ITMI960873A1 - PROCESS FOR THE PREPARATION OF UREIDE DERIVATIVES AND NEW SYNTHETIC INTERMEDIATES - Google Patents

Description

Patent application for Industrial Invention entitled:

"Process for the preparation of urea derivatives and synthetic intermediates."

FIELD OF THE INVENTION

The present invention relates to a new process, with low environmental impact and economically advantageous, for the synthesis of ureid derivatives and in particular antibiotics (β-lactams; said process, which allows the condensation of nitrogenous cyclic compounds and compounds containing a primary amino group with chloro-carbonyl derivatives to give acylureaid derivatives, uses new synthesis intermediates particularly advantageous in the industrial preparation of various classes of semisynthetic antibiotics.

STATE FROM TECHNIQUE

Among the most common β-lactam antibiotics currently there are penicillins and acylureaid cephalosporins, characterized

by the presence of an ureidic bond of formula

piperacillin, mezlocillin and azlocillin are semi-synthetic penicillins, while cefoperazone is a widespread third generation cephalosporin.

These active ingredients have a broad antibacterial spectrum against both Gram-positive and Gram-negative bacteria and show a high resistance to attack by the β-lactamases produced by the bacteria themselves; moreover, they constitute therapeutic tools of fundamental importance in the treatment of bacterial infections, being able to exert a high antibacterial activity even against Pseudomonas aeruginosa, Klebsiella pneumonia and bacterial strains of the Proteus species. The widespread clinical use of semi-synthetic antibiotics has given rise to the need for new procedures for their synthesis on an industrial scale, which were economically convenient and acceptable from the point of view of safety, toxicity and environmental protection.

Acylureaid antibiotics are synthesized in the state of the art starting from amino-penicillins or amino-cephalosporins (for example from amoxicillin or ampicillin, in the case of penicillins), by condensation with a suitable nitrogenous heterocyclic derivative, through the use of isocyanates or phosgene (C0C12) as coupling agents.

However, the use of isocyanates is not industrially satisfactory, as there are considerable difficulties in synthesis, due to the numerous side reactions that take place due to the attack of the primary amino group on the C = N double bond and which considerably reduce the synthesis yields. of the desired compounds.

Phosgene (carbonic acid dichloride), as well known in the state of the art, despite being able to give excellent reaction yields, has been subject to severe regulations in Italy and in many foreign countries, due to its high toxicity. ; its transport by air is prohibited, while its transport by land is regulated by strict regulations. In fact, phosgene, considered to be responsible for most of those killed by gas in the First World War, is a gaseous substance that hydrolyzes in the presence of water, with the consequent development of hydrochloric acid; therefore, it is desirable to limit its use in the chemical industry, which on a large scale has high risk and toxicity factors.

The use of diphosgene (trichloromethyl chloroformate) and triphosgene (bis- (trichloromethyl) -carbonate) as condensation agents is also known in the state of the art (H. Eckert and B. Forster, Angew. Chem. Int. Ed. Engl. 26, 1987. n ° 9). However, the risk and toxicity levels of these reagents, used as substitutes for phosgene, are only slightly lower than those of the phosgene itself; in fact, both diphosgene and triphosgene, although easier to prepare and handle, easily undergo decomposition with the consequent release of phosgene and therefore create serious safety problems as regards their transport, storage and use. Furthermore, the above substitutes for phosgene are previously transformed into phosgene itself in order to give the reactions known in the state of the art, as reported by R. Katakai and Y. Iizuke (J. Org, Chem., 1985 · 50. 716-718 ), which obtain the decomposition of the diphosgene by heating in a suitable solvent or by catalysis on activated carbon. In this way the disadvantages of using phosgene are not eliminated.

The need is therefore felt to have available new chemical reagents capable of promoting the aforementioned coupling between nitrogenous heterocyclic derivatives and primary amines, by means of ureidic bonds, essential in the synthesis of acylureid antibiotics. SUMMARY

The Applicant has now surprisingly found a new process for the preparation of urea derivatives of formula (I):

(THE)

in which the ring P is a 5 or 6-membered nitrogen heterocycle, saturated or unsaturated, optionally also containing one or more heteroatoms selected from N, 0 and S, and in which -L is the radical of a compound "containing a group primary amino; said process comprises the condensation of a nitrogenous heterocycle, of formula PN-H, and of a compound containing a primary amino group, of formula L-NH2. with a chloro-carbonyl derivative of formula (II):

(II)

in which R1 and R2, the same or different from each other, are leaving groups, with the condition that said chloro-carbonyl derivative is different from phosgene, diphosgene and triphosgene.

A further object of the present invention are the new intermediates of formula (III) ':

(III) '

wherein R2 'is selected from the group consisting of "CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl, -0-R3, where R3 is a lower alkyl, and -CO- R10, where R10 is selected from the group consisting of -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl and -O-R3, R3 being defined as above; said intermediates are particularly useful in the synthesis of the urea derivatives of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The characteristics and advantages of the synthesis process and intermediates according to the present invention will be better illustrated in the course of the following detailed description.

The process according to the present invention allows nitrogenous heterocycles and compounds containing primary amino groups to be condensed, in an effective and economical way, by means of chloro-carbonyl derivatives which act as condensation agents, to give acylureidic bonds. This process is particularly advantageous for the preparation of semisynthetic antibiotics, being able to give very high yields in the condensation of nitrogen heterocycles, such as piperazine or pyrrolidine derivatives, with amino-penicillins and amino-cephalosporins, such as ampicillin and amoxicillin , giving piperazine antibiotics (e.g. piperacillin), other penicillin acylureid (e.g. azlocillin and mezlocillin) and cephalosporins (e.g. cefoperazone).

The advantages of the process according to the present invention can be summarized as follows:

- elimination of the use of phosgene, a highly toxic and disadvantageous gas on an industrial level;

- reaction yields comparable to or higher than those obtainable with phosgene, with a much lower quantity of coupling agent than phosgene;

- high levels of security;

- low environmental impact;

- cheapness and simplicity of execution.

In the process according to the present invention, the reaction conditions can vary according to the nature of the reaction reagents; the aforesaid condensation can be carried out in solvent, both protic and aprotic, at a temperature between 0 and 100 ° C, for a time between 30 'and 20 hours, with a molar ratio between said PN-H heterocycle and said chlorocarbonyl derivative between 1: 2 and 2: 1. and between said L-NH2 compound and said chloro-carbonyl derivative between 1: 2 and 2: 1.

The above nitrogenous PN-H heterocycles, in which the P ring is a 5 or 6 membered heterocycle as previously reported, are preferably selected from the group consisting of pyrrole, pyrrolidine, pyrrolines, cyclic amino acids, imldazoles and their derivatives.

When said P ring is the residue of a 6-membered nitrogenous heterocycle, it preferably corresponds to the formula (IV):

(IV)

wherein X, Y and Z, the same or different from each other, can be C = 0 or CH-R5, where R5 is selected from the group consisting of H, halogen, -NH2 and -COOR6, with R6 = H or lower alkyl;

Rty is chosen from the group consisting of -H; -OH; linear or branched C1-C4 alkyl, saturated or unsaturated, optionally substituted with sulphonic or alkylsulfonic groups; saturated or unsaturated C3-C7 cycloalkyl, optionally substituted with sulphonic or alkylsulfonic groups; and aryl.

Said 6-membered nitrogen heterocycle is preferably 1-ethyl-2,3-dioxo-piperazine.

When said P ring is the residue of a 5-membered nitrogenous heterocycle, it preferably corresponds to the formula (V):

(V)

where W can be CH2 or N-R4, where and have the meanings previously reported in formula (IV).

In the process of the invention, the coupling agent is a chloro-carbonyl derivative of formula (II), in which it is preferably selected from the group consisting of -Cl, -CCl3, -O-CCl3, 2,4,6-trichlorophenyl , 2.4,6-trichlorobenzyl and -O-R3, wherein R3 is a lower alkyl, preferably methyl or ethyl; R2 can have one of the meanings of R1, independently of it, or it can be -CO-R1, R1 being defined as above; with the condition that said chloro-carbonyl derivative is different from phosgene, diphosgene and triphosgene.

Said chloro-carbonyl derivative of formula (II) is preferably selected from the group consisting of hexachloroacetone Cl3C-CO-CCl3, trichloroacetyl chloride C13C-C0-C1, oxalyl chloride C1-CO-CO-C1 and methyl chloroformate Cl-CO-O -CH3; even more preferably said chloro-carbonyl derivative is oxalyl chloride.

The aforesaid chloro-carbonyl derivatives can be prepared in advance or generated in situ in the reaction environment, by means of conventional procedures. Preferably, C13C-C0-CC13 is prepared from a solution of gaseous chlorine in acetone by catalysis of red phosphorus or U.V .; Cl3C-CO-Cl and C1-C0-C0-C1 are prepared by bubbling chlorine gas in acetic acid or acetic anhydride, in the presence of a suitable catalyst; finally, Cl-CO-O-CH3 can be advantageously prepared by bubbling chlorine gas in methyl formate, in the presence of a suitable catalyst.

Such chloro-carbonyl derivatives are used in approximately equimolar quantities with respect to the nitrogenous heterocycle and to the compound containing a primary amino group; this represents an advantage over phosgene, which is used in large excess with respect to the other reagents.

Furthermore, these chlorine-carbonyl derivatives eliminate the safety and toxicity problems associated with phosgene, both in the preparation and use phases, and allow the development of non-polluting, low environmental impact synthesis processes.

Said compound containing a primary amino group, of formula L-NH2. it can be for example phenylglycine H2N-CH (Ph) -COOH or parahydroxyphenylglycine H2N-CH (C6H4-OH) -COOH. When this compound is phenylglycine or para-hydroxyphenylglycine, and said nitrogenous heterocycle is 1-ethyl-2,3 "dioxo-piperazine, the process according to the present invention leads to obtaining respectively the a- (4-ethyl-2,3 -dioxo-1-piperazino ~ carbonylamino) -phenylacetic and a- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) -ρ-hydroxyphenylacetic, intermediate products of particular importance in the synthesis of piperacillins. they can be subsequently condensed with the amino group of 6-APA (6-amino-penicillanic acid) and 7 "ACA (7-amino-cephalosporanic acid) or their derivatives, obtaining second and third generation piperacillins and cephalosporins. According to a further aspect of the process of the invention, in the synthesis of acylureido penicillins and cephalosporins, the primary amino group of the compound L-NH2 belongs to the side chain in position 6 of an amino-penicillin (e.g. ampicillin and amoxicillin) or in position 7 of an aminocephalosporin. For example, 1-ethyl-2,3-dioxo-piperazine can be condensed with the amino group on the chain at position 6 of ampicillin and amoxicillin, resulting in the synthesis of piperazine penicillins, such as piperacillin.

The process according to the present invention can be advantageously used in the synthesis of βlactam antibiotics of general formula (VI):

(YOU)

in which the ring P has the meanings reported above and in which Q

can be, where R9 is chosen in the

group consisting of -H, -CH3, -CH2-0Ac, -CH2O-CO-NH2 · halogen, -OH, -CN, -NH4 <+>, pyridinium, quinolinium, pyrimidinium.

and R8 is selected from the group consisting of H. methyl, ethyl and a quaternary ammonium cation.

According to an embodiment of the process of the invention, the condensation can take place in two stages, in the first stage by activating the above nitrogenous heterocycles with chlorocarbonyl derivatives, and in the second stage by condensing the activated heterocycles thus obtained with compounds containing primary amino groups, to give acylureidic bonds. The synthesis intermediates of formula (III) can therefore be isolated from the first stage:

(III)

where R2 is a leaving group as defined in formula (II). The intermediates of formula (III) 'are new:

wherein R2 'is selected from the group consisting of -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl, -O-R3, where R3 is a lower alkyl, preferably methyl or ethyl , and -CO-R10, where R10 is selected from the group consisting of -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl and -O-R3, R3 being defined as above; R2 'is preferably -CCl3, 2,4,6-trichlorophenyl or 2,4,6-trichlorobenzyl.

In particular, according to this embodiment of the process of the invention, the following 2 synthesis stages are envisaged: (1) said nitrogenous PN-H heterocycle is reacted with one of the aforementioned chloro-carbonyl derivatives (II) to give an intermediate activated (III), in which R2 is a good leaving group; preferably the nitrogen heterocycle and the chlorocarbonyl derivative, in equimolar ratio, are reacted in an organic solvent, such as hexane or THF, at a temperature of 40-80 ° C, for a time ranging from 30 'to 4 hours.

According to a particular embodiment of the invention, in step (1) said nitrogenous heterocycle can be made to react initially with an activator, such as trimethyl silyl chloride, and then with the chloro-carbonyl derivative;

(2) the activated intermediate (III), obtained from step (1), is "reacted with a compound containing a primary amino group, of formula L-NH2, molar ratios ranging from 2: 1 to 1: 2, and preferably 1: 1. The reaction is preferably carried out by dissolving the L-NH2 compound in an organic solvent such as water, acetone, hexane, THF, dioxane, acetonitrile, DMF, triethylamine, methanol, ethanol, diethyl ether, isopropyl ether, benzene, toluene, ethyl acetate etc., and by reacting the solution thus obtained the activated intermediate, at a temperature between 0 and 100 ° C, preferably between 20 and 70 ° C, for a time between 30 'and 20 hours, possibly in the presence of an organic and / or inorganic base. Said inorganic base is preferably selected from the group consisting of hydroxides, hydrogen carbonates, carbonates and acetates of alkaline and alkaline-earth metals; said organic base is preferably selected from the group consisting of secondary and tertiary amines, such as diets lamine, trimethylamine, triethylamine, tributylamine, pyridine, N-methylpyridine and N-methylmorpholine. The pH of the reaction can vary, depending on the reagents used, in the range preferably between 2 and 10, and more preferably between 4 and 8.

For illustrative but not limitative purposes of the present invention, the following examples are reported.

EXAMPLE 1

Preparation of 1-ethyl-2,3-dioxo-piperazine (EDP).

32 g (0.21 mol) of oxalic acid diethyl ester were "added in the order 32 ml of ethanol and 18.4 g (0.21 mol) of N-ethyl-ethylenediamine, and the mixture thus obtained is was left to react under stirring for 3 hours, at room temperature. The solution was then heated to remove the ethanol and the residue obtained was separated and crystallized from 40 ml of dioxane. 24 g of EDP were thus isolated, in yield of 80% (m.p. = 124 ° C).

Stage 1: preparation of trichloroacetyl 1-ethyl-2,3-dioxopiperazine.

A suspension of 14.2 g (0.1 mol) of EDP in 50 ml of hexane was slowly added to a solution containing 26.4 g (0.1 mol) of hexachloroacetone (corresponding to formula (II) with = R2 = -CCl ^) dissolved in 40 ml of hexane.

The mixture thus obtained was then kept under constant stirring for 40 minutes, at a temperature of 50 ° C. The solution was then heated to 70 ° C for 1 hour and cooled to room temperature (solution A).

The new intermediate of formula (III) <- 1> was also isolated from this solution, where the ring P is the residue of 1-ethyl-2,3-dioxopiperazine and R2 'is -CCl3

Stage 2 (a): formation of the acylureidic bond with phenylglycine. EDP-CO-CCl3 + D-phenylglycine acid a- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic A solution containing 15.1 g (0.1 mol) of D-phenylglycine irr 50 ml of hexane is was slowly added, under constant stirring over 40 minutes, at a temperature of 50 ° C, to solution (A), prepared in step 1. The mixture thus obtained was heated to 70 ° C for 1 hour and then cooled to temperature environment.

After removal of the hexane by distillation under vacuum, the residue was crystallized, obtaining a- (4-ethyl-2,3-dioxo-1-piperazionocarbonylamino) -phenylacetic acid in a yield of 84% (m.p. = 165 ° C) .

Stage 2 (b): formation of the acylureidic bond with ampicillin.

EDP-CO-CCl3 + ampicillin - piperacillin The solution obtained in step 2 was reacted as described in step 2 (a), replacing D-phenylglycine (15.1 g; 0.1 mol) with anhydrous ampicillin (35 g; 0.1 moles), yielding piperacillin in yields greater than 80 $. having the following chemical-physical characteristics:

- melting point: 183-185 ° C;

- IR spectrum (KBr): stretching C = 01765 cm <-1> (lactam), 1720-1679 cm <-1> (- CON *), 1600 cm <-1> (- C00-).

EXAMPLE 2 - Stage 1: preparation of trichloroacetyl 1-ethyl-2,3-dioxopiperazine.

A mixture of 1.0 g (0.01 mol) of trimethylchlorosilane and 1.0 g (0.01 mol) of triethylamine was added, under constant stirring, to a solution containing 1.4 g (0.01 mol) of 1-ethyl-2,3_dioxo-piperazine in 30 ml of dioxane. The mixture thus obtained was then kept under constant stirring for 20 hours and then filtered to remove the solid suspensions of ammonium salts. The filtrate was percolated in a solution containing 0.75 S of trichloroacetyl chloride (0.01 moles; corresponding to formula (II) with R1 = -Cl and R2 = -CCl3) in 20 ml of tetrahydrofuran; the solution thus obtained was kept under stirring for another 2 hours (solution B).

The new intermediate of formula (III) 'was also isolated from this solution, where the ring P is the residue of 1-ethyl-2,3 ~ dioxopiperazine and R2' is -CCl3 ·

Stage 2 (a): formation of the acylureidic bond with phenylglycines. EDP-CO-CCl3 + D-phenylglycine acid a- (4-ethyl-2.3-dioxo-1-piperazinocarbonylamino) -phenylacetic solution (B), obtained from step 1, was subjected to distillation under vacuum to remove the solvents; the residue thus obtained was then suspended in 50 ml of hexane and the mixture was added to a solution containing 1.5 g (0.01 moles) of D-phenylglycine in 10 ml of hexane. The mixture was left under gentle stirring, at the temperature of 50 ° C, for the time of 40 minutes; the mixture was then heated to 70 ° C for 1 hour and cooled to room temperature.

After removal of the hexane by distillation under vacuum, the residue was crystallized, obtaining a- {4-ethyl-2,3 <_-> dioxo-1-piperazionocarbonylamino) -phenylacetic acid in a yield of 95% Stage 2 ( b): formation of the acylureidic bond with ampicillin.

EDP-CO-CCl3 + ampicillin - - piperacillin The solution obtained in step 1 was reacted as described in step 2 (a), replacing D-phenylglycine (1.5 g; 0.01 moles) with anhydrous ampicillin (3, 5 g; 0.01 moles), obtaining piperacillin in yields of about 90%, the physico-chemical characterization of which corresponds to that of Example 1, stage 2 (b). EXAMPLE 3

Stage 1: preparation of chloroacetyl 1-ethyl-2, 3-dioxopiperazine.

A mixture of 1.1 g (0.01 mol) of trimethylchlorosilane and 1.1 g (0.01 mol) of triethylamine was added, under constant stirring, to a solution containing 1.4 g (0.01 mol) of 1-ethyl-2,3-dioxo-piperazine in 30 ml of dioxane. The mixture thus obtained was kept under constant stirring for 20 hours and then filtered to remove the solid suspensions of ammonium salts. The filtrate was percolated at a temperature of 0-5 ° C in a solution containing 1.3 g of oxalyl chloride (0.01 moles; corresponding to formula (II) with R1 = -Cl and R2 = -C0-C1) in 20 ml of tetrahydrofuran; the solution thus obtained was kept under stirring for another 2 hours, at room temperature. After evaporation of the solvents by distillation under vacuum, a caramel-colored residue was obtained, from which the new intermediate (III) 'was isolated, according to standard purification procedures, where the P ring is the 1-ethyl- 2,3-dioxo-piperazine and R2 'is -C0-C1.

To the above-mentioned residue, not purified, 20 mg of activated carbon were added and the mixture was heated to 80 ° C under vacuum and under constant stirring, in order to completely eliminate the CO released by the reaction, which was trapped in a hydrochloric solution. of CuCl. Finally, the mixture was cooled, suspended in 20 ml of tetrahydrofuran and filtered; after evaporation of the solvent, 2.2 g of chloroacetyl 1-ethyl-2,3-dioxo-piperazine (0.01 moles) were isolated, in the form of a pale yellow crystalline solid, in a yield of 85% . The IR spectrum (KBr) of the reaction product showed peaks at 1789, 1660 cm <-1> (stretching 0 = 0).

Stage 2: formation of the acylureidic bond with phenylglycine or ampicillin.

piperazinocarbonylamino) - phenylacetic

2.0 g of chloroacetyl 1-ethyl-2,3-dioxo-piperazine (0.01 mol) was suspended in hexane (20 ml) and reacted with 1.5 S of D-phenylglycine (0.01 moles), as described in Example 1, stage 2 (a), or with 3.5 S of ampicillin (0.01 moles), as described in Example 1, stage 2 (b), respectively obtaining "acid a- (4 -ethyl-2,3-dioxo-1-piperazionocarbonylamino) -phenylacetic or piperacillin, in yields greater than 90%.

EXAMPLE 4

Stage 1: preparation of chloroacetyl 1-ethyl-2, 3-dioxopiperazine.

A mixture of 1.0 g (0.01 mol) of trimethylchlorosilane and 1.0 g (0.01 mol) of triethylamine was added, under constant stirring, to a solution containing 1.4 g (0.01 mol) of EDP in 30 ml of dioxane. The mixture thus obtained was then kept under constant stirring for 20 hours and then filtered to remove the solid suspensions of ammonium salts. The filtrate was percolated into a solution containing 0.9 g of methyl chloroformate (0.01 moles; corresponding to formula (II) with R1 = -Cl and R2 = -OCH3) in 20 ml of tetrahydrofuran; the solution thus obtained was kept under stirring for another 2 hours. After evaporation of the solvents by distillation under vacuum, the new intermediate (III) 'was isolated from the residue thus obtained, according to standard purification procedures, where the ring P is the residue of 1-ethyl-2,3-dioxo- piperazine and R2 'is -0CH3.

The residue obtained from step (la) was resuspended in 50 ml of hexane and gaseous HCl was bubbled into the solution, in a time of 15 minutes, at a temperature of 50 ° C. After removal of the hexane by distillation under vacuum, the product 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was isolated, with a yield greater than 95%, the chemical-physical characterization of which corresponds to that of example 3 stage 1.

Stage 2: formation of the acylureidic bond with phenylglycine or ampicillin.

The product 1-ethyl-2,3-dioxo-piperazinocarbonyl chloride, obtained from step (1b), was treated as described in example 3. obtaining acid a- (4-ethyl-2,3-dioxo-1-piperazionocarbonylamino ) -phenylacetic and piperacillin, in yields greater than 90%.

EXAMPLE 5

Condensation of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride and 6- [D (-) - a-aminophenylacetamido] -penicillanic acid to give piperacillin.

3.5 <m> S (0.01 moles) of 6- [D (-) - a-aminophenylacetamido] -penicillanic acid was suspended in 50 ml of a 4: 1 (v / v) THF: H2O solution; the suspension was brought to pH 8.0-8.5 with triethylamine and kept under constant stirring until a clear solution was obtained. After cooling to 0-5 ° C, a solution containing 2.0 mg (0.01 moles) of 4-ethyl-2,3 ~ dioxo-lpiperazinocarbonyl chloride, prepared as reported in the previous examples, was added to the solution thus obtained. The reaction mixture was kept under stirring for a time of 30 minutes, at a temperature of 0-5 ° C, maintaining the pH at values of 7.5-8.0 by gradual additions "of triethylamine, and then the temperature was raised at 5-10 ° C for 1 hour. After removing the THF by distillation under reduced pressure, the residue obtained was resuspended in 10 ml of H2O and washed twice with ethyl acetate. 50 ml of acetate were added to the aqueous phases of ethyl and the pH of the resulting mixture was brought to 1.5 with diluted HC1, cooling with ice. The phase of ethyl acetate was removed, washed with water three times and dried over anhydrous magnesium sulfate; by evaporation of the solvent, 5.2 mg of piperacillin in acid form were isolated, in the state of white resinous powder, in a yield of 95% (m.p. = 180 ° C), whose physico-chemical characterization corresponds to that reported in the previous examples.

Claims (17)

CLAIMS 1. Process for the preparation of urea derivatives of formula (I): (I) in which the P ring is a 5 or 6-membered nitrogen heterocycle, saturated or unsaturated, possibly also containing one or more heteroatoms selected from N, 0 and S, and -L is the radical of a compound containing a primary amino group; comprising the condensation of a nitrogenous heterocycle, of formula PN-H, and of a compound containing a primary amino group, of formula L-NH2. P and L being defined as above, with a chloro-carbonyl derivative of formula (II): (II) in which R-L and R2, equal or different from each other, are leaving groups, with the condition that said chloro-carbonyl derivative is different from phosgene, diphosgene and triphosgene. 2. The process according to claim 1, characterized in that said condensation is carried out in solvent, at a temperature of 0-100 ° C, for a time of 30'-20 hours, with a molar ratio between said heterocycle PN-H and said chlorocarbonyl derivative between 1: 2 and 2: 1, and between said L-NH2 compound and said chloro-carbonyl derivative between 1: 2 and 2: 1. 3 The process according to claim 1, characterized in that it takes place in 2 stages: (1) said nitrogen heterocycle PN-H is reacted with said chloro-carbonyl derivative to give an activated intermediate of formula (III): (III) wherein P and R2 are defined as in claim 1; (2) said activated intermediate (III) is reacted with a compound containing a primary amino group L-NH2. wherein L is defined as in claim 1. 4. The process according to one of claims 1 to 3. characterized in that said nitrogenous PN-H heterocycle is selected from the group consisting of pyrrole, pyrrolidine, pyrrolines, cyclic amino acids, imidazoles and their derivatives. 5. The process according to one of claims 1 to 3, characterized in that said P ring is the residue of a 6-membered nitrogenous heterocycle of formula (IV): (IV) wherein X. Y and Z, equal or different from each other, are C = 0 or CH-R5, where it is selected from the group consisting of H, halogen, -NH2 and -COOR6, with R6 = H or lower alkyl; R4 being selected from the group consisting of -H; -OH; branched linear C1-C4 alkyl, saturated or unsaturated, optionally substituted with sulphonic or alkylsulfonic groups; saturated or unsaturated C3-C7 cycloalkyl, optionally substituted with sulphonic or alkylsulfonic groups; and aryl. 6. The process according to claim 5, characterized in that said 6-membered nitrogenous heterocycle is 1-ethyl-2,3_dioxopiperazine. 7. The process according to one of claims 1 to 3, characterized in that said P ring is the residue of a 5-membered nitrogenous heterocycle of formula (V): wherein W is CH2 or N-Rjp R / j being selected from the group consisting of -H; -OH; linear or branched alkyl, saturated or unsaturated, optionally substituted with sulphonic or alkylsulfonic groups; saturated or unsaturated C3-C7 cycloalkyl, optionally substituted with sulphonic or alkylsulfonic groups; and aryl; and R5 being selected from the group consisting of H, halogen, -NH2 and -COOR6, with R6 = H or lower alkyl. The process according to one of claims 1 to 3. characterized in that. in said chloro-carbonyl derivative of formula (II), R1 is selected from the group consisting of -Cl, -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl, and -0- R3, where it is a lower alkyl: and R2 can have one of the meanings of, independently of it, or it can be CO-R1 R1 being defined as above. 9. The process according to claim 8, characterized in that said chloro-carbonyl derivative is selected from the group 10. The process according to claim 9. characterized in that said chloro-carbonyl derivative is C1-C0-C0-C1. 11. The process according to one of claims 1 to 3. characterized in that said compound L-NH2 is a <1> animinopenicillin or an amino-cephalosporin. 12. The process according to claims 1-3 and 11, characterized in that said compound L-NH2, is selected from the group consisting of phenylglycine, para-hydroxyphenylglycine, ampicillin and amoxicillin. 13. The process according to claims 6, 7 and 11, for the preparation of an urea derivative selected from a- (4-ethyl-2.3 ~ dioxo-1-piperazino-carbonylamino) -phenylacetic acid and a- (4-ethyl -2.3-dioxo-1-piperazino-carbonylamino) p-hydroxyphenylacetic, said ureid derivative being optionally subsequently condensed with the amino group of 6-APA, 7-ACA or their derivatives. 14. Synthetic intermediate of formula (III) ': (IH)' wherein the ring P is the residue of a saturated or unsaturated 5 or 6-membered nitrogenous heterocycle, optionally also containing one or more heteroatoms selected from N, 0 and S; and R2 is selected from the group consisting of -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl, -0-R ^. where R ^ is a lower alkyl, and -C0-R10, where R10 is selected from the group consisting of -CCl3, -O-CCl3, 2,4,6-trichlorophenyl, 2,4,6-trichlorobenzyl and -O- R3, R3 being defined as above. 15. The intermediate according to claim 14, characterized in that said P ring is the residue of 1-ethyl-2,3-dioxopiperazine and R2 is -CCl3. 16. The intermediate according to claim 14, characterized in that said ring P is the residue of 1-ethyl-2,3-dioxopiperazine and R2 is -OCH3. 17. The intermediate according to claim 14, characterized in that said ring P is the residue of 1-ethyl-2,3-dioxopiperazine and R2 is -C0-Cl.