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WO2002006209A1 - Synthesis method for n1,n3-bis (2.aminoethyl) propane-1,3-diamine, synthesis intermediates, resulting products and use thereof in synthesis of cyclam - Google Patents

Synthesis method for n1,n3-bis (2.aminoethyl) propane-1,3-diamine, synthesis intermediates, resulting products and use thereof in synthesis of cyclam Download PDF

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WO2002006209A1
WO2002006209A1 PCT/FR2001/002293 FR0102293W WO0206209A1 WO 2002006209 A1 WO2002006209 A1 WO 2002006209A1 FR 0102293 W FR0102293 W FR 0102293W WO 0206209 A1 WO0206209 A1 WO 0206209A1
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Henri Handel
Hélène Bernard
Marine Antoine
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Universite De Bretagne Occidentale
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines

Definitions

  • the present invention relates to a new process for the synthesis of a linear poiyazotated derivative, namely N 1 , N 3 -bis (2-aminoethyl) propane-1,3-diamine, of general formula (I):
  • This linear tetramine (I) serves in particular as a base compound for the preparation of cyclic polyazote derivatives such as cyclam.
  • the object of the present invention is to provide a process for obtaining this compound (I) which makes it possible to remedy all or part of the drawbacks mentioned above.
  • reaction of glyoxal with ethylenediamine thus makes it possible to obtain the bis-aminal compound represented above of trans configuration; this method turns out to be a simple reaction, the compound precipitating during the reaction; the reagents also being basic industrial compounds.
  • the present invention relates to a process for the synthesis of linear tetramine of general formula (I) below:
  • a third step consisting in subjecting the compound (IV) to acid hydrolysis, preferably hydrochloric acid in solution in a water / ethanol mixture, at around 60 ° C., which leads to obtaining the tetramine (I) in the form of a salt, in this case hydrochloride.
  • acid hydrolysis preferably hydrochloric acid in solution in a water / ethanol mixture, at around 60 ° C.
  • the free base form is isolated after passage through an anion exchange resin, or again by reaction with a base (Example III).
  • the present invention also relates to the preparation of a new compound of general formula (III) below:
  • This compound (III) is obtained in the form of a mixture of the cis and trans stereoisomers in variable proportions with the reaction conditions, in particular the temperature and the reaction time (Example I).
  • the starting compounds are glyoxal in aqueous solution or its hydrate and ethylenediamine, which initially make it possible to obtain the following compound:
  • This compound (II) is reacted, preferably in excess, on an acrylic ester (in particular methyl or ethyl acrylate), at a temperature preferably situated around + 10 ° C., in a solvent such as methanol. , leading to the formation of the derivative of formula (III), by nucleophilic addition of one of the nitrogen to the ester and a reaction of Michael of the contiguous nitrogen on the ethylenic carbon in position 4.
  • the reaction of the compound (III) leads easily and surprisingly to the compound (IV) by simple reduction with sodium borohydride in water or an alcohol (Example II ).

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Abstract

The invention concerns a method of synthesis of a linear polynitrogen-containing derivative, namely N<1>,N<3>-bis (2-aminoethyl) propane-1,3-diamine of general formula (I) using as synthesis intermediates compounds (II) and (III). The invention also concerns the resulting products and their use in the synthesis of cyclic polynitrogen-containing derivatives such as cyclam.

Description

Procédé de synthèse de la NI. N3-BIS (2-aminoéthyl)propane-1.3-diamine, intermédiaires de synthèse, produits ainsi obtenus et leur application à la synthèse de cyclamNI synthesis process. N3-BIS (2-aminoethyl) propane-1.3-diamine, synthesis intermediates, products thus obtained and their application to the synthesis of cyclam
La présente invention concerne un nouveau procédé de synthèse d'un dérivé poiyazoté linéaire à savoir la N1,N3-bis(2-aminoéthyl)propane-1,3-diamine, de formule générale (I) :The present invention relates to a new process for the synthesis of a linear poiyazotated derivative, namely N 1 , N 3 -bis (2-aminoethyl) propane-1,3-diamine, of general formula (I):
Figure imgf000003_0001
(I)
Figure imgf000003_0001
(I)
Cette tétramine linéaire (I) sert notamment de composé de base pour la préparation de dérivés polyazotés cycliques tel que le cyclam.This linear tetramine (I) serves in particular as a base compound for the preparation of cyclic polyazote derivatives such as cyclam.
Il s'avère que ce composé (I) n'est obtenu à l'heure actuelle, qu'avec de très faibles rendements et de manière coûteuse du fait notamment de la nature des produits utilisés et des voies de synthèse mises en œuvre.It turns out that this compound (I) is currently obtained only with very low yields and costly due in particular to the nature of the products used and the synthetic routes used.
A ce titre, le but de la présente invention est de proposer un procédé d'obtention de ce composé (I) qui permette de remédier tout ou en partie aux inconvénients mentionnés ci-dessus.As such, the object of the present invention is to provide a process for obtaining this compound (I) which makes it possible to remedy all or part of the drawbacks mentioned above.
Plus particulièrement, elle se propose de synthétiser cette tétramine à partir de produits de bases peu coûteux et par des réactions faciles à mettre en œuvre, à partir d'un composé (II), un bis-aminal obtenu par réaction du glyoxal et de l'éthylènediamine :More particularly, it proposes to synthesize this tetramine from inexpensive base products and by reactions which are easy to implement, from a compound (II), a bis-aminal obtained by reaction of glyoxal and l 'ethylenediamine:
Figure imgf000003_0002
Figure imgf000003_0002
Composé (II)Compound (II)
A titre indicatif, ce produit de base est avantageusement obtenu par une méthode proposée par B. Fuchs et A. Ellenc eig, Recueil, Journal of Royal Netheriands Chem. Soc. 1979, 326.As an indication, this basic product is advantageously obtained by a method proposed by B. Fuchs and A. Ellenc eig, Collection, Journal of Royal Netheriands Chem. Soc. 1979, 326.
La réaction du glyoxal avec l'éthylènediamine permet ainsi d'obtenir le composé bis-aminal représenté ci-dessus de configuration trans ; cette méthode s'avère être une réaction simple, le composé précipitant pendant la réaction ; les réactifs étant en outre des composés industriels de base.The reaction of glyoxal with ethylenediamine thus makes it possible to obtain the bis-aminal compound represented above of trans configuration; this method turns out to be a simple reaction, the compound precipitating during the reaction; the reagents also being basic industrial compounds.
La présente invention, a pour objet un procédé de synthèse de la tétramine linéaire de formule générale (I) suivante :The present invention relates to a process for the synthesis of linear tetramine of general formula (I) below:
3030
Figure imgf000003_0003
caractérisé en ce qu'il comporte :
Figure imgf000003_0003
characterized in that it comprises:
- une étape de condensation du composé (II) en excès sur un ester acrylique, de préférence l'acrylate de méthyle ou d'éthyle, à une température comprise entre -15°C et +20°C, de préférence +10°C, conduisant principalement à la formation du dérivé de formule (III) (mélange d'isomères cis et trans), par addition nucléophile d'un des azotes sur l'ester et une réaction de Michael de l'azote contigu sur le carbone éthylénique en position 4 (Exemple I).- A step of condensing the compound (II) in excess on an acrylic ester, preferably methyl or ethyl acrylate, at a temperature between -15 ° C and + 20 ° C, preferably + 10 ° C , leading mainly to the formation of the derivative of formula (III) (mixture of cis and trans isomers), by nucleophilic addition of one of the nitrogen on the ester and a Michael reaction of the contiguous nitrogen on the ethylenic carbon in position 4 (Example I).
Figure imgf000004_0001
Figure imgf000004_0001
(III)(III)
- une deuxième étape consistant à faire réagir, le composé (III) obtenu ci-dessus avec le borohydrure de sodium (NaBH4) en solution aqueuse ou alcoolique (le méthanol ou l'éthanol) qui de manière inattendue attaque l'amide et conduit ainsi à la formation du dérivé de formule (IV) sous forme d'un mélange d'isomères cis et trans (Exemple II).a second step consisting in reacting, the compound (III) obtained above with sodium borohydride (NaBH 4 ) in aqueous or alcoholic solution (methanol or ethanol) which unexpectedly attacks the amide and leads thus to the formation of the derivative of formula (IV) in the form of a mixture of cis and trans isomers (Example II).
Figure imgf000004_0002
Figure imgf000004_0002
(IV)(IV)
- et une troisième étape consistant à soumettre le composé (IV) à une hydrolyse acide, de préférence l'acide chlorhydrique en solution dans un mélange eau / éthanol, vers 60 °C, ce qui conduit à obtenir la tétramine (I) sous forme de sel, dans ce cas de chlorhydrate. La forme base libre, est isolée après passage sur une résine échangeuse d'anions, ou encore par réaction avec une base (Exemple III).- and a third step consisting in subjecting the compound (IV) to acid hydrolysis, preferably hydrochloric acid in solution in a water / ethanol mixture, at around 60 ° C., which leads to obtaining the tetramine (I) in the form of a salt, in this case hydrochloride. The free base form is isolated after passage through an anion exchange resin, or again by reaction with a base (Example III).
De plus, à partir de ce composé de base (I) obtenu de manière très simple et peu coûteuse, il est possible par une réaction de protection avec la butanedione puis une cyclisation avec un bis-électrophile comme le 1 ,2-dibromopropane suivie d'une déprotection, d'obtenir aisément la synthèse du cyclam comme décrit par G. Hervé, H. Bernard, N. Le Bris, J.-J. Yaouanc, H. Handel et L. Toupet dans Tetrahedron Letters, 1981 , 22, 6861.In addition, from this basic compound (I) obtained in a very simple and inexpensive manner, it is possible by a protective reaction with butanedione and then cyclization with a bis-electrophilic such as 1, 2-dibromopropane followed by 'deprotection, to easily obtain the synthesis of cyclam as described by G. Hervé, H. Bernard, N. Le Bris, J.-J. Yaouanc, H. Handel and L. Toupet in Tetrahedron Letters, 1981, 22, 6861.
La présente invention a également pour objet la préparation d'un nouveau composé de formule générale (III) suivante :The present invention also relates to the preparation of a new compound of general formula (III) below:
Figure imgf000005_0001
Figure imgf000005_0001
(III)(III)
Ce composé (III) est obtenu sous forme d'un mélange des stéréoisomères cis et trans dans des proportions variables avec les conditions de la réaction, notamment la température et le temps de réaction (Exemple I). Les composés de départ sont le glyoxal en solution aqueuse ou encore son hydrate et l'éthylènediamine, qui dans un premier temps permettent d'obtenir le composé suivant :This compound (III) is obtained in the form of a mixture of the cis and trans stereoisomers in variable proportions with the reaction conditions, in particular the temperature and the reaction time (Example I). The starting compounds are glyoxal in aqueous solution or its hydrate and ethylenediamine, which initially make it possible to obtain the following compound:
Figure imgf000005_0002
Figure imgf000005_0002
(II)(II)
Ce composé (II) est mis à réagir, de préférence en excès, sur un ester acrylique (notamment l'acrylate de méthyle ou d'éthyle), à une température de préférence située vers +10°C, dans un solvant comme le méthanol, conduisant à la formation du dérivé de formule (III), par addition nucléophile d'un des azotes sur l'ester et une réaction de Michael de l'azote contigu sur le carbone éthylénique en position 4. La réaction du composé (III) conduit facilement et de manière surprenante au composé (IV) par simple réduction par le borohydrure de sodium dans l'eau ou un alcool (Exemple II).This compound (II) is reacted, preferably in excess, on an acrylic ester (in particular methyl or ethyl acrylate), at a temperature preferably situated around + 10 ° C., in a solvent such as methanol. , leading to the formation of the derivative of formula (III), by nucleophilic addition of one of the nitrogen to the ester and a reaction of Michael of the contiguous nitrogen on the ethylenic carbon in position 4. The reaction of the compound (III) leads easily and surprisingly to the compound (IV) by simple reduction with sodium borohydride in water or an alcohol (Example II ).
Exemple I : Préparation du composé (III) :Example I: Preparation of the compound (III):
1g de (II) est dissous dans 100 mL de méthanol puis refroidi à +10°C. On ajoute VT. équivalent d'acrylate de méthyle (306 mg) et on laisse réagir 3 -jours. Le méthanol est ensuite évaporé à sec puis on reprend le résidu dans CH2Cl2. Après filtration, le filtrat est évaporé à sec. On obtient 0,550 g de (III) qui peut être utilisé tel quel pour la suite, ou encore recristallisé dans CH3CN (rendement 70%). Les données de l'analyse spectrale et celles de l'analyse élémentaire sont compatibles avec la structure proposée.1g of (II) is dissolved in 100 mL of methanol and then cooled to + 10 ° C. We add VT. equivalent of methyl acrylate (306 mg) and left to react for 3 days. The methanol is then evaporated to dryness then the residue is taken up in CH 2 Cl 2 . After filtration, the filtrate is evaporated to dryness. 0.550 g of (III) is obtained which can be used as it is for the rest, or else recrystallized from CH 3 CN (yield 70%). The data of the spectral analysis and those of the elementary analysis are compatible with the proposed structure.
Exemple 2 : Préparation du composé (IV)Example 2: Preparation of the compound (IV)
1g de (III) est dissous dans 100 mL d'eau. On ajoute 10 équivalents de NaBH4 (1 ,9 g) puis on laisse réagir 12 heures. Le solvant est ensuite évaporé, puis on reprend le résidu dans 50 mL de CH2CI2. Après filtration et évaporation du solvant, on obtient 0,604 g du composé (IV), qui peut être utilisé tel quel pour l'étape suivante, ou recristallisé dans un mélange CH2CI2 / THF (rendement 65%). Les données de l'analyse spectrale sont compatibles avec la structure proposée.1g of (III) is dissolved in 100 mL of water. 10 equivalents of NaBH 4 (1.9 g) are added and then left to react for 12 hours. The solvent is then evaporated, then the residue is taken up in 50 ml of CH 2 CI 2 . After filtration and evaporation of the solvent, 0.604 g of compound (IV) is obtained, which can be used as it is for the following step, or recrystallized from a CH 2 CI 2 / THF mixture (yield 65%). The spectral analysis data are compatible with the proposed structure.
Exemple 3 : Préparation du composé (I) :Example 3: Preparation of the compound (I):
1 g de (IV) est dissous dans 200 mL d'un mélange éthanol / HC1 1 N (soit pour 200 ml : 50 mL d'HCI 1 N et 150 mL d'éthanol). Le mélange réactionnel est porté à 60°C pendant deux heures puis refroidi. La solution obtenue est concentrée puis on ajoute la quantité d'acide chlorhydrique concentré nécessaire pour précipiter aussi complètement que possible le chlorhydrate de l'aminé (I). Le précipité obtenu est filtré puis séché, et l'on obtient 1 ,2 g de composé (I) sous forme de chlorhydrate. Après passage sur résine échangeuse d'anions Amberlyst A 26, on obtient le composé (I) sous forme de base libre avec 70 % de rendement (0,713 g ). 1 g of (IV) is dissolved in 200 ml of a 1 N ethanol / HCl mixture (ie for 200 ml: 50 ml of 1 N HCl and 150 ml of ethanol). The reaction mixture is brought to 60 ° C for two hours and then cooled. The solution obtained is concentrated and then the quantity of concentrated hydrochloric acid is added which is necessary to precipitate the hydrochloride from the amine (I) as completely as possible. The precipitate obtained is filtered then dried, and 1.2 g of compound (I) are obtained in the form of the hydrochloride. After passing over anion exchange resin Amberlyst A 26, the compound (I) is obtained in the form of the free base with 70% yield (0.713 g).

Claims

REVENDICATIONS
1- Procédé de synthèse d'une tétramine linéaire de formule générale (I) suivante :1- Process for the synthesis of a linear tetramine of general formula (I) below:
Figure imgf000007_0001
Figure imgf000007_0001
(I)(I)
à partir d'un composé (II) bis-aminal de configuration trans obtenu par réaction du glyoxal ou son hydrate et de l'éthylènediamine,from a bis-amino compound (II) of trans configuration obtained by reaction of glyoxal or its hydrate and of ethylenediamine,
Figure imgf000007_0002
Figure imgf000007_0002
Composé (II)Compound (II)
caractérisé en ce qu'il comporte :characterized in that it comprises:
- une étape de condensation du composé (II) en excès sur un ester acrylique, de préférence l'acrylate de méthyle ou d'éthyle, à une température comprise entre -15°C et +20°C, de préférence +10°C, dans un solvant comme le méthanol, conduisant principalement à la formation du dérivé de formule (III) (mélange d'isomères cis et trans), par addition nucléophile d'un des azotes sur l'ester et une réaction de Michael de l'azote contigu sur le carbone éthylénique en position 4.- A step of condensing the compound (II) in excess on an acrylic ester, preferably methyl or ethyl acrylate, at a temperature between -15 ° C and + 20 ° C, preferably + 10 ° C , in a solvent such as methanol, leading mainly to the formation of the derivative of formula (III) (mixture of cis and trans isomers), by nucleophilic addition of one of the nitrogen to the ester and a Michael reaction of the nitrogen adjacent to the ethylenic carbon in position 4.
Figure imgf000007_0003
Figure imgf000007_0003
(III) - une deuxième étape consistant à faire réagir, le composé (III) obtenu ci-dessus avec le borohydrure de sodium (NaBH4) en solution aqueuse ou alcoolique (le méthanol ou l'éthanol) qui de manière inattendue attaque l'amide et conduit ainsi a la formation du dérivé de formule (IV) sous forme d'un mélange d'isomères cis et trans(III) a second step consisting in reacting, the compound (III) obtained above with sodium borohydride (NaBH 4 ) in aqueous or alcoholic solution (methanol or ethanol) which unexpectedly attacks the amide and leads thus to the formation of the derivative of formula (IV) in the form of a mixture of cis and trans isomers
Figure imgf000008_0001
Figure imgf000008_0001
(IV)(IV)
- et une troisième étape consistant à soumettre le composé (IV) a une hydrolyse acide, de préférence l'acide chlorhydπque en solution dans un mélange eau / ethanol vers 60 °C, ce qui conduit a obtenir la tétramine (I) sous forme de sel, dans ce cas de chlorhydrate, la forme base libre étant isolée après passage sur une résine échangeuse d'anions, ou encore par réaction avec une base- And a third step consisting in subjecting the compound (IV) to an acid hydrolysis, preferably hydrochloric acid in solution in a water / ethanol mixture at around 60 ° C., which leads to obtaining the tetramine (I) in the form of salt, in this case hydrochloride, the free base form being isolated after passage over an anion exchange resin, or by reaction with a base
2- Procédé de synthèse d'un nouveau composé de formule générale suivante2- Process for the synthesis of a new compound of the following general formula
Figure imgf000008_0002
Figure imgf000008_0002
(III) à partir du glyoxal en solution aqueuse ou son hydrate et de l'éthylènediamine, permettant d'obtenir le composé (II) de formule suivante :(III) from glyoxal in aqueous solution or its hydrate and ethylenediamine, making it possible to obtain the compound (II) of the following formula:
Figure imgf000009_0001
Figure imgf000009_0001
(II)(II)
consistant à faire réagir par une condensation ce composé (II) de préférence en excès, sur un ester acrylique (notamment l'acrylate de méthyle ou d'éthyle), à une température de préférence située vers +10°C, dans un solvant comme le méthanol conduisant à la formation du dérivé de formule (III), par addition nucléophile d'un des azotes sur l'ester et une réaction de Michael de l'azote contigu sur le carbone éthylénique en position 4.consisting in reacting, by condensation, this compound (II) preferably in excess, on an acrylic ester (in particular methyl or ethyl acrylate), at a temperature preferably situated around + 10 ° C., in a solvent such as methanol leading to the formation of the derivative of formula (III), by nucleophilic addition of one of the nitrogen to the ester and a Michael reaction of the contiguous nitrogen on the ethylenic carbon in position 4.
3- Composé de formule générale (III)3- Compound of general formula (III)
Figure imgf000009_0002
Figure imgf000009_0002
(III) utile pour la synthèse d'une tétramine linéaire de formule générale (I) :(III) useful for the synthesis of a linear tetramine of general formula (I):
Figure imgf000010_0001
Figure imgf000010_0001
4. Composé de formule générale (III) :4. Compound of general formula (III):
Figure imgf000010_0002
Figure imgf000010_0002
(III)(III)
caractérisé en ce qu'il est obtenu conformément à la revendication 2.characterized in that it is obtained in accordance with claim 2.
5. Composé de formule générale (I) :5. Compound of general formula (I):
Figure imgf000010_0003
Figure imgf000010_0003
(I)(I)
caractérisé en ce qu'il est obtenu par le procédé selon la revendication 1.characterized in that it is obtained by the method according to claim 1.
6. Application du composé selon la revendication 5 à la synthèse de dérivés polyazotés cycliques tels que le cyclam. 6. Application of the compound according to claim 5 to the synthesis of cyclic polyazotated derivatives such as cyclam.
PCT/FR2001/002293 2000-07-19 2001-07-16 Synthesis method for n1,n3-bis (2.aminoethyl) propane-1,3-diamine, synthesis intermediates, resulting products and use thereof in synthesis of cyclam WO2002006209A1 (en)

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