DD211561A5 - PROCESS FOR PREPARING 1-AETHOXY-CARBONYLOXYAETHYL ESTERS OF PENICILLINES, 6-AMINOPENICILANIC ACID OR CEPHALOSPORINS - Google Patents

Abstract

The invention relates to a process for the preparation of 1-Aethoxycarbonyloxyaethylestern of penicillins, 6-aminopenicillanic acid or cephalosporins, which are processed for use in human medicine and veterinary medicine for therapeutic purposes to preparations. The aim of the invention is to simplify the process. It is the task of the invention, the o.g. Process a new intermediate using a new compound. The process according to the invention for the preparation of 1-ethoxycarbonyloxyethyl esters of penicillins, 6-aminopenicillanic acid or cephalosporins consists in reacting the penicillin, 6-aminopenicillanic acid or cephalosporin or a salt thereof with alpha-bromodioethyl carbonate and then optionally splitting off an existing protective group.

Description

Field of application of the invention

The 1-ethoxycarbonyloxyethyl esters prepared by the process of the present invention can be made into antimicrobial preparations for use in human and veterinary medicine. The o-bromoethyl carbonate prepared according to the invention is used for its preparation.

Characteristic of the known technical solutions 10

On the basis of already known methods (see BE-PS 723), bacampicillin hydrochloride can be synthesized by the following two methods:

,

A) Reaction of Kaliumbenzylpenicillin with oC-Chlordiäthylcarbonat in organic solvents or in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained is reacted such that the phenylacetyl chain is removed via iminochloride imino ether to obtain the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, which is isolated as the hydrochloride.

By subsequent condensation of the. latter intermediate with D - (-) - QC-phenylglycine. obtained the compound of the formula I.

B) esterification of 6- (D - (-) - Q ε-azido-C ^ -phenylacetamindo) -penicillanic acid with (^ -chlorodiethyl carbonate in a polar solvent.

Subsequently, by catalytic hydrogenation of the 1-Athoxycarbonyloxyathylesters of 6- (D- (-) -e ^ -Azido - ^ - phenylacetamido) -penicillansäure the compound according to the formula I obtained.

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As can be seen, these methods are quite complex because aie the use of numerous raw materials ¹ ^ a long manufacturing times include.

Object of the invention

The aim of the invention is to improve the production of 1-thethoxycarbonyloxyäthylestern of penicillins, β-aminopenicillanic acid or cephalosporins »

Explanation of the essence of the invention

The object of the invention is a process for the preparation of 1-ethoxycarbonyloxyethyl esters of penicillins, 6-aminopenicillanic acid or cephalosporins, which leads to higher product purity and can be carried out in one operation.

This process for the preparation of I-Äthoxycarbonyloxyäthylestern of penicillins, for example of. Penicillin Gr, penicillin V or, ampicillin, 6-aminopenicillanic acid or gephanosporins is characterized in that the penicillin, the aminopenicillanic acid or the cephalosporin or a salt thereof is reacted with C 1 -C 3 -diethyl carbonate and then optionally an active protecting group is split off *

More particularly, the invention relates to a process for producing the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - O (-Amino - <X-phenyiacetamido) -penicillanic acid of the following formula

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/ Λ /

CH-CO-IH-CH-CH C

CH.

IH,

CO-N-CH-COO-GH-O-COOC ₀ He

by

a) ampicillin, preferably in the form of an alkali salt,

with a reactive derivative of acetoacetic acid with formation of the corresponding enamine of the general formula

CH.

10 15 20 25

/ \\ - -ΓΜ -nn: -NM ru

II

wherein R is an alkyl group having 1 to 4 carbon atoms, a substituted or "unsubstituted aryl group or an aralkyl group, R ^{2 is} a" hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R ³ an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl radical, an aralkyl group, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group or an amino group and X represents an alkali metal, an alkaline earth metal or the radical of an organic base, : .. ·. '- ·. · - .. "- ·

30

b) the resulting intermediate with a C ^ -Bromdiäthylcarbonat the formula

Br-CH-O-COOCΉCH-,

III

to form the corresponding ester of the formula

CH ₃

CH COOCK-O-COOC ₂ H ₅

CH ₃

wherein R, R ² and R ^{3 have} the above meaning, and

c) hydrolyzed in an acidic medium and so the compound

obtained according to the formula I.

Substance I is an ampicillin ester that is extremely important from a therapeutic point of view since it is well absorbed when administered orally and gives much higher levels of ampicillin in the blood than ampicillin itself.

The esterification reaction between compounds II and III can be carried out with or without esterification catalyst.

The addition of a catalyst in this stage shortens the

Reaction times significantly 'and provides higher yields of 25

Product with a higher degree of purity.

For this purpose, the following substances can be used as catalysts: quaternary ammonium salts, such as tetrabutylammonium bromide, the bromides or iodides of alkali metals, and cyclic ethers.

The catalyst may be used in an amount varying from 0.005 to 0.10 mole per mole of compound III to amounts equivalent to compound III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of from 0.01 to 0.10 mole per mole of compound III.

The invention also includes an embodiment of the method mentioned above for the preparation of bacampicillin which consists of reacting a compound of formula II with a compound of general formula

Z-GH-O-COO-C _n H

 CH-,

wherein Z is Cl or I, and this embodiment is characterized in that the process is carried out in the presence of a catalytic amount of a catalyst as defined above

suitably used in an amount of 0.005 to 0.10 moles per mole of the compound V. ^: .

Illustrative examples of R, R ² and R ³ are as follows: 5

Alkyl: CH ₃ , C ₃ H ₅ , 11-C ₃ H ₇ ,! -C ₃ H ₇ , nC ₄ H _g

Alkoxy (R ³ only): OCH ₃ , OC ₃ H ₅ , OCH ₂ CH ₂ CH ₃ , OCH (CH ₃ ) ₂ ,

Aryl: ~ \ /. - '

substituted aryl: with halogen, such as Cl or Br substitu -.

ized phenyl

Aryloxy: -OV 7

Aralkyl: -

The residue X is selected from groups known in the art, such as

Alkali metal: Na, -K . "-.. · ·" .-. ".- ...." .- .. "'V''... - ·.''· Alkaline earth metals: Ca, Mg.:

organic base: organic bases used in the synthesis of

'.. Penicillins are known as tertiary

Ammonium groups, triethylamine, ethylpiperi-, din, methylmorpholine.

In the preferred embodiment of the invention. the aminoprotein protecting group of the ampicillin group is an ^R '! L-methoxycarbonylpropen-2-yl group or a 1-ethoxycarbonylpropene-2-ylyl group, for which the preferred intermediate is the sodium or potassium salt of N- (1 -Methoxycarbonylpropen-2-yl) -penicillanic acid or N- (1-ethoxycarbonyl-propen-2-yl) -penicillanic acid according to the formula II is (R 1 = Me)

thyl, R ² = methyl, R ³ = methoxy or ethoxy and X = Na or K)

The intermediate IV is. stable in a neutral or alkaline medium, while in an acidic medium it is possible to simply, quickly and selectively remove the amino group-protecting group.

The group protecting the amino group of Arnpicillin can be selected, for example, from the groups mentioned in British Pat. No. 991,586 and from other groups known in the art. :

The ct bromo diethyl carbonate, compound III, which is a novel compound and is included as such in the inventive concept., Can be prepared by reacting the corresponding C ~ ~ Chlordiäthylcarbonates with sodium bromide / as for example in the following embodiment. 1 is reproduced. ';

, , ,

More specifically, therefore, the process according to a preferred embodiment of the invention comprises the following steps:

- Transfer of ampicillin trihydrate in a polar solvent, such as Ν, Ν-Oimethylf ormamid, in a salt thereof, such as the potassium salt, and then forming the corresponding enamine (H) by "" reaction with a derivative of acetoacetic acid .

_for example, methyl acetoacetate,. : - ''.,. / ..- ·. , '\' · )

, · Adding an esterification catalyst, preferably tetrabutylammonium bromide,. -. '-.' .;

- Addition of a c ^ -Bromdiäthylcarbonates to the reaction mixture to form the 1-Äthoxycarbonyloxyäthylesters. of ampicillin in the form of the enamine (IV) /

~ Hydrolysis of the protecting group with HCl, diluted with a

organic solvents, such as n-butyl acetate / water,

Recovery of the bacampicillin hydrochloride by saturation 5 in the aqueous phase, such as with sodium chloride,. and extraction with a suitable solvent, such as n-butyl acetate,

Concentration of the solution at low pressure in n-butyl acetate to crystallize the product with a high degree of purity, the product then being isolated by filtration.

Among the main advantages of the process according to the invention there is the principal advantage that, according to this process, it is possible to obtain bacampicillin hydrochloride practically in one operation and with a high degree of purity. '' · '·.

In fact they are. Impurities present in the product obtained by the process according to the invention, negligible 'compared with the known methods of the prior art. ? , _ - "/.-" ^: '..- '. '.. .-''i

Another equally important advantage is that ampicillin trihydrate is used as the starting material, and this is a known one. Antibiotic that is easily available in pure form and at low cost.

Intermediate II can be readily prepared, as described, for example, in British Pat. No. 5,911,586, which gives a yield of more than 95% by mixing ampicillin trihydrate with methyl or ethyl acetoacetate in an amount of 10 ". to 50% more than the stoichiometric ratio in the presence of an organic base or an alkali metal carbonate, such as "of potassium carbonate.

- Q -

The intermediate II can be isolated and added in solid form to the esterification. Instead, the esterification can also be carried out without. Isolation of the intermediate II be carried out in the same solvent in which the reaction for the formation of the enamine (II) took place.

The reaction . for the formation of ampicillinenamine (II)

, in an aprotic polar solvent, such as Ν, Ν-dimethylacetamide, N, N-JD dimethylformamide, Γ> ime t h oxy than, dimethyl sulfoxide, tetrahydrofuran or dioxane carried out.

Om to complete the reaction, it is sufficient that the components of the mixture at a Temperatur.zwischen 0 ° C and 60 ° C ₇ preferably between 20 ° C and 30 ° C, 2nd to 8 hours .vorzugsweise 3 hours in contact with hold.

Compound II can be prepared by acylating 6-aminopenicillanic acid with a corresponding enamine derivative of phenylglycine and forming compound II, which can then be directly esterified and converted to bacampicillin to isolate compound II.

The esterification reaction takes place after the addition of the 4-bromo-diethyl carbonate to this mixture at a temperature between 15 ° C and 80 ° C, preferably between 45 ° C and 55 ° C, for a period of 1 hour 24 hours, preferably from 5 to 10 hours, instead.

The esterification is conveniently carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide and. Oimethylsulfoxid or in. It is possible to use fumed hydrous organic solvent. "" The use of esterification catalyst is desirable when acetone is used as a solvent for the esterification reaction.

In the lightest and most convenient conditions for indu-

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The esterified urnamin (IV) is used for its own purposes. Dilution of the reaction mixture with water and subsequent extraction with a suitable solvent immiscible with water, such as n-butyl acetate, isolated

The acetate phase is stirred with a dilute solution (0.2 to 0.3 N) of Hgl, until the protecting group is completely hydrolyzed, requiring a contact time of 2 to 8 hours, preferably 4 to 5 hours, at ordinary temperatures.

By addition of sodium chloride, the compound I is separated from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, such as, for example, n-butyl acetate.

By concentrating the organic phase at low pressure at a temperature of 40 ⁰ G until a small volume remains, crystallization of the product takes place according to the formula I instead ·

The crystalline product is isolated by filtration, washing and vacuum drying.

The preparation of the new compound O.RTM. Diethyl carbonate used in the process is described in a separate application of the same priority.

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The aspect of the invention which relates to the use of the novel "compound <s" -Brömdiäthylcarbonat in the preparation of Äthoxycarbonyloxyäthylestern of 6-aminopenicillanic acid, penicillins and cephalosporins is now described in summary, this aspect of the invention '

1 · the use of a Λ-bromo diethyl carbonate in the preparation of the ethethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins, such as penicillin G, penicillin V and ampicillin, and of cephalosporin,

2 a process for preparing the ethoxycarbonate oxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporinan, which comprises 6-aminopenicillanic acid, penicillin or cephalosporin;

or a salt thereof with a Gl-bromo-diethylcarbo-

'' .nat reacts to form the Äthoxycarbonyloxyä.thylesters of 6-aminopenicillanic acid, penicillin or cephalosporin,

.3. the improvement of the esterification between a cC-halogenated diethyl carbonate and 6-aminopenicillanic acid, a penicillin or a cephalosporin, which consists in using a quaternary ammonium compound in the esterification step, said quaternary ammonium compound being in an amount of 1 to 25, preferably 1 to 10% of the equimolar amount with respect to the amount of 6-aminopenicillanic acid, penicillin or cephalosporin. , -

The atoxycarbonyloxyethyl ester especially of 6-aminopenicillanic acid and penicillin G is known to be used in the preparation of any desirable, such as semisynthetic penicillin ester, by acylating the 6-NH_ group after removal of the side chain in, for example, the penicillin G ester obtained.

This aspect of the invention is concerned with improvements in the preparation of esters by the reaction of carboxylic acid salts with O-bromo diethyl carbonate.

The reaction of carboxylic acid metal salts with alkyl halides or arylalkyl halides to form esters is known. However, the yields are not particularly high, and generally the reaction requires harsh conditions such as high temperatures and / or long reaction times. These harsh conditions limit the synthetic utility of the reaction and its industrial applicability to heat-sensitive and labile substances,; such as pyrethroids, prostaglandins, peptides, penicillins and cephalosporins.

British Patent 1,443,738 describes the use of a quaternary ammonium salt of penicillins and cephalosporins

instead of a metal salt thereof in the production of penicillin and cephalosporin esters. '

The preparation of the quaternary ammonium salt of the acid can be time consuming and expensive. However, as also described in GBPS 1 443 738, it is not necessary to first prepare the quaternary ammonium salt of a penicillin or cephalosporin, but the reaction can also be carried out by reacting a metal salt of the carboxylic acid, i. 6-aminopenicillanic acid, penicillin or cephalosporin, with the alkyl or arylalkyl halide in the presence of a quaternary ammonium salt other than the salt of the carboxylic acid.

According to the present invention, it has now been found that it is not necessary to add this quaternary ammonium salt in a stoichiometric amount relative to the carboxylic acid, i. 6-aminopenicillanic acid, penicillin or

  Cephalosporins, but that less than stoichiometric amount with respect to the carboxylic acid such as 6-aminopenicillanic acid, penicillin or cephalosporin is sufficient.

A process for preparing 2b position of a Athoxycarbonyloxyathylesters of 6-aminopenicillanic acid, a penicillin or a cephalosporin by reaction of a metal salt of the 6-aminopenicillanic acid, the penicillin or cephalosporin (with -Halogendiäthylcarbonat in the presence of a quaternary ammonium salt, therefore it gets to the invention, the of a salt of this carboxylic acid is different), wherein the quaternary ammonium compound 'in a less than stoichiometric amount with respect to the 6-aminopenicillanic acid, penicillin or cephalosporin is present.

According to the invention, 1 to 25% of one equivalent of the quaternary ammonium salt per equivalent of the metal salt of the carboxylic acid is used, and more preferred is 1% to 10% of one equivalent of the quaternary ammonium salt

used.

The quaternary ammonium salt of the carboxylic acid is conveniently prepared by reacting a metal salt of the carboxylic acid with a quaternary ammonium salt of an acid other than this carboxylic acid, typically a mineral acid such as hydrochloric, hydrobromic or sulfuric acid.

Suitable metal salts of carboxylic acids for use in accordance with the present aspect of the invention (either as or as a precursor to the quaternary ammonium salt of a carboxylic acid) are alkali metal or alkaline earth metal salts such as sodium, potassium, lithium, magnesium or calcium salts. Suitable quaternary ammonium salts of acids other than the carboxylic acid (for use as or as precursors for the quaternary ammonium salts of the carboxylic acids) are, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylammonium bromide, and quaternary pyridinium salts such as cetylpyridinium bromide. Suitable halides are, for example, fluorides, chlorides, bromides and iodides, preferably activated fluorides or activated chlorides or bromides or iodides.

The esterification reaction according to this aspect of the invention can be carried out in the presence or absence of a solvent. Suitable solvents are, for example, low molecular weight aliphatic alcohols, .niedermolekulare aliphatic ketones, low molecular weight aliphatic amides of formic acid and dimethyl sulfoxide. Alternatively, if no solvent is used, an excess of the ester-forming halide may be used, especially if it is a liquid at the temperature of the reaction.

i.

In the aspect of the invention described above, which relates to the use of a d (-bromo diethyl carbonate in the preparation of atoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins, is the use

a catalyst not mandatory, but desirable. Approximately equimolar amounts of the quaternary ammonium salt of the carboxylic acid and the ester-forming halide can be used in the reaction. Preferably, an excess of from 5 to 100% of the ester-forming halide per equivalent of the salt of the carboxylic acid is used, and more preferably an excess of between 20 and 60% of the ester-forming halide is used.

The improvements in the esterification processes according to the invention are particularly suitable for the preparation of the esters of 6-aminopenicillanic acid, penicillins and cephalosporins, and accordingly, according to a preferred embodiment of the invention, the carboxylic acid has the following formula

to have: .. .. .

R ¹ -NH

R ¹ -NH

or

wherein R represents a hydrogen atom or an acyl group, especially a substituted acetyl group such as a phenylacetyl group. oC-aminophenylacetyl group, cC-aminoparahydroxyphenylacetyl group, phenoxyacetyl group, oC-carboxyphenylacetyl group or oC-carboxy-3-thienylacetyl group, or, when the carboxylic acid has the formula XII, a group

STILL.

Nzo-

in which R ^{3 represents} a hydrogen atom or an amino-protecting group such as a benzyloxycarboxyl group, trimethylsilyl group or tertiary-carboxyl group and R ^{2 represents} a hydrogen atom, an alkyl group (such as a methyl group), a substituted alkyl group (eg a hydroxymethylene group, alkoxy or aryloxymethylene group or Acetoxymethylene group) or an acetoxy group or substituted acetoxy group (eg, an alkylacetoxy group, arylacetoxy group or arylalkylacetoxy group or the group C ₅ H ₅ .CHOH.CO-).

In the preparation of esters of penicillins and cephalosporins according to the invention, the ester-forming halide is a ct-halodialkylcarbonate of the general formula

CH 1 -CH (X) -O-CO-O-CR-CH ,,

wherein X is a chlorine, bromine or iodine atom, preferably a bromine atom.

According to a preferred embodiment of the invention for the preparation of esters of penicillins and caphalosporins, the quaternary ammonium salt used is tetra-n-butylammonium bromide.

embodiments

example 1

NaBr + Cl-CH-OCOOC ₂ H ₅ -Br-CH-OCOOC ₂ H ₅ + NaCl

CH.

CH.

Sodium bromide (102.9 g) dissolved in acetone (600 ml) was stirred at ambient temperature (20-25 ° C) for 2 to 3 hours

1-Chlorodiethyl carbonate (152.6 g) dissolved in 100 ml of acetone,

sfg

implemented. The mixture was then concentrated under vacuum at low temperature, maximum 35 ° C until a semi-solid mass was obtained. The reaction mixture was then partitioned between water / ethyl ether. The aqueous phase was separated and then extracted twice with 4 00 ml of ethyl ether.

The combined organic phases containing the c-bromo diethyl carbonate were washed with

800 ml of H ₂ O,

1000 ml of a 1% aqueous solution of sodium metabisulfate / and 1000 ml of saturated NaCl solution

washed.

  The organic phase was dried over magnesium sulfate and then concentrated under vacuum at low temperature, maximum 35 ° C, to give the title product (60%) in the form of a liquid that was initially colorless or slightly yellowish brown.

The product was used directly in the esterification step of Example 2. , ..-.

Example. 2

25.08 g (0.181 mol) of finely ground anhydrous potassium car-

  were suspended in 200 ml of Ν, Ν-dimethylacetamide, and 31.4 ml (0.3 mol) of methyl acetoacetate and 60.4 g (0.15 mol) of ampicillin trihydrate were added thereto.

The mixture was kept for 5 hours at 2 0 to 25 ° C with rapid stirring. Thereafter, 4 6.1 g (0.234 mol) of bromodiethyl carbonate, 6 g (0.02 mol) of tetrabutylammonium bromide and 100 ml of Ν, Ν-dimethylacetamide were added.

The mixture was heated with stirring at 40 to 42 ° C for 10 hours. The reaction mass was poured into a mixture,

which consisted of 1200 ml of water and 400 ml of n-butyl acetate.

The aqueous phase was collected and extracted with a further 100 ml of n-butyl acetate.

The rejoined organic phases were washed twice

washed with 100 ml of water. 150 ml of N HCl and 370 ml of water were added to the organic phase, which was stirred. The mixture was allowed to stand with stirring at 22 to 23 ° C for four hours. .

The aqueous phase was collected and the organic phase extracted with 100 ml of water.

The reunited aqueous phases were brought to pH 4 with a 10% aqueous solution of Na-CO-, then bleach carbon was added thereto and filtered.

300 ml of n-butyl acetate and 80 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated and the aqueous phase extracted with 200 ml of n-butyl acetate. ^ \ -

The rejoined phases in n-butyl acetate were concentrated at low pressure at 40 ° C to a volume of about 300 ml. The product was allowed to crystallize at 5 ° C for 15 hours. It was filtered, washed with n-butyl acetate (100 ml) and ethyl acetate (100 ml). It was dried for 24 hours at 40 ° C in a vacuum.

Yield: 54.2 g (72%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D- (-) -c-amino-o-C-phenylacetamido) -penicillanic acid with mp = 160 to 162 ° C (decomposition) and 'Properties that with

i

of the authentic hydrochloride sample.

-.2-5 "- Example 3

36.4 g (0.075 mol) of potassium N- (1-methoxycarbonyl-propen-2-yl) -6- [D- (-) - CC -amino- d- phenylacetamido] -penicillate were added to a solution of 17 , 8 g (0.116 mol) of oC-Chlordiäthylcarbonat and 3 g (0.01 mol) of tetrabutylammonium bromide in 150 ml of N, N-dimethylformamide was added. With stirring, the temperature was raised to 45 ° C and maintained at 4 5 to 50 ° C for 5 '.

When the heating was completed, the Reaktipnsgemisch was poured into a mixture of 300 ml of a 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture was stirred for 10 minutes, then the organic phase was separated and the aqueous phase extracted with 100 ml of n-butyl acetate. The reunited organic phases were concentrated after washing twice with 75 ml of 14% aqueous sodium chloride solution at low pressure until an oil was obtained.

The oil was mixed with 200 ml of tetrahydrofuran and 100 ml of water, the resulting solution (pH 4.8) was brought to pH 1.5 with stirring by addition of a total of 12 ml of 6N HCl for one hour. ·

, ,

After allowing the solution to stand at ordinary temperature for an additional hour, the tetrahydrofuran was removed at low pressure at 40 ° C, 150 ml of n-butyl acetate was added to the remaining aqueous phase (150 ml), and then 15 g of sodium chloride was added. ;

The organic phase was separated and the aqueous phase. extracted with 100 ml of n-butyl acetate.

The reunited organic phases were concentrated under vacuum at 40 ° C to a volume of 120 ml.

The product was allowed to crystallize at 5 ° C for 15 hours.

It was then filtered, washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml). At 40 ° C, it was dried in vacuo.

There were obtained 25.2 g (66.9%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D- (-) - cC-amino-OC-phenylacetamido) -pencillanic acid hydrochloride with mp = 160-162 ° C.

Analytical determinations: purity: 97.82%. ,

Rotation: 166.3 ° C (c "1, EtOH 95 °) ^:

pH: 4.05 (2% aqueous solution). ':

Moisture content: 0.82%

Residual solvent; Ethyl acetate 0.45, n-butyl acetate 0.98% IR and NMR spectra are standard spectra

Residual ampicillin: 0.06%

Example 4 ^:

16.2 ml (0.15 mol) of methyl acetoacetate and 30.2 g (0.075 mol) of ampicillin trihydrate were added to a suspension of 12.54 g (0.0907 mol) of finely divided powdered anhydrous potassium carbonate in 100 ml of N, N-dimethylformamide . .-. ', - ='

The mixture was stirred for 3 hours at 22 to 23 °. C, and after this. Time, a noticeable fluidization of the mass can be observed.

17.8 g (0.117 mol) of CC-chlorodiethyl carbonate, 3 g (0.01 mol) of SO tetrabutylammonium bromide and 50 ml of Ν, Ν-dimethylformamide were added in this order. ·

The mixture was heated with stirring at 45 to 50 ° C for 5 hours, then allowed to stand at 5 ° C for 15 hours

 · ·. !

The reaction mass was poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and stirred until a complete solution was obtained.

-2T-

ft..

The aqueous phase was collected and extracted with a further 50 ml of n-butyl acetate.

The reunited organic phases were washed twice with 50 ml each of water, 75 ml of N HCl and 85 ml of water were added to the organic phase with stirring and stirred at 22 to 23 ° C for 4 hours.

The aqueous phase was collected and the organic phase extracted with 15 ml of water. The reunited aqueous phases were washed with a 10% aqueous solution of

brought to pH 4, then bleaching carbon was added and then filtered. ,

150.ml. n-butyl acetate and 40 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated and the aqueous phase extracted with 100 ml of n-butyl acetate

 20

The reunited phases in butyl acetate were concentrated at low pressure at 40 ° C to a volume of about 150 ml. '

The product was allowed to crystallize at 5 ° C for 15 hours.

It was filtered, washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml).

It was dried under vacuum of 10 mm Hg in the presence of moisture at 25 ° C for 24 hours.

Yield: 20.8 g (55%) of the .l-Äthoxycarbonyloxyäthylesters of 6- (D (-) - QL-amino-C (_- phenylacetaraido) penicile lan acid hydrochloride with mp = 159-161 ° c ! and properties that matched an authentic sample.

ZS

Example 4a

Example 4 was repeated using ethyl acetoacetate. This gave 16.1 g of a white crystalline product with F. = 144 to 148 °. C (Tottoli apparatus). IR and TLC were in agreement with an authentic sample. pH of a 2% aqueous solution 3.55, yield 95.2%, residual solvent 3/5>%.

In a modification of this example, the o (-chlorodiethyl carbonate was added in two phases, in the first phase immediately 9 g and in the second phase after 2 hours again 9 g, then allowed to stand at 45 ° C. for 3 hours.

It was 13.7 g. crystalline, beige product with F. '' = 143 to 146 ° C (Tottoli apparatus). Its IR spectrum and TLC were in agreement with an authentic sample. pH of a 2% aqueous solution 3.43, yield 94.8%, solvent residue 2.6%.

Example 5

A mixture of 160 ml acetone, 22.6 g (0.075 mol) potassium salt of D - (-) - N-methoxycarbonyl-propen-2-yl-aminophenylacetic acid, 6.9 ml (0.088 mol) ethyl chloroformate. and 3 drops of N-methylmorpholine was stirred for 15 minutes at a temperature of -20 to -30 ° C. To this reaction mixture was added a solution of 16.2 g of 6-aminopenicillanic acid dissolved in 35 ml of water by careful addition of 7.6 g (0.075 mol) of triethylamine with stirring all at once, after which the mixture was diluted with 90 ml of acetone and dried -20 ° C was cooled. , ,

After stirring for 45 minutes, without additional cooling, 23.4 g (0.117 mole) of o (-bromo diethyl carbonate, .3 g (0.01 mole) of tetrabutylammonium bromide and 250 ml of Ν, Ν-dimethylformamide were added in that order 25 ° C. Thereafter, the reaction mass was poured into a mixture

-29-

poured from 600 ml of water and 200 ml of n-butyl acetate _;

existed, and it was stirred until a 'complete solution. had been obtained. The aqueous phase was collected and extracted with a further 50 ml of n-butyl acetate.

The reunited organic phases were washed twice with 50 ml of water. 185 ml of water was added to the organic phase and 1N HCl was added dropwise with stirring to pH 1.9. The mixture was allowed to stand with stirring for 4 hours at 22'to 23 ° C.

The aqueous phase was collected ¹ and the organic phase extracted with 50 ml of water. The combined aqueous phases were washed with a 10% aqueous solution of Na. CCL was brought to pH 4, activated carbon was added and then filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated and the aqueous phase extracted with 100 ml of n-butyl acetate. The combined butyl acetate phases were concentrated at low pressure at 40 ° C to a volume of about 150 ml. The product was allowed to crystallize at 5 ° C for 15 hours. / -

It was filtered, washed with n-butyl acetate {25.ml) and ethyl acetate (25 ml). It. was dried under vacuum of 10 mm Hg at 25 ° C for 24 hours. Yield: 1.17 g of the 1-ethoxycarbonyloxyethyl ester of 6- (D- (-) -Qi.-amino η o -CC-phenylacetamidopenicillanic acid hydrochloride with mp = 159-161 ° C and properties (nmr, tlc) obtained with an authentic sample.

Example 5a '''

The procedure of Example 5 was repeated except that the 6-aminopenicillanic acid was dissolved in 20 ml of water instead of 35 ml.

Yield: 1.05 g of the Athoxycarbonyloxyäthylesters of 6- (D - (-) - oL-amino-Ct-phenylacetamidopenicillansäurehydrochlori.d as a white crystalline powder with mp = 148 to 151 ° C below

Decomposition and properties (TLC, IR) consistent with an authentic sample.

Example 6 ·. ·

6.25 g (0.045 mol) of finely ground anhydrous potassium carbonate were suspended in 50 ml of dimethyl sulfoxide, and 8.1 ml (0.075 mol) of methyl acetoacetate and 15.1 g (0.0375 mol) of ampicillin trihydrate were added.

The mixture was kept under rapid stirring at 2 0 to 25 ° C for 5 hours. Thereafter, 11.5 g (0.059 mol) of bromo diethyl carbonate and 25 ml of dimethyl sulfoxide were added.

It was heated with stirring at 35 to 37 ° C for 17 hours. The reaction mass was poured into a mixture consisting of 300 ml of water and 100 ml of n-butyl acetate.

The aqueous phase was collected and extracted with a further 100 ml of n-butyl acetate. ..: "·.. ^;

The combined organic phases were washed twice with 25 ml of water.

92.5 ml of water and NH 4 Cl (7.0 ml) were added to pH 1.9 until the organic phase was stirred. The mixture was allowed to stand with stirring at 22 to 23 ° C for 2.5 hours.

The aqueous phase was collected and the organic phase extracted with 25 ml of water. , '· ·:

The combined aqueous phases were brought to pH 4 with 10% aqueous solution of Na 2 CO 3, then activated charcoal was added and filtered.

75 ml of n-butyl acetate and 37 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated and the aqueous phase extracted with 50 ml of n-butyl acetate.

The combined n-butyl acetate phases were concentrated at low pressure at 40 ° C to a volume of about 75 ml. .The product was allowed to crystallize at 5 ° C for 15 hours.

It was filtered, washed with n-butyl acetate (25 ml) and ethyl acetate (25 ml). Three hours was dried at 40 ° C in a vacuum

 15

Yield: 1.9 g (10%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - OC-amino-c-C-phenylacetamido) -penicillanic acid with mp = 160 to 162 ° C and properties associated with an authentic Sample of the hydrochloride (eg IR: V 1790 cm " ¹ , ß-lactam carbonyl) agreed.

Example 7

A mixture of acetaldehyde (44 g, 1 mol), carbon tetrachloride (300 ml) and freshly distilled carbonyl bromide

ζψ

(235 g, 1.25 mol) was cooled to 0 ° C and held at this temperature for one hour by external cooling during the addition of pyridine (11.9 g, 0.15 mol).

The mixture was allowed to warm to ambient temperature, then heated to 50 ° C and held at that temperature for 3 hours, during which time a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C gave a semi-solid oily mass which readily dissolved in ethanol (92 g, 2 moles) upon heating and refluxing. After refluxing for a further 2 hours, excess ethanol was removed in vacuo and the residue was triturated with water (100 ml) and methylene dichloride (200 ml).

Separation of the organic layer and fractional distillation gave pure ethyl c (bromoethyl carbonate (13.0 g, 6% yield) with a boiling point of 90 to 92 ° C at 45 mm Hg pressure, and this compound was in every respect identical to an authentic sample.

Example 8 ...

A mixture of .Acetaldehyde (44 g, 1 mol), dichloromethane (3 00 mL) and hexamethylphosphoric triamide (17.9 g, 0.1 mol) was cooled to -10 ° C, and freshly distilled carbonyl bromide (207 g, 1 , 1 mole) was added gradually over 4 hours, during which time the temperature was allowed to rise to 10 ° C.

The mixture was then heated at moderate reflux (about 40 ° C) for 4 hours. While still refluxing, ethanol (69 g, 1.5 mol) was added carefully over a one-hour period, and refluxing was continued for an additional hour.

-33--

Fractional distillation of the resulting mixture directly gave pure ethyl c.sup.-bromoethyl carbonate (114 g, 58% yield).

The authenticity of the formed ethyl C (bromoethyl carbonate was confirmed by analysis and independent synthesis as follows.

Diethyl carbonate (118 g, 1.0 mol) was stirred and heated to 110 to 120 ° C and irradiated with a 150 watt tungsten filament lamp. Bromine (96 g, 0.6 mol) was added dropwise during

3 to 4 hours and added at such a rate that the mixture did not turn pale orange in color. , ,

Upon completion of the bromine addition, the mixture was cooled to ambient temperature and sodium bicarbonate (20 g) was added.

Distillation and fractionation of the resulting mixture gave authentic ethyl C (_- bromäthylcarbonat (84.2 g, 70% yield) with a boiling point of 87 to 88 ° C at

4 0 mm Hg pressure. , ·. "· '

Example 9

A mixture of lithium bromide (43 g, 0.5 mol), ethyl - ^ - chloroethyl carbonate (15.3 g, 0.1 mol), water (100 ml), dichloromethane (100 ml) and cetyltrimethylammonium bromide (1.5

g) was stirred at ambient temperature for 24 hours. The aqueous layer was removed and replaced with a fresh solution of lithium bromide (26 g, 0.3 mol) in water (40 ml) containing cetyltrimethylammonium bromide (1 g). After stirring for an additional <: 24 hours, with the temperature rising to 35 ° C, the organic layer was separated, dried, and distilled in vacuo to give, after repeated fractionation, the new compound ethyl-bromoethyl carbonate (15.0 g, 76% yield) with -einem

Boiling point from 90 to 92 ° C at 35 mm Hg pressure

 Analysis:

Found: C 30.7 H4.8 Br 40.1%

Calculated: C 30.5 H 4.6 Br 40.6%

The NMR spectrum showed the following peaks:

1,2 - 1,6 (3H, triplet) ₂

2.0-2.2 (3H, doublet) -CH-CH ₃

4.1 - 4.5 (2H, quartet) '- CH ₂ .CH

6.5-6.8 (IH, quartet) -CH-CH ₃ Example 10

Lithium bromide (17.4 g, 0.2 mol) was dissolved in dimethylformamide (150 ml) and the mixture was cooled to ambient temperature. Ethyl (X-chloroethyl carbonate (30.5 g, 0.2 mol) was added and the mixture was stirred at ambient temperature for 24 hours The precipitated lithium chloride was filtered off and the filtrate distilled in vacuo to yield ethyl after careful fractionation X-Bromäthylcarbonat in 76% yield, based on the recovered Ääthyl Ü (-chlorathylcarbonat ..

Example 11

The authenticity of the above new compound ethyl-C (bromoethyl carbonate was confirmed by independent synthesis as follows:.

A mixture of diethyl carbonate (35 g, 0.3 mol) in carbon tetrachloride (50 ml) and. CC Azoisobutyronitrile (AIBN) (0-1 g) was heated to moderate reflux conditions and dibromodimethylhydantoin (28.6 g, 0.1 mol) was added in small portions over 8 hours along with a further addition of AIBN (8 χ 0.05 g) was added. This was precaution

taken that the free bromine did not accumulate in the reaction mixture. At the end of the reaction, the mixture was subjected to fractional vacuum distillation to yield pure ethyl-o (-bromoethyl carbonate (32.3 g, 82% yield) identical in all respects to the product of Examples 9 and 10).

Example 12

A mixture of potassium penicillin G (7.4 g, 20 μΜοΙ), ethyl CC-chloroethyl carbonate (4.6 g, 30 μΜοΙ), tetra-n-butylammonium bromide (0.8 g, 2.5 μΜοΙ) and acetone (80 ml) was stirred for 4 hours and heated under moderate reflux. Excess acetone was removed under partial vacuum and the residue was triturated with ice-cold water and methyl isobutyl ketone. Evaporation of the dried methyl isobutyl ketone under vacuum gave a semicrystalline oil (3.8 g) which on trituration with ethanol gave white crystals (0.9 g) of the 0 (- (ethoxycarbonyloxy) ethyl ester of penicillin G with a purity of 98-99%. by HPLC.

Analysis:

·.

Found: C 4 3.0. H 7.4 N 7.7%

Calculated: .. C 43.4 -H 7.4 N8.0%

Example 13 '·.

The above experiment of Example 12 was repeated using ethyl CC-bromoethyl carbonate (5.9 g ~, 30 μΜοΙ) instead of ethyl-O ^ -chloroethyl carbonate to give 6.0 g of semicrystalline oil on evaporation of the methyl isobutyl ketone. Trituration of this oil with warm ethanol followed by cooling gave white crystals (2.5 g, 35% strength by weight).

-3 · 6-1) of the o (- (ethoxycarbonyloxy) ethyl ester of penicillin

Example 14 5

Potassium benzylpenicillinate (25- / 08 g, 66.7 μΜοΙ) sodium bicarbonate (0.50 g, 6.0 μΜοΙ) and tetrabutylammonium bromide (2.15 g, 6.67 μΜοΙ) were carefully stirred in methylene chloride (41 mL) and heated to 40 ° C heated. When this temperature was reached, o-bromo diethyl carbonate (17.16 g, 86.7 μΜοΙ) was added and the slurry was stirred for 4.0 hours. Water (30 ml) was added, followed by a mineral acid to a pH of about 5. The mixture was stirred for about 4 hours during which time sodium hydroxide (4%) was added to bring the pH to between 2 To hold 5 and 3.0. Methylene chloride (50 ml) was then added and the mixture was allowed to separate for a few minutes. The organic phase was washed with water (65 ml) and then evaporated under reduced pressure. The oily product thus obtained was dissolved in methylene chloride (100 ml) and evaporated again. The residual oil was dissolved in methylene chloride to a total volume of 100 ml.

* _; ,

HPLC analysis of the methylene chloride solution showed a yield of Benzylpenicillinäthoxycarbonyloxyäthylester of 96 to 97.%.

SO example 15 ". '

Potassium benzylpenicillinate (5.02 g, 13%, 3%) and potassium bicarbonate (2.99 g, 38.3 μmol) in dimethyl sulfoxide (13.5 ml) were stirred thoroughly in an ice bath. CX Bromo diethyl carbonate (3.70 g, 18.6 μΜοΙ) was added over a period of 30 to. 40 minutes using a syringe pump.

ben. Stirring was continued while maintaining the reaction mixture in the ice bath. HPLC analyzes showed that a yield of about 70% of the benzylpenicillinethoxycarbonyloxyethyl ester was obtained within 5 to 10 minutes.

had been

Example 16

Potassium benzylpenicillinate (47.03 g, 125 μmol), sodium bicarbonate (0.94 g, 11 μΜΜ) and tetrabutylammonium bromide (2.01 g, 6.25 μΜΜ) were carefully stirred in acetone (77 ml) and heated to 40 ° C. When this temperature was reached, oi-bromoethyl carbonate (26.06 g, 131 μL) was added and the slurry was stirred for 4.5 h. Water (56 mL) was added, followed by mineral acid to one pH was about 5. The mixture was stirred for about 3 hours during which time sodium hydroxide (4%) was added to maintain the pH between 4.5 and 4.8. Butyl acetate (100 ml) was then added and the mixture allowed to separate for several minutes. The organic phase was washed with water (80 ml) and then evaporated under reduced pressure. The residual oily product was dissolved in methylene chloride to a total volume of 250 ml. HPLC analysis of the methylene chloride solution showed a benzylpenicillinethoxycarbonyloxyethyl ester yield of 98-99%.

Although the invention is directed primarily to a process for the preparation of the -1-Athoxycarbonyloxyathylesters of 6- (D- (-) -ÖCrAmino- ε (-phenyl acetamido) peri ic acid acid, the invention also relates to compounds of the formulas 35

Br-CH-OCOC ₉ H ₁ , • CH ₃

) and

Br CH ₃ -CH-OCO-Br

In addition, the invention provides a process for the preparation of the compound of the formula

Br 0 CH ₃ -CH-OCOC ₂ H ₅ III

characterized in that: an aldehyde of formula.

CH ₃ CHO. VI

  with carbonyl bromide of the formula

COBr ₂ VII

V.

to form a compound of the formula

br

CH ₃ -CH-OCO-Br. VIII

and then reacting the compound VIII with Ο_Η _ς ΟΗ to form a compound of formula III. This process is conveniently carried out in the presence of a catalyst which is preferably present in an amount of from 0.05 to 0.5, more preferably in an amount of from 0.05 to 0.15 mole per mole of compound VI. The catalyst is suitably a tertiary amine, a tertiary phosphine, an amide, substituted urea or thiourea, a phosphoric acid amide, a tertiary oxonium or sulfonium salt, or a quaternary ammonium or phosphonium salt.

Furthermore, the invention provides a process for the preparation of the compound of the formula

Br O CH ₃ -CH-OCOC ₂ H III

by reacting a compound of the formula

Cl O '

CH ₃ -CH-OCOC ₂ H ₅ IX

with an alkali bromide of the formula

R-Br X

wherein R is an alkali metal, preferably Li, to form a compound of formula III, which process is characterized in that the reaction is carried out in a biphasic solvent system comprising water and a water immiscible organic solvent in the presence of a phase transfer catalyst , The organic solvent is preferably a

halogenated hydrocarbon, especially dichloromethane, or an aromatic hydrocarbon. The phase transfer catalyst is suitably a quaternary ammonium salt.

The invention is also generally concerned with the use of OC bromo diethyl carbonate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins. More generally, one aspect of the invention is a process for preparing the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, Penicillins and cephalosporins by reacting 6-aminopenicillanic acid, penicillin or cephalosporin or a salt thereof with O ^ -Haiogendiäthylcarbonat, and this method is characterized in that a quaternary ammonium salt is used as the catalyst. It is preferably used in an amount of 1 to 25, more preferably in an amount of 1 to 10% of one equivalent per equivalent of 6-aminopenicillanic acid, penicillin or cephalosporin. As the catalyst, tetra-n-butylammonium bromide is preferably used.

Claims (19)

invention claim 1. Process for the preparation of 1-ethoxycarbonyloxyethyl esters of penicillins, 6-aminopenicillanic acid or cephalosporins, characterized in that the penicillin, the 6-aminopenicillanic acid or the cephalosporin or a salt thereof is reacted with DC-bromodiethylcarbonate and then optionally cleaves off an existing protective group. 2. The method according to item 1 for the preparation of 1-Äthoxycarbonyloxyäthylesters of 6- (D- (-) -q (.- amino-OC-phenylacetamido) -penicillansäure the formula ' ^ ^s x κ ⁰¹ * ³ V ^ -CH-CO-NH-CH-CH C 'τ ₉ CO-N CH-COO-CH-O-COOC-H _n . '""' CH ₃ characterized in that one a) Ampicillin, preferably in the form of an alkali salt, with a reactive derivative of acetoacetic acid to form the corresponding enamine of the general formula ^ ⁷ CH - CO - NH - CH - CH C. η 'Γ U CH- ouu / i R ^ - CO 0 R ³ where R is an alkyl group having 1 to 4 carbon atoms --4-Γ- wherein R ^{2 is} a hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R ^{3 is} an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted one, R ^{2 is} a substituted or unsubstituted aryl group or an aralkyl group Aryl radical, an aralkyl group, an alkoxy group having 1 to. 4 carbon atoms, an aryloxy group or an amino group and X is an alkali metal, an alkaline earth metal or an organic base radical, reacts, b) the resulting intermediate with DC "" ^{r 0111} ^ i ethyl carbonate of the formula Br-CH-O-COOC H ₅
CH ₃ to give the corresponding ester of formula 20 CH. ff M-CH-CO-NH-CH-CH C CH ₃ ; .: , N is CO-NCH-COO-CH-O-COOC ₂ H ₅ R ^X -GH CH-, "IV R ² -C, 0 '. ^r3 wherein R, R ² and R ^{3 have} the above meaning, and c) mildly hydrolyzed in an acidic medium. , 3. Procedure according to point. 2, characterized in that as the alkali salt of ampicillin by transfer of ampicillin trihydrate by a method known per se in a polar solvent, preferably N, N- 3Ψ -Azr- Dimethylformamide, salt used. 4. The method according to any one of the items 2 and 3, characterized in that the formation of the enamine (II) by reacting the alkali salt of ampicillin with an alkyl acetoacetate in an aprotic polar solvent at a temperature between 0 ° C and 60 ⁰ C and while stirring a time between 2 and 8 hours. 5. The method according to item 4, characterized in that one carries out the reaction of enamine formation (II) .in the presence of an organic base or an alkali metal carbonate. 6. The method according to any one of items 4 and 5, characterized in that is used as the alkyl acetoacetate methyl or Äthylacetoacetat in an amount of 10 to 50% more than the stoichiometric ratio. 7. The method according to any one of the items 4 to 6, characterized in that is used as the aprotic polar solvent N, N-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxane. ". 8. The method according to any one of the items 4 to 7, characterized in that one carries out the reaction of enamine formation at a temperature between 20 and 30 ° C. 9. The method according to any one of the items 4 to 8, characterized in that one carries out the reaction in a period of 3 hours. 10. The method according to any one of the items 2 to 9, characterized in that one carries out the esterification of the enamine (II) by adding c (-Bromdiäthylcarbonat to the reaction mixture, wherein the reaction at a temperature of 15 to 80 ° C and during a Time from 1 to 24 hours ". is carried out. SS 11. The method according to item IQ, characterized in that one carries out the esterification in the presence of a catalyst. 12. The method according to item 10 or 11, characterized in that adjusting the reaction temperature to 45 to 55 ° C. 13. The method according to any one of the points 10 to 12, characterized in that one carries out the esterification for 5 to 10 hours. 14. The method according to any one of items 11 to 13, characterized in that one uses as a catalyst quaternary ammonium salts, alkali bromides, Älkalijodide or cyclic ether. 15. The method according to item 14, characterized in that tetrabutylammonium bromide is used as the catalyst. 16. The method according to any one of points 2 to 15, characterized in that one hydrolyzed with dilute hydrochloric acid after the isolation of the ester (IV). 17. The method according to one of the items 2 to 9, characterized in that one a) the enamine (II) with a compound of the general formula Z-CH-O-CO-C H V CH ₃ wherein Z is Cl or I, and reacts b) carrying out the reactions between the compounds II and V in the presence of a catalyst. "28 09/02/1984 AP G 07 D / 252 531/8 62 663/12 18 _β Process according to item 17 », characterized in that the catalyst used is quaternary ammonium salts, alkali metal bromides and iodides and cyclic ethers. .19. Process according to item 8, characterized in that tetrabutylammonium bromide is used as the catalyst. 20. The method according to any of items 11 to 19 »characterized by using the catalyst in an amount of 0.005 to 0.1 0 mol, preferably from 0.01 to 0.10 mol per mole of the compound III or V _o 21 * process according to item 1, characterized in that the reaction with the O-bromo-diethyl carbonate is carried out in the presence of a quaternary ammonium salt as catalyst. Method according to item 21, characterized in that the quaternary ammonium salt is used in an amount of 1 to 25, preferably 1 to 10 % of one equivalent of the quaternary ammonium salt per equivalent of penicillin, 6-aminopenicillanic acid or cephalosporin. 23 * Process according to item 22, characterized in that the catalyst used is tetra-n-butylammonium bromide «