DE2411765A1 - DIACYLCEPHALOSPORIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE FOR THE PRODUCTION OF SEMI-SYNTHETIC CEPHALOSPORINES AND DERIVATIVES THEREOF - Google Patents

Description

A nnieldar ; Artur Pereira Da Luz

Al, 1 ^ Esquerdo, Flu a Luciano Cordeiro Lisbon (Portugal)

Diacylcephalospore derivatives, process for their preparation and their use in the manufacture of semi-synthetic Cephalosporins and derivatives thereof

The invention relates to new diacyicephalosporin derivatives a process for their preparation and the use of these compounds as intermediates in a process for the preparation of semisynthetic cephalosporin derivatives or salts thereof; it concerns in particular new diacylcephalosporin derivatives of the general formula

R ² -CO S

N _n -CH - CH ^ ^ CK ₉ ^ULr O = CM - ^ C

CH ₂ X

OOE

409884/1383

V7orin mean:

R is a different from n-butyl-4-amino-4-carboxylic acid organic radical, the alkyl, aryl, aralkyl or hetero cyclic groups and one or more substituents, v; ie, for example alkoxide, hydroxide or amine functions Halogen atoms or others, may contain,

X is a hydrogen atom or an organic radical which can be a hydroxide, acyloxy, heterocycloxide or amine residue,

2
R is an organic radical derived from the starting material, which can be n-butyl ^ -amino ^ i-carboxylic acid, Γ-g phenoxymethyl, 2-pentenyl, pentanyl, heptanyl or p-hydroxybenzyl, and

E a Viasscrstoffatoni or a protecting group for the Carboxylic acid function,

and a method for their production. It also relates to a new process for the production of semi-synthetic Cephalosporin derivatives or salts thereof of the general formula

1 y ^

R —CO — IiII CH CH CH "

fi ι ²

O =: C H C

COOA

4Q9884 / 1383

wherein R and X have the meanings given above and A is a hydrogen atom, an alkali metal or an alkaline earth metal or an ammonium group optionally substituted by organic radicals,

in which the above-mentioned new diacylcephalosporin derivatives of the formula II are used as intermediates.

The semi-synthetic cephalosporins represent an exceptional one Family of antibiotic substances that represent due to their broad spectrum of antibacterial activity, their penicillus nose resistance and, in some cases, their good acid resistance, which makes for effective oral administration enables are extraordinarily valuable for the Treatment of various infections.

In the scientific literature and in the patent literature many processes for the production of semisynthetic cephalosporins have already been described. All these methods are based on the formation of a peptide bridge between the organic acid which the Represents side chain, and a derivative of the "Cephalospörin nucleus", that is, an optionally modified cephalosporanic acid; The derivatives are particularly important of γ-amir.odesacetoxy-cephalosporanic acid and 7-aminocephalosporanic acid. The production of these cephalosporanic acids, which form the "Cephalospor in nuclei" and which, according to the classical processes for the production of semi-synthetic cephalosporins are required as a starting material

Bw 138 ':

241176 !:

difficult and costly. The 7-aminocephalosporanic acid is generally prepared by the enzymatic or chemical derxylation of a fermentation-derived cephalosporin, generally cephalosporin C, each of the known processes being difficult to carry out and giving poor yields. The 7-aminodeacetoxycephalosporanic acid is generally produced in a different way, starting from a penicillin or a 6-aminopcnicillanic acid derivative, the sulfoxide of which, by expanding the thiazolidine ring to a dihydrothiazine ring, gives a compound of the desacetoxy-cephalosporin series. Other cephalosporanic acids, namely those modified in the 3-position of the nucleus (the nomenclature used here corresponds to that of Morin _t "j. Am. Chem. Soc", 84 , 3400 (1962)) are generally selected according to various methods 7-aminocephalosporanic acid produced. In any case, the respective cephalosporanic acids must be isolated at the end of the specified conversions. This isolation always leads to a reduction in the yield, which is exacerbated by the fact that it is impossible to produce a cephalosporic acid which is suitable for subsequent use as a starting material for semisynthetic cephalosporins without it being subjected to a further purification step to free the acid from impurities must be subjected, which can cause undesirable side reactions in the patients treated with the cephalosporins prepared therefrom.

40988 ^ / 138 ':

The method according to the invention avoids the disadvantages described, since it is then semi-synthetic Cephalosporin derivatives can be prepared without using the 7-aminocephalosporanic acids (this general The term here includes not only so-called 7-aminocephalosporanic acid, but also 7-aminodeacetoxycephalosporanic acid and other derivatives modified in the 3-position). Using this procedure it is possible in a whole new way from that by fermentation or by converting penicillins directly obtained cephalosporins to the desired semi-synthetic cephalosporins to arrive without the respective cephalosporanic acids previously isolated and need to be cleaned.

According to one aspect, the present invention relates to a process for the preparation of the intermediate products usable diacylcephalosporin derivatives of the general formula

R ² -CO S II

, ^X N CH-CH ^ ^

COOE

1 2
wherein R, X, R and E have the meanings given above.

The diacylcephalosporin derivatives of the formula II act

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-D-

these are new connections not yet described, which are extremely valuable intermediates for the production of cephalosporins. The procedure for the production of these diacylcephalosporin derivatives falls as well as their use in a process for the production of cephalsoporins within the scope of the present invention.

A diacylcephalosporin derivative of the formula II can very generally be prepared by the process according to the invention are made from a cephalosporin derivative of the formula

R ² - CO - NH - CH - ClI ^ "CH ₀ II I ² O = C - NC

I.
COOH

2
wherein R and X have the meanings given above.

Depending on the case, these cephalosporin derivatives of the formula III can be prepared by various processes, such as are known in the field of chemistry and biochemistry of cephalosporins (for such processes cf., for example, EP Abraham and GGF Newton, "Advances in Chemotherapy", 2, 23 ( 1965), MS Manhas and AK Bose, "Synthesis of Penicillin, Cephalosporin C and Analogs", Marcel Dekker, Ine, New York (1969), and RB Morin and BG Jackson, "Advances Chem. Org. Matur-

40983Λ / 1383

-7- 241176b

stoffe ", 28, 343 (1970)).

In general, taking into account the cases of greatest practical interest, it can be said that when X is an organic radical, the cephalosporin derivatives of the formula III are produced by fermentation can, wherein a starting material suitable for the process according to the invention is cephalosporin C, where-

rin R is an n-butyl-4-amino-4-carboxylic acid radical of the formula

HOOC - CH - (CIL ·) ^ - IV

and X is an acetoxide radical; in other examples, which are also of great interest, X can mean an organic which reads instead of the acetoxy radical according to known methods into the Cephalosx ^ orinmolekül has been introduced; Examples of such radicals are the hydroxide and fyridyl groups; if other since X is a hydrogen atom, the cephalosporin of the formula III can be chemically or enzjinatic Conversion of natural cephalosporins or according to known processes by expanding the thiazolidine ring dos respective penicillins are produced; the most important examples of the latter case are benzyldesacetoxy-cephalosporin of the formula III, where-

2
rin R denotes a radical of the formula

40988 ^ / 138:.?

CH,

or phenoxymethyl desacetoxy-cephalosporin of the formula

2
III, in which R is a radical of the formula

0> 0 CH ₂ VI

both of which are well suited as starting materials for use in the process of the invention.

According to one aspect of the method according to the invention the cephalosporin derivatives of the formula III, for the examples given above by acylation on the nitrogen atom of the 7-acylamide group converted into the diacyl cephalosporin derivatives of the formula II. This conversion can be conveniently carried out in the same manner as the general procedure for amines carried out v / erden by Cramer et al (cf. F. Cramer and K.O. Kumm, "Reports", 48_, 379 (1915), and F. Cramer and K. Baer "Reports", 93, 1232 (1960)) and in the field of penicillins already has been used (cf. I. Busko-Oszczapowicz and J. Cieslak, "Roczniki Chemii", 45, 111 (1971)). These Conversion can in particular be effected by the following sequence of reactions:

U 0 9 8 3 Λ / 1 3 8 '\

ORIGINAL INSPECTED

1) Protection of the carboxylic acid group of a cephalosporin derivative of formula III with an agent which the acid function of the cephalosporin nucleus during the subsequent Effectively protects stages, but at the end of the reaction sequence by methods that reduce cephalosporin activity cannot diminish, can be split off easily;

2) Implementation of the cephalosporin derivative with the protected Carboxylic acid group with an iminohalide-forming agent to produce a protected 7- (acylhalogen —Imid) -cephalosporanic acid of the formula

2 ^pp

R —C — Ν — CH-CH ^ ^ CH ₀ VII

I II I ² Y 0 -C -NC

COOE

2
v; orin X, R and E have the meanings given above and Y is a Halpgen atom. If the starting cephalos

porin derivative of the formula III in which R contains reactive groups, in particular amine or carboxylic acid functions, so these should be protected from the conversion to iminohalide formationj

3) Reaction of the compound VII with a derivative of an organic acid of the formula

409884/1383 ORIGINAL INSPECTED

R ¹ COOH VIII

In this step a diacylcephalosporin derivative with a protected acid function of the formula II is obtained;

If desired, the diacylcephalosporin may be used can be isolated in the state of the free acid, but in general it is used as an intermediate in the Synthesis of semi-synthetic cephalosporin derivatives while retaining the protective group of the carboxylic acid function.

In another aspect, the present invention relates to a method of making semi-synthetic Cephalosporin derivatives from the intermediates of the formula II, the preparation of which is described above has been. This transformation generally involves the following reactions:

4) Elimination of the remainder of the formula

R ² CO IX

by hydrolysis with a selective agent that removes the introduced residue of the formula

R ¹ CO-

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not hydrolyzed, the choice of this agent being of depends on the nature of the remains;

5) hydrolysis of the protective group of the carboxylic acid function, which can be carried out after the previous reaction, and hydrolysis of the protective groups of the reactive Functions of the remainder R, if any.

In doing so, the free acid form becomes the semi-synthetic Obtained cephalosporin derivative and isolated by general methods. It is also possible, if desired the semi-synthetic cephalosporin derivative by reaction with a suitable agent in the form of a salt to isolate.

The protection of the carboxylic acid function in the first stage of the reaction sequence can be through esterification or formation other stable carboxylic acid derivatives, for example a mixed anhydride or hydrazine. In any case, it is preferably carried out with such an agent that the protective group introduced to can be removed again by hydrolysis at the desired point in time. It is also possible to take others mild conditions, for example by catalysis Use protective groups. It is most convenient to use agents that do not isomerize the double bond of the 3-position in the 2-position of the Cephalosporinkcms can cause.

At this stage a compound of the formula is obtained

4098B4 / 1383

χι «s

IT — CO — NH —CH— CH ^ " O = C-A

COOE

wherein R and X have the meanings given above and / .E the protective group introduced in this reaction means for the carboxylic acid function.

Examples of protective groups for the carboxylic acid function which are used in the process according to the invention can are ester groups such as methyl, t-butyl, 2,2,2-trichloroethyl, Benzhydryl, triphenylmethyl, p-nitrophenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, 2,4-diinethoxybenzyl, phenacyl or p-bromophenacyl groups; other protecting groups can also be used can be used for the carboxylic acid function, as is the case in the synthesis of peptides in general and in particular are known in the chemistry of ß-lactara antibiotics.

Groups that contain a silicon atom with organic Residues, such as trimethylsilyl and diaethylsilyl groups and, in general, groups of the formula

^M Ol K

409884/138 3

3 4 5

wherein R _1, R and R, which are the same or different from one another, are each alkyl groups with 1 to 3 carbon

3 4 mean atoms, and those in which R and R have the meanings given and R denotes a cephalosporin radical of the formula III are likewise suitable to protect the cephalosporin carboxylic acid function during the reactions of the invention. The introduction of these groups, which all belong to the class of the esters, is achieved by reacting the cephalosporin with a silicon halogen derivative or a disilazane.

Another set of protecting groups used in the present invention Process can be used, is formed from thei organotin derivatives, such as tri-nbutyltin, Triphenylzine, tri-n-propylzim and in general from groups of the formula

- Sn L ·. R ^{7 XI11}

6 7 8

wherein R, R and R, which are the same or different from one another, are alkyl groups having 1 to 5 carbon atoms or mean aryl groups.

The cephalosporin derivatives protected in this way, belonging to the class of esters, are ornamental

4098 8 4/1383

by reacting the cephalosporin derivative of the formula III with trisubstituted tin oxide, a trisubstituted one Tin hydroxide or a trisubstituted tin halogen derivative.

An example of a protecting group for a carboxylic acid function that forms a mixed anhydride is the acetyl group. The N, N -diisopropylhydrazine group is an example of a protecting group that a hydrazine forms. This first protective effect of the cephalosporin carboxylic acid function is apparently not necessary if the starting cephalosporin was previously in a usable one Protected form is obtained, which is what both the cephalosporins, which are produced by fermentation in which case it is necessary to convert them into an esterified derivative or another derivative, to facilitate the respective extraction from the fermentation medium, as well as with the cephalosporins caused by the enlargement of the penicillin rings, which makes it possible retain the same protecting group as it was used for this conversion, if used for the next reactions is stable enough.

2
If the radical R of the cephalosporin derivative used as starting material contains amine or carboxylic acid functions, as for example in the cephalosporin C, then they should be protected from the next reactions. The protection of the carbonic acid group can expediently be the same

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be effected in good time and with the same agent as the protection of the carboxylic acid group which is connected to the carbon atoms in the 4-position of the dihydrothiazide ring. The amine group can be protected by methods known in peptide chemistry. Examples of suitable protective groups are triphenylmethyl, o-toluenesulfonyl, benzylsulfonyl, oI, ^T itrobenzylsulfonyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trifluoroacetyl and formyl groups, but many other groups can also be used will.

The cephalosporin derivative of the formula XI obtained in this first stage can be an iminohalogonide of the Formula VII to be converted. This conversion can be carried out by reaction with an imine-forming halogen agent, such as a phosphorus halide such as phosphorus oxychloride, phosphorus pentachloride or phosphorus pentabromide, be achieved. This conversion should preferably take place in an anhydrous and inert organic Solvents are carried out, since the imino halides are generally unstable in the presence of water are. Suitable solvents are e.g. chlorinated solvents such as dichloromethane, trichlorethylene, Dichloroethane, trichloromethane, aromatic solvents such as benzene or toluene, acyclic or cyclic ethers, such as ethyl ether, isopropyl ether or tetrahydrofuran.

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The reaction for the production of the iminohalides described above takes place under good conditions, preferably in the presence of a proton acceptor, instead of. As a product acceptor is generally a base soluble in the reaction medium is used. Suitable organic bases are tertiary / firnine, in particular Dimethylaniline, quinoline and pyridine. This Proton acceptor is generally added to the reaction chamber prior to the addition of the imino-forming agent. This reaction generally proceeds satisfactorily at a temperature of +25 to -60 C from, with higher yields being achieved when the reaction temperature between -10 and -45 ° C.

The imino halide formed is generally not isolated from the reaction medium because it is unstable is. Therefore the acylation is carried out immediately using a suitable organic acid derivative (VIII) started; such a derivative should preferably be a salt of the formula

R ¹ - COOM XIV

wherein M is an ion. It is checked whether the iminohalogenide acylation reaction is generally in proceeds satisfactorily when the II ion in the derivative (XIV) of the organic acid (VIII) a metal ion i -1. In particular, one cannot use a lithium,

U 0 9 8 ;,: ■! 1 3 ^8:;

Use the potassium or sodium salt, although a non-alkali metal salt ζ can also be used.

The organic radical R was defined above. Its choice obviously depends on the product desired. Examples of radicals to which the process according to the invention can be applied are the α-aminobenzyl radical, in which the arain group is protected by a suitable blocking group, and its in the benzene ring substituted with one or more substituents from the group consisting of hydroxide, alkoxide, halogen, amine and carboxylic acid are, the aminomethylcyclohexyl radical in which the amine group is protected, the aminomethylcyclohexadienyl radical, in which the amine group is protected, the 2-thienyl radical or the 2-thienyl-aminomethyl radical, in which the amine group is protected as above. If there is an asymmetric carbon atom in the remainder, the process according to the invention is applied both to the raceric as well as to the separate optically active Forms applicable.

Examples of amine protecting groups which are suitable for protecting the amine group of the radicals indicated, if these they contain the following: triphenylmethyl-, o-toluenesulfonyl-, Benzylsulfonyl, o-nitrobenzylsulfonyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trifluoroacetyl, Formyl-, l-methyl-2-benzoylvinyl-, l-methyl-2-acetylvinyl-, l-methyl-2-ethoxycarbonylvinyl and others Protective groups, as they are in peptide chemistry and in particular

: 409884/1383

Derivatives that

especially known in the chemistry of ß-lactam antibiotics are. The removal of these protective groups is carried out by known methods and it can advantageously be carried out in near the end of the sequence of reactions occur immediately before or after, or sometimes simultaneously with the removal of the protective group for the carboxylic acid function.

The above acylation reaction can generally be carried out in an inert organic solvent which is sometimes the same as that used in the previous implementation will. If desired, however, it is possible to use the reaction medium to be modified, for example by concentrating or diluting with a different solvent. In general, the reaction proceeds well at temperatures from +50 to -10 ° C., the optimum being Temperature in each individual case is set according to the rate of reaction to avoid the risk to avoid the decomposition of the cephalosporin nucleus, which increases with temperature.

In the case of the one obtained in the acylation of the cephalosporin iminohalide using the specified method The product is a diacylcephalosporin of the formula II, if desired from the reaction medium can be isolated and cleaned, but also left in the solution and used for manufacture of the desired semi-synthetic cephalos

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porins in the same medium after removing the excess reagent and the by-products can be. This removal can generally be done by simply washing with water or with a dilute aqueous solution of a mineral acid and by filtering.

The process for the preparation of semi-synthetic cephalosporin derivatives of the Diacylcephalosporinderivaten Formula II consists mainly in the fact that the rest (IX) by Hydrol3 ⁷ se is eliminated with a selectiven agent. Such an agent must correspond to

1 2
according to the radicals R and R are selected so that the radical (IX) can be eliminated, while the introduced radical (X) is retained. In general, this selection does not present any difficulty to the person skilled in the art.

1 2
because the radicals R and R are always of different chemical nature. In most common cases,

2
in which the radical R is a benzyl, phenoxymethyl or 4-amino-4-carboxyl-n-butyl acid group, the removal can be carried out by various methods, for example by heating, by reaction with a reducing agent, by reaction with secondary ones or primary amines or diarains and by reaction with a thiophenol or a phenol derivative. Suitable amines and diamines include various amines with an unbranched chain, such as butylamine, pentylamine, llexylamine, hoptylamine, octylamine and the like,

40988A / 1

various dialkylaminoalkylamine such as dimethylaminoethylamine, Dimethylaminopropylamine, dimethylaminobutylamine, cyclic amines such as cyclohexylamine and the like. Among the suitable thioalcohols or Of particular interest are alcohol derivatives, phenoxides or thiophene oxides; Examples are sodium thiophenolate and potassium thiophenolate.

The "" described elimination reaction takes place in the in most cases in a satisfactory manner in a reaction medium which consists essentially of a inert solvent is formed, which in general can be the same as that used in the reactions used to make the diacylcephalosporins. With this reaction you can other solvents are also used, e.g. dimethylformamide, acetone, methyl isobutyl ketone and ethyl acetate.

The most suitable reaction temperature is between -20 and +40 C, often room temperature is used or it is cooled slightly in order to keep the reaction mixture between 0 and +25 ° C. Generally should this temperature must be set for each individual case and it must be taken into account that one higher temperature favors the reaction rate, but that is above a given threshold in addition, the cephalosporin can be broken down (broken down).

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It is convenient and sometimes possible to carry out the reaction to eliminate those present in the cephalosporin molecule Carry out protecting groups simultaneously with the elimination of group (IX). This is for example then achieved when the protective group for the carboxylic acid function is a phenacyl group or a substituted phenacyl group acts and if a thiiphenolate is used in the first-mentioned reaction will.

If the elimination of the protecting group does not occur simultaneously is carried out, both protective groups of the carboxylic acid function or carboxylic acid functions, if present, eliminated one after the other. This elimination takes place according to known methods, for each individual case appropriate methods.

The obtained cephalosporin derivative can be according to various Methods, for example by chromatography, by freeze-drying, by concentration, by Extraction, by changing the medium, by forming salts or derivatives or a combination of two or more of these methods can be isolated. A cephalosporin of the formula I is obtained.

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

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example 1

J-lung ^ de S _- Phenacy! Ester s_der_ 7- £ n- £ NfCarbobenzyloxy) -

To a suspension of 10 g (0.030 mol) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid in 150 ml of dry dimethylformamide were quickly with stirring 6.05 g Phenacyl bromide was added, then 3.1 g of triethylamine were added. The stirring was for 1 hour continued at 25 C. The mixture was poured into 800 ml of ice-cold water with vigorous stirring, and 150 ml Ethyl acetate extracted, the pH of the aqueous layer being adjusted to 1.5 prior to phase separation. The extraction was repeated and the organic extracts were collected and washed with water (60 ml). The organic extract was dried with anhydrous sodium sulfate and on a rotary evaporator evaporated to dryness under reduced pressure.

The residue obtained was taken up in 100 ml of ethanol-free, dry chloroform. While stirring 9.7 g of dry pyridine were added at a temperature of 25 C. It was cooled to -5 C and at at this temperature 6.5 finely ground phosphorus pentachloride was added. The mixture was for 1 hour stirred at -5 ° C and then quickly and successively with

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a 0.1 η aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution. It was dried over silica gel and decanted. While stirring and at a temperature of 30 ° C., 9.7 g of potassium D- (N-carbobenzyloxy) -2-aminophenyl acetate were added over a period of 30 minutes. Stirring was continued at 25 ° C for 15 hours. Then became

quickly and one after the other with a 0.5N chlorinated water purifier 1 η aqueous solution of sodium bicarbonate

säurelösungj material / and washed a saturated aqueous sodium chloride solution. The solution was concentrated ml over silica gel and dried under reduced pressure to a volume of 40th The concentrated solution was passed through a chromatography column containing 50 g of silica gel. The solution was eluted with a chloroform / ethyl acetate (8/2 by volume) mixture. Thin layer chromatography of the eluted fractions showed that the desired product was found in the first fractions that were collected. They were evaporated to almost dryness in a rotary evaporator under reduced pressure, taken up in a little chloroform and precipitated with petroleum ether. The precipitate was then filtered off and washed with petroleum ether. The resulting precipitate had a weight of 11.4 g (53 % of theory). Elemental analysis for C ^ H _{55 OgN 3} S:

Calcd .: C 69.93 H 4.91 N 5.85

found: 70.12 5.04 5.73%

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Example 2

phenvl-acetvl] 4-carboxylic acid

10.44 g (0.030 mole) γ-phenoxyacetamido-S-methyi ^ -cephem-4-carboxylic acid were suspended in 250 ml of ethylene chloride. A suspension of 3.6 g of pyridine hydrochloride was obtained with stirring added in 20 ml of methylene chloride. Stirring was continued for 5 minutes, then were 4.55 g of 2,2,2-trichloroethanol in 15 ml of methylene chloride were added dropwise. After the addition was complete, the solution was rapidly cooled to 15 ° C. and at this temperature 6.2 g of dicyclohexylcarbodiimide in 30 ml of methylene chloride were also added. The stirring was 15 hours carried out at 15 ° C. for a long time and the insoluble reaction by-products were filtered off. The filtrate was under evaporated to dryness under reduced pressure on a rotary evaporator. The solid residue was dissolved in ethyl acetate and successively with a 0.1 η hydrochloric acid solution and an aqueous 5% sodium bicarbonate solution. It was dried over silica gel and then evaporated to dryness in a rotary evaporator under reduced pressure.

The solid residue was dissolved in 100 ml of dry benzene

409884/138 3

2111765

dissolves and cooled to O C. After stirring for 48 hours at a temperature between 0 and +5 C a solid residue appeared, which was removed by filtration from the solution separated and discarded after being identified as an impurity. To that on The filtrate cooled to OC was added to 10.8 ml of dry pyridine. The mixture was cooled to -2 ° C and a solution of 7.6 g of phosphorus pentachloride in 70 ml of dry benzene was added while cooling to keep the temperature below 0C. Stirring at this temperature was continued for 2 hours and the insoluble impurities were filtered off. The mixture was quickly and successively with a aqueous saturated sodium chloride solution, an aqueous 5% sodium bicarbonate solution and water and dried over sodium sulfate.

The dry benzene solution was collected in a flask and kept near 25 ° C with stirring. 12.4 g

while slowly / potassium-D- (N-2 *, 2 *, 2'-trichloroethoxycarbonyl) -2-aminophenyl acetate was admitted. It was warmed to 50 C for 1 hour and slowly to room temperature let cool down. After 15 hours, the insoluble impurities were filtered off and that The filtrate was concentrated to a volume of 60 ml on a rotary evaporator under reduced pressure. The concentrated solution was passed through a chromatography column containing 50 g of silica gel. then was with a benzene / ethyl acetate (9/1, based on the

409884/1383

Volume) mixture eluted. Thin layer chromatography the eluate showed that the desired product could be found in the fractions collected first.

The solution was evaporated almost to dryness in a rotary evaporator and triturated with a small amount of ethyl ether, which promoted crystallization. It was filtered and washed with a small amount of ethyl ether. The resulting precipitate had a weight of 10.8 g (4-6 % of theory).

Elemental analysis for

ber .: C 44, 19th H 3 , 20 N 5, 33 gef.i 44, 27 3 , 30 5, 36 example 3

Production of the dibenzhydryl diester of the 7-FN- (thiophene-

carboxylic acid

17.5 g (0.030 mol) of sodium 7- (D-5 ^f -amino-5'-carboxyvaleramido) -3-acetoxy-methyl-3-cephem-4-carboxylate were suspended in 250 ml of anhydrous methanol. With stirring, under an anhydrous atmosphere and with cooling to keep the temperature at 25 ° C., 57.5 ml of a

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MethanoIisehen solution of 1.5 η hydrogen chloride was added dropwise. It was evaporated to dryness in a rotary evaporator under reduced pressure. The residue was dissolved in 350 ml of dry dimethylformamide and within 20 minutes while stirring at 20 ° C 34 g of diphenydiazomethane were added. After the Addition- the mixture was evaporated under reduced pressure on a rotary evaporator with a little ethyl alcohol triturated and evaporated further to give a pale yellow foam.

The mixture was taken up with 60 ml of tetrahydrofuran. It was cooled to -5 C and slowly became one Solution of 8.5 g of 2,2,2-trichloroethyl chloroformate in 40 ml of dioxane were added. It was stirred for 1 hour at -5 C and then successively with a 5% aqueous sodium bicarbonate solution, a 5% aqueous Hydrochloric acid solution and water washed until neutral. The washed organic phase was dried over anhydrous sodium sulfate and used for Evaporated to dryness. The viscous oil obtained was dissolved in 600 ml of dry benzene. There were 25 ml of anhydrous pyridine were added. The mix was cooled to -20 C and under an inert and anhydrous atmosphere within 15 minutes a Solution of 15.6 g of phosphorus pentachloride in 200 ml of dry Benzene added. The temperature was allowed to rise to -12 ° C and at this temperature was 1 hour

409884/1383

touched. The insoluble impurities were filtered off. The benzene solution came on quickly and one by one with a saturated aqueous sodium chloride solution, a 5% aqueous sodium bicarbonate solution and further washed with a saturated sodium chloride aqueous solution and dried over silica gel.

4.5 potassium thiophene-2-acetate were added to the solution obtained with stirring and at 30 ° C. Es Was stirred for a further 15 hours at 30 G and successively with an aqueous 0.5 η hydrogen chloride acid solution, an aqueous 5% sodium bicarbonate solution and an aqueous saturated sodium chloride solution. It was made over silica gel dried and concentrated under reduced pressure in a rotary evaporator to a volume of 100 ml. The concentrated solution was passed through a chromatography column containing 50 g of silica gel. It was then eluted with a benzene / ethyl acetate (9/1 by volume) mixture. Thin layer chromatography of the eluted fractions showed that the desired product was collected in the first Factions was to be found.

The solution was concentrated to small volume on a rotary evaporator and crystallized by cooling. It was filtered and washed with ice cold benzene. The resulting precipitate had a

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Weight of 8.7 g (28.0 % of theory). Elemental analysis for C ₅₁

Calc .: C 58.48 H A, 43 N 4.01

found: 58.00 4.53 4.12 %.

Example 4-

- ^e f- Zßri Uli liri
carboxylic acid

10 g (0.030 mol) of 7-Pheήylacetamido-3-methyl-3-cephem-4-car ■ bonsäure were slurried with 50 ml of anhydrous methylene chloride. 3.8 ml of dimethylaniline and 4.25 ml of triethylamine were added. 7.2 ml of dimethyldichlorosilane were added with stirring and with cooling, the temperature being kept between 18 and 22 ° C. Stirring was continued at 20 ° C. for 40 minutes. The mixture was cooled to -60 ° C. for 15 minutes and a solution of 6.5 g of phosphorus pentachloride in 80 ml of methylene chloride was added. The temperature was allowed to rise to -40 ° C. and then 12.5 ml of dimethylaniline were added. Stirring was continued for 2 hours at the temperature of -40 ⁰ C. After heating to + 30 ° C., 14.8 g of potassium DN-triphenylmethyl-2-phenyl-2-aminoacetate were quickly added. The solution was warmed to +40 C for 30 minutes and increased

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Cooled +25 C, then stirred for 4 hours at this temperature. The insoluble impurities were filtered off and 50 ml of water was added. The two-phase mixture was stirred for 1 hour while a saturated solution of sodium bicarbonate was added until a pH of 3.5 was reached. The organic layer was separated and the aqueous layer was extracted twice with methylene chloride, the organic extracts were combined with the main organic layer. The combined organic layers were washed with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. They were concentrated under reduced pressure on a rotary evaporator to a volume of 60 ml.

solution

The concentrated was passed through a chromatography column containing 45 g of silica gel. It was eluted with a methylene chloride / ethyl acetate (8/1 by volume) mixture. Thin layer chromatography of the eluted fractions showed that the desired product was found in the fractions collected first. The product was obtained from the eluted solution by freeze-drying; the solid obtained in this way had a weight of 7.8 g (37 % of theory! Elemental analysis for ^c a3 ^H 37 ° 5 ^N 3 ^S

calc .: C 72.96 H 5.27 N 5.94 found: 73.44 5.34 6.00 X

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Example 5

-ghenox ^ acetamido - ^ - methYl - ^ - ceghem - ^ - carboxylic acid

10.44 g (0.030 mol) of γ-phenoxyacetamido-S-raethyl-S-cephem-4-carboxylic acid were suspended in 100 ml of dry dimethylformamide. 6.9 g of p-nitrobenzyl bromide and 4.2 ml of triethylamine were added with stirring. The mixture was ^{stirred at 30 °} C. for 15 hours. 300 ml of ethyl acetate were added, washed with an aqueous sodium bicarbonate solution and four times with water. It was dried over silica gel and evaporated to dryness under reduced pressure on a rotary evaporator. An amorphous yellow solid was obtained, which was taken up in 100 ml of ethyl acetate. The resulting solution was washed twice with water, dried over silica gel and further evaporated to dryness under reduced pressure on a rotary evaporator. The solid obtained was triturated with a small amount of ethyl ether. The ethyl ether was separated by filtration and a residue was evaporated under reduced pressure.

The resulting crystalline solid was dissolved in 100 ml of alcohol-free dry chloroform. Under cooling 10.2 ml of dry pyridine were added to -20.degree.

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7.95 g of finely ground phosphorus pentachloride were added over the course of 15 minutes. The stirring became 2 Continued at -20 C for hours. The solid impurities were filtered off, quickly and one by one with a saturated aqueous sodium chloride solution, an aqueous 5% sodium bicarbonate solution and further washed with a saturated sodium chloride aqueous solution. It was then dried over silica gel.

12.4 g of potassium N- (2 ^f , 2 ', 2'-Trichloräthoxj ^r carbonyl) -2-phenyl-2-aminoacetate were added at room temperature. The solution was warmed to 45 ° C. and stirred for 1 hour. It was cooled and washed with a 1 η aqueous hydrochloric acid solution and a 5% sodium bicarbonate aqueous solution. It was dried over silica gel; the insoluble impurities were removed by filtration simultaneously with the silica. The solution was concentrated under reduced pressure to a volume of 40 ml. The concentrated solution was passed through a chromatography column containing 50 g of silica gel. It was eluted with a benzene / ethyl acetate (9/1 by volume) mixture. Thin layer chromatography of the eluted fractions showed that the desired product was found in the fractions collected first. The product was obtained from the eluted solution by freeze-drying and the solid obtained thereby had a weight of 7.3 g (33% of theory).

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Elemental analysis for C ^ HggO ^ N, S Clber .: C 51.56 H 3.69 N 7.07 Measured values: 51.15 3.55. 7.11%.

Example 6

Preparation of 7- (N-CarbobenzoxY) -2 ^t -amino-2 ^l -ghen £ lacetamido-3-methYl-3-ceghem-4-carboxylic acid

10.8 g (0.015 mol) of the phenacyl ester of 7- [N- (N'-Carbobenzy lox $ -2 '-amino-2 * -phenylacetyl] -phenylacetaraido-3-methyl-3-cephem-4-carboxylic acid were in 40 "ml of dimethylformamide were suspended. With stirring and at room temperature, a solution of 3.95 g of sodium thiophenolate in 15 ml of dimethylformamide was added. Stirring was continued for 1 hour at 20 ° C. The mixture was extracted with a 0.1 M aqueous sodium carbonate solution. The extract was acidified to pH 2 with hydrochloric acid and extracted four times with 50 ml portions of ethyl acetate. The extract was dried over silica gel and concentrated under reduced pressure to a volume of 25 ml. After addition of ethyl ether and cooling, / white solid was precipitated. which was separated by filtration. the product had a weight of 3.5 g (48.5 X of theory).

Elemental analysis for Cg ^ g ^ OgflUS
calc .: C 59.86 H4.81 N 8.73 found: 59.70 4.68 8.67 Z.

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Example 7

7.75 g (0.010 mol) of the 2,2,2-trichloroethyl ester of 7- [N- (N ^l -2 ", 2", 2 "-trichloroethoxycarbonyl) -D-2 ^l -amino-2 ^l phenylacetamidoJ-phenoxyacetamido ^ Methyl-S-cephem-A-carboxylic acid were suspended in 200 ml of dry benzene, 1.26 ml of cyclohexylamine were added dropwise to this suspension with stirring and at 25 ° C. Stirring was continued for 1 hour at 25 ° C. The mixture was continued washed with a 1 η aqueous hydrochloric acid solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in a rotary evaporator to a volume of 50 ml under reduced pressure.

The concentrated solution was passed through a chromatography column containing 40 g of silica gel. It was eluted (based 9 / I ₉ by volume) with a benzene / ethyl acetate mixture. Thin-layer chromatography of the eluted fractions showed that the desired product was contained in three first-collected tractions. The product was obtained from the eluted solution by freeze-drying and the solid obtained in this way had a weight of 2.1 g (32% of theory).

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Elementary analysis for

ber .: C 38, 56 H 2 , 93 N 6th , 42 7th
/ 0. found •
• · ι 38, 61 3 , 11 6th , 36 at game 8th

Preparation of Natriura-7-N-thf ⁾ Dhen-2 ^t -acetamido-3-acetoxpneth ^ l-3-cephem-4-carboxylic acid

7 g (0.014 mol) of the dibenzhydryl diester of 7- [N (thiophene-2 ^ll -acetyl) -D-5 '- (N ^l -2 ^l ' ^% _t 2 ^%%% , 2 * ^f '-trichloroethoxycarbonyl) -amino -5 ^l -carboxy-valeramido] -3-acetoxymethyl-3-cephem-4-carboxylic acid were dissolved in 50 ml of 90% acetic acid at room temperature. After cooling to 5 ° C., 1.37 g of zinc dust were added. After stirring for 2 hours at 5 ° C., a further 10 ml of the 90% strength acetic acid were added. The mixture was then filtered and the filter was washed with acetic acid which was added to the filtrate. The solution was concentrated in a rotary evaporator under reduced pressure until an oily residue was obtained, this was dissolved in 40 ml of trifluoroacetic acid, and 12 ml of anisole was added. After stirring for 20 minutes at room temperature, the mixture was evaporated in a rotary evaporator under reduced pressure and then taken up in 100 ml of ethyl acetate and washed successively with an aqueous 5% sodium bicarbonate solution and with an aqueous saturated sodium chloride solution.

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The solution obtained was dried over sodium sulfate and a solution of 2.8 g of sodium 2-ethyl-hexanoate in 20 ml of ethyl acetate was slowly added at 5 ° C. The mixture was concentrated under reduced pressure to a volume of 40 ml and a precipitate was deposited by adding petroleum ether. This was filtered off and washed with ethyl thread. The product obtained had a weight of 3.4 g (58% of theory).
Elemental analysis for C ₁₆ H ₁₅ OgN ^ S

ber .: C. 9 45 , 93 H 3, 61 N 6th , 70 O/
/ 0 « found: 45 , 78 3, 53 6th , 56 example

Production of the g-bromoghenac ^ ester of the 7- (N-tri |> henyl meth ^ l) -D-2 ^ -arnino-2 '-ghen ^ lacetamido-S-methvl ^ -ceghem-

7.08 g (0.010 mol) of 7- [N- (N ^t -triphenylmethyl) -D-2 ^f -amino-2 ^l -phenylacetyl] -phenylacetamido-3-methyl-3-cephem-carboxylic acid were dissolved in 50 ml of dimethylformamide suspended. Then 2 ml of triethylamine and 2.8 g of p-bromophenacyl bromide were added and the mixture was heated to 40 ° C. and stirred for 15 hours. After cooling to 2O ⁰ C the mixture was diluted with 40 ml of benzene and washed several times with water. After drying over silica

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gel and after cooling to 5 C a solution of 1.25 ml of 3-dimethylaminopropylamine in 6 ml of benzene was added. After stirring at 5 ° C. for 4 hours, it was washed successively with a saturated aqueous sodium chloride solution, with an aqueous 1 η hydrochloric acid solution and with an aqueous 5% sodium bicarbonate solution. The solution was dried over silica gel and evaporated under reduced pressure on a rotary evaporator. Then it was taken up in 50 ml of ethyl acetate and a precipitate was deposited with petroleum ether, which was filtered off and washed with ethyl ether. The product obtained had a weight of 4.8 g (61 % of theory). Parental analysis for Ο ,, Η-, Ο, -Ν, Β Br

calc .: C 65.65 H 4.61 N 5.34 found: 66.08 4.71 5.40%.

Example 10

Preparation of 7- (D-2-amino-2-ghen ^ l-acetamido) -3-meth ^ l-3-ceghem-carboxylic acid

11.9 g (0.015 mol) of the p-nitrobenzyl ester of 7- [N- (N'-2 ", 2", 2 "-Trichlorethoxycarbony1) -D-2'-phenyl-2'-aminoacetyl] -phenoxyacetamido-3 -methyl-3-eephem-4-carboxylic acid were dissolved in 40 ml of dry chloroform. A solution of was at 25 C with stirring 1.5 ml of n-butylamine in 5 ml of chloroform to the mixture

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admitted. It was stirred at 25 ° C. for 1 hour. Then it was successively with an aqueous 0.5 η Hydrochloric acid solution and an aqueous saturated Washed sodium chloride solution. she got dried over magnesium sulfate and evaporated under reduced pressure on a rotary evaporator. Of the The residue was taken up with 15 ml of benzene.

The solution was passed through a 80 g silica gel Chromatography column run. She was with a benzene / ethyl acetate (9/1, based on the volume) · Mixture eluted. Thin layer chromatography of the eluted fractions showed that the desired product was included in the fractions collected first. These fractions were freeze-dried. The freeze-dried Product was suspended in 15 ml of dioxane containing 1.5 ml of water. Were at room temperature 6.9 g of zinc dust and 7 ml of concentrated hydrochloric acid were added. The mixture was stirred for 2 hours stirred at room temperature and filtered. It was made under reduced pressure on a rotary evaporator constricted. The residue was dissolved in 14 ml of water. The solution was allowed to cool to 10 C and it triethylamine was added dropwise until a pH of 3.7 had been reached. There were 200 ml of cold acetone added and stirring was continued at 0 C for 2 hours. The suspension was filtered and with Acetone washed.

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The solid product obtained was taken up in 80 ml of water and the suspension was heated to 65 ° C. for 20 minutes. It was cooled to 10 ° C. and filtered. Then it was washed with a small amount of water. The product obtained in this way had a weight of 11.5 g (21 % of theory). The infrared spectrum, determination of the water content and thin layer chromatography in comparison with an authentic standard showed that this product was identical to 7- (D-2-aminophenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate.

Example 11

Preparation of the_7- (p-2- ^ ino-2-ghenYlacetamido) -3-meth ^ l-3-ceghem-carboxylic acid

10 grams (0.030 moles) of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid were suspended in 100 ml of anhydrous chloroform and 3.8 ml of dimethyl anil in and 4.25 ml of triethylamine were added. 7.2 ml of dimethyldichlorosilane were added with stirring and cooling, with the temperature was kept in the vicinity of 20 C. Stirring was continued for 40 minutes at 20 ° C. It was cooled to -60 ° C. and 6.5 g of finely ground phosphorus pentachloride were added over the course of 15 minutes. During this addition, the temperature was allowed to rise to -38 ° C. and 12.5 ml of dimethylaniline were obtained admitted. It was at for another 2 hours

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-38 C stirred. The mixture was heated to +20 ° C. and 12.4 potassium N- (2 ^I , 2 *, 2'-trichloroethoxycarbonyl) -2-phenyl-2-aminoacetate were quickly added. The resulting mixture was warmed to +30 C and stirred for 30 minutes. After cooling to +10 C, stirring was continued for 14 hours.

The resulting solution was filtered to separate off the solid impurities. A solution of 3.8 g Sodium thiophenolate in 30 ml of dimethylformamide was added dropwise, the temperature of the mixture being kept at 10 ° C. It was stirred for 30 minutes and with mixing, 20 ml of water was added over 30 minutes. There were 2 g sodium bicarbonate was added, the aqueous layer was separated and the organic layer was washed with a 0.5 η aqueous hydrochloric acid solution and then with a saturated sodium chloride aqueous solution. It was dried over sodium sulfate and vacuumed on a rotary evaporator except for concentrated to a volume of 40 ml.

The concentrated solution was passed through a chromatography column containing 80 g of silica gel. she got eluted with a chloroform / ethyl acetate (8/2 by volume) mixture and the fractions containing the desired product were isolated after being identified by thin layer chromatography was. The separated fractions were evaporated under reduced pressure in a rotary evaporator the solid residue obtained in the process was treated with 200 ml of 90% strength

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Formic acid added. The solution was cooled to 5 ° C. 1.9 g of zinc dust were added with stirring. The mixture was stirred at 5 ° C. for 45 minutes and filtered. In a rotary evaporator was evaporated under reduced pressure and then taken up with benzene and again to dryness evaporated. It was taken up in 20 ml of water and triethylamine was added dropwise until a pH value of 3.7 had been achieved. Then the final operations of the last part of Example 10 were repeated, the same product was obtained in an overall yield of 18%.

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Claims (16)

Claims 1. Diacylcephalosporin derivatives, characterized by the general formula R ² -CO S , ^X N-CH-CH ^{y X} CH _O R ¹ —CO ^ I ' ^{! 2} (II) ^K ^ ^u O = C - N. C ^K ' COOE where mean: R is an organic radical different from n-butyl-4-amino-4-carboxylic acid, the alkyl, aryl, aralkyl or heterocyclic radicals Groups and one or more substituents, such as alkoxy, hydroxide or amine functions, halogen atoms or others, R an organic originating from the substrate used Radical from the group n-butyl-4-amino-4-carboxylic acid, benzyl, phenoxymethyl, 2-pentenyl, pentanyl, heptanyl and p-hydroxybenzyl, X is a hydrogen atom or an organic radical in which it can be a hydroxide, acyloxy, heterocycloxide or amine radical, and 409884/1383 E is a hydrogen atom or a protective group for the Carboxylic acid function. 2. Diacylcephalosporin derivatives according to claim 1, characterized characterized in that in the general formula R is a radical from the group a-aminobenzyl radical with protected Amino group, which is optionally substituted in the benzene ring by one or more substituents from the group hydroxide, Alkoxide, halogen, amine or carboxylic acid is substituted, aminomethylcyclohexadienyl radical with protected Amino group, aminomethylcyclohexyl radical with protected Amino group, 2-thienyl and aminomethyl-2-thienyl radical with a protected amino group. 3. Process for the preparation of the diacylcephalosporin derivatives according to claim 1 and / or 2, characterized in that the nitrogen atom of the 7-acylamido group is one Cephalosporin derivative of the general formula R ² - CO - NH - CH - CH ^XX CH _O II I ² / ^C \ ^(III) COOH wherein R and X have the meanings given in claim 1, or a derivative thereof with a protected one Acylated carboxylic acid function. 409884/1383 4. The method according to claim 3, characterized in that the acylation of the nitrogen atom of the 7-acylarai ogruppe by reacting an organic acid derivative of the formula R ¹ COOH wherein R has the meanings given in claim 1 and / or 2 with the iminohalide derivative of the cephalosporin used as a substrate or a derivative of which effected with protected amino and carboxylic acid functions. 5. The method according to claim 3 and / or 4, characterized in that the substrate used is a cephalosporin derivative whose carboxylic acid function is represented by a methyl, t-butyl-2,2,2, trichloroethyl, benzhydryl, triphenylmethyl, p-nitrophenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, 2,4-dimethoxybenzyl, phenacyl, p-bromophenacyl, trimethylsilyl , dimethylsilyl, Tri-n-butyltin-iEriphenyltinn-, Tri-n-propylzim-, acetyl- or N, N ^f -di-isopropylhydrazine group is protected. 6. The method according to at least one of claims 3 to 5, characterized in that when in the general formula of claim 1 E is a hydrogen atom means the protective group of the carboxylic acid function 409884/1383 Completion of acylation removed. 7. The method according to at least one of claims 3 to 6, characterized in that a cephalosporinimine halide is used as the substrate, which is formed by reacting the cephalosporin derivative with an imine
halogenated agent. . 8. The method according to claim 7, characterized in that a phosphorus halide is used as the imine-forming halogenated agent is used. 9. The method according to claim 7 and / or 8, characterized in that the imine halide formation in the presence
a proton acceptor is carried out. 10. The method according to at least one of claims 3 to 9, characterized in that the organic acid derivative a salt of the formula is used R ¹ COOM wherein M represents a metal atom. 11. The method according to claim 10, characterized in that M is an alkali metal from the group consisting of sodium, potassium and
Lithium means. 409884/1383 12. Process for the preparation of semi-synthetic cephalosporins or derivatives thereof of the general formula 1 ^p R-CO-NH-ClI-CH ^ ^X CH ¹¹ I. ¹¹
O = C-N COOA where mean: R is a different from n-Buty1-4-amino-4-carboxylic acid organic radical, the alkyl, aryl, aralkyl or heterocyclic groups and one or more substituents, such as alkoxy, hydroxide or amine functions, halogen atoms or others, may contain X is a hydrogen atom or an organic radical in which it can be a hydroxide, alkoxide, heterocycloxide or amine radical, and A is a hydrogen atom, an alkali metal, an E-alkali metal or an ammonium group optionally substituted by organic radicals, characterized in that one diacylcephalosporin derivatives the general formula 409884/1383 R ² -CO _X / S ^ Ν —CH-CH CH ¹ J ^X CH ₂ X COOE wherein R and X have the meanings given above, 2
R is an organic radical from the group n-butyl-4-amino-4-carboxylic acid, benzyl, phenoxymethyl, 2-pentenyl, pentanyl, heptanyl and p-hydroxybenzyl and E is a hydrogen atom or a protective group for the carboxylic acid function , subjected to selective deacylation. 13. The method according to claim 12, characterized in that after the selective deacylation, the protective group splits off the carboxylic acid function, optionally the Splitting off the protective group of the amino function and that at the same time obtained semi-synthetic cephalosporin derivative isolated. 14. The method according to claim 12 and / or 13, characterized in that that the semisynthetic cephalosporin derivative obtained is obtained by chromatography, freeze-drying, Concentration, extraction, medium change, salt formation, or a combination of two or more of these methods isolated. 409884/1383 15. The method according to at least one of claims 12 to 14, characterized in that the deacylation is carried out Heating, reacting with a reducing agent, reacting with an amine or with a primary or secondary Diamine or a triamine or reacting with a phenol derivative or a thiophenol derivative. 16. The method according to at least one of claims 12 to 15, characterized in that the deacylating agent a compound from the group butylamine, pentylamine, ■ Hexylamine, ileptylarain, octylamine, cyclohexylamine, sodium thiophenolate and potassium thiophenolate are used. 409884/1383