WO2017055885A1 - Procédés de production de dérivés du 1,4,7-triazacyclononane et de nouveaux intermédiaires - Google Patents

Procédés de production de dérivés du 1,4,7-triazacyclononane et de nouveaux intermédiaires Download PDF

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WO2017055885A1
WO2017055885A1 PCT/HU2016/000065 HU2016000065W WO2017055885A1 WO 2017055885 A1 WO2017055885 A1 WO 2017055885A1 HU 2016000065 W HU2016000065 W HU 2016000065W WO 2017055885 A1 WO2017055885 A1 WO 2017055885A1
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group
compound
general formula
carbon atoms
linear
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PCT/HU2016/000065
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József RÉPÁSI
András Szabó
Gergely Tasi
Máriusz KERTÉSZ
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Soneas Kutató Kft.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to processes for the production of compounds of the general formula (I),
  • R 1 is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group;
  • R 2 is, independently of R 1 , a linear or branched alkyl group having 1 to 4 carbon atoms; or a -Z-CH 2 -T group, wherein
  • Z is a linear or branched alkylene group having 1 to 4 carbon atoms; and T is -OH or -NR 10 R 11 group, wherein
  • R 10 and R 1 are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • the invention also encompasses the compound of the formula (Id), which is a novel compound.
  • the compounds of the general formula (I), produced by the novel processes are preferably used as chelators for forming suitable, widely usable complexes (in other words, chelates) with transition metals and rare earth metals.
  • the compounds of the general formula (I) are N-substituted derivatives of 1 ,4,7 triazacyclononane, or by its generally accepted short name, TACN.
  • TACN (Qx)
  • the free electron pairs of the nitrogen atoms can form coordinate bonds with cations of d- and f- elements having vacant electron orbitals.
  • chelate ions of the general formula (Q x ) are formed, wherein the central "core" of atoms M z+ acting as electron pair acceptor is fixed inside the molecular ring by the electron pair donor groups - in this particular case, the nitrogen atoms of the TACN-ring.
  • M represents the d- or f- element
  • z denotes the charge number of the core.
  • TACN-derivative chelates are highly significant from a scientific aspect and have a wide range of practical applications.
  • the simplest and most widely used TACN- based chelator is 1 ,4,7-trimethyl-1 ,4,7-triazacyclononane of formula (la), or, to use the abbreviations used in international literature, Me3-TACN or tmtacn:
  • (la) corresponds to a particular compound of the compounds of the general formula (I) wherein R is hydrogen atom, and R 2 is methyl group.
  • NODAGA-BP 1 peptide conjugates e.g. NODAGE- TATE
  • NODAGA (Q i.e. NODAGA-BP
  • EP 2,708,547 discloses chelates of 99m Tc, 186 Re and 188 Re isotopes complexed by TACN derivate compounds, which can also be applied in the fields of therapeutics and diagnostics.
  • the Q 2 and Q 3 chelates function as oxygen-transferring catalysts in aqueous oxidation processes.
  • the oxygen source can be a peroxide or even oxygen from the air, because they can activate both hydroperoxyl radicals and molecular oxygen. Thus, they can be advantageously applied in the modelling of biochemical oxidation processes [New J. Chem., 26, 1238-45 (2002)].
  • Q 2 and Q3 chelates are the most significant in bleaching fibres, textiles, and papers, as well as in cleaning textiles and clothing. Transition metal chelates had been applied for a longer time as activators in peroxide bleaching processes.
  • the use of TACN chelates is preferred because the amount of organic and inorganic peroxide compounds contained in cleaning/bleaching materials containing such activators can be greatly reduced, using oxygen from the air as an oxidizing reagent. Thereby the environmental load of bleaching plants, laundrettes and households can be reduced by a great extent.
  • Tosyl derivatives of those homologues of the TACN base compound which have higher numbers of ring members were first produced by H. Stetter and E.E. Roos by the cyclization of the sodium salts of ⁇ , ⁇ -disulphonamides with ⁇ ', ⁇ '- dihaloalkanes, with high dilution and poor yield [Chem. Ber., 87, 566-71 (1954)]. Later a process based on a similar principle but being significantly more effective was published by J. E. Richman and T. J. Atkins [J. Am. Chem. Soc. 96, 2268-70 (1974)], which process is often referenced even nowadays.
  • TACN can be produced from the tritosyl derivative (Ci) by boiling in 90% sulfuric acid followed by liberation by a strong base.
  • the TACN base compound - compound (3) of the cited patent description - is produced by catalytic debenzylation of the compound (Iw), in a manner known from prior art.
  • R 6 and R 7 are primary non-bulky alkyl groups, e.g. methyl, ethyl or normal propyl (n-propyl) group.
  • Example J diacylation with the anhydride of the formula (llz), i.e. Boc 2 0, is also presented (Example J), wherein the suitable 1 ,7-diBoc derivative of the formula (lllz) is produced, and by quaternizing same with benzyl bromide (Example K) 1 ,7-diBoc-4-benzyloctahydro- 1 /-/-imidazo[1 ,2-a]pyrazin-4-ium bromide, and then, after removing the Boc protective groups, 4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium bromide is produced [Example L).
  • Example M No example is given for producing TACN derivatives from the bicyclic quaternary salts thus produced.
  • the compound 1 ,7-diBoc-octahydro- 1H-imidazo[1 ,2-a]pyrazine produced on the basis of Example J is quaternized with methyl iodide (IVa) to further produce the compound of the formula (Vz), i.e. 1 ,7- di-Boc-4-methyloctahydro-1H-imidazo[1 ,2-a]pyrazin-4-ium iodide (Example M).
  • the object of the invention is to provide a process that is suitable for producing the above defined TACN derivatives of the general formula (I) with good yield, using inexpensive reagents, and in a direct manner, i.e. without the preparation of the unsubstituted TACN.
  • This object was accomplished by providing the processes according to the invention.
  • the invention is based on the recognition that the different reactivity of the individual nitrogen atoms of the key compound (E) can be preferably exploited and thereby such compounds of the general formula (V) can be produced, from which the TACN derivatives of the general formula (I), among them 1-alkyl-4,7-dimethyl- TACN and the most important one, ,4,7-trimethyl-TACN, i.e. the compound of the formula (la) can be produced.
  • the invention relates to a process for the production of compounds of the general formula (I),
  • R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group;
  • R 2 is, independently of R 1 , a linear or branched alkyl group having 1 to 4 carbon atoms; or -Z-CH 2 -T group, wherein
  • Z is a linear or branched alkylene group having 1 to 4 carbon atoms; and T is -OH or -NR 10 R 11 group, wherein
  • R 10 and R 11 are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • R 8 is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group;
  • W is halogen atom, a linear or branched alkoxy group having 1 to 4 carbon atoms, or an -0-C(0)-R 8 group;
  • R 8 is as defined above for formula (II),
  • Y is R 2 , a -Z-COOR 9 , -ZCN or -Z-CONR 10 R 1 1 group, wherein
  • R 2 is as defined above for formula (I),
  • R 9 is a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • R 10 and R 1 are, independently of each other, hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • X is halogen or an R 2 OS0 3 group, wherein R 2 is as defined above;
  • R 8 , Y and X are as defined above for formulas (II) and (IV),
  • R 8 , Y and X are as defined above for formulas (II) and (IV), is reacted with a complex aluminium hydride, and the compound of the general formula (I) obtained is optionally isolated and is optionally purified.
  • any of the above described processes a), b), or c) can be used according to the invention for producing a compound of the general formula (I).
  • the invention further extends to the compounds of the general formulas (III) and (V) produced in the above described process, which are intermediates of the process a) as described below:
  • R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group; with the proviso that R 8 is a group other than a te/f-butoxy group.
  • R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group;
  • Y is R 2 , a -Z-COOR 9 , -ZCN or -Z-CONR 10 R 11 group, wherein
  • R 2 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a -Z-CH 2 -T group, wherein
  • Z is a linear or branched alkylene group having 1 to 4 carbon atoms
  • T is -OH or -NR 10 R 11 group, wherein R 10 and R 11 are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • R 9 is a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;
  • R 0 and R 1 are, independently of each other, hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group; and X " is a halogen or an R 2 OSO 3 ⁇ ion,
  • the compound is other than 1 ,7 bis[(ferf-butoxy)carbonyl]-4- methyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium-iodide.
  • Preferred compounds according to the invention are 1 ,7-diformyl-octahydro-1 /-/- imidazo[1 ,2-a]pyrazine (formula Ilia, see below) and 1 ,7-diacetyl-4-methyl- octahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium iodide (formula Vc, see below).
  • W is a halogen atom, it is preferably a chlorine atom.
  • the compound of the general formula (II), used as a diacylating agent may therefore be e.g. an acid halide, e.g. acetyl chloride, benzoyl chloride, or preferably an ester, preferably a methyl ester, e.g. methyl formate, or an anhydride, e.g. di-ferf-butyl dicarbonate (Boc 2 0).
  • the compound (E) is highly acid-sensitive, it decomposes quickly under the effect of traces of organic or inorganic acids.
  • the acylation processes are performed with acid chlorides or anhydrides (e.g. with acetic acid anhydride or mixed acetic acid-formic acid anhydride) in the presence of a base (organic or inorganic)
  • the corresponding amides can be produced with much lower yield compared to acylations with esters, several decomposition products can be detected.
  • the acylation reaction is preferably performed in the presence of 0.3 - 3 equivalent of an alkaline or alkaline earth metal carbonate or bicarbonate, said amount is relative to the compound (E), more preferably of 0.5 - 1 equivalent of sodium, potassium or cesium carbonate or sodium alcoholate, preferably sodium methylate or sodium ethylate.
  • an amount of 2 - 5 equivalent of non-reactive organic base for binding the hydrogen halogenide forming in the reaction preferably an amount of 2 - 5 equivalent of non-reactive organic base (relative to the compound (E)), preferably an amount of 2 - 3 equivalent of triethylamine or ethyl diisopropylamine is used.
  • the diacylation reaction performed to produce a compound of the general formula (III) is typically performed at a temperature of -10 °C - 100 °C, preferably at a temperature of 0 - 60 °C.
  • a solvent preferably an excess of the compound of the general formula (II), or an indifferent aprotic solvent - preferably acetonitrile, a halogenated hydrocarbon, such as dichloromethane, chloroform, or an ether or aromatic hydrocarbon, most preferably toluene - is used.
  • a halogenated hydrocarbon such as dichloromethane, chloroform, or an ether or aromatic hydrocarbon, most preferably toluene - is used.
  • the relative molar ratio of the compounds (E) and (II) is preferably 1 : 2 - 1 : 50, more preferably 1 : 2 - 1 : 33.
  • the product of the general formula (III) is optionally isolated.
  • the 4N nitrogen atom of the respective compound of the general formula (III) is alkylated using an alkylating agent of the general formula (IV).
  • Y is preferably methyl group, ethyl group, or ethoxycarbonylmethyl group.
  • X is preferably CI, Br, I, or CH 3 OS0 3 .
  • the alkylation reaction is preferably carried out in a polar organic solvent, e.g. in acetonitrile.
  • the relative molar ratio of the compounds (III) and (IV) is preferably 1 :1 - 1 :5 and/or the reaction temperature is 10-140 °C, preferably 20-120 °C depending on the reactivity of the compound (IV). If the produced quaternary compound of the general formula (V) crystallizes well, it is typically isolated by filtration after crystallization, and in the opposite case chromatographic purification may be applied or most simply isolation and purification can be skipped and the concentrate of the compound of the general formula (V) produced in the reaction can be directly utilized in the subsequent synthesis step.
  • the process a) or b) the 1 ,7-diacyl-4-alkyl-ammonium salt of the general formula (V) obtained in the alkylation reaction is used after isolation or without isolation in the reaction performed with a complex aluminium hydride.
  • the complex aluminium hydride used in the reaction with a complex aluminium hydride is preferably RedAI ® , LiAIH 4 , LiAIH(OMe) 3 , LiAIH(OtBu) 3 or DIBALH.
  • an aprotic, halogen-free, anhydrous organic solvent not reacting with the complex aluminium hydride preferably a solvent identical with the diluent of the applied complex aluminium hydride reagent, e.g.
  • reaction temperature is typically chosen - depending on the reactivity of the particular compound of type (V) - to fall in the range of 0 °C - 140 °C, preferably in the range of 20 °C - 120 °C.
  • Reaction time is typically determined on the basis of monitoring the reaction by chromatography, preferably TLC or HPLC.
  • the molar ratio of the complex aluminium hydride relative to the compound of the general formula (V) may typically be 2.5 - 14, preferably, with RedAI ® , 4 - 12.
  • the reaction mixture is typically quenched by applying a dilute aqueous solution, preferably a basic solution, e.g. 10% NaOH solution.
  • the product of the formula (I) is typically isolated by extraction with an organic solvent, preferably with the inexpensive toluene.
  • the product of the formula (I) can be isolated and purified in a known manner, preferably by vacuum fractioning.
  • a suitable salt of the compound (I) is produced, which can be isolated by filtration and thereby can be purified.
  • the organic extract can be evaporated, and then the pure TACN derivative of the general formula (I) can be obtained by vacuum distillation from the concentrate thus produced.
  • R 8 is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group
  • the R 8 group is not converted in the reaction with the complex aluminium hydride, i.e. R 8 and R 1 are identical.
  • R 8 is a linear or branched alkoxy group having 1 to 4 carbon atoms or phenoxy group
  • the R 8 group is converted into hydrogen in the reaction with the complex aluminium hydride.
  • Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group
  • the Y group is not converted in the reaction with the complex aluminium hydride, i.e. Y and R 2 are identical.
  • Y is -Z-T'-, wherein Z is as defined above, and T' is a terminal group capable of reduction, e.g. -CN, -COOR 9 or -CONR 10 R 11 , wherein R 9 , R 10 , R 11 are as defined above, the -Y group is converted into an -R 2 group of the -Z-CH 2 -T type.
  • the produced compound of the formula (I) is trimethyl-TACN or the compound of the formula (Id).
  • the compound (E) is reacted with methyl formate of the formula (Ma), also functioning as a solvent, followed by methylation at the 4-position, without isolation, of the obtained intermediate product (Ilia) presented in the reaction scheme below.
  • methyl iodide of the formula (IVai) or dimethyl sulfate of the formula (IVa 2 ) or methyl chloride of the formula (IVa 3 ) is applied in a molar ratio of 1-5 : 1 to the compound of the formula (Ilia), in the presence of a halogenide catalyst - preferably sodium iodide - which is used in a molar ratio of 0 - 0.05 calculated for the compound (Ilia) in a polar organic solvent, preferably acetonitrile.
  • the processes according to the present invention can equally be applied for producing complexly substituted TACN derivative chelators, and simpler derivatives to be produced in high volume, e.g. Me 3 -TACN (UB-14054).
  • TACN derivatives that comprise an R 2 terminal linker group which can be characterised by the general formula -Z-CH2-T.
  • Z and T are as defined above.
  • the compound of the formula (Ilia) is quaternized at the 4-position with the bromoacetic acid ethyl ester of the formula (IVd) in acetonitrile solution at room temperature, and, by reacting the thus produced quaternary ammonium bromide compound of the formula (Vd) with 10- equiv. RedAI ® in a toluene solution at reflux temperature, including reducing the carbethoxy group into hydroxymethyl group, and by quenching the reaction mixture with dilute sodium hydroxide solution, and subsequently evaporating the organic phase the compound of the formula (Id) is obtained.
  • a 10-litre double glass reactor equipped with a stirrer is filled with 6000 ml of acetonitrile, 260 g (2.52 mol, 1.00 eq.) of diethylenetriamine and 696 g (5.040 mol, 2.00 eq.) of anhydrous potassium carbonate, and then 435 g (2.77 mol, 1.10 eq) of 50% aqueous chloroacetaldehyde solution is added under stirring at 10 - 20 °C over a period of 21 ⁇ 2 hours. Stirring is continued at 25 °C with gas chromatographic monitoring until the diethylenetriamine content of a sample taken from the reaction mixture drops below 5 area percent. Reaction time: 16 hours.
  • the inorganic salt mixture is filtered from the reaction mixture, and the filtrate is evaporated in a rotary evaporator in vacuum.
  • Me 3 -TACN (la, UB-14054) content is 60% by GC and HPLC.
  • the reactor is cooled to a temperature below 10 °C carefully open, and the precipitated white crystalline substance is filtered, washed with acetonitrile, and dried.
  • the product obtained is 840 mg (3.6 mmol) of 1 ,7-diformyl-4-methyloctahydro-1 H- imidazo[1 ,2-a]pyrazin-4-ium chloride (Va3, UB-15190), which corresponds to a chemical yield of 65%, and can be used in the subsequent reaction similarly to the product produced according to Example 4.
  • the obtained solidifying oil is crude 4-ethyl-1 ,7-diformyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium iodide (Vb, UB-15111) with a weight of 3.5 g, which corresponds to a yield of 46%.

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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des procédés de production de composés de formule générale (I) : dans laquelle R1 représente un atome d'hydrogène, un groupe alkyle linéaire ou ramifié comportant de 1 à 4 atomes de carbone, ou un groupe phényle ; et R2 représente, indépendamment de R1, un groupe alkyle linéaire ou ramifié comportant de 1 à 4 atomes de carbone ; ou un groupe -Z-CH2-T, dans lequel Z représente un groupe alkylène linéaire ou ramifié comportant de 1 à 4 atomes de carbone ; et T représente -OH ou un groupe -NR10R11, dans lequel R10 et R11 sont identiques ou différents, et représentent un atome d'hydrogène, un groupe alkyle linéaire ou ramifié comportant de 1 à 4 atomes de carbone, ou un groupe benzyle. L'invention s'étend en outre à des composés de formule générale (I) dans laquelle R1 représente un groupe méthyle et R2 représente un groupe -CH2-CH2-OH, ainsi qu'à de nouveaux intermédiaires produits dans les procédés conformément à l'invention.
PCT/HU2016/000065 2015-10-02 2016-09-29 Procédés de production de dérivés du 1,4,7-triazacyclononane et de nouveaux intermédiaires WO2017055885A1 (fr)

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HUP1500451 2015-10-02

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014079953A1 (fr) * 2012-11-21 2014-05-30 Université de Bourgogne Synthèse de sels d'imidazo[1,2-a]pyrazin-4-ium utiles dans la synthèse de 1,4,7-triazacyclononane (tacn) et de dérivés de ce composé à fonctionnalisation n- et/ou c
FR3017386A1 (fr) * 2014-02-13 2015-08-14 Ecole Norm Superieure Lyon Nouveau procede de preparation de 1,4,7-triazacyclononane (i) dissymetriques et intermediaires de synthese associes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014079953A1 (fr) * 2012-11-21 2014-05-30 Université de Bourgogne Synthèse de sels d'imidazo[1,2-a]pyrazin-4-ium utiles dans la synthèse de 1,4,7-triazacyclononane (tacn) et de dérivés de ce composé à fonctionnalisation n- et/ou c
FR3017386A1 (fr) * 2014-02-13 2015-08-14 Ecole Norm Superieure Lyon Nouveau procede de preparation de 1,4,7-triazacyclononane (i) dissymetriques et intermediaires de synthese associes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUILLAUME GROS ET AL: "Multigram Four-Step Synthesis of 1,4,7-Triazacyclononanes with 2R a /R b N -Functionalization Pattern by Starting from Diethylenetriamine", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2015, no. 1, 21 January 2015 (2015-01-21), DE, pages 183 - 187, XP055338294, ISSN: 1434-193X, DOI: 10.1002/ejoc.201402821 *
KOEK J H ET AL: "Direct ring functionalisation of 1,4,7-trimethyl-1,4,7-triazacyclononane and its application in the preparation of functional [L"2Mn"2O"3]-type complexes", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 47, no. 22, 29 May 2006 (2006-05-29), pages 3673 - 3675, XP025004147, ISSN: 0040-4039, [retrieved on 20060529], DOI: 10.1016/J.TETLET.2006.03.134 *
PAULINE DÉSOGÈRE ET AL: "Efficient Synthesis of 1,4,7-Triazacyclononane and 1,4,7-Triazacyclononane-Based Bifunctional Chelators for Bioconjugation", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2014, no. 35, 4 December 2014 (2014-12-04), DE, pages 7831 - 7838, XP055338291, ISSN: 1434-193X, DOI: 10.1002/ejoc.201402708 *

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