DD295630A5 - PROCESS FOR THE PREPARATION OF BETA-LACTAMANTIBIOTIKA - Google Patents

Abstract

The invention relates to processes for the preparation of b-lactam antibiotics from carboxylic acid active esters and b-lactams. As active esters find * use. The field of application of the invention is the pharmaceutical industry. b-lactam antibiotics; Carbonsaeureaktivester; * b-lactams; Pharmacy}

Description

Fields of application of the invention

The invention relates to a novel production process for β-lactam antibiotics. how they are used in medical remedies. Field of application of the invention is the pharmaceutical industry.

he n-jnd

,, as

; co ^ l

.eilten;.?

oldjigs ago

Characteristic of the known state of the art

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

A-CO-N-D, '

wherein D denotes a β-Lactamkörper containing radical and R denotes a Substituen: en, can be prepared in a variety of ways. This relates in particular to β-lactam antibiotics of the formulas II-III and IV

A-CO-N-CH-CO-K

, D2

E ^J

A-CO-N-

IV

he

For example, typical substituents in formulas II and IV are: hydrogen for R ^D2 , R ^D4 and R ^DS , phenyl for R ^D3 , sulfur for -X- and the group

(x> -C (-CH ₃₎ 2-CH-CO-OH for-Y-, where (x) denotes the position of the -X-Y- binding to,

while the acyl A-CO- can be derived from a wide range of freely selectable carboxylic acid A-CO-OH. A general synthetic route to compounds of the formulas 1, 11 and IV consists: in the course of an activated acyl component A-CO-G, prepared from a carboxylic acid A-CO-OH or a suitable derivative of a carboxylic acid, having one β-lactam component of the general formula

E-N-D or E-N-D,

wherein R ^D2 , R ^D4 and D have the meaning previously described and E is hydrogen or a suitable leaving group. The result of such reactions consists in β-lactam antibiotics of the formulas I, II or IV. In formula A-CO-G, G denotes any activating radical. The activated acyl component A-CO-G may thus be, for example, acid halide ide (cf. for example G: Cl), simple or mixed anhydrides, acid azides (G: N ₃ ) or activated esters. The production of pharmaceutically important β-lactam antibiotics by means of Sä-jrehalogenidme: hode often fails because of the sensitivity of the particular caric acid A-CO-OH to halogenating agents such as thionyl chloride; the representation of acid azides is often possible only in a very complicated way, and a technical application of the same are set narrow limits, for example, due to any risk of explosion in isolation of the azides. The use of mixed anhydride process leads to the undesired formation of by-products, in particular urethanes. Many Active Terme Thoden contrast, for example, require the harmful N, ^N'-D icyclohexylcarbodiimid (DCC), and esters of N-hydroxysuccinimide (HO-Su) often have only low storage stability. They are also technically disadvantageous. In addition, unwanted side reactions were observed in the preparation of N-hydroxysuccinimide esters A-CO-O-Su. Finally, one has to expect difficult to separate ureas as unwanted by-products of Aktivesterherstellung, or in the ß-Lactamantibiotika production u. U. resulting ydroxyverbindung GH can be very complicated way of the product of the formula

A-CO-ND or A-CO-ND R ⁰² R ^D4

separate. One cause of such difficulties is the particular sensitivity of the β-lactams, sometimes including the specific carboxylic acid A-CO-OH and its derivatives.

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

A-CO-O-NB V

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

H-N

In the hitherto known methods of preparing NB-active ester of the general formula V, it is assumed that carboxylic acids A-CO-OH and the N-hydroxy compound HO-NB are used (Fujino, M., et al .: Chem. Pharm. Bull. 1974], 1857). Unknown, however, are those active esters A-CO-O-NB, which can be used for the preparation of pharmaceutically important 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 when using customary in the ß-lactam antibiotics preparation certain carboxylic acid active ester of the type A-CO-O-NB, preferably without isolation (ie in situ), to ß lactam antibiotics

A-CO-ND or A-CO-ND R ° ² R ^D «

can be implemented, wherein the thus released activation component HO-NB and / or their derivatives should be of low toxicity, easily separated from the reaction mixture and thus recover as possible and reuse after treatment, by-products occur only in small quantities and, if They occur, then also easily separated from the desired product, optionally present protective components of the ß-lactams as well as the carboxylic acid component does not substantially interfere with the reaction, so that finally a high yield of pure product of the desired ß-Lactamantibiotikums is achieved.

This object is to be achieved by using chemically new carboxylic acid A-CO-O-NB that the new production process under mild thermal conditions and in a mild medium, consisting of conventional solvents, in high yield without unwanted by-products and without racemization occurs, expires that eventually the solvents can be selected so that isolation of the active ester A-CO-O-NB before their implementation is not required to ß-lactam antibiotics. Such a process should be characterized by chemical simplicity and economic effectiveness.

Explanation of the essence of the invention

The invention is based on the object by means of a new method β-lactam antibiotics of the general formulas I, II and IV from carboxylic acid active esters A-CO-O-NB of the formula V and β-lactam components

E-N-D or E-N-D

_R D2 _R 04

A, even for a compared to A-CO-O-NB under the formation of the ß-lactam antibiotics as well as the carboxylic acid active ester largely inert, but otherwise arbitrary radical, such as alkyl, alkenyl, alkynyl, aryl or hetaryl, all optionally substituted are, stands. Further, the carboxylic acid active esters generally indicated by Formula V may have the specific structure described in the following Formulas Va to Vz. Therein stands the group designated CO-NAIk for

-CO-N-CE

The symbol δ (Kronecker delta) can take the values 0 and 1, so that (-CO-NAIk) ₅ =, -CO-O-NB is equivalent to -CO-NAIk-CO-O-NB and for

B ^J

-GO-N-CE-CO-O-IiB

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) J "-CO-O-NB

Va1

O-R *

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

VA11

-CO-O-NB

VE12

0-R ^J

-CO-O-NB

VA13

-CO-O-NB

7b 1

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

Vb2

C-CO-IvAlk) j- -CO-O-NB

-13- 295 63 (

0-R

A1

(-CO-NAIk) J- -CO-O-NB

0-R

A1

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

0-R

A1

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

0-R

A1

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

vb22

VB23

VB24

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

-R

A1

(-CO-NAIk) f -CO-O-

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

0-R

A1

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

0-R

A1

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

Vc11

Vc 2

Vc21

Vc22

O-R

A1

(-CO-Naik) j - CO-0-ΝΈ

0-R

A1

(-CO-NAIk) (T -CO-O-IiB

-CO-O-NB Vc23

VC24

Vd1

(-CO-NAIk) J- -CO-O-NB Vd.11

(-CO-NAIk) ^ - CO-O-NB Vd2

R ^A1 -0

(-CO-NAIk) J- -CO-O-NB Vd21

(-CO-NAIk) J- -CO-O-NB Vd3

(-CO-NAIk) j- -CO-O-NB Vd31

R ^A1 -

(-CO-NAIk) ^ - CO-O-NB Vd32

A1 '\

R -NN-CO-NAIk-CO-O-NB

A? ' V

K --NN - CO - KA1 k - CO - O - K B

^D3

R ^D3 -C- (C0-Alk) j ^> -CO-O-NB

^D3

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

NB

15-295 63 (

Ve

Vf Vh

f R ^D3 -C- (CO-Naik) £ -CO-O-R ^D1 NB °

vi

D3

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

D8

_R D9 R ^D3 -C- (CO-NAIk) C-CO-O-NB

Αι Ο

C0-0-R ^D11

vk

D10

(CO-NAIk) ^ -CO-O-NB Vl

QV (CO Naik) ^ - CO-O-NE

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

(CO-NAIk) ^ - CO-O-NB Via

Vn

Vo

R "'^ ^ (CO-NAIk) ^ - CO-O-NB Vp

f ^ C- (CO-NAlk) ^ - CO-O-NB

R ^D8 -NR ^D10

Vq

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

R ¹

, 03

R ^ C- (CO-NAlk) ^ - CO-O-M, D11

N-CH ₂ -R ^J

N = CH-R

D14

> D9

-C- (CO-NAlk) ^ - CO-O-NB N- (R ^D8 or

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

NB

Halogen-CH = CH-S-CH ₂ - (CO-NAlk) J-CO-O-

/ N ^ _n -C- (CO-NAIk) ^ -CO-ON

\ N

^s "^ I Y3

O-CH ₂ -CO-OR

vw

) ^ -CO-O-

NB

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

C- (CO-NAlk) Γ-CO-O-NB

II ^ό

NO-CH ₂ -Q

R ^D11 -CO-NH-N = C- (CO-NAlk) g -CO-O-NB

Vy

vz

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

The symbol R ⁰⁴ denotes hydrogen, alkyl or a protective group and R ^DS 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

CH-

OO

or

CE

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

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

 Κ JJ

CE -.- CO-OH

The groups mentioned can also carry additional substituents. The groups CO-OR ^Y3 represent any ester group, or R ^Y3 denotes a hydrogen atom, a protective group or an electron pair. In the latter case, the compounds of the 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 ^Y6 is hydrogen, hydroxyl, methyl or higher alkyl, R ^y / denoted hydroxyl, amino or NH-R ^A1 , which are optionally protected, or hydrogen, alkyl, alkoxy, halogen , Acetylamino, carboxy, carboxymethyl, carboxyalkyl, which may carry additional substituents, wherein the parentheses {} represent mono-, di- or multisubstitution. R ^A1 is a protective group or 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 respective possible configurations R and S, or in any mixtures thereof.

In the heterocycles of formulas Va 1 to Vz, the symbols -U- and -M- are divalent atoms such as -O- and -S- or the atomic groups ^Ν · 7 ^ _ "θ * · '"' and ^ U-SG ^ -T \, where R ^A1 in-U and-M-must not be identical but can be.

Furthermore, these atoms or groups of atoms may be absent, so that -U- and -M- merely have 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

/ K or ^ C = or -CR ^A2 ,

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.

Finally, the active esters generally indicated by formula V may also have the structure specified in formulas Vf to Vz. It contains the general symbols R ⁰⁸ and R ^DS for the groups

-K = C-

or

-1 \ - \ j- £ i

D11

_R D12 pDI 2

In addition, R ⁰⁸ , R ⁰⁹ , R ⁰¹² and R ^{013 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 carboxylalkoxyalkyl ,

Further, R ° '° is hydroxy, OR ⁰⁸ , amino, NH-R ⁰⁸ , NH-CO-R ⁰⁸ or NR ⁰⁸ R ⁰⁹ , HN-CO-R ⁰⁸ , CO-OH or SO ₂ -OH, if necessary protected. R ⁰¹¹ and R ⁰¹⁴ denote hydrogen, phenyl, hydroxy

CO-R ⁰⁹ 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 _O !

, The symbol Q stands for one of in

the radicals Va 1 to Vz, 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 activating component HO-NB in a known manner (Fujino, M. et al .: Chem. Pharm. Bull. 22 [1974], 1857) is won. The active esters are synthesized with β-lactam components of the general formulas

E-N-D, E-N-D or Formula III to β-lactam antibiotics of

D2

R ^D

E-N-CE-CO-K

III

-19- 295 63C

Formulas I, II or IV implemented. In particular, β-lactam components of the general formula

HN-D R

or Formulas Xa, Xb and Xc

ΐΧ

^CF '

CO-OH

HK-CH-CG-K-

-S. 9 ^Ε 3

Ή-Χ

CE

/ Γ

CO-OH

Xa

Xb

ψ;

CH

CK

CO OE

and carboxylic acid active esters of the formulas

ΓΛ

N-CO-IIH-CH-CO-O-NB N N-COJuH-CH ^- COO-NB

ο o

Xc Va

Vb

be used, so that in particular the ß-lactam antibiotics of the formulas Iaa1 and Iaa2

LOJ

E ₃ C-SO ₂ -FB-CO-NH-CH-CO-EX-pr ^ ^

N-CO-NH-CH-CO-HN-jr-> ^S > (iaa2

0 0

0 CO-OE

arise. All general symbols given in the formulas have the meaning explained above. The reaction is carried out in organic solvents, such as CH ₂ CI _2, dioxane, or water, at temperatures between -20 ⁰ C and 6O ⁰ C, preferably at room temperature, or in a multiphase system consisting of water and organic solvents.

The β-lactam components of the formulas E-N-D, E-N-D or the

R ⁰² R ⁰⁴

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 at the choice of the conditions of the preparation of the approach, the β-lactam antibiotics are obtained in pure form, protected or as salts. To purify the product, one can use the usual methods, such as extraction, crystallization, chromatography, etc.

The advantages of carrying out the reaction via the special carboxylic acid active esters of the formulas V, Va, Vb or Va 1 to Vz are their high reactivity, which makes it possible, for example, to use salts of the β-lactam components in the good yields of β-lactam antibiotics of the formulas I, II, IV, laal and laa 2, the high purity of these products, the avoidance of racemization as much as possible, as well as the prevention of the occurrence of N-acyl-ureas, and finally the possibility to perform a one-step reaction, the means to dispense with the isolation of the active ester. The carboxylic acid active esters of the general formulas (V, Va, Vb) required for the above-described reaction 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 from the carboxylic acids and the compound CI-CO-O-NB in high purity. For this purpose, the carboxylic acid required for the desired β-lactam antibiotic in an inert anhydrous solvent, preferably halogenated hydrocarbons, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide and / or aromatics in the presence of tertiary amines such as triethylamine, N-disubstituted anilines, preferably in pyridine, at Temperatures between -20 ⁰ C and 8O ⁰ C, preferably between -5 ° C and O ⁰ C, reacted with N-tChlorcarbonyloxyl-S-norbornene ^^ - dicarboximide CI-CO-O-NB. The reaction can be accelerated by catalytically acting N, N-4-dimethylaminopyridine (DMAP) or another supernucleophilic amine, for example 4-pyrrolidinopyridine (PPY), N-methylimidazole or diazobicyclo (5,4,0) undecene (DBU). The active esters thus obtained are optionally isolated and purified. It is particularly advantageous to react the active esters without prior isolation, ie in situ, with the desired β-lactam component to the respective β-lactam antibiotic. Further advantages of the described behavior of the reactions consist in the preservation of the absolute configuration of the carboxylic acid component A, if necessary, as well as in the avoidance of the harmful dicyclohexylcarbodiimide and thus of the possibly formed, hard-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. With the use of substituted phenols as the activating component of the esters, the separation is much more difficult because the phenols are generally less soluble in water than HO-NB.

A further advantage of the reaction described 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])

 The following embodiments are intended to explain the invention.

-21- 295 631

example 1

The preparation of a solution of carboxylic acid active ester may be carried out according to one of the following rules: \ v

a) 0.01 mol of carboxylic acid are suspended in dry methylene chloride or dissolved 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 only now, is treated dropwise with 0.01 mol of CI-CO-O-NB per carboxyl group to be reacted. At reaction-inert conditions under these conditions _: carboxylic acids, the addition of CI-CO-O-NB can also be faster. After 30 'to 3 ^h , 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.

b) 0.01 mol of carboxylic acid are suspended or dissolved in dry methylene chloride and mixed with at least 0.02 mol of Ν, Ν, Ν ', Ν'-tetramethylguanidine or other suitable organic base. To the solution or suspension cooled to 0 ° C., 0.015 mole of Cl-CO-O-NB dissolved in dry methylene chloride is added dropwise to 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 N, N'-dimethylaminopyridine (DMAP), the mixture is stirred at 0 ° C. for 30 seconds and then at room temperature for 2 ^hours . 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 directly to the desired subsequent reaction (one-pot process) or isolated by distilling off the solvent and, if desired, purified by recrystallization.

c) 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 treated twice with a small amount of dimethylformamide and then concentrated again to dryness. The triton-B salt of the carboxylic acid obtained in this way is dissolved in dry methylene chloride, cooled to 0 ^° C. and reacted with 0.015 mole of CI-CO-O-NB, likewise dissolved in dry methylene chloride. The reaction is usually complete after 1-3 hours. The further work-up of the batch is carried out as in (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 a-aminobenzylpenicillin in the form of the anhydrous compound, as trihydrate or as the sodium salt are slurried in 100 ml of acetone with the addition of 0.06 mol of triethylamine (or 0.03 mol with the use of the aforementioned Na salt) and about 2 hours stirred vigorously at room temperature. This forms a homogeneous solution. Then it is stirred for about another half hour.

By acidification with 2 η or concentrated HCl pH = 2.0 is adjusted, whereby the formed ß- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -penicillansäure (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 anhydrous 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 of H ₂ O 0.005 mol of sodium salt of Hetacillin, 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 ° C to OX methylene chloride solution of the carboxylic acid active ester with stirring, 30min with further stirring at -5 ° C to 0 ⁰ C and then held 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 [-la-aminophenylacetamidol-penicillanic acid sodium salt (ampicillin) dissolved in about 20 ml H ₂ O are added dropwise at 0 ° C with stirring in a solution of 0.01 mol of a carboxylic acid active ester of formula V , Va, Vb, or Va 1 in methylene chloride to Vz. After completion of the addition, 30 is further stirred until 60min with cooling and then at least 1 hour at room temperature. the mixture or solution is then concentrated at temperatures up to 30 ⁰ C in vacuo The residue is taken up in about 300 ml of ice-water and filtered, the filtrate is adjusted to pH = 2.0 to pH = 3 with 2 N HCl and extracted 2 to 3 times with ethyl acetate The extract is washed several times with H ₂ O and then over Dried. 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 ° 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 6- (D [-] - a-amino-phenylacetamido) -penicillansäure be suspended in about 30ml H ₂ O and brought into solution by adding triethylamine. This solution is treated as the solution of the ampicillin sodium salt in Example. 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

(R * ¹ or R

^A2

) -H ^ _Ν , K-CO-KH-CH-CO-OB

D; L

in 50 ml of dichloromethane is added 4 mmol of pyridine and cooled to -8 ° C. With stirring and cooling, 4 mmol of N-hydroxy-S-norbornene N-hydroxy-S-norbornene ^ - dicarboximidester CI-CO-O-NB dissolved in 25 ml of dichloromethane, added dropwise, the temperature should not rise above -5 ° C. After adding a catalytic amount of 4-N, N-dimethylaminopyridine is stirred for half an hour at 0 ° C and then to completion of the reaction (ie, 2 to 70 hours) at room temperature. After the solution has optionally been filtered, the isolation of the resulting carboxylic acid reactant A-CO-O-NB, or when using the above-mentioned carboxylic acid, the isolation of the active ester of the formula

or R

^A1

A2

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 Tables 1 and 2.) The further reaction to ß-lactam antibiotics is carried out according to Example 4 or 5. Replacing the ampicillin by 6-aminopenicillanic acid, we obtain with the above specified carboxylic acids or their active esters, the compounds of the formula

Loj

/ Al A2 Γ ~ Λ

(R or R) _Κ. .K-CO-NE-CH-CO-NB, (

I 0

D, L

_β CH ₃ 'JS CH,

Α1

OOH

-SO ₉ -CH-,

or their sodium salts.

Example 7

4 mmol of N-hydroxy-S-norbornene N-hydroxy-S-norbornene ^^ - dicarboximide ester CI-CO-O-NB are dissolved in 25 ml of tetrahydrofuran and added dropwise with stirring and cooling (-8 ° C) to a solution of 2 mmol of a carboxylic acid, For example, given in Example 6, and 4 mmol of pyridine in 25 ml of tetrahydrofuran, the temperature does not rise above -5 ° C.

should.

The reaction mixture is treated with a catalytic amount of 4-N, N-dimethylaminopyridine and stirred for half an hour at 0 ⁰ C and then at room temperature until complete formation of the active ester.

After addition of about 10 ml of water and completion of the evolution of gas, the mixture is cooled again to 5 ⁰ C. 3 mmol of 6-aminopenicillanic acid triethylammonium salt dissolved in 80% tetrahydrofuran are now added dropwise to the reaction mixture. It is stirred for half an hour at 5 ^C 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 ethyl acetate phase is separated off and the acidic aqueous phase is extracted twice more 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 organic solvent from the reaction mixture by acidification of the aqueous residue with dilute hydrochloric acid to pH = 3. The failed precipitation is in

sucked off in this case, washed with water and dried.

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-YTB

taken up in dichloromethane and cooled to 0 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 ° C and a further 2V2 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 ethyl acetate. 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

0 protection group

CH-

or -D-CO-CE ₃ )

CO OE

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.

Table 1

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

LQ

A-CO-NH-CH-CO-NH-

CH-

'CK

D, L 0

COOI

and / or their salts

No.

A-CO-O-NB FP ( ⁰ C)

(D, L)

Product IRtcm " ¹ )

1.1

, Q

135-138 D

1750

1.2

19 & -199 D

140-142 D

1770 1780

148-150 D

1780

181-183 D

1760

175-177

1790

1.7

251-253 D

1780

1.8

180-189 D

1760

121-125

1760

table

carboxylic acids

A-C 0 -NH-CH-CO-OE

D, L

and their activeest

I-CO-NK-CE-CO-O-EB

D, L

and the products

ΐ-CE-CO-NB k τ Ο

'CH-J)

COOK

Active ester FP ( ⁰ C)

(D, L)

Product IRtcm " ¹ )

0

racemate

Κ

Ι 72-173 D

77-79 186 D, L D

1 785.1 720.1 680.1

1 785.1 720.1 680.1 1780

2.3 racemate

2.4 _F η ji

AC

^2K 5

112

D, L 1 780

1750

Claims (12)

(-00-HAIk) J-CO-O-HB Vd21 -CO-NAIk) J-CO-O-NB Vd3 RA1- (-CO-NAIk) j- -CO-O-NB Vd31 (-CO-) NAIk) J "-CO-O-NB Vd32 RA1-N N-CO-NAIk-CO-O-NB RA2-N N-CO-NAlk-CO-O-NB 0 D9 yC- (CO-NAlk) £ - CO-O-NB D8 Ve Vf f3 RD3-0-C- (CO-NAlk) £ -CO-O-NB RD8> D3 -C- (CO-NAlk) J- CO-O-NB D10 (CO-) NAIk) ^ - CO-O-NB, D9 -C- (CO-NAlk) ^ - CO-O-NB CO-OR D11 Vi Vk D10 - ^ MCO-NAIk) ^ -CO-O-: VlO-RD9 (CO-NAIk) ^ - CO-O-NBO-RD9 (CO-NAIk) ^ -CO-O-NB D3 (CO-NAlk) ^ -CO-O-NB (CO-NAlk) ^ -CO-O -NB D3 f RD35C- (CO-IiAlk) ^ -CO-O-NB D3 RD3SC- (CO-NAlk) ^ -CO-O-NB 5C- (, CO-NAlk) ^ -CO-O-NB F- CH2-R D11 N = CH-R Dl4 D3 RD3-C- (C0-NAlk) ^ -GO-O-NB Vm Vn Vo Vp Vq Vr Ve Vt RD3-C- (CO-NAlk) ^ - CO-O -NB Vu Halo-CH = CH-S-CH2- (C0-NaCl) o-C0-0-NB Vv C- (CO-NAlk) ^ - CO-O-OTB Vw Y3 O-CH2-CO-OR R ^ -C- (CO-NAlk) ^ -CO-O-NB VxNO- (R08 or RD11) C- (CO-NAlk) ^ - CO-O-NB VySiO-CH2-QRD11-CO-NH -N = C- (CO-NAIk) g -CO-O-NB Vz given structure, and in which NB has the meaning described in claim 1, wherein the other -CO-NaIk- stands for the substituent RD2 and RD3 and the star * have the meaning formulated in claim 2 and the symbol δ (Kronecker delta) can assume the value zero or one, and consequently the group CO-NAIk is absent (δ = 0) or present ( δ = 1), wherein each of the symbols T and L used in the formulas Va 1 to Vz represents 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 Ni R 1 represents, in the RA 1, methyl, ethyl or other alkyl which may carry all substituents or represents a protective group, where the symbol denotes an N or C bridging atom or, if the cycle denoted by W is absent, an N- or C-atom, which may also carry substituents, where the substituent RA2 stands for a protective group or for-SO2-RA1 with the previously explained meaning of RA1, wherein RD8 and RD9 represent the groups -N = C-R013 or -N = C-R011rD12 rb «, but R08 and RD9 are exactly like RD12 and R 013 denote both hydrogen, alkyl, alkenyl, alkynyl, aryl or hetaryl which may carry substituents, as well as azido, optionally protected amino, hydroxy or carbonyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, alkylaminoalkyl, alkoxyalkyl or carbalkoxyalkyl, furthermore RD 1 ° is hydroxy, O-R08, amino, NH-R08, NH-CO-R08, all optionally protected, or NR08R09, N-CO-R08, CO-OH or SO2-OH, CO-R09 is protected if necessary, wherein R011 and R 014 is hydrogen, phenyl, protected 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 can carry all substituents. Cyano or, if desired, protected where the symbol Q denotes a radical of the group 0-NB given in the formulas Va 1 to Vz, where RY1 and RY3 have the meaning given in claim 2 and finally the radical ## STR6 ## in the formulas VaI to Vd32 with W ring may be present, but need not be and, if present, for a mono- or polycyclic aryl or hetaryl, which may be wholly or partially hydrogenated and / or also bears substituents. claims: 1. Process for the preparation of β-lactam antibiotics of the general formula I, A-CO-N-D I in the D denotes a radical containing β-lactam body, R denotes hydrogen, alkyl or a protective group and A-CO denotes the acyl component of a carboxylic acid A-CO-OH, characterized in that carboxylic acid reactive ester of the formula V, A-CO-O-NB in the A-CO has the meaning previously described and NB the B-norbornene ^ .S-dicarboximide radical of the formula VIa denoted by β-lactams of general formula X, H-N-D X in which R and D have the meaning described above, are converted to compounds of formula I. 2. The method according to claim!, Characterized in that ß-lactam antibiotics of the general formula I are prepared which are those in the formulas II and IV , D5 A-CO-N-CH-CO-. D2 iD4 D5 A-CO-N- have specified 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 ^{04 is} hydrogen, alkyl or a protective group, R ^D5 denotes hydrogen, alkyl or O-alkyl and
X is S, O, SO, SO ₂ or CH ₂ , Y is Cx) CH ₂ or it C-CH ₂ -R J 2 and the character (x) denotes the point of attachment of Y to X, where R ^{Y1 is} CO-O-Ft ^Y3 CO-R ^Y4 or ff-V -N-R ι Y 3, R ^Y2 represents hydrogen, alkyl-CO-0, hydroxyl, pyridinium, Aminopyridinium, azido, cyano, thiocarbamoylthio, carbamoyl, alkyl-substituted carbamoyl, carbamoyloxy, alkylcarbamoyl-alkoxy, alkoxycarbamoyl, S-aryl, S-hetaryl or S- Il which optionally carry substituents, CH ₂ -CO-CH wherein CO-OR ^{Y3 represents} any ester group or R ^Y3 denotes a hydrogen atom, a protective group or an electron pair, so that in the latter case, the compounds of formulas II and IV are anions, to which any one, in claim 1 formulated formation reaction of the compounds of the formulas I or Il 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, where {R ^Y6 } is hydroxyl, amino or NH-R ^A which may be 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 chiral center, wherein the compounds of formula II in the respective possible configurations R and S, or in any mixtures thereof, may be present. Process according to Claims 1 and 2, characterized in that β-lactams of the general formula X are used which have the meanings given in the formulas VII to IX HN-CH-C O-N E ^D2 HN-CH-CO-N have specific meaning and wherein R ^D6 and R ^{07 represent} methyl, ethyl or higher alkyl and the substituents R ^D2 , R ⁰³ , R ⁰⁴ and R ^D5 and the groups X and Y are as defined in claim 2, wherein the asterisk * 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 active esters of the general formula V are used, which on optionally present reactive groups, such as hydroxyl, amino, monosubstituted amino or carboxyl, provided that they can interfere with the formation of the compounds of formula I quantitatively , are protected. 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-NB Va1 0-R * A1 -CO-O-NB VA11 (-CO-NAIk) j- -CO-O-NB va12 0-R * C-CO-NAIk) j- -CO-O-NB VA13 ^ \ p C-CO-NAIk) j -CO-O-NB Vb 1 -CO-O-NB Vb2 C-CO-Naik) J - CO-O-NB VB21 OR ^x (-CO-NAIk) J- -CO-O-NB 0-R A1 (-CO-NAIk) j'-CO-O-NB 0-R A1 (-CO-NAIk) j'-CO-O-NB 0-R A1 -CO-O-NB M vb22 VB23 VB24 (-CO-NAIk) g -CO-O-NB -R A1 C-CO-NAIk) J-CO-O-NB | v- (-CO-NAIk) j- -CO-O-NB 0-R A1 (-CO-NAIk) j'-CO-O-NB 0-R A1 (-CO-NAIk) j'-CO-O-NB Vd Vd 1 Vc2 Vc21 Vc22 O-R A1 (-CO-Naik) ^ - CO-O- 0-R A1 -CO-O-NB (-CO-NAIk) j'-CO-O-HB Vc23 Vc24 Vd1 (-CO-NAIk) χ -CO-O-NB Vd11 (-CO-NAIk) ^ - CO-O-NB Vd2 κ "-0. 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. Process according to Claims 1 to 8, characterized in that carboxylic acid reactive esters of the formulas V and Va 1 to Vz find use by reaction of carboxylic acids of the formula A-CO-OH, wherein A has the meaning explained in the preceding claims, with N- (Chlorocarbonyloxyl-B-norbornene ^^ - dicarboximide, abbreviated CI-CO-O-NB, wherein NB has the meaning described in formula VI a, 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 is N- (hydroxy) -5-norbornene-2,3-dicarboximide to understand, have been prepared. 10. The method according to claims 1 to 9, characterized in that carboxylic acid reactive esters of the formulas V and Va 1 to Vz find use by reacting carboxylic acids of the formula A-CO-OH with CI-CO-O-NB in the presence of a tertiary Amines 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] -undecen have been produced. 11. The method according to claims 1 to 10, characterized in that carboxylic acid reactive esters of the formulas V and Va 1 to Vz are used, which are isolated after the reaction of carboxylic acids with CI-CO-O-NB and, if desired, purified and then with ß-lactams converted to ß-lactam antibiotics or without prior isolation, ie in situ, with ß-lactams to ß-lactam antibiotics of the formulas I, II and IV are implemented. 12. The method according to claims 1 to 11, characterized in that the thus prepared N- and / or CO-0-protected ß-lactam antibiotics of the formulas I, II and IV are isolated and purified if desired, and then splits off the mentioned protective groups or the Cleavage of the protective groups carried out in situ or as in ß-lactam antibiotics, which by reaction of ß-lactams of the formula VIII are formed, by suitable choice of the reaction medium in the course of the reaction of the carboxylic acid active with the ß-lactams brought about and then the ß-lactam antibiotics, if desired, converted into their non-toxic, physiologically acceptable salts or from the optionally obtained salts, if desired, the free Produces acids.