WO1997042177A1 - Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese - Google Patents

Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese Download PDF

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Publication number
WO1997042177A1
WO1997042177A1 PCT/EP1997/002221 EP9702221W WO9742177A1 WO 1997042177 A1 WO1997042177 A1 WO 1997042177A1 EP 9702221 W EP9702221 W EP 9702221W WO 9742177 A1 WO9742177 A1 WO 9742177A1
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WIPO (PCT)
Prior art keywords
chosen
group
process according
formula
ethyl
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PCT/EP1997/002221
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English (en)
Inventor
Giuseppe Tassone
Victor Rizza
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Abres Associated Biotechnology Research S.R.L.
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Publication date
Application filed by Abres Associated Biotechnology Research S.R.L. filed Critical Abres Associated Biotechnology Research S.R.L.
Priority to AU27755/97A priority Critical patent/AU2775597A/en
Publication of WO1997042177A1 publication Critical patent/WO1997042177A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention regards a new low environmental impact and economically
  • 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
  • N - C - N ureide bond having the formula y x Piperacillin, mezlocillin and azlocillin are semisynthetic penicillins, whilst cefoperazone is a widespread third-generation cephalospo ⁇ n
  • aminopenicilhns or aminocephalospo ⁇ ns for example, from amoxycillin or ampicilhn, in the case of penicillins
  • condensation with a suitable nitrogen heterocyclic derivative with the use of isocyanates or phosgene (COCI 2 ) as coupling agents
  • Phosgene which is considered to be responsible for the majority of casualties due to gas in the First World War, is a gaseous
  • diphosgene t ⁇ chloromethyl chloroformiate
  • triphosgene b ⁇ s-(tr ⁇ chloromethyl)-
  • 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
  • R ⁇ and R 2 which are the same or different from each other, are leaving groups, with the condition that said chlorocarbonyl derivative is different from
  • R 2 ' is chosen from the group consisting of -CCI 3 , -O-CCI 3 , 2,4,6- t ⁇ chlorophenyl, 2,4,6-tnchlorobenzyl, -O-R 3 , where R 3 is a lower alkyl, and -CO-
  • R1 0 where R 10 is chosen from the group consisting of -CCI 3 , -O-CCI3, 2,4,6- trichlorophenyl, 2,4,6-tnchlorobenzyl and -O-R 3 , R3 being defined as above
  • Said intermediates are particularly useful in the synthesis of ureide derivatives of
  • 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
  • amino-cephalospo ⁇ ns such as ampicillin and amoxycillin, yielding piperazine antibiotics (e g , piperacillm), other acylureide penicillins (e g , azlociliin and mezlocillin) and cephalosporins (e g , cefoperazone)
  • reaction conditions may
  • 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
  • PN-H nitrogen-containing heterocycles where the P ring is a 5- or 6-member heterocycle, as mentioned previously, are chosen preferably from the
  • R 4 is chosen in the group consisting of -H, -OH, saturated or unsaturated, linear or branched C ⁇ -C 4 alkyl, possibly substituted by sulphone or alkyl sulphone groups saturated or unsaturated C 3 -C 7 cyclo-alkyl, possibly replaced with
  • Said 6-member nitrogen heterocycle is preferably 1 -ethyl-2,3-d ⁇ oxo-p ⁇ peraz ⁇ ne
  • the coupling agent is a chlorocarbonyl derivative
  • R ⁇ is chosen preferably from the group consisting of -Cl,
  • R 3 is a lower alkyl, preferably methyl or ethyl
  • R 2 may have one of the meanings of R 1 ⁇
  • chlorocarbonyl derivative is different from phosgene diphosgene and triphosgene
  • the said chlorocarbonyl derivative of formula (II) is preferably chosen from the
  • chlorocarbonyl derivative is oxalyl chloride
  • the aforesaid chlorocarbonyl derivatives may be prepared previously or generated in situ in the reaction environment, using conventional procedures
  • CI 3 C-CO-CCI 3l is prepared from a solution of chlorine gas in acetone by catalysis of red or UV phosphorous
  • CI 3 C-CO-CI and CI-CO-CO-CI are prepared by aeration of chlorine gas in acetic acid or in acetic anhydride in the
  • CI-CO-O-CH 3 may be advantageously prepared by aeration of chlorine gas in methyl formate in the presence of a suitable catalyst
  • 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,
  • 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
  • the said compound containing a primary amine group, of the L-NH 2 formula may be, for example phenylglycme H 2 N-CH(Ph)-COOH or parahydroxyphenylglycme H 2 N-CH(C 6 H 4 -OH)-COOH
  • this compound is phenylglycme or parahydroxyphenylglycme and said nitrogen-containing heterocycle is 1 -ethyl-2,3-
  • the process according to the present invention leads to the obtaining of ⁇ -(4-ethyl-2,3-d ⁇ oxo-1-p ⁇ peraz ⁇ necarbonylam ⁇ ne)-phenylacet ⁇ c acid
  • these phenylacetic acids may be subsequently condensed with the amine group of 6-APA (6-am ⁇ no-pen ⁇ c ⁇ llan ⁇ c acid) and of 7- ACA (7-am ⁇ no-cephalosporan ⁇ c acid) and their derivatives, obtaining second- and
  • ampicillin and amoxycillin or in position 7 of an amino-cephalospo ⁇ n
  • 1 -ethyl-2,3-d ⁇ oxo- ⁇ peraz ⁇ ne may be condensed with the amme group on
  • piperazine penicillins such as piperacillm
  • R 9 is chosen from the group consisting of -H, -CHs
  • R 7 is chosen from the group consisting of -C 6 H 5 , -C 6 H 4 -OH and ,
  • R 8 is chosen from the group consisting of H, methyl, ethyl and a quaternary
  • condensation may take place in two stages in the first stage by activating the aforesaid nitrogen-containing heterocycles with chlorocarbonyl derivatives, and in
  • R 2 ' is chosen from the group consisting of -CCI 3 , -O-CCI 3 , 2,4,6- t ⁇ chlorophenyl, 2,4,6-tnchlorobenzyl, -O-R 3 , where R 3 is a lower alkyl, preferably methyl or ethyl, and -CO-R 10 , where R 10 is chosen from the group consisting of -
  • R 2 ' is preferably -CCI 3 , 2,4,6-t ⁇ chlorophenyl or 2,4,6-
  • 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 R 2 is a good leaving group, preferably, the nitrogen heterocycle and the chlorocarbonyl derivative, in equimolar ratio, are reacted in an organic solvent,
  • nitrogen-containing heterocycle may reacted first with a promotor, such as
  • the L-NH 2 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
  • 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, t ⁇ butyl amme, pindine, N-methylpi ⁇ dine, and N-methylmorpholine
  • secondary and tertiary amines such as diethyl amine, trimethyl amine, triethyl amine, t ⁇ butyl amme, pindine, N-methylpi ⁇ dine, and N-methylmorpholine
  • reagents used in the range 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
  • Stage 1 preparation of trichloroacetyl 1-ethyl-2,3-dioxo-piperazine
  • Stage 1 preparation of trichloro-acetyl 1-ethyl-2,3-dioxo-piperazine
  • stage (1a) 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
  • Stage 2 formation of the acylureide bond with phenylglycine or ampicillin
  • 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
  • the residue obtained was re-suspended in 10 ml of H 2 O and washed twice with ethyl acetate

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

On décrit un nouveau procédé de synthèse de dérivés d'uréide de la formule (I), où le noyau P est un hétérocycle d'azote, saturé ou non saturé, à 5 ou 6 chaînons, pouvant en outre contenir un ou plusieurs hétéroatomes choisis entre N, O et S, et où -L est le radical d'un composé contenant un groupe amine primaire. Selon la présente invention, le procédé consiste à condenser ledit hétérocycle d'azote PN-H et ledit composé L-NH2 contenant un groupe amine primaire avec des dérivés de chloro-carbonyle. En particulier, par l'emploi de nouveaux intermédiaires de synthèse, ledit procédé permet la synthèse d'antibiotiques β-lactame, laquelle présente une faible incidence sur l'environnement et est d'un coût peu élevé.
PCT/EP1997/002221 1996-05-03 1997-04-30 Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese WO1997042177A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27755/97A AU2775597A (en) 1996-05-03 1997-04-30 Process for the preparation of ureide derivatives and new intermediates of synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI000873A IT1282955B1 (it) 1996-05-03 1996-05-03 Processo per la preparazione di derivati ureidici e intermedi di sintesi
ITMI96A000873 1996-05-03

Publications (1)

Publication Number Publication Date
WO1997042177A1 true WO1997042177A1 (fr) 1997-11-13

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AR (1) AR006997A1 (fr)
AU (1) AU2775597A (fr)
IT (1) IT1282955B1 (fr)
WO (1) WO1997042177A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2321153A1 (es) * 2007-10-11 2009-06-02 Astur Pharma S.A. Intermedio para la sintesis de piperacilina.
CN101857574A (zh) * 2010-07-05 2010-10-13 山东鑫泉医药中间体有限公司 一种n-乙基-2，3-双氧哌嗪的合成方法
CN103360343A (zh) * 2012-03-30 2013-10-23 凯惠药业(上海)有限公司 一种哌嗪酰胺类化合物的制备方法
CN104910178A (zh) * 2015-05-22 2015-09-16 华北制药集团先泰药业有限公司 一种哌拉西林酸的制备方法
CN109438476A (zh) * 2018-12-24 2019-03-08 常州红太阳药业有限公司 哌拉西林酸的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0018546A2 (fr) * 1979-04-25 1980-11-12 BIOCHEMIE Gesellschaft m.b.H. Procédé de production de chlorhydrates du chlorure de phénylglycyle
BE892370A (fr) * 1981-10-06 1982-07-01 Kim Young Sul Nouveau procede de preparation de derives de la penicilline et de la cephalosporine
EP0249176A2 (fr) * 1986-06-11 1987-12-16 BASF Aktiengesellschaft Procédé de préparation de dérivés de 2,3-dioxo-4-oxycarbonylpipérazine
EP0317484A2 (fr) * 1987-11-16 1989-05-24 Gema S.A. N,N'-Carboxyl-bis-(4-éthyl-2,3-dioxo)-pipérazine, procédé de préparation et son application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0018546A2 (fr) * 1979-04-25 1980-11-12 BIOCHEMIE Gesellschaft m.b.H. Procédé de production de chlorhydrates du chlorure de phénylglycyle
BE892370A (fr) * 1981-10-06 1982-07-01 Kim Young Sul Nouveau procede de preparation de derives de la penicilline et de la cephalosporine
EP0249176A2 (fr) * 1986-06-11 1987-12-16 BASF Aktiengesellschaft Procédé de préparation de dérivés de 2,3-dioxo-4-oxycarbonylpipérazine
EP0317484A2 (fr) * 1987-11-16 1989-05-24 Gema S.A. N,N'-Carboxyl-bis-(4-éthyl-2,3-dioxo)-pipérazine, procédé de préparation et son application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 104, no. 17, 28 April 1986, Columbus, Ohio, US; abstract no. 148590, YAO Q. ET AL.: "Synthetic studies of piperacillin" XP002037154 *
SHENYANG YAOXUEYUAN XUEBAO, vol. 2, no. 2, 1985, CHINA, pages 128 - 130 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2321153A1 (es) * 2007-10-11 2009-06-02 Astur Pharma S.A. Intermedio para la sintesis de piperacilina.
CN101857574A (zh) * 2010-07-05 2010-10-13 山东鑫泉医药中间体有限公司 一种n-乙基-2，3-双氧哌嗪的合成方法
CN103360343A (zh) * 2012-03-30 2013-10-23 凯惠药业(上海)有限公司 一种哌嗪酰胺类化合物的制备方法
CN103360343B (zh) * 2012-03-30 2017-04-19 凯惠药业(上海)有限公司 一种哌嗪酰胺类化合物的制备方法
CN104910178A (zh) * 2015-05-22 2015-09-16 华北制药集团先泰药业有限公司 一种哌拉西林酸的制备方法
CN104910178B (zh) * 2015-05-22 2017-06-13 华北制药集团先泰药业有限公司 一种哌拉西林酸的制备方法
CN109438476A (zh) * 2018-12-24 2019-03-08 常州红太阳药业有限公司 哌拉西林酸的制备方法

Also Published As

Publication number Publication date
IT1282955B1 (it) 1998-04-02
ITMI960873A1 (it) 1997-11-03
ITMI960873A0 (fr) 1996-05-03
AU2775597A (en) 1997-11-26
AR006997A1 (es) 1999-10-13

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