NL8302286A - METHOD FOR PREPARING ANTIBIOTICS. - Google Patents

Description

L 4 N.0. 31,890

Method of preparation of antibiotics.

The present invention relates to a new process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid of formula 1.

The invention furthermore relates to the new compound 5 ct-bromo-diethyl carbonate, which is used to great advantage in the present new process for the preparation of bacampicillin of formula 1, and which in a more general sense is also used with great advantage in the preparation. of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins, 10 - new processes for the preparation of ot-bromo-diethylcarbonate, - new intermediates in the preparation of cc-broradiethylcarbonate, in the preparation of α-bromo-diethylcarbonate-ethylethyl-carbonylate, of the preparation of 6-aminopenicillanic acid, penicillins, such as penicillin G, penicillin V and ampicillin, and cephalosporins, - improvements in the process for preparing ethoxycarbonyl ethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins.

The compound of formula 1 in question is an ampicillin ester, which is extremely important from a therapeutic point of view, since the compound is well absorbed when administered orally and gives much higher blood levels of ampicillin than ampicillin itself.

This ester is isolated in the form of a hydrogen chloride and is known as bacampicillin hydrochloride.

Based on previously known methods (see Belgian Patent No. 772,723), bacampicillin hydrochloride can be synthesized by either of the following methods: A) Reaction of potassium benzylpenicillin with o-chlorodiethyl carbonate in organic solvents or in an aqueous solution of 70% dioxane at presence of sodium hydrogen carbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin, which is obtained, is subjected to a reaction to remove the phenyl acetic acid chain, via the imine chloride imino ether, to form the 1-ethoxycarbonoxyethyl ester of 6-aminopenicillanic acid, which is isolated as the hydrochloride.

By subsequent condensation of the latter intermediate with D - (-) - α-phenylglycine, the compound of formula 1 is obtained.

B) Esterification reaction of the 6- (D - (-) - α-azido-α-phenylacetamido) -8302286 * 2 penicillanic acid with chlorodiethyl carbonate in a polar solvent.

The compound of formula 1 is then obtained by catalytic hydrogenation of the 1-ethoxy-carbonyloxyethyl ester of 6- (D - (-) - α-azido- <x-phenylacetamido) penicillanic acid.

As can be seen, these methods are quite complex since they involve the use of numerous raw materials and long processing times.

A first object of the present invention is to provide a process for the preparation of the active substance concerned, which is easier and industrially more advantageous to carry out.

A more specific object of the present invention is to provide a process for preparing bacampieillin using ampicillin as a starting material, with considerable simplification of the process in question and producing the desired product with a high degree of purity.

The invention also provides the new compound C-bromoethyl ethyl carbonate, new methods of preparing it; new intermediates in the preparation of bromo-diethylcarbonate; the use of α-bromo-diethyl carbonate in the preparation of the ethoxycarbonyloxyethyl-ester of 6-aminopenicillanic acid and penicillins such as penicillin G, penicillin V and ampicillin and improvements in the method of preparing ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillinic acid.

α-Bromodiethyl carbonate is used to great advantage as reagent in these esterification processes. The use of o-bromo-diethyl carbonate results in end products, such as bacampieillin, in high yield and high purity.

It is possible to achieve the first objective of preparing the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-ct-phenylacetamido) penicillanic acid of formula 1, characterized by the following steps: a) reaction of ampicillin , preferably in the form of an alkali metal salt, with a reactive derivative of acetoacetic acid to form the corresponding enamine of formula 2, wherein: 35 R * an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or a aralkyl group, R 1 represents hydrogen, an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, 40 R 1 represents an alkyl group of 1 to 4 carbon atoms, a substituted or 8302286 * * 3 unsubstituted aryl group, 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 an organic base; B) reaction of the resulting intermediate with an α-bromo-diethyl carbonate of the formula 3 to form the corresponding ester of the formula 4, wherein R 1, R 1, and R 1 have the aforementioned significance, and c) hydrolysis in an acid environment to form compound 10 of formula 1

The esterification reaction between compounds 2 and 3 can be carried out with or without an esterification catalyst present.

The addition of a catalyst at this step significantly shortens the reaction times and provides higher yields of the product 15 with a greater degree of purity.

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

The catalyst can be used in an amount ranging from 0.005 to 0.10 moles per mole of compound 3 to amounts equimolar with compound 3. In a preferred embodiment, tetrabutyl ammonium bromide is used in an amount of 0.01 to 0, 10 moles per mole of compound 3.

The invention also includes an embodiment of the method set forth above for the preparation of bacampicillin, which comprises reacting a compound of formula 2 with a compound of formula 5, wherein Z is Cl or J, which embodiment is characterized in that the method is carried out in the presence of a catalytic amount of a catalyst as specified above. The catalyst is usually used in an amount of 0.005 to 0.10 moles per mole of compound 5.

Examples of the groups R ^ -, R ^ and B? are: alkyl: CH3, C ^ Hg, 11-C3H7, iso-CgHy, η-Οή, Η ^ 35 alkoxy (R ^ only): OCH3, OC2H5, OCH2CH2CH3,0CH (CH3) 2,0 ^ 2) 3 ( Aryl: -CgH5 substituted aryl: phenyl substituted with halogen such as Cl and Br aryloxy: -O-CgHg 40 aralkyl: -Ci ^ CgHg 8302286 4

The group X is selected from groups known in the art, for example, alkali metal: Na, K alkaline earth metal: Ca, Mg 5 organic base: organic bases known for the synthesis of penicillins, for example, tertiary ammonium groups, triethylamine, ethylpiperidine and methylmorpholine.

In the preferred embodiment of the invention, the group protecting the amino group of ampicillin is a 1-methoxycarbonylpropylene-2-yl group or a 1-ethoxycarbonylpropylene-2-yl group, for which the preferred intermediate is the sodium or potassium salt of the N- ( -1-methoxycarbonyl-propylene-2-yl) penicillanic acid is N- (1-ethoxycarbonylpropylene-methyl; methoxy or ethoxy and X * Na or K), respectively.

The intermediate 4 is stable in a neutral or alkaline medium, while in an acid medium it is possible to remove the group protecting the amino group simply, quickly and selectively.

For example, the group protecting the amino group of the ampicillin may be selected from the groups disclosed in British Patent 991,586 and from other groups known in the art.

The α-bromo diethyl carbonate, compound 3, which is a new compound and as such is encompassed by the scope of the invention, can be prepared by reacting the corresponding α-chlorodiethyl carbonate with sodium bromide, as illustrated in Example I.

More particularly, therefore, the method according to a preferred embodiment of the present invention comprises the following steps: conversion of ampicillin trihydrate in a polar solvent, for example Ν, Ν-dimethylformamide, to a salt thereof, for example potassium, and subsequent formation of the corresponding amine of formula 2 by reaction with a derivative of acetoacetic acid, for example methyl acetoacetate, addition of an esterification catalyst, preferably tributyl ammonium bromide, addition of α-bromo diethyl carbononate to the reaction mixture to form the 1-ethoxycarbonyloxyethyl ester of the ampicillin form of the enamine of formula 4, - hydrolysis of the protecting group with dilute HG1 in an organic solvent, for example n-butyl acetate / water, - recovery of the bacampicillin hydrochloride by saturation of the aqueous phase, 8302286 ~~ 5. for example with sodium chloride and extraction with a sc hiccups solvent, for example n-butyl acetate, - concentration of the solution at low pressure in n-butyl acetate to crystallize the product to a high purity level, after which the product is isolated by filtration ♦

Among the main advantages of the method according to the invention, the principal advantage is that according to this method it is possible to obtain bacampicillin hydrochloride practically in one operation and with a high degree of purity. In fact, the impurities contained in the product obtained by the method of the present invention are negligible compared to the known prior art methods.

Another equally important advantage is that ampicillin trihydrate is used as the starting material, which is a known antibiotic, which is readily available in pure form and at a low cost.

The intermediate of formula 2 is readily prepared, as described, for example, in British Patent 991,586 in a yield of more than 95% by reaction of ampicillin trihydrate with methyl or ethyl acetoacetate, 10 to 50% more than the stoichiometric ratio in the presence of an organic base or an al-potassium carbonate, for example potassium carbonate.

The intermediate of formula 2 can be isolated and the esterification reaction can be added in solid form. Also, without isolation of the intermediate of formula 2, the esterification reaction can be carried out in the same solvent in which the reaction for the formation of the enamine of formula 2 took place.

The reaction for the formation of ampicillin-enamine of the formula II is carried out in an aprotic polar solvent, such as N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxane.

To complete the reaction it is sufficient to leave the components of the mixture in contact at a temperature between 0 ° C and 60 ° C, preferably between 20 ° G and 30 ° C, for 2 to 8 hours, preferably 3 hours .

The compound of formula 2 can be prepared via acylation of 6-aminopenicillanic acid with a corresponding enamine derivative of phenylglycine, which can then be directly esterified and converted to bacampicillin without isolation of the compound of formula 2.

The esterification reaction after the addition of the α-bromo diethylcarbonate to the mixture takes place at a temperature between 15 ° C and 8302286 4 ° 6 * 9 80 ° C, preferably between 45 ° C and 55 ° C , for a period of time from 1 hour to 24 hours, preferably from 5 to 10 hours.

The esterification reaction is suitably carried out in an organic solvent, such as dichloromethane or acetone, dimethylacetamide, dimethylformamide or dimethyl sulfoxide, or in a mixture of organic solvents. It is also possible to use an aqueous organic solvent. The use of an esterification catalyst is desirable when acetone is used as a solvent for the esterification reaction.

In the easiest and most suitable conditions for industrial purposes, the esterified amine of formula 4 is isolated by dilution of the reaction mixture with water and subsequent extraction with a suitable solvent, which is miscible with water, for example nr-butyl acetate.

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

The addition of sodium chloride separates the compound of formula 1 from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example nr-butyl acetate.

By concentrating the organic phase at low pressure at a temperature of 40 ° C to a small volume, crystallization of the product of the formula 1 takes place.

The crystalline product is isolated by filtration, washing and drying under reduced pressure.

Example I

Preparation of α-bromo-diethyl carbonate (see figure 1 of the formula sheet). 102.9 g of sodium bromide dissolved in 600 ml of acetone were dissolved in 152.6 g of chlorine-diethyl carbonate in ambient temperature (20-25 ° C) for 2-3 hours. 100 ml of acetone converted. The mixture was then concentrated under reduced pressure at a low temperature, maximum 35 ° C, until a partially solid mass was obtained. The reaction mixture was then partitioned with 2 O / diethyl ether. The aqueous phase was separated and then extracted twice with 400 ml diethyl ether.

The combined organic phases containing the α-bromo-diethyl carbonate were washed with 40 800 ml H 2 O 8302286

• V

7 1000 ml of a 1% aqueous sodium hydroxide sulfate solution 1000 ml of a saturated NaCl solution

The organic phase was dried over magnesium sulfate and then concentrated at low temperature, maximum 35 ° C, under reduced pressure to give the title product (60%) as a liquid which was initially colorless or slightly light brown.

The product was used directly in the esterification step of Example II.

Example II

25.08 g (0.181 mol) of finely ground anhydrous potassium carbonate are suspended in 200 ml of Ν, Ν-dimethylacetamide and 32.4 ml (0.3 mol) of methyl acetoacetate and 60.4 g (0.15 mol) of ampicillin trihydrate are added . The mixture is stirred rapidly at 20 ° C-25 ° C for 5 hours; after this time, 46.1 g (0.234 mole) of brothiethyl carbonate, 6 g (0.02 mole) of tetrabutyl ammonium bromide and 100 ml of Ν, Ν-dimethylacetamide are added.

The mixture is heated at 40 ° C-42 ° C for 10 hours with stirring; the reaction mass is poured into a mixture consisting of 1200 ml water and 400 ml n-butyl acetate.

The aqueous phase is collected and extracted with an additional 100 ml of butyl acetate.

The combined organic phases are washed twice with 100 ml of water each time. 150 ml of N HCl and 370 ml of water are added to the organic phase, which is subjected to a stirring treatment; the mixture is stirred at 22 ° C-23 ° C for 4 hours.

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

The combined organic phases are adjusted to a pH of 4 with a 10% aqueous solution of Na 2 CO 3, then 30 decolorizing carbon is added and filtered.

300 ml of n-butyl acetate and 80 g of sodium chloride are added to the aqueous filtrate. The organic phase is separated and the aqueous phase is extracted with 200 ml of n-butyl acetate. The phases reconstituted in n-butyl acetate are concentrated at low pressure at 40 ° C to a volume of about 300 ml. The product is crystallized at + 15 ° C for 15 hours. The product is filtered off, washed with 100 ml of n-butyl acetate and 100 ml of ethyl acetate. It is then dried under reduced pressure at 40 ° C for 24 hours.

40 Yield: 54.2 g (72%) 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - 8302286 8 *

α-amino-α-phenylacetamido) penicillanic acid with melting point 160-162 ° C (dec.) and properties according to the authentic hydrocloride sample. Example III

36.4 g (0.075 mol) of potassium N - (- 1-methoxycarbonylpropen-2-yl) 5 6- (D - (-) - α-amino-α-phenylacetamido) penicillate in a solution of 17.8 g ( 0.116 mol) α-chloro-diethyl carbonate and 3 g (0.01 mol) tetrabutyl ammonium brimide in 150 ml Ν, Ν-dimethylformamide are added. The temperature is raised to 45 ° C with stirring and kept at 45 ° -50 ° C for 5 hours.

When the heating is finished, the reaction mixture is poured into a mixture consisting of 300 ml of a 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture is stirred for 10 min, then the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The combined organic phases, after two washings with 75 ml of a 14% aqueous sodium chloride solution, are concentrated at low pressure until an oil is obtained.

The oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water; the resulting solution (pH 4.8) is brought to a pH of 1.5 with stirring by adding a total of 12 ml of 6 N HCl over 1 hour.

After the solution has been stored at ordinary temperature for an additional 1 hour, the tetrahydrofuran is removed at low pressure at 40 ° C, 150 ml of n-butyl acetate are added to the residual aqueous phase (150 ml) and then 15 g of sodium chloride are added.

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

The combined organic phases are concentrated under reduced pressure at 40 ° C to a volume of 120 ml.

The product is allowed to crystallize at 5 ° G for 15 hours.

The product is then filtered, washed with 50 ml of no-butyl acetate and 50 ml of ethyl acetate.

Then it is dried under reduced pressure at 40 ° C.

25.2 g (66.9%) of 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride, melting point 160-162 ° C, are obtained.

Analytical determinations: content: 97.82% rotation capacity: + 166.3 ° (c = 1, EtOH95 °) pH: 4.05 (2% solution in water) 40 moisture content: 0.82% 8302286 * «9 residual solvents: ethyl acetate 0.45; n-butyl acetate 0.98% IR and NMR spectra are standard residue ampicillin: 0.06%

Example IV

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

The mixture is stirred at 22 ° C-23 ° C for 3 hours, after which time a substantial fluidization of the mass can be observed.

Now 17.8 g (0.117 mol) of a-chlorodiethyl carbonate, 3 g (0.01 mol) of tetrabutyl ammonium bromide and 50 ml of Ν, Ν-dimethylformamide are added in that order.

The mixture is heated to 45 ° C-50 ° C for 5 hours with stirring and then stored at + 5 ° C for 15 hours.

The reaction mass is poured into a mixture consisting of 600 ml water and 200 ml n-butyl acetate and stirred until complete solution is obtained, the aqueous phase is collected and extracted an additional 50 ml n-butyl acetate.

The combined organic phases are washed twice with 50 ml of water each time. 75 ml of N HCL and 185 ml of water are added to the stirred organic phase; it is stirred at 22 ° C-23 ° C for 4 hours.

The aqueous phase is collected and the organic phase 25 is extracted with 50 ml of water. The combined aqueous phases are adjusted to a pH of 4 with a 10% solution of Na 2 CO 3, decolorizing charcoal is then added and filtered.

150 ml of n-butyl acetate and 40 g of sodium chloride are added to the filtrate containing water.

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

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

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

The product is filtered off and washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate.

It is dried under reduced pressure of 1.3 kPa in the presence of moisture at 25 ° C for 24 hours.

40 Yield: 20.8 g (55%) 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - 8302286 4 10

α-amino-α-phenylacetamido) penicillanic acid hydrochloride with a melting point of 159-161 ° C and properties according to an authentic sample. Example V

A mixture of 100 ml of acetone, 22.6 g (0.075 mol) of the potassium-5 salt of D (-) - N-methoxycarbonylpropen-2-yl-aminophenylacetic acid, 6.9 ml of 0.088 mol) ethyl chloroformate and 3 drops of N- methyl morpholine is stirred at a temperature of -20 to -30 ° C for 15 min. To this reaction mixture is added in one go a solution of 16.2 g of 6-amlno-penicillanic acid dissolved in 35 ml of water by the gentle addition of 7.6 g (0.075 mol) of triethylamine with stirring, after which it is the mixture is diluted with 90 ml of acetone and cooled to -20 ° C.

After stirring for 45 minutes, without any additional cooling, 23.4 g (0.117 mol) of α-bromo-diethyl carbonate, 3 g (0.01 mol) of tetrabutylammonlum-15 bromide and 250 ml of Ν, Ν-dimethylformamide are added in that order. The mixture is stirred at 25 ° C for 18 hours. After that time, the reaction mass is poured into a mixture consisting of 600 ml water and 200 ml nrbutylacetate and stirred until complete solution is obtained. The aqueous phase is collected and extracted with 50 ml of no-butyl acetate.

The combined organic phases are washed twice with 50 ml of water each time. 185 ml of water are added to the organic phase and 1 N HCl is added dropwise with stirring to a pH of 1.9. The mixture is stirred at 22-23 ° C for 4 hours.

The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The combined aqueous phases are adjusted to a pH of 4 with a 10% aqueous solution of Na 2 CO 3, activated carbon is added thereto and filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate.

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

The product is filtered off and washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate. It is dried at 25 ° C for 24 hours under a reduced pressure of 1.3 kPa.

Yield: 1.17 g of 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-40 amino-α-phenylacetamido) penicillanic acid hydrochloride, mp 8302286 r - Γ 11 of 159-161 ° C and properties (NMR, DLC ) according to an authentic sample.

Example Va

The method of Example V was repeated with the difference that the 6-aminopenicillanic acid was dissolved in 20 ml of water instead of 35.

Yield: 1.05 g of 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride as a white crystalline powder with a melting point of 148-151 ° C older decomposition and properties (TLC, IR) according to an authentic sample.

Example VI

6.25 g (0.045 mol) of finely ground anhydrous potassium carbonate are 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 are added.

The mixture is stirred rapidly at 20 ° C-25 ° C for 5 hours; after this time, 11.5 g (0.059 mol) of bromo-diethyl carbonate and 25 ml of dimethyl sulfoxide are added.

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

The aqueous phase is collected and extracted with an additional 100 ml of butyl acetate.

The combined organic phases are washed twice with 25 ml of water each time.

92.5 ml of water and 7.0 ml of NHCl are added to the stirred organic phase to a pH of 1.9, the mixture is stirred at 22 ° C-23 ° C for 2.5 hours.

The aqueous phase is collected and the organic phase is extracted with 25 ml of water.

The combined aqueous phases are adjusted to a pH of 4 with a 10% aqueous solution of Na 2 CO 3, then activated charcoal is added and filtered.

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

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

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

The product is filtered off and washed with 25 ml of n-butyl acetate and 12 ml of 8302286 ethyl acetate. It is dried under reduced pressure at 40 ° C for 3 hours.

Yield: 1.9 g of 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-ami-no-α-phenylacetamido) penicillanic acid with a melting point of 160-162 ° C and 5 properties according to an authentic sample of the hydrochloride ( for example IK: V 1790 cm (0, -Lactamcarbonyl).

The novel compound α-bromo-diethyl carbonate of the invention, new and inventive methods for its preparation and its use in the preparation of the ethoxycarbonyloxyethyl esters of 6-amLno-10 penicillanic acid, penicillins such as penicillin G, penicillin V and am-picillin, and cephalosporins, will now be described in more detail.

This aspect of the invention relates to improvements in and with regard to the preparation of α-bromo-diethyl carbonate of formula 3.

The C-bromo-diethylcarbonate of formula 3 may be used in the synthesis of ar- (ethoxycarbonyl) ethyl esters of 6-amino-penicillanic acid, penicillins and cephalosporins, for example the anti-20, according to a further aspect of the invention, which will be discussed later. biotic bacampicillin. Therefore, α-bromo-diethyl carbonate can be advantageously used in the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillin G, penicillin V and ampicillin.

According to the invention, two new and inventive methods, hereinafter referred to as Method A and Method B, are provided for the preparation of α-bromo-diethyl carbonate of formula 3.

A. The first of these methods, method A, comprises the steps: (a) reaction of an aldehyde of formula 6 with carbonyl bromide of formula 7 to form an α-bromo-bromoformate of formula 8 and (b) reaction of the ar-bromo-bromoformate of formula 8 with an alcohol of formula C 1 HgOH to form the desired arbromo-diethyl carbonate of formula 3.

Therefore, the method A according to the invention can be summarized by the reaction comparison with Fig. 2 of the formula sheet. The α-bromo-bromo-formate of formula 8 is itself a new compound and is provided according to another feature of the invention.

The reaction between the aldehyde, CH 3 CHO and carbonyl bromide is most suitably carried out in the presence of a catalyst containing, for example, a tertiary amine (eg, a tertiary aliphatic 8302286 13 ml amine, a tertiary mixed alkyl / arylamine or a tertiary aromatic amine), tertiary phosphine, amide, substituted urea or thiourea, phosphoric acid amide, tertiary oxonium or sulfonium salt or a quaternary ammonium or phosphonium salt. Examples of preferred catalysts for use in process A of the invention include pyridine, dimethylformamide, tetra-n-butyl urea, hexamethylphosphoric acid triamide, and benzyl trimethyl ammonium bromide.

The catalyst is suitably used in an amount of from 0.05 to 0.5, preferably from 0.05 to 0.15 moles of catalyst per mole of aldehyde.

The reaction between the aldehyde and the carbonyl bromide is suitably carried out in the presence of a solvent, which may be, for example, an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorobenzene. The reaction between the aldehyde and the carbonyl bromide is suitably carried out at a temperature of -40 to 120 ° C, preferably 0-40 ° C. The carbonyl chloride will usually be used in molar excess with respect to the aldehyde, suitably in a molar excess of from 10 to 100%, preferably from 20 to 50%.

The intermediate bromo-bromo-formate of formula 8, prepared in step (a) of process A of the invention does not need to be isolated prior to reaction with the alcohol C 2 H 5 OH and in fact it is generally preferred not to do so.

Therefore, according to a preferred embodiment of the invention, the reaction mixture obtained in step (a) is freed from excess carbonyl bromide, for example by heating under reduced pressure or by purging with nitrogen. The crude α-bromo-bromo-formate-containing reaction mixture is then reacted with an excess of the alcohol. The reaction can be conveniently carried out by refluxing the mixture until hydrogen bromide development ceases or by adding a tertiary base to the mixture and heating it if necessary. Any remaining catalyst from step (a) or its complex with carbonyl bromide 35 does not appear to interfere with the subsequent reaction and appears favorable in some cases.

The crude cc-bromocarbonate obtained can be separated from the reaction mixture in the usual manner by fractional distillation under reduced pressure.

40 Method A is illustrated in Examples VII and VIII.

8302286 · / v 14 B. The second method, Method B, of the invention for the preparation of α-bromo-diethyl carbonate will now be described. Method B is illustrated in Example IX.

Method B of the invention relates to improvements in 5 and to the preparation of α-bromo-diethyl carbonate according to a modification of the Finkelstein reaction, ie, by reaction of an alkyl chloride on aryl chloride (or a compound containing such a group) with an alkali metal bromide or an alkali metal iodide to replace the chlorine substituent with resp. a bromine or iodine-10 substituent; or by the reaction of an alkyl bromide or arylalkyl bromide (or a compound containing such a group) with an alkali metal iodide to replace the bromine substituent with an iodine substituent.

The Finkelstein reaction is suitable since the iodides obtained are generally more reactive than the bromides, which in turn are more reactive than the chlorides. In some instances, only catalytic amounts of the alkali metal bromide or iodide are necessary and the resulting more reactive species reacts with the desired substrate to regenerate the alkali metal bromide or iodide to continue the reaction.

Not all optionally substituted alkyl chlorides or arylalkyl chlorides undergo the reaction and, in particular, it has proved difficult to carry out the reaction with α-chloro esters and α-chloro carbonates, ie compounds in which the chlorine atom is bonded to a carbon atom 25 in turn is bound to one of the ends of a -C (0) -0 group. An example of such α-chlorocarbonate is α-chloroethyl ethyl carbonate, which is a known intermediate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid and of penicillins, as described above.

According to the present invention, it has now been found that this problem can be overcome by carrying out the reaction using a two-phase solvent system, one phase being water and the other phase being water-immiscible organic solvent, in the presence of a phase transfer catalyst.

According to process B of the invention, there is therefore provided a process for the preparation of α-bromo-diethyl carbonate by reaction of α-chlorodiethyl carbonate with an alkali metal bromide, which process is characterized in that the reaction is carried out in a two-phase solvent system comprising water and a water-immiscible organic solvent contains in the presence of a phase transfer catalyst.

Suitable organic immiscible organic solvents for use according to the invention include halogenated hydrocarbons, for example halogenated alkanes such as dichloromethane and aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts, for example, tetraalkylammonium salts such as cetyl trimethyl ammonium bromide and tetra-n-butylammonium hydrogen sulfate. The alkali metal bromide can be, for example, sodium, potassium or lithium bromide, with lithium bromide being preferred.

Therefore, in process B of the invention, chloroethyl diethyl carbonate of formula 9 is reacted in a two-phase solvent system, one phase being water and the other phase being a water immiscible organic solvent, reacted with an alkali metal bromide of formula 15, which formula R is an alkali metal, such as Na, K and Li, to form the compound of formula 3.

As mentioned above, the preferred alkali metal R is Li, so that LiBr is a preferred reagent of formula 10.

In connection with method B, it has been found that lithium bromide can be advantageously used in a conventional Finkelstein reaction (i.e., using a single phase organic solvent system), for example to halogenate an α-chlorocarbonate.

This method is mentioned in Example X.

Accordingly, the present invention also provides, according to a further embodiment thereof, the process for the preparation of α-bromo-diethyl carbonate, characterized in that α-chloro-diethyl carbonate is reacted with lithium bromide.

Suitable solvents for such a process include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and lower aliphatic amides of formic acid.

The aspect of the invention which relates to the use of the new compound α-bromo-diethylcarbonate for the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins will now be described.

In summary, this aspect of the invention includes: 1. the use of α-bromo-diethylcarbonate in the preparation of the ethoxycarbonylethyl esters of 6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin, and cephalosporins, 2. a process for preparing the ethoxycarbonyloxy 40 of 6-aminopenicillanic acid, penicillins and cephalosporins, characterized 8302286 * 16 by a reaction of 6-aminopenicillanic acid, the penicillin or the cephalosporin, or a 20 thereof thereof, with α-bromo-diethylcarbonate to form the ethoxycarbonyloxyethyl ester of reap, aminopenicillanic acid, the penicillin and the cephalosporin, 5 3. the improvement in the esterification reaction between an α-halodiethyl carbonate and 6-apa, a penicillin or a cephalosporin, the improvement comprising the use of a quaternary ammonium compound in the esterification step, wherein this quaternary ammonium compound is present in an amount of 1-25, preferably ur 1-10% of the 10 equimolar amount with respect to the amount of 6-apa, penicillin or cephalosporin.

The ethoxycarbonyloxyethyl ester in particular of 6-apa and of penicillin G are used, as known in the art, for the preparation of any desired, for example, partially synthetic penicillin-lineester, by acylation of the 6-amino group after side chain removal in, for example, the penicillin G ester obtained.

This aspect of the invention relates to improvements in and with regard to the preparation of esters by the reaction of carboxylic acid salts with α-bromo-diethyl carbonate.

The reaction of metal salts of carboxylic acids with alkyl halides or arylalkyl halides to form esters is known.

However, the yields are not particularly high and the reaction generally requires forcing conditions such as high temperatures and / or extended reaction times. These forcing conditions limit the synthetic utility of the reaction and its commercial 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 in place of a metal salt thereof for the preparation of esters of penicillins and cephalosporins.

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

According to the present invention, it has now been found that it is not necessary to use that quaternary ammonium salt in a stoichiometric amount with respect to the carboxylic acid, ie 6-apa, penicillin or cephalosporin, but that less than stoichiometric amount with respect to the carboxylic acid, for example the 6-apa, penicillin or cephalosporin, will be sufficient.

According to the invention there is therefore provided a process for the preparation of an ethoxycarbonyloxyethyl ester of 6-apa, a penicillin or a cephalosporin by reaction of a metal salt of the 6-apa, penicillin or cephalosporin with the o-halo-diethyl carbonate in the presence of a quaternary ammonium salt (other than a salt of the carboxylic acid), wherein the quaternary ammonium compound is present in a less than stoichiometric amount with respect to the 6-apa, penicillin or cephalosporin.

According to the invention, between 1% and 25% of an equivalent of the quaternary ammonium salt is used for each equivalent of the metal salt of the carboxylic acid, and more preferably, between 1% and 10% of an equivalent of the quaternary ammonium salt is used.

The quaternary ammonium salt of the carboxylic acid is suitably prepared by reacting a metal salt of the carboxylic acid with a quaternary ammonium salt of an acid other than the carboxylic acid, usually an inorganic acid such as hydrogen chloride, hydrogen bromide or sulfuric acid.

Suitable metal salts of carboxylic acids for use in the present aspect of the invention (either as precursors of the quaternary ammonium salt of the carboxylic acid or as such) are alkali or alkaline earth metal salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salt and of acids other than the carboxylic acid (for use either as precursors of the quaternary ammonium salts of the carboxylic acid or as such) are, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethyl ammonium bromide and quaternary piperidinium pyridium pyridinium pyridine. Suitable halides include 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 include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and diethyl sulfoxide. Also, when no solvent is used, an excess of the ester-forming halide can be used, especially when it is a liquid at the temperature of the reaction.

In the aspect of the invention described above, which relates to the use of ci-bromo-diethylcarbonate in the preparation of ethoxycarbonyloxyethyl esters of 6-apa, penicillins and cephalosporins, the use of a catalyst is optional. About equivalent amounts of the quaternary ammonium salt of the carboxylic acid and the ester-forming halide can be used in the reaction. Preferably, between 5% and 100% excess of the ester-forming halide is used for each equivalent of the salt of the carboxylic acid, and more preferably, the excess is used between 20% and 60% of the ester-forming halide.

The improvements in the esterification processes of the invention are particularly suitable for the preparation of the esters of 6-apa, penicillins and cephalosporins and, therefore, according to a preferred embodiment of the invention, may contain the carboxylic acid of the formula 11 or 12, wherein R? hydrogen atom or an acyl group, in particular a substituted acetyl group such as a phenylacetyl, α-amLno-20 phenylacetyl, α-amino-p-hydroxyphenylacetyl, phenoxyacetyl, α-carboxy-phenylacetyl or α-carboxy-3-thi enylacetyl group, or, when the carboxylic acid has formula 12, a group of formula 13, wherein B? a hydrogen atom or an amino group protecting group, such as a benzyl oxycarbonyl, trimethylsilyl or tert-butyloxycarbonyl group, and r 2 is a hydrogen atom, an alkyl group (eg a methyl group), a substituted alkyl group, eg hydroxymethylene, alkoxy or arylalkoxymethylene - or acetoxymethylene group) or an acetoxy or substituted acetoxy group (for example, an alkyl acetoxy, arylacetoxy or arylalkylacetoxy group or the group CgHg.CHOH. CO-).

In the preparation of esters of penicillins and cephalosporins of the invention, the ester-forming halide is an α-halo-dialkyl carbonate of the formula ch3-ch (x) -o-co-o-ch2-ch3 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 cephalosporins, the 40 quaternary ammonium salt used is tetra and butylammonium bromide.

8302286 «* 19

Example VII

A mixture of 44 g (1 mole) of acetaldehyde, 300 ml of tool tetrachloride and 235 g (1.25 mole) of freshly distilled carbonyl bromide was cooled to 0 ° C and by external cooling over the 1 hour period of 11.9 g (0.15 mol) of pyridine are maintained at this temperature.

The mixture was allowed to warm to ambient temperature then warmed to 50 ° C and maintained for a period of 3 hours during which a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C gave a partially solid oily mass, which readily dissolved in 92 g (2 mol) of ethanol under reflux upon heating and heating. After heating for 2 more hours under reflux, the excess ethanol was removed under reduced pressure and the residue was triturated with 100 ml of water and 200 ml of dichloromethane.

Separation of the organic layer and fractional distillation yielded 130 g (66% yield) of pure ethyl o-brocmethyl carbonate with a boiling point of 90-92 ° C at 6.0 kPa and identical in all respects to an authentic sample »

Example VIII

A mixture of 44 g (1 mole) of acetaldehyde, 300 ml of dichloromethane and 17.9 g (0.1 mole) of hexamethylphosphoric acid triamide was cooled to -10 ° C and 207 g (1.1 mole) of newly distilled carbonyl bromide was gradually introduced over a period of time. of 4 hours during which time the temperature rises to 10 ° C tons.

Then, the mixture was heated under gentle reflux (about 40 ° C) for 4 hours. Still under reflux, 69 g (1.0 mol) of ethanol were carefully added over a 1 hour period and refluxing was continued for an additional 1 hour.

Fractional distillation of the resulting mixture directly yielded 114 g (58% yield) of pure ethyl α-bromoethyl carbonate.

The authenticity of the ethyl α-bromoethyl carbonate formed was confirmed by analysis and independent synthesis in the following manner.

118 g (1.0 mol) diethyl carbonate was stirred and heated to between 110 ° C and 120 ° C and exposed with a 150 Watt tungsten lamp. 96 g (0.6 mol) of bromine were added dropwise over a period of 3 to 4 hours and at such a rate that the mixture did not discolour beyond 40 a light orange color.

8302286 20

After the addition of bromine was completed, the mixture was cooled to ambient temperature and 20 g of sodium bicarbonate were added.

Distillation and fractionation of the resulting mixture gave 84.2 g (yield 70%) of authentic ethyl α-bromoethyl carbonate, bp 87-88 ° C at 5.3 kPa.

Example IX

A mixture of 43 g (0.5 mol) of lithium bromide, 15.3 g (0.1 mol) of ethyl 0-chloroethyl carbonate, 100 ml of water, 100 ml of dichloromethane and 1.5 g of cetyl trimethyl ammonium bromide was stirred at ambient temperature for 24 hours stirred. The aqueous layer was removed and replaced with a fresh solution of 26 g (0.3 mol) of lithium bromide in 40 ml of water containing 1 g of cetyl trimethyl ammonium bromide. After stirring for an additional 24 hours, during which time the temperature rose to 35 ° G, the organic layer was separated, dried and distilled under reduced pressure to form, after repeated fractionation, the new compound ethyl α-bromoethyl carbonate (15.0 g, yield 76%) with a boiling point of 90-92 ° C at 4.65 kPa.

Found: C 30.7 H 4.8 Br 40.1% 20 Calculated: C 30.5 H 5.6 Br 40.6%

The NMR spectrum showed the following peaks: 1.2 - 1.6 (3H, triplet) -CH? .CH ^ 2.0 - 2.2 (3H, doublet) -CH.CH ^ 4.1 - 4.5 (2H, quartet ) -CHp.CHq 25 6.5-6.8 (1H, quartet) -CH.CH3

Example X.

17.4 g (0.2 mol) of lithium bromide were dissolved in 150 ml of dimethylformamide and the mixture was cooled to ambient temperature. 30.5 g (0.2 mol) of ethyl achloroethyl carbonate were added and the mixture was stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate was distilled under reduced pressure to obtain ethyl α-bromoethyl carbonate in a yield of 76%, based on recovered ethyl α-chloroethyl carbonate, after careful fractionation.

Example XI

The authenticity of the previous new compound ethyl α-bromoethyl carbonate was confirmed by the following independent synthesis:

A mixture of 35 g (0.3 mole) of diethyl carbonate in 50 ml of carbon-40 tetrachloride and 0.1 g of α-azoisobutyronitrile (AIBN) was refluxed gently and 28.6 g (0.1 mol) dibromodimethylhydantoin were heated in small fractions over a period of 8 hours together with a further 8 x 0.05 g AIBN: Care should be taken to ensure that free bromine does not accumulate in the reaction mixture. At the end of the reaction, the mixture was subjected to fractional distillation under reduced pressure to obtain pure 32.3 g (82% yield) of ethyl or bromoethyl carbonate, which was identical in all respects to the product of the examples. IX and X.

Example XII

Benzylpenicillin ethoxycarbonyloxyethyl ester

A mixture of 7.4 g (20 mmol) of potassium penicillin G, 4.6 g (30 mol) of ethyl α-chloroethyl carbonate, 0.8 g (2.5 mmol) of tetra-n-butylammonium bromide and 80 ml of acetone was stirred and heated under reflux for 4 hours. Excess acetone was removed under partial reduced pressure and the residue triturated with ice cold water and methyl isobutyl ketone. Evaporation of the dried methyl isobutyl ketone under reduced pressure gave a partially crystalline oil (3.8 g) which, after trituration with ethanol, separated 0.9 g of white crystals of the a- (ethoxycarbonyloxy) ethyl ester of penicillin G with a purity from 98-99% by high pressure liquid chromatography.

Found: C 43.0 H 7.4 N 7.7%

Calculated: C 43.4 H 7.4 N 8.0%

Example XIII

Benzylpenicillin ethoxycarbonyloxyethyl ester

The previous experiment of Example XII was repeated using 5.9 g (30 mmol) of ethyl α-bromoethyl carbonate instead of ethyl α-chloroethyl carbonate, whereby 6.0 g of a partly crystalline oil were obtained after evaporation of the methyl isobutyl ketone. 30 gene. Trituration of this oil with warm ethanol followed by cooling gave white crystals (2.5 g, yield 25%) of the α- (ethoxycarbonyl-oxy) ethyl ester of penicillin G.

Example XIV

Benzylpenicillin ethoxycarbonyloxyethyl ester 35 25.08g (66.7mmol) potassium benzylpenicillinate, 0.50g (6.0mmol) sodium hydrogen carbonate and 2.15g (6.67mmol) tetrabutyl ammonium bromide were gently stirred in 41ml dichloromethane and mixed to 40 ° C heated. When this temperature was reached, 17.16 g (86.7 mmol) of α-bromo-diethyl carbonate were added and the suspension was stirred for 40 hours. 30 ml of water were added, followed by an anoric acid to a pH of about 5. The mixture was stirred for about 4 hours, during which time 4% sodium hydroxide was added to adjust the pH between 2.5 and 3.0. 50 ml of dichloromethane were then added and the mixture was allowed to separate for 5 minutes. The organic phase was washed with 65 ml of water and then evaporated under reduced pressure. The oily product thus obtained was dissolved in 100 ml of dichloromethane and evaporated again. The residual oil was dissolved in dichloromethane to a total volume of 100 ml.

High pressure liquid chromatography analysis of the dichloromethane solution showed a 96-97% yield of benzylpenicillin ethoxycarbonyloxyethyl ester.

Example XV

Benzylpenicillin ethoxycarbonyloxyethyl ester 15 5.02 g, 13.3 mmol) potassium benzyl penicillinate and 2.99 g (38.3 mmol) potassium hydrogen carbonate in 13.5 ml dimethyl sulfoxide were gently stirred in an ice bath. 3.70 g (18.6 mmol) of a-bromo diethyl carbonate were added over a 30-40 minute period using a syringe pump. Stirring was continued while the reaction mixture was kept in the ice bath. High pressure liquid chromatography analysis showed that a yield of about 70% of the benzylpenicillin ethoxycarbonyloxyethyl ester was obtained in 5-10 min.

Example XVI

Benzylpenicillin ethoxycarbonyloxyethyl ester 47.03g (125 mol) potassium benzylpenicillinate, 0.94g (11mmol) sodium hydrogen carbonate and 2.01g (6.25mmol) tetrabutyl ammonium bromide were gently stirred in 77ml acetone and heated to 40 ° C. When this temperature was reached, 26.06 g (131 mmol) of a-bromoethyl ethyl carbonate were added and the suspension was stirred for 4.5 hours. 56 ml of water were added, followed by an inorganic acid to a pH of about 5. The mixture was stirred for about 3 hours, during which time sodium hydroxide (4%) was added to maintain the pH between 4.5-4.8 . Then 100 ml of butyl acetate was added and the mixture was allowed to separate for a few minutes. The organic phase was washed with 80 ml of water and then evaporated under reduced pressure. The residual oily product was dissolved in dichloromethane to a total volume of 250 ml.

High pressure liquid chromatography analysis of the dichloromethane solution showed a 98-99% yield of benzylpenicillin ethoxycarbonyloxy-40 ethyl ester.

8302286 & s * 23

Example XVII

Esterification of apeicillin "dane" salt with ethyl acetoacetate according to Example IV.

Results: 5 obtained 16.1 g of a white crystalline product melting point 144-148 ° C (Tottoli apparatus) IR / DLC conforming to k.f. 0.35% pH 3.55 (2% solution in water) 10 content 95.2% total residual solvent 3.5%

Modifications: the addition of chloro-diethyl carbonate is carried out in two stages: first stage 9 g immediately; second stage another 9 g after 2 hours.

Heat for 3 hours to 45 ° C.

Results: obtained 13.7 g of crystalline beige product melting point 143-146 ° C (Tottoli apparatus) 20 IR / DLC conforming to k.f. 0.2% pH 3.43 (2% solution in water) content 94.8% residual solvents 2.6% ♦ 8302286

Claims (33)

Process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid of formula 1, 5 characterized in that a) ampicillin, preferably in the form of an alkaline salt, reacted with a reactive derivative of acetoacetic acid to form the corresponding enamine of formula 2, wherein: R 1 represents an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R 1 hydrogen, an alkyl group with 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, an aralkyl group, an alkoxy group of 1 to 4 carbon atoms, an aryloxy group or an amlno group , and X represents an alkali metal, an alkaline earth metal or an organic base; b) reacting the resulting intermediate with an α-bromo-diethylcarbonate of formula 3 to form the corresponding ester of formula 20, wherein R 1, R 2 and R 2 have the above meanings, and c) hydrolyses gently in an acid medium to form the compound of formula 1. 2. Process according to claim 1, characterized in that the basic salt of ampicillin is obtained by converting ampicillin trihydrate according to a known method in a polar solvent, preferably Ν, Ν-dimethylformamide. 3. Process according to claim 1, characterized in that the enamine of formula 2 is formed by reacting the basic salt of ampicillin with an alkyl acetoacetate in an aprotic polar solvent at a temperature between 0 ° C and 60 ° C and for a period between 2 and 8 hours. 4. Process according to claim 3, characterized in that the enamine of formula 2 is formed in the presence of an organic base or a basic carbonate. Process according to claim 3, characterized in that the alkyl acetoacetate used is methyl or ethyl acetoacetate in an amount of 10-50% more than the stoichiometric ratio. 6. Process according to claim 3, characterized in that the aprotic polar solvent used is Ν, Ν-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran and / or dioxane 8302286. Process according to claim 3, characterized in that the enamine is formed at a temperature between 20 ° C and 30 ° C. 8. Process according to claim 3, characterized in that the reaction is carried out in a time period of 3 hours. 9. Process according to claim 1, characterized in that the esterification reaction of the enamine of formula 2 is carried out by adding ae-bromo-diethyl carbonate to the reaction mixture, the reaction being carried out at a temperature between 15 ° C and 80eC and 10 lasting from 1 hour to 24 hours. 10. Process according to claim 9, characterized in that the esterification is carried out in the presence of a catalyst. Process according to claim 9, characterized in that a reaction temperature is used between 45 ° C and 55 ° C. 12. Process according to claim 9, characterized in that the esterification reaction is carried out in a period of 5-10 hours. Process according to claim 10, characterized in that the catalyst used is quaternary ammonium salts, alkali metal bromides, alkali metal iodides and cyclic ethers. Process according to claim 13, characterized in that tetrabutyl ammonium bromide is used as the catalyst. Process according to claim 1, characterized in that the hydrolysis is carried out with dilute hydrochloric acid after isolation of the ester of formula 4. Process according to one or more of claims 1 to 8, characterized in that a) the enamine of formula 2 is reacted with a compound of formula 5, wherein Z is Cl or J, and b) the reaction between the compounds of formulas 2 and 5 in the presence of a catalyst. Process according to claim 16, characterized in that the catalyst used is quaternary ammonium salts, alkali metal bromides and iodides and cyclic ethers. 18. Process according to claim 17, characterized in that tetrabutyl ammonium bromide is used as the catalyst. Process according to claim 10, 11, 12, 13, 14, 16 and 17, characterized in that the catalyst is used in an amount of 0.005 to 0.10 mol, preferably 0.01 to 0.10 mol per mole of resp. the compound of formula 3 and 5. 20. The compound of formula 3. 8302286 - f \ 21. The compound of formula 8. 22. Process for preparing the compound of formula 3, characterized in that a) an aldehyde of formula 6 is reacted with carbonyl bromide of formula 7 to form a compound of formula 8, after which the compound of formula 8 with C2H5OH to form a compound of formula 3. Process according to claim 22, characterized in that the reaction is carried out in the presence of a catalyst. 24. Process according to claim 23, characterized in that the catalyst is used in an amount of 0.05 to 0.5, preferably from 0.05 to 0.15 mol per mol of the compound of the formula 6. 25. Process according to claim 24, characterized in that a tertiary amine, a tertiary phosphine, an amide, a substituted urea or thiourea, a phosphoric acid amide, a tertiary oxonium or sulfonium salt or a quaternary ammonium or phosphonium salt are used as catalyst. . 26. Process for preparing a compound of formula 3 by reacting the compound of formula 9 with an alkali metal bromide of formula 10, wherein formula R is an alkali metal, preferably lithium, to form the compound of formula 3, with the characterized in that the reaction is carried out in a two-phase solvent system containing water and a water-immiscible organic solvent, in the presence of a phase transfer catalyst. 27. Process according to claim 26, characterized in that a halogenated hydrocarbon or an aromatic hydrocarbon is used as the organic solvent. 28. Process according to claim 27, characterized in that dichloromethane is used as the organic solvent. 29. Process according to claim 26, characterized in that a quaternary ammonium salt is used as the phase transfer catalyst. 30. Use of α-bromo diethyl carbonate in the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins. 31. A process for preparing the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporins, by reacting 6-aminopenicillanic acid, the penicillin or the cephalosporin, or a salt thereof, with a α-halo-diethylcarbonate, which is used as a catalyst apply a quaternary ammonium salt. The process according to claim 31, characterized in that the 8302286 quaternary ammonium salt is used in an amount of 1Z to 25%, preferably 1% to 10%, of an equivalent of the quaternary ammonium salt for each equivalent of the 6 -apa, penicillin or cephalosporin. 33. Process according to claim 32, characterized in that tetra-n-butylammonium bromide is used as the catalyst. 8302285