LU84882A1 - IMPROVEMENTS IN THE PREPARATION OF ANTIBIOTICS - Google Patents

Description

IMPROVEMENTS IN THE PREPARATION OF ANTIBIOTICS.

The invention relates to a new process for manufacturing the 1-ethoxycarbonyloxyethyl ester of 5 6— (D - (-) - α-amino-a-phenylacetamido) penicillanic acid of formula I: / Τ-Λ / CH3 Y = / I! i! υΗ3 - 10. NH “CO-N-CH —C00— CH - 0 - C00C“ H “C: 2 5” CH “j The invention also relates to: 15 - the new carbonate compound of a-bromodiethvle, used advantageously in the process according to the invention for preparing bacampicillin of formula I, which can generally be advantageously used for the preparation of ethoxycarbonyloxyethyl aster of 6-aminopenicillanic acid, penicillins and cephalosporins; - 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 to the process for preparing the ethoxycarbonyloxyethyl esters of 6-amino-penicillanic acid, penicillins and cephalosporins.

Substance I according to the invention is one. ester of ampicillin, which is of great therapeutic importance since it is well absorbed when administered orally and leads to a much higher blood level of ampicillin 2 than ampicillin itself -even .

This ester is isolated as a hydrochloride, and it is known as bacampi-5 cillin 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- ”picillin hydrochloride by the following two processes: '10 A) Reaction of potassium benzylpenicillinate on α-chlorodiethyl carbonate in organic solvents

at X

or in a 70% aqueous dioxane solution in the presence of sodium bicarbonate. The benzylpenicillin 1-ethoxycarbonyloxyethyl ester obtained is subjected to the reaction of removing the phenylacetic chain via iminochloride-iminoether to obtain the 1-ethoxycarbonyloxyethyl ester of 6-amino acid. penicillanic, 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-phenyl-glycine.

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 (-) - α-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 object of the invention is essentially to create a process for preparing the active ingredient mentioned above, a process which is simpler to implement and which is industrially more advantageous. The object of the invention is also to create a process for the preparation of bacampicillin, starting from ampicillin, this process being greatly simplified compared to the current state of the art while obtaining a high purity. of the product sought.

, The invention also aims to create the new d1α-bromodiethyl carbonate compound / new processes 5 for its preparation; new intermediates in the preparation of carbonate-bromodiethyl; the use of x-bromodiethyl carbonate to prepare the ethc-xycarbonyloxyethyl ester of 6-aminopenicillanic acid and penicillins such as penicillin G, 10 V penicillin and ampicillin; and these improvements made to the preparation process these ethcxvcarbonyloxyethyl esters of ô-aminopenicillanic acid, penicillins and these cephalosporins.

Advantageously, c-bromo-diethyl carbonate is used as a reagent 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-phenylacetamido) penicillanic acid, having the following formula: U V - CH— CO — NH — CH — CH C'f m 25 l \ h (NH, L CO - N-CH-C00 - CH — 0 — CD0C2H5 ch3- 30 characterized in that it comprises the stages consisting: 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. t —CH — CO — NH — CH — CH- ^ ^ sT 3 (II) \ = / I I I | Xch3

N CO— N-CH-COOX

5 tl> R CNc ^ l3

R

Where 10 "* represents an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted arvie group, or an aralkyie group; R represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, or an aralky rump; RJ represents an aikyl group with 1 to 4 carbon atoms, a substituted or unsubstituted aryl rump, an aralkyie group, an alkoxy group with 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 formula following: 25 Br — CH— 0 — COOC, Hc (III)! CH3 to form the corresponding ester, having the following formula: 5 * »Ù ^ V— CH— CO— NH -CH —CH ^ ^ C 3 (IV) \ = JIIII “3, N CO — N-CH — COû-CH — O — COOC, H,

5 R1 — c ^ \ H I

R2— {J CH3

\ cZ

l3 r 10 12 3 where R, R and R 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.

The following substances can be used as caualysers: quaternary ammonium salts, for example tetrabutylammonium bromide, alkali metal bromides or iodides, and cyclic ethers.

The catalyst can be used in an amount between 0.005-0.10 moles 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 compound III.

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 Z-CH-0-C00-C2H5 '(V)

35 I

CH3 6 where Z is Cl or I, form of. embodiment characterized in that the process is carried out in the presence of a catalytic amount of a catalyst as mentioned above. Advantageously, the catalyst is used in an amount of 0.005 to 0.10 mole per mole of compound V.

1 2

By way of example, mention may be made of. radicals R, R and R3: alkyl: CH ^, ^ 2 ^ 5, n — C3H.y1 ^ "" ^ 3 ^ 71 alkoxy (R3 only): 0CH3, OC2H3, OCH2CH2CH3, 10 och (ch3) 2, o ( ch2) 3ch3 aryl: · ^ substituted aryl: phenyl substituted by your halogen 15 such as Cl and Br aryloxy: 1 _ - CH? - (fr ^) 20 aralkyl: 2 W /

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 of ampicillin is a 1-methoxy-carbonyl-propenyl-2 group, or a 1-methoxy-carbonyl-propenyl-2 group, the intermediate of which preferred 35 is the. sodium or potassium salt, respectively of N = - (1-methoxy-carbonyl-propenyl-2) penicillanic acid and Nm {1-ethoxy-carbonypropenyl) -2) penicillanic acid according to 7 12 7 formula II (R = methyl, R = methyl, R = methoxy or ethoxy, X = Na or K).

Intermediate IV is stable in neutral or alkaline medium, while in acidic medium it is possible to remove the group protecting the amino group simply, quickly and selectively.

The group protecting the amino group of ampicillin can be chosen, for example, from the radicals mentioned in British Patent No. 991,586, or from other radicals known in the art.

Compound III, d1α-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 a-chlorodiethyl carbonate on bromide 15 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 Ν, Ν-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 methyl acetoacetate; - adding 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 enamine (IV); - hydrolyzing the protective group with HCl diluted in an organic solvent, for example n-butyl acetate / water; - to recover - bacampici1line hydrochloride by saturation in aqueous phase, for example with, chloride. sodium, and to extract it using a suitable solvent, for example n-butyl acetate; 8! to concentrate 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 bacam-picillin hydrochloride, so to speak, in a single operation, and with high purity.

"10 Indeed, the impurities present in the product obtained by the process according to the invention are negligible compared to those that have 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 is readily available in a pure form and at low cost.

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 with methyl acetoacetate or ethyl, at 10 to 50% more than the stoichiometric ratio, in the presence of an organic base or an alkali metal carbonate, for example potassium carbonate.

: Intermediate (II) can be isolated and added to 1a.

esterification reaction in solid form. Or else, without isolating the intermediate (II), one can carry out the. esterification reaction in the same solvent as that 30 '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. Ν, Ν-dimethylacetamide, N., N-dimethyl-35 formamide, dimethoxyethane, dimé.thylsulf oxide, t.trahydrofuran- or dioxane.

To finish the. reaction, it suffices to leave the 9 components of the mixture in contact at a temperature between 0 and 60 ° C. preferably between 20 and 30 ° 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 - phenylglvcine 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 the α-bromodiethyl carbonate to the mixture, takes place at a temperature. erection between 15 and 80 ° C, preferably between 45.

and 55 ° C, for a time between 1 and 24 hours, 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 (IV) 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 the protective group is completely hydrolyzed, which requires, at ordinary temperatures, a contact time of 2 to 8 hours, preferably 4 to 5 hour s.

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 n-butyl acetate.

If the organic phase is concentrated under low pressure at a temperature of 40 ° 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 in. look at the examples below:

Example 1. Preparation of g-bromodiethyl carbonate 10 acstone

NaBr + C1-CH-0C00C2H5- ^ Br-ÇH-OCOCK ^ Hg + NaCl

I L α I

, ch3 ch3

102.9 g of sodium bromide in 600 ml of acetone over 152.6 g of α-chlorodiethyl carbonate were reacted for 2-3 hours at room temperature (20-25 ° C). The mixture was then concentrated in vacuo at low temperature (maximum 35 ° C) 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 the α-bromodiethyl carbonate were washed with 800 ml of H 2 O, 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 35 ° C) 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 carbo-nate was suspended in 200 ml of Ν ', Ν-dimethylacetamide, and 32.4 ml (0.3 mole) of methyl acetoacetate and 60.4 g (0.15 mole) of ampicillin 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 tetrabutylammonium bromide and 100 ml of N, N-dimethylacetamide are added.

The mixture is heated with stirring for 10 hours at 40-42 ° 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 stirred continuously for 4 hours at 22-23 ° C.

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% aqueous solution of, 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 on. extracts the 25 'aqueous phase with 200 ml of n-butyl acetate.

The n-butyl acetate phases after recombination are concentrated under low pressure at 40 ° C to one. volume of about 300 ml. The product is left 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 r-ethoxycarbonyl-oxyethyl ester of 6- (D (-) - a-amino-a-phenylacetamido) penicillanic acid, mp 160-162 ° C with decomposition, and having characteristics in accordance with the sample of authentic hydrochloride.

d12

Example 3 t

36/4 g (0/075 mol) of N- (1-methoxycarbonyl-propenyl-2) -6- (D (-) -a-amino-a ~ phenylacetamido) potassium penicillate are added to a solution of 17, 8 g (0.116 mole) of 5 α-chloroethyl acetate and 3 g (0.01 mole) of tetrabutylammonium bromide in 150 ml of Ν, Ν-dimethylformamide. With stirring, the temperature is raised to 45 ° C and maintained at 45-50 ° C 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 ml 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 1 hour period.

After allowing the solution to 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 ml) 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 40 ° C to a volume of 120 ml.

The product is left to crystallize for 15 hours at 5 ° C.

It is filtered, washed with 50 ml of 35 n-butyl acetate and 50 ml of ethyl acetate before drying under vacuum at 40 ° C.

25.2 g (66.9%) of the hydrochloride of the ester 13 1-ethoxycarbonyloxyethyl of 6- (D) - (-) - a-amino-α-phenylacetamido) penicillanic acid, PF 160- are obtained. 162 ° C.

Analytical results:

Title: 97.82%.

5 Rotatory power: + 166.3 ° (c = 1, EtOH 95 °). pH: 4.05 (2% aqueous solution).

Moisture content: 0.82%.

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

The IR and NMR spectra are normal.

Residual ampicillin: 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 carbonate finely sprayed in 100 ml of N, N-dimethylformamide.

It is kept under stirring at 22-23 ° C for 3 hours at the end of which a strong fluidization of the mass can be observed.

We now add, in this order, 17.8 g (0.117 mole) of α-chlorodiethyl carbonate, 3 g (0.01 mole) of tetrabutylammonium bromide and 50 ml of Ν, Ν-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 consisting of 600 ml of water to 200 ml of n-butyl acetate, it is stirred until complete dissolution, the aqueous phase is collected 30 and it is extracted with a further 50 ml of 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 22-23 ° 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 an aqueous solution 14 at 10% of Na2CO3, then bleaching carbon is added thereto and 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 40 ° C to a volume of about 150 ml.

..10 The product is left to crystallize for 15 hours at + 5 ° C, filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate before drying under a vacuum of 10 mm of mercury (1.33 kPa) in the presence of humidity at 25 ° C for 24 hours.

Yield: 20.8 g (55%) of the hydrochloride of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - a-amino-a-phenylacetamido) penicillanic acid, mp 159-1 6.1 ° C., with characteristics consistent with a control sample.

Example 4a

20 A DÄNE salt esterification test was carried out

ampicillin with ethyl acetoacetate according to Example 4. The following results were obtained:

Product: 16.1 g of a white crystalline product.

Mp: 144-148 ° C (Tottoli apparatus) 25 IR / CCM: K.F. compliant : 0.35% pH: 3.55 (2% aqueous solution)

Analysis: 95.2%

Total residual solvents: 3.5% 30 If, in a variant of this test, the addition of chlorodiethyl carbonate is carried out in two phases, the first phase consisting in immediately adding 9 g, and the second phase in adding 9 others grams after two hours, we obtain, after heating for 3 hours at 45 ° C, 35. the following results. :

Product: 13.7 g of a beige crystalline product PF: 143-146 ° C (Tottoli apparatus) i 15 IR / CCM: K.F. : 0.2% pH: 3/43 (2% aqueous solution)

Analysis: 94.8% 5 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-methoxycarbonyl- acid is stirred for 15 minutes at a temperature of -20 to -30 ° C. 10-propenyl-2-aminophenylacetic, 6.9 ml (0.088 mole) of ethyl chloroformate and 3 drops of N-methylmorpholine. A solution of 16.2 g of 6-aminopenicillanic acid dissolved in 35 ml of water is added to this reaction mixture at once by moderate addition of 7.6 g (0.075 mol) of triethylamine with stirring. , after which the mixture is diluted with 90 ml of acetone and cooled to -20 ° C.

After having stirred 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-dimethyl-formamide. The mixture is stirred at 25 ° C for 18 hours, at the end of 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 25 and extracted with another 50 ml of n-butyl acetate.

The organic phases, 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 with 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 are brought, after recombination, to pH 4 with a 10% aqueous Na 2 CO 4 solution, activated carbon is added thereto and filtered. 150 ml of 16 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 40 ° C to a volume of about 150 ml. The product is left to crystallize for 15 hours at + 5 ° C.

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 25 ° C. for 24 hours.

Yield: 1.17 g of hydrochloride of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - a-amino-a-phenyl-acetamiao) penicillanic acid, mp 159-161 ° C, with 15 characteristics (NMR, TLC) in accordance with a control sample.

Example 5a

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

Yield: 1.05 g of hydrochloride of the ethoxy-carbonyloxyethyl ester of 6- (D (-) - a-amino-a-phenyl-acetamido) penicillanic acid in the form of a white crystalline powder, PF 148 -151 ° C with decomposition and presenting characteristics (TLC, IR) consistent with a control sample.

Example 6

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

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

It is heated with stirring for 17 hours at 35-3.7 ° C, and the reaction mass is poured into a mixture consisting of 300 ml of water and 100 ml of butyl acetate.

1 7

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 N HCl 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 is extracted with 25 ml of water.

The aqueous phases, after recombination, are brought to pH 4 with a 10% aqueous solution of, then activated carbon is added thereto and 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 about 75 ml. The product is left 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 1-ethoxycarbonyl-25-oxyethyl ester of 6- (D (-) - a-amino-a-phenylacetamido) penicillanic acid, mp 160-162 ° C and having characteristics in accordance with a control sample of the hydrochloride _ -î (for example IR: v 1790 cm, ß-lactamecarbonyl).

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 G, 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-bromodiethyl carbonate, having the formula:

Br CH3 — CH.O.CO.O.C ^ (III) 5

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 alpha (ethoxycarbonyloxy) ethyl esters ^ 10 of l β-aminopenicillanic acid, penicillins and cephalosporins, for example the antibiotic bacampi-cillin. Alpha-bromodiethvla carbonate can therefore be advantageously used to prepare the ethoxy-carbonyloxvethyl esters of β-aminopenicillanic acid, penicillin G, penicillin V and ampicillin.

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

A. The first of these methods, Method A, includes the. steps consisting in: (a) reacting an aldehyde of formula

ch3cho VI

on carbonyl bromide

25 COBr2 VII

to obtain an alpha-bromo-bromoformate of formula:

Br

CH3-CH.0.CO.Br VIII

30 and; (b) reacting · the alpha-bromo-bromoformate of formula VIII s.ur an alcohol of formula C-, Η ^ -ΟΗ to obtain the desired alpha-bromo-diethyl carbonate of formula III.

The process A according to the invention can thus be summarized by the. series of. reactions- following: 1 9 Γ

Br + CoH (-0H Br i 2 5 i CH3CH0 + COBr2 -> CH3 — CH.O.CO.Br-> CH3 ~ CH.O.CO.CgHg + HBr 5 The alpha-bromo-bromoformate of formula VIII is in itself a new compound and falls within the scope of the invention.

The reaction between the aldehyde CH3CKO and the carbonyl bromide is best carried out in the presence of a catalyst which can be, for example, a tertiary amine (for example a tertiary aliphatic amine, a mixed alkyl / tertiary aryl amine or an amine tertiary aromatic), tertiary phosphine, amide, urea or substituted thiourea, phosphoramide, an oxonium or tertiary sulfonium salt or an ammonium or quaternary phosphonium salt. Mention may be made, as preferred examples of catalysts which can be used in process A according to the invention, of pyridine, dimethylformamide, tetra-n-20-butyl-urea, triamide of hexamethvlphosphoric acid and benzyltrimethylammonium bromide. .

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

The reaction between the aldehyde and the carbonyl bromide is advantageously carried out in the presence of a solvent which can be, for example, an aromatic hydrocarbon such as toluene, or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chloro-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. Carbonyl bromide is usually used in a molar excess relative to the aldehyde, this molar excess being advantageously from 10 to 100%, preferably from 20 to 50%.

The intermediate alpha-bromo-bromoformate of formula VIII obtained in step (a) that process A according to the invention does not need to be isolated before the reaction with the alcohol C2H6.OH and, in fact, it is generally preferred that it is not. Thus, according to a preferred embodiment of the invention, the reaction mixture obtained in step (a) 5 is freed from excess carbonyl bromide, for example by heating under reduced pressure or by flushing with 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 with. 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 appear that the possible residual catalyst from step (a) or its complex with carbonyl bromide does not interfere with the subsequent reaction and, in some cases, it even proves advantageous.

L! Crude alphabromocarbonate 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 by way of 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 in the preparation of α-bromodiethyl carbonate, by means of a variant of the Finkelstein reaction, that is to say a reaction of a chloride of alkyl or 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 the reaction of 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 .

21

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 certain cases, catalytic quantities of the alkali metal bromide or iodide are sufficient, and the more reactive species obtained can react with the desired substrate, which regenerates the alkali metal bromide or iodide, which allows the reaction to continue.

The reaction cannot proceed with all of the substituted alkyl or arylalkyl chlorides: in particular, it has proved difficult to carry out the reaction with alpha-chloroesters and alpha-chlorocarbonates, that is to say i.e. compounds in which the chlorine atom is attached to a carbon atom which, in turn, is attached to either end of a group -C (0) -0- . An example of such an alpha-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate in the preparation of the ethoxycarbonyloxyethyl 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. 25 immiscible with water in the presence of a phase transfer catalyst.

According to process 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 4, process characterized in that the reaction takes place 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 dichloromethane; and hydrocarbons 22! aromatic 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 can be, for example, sodium, potassium or lithium bromide, lithium bromide being preferred.

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

Cl 0 1 it’s

ch3 — ch — o-c — o — c2h5 IX

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:

Br 0

I II

CHj-CH — 0-C- 0-C2H5 III

25 As noted above, the alkali metal R

preferred is Li, of. so that LiBr is a preferred reagent of formula X.

In connection with method B, it has been found that lithium bromide can be advantageously used in one. classic Finkelstein reaction (i.e. a reaction using a single-phase organic solvent system), for example to halogenate an alpha-chlorocarbonate. This process is presented in Example 10.

The invention therefore relates, according to one. another embodiment, one. process for preparing α-bromodiethyl carbonate, consisting in reacting · α-chlorodie.thyle carbonate. on lithium bromide.

Γ 23

Examples of solvents that 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 ethoxy-carbonyloxyethyl esters 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 l ampicillin, and cephalosporins, 2. a process for the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporins, characterized in that it reacts acid 6 -aminopenicillanic, penicillin or cephalosporin, or a salt thereof, on α-bromodiethyl carbonate to form the ethoxycarbonyloxyethyl ester, respectively 6-aminopenicillanic acid, penicillin and cephalosporin, 25 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 quaternary ammonium compound being present in an amount of 1-25%, preferably 1-10% of the equimolar amount corresponding to the amount of 6-apa acid, penicillin or cephalosporin (amino acid penicillanic).

Ethoxycarbonyloxyethyl ether, in particular 6-apa acid and penicillin G, is used, as is known in the art, to prepare any such semi-synthetic penicillin ester 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-bromo-diethyl 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 times. very long reaction. These severe conditions limit the usefulness of the. reaction within the framework 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 β-apa, penicillin or cephalosporin,. 'On 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 was not necessary to use the quaternary ammonium salt in a stoichiometric amount relative to the carboxylic acid, i.e. say β-apa, penicillin or cephalosporin, but that 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 ethoxycarbonyloxyethyl ester of 6-apa acid, a penicillin or a cephalosporin by reaction of a metal salt of 6-apa, penicillin or cephalosporin on an α-halogenodiethyl 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 -in relation to 6-apa, penicillin or cephalosporin.

According to the invention, 1 to 25% of an equivalent of the quaternary ammonium salt is used for each equivalent of the metal salt of the carboxylic acid, and, more particularly, 1 to 10% of an equivalent of the quaternary ammonium salt.

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. mineral acid such as hydrochloric, hydrobromic or sulfuric acid.

The metallic 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 alkaline earth metals, such as sodium, potassium, lithium, magnesium and calcium salts. Mention may be made, as quaternary ammonium 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 tetra-n-butylammonium bromide and cetyltrimethylammonium bromide, and quaternary pyridinium salts, such as cetylp.yridinium 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 may be used include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethyl sulfoxide. Or. again, when no solvent is used, an excess of the halide forming the ester can be used, particularly if it 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 the ethoxycarbonyloxyethyl esters of β-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% excess of this halide. * 25 The improvements made to the esterification processes according to the invention are particularly suitable for the preparation of β-apa esters, penicillins and cephalosporins. According to a preferred embodiment of the invention, the carboxylic acid may have the following formula: i S ^ / CH, R -NH - | -3! î CH,

35 I I XI

J-N -1 '/ rn h 0 uu2 or 27 R1-NH —- ^

I 2 XII

N S? R

5) - * "r 0

C02H

10 where R is a hydrogen atom or an acyl group, in particular a substituted acetyl group such as phenyl acetyl; an alpha-aminophenylacetyl group; alpha-aminoparahydroxyphenylacetyl; phenoxyaceticia; alpha-carboxyphenylacétvle or alpha-carboxy-3-thienylacétyle or 15, when the carboxylic acid is of formula XII, a group: N-OCHo _ "3 20 'H Γ CXsC0- ΧΠΙ r3-" hl] where R ^ is a hydrogen atom or a group protecting an amino group such as a benzyloxycarboxyl group, 2-trimethylsilyl or tert-butyloxycarboxyl group, and R 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 substituted acetoxy or acetoxy group (for example an alkylacetoxy, arylacetoxy or arylalkylacetoxy group, or the group CgH ^ .CHOH.CO-).

In the preparation of the penicillin and cephalosporin esters according to the invention, the ester forming the halogenide is an alpha-halogenodialkyl carbonate of formula CH.3-CH (X) -o-co-o-ch2-çh3 , where X is a chlorine, bromine or iodine atom, preferably a bromine atom.

. ï

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 maintained 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 mole) of freshly distilled carbonyl bromide.

The mixture was allowed to warm to room temperature, then heated to 50 ° C and maintained at that temperature for 3 hours, during which time a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C gave a semi-solid oily mass dissolving easily in ethanol (92 g, 2 moles) by heating and boiling under reflux. After heating at reflux for a further 2 hours, the excess ethanol was removed in vacuo and the residue was triturated with 100 ml of water and 200 ml of methylene dichlorurea.

Separation of the organic layer and fractional distillation gave 130 g (yield 66%) of pure ethyl alpha-bromoethylcarbonate, having a boiling point of 90-92 ° C under 45 mm of mercury (5.99 kPa), and identical in all respects 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 hexamethylphosphoric acid triamide was cooled to -10 ° C and gradually added 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 10 ° C.

Γ 29 ι

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%).

; The nature of the ethyl alpha-bromoethylcarbonate 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 120 ° C. It was lit by a 150 W tungsten filament lamp. 96 g (0.6 mole) of bromine was added dropwise over 3 to 4 hours, and at this speed the mixture did not darken. not 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 (0.1 mole) of ethyl alpha-chloroethyl carbonate, 100 ml of water was stirred at room temperature for 24 hours. 100 ml of dichloromethane and 1.5 g of cetyl-trimethylammonium bromide. The aqueous layer was removed and replaced with a fresh solution of 26 g (0.3 mole) lithium bromide in 40 ml of water containing 1 g of 35-cetyl trimethylammonium bromide. After stirring for a further 24 hours, during which time the temperature rose to 35 ° C, the organic layer was separated, dried and distilled under vacuum to give, after repeated fractionation, the "new alpha compound". ethyl bromoethylcarbonate (15.0 g yield 76%), with a boiling point of 90-92 ° C under 35 mm of mercury (4.66 kPa).

5 Found: C '30, 7; H 4.8; Br 40.1 I Calculated: C 30.5; H 4.6; Br 40.6%

The following results were obtained in the NMR spectrum: 1.2-1.6 (3H, triplet) -CH2.CH3 2.0-2.2 (3H, doublet) -CH.CH ^ - 10 4.1-4 , 5 (2H, quadruplet) -C ^ .CH ^ s 6.5-6.8 (1H, quadruplet) -CH.CH ^ s - 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 cooling, ethyl alpha-bromethylcarbonate, with a yield of 76% on the basis of ethyl alpha-chlorethylcarbonate recovered.

Example 11 - - -

The conformity of the above new ethyl alpha-bromethylcarbonate compound was confirmed as follows, by 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. 30 added in small portions 28.6 g (0.1 mole) of dibromodimethylhydantoin, over an 8 hour period, together with additional additions of ΆΙΒΝ (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 a. was subjected to vacuum fractional distillation to give pure ethyl alpha-bromethylcarbonate (32.3 g, 82%) identical in all respects to the product ’31 of Examples 9 and 10.

Example 12 Ester, ethoxycarbonyloxyethyl of benzyl-penicillin

A mixture of 7.4 g (20 millimoles) of the potassium salt of penicillin G, 4.6 g (30 millimoles) of ethyl alpha-chlorethylcarbonate, 0 was stirred and heated under moderate reflux for 45 hours. , 8 g (2.5 millimoles) of tetra-n-butylammonium bromide and 80 ml of acetone. The excess acetone was removed under partial vacuum and the residue 10 was triturated with ice water and methyl isobutyl ketone. Evaporation in vacuo of the dried methyl isobutyl 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- ester ( ethoxycarbonyloxy) -15 ethyl of 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 Benzoxy-penicillin ethoxycarbonyloxyethyl ester

Example 12 was repeated using 5.9 g. (30 millimoles) of ethyl alpha-bromethylcarbonate in place of ethyl alpha-chloroethyl carbonate, and there was obtained, after evaporation of the methyl isobutyl ketone, 6.0 g of an oil, semi-crystalline, which was then triturated with hot ethanol and then cooled to give white crystals (2.5 g, 35% yield) of the alpha- (ethoxycarbonyloxy) ethyl ester of penicillin G.

EXAMPLE 14 Benzyl-penicillin, ethoxycarbonyloxyethyl ester

Carefully mixed in 41 ml of methylene chloride and heated to 40 ° C 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 35. tetrabutylammonium bromide. As soon as this temperature has. summer. reached, we have. 17.16 g (86.7 millimoles) of α-bromodiethyl carbonate was added, and the suspension 32 was stirred for 4 hours. 30 ml of water were added, followed by 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 again evaporated. Residual oil a. 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% for the ethoxycarbonyloxyethyl ester of benzylpenicillin.

Example 15. Ester, ethoxycarbonyloxyethyl of benzyl-penicillin

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 thoroughly stirred in an ice bath. 3.70 g (18.6 millimoles) of α-bromodiethyl carbonate was added over a period of 30-40 minutes using a pump. syringe. Stirring was continued while keeping the reaction mixture in the ice bath. High performance liquid chromatography showed that one had obtained in 5-10 minutes. yield of approximately 70% of the ethoxycarbonyloxyethyl ester of benzylpenicillin.

Example 16. Benzoxypenicillin ethoxycarbonyloxyethyl ester

Stirred thoroughly in 70 ml of acetone and heated to 40 ° C 47.03 g (125 millimoles) of potassium benzylpenicillinate, 0.94 g (11 millimoles) of bicarbonate 35. sodium and 2.01 g (6.25 millimoles) of tetrabutylammonium bromide. As soon as this temperature has. been reached, we. added 26.06 g. (131 millimoles) a-bromodiethyl carbonate and the suspension was stirred for 4.5 hours. Qn was added 56 ml of water and then a mineral acid until a pH of approximately 5 was obtained. The mixture was stirred for approximately 3 hours, during which time 4% sodium hydroxide was added to keep 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 remaining oily product was dissolved in methylene chloride to a total volume of 250 ml. High performance liquid chromatography of the methylene chloride solution showed a 98-99% yield of the benzoxypenicillin ethoxycarbonyloxyethyl ester.

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 going beyond the ambit of 1 ' invention.

Claims (14)

34 1. Process for the preparation of the 1-ethoxy-carbonyloxyethyl ester of 6- (D - (-) - a-aiaino-a-phenyl-acetamido) penicillanic acid of formula 5 CH - CO - NH - CH - CH C (I) \ = / i III CH3 NH "CO - N-CH - C00 - CH - 0 - COOC ^ H, 2! 25 • .. 10 ch3 characterized in that it comprises the stages consisting in: a) reacting the ampicillin, preferably in the form of an alkaline salt, with a reactive derivative of acetoacetic acid to form l 'corresponding enamine of formula: r— // - CH - CO - NH - CH - CH' “fl il I CH3 20 i / \ CO - N - CH - C00X (II) R1— CHR * -! ο V 13 25 * where R is an alkyl group having 1-4 carbon atoms, a substituted or unsubstituted aryl or aralkyl group; R is hydrogen, an alkyl group having 1-4 carbon atoms, or a substituted or unsubstituted aryl or aralkyl group? "3 30. is an alkyl group having 1-4 carbon atoms, a substituted or unsubstituted aryl group, an aralkyl group, an alkoxy group having 1-4 carbon atoms, an aryloxy group or an amine group, and X is an alkali metal, an alkaline earth metal or an organic base; 35 b) reacting the intermediate obtained on α-bromodiethyl carbonate, of formula: 35 Br-CH-O-COO C ~ Hc (III) i ^ D ch3 to form the corresponding ester, of formula: 5 _ ^ S ^ CHj (/ x \ - ch - CO - NH - CH - CH CWI | | | xch3 / N \ CO - N - CH - C00 - CH - 0 - C00C2H5 R - CH I 9 il: CH- · - 10 r2— cq 3? \ // 'f3 R (ÏV) 15 12 3 where R, R and R have the meaning given above and c) to carry out a moderate hydrolysis in acid medium to obtain the compound of formula (I). 2. Method according to claim 1, characterized in that the alkaline salt of ampicillin is obtained by transformation of ampicillin trihydrate, by a method known per se in a polar solvent, preferably N, N-dimethylformamide. 3. Method according to claim 1, characterized in that the reaction for the formation of enamine (II) is carried out, preferably in the presence of an organic base or of an alkali carbonate, by reacting the alkali salt of ampicillin on an alkyl acetoacetate, preferably methyl or ethyl acetoacetate in an amount of 10 to 50% greater than the stoichiometric ratio, in a polar aprotic solvent, preferably chosen among Ν, Ν-dimethylacetamide, 'Ν, Ν-dimethylformamide, dimethoxyethane, dimethvlsulfox.yce, tetrahvdrofuran and dioxane, at a temperature between 0 and 60 ° C, 35 and preferably between 20 and 30 ° C, 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 the enamine (II) is carried out, by addition, to the reaction mixture, of α-bromodiethyl carbonate, the reaction taking place at a temperature from 15-80 ° C, preferably between 45-55 ° C, 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 Cyclic ethers, especially in particular tetrabutylammonium bromide. 4 6. Method according to claim 1, characterized in that the hydrolysis is carried out with dilute hydrochloric acid after isolation of the ester (IV). 7. Method according to any one of claims 1 to 3, characterized in that a) reacting enamine (II) on a compound of formula Z - CH - 0 - C00 - C2H5 CH3 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 tetrabutylammonium bromide. 8. Method according to any one of claims 4, 5 or 7, characterized in that the catalyst is present. i in an amount of 0.005 to 0.10 mole, preferably 0.01 to 0.10 mole per mole of compound III and V respectively. 9. Compound of formula: Br - CH - 0 - C - O - C2H5 ch3 10 Br CH-, - CH - OCO - Br VIII "6, # and reacting compound VIII with C2H50H to form a compound of formula III, this process preferably being 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 substituted urea or thiourea, a phos-phoric acid amide, an oxonium or tertiary sulfonium salt, or an ammonium or quaternary phosphonium salt. 10. Compound of formula: Br t CH3 - CH - 0C0 - Br r 37 11. Process for the preparation of a compound of formula: Br O ch3 -ch-oco c2h5 III characterized in that it consists of 5 a) reacting an aldehyde of formula ch3cho VI on carbonyl bromide COBr2 VII to form a compound of formula 12. Process for the preparation of a compound of formula Br 0 ch3 -ch-oco -c2h5 III 25 consisting in reacting the compound of formula Cl 0: CH3 -CH-OCO-C2H5 IX on an alkalinepromide of formula .R - Br X 30 where R is an alkali metal, preferably Li, to form the compound of formula III, characterized in that the reaction takes place in a two-phase solvent system comprising water and an organic solvent immiscible 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. V * 38 13. Use of alpha-bromodiethyl carbonate, characterized in that it applies to the preparation of ethoxycarbonyloxyethyl esters of 1 '- 6-amino-penicillanic acid, penicillins and cephalosporins. 14. Process for the preparation of the ethoxycarbonyloxyoxy ester of 6-aminopenicillanic acid, penicillins and cephalosporins, consisting in reacting 6-aminopenicillanic acid, penicillin or cephalosporin, or a salt thereof on alpha-halogenodiethyl carbonate, 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 one equivalent of the quaternary ammonium salt for each equivalent of 6-apa acid, penicillin or cephalosporin, the catalyst used being very particularly tetra-n-butylammonium bromide.