CH656377A5 - ALPHA-BROMEDIAETHYLCARBONATE, METHOD FOR THE PRODUCTION THEREOF AND ITS USE FOR THE PRODUCTION OF PENICILLIN AND CEFALOSPORINE ESTERS. - Google Patents

Description

The invention relates to a-bromo-diethyl carbonate as a new compound which is of great advantage in the new process for the preparation of bacampicillin 1-ethoxycarbonyl-oxyethyl ester of 6- (D- (-) -a-amino-a-phenyIacetamido) peni-cillanic acid of formula I.

/ S \ CH3 CH - CO - NH - CH - CH C.

(I)

-CH,

NH.

CO - N-

■ CH - C00 - CH - 0 - COOC2K5

CH,

can be used and can also be used in a more general sense with great advantage for the production of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins.

Furthermore, the invention relates to a process for the preparation of a-bromo-diethyl carbonate, to a new intermediate in the production of a-bromo-diethyl carbonate b) reaction of the alpha-bromo-bromoformate of the formula VIII with an alcohol of the formula G> Hs-OH desired alpha-bromo diethyl carbonate of the formula (III). 50 The process can thus be summarized using the following reaction scheme:

Br + C2HsOH Br CH3CHO + COBr2— »CH3 — CH • O - CO - Br —— CH-O-CO-C ^ + HBr

55 The alpha-bromo-bromoformate of the formula (VIII) is itself a new compound and is to be regarded as a further aspect of the invention.

The reaction between the aldehyde of the formula (VI) and the carbonyl bromide of the formula f VII 1 is carried out in a particularly expedient manner in the presence of a catalyst. Examples of suitable catalysts are: tertiary amines (e.g. a tertiary aliphatic amine, a tertiary mixed alkyl / arylamine or a tertiary aromatic amine), tertiary phosphines, amides. substituted ureas or 65 thioureas, phosphoric acid amides, tertiary oxonium or sulphonium salts, or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts for use in carrying out process A include

3rd

656 377

Pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

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

The reaction between the aldehyde and the carbonyl bromide is conveniently carried out in the presence of a solvent, 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 expediently carried out at a temperature from -40 ° C. to 120 ° C., preferably from 0 ° C. to 40 ° C. The carbonyl bromide is advantageously used in a molar excess with respect to the aldehyde, advantageously in a molar excess of 10 to 100%, preferably 20 to 50%.

The alpha-bromo-bromoformate of the formula (VIII) formed as an intermediate in process step a) of the process does not need to be isolated before the reaction with the alcohol C2H5OH, which in fact is generally also preferably not done. In accordance with a preferred embodiment of the process according to the invention, the reaction mixture obtained in step a) is freed of excess carbonyl bromide, for example by heating under reduced pressure or by blowing nitrogen through it. The crude reaction mixture containing alpha-bromine bromate is then reacted with an excess of the alcohol. The reaction may conveniently be carried out by refluxing the reaction mixture until the evolution of hydrogen bromide ceases, or by adding a tertiary base to the mixture and heating if necessary. Remaining residues of the catalyst from stage a) or its complex with carbonyl bromide do not appear to interfere with the subsequent reaction and in some cases are even favorable.

The resulting crude alpha-bromocarbonate can conveniently be isolated from the reaction mixture by fractional distillation under reduced pressure.

The process is illustrated in the examples, which are used for the purpose of illustration only.

The aspect of the invention which relates to the use of the new compound a-bromo-diethyl carbonate for the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins is described below.

In summary, this aspect has the following characteristics:

1. The use of a-bromo diethyl carbonate for the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin and cefalosporins.

2. A process for the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins, which is characterized in that 6-aminopenicillanic acid, the penicillin or the cefalosporin or a salt thereof with a-bromo-diethyl carbonate to form the ethoxycarbo-nvioxy-aminic acid acid 6-aminate , the penicillin or the cefalosporin is implemented.

3. The improvement in the esterification reaction between an a-bromo diethyl carbonate and 6-aminopenicillanic acid. a penicillin or a cefalosporin, the improvement comprising using a quaternary ammonium compound in the esterification step, the quaternary ammonium compound in an amount of 1 to 25%, or more preferably 1% to 10%, of the equimolar amount with respect to the amount of 6 -

Aminopenicillanic acid, penicillin or cefalosporin is present.

The ethoxycarbonyloxyethyl ester, in particular of 6-aminopenicillanic acid and penicillin G, is used in accordance with the state of the art in the production of desired semi-synthetic penicillin esters by acylation of the 6-amino group. After removal of the side chain, the ester of penicillin G is obtained, for example.

The reaction of metal salts of carboxylic acids with 10 alkyl halides or aryl alkyl halides to form esters is well known. However, the yields obtained are not particularly high. In addition, the reaction generally requires the use of vigorous conditions such as high temperatures and / or extended reaction times. 15 This limits the usefulness of the reaction for synthesis and its commercial applicability to heat sensitive and labile substances such as pyrethroids, prostaglandins, peptides, penicillins and cefalosporins.

GB-PS 1443 738 discloses the use of a quaternary ammonium salt of penicillins and cefalosporins instead of a metal salt in the preparation of esters of penicillins and cefalosporins.

The preparation of the quaternary ammonium salt of the acid can be time consuming and expensive. However, GB-PS 1443 738 also discloses that it is not necessary to first prepare the quaternary ammonium salt of a penicillin or cefalosporin, but that the reaction can also be carried out by using a metal salt of the carboxylic acid, i. H. 6-aminopenicillanic acid, penicillin or cefalosporin, with 30 the alkyl or arylalkyl halide in the presence of a quaternary ammonium salt other than the salt of the carboxylic acid.

It has now been found that it is not necessary to add the quaternary ammonium salt in a stoechiometric amount 35 with respect to the carboxylic acid, i. H. 6-aminopenicillanic acid, penicillin or cefalosporin, but also a smaller than stoechiometric amount with respect to the carboxylic acid, i. H. 6-aminopenicillanic acid, penicillin or cefalosporin is sufficient.

40 For example, in a process for producing an ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, a penicillin or cefalosporin by reacting a metal salt of 6-aminopenicillanic acid, penicillin or cefalosporin with a-bromo-diethyl carbonate in the presence of a 43 quaternary ammonium salt (different from the salt of this carboxylic acid) the quaternary ammonium compound is present in an amount less than the stoechiometric amount with respect to the 6-aminopenicillanic acid, penicillin or cefalosporin.

For example, 1 to 25% of an equivalent of the quaternary ammonium salt can be used for each equivalent of the metal salt of the carboxylic acid or better between 1% and 10% of an equivalent of the quaternary ammonium salt.

55 The quaternary ammonium salt of the carboxylic acid is conveniently prepared by reacting a metal salt of the carboxylic acid with a quaternary ammonium salt of an acid other than the carboxylic acid, typically using quaternary ammonium salts of a mine 60-acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid .

Suitable metal salts of carboxylic acids (both as precursors for the quaternary ammonium salt of carboxylic acid or as such) are alkali metal or alkaline earth metal salts, 65 for example sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salts of acids other than carboxylic acid (for use both as a precursor to the quaternary ammonium salts

656 377

4th

of carboxylic acids or as such) include, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylammonium bromide, and quaternary pyridium salts such as cetylpyridinium bromide. Suitable halides include fluorides, chlorides, bromides and iodides, with activated fluorides or activated chlorides or bromides or iodides being preferred.

The esterification reaction can be carried out in the presence or absence of a solvent. Suitable solvents are, for example, lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethyl sulphoxide. Alternatively, if no solvent is used, an excess of the ester-forming halide can be used, especially if this is present as a liquid at the reaction temperature.

In the use of an a-bromo-diethyl carbonate described above for the production of ethoxycarbonyl-oxyethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins, the use of a catalyst is optional. When carrying out the reaction, approximately equimolar amounts of the quaternary ammonium salts of the carboxylic acid and of the ester-forming bromide can be used. For example, an excess of 5% to 100% of the ester-forming halide is used for each equivalent of the salt of the carboxylic acid, an excess of between 20% and 60% of the ester-forming bromide being even better.

The improvements in the esterification process mentioned are particularly useful for the preparation of the esters of 6-aminopenicillanic acid, penicillins and cefalosporins. Accordingly, the carboxylic acid can be an acid of formula XI

1 ^ S. - ch

10th

Butyloxycarboxyl group, and R2 represents a hydrogen atom, an alkyl group (e.g. a methyl group), a substituted alkyl group (e.g. a hydroxymethylene, alkoxy or aryloxymethylene or acetoxymethylene group) or an acetoxy or substituted acetoxy group (e.g. an alkyl-acetoxy, arylacetoxy, or arylalkylacetoxy group or the group QHs-CHOH-CO-).

To better understand the invention, the following examples are given for illustration.

example 1

Manufacture of a-bromo diethyl carbonate

acetone

15

NaBr -i- Cl-CH-OCOOC2H5

CH "

> Br-CH-OCOOC H + NaCl

I.

CH-

ch.

cooh

(XI)

20th

25th

30th

35

102.9 g of sodium bromide, dissolved in 600 ml of acetone, are reacted for 2 to 3 hours at room temperature (20 to 25 ° C.) with 152.6 g of a-chlorodiethyl carbonate, dissolved in 100 ml of acetone. The mixture is then under vacuum at low temperature, max. 35 ° C, concentrated until a semi-solid mass is obtained. The reaction mixture is then partitioned between water and ethyl ether. The aqueous phase is separated off and then extracted twice with 400 ml of ethyl ether.

The combined organic phases containing the a-bromo-diethyl carbonate were washed with the solvents or solutions listed below:

800 ml of water

1000 ml of a 1% aqueous sodium metabisulfate solution 1000 ml of a saturated sodium chloride solution.

The organic phase was dried over magnesium sulfate and then under vacuum at low temperature, max. 35 ° C, concentrated and gave the title compound (60%) in the form of a liquid which was initially colorless or slightly yellow-brown. This product was fed to the esterification stage in accordance with Example 2.

or the formula XII

(xii)

ooh, where R1 is a hydrogen atom or an acyl group, especially a substituted acetyl group, such as a phenyl-acetyl-, alpha-aminophenylacetyl-, alpha-aminoparahydroxy-phenylacetyl-, phenoxyacetyl-, alpha-carboxyphenylacetyl- or alpha-carboxy-3- thienylacetyl group or, if the carboxylic acid corresponds to the formula (XII), a group of the formula (XIII)

n-och3

n-

"co- (xiii)

r3-nh-

wherein R 'is a hydrogen atom or an amino protecting group, for example a benzyloxycarboxyl, trimethylsilyl or t-

Example 2

25.08 g (0.181 M) of finely ground, anhydrous potassium carbonate 40 is suspended in 200 ml of N, N-dimethylacetamide and 32.4 ml (0.3 M) of methyl acetoacetate and mixed with 60.4 g (0.15 M). cleaned ampicillin trihydrate added.

The mixture is kept at a temperature of 20 ° C. to 25 ° C. for 5 hours with vigorous stirring; then 43, 46.1 g (0.234 M) bromine diethyl carbonate, 6 g (0.02 M) tetrabutylammonium bromide and 100 ml N, N-dimethylaceta-mid are added.

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

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

The combined organic phases are washed twice with 100 ml of water. To the organic phase, which is stirred 55, 150 ml of HCl and 370 ml of water are added and the mixture is kept at 22 ° C. to 23 ° C. with stirring for a further 4 hours.

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

60 The combined, aqueous phases are adjusted to pH 4 with a 10% aqueous sodium carbonate solution, then carbon is added to decolorize and the mixture is filtered.

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

The organic phase is separated off and the aqueous phase is extracted with 200 ml of n-butyl acetate.

The combined phases in n-butyl acetate are at low pressure and 40 ° C to a volume of approximately 300 ml

5

656 377

constricted. The product is left to crystallize at 15 ° C. for 15 hours.

The product is then filtered off, washed with 100 ml of n-butyl acetate and with 100 ml of ethyl acetate. It is dried in vacuo at 40 ° C for 24 hours.

Yield: 54.2 g (72%} of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - a-amino-a-phenylacetamido) penicillanic acid, melting point 160 to 162 ° C. (D) and characteristics match those of the authentic ones Hydrochloride sample.

Example 3

A mixture of 160 ml acetone, 22.6 g (0.078 mol) of the potassium salt of D - (-) - N-methoxycarbonylpropen-2-yl-aminophenylacetic acid, 6.9 ml (0.088 mol) of ethyl chloroformate and 3 drops of N- Methylmorpholine is stirred at a temperature of -20 to 30 ° C for 15 minutes. A solution of 16.2 g of 6-aminopenicillanic acid, dissolved in 35 ml of water, is added all at once to this reaction mixture by careful addition of 7.6 g (0.075 M) of triethylamine, with stirring, and the mixture is diluted with 90 ml of acetone and cooled to -20 ° C.

The mixture is stirred for a further 45 minutes without any additional cooling, whereupon 23.4 g (0.117 M) a-bromo diethyl carbonate, 3 g (0.01 M) tetrabutylammonium bromide and 250 ml N, N-dimethylformamide are added in the order given. The mixture is stirred at 25 ° C for 18 hours. After this time, the reaction mass is poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate and the resulting mixture is stirred until a complete solution is reached. The aqueous phase is collected and extracted with a further 50 ml of n-butyl acetate.

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

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

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

The mixture is then filtered and the crystals obtained are washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate and dried under reduced pressure of 10 mmHg at 25 ° C. for 24 hours.

Yield: 1.17 g of the 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - a-amino-a-phenylacetamido) peniciIlansäurehydrochlo-rid with a melting point at 159 to 161 ° C and characteristics (NMR, DC) in accordance with an authentic sample .

Example 4

The procedure of Example 3 is repeated with the difference that the 6-aminopenicillanic acid is dissolved in 20 ml of water instead of 35 ml.

Yield: 1.05 g of the ethoxycarbonyloxyethyl ester of 6- (D - (-) - a-amino-a-phenylacetamido) penicillanic acid hydrochloride as a white crystalline powder with a melting point of 148 ° C-151 ° C with decomposition and characteristics (TLC , IR) in accordance with an authentic sample.

Example 5

6.25 g (0.045 M) of finely ground, anhydrous potassium carbonate are dissolved in 50 ml of dimethylsulphoxide by 8.1 ml (0.075 M) of methyl acetoacetate, and 15.1 g (0.0375 M) of ampicillin-5 trihydrate are added.

The mixture is kept at a temperature of 20 ° C. to 25 ° C. for 5 hours with vigorous stirring. At the end of this time, 11.5 g (0.059 M) of bromoethyl carbonate and 25 ml of dimethylsulphoxide are added.

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

The aqueous phase is collected and extracted with a further 100 ml of 15 n-butyl acetate.

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

92.5 ml of water and 7.0 ml of NHC1 are added to the organic phase, a pH of 1.9 being set. The mixture is stirred at 22 ° C to 23 ° C for 2.5 hours.

The aqueous phase is collected and the organic phase extracted with 25 ml of water. The combined aqueous phases are adjusted to pH 4 with 10% aqueous sodium carbonate solution, then activated carbon is added and the mixture obtained is filtered.

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

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

The combined phases in n-butyl acetate are concentrated at a low pressure and a temperature of 40 ° C. to a volume of approximately 75 ml. The product is left to crystallize at 15 ° C. for 15 hours. It is then filtered, washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate. The product obtained is dried at 40 ° C for 3 hours in vacuo.

Yield: 1.9 g (10%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - a-amino-a-phenylacetamido) penicillanic acid with a melting point at 160 ° C to 162 ° C and characteristics in accordance with one Authentic sample of the hydrochloride (e.g. IR: V 1790 cm "1, ß-lactamcarbonyl).

Example 6

45 A mixture of 44 g (1 M) acetaldehyde, 300 ml tetra-chlorocarbon and 235 g (1.25 M) freshly distilled carbonyl bromide is cooled to 0 ° C and by external cooling at this temperature during the addition of 11.9 g (0.15 M) pyridine held over an hour.

5 () This mixture is allowed to warm to room temperature and then warmed to 50 ° C and maintained at this temperature for a period of 3 hours, during which time a precipitate is formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C. gives a semi-solid oily mass which easily dissolves in 92 g (2 M) ethanol when heated and heated under reflux. After heating under reflux for a further 2 hours, excess ethanol is removed in vacuo and the residue is triturated with 100 ml of Walser and 60 200 ml of methylene dichloride.

Separation of the organic layer and fractional distillation gave 130 g of pure ethyl-alpha-bromo-ethyl carbonate (66% yield) with a boiling point of 90 ° C. to 92 ° C. at 45 mmHg, which was identical in all respects to an authentic “sample”.

f> 5

Example 7

A mixture of 44 g (1 M) acetaldehyde, 300 ml dichloromethane and 17.9 g (0.1 M) hexamethylphosphoric triamide

656 377

was cooled to -10 ° C. and 207 g (1.1 M) of freshly distilled carbonyl bromide were added. The carbonyl bromide was added in portions over the course of 4 hours. During this time the temperature was allowed to rise to 10 ° C.

The mixture was then heated under gentle reflux (about 40 ° C) for 4 hours. While still under reflux, 69 g (1.5 M) of ethanol were carefully added to the mixture over the course of one hour and the heating under reflux was continued for a further hour.

The fractional distillation of the resulting mixture gave directly pure ethyl-alpha-bromoethyl carbonate (114 g, 58% yield).

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

118 g (1.0 M) of diethyl carbonate were stirred and heated to a temperature between 110 ° C. and 120 ° C. and irradiated with a 150 watt tungsten filament lamp. 96 g (0.6 M) of bromine was added dropwise over the course of 3 to 4 hours, the speed being adjusted so that the color of the mixture did not deepen more than a pale orange color.

After the bromine addition had ended, the mixture was cooled to room temperature and 20 g of sodium bicarbonate were added.

Distillation and fractionation of the resulting mixture gave authentic ethyl alpha-bromoethyl carbonate (84.2 g, 70% yield) with a boiling point of 87 ° C to 88 ° C at 40 mmHg.

Example 8

The authenticity of the previously described new compound ethyl-alpha-bromoethyl carbonate was confirmed by independent synthesis as follows:

A mixture of 35 g (0.3 M) diethyl carbonate in 50 ml carbon tetrachloride and 0.1 g alpha-azo-isoutyronitrile (AIBN) was heated under gentle reflux and 28.6 g (0.1 M) dibromodimethylhydantoin was added. Dibromodimethylhydantoin was added in small aliquots over a period of 8 hours with the addition of AIBN (8x0.05 g), taking care that no free bromine accumulated in the reaction mixture. After the reaction was completed, the mixture was subjected to fractional distillation in vacuo. 32.3 g (82% yield) of pure ethyl-alpha-bromoethyl carbonate were obtained.

Example 9

Benzylpenicillin ethoxycarbonyloxy ethyl ester

A mixture of 7.4 g (20 mM) potassium penicillin G, 5.9 g (30 mM) ethyl alpha-bromoethyl carbonate, 0.8 g (2.5 mM) tetra-n-butylammonium bromide and 80 ml acetone was stirred and heated under gentle reflux for 4 hours. Excess acetone was removed under reduced pressure and the residue was triturated with ice-cold water and methyl isobutyl ketone. Evaporation of the dry methyl isobutyl ketone under vacuum gave 6.0 g of a semicrystalline oil, from which white crystals (2.5 g) of the alpha (ethoxycarbonyloxy) ethyl ester of penicillin G were precipitated when triturated with warm ethanol and then cooled ( 35% yield).

10th

Example 10

Benzylpenicillin ethoxycarbonyloxyethyl ester 25.08 g (66.7 mM) potassium benzyl penicillinate, 0.50 g (6.0 mM) sodium bicarbonate and 2.15 g (6.67 mM) tetrabutylammonium bromide were carefully stirred in 41 ml methylene chloride and brought to 40 ° C warmed up. When this temperature was reached, 17.16 (86.7 mM) a-bromo-diethyl carbonate was added and the slurry obtained was stirred for 4.0 hours. Then 30 ml of water were added and the pH was adjusted to approximately 5 using a mineral acid. The mixture was stirred for about 4 hours, during which time sodium hydroxide (4%) was added to maintain a pH between 2.5 and 3.0. 50 ml of methylene chloride were then added and the mixture was left to stand for a few minutes. The organic phase was washed with 65 ml of water and then evaporated under reduced pressure. The oily product obtained was dissolved in 100 ml of methylene chloride and evaporated again. The remaining oil was dissolved in methylene chloride and made up to a total volume of 100 ml.

Analysis of the methylene chloride solution by HPLC showed a yield of benzylpenicillin ethoxycarbonyloxyethyl ester of 96% to 97%.

25th

Example 11

Benzylpenicillin ethoxycarbonyloxy ethyl ester 5.02 g (13.3 mM) potassium benzyl penicillinate and 2.99 g 30 (38.3 mM) potassium bicarbonate in 13.5 ml dimethyl sulfoxide were gently stirred in an ice bath. 3.70 g (18.6 mM) of a-bromo diethyl carbonate was added over 30 to 40 minutes using an injection pump. Stirring was continued while the reaction mixture was kept in an ice bath. HPLC analyzes showed that a yield of about 70% of benzylpenicillin ethoxycarbonyloxyethyl ester was obtained within 5 to 10 minutes.

40 Example 12

Benzylpenicillin ethoxycarbonyloxyethyl ester 47.03 g (125 mM) potassium benzyl penicillinate, 0.94 g (11 mM) sodium bicarbonate and 2.01 g (6.25 mM) tetrabutylammonium bromide were carefully stirred in 77 ml acetone and heated to 40 ° C 45. After this temperature was reached, 26.06 g (131 mM) of a-bromo diethyl carbonate was added and the slurry was stirred for 4.5 hours. 56 ml of water were added and then the pH was adjusted to approximately 5 using a mineral acid. The mixture was stirred for about 50 hours, during which time sodium hydroxide (4%) was added to maintain a pH between 4.5 and 4.8.

Then 100 ml of butyl acetate were added and the mixture was allowed to stand for a few minutes for separation. The 55 organic phase was washed with 80 ml of water and then evaporated under reduced pressure. The remaining oily product was dissolved in methylene chloride and made up to a total volume of 250 ml.

HPLC analysis of the methylene chloride solution showed a 60% yield of benzylpenicillin ethoxycarbonyloxyethyl ester from 98% to 99%.

M

Claims (5)

656 377 PATENT CLAIMS 1. Compound of Formula III O Br - CH - CH_ 0 - C - 0 - C2H5 (iii). 2. Process for the preparation of the compound of formula III 0 CH, Br - CH - O - C - 0 - C2H5 characterized in that an aldehyde of the formula VI CH, CHO with carbonyl bromide of the formula VII and on the use of cx-bromine diethyl carbonate for the production of the ethoxycarbonyloxyethyl esters of 6-aminopenicil-lanoic acid, of penicillins such as penicillin G, penicillin V and ampicillin, and of cefalosporins. α-Bromoethyl carbonate is used with great advantage as a reactant in this latter esterification process. The use of a-bromo-diethyl carbonate leads to particularly high yields and to a particularly high purity of the end product, e.g. Bacampicillin. The novel compound a-bromo-diethyl carbonate according to the invention, new and inventive processes for its preparation and its use for the production of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin, and cefalosporins will be explained in more detail below. (VI) This aspect of the invention relates to improvements in the manufacture of a-bromo diethyl carbonate of Formula III Br 10th (iii). COBr, (VII) - »CH, to form a compound of formula VIII Br CH3 - CH - OCO - Br (VIII) 25 is reacted, whereupon the compound of formula (VIII) is reacted with C: HsOH to form a compound of formula (III). 3. The method according to claim 2, characterized in that 30 in the first stage as a catalyst, 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 in an amount of 0.05 to 0.5, preferably 35 from 0.05 to 0.15 mol per mol of the compound of the formula (VI) is used. 4. Use of the compound according to claim 1 for the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins. 40 5. The compound of formula VIII Br -CH • O • CO • O ' C2H5 (III). According to a further aspect of the invention, the a-bromo-diethyl carbonate of the formula (III) can be dealt with below, in the synthesis of alpha (ethoxycarbonyloxy) ethyl esters of 6-aminopenicillanic acid, penicillins and cefalosporins, for example antibiotic bacampicillin, be used. Alpha-bromo-diethyl carbonate can thus be used advantageously for the production of the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillin G, penicillin V and ampicillin. The process for the preparation of alpha-bromo-diethyl carbonate has the following process steps: a) reaction of an aldehyde of the formula VI CH3 - CH - OCO "Br (VIII) CH3CHO with carbonyl bromide of the formula VII COBr, to an alpha-bromo-bromoformate of the formula VIII Br CH, -CH • O • CO - Br as an intermediate for the preparation of the compound according to claim 1. 45 (VI) (VII) (VIII) and