DD279875A1 - PROCESS FOR PREPARING ACTIVATED CARBONIC ACID ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of carboxylic acid active esters, more particularly carboxylic acid N-hydroxy-norborn-5-ene-2,3-dicarboximidestern, which are obtained from carboxylic acids or carboxylic acid derivatives, such as acid halides or acid anhydrides and N-hydroxy-5-norbornene derivatives. 2,3-dicarboximide or its suitable derivatives. These active esters are important intermediates, eg. For the production of b-lactam antibiotics. The field of application of the invention is the pharmaceutical industry.

Description

wherein E 'denotes a suitable leaving group, with amines of the general formula V

H-N-D

I ν

completed. Due to the thermal and chemical sensitivity of the commonly used ß-lactams, the work-up of the products is often problematic. In addition, biologically active antibiotics usually require carboxylic acids, which are also very sensitive. Thus, there is a need for new carboxylic acid active esters whose preparation is possible under mild conditions and which are characterized by good storability and high reactivity, as well as ease of handling both in the reaction itself and by easy handling of the released in this reaction hydroxy compound of general formula Vl

HO-E 'Vl

distinguished. Known carboxylic acid active esters, as described by reaction of phenols (Bodanszky, M .: Nature 175 [1955] 685), N-hydroxyphthalimide (Nefkens et al .: Rec. Trav. Chim. 8111962) 683) or other N-hydroxy compounds of the general formula VI can be obtained with carboxylic acids of general formula II in the presence of carbodiimides, often have a number of disadvantages. These include the occurrence of by-products which are difficult to separate, a low resistance of the active esters and finally difficulties in the work-up of the products after the use of the carboxylic acid active esters, ie after their acyl component has been transferred, in particular by the compounds of general formula VI which are liberated in the process

 From the N-hydroxy-5-norbornene-2,3-dicarboximide of the formula HIa or abbreviated HIb

HO-NB INb

as activating component dissipative carboxylic acid active esters of the general formula I.

A-CO-O-NB I

are, with a few exceptions, unknown.

The active-site esters of general formula I known from the literature were prepared by means of Ν, Ν'-dicyclohexylcarbodiimide (DCC) or via mixed anhydrides (Fujino et al .: Chem. Pharm. Bull. 2 [1974 | 1857]. Unknown, however, are active esters of the general formula I, which are formed with those carboxylic acids of the general formula II, which are particularly important for the production of β-lactam antibiotics. Thus, the advantages that result from the use of these special carboxylic acid active esters are also unknown.

Object of the invention

The object of the invention is the synthesis of chemically novel carboxylic acid active esters of general formula I a under chemically and thermally sufficiently mild conditions, d. h., Without racemization occurs, where this would be possible in principle. For this purpose, per se known methods of esterification to special hydroxy compounds of the general formula VI are applied. The use of the method should be carried out in such a way that high yields of target product occur in high purity. In particular, the target products should be free of such by-products which could interfere with the later reaction of the active esters or be difficult to remove from the reaction media of interest in which ester formation or later reaction of the esters occurs.

The processes should be chemically simple and effective, and the new carboxylic acid reactants should in turn be characterized by good shelf life and on the other hand by high reactivity. In addition, the component HO-E ¹ liberated in the further reaction of the carboxylic acid active esters should be readily removable from the particular reaction medium.

A particular object of the invention is the synthesis of particularly suitable starting materials for the production of β-lactam antibiotics.

Explanation of the essence of the invention

The invention has for its object to develop a working under mild conditions production process for new carboxylic acid active. The achievement of this object is the implementation of specific carboxylic acids A-CO-OH of the general formula II or suitable reactive derivatives of these carboxylic acids with N-hydroxy-5-norbornene-2,3-dicarboximide HO-NB of the formulas III a and III b or with suitable reactive derivatives of this compound, which satisfy the general formula VII.

E-O-NB VII

Here E denotes a protective or leaving group such as alkylsilyl, in particular trimethylsilyl. However, the compounds of the general formula VII may also be salts, so that E denotes a metallic cation, in particular Na.sup. ⁺ , K.sup.-, Li.sup. ⁺ Or T.sup. ⁺ . In addition, E also represents ammonium ions, in particular quaternary ammonium ions, such as trimethylbenzylammonium or tetraethylammonium ion. Among reactive Dei ivates of the carboxylic acids are acid halides, in particular acid chlorides, acid anhydrides, and mixed anhydrides, for example those derived from pivalic acid or from a Alkoxykohlensäureester the general formula VIII

A-CO-O-CO-O-alkyl VIII

to derive, to understand. Furthermore, derivatives of the so-called Amidchlc ride, for example, the Dimethylchlormothylidenammoniumchiorids come as reactive carboxylic acid derivatives of general formula IX

[(H ₃ C) ₂ N ⁺ = CH-O-CO-AlCr IX

in question (Stadler, P.A .: HeIv. Chim: Acta 6111978], 1675).

The reaction of the carboxylic acids of general formula II with HO-NB is carried out in inert solvents, for example in a mixture of dioxane and tetrahydrofuran, by means of dicyclohexylcarbodiimide in the temperature range from -3O ⁰ C to 2O ⁰ C, in particular at O ⁰ C.

The reaction of acid halides and HO-NB is also carried out in a manner known per se, for example in pyridine.

The reaction of the carboxylic acids with dimethylformamide chloride is preferably carried out in the temperature range from -3O ⁰ C to 20 ⁰ C in inert solvents, such as acetonitrile.

All carboxylic acid reactants of the formula I could, as far as chiral carboxylic acids were used, be synthesized while preserving the given chirality. By-products were detected only in minor amounts. The yields of active ester were high. As reaction media, in addition to those already mentioned, such inert solvents, such as methylene chloride, ethyl acetate or chloroform can be used.

Carboxylic acids of the general formula II which, in addition to the carboxyl group indicated in this formula and to be reacted, have further carboxyl groups or other reactive groups, such as hydroxyl or primary or secondary amino groups, can or should be protected therefrom. Disruptions in the implementation of such protective groups, such as trialkylsilyl (for example, trimethylsilyl) containing carboxylic acids or their reactive derivatives with HO-NB were not observed. As will be explained in more detail in the examples, in particular in cases where the radical designated A is a heterocycle which carries a hydroxyl group ortho to the carboxyl group, the introduction of a protective group is usually unnecessary. This also applies if an N-heterocycle is present and this is capable of tautomerism. The following equation X

0-OH

/COOK

! N I H

explains the tautomerism possibilities. The same applies to the tautomerism of a heterocycle which carries a hydroxy group relative to the nitrogen in the 2 or generally 2 n position fn = 1,3,4, G ... etc.). The case analogous to equation X is for η = 1 in equation XI

CO-OH ^ - ^ / ^ ^ CO-OH

V A L Xl

specified. In formulas X and Xl, W denotes an additional possible heterocyclic system and the dots indicate bridging atoms which may be considered both carbon and nitrogen.

In the case of the hydroxyl group adjacent to the carboxyl group, it is also possible in particular to use the so-called, "internal" anhydrides ## STR5 ## of formula XII,

as are obtainable, for example, by reaction of the carboxylic acids with phosgene or with alkyl chloroformates, are used as reactive carboxylic acid derivatives and reacted with HO-NB, CO _{2 being} liberated and the hydroxy group being reformed. The desired active ester of the reaction is shown in Formulas XIII.

CO-O-NB

OH

The formation of the "internal" anhydrides and their reaction to the carboxylic acid reactive ester can often also be carried out in a one-pot reaction. The above-mentioned general reaction conditions determined more precisely in the concrete case, depending on the thermal sensitivity of the reacted components and the possible pressure ratios.

The carboxylic acid active esters thus prepared can be isolated and purified, the latter for example by recrystallization in an inert solvent. Under some of the reaction conditions described above, but they also fall so that they can be further salted without prior purification, and in particular without isolation, ie in situ. This variant of the reaction procedure can be advantageous, in particular from a process engineering point of view (one-pot process). It has been found that the laboratory further implementation of the carboxylic acid active in situ with amines bearing ß-Lactamkörper as substituents, is possible. Examples of de'trtige amines are the 6-amino-penicillanic acid (6-APS), 7-amino-cephalosporanic acid (7-ACS) or ampicillin.

The process described here is applicable in general and without any further restrictions to any carboxylic acids, in particular to those which are important for the preparation of effective β-lactam antibiotics. Very particularly suitable for the rest in the formulas I, I, II, IV, VIII, IX designated A heterocycles which carry hydroxyl, amino and / or Ketcgruppen. In addition, amido-carboxylic acid residues of the type A- (CO-NAIk) are of great importance, whereby under CO-NAIk- the group

D3

I -CO-N-gH-

D2

to understand. Here R ^{D2 is} hydrogen, alkyl or a protective group and R ^{D3 is} hydrogen, phenyl, p-hydroxyphenyl, if necessary, O- or N-protected hydroxyphenyl or aminophenyl, o-chlorophenyl, o-dichlorophenyl, o-fluoro Chlorophenyl, other aryl or hetaryl, cyclohexenyl or cyclohexadienyl, O-aryl, O-hetaryl, S-aryl or S-hetaryl or thiazolyl. All of the abovementioned groups may carry substituents, in particular amino and / or hydroxyl groups, which may also be protected. Especially comes the

group,

optionally in protected form, as substituents R ^D3 in question, and also cyano is possible.

The star denotes a center of chirality and the compounds can be present in the respective possible configurations R and S or in any mixtures thereof.

According to the invention, the desired active esters of general formula I can be synthesized from the corresponding carboxylic acids, in particular those compiled in formulas Ha 1 to Hz or their reactive derivatives. Thus, the formulas of the Aktivefer are obtained by replacing the group CO-OH explicitly described in the formulas Ha 1 to Hz

by the group CO-O-NB. The formulas of the reactive carboxylic acid derivatives, with which the formation of carboxylic acid active esters according to the invention is also possible, are obtained analogously by replacing the COOH group according to the previously indicated rules, for example according to formula VIII by the group CO-O-CO-O-alkyl and corre ., Formula IX by the group CO-O-CH ^ = N (CH ₃ I ₂ and addition of the respective anion, in particular Cl ".

(-CO-Haïk) ^ - CO-OH

(-CO-MIk) j'-CO-OH

(-CO-MIk) £ -CO-OH

O-R

^A1

(-CO-MAIk) j · -CO-OH

shark

HallHa 12Ha 13

-CO-OH

(-CO-HAIk) j · -CO-OH

-R

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

0-R ^A '

- (-CO-WAIk) J'-CO-OH

Ilb2

Ilb21

Ilb22

0-R ^A1 U "-γ - (-CO-NAlk) j / -CO-OH

A1

0-R

C-CO-NAIk) j / -CO-OH

0-R

A1

(-CO-NAlk) j / -CO-OH

-CO-OH

A1

(-CO-NAIk) j- -CO-OH

(-CO-NAIk) j - CO-OH

0 ~ R

^A1

(-CO-NAIk) j / -CO ^ -OH

0-R

A1

-CO-OH

0-R

A1

(-CO-NAIk) j ^ -CO-OH

mb

Hb 24th

Ilb25

lld

Ilc2 Ilc21 Ilc22 Ilc23

O-R

A1

(-CO-NAIk) cT-00-0H

Il c 24

(-CO-NAIk) ^ -CO-OH

Il ci 1

R ^A1 -

(L-CO-NAIk) J - CO-OH

11

(-CO-NAIk) f -CO-OH

Il cl 2

(-CO-NAIk) J- -CO-OH

Ild21

_ _co _ _{o H}

(if

ILD3

R ^A1 -

Ild31

R ^A1 -

(-CO-Naik) J ^ -CO-OH

Ild32

R ^A1 -N JtMJO-NAIk-CO-O K

lie

R ^A2 -N N-CO-NAIk-CO-OH

D9

R jO- (CO-NAIk) J * -CO-OH

D8 Hf

R ¹

, D3

R ¹⁷ ^ -OC- (CO-NAIk) ^ -CO-OH

D8 Mh

^D3

R ^D3 _s C- (CO-NAlk) ^ -CO-OH R ·

D10 Wed

ΐ V (CO-NAIk) ^ - CO-OH

D8

R ^; R ^D3 ₅ C- (CO-NAlk) ^ - CO-OH

CO-O-R

D11 Hk

D10

-> ί- (CO-NAIk) ^ -CO-OH

0-R ^D9 (CO-NAIk) ^ - CO-OH

D3 (CO-NAIk) ^ -CO-OH Um

hn

lio

(CO-NAIk) ^ - CO-OH lip

R, D3 '

D9

R ^ C- (CO-NAIk) ^ - CO-OH

R ^D8 -NR ^D10

hq

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

N = CH-R

D11

Mr

R ¹

, 03

IC ^J ~ G- (, CO-NAIk) ^ -CO-OH

N-CH ₂ -R '

D11

N = CH-R

DH

ils

'D3_'

R ^D9

KT ^:

) -CH ₂ -CO-OR ^J

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

_R D13

R ^ -C- (CO-NAlk) ^ -CO-OH L (R ^D8 or R ^D11 )

R ^D3 -C- (CO-NAIk) X-CO-G

Halogen-CH = CH-S-CHHCO-NAlk) s-CO-OH Hv

- (CO Naik) ^ OO OH

Hw Hx

-C- (CO-Naik) T-CO-OH

HoN -? Il

NO-CH ₂ -Q Hy

R ^D11 -CO-NH-N = C- (CO-NAIk) ΐ -CO-OH R ¹

Assuming the case that the carboxylic acids of the formulas Ha 1 to Hz contain a hydroxyl group adjacent to the carboxyl group and it is a heterocyclic carboxylic acid, the formulas of the "internal" anhydrides according to the invention which are used as reactive carboxylic acid derivatives are formed in accordance with the principles XIII The formulas of the desired carboxylic acid derivatives are given on the basis of formulas XIII For the sake of simplicity, the formulas Hai to Hz are omitted, and the formulas are therefore to be supplemented if necessary. Naik has in ^the;.. or '- Ha 1 ELN the previously stated meaning until Hz the symbol δ (Kronecker delta), which is attached as a lower index of this group, it has the meaning that the value zero or one Accordingly, the group is absent or present, and in the case of δ = 1, the amido carboxylic acids are present. Specifically, the formulas Il e and Hf are si In addition to Ureido carboxylic acids.

The symbols T and L used in the formulas Il a 1 to Il stehen stand for the atoms N or C, where the C atom can also carry substituents. The symbols M and U stand for the O atom or the atomic group

where R ^{A1 is} hydrogen, methyl, ethyl or another alkyl radical or a protective group. The alkyl radicals may also carry substituents. As in the formulas X to XIII, in the formulas Ila 1 to Hz the symbol denotes an N or C bridge atom. If the cycle denoted by W is absent, these "former" bridge atoms may also carry substituents. In the formulas II a 1 to Il ζ of the substituent R ^A2 is hydrogen, a protecting group or SO ₂ -R ^A \ wherein R ^A1 is previously The symbols R ⁰⁸ and R ^D9 stand for the groups

or

In addition, R ⁰⁸ and R ^D9 , like R ⁰¹² and R ^013, are hydrogen, alkyl, alkenyl, alkynyl, aryl or hetaryl, all of them

As well as azido, if necessary protected amino, hydroxy or carbonyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, alkylaminoalkyl, alkoxyalkyl or carbalkoxyalkyl. Where R ^D '° is hydroxy, the group -O-R ^D8 , amino, NHR ⁰⁸ , NH-CO-R ⁰⁸ , CO-OH or SO ₂ -OH, all if desired protected, or for NR ⁰⁸ R ⁰⁹ or N-CO-R ⁰⁸ .

Furthermore, the symbols R ° "and R ⁰¹⁴ denote hydrogen, phenyl, protected or unprotected hydroxy or aminophenyl, o-chlorophenyl, o-dichlorophenyl, o-fluoro-chlorophenyl, other aryl, hetaryl, cyclohexenyl, cyclohexadienyl, O-aryl, O-hetaryl, S-aryl, S-hetaryl, protected or unprotected

.N-

or cyano. Apart from the last example, all of these radicals R ⁰ "and R ⁰ 'may bear ⁴ substituents, in particular hydroxyl and / or amino groups Finally, the symbol Q stands for each of the hydroxy groups indicated in formulas Ha 1 to Hz located radicals.

R ¹¹ represents for one group CO-OR ¹³ , CO-R ^ or C NR ^Y3 ,

N N

wherein CO-OR ^{Y3 represents} any Este group, or R ^Y3 denotes a hydrogen atom or a protective group. In this case, R ^{Y4 is} a required protected hydroxyl group. The ring labeled W may but need not be present. When present, W is a mono- or polycyclic aryl or hetaryl which is fully or partially hydrogenated

can and optionally bears substituents. If a C atom in the formulas Il a 1 to Il ζ is marked with an asterisk *, this means a center of chirality. As in the case of the CO-NAIk group already described, both of the possible chiral compounds or mixtures thereof are possible in the sense of the invention described herein.

Unless mentioned or written in the preceding explanations of the formulas unprotected amino groups, including protonated amino groups to understand. These are with the protonation "quasi-protected".

The following examples are intended to illustrate the invention.

Example 1.1

0.01 mol of carboxylic acid chloride are dissolved in dry pyridine and added dropwise at 0 to -2O ⁰ C with stirring in a suitably pre-cooled solution of 0.01 to 0.02 mol HO-ND in pyridine. The solution is kept at the initial temperature for about 24 hours or, if the thermal stability of the carbonyl compound and the desired active ester allows it, heated and worked up after 10 minutes to 3 hours. (The resulting mixture of active ester and HO-NB can also be used directly for further reactions - one-pot reaction.) For this purpose, the pyridine is distilled off, the active ester in a suitable inert solvent, for example methylene chloride, taken, possibly washed with water (for Removal of unreacted residues of HO-NB), the organic phase dried and the carboxylic acid, if necessary, purified by recrystallization.

Example 1.2

0.01 mol of a HO-NB salt, preferably the sodium or triethylammonium salt, are suspended in an anhydrous, suitable medium, preferably ber, and depending on the reactivity of the components and the melting point of the reaction medium used at 20 ^° C. to -20 ° C, preferably at to 10 ⁰ C, added dropwise with 0.01 mol of the carboxylic acid chloride. The carboxylic acid chloride is advantageously dissolved in the suspension medium of the HO-NB salt. The HO-NB salt can also be used in excess. If necessary, the solution, mixture or suspension is stirred for several hours. If a suitable solvent or suspension medium, such as, for example, benzene, is selected, the chloride which has formed during the course of the reaction and which has been formed with the cation of the HO-NB salt used can then be removed by suction. If the resulting carboxylic acid active is soluble in the reaction medium used *, the filtrate is worked up as in Example 1.1. However, it can also be used directly for further reactions.

Table 1 contains a compilation of the carboxylic acid reactant prepared according to the Synthesis Chart of Examples 1.1 and 1.2.

Example 2

0.01 mol of carboxylic anhydride are dissolved or suspended in an inert organic phase, for example in pyridine, and cooled to about 0 to 10 ⁰ C. With cooling, 0.01 mol of HO-NB, dissolved in the same or another solvent, are added dropwise. One can also work with an excess of HO-NB.

After prolonged stirring at room temperature (about 5 h), the mixture is applied in the usual way in peptide chemistry (cf.

Houben / Weyl, Vol. 15 / I and 15 / II). In the case of inert anhydrides, the reaction time must be prolonged and / or the reaction temperature must be increased. The possible temperature depends on the stability of the carboxylic anhydride and the HO-NB. 70 ⁰ C should generally not be exceeded.

A summary of the carboxylic acid active esters so prepared is given in Table 2.

Example 3

0.01 mol of carboxylic acid are dissolved or suspended in about 50 ml of an inert solvent, preferably in methylene chloride or tetrahydrofuran, and treated with 0.01 mol of a base, preferably with triethylamine or N-methylmorpholine. The carboxylic acid may also be used in the form of one of its salts, preferably the sodium or potassium salt.

The mixture is cooled to 0 to -40 ° C and treated with 0.01 mol of a alkyl chloroformate, preferably ethyl or isobutyl ester.

The resulting Miüchanhydrid is 3 to 15 min. stirred at ^{0 0} C, and with stirring, 0.01 mol HO-NB (a slight excess is possible) is added. It will take about 30min. at 0 to 5 ⁰ C ur; d then stirred until the completion of the reaction at room temperature (about 1 to 2 h).

The solvent is distilled off, the residue is taken up in ethyl acetate or another suitable solvent. It is then washed with 5% aqueous NaHCO ₃ solution and then with water. It is dried over magnesium sulfate and obtained by removal of the solvent, the desired carboxylic acid active.

Table 3 contains a summary of the HO-NB ester thus prepared.

Example 4

C was 0.01 mol carboxylic acid added at ⁰ to a suspension of -2O Dimethylchlormethylidenammoniumchlorid in acetonitrile. With stirring at this temperature then 0.01 to 0.02 mol of HO-NB in pyiidine, also cooled, added and stirred for up to 24 h further. Thereafter, the approach, if desired, worked up.

Table 4 gives an overview of the carboxylic acid active esters thus prepared.

table

No.

formula

PP (C) output (%)

1 .1

CO-O-NB 123-125 75

1.2

CO-O-NB

1 A

CO-O-NB

168-171 75

174-177 80

0-O-NB

155-160 80

CO-O-NB

CO-O-NB

table

No. "Formula

CO-O-EB Cl PP CC) Yield {%

140-142 80

2.2

2.3

br

a "

CO-O-NB

148-150 75

223-225 80

2. 4

H ₀ -CO-O-NB

C.

175-177 85

121-125 70

2.6

181-183 85

CO-O-NB

223-225 60

table

No formula

FP ( ⁰ C) yield {%)

3.11 3.12

_r (CO-NAIk) ³ ^ -CO-O-NB

3.11 Raoeraat

 3.21 3.22

3.31 3.32

3.51 3.52

(CO-NA Ik r -CO-0-NB

(CO-NAIk) ^X -CO-O-NB 215

228

(CO-NAIk) ³ ^ -CO-O-NB 210

(CO-NAIk) ³ ^ CO-O-NB 216

90

70

3 B1 3.62

H ₅ CN E- (CO-NaCl) ^x ~ CO-O-NB

O

3 .61 racerate 170

77

No. Formula PP ( ⁰ C) Yield (%)

I \ 223-224 90

HN N- (CO-NAlk) ^x --CO-O-HB

3 ' 81 racemate Third , 82 , 71 .81 HQC-G »72 -Raceinat 3.71 Third Third 3

217-219 85

I \ 186 85

N- (CO-HAIk) ^X -CO-O-NB

112 70

In Table 1, - (CO-NAIk) * - with χ = 1 means the group

-CO-NH-CH- and - (CO-HAIk) * -

3f

with χ = 2 the group -CO-NH-CH-,

where the last digit (χ) of the serial number 1 .nx of the compounds corresponds to the upper index (x) of - (CO-NAIk) "- The absolute configuration of the C atoms marked with an asterisk * is R. If next to the number is the comment "racemate", so it is the racemic mixture of the compound with R and S configuration.

table

No.

Formula FP ( ⁰ G) Yield {%

4.1

4.24.3

4.4 · 4.5

O-O-NB

251-253 65

4.6

CH-CO-O-NB

180-186 80

Claims (8)

1. A process for the preparation of carboxylic acid active esters of the general formula I, A-CO-O-NB I in the A-CO, the acyl component of a carboxylic acid of the formula II A-CO-OH II and NB is the 5-norbornene-2,3-dicarboximide residue of formula III O. characterized in that carboxylic acids are in the following formulas Il a 1 to Hz specified structure, wherein -CO-NAIk for _R D3 -oo-n-JH the substituent R ^{D2 is} hydrogen, alkyl or a protective group, R ^{D3 is} hydrogen, phenyl, if necessary 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 may carry all substituents, cyano or, if desired, protected in which the star * denotes centers of chirality and the compounds can be present in the respective possible configurations R and S or in any mixtures thereof in which the symbol δ (Kronecker delta) can assume the value zero or one, so that the group CO-NAIk absent (δ = O) or present (δ = 1), it is in the latter case thus active esters of amido-carboxylic acids, wherein each of the symbols used in the formulas la 1 to lz T and L for the atoms N and C, the latter also being able to carry substituents, where each of the symbols M and U is the atom O or the atomic group where R ^{A1 is} hydrogen, methyl, ethyl or other alkyl which may carry all substituents or a protecting group, where the symbol is an N or C bridge atom or, if the cycle denoted by W is absent, an N- or C-atom, which may also carry substituents, where the substituent R ^{A2 is} hydrogen, a protective group or -SO ₂ -R ^A1 with the previously described meaning of R ^A1 , where R is ^D8 and R ^{09 represents} the groups -N * Ü-R ^D13 or -N ⁰¹¹ but R ^D8 and R ^D9 , as well as R ^DI2 and R ⁰ ' ^3, are hydrogen, alkyl, alkenyl, alkynyl, aryl or hetaryl, all of which may carry substituents, as well as azido, if necessary protected amino, hydroxy or carbonyl, Aminoalkyl, hydroxyalkyl, carboxyalkyl, Alkylaminoaikyl, alkoxyalkyl or carbalkoxyalkyl where furthermore R ^{D1 &} for hydroxy, -OR ⁰⁸ , amino, NHR ⁰⁸ , -NH-CO-R ⁰⁸ , CO-OH or SO ₂ -OH, all if desired protected, or -NR ⁰⁸ R ⁰⁹ , no -Ν-σο-ir ⁰ where R ⁰¹ 'and R ^{014 represent} hydrogen, phenyl, protected hydroxy or aminophenyl, o-chlorophenyl, o-dichlorophenyl, o-fluorochlorphene / 1, other aryl, hetaryl, cyclohexenyl or cyclohexadienyl, -O-aryl, -O-hetaryl, -S-aryl, -S-hetaryl, which can protrude all substituents', cyano or, if desired, protected Ν ₂ .Ν- <ζ where the symbol Q denotes groups which are present in formulas Ia1 to Iz1, group O-NB, where R ^{Y1 represents} CO-OR ^YJ , CO-R ^Y4 or O NR ^Y3 1 'I wherein CO-OR ^{Y3 represents} any ester group or R ^Y3 denotes a hydrogen atom or a protective group, wherein R ^{Y4 denotes} a protected if necessary protected hydroxyl group and wherein finally the ring designated in the formulas I a 1 to I d 32 with W be present may, but need not and, if present, be a mono- or polycyclic aryl or hetaryl which may be wholly or partially hydrogenated and / or also carries substituents, or suitable reactive derivatives of the carboxylic acids of the formulas Il a 1 to Hz, such as their carboxylic acid halides, especially chlorides, their anhydrides or suitable mixed anhydrides, such as those derived from the carboxylic acids of formulas IIa to Mz and pivalic acid or an alkoxy-carbonic acid ester, with N-hydroxy-5-norbertin; 2,3-dicarboxinide, abbreviated HO-NB, or suitable reactive derivatives of the general formula EO-NEl, wherein E represents a protecting or leaving group, such as Al kylsilyl or a metallic cation, in particular Na ⁺ , K ⁺ , Li ⁺ or Tl ⁺ , are reacted. 2. The method according to claim 1, characterized in that carbohydrates of the formulas Ua 1 to Hz or their derivatives claimed in claim 1 are used which, if necessary, further reactive groups, such as hydroxyl, amino or monosubstituted amino or other carboxyl groups, that is, provided that these groups can interfere with the formation of the desired compounds of formula I are protected. 3. Process according to claims 1 and 2, characterized in that carboxylic acids of the formulas Il a 1 to Il ζ or their reactive derivatives find use in which protecting groups radicals, such as trimethylsilyl or trialkylsilyl generally mean. 4. The method according to the Anspi sue 1 to 3, characterized in that the reaction of the carboxylic acids of the formulas Il a 1 to Hz with the compound HO-NB to the carboxylic acid active of the formula I in an inert solvent such as CH ₂ Cl ₂ , in the temperature range from -30 ⁰ C to 20 "C with the addition of Dicyclohexylcarbod'imid occurs. Process according to Claims 1 to 4, characterized in that the reaction of the halides of the carboxylic acids of the formulas Hai to III with the compound HO-NBodtv is as defined in claim 1 reactive derivatives of the formula EO-NB, to carboxylic acid reactants of formula I in an inert solvent such as CH ₂ Cl ₂ , in the temperature range from -30 ⁰ C to PO ⁰ C, takes place. 6. Process according to claims 1 to 3, characterized in that aie carboxylic acids of the formulas Il a 1 to Mz in the presence of a tertiary amine by one of the usual methods in peptide chemistry with alkyl chloroformate, such as isobutyl ester, or another chloride of an organic acid such as Pivaloylchloriü be converted to mixed anhydrides and di'.se be reacted in an inert solvent in the temperature range from -30 ⁰ C to 3O ⁰ C with HO-NB to carboxylic acid active esters of the formula I. 7. Process according to claims 1 to 3, characterized in that the carboxylic acids of the formulas Il a 1 to Il ζ with the compound HO-NB in the presence of amide chloride, such as dimethylchloromethylidenammonium chloride, which by known methods from an inorganic acid halide, such as phosgene, Thionyl chloride, phosphorus oxychloride or phosphorus-lll-chloride, or an organic acid chloride, such as oxalyl chloride, was obtained by reaction with dimethylformamide, are reacted to carboxylic acid active esters of the formula I. 8. The method according to claims 1 to 7, characterized in that the reaction at temperatures in the above ranges, depending on the thermal sensitivity of the reacted components and the possible pressure ratios depending on the reaction medium used to determine more accurately, and if desired with the addition of a tertiary amine. Field of application of the invention The invention relates to a process for the preparation of novel carboxylic acid active esters of N-hydroxy-5-norbornene-2,3-dicarboximide of the formula IIIa. HO: The new carboxylic acid reactive esters can be used universally in the chemical or pharmaceutical industry both because of the structure of their acyl components and because of their special properties and / or the properties of their components, namely reactivity, specificity, solubility, etc. They are particularly suitable for the β-lactam antibiotics production. Characteristic of the known state of the art Carboxylic acid active esters are of general importance as reactive intermediates of organic synthesis. For example, in β-lactam antibiotics production, a crucial step in the synthesis of the acyl component A-CO of specific carboxylic acids A-CO-OH II with those primary or secondary amines whose amino group is directly or indirectly linked to a β-lactam body D. This formation of amides of general formula IV, A-CO-N-D I iv wherein R denotes hydrogen or a radical such as alkyl or a protective group is in many cases via the reaction of carboxylic acid active esters of the general formula I a, A-CO-O-E 'la