FR2532933A1 - Improvements made to the preparation of antibiotics - Google Patents

Abstract

Improvements made to the preparation of antibiotics. The invention relates to the new compound alpha-bromodiethyl carbonate, to new processes for preparing it, to its use for preparing 1-ethylcarbonyloxyethyl esters of penicillins and cephalosporins and to improvements made to the processes for preparing these esters. The invention finds its main application in the manufacture of antibiotics.

Description

The invention relates to a new process for the manufacture of 1-ethoxycarbonyloxyethyl ester of 6- (D- (-) -a-amino-a-phe'nylacetamido) penicillanic acid of formula I

The invention further relates to
the new α-bromodiethyl carbonate compound, advantageously used in the process according to the invention for preparing the bacampicillin of formula i, and which can generally be advantageously used for the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporins;
- new processes for the preparation of a-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 to the process for preparing the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins.

 The substance I according to the invention is an ester of ampicillin, which is of great therapeutic importance, since it is well absorbed when it is administered orally and leads to a much higher blood level of ampicillin. higher than ampicillin itself.

 This ester is isolated in the form of a hydrochloride, and. it is known as bacampicillin hydrochloride.

Taking into account the processes of the current state of the art (cf. Belgian patent NO 772 723), it is possible to synthesize by bacam penicillin hydrochloride
A) Reaction of potassium benzylpenicillinate on α-chlorodiethyl carbonate in organic solvents or in an aqueous solution of dioxane at 70 t in the presence of sodium bicarbonate. The benzylpenicillin 1-ethoxycarbonyloxyethyl ester obtained is subjected to the reaction consisting in removing the phenylacetic chain via the iminochloride-iminoether to obtain the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, which is isolated in the form of the hydrochloride.

 The compound of formula I is obtained by subsequent condensation of the latter compound with D - (-) - a-phenylglycine.

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

 The compound of formula I is then obtained by catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ester of 6- (D (-) -a-azido-a-phenylacetamido) penicillanic acid.

 As can be seen, these processes are rather complex, since they involve numerous raw materials and long-term reactions.

 The main object of the invention is to create a process for the preparation of the active ingredient mentioned above, a process which is simpler to implement and which is industrially more advantageous. The invention also aims to create a process for preparing bacampicillin, starting from ampicillin, this process. being greatly simpli fied compared to the current state of the art, while obtaining a high purity of the desired product.

The invention also aims to create the new carbonate compound of a-bromodiethyl, of. new processes for its preparation; new intermediates in the preparation of α-bromodiethyl carbonate) the use of α-bromodiethyl carbonate to prepare the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid and penicillins such as penicillin G, penicillin
V and ampicillin; and improvements made to the process for preparing the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins.

procédé caractérisé en ce qu'il comprend les.étapes consis- tant
a) à faire réagir l'ampicillinegde préférence sous la forme d'un sel d'un métal alcalin, sur un dérivé réactif de l'acide acétoacétique-pour former l'énamine ayant la formule suivante

où R1 représente un groupe alkyle à 1 à 4 atomes de carbone, un groupe aryle substitué ou non-substitué, ou un groupe aralkyle ; R représente l'hydrogène, un groupe alkyle à 1 à 4 atomes de carbone, un groupe aryle substitué ou nonsubstitué, ou un groupe araîkyle ;R représente un groupe alkyle à 1 à 4 atomes de carbone, un groupe aryle substitué ou non-substitué, un groupe araîkyle, un groupe alcoxy à 1 à 4 atomes de carbone, un groupe aryloxy ou un groupe amino ; et X est un métal alcalin, un métal alcalinoterreux ou une base organique
b) à faire réagir-l'intermédiaire obtenu sur du carbonate d'a-bromo-diéthyle, ayant la formule suivante

pour former l'ester correspondant, ayant la formule suivante

ou R1, R2 et R3 ont la même signification que ci-dessus ; et
c) à effectuer une hydrolyse en milieu acide pour obtenir le composé de formulé (I).Advantageously, α-bromo-diethyl carbonate is used as a reactant in these esterification processes. The use of α-bromodiethyl carbonate leads to a particularly high yield and high purity of the finished products such as bacampicillin
The invention relates for this purpose to a process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - a-amino-a phenylacetaìdo) penicillanic acid having the following formula

process characterized in that it comprises the steps consisting:
a) reacting the ampicillin preferably in the form of an alkali metal salt, on a reactive derivative of acetoacetic acid-to form the enamine having the following formula

where R1 represents an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, or an aralkyl group; R represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, or an arakyl group; R represents an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group , an arakyl group, an alkoxy group having 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
b) reacting the intermediate obtained on α-bromo-diethyl carbonate, having the following formula

to form the corresponding ester, having the following formula

or R1, R2 and R3 have the same meaning as above; and
c) carrying out a hydrolysis in an acid medium to obtain the compound of formula (I).

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

 The presence of a catalyst, at this stage, considerably reduces the reaction times and leads to high yields of the product, with higher purity.

For this purpose, the following substances can be used as catalysts. quaternary ammonium salts, for example tetrabutylammonium bromide, alkali metal bromides or iodides, and cyclic ethers! ''
The catalyst can be used in an amount of between 0.005-0.10 mole per mole of compound III, and equimolar amounts with compound III. In a preferred embodiment, 0.01 to 0.10 mole of tetrabutylammonium bromide is used per mole of the compound
III.

où Z est Cl ou I, forme de réalisation caractérisée en ce que le pro'cédé est mis en oeuvre en présence d'une quantité catalytique d'un catalyseur tel que mentionné ci--dessus Le catalyseur est avantageusement utilisé en une quantité de 0,005 à 0,10 mole par mole du composé V.One embodiment of the process described above for the preparation of bacampicillin consists in reacting a compound of formula II with a compound of formula

where Z is Cl or I, 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 0.10 mole per mole of compound V.

Examples of the radicals R1, R2 and R3 that may be mentioned:
alkyl: CH3, C2E5, n-C3H7, i-C3H7, 4 9
alkoxy- (R3 only): OCH3, OC2H5, OCH2CH2CH3,
OCH (CH3) 2, O (CH2) 3CH3

substituted aryl: phenyl substituted by a halogen such as Cl and Br aryloxy aralkyl:

The radical X is chosen from the 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 which protects the amino group from ampicillin is a 1-methoxy-carbonyl-propenyl-2 group, or a 1-ethoxy-carbonyl-propenyl-2 group, of which l 'preferred intermediate is the sodium or potassium salt, respectively of N- (1 -, methoxy-carbonyl-propenyl-2) penicillanic acid and N- (1-ethoxy-carbonypropenyl) -2) penicillanic acid - according to formula II (R1 = methyl, R2 = methyl, R3 = methoxy or ethoxy, X = Na or K).

Intermediate IV is stable in neutral or alkaline medium, while in acidic medium it is possible to simply, quickly and selectively remove the group protecting the amino group
The group protecting the amino group of ampicillin can be chosen, for example from the radicals mentioned in British patent N 991 586, or from other 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 d: a-chlorodiethyl carbonate on bromide sodium, as shown by way of illustration in Example 1 below
More particularly, the method according to a preferred embodiment of the invention comprises the steps consisting
in transforming the ampicillin trihydrate in a polar solvent, for example N, N-dimethylforinamide, into one of its salts, for example potassium, and in then forming the corresponding enamine (II) by a reaction on a derived from acetoacetic acid, for example methyl acetoacetate;
- to add an esterification catalyst, preferably tetrabutylammonium bromide
- adding α-bromodiethyl carbonate to the reaction mixture to form the 1-ethoxycarbonyloxyethyl ester of ampicillin in the form of cheesecloth (IV)
- hydrolyzing the protective group with HCl diluted in an organic solvent, for example n-butyl acetate / water
to recover the bacampicillin hydrochloride by saturation in the aqueous phase, for example with sodium chloride, and to extract it using an appropriate solvent, for example n-butyl acetate.
- Concentrating the solution under low pressure in n-butyl acetate to crystallize the product with high purity, this product then being isolated by filtration.

 Among the main advantages of the process according to the invention, the most important lies in the fact that it is now possible to obtain bacampicillin hydrochloride, so to speak, in a single operation, and with high purity.

 Indeed, the impurities present in the product obtained by the process according to the invention are negligible compared to those which one has with the processes known from the current state of the art.

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

 The intermediate (II) can easily be prepared, as described for example in British patent NO 991 586, with a yield greater than 95%, by reacting ampicillin trihydrate on methyl acetoacetate or d ethyl, at 10 to 50% more than the stoichiometric ratio, in the presence of an organic base or of an alkali metal carbonate, for example potassium carbonate.

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

 The reaction leading to the formation of the ampicillin (II) enamine takes place in a polar aprotic solvent such as N, N-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane .

 To complete the reaction, it suffices to leave the components of the mixture in contact at a temperature of between 0 and 600C, preferably between 20 and 300C 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 into bacampicillin with isolation of compound II.

 The esterification reaction, after the addition of α-bromodiethyl carbonate to the mixture, takes place at a temperature between 15 and 80 ° C., preferably between 45 and 550 ° C., for a time between 1 and 24 hours, from preferably between 5 and 10 hours.

 The esterification reaction advantageously takes place in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide and dimethylsulfoxide, or in a mixture of organic solvents. An organic solvent containing water can also be used. It is desirable to use an esterification catalyst when the solvent used for the esterification reaction is acetone.

 Under the simplest conditions and most suitable for industrial application, the esterified enamine (IVr is isolated by diluting the reaction mixture with water, then extraction with a suitable solvent immiscible with water, for example n-butyl acetate.

 The acetate phase is stirred with a dilute solution (0.2-0.3 N) of HCl until complete hydrolysis of the protective 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 an appropriate solvent, for example n-butyl acetate.

 If the organic phase is concentrated under low pressure at a temperature of 400 ° C. until a small volume remains, crystallization of the product according to formula (I) takes place.

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

The invention will be better understood with reference to the examples below
Example 1. Preparation of α-bromodiethyl carbonate

 102.9 g of sodium bromide in 600 ml of acetone was reacted for 2-3 hours at room temperature (20-2506) over 152.6 g of α-chlorodiethyl carbonate. The mixture was then concentrated under vacuum at low temperature (maximum 350C) until a semi-solid mass was obtained. The reaction mixture was then partitioned with H2O and ethyl oxide. The aqueous phase was separated and then extracted twice with 400 ml of ether.

 The combined organic phases containing a-bromodiethyl carbonate were washed with 800 ml of H2O, 1000 ml of a 1% aqueous solution of sodium metabisulfite, 1000 ml of a saturated NaCl solution.

 The organic phase was dried over Mg sulfate and then concentrated in vacuo at low temperature (maximum 350C) to obtain the product of the title (60%) in the form of a liquid which, at the start , was colorless or slightly yellow-brown.

 It was used directly in the esterification step of Example 2 below.

Example 2
25.08 g (0.181 mole) of finely ground anhydrous potassium carbonate was suspended in 200 ml of N, N-dimethylacetamide, and 32.4 ml (0.3 mole) of methyl acetoacetate and 60 , 4 g (0.15 mole) of ampi cillin trihydrate.

 The mixture is kept under rapid stirring for 5 hours at 20-25 C. At the end of this period, 46.1 g (-0.234 mole) of bromodiethyl carbonate, .6 g (0.02 mole) of bromide are added. tetrabutylammonium and 100 mi.

 N, N-dimethylacetanide.

 The mixture is heated with stirring for 10 hours at 80-42 ° C. The reaction mass is poured into a mixture formed of 1200 ml of water and -400 ml of n-butyl acetate.

 The aqueous phase is collected and extracted with 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 N HCl and 370 ml of water are added to the organic phase, which is subjected to continuous stirring for 4 hours. 22-230C
The aqueous phase is collected and the organic phase is extracted with 100 ml of water.

 The aqueous phases, after recombination, are brought to pH 4 with a 10 t aqueous solution of Na2CO31, then bleaching charcoal is added and filtered.

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

 The organic phase is separated and the aqueous phase is extracted with 200 ml of nitrbutyl acetate.

 The n-butyl acetate phases after recombination are concentrated under low pressure at 40 ° C to a volume of approximately 300 ml. The product is left to crystallize for 15 hours at + 50C.

 The product is filtered, washed with 100 ml of n-butyl acetate and 100 ml of ethyl acetate before being dried under vacuum at 400C for 24 hours.

 Yield: 54.2 g (72%) of the 1-ethoxycarbonyl-oxyethyl ester of 6- (D (-) - α -amino- α -phenylacetamido) penicillanic acid, PF 160-1620C with decomposition, and having characteristics consistent with the authentic hydrochloride sample.

Example 3.

 36.4 g (0.075 mole) of N- (1-methoxycarbonyl propenyl-2) -6- (D (-) -a-amino-a-phenyiacetamido) potassium penicillate are added to a solution of 17.8 g ( 0.116 mol) of α-chiorodiethyl carbonate and 3 g t0.01 mol) of tetrabutylammonium bromide in 150 ml of N, N-dimethylformamide.

With stirring, the temperature is raised to 450C and maintained at 45-500C for 5 hours.

 When the heating is complete, the reaction mixture is poured onto a mixture consisting of 300 ml of a 14% aqueous solution of sodium chloride and 600 ml of n-butyl acetate. The mixture is stirred for 10 minutes then the organic phase is separated, 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 mol of water, and the solution obtained (pH 4.8) is brought to pH 1.5 with stirring, adding a total of 12 ml of 6 N HCl over a period 1 hour.

 After having let the solution stand for another hour at room temperature, the tetrahydrofuran is removed under low pressure at 40 "C, 150 ml of n-butyl acetate are added to the remaining aqueous phase (150 ~ mol) and then an add 15 g of sodium chloride.

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

 The organic phases are concentrated, after recombination, under vacuum at 400C to a volume of 120 m.

 The product is left to crystallize for 15 hours at 50C.

 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 are obtained. (66.9%) of the hydrochloride of 1-ethoxycarbonyloxyethyl ester of 6- (D) - (-) -a-amino- a-phenylacetamido) penicillanic acid, PF 1 60-1 62 0C.

Analytical results:
Title: 97.82 t.

Rotatory power: +166.30 (c = 1, EtOH 950).

pH: 4.05 (2 e aqueous solution).

Moisture content: 0.82%.

Residual solvents: 0.45 ethyl acetate; 0.98% n-butyl acetate.

The IR and NMR spectra are normal.

Residual ampicillin: 0.06%.

Example 4
16.2 mi (0.15 mole) dl.acetoacetate methyl 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 carbonate, finely pulverized in 100 ml of N, Ndimethylformamide.

 It is kept under stirring at 22-230C for 3 hours at the end of which a strong fluidization of the mass can be observed.

 Now, in this order, 17.8 g (0.117 mole) of α-chlofqdiethyl carbonate, 3 g (0.01 mole) of tetrabutylammonium bromide and 50 ml of M, N-dimethylformamide are added.

 The mixture is heated with stirring for 5 hours at 45-500C and then allowed to stand at + 50C for 15 hours.

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

 The organic phases are combined and washed twice, each time with 50 ml of water. 75 ml of N HCl and 185 ml of water are added to the organic phase, which is stirred at 22-230C 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 Na2CO3, then bleaching carbon is added thereto and filtered.

 150 ml of nbutyl acetate and 40 g of sodium chloride are added to the aqueous filtrate.

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

 The butyl acetate-1 phases after recombination are concentrated under low pressure at 400C to a volume of approximately 150 ml.

 The product is left to crystallize for 1 hour at + 50 ° C., it is filtered and washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate before drying under a vacuum of 10 mm. mercury (1.33 kPa) in the presence of humidity at 250C for 24 hours.

 Yield: 20.8 g (55%) of the hydrochloride of ester 1 ethoxcarbonyloxyethylLque of 6- (D (-) -a-amino-a- phenylacetamido) penicillanic acid, PF 159-1610C, with characteristics in accordance with a control sample.

EXAMPLE 4a
An esterification test of the DANE salt of ampicillin was carried out with ethyl acetoacetate according to Example 4. The following results were obtained
Product: 16.1 g of a white crystalline product.

PF: 144-1480C (Tottoli apparatus)
IR / CCM: compliant
KF: 0.35%
pH: 3.55 (2% aqueous solution)
Analysis: 95.2%
Total residual solvents: 3.5%
If, in a variant of this test, the addition of the chlorodiethyl carbonate is carried out in two phases, the first phase consisting in immediately adding 9 g, and the second phase in adding another 9 grams after two hours, after heated for 3 hours at 450C, the following results
Product: 13.7 g of a beige crystalline product
PF: 143-1460C (Tottoli apparatus)
IR / CCM: compliant
KF: 0.2%
pH: 3.43 (2 t aqueous solution)
Analysis: 94.8%
Residual solvents: 2.6%
Example 5
A mixture of 160 ml of acetone, 22.6 g (0.075 mol) of the potassium salt of D (-) - N-methoxycarbonylpropenyl- is stirred for 15 minutes at a temperature of -20 to -300 ° C. 2-aminophenyiacetic, 6.9 mi (0.088 mole) of ethyl chioroformate and 3 drops of N-methyimorpholine.

To this reaction mixture is added at once a solution of 16.2 g of 6-aminopenicillanic acid dissolved in 35 ml of water by the moderate addition of 7.6 g (0.075 mole) of triethylamine with stirring. , after which the mixture is diluted with 90 ml of acetone and cooled to -200C.

 After stirring for 45 minutes without additional cooling, 23.4 g (0.117 mole) of α-bromodiethyl carbonate, 3 g (0.01 mole) of tetrabutylammonium bromide and 250 ml of N are added in this order. N-dimethylformamide. The mixture is stirred at 250C for 18 hours after which the reaction mass is poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate, and it is stirred until complete dissolution; The aqueous phase is collected and extracted with another 50 ml of n-butyet acetate.

 The organic phases r after recombination are washed twice, each time with 50 ml of water. 185 ml of water are added to the organic phase and 1N HCl is added dropwise with stirring to a pH of 1.9. The mixture is then left to stir 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 are brought, after recombination, to pH 4 with an aqueous 10% Na2CO3 solution, activated carbon is added thereto and they are filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate.

 The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate The butyl acetate phases, after recombination, are concentrated under low pressure at 400C to a volume of approximately 150 ml. The product is left to crystallize for 15 hours at + 50C.

 It is filtered, washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate, then it is dried under a vacuum of 10 mm of mercury (1.33 kPa) at 250C for 2 hours. .

 Yield: 1.17 g of hydrochloride of 1- (D (-) - a-amino-a phenyl-acetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester, PF 159-1610C, having characteristics ( NMR, TLC) in accordance with a control sample.

Example Sa
The procedure of Example 5 was repeated, except that the 6-aminopenicillan.que acid was dissolved in 20 ml of water instead of 35.

 Yield: 1.05 g of hydrochloride of 6- (D (-) -a-amino-a-phenyl-acetamido) penicillanic acid ethoxycarbonyloxyethyl ester in the form of a white crystalline powder, PF 148-1510C with decomposition and presenting characteristics (TLC, IR) conforming to a control sample.

Example 6
6.25 g (0.045 mole) of finely ground anhydrous potassium carbonate are suspended in 50 ml of dimethyl sulfoxide, and 8.1 ml (0.075 mole) of methyl acetoacetate and 15.1 g (0.0375) are added. mole) of ampicillin trihydrate.

 The mixture is kept under rapid stirring for 5 hours at 20-250C, then 11.5 g (0.059 mole) of bromodiethyl carbonate and 25 ml of dimethylsulfoxide are added.

 It is heated with stirring for 17 hours at 35 ° C. to 70 ° 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-butyet 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 N HCl are added to a pH of 1.9 to the organic phase subjected to continuous stirring at 22-230C for 2.5 hours.

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

 The aqueous phases, after recombination, are brought to pH 4 with a 10% aqueous solution of Na2CO3, then activated carbon is added thereto and they are filtered.

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

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

 The n-butyl acetate phases, after recombination, are concentrated under low pressure at 40 C to a volume of approximately 75 ml. The product is left to crystallize for 15 hours at + 50C.

 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 1-ethoxyzarbonyl-oxyethyl ester of 6- (D (-) -a-amino-a-phenylacetamido) penicilianic acid, PF 160-1620C and having conforming characteristics to a control sample of the hydrochloride (for example IR: v 1790 cm li S-lactamecarbonyle).

 The new α-bromodiethyl carbonate compound according to the invention, the new processes for its preparation and its use for preparing the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillins such as penicillin Gicla penicillin V and ampicillin, and cephalosporins, will now be described in more detail.

The invention relates in particular to improvements made in the preparation of α-bromo diethyl carbonate, having the following formula

 According to another embodiment of the invention, which will be explained in more detail below, it is possible to use α-bromodiethyl carbonate of formula (III) for the synthesis of the aipha (ethoxycarbonyloxy) ethyl esters of the acid. 6-aminopenicillanic, penicillins and cephalosporins, for example the antibiotic bacampicillin. Alpha-bromodiethyl carbonate can therefore be advantageously used to prepare the ethoxycarbonyloxyethyl esters of 6-aminopenicillanic acid, penicillin G, penicillin V and ampicillin.

The invention relates more particularly to two new methods, hereinafter called method A and the method
B, used to prepare the alpha-bromodiethyl carbonate of formula III.

et
(b) à faire réagir l'alpha-bromo-bromoformiate de formule VIII sur un alcool de formule C2 H5 -OH pour obtenir le carbonate d'alpha-bromo-diéthyle de formule III souhaité.A. The first of these methods, method A, includes the steps of
(a) reacting an aldehyde of formula
CH3CHO VI on carbonyl bromide
COBr2 VII to obtain an alpha-bromo-bromoformate of formula

and
(b) reacting the alpha-bromo-bromoformate of formula VIII with an alcohol of formula C2 H5 -OH to obtain 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

 The alphabromo-bromoformate of formula VIII is in itself a new compound and falls within the scope of the invention.

The reaction between the aldehyde CH3CHO and the carbonyl bromide is best carried out in the presence of a catalyst which may for example be a tertiary amine (for example a tertiary aliphatic amine, a mixed tertiary alkyl / aryl amine or a tertiary aromatic amine ), a tertiary phosphine, an amide, a urea or a substituted thiourea, the phosphoramide, an oxonium or tertiary sulphonium salt or an ammonium or quaternary phosphonium salt. preferred examples of catalysts which can be used in process A according to the invention pyridine, dimethylformamide, tetra-nbutyl-urea, hexamethylphosphoric acid triamide and benzyltrimethylammonium bromide
The catalyst is advantageously used in an amount of from 0.05 to 0.5, preferably from 0.15 to 0.15 moles 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 for example be an aromatic hydrocarbon such as toluene, or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorine benzene. The reaction between the aldehyde and the carbonyl bromide is advantageously carried out at a temperature of -40 to 1200C, and preferably between 0 and 40 C. The carbonyl bromide is usually used according to a molar excess relative to the aldehyde, this molar excess. advantageously being from 10 to 100%, preferably from 20 to 50% O
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 the alcohol CH OH and, in fact, it is generally prefers that it is not. Thus, according to a preferred embodiment of the invention, the reaction mixture obtained in step (a) is freed from excess carbonyl bromide, for example by heating under reduced pressure or by nitrogen sweeping. The crude reaction mixture containing the alphabromo-bromoformate is then reacted with an excess of the alcohol. The reaction can advantageously be carried out by heating the mixture at reflux until the end of the evolution of hydrogen bromide, or by adding a tertiary base to the mixture and, if necessary, heating the latter. It does not seem that the possible residual catalyst from step (a) or its complex with carbonyl bromide does not interfere with the subsequent reaction and, in certain cases, it even proves to be advantageous.

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

 Method A is illustrated in Examples 7 and 8, which are presented for illustration only.

 B. The description below relates to method B, or second method according to the invention for preparing α-bromodiethyl carbonate. This method B is presented, by way of illustration only, in Example 9.

 Process B according to the invention relates to improvements made to the preparation of carbonate from to bromodiethyl, thanks to a variant of the Finkelstein reaction, that is to say a reaction of an alkyl chloride or of an arylalkyl chloride (or a compound containing such a group) on an alkali metal bromide or an alkali metal iodide to replace the chlorine substituent, respectively by a bromine substituent or an iodine substituent; or by reacting an alkyl bromide or an arylalkyl bromide (or a compound containing such a group) on an alkali metal iodide to replace the bromine substituent with an iodine substituent.

 The Finkelstein reaction is useful because the iodides obtained are generally more reactive than the bromides, which, for their part, are more reactive than the chlorides. In some cases, catalytic amounts of the bromide or alkali metal iodide are sufficient, and the more reactive species obtained can react with the desired substrate, which regenerates the bromide or the alkali metal iodide, which allows further the reaction.

 The reaction cannot take place with all the substituted alkyl or arylalkyl chlorides: in particular, it has proved difficult to carry out the reaction with alpha-chloroesters and alpha-chloroearbonates, that is to say compounds in which the chlorine atom is attached to a carbon atom which, for its part, - is attached to one or the other of the ends of a group -C (O) -O-. An example of such an alpha-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate in the preparation of the ethoxycarbononyxyxybybetic esters of 6-aminopenicillanic acid and penicillins as described above.

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

 According to method B of the invention, there is therefore created a process for the preparation of α-bromodiethyl carbonate by reaction of α-chlorodiethyl carbonate on an alkali metal bromide, process characterized in that the reaction takes place in a two-phase solvent system comprising water and an organic solvent immiscible with water in the presence of a phase transfer catalyst.

 The water-immiscible organic solvents which can be used in the context of the invention include halogenated hydrocarbons, for example halogenated paraffins such as dichioromethane; and aromatic hydrocarbons such as toluene. The phase transfer catalysts that can be used include quaternary ammonium salts, for example tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate. The alkali metal bromide may for example be sodium, potassium or lithium bromide, lithium bromide being preferred.

dans un système solvant à deux phases, l'une des phases étant de l'eau et l'autre un solvant organique non-miscible à l'eau, sur un bromure de métal alcalin de formule
R-Br X où R est un métal alcalin tel que Na, K et Li, pour former le composé de formule

Thus, in process B according to the invention, a-chlorodiethyl carbonate of formula is reacted

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

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

 In connection with method B, it has been found that lithium bromide could advantageously be used in a conventional Finkelstein reaction (that is to say a reaction using an organic solvent system in a single phase), for example for halogenating an alpha-chlorocarbonate.

This process is presented in Example 10.

 The invention therefore relates, according to another embodiment, to a process for the preparation of abromodiethyl carbonate, which consists in reacting the chiorodiethyl carbonate with lithium bromide.

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

 The description below relates to the part of the invention which relates to the use of the new α-bromodiethyl carbonate compound for preparing the ethoxycarbonyloxyethyl esters of 1-6-aminopenicylic acid, penicillins and cephalosporins.

In summary, this part of the invention includes
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 7 and cephalosporins,
2 a process for the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopniciilanic acid, penicillins and cephalosporins, characterized in that it consists in reacting 6-aminopdnicillanic acid, penicillin or cephalosporing or one of their salts, on α-bromodiethyl carbonate to form the ethoxycarbonyloxyethyl ester, respectively of 6-aminopenicillanic acid, penicillin and cephalosporin,
-3. an improvement made to the esterification reaction between an α-halogenodiethyl carbonate and 6-apa, a penicillin or a cephalosporin / improvement consisting in using a quaternary ammonium compound during the esterification step, the compound quaternary ammonium being present in an amount of? -25%, preferably 1-10% of the equimolar amount corresponding to the amount of 6-apa acid, penicillin or cephalosporin (apa = acid amino-penicillanic) O
Ethoxycarbonyloxyethyl ether, in particular 6-apa and la-penicillin G, is used, as in the art, to prepare any semi-synthetic penicillin ester of this type by acylation of group 6- NH2 after elimination of the side chain, for example in the penicillin G ester obtained.

 This part of the invention relates to improvements made to the preparation of esters by the reaction of salts of carboxylic acids with α-bromodiethyl carbonate.

 The reaction of metal salts of carboxylic acids with alkyl or arylalkyl halides to form esters is known. However, the yields are not particularly high, and the reaction generally requires harsh conditions, for example high temperatures and / or very long reaction times. These severe conditions limit the usefulness of the reaction in the context of a synthesis and its possibilities of commercial application to substances which are not very stable and sensitive to heat, such as pyrethroids, prostaglandins, peptides, penicillins and cephalosporins. .

 British Patent No. 1,443,738 discloses the use of a 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 lengthy and expensive. However, as also described in British Patent No. 1,443,738, it is not necessary to start with the preparation of the quaternary ammonium salt of a penicillin or a cephalosporin; on the contrary, the reaction can be carried out by reacting a metal salt of the carboxylic acid, that is to say 6-apa, penicillin or cephalosporin, on the alkyl or arylalkyl halide in the presence a quaternary ammonium salt other than the salt of carbo :: ylique 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 relative to the carboxylic acid, i.e. the 6-apa , penicillin or cephalosporin, but it was enough to have an amount less than the stoichiometric amount with respect to the carboxylic acid, for example 6-apa, penicillin or cephalosporin.

 The invention therefore creates a process for the preparation of an ethoxycarbonyioxyethyl ester of 6-apa acid, of a penicillin or of a cephalosporin by reaction of a metal salt of 6-apa, of penicillin or of cephalosporin on a halododiethyl 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-à-vis 6-apa, penicillin or cephalosporin.

1 to 25% of an equivalent of the quaternary ammonium salt is used according to the invention for each equivalent of the metal salt of the carboxylic acid, and, more particularly, 1 to 10% of one equivalent of the salt is used quaternary ammonium
The quaternary ammonium salt of the carboxylic acid is advantageously prepared by a reaction of the metal salt of the carboxylic acid with a quaternary ammonium salt of an acid other than said carboxylic acid, in a representative manner a mineral acid such as hydrochloric, hydrobromic or sulfuric acid.

 The metal salts of carboxylic acids which can be used within the framework of this part of the invention (in the form of precursors of the quaternary ammonium salt of the carboxylic acid, or as such) are salts of alkali metals or of metals alkaline earth, such as sodium, potassium, lithium, magnesium and calcium salts. Mention may be made, as ammonium quater naira salts of acids other than the carboxylic acid (for use as precursors of the quaternary ammonium salts of carboxylic acids, or as such), tetraalkylammonium salts such as tdtra-n-butylammonium bromide and cetyltrimethylammonium bromide, and quaternary pyridinium salts, such as cetylpyridinium bromide. The halides which can be used include fluorides, chlorides, bromides and iodides, preferably activated fluorides or activated chlorides or bromides or iodides.

 The esterification reaction according to this part of the invention can be carried out in the presence or in the absence of a solvent. Solvents which can be used include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethyl sulfoxide. Alternatively, when no solvent is used, an excess of the ester-forming halide may be used, particularly if it is liquid at the reaction temperature.

 In the part of the invention described above, which relates to the use of α-bromodithyl carbonate in the preparation of ethoxycarbonyloxyethyl esters of 6-apa acid, penicillins and cephalosporins, the use of a catalyst is optional. Approximately equimolar amounts of the quaternary ammonium salt of the carboxylic acid and the halide forming the ester can be used in the reaction. Preferably, from 5 to 100% excess of the halide forming the ester is used for each equivalent of the salt of the carboxylic acid used, and preferably a 20 to 60 e excess of this halide.

ou

où R1 est un atome d'hydrogène ou un groupe acyle, en particulier un groupe acétyle substitué tel qu'un phénylacétyle ; un groupe alpha-aminophénylacétyle ; alphaaminoparahydroxyphénylacétyle ; phénoxyacétyle ; alphacarboxyphénylacétyle ou alpha-carboxy-3-thiényiacétyie ou bien, quand l'acide carboxylique est de formule XII, un groupe

où R3 est un atome d'hydrogène ou un groupe protégeant un groupe amino tel qu'un groupe benzyloxycarboxyle, triméthylsilyle ou tert-butyloxycarboxyle, et R est un atome d'hydrogène, un groupe alkyle (par exemple un groupe méthyle), un groupe aikyle substitué (par exemple un hydroxyméthylène, un groupe alcoxy ou aryloxyméthylène ou acétoxyméthylène) ou un groupe acétoxy ou acétoxy substitué (par exemple un groupe aikylacétoxy, arylacétoxy ou arylalkylacétoxy, ou le groupe C6H5.CHOH.CO-). C6H5.CHOH.CO-).The improvements made to the esterification processes according to the invention are particularly suitable for the preparation of 6-apa esters, penicillins and cephalosporins. According to a preferred embodiment of the invention, the carboxylic acid can have the following formula

or

where R1 is a hydrogen atom or an acyl group, in particular a substituted acetyl group such as a phenylacetyl; an alpha-aminophenylacetyl group; alphaaminoparahydroxyphenylacetyl; phenoxyacetyl; alphacarboxyphenylacetyl or alpha-carboxy-3-thienyiacétyie or, when the carboxylic acid is of formula XII, a group

where R3 is a hydrogen atom or a group protecting an amino group such as a benzyloxycarboxyl, trimethylsilyl or tert-butyloxycarboxyl group, and R is a hydrogen atom, an alkyl group (for example a methyl group), a group substituted aikyl (for example a hydroxymethylene, an alkoxy or aryloxymethylene or acetoxymethylene group) or a substituted acetoxy or acetoxy group (for example an aikylacetoxy, arylacetoxy or arylalkylacetoxy group, or the group C6H5.CHOH.CO-). C6H5.CHOH.CO-).

 In the preparation of the penicillin and cephalosporin esters according to the invention, the halide-forming ester is a carbonate dBalpha = halogdnodialkyle of formula CH3-CH (X) -O-CO-O-CH2-CH3, where 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 following examples will 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 mol) of pyridine, 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.

 The mixture was allowed to warm to room temperature, then heated to 500C and kept at this temperature for 3 hours, during which time a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 500C gave a semi-solid oily mass dissolving easily in ethanol (92 g, 2 moles) by heating and boiling under reflux After heating under reflux for a further 2 hours, the ethanol excess was removed in vacuo and the residue was triturated with 100 ml of water and 200 ml of methylene chloride
Separation of the organic layer and fractional distillation gave 130 g (yield 66%) of pure ethyl alphabromoethylcarbonate, having a boiling point of 90-920C under 45 mm of mercury (5.99 kPa) , and identical in every respect to an authentic sample.

Example 8
A mixture of 44 g (1 mole) of acetaldehyde, 300 ml of dichioromethane and 17.9 g (0.1 mole) of 1 t triamide of hexamethylphosphoric acid was cooled to -10 ° C. and 207 g (1 , 1 mole) of freshly distilled carbonyl bromide, over a period of 4 hours during which the temperature was allowed to rise to 100C.

The mixture was then heated under moderate reflux
(approx. 40 C) for 4 hours. Still under reflux, 69 g (1.5 mole) of ethanol was carefully added over a period of 1 hour and heating under reflux continued for another hour.

 Fractional distillation of the mixture obtained directly gave pure ethyl alpha-bromoethylcarbonate (114 g, yield 58 0).

The nature of the ethyl bromethyl ethyl carbonate thus formed was confirmed as follows by independent analysis and synthesis
118 g (1.0 mole) of diethyl carbonate was stirred and heated to a temperature between 110 and 1200C. It was lit by a 150 W tungsten filament lamp. 96 g (0.6-6 moles) of bromine was added dropwise over a period of 3 to 4 hours and, at this speed, the mixture did not darken beyond a pale orange color.

After the addition of the bromine was complete, the mixture was cooled to room temperature and 20 g of sodium bicarbonate was added
Distillation and fractionation of the resulting mixture actually gave ethyl alpha-bromoethylcarbonate
(84.2 g, 70%), with a boiling point of 87-88 C under 40 mm of mercury (5.3 kPa)
Example 9
A mixture of 43 g (0.5 mole) of lithium bromide, 15.3 g, was stirred at room temperature for 24 hours.
(0.1 mole) of methyl chloroethyl carbonate, 100 ml of water, 100 ml of dichloromethane and 1.5 g of cetyltrimethylammonium bromide. The aqueous layer was removed and replaced with a fresh solution of 26g (0, 3 mol) of lithium bromide in 40 ml of water containing 1 g of cetyltrimethylammonium bromide. After stirring for a further 24 hours, during which time the temperature was raised to 350 ° C., the organic layer was separated, dried and distilled in vacuo to give, after repeated fractionation, the new ethyl alpha-bromoethylcarbonate compound (15 , 0 g yield 76%), with a boiling point of 90-92 "C under 35 mm of mercury (4.66 kPa).

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 in the NMR spectrum 1.2-1.6 (3E, triplet) GH2.CH3 2.0-2.2 (3H, doublet) -CH.CH3 4.1-4.5 (2H, quadruplet) -CH2.CH3 6.5-6.8 (1H, quadruplet) -CHCH3
Example 10
17.4 g (0.2 mole) of lithium bromide was dissolved in 150 ml of dimethylformamide, and the mixture was cooled to room temperature. 30.5 g (0.2 mole) of ethyl alpha-chloroethylcarbonate was added, and the mixture was stirred at room temperature for 24 hours. The precipitated lithium chloride was extracted by filtration, and the filtrate was distilled in vacuo to give, after careful refraction, ethyl alpha-bromethylcarbonate, with a yield of 76% based on the recovered ethyl alpha-chloroethyl carbonate.

Example 11
The conformity of the above new ethyl alpha-bromethylcarbonate compound was confirmed as follows, by an independent synthesis.

 A mixture of 35 g (0.3 mole) of diethyl carbonate in 50 ml of carbon tetrachloride and 0.1 g of alpha-azo-isobutyronitrile (AIBN) was heated to moderate reflux, and added by weak builders. 28.6 g (0.1 mole) dibromo dimethylhydantolne, over an 8 hour period, along 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 mixture was subjected to fractional distillation under vacuum to give pure ethyl alpha-bromethylcarbonate (32.3 g, 82%) identical in all respects to the product of Examples 9 and 10.

Example 12. Ester. la.benzylpenicillin ethoxycarbonyloxyethylioue
A mixture of 7.4 g (20 mmol) of the potassium salt of penicillin G, 4.6 g (30 mmol) of ethyl alpha-chlorocarbonate, 0, was stirred and heated under moderate reflux for 4 hours. 8 g (2.5 millimoles) of tetra-n-butylammonium bromide and 80-ml of acetone. The excess acetone was removed in partial vacuum and the residue was triturated with ice water and methylsobutyl ketone. Evaporation in vacuo of the dried methyl isobutyl ketone gave 3.8 g of an oil -semi-crystalline which, after trituration with ethanol, deposited 0.9 g of white crystals of alpha- (ethoxycarbonyloxy) ethyl ester of penicillin G, with a purity of 98-99% (high liquid chromatography - performances).

Found o C 43.0; H 7.4 g N 7.7%
Calculated: C 43.4; H. 7.4; N 8.0%
EXAMPLE 13 Benzoxypenicillin ethoxycarbonyloxyethyl ester
Example 12 was repeated using 5.9 g (30 millimoles) of ethyl alpha-bromethylcarbonate in place of the ethyl alpha-chlorethylcarbonate t, after evaporation of the methyl isobutyl ketone, 6.0 was obtained g of a semi-crystalline oil, which was then triturated with hot 1.8 methanol and then cooled to give white crystals (2.5 g, 35% yield) of the alpha- (ethoxycarbonyloxy) -ethyl ester penicillin G.

Example 14. Ester. benzols penicillin ethoxycarbonyloxyethyl
Carefully mixed in 41 ml of methylene chloride and heated to 400C 25.08 g (66.7 millimoles) of potassium benzylpenicillinate, 0.50 g (6.0 millimoles) of sodium bicarbonate and 2.15 g - ( 6.67 millimoles) of tetrabutylammonium bromide. As soon as this temperature has. when reached, 17.16 g (86.7 millimoles) of α-bromodiethyl carbonate was added, and the suspension was stirred for 4 hours. 30 ml of water were added and then a mineral acid until a pH of approximately 5 was obtained. The mixture was stirred for approximately 4 hours, during which time 4% sodium hydroxide was added. to keep the pH between 2.5-3.0. Then 50 ml of methylene chloride was added and the mixture was allowed to separate for a few minutes. The organic phase was washed with 65 ml of water and then evaporated under reduced pressure. The oily product thus obtained was dissolved in 100 ml of methylene chloride and then evaporated again. The residual oil was dissolved in methylene chloride to a total volume of 100 ml.

 High performance liquid chromatography of the methylene chloride solution showed a yield of 96-97 th for the ethoxycarbonyloxyethyl ester of benzylpenicillin.

EXAMPLE 15 Benzoxypenicillin ethoxycarbonyloxyethyl ester
5.02 g (13.3 millimoles) of potassium benzylpenicillinate and 2.99 g (38.3 millimoles> of potassium bicarbonate in 13.5 ml of dimethyl sulfoxide were carefully stirred in an ice bath. , 70 g (18.6 millimoles) of α-bromodiethyl carbonate over a period of 30-40 minutes using a syringe pump. Stirring was continued while keeping the reaction mixture in the bath. High performance liquid chromatography showed that a yield of about 70% of the ethoxycarbonyloxyethyl ester of benzylpenicillin was obtained in 5-10 minutes.

EXAMPLE 16 Benzoxypenicillin thoxycarbonyloxyethyl ester
It was carefully stirred in 70 ml of acetone and heated to 400C 47.03 g (125 millimoles) of potassium benzylpdnicillinate, 0.94 g- (1-1 millimoles) of sodium bicarbonate and 2.01 g ( 6.25 millimoles) of tetrabutylammonium bromide. As soon as this temperature was reached, 26.06 g were added. (131-millimoles) of bromodiethyl carbonate and the suspension was stirred for 4.5 hours. 56 ml of water was added, followed by a mineral acid, until a pH of approximately 5 was obtained. mixing for about 3 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 a few minutes. The organic phase was washed with 80 ml of water and then evaporated under reduced pressure. The oily product remaining was dissolved in methylene chloride to a total volume of 250 ml. High performance liquid chromatography of the methylene chloride solution showed a yield of 98-99% of the ethoxycarbonyloxyethyl ester of b.enzylpenicillin
Of course, the invention is not limited to the embodiments described above and shown, from which other modes and other embodiments can be provided, without thereby departing from the scope of the invention .

Claims (11)

Claims  1. Process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D- (-) -a-amino-a-phenyl-acetamido) penicillanic acid of formula

 characterized in that it comprises the stages consisting  a) reacting the ampicillin, preferably in the form of an alkaline salt, with a reactive derivative of acetoacetic acid to form the corresponding cheesecloth of formula

 where R1 is an alkyl group having 1-4 carbon atoms, a substituted or unsubstituted aryl or arakyl group; is hydrogen, an alkyl group having 1-4 carbon atoms, or a substituted or unsubstituted aryl or arakyl group R3 is an alkyl group having 1-4 carbon atoms, a substituted or unsubstituted aryl group, an aralkyl group, an alkoxy group containing 1-4 carbon atoms, an aryloxy group or an amine group, and X is a metal alkaline, an alkaline earth metal or an organic base  b) reacting the intermediate obtained on α-bromodiethyl carbonate, of formula

 to form the corresponding ester, of formula

 where R11 R2 and R3 have the meaning given above and  c) carrying out a moderate hydrolysis in an acid medium in order to obtain the compound of formula (I) 2 Method according to claim 1 e characterized in that the alkaline salt of ampicillin is obtained by, transformation of m 'ampicillin trihyarate, by a process known per se in a polar solvent, preferably the N, N-dimethylformamide  3. Method according to claim 1, characterized in that the reaction for forming the stamen (II) is carried out, preferably in the presence of an organic base or an alkali carbonate, by reacting the alkali salt of l ampicillin on an alkyl acetoacetate, preferably methyl or ethyl acetoacetate in an amount of 10 to 50% greater than the stoichiometric ratio, in an aprotic polar solvent, preferably chosen from NjN-dimethylacetamide / ae NN.-dimethylformamide, dimetboxyethane, dLmethylsulfox.yde / tetrahydrofuran and dioxane1 at a temperature between 0 and 60 C, and preferably between this 3dot, for a time between 2 and 8 hours, preferably for 3 hours.  4. Method according to claim 1, characterized in that the esterification reaction of enamine (II) is carried out by addition, to the reaction mixture, of i -bromodiethyl carbonate, the reaction taking place at a temperature from 15-800C, preferably between 45-550C, for 1-24 hours, preferably for 5-10 hours.  5. Method according to claim 4, characterized in that the esterification reaction is carried out in the presence of a catalyst preferably chosen from quaternary ammonium salts, alkali metal bromides, alkali metal iodides and ethers cyclic, especially tetrabutylammonium bromide.  6. Method according to claim 1, characterized in that the hydrolysis is carried out with dilute hydrochloric acid after isolation of the ester (il.).  7.- Method according to any one of claims 1 to 3, characterized in that  a) reacting enamine (11) on a compound of formula

 where Z is Cl or I, and  b) the reaction between compounds II and V is carried out in the presence of a catalyst, preferably chosen from quaternary ammonium salts, bromides and iodides of alkali metals and cyclic ethers, the catalyst being more particularly bromide of tetrabutylammonium.  8. Method according to any one of claims 4, 5 or 7., characterized in that the catalyst is present in an amount of 0.005 to 0.10 mole, preferably from 0.01 to 0.10 mole per mole respectively of compound III and V.  9. Compound of formula

 10. Compound of formula

  11. Process for the preparation of a compound of formula

 characterized in that it consists  a) reacting an aldehyde of formula  CH3CHO VI on carbonyl bromide  COBr2 VII to form a compound of formula

 and reacting compound VIII with C2H5OH to form a compound of formula III, this process being preferably carried out in the presence of a catalyst, which is preferably used in an amount of 0.05-0.5, in particular 0.05-0.15 mole per mole of compound VI, the catalyst preferably being a tertiary amine, a tertiary phosphine, an amide, a urea or a substituted thiourea, an amide of phosphoric acid, a salt tertiary oxonium or sulfohium, or a quaternary ammonium or phosphonium salt.  12. Process for the preparation of a compound of formula

 consisting in reacting the compound of formula

 on an alkaline bromide of formula  R - Br X where R is an alkali metal, preferably 'la, to form the compound of formula III, characterized in that the reaction takes place in a two-phase solvent system comprising water and a non-organic organic solvent miscible with water, preferably a halogenated hydrocarbon or an aromatic hydrocarbon, in particular dichloromethane, in the presence of a phase transfer catalyst, preferably a quaternary ammonium salt.  13. Use of alpha-bromodiethyl carbonate, caracterized in that it applies to the preparation of  s ethoxycarbonyloxydthyl esters of 6-aminopenicillanic acid, penicillins and cephalosporins.  14. Process for the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporins, comprising reacting 6-aminopenicillanic acid, penicillin or cephalosporin, or a salt thereof on carbonate of alphahalodiethyl, characterized in that a quaternary ammonium salt is used as catalyst, preferably in an amount of 1 to 25%, in particular from 1 to 10% of an equivalent of the salt of quaternary ammonium for each equivalent of 6-apa acid, penicillin or cephalosporin, the catalyst used being very particularly tetra-n-butylammonium bromide.