FR2543957A1 - PROCESS FOR THE PREPARATION OF BACAMPICILLIN - Google Patents

Abstract

THE PROCESS FOR THE PREPARATION OF BACAMPICILLIN CONSISTS OF REACTING AN ENAMINE (CF DRAWING IN BOPI) OR R REPRESENTS AN ALKYL GROUP WITH 1 TO 4 CARBON ATOMS, A SUBSTITUTE OR NON-SUBSTITUTED ARYL GROUP, OR AN ARALKYL GROUP; R REPRESENTS HYDROGEN, AN ALKYL GROUP WITH 1 TO 4 CARBON ATOMS, A SUBSTITUT OR NON-SUBSTITUTE ARYL GROUP, OR AN ARALKYL GROUP; R REPRESENTS AN ALKYL GROUP WITH 1 TO 4 CARBON ATOMS, A SUBSTITUTE OR NON-SUBSTITUTE ARYL GROUP, AN ARALKYL GROUP, AN ALCOXY GROUP WITH 1 TO 4 CARBON ATOMS, AN ARYLOXY GROUP OR AN AMINO GROUP; AND X IS AN ALKALINE METAL, AN ALKALINE EARTH METAL OR AN ORGANIC BASE ON A COMPOUND OF FORMULA: (CF DRAWING IN BOPI) OR Z IS CL OR I, THE REACTION BEING CARRIED OUT IN THE PRESENCE OF A CATALYST.

Description

The invention relates to a novel process for producing ester 1-

  6- (D- (-) - α-amino-α-phenylacetamido) penicillanic acid ethoxycarbonyloxyethyl of formula I:

CH 3 CO-NH-CH 3

  The invention also relates to: the novel ac-bromodiethyl carbonate compound, advantageously used in the process according to the invention for preparing bacampicillin of formula I, and that 6-aminopenicillanic acid, penicillins and cephalosporins can advantageously be used for the preparation of the ethoxycarbonyloxyethyl ester; new processes for the preparation of α-bromodiethyl carbonate; new intermediates in the preparation of α-bromodiethyl carbonate; the use of α-bromodiethyl carbonate in the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin, and cephalosporins; improvements in the process of preparation of

  ethoxycarbonyloxyethyl esters of 6-amino acid

  penicillanic, penicillins and cephalosporins.

  Substance I according to the invention is an ampicillin ester, which is of great therapeutic importance because it is well absorbed when administered orally and leads to a blood level of

2-543957

  ampicillin much higher than ampicillin itself

  even. This ester is isolated in the form of a hydrochloride,

  and it's known as bacampi hydrochloride

cillin.

  Given the processes of the current state of the art,

  that (cf the Belgian patent N 772 723), it is possible to synthesize

  by the following two methods bacamidine hydrochloride

  picillin: A) Reaction of potassium benzylpenicillinate on α-chlorodiethyl carbonate in organic solvents or in a 70% aqueous solution of dioxane in the presence

  of sodium bicarbonate The 1-ethoxy ester is

  carbonyloxyethyl benzylpenicillin obtained in the reaction of removing the phenylacetic chain via the iminochloride-iminoether to obtain

  6-amino acid 1-ethoxycarbonyloxyethyl ester

  penicillanic, which is isolated in the form of chlorhy-

  drate. The compound of formula I is obtained by condensation

  of the latter compound with D - (-) - a-phenyl-

glycine.

  B) esterification reaction of 6- (D) - (-) - a-

  azido-a-phenylacetamido) -penicillanic with carbonate

  of a-chlorodiethyl in a polar solvent.

  The compound of formula I is then obtained by hydrolysis.

  catalytic genesis of 1-ethoxycarbonyloxyethyl ester

  6- (D (-) -? - azido-a-phenylacetamido) penicillan acid than 4.

  - "As we see, these processes are rather complex because they involve many raw materials and

long-lasting reactions.

  The object of the invention is essentially to create a process for the preparation of the active principle mentioned above, a process which is simpler to implement and which is industrially more advantageous. The invention also aims at creating a process for the preparation of bacampicillin,

  starting from ampicillin, this process being greatly simplified

  with respect to the current state of the art, while

  obtaining a high purity of the desired product.

  The object of the invention is also to create the novel abromodiethyl carbonate compound, new processes for its preparation; new intermediates for the preparation of α-bromodiethyl carbonate; use

  α-bromodiethyl carbonate to prepare the ethoxylated ester

  xycarbonyloxyethyl of 6-aminopenicillanic acid and penicillins such as penicillin G, penicillin V and ampicillin; and improvements in the process for preparing the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins.

  Advantageously, the α-bromine carbonate is used

  diethyl as a reagent in these esterification processes.

  The use of α-bromodiethyl carbonate leads to a particularly high yield and high purity

  finished products such as bacampicillin.

  To this end, the invention relates to a prepa-

  of 6- (D (-) -? - amino-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester having the following formula:

A'N CH 3

CH CO-NH-CH-CCH c

NH 2 I 3

CH 3

  characterized in that it comprises the steps of

  both: a) reacting ampicillin, preferably in the form of an alkali metal salt, with a reactive derivative of acetoacetic acid to form the enamine having the following formula:

4 2543957

C 0, / CH 3 CH 2 CH 3 CH 3 (II)

-I I \ CH 3

CO N CH COOX

R 12 c-

R -C O

  R 3 R 0 R represents an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, or an aralkyl group; R 2 represents hydrogen, an alkyl group at 1

  to 4 carbon atoms, a substituted or unsubstituted aryl group

  substituted, or an aralkyl group; R 3 represents an alkyl group with 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, an aralkyl group, an alkoxy group with 1 to 4 carbon atoms, an aryloxy group or a group

  amino; and X is an alkali metal, an alkali metal

earthy or organic hase

  (b) in the case of intermediates obtained from carbons

  α-bromo-diethyl nate having the following formula 2 Br-CH-OCOOC H (III) R 22 CH 3

  to form the corresponding ester, having the following formula:

boasts:

S CH

CH-CO-NH-CH CH 3 (I

1 1 i "CH 3

HCO N ,, CH COO CH-O O-COOC 2 H 5

  It CO R 3 R 4 R o R 1, R 2 and R 3 have the same meaning as above; and c) hydrolyzing in an acidic medium to

obtain the compound of formula (I).

  The esterification reaction between compounds II and III can be carried out in the presence or absence of a

esterification catalyst.

  The presence of a catalyst at this stage considerably reduces the reaction times and leads to

  high yields in the product, with higher purity.

  For this purpose, the following substances may be used as catalysts: quaternary ammonium salts, for example tetrabutylammonium bromide, bromides

  or alkali metal iodides, and cyclic ethers.

  The catalyst can be used in a

  between 0.005-0.10 mol per mole of compound III, and equimolar amounts with compound III. In a preferred embodiment, 0.01 to 0.10 is used.

  mole of tetrabutylammonium bromide per mole of the compound.

  III. One embodiment of the above-described method of preparing bacampicillin is to react a compound of formula II with a compound of formula

Z-CH-0-C 00 C 2 H CY

1

  CH 3 O Z is Cl or I, an embodiment characterized in that the process is carried out in the presence of a catalytic amount of a catalyst as mentioned above. The catalyst is advantageously used in an amount of 0.005 to 0.10 mole per mole of compound V. Examples that may be mentioned are R 1, R 2 and R 3: alkyl: CH 3, C 2 H 5, nC 3 H 7, C 3 H 7, nC 4H 9 alkoxy (R 3 only): OCH 3, OC 2 H 5, OCH 2 CH 2 CH 3,

OCH (CH 3) 2, O (CH 2) 3 CH 3

  aryl: substituted aryl: phenyl substituted by a halogen such as Cl and Br aryloxy: aralkyl: CH 2 The radical X is selected from groups known in the art, for example: alkali metal: Na, K alkaline earth metals : Ca, Mg organic base: organic bases known in 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-methoxycarbonylpropenyl-2 group, or a 1-ethoxycarbonylpropenyl-2 group, the intermediate of which is preferred is the sodium or potassium salt, respectively N- (1-methoxycarbonylpropenyl-2) penicillanic acid and N- (1-ethoxycarbonpropenyl) -2) penicillanic acid according to the formula II (R 1 = methyl, R 2 methyl, R 3 = methoxy

or ethoxy, X = Na or K).

  Intermediate IV is stable in a neutral medium or

  while in acidic conditions it is possible to remove

  simply, quickly and selectively the group pro-

protecting the amino group.

  We can choose the group protecting the amino group

  ampicillin for example from the radicals mentioned above.

  British Patent No. 991,586, or among others

radicals known in the art.

  Compound III, α-bromodiethyl carbonate, which is a new compound and which, as such, falls within the scope of the invention, can be prepared by reaction of the corresponding α-chlorodiethyl carbonate on bromide. of sodium, as it is presented as an illustration

in Example 1 below.

  More particularly, the method according to a preferred embodiment of the invention comprises the steps of: converting the ampicillin trihydrate in a polar solvent, for example N, N-dimethylformamide, into one of its salts, for example potassium , and then to form the corresponding enamine (II) by a reaction on

  a derivative of acetoacetic acid, for example acetoacetic acid,

methyl acetate;

  to add an esterification catalyst, preferably

  Tetrabutylammonium bromide; adding abbreviated to the reaction mixture to form the ethoxycarbonyloxyethyl ester of ampicillin as the enamine (IV); hydrolyzing the protecting group with HCl diluted in an organic solvent, for example n-butyl acetate / water; recovering the bacampicillin hydrochloride by saturation in aqueous phase, for example with sodium chloride, and extracting it with the aid of a suitable solvent, for example n-butyl acetate to concentrate the solution under low pressure in n-butyl acetate to crystallize the product with high purity, this product being then isolated by filtration. Among the main advantages of the method according to the invention, the most important is that it

  It is now possible to obtain bacam-

  picillin so to speak in one operation, and with

high purity.

  In fact, the impurities present in the product obtained

  by the process according to the invention are negligible compared with those which are known

the current state of the art.

  Another equally important advantage is that ampicillin trihydrate is used as the starting material, which is a known antibiotic that is

  can easily get in pure form and low cost.

  Intermediate (II), as described for example in British Patent No. 991586, can be easily prepared in greater than 95% yield by reacting ampicillin trihydrate with methyl acetoacetate or at 10 to 50% more than the stoichiometric ratio, in the presence of an organic base or an alkali metal carbonate, for example

potassium.

  Intermediate (II) can be isolated and added to the esterification reaction in solid form or alternatively, without isolating intermediate (II), the esterification reaction can be carried out in the same solvent as that in which carried out the reaction intended to form

enamine (II).

  The reaction leading to the formation of the ampicillin (II) enamine takes place in an aprotic solvent

  such as N, N-dimethylacetamide, N, N-dimethyl-

  formamide, dimethoxyethane, dimethylsulfoxide,

  tetrahydrofuran or dioxane.

  To terminate the reaction, it suffices to leave the components of the mixture in contact at a temperature of between 0 and 60 [deg.] C., preferably between 20 and 30 [deg.] C. for 2 to

  8 hours, preferably for 3 hours.

  Compound II can be prepared by acylation of 6-aminopenicillanic acid with an enamine derivative of phenylglycine corresponding to the formation of compound II, which can then be directly esterified and converted

  in bacampicillin with isolation of compound II.

  The esterification reaction, after the addition of

  a-bromodiate carbonate to the mixture, takes place at a temperature of

  between 15 and 80 ° C., preferably between 45 ° and 55 ° C., for a time of between 1 and 24 hours,

preferably between 5 and 10 hours.

  The esterification reaction is advantageously carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide and dimethylsulfoxide, or in a mixture of solvents.

  Organic solvents can also be used.

  Holding water It is desirable to use an esterification catalyst when the solvent for the reaction

Esterification is acetone.

  In the simplest and most appropriate conditions for an industrial application, the enamine

  Esterified (IV) is isolated by dilution of the reaction mixture

  with water, followed by extraction with a suitable water-nonmiscible solvent, for example n-butyl acetate. The acetate phase is stirred with a dilute solution (0.2-0.3N) of HCl until complete hydrolysis of the protecting group, which requires, at ordinary temperatures, a contact time of 2 to 8 hours, preferably 4 to 5 hours. By addition of sodium chloride, the compound (I) separates from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example acetate

n-butyl.

  If the organic phase is concentrated under low pressure at a temperature of 40 ° C. until a small volume remains, crystallization of the product occurs.

formula (I).

  The crystalline product is isolated by filtration, washing and drying under vacuum. The invention will be better understood with reference to the following examples: EXAMPLE 1 Preparation of α-bromodiethyl carbonate acetone Na Br + ClCH-0 COOC 2 H 5 Br-CH-C 00 CH 5 + NaCl

I I-

CH 3 CH 3

  102.9 g of sodium bromide in 600 ml of acetone and 152.6 g of α-chlorodiethyl carbonate were reacted for 2-3 hours at room temperature (20-25 ° C.). vacuum mixture at low temperature (maximum 35 C) until a semisolid mass was obtained. The reaction mixture was then partitioned with H 2 O and diethyl ether.

  extracted twice with 400 ml of ether.

  The combined organic phases containing abbromodiethyl carbonate were washed with 800 ml of H 2 O, 1000 ml of a 1% aqueous solution of sodium metabisulphite,

  1000 ml of a saturated solution of Na Clo.

  The organic phase was dried over Mg sulphate and then concentrated under vacuum at low temperature (maximum 35 C) to give the title product (60%) as a liquid which initially was colorless

or slightly yellow-brown.

  It was used directly in the esterification step

cation of Example 2 below.

Example 2

  25.08 g (0.118 mol) of finely ground anhydrous potassium carbohydrate were suspended in 200 ml of N, N-dimethylacetamide and 32.4 ml (0.3 mol) were added.

  methyl acetoacetate and 60.4 g (0.15 mole) of

cilline trihydrate.

  The mixture is stirred rapidly for 20-25 hours. At the end of this period, 46.1 g (0.234 mol) of bromodiethyl carbonate, 6 g (0.02 mol) of tetrabutylammonium bromide and 100 ml are added. N, N-dimethylacetamide. It is heated with stirring for 10 hours at 40-42 ° C .; the reaction mass is poured into a mixture formed

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

  The aqueous phase is collected and extracted with a

  another 100 ml portion of n-butyl acetate.

  The organic phases, after recombination, are

  washed twice, each time with 100 ml of water.

  150 ml of HCl N and 370 ml of water are added to the organic phase, which is subjected to continuous stirring for 4 hours.

hours at 22-23 C.

  The aqueous phase is collected and the phase is extracted

organic with 100 ml of water.

  The aqueous phases, after recombinasion, are brought to pH 4 with a 10% aqueous solution of Na 2 CO 3, and then

  add bleaching charcoal and filter.

  300 ml of n-butyl acetate are added to the aqueous filtrate.

and 80 g of sodium chloride.

  Separate the organic phase and extract the phase

  aqueous with 200 ml of n-butyl acetate.

  The n-butyl acetate phases after recombination are concentrated under low pressure at 4 ° C. to a volume of approximately 300 ml. The product is allowed to crystallize.

for 15 hours at +5 C.

  The product is filtered, washed with 100 ml of n-butyl acetate and 100 ml of ethyl acetate before being dried.

  under vacuum at 40 C for 24 hours.

  Yield: 54.2 g (72%) of the 1-ethoxycarbonyl ester

  6- (D (-) - α-amino-α-phenylacetamido) oxyethyl acid

  penicillanic, PF 160-162 C with decomposition, and

  characteristics conforming to the sample of

authentic hydrochloride.

Example 3

  36.4 g (0.075 mole) of N- (1-methoxycarbonyl)

  potassium propenyl-2) -6- (D (-) - α-amino-α-phenylacetamido) penicillate to a solution of 17.8 g (0.116 mol) of α-chlorodiethyl carbonate and 3 g (0.01 g) mole) of bromide

  tetrabutylammonium in 150 ml of N, N-dimethylformamide.

  With stirring, the temperature is raised to 45 ° C and

held at 45-50 C for 5 hours.

  When the heating is finished, pour the mixture

  reaction on a mixture of 300 ml of a solution of

  14% aqueous solution of sodium chloride and 600 ml

  The mixture is stirred for 10 minutes.

  The organic phase is then separated off and the aqueous phase is extracted with 100 ml of n-butyl acetate. The organic phases, after recombination and two washes with 75 ml of a 14% aqueous solution of sodium chloride, are concentrated under low pressure until an oil is obtained. The oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water, and the solution obtained (p H 4.8) is brought to pH 1.5 with stirring, adding in all 12 ml of HCl 6 N.

over a period of 1 hour.

  After letting the solution sit for a while

  one hour at room temperature, the tetra-

  hydrofuran under low pressure at 40 C, 150 ml of n-butyl acetate is added to the remaining aqueous phase (150 ml)

  then 15 g of sodium chloride are added.

  Separate the organic phase and extract the phase

  aqueous solution with 100 ml of n-butyl acetate.

  The organic phases are concentrated after recombination.

  under vacuum at 40 ° C to a volume of 120 ml.

  The product is allowed to crystallize for 15 hours

at 5 C.

  It is filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate before drying

under vacuum at 40 C.

  25.2 g (66.9%) of the ester hydrochloride are obtained.

  6- (D) - (-) - α-amino-1-ethoxycarbonyloxyethyl

  a-phenylacetamido) penicillanic, mp 160-162C.

Analytical results:

Title: 97.82%.

  Rotatory power: + 166.3 (c = 1, and OH 950).

  p H: 4.05 (2% aqueous solution).

Moisture content: 0.82%.

  Residual solvents: ethyl acetate 0.45; acetate of

n-butyl 0.98%.

  IR and NMR spectra are normal.

Ampicillin residual: 0.06%.

Example 4

  16.2 ml (0.15 mole) of methyl acetoacetate and 30.2 g (0.075 mole) of ampicillin trihydrate are added to a suspension of 12.54 g (0.0907 mole) of

  anhydrous potassium finely pulverized in 100 ml of N, N-

  dimethylformamide. It is kept stirring at 22-23 ° C. for 3 hours.

  hours after which we can observe a strong fluidi-

sation of the mass.

  17.8 g (0.117 mole) of α-chlorodiethyl carbonate, 3 g (0.01 mole) of

  tetrabutylammonium bromide and 50 ml of N, N-dimethyl-

  formamide. The mixture is heated with stirring for 5 hours.

  at 45-50 ° C. and then allowed to stand at +5 ° C. for 15 hours.

  The reaction mass is poured into a mixture of

  600 ml of water and 200 ml of n-butyl acetate are added and the mixture is stirred.

  until complete dissolution, the aqueous phase is collected

  and extracted with another 50 ml of n-butyl acetate.

  The organic phases are combined and washed twice, each time with 50 ml of water. 75 ml of HClN and 185 ml of water are added to the organic phase, subjected to

  stirring at 22-23 C for 4 hours.

  The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The aqueous phases, after recombination, are brought to pH 4 with a 10% aqueous solution of Na 2 CO 3, then discolouring charcoal is added thereto.

and filtered.

  150 ml of n-acetate are added to the aqueous filtrate.

  butyl and 40 g of sodium chloride.

  Separate the organic phase and extract the phase

  aqueous solution with 100 ml of n-butyl acetate.

  The butyl acetate phases, after recombination, are concentrated under low pressure at 40.degree.

volume of about 150 ml.

  The product is allowed to crystallize for 15 hours at + 5 ° C., filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate and dried under a vacuum of 10 mm. of mercury (1.33 k Pa) in the presence

  humidity at 25 C for 24 hours.

  Yield: 20.8 g (55%) of the ester hydrochloride

  6- (D) - α-amino-α-1-ethoxycarbonyloxyethyl

  phenylacetamido) penicillanic acid, MP 159-161 C, with

  characteristics in accordance with a control sample.

  EXAMPLE 4 An esterification test of the ampicillin DANE salt with ethyl acetoacetate was carried out according to Example 4. The following results were obtained:

* Product: 16.1 g of a white crystalline product.

  PF: 144-148 C (Tottoli apparatus) IR / CCM: compliant

K.F: 0.35%

  p H: 3.55 (2% aqueous solution) Analysis: 95.2% Total residual solvents: 3 rd 5%

  If, in a variant of this test, the addi-

  chlorodiethyl carbonate in two phases, the first phase of adding immediately 9 g, and the second phase to add another 9 grams after two hours, the following results are obtained after heating for 3 hours at 45 ° C. : 13.7 g of a beige crystalline product PF: 143-146 C (Tottoli apparatus) IR / CCM: compliant

K.F: 0.2%

  p H: 3.43 (2% aqueous solution) Analysis: 94.8% Residual solvents: 2.6%

Example 5

  A mixture of 160 ml of acetone and 22.6 g (0.075 mol) is stirred for 15 minutes at a temperature of -20 to -30 ° C.

  potassium salt of D (-) - N-methoxycarbonyl acid

  propenyl-2-aminophenylacetic acid, 6.9 ml (0.088 mole) of

  ethyl chloroformate and 3 drops of N-methylmorpholine.

  To this reaction mixture is added at once, a solution of

  16.2 g of 6-aminopenicillanic acid dissolved in ml of water by the addition of 7.6 g (0.075 mole) of triethylamine with stirring, after which the mixture is diluted

  mixture with 90 ml of acetone and cooled to -20 ° C.

  After stirring for 45 minutes without cooling

  In this order, 23.4 g (0.117 mol) of α-bromodiethyl carbonate, 3 g (0.01 mol) are added in this order.

  of tetrabutylammonium bromide and 250 ml of N, N-dimethyl-

  formamide The mixture is stirred at 25 ° C. for 18 hours, after which the reaction mass is poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate, and stirred until complete dissolution The aqueous phase is collected and extracted with another 50 ml

n-butyl acetate.

  The organic phases, after recombination, are washed twice, each time with 50 ml of water. The mixture is then added with water to the organic phase and HCl 1 N is added dropwise with stirring to a pH of 20%. of 1, 9 The mixture is then left stirring at 22-231 ° C. for

4 hours.

  The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The aqueous phases are brought, after recombination, to pH 4 with an aqueous solution of Na 2 CO 3 and activated charcoal is added thereto. 150 ml of acetate acetate are added to the aqueous filtrate.

  n-butyl and 40 g of sodium chloride.

  The organic phase is separated off and the aqueous phase is extracted with 100 ml of n-butyl acetate. The butyl acetate phases, after recombination, are concentrated under low pressure at 40 ° C. to a volume of approximately 1 ml. product crystallize for 15 hours

at + 5 C

  It is filtered, washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate and then dried under a vacuum of 10 mm Hg (1.33 k Pa) at 25 ° C. 24 hours.

  Yield: 1.17 g of the 1-ethoxy ester hydrochloride

  carbonyloxyethyl acid of 6- (D (-) amino-c-phenyl-

  acetamido) penicillanic, MP 159-161 C, exhibiting characteristics (NMR, TLC) consistent with a control sample.

Example 5 a

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

of water instead of 35.

  Yield: 1.05 g of the ethoxy ester hydrochloride

  carbonyloxyethylic acid of 6- (D (-) - α-amino-caphenyl-

  acetamido) penicillanic in the form of a crys-

  white talline, PF 148-151 C with decomposition and

  characteristics (CCM, IR) conforming to an exchange

witness sample.

Example 6

  6.25 g (0.045 mol) of carbonate are suspended

  of anhydrous potassium finely ground in 50 ml of dimethyl

  sulfoxide, and 8.1 ml (0.075 mole) of acetoacetate are added

  of methyl and 15.1 g (0.0375 mol) of ampicillin trihydrate.

  The mixture is stirred rapidly for 20 hours at 20.degree. C. and then 11.5 g (0.059 mol) of

  bromodiethyl carbonate and 25 ml of dimethylsulfoxide.

  It is heated with stirring for 17 hours at 35.degree.

  37 C, and 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

  another 100 ml of n-butyl acetate.

  The organic phases, after recombination, are washed

  twice, each time with 25 ml of water.

  92.5 ml of water and 7.0 ml of HCl N are added to a pH of 1.9 to the organic phase subjected to continuous stirring.

at 22-23 C for 2.5 hours.

  The aqueous phase is collected, and the

organic phase with 25 ml of water.

  The aqueous phases, after recombination, are brought to pH 4 with a 10% aqueous solution of Na 2 CO 3,

  then activated charcoal is added and filtered.

  75 ml of acetate acetate are added to the aqueous filtrate.

  n-butyl and 37 g of sodium chloride.

  Separate the organic phase and extract the phase

  aqueous solution with 50 ml of n-butyl acetate.

  The n-butyl acetate phases, after recombination, are concentrated under low pressure at 40 ° C. to a volume of approximately 75 ml. The product is allowed to crystallize.

for 15 hours at +5 C.

  It is filtered and then washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate before drying

  under vacuum at 40 C for 3 hours.

  Yield: 1.9 g (10%) of the 1-ethoxycarbonyl ester

  6- (D (-) - α-amino-α-phenylacetamido) oxyethyl acid

  penicillanic, PF 160-162 C and with characteristics

  ticks consistent with a control sample of the hydrochloride

  (eg IR: v 1790 cm 1, β-lactamecarbonyl).

  The new α-bromodiethyl carbonate compound according to the invention, the new processes for its preparation and its

  use to prepare ethoxycarbonyloxy esters

  of 6-aminopenicillanic acid, penicillins

  such as penicillin G, penicillin V and ampicillin

  cillin, and cephalosporins, will now be

described in more detail.

  The invention relates in particular to improvements

  added to the preparation of the carbonate of a-bromo-

2543957-

  diethyl, having the following formula: Br

CH 3 -CH O CO O C 2 H 5 (III)

  According to another embodiment of the invention,

  which will be explained in more detail below, we can use

  α-bromodiethyl carbonate of formula (III) for the synthesis of alpha (6-oxycarbonyloxy) ethyl esters of 6-aminopenicillanic acid, penicillins and

  cephalosporins, for example bacampi antibiotic

  cillin The alpha-bromodiethyl carbonate can therefore be

  advantageously used to prepare the ethoxylated esters.

  carbonyloxyethyls of 6-aminopenicillanic acid,

  penicillin G, penicillin V and gampicillin.

  The invention relates more particularly to two

  New Substances, hereinafter referred to as Process A and Process B, used to prepare alpha-bromodiethyl carbonate

of formula III.

  The first of these processes, Process A, comprises the steps of: (a) reacting an aldehyde of formula

CH 3 CHO VI

  on carbon monoxide bromide CO Br 2 VII to obtain an alpha-bromobromoformate of formula Br I and H; (b) reacting the alpha-bromo-bromoformate of formula VIII with an alcohol of formula C 2 H 5 -OH to give the desired alpha-bromo-diethyl carbonate of formula III. Process A according to the invention can thus be summarized by the following series of reactions X Br + C 2 Hs OH Br I CH 3 CHO + CO Br 2 CCH 3 CH OCO Br> CH 3 CH O CO C 2 H 5 + H Br 'Alpha-bromobromoformate of formula VIII is in

  a new compound and falls within the scope of the invention.

  tion. The reaction between the CH 3 CHO aldehyde and the carbonyl bromide is best carried out in the presence of a catalyst which may be for example a tertiary amine (for example a tertiary aliphatic amine, a mixed tertiary alkyl / aryl amine or an amine tertiary aromatic), tertiary phosphine, amide, urea or thiourea

  phosphoramide, an oxonium or sulpho

  Tertiary nium or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts which can be used in process A according to

  pyridine, dimethylformamide, tetra-n-

  butyl urea, the triamide of hexamethylphosphoric acid

  and benzyltrimethylammonium bromide.

  The catalyst is advantageously used in an amount of from 0.05 to 0.5, preferably from 0.05 to 0.15 mole.

of catalyst per mole of aldehyde.

  The reaction between the aldehyde and the carbonyl bromide is advantageously 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 chlorinated

  Benzene The reaction between the aldehyde and the carbonyl bromide is advantageously carried out at a temperature of -40 to 120 ° C., and preferably between 0 and 40 ° C. The carbonyl bromide is usually used in a molar excess relative to the aldehyde , this molar excess being

  preferably from 10 to 100%, preferably from 20 to 50%.

  The intermediate alpha-bromo-bromoformate of formula VIII obtained in step (a) of process A according to the invention does not need to be isolated before the reaction with alcohol C 2 H 5 OH and, in It is generally preferred that it not be so. In accordance with 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 sweeping to

  Nitrogen The crude reaction mixture containing the alpha-

  bromo-bromoformate is then reacted with an excess of the alcohol. The reaction can advantageously be carried out

  by heating the mixture to reflux until the end of

  hydrogen bromide, or by adding a tertiary base to the mixture and, if necessary, heating

  It does not seem that the possible catalyst

  of the step (a) or its complex with the carbonyl bromide interferes with the subsequent reaction and, in

  in some cases it is even advantageous.

  The crude alphabromocarbonate obtained can

  be conveniently isolated from the reaction mixture by distillation

  fractionation under reduced pressure.

  Process A is illustrated in Examples 7 and 8,

  which are presented for illustrative purposes only.

  B The description below relates to process B, or

  second method according to the invention to prepare the carbo-

  a-bromodiethyl nate This process B is presented, only

  for illustrative purposes, in Example 9.

  Process B according to the invention relates to

  made to the preparation of carbonate of

  with a variant of the Finkelstein reaction, that is to say a reaction of an alkyl chloride or an arylalkyl chloride (or a compound containing such a group) on a bromide bromide; an alkali metal or an alkali metal iodide to replace the chlorine substituent, respectively with a brominated substituent or an iodine substituent; or alternatively by reacting an alkyl bromide or an arylalkyl bromide (or a compound containing such a group) with an alkali metal iodide to replace the brominated substituent with an iodine substituent Finkelstein's reaction is useful because the iodides obtained are generally more reactive than the bromides,

  which, for their part, are more reactive than chlorine

  In some cases, only catalytic

  alkali metal bromide or iodide, and the more reactive species obtained can react with the desired substrate, regenerating the alkali metal bromide or iodide,

  which allows to continue the reaction.

  The reaction can not take place with all the alkyl chlorides or substituted arylalkyl: in particular, it has proved difficult to carry out the reaction with

  alpha-chloroesters and alpha-chlorocarbonates, that is,

  compounds in which the chlorine atom is attached to a carbon atom which, for its part, is attached to one or the other end of a -C (O) -O- group. one such alpha-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate in the preparation of 6-aminopenicillanic acid ethoxycarbonyloxyethyl esters and penicillins as it is

described above.

  It has now been found, in accordance with the invention, that this problem could be solved by carrying out the reaction in a two-phase solvent system, one of the phases being water and the other a solvent. organic

  not put in the water, in the presence of a catalyst for

live fertility.

  According to process B of the invention, a process for the preparation of α-bromodiethyl carbonate is thus obtained by reacting achlorodiethyl carbonate with an alkali metal bromide, characterized in that the reaction takes place in a system two-phase solvent comprising water and an organic solvent immiscible with water in

  presence of a phase transfer catalyst.

  The water-immiscible organic solvents which can be used in the context of the invention comprise the

  halogenated hydrocarbons, for example halogenated paraffins

  genes such as dichloromethane; and hydrocarbons

  aromatics such as toluene.

  phase of which can be used include salts

  quaternary ammonium compounds, for example the salts of

  alkylammonium such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate The alkali metal bromide may be, for example, sodium, potassium or lithium bromide, lithium bromide being preferred. Thus, in process B according to the invention, α-chlorodiethyl carbonate of formula

C 1 O

t He

CH 3 CH O C O -C 2 H 5 IX

  in a two-phase solvent system, one of the phases being water and the other a water-immiscible organic solvent, on an alkali metal bromide of formula R-Br X o R is a metal alkali such as Na, K and Li, to form the compound of formula: Br O l

CH 3 CH O C O C 2 H 5 III

  As noted above, the preferred alkali metal R is Li, so that Li Br is a preferred reagent of formula X.

  In connection with method B, it has been found that the broach

  Lithium chloride could be advantageously used in a conventional Finkelstein reaction (ie a reaction using a single-phase organic solvent system), for example to halogen an alpha-chlorocarbonate.

  This process is presented in Example 10.

  The invention thus relates, according to another form of

  realization, a process for preparing the carbonate of

  bromodiethyl, consisting in reacting the carbonate of

  chlorodiethyl on lithium bromide.

  Examples of solvents that can be used in this process are lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers, and lower aliphatic formic acid amides.

  The description below deals with the part of the invention

  concerning the use of the new carbohydrate compound

  α-bromodiethyl compound to prepare the ethoxylated esters

  carbonyloxyethyls of 6-aminopenicillanic acid,

  penicillins and cephalosporins.

  In summary, this part of the invention comprises: 1 the use of α-bromodiethyl carbonate to prepare the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins such as penicillin G, penicillin V and ampicillin , and cephalosporins,

  2 a process for the preparation of the ethoxy ester

  carbonyloxyethylic acid of 6-aminopenicillanic acid, penicillins and cephalosporins, characterized in that it consists in reacting 6-aminopenicillanic acid, penicillin or cephalosporin, or a salt thereof, on

  α-bromodiethyl carbonate to form the ethoxy ester

  carbonyloxyethyl or 6-amino

  penicillanic, penicillin and cephalosporin,

  3 an improvement to the esterification reaction

  between a halogenodiethyl carbonate and the

  6-apa, a penicillin or a cephalosporin,

  consisting of using a quaternary ammonium compound

  during the esterification step, the quaternary ammonium compound being present in an amount of I-25%, preferably 110% of the equimolar amount

  corresponding to the amount of 6-apa acid, penicillin

  cillin or cephalosporin (apa = amino-penicillanic acid).

  Ethoxycarbonyloxyethyl ether, especially 6-apa acid and penicillin G, is used, as known in the art, to prepare any such semi-synthetic penicillin ester by group-6 acylation. NH 2 after removal of the side chain, by

  example in the penicillin G ester obtained.

  This part of the invention relates to improvements

  to the ester preparation by the reaction of carboxylic acid salts with α-bromo-diethyl carbonate. The reaction of the metal salts of the carboxylic acids with the alkyl or arylalkyl halides to form esters is known. However, the yields are not

  not particularly-high, and the reaction generally requires

  These severe conditions limit the usefulness of the reaction in the context of a synthesis and its commercial applicability to unstable and sensitive substances, such as high temperatures and / or very long reaction times. heat, such as pyrethroids, prostaglandins,

  peptides, penicillins and cephalosporins.

  British Patent No. 1,443,738 discloses the use of

  quaternary ammonium salt of penicillins and cephalosporins in place of their metal salt to

  prepare esters of penicillins and cephalosporins.

  The preparation of the quaternary ammonium salt of the acid can be long and expensive However, as also described in British Patent No. 1,443,738, it is not necessary to start with the preparation of the salt.

  quaternary ammonium of a penicillin or a cephalosphere

  sporine; instead, the reaction can be carried out by reacting a metal salt of the carboxylic acid, i.e., 6-apa, penicillin or cephalosporin, with the alkyl or arylalkyl halide. in the presence of a quaternary ammonium salt other than the salt of the carboxylic acid. It has now been found, according to the invention, that it is not necessary to use the quaternary ammonium salt in a stoichiometric amount with respect to the carboxylic acid, i.e. 6-apa, penicillin. or cephalosporin, but it was sufficient to have less than the stoichiometric amount vis-à-vis the carboxylic acid, for example 6-apa, penicillin

* or cephalosporin.

  The invention thus creates a process for the preparation of an ethoxycarbonyloxyethyl ester of 6-apa acid, a penicillin or a cephalosporin by reaction of a

  metal salt of 6-apa, penicillin or cephalobia

  spore on an α-halogenoethyl carbonate in the presence of a quaternary ammonium salt (other than a salt of said carboxylic acid), the quaternary ammonium compound being present in an amount less than the stoichiometric amount -vis the 6-apa, penicillin or

cephalosporin.

  According to the invention, from 1 to 25% of an equiva-

  slow quaternary ammonium salt-for each equivalent

  metal salt of the carboxylic acid, and more particularly

  In particular, from 1 to 10% of an equivalent of

of quaternary ammonium.

  The quaternary ammonium salt of the carboxylic acid

  is advantageously prepared by a reaction of the metal salt

  than carboxylic acid on a quaternary ammonium salt

  of an acid other than said carboxylic acid, typically a mineral acid such as

  hydrochloric, hydrobromic or sulfuric.

  The metal salts of carboxylic acids that can be used within the scope of this part of the invention (in the form of precursors of the quaternary ammonium salt of the carboxylic acid, or as such) are alkali metal or metal salts. alkaline earth metals, such as sodium, potassium, lithium, magnesium and

  Of calcium may be mentioned as quaternary ammonium salts

  acids other than the carboxylic acid (for use as precursors of the quaternary ammonium salts of carboxylic acids, or

  tetraalkylammonium salts such as tetrabromide

  n-butylammonium and cetyltrimethylammonium bromide, and quaternary pyridinium salts, such as cetylpyridinium bromide. The halides that can be used include fluorides, chlorides, bromides and the like.

  iodides, preferably active fluorides or chlorine

  active bromides or iodides.

  The esterification reaction according to this part of the invention can be carried out in the presence or absence of a solvent. The solvents that can be used include the lower aliphatic alcohols, the ketones.

  lower aliphatic, lower aliphatic amides.

  formic acid and dimethylsulfoxide or even when no solvent is used, an excess of the ester-forming halide can be used, particularly if

  is liquid at the temperature of the reaction.

  In the part of the invention described above, which relates to the use of α-bromodiethyl carbonate in the preparation of ethoxycarbonyloxyethyl esters of 6-apa acid, penicillins and cephalosporins, the use of a catalyst is optional It is possible to use

  in the reaction of approximately equal amounts

  In a preferred embodiment, from 5 to 100% of excess of the ester-forming halide is used for each equivalent of the salt of the carboxylic acid and of the ester-forming halide. carboxylic acid used

  and, preferably, an excess of 20 to 60% of this halide.

  Improvements made to the esterification processes

  According to a preferred embodiment of the invention, the carboxylic acid may have the following formula: ## STR2 ## according to the invention are particularly suitable for the preparation of esters of 6-apa, penicillins and cephalosporins.

$ CH 3

R 1-NH CH 3

CH 3 i "XI

N C 02 H

or O or

R 1-NH

I R 2 XII

C 02 H

  R 1 is a hydrogen atom or an acyl group, in particular

  particular a substituted acetyl group such as a phenyl-

  acetyl; an alpha-aminophenylacetyl group; alpha-

  aminoparahydroxyphénylacétyle; phenoxyacetyl; alpha-

  carboxyphenylacetyl or alpha-carboxy-3-thienylacetyl or, when the carboxylic acid is of formula XII, a group:

N-OCH 3

3 l 3

CO XIII

R 3-NH

  o R 3 is a hydrogen atom or a group protecting a

  amino group such as benzyloxycarboxyl, trimethyl-

* silyl or tert-butyloxycarboxyl, and R 2 is a hydrogen atom, an alkyl group (for example a methyl group), a substituted alkyl group (for example a hydroxymethylene, an alkoxy or aryloxymethylene or acetoxymethylene group) or a group acetoxy or substituted acetoxy (for example an alkylacetoxy, arylacetoxy or arylalkylacetoxy group, or

the group C 6 H 5 CHOH CO-).

  In the preparation of penicillin esters and

  cephalosporins according to the invention, the ester forming the halogen

  is a alpha-halodialkyl carbonate of formula

CH 3 -CH (X) -O-CO-O-CH 2 -CH 3

  o X is a chlorine, bromine or iodine atom, preferably

a bromine atom.

  According to a preferred embodiment of the invention,

  For the preparation of penicillin and cephalosporin esters, the quaternary ammonium salt used is tetra-n-butylammonium bromide. The examples below will make it possible to better understand the invention.

Example 7

  It was cooled to 0 C, and kept at this temperature.

  by external cooling during the addition, over a period of one hour, of 11.9 g (0.15 mole) of pyridine, a mixture of 44 g (1 mole) of acetaldehyde, 300 ml of carbon tetrachloride and 235 g (1.25 moles) of

  carbonyl bromide freshly distilled.

  The mixture was allowed to warm to room temperature

  room temperature, then heated to 50 ° C and maintained at this temperature for 3 hours, period over which

a precipitate has formed.

  Evaporation of the reaction mixture under reduced pressure at 500 ° C. gave a semi-solid oily mass dissolving easily in ethanol (92 g, 2 mol) by heating and boiling under reflux. After refluxing for a further 2 hours, excess ethanol was removed under vacuum and the residue was triturated with 100 ml of water and

  20-0 ml of methylene dichloride.

  A separation of the organic layer and a distillation

  fractionation gave 130 g (66% yield) of alpha-

  bromoethylcarbonate of pure ethyl, having a boiling point

  90-92 ° C at 45 mm mercury (5.99 kPa), and

  in every respect, to an authentic sample.

Example 8

  A mixture of 44 g (1 mole) of acetaldehyde, 300 ml of dichloromethane and 17.9 g (0.1 mole) of the hexamethylphosphoric triamide was cooled to -10 ° C. and 207 g were gradually added thereto. (1.1 moles) of freshly distilled carbonyl bromide over a period of 4 hours during which the temperature was allowed to rise to

1 O C.

  The mixture was then heated under gentle reflux (ca. 40 ° C.) for 4 hours. Still under reflux, 69 g (1.5 mol) of ethanol was carefully added over a period of 1 hour and heating continued at room temperature. reflux

for another hour.

  Fractional distillation of the resulting mixture gave ethyl alpha-bromoethylcarbonate directly

pure (114 g, 58% yield) o.

  The nature of the ethyl alpha-bromoethylcarbonate thus formed was confirmed as follows by independent analysis and synthesis: 118 g (1.0 mol) of diethyl carbonate was stirred and heated to a temperature of between 110 and 120 ° C. It was illuminated by a 150 W tungsten filament lamp. 96 g (0.6 mol) of bromine were added dropwise over a period of 3 to 4 hours and at this rate the mixture did not darken past a pale orange color. After the addition of the bromine was complete, the mixture was cooled to room temperature and 20 g were added.

of sodium bicarbonate.

  Distillation and fractionation of the resulting mixture gave the actual ethyl alpha-bromoethylcarbonate (84.2 g, 70%), with a boiling point of 87-88 ° C in mm Hg (5.3 kPa). ) o

Example 9

  A mixture of 43 g (0.5 mole) of lithium bromide, 15.3 g (0.1 mole) of ethyl alphachlorethylcarbonate, 100 ml of water was stirred at room temperature for 24 hours.

  ml of dichloromethane and 1.5 g of cetyl bromide

  trimethylammonium The aqueous layer was removed and replaced with a fresh solution of 26 g (0.3 mole) of bromide.

  lithium in 40 ml of water containing 1 g of cetyl bromide

  trimethylammonium After stirring for a further 24 hours, during which time the temperature rose to C, the organic layer was separated, dried and distilled under vacuum to give, after repeated fractionation, the new compound ethyl alpha-bromoethylcarbonate (15.0 g, 76% yield), with a boiling point of 90-92 C.

mm Hg (4.66 k Pa).

  Found: C 30.7; H, 4.8; Br 40.1% Calculated: C, 30.5; H, 4.6; Br 40.6% The following results were obtained on the NMR spectrum: 1.2-1.6 (3H, triplet) CH 2 CH 3 -C 2 o CH 3 2.0-2.2 (3H, doublet ) -CH CH 3 4.1-4.5 (2H, quadruplet) -CH 2 CH 3 6.5-6.8 (1H, quadruplet) -CH-CH 3

Example 10

  17.4 g (0.2 mol) of lithium bromide were dissolved in 150 ml of dimethylformamide, and the mixture was cooled to room temperature. 30.5 g (0.2 mol) of ethyl chloride, and the mixture was stirred at room temperature for 24 hours. The precipitated lithium chloride was filtered off, and the filtrate was distilled under vacuum to give, after careful refraction, alpha-bromethyl carbonate.

  with a yield of 76% on the basis of alpha-

  recovered ethyl chlorethylcarbonate

Example 11

  It was confirmed as follows, by an independent synthesis,

  the compliance of the above new compound alpha-bromethyl-

ethyl carbonate.

  A mixture of 35 g (0.3 mole) of diethyl carbonate in 50 ml of carbon tetrachloride and 0.1 g of alpha-azoisobutyronitrile, (AIBN) eetone was heated under moderate reflux.

  added in small portions 28.6 g (0.1 mole) of dibromo

  dimethylhydantoin, over a period of 8 hours, together with additional additions of AIBN (8 x 0.05 g), being careful to avoid any accumulation of free bromine in the reaction mixture. At the end of the reaction, the The mixture was subjected to fractional distillation under vacuum to give pure ethyl alpha-bromethylcarbonate (32.3 g, 82%) identical to all product points of view.

Examples 9 and 10.

  Example 12 Ethoxycarbonyloxyethyl ester of benzyl

  Penicillin A mixture of 7.4 g (20 millimoles) of the potassium salt was stirred and heated under gentle reflux for 4 hours.

  penicillin G, 4.6 g (30 millimoles) of alpha-

  ethyl chloride, 0.8 g (2.5 millimoles) of

  tetra-n-butylammonium bron- ture and 80 ml acetone Acetone

  excess tone was removed under partial vacuum and the residue

  was triturated with ice water and methylisobutyl-

  ketone Evaporation, under vacuum, of methyl isobutyl

  dried ketone gave 3.8 g of a semi-crystalline oil which, after trituration with ethanol, deposited 0.9 g of

  white crystals of the alpha- (ethoxycarbonyloxy) ester -

  Ethyl penicillin G, with a purity of 98-99%

  (high performance liquid chromatography).

  Found: C 43.0; H, 7.4; N, 7.7% Calculated: C, 43.4; H, 7.4; N 8.0% Example 13 Ethoxycarbonyloxyethyl ester of benzyl

penicillin

  Example 12 was repeated using 5.9 g (30 milligrams

  moles) of ethyl alpha-bromethylcarbonate to replace ethyl alphachlorethylcarbonate, and after evaporation of the methyl isobutyl ketone, 6.0 g of a semi-crystalline oil which was then triturated with l. ' hot ethanol then cooled to give crystals

  (2.5 g, 35% yield) of the alpha- (ethoxy-

  carbonyloxy) -ethyl penicillin G.

  Example 14 Ethoxycarbonyloxythyl ester of benzyl

  Penicillin 25.08 g (66.7 mmol) of potassium benzylpenicillinate, 0.50 g (6.0 mmol) of sodium bicarbonate and 2 ml of sodium bicarbonate were thoroughly mixed in 25 ml of methylene chloride and heated at 40 ° C. 15 g (6.67 millimoles) of t-trabutylammonium bromide When this temperature was reached, 17.16 g (86.7 mmol) of α-bromodiethyl carbonate was added, and the suspension was stirred. for 4 hours 30 ml of water and then a mineral acid were added until a pH of about 5 was obtained. The mixture was stirred for about 4 hours, during which time sodium hydroxide was added. at 4% to maintain the pH between 2.5-3.0. Then 50 ml of methylene chloride was added and the mixture was allowed to mix.

  separate for a few minutes The organic phase was washed

  with the 65 ml of water and then evaporated under reduced pressure. The oily product thus obtained was dissolved

  in 100 ml of methylene chloride and then again

  pored The residual oil was dissolved in chloride

  methylene to a total volume of 100 ml.

  High performance liquid chromatography

  of the methylene chloride solution has shown a

  96-97% for the ethoxycarbonyloxyethyl ester of

benzylpenicillin.

  Example 15 Ethoxycarbonyloxyethyl ester of benzyl

  Penicillin 5.02 g (13.3 mmol) of potassium benzylpenicillinate and 2.99 g (38.3 mmol) of potassium bicarbonate in 13.5 ml of dimethylsulfoxide were carefully stirred in an ice bath. 70 g (18.6 mmol) of α-bromodiethyl carbonate over a period of 30-40 minutes using a syringe pump.

  continued agitation while maintaining the reaction mixture

  in the ice bath High performance liquid chromatography showed that within 5-10 minutes a yield of about 70%

  the ethoxycarbonyloxyethyl ester of benzylpenicillin.

  Example 16 Ethoxycarbonyloxythyl ester of benzyl

  Penicillin was thoroughly shaken in 70 ml of acetone and

  heated to 40 ° C. 47.03 g (125 millimoles) of benzylpenicillin

  potassium nate, 0.94 g (11 millimoles) of sodium bicarbonate and 2.01 g (6.25 millimoles) of tetrabutylammonium bromide. As soon as this temperature was reached, 26.06 g (131 g) were added. millimoles) of bromethyl carbonate and the suspension was stirred for 4.5 hours. 56 ml of water was added followed by a mineral acid to a pH of about 5. The mixture was stirred for about 3 hours. hours, during which time 4% sodium hydroxide was added to maintain the pH between 4.5 and 4.8 Then 100 ml of butyl acetate was added and the mixture was allowed to separate for The organic phase was washed with 80 ml of water and then evaporated under reduced pressure. The remaining oily product was dissolved in methylene chloride to a total volume of 250 ml. High liquid chromatography performance of the methylene chloride solution showed a 98-99% yield of the ester

  ethoxycarbonyloxyethyl benzylpenicillin.

  Of course, the invention is not limited to the embodiments described above and shown, from which we can provide other modes and other embodiments, without departing from the scope of

the invention.

34 2543957

Claims (2)

  1 Process for preparing bacampicillin   line, characterized in that a) lenamine is reacted S _XH 3 CH-CO-NH-CH H -CH (II) N CO N CH COOX R C R 2 \ Cl R   R 1 represents an alkyl group with 1 to 4 carbon atoms;   ne, a substituted or unsubstituted aryl group, or a group   aralkyl; R 2 represents hydrogen, an alkyl group with 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, or an aralkyl group; R 3 represents a group   alkyl with 1 to 4 carbon atoms an aryl substituted group   killed or unsubstituted, an aralkyl group, an alkoxy group of 1 to 4 carbon atoms, an aryloxy group or an amino group; and X is an alkali metal, an alkaline earth metal or an organic base; on a compound of formula Z CH O COO C 2 H 5 (V) CH 3 o Z is C 1 or I, and 7541 FR D 1 2543957   b) the reaction between compounds II and V is carried out in the presence of a catalyst, preferably chosen   quaternary ammonium salts, bromides and io-   of alkali metals and cyclic ethers, the cat-   the lyser being more particularly tetrabutylammonium bromide.   The process according to claim 1, wherein   characterized in that the catalyst is present in an amount of 0.005 to 0.10 mol, preferably 0.01 to 0.10 mol per mol of the compound V.