DE2432190A1 - NEW CHEMICAL COMPOUNDS, PROCEDURES FOR THEIR PRODUCTION AND THEIR USE IN PHARMACEUTICAL PREPARATIONS - Google Patents

Description

Applicant: Fujisavra. Pharmaceutical Co., Ltd.

- U _{0 #} 3 _f Dosho-machi 4-chorae, Higashi-ku,

Osaka-shi, Osaka-fu, Japan

ileue chemical compounds, processes for their Manufacture and use in pharmaceuticals Preparations

The invention relates to new chemical compounds, preferably new amino acids, processes for their production and their use in pharmaceutical preparations; It applies in particular to amino acids which are suitable for the formation of side chains in the 7-position of cephalosporin compounds, as well as the cephalosporin antibiotics formed by using these amino acids and processes for their preparation.

There is already a large number of cephalosporin compounds has been manufactured. However, this will only be

40988A / U65

a few practically used and there is an incessant one Need for new cephalosporin antibiotics that are practical.

After extensive research it has now been found. da.i Cephalosporin compounds which have an acylamino group in the 7-position have the general formula

CH-CONH- (A)

where R ^ is hydrogen or hydroxyl, R _{2 is} lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl), E ^ ".Vaκ-hydrogen or lower alkanesulphonyl (e.g. methanesulphony1, ethanesulphonyl) and Y -SO ₂ -, -NHSO ₂ -, -KHGO- or -KHC3-, with the proviso that R, is hydrogen when ΐ =

-NHSO ₂ -, -NHCO- or -KHCS-, have a strong antimicrobial activity (effectiveness) against a wide variety of microorganisms including gram-positive and gra: nneg3-tive bacteria. It is particularly noteworthy that its antimicrobial effectiveness against some types of pathogenic microorganisms is higher than that of cephalexin, a known cephalosporin antibiotic. It is also noteworthy that when oral VeraD is given to mammals, its antibiotic activity is maintained at a hone level for a long period of time. They are therefore suitable as orally administrable, long-acting antibiotics.

Among the here in connection with an alkyl group or

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Another Eest used term "low" is to understand such an Eest, the 1 to 8 carbon atoms, preferably contains 1 to 5 carbon atoms.

The amino acids of the general given below Formula (I) leading to the formation of the acylamino group of the formula (A) in the 7-position of a cephalosporin nucleus are used, can in principle be represented by the general formula

CH-COOH (I)

wherein R ^, Rp, R ^ and Y have the meanings given above. If the radical E means a lower alkanesulphonyl group, it corresponds to a group of the formula Rp-Y-.

The aim of the invention is to find new chemical compounds, in particular new amino acids and their derivatives and processes to be specified for their production.

The term "derivative or derivatives" used here is to be understood in a broad sense and includes any modified Form of the amino acid of the formula (I), which is used to improve the ^ reactivity of the carboxyl group (so-called "reactive derivative") or to protect their carboxyl group and / or et-amino group against the influence any reaction (so-called "protected derivative") is used. Examples of derivatives on the carboxyl group are salts, esters, halides, amides, anhydrides,

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and the same. Examples of derivatives on the -n-amino group are salts, acylamides, Schiff bases and the like.

According to the invention, the amino acids of the formula (I) can be prepared by various processes; a typical one suitable method comprises reacting a compound of the general formula

(II)

wherein E- is as defined above, in a free or protected one Form on the carboxyl group and / or the oil-amino group with an acylating agent of the general formula

E ₂ -YZ (III)

wherein ¹ Z denotes the best of an acid and Ep and Y are each as defined above.

If the & -amino group is protected, 1 or 2 hydrogen atoms, for example by acyl, such as substituted or unsubstituted benzyloxycarbonyl (e.g. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4— (phenylazo) benzyloxycarbonyl, 4— (4— methoxyphenylazo) benzyloxycarbonyl), substituted or unsubstituted alkoxycarbonyl or cycloalkoxycarbonyl (e.g. t-butoxycarbonyl, t-pentyloxycarbonyl, isopropoxycarbonyl, Diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl,

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2,2,2-Trichloräthoxycarbonyl, 2,2,2-Tribromäthoxycarv ^ n _t / l, 1-Cyclopropyläthoxycarbonyl, 3-Jodpropoxycarbonyl, 2-iurfuryloxycarbonyl, 1-Adamantyloxycarbonyl), (heterocyclic.es ring) oxycarbonyI (z. B. B. 8-quinolyloxycarbonyl) or substituted alkanoyl (e.g. trifluoroacetyl); Trityl; Trialkylsilyl (e.g. trimethylsilyl, triethylsilyl); substituted phenylthio (e.g. 2-nitrophenylthio, 2,4-dinitrophenylthio) and the like. The oil-amino group can also be protected in the form of a Schiff base and in such a case the two loose atoms in it are substituted by alkylates (e.g. 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy -1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-a'thoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-propionyl -2-propylidene, 1-benzoyl-2-propylidene, 1,3-bis (ethoxycarbonyl) -2-propylidene, 1,3-bis (ethoxycarbonyl) -2-propylidene, 1- (K-methylcarbamoyl) -2-propylidene , 1- (K, K-dimethylcarbamoyD-2-propylidene, 1-fK- (2-methoxyphenyl) carbamoyl | -2-propylidene, 1-jJN- (4-methoxyphenyl) carbamoyl | -2-propylidene, i-iii- Phenylcarbamoyl) -2-propylidene, 2-ethoxycarbonylcycloi.entylidene, 2-ethoxycarbonylcyclohexylidene, 2-acetoxycyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene) or the like. The (X -amino group can also be protected in the form of an acid addition salt, for example in the form of the hydrochloride, hydrobromide, hydroiodide or the like.

The carboxyl group can be protected by any conventional protecting group. The most preferred protected The form on the carboxyl group is a silyl ester, which is produced by reaction with a silyl compound such as trialkylhalosilane Dialkylhalosilane, alkyltrihalosilane, hexaalkylcyclotrisilazane, octaalkylcyclotetrasilazane, trialkylsilylacetamide or bis (trialkylsilyl) acetamide

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can be.

In addition, the r% amino group and the carboxyl group can be protected at the same time, for example by means of a metal compound which forms a celate. Examples of suitable metal compounds are sinu. those that can form a chelation with the ol-amino group and the carboxyl group, such as. B. organic and inorganic copper, cobalt, nickel and magnesium compounds. Suitable examples are in particular copper (II) chloride, copper (II) ογ · οχ, id, copper (II) fluoride, copper nitrate, copper sulfate, copper borate, copper phosphate, copper cyanide, copper formate, copper acetate, copper propionate, copper citrate, copper tartrate, copper benzoate, copper salicylate and like that.

In the acylating agent of the formula (III), the Rer., 1 Z an acid, for example, the remainder of an acid «lc ^ enide, z. B. an acid chloride or acid chloride, a Siui-ecnhydride, an acid ester or an acid azide.

The reaction is usually carried out in an inert solvent. Examples of suitable inert solvents are acetone, moxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine and the like. If the solvent is miscible with water, it can be used in the form of a mixture with water. There is no particular restriction on the reaction temperature, but in most cases the reaction can be carried out with cooling or at room temperature. .Venn the radical Y in the amino acid of the formula (I) -In ¹ HCO- or -F. HCo means, a compound of the general formula can be used as acylating agent instead of the compound of the formula (III):

4-0988AVU65

R ₂ -Y ¹ (III ¹ )

wherein Y ^{1 is} isocyanato or thioisocyanato. The reaction can be carried out in a manner similar to that when using the compound (III).

Another typical method for preparing the amino acid of formula (I) comprises (1) reacting a: • Compound the general formula

^ CHO (IV)

wherein R ^ is as defined above, with the acylating agent of the formula (III) or (III ¹ ), (2) the reaction of the product of the general formula obtained thereby

GHO (V)

R ₂ -YN

wherein R ^, R ₂ , R, and Y each have the meanings given above, with hydrogen cyanide in the presence of ammonia and hydrolysis of the product of the formula obtained thereby

^R 1

(VI)

^R 3

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wherein R-, E ₂ » ^R 3 ^{and Y are as} defined above.

The reaction (1) can be easily carried out by treating the compound of the formula (IV) with the acylating agent of the formula (III) or (III ¹ ) in an inert solvent (e.g. water, dioxane, tetrahydrofuran, ether), if necessary in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline). The starting compound of the formula (IV) is sometimes commercially available in a polymerized form and it can be reacted as such in the same manner as when using its monomeric form.

The implementation (2) is the so-called "Strecker amino acid synthesis" and it can be based on known methods Way to be carried out. For example, it can be carried out by treating the compound of the formula (V) with an alkali metal cyanide (e.g. sodium cyanide, potassium cyanide) and an ammonium halide (e.g. ammonium chloride, Ammonium bromide) in aqueous ammonia.

The hydrolysis (3) can also be carried out in a manner known per se, for example by treating the Compound of the formula (VI) with an acid (e.g. hydrochloric acid, nitric acid, sulfuric acid) in an aqueous one Medium. If the treatment is carried out under relatively severe conditions, for example using a higher concentration of acid and / or one x ^ higher Temperature, is carried out, the cyano group is hydrolyzed to a carboxyl group in a single step. if on the other hand the treatment under relatively mild conditions, for example using a lower one Concentration of the acid and / or is carried out at a lower temperature, the cyano group is only

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hydrolyzed to a carbamoyl group, the main product being a compound of the following general formula is obtained

'CH-COWH ₃ (VII)

wherein R _x ,, Ep, R ^ and Y have the meanings given above. In the latter case, the carbamoyl group can be easily hydrolyzed to a carboxyl group by treatment under relatively severe conditions as mentioned above. The hydrolysis is carried out in two stages.

The protective group in the amino acid of the formula (I) thus prepared can, if desired, be known per se Manner, with or without prior isolation or purification of the product. One of the typical elimination procedures for the protecting group on the ot amino group is carried out by treatment with an acid, as is usually the case for benzyloxycarbonyl, substituted or unsubstituted Benzyloxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted Aralkoxycarbonyl, adaiaantyloxycarbony], trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like is applied. A wide variety of acids can be used as the acid, which is particularly preferred one is used that can easily be distilled off under reduced pressure (e.g. formic acid, trifluoro

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acetic acid). The elimination sometimes turns into an inert Solvent, usually in one miscible with water organic solvents or in water or a mixture thereof.

Another typical process is catalytic reduction, as they usually refer to substituted or unsubstituted benzyloxycarbonyl, 2-pyridylniethoxycarbor.yl and the like is applied. The most commonly used catalyst is a palladium catalyst, it can also cause cancer any other catalyst can be used. Other typical procedures include treatment with water based on trifluoroacetyl is applicable, and treatment with a heavy metal (e.g. copper, zinc) based on haloalkoxycarbonyl and 8-quinolyloxycarbonyl is applicable.

When the c * amino group is in the form of an acid addition salt is protected, the elimination can be carried out by treatment with an organic base (e.g. tri-ethylamine, triethylamine, N-methylpiperazine, Ν, Ν-dimethylaniline or pyriaine) or an inorganic base (e.g. sodium hydroxide, potassium hydroxide, Ammonium hydroxide, sodium carbonate, potassium carbonate or ammonium carbonate). If the Ol amino group is protected together with the carboxyl group in the form of a chelate, the elimination of the Metal compounds used chelation in a conventional manner, for example by treatment with hydrogen sulfide or an ion exchange resin.

The elimination of the silyl ester to recover a carboxyl group can be carried out quite easily in the presence of 'barrels be performed. For example, the work-up leads containing the amino acid of the formula (I) in which the carboxyl group is protected in the form of a silyl ester

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Reaction mixture in the usual way in the presence of water for easy elimination of the silyl group. There is one special procedure for eliminating the silyl group is usually not required. When the carboxyl group in any form other than a silyl ester is, the elimination of this protective group can be carried out by an ordinary method.

As indicated above, however, the amino acid of the formula (I) is suitable for the formation of the acylaraino group in the 7-position of cephalosporin compounds and if of this If use is made of the property, the elimination of the protective group on the et -amino group is usually not necessary.

The amino acid of the formula (I) can exist in the form of the D-isomer or the L-isomer or in the form of a racemic mixture. When obtained in the racemic form, it can be subjected to racemic resolution at any stage of preparation. In the preparation of the amino acid of the formula (I) by a process which comprises three steps, ie the reaction (1), the reaction (2) and the hydrolysis 0), the end product is generally obtained in the form of a racemic mixture the splitting of the racemic mixture into the optical antipodes can be carried out in the stage after the reaction (2) (ie with the compound of the formula (VI)) or in the stage after the hydrolysis (3) (ie with the compound of the formula (I) ) be performed. In general, the optical resolution of the racemic mixture after reaction (2) is favorable because better results are obtained.

To prepare the cephalosporin compound having the acylamino group (A) at the 7-position by using the above

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Amino acid of the formula (I) prepared can be a 7-aluino-3-substituted-5-cephem-4-carboxylic acid the general formula

(VIII)

COOH

wherein R ^ is hydrogen, a lower alkanoyloxy or a denotes heterocyclic thio group, the heterocyclic group being substituted by lower alkyl, or its derivative at the amino group and / or the carboxyl group with the amino acid of the formula (I) or its reactive Derivative on the carboxyl group by a coupling process known per se, as it is for the production of a Amide bridge bond is applied, are implemented under Formation of a cephalosporin compound of the general formula

COOH

wherein Rp R ₂ , Rz »R ^. and Ϊ have the meanings given above, or a derivative thereof.

The term "heterocyclic thio group" as used herein embraces the remainder of a thiol compound with a heterocyclic one Group that is the rest of furan,

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Thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, Oxazole, isoxazole, thiadiazole, oxadiazole, thiatriazole, Oxatriazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzothiophenes benzofuran, indole, indazole, Benzimidazole, Benzothiazole, Benzothiadiazole, Benzoxazole, Purine, quinoline, isoquinoline, phthalazine, naphthyridine, Quinoxaline, quinazoline, pyrrolidine, imidazolidine, piperidine, piperazine or the like. The heterocyclic one The remainder of the “heterocyclic thio group” can be substituted by one or more lower alkyl residues.

The derivative on the carboxyl group of the compound of formula (VIII) can be a salt, e.g. B. a magnesium, Calcium, triethylamine salt and the like; an ester, e.g. B. a methyl, ethyl, propyl, butyl, pentyl, trimethylsilyl, 2-mesylethyl, 2-iodoethyl, 2,2,2-trichloroethyl, Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenacyl, Phenethyl, trityl, diphenylmethyl, bis (methoxyphenyl) -niethyl-, 3,4-dimethylbenzyl-, (1-cyclopropydäthyl-, Ethynyl, 4-hydroxy-3,5-d.i-t-butylbenzyl esters and the like; act as an amide or the like. The derivative on the carboxyl group and / or the amino group of the compound of Formula (VIII) can be the reaction product of the compound of Formula (VIII) with a silyl compound, such as. B. bis (trimethylsilyl) acetamide, be.

The derivative on the amino group of the amino acid of the formula (I) is, for example, one in which 1 or 2 hydrogen atoms the amino group by acyl, for example by substituted or unsubstituted benzyloxycarbonyl (e.g. B. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bronbenzyloxycarbonyl, 4-methoxybenayloxycarbonyl,

3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) -benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl),

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substituted or unsubstituted alkoxycarbonyl or cycloalcoxycarbonyl (e.g. t-butoxycarbonyl, t-pentyloxycarbonyl, isopropoxycarbonyl, diphenylinethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 3-cyclopropoxycarbonyl, 3-cyclopropyl , 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl), (heterocyclic ring) oxycarbonyl (e.g. 8-quinolyloxycarbonyl) or substituted alkanoyl (e.g. trifluoroacetyl), trityl, trialkylsilyl (e.g. trimethylsilyl, triethylsilyl) or substituted Ph .enylt.bio (e.g. 2-nitrophenylthio, 2,4-dinitrophenylthio) is replaced; bz'.v. are. This also includes those in which protected Air.inogruppe in the form of a Schiff Base isb and the two hydrogen atoms are replaced by substituted alkylidene (eg., 2-hydroxybenzylidene _t 2-hydroxy-chlorben2yliden 5, 2-hydroxy-naphthylmethylene 1, 3-Hydroxy-4-pyridylmethylene, 1-Mcr.hoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-proj.'ylidene, 3-ethoxycarbonyl-2-butylidene, i-acetyl-2-propylidene, 1-propionyl-2 -propylidene, i-benzoyl-2-propylidene, 1,3-bis (ethoxycarbonyl) -2-propylidene, 1,3-bis (ethoxycarbonyl) -2-propylidene, 1- (N-methylcarbamoyl) -2-propylidene, 1- _(N-1 K-dimethylcarbamoyl) -2-propylidene, 1- £ N (2-methoxyphenyl) carbamoyl] -2-propylidene, 1- [N- (4-methoxyphenyl) carbf;? Moyles] -2-propylidene, 1 - (N-phenylcarbamoyl) -2-propylidene, 2 - \ thoxycarbonylcyclopentylidene, 2-ethoxycarbonylcyclohexylidene, 2-acetoxycyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene) are replaced. These also include those in which the amino group is protected in the form of an acid addition salt, for example in the form of a hydrochloride, hydrobromide, hydroiodide or the like.

The reactive derivative on the carboxyl group of the amino acid of the formula (I) can be an acid halide, an acid anhydride, an activated amide, a

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act activated ester or the like. Suitable examples are an acid chloride, an acid azide, a mixed acid anhydride with an acid, such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, a halogenated phosphoric acid, dialkyl phosphoric acid, sulfurous acid, thiosulfuric acid, sulfuric acid, e.g. , Phenoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroesslgic acid) or an aromatic carboxylic acid (e.g. benzoic acid), or a symmetrical acid anhydride; an acid amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an ester Cz. B. a cyanomethyl, methoxymethyl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, methanesulfonylphenyl, phenylazophenyl, Phc-nylthio, p-Mtrophenylthio, p -Cresylthio, carboxymethylthio, pyranyl, pyridyl, piperidyl, 8-quinolyl thioester or an ester with N ₁ N-dimethyxylamine, 1 "-hydroxy-2- (1H) pyridone, N-hydroxysuccinimide, N- Hydroxyphthalimide) or the like.

When the amino acid of the formula (I) is used in the form of the free acid or in the form of a salt, the coupling reaction is preferably carried out in the presence of a condensing agent which is suitably selected from N, N ¹ -dicyclohexylcarbodiimide, N-cyclohexyl-N ¹ -morpholinoäthylcarbodiimid, N-Cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide, N ^' - Diethylcarbodiimid, Κ, Ν'-Diisopropylcarbodiimid, N-Ethyl-N'-O-Aimethylaminopropyl) -carbodiimid, Carbonyldi (2-methylimidazole), pentamathylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-i-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl oxychloride, phosphorus trichloride,

A09884 / U65

Triphenylphosphine, 2-ethyl-7-hyd.roxybenzisoxazolium oil, intramolecular 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide salt, (ChloromethyleneMimethylammoniumchlorid and like that. The salt of the amino acid of the formula (I) can be an alkali metal salt, an alkaline earth metal salt, an ammonium salt, a salt with an organic base such as trimethylamine, dicyclohexylamine or the like Act.

The coupling reaction can be carried out in the presence of a base such as alkali metal bicarbonate, trialkylamine, N, N-I) ialkylbenzylamine or pyridine, usually in an inert solvent. Examples of suitable solvents are acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, Pyridine and the like. Among these, the hydrophilic solvents can be mixed with water be used. When the base or the condensing agent is liquid, it can also be used as a solvent. The reaction temperature is in none Manner limited and the reaction is carried out in the cone with cooling or at room temperature.

Depending on the type, the protective group for the amino group can be used in the course of the coupling reaction or as a result of an aftertreatment removed. If the product has a protected amino group, the protecting group can, if desired can be eliminated by using any of the above appropriate methods.

The cephalosporin compound (Formula IX: R ^ * a heterocyclic Thio group (optionally substituted by lower alkyl) or its derivative can also be prepared by implementing the corresponding cephalosporin

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compound (Formula IX: R ^ = lower alkanoyloxy) or theirs Derivative with a thiol compound of the general formula

H4.-H (X)

wherein R / denotes a heterocyclic thio group which may be substituted by lower alkyl, corresponding to the radical R ^, in the compound of the invention or its Alkali metal salt. The alkali metal salt of the thiol compound of the formula (X) may be sodium, potassium salt or the like be.

The above reaction can be carried out in an inert solvent such as water, acetone, chloroform, nitrobenzene, dimethylformamide, methanol, ethanol or dimethylsulfoxide. Among these solvents, the hydrophilic solvents can be used in admixture with water. The reaction is preferably carried out at a pH around 7 or in a nearly neutral medium. If the cephalosporin starting compound (formula IX: R _1. = Heterocyclic thio group (optionally substituted by lower alkyl)) or the thiol compound of the formula (X) is used in free form, the reaction is advantageously carried out in the presence of a base, such as. B. an alkali metal hydroxide, an alkali metal carbonate, egg »ies alkali metal bicarbonate, a trialkylamine or pyridine base, carried out. The reaction temperature is in no way restricted and the reaction is usually carried out at room temperature or with heating. The reaction product can be isolated from the reaction mixture by any conventional method. If the reaction product is protected at the amino group, the protecting group can be eliminated by any of the above-mentioned suitable methods.

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The cephalosporin compound of the formula (IX) thus obtained can by a method known per se, for example by reaction with an inorganic base, such as. B. an alkali metal hydroxide, an alkali metal bicarbonate or an alkali metal carbonate, or an organic base into their pharmaceutically acceptable, essentially non-toxic salts are transferred. The preferred method for preparing the salts is that the Cephalosporin compound of the formula (IX) dissolves in free form in a solvent in which the salt is insoluble, and then adding a solution of the base, whereby the Balz is precipitated from the reaction mixture.

The cephalosporin compounds of the formula (IX) are excellent in antimicrobial activity (effectiveness). The csphalosporin compound (formula IX: R _7. = Hydrogen, R ₂ = methyl, R ₅ = hydrogen, R ^ = Y, hydrogen, T = -SO ₂ - (the group R ₂ -YN- is in the m-position on the benzene

«3
ring vor) (hereinafter referred to as compound B) has a higher antimicrobial activity than cephalexin, which can be seen from Table I below.

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Table I.

Minimal inhibition concentration of compound B and on cephalexin in microorganisms, determined by the two-fold agar plate dilution method

Test organisms I.
.Minimal inhibition con-
centration C _x U g / ml) Cephalexin 3taph. aureus Terashima
3taph. aureus Smith
B. subtilis ATCC-6633
B. subtilis PCI-219
tQebsiella IiCTC-418
3al. typhi T-287
3al. typhi 0-901
3al. para A 1015
3al. typhimurium 1406
3al. enteritidis 1891 Connection B 25th
6.25
1.56
1.56
6.25
6.25
6.25
12.5
12.5
6.25 12.5
3.13
0.78
0.78
3.13
3.13
3.13
6.25
3.13
3.13

In addition, the cephalosporin compounds of the formula (IX) Maintain their antibiotic effectiveness at high levels for extended periods of time when taken orally administered. In the following Table II, for example, the serum contents of the compound B and Cephalexin given with the passage of time after oral administration to mice and rats.

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2432-90

Table II

Seruffig levels of compound B and cephalexin in mice and rats

Examined
Pier and dose Examined
link Serum gphalt ( yU. G / ml) 2 3td. 4 hours 6 pcs. iJaus (ICR)
100 mg / kg Connection E
Cephalexin 1 H. 25.0
4.6 14.7 8.4 Rat (SD)
100 mg / kg Connection B
Cephalexin 57.6
10.4 44.8
12.5 41.1
6.6 59.0
5.9 49.8
25.1

As indicated above, those according to the invention are suitable Cephalosporin compounds of the formula (IX) as orally administrable antibiotics with a long duration of action. "7 for them For therapeutic administration, the cephalosporin compounds of the formula (IX) are in the form of pharmaceutical preparations used which these compounds in admixture with a pharmaceutically acceptable organic or inorganic Contain solid or liquid carrier or excipient suitable for oral, parenteral, intestinal or percutaneous administration. The pharmaceutical preparations can be in solid form, e.g. B. in the form of capsules, Tablets or dragees, or in liquid form, e.g. B. in the form of solutions, suspensions or emulsions. They can also be in any other form, for example in the form of suppositories and ointments. If so desired the above-mentioned preparations can also contain auxiliary substances, stabilizers, wetting agents or emulsifiers, Contain buffers and other commonly used additives.

Although the dosage of the cephalosporin compounds of the

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Formula (IX) varies and also depends on the age and condition of the Depending on the patient, a mean single dose of about 100 mg, 250 mg and 500 mg has been found to be effective for treatment of diseases caused by bacterial infection. In general, amounts between 10 and about 1000 mg or even larger amounts can be administered.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

Example 1 A

(1) 8 »7 g of N-t-butoxycarbonyl-2- (3-aminophenyl) -D-glycine

and 15.1 g of N-trimethylsilylacetamide made 166 ml Methylene chloride was added and the resulting mixture was stirred at room temperature for 1.5 hours. To the obtained mixture were 13.1 g of ivridine with ice cooling was added dropwise and then at a temperature of 3 to 5 ° C, a solution of 8.45 g of methanesulfonyl chloride in 35 nil Methylene chloride was added dropwise. It was kept at the same temperature for another 30 minutes and then for 4 hours stirred at room temperature. The reaction mixture was with shaken with an aqueous citric acid solution, with water washed, and then the methylene chloride layer was separated. The methylene chloride layer was washed with a 5% shaken aqueous sodium hydrogen carbonate solution and the water layer was separated. The water layer was with adjusted to pH 5 with an aqueous citric acid solution and salted out to form a resinous substance. The resinous substance was extracted with methylene chloride and the extract was washed with a dilute sodium chloride aqueous solution, dried and reduced under reduced pressure Concentrated under pressure, 6.3 g of N-t-butoxy

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carbonyl-2-Q-mesylaminophenyl) -D-glycine in the form of an amorphous powder, NMR: (DMSO-d ^) 6 ppm: 1.38 (9H, s); 2.99 OH, s); 5.09 (1H, d, J »7.5Hz); 7.00 to 7.60 (4H, m).

(2) 4-, O g of the N-t -But oxy car bony 1-

-2- (3-mesylaminophenyl) -D-glycine were dissolved in ΙΟ ¹ - * ml of formic acid, the solution was stirred for 1 hour at room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of 10% aqueous acetonitrile and filtered. 10 ml of acetonitrile were added to the filtrate, and the precipitated crystals were collected by filtration and dried to obtain 2.7 g of 2- (3-mesylaminophenyl) -D-glycine in the form of colorless prisms, mp 196-198 ° C , IR (Nujol) V cm ^-1 : 3240, 2580, 1616, 1147; NMR (D ₂ O + DCl) 6 ppm: 3.18 (3H, s); 5.32 (1H, s), 7.47 (4H, m).

Example 2 A

As in Example 1, the sodium salt of D- (3-mesylaminophenyl) -N- (1-methoxycarbonyl-1-propen-2-yl) glycine was obtained from the sodium salt of D- (oL -3-aminophenyl) -N- (1-methoxycarbonyl-1-propen-2-yl) glycine and methanesulfonylc'aloride prepared, m.p. 141 to 143 ° C, IR (Nujol) ν cm " ¹ : 3250, 1650, 1610, 1150; NMR (DMS0-d ₆ ) J ppm: 1.68 (3H, s), 2.92 (3H, s), 3.52 (3H, s), 4.31 (1H, s), 4.78 (1H, d, J = 5.6Hz), 6.90 to 7.25 (4-H, m), 9.58 (iH, d, J = 5.6Hz).

Example 3 A

To a solution of 1.34 g of D-oL- (3-aminophenyl) -Nt-butoxycarbony! Glycine and 924 mg of sodium hydrogen carbonate in 25 ml

A09884 / U65

Water which ^{had been cooled to −2 °} C. was added dropwise within 10 minutes 860 mg methanesulfonyl chloride and the resulting mixture was stirred for 1 hour at the same temperature. After adding 164 mg of sodium hydrogen carbonate, stirring was continued at the same temperature for 2 hours and then for 1 hour at room temperature. The reaction mixture was washed with 30 ml of ether twice, and a small amount of insoluble materials was separated by filtration. The filtrate was adjusted to pH 3 with 10% hydrochloric acid, salted out and extracted twice with 40 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.4 g of ct- (3-mesylamiriophenyl) -Nt-butoxycarbonylglycine, fci] j) = -96 ° (methanol, C = 1).

Example 4 A

(1) To a solution of 5.326 g of N-t-butoxycarbonyl-2- (3-

aminophenyl) -D-glycine in 100 ml of methylene chloride were added 8 0 g of N, N-bis (trimethylsilyl) acetamide with stirring at room temperature. Stirring was continued for 1 hour at room temperature. Then / i was added 3 »165 g I ^ yridin under ice cooling (2 to 3 ⁰ C) and within 30 minutes a solution of 4.58 g of methanesulfonyl chloride in Γ.5 ml of methylene chloride was added dropwise under Biskühlung. Stirring * was continued for 30 minutes with ice-cooling and then for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was shaken with 100 ml of ethyl acetate and 50 ml of a 2M citric acid solution. The ethyl acetate layer was separated and washed with 50 ml of a 2M citric acid solution

409884 / U65

washed. The washing water was extracted with 30 ml of ethyl acetate. The extract was combined with the ethyl acetate layer with an aqueous saturated sodium chloride solution washed and extracted three times with 40 ml of an aqueous sodium hydrogen carbonate solution. The extracts were combined with one another, washed with 50 ml of ethyl acetate, adjusted to pH 4 with a 2M citric acid solution and salted out with sodium chloride. The precipitate was extracted four times with 50 ml of ether and the extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and reduced under reduced pressure Pressure concentrated to give 6.15 S N -t -butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine in the form of a powder, NMR (DJflSO-dg) J ppm: 1.40 (9H, s), 3.00 (3H, s), 5.11 (1H, d, J-8Hz), 7.00 to 7.60 (5H, m).

(2) The N-t-butoxycarbonyl-2- (3-

mesylaminophenyl) -D-glycine was as in Example 1 (2) treated to form 2- (3-mesylaminophenyl) -D-glycine.

Example 5 A

16.6 g of D-2- (3-aminophenyl) glycine were in 100 ml of a 1N sodium hydroxide solution and there were 40 ml of dioxane admitted. A solution of 26.2 g of copper (II) sulfate pentahydrate in 50 ml of water was added to the resulting solution Room temperature was added and stirring was continued for 40 minutes. The mixture obtained was with a 20% sodium hydroxide solution adjusted to pH 7.0 and a solution of 17.1 g of methanesulfonyl chloride in 20 ml of dioxane was added at 26 to 28 ° C within 1 hour, during this time 47 ml of a 20 # sodium

A09884 / U65

Hydroxide solution were added dropwise to keep the pH at 6.0 to 6.5. The reaction mixture was stirred at room temperature for 1 hour and adjusted to pH 3.0 with 10% hydrochloric acid. Removal of the organic layer by distillation under reduced pressure gave copper (II) -2- (3-mesylaminophenyl) -D-glycinate, which was adsorbed on an OÄmberlite IR 120B ion exchange resin "from Rohm & Haas, Co.). and it was washed with water until the eluate was neutral. The ion exchange resin was then eluted with ammonia water (water: 30% ammonia water = 14: 1 by weight). The eluate was concentrated under reduced pressure. The residue was concentrated dissolved in a small amount of methanolic hydrochloric acid and adjusted to pH 5 with methanolic ammonia, the resulting solution was allowed to stand overnight, the precipitated crystals were collected by filtration and dried to give 15.6 g of 2- (3-mesylaminophenyl) -D- glycine in the form of pale brown needles, F. 186.5 to 187 ⁰ C, IR (Nuool) V-cm " ¹ : 1605 (broad), 1150, NMR (DCl + D ₃ O) <J ppm: 3.17 ( 3H, s), 5.16 (1H, s), 7.4-5 (4H, m).

Example 6 A

To the mixture obtained using 16.6 g of D-2- (3-aminophenyl) glycine and 26.2 g of copper (II) sulfate pentahydrate in Example 5, a solution of 27.5 g of methosulfonyl chloride in 27 ml of dioxane was added within 1 Hours at 26 to 28 ⁰ C was added dropwise, during this time a 20% sodium hydroxide solution was added dropwise in order to keep the pH at 8 to. The reaction mixture was treated as in Example 5, with formation of 2- (3-dimesylaminophenyl) -D-glycine in the form of colorless prisms, mp 17-173 ° C

A0988A / U65

(Dec.); IR (Nujol) y cm " ¹ : 1650, 1160; NMR (DCi + j ppm: 3.50 (6H, s), 5.33 (1H, s), 7.61 (4H, m).

Example 7 A

A solution of 5 g of D- (oL -4-aminophenyl) -Kt-butoxycarbonjrlglycine and 11.0 g of bis (trimethylsilyl) acetamide in 120 ml of methylene chloride was stirred for 2 hours at Räumteniperatur and at 2 to 3 ° C was within 30 A solution of 4.12 g of methanesulfonyl chloride in 40 ml of methylene chloride was added dropwise in minutes. The obtained mixture was stirred at the same temperature for 30 minutes and then allowed to stand at room temperature overnight. After removing the solvent under reduced pressure, ethyl acetate and a 1M citric acid solution were added to the residue. The ethyl acetate layer was burned off and washed with an aqueous citric acid solution. The washing waters and the aqueous layer were combined and extracted with ethyl acetate. The ethyl acetate extract and the previously obtained ethyl acetate layer were combined, washed with water and shaken with an aqueous saturated sodium hydrogen carbonate solution. The aqueous layer was separated, adjusted to pH 4 with a 2M citric acid solution and extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous saturated sodium chloride solution and dried. After removing the solvent by distillation under reduced pressure, the obtained oil (6.0 g) was pulverized with ether and isopropyl ether to obtain 5.5 g of D-0L- (4-mesylaminophenyl) -Nt-butoxycarbonylglycine in the form of crystals; F. 165 to 183 ° C, IR (Nujol) V cm " ¹ : 3325, 3125, 174-7, 1673; NMR ((CD,) ₂ CO) έ ppm: 1.32 (9H, s), 2, 84 (3H, s), 5.0 (1H, d), 6.90 to 7.3 (4H, m).

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Example 8 A

3.99 g of Nt-butoxycarbonyl-2 - ($ - aminophenyl) -D-glycine and 6.12 g of N, N-bis (trimethylsilyl) acetamide were added to 40 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 2 hours . 2.4 g of pyridine and 3.84 g of ethanesulfonyl chloride were added dropwise to the mixture obtained while cooling with ice. Stirring was continued for 2 hours at 0-5 ° C and then for 1 hour at room temperature. The reaction mixture was washed twice with 20 ml of 2% hydrochloric acid, twice with 20 ml of water and once with a saturated aqueous sodium chloride solution in the order given. The methylene chloride layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether and 4.4 g of Nt-butoxyearuonyl-2- (3-ethanesulfonamidophenyl) -D-glycine were obtained in the form of a powder; IR (film) V cm " ¹ : 3230, 1720, 1680; IMR (CDCl3,) k Ppm: 1.18 (3H, t, J = 7.5 Hz), 1.36 (9H, s), 3, 05 (2H, q, J = 7.5 Hz), 3.16 (1H, broad, s), 7.23 (4H, s), 7.71 (111, broad s), 8.59 (1H, broad ' s).

Example 9 A

A solution of 0.5 g of D- ot - (3-aminophenyl) -N-t-butoxycarbonylglycine and 1.15 g of bis (trimethylsilyl) acet.aruid in 20 ml of methylene chloride was stirred for 2 hours at room temperature and cooled to 2 to 3 ° C. It was 0.3 g lyridine and a solution of 0.54 g of ethylaminosulfonyl chloride in 6 ml of methylene chloride were added dropwise. The received The mixture was stirred at the same temperature for 30 minutes and then for 15 hours at room temperature. To

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After removing the solvent, ethyl acetate and a 1M citric acid solution were added to the residue. The ethyl acetate layer was separated and washed with an aqueous citric acid solution. The wash water and the water layer were combined, salted out and extracted with ethyl acetate. The ethyl acetate extract and the previously obtained ethyl acetate layer were combined with each other, and an aqueous sodium hydrogen carbonate solution was added. The water layer was separated off, washed with ethyl acetate, adjusted to pH 4 with a 2M citric acid solution and extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous saturated sodium chloride solution and dried. Removal of the solvent by distillation under reduced pressure gave 0.5 g of Do * .- (I-ethylaminosulfonamidophenyl) -Nt-butoxycarbonylglycine in the form of an oil; IE (film) ν cm " ¹ : 3250, 1700 (broad); NMR (CDCl ₃ ) ei ppm: 0.97, OH, t), 1.35 (9H, s), 3.00 (2H, q) , 5.20 (1H, broad s), 7.20

Example 10 A

To a solution of 8.0 g of D- oL- (3-amino-4-hydroxyphenyl) -N-t-butoxycarbonylglycine in 150 ml of methylene chloride 11.5 6 bis (trimethylsilyl) acetamide were added and the resulting Solution was stirred at room temperature for 30 minutes. After cooling with ice, 4.5 g of pyridine were added and then 6.5 g of methanesulfonyl chloride was added dropwise to the obtained mixture. The stirring was 30 minutes with ice-cooling and then continued for 2 hours at room temperature. The reaction mixture was reduced under Pressure restricted. The residue was mixed with ethyl acetate and water, made acidic with phosphoric acid

409884 / U65

and the ethyl acetate layer was separated from the water layer. The ethyl acetate layer was back extracted with an aqueous sodium hydrogen carbonate solution and the Y / water layer was separated, made acidic with phosphoric acid and back extracted again with ethyl acetate. The ethyl acetate extract was washed with water, dried and treated with activated charcoal. The resulting solution was then concentrated to give 6.0 g of D-oC- (3-mesylamino-4-hydroxyphenyl) -Nt-butoxycarbonylglycine; IR (chloroform) V cm " ¹ : 1730 (shoulder), 1715; NMR (D ₂ O-NaHCO ₃ ) Ci ppm: 1.4

(9H, s), 3.05 OH ( ₁ S), 4.83 (1H, s), 6.87 (1H, d, J = 8Hz).

Example 11 A

To a solution of 7.0 g of D-et- (3-aminophenyl) -i4-t-Dutoxycarbonylglycine and 2.92 g of triethylamine in 100 ml of methylene chloride, which had cooled to 5 ° C, was a solution of 3.0 g .Methylisocyanat in 25 ml of methylene chloride within of 5 minutes was added dropwise and the resulting mixture was stirred for hours at room temperature. After removal d'es solvent by distillation, the residue was dissolved in ethyl acetate and made up with a 2M citric acid solution washed. The organic solvent layer was washed with water and with an aqueous sodium hydrogen carbonate solution extracted. The water layer was separated, washed with ether and with 10% sulfuric acid adjusted to pH 6. The original solution was made with citric acid adjusted to pH 3 to 4, salted out and with. Ether extracted. The ether extract was washed with water, dried over anhydrous magnesium sulfate and taken under concentrated under reduced pressure to form D-oA- \ 3- (3-Methylureido) phenyl? -N-t-butoxycarbonylglycine (5.7 g) in the form of a foamy material; NMR (DMSO-dg) <f ppm:

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1.57 (9H ₁ S), 2.54 (3H, d, J «4.5Hz), 4.97 (1H, d, J = SHz), 5.96 (1H, d, J = 4.5Hz ), 6.7 to 7.6 (6H, m), 8.4? (iH, s); CdJ _Q = 111 ° (99% ethanol).

Example 12A

A mixture of 9.00 g of D-cL- (3-aminophenyl) -Nt-butoxycarbonylglycine, 3.41 g of triethylamine and 3.70 g of methyl thioisocyanate in 45 ml of methanol was refluxed for 2 hours. After removing the solvent by distillation, the residue was dissolved in 100 ml of ethyl acetate and the resulting solution was washed four times with 40 ml of a 2M citric acid solution and once with an aqueous saturated sodium chloride solution, and then extracted four times with a saturated aqueous sodium hydrogen carbonate solution (40 ml). The barrel layer was separated, washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted three times with 50 ml of ether. The extract was dried over anhydrous magnesium sulfate and treated with activated charcoal. After removing the activated carbon by filtration, the piltrate was concentrated under reduced pressure to obtain 8.60 g of D-cL- {3- (3-methylthioureido) phenylj-N-t-butoxycarbonylglycine; IR (Nujol) V cm " ¹ : 3350, 1740-1670 (several), 1370, 1250, 1163, 1052; NMR (DMS0-d ₆ ) 4 ppm: 1.37 (9H, s), 2.93 (3H , d), 5.07 (1H, d, J = 9Hz), 6.9 to 7.9 (6H, m), 9.21 (1H, s); folj3-101 ° (methanol, C = 1 ).

Example 13A

(1) 5 _f 16 g of 3-aminobenzaldehyde (polymerized form;. Water content 3 wt%) and 3.3 ml of water were added to 80 ml

409884/1465

Tetrahydrofuran was added and the mixture was cooled to 5 to 10 ⁰ C. After the addition of 7.9 g of pyridine, 11.5 g of methanesulfonyl chloride were added dropwise at the same temperature over the course of 15 minutes and stirring was continued for 3.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, 120 ml of 5% hydrochloric acid, 60 ml of ethyl acetate and sodium chloride were added, and the precipitate was collected by filtration and recrystallized from ethyl acetate to give 1.8 g of 3-mesylaminobenzaldehyde as crystals ; P. 142-144 ⁰ C. The ethyl acetate layer was separated, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the same product as above (4.36 g). A further 0.83 g of the same product obtained above was obtained from the ethyl acetate mother liquor; Total yield 6.99 g; IR (Nujol) y cm " ¹ : 3120, 1670, 1600, 1580, 1320, 1242, .116O ₁ 1143, 997, 970, 890, 788, 755, 670; NMR g ti ppm: 3.05 (3H, s ), 7.4 to 7.8 (4H, m), 9.95 (1Π, β), 10.07 (1H, broad s).

(2) To a mixture of 2.18 g sodium cyanide, 2.19 g

Ammonium chloride and 17 ml of 28% ammonia water, cooled to 10 ⁰ C, was added within 4 hours, with stirring, 3.98 g of 3-Mesylaminobenzaldehyd at 10 to 15 ° C. After removal of the excess ammonia from the reaction mixture at 15 ° C under reduced pressure, the pike stand with concentrated hydrochloric acid to pH 7 was set and extracted five times with ml üthylacetat 30th The extract was washed with 30 ml of an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under

4098Ö4 / 1465

Formation of 4.19 g DL-oi-amino-oL-O-mesylaminophenyl) acetonitrile in the form of an oil; IR (film) ν cm "': 3270, 1608, 1595, 1477, 1400, 1327, 1148, 972, 090, 795, 768, 697; MR (DI! S0-d ₆ ) J ppm: 3.00 (3H , s), 5.01 (IH, s), 7.0 to 7.7 (4H, m).

(3) 7 ml of sis acetic acid and 1.56 g of finely powdered L (+) - tartaric acid were added to 2.10 g of DL-oL-amino-oL- (3-mesylaminophenyl) acetonitrile. To the resulting solution, 4.7 ml / ithyl acetate was added in portions with stirring, and stirring was continued overnight at room temperature. The precipitated crystals were collected by filtration, washed with a mixture of ethyl acetate and acetic acid and with ethyl acetate in the order given, and dried to give 3.25 g of D-Ql-aminocc- (3-mesylaminophenyl) aoetonitrile-L (+) -tartrate (with 1 molecule of acetic acid) received; 97 to 98 ° C .; IR (Hu.jol) V cm " ¹ : 3220, 2670, 1735, 1692, 1593, 1542, I520, 1422, 1405, 1310, 1262, 1237, 1220, 1165, 1153, 1070, 978, 903, 800, 782 , 663, 602; MR (D ₂ O-DCl) J ppm: 2.13 (3H, s), 3.20 (3H, s), 4.78 (2H, s), 5.87 (1H, s ), 7.3 to 7.7 (4H, m); fci] _D - + 31 ° (1N HCl, C = 1).

(4) A solution of 434 mg of D- ö - amino- a- (3-mesylaminophenyl) acetonitrile-L (+) - tartrate (with 1 molecule of acetic acid) in 1.9 ml of 23.2% hydrochloric acid became 4 Refluxed for hours, after removal of the hydrochloric acid under reduced pressure about 5 ml of methanol were added to the residue. The resulting solution was adjusted to pH 6 with methanolic ammonia and left to stand in a refrigerator overnight. The precipitated crystals were through. Filter collected} the collected crystals (132 mg) were dissolved in 0.5 ml of water while hot, becoming 2 ml of methanol

409894/1466

was added and the resulting mixture was left to stand in a refrigerator overnight. The precipitated crystals were collected by filtration and washed with methanol to give 54.3 mg D-ol ~ (3-Mesylaminophenyl) glycine, F. 193 to 194- ⁰ C (dec.) IR (Nujol) V cm ^"1 : 3230, 272O ₁ 2550, 1610, 1508, 1400, 1330, 1310, 1260, 1145, 985,? 83, 695, 662; HMR (D ₂ O-HCl) d ppm: 3.20 (3H, s), b, 38 (1H, s), 7.3 to 7.7 (4H, m); fcLJ _D = -100 ° (1N HCl, C = 1).

(5) To a solution of 1.08 g of sodium cyanide (purity

90%) and 1.18 g of ammonium chloride (purity 98.5 #) in 17 ml of 30% aqueous ammonia were added at 15 ° C. to 1.99 g of m-mesylaminobenzaldehyde and the resulting mixture was kept at the same temperature for 4.5 hours stirred for a long time, the excess ammonia was distilled off at 35 ° C. under reduced bridge. The resulting solution was adjusted to pH 7 with 10% hydrochloric acid and extracted four times with 15 ml ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and concentrated to about 10 ml under reduced pressure. The concentrated solution was extracted four times with 5 ^ lL of 10% hydrochloric acid. The extract was washed with 5 ml of ethyl acetate, mixed with 8.6 ml of 35% hydrochloric acid, and refluxed for 3 hours. The reaction mixture was treated with activated charcoal, concentrated under reduced pressure to remove hydrochloric acid and mixed with 5 ml of ethanol and then evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of methanol by heating and adjusted to pH 5 with methanolic ammonia. The precipitated crystals were after standing. Ueker overnight in a refrigerator was collected by filtration, washed with methanol and dried under suction to ZIe obtained crystals (1.93 g) were durci heater al In 4

408804 / 146S

Dissolved water, δ ml of ethanol was added and the resulting mixture was left to stand in a refrigerator overnight. The precipitated crystals were collected by filtration and dried to obtain 0.98 g of B-ci .- (3-mesylaniinophenyl) 3; iycin; IE (Nujol) ν cm ": 3260, 1695, 1605, 1590, 1477, 1400, 1530, 1250, 1150, 973, 8 * 0, 790, 760; NMR (D ₂ O + DCl) J ppm: 3.18 ($ H, s>, 5.38 (IH, s), 7.2 to 7.6 (4H, ia).

Example 14 A

(1) 435 mg D-ά-Affiino-x-Cr

L {+) - tartrate (old 1:.! Oi acetic acid) were dissolved in 1.5 tablespoons of concentrated hydrochloric acid and the resulting solution was heated under Biicxfiufi Püakstsnd was applied to an ion exchange resin column ("lir-bsrlite IP: - •; 20B", _ H ⁺ type from Rohm & Haas Co.) ^ 10 121) and washed with water until the wash was neutral became. Bann was 7 / fei & es aqueous Ainaonii ;. ": aiii the column was given up, the eluate was whipped up and concentrated under reduced pressure, the residue was crystallized from ifsthancl and 220 mg of r-0L- (? .-? * esylaminD-phenyl) glycine in the form of crystals, F. 20 "" 5 (decomp.), r <iJ _D = -100 ° (1N hydrochloric acid, G = ".) ■,

(2) In a suspension of 3.0 5 of the above D-cL - (. 3-Mesylaminopiienyl) gl7Cins in 60 si

anhydrous. Methanol, di- · = ¹ are cooled n_it 3iswasser warj Dried hydrogen chloride gas was eingslsitet in order to Dasit. saturate _t ^ PIe obtained iseiiung was 40 hours Del ^ to ^ ⁰ Z stehengslassei :, the EaeI

409884 / U65

Removal of the solvent by distillation under reduced pressure, the precipitates were collected by filtration, dried under reduced pressure, washed with acetone and then dried again to give 3.8 g of the hydrochloride of D-ct- (3-mesylaminophenyl) glycine methyl ester (containing 1 / 2 moles of acetone); MMR (CD ₅ OD-D ₂ O) 6 ppm: 2.16 (3H, s), 3.05 (3H, s), 3.81 0H, s), 5.23 (1H, s), 7, 16 to 7.5

Example 15 A

A solution of 1.3 g of D- δ-amino- oC- (3-mesylaminophenyl) acetonitrile-L (+) - tartrate (with 1 mole of acetic acid) in 10 ml of concentrated hydrochloric acid was allowed to stand at room temperature for 1.5 hours . The reaction mixture was concentrated under reduced pressure and dried in vacuo. The yellow viscous solid obtained was washed with 10 ml of acetone and collected to give 580 mg D-OL (5-Mesylaminophenyl) glycinamide hydrochloride in the form of a greenish-white powder, mp 236-240 ⁰ C, IR (Nujol) V cm " ¹ : ¹ 3450 to 3350, 3240, 3I8O, 1695, 1605, 1590, II50.

Example 16 Δ

To a methanol solution saturated with 10 ml of hydrogen acid were water (1 drop) and 435 mg of D-α-Ami no- οι - (3-mesylaminophenyl) acetonitrile-L (+) - tartrate (with 1 mole of acetic acid) was added and the resulting mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, 20 ml of water was added, and the resulting solution was washed with an aqueous Sodium hydrogen carbonate solution neutralized. the

409884/1465

neutralized solution was then extracted with chloroform. The Chlorofora extract was concentrated under reduced pressure and 2J0 mg of D- <x- (3-i - ,: esylaminophenyl) glycine methyl ester, mp 101 to 153 ° C, IR (KuJoI) V cm " ¹ : 3370, 3300, 1740, 1605, 1590.

example 1

To a suspension of 3820 ug of the hydrochloride of 2,2,2-trichloroethyl-7-arairiO-3-methyl-3-cepr.eri-4-carboxylate 810 ng of triethylamine were added dropwise to 50 ml of absolute methylene chloride and 245 ag Ν, Ν-Eiiaethylsnilin with stirring and with ice cooling given. The mixture became 3o kin. at room temperature touched. 3440 mg K-tert, -r-utoxycarbonyl-2- (3-mesylaniiicphenyl) D-glycine, 1010 mg triethylasine and 4 drops Ν, Ν-dinethylbenzylaniine were added to 50 ml of absolute methylene chloride

409884/146 5 _ ₃₇

and the mixture was stirred while cooling with dry ice-acetone. A solution of 1085 mg of ethyl chloroformate in 25 ml of absolute methylene chloride was your mixture at -25 to -30 ⁰ C for 10 kin. added dropwise. This mixture was stirred at the same temperature for 15 minutes. To the mixture, the mixture prepared above was added in a single fraction, which had been pre-cooled to -15 ⁰ C. The resulting mixture v / urde stirred for 4 hours at -25 to 3O ⁰ C and then sraschen with water, 3 ^ hydrochloric acid and again with V / ater overall \. The organic layer was separated off, washed thoroughly with a 3% aqueous solution of sodium carbonate and water and washed. dried. The methylene chloride was removed under reduced pressure and the residue was dissolved in 10 ml of ethyl acetate. Ether was added and the crystals which appeared were filtered off. 4195 mg of 2,2,2-irichloroethyl ester of 7 -, / DN-tert.-butoxyuarbonyl-2- (3-mesylaminophenyl) glycinanid £ 7-3-methyl-3-cephem-4-carboxylic acid, F. 204 to 205 ⁰ C (decomposition) obtained.

The above-obtained 2,2,2-trichloroethyl-7- / D-lT-tert-butoxycarbonyl-2- (3-mesyäHminophenyl) glycinamide _i p7-3-methyl-3-cephem-4-carboxylate (3985 mg) was dissolved in 17 ml of dimethylformamide. To the solution were 5.0 ml of acetic acid and 398f. mg of zinc powder was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 2 hours. After an insoluble product was filtered off, the piltrate was washed with 3 ml of dimethylformamide. The washing liquid and the previously obtained filtrate were combined with each other and poured into 100 ml of 5% hydrochloric acid while cooling with ice. 50 ml v / water was added and the resulting mixture was extracted three times with ethyl acetate (50 ml). The extract was washed with water and back-extracted three times with a 5% aqueous solution (50 ml) of sodium bicarbonate and the aqueous layer was acidified with hydrochloric acid. The aqueous solution was again with

409884 / U65 - 38-

Ethyl acetate back-extracted and the extract was washed with '.fescor rev. ^r waste and dried. The solvent was removed under reduced pressure and the residue was dissolved in 10% ethyl acetate. The solution was allowed to stand at room temperature for one hour and then ether was added to the solution. 2s crystals of -7- / D-IT-te-rt.-3utoxycarbonyl-2- (3-mesylar.iincphenyl) -glycinamido / -3-methyl-3-cephera-4-carboxylic acid (2,667 mg) , M.p. 187 Ms 1E9 ° C (decomposition).

Example 2

To a suspension of 26.8 g of the hydrochloride of 2,2,2-tr-ichluräthyl-7-aninc-3-: r.ethyi-3-cephem-4-carboxylate in 500 ml dry! Ethylene chloride were gradually a solution of 7 g of triethylamine in dry l'ethylene chloride (25 ml) lind, danac? a solution of 2.14 g of 2,6-lutidine in 25 ml of methylene chloride was added while cooling with ice. In addition, 26.0 g of N-tert-butoxycarbonyl-2- (3-2iesylaiTiinophenyi) -D-glycine are then gradually added in 15 g of bicyclohexylcarbodiiniide and the mixture is stirred for 1.5 hours while cooling. After removing an insoluble product by filtration, the filtrate was washed four times with ice-cold 5% hydrochloric acid (100 ml), once with water, three times with 10% aqueous sodium carbonate solution and once with an aqueous saturated sodium chloride solution washed and then dried over magnesium salad. The solution was treated with activated charcoal and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate and left to stand overnight at room temperature. The crystals which formed were filtered off, with 31.3 g of 2,2,2-trichloroethyl ester of 7- / l) -li-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -glycinai! IiaG / -3-methyi -3-cephem-4-carbonsäui * e were obtained in the form of colorless plates. 189 to 191 ° C (decomposition).

The 2,2,2-trichloroethyl-7- / i) -tert-butoxyoarbonyl-2- (3-mesylaminophenyl) -glycine amide 557-3-diethyl-3-cephem-4-carboxylate (12.01 g) obtained above was dissolved in 40 ml of dimethylformamide. 15 ml of glacial acetic acid and 12 g of zinc powder became the solution gradually

409884 / U65

Untsr · Siskühiung added mid aas Gsniisch was "at the global

Stirred at temperature for one hour. After the reaction was finished, an insoluble product was filtered off and washed with ethyl acetate. The filtrate and the ash liquid were poured into 3 / $ strength chlorohydric acid (300 ml) while being cooled with ice. The mixture was extracted three times with ethyl acetate (150 nil). The ethyl acetate extract was washed with water and then back-extracted three times with a 5% aqueous sodium carbonate solution (150 ml). The aqueous solution was washed with ethyl acetate and adjusted to a pH of 2 with 10% hydrochloric acid. The product obtained was extracted three times with 150 ml of ethyl acetate. The extract vairde. washed with water and dried over magnesium sulfate and the solvent was removed under reduced pressure. The crystals which appeared were washed with ethyl acetate and with ether. Here vairden 8.38 g of 7- / DN-tert-butoxycarbonyl-2- (3-rnesylaminophenyl) -glycinamidoJ ^r -3-methyl-3-cephem-4-carboxylic acid, mp 188-189 ⁰ C (decomposition) .

IR. , _Λ

V "'): 3330, 3290, 3240, 1769, 1720,

1690, 1668, 1524, 1308, 1220, 1146, 912, 890, 772

«I.

NMR.

<Where d ^{(P pm:} 1:40 (9H _f s) _f 2:00 (3H, s)

⁶ 2.99 (3H, s), 3.37 (2H, broad s), 4.96 (1H, d, J = 4.4Hz), 5.30 (1H, broad d, -J = 8Hz), 5.63 (1H, d, d, J = 4Hz, 7Hz), 6.90- <7.50 (4H, m)

8.28 g of the 7- / D-N-tert-butoxycarbonyl-2- (3-mesylamino) -glycinamido_7-3-methyl-3-cephem-4-carboxylic acid obtained above were added to 140 ml of formic acid after cooling with the ice and then vairde stirred the mixture at room temperature for 1.5 hours. After removing the formic acid at 35 ° C. under reduced pressure vairde the residue dissolved in 30 ml of 5% hydrochloric acid. The solution was washed with 20 ml of ethyl acetate, with

409884/1466

-40 '

Treated activated charcoal and set it up to pH 3 with a 10% aqueous solution of sodium hydroxide. The red-red crystals were filtered, washed with water and dried, whereby 6.18 g of 7- / D- (3-l'esylaminopheryl) giycin-iiniidoy-3-methyl-3-cephen-4-carbonic acid, F. 199 up to 199.5 ⁰ C (decomposition) obtained vairden.

(O, 1n HCl,

UV.

pH 6.4 phosphate buffer ₂ 63.5 ηα, Ε = 172

Λ- ι

Max

pH 6.4 phosphate buffer _{228 fo E = 299}

Nl'IR IR.

_{0 + DC1}

(PPm)

^(cE1

2.08 (3H, s), 3.19 (3H, s), 3.21,3.44 (211, ABq, J = 18Hi ·.), 5.04 (in, d, J = 5H3), 5.37 (lH, s), 5.67 (lH , d, J = 5Hz) _f 7.4-7.67 (4H, m)

3610, 3510, 3330, 1750, 1700, 1600, 1526, 1380, 1366, 1328,

Example 3

A solution of 1.32 g of chlorofomate in 20 ml of dry methylene chloride was cooled to ~ 10 ° C. A solution of 4.4 g of nitrogen was added dropwise to this solution within 10 minutes. -Butoxycarbonyl-2- (3-äthansulionamidophenyl) -D-glycine and 1.22 g of triethylamine in 20 ml of methylene chloride and 2 drops of Ν, Ν-dimethylbenzylamine were added and then the mixture was stirred for one hour at room temperature. On the other hand, 3.82 g of 2,2,2-trichloroethyl ester of 7-amino-3-ynethyl-3-cephein-

A09884 / U65

- 41 -

4-carboxylic acid, 0.9 g of triethylamine and 0.12 g * K, O-bis (tri: aothylsilyl) acetamide dissolved in 40 ial of absolute methylene chloride. The solution was added dropwise within 10 minutes to the above-prepared mixture at a temperature of -15 ⁰ C. The resulting solution was stirred at the same temperature for 2 hours and then washed twice with 2% hydrochloric acid, an aqueous solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride and dried over magnesium sulfate. After the solvent had been removed from the solution under reduced pressure, the residue was pulverized with a small amount of ethanol, 4.2 g of the 2,2,2-trichloroethyl ester of 7- / DN-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) -glycina! Iido7-S-methyl ^ -cephem - ^ - carboxylic acid in the form of colorless crystals. 117 ^° C

'- ^ _Nudol (cnf ¹ ): 3400, 3230, 1762, 1735, 1690

NMR. , 1.28 (3H, t, J = 7H3) ', 1..38 (9H, s),

■ ö ()

(pprc)!
^CDC1 3 · · 2.16 (3Η, 8), 2.75 ~ 3.50 (4Η, ιπ:,.

4.82, 4.95 (2H, A3q, J = 12Hz),

4.95 (lH, d, J = 5Hz), 5.24 (lH, d, J =

6Hz), 5.81 (lH, d, d, J = 5Ha,

J = 8Hz), 7.25 (4H, s).

The 2,2,2-trichloroethyl-7- ^) - H-tert-butoxycarbonyl-amino-2- (3-ethanesulfonamidophenyl) -glycinamido7-3-methyl-3-cephem-4-carboxylate obtained above (4.2 g) was dissolved in a mixture of 15 ml of absolute dimethylformamide and 45 ml of acetic acid. 3.6 g of zinc powder was added to the solution while cooling with ice, and the mixture was stirred for two hours. After the zinc powder was filtered off, the filtrate became a mixture from 40 ml of 2 # strength hydrochloric acid and 40 ml of ethyl acetate poured and the ethyl acetate layer was separated. The watery one Layer was extracted with 20 ml of ethyl acetate. the

409884/1465

- 42

Itthylacetatochicht and the extract with each other iicr.binic: - washed with 20 ni 2> J-iger hydrochloric acid and 20 ml eir. ^ - rv ^: el; 3ri ;;.: saturated solution of sodium chloride one after the other and dried over magnesium sulfate. The solvent was removed from the solution under reduced pressure and the residue was washed with diisopropyl ether to give 3.2. g of 7- / ß- N-tert, -Butoxycarbonyl-2- (3-äthansulfonaaidophenyl) -glycins.r.:idcj -3-methyl-3-cepheni-4-carboxylic acid were obtained in the form of an oily product,

IR. _{from left Λ}

V _Filn (cm ~ ') i 3300, 1765, 1700

(ppm): 1.22 (3Κ, ΐ ^ τ = 7.5Η3), 2.09 (3ϊϊ, 3),

2.75 ^ .75 (4H, ri), 4.96 (lH, d, J =:

4.5Hz), 5.26 (lH _f s), 5.67 (lI,

d, J-4.5Hs), 7.25 (4H, s). ■

A solution of 3.1 g of the 7 ~ / i) -H-tcrt.-3utoxycarbonyl-2- (3-ethanesulfonanidophenyl) -glycinaEido7-3-methyl-3-cephem-4-carbonsDare obtained above in 15 ml of formic acid was stirred at room temperature for 2 hours. The formic acid was added Removed room temperature from the solution under reduced pressure. The residue was pulverized with ether and filtered. That resulting powder became 20 ml of a 10% aqueous solution given of acetonitrile, stirred for one hour while cooling with ice and then the crystals which appeared were filtered off. 1.7 g of 7- / b-2- (3-ethanesulfonamidophenyl) -glycinaniido7 3-methyl-3-cephem-4-carboxylic acid obtained in the form of white crystals. M.p. 179 to 182 ° C (decomposition).

^IR * »Nujol < ^cnr1 > ^{! 1770} ' ¹⁶⁹⁵ ' ¹⁶⁰ °

o + NaHCO fe ⁿ ^ ^: 1.29 (3H, t, J = 7.5Hs), 1.90

3 "43 -

A0988A / U65 ~

BATH ORIGINAL

(j5H, s), 2.75 ~ 3.67 (4: i ₅ b),

(lH, s), 5.59 (lH, d, J = 4.5: i2), 7.34 (4: 1.3)

Beism'sl_ 4

2,2,2-trichloroethyl ester of 7-ZÖ-N-tert-butoxycarbonyl-2- (2-mesylatino-phenyl) glycine arid-3-methyl-3-cephein-4-carboxylic acid (1.0 g) v. It was added to 20 ml of ice-cold formic acid and the mixture was stirred at room temperature for 2 hours. After removing the formic acid from the mixture under reduced pressure, V.'asser was added to the oily residue. The mixture was brought to pH-V with the aid of a saturated aqueous solution of sodium bicarbonate with ice-cooling. ^r ert from 8 to about 9 is set. The crystals which appeared were filtered off, washed with water and dried over phosphorus pentoxide. 0.78 g of 2,2,2-trichloroethyl-7- ^ D-2- (3-mesylainiiiophenyl) glycine anido7-3-ethyl-3-cephem-4-carl) ozylate, m.p. 107 to 110 ⁰ C ( Decomposition).

IR. '· _Λ

^ ^{>1785>1740> 1685}

BeisDiel b

To a suspension of 5 9 of the _f Hydroclilorids g of 2,2,2-trichloroethyl ^{7-amino-3-methyl-3-cephem-4-r} carboxj lat in 100 ml of methylene enchlorid v / urde a solution of 1.55 g of triethylamine in 10 ml of methylene chloride and a solution of 0.16 g of 2,6-lutidine in 10 ml of methylene chloride. 5.8 g of N-tert-butoxycarbonyl-2- (4-mesylinophenyl) -D-glycine and 3.3 g of dicyclohexylcartodiimide were added to the resulting solution while cooling with ice. The mixture was stirred at the same temperature for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and 200 ml of ethyl acetate were added to the residue.

409884/1465 -44, -

joined. The mixture was washed in succession with a 5% hydrochloric acid solution, water, a saturated aqueous solution of sodium bicarbonate and with water, dried and then concentrated, with 10.83 g of 2.2 _f 2-trichloroethyloster of 7- Zö-N-tert-Butoxycarbcnyl-2 ~ (4-rnesylaminophenyl) -glycine amide (^ - 3-methyl-3-cephem-4-carboxylic acid, mp 129 to 136 ° C (decomposition) were obtained.

IR. _Λ

^ ³²⁹⁰ ' ¹⁷⁷⁰ ' ¹⁶⁸ °

NI-IR.

<r _cDcl (ppm): 1.43 (s, 9H), 2.20 (s, 3H),

³ 3.32 (AB-q, 2H), 4.8-5.0 (ra, 3H)

5.2 ~ 6.0 (m, 3H), 7.0 ~ 7.7 (rn, 4H), 7.9 (broad s, 1H)

"2.5 ml of acetic acid and 10 g of zinc powder are added to a solution of 10 g of 2,2,2-trichloroethyl-7- / DN-tert-butoxycc.rbonyl-2- (4-mesylaminophenyl) -glycine amideq7-3 methyl-3-cephem-4-carboxylate in 33 ml of dimethylformamide while cooling with ice. The resulting equipment was stirred at the same temperature for one hour and then filtered. The filtrate was added to a mixture of 100 ml of 5% chlorinated water Often, 50 ml of ice water and 100 ml of ethyl acetate were added and then extracted three times with 100 ml of ethyl acetate. The extract was back-extracted twice with a 5% aqueous solution of sodium bicarbonate (100 ml). The aqueous layer was extracted with ethyl acetate washed, adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate, the ethyl acetate extract was washed with water and dried, and then the solvent was removed under reduced pressure -tert. -Butoxycarbonyl-2- (4-mesylaminophen yl) -glycinamidq / -3-methyl-3-cephem-4-carboxylic acid, m.p. 180 to 200 ⁰ C (decomposition).

l / _Nuiol (cin ~ ¹ ): 3300, 1770, 1710 (shoulder), 1695, 168C

409884/1465

- At) -

(i _DliIS0 " _d ^ (ppm): 1.40 (3.9Ii), 2.02 (3.3H), 2.95 (s, 3H),

3.2-3.7 (m _f 2K), 4.97 (d, lH), 5.2-5.8 (m, 2H), 7.30 (AE-O ₁ , 4H)

4.6 g of 7- _{/bN-ter.-Butoxycarbonyl-2-(4-niesylaininophenyl )} -glyc.inamidq7-3-niethyl-3-c8ph3in-4-carboxylic acid were added to 70 ml of formic acid while cooling with ice. The resulting mixture was stirred at the same temperature for 2 hours and then evaporated under reduced pressure. Iesser was added to the residue. The resulting aqueous mixture was washed with ethyl acetate, adjusted to pH 6 with an aqueous solution of sodium bicarbonate, concentrated to half its original volume, adsorbed on a resin adsorbent (Amberlite XAD-2) (460 g) which was mixed with methanol and V water had been pre-washed, and then eluted with water and methanol. The bluate was concentrated and the crystals which appeared were filtered off and washed with methanol. This gave 2.1 g of 7- / D-2- (4-mesylaminophenyl) glycine amideq7-3-methyl-3-ce? Hem-4-carboxylic acid, mp 205-207 ° C. (decomposition).

IR. ' _Λ

^ ¹⁷⁶⁰ ' ¹⁶⁷ °

NMR. . '

a _{D 0} (ppm): i.80 (3H, s), 3.O5 (3H, s), 3.15 (211,

AB-q), 4.85 (] H, d), 5.l (lH, s), 5.54 (lH, d), 7.35 (4H, O-q)

example 6 *

2.066 g of N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine, 0.606 g of triethylamine and 15 ml of N, N-dimethylbenzyl ain were added to 20 ml of tetrahydrofuran and the mixture was increased to -10 to -12 ° C chilled. A solution of 0.820 g of isobutyl chloroformate in 10 ml of tetrahydrofuran was added dropwise thereto at the same temperature over 2 minutes, and the result

40988A / U65 _ ₄₆ .

- 4b -

The mixture was then stirred at the same temperature for 30 minutes.

On the other hand, 1.070 g of 7-araino-3-eisthyl-3-cephem-4-carboxylic acid and 0.581 g of triethylamine were added to 30 ml of 50% aqueous tetrahydrofuran while cooling with ice. The solution was added in a single portion to the mixture obtained above, which was cooled to -6 ⁰ C. The mixture obtained in this way was stirred for one hour while cooling with ice and stirred for an additional 2 hours at room temperature, after which the tetrahydrofuran was removed under reduced pressure. 15 ml of an aqueous saturated solution of sodium bicarbonate was added to the residue, and the resulting aqueous phase was washed twice with 10 ml of ethyl acetate. The washings were extracted with a saturated aqueous solution of sodium bicarbonate (10 ml). The aqueous extract was combined with the aqueous solution obtained above, and then 30 ml of ethyl acetate was added to the combined aqueous solution. Further, 10% hydrochloric acid was added to adjust the pH to 2. The aqueous layer and the ethyl acetate layer were thoroughly shaken together, and an insoluble product was filtered off. The ethyl acetate layer was separated and the aqueous layer was extracted twice with 20 ml of ethyl acetate. The extract thus obtained and the ethyl acetate layer obtained beforehand were combined and washed with 10 ml of water. The aqueous washings were extracted twice with ethyl acetate (5 ml) and the extract thus obtained was combined with the previously obtained ethyl acetate solution. The mixed solution was washed with 10 ml of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate and treated with activated charcoal. After removing the solvent, 3.47 g of a pasty residue were obtained. 3.42 g of the residue were added to 30 ml of absolute ether and the mixture was stirred at room temperature overnight. The obtained crystals were filtered off, washed with ether and dried, whereby 2.326 g of 7- / bN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamidoJ-3-ynethyl-3-cephem-4-carboxylic acid were obtained. Mp 174 ° C (decomposition).

409884/1465

^ = 57 ° (c = 1, methanol)

Example 7

3, V + g N ~ tert-butoxycarbonyl-2- (3-kiesylaminophenyl) -D-glycine and 1.01 g of triethylarain were dissolved in 25 ml of absolute methylene chloride. The solution was tropfenvreise to -1, 36 g of a solution of Isobutylchlorforniiat in 35 ml of absolute Methylenchlcrid at a temperature from -10 to -15 ⁰ C within 5 minutes and added gorührt 15 I-Iinuten at the same temperature. On the other hand, 3.5 g of N, O-bis (trimethylsilyl) acetamide in a suspension of 3 ₅ 44 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thioniethyl 3-cephein-4-carboxylic acid dissolved in 30 ml of absolute methylene chloride. The resulting mixture was tropfenvreise added to the above prepared solution of the mixture th anhydride at -15 ° C and then stirred at the same tem perature 1.5 hours and additionally at 10 ⁰ C for three hours. The resulting mixture was washed with 5% hydrochloric / hydrochloric acid and vapors, dried, and then the solvent was removed. The oily residue was purified by column chromatography on silica gel (eluent chloroform), whereby 3.8 g of 7-ZP * -N-tert-butoxycarbonyl-2- (3-mesylaminoph "e'nyl) glycinamidoy-3- (5- methyl-1,3,4-thiad? azol-2-yl) thio methyl-3-cephem-4-carboxylic acid in the form of an oily product.

IR. _{Λ Λ}

(" ¹ 3300, 1780, 1725, 1685, 1670

2.23 g of the 7- / DN-tert-butoxycarbonyl-2- (3-methylaninophenyl) glycinaraido. 7-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiocethyl- 3-ceph.eis-4-carboxylic acid vnirden dissolved in 35 ml formic acid and stirred for 4 hours at 18 to 20 ⁰ C. The resulting mixture was concentrated under reduced pressure, pulverized with ethyl acetate, and then filtered to obtain 1.95 g of 7- / D-2- (3-Mssylaminophenyl) -glycinamido7-3- (5-methyl-1,3,4-thiadiazole -2-yl) -thiomethyl-3-cephen-4-carboxylic acid. The product was added to 30 ml of acetone, "at 15 to 20 ⁰ C a

409884/1465

Stirred for hour> left to stand and then v / urdc the supernatant solution removed by decanting. To the residue was added 30 nl Λ.ατταοη acetone, the mixture was stirred for 3 hours at 15 to 20 ⁰ C and then the precipitate was filtered off. The precipitate was washed with acetone and with ether, whereby the desired pure compound was obtained in the form of a pale yellow powder.

IR. _N

V (" ¹ ) 1765, 1690, 1605

NMR. c

₀ _ _Dcl (ppm): 2.97 (3H, s), 3.01 (3H, s), 3.38,

.3.78 (2H, AB-q, J = 18Hz), 4.26, 4.47 (2H, A3-q, J = I4 Ha), 5.12 (IH, d _f J = 4Hr.), 5.35 (lU _f s) _f 5.71 (lH, d, J = 4Hz)

- 49 -

Example 8

(1) 2, above-mentioned dicyclohexylcarbodiimiä were cooled with ice and with stirring to a solution of 5.2 g Ιϊ-tert-butoxycarbonyl-2- (3-2iesylanirio-4-hydroxyphenyl) -D-glycine, 5> 52 g 2, 2,2-trichloroethyl-7-araino-5-2iethyl-5-cepheni-4-carboxylate hydrochloride and 1.7 g of 2,6-lutidine in 180 ml of absolute ethylene chloride. The resulting mixture was stirred at the same temperature for one hour and stirred for an additional three hours at the same temperature. An insoluble product was filtered off, and the piltrate was condensed under reduced pressure. Ethyl acetate was added to the residue, and then the pH was checked. The solution was adjusted to about 2. The ethyl acetate layer was separated off, washed with water and dried over magnesium sulfate after the removal of the ethyl acetate from the solution under reduced pressure, the residue was pulverized with isopropyl ether, whereby 6.75 S 2 , 2,2-trichloroethyl ester of 7- / K-text. -Butoxycarbonyl-2- (3-methylariino-4- hydroxyphenyl) D-glycinaiaidq / -3-diethyl-3-cephem- ^/ l-carboxylic acid The product was recrystallized from ethyl acetate to give the purified substance, mp 185 to 188.5 ° G (decomposition).

IE.

-50 -

4 W- i; -i ti * ■ / 1 * ■) S

BATH ORIGINAL

² (3H, s), 3.34,3.59 (2R, AB-q, J = I8H-Z), 4 · 87.5.07 (2ϊΙ, Λ3-ο, J = 12.5HO, 5.O7 (lH, d, J = 4.5Hz), 5.35 (1H, Ί, J = SHz), 5-8O (1H, d, d, J = ^ l. 5Kz, SHz), 6. 3-6. 5 (IH, η), 6.90 (lH, d. J = SHz), 7 ·. 20 (lH, d, d, J = 2Kz, 8Hz), 7.52 (IH, d, J = 2Hz), 8.0-8.3 (2H, rri)

(2) 3.5 ml of acetic acid and 2.6 g of zirconia powder were cooled with Si to form a solution of 3% of 2,2,2-trichlorethylene-7% trichlorethylene. -but oxycarbonyl-2- (I-mesylanino-il-hydrox D-glycine anido / -3-nietliyl-3-cepiien- ^ - carbo: cylate in 9 "1 whore thylfomanid. The mixture was at the same temperature 4 After the reaction was complete, the zinc powder was filtered off and washed with a small amount of di-ethyl formamide, and the filtrate and washing liquids were combined. Ethyl acetate and dilute phosphoric acid were added to the mixture, and the ethyl acetate layer was removed. The extract: was washed with water and back-extracted with an aqueous solution of sodium bicarbonate. The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over magnesium sulfate, and the solvent was reduced under reduced pressure The residue was washed with ether, ^{whereupon 1.58 κ%} ^ -i5i-tert-butoxycarbonyl-2- (3-aesylamino- ⁱ l ~ hydroxyphenyl} -D-slycina nidq / -3-ethyl-3-cephein-4-carboxylic acid was obtained in the form of "a powdery product"

- 51 -

cm- ¹ ): 1765

NMR.

: 1.4O (9H, s), 1.9O (3H, s),

DpO + lJaHCO,

3.O5 (3H, s), 3.OO, 3:39 _(2H,:

AB-q, J = 18Hz), 4.90 (lH, d, J = 4.5Hz), 5.O8 (i: i, s), 5.52 (lH, d, J = 4.5Hz), 6.8-7.4 (3H, m)

(3) Its solution of 1,4-5 6 7- / n ~ tert-butoxycarbonyl-2- (3-mesylanino- ^z i ~ h3v'-droxyphenyl) -D-glycine anido7-3-r ₁ ethyl-3- cephem-4-carboxylic acid in 6 ml of formic acid was stirred at 40 ° C. for 1.5 hours. After the completion of the reaction, the acetic acid was removed under reduced pressure, and then 30 ml of acetonitrile and 0.5 ml of v / water were added to the residue with stirring, and the mixture was stirred for 30 minutes. The powder obtained was filtered off and vitrified with acetonitrile and with ilther, where 1.13 g of 7-Z2- (3- ^ e3ylamino-4-hjrdroxyphenyaVL-gl ^ rcinamido / -3-methyl-3-cephem-4 ~ carboxylic acid, M.p. 186 to 192 ° C (decomposition) were obtained.

IR.

A09884 / U65

(PPIN) 2.12 (3H, 3), 3.2O (3H, s) ', 3.25, 3. 5O (2H, i3-q, J =] ^T 8 iz), 5. 09 (IH, d, J = I.5Hz),
5.33 (lH, s) _f 5.66 (l: I, d, J = 4.5Hz), 7.15 (HI, d, J = 8Hz), 7.4O (lH, d, d, J = 2Hz, 8iIz), 7.53 ( lH, d, J = 2Hz).

Example 9

(1) A solution of 140 mg of triethylamine in 5 ml of methylene chloride and 15 mg of 2,6-lutidine was converted into a solution of 54-0 mg of the hydrochloride of the 2,2,2-urichloroethyl ester of 7-alino-3-methyl - 3-cephem-4-carboxylic acid in 10 ml of dry diethylene chloride with ice-cooling. To the mixture, a ethylene chloride solution (5 ml) containing 53o mg of K-tert-butoxycarbonyl-2- (3-ethylarainosulfonainidopLenyl) -D-glycine was added with stirring while cooling with ice. After 32o mg of ITjN'-dicyclohexylcarbodiimide was added to the mixture, the resulting mixture was stirred at room temperature for three hours. An insoluble product was filtered off from the resulting mixture and washed with ethylene chloride. The filtrate and liquors were combined and then the mixture was evaporated under reduced pressure. Ethyl acetate was added to the residue and an insoluble product was filtered off. The ethyl acetate layer was washed with cold 5% hydrochloric acid, water, an aqueous saturated solution of ITafcrium bicarbonate and with a saturated aqueous solution of sodium chloride, and then dried. Ethyl acetate was added to the solution and an insoluble product was filtered off, after which the resulting solution was concentrated under reduced pressure, whereby 1.07 g of 2,2,2-trichloroethyl-7- / i: -tert.-butoxycarbo-

409884/1465

ny l-2- (5-ethyla: .iino £

in ethyl-3-cephen-4-carboxylate in an araorphic product were obtained. F. 7 ° to 73 ° C (decomposition).

IR.

H ⁽ "' ¹⁾ > ¹⁶⁸⁰

(2) 1.2 ml of acetic acid and 0.96 g of zinc powder were mixed with ice-cooling to form a solution of 0.94-S 2,2,2-Trichlo ^ ethyl-7- / N-tert-butoxycarbohyl-2- (3-ethylaminosulfonamidophenyl ) -D-glycinanido7-3-cepheia- ^z J-carboxylate in 5 ml of dimethyliorinamide. The mixture was stirred at the same temperature for an additional hour. When the reaction was complete, the zinc powder was filtered off, washed with ethyl acetate, and the washing liquids were combined with the filter.

The mixture was poured into cold 5% hydrochloric acid (20 ml) and extracted twice with ethyl acetate, after which the extract was washed with a saturated aqueous solution of sodium chloride and back-extracted with 5% aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 1 to 2 with 10 / o hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure, v / obei ο.6S g of 7- / N-tert-butoxycarbonyl-2- (3-ethylaminosulfonamidophenyl) -D-glycinamido7-3 -niethyl-3-cephen-4-carbQnsäure were obtained in the form of an amorphous product. F. 122 to 128 ⁰ C (decomposition). .

409I64 / U6S

BATH ORIGINAL

ύηοΐ ^{(cm λ) : 33OOi 1Ίβ5} > ^l69 °

(ppm): 1.03 (3Η, t), lJtO (9Η, s), 1.93 (3H, s), 2.6 - 3.5 ('4K, π), 5.o (IH, d) 5 3Ο (IH, s), 5..60 (IH, d), 7.3O (4H, m)

A genic from 59o ng ^ - / li-tcvt. -Buto: ί: ycarboϊlyl-2- (3-äthylaninoΞulfonamidophenyl) -D ■ -glycinanid <^ ⁷ -3 - :: - etίIyl-3-cephem-4-carboxylic acid in 8 ml of formic acid was stirred for two hours at room temperature. The reaction odor was concentrated under reduced bridge, and the residue was dissolved in water. To the solution, ethyl acetate was added and the resulting mixture was shaken. After the aqueous layer was separated and concentrated, the pH became 7 of the residue with 5% aqueous solution of sodium hydroxide to a V. ^r ert of 5 set and the residue was purified on a resin-Adsorptionsnittel (XAE-2 of the Rohm and Haas Go.) adsorbed, washed with \ 7asser and! The solvent obtained with methanol was concentrated under reduced pressure, and the residue was washed with acetonitrile, whereby 35o ng of 7- / 2- (3- ^ thylaminosulfonamidophenyl) -D-glycine amideQ / -3-methyl-3- cephea-A-carboxylic acid, m.p. 162 to 166 ⁰ C, were obtained.

IR.

^{! 5200} · ¹⁷⁶ ° » ¹⁶⁹ °

BAD ORiGrNAL.

ζ (ρό: τι): 1.03``3K, t), 3 · Ο3 (2il, q), 3.0, 1) O

² 3- ² IS (211, d, d, J = IQHz), 4.95

(HI, d), 5.27 (HI, broad α), '5.61 (IH, d), 7.3Q ( ^ U m)

Example 10

(1) To a suspension of 3 »61 g of the hydrochloride of 2,2,2-trichloroethyl ^ -anino ^ -methyl ^ -cephem-A'-carbxylat in 50 ial IJethylene chloride were ο, 95 g xriäthylamin in a portion 5 C. The mixture was gradually added 3 »37 g of N-tert.-3ut; oxycarbony 1-2- / 3- (3-nethylureido) ph.er:yl7-D-glycine and 2.88 g of Ιί, ¹ -dicyclohexyicarbodiimide was added, and the resulting mixture was stirred at room temperature for one hour. An insoluble product was filtered off, and the filtrate was concentrated under reduced pressure. Thereafter, iithylacetate was added to the residue. The resulting solution was added three times with 5 Show hydrochloric acid, washed with water, with an aqueous solution of sodium bicarbonate (three times), with water and with an aqueous solution of sodium chloride (three times), dried and then concentrated. The concentrate was left to stand in a cold environment and the obtained Crystals were filtered off, giving 3.96 g of 2,2,2-Tri chloroethyl ester 7-2> I-tert-butoxycarbonyl-2- <3- (methylureido) phenyl I-D-glycinamido7-3-ynethyl-3-cephem-4-carboxylic acid, mp 152 ° to 160 ° C. (decomposition).

IR.

.56-

409Θ8Α / 1465

BATH ORIGINAL

HMR.

(ppm): ll \ 2 { 9H, s), 2.08 (3H, s),

2.63 (311, d, J = 5 Kz), 3. ^ 7 (2H ₃
t, J = 20Hz), Ί - 8—5 - ¹ ^ ( ² IH, in),

5-95 (IH, d, J = 5Hz), 6.7 - 7.6
(4-H, m), 8.37 (1H, s), 9.Ö5C 11
d, J = 7Kz)

(2) 5.7 S zinc powder and 5j7 ⁿ l glacial acetic acid were at a temperature of 5 ° C to a solution of 5 ₅ 7 S 2,2,2-Trichlkräthyl-7- / ΪΪ-1

phenyl] -D-glycine amide c ^ -3-methyl-3-cephem-4-carboxylate in 57 ml of dimethylformamide. The mixture was stirred for one hour at room temperature and filtered. Some ice, 5% hydrochloric acid and ethyl acetate were added to the filtrate. The organic layer was separated, washed twice with water and washed with. back extracted from an aqueous solution of sodium bicarbonate. The aqueous layer was separated, extracted with ethyl acetate, acidified with 5% hydrochloric acid, and then extracted with ethyl acetate. The extract
was washed with water, dried over magnesium sulfate, and then the solvent was removed from the extract. 3.29 g of 7- £ Ti-tert-butoxycarbonyl-2- £ 3- (3-methylureido) phenyl] -D-glycinamido / -3-diethyl-3-cephem- ^ ~ carboxylic acid, mp 143 bis 150 ° C (decomposition) obtained.

IE.

¹ ): 3370, 1780

A0988A / U65

MMiI. ~ ^Vj ^

O _r "" _r . , '(DDn): 1.3S (pH, 3), 1.99 ( 3H, s),

2.63 (-3K, d, J = 5Kz), · 3.28, 3 · 'Ι5 (2H, AE-o, J = ISlIz), ^. 96 (III, d, J = 51 z!), 5.28 (IK, broad d, J = SHA), 5.62 (IH d, d, J = 5 ^Hz:, 8 Hz), 5.97 (IH, broad d, J = 5Hz) ', 6.8 - 7.6 (ilH, n), 8. it ^ i (IH, s),

9-02 (IK, broad d, J = 8 Hz)

(3) 3 "18 g of 7 - ^ -" tert-3ütox7carbonyl-2- [3- (3-nethylureiäo) phenylj-D-glycinamido / ^{-5-netiiyl-3-cephem-i} J-carboxylic acid were added to 60 ml Anicic acid of 10 ° C. was added, and the device was stirred for two hours at room temperature and then concentrated under reduced pressure. The residue was pulverized with 70 ml of ether, and the filtered powder was added to 10 ml of 5% aqueous acetonitrile, Jo stirred for minutes and then filtered off. It was added 2.2 g of 7- / 2 ^ ~ 3- (3-methylureido) -phenylj-D-glycinamido / ^{-3-methyl-3-cephem-z} l ~ carboxylic acid obtained in the form of crystals .?. 215 to 218 ° C (decomposition).

_T. "(cd" ¹
Nujol

NMR

_rT . "(cd" ¹ ): 3350, 1760
Nujol

_n (ntjm): 2.2 (3H, s), 2.85 (3H, s),

DpO + DGl -

3.23, 3.51 (2H, AB-Q, J = 19? N Hz), 1.95 "(IH, d, J = 5Hz),

5-33 ( IH, s), 5-7 ( IH, d, J = 5Hz), 7-2 - 7.7 ( ¹ JH, m)

-58 -

A0988A / U65

Example 11

(1) 2ino solution of 1.79 g of ethyl chlorocarbonate in 10 ml of ..: ethylene chloride became a solution of 6.4-5 E u-tert-3utoxycarbonyl-2-p-O-methylthioureidOphenylj-D-glycine and 1.82 g of triethylamine in 75 al: .Ie Uhylenechloride at -25 to -3o G added within ten minutes, and the mixture was another fifteen minutes at the same "J v.:i temperature stirred. A solution of 5> 73 g of 2,2,2-Trichlcr-

and 1.52 g of triethylarain in 75 ml of ethylene chloride v-urde in a single portion at -4o ° C to the mixture obtained above. The resulting Geraisch vvr-de gradually warmed to C ° 2 over four hours and concentrated under reduced pressure. The residue was dissolved in 150 ml of ithylacetate. The solution was washed with 5% hydrochloric acid, a saturated aqueous solution of atrium bicarbonate and a saturated aqueous solution of sodium chloride, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 5 parts benzene + 1 part acetone). 3.83 g of 2,2,2-2richloroethyl-7-i ^ <- tert were. -buto: cycarbonyl-2- £ 3- (3-methyloethioureido) phenyl] -D-glycinamidq7-3-ethyl-3-CePhCm - ^ - carcoxylate ,, F. 123 to 130 ° C.
IR. .

(cm " ¹ ) ^{: 3320} > ¹⁷⁷³ > ^l68 ° - '! 535, .136T, 1306, jol ^cm _{12l} 3j 1217j ll62j 111Oj 1O5Oj} 787, 715

NMR.

0 MSe-d ^(Όρπ) :! -39 (9H ₁ S), 2.08 (3H, 3), 2.?1(3H,

d _s J = A Kz), 3.4l (2H, broad s),

M; 8 - 5.K2H, η). 5 23 (1Η, broad d, J = 7Hs), 5.5 - 5.8 (lK, o), 7.0 7.75C5H, m), 9.IH (IR, broad d,

40988A / U6S

BATH ORIGINAL

(2) To a solution of 355 g of 2,2,2-tric2ilora.thyl-7- / Ii-tert.-butoxycroconyl-2- p- (^ -liiethylthioureidc) j; henylj -D-glycine-Gr.'iido7 -3- ^ e1: hyl-3-carboxylate and 3 cepheni- ^z} nl EISC-ßir; 3) O g of zinc powder were added to 15 parts of Bin: ethylfor: .ia3iid, and the mixture was stirred for 1.5 hours while cooling with ice. After completion of the reaction, the zinc powder was filtered off and washed with 50 KiI ethyl acetate, and then the ".Vash liquids and the filtrate were combined with one another, after the mixture had been washed with water, the aqueous layer was separated and washed twice with ethyl acetate (30 ml). The extract was combined with the ethyl acetate layer obtained above. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and then back extracted with an aqueous saturated solution of sodium bicarbonate ( ⁷ JO .. ml). The aqueous layer was back-extracted with ethyl acetate washed, adjusted to pH 2 with 10% hydrochloric acid and then extracted five times with ethyl acetate (60 ml) The extract was washed with water and dried over magnesium sulfate and then the solvent was evaporated under reduced pressure removed, where 2.45 2; 7 - / ^ - tert-Bu ¹ boxycarbonyl-2-i5- (3-2iet hylthioureido) phenylj-D-glycinamido7-3-laethyl · ■ 3-cepheEl-4-carboxylic acid in powder form.

IE.

¹ ): 3320, -1700, 1670, 1540, 1370,

1250, 1165, 1110, 1056, 866, 718

- 60 -

409884/1466

MiIR.

l. '! O (9H, 3), 2.00 (3H, broad) 3), 2.92 (3H, s), 3.1 - 3.7 (2I-i, broad s), ^ .99C IH, d, J = 5Hz) , 5.33 (-IK, wide 3, J = SHz) ₃ 5 ··· 5 - 5-3 (IH, m), 7.0 - 7.7 (1H, m), 9.07 (IH ₃ wide d, J = bras), 9.50 (IK, broad s)

(3) A solution of 2.1 g of 7- / W-tert-butoxycarbony1-2- ^ 3- (5-nethylthioureido) phenylj-D-gl; rcinaLiiao7-3-ethyl-3-cephem-4-carboxylic acid in 20 ml of formic acid was stirred for three hours at room temperature. When the reaction had ended, the formic acid was removed under reduced pressure, and the residue was dissolved in 20 ml of 10%
stirred aqueous acetonitrile. The precipitate was filtered off and washed with acetonitrile, with 1.21 g of 7- / 2- /3-(3-"'Sh.tlythioureido) phenylj -D-glycinanido7-3-methyl-3-cephem-4-carboxylic acid, F. 198 to 19 ° C (decomposition) were obtained.

IR.

2) (cm " ¹ ): 3500, 3 ^ 30, 3230, 2600-2700,
Nujol

1767, 1700, 1608, 1550, 1328, 1280, 1230, 1178, 1160, 1130, 978, 812, 788, 757, 711

- 61 -

40988A / U65

, (τ ^ π :): 2.0? (> \ ^ ₁ y.02 (I '/ a, "* 3.5 ^ -, 5.57 (2; ϊ, AU-q, J

Kz), 5.O9C ^ I ₁ d / ci ^ .5 5: 7.), 5.37 (i: -i, ₃ ), ?. ** i «I, t- _; iT. s)
Example 12

(1) To a solution of 9.93 S N-t-3utoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine in a mix of

140 ml of tetrahydrofuran and 3.22 g of triethylamine, which in -10 ° C was maintained, 3.95 isutyl chloroformate were added and the resulting mixture was stirred at -10 C for 20 minutes. Ss became a cold solution of 7.87 g 7-aminocephalosporanic acid in a mixture of 5.5 g triethylamine, 40 ml tetrahydrofuran and 40 ml v / water at once was added and the resulting mixture was cooled with ice For 1 hour and for 2 hours at room temperature touched. After the completion of the reaction, the tetrahydrofuran was removed by distillation and 100 ml-water became there admitted. The solution obtained was diluted with 10? Hydrochloric acid adjusted to pH 2.5 with ice cooling and shaken with ethyl acetate. The ethyl acetate layer was separated off, washed with water / water, dried and concentrated under reduced pressure. The leftover oil was treated with nit-'Xther and 10.2 g were obtained 7 "[* D-N-t-butoxycarbonyl-2- (3-mesylaaiinophenyl) glycinamido] -3-acetioxyiaethyl-3-cephem-4-carboxylic acid in the form of a yellow powder, P- 83 to 84 ° C (decomp.)

• *

(2) A solution of 1 g of 7-fD-K-t-butoxycarbonyl-2- (3-mesylaminophenyl) glyc ynamido] -3-acetoxy methyl-3-cephem-

4-carboxylic acid in 15 ml of formic acid was at room temperature Stirred for 5 hours. After the formic acid had been removed by distillation, 10 ml of water were added and the resulting solution was washed with ethyl acetate and treated with a solution of an ion exchange resin ("Aoberlite LA-1 "from Rohm & Haas Co.) in 3 ml of methyl isobutyl ketone Stirred for 1 hour. The water layer was separated, washed with ether and lyophilized, whereby one

409884 / U65

- 62 -

BATH ORIGINAL

0.63 g of 7-fD-2- (3-Mes, 7laminophenyl) glycinaniidoJ-3-acetoxymethyl-3-cephem-4 ~ carboxylic acid in the form of a colorless powder received, F. 240 ⁰ G (dec.).

At s ρ i e 1 13

howling-

0.8o g of tetriurabicarbonate were added to a stirring suspension of 7- / 5-: i-tert-butoxycarbonyl-2- (3-r _i esy3ar ₁ iinophenyl) -glycinamido / cephalosporanic acid / n 130 ml of phosphate buffer from pE - ". Vert 6, ^ * - given, and then so ml of acetone were added. The solution was added ο, 68 g of 5-i''-ethyl-1,3,4-thiadiaz-oil-2-thiol, and that The mixture was stirred for six hours at 60 to 65 ° C. From the resulting mixture, acetone was removed under reduced pressure, and the leaded aqueous layer was washed with jither. The aqueous solution was adjusted to pH 2 with dilute hydrochloric acid and then with Ethyl acetate extracted. The extract was washed with water, dried over magnesium sulfite, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: chloroform), whereby 1.8 g of 7-Zi ⁾ ^ N- "tei't.-Butoxycarbon7l-2- (3-nie3ylaminophenyl) gly cinamido / -3- (5-ethyl-1,3, ^z- thiadiazol-2-yl) "fchiomethyl-3-cephem- ^/ ~ carboxylic acid.

^: 53CO, 1780, 1725, 1685, 1670

409884/1466

Example 14

N-t-butoxycarbonyl-2- (3-dimesylarainophenyl) -D-glycine, in a manner known per se from 2- (3-dimesylaminophenyl) -D-glycine was prepared with 2,2,2-trichloroethyl-7-amino-3-methyl-3-cephem-4-carboxylate with formation of 2,2,2-trichloroethyl-7-JN-t-butoxycarbonyl-2- (3-dime syl-aminophenyl) -D-glycinamidoj-3-methyl-3-cephem-4-carboxylate coupled.

From the substance obtained, 2,2,2-trichloroethyl-7-jTl'I-t-butoxycarbonyl-2 · - (3-dimesylaminophenyl) -D-glycinamidoj-3-methyl-3-cephem-4-carboxylate, the 2,2,2-trichloroethyl group was eliminated, with 7- [N-t-butoxycarbonyl-2- (3-dimesylaminophenyl) -D-glycinamidoJ-3-methyl- 3-cephem-4-carboxylic acid was obtained. The t-butoxycarbonyl group has been eliminated from this compound, 7- (2- (3-Dimesylaminophenyl) -D-glycinamide-3-methyl-3-cephem-4-carboxylic acid described in a manner similar to that in Example 3 was obtained.

A098SA / U65

Claims (1)

Claims 1. Compound characterized by the general formula R ₂ -YN where: R ^ hydrogen or hydroxyl, R ₂ lower alkyl, R ₇ . Hydrogen or lower alkanesulfonyl, Y -SO ₂ -, -WiSO ₂ -, -KHCO- or -NHCo-, with the proviso that R ^ is hydrogen when Y = -NHSO ₂ -, -NHCO- or -NHCS-, and X -CH-COOH, -CHO or -CHCN, where X is preferably -CH-COOH, NH ₂ and their derivatives on the carboxyl and / or cL amino group. 2. A compound according to claim 1, characterized in that in the general formula R ^ is hydrogen or hydroxyl, R _{2 is} lower alkyl, R ^ is hydrogen or lower alkanesulfonyl and Y is -SO ₂ -, and their derivatives on the carboxyl and / or QL - Amino group. 3. A compound according to claim 1, characterized in that in the general formula R ^ hydrogen, R ₂ low- 409884 / U66 alkyl, R _{3 is} hydrogen and Y is -MSO ₂ -, -NHCO- or -NHCS-, and their derivatives on the carboxyl and / or cL-amino group. 4. A compound according to claim 2, characterized in that R ^ hydrogen, Rp methyl or ethyl, R ^ hydrogen and Y mean -SOp-, and their derivatives on the carboxyl and / or cL-amino group. 5. A compound according to claim 2, characterized in that R ^ is hydrogen, R _{2 is} methyl, Ev mesylamino and Y is -SO ₂ - and their derivatives on the carboxyl and / or cL amino group. 6. A compound according to claim 2, characterized in that R ^ is hydroxyl, R _{2 is} methyl, R, hydrogen and Y is -SO ₂ -, and their derivatives on the carboxyl and / or d -amino group. 7. 2- (3-Mesylaminophenyl) -D-glycine and its derivatives the carboxyl and / or ot-amino group. 8. N-t-Butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine. 9. N- (1-methoxycarbonyl-1-propen-2-yl) -2 - (^ - mesylaminophenyl) -D-glycine. 10. 2- (3-Mesylaminophenyl) -I) -glycine methyl ester. 11. 2- (3-Mesylaminophenyl) -D-glycine methyl ester hydrochloride. 12. 2- (3-Mesylaminopheny1) -D-glycynamide. 13.2- (3-Mesylaminopheny1) -D-glycinamide hydrochloride. 409884/1465 14. Copper (II) -2- (3-mesylaminopheny1) -D-glycinate. 15 · 2- (4-mesylaminophenyl) -D-glycine and its derivatives the carboxyl and / or ol-amino group. 16. N-t -Butoxycarbonyl-2- (4-mesylaminophenyl) -D-glycine. 17. 2- (3-Ä \ thansulfonamici.ophenyl) -D-glyc in and its derivatives on the carboxyl and / or & -amino group. 18. N-t-Butoxycarbony 1-2- (3-ethanesulfonamidophenyl) -D-glycine. 19. 2- (3-Dimesylaminophenyl) -D-glycine and its derivatives the carboxyl and / or CL amino group. 20. 2- (3-Mesylamino-4-h "'- droxyphenyl) -D-glycine and its derivatives on the carboxyl and / or α-amino group. 21. N-t -Butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycine. 22. 2- ^l (3-Ä.thylaminosul £ onamidophenyl) -D-glycine and its derivatives on the carboxyl and / or CL-amino group. 23. N-t-Butoxycarbonyl-2- (3-ethylaminosulfonamidophenyl) -D-glycine. 2A-. 2 - [* 3- (3-Methylureido) phenyl] -D-glycine and its derivatives on the carboxyl and / or ate, amino group. 25. N-t-Butoxycarbonyl-2-f3- (3-methylureido) phenyl] -D-glycine. 26. 2- [3- (3-Methylthioureido) phenylJ-D-glycine and its 409884/1465 Derivatives on the carboxyl and / or αί -A mi no group. 27. N-t -Butoxycarbonyl-2-f5- (3-methylthioureido) phenyl] -D-glycine. 28. binding according to claim 1, characterized by the general formula ^N VCHO wherein R _{1 is} hydrogen or hydroxyl, Ep is lower alkyl, R ^ V / hydrogen or lower alkanesulfonyl and Y is -SO ^ -, -NHSO ₂ -, -NHCO- or -NHCS-, with the proviso that R _{5 is} hydrogen when Y = -NHSO ₂ -, -KHCO- or -NHCS-. 29. A compound according to claim 28, characterized in that R ^ is hydrogen, R _{2 is} lower alkyl, R ^ is hydrogen and Y is -SO ₂ -. 30. 3-mesylaminobenzaldehyde. 31. A compound according to claim 1, characterized by the general formula ^ CHCN NH ₂ ^R 3 409884/1465 wherein B ^ is hydrogen or hydroxyl, R _{2 is} lower alkyl, E, hydrogen or lower alkanesulfonyl and Γ -SOp-, -NHSO ₂ -, -NHCO- or -JJHCS-, with the proviso that R, is hydrogen when Y = - NHSO ₂ -, -NHCO- or -NHCS-, and their derivatives on the amino group. 32. A compound according to claim 31, characterized in that in the general formula R ^ is hydrogen, R _{2 is} lower alkyl, E ^ is hydrogen and Y is -SO ₂ -. 33. OL-amino- oL- (3-mesylaminophenyl) acetonitrile. A09884 / U65 34 ·. Process for the preparation of a compound of the general formula NH, I ^R 3 wherein R ^ is hydrogen or hydroxyl, Rp is lower alkyl, R, is hydrogen or lower alkanesulfonyl and Y is -SO ₂ - * -NHSOp-j -NHCO- or -NHCS-, with the proviso that R, is hydrogen when Y = -NHSO ₂ -, -NHCO- or -NHCS-, characterized in that there is a connection of the formula Ver H-COOH wherein R ₄ . has the meaning given above with a reagent of the formula R ₂ -YZ wherein Z is the radical of an acid and R ₂ and Y have the meanings given above, or, if Y »-NHCO- or -NHCS-, with a reagent of the formula * R ₂ -Y ' in which Y ^{1 is} isocyanato or thioisocyanato and R _{2 has} the meanings given above. 35 · The method according to claim 34 · »characterized in that 409884/1465 the starting compound in a form with protected Carboxyl and / or OL -Ami no group subjected to the reaction . 36. Process for the preparation of the compound of the general formula given in claim 34, characterized in that that one is a compound of the general formula NH wherein R ₁ , Rp ₁ R, and Y have the meanings given in claim 34 · hydrolyzed. Process for the preparation of the compound of the general formula given in claim 34, characterized in that that one (1) a compound of the general formula ^B 1 ^ "HO wherein R ^ has the meanings given in claim 34- has, with a reagent of the general formula R ₂ -YZ wherein Z is the radical of an acid and R ₂ and Y have the meanings given in claim 34, or 409884/1465 then, when Y = -IiHCO- or -KHCS-, with a reagent of the formula
_O "A wherein Y ^{1 is} isocyanato or thioisocyanato and R _{0 has} the meanings given in claim 3 ^ -, converts (2). the product of the general formula obtained in this way R ₀ -YN
² I. ^H 3 wherein R ,,, Rp, Rz and Y are those given in claim 3 ^ Have meanings, reacts with hydrogen cyanide in the presence of ammonia and (3) the product obtained in general formula E ₁ CHCN R ₀ -YN ^ >'NH ₀ ² I ^{2 R} 3 wherein R ^, R ₀ , R, and Y have the meanings given in claim 34-, hydrolyzed. 38. Compound characterized by the general formula 409884 / U65 COOH where R _x , hydrogen or hydroxyl, Ep lower alkyl, R, hydrogen or lower alkanesulfonyl, E ^ hydrogen, lower alkanoyloxy or a heterocyclic TMo group in which the heterocyclic group can be substituted by lower alkyl, and Y -SOp-, -NHSO ₂ -, - MCO- or -MHCS-, with the proviso that R, always denotes hydrogen when Y = -WHSOp-, -NHCO- or -NHCS-, and their derivatives on the carboxy and / or amino group. 39. A compound according to claim 38, characterized in that in the general formula R ^ and R, each hydrogen, R ^ hydrogen or lower alkyl substituted thiadiazolylthlo and Γ -SO ₂ -. 4-0. Compound according to Claim 391, characterized in that R _{2 is} methyl and R ^ is hydrogen. 4-1. Connection according to claim 39 _? characterized in that R _{2 is} methyl and R ^ is 5-methyl-1,3,4-thiadiazol-2-ylthio. 42. Process for the preparation of a compound of the general formula 409884 / U65 E ₂ -YN CH-CQNH COOH wherein R ^ is hydrogen or hydroxyl, R _{2 is} lower alkyl,
fi. Hydrogen or lower alkanesulfonyl, R ^ hydrogen, lower alkanoyloxy or a heterocyclic one
Thio group, where the iieterocyclic thio group can be substituted by lower alkyl, and Y -SOp-,
-NHoO ₂ -, -NHCO- or -NHCS- mean, with the proviso that "Rz is always hydrogen when Y = -NHSO ₂ -, -NHCO- or -NHCS-7, characterized in that a compound of the general formula wherein R ^ has the meanings given in claim 38, reacts with the compound according to claim 1 and if appropriate, a protective group in the product obtained in this way is removed. A method of making the compound of claim 42, characterized in that R ^, a heterocyclic Thio group means in which the heterocyclic Group can be substituted by lower alkyl, characterized in that the compound of the general formula according to Claim 38 409884/1465 -X- "H wherein R ^ is lower alkanoyloxy, or its derivative with a thiol compound of the formula R4.-H wherein R / denotes a heterocyclic thio group, in which the heterocyclic group may be substituted with lower alkyl or, if necessary, with converts its alkali metal salt and then the protective group present in the product obtained can be eliminated. 44. Pharmaceutical preparation, characterized in that that they at least one compound according to claim 3Q as contains active ingredient as well as pharmaceutically acceptable non-toxic carriers. 409884 / U6I