, conventionally conducted in the presence of a solvent. In general, other conditions, such as mixing, shaking, closing the working space with inert gas or drying, may also be employed in carrying out the process of the present invention. Examples of typical solvents for the reaction are hydrocarbons such as pentane, hexane, octane, benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane or chlorobenzene, ethers such as diethyl ether, methyl isobutyl ether, dioxane or tetrahydrofuran ketones, for example acetone, methyl ethyl ketone or cyclohexanone, esters, for example ethyl acetate, isobutyl acetate or methyl benzoate, nitrated hydrocarbons, for example nitromethane or nitrobenzene, nitrols, for example acetonitrile or benzonitrile, amides such as formamide, acetamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, sulfo- xides, for example dimethylsulfoxide, carboxylic acids, for example formic acid, acetic acid, propionic acid, organic bases, for example diethylamine, triethylamine, pyridine, picoline, collidine or quinoline, alcohols such as methanol, ethanol, propanol, hesanol, octano 1 or benzyl alcohol or water and other industrial solvents and mixtures thereof.

The products can be recovered from the reaction mixture by removing impurities, for example by dissolving the debris, unreacted starting materials or by-products, by conventional methods, for example extraction, evaporation, washing, concentration, precipitation, filtration or drying and isolation product by conventional processing, for example, adsorption, elution, distillation, precipitation, separation or chromatography, or a combination of these.

For the production of the starting sulfoxide, the cefem compound can be oxidized with an oxidizing agent such as hydrogen peroxide, a percarboxylic acid or iodobenzene dichloride in an inert solvent at 0 to 60 ° C for 0.2 to 5 hours corresponding to cefem-1-oxide In the Examples, "parts" refer to parts by weight and "equivalent" to molar equivalents of the lactam starting material. The symbols "cis" and "trans" refer to the relative position of the amide and carboxyl substituents attached to the double bond of the side chain. The chemical chemical constants of the products are summarized in the tables, where the IR is a mixture of geometric isomers.

Usually the reaction mixture is. If necessary, after addition of a solvent, for example water, acid or dichloromethane, wash, dry and evaporate and separate the product. All evaporation is carried out under reduced pressure.

Abbreviations have the following meanings: AOM acetoxymethyl BK diphenylmethyl

Bu butyl BOC tert-butyloxycarbonyl

Bzl benzyi

Chz benzyloxycarbonyl ring in the hetero ring of the structural formula exo

Me

MEM

Ph

PMB

PNB

POM aromatic ring double bond at the 3,4-position isomer position in the acyl side chain at the 7-methyl methoxyethoxymethylphenyl p-methoxybenzyl p-nitrobenzyl pivoloyloxymethyl position Example 1 1. A solution of the tert-butyl ester, p-methoxybenzyl ester or diphenylmethyl ester of the compounds of of Table 1 in a mixture of 0.3 to 3 parts of dichloromethane, 0.3 to 3 parts of trifluoroacetic acid and 0.5 to 5 parts of anisole are stirred for 10 minutes to 3 hours at -10 to + 40 ° C. The solution was evaporated to remove solvent and reagent. The residue is washed with benzene or ether to give the corresponding acid in 70-90% yield. 3. To a solution of tert-butyl ether, benzyl ester, p-methylbenzyl ester, p-methoxybenzyl ester or diphenylmethyl ester listed in Table 1 with 5 to 9 parts of dichloromethane and 2 to 8 parts of anisole are added 3 to 12 equivalents of titanium tetrachloride under temperatures between -10 and + 10 ° C and the mixture is stirred for 1 to 24 hours. The mixture was washed with dilute hydrochloric acid and water, dried and evaporated to give the corresponding free acid in 80-95% yield. When tert-butoxycarbonylamino, N-tert-butoxycarbonyl-N-methoxyethoxymethylamino or benzyloxycarbonylamino is present, the protecting portion is removed to give the amino group. 3. To a solution of the tert-butyl ester, benzyl ester, p-methylbenzyl ester, p-methoxybenzyl ester or diphenylmethyl ester listed in Table 1, 5 to 6 parts of 90% 8 of CS 268527 B2 formic acid and 2 to 3 parts of anisole are added. The mixture was stirred at 50-60 ° C for 1-4 hours to give the corresponding carboxylic acid in 40-50% yield. 4. To a solution of the p-nitrobenzyl ester from Table 1 in 60 parts of dichloromethane is added 10 parts of acetic acid and 2 parts of zinc dust. After stirring for 2 hours at 0 ° C, the mixture was filtered to remove the solid, diluted with water and extracted with dichloromethane. The extract was washed with water and extracted with aqueous sodium bicarbonate solution. Wash the aqueous layer with hydrochloric acid until pH 2 is reached and then extract with dichloromethane. The organic layer obtained is washed with water, dried and evaporated in vacuo. The corresponding free acid is obtained in a yield of 60 to 80%. 5. The same ester can be de-esterified by shaking with hydrogen in the presence of a small amount of 5% palladium on charcoal in dioxane at room temperature for 2 hours. 6. To a solution of 7- [2- (2-benzyloxycarbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino} -3- (14-methyl-5-tetrazolyl) thiomethyl-3-chloro-4-diphenylmethyl ester -carboxylic acid in 12 parts of anisole was added with 9 equivalents of aluminum chloride. After stirring at 0 ° C for four hours, the mixture was neutralized with 5% aqueous sodium hydrogen carbonate solution, the solid was removed with hydrochloric acid, washed with ethyl acetate and passed through a column packed with synthetic adsorbent [HP 20 or SP 207, produced by Mitsubishi Chemical KKJ]. eluting with 80% methanol to give 7- [2- (2-amino-4-thiazolyl) 4-carboxy-2-butenoylamino-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4 -carboxylic acid. The yield was 65%. 7. To a suspension of 7- [2- (2-benzyloxycarbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino] -3-pyridiniummethyl-3-cephem-4-carboxylic acid in 2 parts of anisole was added a solution of 9 equivalents of aluminum chloride in 2 parts of anisole at 0 ° C. After stirring for 3.5 hours, the mixture was acidified with 10% hydrochloric acid and washed with ethyl acetate. The aqueous layer is passed through a column filled with ion exchange [DiaionHP-20]. The adsorbed material is eluted with 5% acetone and the eluate is lyophilized. A yield of 55% yielded 7- [2- (2-amino-4-thiazolyl) -3-carboxymethylacrylamido] -3-pyridinomethyl-3-cephem-4-carboxylic acid. 8. In the same manner as above 1-7, the compounds listed in Table 3, which have a free carboxy group, are prepared from the corresponding carboxy-protected compounds listed in Table 1. Example 2 1. To a solution of the compound shown in Table 1 which contains ethanesulfonyloxy or chloro as substituent R 1, 10 parts of acetic acid and 2.5 parts of zinc dust are added in 13 parts of dichloromethane and the mixture is heated to 50 ° C after for 5 hours. The reaction mixture was filtered to remove the solid, diluted with ethyl acetate, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and water, dried and evaporated. The residue was purified by chromatography on silica gel eluting with benzene / ethyl acetate. The corresponding compound is obtained from Table 1 or 3, which contains hydrogen as R5 in a yield of 50 to 80%. 2. The reaction 1 described above is carried out at room temperature for 5 to 10 hours in the presence of 4 parts of isopropanol as diluent. The same product is obtained in a yield of 40 to 60%. 3. Add 6 equivalents of pyridine to a solution of diphenylmethyl 7'-2- (2-benzyloxycarbonylamino-thiazol-4-yl) -4-benzyloxycarbonylbut-2-enoylamino-3-hydroxy-cepham-4-carboxylate sulfoxide. and 6 equivalents of acetic anhydride. After stirring for 13 hours at 0 ° C, the mixture was mixed with 3 equivalents of triethylamine and stirred for 24 hours. The reaction mixture was washed with water, aqueous sodium bicarbonate solution and water, dried and evaporated. Diphenyl sulfoxide CS 268527 82 9 of methyl β-β-2- (2-benzyloxycarbonylamino-thiazol-4-yl) -4-benzyloxycarbonyl-2-butenoylamino "-3-cephem-4-carboxylic acid is obtained in a yield of 40-60% .

5 J (R = cyanomethylthiomethyl). 4. The bromomethyl-containing compound R 4 is treated in the same manner as described in Preparation 4 with sodium cyanomethyl mercaptide at 65-70 ° C for 2 hours. The corresponding compound of Table 1 is obtained, which contains cyanomethylthiomethyl as a substituent r5 in a yield of 50 to 60%. Example 3

Process for carrying out the sulfoxidation reaction

In the same manner as described in Example 4 below, using the same ratios of reaction compounds and solvents, the corresponding sulfoxide is reduced to the cephemous compound / sulfide / from Table 1. Example 4

Processes for the preparation of 3- [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenamido] -3-cyano-methylthiomethyl-3-cephem-4-carboxylic acid (5)

/ 1 /

/ 3/10 CS 268527 B2

CbzNH

COOBu-t COOCKFHG / 4 /

Ji Ji

C-CONH

II

CH

I CH2 i

COOH

CH 2 CH 2 CN / 57 1. To a solution of 340 mg of bromomethyl compound (2) produced by amidaciamine (1) in 3 ml of N, N-dimethylformamide was added an ethanolic solution of sodium cyanomethylmercaptide prepared from 71 mg at -70 ° C. sodium cyanomethylthioacetate and sodium ethoxide in ethanol. After stirring for 2 hours at 65-70 ° C, the mixture was poured into ethyl acetate, washed with water, dried and evaporated. The residue was purified by chromatography on silica gel, eluting with a 3: 1 mixture of benzene and ethyl acetate. An excess of 57.2% yielded an oxide (3). 2. To a solution of 690 mg of oxide (3) in 10 mL of acetone was added 883 mg of potassium iodide and 0.339 mL of acetyl chloride at -35 ° C. After stirring for 90 minutes at -20 to -25 ° C, the mixture is diluted with ethyl acetate, washed with dilute sodium thiosulfate solution and aqueous sodium bicarbonate solution, dried and evaporated to yield a sulfide (4) of 85.6%. 3. To a solution of 550 mg of sulfide (4) in 10 mL of anisole was added a solution of 1.24 g of aluminum chloride in 5 mL of anisole at -30 ° C. After stirring for 3 hours, the mixture was diluted with hydrochloric acid and washed with ethyl acetate. The aqueous layer was purified on a [HP 20] synthetic adsorbent (Mitsubishi Chemical KK) J and eluted to give the aminocarboxylic acid (5) in 74.4% yield. Example 5 1. A solution of 1 g of carboxylic acid (1) from Table 3 in 6 ml of 0.5% aqueous sodium bicarbonate solution, adjusted to pH 7 with hydrochloric acid, was washed with ethyl acetate, desalted and poured into a 10 ml vial. Here, the corresponding sodium salt (2) is freeze-dried in the form of a powder. 2. Similarly, an aqueous solution of sodium carbonate is added to the suspension of 1 g of carboxylic acid I from Table 3 in order to obtain a solution of pH 6.5. The salt solution was poured into a 10 mL vial where it was lyophilized. The sodium salt is obtained as above. 3. 1 g of the sodium salt produced under sterile conditions is dissolved in 4 ml sterile water and administered twice a day orally or intravenously to a patient suffering from CS 268527 B2 infection

HER

Staphyllococcus aureus to treat this disease. 4. Always One of the carboxylic acids listed in Table 3 is dissolved in an aqueous sodium bicarbonate solution and assayed as the sodium salt for the minimum inhibitory concentration (MIC) by a standard method described by the Dapon Prochemotherapy Society. Determine 3.1 to 0.2 micrograms per milliliter against Streptococcuspyogenes C-203 and 0.8 to 0.025 micrograms per milliliter against Escherichia coli H. Example 6

Method for Deprotection of the Amine Group 1. The solution of the tert-butoxycarbonylamino compound listed in Table 1 is mixed with 0.3 to 3 parts of dichloromethane, 0.3 to 3 parts of trifluoroacetic acid and 0.5 to 5 parts of isisole and stirred for 10 minutes to 3 hours. hours at a temperature between -10 and +40 ° C. The solution is evaporated to remove solvent and reagent. The residue is washed with benzene and the corresponding amino compound of Table 1 or 3 is obtained in a yield of 70 to 80%. 2. Add 3 to 12 parts of aluminum chloride to a solution of the tert-butoxycarbonylamino compound, the benzyloxycarbonylamino compound, the methylbenzyloxycarbonylamino compound, the methoxyethoxymethylamino compound or the trityl compound listed in Table 1 in 1 part in a mixture of 5 to 9 parts dichloromethane and 2 to 8 parts of anisole. , chloride or titanium tetrachloride at a temperature between -10 and + 10 ° C and the mixture is stirred for 1 to 24 hours. The mixture was then extracted with dilute hydrochloric acid and water. The aqueous layer is passed through a column filled with adsorbant [hp 2 OJ]. The corresponding free amino compound of Table 1 or 3 is obtained in a yield of 60 to 80%. When tert-butyl, benzyl ester, p-methylbenzyl ester, p-methoxybenzyl ester or diphenylmethyl ester is present, it is removed to give the free carboxy group. 3. To a solution of the chloroacetamido compound of Table 1 in a mixture of 15 parts of tetrahydrofuran and 15 parts of methanol was added 4 equivalents of thiourea or 4-methyldithiocarbamate and 2 equivalents of sodium acetate. The mixture was allowed to stand at room temperature for several hours, then evaporated, diluted with ethyl acetate, washed with brine, dried and evaporated. The residue was chromatographed to give the corresponding amino compound. 0.1 to 3 parts of 1 to 3N hydrochloric acid are added to a solution of the formamide compound, the Schiff base, the silylamino compound or the trityl amino compound listed in Table 1, and 0.1 to 3 parts of hydrochloric acid are added and the mixture is stirred at room temperature. 1 to 3 hours. The reaction mixture was evaporated, diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and water, dried. The residue is purified by a conventional method to give the corresponding free amino compound shown in Table 1 or 3. 5. To a solution of the benzyloxycarbonylamino compound of Table 1 in 30 parts of 1: 1 mixture of ethanol and ethyl acetate is added 0.5 parts of 5% palladium on active substance. the coal is shaken under hydrogen until the starting material is consumed. Filter the reaction mixture to remove solids and evaporate to give the corresponding amino compound listed in Table 1 or 3. Example 7

Process for preparing an amine salt Acetonitrile is added to a solution of the amino compound shown in Table 3 in dilute hydrochloric acid. The precipitated material was collected by filtration to give the corresponding hydrochloride addition salt in good yield. 12

H

AND

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Pl ω 4-> co

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St ro r * * 0 H ta X. r • 4 · tú tú r i 1-4 -P o (IX · * * -><X CJ í ú ú ú.. <43 and X IPi CJ CJ II ** tú-r- (—1 o ro CJ r * e * rs Ό Ό o -4- <r * X CTx X 1X0 CJ · CJ ί KO Ό o- co r- cn CJ H a ro ir J3 rH Γ—

CJ g ** o r • 1 • c c • ir • r • 1 • x r-1 the same CJ • X t • x CJ (CJ N • X the t o IT) \ t if CO - II cr «•" 3

H tú

CJ

- tún H tú Λ

Q cj tr Ό Ό \ t

CJ lf \ t

II Όr — I σ \ t

What about O {1 o 1 o O 1 o o 1 o 1 o 1 o 1 o o 1 o o 1 o o 1 o 1 o 1 1 o> 1 o 1 o g | H Ol tí 4 1 3 1 1 1 JP t 1 1 1 pi I tú and tf \ t

The pH3HP1O-P is equal to &lt; tb >

— ú ú ú m m h h h h h h h h h h h h h h h h h h J J J J J J J J J o CJ c - l> 1 Γ- HH Η O ** ·· T3 o IT

N 03 thou what Ή

O

CJ r \ t

/ —CD-> S0CD

i — I • ÚCOI t o o ro

Pm o CS 268527 B2 13 Ό

P

r — I * Λ4 raMH>P> 0 0 PP

«O m

H

O

a aaa kO II trk a kD * 7> H 04 ar * II kO ta X tfk 04 a h 03 h · * tr x a · * tn and tn NH OJ-OJ M- rH and II «· ** **» τ> Ok tr IT II% **% a HP HP X X X X X X A x Ό VO t - O Ok X Ό “·> w O? On \ O an M · · · O O O O O O O O O O O O O O O O a a a a a a a

Ck 1 04 tfk 1 04 04 [m Ι Ο- Γ- 1 H Ι. 1 Η HO 1 O and I ** X • OH3 OH ι o tfk P I ia 00, P> o -gH O 1 04 i co | 1- Η k k 1 1 K í a tn «

i — I <3M

I aooon

W PmO \ t

AND

H ta · * * * aao r-1 oa Ok m 04 1 Ok tn 04 • sa kO H · * 01 kO a «« X a Ok a ta ta tn Ok aaa -Φ i — 1 trk rH • sva 01 tn? K · o · o · o · o · o · o · o · o · o · o · o o · o · o · o · o o A Ok 04 kO X c tr trk tn O n n · · a a 04 01 O 04 04 04 04 04 04 04 04 04 04 * m ΓΟ 04 rk tn w rH 01 · * 0-kl opo> o

P

P

• P 01 dl

P and Table 1-1 continued

Ok

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 -í | • 1 1 1 1 01 1 1 1 M 1 M 1> 1 1 14 \ t

Ό Λ Λ 05 · · · · 05 05 05 05 05 05 05 05 05 05 CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO Thursday ~ 1

CO 00 and what

t-I 1 CT 1-W 04 and r-1 · 1 T 1 CA 1 ir-CO ·% c- 0 1 - l what tri cx 1 a CO K 1 K? a rd fX 1 W 01 i — 1 1 r4 I — 1 1 UA • sr — 1 1 · «♦ · II Λ lf \ t 1-iai 1 1 r-1 aia CO a 1 1 1 rH n c Ό - tr t o 1 o o o 1 II 11 T a H 1 CO »-1 and 1 o 1 "O« »1 r ~ 1 o O 1 00 and 00 o 0- 1 -» · «· 1 o rH CO Ό -P r!? Lf from« C4 and rH I <CO and rH O and 1 'í · ». OO | 04 'Thu 2 1 00 • τ' «Μ O 1. O, o and I ** a ** i **! L · * co l 1 on m 04 k 0- I lOi>-> 1 i OII 1 o OO 1 0- - 1 C Η 1 C co 1 O 1 — 1 1 a lt lt lt lt lt lt lt lt lt lt + + + + + + + + 1 1 - CO iw Η O 1 t oo r ~ 1 i — 1 1 OJ r * aa ko flT \ t

CO 05 • P J-OO -P co

M

O

rH

CQ

J and LO 15

a 1 1 X cO 1 X 1 r4 rH 1 OJ 1 Λ4 • 1 1 1 r-1 1 w 1 a fa M 1 I P-> oi - · 1 ** 1 IO 1 1 · * 1 IO 1 'd * 1 «Ο 1 1 xi and σ rH · * to af Λ to 0 * 63 and X and rl 63 and what X and OJ 03 X 00 what · <* • s 03 X What rl IO ** «· 63 a II rl a • a OJ to VO X a rl ** 63 aoo co X a to ra 63 a 00 ((o co II and lP X and I- 1 - CO and I Ol ►o XX II XH to X p I OJ OJ OJ x x x x x x x x x x x x x x x x x x x x a j j c 63 63 63 63 63 63 63 X r * IO OJ · and X X I 63 c— c— X IX. ta - a -p - ΓΊ 1 and II 1 X that it — l X χ rd 1 to X what II and Q 1 ο- to rH rH o what «oa - K - - II o to ·» oc - what 63 OJ O 1 X a »- what about *» - c- and it - I Λ c - c - ama - - what r * am X this what X and 1 r-1 aa ** to a 1 to XXX OJ p 00 to • k * · X OJ OJ aa 1. m OXX OJ 1 XXX r — 1 rH co \ t - »and OJ and 9 · 1 CO to OJ aac—

From o tt

• H xn

X - to OJr-i 63 and what

II and tx. 1 1 h cd 1 1 1 0 OJ X 1 CO 1 o H 1 O 1 r-CO 1 [X, O 1 c-TO 1 ο- O ai 1 r 2 2 aaaa O 1 X 1. H 1 * »XI I ** **" TO 1 1 i "(by 1 o <0 oo 3 XD g g 1 o í í 4 4 4 4 4 4 4 4 4 β rH 1 cn C-r 2 <j

Table 1-1 continued

IO a

CO «1 1 1 and 1 1 1« 1 and 1 1 o r 1 1 ·· α 1 OJ ω co 1 ·· Ή ø-l-1 1 1 1 H • 1 w 1 c-1 XD · 1 oo

Honor and About

H 63

CQ

O

O

OJ ao 00 16 EN 268527! Β2 Ό

CO i — i · Λ4 tuΉΉ> ί-ι κ> Ρμ

S Ρ, α m γ4 Ο Ο Ρη and ΓΩ r — tΟ

Η. I> ο -gH ο

H l HI es m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m C and CM and CM c - es and CM r à CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM <m OK t • t - CO »m CM —» »>>>> t t t t t t t t t • • • c a CM ** CM · A · 4 r4 a a a CM a a a — a — — — — — — — — — — — — — — — — — — 03 lf a Co 1 co co co co co co co co co co co co co co — — — — — — — — J J J J J J <4 r4 tr o c c m m o CO i — 1 CM Ολ CM • c3 c- CO CM i — 1 Γ-, 3 r — 1 / —1 i — 1 CM 1—1 es O o CM 00 rubs CM ο- n What is t> ι — 1 t — n rH C — what is — 1 r ~ 1 ΓΊ I — 1 H / nujol / / 2xm, 1Η /, 5.96 / d, J = 16 Hz W, 6.65 / m, 0.5 H, 6.91 (s, 1H), 7.0 7.5 / m, 10.5 H / 7.86 / d, J = 16 Hz, 1H /

CO 1 M 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 CM 1 aaia 1 I or 1 1 03 1 1 1 i-l <—1 1 03 C 1 ·· 1 H 05 CM <0 1 o P 1 i — 1 3 a 1 · i ω • P 1 1 1 1 CTe and -P 1 Ή I> O 1 1 ο ο ο

W ο

II and ο

i — I

tšJ

CQ ο

ί — I ο

»R r r r r ij H H H H H H H H H H H H H H H H H H r r H r r r r r r r r r r r 1 0 and 1 I CM ΙΛ and | 1 σ 'tr- V 1 VO m * »i — 1 1 CM and N · * VO 1 H aa VD 0% ima I mm? ii I? b3 H aap, 1 t * and II. II or ~ lc— r4 CX 1 1 co * "3 lOi 1 1 to> tf \ t 1 A Ό * «ζ. T I ** <3 Ό r "lo co 1 o 1 Ό and V0 Γ" 1 nia 1 and H «» 0 * II r-i i Φ i σ H M3 0 0- ^ 3 o 1> 1 O m 0- · * K 1 o 1 ** C— r * s · * 0 »o 1 C 1 03 ir and 1 1 (0 1 M- K and 1 -P 1 ·» 00 rH rH and 1 ω 1 Ι- co C— with 1 Φ im o o II ** »· 1 £ 5 1 ** a ·» cm and 03 I 1 H • M- l £ r \ t O

1 ί c 1 f f t t t t t t t t t t t t t t t t t t t t 3 3 3 3 3 3 3 3 3 a a a 1 xo l X $ 5 o 1 «* • r * ·» CO 1 lo o o 1 c- C- 1- 1 ΓΊ CM m CM XU '8 1 t — 1 c— ΚΟ 1 ΓΟ C- VO VO HO 1 1 mr — 1 1 “1 1 1 CO rl Η H VO 1 1 1 1 a 1 a 1 a 1 1 • A Table 1-1 continued ir \ t

CM

Pm

O

CM aow O and 1 rH 1 £ 1 and 1 1 0 1 1 Φ 1 -P 1 3 1 1 1 (3 1 1 1 N and 1 and 1 and 1 0 1 0 1 03 1 1 1 1 03 • · a 1 1 ΰ 03 a) 1 1 (0 • H £ 4 1 1 OP 1 1 -p | • V 1 1 03 1 1—1 1 CM Ή 1 r ~ 1 1 rS O 1 1 18 CS 268527 B2:

1 1 (CM 1 CM CO • 1 1 A CM A CM Λ2 M 1 1 Ή> O 1 CM xt 1 PM 1 1 CO «X 1 es>·> 32 1 C Ό 32 0 A 1 32 w 0 CM xi- 1 CM of A ex • X • X ex r- • X tr ~ * x ca x x -t 1 ex CO σ 32 t and 32 v 32 1 0 · »N 0« X co CM 32 Ο- 1 32 co • X tfc <X χ CD 1 32 Φ CM <A 1 A • X IT A A A II O A AA 0 1 II · »A CM AOA 1 x» w A · »»> ►3 A ex rH A {A σ 03 3! what ►O what ex • X Ό I t tr ex ex ř ex ex ř ex o ex ΓΊ <7 1 n 32 CO 'and · 32 1 1 IC ex CD Ό co co Ό Ό 1 1 1 C C 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 A trs r Í CM | | f | es | | f f f 1 1 1 1 1 1 1 1 1 1 1 32 32 32 32 32 32 32 32 32 32 32 0 A ». I> ta CD K Cf 1 32 t t <32 • x ** HA 1 x) - 00 ir A 1 xf CO irc what CO trc VO ·> 1 O ir • x CM X Oc 1 ex II • X ». cm and es and 1 * x and CM - 1 CM to. CO 1 n χί- co A- 1 .. 1 1 OA 1 I X X 0 I ir Ο 0 irc • A | n 1 r- - what r- A m 1 - 1 1 c ~ CO c - what • A 0 1 AAAAA 32 1 «a 0 1 *» * x ca \ t xi-Cm m CM m A> 0 and 1 mt> CD r-co ΓΊ A 0 1 m A m AAA

1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1, 1 1 1 1 1 1 1 1 1 1 IOA 1 1 1 1 (0 1 A 1 ·· G 1 x-1 CO 1 • 1 c 1 1 11 1 0 A 1 A 1 1 3 | · | A 1 03 1 ca 1 Ή 1 m A 1 > o 1 A 32

1 — itaCQ ta X2

What and what ga 19 Ό « <35 • I xt rH CO 1 I 04 M 1 CM MX) 1> Ct 1 cx 1 1 co

I — I ♦% · * * »lf and cx cx

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X m Ό Ό x x ítí x c co x Ό X rH CO tr σ CM> a X x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x o o. • X II Ό CM ·. CPi and CO X CM r »-« X xx CM Ό) and x xt * X xx ·· rH X 4- Γ "ir ~ 1 what Lf rH ·. II XX • x • x CO» -3 X X CM CO-χ CO CO XX t t t XX XX v v v v v---O O O O O O O O <II xx r "í xx ** II CM

1 1 1 1 trs O o 1 1 x m m r r 1 1 c c Ό 1 1 1 1 1 1 1 1 1 1 0 0 0 CO> o -a 1 CM 0-CO trs HO 1 <co r- | i — IH what a bunch of Pi x

CQ Table 1-1 continued n P o o p co co

CO CO • H--O-P co Ή

XJ

X

O

CM

X

O ω

CM xo

H

WHAT

WHAT WHAT XO BROWS

rH 20 Table 1-1 - Continued CS 248527 B2

R 0 r4 34 »M 0 £ Ή> O o. O, m

rH 8

O Pí m

rH

O a

About HI

> o aH O trc «ro

W

CO - β CO 0 Η β

O -P i

CO to N and K to and to CO to ~ xt to xt — 1 to tl CD to ~ x tt M r> a rH a es es \ t a * «0 II rH N h> CO rt 00 th e th e ci es es zx w co • x • t m m a a ii CD - CM CTc II - tc tc and CM-p and 00 ~ CM m 34 O HO »((0 to to to Q Q Q Q Q Q Q Q Q Q <0 CD 00 xj- t- - CD-es II ex r * es fQ-r-1 1 CD r- * thre - ir \ t K Ό Ζ Ζ co co c c c c c r r r r r r r r

O-CDI-I-I a

CQ

WHAT

H

O 0

CD> O O m- i

CO l> ~ - to es 06 M · Ό -sa 0 II · * v _> * z — x Xs-Z * ~ 3 ςρ and cn es> CM CM II mz— * x v. Σ CM CO + »a tfc • s ►3 ·. M ex ex ex es es es es es es mi mi mi mi mi mi mi ex ex ex ex ex ex Q Q Q Q Q Q Q <* - X »and II • x M · and CM ·» σ r-1 es z- * s ex i — t 0 IDe ►3 Z — Xs ar ~ # * ex and rH • s «* N li es rH a Ό »» co »» co co co co co co co e e e e e e e e e e e - - - - - - - x es N N a a N a a a a N N N N N N N N N N N-------------- nc— «—o what

CM r — i

it. 0000 C ~ -C-voi-ti

W

CQ cL · and 02 β 0 β +> i

CO 34 es - oe * Ό t9 C) ** a • H XO and ** Z * x +> CM rubs \ t <n es es Ό e »tr \ t and es t es es es x x CM tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr tr 0 0 — — — zx aar ~ H rH M- CM m CM CO X X rH OC es es N CO CM N and ir es and ω z cn co Χ-Χ »Z ~ Xs II tr <n ►o r4 CM • 3 co

CM 03CM OC - CMΗ H CM O00. > -

CDΗ K

TO

CQ

i — INCQ 0 • Η

O 00

H C3 268527 B2 21 σ i 44 · m mΉ> oao,

H

Oò o

mr-1O w

O «II

> o aH O M0 w LT \ t

A oo

N

W 00

II ~ ►o ^ x tti »· Ό Ό ro

CO 'COCT>

CO WC — ΗΗ Φ ”t— N x W <<—1

CO CM r-xII ~ W * -0 O- H • X tr 1 z xv * II • rl m vt «c- h> X0» z ~ x ι — 1 A x ^ \ t CO G CM «« «« «« «CO CO G G G G CM CM CM CM CM CM CM CM CM CM CM CM CM CM co w * »v v v v v v v v v v v CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT &amp; «Η vx JE Vt x x ^ ^ H LCA *> c - x Vx N li m tn r» w tr \ t <0 CO Z — X CM II VO-P ZX> w CM X Xx co c rd G <. o '> 3 O m * »44 * x ir rd zx N o« ·> ·% and CO ffi GW Ό c- x_z

H OCM COC-CMr-IH

OO t t - t0 VOi-1 H w

CQ Table 1-1 continued m 04 o 04 03 • rl

O 03

G <σ

G

P

i — INCO ffi w

G οσ

G +> ra vt> o σ \ t

rH 22

CS 268 ^ 27 B2 Ό CA H ·

> 4 wi MJCi KJ

oo

I ooo — o-

JtJ a 1 1 to o- II ca 1 1 and what about 1 1 ο- mar ~ t— r-1 rH l ι II 04 · »It 1 i hj r * 04 CO 0- h> xt tr \ t 1 · 04 * ť Ό · s s ť Ό ť O ť ť ť ť ť ť ť ť ť ť 1 1 1 1 1 1 1 1 1 1 I ** and 04 lfC e * ÍM OJ · 1 · · 1 0Ί 04 co a X OC! <o 1 · * «wo xr * *» 1 1 aa H o 1 1 a 1 1 r-1 1 04 C— 04 II CO o IO o | —1 04 1 ot CO II N »> 04 1 o 1 oj o OJ * Ί> 1 1 aaa I ·» to. 1 s 1 rl 1 what II d - H and ir 1 S i - a í • * OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ 1 OJ CM h> ir. HfO 4 · cO 4 · f · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · HH04;

A rl oa

OH I

yo-aH OOO 04 OO OC ~ - mcm co co uam-i-i-l

SJ X!

O ir and 04 «and 04 ffi

O ω 04 and 04 a

O

Esters of general formula

rI

OJ oj fl ca -p oj Ή> o CS 268527 B2 23

Pharmaceutically active esters of the general formula

X) 1 as 1 CM 1 Λ5 Ή J 1 Ή K) 1 r * 4> tu 1 1 1 1 J • X atr * 4 Ό CM J • x 00 1 and ♦ X «X 1 ir \ t 1 σ 1 lf X X 1 C "1 x xat — 1 m rH» 1 X 1 co 1 • X and 1 aS CM Xsl and 1 a as Λ 1 ir rx cu lr — 1 i OI * x II and 'Φ 1 r ~> ►a * x • * 1 what l • X rx II • ^ 3 1 Ό * "> ola 1 CSC« X ami — 1 i 1 • x M - O gr -! 1 1 W e * P l l l l Q al al al CM CM CM CM M M M M M M M M M M M M M 1 1 1 1 1 co lf 1 1 1 cr> O c - Xf o 1 CM rH (Ί rl and 1 o «• X« X ^ x • X rH 1 oooo 1 1 CM co CO m> oa 1 O 1 J ΓΊ i — 1 r-1 t — 1 IS 1 OC £> 1 aa (1 m 1 1 aa 1 1 o 1 1 aa co 1 1 1 1 • · β 1 co ca as 1 • H • H l 1 OO -P 1 I • 1 CO 1 Ή 1 H> o · 1390 / KBr / 7.35 / s, 1H / 24 CS 268537 B2 Ό 1 ώ 1 H • 1 and 1 CM 1 Ή 1 1> r4 P4 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 ** Q tw L Fri (o 1 CM 1 1 HN «w IA co m II II o« * »►o ►ot ~ 1 C— · * XS3 Ό X <<0 CM -4 what IA CO CM CO CM · CO O cn IA · * • s * · * tr XS XS o as c- r » <»Rd IA CO O 00 00» »XM IA IA IA HH M CM CM / / m m m 2H / / / 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7

1 1 o mi what rH 1 σ 1 l o Ό · a! CM 1 O 1 S CO I o P | Ph OOO β IA what CQ t> - what M i — 1 r — 1 i — 1 ** oooa 00 what m crc C- what ir — 1 r ~ t rH i — 1 table 2 - continue m Pi 1 wt 1 o 1 1 W Pi 1 ca 1 1 1 ·· β 1 H ca gj I ** • rl line 1 rH O -PI • 1 1 ai 1 X 1 CM xo 1 CS 268527 Β2 25 Ό © rH, * · ·4 · Μ ro fn Μ »

>η> Ο CO &amp; ο &amp;χ> ι — 1 ο ο f ~ l ο and ο

'- — — I

I> ο aΗ Ο o r Φ> o 8 © +> © Φ Cl o O cr> ICC C - rH rH rH o ICC CM ω nn rH «* r * ir \ t cr>

CM

AND

WHAT

W m ir · * v rH what J3 C7C • X σ 'v * • v what u \ t <: c-> · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · rH and CP> IA o CO xz rH CO · N oa ΙΛ z — x «4 a ·» and © • • © rH co c rr co li O co tr \ t 1Λ © IfC - aamm -PO ». · ICC M CM what · <o II CM ♦ * II rH ► o c- oaa σ CM • s. O- * v Ό o Z "X Ό - • ~ XM © N CM c- rH CM aa · - * CM» * ** o CM CM lf CM rH in co 00 00 Ο α ο> ο

G

GS +> 00 ο α

S Ο Ρ <

CM có tr \ t

G φ> ο í © +> © φ β ο

rH <η fn Ο

CO m π ~> ι — 1 "Μ" C - «- Η οσ - {1687, 1150,985 Μ> χ χο © • ο &amp;

AND

CM

N

CQ

N

XJ

O ©

rM

rH

S £> ©

Ra 1 · © © 1 -H f-, O +> © Ή

> O

rH · *

rH

rH • ·

rH ΙΛ

rH ”4 · 26 CS 268527 B2 o. <o

cM. 03

X_ MQ_> O

AI

CM

i — I

AND

ι — I

Η «-I I

ι — I CO

Whatever

Table 3-1

Carboxylic acids of the general formula

r ~ I

cA ta - x »r 1 1 Γ ta ta ta X X X * * * II II II k k k k k k <- »CM CM CM CM X_X X *" M- xx. ** · * rd ta CO rd H -~ S N ~ N N N N-------k k k k k k k k k k k k k k k k k k k k k k k CO te- z ** »Ό A li ta XX O • 3 CM ** 1 rd z — x X * 00 w Ό 01 ** rd O IA or * o CM ox * ca what CM CO χ-χ A · »·» W CM O co co rd l_>

IA

O c ~ -

r — I cocot- <-i ta coco (—i CO Ό Xk CO * X — X Xk ta co cn CM XSl - .Xk ΓΟ ca IA • • Μ- CfO coΑ x t ta '' rv X X X X X X X X x X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X CM rd Xk Ό 0 »TO X — IA IA (((((((((((00 00 00 00 co co co co 1 1 1 1 1 1 1 Xk r4 -O iA o ΙΛ ο>> co co co co co co co co>>> co CO CO <3

WHAT

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CO ca 01 • rl

O 03

CJ 03 &amp; + »Ta r ~ i ·· rd ta 03 • rl

O ta

M> oo • PM TO ta HO rd X) xk o M- CM II XX X * CM X ~>. Xk x * x what x CM x II x (x 1 x x x x x x x x x x x x x x) the <5 * 3 A ta II Ό rl -P * 3 TO-TO OT »» x_> CO X m co - »o O CM co O Γ- CM t- ΙΑ co« —1 A «X Xk ooo co Γ- IA IA - CO CO Η «—1 ta ta 01

• H

About you

CM co 27 EN 268527 B2 Ό

O γΉ K. Q_ ♦ 09 Ή

&Lt; tb >

I> o

SO «

OJ OJ ii, p

Ol rl OJ

III

rl IO SO

OJ OJ I t

rl ΙΟ KO trs

W

Woi cqOJ

to x x x x x Z Z Z Z 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 W OJ W 4 4 4 X X X X X X X X r r r r r 4 4 4 4 r r r r r r r r r r r r r r r r r r r r r l l l l l «Ta 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 II II II II II II II II zX TO ** q \ N Q OJ Q Q • Q Q Q Q Q Ό Ό Ό Ό X X X X X X X X a xt- cq ZX «X trs *» Ζ »N Ό II π rl Ol os rl x — x and SO Μ- z- * xw O o · \ t X OJ Os «X Zx rl SO A OJ · Z — X. Ol r4 to O CQ A cq N to O SO * x II cq CP 1» »W · | - os w xt trs z * Zs cq cq Zx N rl AN x W Ό so so so — — W W W W W W W W W W W x x x x x 3 3 3 3 3 3 OJ OJ * * z OS W W x x x x x x OJ OJ OJ OJ OJ OJ OJ OJ OJ II II II • -3 ** 1 * O OJ A rQ to cH x> o rl χ-χ OJ Ol x} - Ζ »Zs C- xj" so «Mon zx - zx WA *« SO II xt- N 4X - rs Z * X XX, z — x CO Ό ZX Ό i — i O • · * * W W W W W W W W W W 3 3 3 3 3 3 3 ~ TO s z z * m m m TO TO TO TO TO C C Q Q Q C C Q z z z z z z HA HA HA HA ZS II OJ o * W OJ A - 11 » <»» Rl SO w XX OJ to L_l m Ol XX LJ CQ trs SO

OJ so cq Η nrH- oso · οxl 3 3 S 5 O mrl

Ο (1r1 M

O Oso cqc- soi — I i — I rl O OSO - 3 ~ 10-3H .3. O oco cqoj soCQ rl to o

OJ rl rl ol sorl rl

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s a a X X X X X X r a-r Π O r r r r r r r r r r r r r r r r r r — — — — CM 1 0 * PO and CO - n o o xs IT - ca ca o c c o • c. and x t 0 co 0 0 k a, χ-χ c and t r l l xh m · χ χ <a K and r II II II X wa rH l_J CM * 3 * "3 *" 3 what iH _ _ ΓΟ i — 1 o O c— • rs c— O «—1 5 c ~ - OJ CO i —1 CM Ό PO rH 7 B2

CM CM H t J «I-----P P P P P P%%%%%%%%%%%% c c% II CM CM c - --- Z * "3 CO m • Z Oc P-> x Ό X rH N - X co X and zx CM tP- and XZ · xo CM ^ x 0 * r4 m 'and ir \ t - c- CM O • "3 St X and tf" 0 »x-jn J3 co O 0% XX CM x t'- ZX CM« - t oa —- 1 II 0 * - rl ΡΊ p> m X CD O Ό X CO X X X NX a Ό XS ac a and ca and CM X c->>> z z z z z z z z z z z z z z z "3 c - i - 1 o n n - xl - P - CO ff r - 4 r4 W L_l» xr »o CO o xt op"> P3 r- ire 1 r-1 I-1 table 3-1 - continued aooo trc 03

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Ό ta r4 Λ1 * M what M £>O> o

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Table 3-2

Carboxylic acids of the general formula

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CM ca r Ȥ

IA ca! § ta

Sas oo ί- ο

CM

WHAT

H £ £ c - what i-1 r-1 iaΜ-ΙΑHn

ι-Ι-© · · ΓΓΙ-PΙΑ CHO

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CM

AND

O co • rl

O <a

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CM CM

II

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CM z- \ t

CM ta o CDo0-NaHC0 „3 Μ- Η

IA

H CS 268527 B2 39 Ό Φ

H M · M Ol * 4 MP X)

CM CM CM

III

Η m KO

CM CM CM

II IH <A CM x * L L 3 3 3 L L L L L L L L L L L L L or or or or or or or or or or or l_J Z **. C * ζ w CO CO V V V V CO CM CM CM CM CM CM CM CM CM CM CM CM q q q q q q q i • "3 ** o CM tr" t J3 τϊ CM - 'c— x-' »

Wr-1 W Ό CM Φ N w 01 CM m II π vo * 3 m O i — t »· o λ <>. P w Wr-1 - what 'Z' x M · 1 Z ~ X - t- ow N CM CM K in P L_) tn - a ·> -4 · w II H wm * 3 rd "Ό N Ό w 01 q ir q q · · · · · c c c c c c c c c c

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P (0 <0 a <0 55 LT «table 3-2 - continuation of what cn

CM

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CM

«Z r — 1 r4« O .. CO 01 G i- (• rl co * · O r4 OP • rH • CO M VO XD (H

CM w

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WHAT

i — IO CS 268527 B2 40 * d ca

rH

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Table 3-3

Carboxylic acids of the general formula

X

CQ · í t • • po po po »» »po po po po po S S S S S S S S S S S S S S S S S S S S S X ♦ X ZX x x · X X X X X X X X X X X X X x x X X X «« «« «x x x Ζ Ζ It N X X X X • X X r r r r r r r r r r r r r r CM CM CM CM CM X X X X xt trs Ό CO +> OQ r l K K N K K K K K CM CM CM CM CM CM CM CM CM CM CM CM CM CM ->-> mm and x - from what t - r - trs trs oc - CM co t- trs <n i-1 r — 1 <—1 a- ZX o O o O st- 8 rd χφ rn rd oa

CM o CO o «X - z ~ CM CM CM | 1 1 rd trs co XS) ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX ZX Ζ • X c c z-X X X a a a a a a a a a a a a a a X X X X a CM CM CM CM CM s s s s »» » xf- ZX xf- II zx m Zx »x ^ 3 and trs ta V_z - and trs ZX Ό CM what Z — x Xt X CO ·> a | t CM - m CM * -3 co O trs O t> CM CO c- trs cn 1-1 r ~ 1 i — 1 OO o OH xt- CO xf- i — 1 rl and a

CM and what <*. <—T * ·

rH axes Ή 00> O fl CS 268527 B2 41 Ό ar 03 Ή

XJ o

CM

Q

Mi tí s

'-' rH

AND

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CM

I w

O tí Φ>

About them ar

CM, IA M3 xk CM CM X "to CM 1 1 1 rl A M3 CA CA z — x Z" X • k • ka am Qft rl 03 rl • S- * and • k ** x ~ x &amp; 09 co ca a m II CM Ex CM h> CM * -x kX * k (3 »k CO P m W Ό rl a» »k • km • k <nm -M- A * k VO • k O Ό CM b- Ex kX XX A b- O c- r. <· (* 3 VO rd

O tí Φ>

About them are what they are

CM

O

II ob-M9r ~ 1 <n oc - cno M0 o ti o j> o ti ar p 03 o ti ar a

Table 3-3 - Continuation

CM

X 09 ·· t 09 ar

• rl tíO P 09 M ca

> OH

CM ao

O m «*

CM

O

CM

CM

TO

O

CM ao

H ··

H

CM

CM rl

CM CS 268527 B2 42 • o

CS

"-AND

.MV »£ co Ή κ>

CM CM

IIH tn

Table 3-4

Carboxylic acids of the general formula

what they are

WHAT <0 • c rcO -P (0

M

O IA O O--------------CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM o N ** - x ** ** X— CO CO CO CO CO CO CO CO CO CO · · · · · * * * * * * * * * * * * * y y y%%% CM NW - aa rd A- · * * · J J J J J J J J J J J J J J---------------- o ia rd -3- vo IA <ai 1 rd ca a

CM

ÍU

£ P4 and ca ft -p

i — I

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CM ca and ca to -p

CM

AT

OT

CQ

MX)

CM CM

II

CS CS N CS 208527 82 43 ου

AND

H CM

>

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HIM

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CD

• H

O 09 th as • p 00 • ·

CM ··

CM 09

> O co xh 44 CS 268527 B2

JGJi — I ΛΙ ro Ή> o 04 04

I in I Η 'P Ό lp 04

AND

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I trs 04

I 43

And Pi

H

AND

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P Φ> o

P

OJ

-P tn o

P op- o-

i — I

04 43IP i-Iop o-op H

Claims (10)

OBJECT OF THE INVENTION A process for the preparation of 7β- / carboxyalkenoylamino / -3-cephem-4-carboxylic acids of the general formula I wherein R is phenyl or a 5 or 6 membered monocyclic heterosulfide having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by amino, optionally protected with an 8 to 15 carbon aralkyl alkyloxycarbonyl group, 2 to 12 alkoxycarbonyl carbon atoms in alkoxy, C 1 -C 8 alkanoyl, C 1 -C 8 haloalkanoyl, dimethyl tert-butylsilyl, methoxyethoxymethyl or p-nitrobenzal, R 1 represents a hydrogen atom or a halogen atom, 2 R represents a single bond, an alkylene group having 1 to 3 carbon atoms which is optionally branched, or a thiomethylene group, R 3 and R 6 represent a hydrogen atom, a light metal atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 7 carbon atoms which are optionally substituted the phenyl group, a 7 to 15 carbon aralkyl group optionally substituted with a methyl, methoxy or nitro group, or an alkanoyloxyalkyl group having 2 to 12 carbon atoms, R4 represents a hydrogen atom or a methoxy group, X represents a -S- group, - SO- or -O-, with the proviso that when R represents a thiaalkylene group, R 1 represents a halogen atom, characterized in that the cefem compound derivative of general formula II 45 CS 268527 B2 wherein X, R 1, R 2, R 3, R 4 and are as defined above and R 5 is a halogen atom or an alkanesulfonyloxy group having 1 to 3 carbon atoms, is reduced with hydrogen atom or a reducing metal and alkanoic acid of 1 to 3 carbon atoms and then optionally further recovering the carboxy and / or amino protecting groups with hydrogen halide, trihaloacetic acid, thiourea, zinc and an acid or Lewis acid selected from the group consisting of aluminum halide, titanium halide. and a tin halide, if necessary in the presence of isisol and / or is converted to the salt by treatment with an aqueous solution of alkali metal bicarbonate. 2. A process according to claim 1, wherein a compound of formula (I) wherein the 7-acylamide double bond is an amide substituent and a carboxy substituent in cis is produced using the appropriate starting materials. 3. A process according to claim 1, wherein a compound of formula (I) wherein R is a phenyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl or thiadiazolyl group, or in particular R is optionally protected. aminoisoxazolyl or aminothiazolyl and the other substituents are as defined in 1. 4. A process as claimed in claim 1, wherein a compound of formula (I) wherein R is an optionally protected amino-thiazolyl group and the other substituents are as defined in (1). 5. A process as claimed in claim 1, wherein a compound of formula (I) wherein R1 is hydrogen and other substituents are as defined in (1). 6. A process according to claim 1, wherein a compound of formula (I) wherein R is optionally branched alkylene having 1 to 3 carbon atoms and other substituents are as defined in (1). 1. 7. A process according to claim 1, wherein a compound of formula (I) wherein R4 is hydrogen and other substituents are as defined in (1). 8. A process as claimed in claim 1, wherein a compound of formula (I) wherein R3 and / or R6 are hydrogen, an alkali metal or a pharmaceutically acceptable ester as defined in (1), and the others are prepared using the appropriate starting materials. the substituents are as defined in point 1. 9. A process according to claim 1, wherein a compound of formula (I) is produced using the appropriate starting materials, R3 and / or R3 are CS 268527 82 47 forming the alkyl ester or aralkyl ester defined in point 1 and the other substituents having the meanings given in point 1. 10. A process according to claim 1, wherein a compound of formula (I) wherein X is a sulfur atom and other substituents are as defined in (1).