DE2345236A1 - QUARTERLY AMMONIUM COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

Priority; v. February 19, 1973 in Sweden Note No .: 7 302 279 - 0

The present invention relates to new chemical intermediates, which also have valuable pharmacological properties themselves. More particularly, the invention relates to new salts of penicillins and cephalosporins. As chemical intermediates, these are new salts of penicillins and cephalosporins especially valuable for the production of esterified penicillins and cephalosporins, since the use of the new ones Salts esters of high purity and yields in an expansion that is significantly better than the yield of such esters, if these are manufactured using conventional methods. The invention also relates to new salts of 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA) as chemical intermediates. As pharmacologically active compounds

409834/1077

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the new penicillin and cephalosporin salts according to the invention have good antibacterial properties which are inherent Properties of the specially used penicillins and cephalosporins are, and these are pharmacologically active compounds are well absorbed after oral administration. The invention also relates to a method for treating infectious Disease in animals and humans which consists in giving a patient a therapeutically effective amount of a Penicillin or cephalosporin salt administered according to the invention. Pharmaceutical preparations containing at least one penicillin or cephalosporin salt according to the invention are also in the concept of the invention. Such preparations, such as tablets and capsules, can be used in a known manner using common binders, casings and diluents.

Esters of penicillins and cephalosporins are of interest because of their better absorbability when administered orally, which shows up with some such compounds, as well as intermediate products in the production of other ß-lactam antibiotics, derived from penicillins and cephalosporins. For the production of esters of penicillins and cephalosporins it is common to use a metal salt of penicillin or cephalosporin with a halide of the desired ester radical in one proton-free (aprotic) dipolar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or hexamethylphosphotriamide (HMPT). The esters are then by diluting the reaction mixture with water and extracting with

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23A5236

obtained in a suitable solvent. The solvents mentioned have the advantage of solvating cations specifically, however, anions are poorly solvated (A.J. Parker, Quart. Rev. 16, p. 163, 1962), which means that Anion becomes available for reaction with the halide. When solvents such as alcohols and the like. be used, i.e. solvents that solvate both anions and cations, poor yields of the desired ester are obtained (C.Reicharät, solvent effects in the organic Chemistry). Poor yields are also obtained in tetrahydrofuran (THF>, acetone, dioxane and dioxane / water. Salts of peni- cillins and cephalosporins are too poorly soluble in THF to permit an acceptable degree of conversion, while Dioxane / water solvates the anion so strongly that it does not take part in the reaction to the desired extent.

For the reasons mentioned above, the polar, proton-free solvents DMSO, DMF and HMPT are more suitable as reaction media at the esterification step than the other solvents mentioned. However, DMSO, DMF, and HMPT have a number of other important disadvantages:

it

1. They are miscible with water, which makes them difficult to completely use to remove from the reaction product.

2. They have fairly high boiling points, which means that they cannot be removed by ordinary evaporation in a vacuum can. Such high temperatures have to be used

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den that the penicillin and cephalosporin structures to be broken up.

3. DMSO often produces sulfur-containing breakdown products that are difficult to remove.

4. DMSO, DMF, and HMPT are all somewhat hygroscopic. Contains commercially available qualities of these solvents Water and must be dried before they can be used in esterification. Both penicillins as well as cephalosporins are extremely sensitive to water at temperatures between about 50 to about 60 ° C, those in the esterification stage with these solvents must be applied.

5. The rate of conversion of penicillin and Cephalosporin metal salts with secondary alkyl halides in DMSO, DMF and HMPT is noticeable versus rate the conversion with primary alkyl halides is reduced because of the steric hindrance at the Reaction point.

The disadvantages of the esterification methods used hitherto are now overcome according to the present invention by quaternary ammonium salts of 6-APA, 7-ACA, penicillins and cephalosporins. These new salts of Penicillins and cephalosporins, which are further described in detail below, are soluble in solvents,

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such as acetone, ethyl acetate, butyl acetate, methyl isobutyl ketone, Methylene chloride, benzene and chloroform, and they easily react with halogenated ester groups in such solvents and give esters of penicillins or cephalosporins in high yields and easy to isolate. The new Salts of cephalosporins and penicillins can also be used advantageously for the esterification of penicillins and cephalosporins using solvents other than alcohols, DMSO, DMF and HMPT.

The new salts of 6-APA, 7-ACA, penicillins and cephalosporins according to the present invention are salts of 6-APA, 7-ACA, penicillins or cephalosporins with a quaternary Ammonium ion and have the general formula

- ^ - - 0 / R ¹ R ² R ³ R ⁴ N? © & - ^C ° y ^Z

wherein R is a straight or branched chain alkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted one Aryl radical or substituted or unsubstituted

2 4

th aralkyl radical, R to R, which are identical or different can be straight-chain or branched-chain alkyl groups

2 3

pen with 1 to 6 carbon atoms, where R, R and

4 1

R are alkyl groups of 3 to 6 carbon atoms when R

is an alkyl group, and P-COO ^ means the residue of 6-APA, 7-ACA, a penicillin or cephalosporin, which contain the group -COO W in the 6-aminopenicillanic acid residue or 7-aminocephalosporanic acid residue. The remainder P means the group

- 6 -

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^ N - CH - CH - S n. ^ ' I 1 I

wherein E and G both represent hydrogen atoms or wherein E represents a hydrogen atom and G represents the side chain in a penicillin or cephalosporin and wherein A represents one of the groups

; I i

^J ι CH ₂ ; ι

'CH ₃ ! or C - CH ₀ - B;

-CH- i _ _c _

C ₀ C

denotes in which B denotes a radical known from cephalosporin chemistry, such as H, CH ₃ COO-, 1-pyridinium or 2-methyl- 1,3,4-tiadiazol-5-ylthio.

Examples of the radical R are as follows:

'CH ₃ -CH ₉ CH ₉ CH ,, -CH (CH -) «, - (CH ₉ ) ^ CH ,, -CH ₉ CH, -C-CH ,,. -

CH ₃ . CH ₃ CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₂ CH ₃

- H ₉ CH j —C — CH ^ r - \ CH ₉ yς-CH ^ rj -CH ₉ CHoCH _t —y — CJtl ^ r CH ₃ CH ₃ CH ₃ CH ₃

_C1 __ </ \ y— CH ₃ " V

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ο λ

Illustrative examples of the radicals R to R are as follows:

-CH ₃ , -CH ₂ CH ₃ -

CH, -CH

I ³ I.

I I

-I ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , - (CHg) ₃ CH ₃ , -CH ₂ CH, -C-CH ₃ , - (C ^) ₄ CH ₃ ,

CHpCH, CH ₉ CH, CH ₀ CH, CH ₉ CH ₉ CH,

ZIr. , -C-CH ₃ , - (CH ₂ J ₅ CH ₃ , -CH ₂ CH ₂ CH, -C-CH ₃ ZH CH CH

CH ₃ CH ₃

It is understandable that steric considerations in the

12 3 4

Choice of combinations of R, R, R and R groups Restrictions impose. Such steric considerations, for example, that difficulties in the preparation of Tetraalkylaiimonium structures, wherein all alkyl groups R to

R are branched, occur are known to the person skilled in the art known and are not to be regarded as a limitation of the inventive concept.

1 2 Illustrative examples of suitable combinations of R, R, R and R in the quaternary ammonium ion are as follows listed:

R ¹ R ² R ³ R ⁴ N ^ II

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Table I.

1 to 4 examples of suitable combinations of the radicals R to R

in the ion

R ¹ R ² R ³ R ⁴ U

n-propyl n-propyl n-propyl n-propyl n-butyl n-butyl n-butyl n-butyl n-pentyl n-pentyl n-pentyl n-pentyl n-hexyl n-hexyl n-hexyl n-hexyl Phenyl methyl methyl methyl Phenyl ethyl ethyl ethyl p-tolyl ethyl ethyl ethyl p-chlorophenyl ethyl ethyl ethyl

1 4 The preferred combinations of the radicals R to R are Tetra-n-butyl, tetra-n-pentyl and T-etra-n-hexyl. Of these the combination tetra-n-butyl is particularly preferred.

1 4 If the radicals R to R are all different or if

1 4 any of the radicals R to R contains an asymmetric center or if the side chain in the penicillin or the cephalosporin contains an asymmetric center, the resulting compounds of the formula I occur in different epimeric forms. The invention is intended to encompass both the pure epimers of such compounds of the formula I and mixtures of the epimers.

The radical P in the formula I denotes a 6-APA radical _f 6-ACA radical or any penicillin or cephalosporin residue which

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contain a group -COO ^ in the 6-APA or 7-ACA radical. Illustrative examples of suitable penicillins and cephalosporins are given below. These examples are intended to However, do not limit the inventive concept.

Benzyl penicillin, phenoxymethyl penicillin, phenoxyethyl penicillin, Phenoxypropyl penicillin, 2,6-methoxyphenyl penicillin, S-phenyl-S-methyl ^ -isoxazoly! Penicillin, 3-o-chlorophenyl-5-methyl-4-isoxazolylpenicillin, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylpenicillin, 3- (2-fluoro-6-chlorophenyl) -5-methyl-4-isoxazolylpenicillin, 6- (2-Ethoxy-1-naphthamido) -penicillanic acid, O \ -Carboxybenzylpenicillin, 6- (D-O {-aminophenylacet- amido) -penicillanic acid, 6- (D- ^ A-amino-p-hydroxyphenylacetamido) penicillanic acid, ^ a -carboxy-3-thienyl-methylpenicillin, 6- (D-0 \ -Sulfoaminophenylacetamido) -penicillanic acid, o (-Hydroxysulfony! Benzylpenicillin, ^ -Indanyloxycarbonylbenzyl-penicillin, 6- (D-Q \ -Ainino-3-thienylacetamido) -penicillanic acid, 6- (D- ^ -Azidophenylacetamido) -penicillanic acid, 6- (D- ° (-Azido-rafluorophenylacetamido) -penicillanic acid, 2-thienylcephalosporin, benzylcephalosporin, cyanomethylcephalosporin, 4-pyridylthiorae thy! cephalosporin, 7- (D-iA-aminophoenylacetamido) -cephalosporanic acid, 7- (D-O ^ -aminophenylacetamido) -desacetoxycephalosporanic acid, 7- (2-thienyl) acetamido-3- (1-pyridylmethyl) -3-cephem-4-carboxylate betaine, 7- (1H-Tetrazol-1-yl) -acetamido-3- (2-methyl-1,3,4-thiadiazol-5-ylthio) -methyl-3Tce phem-4-carboxylic acid and compounds according to Dutch patent application 70 16 435..

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The. quaternary ammonium salts of 6-APA, 7-ACA, penicillins and cephalosporins according to the present invention can be obtained by reacting 6-APA, 7-ACA or a penicillin or of a cephalosporin of the general formula

III

wherein P is the above-mentioned residue of 6-APA, 7-ACA, a penicillin or a cephalosporin, with a quaternary ammonium salt of the general formula

R ¹ R ² R ³ R ⁴ N ⁺ X ^ II

wherein R, R, R and R are as defined above and X is

suitable monovalent anion such as HSO. ^, Cl ^ or

CH ₃ COO ^ - 'means with formation of a quaternary salt

of 6-APA, 7-ACA, penicillin or cephalosporin rait the general formula

/ ^ / p-coo

wherein R to R and P have the above meaning v / earth. The salts of the formula II can be prepared in a known manner analogous to the example of Belgian patent specification 751,791 will. In the preferred embodiment, the anion X ^ is HSO. ^, but other anions are also possible too

use as Cl ^ and CH ₃ COO- ^v - ^/ .

The new salts of the formula I are advantageously prepared in a mixture of water and an organic solvent, which is essentially immiscible with water. The organic solvent can be methylene chloride, monochlorobenzene, Dichlorobenzene or chloroform or a mixture thereof.

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ORIGiMAL INSPECTED

The term "dichlorobenzene" means 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene or mixtures thereof.

The quaternary ammonium salt I is in the organic phase

(2)
enriched, while the anion X ^v - ^/ and the cation of the penicillin or cephalosporin salt used as starting material are enriched in the aqueous phase. Suitable combinations of organic solvents and anions X ^ can be found with simple experiments.

The new penicillin and cephalosporin salts according to the present Invention including the 6-APA and 7-ACA salts * found particularly useful as intermediates in the manufacture of esters of penicillins and cephalosporins. The use of the new quaternary 6-APA, 7-ACA, penicillin and cephaiosporin salts gives a high yield and high purity of the desired ester. Illustrative, but not limiting, examples of groups easily included in the carboxyl group of the penicillin or cephalosporin nucleus can be introduced into 6-APA, 7-ACA, penicillins or cephalosporins, are alkyl groups, aralkyl groups such as benzyl, with a or more substituents from the group of halogen atoms, such as F, Cl or Br, of the alkyl groups having 1 to 3 carbon atoms and alkoxy groups with 1 to 3 carbon atoms substituted benzyl, phenacyl, with one or more substituents from the group of halogen atoms, such as F, Cl or Br, alkyl groups with 1 to 3 carbon atoms and alkoxy groups with 1 to 3 carbon atoms substituted phenacyl or one of the radicals

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ORlGiNAL INSPECTED

O .ο

-CH-OCO-R ⁶ , -CH-OCR ⁶

R ⁵ A ⁵

wherein R is H or an alkyl group having 1 to 3 carbon atoms and R is an alkyl group having 1 to 3 carbon atoms means.

The above list of ester residues comprises only a few examples and is not intended to limit the spirit of the invention. The nature of the ester residue attached to 6-APA, 7-ACA, penicillin or to be bound to cephalosporin is not critical for the advantageous use of the new salts of the present invention.

Illustrative, but not limiting, examples of specific esters made using the novel salts of the present invention are listed in Examples 11-33.

In the manufacture of esters of penicillins and cephalosporins using the new salts according to the present invention, the following reaction is carried out:

/ P-C00_ / ^ / R ¹ R ² R ⁵ R ^ N / ® + Hai / Esterrest / -} P-COO fEsterrest /,

1 4
where P and R to R have the above meanings, Hal means a halogen atom, such as Cl, Br or I and the term "Estarrest ' ^{1 means} the special ester group which is used in the reaction

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to be bound to the penicillin or cephalosporin or the 6-APA or 7-ACA residue. The implementation becomes appropriate using acetone, methylene chloride, chloroform, Ethyl acetate, butyl acetate, methyl isobutyl ketone or benzene are carried out as solvents. Acetone, methylene chloride and chloroform are the preferred solvents.

The quaternary ammonium salts of the formula I can be used in the
Ester synthesis in the form of isolated and / or purified
Compounds are used, but it is also possible to prepare and use the salts in the esterification reaction in situ, ie without isolating or purifying the quaternary ammonium salt used as the starting material.

The good and improved yields of esters obtained by using the penicillin or cephalosporin salts The present invention used can be exemplified with the preparation of the compound

(/ \\ __ CH _o -C0-NH-CH - CiT

O IV

Il ·

CO - N -CH-COO-CH-OCO-CpH ₅

being represented.

In Table III below are the yields of the ester IV using a method according to the prior art,

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ie reacting a potassium or sodium _e Äthylpiperidinsalzes of benzylpenicillin in solvents vie dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and listed Hexaraethylphosphortriamid (KMPT) compared with the results obtained when using a WAN Tetrabutylaimnoniunisalzes of benzylpenicillin in the solvents methylene chloride, methyl isobutyl ketone, chlorobenzene, ethyl acetate, butyl acetate and chloroform obtained. The reaction was carried out in all cases using an excess of 10 to 40% of the reactant CA chlorine diethyl carbonate. About 0.02 moles of benzylpenicillin were used in each experiment. The esterification according to the known methods took place in the usual manner. The esterification using the new salt according to the present invention was carried out analogously to Examples 11 to 33.

Table II

Yield of benzylpenicillin-CA-chlorodiethylcarboxylic acid ester

Solvent yield (%) of ester using

from

Benzyl benzyl benzyl benzyl penicillin penicillin penicillin penicillin potassium salt ethylpipe sodium tetrabutyl

ridin salt salt amrr.oniuir.- ^ salt

0 - 84

51 * 9

46 * 78

- 46

. - 75

- - € 6

79 30 76 *

/ 107-7 - ~ ¹⁰⁰ *

acetone - Dimethyl sulfoxide 19th Dimethylformamide 49 * Hexamethylphosphorus triamid 49 * Methylene chloride - Methyl isobutyl ketone - Chlorobenzene - Ethyl acetate - Butyl acetate - chloroform /. η Q Q '

"-" means that no experiment was carried out.

"*" means that the yield is not adequate the purity of the product has been corrected.

As can be seen from Table II, the results so far salts used a yield of at most about 50%, while the new salt according to the present invention a yield of up to about 100%.

The compounds of the formula I can easily be used in pharmaceutical preparations, and they can be mixed with solid Carriers or auxiliaries or both are mixed. In such preparations, the ratio between the therapeutic substance and the carriers and excipients can be between 1% and 95% vary. The preparations can either be processed into tablets, pills or coated tablets, for example or they can be filled into medical containers, such as capsules, or, for mixtures, they can too to be bottled. Pharmaceutically acceptable organic or inorganic, solid or liquid carriers can are used in the manufacture of the preparations, and expediently those for oral or enteral or local or parenteral administration. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal Fats and oils, vegetable gum and polyalkylene glycol and other known carriers for pharmaceuticals are all suitable for manufacture of preparations of these compounds. In addition, the preparation can also contain other pharmaceutically active components, which is useful together with the connections according to the

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Invention may be administered in the treatment of infectious diseases, such as other suitable antibiotic Substances such as gentamicin and polymyxin.

The invention is further illustrated by the following examples.

I. Preparation of penicillin and cephalosporin salts

example 1
Tetrabutylairanonium phenoxymethyl penicillinate

To a mixture of potassium phenoxymethyl penicillinate (7.8 g, 0.02 mol) in methylene chloride (20 ml) and water (10 ml) was tetrabutylammonium hydrogen sulfate (6.8 g, 0.02 mol) was added while stirring and cooling with ice the pH was kept at 7 by adding 2η NaOH. The organic layer was evaporated in vacuo, the last Residual methylene chloride was removed azeotropically with cyclohexane. A semi-crystalline mass was obtained, purity 94%, β-lactam absorption at 1765 cm

Example 2
Tetrabutylairanonium - ^ - phenoxypropyl penicillinate

This compound was prepared as in Example 1, using potassium CN-phenoxypropyl penicillinate (4.16 g, 0.01 mol) and tetrabutylammonium hydrogen sulfate (3.4 g, 0.01 mole) ran out and a light yellow oil with a purity of 33% and obtained a β-lactam absorption at 1765 cm.

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Example 3

Tetrabuty ammonium 2,6-dimethoxyphenyl penicillinate

This compound was prepared according to Example 1, using from. Potassium _2/6 dimethoxyphenylpenicillinat (4.02 g, 0.01 mole) and tetrabutylammonium hydrogen sulfate (3.4 g, 0.01 mol) was assumed. A pale yellow oil with β-lactam absorption at 1770 cm "was obtained. NMR: 60 to 100 cps (multiplets, dimethyl of the penicillin nucleus and propyl of tetrabutyl), up to 215 cps (multiplet of methylene adjacent to nitrogen in tetrabutyl), 230 cps (Dimethoxy), 256 cps (3-position of the penicillin nucleus), 347 cps (quartet, 5- and 6-position of the penicillin nucleus), 391 to 448 cps (multiplet for phenyl and nitrogen in 6-position of the penicillin nucleus).

Example 4

Tetrabutylammonium - ^ - aminobenzylpenicillinate

This compound was prepared as in Example 1, starting with ¹ ^ -aminobenzylpenicillin (6.98 g, 0.02 mole) and tetrabutylammonium hydrogen sulfate (6.8 g, 0.02 mole). An oil was obtained, IR absorption at 1760 cm ·, (β-lactam); NMR: 58 to 98 cps (multiplets for dimethyl in the 2-position of the penicillin nucleus and propyl of tetrabutyl), 180 to 198 cps (broad signal for methylene in the vicinity of nitrogen in tetrabutyl), 252 cps (singlet for the 3-position of the penicillin nucleus ), 269 cps (singlet for methine in the vicinity of phenyl), 313 to 336 cps (multiplet for the 5- and 6-position of the penicillin residue), 438 cps (phenyl).

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Example 5

Tetrabutylammonium 4- (2'-chlorophenyl) -S-methylisoxazolyl-3-penicillinate

This compound was prepared according to Example 1, using Kalitan-4-o-chlorophenyl-5-methylisoxazolyl-3-penicillinate (4.6 g, 0.1 mol) and tetrabutylammonium hydrogen sulfate (3.4 g, 0.1 mol) was assumed. An oil, IR absorption at 1765 cm " ¹ (β-lactam), NI-IR: 54 to 90 cps (multiplets _r for dimethyl in the 2-position of the penicillin nucleus and propyl of tetrabutyl), 163 cps (methyl in isoxazole), 186 to 210 cps (multiplet for methylene in the vicinity of nitrogen in tetrabutyl), 246 (singlet for the 3-position of the penicillin nucleus), 33.6 cps (quartet for the 5- and 6-position of the penicillin nucleus), 368 cps (Doublet for 6-amido, J = 8 cps), 450 cps (phenyl).

Example 6

Tetrabutylairanonium 4- (2x, 6'-dichlorophenyl) -5-methylisoxazolyl-3-penicillinate

This compound was prepared as in Example 1, using potassium 4- (2 ', 6'-dichlorophenyl) -5-methylisoxazolyl-3 -'-penicillinate (2.25 g, 0.0045 mol) and tetrabutylammonium hydrogen sulfate (1 , 5 g, 0.0045 mol) ran out and an oil was obtained. IR absorption 1770 cm " ¹ (β-lactam), NMR: 58 to 94 cps (multiplets for dimethyl in the 2-position of the penicillin nucleus and propyl of tetrabutyl), 168 cps (singlet for methyl in the 5-position of the isoxazole), 188 up to 204 cps (multiplet for methylene in tetrabutyl), 252 cps (singlet for the 3-position of the penicillin nucleus), 330 to 342 cps (multiplet for the 5- and 6-position

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of the penicillin nucleus), 366 cps (doublet for amido J = 8 cps) , 450 cps (phenyl).

Example 7
Tetrabutylammonium - ^ - azidobenzylpenicillinate This compound was prepared as in Example 1 from potassium ^ -azidobenzylpenicillinate (4.13 g, 0.01 mol) and tetrabutylammonium hydrogen sulfate (3.4 g, 0.01 mol), giving white crystals (from Ethyl acetate). IR absorption at 1760 cm (β-lactam) and 2070 cm " ¹ (azido); NMR: 58 to 98 cps (multiplets for dimethyl in the 2-position of the penicillin nucleus and propyl in tetrabutyl), 187 to 203 cps (multiplet for methylene in tetrabutyl), 255 cps (singlet for the 3-position of the penicillin nucleus), 306 cps (singlet for methine in the vicinity of phenyl), 318 to 340 cps (multiplet for the 5- and 6-position of the penicillin nucleus and for amido), 443 cps (phenyl).

Example 8

Tetrabutylammonium 7- (2-thienylacetamido) cephalosporanate

This compound was prepared according to the procedure of Example 1, using sodium 7- (2-thienylacetamido) cephalosporanate (2 g, 0.0048 moles) and tetrabutylammonium hydrogen sulfate (1.63 g, 0.0048 mol) was assumed and an oil with IR absorption at 1770 cm (β-lactam) was obtained.

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Example 9
Tatrabutylammoniumabenzylpenicillinate

Tetrabutylaromonium hydrogen sulfate (85 g, 0.25 mol) was added to 1 η NaOH (225 ml) and methylene chloride (300 ml) with ice-cooling and stirring. Potassium benzyl penicillinate (93 g, 0.25 mol) was added and the pH was adjusted to 7.1 by the addition of 1 η NaOH (18 ml). The organic layer was evaporated in vacuo and ethyl acetate (1000 ml) was added to the residue . Half of the ethyl acetate was evaporated in vacuo while the product began to crystallize. The salt was slurried with ethyl acetate (750 ml), filtered and washed with ethyl acetate and petroleum ether to give white crystals (87.2 g, (60%). The mother liquor was again evaporated in vacuo and the remaining crystals were dissolved in ethyl acetate Slurried and filtered. After washing with ethyl acetate and petroleum ether, a further product yield of 33.3 g was obtained. Overall yield 83%, mp = 148 to 151 ° C, IR absorption at 17 60 cm " ¹ (β-lactam), Purity 97.6%.

Example 10

tr

Tetxabutylammonium- * A-carboxyl penicillinate

This compound was obtained by following the procedure of Example 1 starting with tetrabutylammonium hydrogen sulfate (6.8 g, 0.02 mole) and disodium α-carbojcybenzyl penicillinate (4.22 g, 0.01 mole) to give an oil. IR absorption at 177Ο cm " ¹ (ß-lactam).

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II. Use of the salts for ester production

HA. Ester production using isolated quaternary ammonium salts

Example 11
Benzylpenicillindiäthylcarbonsäureester Tetrabutylammoniumbenzylpenicillinat (0.05 mol) and ^ diethyl carbonate (0.07 mol) were mixed together in acetone (200 ml) and brought to 55 ° C with stirring. Solution occurred after 15 minutes. After 20, 40, 60, 90, 120, 180 and 240 minutes, 10 ml of the reaction solution were partitioned between water (7 ml) and ether (20 ml). The aqueous phase was washed with water-saturated ether and made up to 10 ml. 4 ml of this solution were titrated for chloride with 0.1 μm silver nitrate on a potentiometer (mercury sulfate silver electrodes).

The remaining reaction mixture was concentrated in vacuo and then partitioned between water (200 ml) and butyl acetate (300 ml). The organic layer was washed with bicarbonate solution, which was then extracted once with butyl acetate (50 ml). The combined organic phases were washed with brine, treated with activated charcoal (1.4 g), _{dried with Na 2} SO ₄ and evaporated. The residue was rubbed with petroleum ether and dried. Light yellow semi-crystalline material was obtained, 74% purity, 84.4% yield (corrected for purity).

This product could be recrystallized from ether or isopropanol to give one of the diastereoisomic forms. To

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three crystallizations from isopropanol, this had a constant melting point, F = 110 ° C. and an optical rotation

/ "cK.7 ²⁰ = 109 (el"., chloroform).

Example 12

Benzylpenicillin diethyl carboxylic acid ester

In the same manner as described in Example 11, tetrabutylammonium benzyl penicillinate (0.05 mol) and ^ diethyl carbonate (0.02 mol) in methyl isobutyl ketone (200 ml) implemented three hours together. Samples (10 ml) were after 40, 90 and 180 minutes removed and treated as described in Example 11. 107 ml of the remaining reaction mixture were worked up as described in Example 11, 8.1 g of product being obtained. Purity 81.6%, yield 66%.

Example 13
Benzylpenicillin diethyl carboxylic acid ester tetrabutylammonium benzyl penicillinate CO.05 mol) and o (-chlorodiethyl carbonate (0.05 mol) were mixed with one another in acetone (200 ml) and brought to 55 ° C. with stirring. Solution occurred after 15 minutes. 6O, 90, 120, 240 and 360 minutes, samples of 10 ml were taken and treated as in Example 11. After 7 hours, the remaining reaction mixture was worked up as described in Example 11, and gave 11.7 g of product with a purity of 90.2%, yield 71%.

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Example 14

1 * -Kthoxycarbonylooqratirflljenzylpenicil llnat

Tetxabutylamnoniuaiieiaz ^ lpenicillinate (0.05 moles) was found in Dimethyl sulfoxide at room temperature with stirring (15 minutes) dissolved ^ -ChlardiätiBflcarljonat (0.07 mol) was added, and the reaction mixture was brought to 55 ° C with stirring.

Each 24O minutes wmnflp the reaction solution between water (2OO ml) and butyl acetate (3OO ml). The organic layer was washed with B & carbonate solution and water, which were then extracted twice with ethyl acetate (2 times 50 ml). The combined organic phases were washed with brine, treated with activated charcoal, over MgSO. dried, filtered and eingedaaipCtv leaving an oily residue of Ί ^> -XHH | r> ^ Y * 'jir-lir> »iyllif» wgy1p «» ii ^ o <1 Hnqf received. yield 9.3 g (9% corrected for purity), 22.6% purity.

Example 15

1 * ethoxy carbonyl benzyl peniclllinate

Example 14 was repeated except that dimethylformamide was used as the solvent in place of dimethyl sulfoxide.

1'-Ääiaaqpcarbonyloxyäthylbenzylpenicillinat as an oily, semi-crystalline residue. Yield 21.9 g (73% in total) " " elimieit 80.1%.

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Example 16

1'-ethoxycarbonyloxyethylbenzyl penicillinate

Example 14 was repeated with the exception that hexamethylphosphoric triamide as. Solvent was used instead of dimethyl sulfoxide. The l'-ethoxycarbonyloxyäthy! Benzylpenicillin was obtained as an oily residue. Total yield 16.0 g (46%) ", purity 64.7%.

BeisDiel 17

n-butyl benzyl penicillinate

To an ice-cold mixture of tetrabutylammonium hydrogen sulfate (8.5 g, 0.025 mol) in 1 η NaOH (25 ml). and chloroform (50 ml) was potassium benzyl penicillinate (9.3 g, 0.025 mol) added with stirring. The mixture was transferred to a separatory funnel and the aqueous layer was after a Thrown away hour. n-Butyl bromide (3.4 g, 0.025 mol) was added to the organic phase and the solution was left for 3 hours heated to 50 ° C. The mixture was then poured onto 100 ml of ice water and 100 ml of ether. The water phase was separated off Extract one more time with ether (100 ml). The combined organic layers were successively washed with sodium bicarbonate solution. Washed water and brine and the solvent was removed in vacuo leaving a yellow oil, which was rubbed several times with petroleum ether in order to remove unreacted butyl bromide, whereby light yellow Got crystals. The product shows strong IR absorption

at 1780 cm ¹ (β-lactam).

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Example 18

1'-acetoxyethylbenzyl penicillinate

This compound was prepared from tetrabutylammonium hydrogen sulfate as in Example 17 (4.25 g, 0.013 mole), potassium benzyl penicillinate (4.65 g, 0.013 mole), and 1-chloroethyl acetate and gave a yellow oil, which was obtained from ethanol / petroleum ether could be recrystallized. IR absorption at 1780 cm (β-lactam).

Example 19
Phenoxycarbonyloxymethylbenzyl penicillinate

This compound was prepared from tetrabutylammonium hydrogen sulfate as in Example 17 (17 g, 0.05 mole), potassium benzyl penicillinate (18.6 g, 0.05 mole) and phenoxycarbonyloxymethyl chloride produced and gave a yellow oil. IR absorption 1770 cm (β-lactam).

Example 20
Ethoxycarbonyloxymethylbenzyl penicillinate

This compound was prepared from tetrabutylammonium hydrogen sulfate as in Example 17 (17 g, 0.05 mole), potassium benzyl penicillinate (18.6 g, 0.05 mol) and ethoxycarbonyloxymethyl chloride (6.9 g, 0.05 mol) to give a yellow oil. IR absorption 1780 cn (β-lactain).

409834/107 7

Example 21

2 ', 6'-dichlorobenzyl benzyl penicillinate

A mixture of tetrabutylammonium benzyl penicillinate (2.88 g ,. 0.005 mol) and 2,6-dichlorobenzyl bromide (1.20 g, 0> 005 mol) in acetone (20 ml) was heated to 55 ° C. for 4 hours. The acetone was evaporated in vacuo and the residue was partitioned between ether (20 ml) and water (20 ml). After the separation the ether phase, the aqueous layer was extracted a further 2 times with ether, the combined ether phases were successively washed with bicarbonate solution and salt water, dried and stripped. The residue was washed out with petroleum ether treated and gave white crystals. IR absorption 1665 cm (β-lactam).

Example 22
p-Bromophenacylbenzyl penicillinate

This compound was prepared from tetrabutylammonium benzyl penicillinate as in Example 21 (28.8 g, 0.05 mol) and p-bromophenacyl bromide (13.9 g, 0.05 mol) in acetone (200 ml) and resulted in a yellow oil, IR absorption 1780 cm (β-lactam).

HB. Ester preparation using in situ prepared

quaternary ammonium salts

Example 23

Illustration of 6- (tA -Carboxyphanylacetamido) -penicillanic acid-3- (1'-ethoxycarbonyloxyethyl) -monoester sodium salt

To a stirred and ice-cooled solution of tetrabutylammonium hydrogen sulfate (17.0 g, 50 nl) in V7asser (25 ml)

- 27 -409834/1077

Chloroform (50 ml) was added and the pH was adjusted to 7.0 with 2 η matron liquor. 6- (^ -Carboxyphenylacetanido) -penicillanic acid-iA-benzyl monoester potassium salt (25.3 g, 50 mmol) was added portionwise, then the organic Phase separated, and after drying with anhydrous magnesium sulfate was ^ -Chlordiethylcarbonat (7.6 g, 50 mmol) added. The solution was left to stand at 40 ° C. for 16 hours.

The reaction mixture was evaporated, water (150 ml) was added and the product was extracted with ether (3 times 100 ml). The collected organic phase was washed successively with water, saturated sodium bicarbonate solution and water. Drying and evaporation gave an oily residue (17.4 g) which was chromatographed using silica gel (250 g) and the usual technique. The diester (8.9 g, 30.5%) was isolated as a foam which was pure by TLC analysis. IR (CHCl ₃ ): 1780 to 1740 (β-lactam, ester and carbonate-C = 0), 1680 (amide-C = 0. NMR (CDCl ₃ ): 7.28 (d, 2 CgH ₅ ) -, 6th , 77 (q, OCH (CH ₃₎ O), 5.80 to 5.40 (m, 5-H and 6-H), 5.16 (s, C ₆ H ₅ CH ₂ O), 4.61 (d, C ₆ H ₅ CHCO), 4.42 (d, 3-H), 4.20 (q, OCH ₂ CH ₃ ), 1.60 - .1.10 (m, mixed, CH ₃ , OCH ₂ CH ₃ and OCII (CH ₃ ) O).

Analysis: Calculated for C ₂₉ H ₃₂ O ₉ N ₃ S (584.66): C 59.58, H 5.52, 0 24.63, N 4.79, S 5.49, Found: C 59.66 , H 5.60, 0 24.34, N 4.64, S 5.32.

Hydrogenation of the diester over a pre-hydrogenated palladium-carbon catalyst (Palladium content 10%) in a mixture of ethanol and sodium bicarbonate at normal pressure and room temperature

409834/1077 " ²⁸ "

the the title compound (5.4 g, 9 6%), which by TLC analysis (butanone-pyridine-water-acetic acid-Syjiiem) was pure. IR (KBr): 1780-1760 (β-lactam, ester and carbonate-C = 0), 1675 (AnId-C = O), 1615 (carboxyl-C = 0). NxMR (D ₂ O): 7.35 (s, CgH ₅ ), 6.71 (q, OCH (CH ₃ ) O), 5.70-5.60 (m, 5-H and 6-H), 4.42 (s, 3-H), 4.15 (q, OCH ₂ CH ₃ ), 1.50 - 1.10 (m, mixed, CH ₃ , OCH ₂ CH ₃ and OCH (CH ₃ ) O) .

Example 24

Preparation of 6- (D- ^ -acetylureido-phenylacetamido) -penicillanic acid 3- (I ¹ -phenoxycarbonyloxyethyl) ester 6- (DC ^ -acetylureido-phenylacetamido) -penicillanic acid sodium salt (9.15 g, 20 mmol) became a added to the stirred and ice-cold mixture of tetrabutylammonium hydrogen sulfate (6.8 g, 20 mmol), sodium hydroxide (10 ml, 2 m solution), water (10 ml) and chloroform (20 ml). The pH was kept at 7.5 with tetrabutylammonium hydrogen sulfate. The organic phase was separated, dried, and C 1-4 chloroethyl phenyl carbonate (5.1 g, 25 mmol) was added. The reaction mixture was stirred at 40 ° C. for 16 hours.

Water (100 ml) and ether (100 ml) were added and the Organic layer was successively washed with 0.5 η sodium bicarbonate solution and washed water. After drying, the organic phase was evaporated to dryness and that was obtained yellow oil (4.9 g) was chromatographed on a silica gel column (100 g) with an isopropyl ether-acetone mixture (6: 4). The desired Product was isolated as a foam (1.0 g, 8.4%) and showed only one spot on TLC analysis.

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IR (KBr): 1790-1780 (β-lactam and ester) , 169O (amide).
i :: iR (CDCl ₃ ): 7.36 (s, CgH ₅ ), 6.85 (q, OCH (CH ₃ ) O), 5.90 (s,
COCHC ₆ H ₅ ), 5.40 (s, 5-H to 6-H), 4.33 (s, 3-H), 2.10 (s,
MHCOCH ₃ ), 1.65 - 1.40 (m, according to CH ₃ , OCH (CH ₃ ) O).

Analysis: Calculated for C ₉₃ H ₃₀ N ₄ O ₉ S (598.65, C 56.18,
H 5.05, N 9.36, 0 24.05, S 5.36.

Found: C 56.33, H 5.19, N 9.14, 0 23.94, S 5.16.
Degree of hydrolysis: B 3 = 5.9%, H3 = 25.7%, R 1 = 92.5%,. ! G 0.5 = 65.6%. j

In the same way, the analogous 3- (l'-Äthoxycarbonyl- · oxyäthyl) - and 3- (I ¹ -phenoxycarbonyloxyethyl) esters of in
connection specified in the heading.

Example 25 ^:

D1- / 7- (D-O4 -azidophenylacetamido) -cephalosporanyl-;

methylT carbonate

Tetrabutylammonium hydrogen sulfate (3.4 g, 10 mmol) was in; 10 ml of ice-cold 1 η sodium hydroxide solution dissolved. Potassium-7- {D-Ck'-

azidophenylacetamido) cephalosporanate (4.7 g, 10 mmol} and j

10 ml of methylene chloride was added. The mixture was j.

shakes and the methylene chloride layer is separated. !

Dichloromethyl carbonate (0.8 g, 5 mmol) was added and '-die Solution was stirred at 40 ° C. overnight. The reaction mixture was dissolved in 50 ml of ice-cold sodium bicarbonate solution;

- 3o -

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poured and extracted with 3 × 50 ml of thylacetate. The United organic extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated and gave 3.5 g of brown gum.

The product was dissolved in chloroform (75 ml) with ice cooled while 90% m-chloroperbenzoic acid (1.7 g, 10 mmol), dissolved in 50 ml of chloroform, added over a period of 10 minutes became. Stirring was continued for 3 hours at room temperature. The solution was made with sodium bicarbonate solution and Washed with salt water, dried and evaporated to give 3.2 g of a dark oil.

• The oil was dissolved in 25 ml of dimethylformamide. Sodium Dithionite (2.1 g, 12 mmol) was added. 2u of the stirred * cooled suspension was acetyl chloride, (1.2 ml, 17 mmol) added over a period of 10 minutes. Stirring was continued at room temperature for 30 minutes. The mixture was Poured into 50 ml of ice-cold sodium bicarbonate solution and extracted with 3 × 50 ml of ethyl acetate. The united organic Extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated in vacuo, whereby the product indicated in the title was obtained in an amount of 1.4 g as a dark oil.

The product shows strong IR absorption at 2100 cm and at 1785 to 1730 cm "due to the azido group and the ß-lactam group as well as the ester carbonyl groups.

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Example 26

Di- / 6- (2,6-dinethoxybenzamido) penicillanyl methyl / carbonate

Tetrabutylammonium hydrogen sulfate (3.4 g, 10 mmol) was dissolved in 10 ml of ice-cold 1 η sodium hydroxide solution. Sodium 6- (2,6-dimethoxybenzamido) penicillanate (7.0 g, 10 mmol) and 10 ml of methylene chloride were added. The mixture was shaken and the methylene chloride layer was separated. Dichloromethyl carbonate (0.8 g, 5 mmol) was added and the solution was stirred at 40 ° C overnight. The reaction mixture was poured into 50 ml of ice-cold sodium bicarbonate solution and extracted 3 × 50 ml of ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated to give the title product in an amount of 1.2 g as a white foam. The product showed IR absorption at 1790 to 1750 cm "" ¹ on Gruad, containing B-Lactaiu ™ and ester carbonyl groups.

NMR (CDCl ₃ , tetramethylsilane as internal standard). = 1.50 to 1.70 (d), 3.80 (s), 4.45 (s), 5.60 - S, 10 (m), 6.50 7.45 (m) ppm.

Example 27

Di- / T- (phenylacetamido) -cephalosporanyl-methyl / carbonate

In the same manner as in Example 26, it was made in the heading specified product of potassium 7- (phenylacetamido) -

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cephalosporanate (3.7 g, 10 mmol) and dichloromethylcarbon.at (0.8 g, 5 mmol) in 10 ml of methylene chloride. After the oxidation and reduction, this is what you got in the heading specified product in an amount of 0.6 g as a yellowish oil.

The product showed strong IR absorption at 1785-1730 cm due to the ß-lactam and ester carbonyl groups.

Example 28

Phenoxycarbonyloxymethyl 1-m-F-C ** -azidobenzyl penicillinate

To an ice-cold, stirred solution of tetrabutylammonium hydrogen sulfate (6.8 g, 0.02 mol) in 20 ml of 1M sodium hydroxide solution (0.02 mol) were 20 ml of methylene chloride and sodium m-F-C ^ azidobenzyl penicillinate (8.3 g, 0.02 mol) added. The mixture was shaken and the layers separated separated. Phenyl chlorine thy 1-carbonate was added to the organic solution (3.72 g, 0.02 mol) was added and the solution was stirred at 40 ° C overnight. The solution was in 80 ml of ice water poured and extracted with 80 + 40 ml of ether. The combined organic extracts were washed with sodium bicarbonate solution, Washed water and salt water, dried and evaporated in vacuo at 30 ° C, giving 6.7 g of a green Received oil. The product was washed repeatedly with petroleum ether to remove phenylchloromethyl carbonate, in Dissolved toluene and evaporated in vacuo at 30 C to give the product indicated in the title in an amount of 6.0 g than to yield a green, heavy oil. The product showed

409834/1077

strong IR absorption at 2130 cm " ^x due to the azido group and at 1790 to 1750 cm due to the ß-Lactam ™ and ester carbonyl groups. The product was rapidly hydrolyzed in the presence of human serum. NMR CCDCl ₃ , tetramethylsilane as internal standard) = 1.45 - 1.65 (d), 450 (s), 5.05 (s), 5.50 - 5.90 (m), 6.80 - 7.30 (m) ppm.

Example 29

Cyclopentoxycarbonyloxyethyl-e- (4-phenyl-2; 5-thiazolylacetamido) penicillinate

In the same way as in Example 28, the product given in the title was prepared from sodium 6- (4-phenyl-2,5-thiazolylacetamido) penicillinate (1.0 g, 0.0022 mol) and ^ -chloroethylcyclopentyl carbonate ( 0.42 g, 0.022 mol) synthesized. The product was obtained in an amount of 250 mg as a yellow heavy oil. The IR spectrum showed strong absorption at 1780 to 1740 cm due to β-lactam and ester carbon groups.

Example 30

(Diethylamino) ethoxycarbonyloxy methyl benzyl penicillinate

In the same manner as in Example 28, the title product of potassium benzyl penicillinate (3.7 g, 0.01 mol) and (diethylamino) ethylchloromethyl carbonate freshly prepared from its hydrochloride (2.5 g, 0 .01 mol), but was extracted with ethyl acetate instead of with ether. The title product was obtained in an amount of 1.3 g as a yellowish gum. The product showed strong IR absorption at 1780 bis

40983A / 1077 - 34 -

1730 cm due to ß-lactam and ester carbonyl groups. The product would rapidly hydrolyze in the presence of human serum.

Example 31

(Diethylamino) ethoxycarbonyloxy-methyl-OS-hydroxybenzyl penicillinate

In the same way as in Example 30, the product given in the title was prepared from sodium <A-hydroxybenζylpenicillinate (3.7 g, 0.01 mol) and (diethylamino) ethylchloromethyl carbonate. The product was in a lot of 0.6 g obtained as a yellow, solid foam. The product showed strong IR absorption at 1780 to 1740 cm "due to ß-lactam and ester carbonyl groups.

Example 32

Ethoxycarbonyloxymethyl 7- (D-Q \ -azidophenylacetamido) -cephalosporanate

Tetrabutylammonium hydrogen sulfate (3.4 g, 10 mmol) was dissolved in 10 ml of ice-cold 1 η sodium hydroxide solution. Potassium 7- (D-OS-azidophenylacetamido) cephalosporanate (3.7 g, 10 mmol) and 10 ml of methyl chloride were added. The mixture was shaken and the methylene chloride layer separated, ethyl chloromethyl carbonate (1.4 g, 10 mmol) was added and the mixture was stirred at 40 ° C overnight. The solution was poured into 50 ml of ice-cold sodium bicarbonate solution and extracted with 3 × 50 ml of ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated to give an oil which

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washed repeatedly with petroleum ether to make 3.8 g brownish To yield rubber.

3.0 g of the product were treated with m-chloroperbenzoic acid (1.5 g, 8 mmol) in 50 + 25 ml of chloroform. The product was obtained in an amount of 3.3 g as a dark brown oil.

All of the product was washed with sodium dithionite (3.3 g, 13 mmol) reduced in 30 ml of dimethylformamide and acetyl chloride (1.2 ml, 17 mmol) and gave the product indicated in the title in an amount of 2.0 g as a dark brown oil.

1.0 g of the product was used in the smallest possible amount Benzene dissolved and after the gradient elution method on a silica gel column (100 g) using isopropyl ether / Chromatograph acetone (1: 1) as the second solvent. The desired compound named in the title was obtained as a brownish foam (0.1 g) from the middle fraction isolated. The compound showed strong IR absorption 1780 to 1750 cm, indicating the presence of a β-lactam ring and ester groups. The product was made by human Serum hydrolyzed to the corresponding cephalosporanic acid.

In the same way, cyclopropyloxycarbonyloxyethyl -? - (m-fluoro-O ^ -azidophenylacetamido) -cephalosporanate will.

4 09834/1077

Example 33

Methoxycarbonyloxymethyl-7- (enanthamido) -. cephalosporanate

In the same manner as in Example 32, the title product was synthesized from potassium 7- (enanthamido) cephalosporanate (4.2 g, 10 mmol) and methylchloromethyl carbonate (1.2 g, 10 mmol). After the oxidation and reduction in Example 5, the product indicated in the title was obtained in an amount of: 2.6 g as a brown, solid foam. The product showed strong IR absorption at 1780 to 1730 cm due to β-lactam and ester carbonyl groups. ^v

40983Α / Ί077

Claims (15)

Claims i) Salts of 6-aminopenicillanic acid, 7-aminocephalosporanic acid, penicillins and cephalosporins with a quaternary Ammonium ion of the general formula 2 * wherein R is a straight or branched chain alkyl group with 3 to 6 carbon atoms, a substituted or unsubstituted aryl radical or a substituted one 2 3 or is an unsubstituted aralkyl group and R _r R and R, which can be the same or different, straight-chain or branched-chain alkyl groups with 1 to 6 carbon 2 3 4 are lenstoffatomen, where R, R and R are alkyl groups of 3 to 6 carbon atoms when R is an alkyl group is. 2.) Salts according to claim 1, wherein the "quaternary ammonium ion is a tetrabutylammonium ion. 3.) Tetrabutylammonium phenoxymethyl penicillinate.
4.) Tetrabutylairünonium-Ok-phenoxypropylpenicillinate. 409834/1077 5.) Tetrabutylanunonium-2,6-dimethyloxyphenylpenicillinate. 6.) Tetrabutylammonium - ^ - aminobenzylpenicillinate. 7.) Tetrabutylammonium 4- (2'-chlorophenyl) -5-methyl-isoxazolyl-3-penicillinate. 8.) Tetrabutylammonium 4- (2 * 7 6'-dichlorophenyl) -5-methylisoxazolyl 3-penicillinate. 9.) Tetrabutylammonium CA azidobenzyl penicillinate. 10.) Tetrabutylammonium 7- (2-thienylacetamido) -cephalosporanate. 11.) Tetrabutylammonium benzyl penicillinate. 12.) Process for the preparation of salts according to claim 1 to 11, characterized in that 6-aminopenicillanic acid, 7-Aminocephalosporanic acid, a penicillin or a cephalosporin with a quaternary ammonium salt of the general formula R ¹ R ² R ³ R ⁴ N ^ y X ^ wherein X is a monovalent anion such as HSO ₄ ^, Cl ^ or means. 13.) The method according to claim 12, characterized in that a quaternary ammonium salt is used in which X ^ HSO ₄ ^. - 39 - 409834/1077 14.) Process according to claim 12 and 13, characterized / that the reaction in methylene chloride, benzene, monochlorobenzene, Performs dichlorobenzene, chloroform or a mixture thereof as a solvent. 15.) Medicines, characterized by the content at least of a salt, in particular at least one penicillin or cephalosporin salt according to claims 1 to 11, particularly in conjunction with a pharmaceutically acceptable carrier material. 409834/1077