FI86182B - Method for production of the 1-ethoxycarbonyloxyethyl ester of 6-(D-(-)-&alpha-amino-&alpha- phenylacetamido)penicillanic acid - Google Patents

Description

1 86182

Process for the preparation of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester 5 Separated from application 832363

The present invention relates to a new process for the preparation of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester of formula 10 / CHa CH-CO-NH-CH-CH cC (I) I III ch3 15 NH, CO - N - CH - C00 - CH - 0 - C00C, H5 CH3

Said compound I is an ampicillin ester which is very important from a therapeutic point of view because it is well absorbed when administered orally and provides much higher concentrations of ampicillins in the blood than the ampicillin itself.

This ester is separated in the form of the hydrochloride and is called bacampicillin hydrochloride.

Based on previously known methods (cf. BE patent 772,723), bacampicillin hydrochloride ‘30 can be prepared synthetically by the following two methods:. A) By reacting potassium benzylpenicillin with α-chlorodiethyl carbonate in organic solvents or in a 70% aqueous solution of dioxane in the presence of sodium bicarbonate. via an imino ether to give 6-aminopenicillanic acid 1-ethoxycarbonyloxyethyl ester, which is separated as the hydrochloride 40 Subsequent condensation of the latter intermediate 2 86182 with D - (-) - α-phenylglycine gives a compound of formula I. .

B) Esterification of 6- (D - (-) - α-azido-α-phenylacetamido) penen-5-silanoic acid with α-chlorodiethyl carbonate in a polar solvent.

Thereafter, catalytic hydrogenation of 6- (D - (-) - α-azido-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxy-10-ethyl ester gives a compound of formula I.

As can be seen, these methods are very complex because they involve the use of several raw materials and long processing times.

In addition, U.S. Pat. No. 4,072,677 discloses a process for preparing an ester of formula I. According to this method, an aqueous solution of enamine-protected ampicillin of formula II below is reacted with a solution of ethoxycarbonyloxyethanol or a reactive esterifying derivative thereof in a water-immiscible organic solvent in the presence of a phase transfer catalyst. Working in the two-phase system 25 is complex and requires additional process steps, such as the removal of the acetone used to form the enamine. under its reduced pressure.

:. ·. It is an object of the present invention to provide such a process for the preparation of bacampicillin using am- !! picillin as a starting material, which is easier to implement on an industrial scale, giving the desired product in high purity.

The process according to the invention for the preparation of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid of the formula I 1-ethoxycarbonyloxyethyl ester is characterized in that 3 86182 a) ampicillin, which is preferably in the form of an alkali salt , is reacted with a reactive derivative of acetoacetic acid in an aprotic, polar solvent to form the corresponding enamine of formula 5 / - \ / S \ U> CH - CO - NH - CH - CH (II) V = / | | | | CH3

10 N CO - N - CH - COOX

R1-C H

a 11

R2-C O

15 V

i.

Wherein R1 is an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, R3 is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or an amino group, and X is an alkali metal, alkaline earth metal or organic b) adding a quaternary ammonium salt as an esterification catalyst and α-chlorodiethyl carbonate of formula

Cl -CH-O-C00C2H5 (III) •: 30 | : CH3 to form the corresponding ester of formula V: 35 / V "W / I III ^ CH3 N CO - N - CH-C00-CH-O-C00C2H5

: ·: / \ I

... 40 R1-C H CH3

R2-C O

'r 45 | R 3 (IV) 4 86182 wherein R 1, R 2 and R 3 are as defined above, and c) a careful hydrolysis is carried out in a manner known per se in an acidic medium to form a compound of the formula I.

5

The use of an esterification catalyst considerably shortens the reaction times and results in high product yields as well as a higher degree of purity.

For example, tetrabutylammonium bromide can be used as the esterification catalyst.

The catalyst can be used in an amount ranging from 0.005 to 0.10 moles per 1 mole of the compound of formula III, up to amounts equimolar with the compound III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of 0.01 to 0.10 moles per 1 mole of compound III.

Illustrative examples of R, R and R are as follows: alkyl: CH3, C2H5, n-C3H7, i-C3H7, n-C4H9 alkoxy (R3 only): OCH3, OC2H5, OCH2CH2CH3, OCH (CH3) 2, CH2 ) 3CH3 • .25 The radical X is selected from groups well known in the art, such as: alkali metal: Na, K * · * · 'alkaline earth metal: Ca, Mg ·.'. : organic base: organic bases known from the synthesis of penicillins, for example tertiary amino groups, triethylamine, ethylpiperidine and methylmorpholine.

• ·. ·; ·. In a preferred embodiment of the invention, the group protecting the amino group of ampicillin is a 1-methoxycarbonyl-propen-2-yl group or a 1-ethoxycarbonyl-propen-2-yl group, wherein the preferred intermediate of formula II is the sodium or potassium salt of N- (1-methoxycarbonylpropen-2-yl) penicillanic acid and N- (1-ethoxycarbonylpropen-2-yl) penicillanic acid, respectively (R1 = methyl; R 2 = methyl; R 3 = methoxy or ethoxy and X = Na or K).

Intermediate IV is stable in a neutral or alkaline medium, while in an acidic medium it is possible to deprotect the amino group simply, rapidly and selectively.

More specifically, the process according to a preferred embodiment of the invention comprises the steps of - converting ampicillin trihydrate in a polar solvent, for example N, N-dimethylformamide, to a salt, for example a potassium salt, and then reacting the corresponding enamine (II) with an acetoacetic acid derivative, for example with methyl acetoacetate, - addition of an esterification catalyst, preferably tetrabutylammonium bromide, -butyl acetate / water,. . - recovery of bacampicillin hydrochloride by saturation in the aqueous phase with, for example, sodium chloride and extraction with a suitable solvent such as n-butyl acetate, - concentration of the solution under reduced pressure in n-butyl acetate to crystallize the product to very pure, whereupon the product is separated.

____: Among the main advantages of the process according to the invention, the most important is that with this process it is possible to obtain bakampicillin hydrochloride in practically one treatment and in high purity.

6 86182

In reality, the impurities present in the product obtained by the process according to the invention are negligible in comparison with the previously known processes.

5 Another important advantage is that ampicillin trihydrate, a known antibiotic and easily obtained in pure form and at low cost, is used as a starting material.

Intermediate (II) can be readily prepared as described, for example, in GB 991,586, in more than 95% yield by reacting ampicillin trihydrate with methyl or ethyl acetoacetate using this 10-50% higher amount compared to the stoichiometric amount of the organic base. or in the presence of an alkali metal carbonate such as potassium carbonate.

As the aprotic, polar solvent, for example, N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxane can be used.

In order to complete the reaction, it is sufficient to keep the components of the mixture in contact with each other at a temperature between 0 and 60 ° C, preferably between 20 and 30 ° C, for 2-8 hours, preferably 3 hours.

The esterification reaction takes place after the addition of α-chlorodiethyl carbonate to this mixture at a temperature between 15 and -30 ° C, preferably between 45 and 55 ° C, for 1-24 hours, preferably. within 5 to 10 hours.

Under the lightest and most suitable conditions for industrial purposes, the esterified enamine (IV) is separated by diluting the reaction mixture with water and then extracting with a suitable solvent which is immiscible with water, for example n-butyl acetate.

Il 7 86182

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

5

Upon addition of sodium chloride, compound (I) separates from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example n-butyl acetate.

When the organic phase is concentrated under reduced pressure at 40 ° C until the volume is small, crystallization of the compound of formula (I) takes place.

The crystallized product is separated by filtration, washing and a diatomaceous earth in a vacuum.

According to the invention, it is not necessary to use the quaternary ammonium salt in a stoichiometric amount relative to ampicillin, but less than the stoichiometric amount is sufficient.

According to the invention, 1-25% of 1 equivalent of a quaternary ammonium salt per equivalent of the metal salt of ampicillin can be used, and even more preferably. 1-10% of the equivalent amount of quaternary ammonium salt; calculated on the basis of.

Suitable metal salts of ampicillin include alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salts of ampicillin include, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and - | cetyltrimethylammonium bromide, and quaternary pyridinium salts such as cetylpyridinium bromide.

The quaternary ammonium salt of ampicillin is conveniently prepared by reacting the metal salt of ampicillin with a quaternary ammonium salt of the acid. The acid is usually • 35 8 86182 a mineral acid such as hydrochloric, hydrobromic or sulfuric acid.

According to the invention, 5-100% of an excess of 5 α-chloro-diethyl carbonate per equivalent of ampicillin salt is preferably used, and even more preferably this excess is 20-60%.

The following example illustrates the invention.

10

Example 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 anhydrous potassium carbonate in 100 ml of N, N dimethylformamide.

The mixture was kept under stirring at 22-23 ° C for 3 hours, after which time considerable fluidization of the pulp could be observed.

17.8 g (0.117 mol) of α-chloro-diethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 50 ml of N, N-dimethylformamide were then added in this order.

. 25

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

The reaction mass was poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate and was therefore stirred until complete dissolution, the aqueous phase was collected and extracted with a further 50 ml of n-butyl acetate.

Again, the combined organic phases were washed twice each time with 50 ml of water. 75 ml of 1N HCl and 185 ml of water were added to the organic phase while stirring, and stirring was continued at 22-23 ° C for 4 hours.

The aqueous phase was collected and the organic phase was extracted with 50 ml of water. The recombined aqueous phases were adjusted to pH 4 with 10% aqueous Na 2 CO 3, then bleached carbon was added and 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 was extracted with 100 ml of n-butyl acetate.

15

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

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

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

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

Yield: 20.8 g (55%) of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride, m.p. 159-161 ° C, the properties of which corresponded to the authentic sample.

Results of esterification of ampicillin salt with ethyl acetoacetate according to the above example 35

Yield: 16.1 g of a white crystalline product

Sp. 144-148 ° C (Tottoli apparatus) IR / TLC corresponds to product 10 861 82 KF 0.35% pH 3.55 (2% aqueous solution)

Koe T.Q. 95.2% Residual solvents 5 total 3.5%

transformations:

The addition of chloro-diethyl carbonate was performed in two phases: 10

First phase 9 g immediately, second phase, another 9 g after 2 hours. Heated at 45 ° C for 3 hours.

Results: 15 Yield: 13.7 g of crystalline yellowish product

Sp. 143-146 ° C (Tottoli apparatus) IR / TLC corresponds to KF 0.2% pH 3.43 (2% aqueous solution) 20 Experiment T.Q. 94.8% Residual solvents 2.6%

II

11 86182 For the preparation of 1-ethoxycarbonyloxyethyl esters of 6- (D- (-) -. Alpha.-amino-.beta.-phenylacetamido) penicillans 5 (D - (-) - α-amine-ηο-α-phenylacetamido) penicillan with the formula 10 / H, </ \ cH-CO-NH-CH - CH cC (I) \ = / 1 III CH3 15 NH2 CO - N - CH - COO - CH - O - COOC2Hs CH3 These are in the form of an ampicillin ester which is extremely extreme in terms of the therapeutic effect of the absorber in the oral administration and in the case of amphicillin and the ampicillin.

The ester is isolated in the form of the hydrochloride and bacampicillin hydrochloride.

The reaction process of the bacampicillin hydrochloride (Jämför BE patent patents 772723) can be synthesized according to the following method:::: A) and dioxane in water and sodium bicarbonate. The title 1-ethoxycarbonyloxyethyl ester of benzylpenicillin - 35 cycles of the reaction of the phenylmethyl ester, via iminochloride iminoethers, and the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, preferably isolated from hydrogen. The genome is then condensed from the system of products with D - (-) - α-phenylglycine to form 40 compounds of formula I.

i2 861 82 B) Preparation of 6- (D - (-) - α-azido-α-phenylacetamido) penicillan-lansyran with α-chlorodiethylcarbonate and polar solution.

5 Derivatives according to formula I of the genome catalytic hydration of 1-ethoxycarbonyloxyethyl esters of 6- (D - (-) - α-azido-α-phenylacetamido) penicillansyran.

The method used in the preparation of this Regulation is based on the composition of the flammable materials and the crankshaft.

The genome of U.S. Pat. esterifiers are derived from an organic leaching medium which is a mixture of water and a nerve from the fas-20 reaction catalyst. It is considered that the TV and the fuse system are also equipped with a mixture of acetone, which can be treated with acetone, under reduced pressure.

25 Syftet med föreliggande uppfinning är att ästadkomma ett: förfarande för framställning av bacampicillin under använd Ning av ampicillin som utgängsmaterial, a är enklare att fververkliga i industriell Skala ocer ger ger selfskade produc-ten en hög renhetsgrad.

. · JO

For example, the addition of 1-ethoxycarbonyloxyethyl esters of 6- (D - (-) - α-amino-α-phenylacetamido) to penicillan compounds of formula I comprises the following: (a) the addition of ampicillin, in the form of a mixture of 35 - in addition, a reactive derivative of an acetoacetic acid and an aprotic, non-reactive form of a compound of the same form as most of the formula 11 i3 861 82 / S \ yC «3 CH - CO - NH - CH - CH c'f (II) IIII ch3

y N. CO - N - CH - COOX

R1-C H

2 I

10 R-C, 0

V

R3 color R1 is an alkyl group having 1-4 colaters, R2 is an alkyl group having 1-4 colaters, R3 is an alkyl group having 1-4 colaters, an alkoxy group having 1-4 colaters or an amino group, and 20 X is in the case of alkali metal and non-alkali metal or organic bases, b) for the reaction reaction of the quaternary amine monounitically with a reaction catalyst and a chlorodiethylcarbonate in formula 25

Cl-CH-O-C00C2H5 (III) is as described for the ester ester. .30

S CHS

'35 (f' S-CH - CO - NH - CH - CH cf \ = / | I I I ^ ch3 jj co - n - ch-coo-ch-o-cooc2h5

! X \ I

. . RC H CH3 '••' • 40 I i R \ / ° c (IV): .. 4 5 R3 i4 86 1 82 color R1, R2 and R3 have an angular lettering, and c) utför pä i och för sig känt the composition of the hydrolysis and the medium to the form of the formulation in Form I.

5 The preparation of the reaction catalyst for the reaction reaction and the production of the product and the reaction process.

The reaction catalyst is exempted from tetra-10 butylammonium bromide.

The catalytic converter may be set at a rate of 0.005 to 0.10 mol per mol of the third equivalent of the third equimolar form. The tetrabutylammonium bromide in the formulation of an-15 torsion is then added to 0.01 to 0.10 mol per mol of the compound III.

The group is selected from the group consisting of R1, R2 and R3: alkyls CH3, C2H5, n-C3H7, i-C3H7, n-C4H9 alkoxy (of R3): OCH3, OC2H5, OCH2CH2CH3, OCH (CH3) 2, 0 (CH2) 3CH3.

Radikalen X är vald bland grupper som är välän kända inom tek-Nike, account exempel:

. 25 alkali metal: Na, K

alkali jordartsmetall: Ca, Mg organisk bass organiska baser som är kända vid synthetization av penicilliner, account exempt tertiary ammonium group, tri-ethylamine, ethylpiperidine and methylmorpholine.

30

In the case of the above-mentioned form of the addition group, the amino groups of the ampicillin and the 1-methoxycarbonyl-propen-2-yl group or of the 1-ethoxycarbonyl-propen-2-yl group can be used to form the intermediate products. II is sodium or potassium salt of N- (1-methoxycarbonylpropen-2-yl) penicillan or N- (1-ethoxycarbonyl-12'-propen-2-yl) penicillan (R = methyl; R = methyl, R = methoxy or ethoxy and X = Na or K).

is 86182

Mellan products IV are stable and neutral to alkaline medium, under which a group of amino groups can be used, preferably and selectively adjusted.

5 For example, the use of ampicillin trihydrates in the form of a solution of 10 to give an exemption for N, N-dimethylformamide, which is exempted, in the case of most of the (II) genomic reaction with a compound of acetoacetate, - methylation-acetylated acetic acid, av enaminen (IV), - hydrolysis of the reaction group with HCl to 20 organic solvents, with an exemption for n-butyl acetate / water, - addition of bacampicillin hydrochloride to the water phase, exemption of sodium chloride and extraction with heat exempted n-butylacetate, - concentration at the bottom t tryck in n-butyl acetate 25 for crystallization from the product and the above, •: a different product for isolation by genomic filtration.

For example, a bacampicillin hydrochloride can be used as an additive in the form of a batch-to-batch process.

However, the use of the product and the product in question may not be up to the actual cost of .35 bar and the value of the product may be higher than that of the technician. : stand.

* · I do not allow any other ampicillin trihydrate to be added to any of the excipients, and the antibiotic is said to be 86182.

Mellan products (II) can be obtained in the form of exemptions from GB patent 991586 and that 5 over 95% of the genomic reaction is carried out with ampicillin trihydrates and methyl or ethyl acetate, 10 to 50% by volume of the reaction mixture. organic compounds based on alkali metal carbonate are exempted from potassium carbonate.

10 Some aprotic solvents can be exempted from N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

For this reaction, the temperature is at least 15 ° C to 60 ° C, warm to 20 ° C to 30 ° C, warm to 20 ° C and 30 ° C.

The reaction reaction is then carried out at a temperature of 15 ° C to 80 ° C, at a temperature of 45 ° C to 55 ° C, at a temperature of 45 ° C to 5 ° C. 10 timmar.

In the case of an individual and a warming agent for the industrial-25 species, the isolates of the enrichment (IV) of the genomic spindle are further reacted with water and after extraction with a warmed-up solution of the substance and the water is exempted.

30 Acetate phase with a total solution (0.2-0.3 N) of HCl in the form of hydrolysers of the group, fully contacted with 2 contacts at 8 times, warmed to 4-5 times at normal temperature.

V "35 The genome is saturated with sodium chloride in the form of (I) from the water phase in the form of hydrochlorides, which are additionally prepared and heated to a solution, with n-butyl acetate being exempted.

Il i7 86182

Concentration of the organic phase in the organic phase at a temperature of 40 ° C is carried out at the same volume as the crystallization from the products of formula (I).

5 The crystals of the product are isolated by genomic filtration, drying and vacuuming.

The use of upstream refining is based on the presence of quaternary ammonium salts in the stoichiometric game for a period of 10 days without the use of stoichiometric methods.

It is possible to add up to 1% and 25% of the equivalent of a quaternary air salt to a shield of 15 equivalents of a metal salt of an ampicillin, and to give 1% and 10% of the equivalent of a quaternary ammonium salt.

Lämpliga metallsalter av ampicillinet är alkalimetalsalter 20 och alkaliska jordartsmetallsalter säsom sodium, potassium, lithium, magnesium and calcium salt. The quaternary ammonium salt with ampicillin is exempt from tetraalkyl ammonium salt with tetra-n-butyl ammonium bromide and cetyltrimethylammonium bromide and quaternary pyridinium salt with 25 cetylpyridinium bromides.

The quaternary ammonium salts from the ampicillin framställes warm the genomic reaction with the metal to the ampicillin and the quaternary ammonium salts with enyra. Syran is a mixture of 30 or more minerals with salts, bromine or sugar.

It is possible to add a maximum of 5 to 100% of α-chlorodiethylcarbonate for a shade equivalent to 5% and 60% to give a mixture of 20 to 60%.

. ··. Följande exempel belyser uppfinningen.

ib 86182

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

Blandningen hälles under omröring vid 22 ° C-23 ° C i 3 timmar och efter denn tid kan man iakta en avsevärd fluidisering av massan.

17.8 g (0.117 mol) of α-chlorodiethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 50 ml of N, N-dimethylformamide are added after cooling.

15 Up to 25 ° C in the range of 45 ° C to 50 ° C and + 15 ° C in 15 ° C.

The reaction mass is mixed with 600 ml of water and 200 ml of n-butyl acetate and the mixture is completely ground to a total of 20 ml, the water is then mixed up and extra 50 ml of n-butyl acetate are added.

D & äterförenade organiska faserna was fed 2 gangers with a total of 50 ml of water. 75 ml of 1N HCl and 185 ml of water are added 25 to the organic phase; the temperature is reduced to between 22 ° C and 23 ° C and 4 ° C.

•:: The water phase is mixed and the organic phase is extracted with 50 ml water. At the pH of .30 at pH .30 with a 10% addition of Na2CO3, the water is then filtered off and filtered.

150 ml of n-butyl acetate and 40 g of sodium chloride were added. „Wattenhaltiga filtrate.

:, / 35

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

The mixture of butyl acetate is concentrated at 40 ° C to 40 ° C in a volume of about 150 ml.

li i9 86182

The products are crystallized at 15 ° C, at + 5 ° C.

The filtrate was taken up in n-butyl acetate (50 ml) and ethyl acetate (50 ml).

5

The puncture was performed under a vacuum of 10 mm Hg and nervous at a temperature of 25 ° C for 24 hours.

Yield: 20.8 g (55%) of 1-ethoxycarbonyloxyethyl ester of 6- (D-10 (-) -. Alpha.-amino-phenylacetamido) penicillansyrohydrochloride, m.p.

The result was obtained by forest distillation with ethyl acetate-15 acetate and increased by the sample.

Yield: 16.1 g of crystalline product

Sp. 144-148 ° C (Tottoli apparatus) IR / TLC product with 20 KF 0.35% pH 3.55 (2% water)

Analyzes T.Q. 95.2%

Restlösnings- medel total 3.5% 25

Modifieringar:

The production of chlorodiethylcarbonates is carried out. faser: Första fasen 9 g omedelbart, andra fasen, ytterligare 9 g 30 efter 2 timmar. Up to 3 ° C at 45 ° C.

resultat:

Yield: 13.7 g of crystalline beige product

Sp. 143-146 ° C (Tottoli apparatus) * - '35 IR / TLC with product KF 0.2% pH 3.43 (2% to water)

Analyzes T.Q. 94.8%

Restriction rate 2.6%

Claims (7)

20 861 82 A process for the preparation of 6- (D- (-) - α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester of the formula 5 / c <3 V-CH-CO-NH-CH-CH ( I) \ = / | I I I> h3 NHZ CO - N - CH - COO - CH - O - COOC2H5 ch3 characterized in that a) ampicillin, preferably in the form of an alkali salt, is reacted with a reactive derivative of acetoacetic acid in an aprotic, polar solvent to form the corresponding enamine of formula 20 / \ / CH3 QCH - CO - NH - CH - dH cC (II) IIII ^ CH3 25 ✓Nv CO - N - CH - COOX R1-C H 2 “RC O 30 \ / C l3 R '35 where R1 is 1- An alkyl group having 4 carbon atoms, 2 R is hydrogen or an alkyl group having 1 to 4 carbon atoms, 3 R is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or an amino group, and .40 X is an alkali metal, alkaline earth metal or organic base, b) a quaternary ammonium salt is added to the reaction mixture as an esterification catalyst and α-chlorodiethyl carbonate of formula 2i 86182 Cl-CH-O-C00C2H5 (III) ch3 5 to form the corresponding ester of formula Sc ', /' / -CH- CO - NH - CH - CH 10 \ = / I I I I ^ chj / Nv CO - N - CH-C00-CH-O-C00C2H5! / \ I R-C H CH3 2 » R-Cv O \ / C (IV) R3 wherein R1, R2 and R3 are as defined above, and c) a careful hydrolysis is carried out in a manner known per se in an acidic medium to form a compound of the formula I. 25 Process according to Claim 1, characterized in that tetrabutylammonium bromide is used as catalyst. Process according to Claim 1 or 2, characterized in that 0.005 to 0.10 moles, preferably 0.01 to 0.10 moles of catalyst per mole of α-chloro-diethyl carbonate (III) are used. Process according to one of Claims 1 to 3, characterized in that the formation of the enamine (II) is carried out by reacting the alkali salt of ampicillin with an alkyl acetoacetate, preferably methyl or ethyl acetoacetate, in an amount preferably greater than 10 to 50%. 40 stoichiometric amount, at a temperature between 0 and 60 ° C for 2-8 hours, preferably in the presence of an organic base or alkali metal carbonate. 22 861 82 Process according to one of Claims 1 to 4, characterized in that N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane is used as the aprotic, polar solvent. Process according to Claim 4 or 5, characterized in that the enamine formation reaction is carried out at a temperature between 20 and 30 ° C. 10 Process according to one of Claims 1 to 6, characterized in that the hydrolysis is carried out using dilute hydrochloric acid after separation of the ester (IV). 15