DD279887A1 - METHOD OF PREPARING D-ALPHA- (4 (1H) -1,5-NAPHTHYRIDONE-3-CARBOXAMIDO) -BENZYLPENICILLIN AND OTHER BETA LACTAMANTIBIOTICS - Google Patents

Abstract

The invention relates to a process for the preparation of D-alpha (4 (1H) -1,5-naphthyridone-3-carboxamido) -benzylpenicillin and other beta-lactam antibiotics which consist of carboxylic acid active esters or of ureidocarboxylic acid active esters, in particular of the 5-norbornene 2,3-dicarboximidester and beta-lactams are produced. The field of application of the invention is the pharmaceutical industry. Beta-lactam antibiotics; D-alpha- (4 (1H) -1,5-naphthyridone-3-carboxamido) -benzylpenicillin; Carbonsäureaktivester; Ureidocarbonsäureaktivester; 5-2,3-dicarboximide ester Norborner-; Beta-lactams; Pharmacy}

Description

Field of application of the invention

The invention relates to a novel process, ί for the production of ß-Lactarr.antibiotika, in particular of the title compound, which are soaped as a drug in medicine. Field of application of the invention is the pharmaceutical industry.

Characteristic of the known technical solutions

It is known that β-lactam antibiotics of general formula I

A-CO-N-D, I

wherein D denotes a β-lactam containing radical, R is a substituent and A-CO denotes the acyl moiety of a carboxylic acid carrying one or more hydroxyl and / or secondary amino groups can be prepared in a variety of ways. This relates in particular to β-lactam antibiotics of the formulas II and IV and the realizations of the invention thus detected

A-CO-C-CH-CO-K

35 I

A-CO-N

IV

Substituents D. Typical substituents in the formulas I, II and IV are, for example, hydrogen for R, R ⁰² , Ί ⁰⁴ and R ⁰⁵ , phenyl for R ^D3 , sulfur for X and the group (X) -CI-CH ₃ I ₂ -CH-CO-OH for Y, where si (x) denotes the point of attachment of Y to X. The acyl component A-CO can be derived from a wide range of freely selectable carboxylic acid A-CO-OH. The synthesis of compounds of the formula I, II and IV requires mostly activated acyl components A-CO-G, as can be prepared from the carboxylic acids A-CO-OH or other suitable carboxylic acid derivatives. In general, however, the hydroxyl and / or amino groups present therein must first be protected. _(In actual fact, it would then be possible to differentiate between the unprotected and the protected Res.A.) However, in simplifying terms A or A-CO-G Accordingly, the activated acyl component A-CO-G may be, for example, acid halides, in particular acid chlorides, simple or mixed anhydrides, acid azides (G: N ₃ ) or so-called activated esters the activated acyl components A-CO-G with a ß-lactam component of the general formula END or END, wherein R ⁰² , R ^D4 and D

R ⁰² R ^D4

have the meaning explained above and E is hydrogen or a suitable leaving group, or with a β-lactam component of the general formula III to β-lactamantibiota ka of the formulas I,

Il odor IV, or their derivatives protected at the amino and / or hydroxyl groups of the acyl components A-CO, to. In the last step, if necessary, the protective groups are removed.

In the preparation of pharmaceutically important β-lactam antibiotics, the acid halide method (G: halogen) often fails due to the sensitivity of the particular carboxylic acid A-CO-OH to typical halogenating agents such as thionyl chloride. The preparation of the acid azides is often possible only in a very complicated way, and a technical application of the same: 'ind set narrow limits, for example, due to any risk of explosion in isolation of the azides. The use of Mischanhydf idverfahren leads to the undesirable formation of by-products, especially of urethanes. By contrast, many active ester methods, for example, require the harmful N, N'-dicyclohexylcarbodiimide (DCC), and esters of N-hydroxysuccinimide (HO-Su) often have only low storage stability. They are thus technically disadvantageous. In addition, unwanted side reactions were observed in the preparation of N-hydroxysuccinimide esters A-CO-O-Su. Finally, it is also difficult to separate ureas as unwanted byproducts of Aktivestorherstellung to be expected, or incurred in the ß-Lactamaniibiotika preparation Hyd ^r uxyvcrbindung GH can be separated only in a very complicated way of the products of formulas I, II and IV. One cause of such difficulties is the particular sensitivity of the β-lactams, sometimes including the specific carboxylic acids A-CO-OH and their derivatives.

In the preparation of such compounds of formulas I, II and IV characterized in that their acyl component A-CO has the following specific structure

ie rings (^])

in the rings

and (ο 'represent any optionally substituted carbo- or heterocycles.

I Ο I

the ring _v / but need not be present, it is also possible, from the carboxylic acids with phosgene or chloroformates internal anhydrides of the structure

to build. These are then reacted as activated acyl components, just like the compounds of the formula A-CO-G, directly with β-lactam components of the formulas E-N-U, E-N-D or of the formula III to form β-lactam antibiotics of the formulas I, II or IV

R ⁵² V ^D *

(see DE 2362279 C2 and DO 2416449). The disadvantage here is the necessity of direct use of highly toxic Rec ^ nzien as phosgene or Chlo ^r ameisensäureester where | S Lactamantibiotikaherstellung because the inner Anhydrido are often poorly-storage products, so beautiful | l need to be further processed so that their Synthesis can not be separated from the actual ß-Lactamantibiotikaherstellung

 It is also known that certain active esters of the general formula

A-CO-O-NB V

are representable, wherein

H-NB is the 5-norbornene-2,3-dicarboximide indicated in Formula VI.

HK Kl ^Vl

Carboxylic acids A-CO-OH and the N-hydroxy compound HO-NB are assumed in the previously known processes for preparing NB-active esters of the general formula V (Fujino, M. et al .: Chem. Pharm. Bull. 22 (1974 ), 1857). However, unknown are active esters of hydroxy and / or amino groups of unprotected carboxylic acids. In particular, those active esters of this type are unknown, which can be used for the production of pharmaceutically significant ß-lactam antibiotics, and thus the consequences of the use of such active esters in the ß-Lactamantibiotikaherstellung are unknown.

Object of the invention

The aim is to find a method according to which, under mild conditions and with the use of solvents customary in β-lactam antibiotic production, certain carboxylic acid active esters of the type A-CO-O-NB, preferably

without isolation (ie in situ), to β-lactam antibiotics A-CO-N-D or A-CO-N-D can be implemented. Hydroxy and / or

_R D2 _R D4

If possible, secondary amino groups should be able to be present unprotected in the carboxylic acid active esters. The released in the implementation activation component HO-NB and / or their Deriva.j should be of low toxicity, easily separated from the reaction mixture and thus recover as possible and reuse after treatment, by-products should occur only in small quantities and, if They occur, then also easily separated from the desired product, possibly existing protective components of the ß-lactams as well as the carboxylic acid component should not significantly interfere with the reaction, so that finally a high yield of pure product of the desired ß-Lactamantibiotikums can be achieved. This object is to be achieved by using chemically new carboxylic acid A-CO-O-NB, which can be prepared in such a way that under mild thermal conditions and in a mild medium, consisting of conventional solvents, can be worked and that Finally, the solvents can be chosen so that isolation of the active ester A-CO-O-NB prior to their further conversion to ß-lactam antibiotics is not required. Overall, the process should be characterized by chemical simplicity and economic effectiveness.

Explanation of the essence of the invention

The invention has the object zugrinde, by means of a new method ß-Lzctamantibiolika the general formulas I, II and IV of carboxylic acid active esters A-Cl "-O-NB of the formula V and ß-lactam components of the formulas E-N-D, E-N-D or

_R D2 _R D4

Formula II ', wherein the substituents have the meaning previously explained and A is a largely inert to A-CO-O-NB under the conditions of this carboxylic acid activestor as well as dor ß-lactam antibiotics, but otherwise arbitrary radical, such as alkyl, alkenyl, Alkynyl, aryl or hetaryl, which are optionally substituted. In addition, the carboxylic acid active esters generally indicated by Formula V may have the specific structure described in Formulas Va 1 to Vz. Therein stands the group designated by -CO-NAIk for

-CO-H-CH

The symbol δ (Kronecker delta) can take the values 0 and 1, so that (-CO-NAIk) ₈ = i-CO-0-NB is equivalent to -CO-NAIk-CO-O-NB and for

D3

-CO-N-CH-CO-O-KB ι κ

while (CO-NAIk) ₀ -CO-O-NB corresponds only to -CO-O-NB. In the abbreviation -CO-NAIk- explanatory formula or in the formulas II to IV R ^{02 is} hydrogen, alkyl or a protective group and R ^{D3 is} phenyl or other aryl, hetaryl, especially thienyl, hydroxy or amino-aryl or -Hetaryl, in particular p-hydroxyphenyl and 2-amino-thiazolyl, further for

(-CO-Naik) ^ - CO-O-:

OH

(-CO-Naik) ^ - CO-O-

Va 1 Va11

-CO-O-NB

Va 12

(-CO-NAIk) j- -CO-O-:

Va 13

(-CO-NAIk) ^ -CO-O-

Vb 1

(-CO-NAIk) j- -CO-O-NB

Vb2

OH

-CO-O-NB

OH

(-CO-NAIk) Γ -CO-O-NB

OH

(-CO-Naik) ^ - CO-O-NB

OH

-CO-NAIk) j * -CO-O-NB

OH

-CO-O-NB

(-CO-NAIk) £ -CO-O-NB

(-CO-NAIk) j- -CO-O-NB

(-CO-NAIk) j- -CO-O-NB

VB21

Vb 22

Vb23 Vb 24 Vb25

vd

Vc 11

Vc 2

(-CO-NAIk) j'-CO-O-NB

Vc21

OH

- (- CO-Naik) j - CO-O-NB

(-CO-NAIk) jv -CO-0-NB

(-CO-NAIk) cf -CO-O-NB Vc 22

Vc 23

Vc 24

(-CO-NAIk) j ^ -CO-O-NB Vd 1

(-CO-NAIk) £ -CO-O-NB Vd 11

-CO-O-NB Vd 2

H-O

(-CO-NAIk) J ^ -CO-O-NB Vd 21

(-CO-NAIk) j- -CO-O-NB Vd 3

H-

-CO-O-NB Vd31

H-

(-CO-NAIk) J ^ -CO-O-NB Vd 32

H-N N-CO-NAIk-CO-O-NB Ve

H-N N-CO-Na-lk-CO-O-NB

Y 0

.-00-0-HB

Ji

^D8 Vf

Vg

R ¹

) χ -CO-O-NB Vh

R ^D3 ^ C- (CO-NAIk) j- CO-O-NB

D10 Vi

, D3

T V (CO-NAIk) ^ - CO-O-NB

, D8

CO-O-R

D11

vk

k) ^ -CO-O-N

Vl

0-R

^D9

(00-HAIk) J-CO-O-HB

0-R

^D8 Vm

- (CO-Naik) ^ - CO-O-NB

(CO-Naik) ^ - CO-O-NIlVnVo

(CO-NAIk) ^ -CO-O-NBVp

D9

R ^D3 ₅ C- (CO-NAlk) J-CO-O-NB

R ^D8 -NR ^D10

Vq

R "

R ^UJ -C- (CO-NAIk) ^ - CO-O-NB

N = CH-R

D11 Vr

R ^D3 _S C- (CO-NAIk) ^ -CO-O-NB Vs

N = CH-R ^D14

R » ⁹

R ^D 3_C- (CO-NAIk) J'-CO-O-NB N- (R ^D8 or R ^D11 )

-C- (CO-Naik) ^ - CO-O-NB

- (CO-Naik) ^ - CO-O-NB

o-ch ₂ -co-or ^{y: 3}

D13

VtVu

_H D11 _}

Halo-CH = CH-S-CHr- (CO-NAlk) o-CO-O-NB Vv

_vw

) ^ -CO-O-NB _Vx

N-0- (R ^D8 or R ^D11 )

$ ^ rC- (CO-NAIk) J-CO-O-NB

\ 'Vy

X ₃ ^ NO-CH ₂ -Q

R ^D11 -CO-NH-N = C- (CO-NAIk) Γ -CO-O-NB

Cyclohexenyl and cyclohexadienyl, o-Clvurphenyl, o-dichlorophenyl, o-fluoro-chlorophenyl, -O-aryl, -O-hetaryl, -S-aryl, -S-hetaiyl, all of which may optionally bear substituents.

The symbol R ^D4 denotes hydrogen, alkyl or a protective group and R ⁰⁵ represents hydrogen, alkyl or O-alkyl. In the general formula III R ^D6 and R ^{07 are} methyl, ethyl or higher alkyl. Representative of S, O, SO, SO ₂ or CH ₂ , in the formulas II to IV the symbol X has been written and Y stands for

-20- P.79 CH ^ (x) CHp

3 or C-GH ~ -R ^{X £;}

OH OH, O

I ... ³

wherein the sign (χ) denotes the site of binding of Y to X. Here, R ^{Y1 has} the meaning of -CO-OR ^Y3 , -CO-R ^Y4 or

-C-NR ^T3 .

and R ^Y2 is hydrogen, alkyl-CO-O-, hydroxyl, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, thiocarbamoylthio, -S-aryl or -S-hetaryl, carbamoyl, alkyl-substituted carbamoyl, alkylcarbamoyl-alkoxy, alkylcarbamoyl or

^N N-N

IJ [I Il

^{H is} CH ₀ -CO-OH

The groups mentioned can also carry additional substituents. The group CO-O-R ^Y3 represents any ester group, or R ^Y3 denotes a hydrogen atom, a protective group or an electron pair. In the latter case, the compounds of formulas II and IV are anions. This may include any cation, in particular a physiologically acceptable, such as Na ⁺ , or a cation compatible with the above-described formation reaction of the β-lactam antibiotics. R ^Y4 is an optionally protected hydroxyl group and R ^Y5 is hydrogen, hydroxyl, methyl or higher alkyl, \ R ^Ye / denotes hydroxyl, amino odi -NH-R ^A \ which are optionally protected, or hydrogen, alkyl, alkoxy, halogen, Acetylamino, carboxy, carboxymethyl, carboxyalkyl, which may carry additional substituents, wherein the parentheses {} are mono-, di- or multi-substituents. R ^A1 is a protecting group or hydrogen, methyl, ethyl or other alkyl, also cyclic, for example cyclopropyl, optionally substituents bearing. The asterisk * denotes in all cases a center of chirality, and the compounds can be present in the respectively possible configurations R and S or in any mixtures thereof.

In the heterocycles of the formulas Va 1 bif, Vz, the symbols -U- and -M- are divalent atoms such as -O- and -S- or the atomic groups

^ KR UHd Μί-80 _ο "ίί where R ^A 'in-U and-M-must not be identical, but can be

For example, these atoms or atum groups may be absent so that -U- and -M- have only the meaning of a bond line.

The symbols L and T stand for the atoms N and C.

The bridge atoms denoted by the point · stand for / N or

s' A2

/ O = or -C-R ι so that the ring W for carbo- and heterocycles, in particular aryl and hetaryl,

also fully or partially hydrogenated and provided with any substituents of the type R ^A2 is. The ring W can, but he does not have to be present. In this case, R ^A2 in particular denotes hydrogen, hydroxyl, halogen, nitro, alkyl or other substituents. In the case where in formula Vd or Vc2 the symbol -U-for-NH-, = T-for = CH- and -L = for -N =, are the two tautomeric forms of the same heterocyclic, namely

and

Finally, the active esters indicated by formula V general may also have the structure specified in formulas Vf to Vz. It contains the general symbols R ⁰⁹ and R ⁰⁹ for the groups

-N = C-E

D13

OAER

-N = G-E

D11

In addition, R ⁰⁸ , R ^D9 , R ⁰ ' ² and R ^{DI 3 may} be hydrogen, alkyl, alkenyl, alkynyl, aryl or hetaryl, optionally substituted, as well as azido, amino, hydroxy or carbonyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, alkylaminoalkyl, alkoxyalkyl or carbalkoxyalkyl

Furthermore, R ^D1 ° is hydroxy, OR ^D8 , amino, NH-R ^DS , NH-CO-R ⁰⁸ or NR ⁰⁸ R ⁰⁹ ,

D8

HN-CO-B C0-E ^D9

CO-OH or SO ₂ -OH, all protected if necessary. R "and R ⁰¹⁴ denote hydrogen, phenyl, hydroxy or aminophenyl, o-chlorophenyl, o-dichlorophenyl, o-fluoro-chlorophenyl, other aryl, hetaryl, cyclohexenyl or cyclohexadienyl, O-aryl, O-hetaryl, S-aryl, S-hetaryl, cyano or

The symbol Q stands for a radical which is in the formulas Va 1 to Vz and is located on the group O-NB. According to the invention this object is achieved in that carboxylic acid active esters of the general formula V are used, wherein the required for their preparation activation component HO-NB in a known manner (Fujino, M., et al .: Chem. Pharm. Bull. 24 (1974) The active esters are synthesized with β-lactam components of the general formulas

END

END

D2

or of formula III converted to ß-lactam antibiotics of the formulas I, II or IV. In particular, β-lactam components of the general formula

HN-D R

or Formulas Xa, Xb and Xc

H ₀ N-CH-CO-NH 2 κ

Xa

HN-CH-CO-N \ *

Xb

xc

CO-OH

and carboxylic acid active esters of the formulas Va or Vb

Ir-CO-O-NB

Va

CO-NH-CH-CO-O-KB

Vb

be used, so that in particular the D-a- (4 (1 Hl-I.B-naphthyndone-S-carboxamidoJ-benzylpenicilliri of formula lan

NH- ^. '.-CO-NH-J r

Iaa1

or whose tautomare arise. All general symbols argegebonen in the formulas have the previously explained meaning. The reaction is performed in organic solvents such as CH ₂ CI _2, dioxane, or water, at temperatures between -20 ° C and 6O ⁰ C, preferably at room temperature, or in a multiphase system, oestehend of water un: performed i organic solvents

 The β-lactam components of the formulas

END, END _E D2

or of formula III can be used in free form, as hydrates or generally as solvates, silylated or as salts, preferably of sodium or tertiary amines. Accordingly, and depending on the conditions of the working up of the mixture, the β-lactam antibiotics are obtained in pure form, or as salts. To purify the product, one can use the usual methods, such as extraction, crystallization, chromatography, etc.

The advantages of the reaction on the special Carbi> iureaktivester of formulas V, Va, Vb, or Va 1 to Vz consist in their high reactivity, for example, allows te too .. 'the ß-l.actamkomponenten use, in the good Yields of β-lactam antibiotics of the formulas I, II, IV and LAA, the high purity of these products, the avoidance of racemization as much as possible, and the avoidance of the occurrence of N-acyl hornstoifen, and finally the possibility of a one-step -Rcaktion, that is, to the isolation of the active ester to ve. ziehten. The carboxylic acid active esters of the general formulas (V, Va, Vb) required for the reaction described above can be prepared by reacting the carboxylic acid A-CO-OH or an activated derivative with HO-NB in a manner known per se. It has been found that surprisingly, these active esters can also be prepared in high purity from the carboxylic acids and the compound CI-CO-O-NB. For this purpose, the required for the desired ß-Lactamantibiotikcim carboxylic acid in an inert anhydrous solvent, preferably halogenated hydrocarbons, tetrahydrofuran, dioxane, acetonitrile and / or aromatics in the presence of tertiören amines, such as triethylamine, N-disubstituted anilines, preferably in pyridine, at temperatures between -2O ⁰ C and 8O ⁰ C, preferably between -5 ° C and O ⁰ C, reacted with N-IChlorcnrbonyloxyl-B-norbornene ^ .S-dicarboximide CI-CO-O-NB. The reaction can be carried out by catalytically active N, N-4-dimethylaminopyridine (DMAP) or another supernucleophilic amine, for example 4-pyrrolidinopyridine (PPY), N-methylimide-fiol or diazobicyclo (5,4,0) -undecene ( Accelerate DBU). The active esters thus obtained are optionally isolated and purified. It is particularly advantageous to react the active esters without prior isolation, ie ir iitu, with the desired β-lactam component to the respective β-lactam antibiotic.

Further advantages of the beschb jbenen leadership of the reactions consist in the preservation of the absolute configuration of the carboxylic acid component Λ, if necessary, and in the prevention of harmful dicyclohexylcarbodiimide and thus the resulting, difficult to separate dicyclohexylurea. The carboxylic acid active esters prepared according to the invention are, for example, in contrast to N-hydroxysuccinimide esters, in most cases readily storable products. The side reactions described for N-hydroxysuccinimide esters have not hitherto been observed.

Finally, the good solubility of the active component HO-NB in water and in many organic solvents in the isolation of ß-lactam antibiotics proves to be advantageous. The antibiotics can be selectively precipitated with a suitable choice of medium, leaving HO-NB in solution. In the use of substituted phenols as the activating component of the esters, the separation is far more difficult since the phenols are generally less water soluble than HO-NB.

A further advantage of the described reaction procedure is the recovery of the active esters under very mild conditions which make it possible to work not only racemization-free but also active esters of particularly sensitive carboxylic acids, for example 6-amino-penicillanic acid or tetracyclines (in this case by conversion of the CO-NH ₂ group in -CO-O-NB [in several steps)].

A very particular advantage of the process is that it is also possible to use carboxylic acid active esters in which the hydroxyl and / or amino groups of the basic carboxylic acid A may be present unprotected or quasi-protected in the case of protonated amino groups.

The following embodiments are intended to explain the invention.

example 1

The preparation of a solution of carboxylic acid active ester can be carried out according to one of the following instructions:

0.01 mol of carboxylic acid are suspended or dissolved in dry methylene chloride and treated with at least 0.02 mol of triethylamine or pyridine. The solution / suspension, which has already been cooled to ⁰ ° C. previously or now, is treated dropwise with 0.01 mole of CI-CO-O-NB per carboxyl group to be reacted. In case of inert carboxylic acids under these conditions, the addition of CI-CO-O-NB can also be faster. After 30 'to 3h the reaction is usually over. The solution / suspension can be washed with NaCl-saturated aqueous solution and dried over MgSO ₄ . It can then be further processed directly (one-pot process), or the methylene chloride is distilled off, and the carboxylic acid active esters are isolated and, if desired, purified by recrystallization.

0.01 mol of carboxylic acid are suspended or dissolved in dry methylene chloride and treated with at least 0.02 mol of Ν, Ν, Ν ', Ν'-tetramethylguanidine or other suitable organic base. 0.015 mol of CI-CO-O-NB, dissolved in dry methylene chloride, is added dropwise to the solution or suspension cooled to ⁰ ° C. for each carboxyl group to be reacted. In case of inert carboxylic acids under these conditions, the addition can also be faster. After addition of catalytic amounts of Ν, Ν'-dimethylaminopyridine (DMAP) is 30 'at ^{0 0} C and then stirred for 2 h at room temperature. After being filtered if necessary, the reaction mixture is washed with NaCl-saturated aqueous solution and dried over MgSO ₄ . The solution of the carboxylic acid active ester thus obtained can now be subjected to the desired subsequent reaction directly (one-pot process) or isolated by distilling off the solvent and, if desired, purified by recrystallization.

0.01 mol of the carboxylic acid are taken up in methanol and admixed with at least 0.01 mol of a 40% methanolic solution of trimethylbenzylammonium hydroxide (Triton-B). The resulting clear solution is evaporated to dryness and the residue is added twice with a little dimethylformamide and then concentrated again to dryness. The triton-B salt of the carboxylic acid thus obtained is dissolved in dry methylene chloride, cooled to ⁰ ° C. and reacted with 0.015 mole of CI-CO-O-NB, also dissolved in dry methylene chloride. The reaction is usually complete after 1-3 hours. The further work-up of the batch 6 follows as under (a) or (b).

Example 2

The preparation of the β-lactam components of the general formula III or of the formula Xb can be carried out according to the following procedure:

0.04 mol of α-aminobenzylpenicillin in the form of the anhydrous compound, as trihydrate or as sodium salt are slurried in 100 ml of acetone with the addition of 0.06 mol of triethylamine (or 0.03 mol when using the aforementioned Na salt) and about 2 Stirred vigorously at room temperature for hours. This forms a homogeneous solution. Then it is stirred for about another half hour.

By acidification with 2 η or concentrated HCl pH is adjusted to 2.0, wherein the formed ß- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinylj-penicillanic acid (hetacillin - formula Xb) separates.

Example 3

0.005 mol of the salt of a carboxylic acid of the formula A-CO-OH with an organic base, for example N'N'NN-tetramethylguanidine, according to Example 1 in Wusserfreien methylene chloride with CI-CO-O-NB to the carboxylic acid active ester of the general formula V, Va , Vb or Va 1 to Vz implemented. Subsequently, the finished solution is filtered and used as follows.

In 10 to 15 ml H ₂ O 0,005MoI Hetacillin sodium salt, prepared according to Example 2 and DE-PS 1445517, dissolved and cooled to ⁰ ° C. This cooled solution is added dropwise to the cooled to -5 ⁰ C to O ⁰ C methylene chloride solution of the carboxylic acid activester with stirring, 30min with further stirring at -5 ⁰ C to O ⁰ C and then kept at room temperature for 60 min.

The organic solvents are removed in vacuo, and the residue is dissolved in 50 ml of water, then filtered and the solution with stirring with ice cooling with 2 η HCl adjusted to the pH range 2.0 to 2.5. The finished product fails. It is filtered off, washed with H ₂ O and dried. Otherwise, it will be worked up according to one of the following examples.

Example 4

0.01 mol of 6- [D (-) - a-aminophenylacetamidol-penicillanic acid-Nh ^l urn brurn (ampicillin), dissolved in about 20ml H ₂ O, are added dropwise at ^{0 0} C with stirring in a solution of 0.01 mol a carboxylic acid active ester of the formula V, Va, Vb or Va 1 to Vz in methylene chloride. After completion of the addition, stirring is continued for a further 30 to 60 minutes with cooling and then for at least 1 hour at room temperature. The mixture or solution is then concentrated at temperatures up to 3O ⁰ C in vacuo, the residue taken up in about 300 ml of ice water and filtered. The filtrate is adjusted with 2 η HCl to pH = 2.0 to pH = 3 and extracted 2 to 3 times with ethyl acetate. The extract is washed several times with M ₂ O and then dried over Na ₂ SO ₄ .

The acidity of the extract is determined and extracted therefrom with about 60 ml of aqueous solution of the equivalent amount of sodium bicarbonate. The aqueous solution is concentrated at 30 to 40 ⁰ C, the residue washed with ethyl ether and dried. In this way, the sodium salt of the desired β-lactam antibiotic is obtained.

Example 5

0.01 mol of the trihydrate of e-1DI-Ja-amino-phenylacetamidol-penicillanic acid are suspended in about 30 ml of H ₂ O and brought into solution by addition of triethylamine. This solution is treated as the solution of the ampicillin sodium salt in Example 4. Working up to the sodium salt of the desired β-lactam antibiotic is likewise carried out as in Example 4.

Example 6

A solution of 2 mmol of a carboxylic acid, for example the formula

ΓΛ

HN

ΓΛ

H-H N-CO-NH-CH-CO-OH

D ₁ L

in 50 ml of dichloromethane is added 4 mmol of pyridine and cooled to -8 ⁰ C. With stirring and cooling, 4 mmol of N-hydroxy-5-no chloroformate; Bornen-2,3-dicarboximidester CI-CO-O-NB, dissolved in 25ml dichloromethane, is added dropwise, the temperature should not rise above -5 ⁰ C. After adding a catalytic amount of 4-N ₁ N-dimethylaminopyridine is stirred for half an hour at ^{0 0} C and then until the reaction is complete (ie, 2 to 70 hours) at room temperature. After the solution has optionally been filtered, the isolation of the carboxylic acid reactant A-CO-O-NB formed, or when using the above-mentioned carboxylic acid, the isolation of the active ester is represented by the formula

"Π

HN ^ H-CO-NH-CH-CO-O-NB, ⁰ D ₁ L

by shaking with water (saturated sodium chloride), with 5% sodium bicarbonate solution (saturated sodium chloride) and water again. The organic phase is now dried over magnesium sulfate, filtered and concentrated almost to dryness. The product is precipitated with hexane and dried. (The melting points and other data of the compound and the starting materials are taken from Table 1.) The further reaction to ß-lactam antibiotics takes place according to Baispiel 4 or 5. Substituting the ampicillin in this by 6-aminopenicillanic acid, we obtain with the above carboxylic acid the compound of the formula

N-CO-NH-CH-CO-NH-,

0 I 0

D ₁ L

or your sodium siz.

Example 7

4 mmol of chloroformic acid N-hydroxy-S-norbornene ^. S-dicarboximidester CI-CO-O-NB are dissolved in 25 ml of tetrahydrofuran and added dropwise with stirring and cooling (-8 ⁰ C) to a solution of 2mmol of a carboxylic acid, for example the in Example 6 given, and 4mmol pyridine in 25 ml of tetrahydrofuran, wherein the temperature should not rise above -5 ° C. The reaction mixture is catalytically! Amount of 4-N, N-dimethylaminopyridine and stirred for half an hour at ^{0 0} C and then stirred at room temperature until complete formation of the active ester.

After addition of about 1OmI of water and completion of the gas evolution, the mixture is cooled again to 5 ⁰ C. 3 mmol of e-aminopenicillanic acid triethylammonium salt, dissolved in 80% strength tetrahydrofuran, are then added dropwise to the reaction mixture. It is stirred for half an hour at 5 ⁰ C and a further 2 hours at room temperature. For working up, it is filtered, about 40 ml of water are added and the organic solvent is distilled off iV. It covers the remaining aqueous residue with ethyl acetate and acidified with dilute hydrochloric acid with stirring and cooling to pH = 3 at. The Essigsä'jreethylester phase is separated and the acidic aqueous phase extracted 2 more times with fresh ethyl acetate. The combined organic phases are washed neutral with water and dried over MgSO ₄ . The penicillin derivative is obtained after filtration and removal of the solvent. The workup can also be carried out after filtration and distilling off the organise th solvent from the reaction mixture by acidification of the aqueous residue with dilute hydrochloric acid to pH = 3. The precipitate is filtered off, washed with water and dried in this case.

Example 8

3 mmol of ampicillin are suspended in 20 ml of dichloromethane and brought into solution by addition of 6 mmol of triethylamine. Subsequently, 2 mmol of a carboxylic acid active ester, for example of the formula

CO-O-KB

taken up in dichloromethane and cooled to ⁰ ° C. While stirring, the ampicillin triethylammonium salt is now added dropwise at ⁰ ° C. to the active ester. It is stirred for half an hour at ^{0 0} C and a further 2'Λ hours at room temperature. The resulting clear solution is concentrated to dryness, taken up in distilled water, optionally filtered and layered with ethyl acetate. With stirring and cooling is acidified with dilute hydrochloric acid to pH = 3, the organic phase separated and extracted the acidic aqueous phase 2 more times with fresh Essigsäuroethylester. The combined organic phases are washed neutral with water, dried over magnesium sulfate, filtered and the final product (formula laa 1 in the case of the carboxylic acid indicated above) is recovered by evaporating off the solvent. The penicillin derivative can also be obtained by precipitation from the aqueous phase with dilute hydrochloric acid to pH = 3. The β-lactam components given in the examples are interchangeable with others. In particular, the following compounds or their derivatives can be used

H ₂ K-CH-CO-KH

- (H or -O-CO-CHO

CO-OH

be used.

Tables 1 and 2 contain examples of carboxylic acid active esters used and β-lactam antibiotics prepared therefrom. In addition, the compounds given in the following list were synthesized. Derivatives of 4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid:

6- [[amino (4-hydroxyphenyl) acetyl] aminol-3,3-dimethyl-7-oxo, trihydrate [2S- (2alpha, 5alpha, 6beta (S *)]] -; 6 - [(aminophenylacetyl) amino ] -3,3-dimethyl-7-oxo-, [2S-I2alpha, 5alpha, 6beta (S ·)]] -; 6-l (aminophenylacetyl) -aminol-3,3-dimethyl-7-oxo, 1 - [ (ethoxycarbonyl) oxy) ethyl ester, [2S- [2alpha, 5alpha, 6bota (S *) U-6 - ((carboxyphenylacetyl) amino] -3,3-dimethyl-7-oxo-, (6S- (2alpha, 5alpha, 6beta )] - 6 - [[13- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-diamino] -3,3-dimethyl-7-oxo, [2S- (2alpha, 5alpha, 6beta) | -

-oxo-, [2S- (2alpha, 5alpha, 6beta) | - 6 - ([(3- (2,6-dichloiopheny!) - 5-methyl-4-isoxazolyl] carbonyl] -amino | -3,3- dimethyl-7-oxo-, | 2S- (2alpha, 5alpha, 6beta)] - 6 - [(2,6-dimethoxybenzoyl) amino} -3,3-dimethyl-7-oxo, [2S- (2alpha, 5alpha, 6beta ) J-6 - [[(2-ethoxy-1-naphthalenyl) carbonyl] amino] -3,3-dimethyl-7-oxo, [2S- (2alpha, 5alpha, 6beta)] SS-dimethyl-e-IKB -methyl-a-phenyl ^ -isoxazolydcarbonyl-aminol-y-oxo, [2S- (2alpha, 5alpha, 6beta)] - e-carboxy-S-thienylacetyl-amino-ol-SS-dimethyl-y-oxo, [2S- [2alpha , 5alpha, 6beta (S *))] - derivatives of 5-thia-1-azabicylot4.2.0] oct-2-ene-2-carboxylic acid: 7 - [(aminophenylacyl) amino] -3-chloro-8-oxo , [6R- [6alpha, 7beta (R *)!], Hydrate, y-llaminol, hydroxyphenyacetylaminol-S-methyl-B-oxo, (eR-IBalpha; betafR ¹ *))), monohydrate, and ilhydroxyphenylacetylaminol-a-Kd-methyl-IH-tetrazol-B-ydthiolmethyl-B-oxo, [6R- [6alpha, 7beta (R *)] | -

7-l (hydroxyphenylacetyl) amino] -8-oxo-3 - [[[1- (sulfomethyl) -1H-tetrazol-5-yl] thio] methyl], [6R- [6alpha, 7beta (R)] 7 - [[[2- (aminomethyl) phenyl] acetyl] amino] -3 - [([1- (carboxymethyl) 1H-tetrazol-5-yl] thio] methyl] -8-oxo, (6R trans) -7- [i [[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] (4-hydroxyl-phenyl) acetyllamino] -3 - ([(1-methyl-1H-tetrazole -5-yl) thio] niethyl | -8-oxo-, (6R- [6alpha, 7beta (R *)) | -

3 - [(actyloxy) methyl] -7-I [(2-amino-4-thiazolyl) (r.ethoxyimino) acelyllamino) -8-oxo, [6R [6alpha, 7beta (Z)] | - 3- [ [(aminocarbonyl) oxylmethyl] -7-methoxy-8-oxo-7- | i2-thienyl-acetyl) -amino | -, (6R-cis) -7 - [[(2,3-dihydro-2-imino-4 -thiazolyl) (methoxyimino) actyl] amino] -8-oxo, [6R- [6alpha, 7beta (Z)]] - 7 - [({2-amino-4-thiazolyl) (methoxyimino) acetyl] -amino | -8-oxo-3 - [[{1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thio] methyl | -, ( 6R- (6alpha, 7beta (Z)]] -

3 - [[(aminocarbonyl) oxy] methyl] -7 - [[2-furanyl (methoxyimino) acetyl] arnino] -8-oxo-, [6R- [6alpha, 7beta (Z)) | - 7 - [{arninophenylacetyl ) amino] -3-methyl-8-oxo, [6R- [6alpha, 7beta (R *)) |, monohydrate 3-I (acetyloxy) methyl) -8-oxo-7 - [(2-thienylacetyl) amino) -, (6R-trans) -3- ((acetyloxy) methyll-8-oxo-7 - [[(4-pyridylthio) acetyl) aminole-, [6R-trans] -7-i (amine) - cyclohexadiene-i-ylacetato-amino-S-methyl-e-oxo-, [6R- [6alpha, 7betaJR *)]) - as well as dds derivative of 5-oxa-1-azabicyclo [4.2.0] oct-2-ene-2 carboxylic acid: 7 - [[carboxy (4-h ^l _l 'droxyphenyl) acetyllamino) -7-methoxy-3 - [[(1-methyl-1H-tetrazn | -5-yl) thiolmethyl] -8-oxo-, sodium salt

Table 1:

Carboxylic acids A-CO-OH, their active esters A-CO-O-NB and the products of the reaction with 6-Ia-amino-phenylacetamido] -penicillanic acid (ampicillin) to compounds of the type

_n , w COOH

and / or their salts

Table 1

1.3

A-CO-O-ITB I) ¹ P ( ⁰ C)

122-124

122-124

168-171

Product IR (cm " ¹ )

1780, 1670, 1620, 1525

1780, 1670, 1620, 1525

1770

1770

174-179

1.5

155-159

1780

176c

1.6

OH

ίο

1750

1.7

1790

table

LQ

Cai'bobsäaren I-CO-NH-CH-CO-OH,

D, L

Aktivester

I-CO-NH-GH-CO-O-NB

D ₁ L

and the products

Ca

Α-ΌΟ-ΝΗ-ΟΗ-ΟΟ-ΝΗη S

D, L

³ CO-OH

A "most active

EP ( ⁰ C) (D ₁ L)

Product IR (om " ¹ )

1.1 Eacemat

215-217

227-229

D 1780, 1670, 1620,

1525

D, L 1780, 1670, 1620,

1525

1770

210-212

1770

table

Active ester g

EP ( ⁰ C) (D, L) Product IR (cm ^-1 )

O ₂ N

216

1780

1760

OH

17 50

1790

1.8 ΓΛ

223-224

1790

1.8 Eacemat 217-219 D, L 1790

Claims (12)

-1- 279 Q87 claims: ι. Process for the preparation of D-a- (4 (1 H) -1,5-naphthyridone-3-carboxamido) -benzylpenicillin of the formula Iaa1 ^ OT ^ VCO-NH-CH-CO-NH-I \ ^ \ / Cn ₃ N ^ $ N ^ / CHo O \ 3 CO-OH Iaa1 or its tautomers and other β-lactam antibiotics of the general formula I, A-CO-N-D, I in the D denotes a radical containing β-lactam body, R is hydrogen, alkyl or a protective group, and A-CO denotes the acyl component of a carboxylic acid A-CO-OH, characterized in that 4 (1 HH ^ -naphthyridone-S-carboxylic acid most active of the formula Va, CO-O-NB Amido-carboxylic acid active esters of the formula Vb Va -CO-NH-OH-CO-U-EB Vb or Carbonsäureaktive.ster the general formula V, A-CO-O-NB in which A-CO has the meaning described above and NB the B-norbornene ^^ - dicarboximide of the formula VIa Via denotes, with ß-lactams of the formula Xa, \ b, Xc H ₂ H-CH-CO-NH. CO-OH Xa CO-OH Xb CH,
CH. CO-OH or with β-lactams of the general formula X, HisJ-D
R xc in which R and D have the meaning previously explained, are converted into compounds of formulas Iaa 1 or I. 2. The method according to claim 1, characterized in that ß-lactam antibiotics of general formula I are prepared which are those in the formulas II and IV L-CO-N-gH-CO-N 1 D5 A-CO-N 1 i ^ " ^X \ IV have specific structure and wherein R ^{D2 is} hydrogen, alkyl or a protective group, R ^{D3 is} phenyl or other aryl, hetaryl, cyclohexenyl or cyclohexadienyl, which may also carry substituents, further R ^D4 = hydrogen, alkyl or a protective group , R ^{D5 is} hydrogen, alkyl or O-alkyl and X is S, O, SO, SO ₂ or CH ₂ , Y is (Χ) , X1 CH, 'CH. or ., C-CH ₂ -R * ² s'.dht and the sign (χ) denotes the point of attachment of Y to X, where R ^{Y1 is} CO-OR ^Y3 , CO-R ^Y4 or P NR ^Y3 , Il
NN R ^{Y2 is} hydrogen, alkyl-CO-O, hydroxyl, pyridinium, amiophenidinium, azido, cyano, Thiocarbamoylthio, carbamoyl, alkyl-substituted carbamoyl, carbamoyloxy, alkylcarbamoyl alkoxy, alkoxycarbamoyl, S-aryl, S-hetaryl or N- S-U -N Il N CHp -CO-OH, which may carry substituents, where CO-OR ^{Y3 represents} any ester group. However, ^Y3 denotes a hydrogen atom, a protective group or an electron pair, so that in the latter case the compounds of the formulas II and IV are anions, to which any one with Claim 1 formulated reaction of the compounds of formulas I and II and IV compatible cation, such as Na ⁺ , in particular a physiologically acceptable cation, wherein R ^{Y4 denotes} an optionally protected hydroxyl group, wherein R ^{Y5 is} hydrogen, hydroxyl, methyl or higher alkyl stands, where {R ^Y6 } is hydroxyl, amino or NH-R ^A1 , which are optionally protected, or is hydrogen, alkyl, alkoxy, halogen, acetylamino, carboxy, carboxymethyl, carboxyalkyl, which may bear substituents, the parentheses {} Mono-, di- or multisubstitution mean wherein R ^{A1 represents} hydrogen, methyl, ethyl or other alkyl, optionally substituents, or a protective group and the star * denotes a Chiralitättzcntrum, wherein the compounds of formula II in the respective possible configurations R and S, or in any mixtures thereof, may be present. 3. Process according to Claims 1 and 2, characterized in that β-lactams of the general formula X are used, which are those in the formulas VII to IX R ¹ D5 HN - ^ H-CO-N R ^D2 R ^D4 N ^ "/ D3 HN-CH-CO-N- Ti) VIII R ¹ HN
_R D4 IX in which R ⁰⁶ and R ^{DV represent} methyl, ethyl or higher alkyl and the substituents R ^D2 , R ⁰³ , R ^D4 and R ^D5 and the groups X and Y have the meaning given in claim 2, where the star * characterized in the formulas VII and VIII chiral centers and these compounds in the respective possible configurations R and S, or in any mixtures thereof, may be present. 4. Process according to claims 1 to 3, characterized in that carboxylic acid reactive esters of the general formula V are used which on optionally present reactive groups such as carboxyl, provided that they can interfere with the formation of the compounds of formulas I and / or V quantitatively protected are. 5. Process according to Claims 1 to 4, characterized in that carboxylic acid reactive esters of the general formula V are used, which, except for the necessary case according to claim 4 to be added protecting groups in the following formulas Va 1 to Vz (-CO-NAIk) J'-CO-O- Va1 OH (-CO-Naik) ^ - CO-O-NB VA11 OE - (-CO-NAIk) j- -CO-O- va12 OH (-CO-NAIk) j- -CO-O-NB VA13 ü
"yC-CO-NAIk) ^ -CO-O-NB Vb1 -CO-NAIk) j · -CO-O-NB QH (-CO-NAIk) f -CO-O-NB PH (-CO-NAIk) J -CO-O-NB Vb2 Vb21 Vb22 OH (-CO-NAIk) j -CO-O-NB OH (-CO-NAIk) £ -CO-O-NB OH ITS- (-CO-NAIk) j »-CO-O-NB -CO-O-NB '\ _ (-CO-NAIk) ^ - CO-O-NB Vb23 Vb24 Vb25 vd Vc11 -CO-O-NB (-CO-NAIk) j'-CO-O-NB OH -CO-O-NB OH (-CO-NAIk) j -CO-O-NB -CO-O-NB (-CO-NAIk) g -CO-O- ⁰ ^ ¹ Kp (-CO-NAIk) J- -CO-O-NB Vc2 Vc21 Vc22 Vc23 Vc24 Vd1 VD11 (-CO-NAIk) g -CO-O-NB Vd2 ^H O ^^ · ¹ ^ (- CO-NAIk) χ -CO-Oj-NB VD21 (-CO-NAIk) J- -CO-O-NB Qf Vd3 ' ³ SpC-CO-NAIk) ^ - CO-O-NB Vd31 ⁰ Nj ^ pC-CO-NAIk) J "-CO-O-NB df Vd32 H N V-CO-NAlk-CO-O-NB HN N-CO-NAlk-CO-O-NB 0 Ve Vf D9 R ^ -C- (CO-SAlk) ^ -CO-O-NB D8 Vg R ^D3 -O-C- (CO-NAIk) ^ -CO-O-NB D8 Vh R ^D ^ -C- (CO-NAIk) j- CO-O-NB D10 vi J V (CO-NAIk) ^ - CO-O-NB vj R ¹ - (CO-NAIk) ^ - CO-O-NB CO-OR ⁰¹¹ vk -CO-O-NBVl O-R D9 ί ^C0 - ^NAlk ) J-CO-O- vm (CO-NAIk) ^ - CO-O-NBν η / R ^D / QV (CO-NAIk) ^ - CO-O-NB Vo vp R ^^ - C (CO-Naik) ^ - CO-O-NB R ^D8 -NR ^D10 Vq R ^D9 R ^ C- (CO-NAlk) J-CO-O-NB N = CH-R ⁰¹ -C- (CO-Naik) J-CO-O-NB / N ^ ^H 2 ^N \ Jl 1 Y3 0-CH ₂ -CO-OR ¹ - ⁵ R ^D11 -CO-NH-N = C- (CO-NAlk) g -GO-O-NB -9- 379 887 Vr jC- (CO-NAIk) ^ - CO-O-NB Vs H-CH ₂ -R ⁰¹¹
N = CH-R ^DU R ⁰ ^ -C- (CO-NAIk) ^ -CO-O-NB Vt L (R ⁰⁸ or R ⁰¹¹ ) Vu Halogen-C'H = CH-S-CH 2 - (CO-NAIk) ₀ -CO-O-NB Vv - (CO-NAIk) ^ - CO-O-NB ' R ^D3 -C- (CO-NAlk) ^ -CO-O-NB Vx NO- (R ⁰⁸ or R ⁰¹¹ ) -0- (CO-NAIk) jT-CO-0-NB H ₂ NH / || Il ⁰ Vy \ ¹ J NO-CH ₂ -Q _V z and wherein NB has the meaning described in claim 1, wherein further -CO-NAIk-for f
-CO-N-gH- The substituents R ⁰² and R ⁰³ and the star * have the meaning formulated in claim 2 and the symbol δ (Kronecker delta) can assume the value zero or one, and accordingly the group -CO-NAIk absent (δ = O) or present (δ = ί), wherein each of the symbols T and L used in formulas Va 1 to Vz is the atoms N and C, the latter also being able to carry substituents, each of the symbols M and U being the atom O or the atomic group in which R ^{A1 is} in particular hydrogen, but also methyl, ethyl or other alkyl which may carry all substituents, or a protective group, where the symbol is an N or C bridge or, if the cycle denoted by W is absent , denotes an N or C atom which may also carry substituents, where R is ^D8 and R is ^D9 for the groups or -N Ε ⁰¹² however, R ⁰⁸ and R ⁰⁹ , as well as R ⁰¹² and R ^013, are hydrogen, alkyl, alkenyl, alkynyl, aryl or hetaryl which may bear substituents, as well as azido, amino, hydroxy or carbonyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, Alkylaminoalkyl, alkoxyalkyl or carbalkoxyalkyl,
wherein further R ^{010 is} hydroxy, OR ⁰⁸ , amino, -NH-R ⁰⁸ , NH-CO-R ⁰⁸ or NR ⁰⁸ R ⁰⁹ , -N-CO-B ¹¹⁸ , CO-OH or SO ₂ -OH, if necessary protected, wherein R ⁰¹¹ and R ^{014 is} hydrogen, phenyl, hydroxy or aminophenyl, o-chlorophenyl, o-dichlorophenyl, o-fluoro-chlorophenyl, other aryl, hetaryl, cyclohexenyl or cyclohexadienyl, O-aryl, O-hetaryl, S-aryl, S-hetaryl, which may carry all substituents, cyano or c. in which the symbol Q denotes a radical of the group O-NB given in the formulas Va 1 to Vz, where R ^Y1 and R ^{Y3 have} the meaning given in claim 2, and finally that in the formulas Va 1 to Vd32 with W ring may be present, but need not be and, if present, for a mono or multi-cyclic aryl or hetaryl, which may be wholly or partially hydrogenated and / or also bears substituents. 6. Process according to Claims 1 to 5, characterized in that compounds of the formulas V, Va 1 to Vz and VII to X find use in which protecting groups radicals such as trialkylsilyl or trimethylsilyl mean. 7. Process according to Claims 1 to 6, characterized in that the reaction of the carboxylic acid active esters with ß-lactams to ß-lactam antibiotics in inert solvents, such as methylene chloride, chloroform, dioxane, water or in a multiphase system consisting of water and organic solvents, at Temperatures between -20 ⁰ C and 60 ⁰ C, depending on the choice of solvents and the thermal sensitivity of the reacted components made. . 8. Process according to Claims 1 to 7, characterized in that the reaction of the carboxylic acid active esters with β-lactams to β-lactam antibiotics is carried out so that the N- and / or CO-0-protected β-lactam antibiotics of the formulas II and IV only occur in situ and at the end of the reaction, the protection group-free ß-lactam antibiotics are present. 9. Veifahren according to claims 1 to 8, characterized in that carboxylic acid active esters of the formulas V and Va 1 to Vz find use by reaction of carboxylic acids of Formula A-CO-OH, wherein A has the meaning given in the preceding claims, with N-chloro-carbonyloxy-S-norbornene-S-dicarboxime. abbreviated CI-CO-O-NB, wherein NB has the meaning described in formula VIa, or by reacting carboxylic acids A-CO-OH or suitable reactive derivatives of the general formula A-CO-E, wherein E is a leaving group such as halogen or Azido, with the compound HO-NB or a suitable derivative JO-NB, wherein J denotes a protecting group such as trimethylsilyl or a leaving group, such as a metal atom, and wherein among HO-NB, the N- (hydroxy) -5-norbornene-2 , 3-dic3rboyimid iu understand, have been manufactured. 10. The method according to claims 1 to 9, characterized in that the carboxylic acid reactive ester & t: Formuleln V and Va 1 to Vz are used, which by Umsetzuno ^of carboxylic acids of the forms! A-CO-OH with CI- (OO-NB in the presence of a tertiary amine and / or suitable quaternary ammonium hydroxides, such as trimethylbenzylammonium hydroxide or for an accelerated reaction in the presence of additional catalytic amounts of a supernucleophilic amine, such as 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, N-methylimidazole or diazobicyclo [5,4,0] undecene. 11. The method according to claims 1 to 10, characterized in that the carboxylic acid active '3ider formulas V and Va 1 to V? Use, which is isolated after the reaction of carboxylic acids with CI-CO-O-NB and purified if desired and then reacted with ß-Lactcmen iu ß-lactam antibiotics or without prior isolation, ie in situ, with ß-lactams to ß-lactam antibiotics of Formulas I, II and IV are implemented. 12. The method according to claims 1 to 11, characterized in that isolating the N- and / or CO-0-protected ß-latamantibiotics of the formulas I, II and IV, if desired, and then eliminates the mentioned protective groups or the Cleavage of the protecting groups in situ or as in ß-latam antibiotics, which are formed by reaction of ß-lactams of formula VIII, by suitable choice of the reaction medium in the course of the reaction of the carboxylic acid active with the ß-lactams causes and then the ß-lactam antibiotics, if desired converted into their non-toxic, physiologically acceptable salts or optionally free acids from the optionally obtained salts.