WO1997042177A1

WO1997042177A1 - Process for the preparation of ureide derivatives and new intermediates of synthesis

Info

Publication number: WO1997042177A1
Application number: PCT/EP1997/002221
Authority: WO
Inventors: Giuseppe Tassone; Victor Rizza
Original assignee: ABRES ASSOCIATED BIOTECHNOLOGY RESEARCH Srl
Current assignee: ABRES ASSOCIATED BIOTECHNOLOGY RESEARCH Srl
Priority date: 1996-05-03
Filing date: 1997-04-30
Publication date: 1997-11-13
Anticipated expiration: 1998-11-03
Also published as: ITMI960873A1; ITMI960873A0; IT1282955B1; AR006997A1; AU2775597A

Abstract

A new process is described for the synthesis of ureide derivatives having formula (I) where the P ring is a saturated or unsaturated nitrogen heterocycle with 5 or 6 members, possibly containing, in addition, one or more hetero-atoms chosen from N, O and S, and in which -L is the radical of a compound containing a primary amine group. The process according to the invention comprises the condensation of said PN-H nitrogen heterocycle and of said L-NH2 compound containing a primary amine group with chloro-carbonyl derivatives. In particular, said process enables the low environmental impact and economically advantageous synthesis of β-lactam antibiotics, using new intermediates of synthesis.

Description

Process for the preparation of ureide derivatives and new intermediates of

synthesis

FIELD OF THE INVENTION

The present invention regards a new low environmental impact and economically

advantageous process for the synthesis of ureide derivatives, and in particular β-

lactam antibiotics Said process, which enables the condensation of cyclic

nitrogen compounds and compounds containing a primary amme group with

chloro-carbonyl derivatives to give acylureide derivatives, uses new intermediates of synthesis that are particularly advantageous in the industrial preparation of various classes of semisynthetic antibiotics

STATE OF THE ART

Among the β-lactam antibiotics that are currently most widespread there are

acylureide penicillins and cephalosporins characterized by the presence of a o

\ II /

N - C - N ureide bond having the formula ^{y x} Piperacillin, mezlocillin and azlocillin are semisynthetic penicillins, whilst cefoperazone is a widespread third-generation cephalospoπn These active principles have a wide antibacterial spectrum against both Gram-

positive and Gram-negative bacteria and present a high resistance to the attack of the β-lactamases produced by the bacteria In addition, they constitute therapeutic

tools of fundamental importance in the treatment of bacterial infections since they are able to exert a high antibacterial activity also in regard to Pseudomonas

aerugmosa, Klebsiella pneumonia, and bacterial strains of the Proteus species The widespread clinical use of semisynthetic antibiotics has given rise to the need for new processes for their synthesis on an industrial scale that might be

economically advantageous and acceptable from the standpoints of safety, toxicity and safeguarding of the environment

The acylureide antibiotics are synthesized in the current state of the art starting

from aminopenicilhns or aminocephalospoπns (for example, from amoxycillin or ampicilhn, in the case of penicillins), by condensation with a suitable nitrogen heterocyclic derivative, with the use of isocyanates or phosgene (COCI₂) as coupling agents

However, the use of isocyanates is not industrially satisfactory, because of considerable difficulties of synthesis are encountered due to the numerous side reactions which take place owing to the attachment of the primary amine group to

the double C=N bond and which notably reduce the yields of synthesis of the

desired compounds As is well known in the state of the art, although phosgene (carbon di-chlonde) is able to give excellent reaction yields, it has been the subject of severe regulation

in Italy and in many other countries on account of its high level of toxicity

Transportation of phosgene by air is forbidden, whilst its transportation over land is subjected to strict regulations Phosgene, which is considered to be responsible for the majority of casualties due to gas in the First World War, is a gaseous

substance which hydrolyses in the presence of water, with the consequent

development of hydrochloric acid Consequently, the limitation of its use in the chemical industry is desirable in so far as on a large scale it presents high factors

of risk and toxicity Likewise well known in the state of the art is the use of diphosgene (tπchloromethyl chloroformiate) and of triphosgene (bιs-(trιchloromethyl)-

carbonate) as agents of condensation (H Eckert and B Forster, Angew Chem

Int Ed Engl , 26, 1987, No 9) However, the levels of risk and toxicity of these reagents which are used as substitutes for phosgene are only slightly lower than those of phosgene itself In fact, although both diphosgene and triphosgene are

easier to prepare and handle, they readily undergo decomposition, with the consequent liberation of phosgene, and hence create serious safety problems as regards their transportation, warehousing and use Furthermore, the aforesaid phosgene substitutes must first be transformed into phosgene to be able to give

the reactions known in the state of the art, as reported by R Katakai and Y hzuke (J Org Chem , 1985, 50 716-718), which lead to the decomposition of diphosgene by means of heating in an appropriate solvent or by catalysis on

activated carbon In this way, the disadvantages of using phosgene are not

eliminated

The need is therefore felt of having available new chemical reagents that can promote the aforesaid coupling between nitrogen heterocyclic derivatives and primary amines, by means of ureide bonds, which are essential in the synthesis of

acylureide antibiotics SUMMARY

The Applicant has now surprisingly found a new process for preparing ureide

derivatives of formula (I)

where the P ring is a saturated or unsaturated nitrogen heterocycle with 5 or 6 members, possibly containing in addition one or more hetero-atoms chosen from among N, O and S, and in which -L is the radical of a compound containing a primary amine group The said process comprises the condensation of a PN-H

nitrogen heterocycle and of an L-NH₂ compound containing a primary amine group with a chloro-carbonyl derivative, of formula (II) o

II R! -C-R_{2 ( | [)}

where R^ and R₂, which are the same or different from each other, are leaving groups, with the condition that said chlorocarbonyl derivative is different from

phosgene

A further subject of the present invention is represented by the new intermediates

of formula (III)'

where R₂' is chosen from the group consisting of -CCI₃, -O-CCI₃, 2,4,6- tπchlorophenyl, 2,4,6-tnchlorobenzyl, -O-R₃, where R₃ is a lower alkyl, and -CO-

R1₀, where R₁₀ is chosen from the group consisting of -CCI₃, -O-CCI3, 2,4,6- trichlorophenyl, 2,4,6-tnchlorobenzyl and -O-R₃, R3 being defined as above Said intermediates are particularly useful in the synthesis of ureide derivatives of

formula (I)

DETAILED DESCRIPTION OF THE INVENTION

The characteristics and advantages of the process and of the intermediates of synthesis according to the present invention are further illustrated in the course of the detailed description that follows

The process according to the present invention enables the condensation, in an effective and economic way, of nitrogen-containing heterocycles and compounds containing primary amme groups, by means of chlorocarbonyl derivatives which

function as agents of condensation to give acylureide bonds This process proves

particularly advantageous for the preparation of semisynthetic antibiotics since it is able to give very high yields in the condensation of nitrogen-containing heterocycles, such as piperazine or pyrrolidine derivatives, with ammo penicillins

and amino-cephalospoπns, such as ampicillin and amoxycillin, yielding piperazine antibiotics (e g , piperacillm), other acylureide penicillins (e g , azlociliin and mezlocillin) and cephalosporins (e g , cefoperazone)

The advantages of the process according to the present invention may be

summarized as follows - elimination of the use of phosgene, which is a highly toxic gas that is disadvantageous at an industrial level

- reaction yields comparable to or higher than those obtainable with phosgene,

with quantities of the coupling agent much lower than those of phosgene, - high safety levels,

- low environmental impact,

- economy and simplicity of execution

In the process according to the present invention, the reaction conditions may

vary according to the nature of the reagents The aforesaid condensation may be carried out in either protic or aprotic solvent at a temperature between 0 and 100°C for a period of time between 30 minutes and 20 hours, with a molar ratio between said PN-H heterocycle and said chlorocarbonyl derivative of between 1 2

and 2 1 , and between said L-NH₂ compounds and said chloro-carbonyl derivative of between 1 2 and 2 1

The aforesaid PN-H nitrogen-containing heterocycles, where the P ring is a 5- or 6-member heterocycle, as mentioned previously, are chosen preferably from the

group consisting of pyrrole, pyrrolidine, pyrroline, cyclic ammo acids, imidazoles and their derivatives When the said P ring is the residue of a 6-member nitrogen heterocycle, it

corresponds preferably to the formula (IV)

,^Y~^Xv

*- ' (IV) where X, Y and Z, which may be the same or different from one another, may be C=O or CH-R₅, where R₅ is chosen in the group consisting of H, halogen, -NH₂,

and -COOR₆, with R₆=H or lower alkyl,

R₄ is chosen in the group consisting of -H, -OH, saturated or unsaturated, linear or branched Cι-C₄ alkyl, possibly substituted by sulphone or alkyl sulphone groups saturated or unsaturated C₃-C₇ cyclo-alkyl, possibly replaced with

sulphone or alkyl sulphone groups, and aryl

Said 6-member nitrogen heterocycle is preferably 1 -ethyl-2,3-dιoxo-pιperazιne

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

where W may be CH₂ o N-R₄, where R₄ and R₅ have the meanings previously given in formula (IV) In the process of the invention, the coupling agent is a chlorocarbonyl derivative

as per formula (II), where R_λ is chosen preferably from the group consisting of -Cl,

-CCI₃, -O-CCI3, 2,4,6-trιchlorophenyl, 2,4,6-tnchlorobenzyl, and -O-R₃, where R₃ is a lower alkyl, preferably methyl or ethyl, R₂ may have one of the meanings of R_{1 τ}

independently of the latter, or else may be -CO-Ri, Ri being defined as above,

with the condition that said chlorocarbonyl derivative is different from phosgene diphosgene and triphosgene

The said chlorocarbonyl derivative of formula (II) is preferably chosen from the

group consisting of hexachloro-acetone, CI₃C-CO-CCI3, tπchloro-acetyl chloride CI3C-CO-CI, oxalyl chloride CI-CO-CO-CI, and methyl chloroformate CI-CO-O- CH_3l still more preferably, said chlorocarbonyl derivative is oxalyl chloride The aforesaid chlorocarbonyl derivatives may be prepared previously or generated in situ in the reaction environment, using conventional procedures

Preferably, CI₃C-CO-CCI_3l is prepared from a solution of chlorine gas in acetone by catalysis of red or UV phosphorous, CI₃C-CO-CI and CI-CO-CO-CI are prepared by aeration of chlorine gas in acetic acid or in acetic anhydride in the

presence of a suitable catalyst, finally CI-CO-O-CH₃ may be advantageously prepared by aeration of chlorine gas in methyl formate in the presence of a suitable catalyst

These chlorocarbonyl derivatives are used in approximately equimolar quantities with respect to the nitrogen-containing heterocycle and to the compound containing a primary amme group This represents an advantage over phosgene,

which is used in marked excess with respect to the other reagents

Furthermore, these chlorocarbonyl derivatives eliminate the problems of safety and toxicity associated with phosgene, both in the phase of preparation and in that of use, and enable the development of non-pollutant processes of synthesis

with low environmental impact

The said compound containing a primary amine group, of the L-NH₂ formula, may be, for example phenylglycme H₂N-CH(Ph)-COOH or parahydroxyphenylglycme H₂N-CH(C₆H₄-OH)-COOH When this compound is phenylglycme or parahydroxyphenylglycme and said nitrogen-containing heterocycle is 1 -ethyl-2,3-

dioxo-piperazine, the process according to the present invention leads to the obtaining of α-(4-ethyl-2,3-dιoxo-1-pιperazιnecarbonylamιne)-phenylacetιc acid

and α-(4-ethyl-2,3,-dιoxo-1-pιperazιnecarbonylamιne)-p-hydroxy-phenylacetιc

acid, respectively, which are intermediate products of particular importance in the

synthesis of piperacillins In fact, these phenylacetic acids may be subsequently condensed with the amine group of 6-APA (6-amιno-penιcιllanιc acid) and of 7- ACA (7-amιno-cephalosporanιc acid) and their derivatives, obtaining second- and

third-generation piperacillins and cephalosporins According to a further feature of the process of the invention, in the synthesis of

acylureide penicillins and cephalosporins, the primary amine group of the L-NH₂

compound belongs to the side chain in position 6 of an ammo-penicillin (e g ,

ampicillin and amoxycillin) or in position 7 of an amino-cephalospoπn For

5 example, 1 -ethyl-2,3-dιoxo-ριperazιne may be condensed with the amme group on

the chain in position 6 of ampicillin and amoxycillin, obtaining the synthesis of

piperazine penicillins, such as piperacillm

The process according to the present invention may be advantageously used in

the synthesis of β-lactam antibiotics as per the general formula (VI)

where the P ring has the meanings given above and where Q may be

⁹ , where R₉ is chosen from the group consisting of -H, -CHs

CH₂-OAc, -CH₂O-CO-NH₂, halogen, -OH, -CN, -NH₄ ⁺, pyridine, quinilme,

pyπmidine,

N — N -Cϊr-i- 5 ^N-^{^} ) 5 CH_^CCXDH

R₇ is chosen from the group consisting of -C₆H₅, -C₆H₄-OH and

,

and R₈ is chosen from the group consisting of H, methyl, ethyl and a quaternary

ammonium cation According to a mode of execution of the process of the invention, the

condensation may take place in two stages in the first stage by activating the aforesaid nitrogen-containing heterocycles with chlorocarbonyl derivatives, and in

the second stage by condensing the activated heterocycles so obtained with

compounds containing primary amine groups, to give acylureide bonds From the first stage the following intermediates of synthesis of formula (III) may thus be isolated

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

where R₂' is chosen from the group consisting of -CCI₃, -O-CCI₃, 2,4,6- tπchlorophenyl, 2,4,6-tnchlorobenzyl, -O-R₃, where R₃ is a lower alkyl, preferably methyl or ethyl, and -CO-R₁₀, where R₁₀ is chosen from the group consisting of -

CCI₃, -O-CCI₃, 2,4,6-trιchlorophenyl, 2,4,6-tnchlorobenzyl and -O-R₃, R₃ being defined as above, R₂' is preferably -CCI₃, 2,4,6-tπchlorophenyl or 2,4,6-

tnchlorobenzyl

In particular, according to this mode of execution of the process of the invention,

the following two stages of synthesis are provided (1 ) the said PN-H nitrogen-containing heterocycle is reacted with one of the aforesaid chlorocarbonyl derivatives (II) to give an activated intermediate (III), where 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 period of between 30

minutes and 4 hours

According to a particular mode of execution of the invention, in stage (1 ) said

nitrogen-containing heterocycle may reacted first with a promotor, such as

trimethyl silylchloπde, and then with the chlorocarbonyl derivative, (2) the activated intermediate (III) obtained from stage (1 ) is reacted with an L-NH₂ compound containing a primary amine group, in molar ratios varying between 2 1 and 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 then reacting the activated intermediate in the solution so obtained at a temperature of between 0

and 100°C, preferably between 20 and 70°C, for a period of between 30 minutes and 20 hours, possibly in the presence of an organic and/or inorganic base The said inorganic base is chosen preferably from the group consisting of hydroxides, bicarbonates, carbonates and acetates of alkaline and alkaline-earth metals, said

organic base is chosen preferably from the group consisting of secondary and tertiary amines, such as diethyl amine, trimethyl amine, triethyl amine, tπbutyl amme, pindine, N-methylpiπdine, and N-methylmorpholine The pH of the reaction

may vary according to the reagents used in the range preferaoly of between 2 and 10, and more preferably still of between 4 and 8

Purely as an illustration of the present invention, but in no way limiting the possibilities thereof, the following examples are given EXAMPLE 1

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

To 32 g (0 21 moles) of diethylester of oxalic acid were added in the order 32 ml of ethanol and 18 4 g (0 21 moles) of N-ethyl-ethyienediamine, and the mixture thus obtained 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 In this way 24 g of EDP were isolated, with an 80% yield (m p = 124°C)

Stage 1 : preparation of trichloroacetyl 1-ethyl-2,3-dioxo-piperazine

EDP + CI3C-CO-CCI3 > EDP-CO-CCI3

A suspension of 14 2 g (0 1 moles) of EDP in 50 ml of hexane was slowly added to a solution containing 26 4 g (0 1 moles) of hexachloroacetone (corresponding

to formula (II) with R_λ = H₂ = -CCI₃₎) dissolved in 40 ml of hexane

The mixture so obtained was kept constantly stirred for 40 minutes at a temperature of 50°C The solution was then heated and kept at 70°C for 1 hour

and then cooled to room temperature (solution A)

From this solution the new intermediate of formula (III)' was isolated, where the P

ring is the residue of 1-ethyl-2,3-dιoxopιperazιne, and R₂' is -CCI3 Stage 2(a): formation of the acylureide bond with phenylglycine

EDP-CO-CCI₃ + D-phenylglycme > α-(4-ethyl-2,3-dιoxo-1 -

pιperazιnecarbonylamιne)-phenyiacetιc acid

A solution containing 15 1 g (0 1 moles) of D-phenylglycme in 50 ml of hexane was slowly added under constant stirring, for a period of 40 minutes at a temperature of 50°C , to solution (A), prepared in stage 1 The mixture thus

obtained was heated and kept at 70°C for 1 hour, and then cooled to room

temperature

After removal of the hexane by vacuum distillation, the residue was crystallized

obtaining α-(4-ethyl-2,3-dιoxo-1 -pιperazιnecarbonylamιne)-phenylacetιc acid with

an 84% yield (m p = 165°C)

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

EDP-CO-CCb + ampicilhn > piperacillin

The solution obtained at stage 2 was reacted as described in stage 2(a),

replacing D-phenylglycme (15 1 g, 0 1 moles) with anhydrous ampicilhn (35 g, 0 1

moles), obtaining piperacillin in yields higher than 80%, having the following chemico-physical characteristics

- melting point 183-185°C

- IR spectrum (KBr) stretching C=O 1765 CΓTΓ¹ (lactam), 1720-1679 cm^"1 (-CON=),

1600 cm^"1 (-COO^")

EXAMPLE 2

Stage 1 : preparation of trichloro-acetyl 1-ethyl-2,3-dioxo-piperazine

EDP + CI3C-CO-CI > EDP-CO-CCI3

A mixture of 1 0 g (0 01 moles) of tnchlorosilane and 1 0 g (0 01 moles) of triethylamine was added, under constant stirring, to a solution containing 1 4 g

(0 01 moles) of 1-ethyl-2,3-dιoxo-pιperazιne in 30 ml of dioxane The mixture thus obtained was then kept under constant stirring for 20 hours, and was next filtered to remove the solid suspensions of ammonium salts The filtrate was percolated in a solution containing 0 75 g of tnchloro-acetylchloride (0 01 moles), corresponding to formula (II) with Ri = -Cl and R₂ = -CCI₃) in 20 ml of

tetrahydrofuran, the solution thus obtained was kept stirred for a further 2 hours

(solution B)

From this solution the new intermediate of formula (III)' was moreover isolated,

where the P ring is the residue of 1 -ethyl-2,3-dιoxo-pιperazιne, and R₂' is -CCI₃

Stage 2(a): formation of the acylureide bond with phenylglycine

EDP-CO-CCb + D-phenylglycme > α-(4-ethyl-2,3-dιoxo-1 -

pιperazιnecarbonylamιne)-phenylacetιc acid

The solution (B), obtained from stage 1 , was distilled under vacuum to remove the

solvents The residue so obtained was then suspended in 50 ml of hexane and

the mixture was next added to a solution containing 1 5 g (0 01 moles) of D-

phenylglycme in 10 ml of hexane The mixture was kept under gentle stirring, at a

temperature of 50°C for a period of 40 minutes The mixture was then heated and

kept at 70°C for 1 hour, and then cooled to room temperature

obtaining α--(4-ethyl-2,3-dιoxo-1 -pιperazιnecarbonylamιne)-phenylacetιc acid with

a 95% yield

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

EDP-CO-CCI3 + ampicillin > piperacillin The solution obtained in stage 1 was reacted as described in stage 2(a), replacing

D-phenylglycine (1 5 g, 0 01 moles) with anhydrous ampicilhn (3 5 g, 0 01 moles)

obtaining piperacillin in yields of approximately 90%, having chemico-physical

characteristics corresponding to those of example 1 , stage 2(b) EXAMPLE 3

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

EDP + CI-CO-CO-CI > EDP-CO-CO-CI > EDP-CO-CI + CO

A mixture of 1 1 g (0 01 moles) of tπmethylchlorosilane and 1 1 g (0.01 moles) of

triethylamine was mixed, under constant stirring, with a solution containing 1 4 g

(0 01 moles) of 1-ethyl-2,3-dιoxopιperazιne in 30 ml of dioxane The mixture so obtained was kept under constant stirring for 20 hours and then filtered to remove the sohd 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 R, = -Cl and R₂ = -CO-CI) in 20 ml of tetrahydrofuran The solution so obtained was kept under stirring for a further 2 hours at room temperature After evaporation of the solvents by vacuum distillation, a caramel-coloured residue was obtained, from which, the new

intermediate (III)', where the P ring is the residue of 1-ethyl-2,3-dιoxo-pιperazιne and R₂' is -CO-CI, was isolated, according to standard procedures of purification To the aforesaid non-purified residue, 20 mg of activated carbon were added, and the mixture was heated to 80°C in a vacuum and under constant stirring, so as to

eliminate completely the CO liberated by the reaction, this being trapped in a chloride solution of CuCI Finally, the mixture was cooled off, suspended in 20 ml of tetrahydrofuran, and filtered After evaporation of the solvent, 2 2 g of

chloroacetyl 1-ethyl-2,3-dιoxopιperazιne (0 01 moles) were isolated, in the form of a pale yellow crystalline solid, with a yield of 85% The IR spectrum (KBr) of the reaction product presented peaks at 1789, 1660 cm^"1 (stretching C = O) Stage 2: formation of the acylureide bond with phenylglycine or ampicillin

a) EDP-CO-CI + D-phenylglycme > α-(4-ethyl-2,3,-dιoxo-1 -

ριperazιnecarbonylamιne)-phenylacetιc acid

b) EDP-CO-CI + ampicilhn > piperacillin 2 0 g of chloroacetyl 1 -ethyl-2,3-dιoxo-pιperazιne (0 01 moles) were suspended in hexane (20 ml) and reacted with 1 5 g of D-phenylglycme (0 01 moles), as described in example 1 Stage 2(a), or with 3 5 g of ampicilhn (0 01 moles), as

described in example 1 , Stage 2(b), obtaining respectively α-(4-ethyl-2,3,-dιoxo-1-

pιperazιnecarbonylamιne)-phenylacetιc acid or piperacillin, respectively, with

yields of over 90%

EXAMPLE 4

Stage 1 : preparation of chlorocarbonyl 1-ethyl-2,3-dioxo-piperazine

1 a) EDP + CI-CO-OCH₃ > EDP-CO-OCH3

A mixture of 1 0 g (0 01 moles) of tnmethylchlorosilane and 1 0 g (0 01 moles) of

triethylamine was added, under constant stirring, to a solution containing 1 4 g

(0 01 moles) of EDP in 30 ml of dioxane The mixture so obtained was 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 9 g of

methyl chloroformate (0 01 moles, corresponding to formula (II) with R, = -Cl and R₂ = -OCH₃) in 20 ml of tetrahydrofuran The solution so btamed was kept under stirring for a further 2 hours After evaporation of the solvents by vacuum distillation, from the residue so obtained the new intermediate (III)', where the P ring is the residue of 1 -ethyl-2,3-dιoxo-pιperazιne and R₂' is -OCH₃, was isolated, according to standard procedures of purification 1 b) EDP-CO-OCH₃ + HCI > EDP-CO-CI + CH₃OH

The residue obtained from stage (1a) was re-suspended in 50 ml of hexane, and

gaseous HCI was bubbled through the solution for a period of 15 minutes, at a

temperature of 50°C After removal of the hexane bv vacuum distillation, the product 4-ethyl-2,3-dιoxo-1 -pιperazιnecarbonyl chloride was isolated, with a yield of over 95%, the chemico-physical characteristics of which correspond to those of example 3, stage 1

Stage 2: formation of the acylureide bond with phenylglycine or ampicillin

The product 1-ethyl-2,3-dιoxo-pιperazιnecarbonyl chloride obtained from stage

(1 b) was treated as described in example 3, obtaining α-(4-ethyl-2,3-dιoxo-1 -

pιperazιnecarbonylamιne)-phenylacetιc acid and piperacillin, with yields of over 90%

EXAMPLE 5

Condensation of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride and 6-[D(-)-

α-aminophenylacetamide]-penicillanic acid to give piperacillin

3 5 g (0 01 moles) of 6-[D(-)-α-amιnophenylacetamιde]-penιcιllanιc acid were

suspended in 50 ml of a THF H₂O 4 1 (v/v) solution The suspension was brought

up 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, to the solution so obtained, a solution was added containing 2 0 g (0 01 moles) of 4-ethyl-2,3-dιoxo-1 - piperazmecarbonyl chloride, prepared as described in the previous examples

The reaction mixture was kept under stirring for a period of 30 minutes, at a temperature of 0-5°C, keeping the pH at values of 7 5-8 0 by means of gradual addition of triethylamine, and then the temperature was raised to 5-10°C for an hour After removal of the THF by reduced-pressure distillation, the residue obtained was re-suspended in 10 ml of H₂O and washed twice with ethyl acetate To the aqueous phases 50 ml of ethyl acetate were added, and the pH of the

resulting mixture was brought to 1 5 with diluted HCI, cooling with ice The ethyl

acetate phase was removed, washed with water three times, and dried on anhydrous magnesium sulphate By evaporation of the solvent, 5 2 g of piperacillin in acidic form were isolated, in the state of a white resinous powder, with a yield of 95% (m p = 180°C), the chemico-physical characteristics of which

correspond to those given in the previous examples

Claims

1 Process for the preparation of ureide derivative of formula (I)

where the P ring is a saturated or unsaturated nitrogen-containing heterocycle with 5 or 6 members, possibly containing in addition one or more hetero-atoms chosen from among N, O and S, and in which -L is the radical of a compound containing a primary amme group,

the said process comprises the condensation of a nitrogen-containing heterocycle of formula PN-H and of a compound containing a primary amine group of formula

L-NH₂, P and L being defined as above, with a chloro-carbonyl derivative, of formula (II) o

II ^Rι^'c'R2 (II) where R_T and R₂, which are the same or different from each other, are leaving

groups, with the condition that said chlorocarbonyl derivative is different from

phosgene 2 The process according to Claim 1 , characterized in that said condensation is carried out in a solvent, at a temperature of 0-100°C for a period 30 mιnutes-20 hours, with a molar ratio between said PN-H heterocycle and said chlorocarbonyl

derivative of between 1 2 and 2 1 , and between said L-NH₂ compound and said chloro-carbonyl derivative of between 1 2 and 2 1 3 The process according to Claim 1 , characterized in that it takes place in 2 stages (1 ) said PN-H nitrogen-containing heterocycle is reacted with said chlorocarbonyl derivative to give an activated intermediate, of formula (III)

where P and R₂ are defined as in Claim 1 ,

(2) said activated intermediate (III) is reacted with an L-NH₂ compound containing

a primary amine group, where L is defined as in Claim 1 4 The process according to one of the Claims from 1 to 3, characterized in that said PN-H nitrogen-containing heterocycle is chosen from the group consisting of pyrrole, pyrrolidine, pyrrohne, cyclic ammo acids, imidazoles and their derivatives

5 The process according to one of the Claims from 1 to 3, characterized in that said P ring is the residue of a 6-member nitrogen-containing heterocycle as per formula (IV)

where X, Y and Z, which may be the same or different from one another, are C=O or CH-R₅, where R₅ is chosen in the group consisting of H, halogen, -NH₂, and -

COOR₆, with R₆=H or lower alkyl, R₄ is chosen in the group consisting of -H, -OH, saturated or unsaturated, linear or branched C_rC₄ alkyl, possibly substituted by sulphone or alkyl sulphone groups, saturated or unsaturated C₃-C₇ cyclo-alkyl, possibly replaced with

sulphone or alkyl sulphone groups, and aryl 6 The process according to Claim 5, characterized in that said 6-member nitrogen-containing heterocycle is 1 -ethyl-2,3-dιoxo-pιperazιne 7 The process according to one of the Claims from 1 to 3, characterized in that

said P ring is the residue of a 5-member nitrogen heterocycle as per formula (V)

where W is CH₂ or N-R₄₎ R₄ being chosen from the group consisting of -H, -OH, saturated or unsaturated, linear or branched Cι-C₄ alkyl, possibly substituted by sulphone or alkyl sulphone groups, saturated or unsaturated C₃-C₇ cyclo-alkyl, possibly replaced with sulphone or alkyl sulphone groups, and aryl, and R₅ being

chosen from the group consisting of H, halogen, -NH_2l and -COOR₆, with R₆ = H or lower alkyl 8 The process according to one of the Claims from 1 to 3, characterized in that, in

said chlorocarbonyl derivative of formula (II), R, is chosen from the group

consisting of -Cl, -CCI₃, -O-CCI₃, 2,4,6-trιchlorophenyl, 2,4,6-tnchlorobenzyl, and - O-R₃, where R₃ is a lower alkyl, and R₂ can have one of the meanings of R_{1 (} independently of the latter, or else may be -CO-R_L R-, being defined as above

9 The process according to Claim 8, characterized in that said chlorocarbonyl

derivative is chosen from the group consisting of CI3C-CO-CCI3, CI3C-CO-CI, Cl- CO-CO-CI, and CI-CO-O-CH3 10 The process according to Claim 9, characterized in that said chlorocarbonyl

derivative is CI-CO-CO-CI 11 The process according to one of the Claims from 1 to 3, characterized in that the said L-NH₂ compound is an ammo penicillin or an amino-cephalospoπn 12 The process according to one of the Claims from 1 to 3 and 11 , characterized in that said L-NH₂ compound is chosen from the group consisting of

phenylglycme, para-hydroxyphenylglycme, ampicilhn, and amoxycillin 13 The process according to Claims 6, 7 and 11 for the preparation of a ureide

derivative chosen from α-(4-ethyl-2,3-dιoxo-1 - pιperazιnecarbonylamιne)-phenyl

acetic acid and α-(4-ethyl-2,3-dιoxo-1 -pιperazιnecarbonylamιne)-p-hydroxyphenyl

acetic acid, said ureide derivative being possibly condensed subsequently with the amine group of 6-APA, 7-ACA or their derivatives 14 Intermediate of synthesis as per formula (III)'

where the P ring is the residue of a saturated or unsaturated nitrogen-containing

heterocycle with 5 or 6 members, possibly containing in addition one or more

hetero-atoms chosen from among N, O and S, and R₂' is chosen from the group

consisting of -CCI₃, -O-CCI₃, 2,4,6-trιchlorophenyl, 2,4,6-tnchlorobenzyl, -O-R₃, where R₃ is a lower alkyl, and -CO-R₁₀, where R₁₀ is chosen from the group consisting of -CCI₃, -O-CCI₃, 2,4,6-tπchloroρhenyl, 2,4,6-tnchlorobenzyl 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-dιoxo-pιperazιne and R₂' is -CCI₃ 16 The intermediate according to Claim 14, characterized in that said P ring is

the residue of 1 -ethyl-2,3-dιoxo-pιperazιne and R₂' is -OCH₃ 17 The intermediate according to Claim 14, characterized in that said P ring is the residue of 1 -ethyl-2,3-dιoxo-pιperazιne and R₂' is -CO-CI