NL194081C - Method for preparing bacampicillin. - Google Patents

Description

1 194081

Method for the preparation of bacampiciliine

The invention relates to a process for the preparation of the 1- (ethoxycarbonyloxy) ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid (bacampiciliine) of formula 1 of the formula sheet.

Bacampiciliine of Formula 1 is a therapeutically important ester of ampicillin (6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid), as the compound is well absorbed when administered orally and gives much higher blood levels of ampicillin than ampicillin itself.

German patent application 2,345,236 discloses tetralkylammonium bromide salts of 6-aminopenicillanic acids, which are suitable as intermediates for the preparation of esters of those 10 penicillanic acids. As an example of penicillanic acid ester which can thus be prepared, the α-ethoxycarbonylethyl esters are described, in which the tetraalkylammonium penicillanate in acetone is treated with α-chlorodiethyl carbonate.

On the other hand, it is known from German patent application 2,656,062 that it is possible to esterify 6-aminopenicillanic acids, inter alia with the α-chloro-diethyl carbonate, in water and a water-immiscible organic solvent using a quaternary ammonium bromide as phase transfer catalyst. These and other known methods have the drawback that they are not directly applicable to ampicillin, but that the α-amino-α-phenylacetamido group must be introduced afterwards. These methods are therefore complicated and the total yields are insufficient.

We have now found a method for the preparation of bacampiciliin starting from ampicillin, which can be carried out in one reaction system. Therefore, this method represents a considerable simplification and provides a high purity product.

The process according to the invention for preparing the 1- (ethoxycarbonyloxy) -ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanic acid of formula 1 of the formula sheet is characterized in that 25 a. ampicillin or a salt thereof in an aprotic polar solvent with a reactive derivative of acetoacetic acid converts to the enamine of formula 2 of the formula sheet, wherein: R 1 represents an alkyl group of 1-4 carbon atoms, an unsubstituted or substituted aryl group or an aralkyl group, R2 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, an unsubstituted or substituted aryl group or an aralkyl group, R3 an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, an unsubstituted or substituted aryl group, an aralkyl group , an aryloxy group or an amino group, and X represents an alkali or alkaline earth metal atom or a cation of an organic base; b. to the reaction mixture obtained in step a) add a quaternary ammonium salt as esterification catalyst 35 and an α-chloro or 8,1-bromo-diethyl carbonate of formula 3 and 5, respectively, and converts the enamine of formula 2 into the corresponding ester of formula 4 of the formula sheet, wherein R1, R2 and R3 have the above meanings, and c. the ester of formula 4 carefully hydrolyses in an acid medium to form the compound of formula 1.

The addition of a catalyst in step b) significantly shortens the reaction times and provides higher yields of the product with a greater degree of purity.

The catalyst can be used in an amount ranging from 0.005 to 0.10 moles per mole of compound 3, respectively. 5 to amounts equimolar with compound 3 and. 5. In a preferred embodiment, tetrabutyl ammonium bromide is used in an amount of 0.01 to 0.10 moles per mole of compound 3, respectively. 5.

Examples of the groups R1, R2 and R3 are: alkyl: CHg, C2H6, IVC3H7, iso-CgHy, n-C4H3 alkoxy (R3 only): OCH · ^, OCHaPHg, OCH (CH3) 2, CKCH ^ CHg aryl: -CeH5 substituted aryl: phenyl substituted with halogen such as Cl and Br 50 aryloxy: -0-CeHs aralkyl: -CH2-CeH5

The group X is selected from groups known in the art, for example, alkali metal: Na, K alkaline earth metal: Ca, Mg 55 organic base: organic bases known for synthesis and penicillins, for example, tertiary ammonium groups, triethylamine, ethylpiperidine and methyl morpholine.

In the preferred embodiment of the invention, the group protecting the amino group of ampicillin 194081 2 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-methoxycarbonylpropylene-2-yl) penicillanic acid is N- (1-ethoxycarbonylpropylene methyl; R 3 = methoxy or ethoxy and X = Na or K), respectively.

5 The intermediate 4 is stable in a neutral or alkaline environment, while in an acidic environment it is possible to remove the group protecting the amino group easily, 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-halo-diethyl carbonate can be the α-chloro or the α-bromo compound.

The α-bromo-diethyl carbonate, compound 3, can be prepared by reacting the corresponding α-chlorodiethyl carbonate with sodium bromide (see Figure 1 of the formula sheet), as explained in Preparation A below, or with lithium chloride, as in Preparation D and Preparation E below explained.

Furthermore, it can be prepared by reaction of acetaldehyde with carbonyl bromide to α-bromoethyl-15 bromoformate of formula 6, followed by reaction with ethanol (see Figure 2 of the formula sheet), as illustrated in Preparation and Preparation C below.

In particular, 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 enamine with formula 2 by reaction with a derivative of acetoacetic acid, for example methyl acetoacetate, - addition of an esterification catalyst, preferably tributylammonium bromide, - addition of α-chloro or α-bromo-diethylcarbonate to the reaction mixture to form the 1-ethoxycarbonyloxyethyl ester of the ampicillin of the enamine of formula 4, 25 - hydrolysis of the protecting group with dilute HCl in an organic solvent, for example n-butyl acetate / water, - recovery of the bacampicillin hydrochloride by saturation of the aqueous phase, for example with sodium chloride and extraction with a suitable 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 present 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 can be easily prepared, as described, for example, in British Patent 991,586 in a yield of more than 95% by reaction of ampicillin trihydrate 40 with methyl or ethyl acetoacetate, 10 to 50% more than the stoichiometric ratio, at presence of an organic base or an alkali metal carbonate, for example potassium carbonate

The intermediate of formula 2 can be isolated and added to the esterification reaction 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 ampidlline-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 ° C and 30 ° C, for 2 to 8 hours, preferably 3 hour.

The compound of formula 2 can be prepared via acylation of 6-aminopenicillic 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-halo diethyl carbonate to the mixture takes place at a temperature between 15 ° C and 80 ° C, preferably between 45 ° C and 55 ° C, for 1 hour to 24 hours, preferably from 5 to 10 hours.

3 194081

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 enamine 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 n-butyl acetate.

The acetate phase is stirred with a dilute solution (0.2-0.3 N) HCl until the protecting group 10 is completely hydrolyzed, which requires a contact of 2 to 8 hours, preferably 4-5 hours, at ordinary temperatures.

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

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

The crystalline product is isolated by filtration, washing and drying under reduced pressure. Preparation A - Preparation of α-bromo-diethyl carbonate 102.9 g of sodium bromide dissolved in 600 ml of acetone were reacted with 152.6 g of α-chloro-diethyl carbonate dissolved in 100 ml of acetone for 2-3 hours at ambient temperature (20-25 ° C). The mixture was then concentrated under reduced pressure at a low temperature, maximum 35 ° C, until a partially solid mass was obtained. A reaction mixture was then partitioned with H 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 800 ml of H 2 O 1000 ml of a 1% aqueous solution of sodium metabol sulfate 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 I.

Example I

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

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

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

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

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

The combined organic phases were adjusted to a pH of 4 with a 10% aqueous solution of NasCOg, then decolorizing carbon was added and filtered.

300 ml of n-butyl acetate and 80 g of sodium chloride were added to the aqueous Altrate. The organic phase was separated and the aqueous phase extracted with 200 ml of n-butyl acetate. The phases reconstituted in n-butyl acetate were concentrated at low pressure at 40 ° C to a volume of about 300 ml. The product was crystallized at + 5 ° C for 15 hours. The product was filtered off and washed with 100 ml n-butyl acetate and 100 ml ethyl acetate. It was then dried under reduced pressure at 40 ° C for 24 hours.

55 Yield: 54.2 g (72%) 1- (ethoxycarbonyloxy) ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid, melting point 160-162 ° C (dec.) And properties according to the authentic hydrochloride sample.

194081 4

Example II

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

When the heating is finished, the reaction mixture is 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 min, then the organic phase was separated and the aqueous phase was extracted with 100 ml of n-butyl acetate. The combined organic phases, after two washes with 75 ml of a 14% sodium chloride aqueous solution, were concentrated at low pressure until an oil was obtained.

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

After the solution was kept at ordinary temperature for 1 hour more, the tetrahydrofuran was removed at low pressure at 40 ° C, 150 ml of n-butyl acetate was added to the residual aqueous phase (150 ml) and then 15 g of sodium chloride were added.

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

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

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

The product was then filtered and washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate. Then it was dried under reduced pressure at 40 ° C.

25.2 g (66.9%) of 1- (ethoxycarbonyloxy) ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride m.p. 160-162 ° C were obtained.

Analytical determinations: content: 97.82% rotational power: + 166.3 ° (c = 1, EtOH95 °) pH: 4.05 (2% solution in water) 30 moisture content: 0.82% residual solvents: ethyl acetate 0.45; n-butyl acetate 0.98% IR and NMR spectra are standard residual ampidlline: 0.06%

Example III

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 powdered anhydrous potassium carbonate in 100 ml of N, N-dimethylformamide.

The mixture was stirred at 22 ° C-23 ° C for 3 hours, after which significant fluidization of the mass was 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 were successively added.

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

The reading mass was poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate and stirred until complete solution was obtained. The aqueous phase was collected and extracted another 50 ml of n-butyl acetate.

The combined organic phases were washed twice with 50 ml of water each time. 75 ml of HCl and 185 ml of water were added to the stirred organic phase. Stirred at 22 ° C-50-23 ° C for 4 hours.

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

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

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

The phases combined in butyl acetate were concentrated at low pressure at 40 ° C to a volume of approximately 150 ml 194081.

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

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

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

Yield: 20.8 g (55%) of 1- (ethoxycarbonyloxy) ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride, m.p. 159-161 ° C and properties according to a authentic monster.

Example IV

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

After stirring for 45 min, without any additional cooling, 23.4 g (0.117 mol) of α-bromo-diethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 250 ml of N, N-dimethylformamide were added successively. The mixture was stirred at 25 ° C for 18 hours. Then the reaction mass was poured into a mixture consisting of 600 ml water and 200 ml n-butyl acetate and stirred until complete solution was obtained. The aqueous phase was collected and extracted with 50 ml of n-butyl acetate.

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

The aqueous phase was collected and the organic phase was extracted with 50 ml of water. The combined aqueous phases were adjusted to pH 4 with 10% aqueous Na 2 CO 3 solution, activated carbon was added thereto 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. The combined 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 + 5eC for 15 hours.

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

Yield: 1.17 g of 1- (ethoxycarbonyloxy) ethyl ester of 6- {D - (-) - α-amino-α-phenylacetamido) penicillanic acid hydrochloride, m.p. 159-161 ° C and properties (NMR, DLC) according to an authentic sample.

Example IVa

The method of Example IV was repeated with the difference that the 6-aminopencillanic acid was dissolved in 20 ml of water 40 instead of 35 ml.

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

45 Example V

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

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

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

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

92.5 ml of water and 7.0 ml of 1N HCl were added to the stirred organic phase to a pH of 1.9. The mixture was stirred at 22 ° C-23 ° C for 2.5 hours.

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

The combined aqueous phases were adjusted to a pH of 4 194081 6 with a 10% aqueous solution of Na 2 CO 3. Activated charcoal was then 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 phases in n-butyl acetate 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.

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

Yield: 1.9 g of 1- (ethoxycarbonyloxy) ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) penicillanic acid, m.p. 160-162 ° C and properties according to an authentic sample of the hydrochloric acid. Ride (e.g. IR: V 1790 cm -1, B-lactam carbonyl).

Preparation B - Preparation of ethyl α-bromoethyl carbonate

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

The mixture was allowed to warm to ambient temperature and then heated to 50 ° C for 3 hours, during which time 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 refluxing for an additional 2 hours, 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 gave 130 g (yield 66%) of pure ethyl α-bromoethyl carbonate, boiling at 90-92 ° C at 6.0 kPa and identical in every respect with an authentic sample.

Preparation C - Preparation of ethyl α-bromoethyl carbonate. A mixture of 44 g (1 mol) of acetaldehyde, 300 ml of dichloromethane and 17.9 g (0.1 mol) of hexamethylphosphoric acid triamide was cooled to -10 ° C and 207 g ( 1.1 mol) of freshly distilled carbonyl bromide was gradually added over a period of 4 hours, during which time the temperature could rise to 10 ° C.

The mixture was then heated under gentle reflux (about 40 ° C) for 4 hours. Still under reflux, 69 g (1.0 mole) of ethanol was carefully added over a 1 hour period and refluxing was continued for 1 hour.

Fractional distillation of the resulting mixture directly yielded 114 g (58% yield) of pure ethyl α-bromoethyl carbonate 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 3 to 4 hours at a rate such that the mixture did not discolour beyond a light orange color.

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

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

40 Preparation D - Preparation of ethyl α-bromoethyl carbonate

A mixture of 43 g (0.5 mole) of lithium bromide, 15.3 g (0.1 mole) of ethyl α-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. 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 45 hours, during which time the temperature rose to 35 ° C, the organic layer was separated, dried and distilled under reduced pressure to form, after repeated fractionation, the compound ethyl-a-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% 50 Calculated: C 30.5 H 4.6 Br 40.6%

The NMR spectrum showed the following peaks: 1.2-1.6 (3H, triplet) -CH2.CH3 2.0-2.2 (3H, doublet) -CH.CHa 4.1 - 4.5 (2H, quartet) -CH2 .CH3 55 6.5-6.8 (1H, quartet) -CH.CH3

Preparation E - Preparation of α-bromo-diethyl carbonate 17.4 g (0.2 mol) of lithium bromide was dissolved in 150 ml of dimethylformamide and the mixture was

Claims (5)

7 194081 ambient temperature cooled. 30.5 g (0.2 mol) of ethyl α-chloroethyl carbonate was 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-5 chloroethyl carbonate after careful fractionation. Preparation F - Preparation of ethyl a-bromoethyl carbonate The authenticity of the previous compound ethyl-a-bromoethyl carbonate was confirmed by the following independent synthesis: A mixture of 35 g (0.3 mol) diethyl carbonate in 50 ml of carbon tetrachloride and 0.1 g 10 α-azoisobutyronitrile (AIBN) was heated under reflux and 28.6 g (0.1 mol) of dibromodimethylhydantoin was heated in small fractions for 8 hours together with a further 8 x 0.05 g of AIBN: 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 α-bromoethyl carbonate, which was identical in all respects to the product of the Preparation D and E. EXAMPLE VI Tests for the esterification of ampicillin "dane" salt with ethyl acetoacetate according to example III. Results: obtained 16.1 g of a white crystalline product melting point 144-148 ° C (Tottoli device) IR / DLC conforming to k.f. 0.35% 25 pH 3.55 (2% solution in water) content 95.2% total residual solvent 3.5% Modifications: the addition of chloro-diethyl carbonate was carried out in two phases: first phase 9 g immediately; second stage another 9 g after 2 hours. Heat for 3 hours to 45 ° C. Results: 35 obtained 13.7 g of crystalline beige product melting point 143-146 ° C (Tottoli device) IR / DLC conforming to k.f. 0.2% pH 3.43 (2% solution in water) 40 content 94.8% residual solvents 2.6% 45 Process for the preparation of bacampicillin of formula 1 of the formula sheet, characterized in that a. Ampicillin or a salt thereof is converted in an aprotic polar solvent with a reactive derivative of acetoacetic acid into the enamine of formula 2 of the formula sheet, wherein : R1 represents an alkyl group of 1-4 carbon atoms, an unsubstituted or substituted aryl group or an aralkyl group, R 2 represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, an unsubstituted or substituted aryl group or an aralkyl group, R 3 an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, an aryl or unsubstituted aryl group, an aralkyl group , an aryloxy group or an amino group, and X represents an alkali metal or an alkaline earth metal atom or a cation of an organic base; 55 b. to the reaction mixture obtained in step 1) a quaternary ammonium salt as an esterification catalyst and an α-chloro or a-bromo-diethyl carbonate of formula 3, respectively. 5 and converts the enamine to 194081 8 formula 2 into the corresponding ester of formula 4 of the formula sheet, wherein R 1, R 2 and R 3 have the aforementioned meanings, and c. the ester of formula 4 carefully hydrolyses in an acid medium to form the compound of formula 1. Drawing 2 sheets