MD4150C1 - Process for producing coordinative compounds of Co(II), Ni(II) and Zn(II) with 2-nitro-4,5-diphenylimidazole starting from 4,5-diphenylimidazole and nitrates of said metals - Google Patents
Process for producing coordinative compounds of Co(II), Ni(II) and Zn(II) with 2-nitro-4,5-diphenylimidazole starting from 4,5-diphenylimidazole and nitrates of said metals Download PDFInfo
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- MD4150C1 MD4150C1 MDA20110087A MD20110087A MD4150C1 MD 4150 C1 MD4150 C1 MD 4150C1 MD A20110087 A MDA20110087 A MD A20110087A MD 20110087 A MD20110087 A MD 20110087A MD 4150 C1 MD4150 C1 MD 4150C1
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- diphenylimidazole
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- CPHGOBGXZQKCKI-UHFFFAOYSA-N 4,5-diphenyl-1h-imidazole Chemical compound N1C=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 CPHGOBGXZQKCKI-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000008569 process Effects 0.000 title claims abstract description 10
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 title claims abstract description 9
- STGHAEAHYGLKLG-UHFFFAOYSA-N 2-nitro-4,5-diphenyl-1h-imidazole Chemical compound N1C([N+](=O)[O-])=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 STGHAEAHYGLKLG-UHFFFAOYSA-N 0.000 title claims abstract description 8
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 title abstract description 9
- 239000002184 metal Substances 0.000 title abstract description 9
- 150000002823 nitrates Chemical class 0.000 title abstract description 5
- 150000002739 metals Chemical class 0.000 title abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- 150000002500 ions Chemical class 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 230000003993 interaction Effects 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 238000006396 nitration reaction Methods 0.000 abstract description 21
- 239000003795 chemical substances by application Substances 0.000 abstract description 14
- 230000000802 nitrating effect Effects 0.000 abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 7
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 abstract description 5
- 150000004957 nitroimidazoles Chemical class 0.000 abstract description 5
- 230000009920 chelation Effects 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000007795 chemical reaction product Substances 0.000 abstract description 3
- 229910001960 metal nitrate Inorganic materials 0.000 abstract description 3
- 239000013110 organic ligand Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 206010021143 Hypoxia Diseases 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000001146 hypoxic effect Effects 0.000 description 5
- 150000002460 imidazoles Chemical class 0.000 description 5
- 229910017604 nitric acid Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- GNWBLLYJQXKPIP-ZOGIJGBBSA-N (1s,3as,3bs,5ar,9ar,9bs,11as)-n,n-diethyl-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1h-indeno[5,4-f]quinoline-1-carboxamide Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(CC)CC)[C@@]2(C)CC1 GNWBLLYJQXKPIP-ZOGIJGBBSA-N 0.000 description 3
- 150000004959 2-nitroimidazoles Chemical class 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- -1 imidazole nitrocompounds Chemical class 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003904 antiprotozoal agent Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 description 1
- ODKHOKLXMBWVOQ-UHFFFAOYSA-N 4,5-diphenyl-1,3-oxazole Chemical class O1C=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 ODKHOKLXMBWVOQ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 229910001579 aluminosilicate mineral Inorganic materials 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(II) nitrate Inorganic materials [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 1
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004729 solvothermal method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910002001 transition metal nitrate Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Inorganic materials [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
Invenţia se referă la chimia compuşilor coordinativi cu liganzi organici din clasa nitroimidazolilor, care pot fi utilizaţi în calitate de compuşi biologic activi, catalizatori etc. The invention refers to the chemistry of coordinating compounds with organic ligands from the class of nitroimidazoles, which can be used as biologically active compounds, catalysts, etc.
Imidazolii reprezintă o clasă foarte importantă de compuşi, din care fac parte preparate farmaceutice şi substanţe biologic active cu diverse aplicări ca agenţi antibacterieni, antifungici, chemoterapeutici etc. Nitroimidazolii sunt utilizaţi şi în calitate de agenţi citotoxici selectivi la hipoxie. Imidazoles represent a very important class of compounds, which include pharmaceutical preparations and biologically active substances with various applications as antibacterial, antifungal, chemotherapeutic agents, etc. Nitroimidazoles are also used as hypoxia-selective cytotoxic agents.
Ciclul imidazolic intră în componenţa histidinei, component esenţial al multor proteine. El joacă un rol important în activitatea enzimelor [1], datorită faptului că atomii de azot imidazolici nu sunt încorporaţi în legătura peptidică şi sunt liberi pentru a forma în continuare o structură supramoleculară în prezenţa ionilor multor metale [2, 3]. Din acest punct de vedere compuşii coordinativi ai imidazolului prezintă un interes deosebit pentru a investiga reacţiile care au loc cu gruparea imidazolică din proteine în vederea obţinerii compuşilor biologic activi. The imidazole cycle is part of histidine, an essential component of many proteins. It plays an important role in enzyme activity [1], due to the fact that imidazolic nitrogen atoms are not incorporated into the peptide bond and are free to further form a supramolecular structure in the presence of many metal ions [2, 3]. From this point of view, the coordination compounds of imidazole are of particular interest to investigate the reactions that take place with the imidazole group in proteins in order to obtain biologically active compounds.
Pe de altă parte, este cunoscut faptul că nitrocompuşii imidazolului au o activitate înaltă antimicrobiană şi sunt folosiţi pe larg în medicină [4]. Compuşii cu nucleul 2-nitroimidazolic manifestă o afinitate puternică faţă de celulele hipoxice din tumorile canceroase. De exemplu, 2-nitroimidazolii au fost propuşi în calitate de radiosensibilizatori pentru celulele tumorale hipoxice, de asemenea şi ca agenţi antiprotozoici [5]. Afinitatea puternică faţă de celulele hipoxice a permis ca 2-nitroimidazolii să fie utilizaţi în calitate de agenţi hipoxici selectivi, anume ca biomarkeri bioreductibili pentru tumorile hipoxice (v. referinţele din [6]). On the other hand, it is known that imidazole nitrocompounds have a high antimicrobial activity and are widely used in medicine [4]. Compounds with the 2-nitroimidazole nucleus show a strong affinity towards hypoxic cells in cancer tumors. For example, 2-nitroimidazoles have been proposed as radiosensitizers for hypoxic tumor cells, also as antiprotozoal agents [5]. The strong affinity towards hypoxic cells allowed 2-nitroimidazoles to be used as selective hypoxic agents, namely as bioreducible biomarkers for hypoxic tumors (see references in [6]).
Reacţia de nitrare directă a compuşilor imidazolului în poziţia C2 este dificilă şi poate fi efectuată în mod practic numai indirect în mai multe stadii [7]. Compusul natural „azomicin”, care este un antibiotic antiprotozoic puternic şi reprezintă 2-nitroimidazolul, se formează sub acţiunea enzimelor, iar mecanismul acestei reacţii nu este bine cunoscut la moment. The direct nitration reaction of imidazole compounds in the C2 position is difficult and can practically only be carried out indirectly in several stages [7]. The natural compound "azomycin", which is a strong antiprotozoal antibiotic and represents 2-nitroimidazole, is formed under the action of enzymes, and the mechanism of this reaction is not well known at the moment.
Datorită spectrului larg de proprietăţi utile sus-menţionate, prezintă interes sinteza nitroderivatului 4,5-difenilimidazolului, proprietăţile chimice şi biologice ale căruia vor fi puternic influenţate de prezenţa a doi substituenţi voluminoşi şi aromatici cu efecte stereoelectronice pronunţate asupra inelului heterociclic. Due to the wide spectrum of useful properties mentioned above, the synthesis of the nitro derivative of 4,5-diphenylimidazole is of interest, the chemical and biological properties of which will be strongly influenced by the presence of two bulky and aromatic substituents with pronounced stereoelectronic effects on the heterocyclic ring.
Este cunoscut, că la încercarea de a introduce gruparea nitro în nucleul heterociclic al 4,5-difenilimidazolului cu un agent acid de nitrare standard (HNO3 + H2SO4), nitrarea are loc doar în nucleul aromatic - se obţine cu un randament redus 4,5-bis-(p-nitrofenil)imidazolul [8]. Ulterior a fost elaborat un procedeu de nitrare similară în poziţia para- cu un randament bun, efectuându-se nitrarea cu agentul nitrant acid sus-menţionat în prezenţa ureei [9, v. exemplul nr. 3]. În ambele procedee nu este posibil de a introduce grupa NO2 în poziţia C2 a inelului heterociclic, iar inelul imidazolic posedă o rezistenţă înaltă la aceşti agenţi de oxidare puternici. It is known that when trying to introduce the nitro group into the heterocyclic nucleus of 4,5-diphenylimidazole with a standard acidic nitrating agent (HNO3 + H2SO4), the nitration takes place only in the aromatic nucleus - it is obtained with a reduced yield 4.5 -bis-(p-nitrophenyl)imidazole [8]. Later, a similar nitration procedure was developed in the para position with a good yield, performing the nitration with the above-mentioned acidic nitrating agent in the presence of urea [9, see example no. 3]. In both processes it is not possible to introduce the NO2 group in the C2 position of the heterocyclic ring, and the imidazole ring possesses a high resistance to these strong oxidizing agents.
Anterior a fost propus un procedeu de obţinere a unor derivaţi cu proprietăţi antiinflamatorii, în special pentru tratarea artritei, şi anume a 4,5- bis(4-R-fenil)-2-nitroimidazolului prin nitrarea indirectă a 4,5-difenilimidazolului. Reacţia include mai multe stadii: Previously, a process was proposed for obtaining derivatives with anti-inflammatory properties, especially for the treatment of arthritis, namely 4,5-bis(4-R-phenyl)-2-nitroimidazole by indirect nitration of 4,5-diphenylimidazole. The reaction includes several stages:
- protejarea atomului N1 al 4,5-difenilimidazolului, având diferiţi substituenţi în poziţia para- a inelului aromatic; - protecting the N1 atom of 4,5-diphenylimidazole, having different substituents in the para-position of the aromatic ring;
- tratarea produsului protejat cu o bază puternică, de exemplu, butillitiu (n-BuLi), urmată de tratarea cu un agent de nitrare, de exemplu, dinitrogen tetraoxid (N2O4) sau acetil nitrat şi, în final, deprotecţia în mediu acid [10]. - treatment of the protected product with a strong base, for example, butyllithium (n-BuLi), followed by treatment with a nitrating agent, for example, dinitrogen tetraoxide (N2O4) or acetyl nitrate and, finally, deprotection in an acid environment [10 ].
Dacă 4,5-difenilimidazolul este tratat (70…80ºC, 4 ore) cu un exces mare de acid azotic dizolvat în acid acetic glacial, compusul iniţial se oxidează complet până la benzil. În cazul în care reacţia se efectuează cu un mic exces de acid azotic, după primele 5 min se poate de izolat cu un randament bun heterociclul nitrat în poziţia C2: 2-nitro-4,5-difenilimidazolul [11]. Deşi randamentul nitrării este mare, reacţia descrisă este bazată pe utilizarea unui agent chimic foarte activ, în primul rând ca oxidant extrem de puternic, coroziv şi periculos, fapt ce poate crea probleme privind securitatea realizării procedeului de nitrare. Agenţii de nitrare sus-menţionaţi de asemenea nu sunt „prietenoşi” pentru mediul ambiant. If 4,5-diphenylimidazole is treated (70...80ºC, 4 hours) with a large excess of nitric acid dissolved in glacial acetic acid, the starting compound is completely oxidized to benzyl. If the reaction is carried out with a small excess of nitric acid, after the first 5 min it is possible to isolate with a good yield the nitrated heterocycle in the C2 position: 2-nitro-4,5-diphenylimidazole [11]. Although the yield of nitration is high, the reaction described is based on the use of a very active chemical agent, primarily as an extremely strong, corrosive and dangerous oxidant, which can create problems regarding the security of the nitration process. The above-mentioned nitrating agents are also not "friendly" to the environment.
Anterior au fost propuşi în calitate de agenţi de nitrare alternativi unii nitraţi ai metalelor de tranziţie 3d (Cu, Co, Zn, Ni, Fe, Cr, Cd, Mn) pe suporturi minerale de alumosilicaţi, în special argile montmorillonitice [12]. Reacţia decurge într-un regim eterogen în prezenţa anhidridei acetice şi a unui adaos mic de acid azotic. Deşi alumosilicaţii modificaţi cu nitraţii sus-menţionaţi reprezintă agenţi de nitrare mai inofensivi şi mai prietenoşi pentru mediu, ei sunt efectivi doar pentru mononitrarea sau polinitrarea nucleelor aromatice carbociclice. Previously, some nitrates of 3d transition metals (Cu, Co, Zn, Ni, Fe, Cr, Cd, Mn) on aluminosilicate mineral supports, especially montmorillonite clays, were proposed as alternative nitrating agents [12]. The reaction proceeds in a heterogeneous regime in the presence of acetic anhydride and a small addition of nitric acid. Although the above-mentioned nitrate-modified aluminosilicates represent more harmless and environmentally friendly nitrating agents, they are only effective for the mononitration or polynitration of carbocyclic aromatic nuclei.
În calitate de agent de nitrare pentru alchilfenolii, care au şi substituenţi heterociclici, inclusiv imidazolul, a fost propus nitratul de aluminiu [13]. Reacţia se produce numai la nucleul aromatic cu eliminarea alchilului (ipsonitrarea), iar substituenţii heterociclici nu sunt supuşi nitrării. Ionul de aluminiu rămâne necoordinat la produsul reacţiei din cauza afinităţii slabe la liganzii organici cu atomi de azot donor şi, nu în ultimul rând, datorită condiţiilor nefavorabile pentru coordinare. Aluminum nitrate was proposed as a nitrating agent for alkylphenols, which also have heterocyclic substituents, including imidazole [13]. The reaction occurs only at the aromatic nucleus with the elimination of the alkyl (ipsonitration), and the heterocyclic substituents are not subject to nitration. The aluminum ion remains uncoordinated to the reaction product due to the weak affinity to organic ligands with donor nitrogen atoms and, last but not least, due to unfavorable conditions for coordination.
Până în prezent nu au fost propuse metode alternative de nitrare directă a 4,5-difenilimidazolului cu agenţi de nitrare mai blânzi şi acceptabili ecologic. Elaborarea noilor metode de nitrare cu utilizarea agenţilor alternativi de nitrare, mai inofensivi pentru mediu, reprezintă un imperativ al chimiei verzi. Up to now, alternative methods of direct nitration of 4,5-diphenylimidazole with milder and environmentally acceptable nitrating agents have not been proposed. The development of new nitration methods with the use of alternative nitration agents, more harmless to the environment, represents an imperative of green chemistry.
Pe de altă parte, până în prezent nu au fost sintetizaţi compuşii coordinativi ai metalelor cu 2-nitro-4,5-difenilimidazolul cunoscut, care ar putea poseda diverse proprietăţi utile, inclusiv să manifeste diverse activităţi biologice, pornind de la faptul că la coordinare pot participa doi parteneri activi - atât ionii metalelor, cât şi derivatul nitroimidazolului. On the other hand, until now the coordination compounds of metals with the known 2-nitro-4,5-diphenylimidazole have not been synthesized, which could possess various useful properties, including exhibiting various biological activities, starting from the fact that upon coordination two active partners can participate - both metal ions and the nitroimidazole derivative.
În literatura de specialitate nu sunt menţionate metode de nitrare a nucleului imidazolic cu utilizarea nitraţilor de metal şi, în plus, ionul de metal din nitratul utilizat să fie coordinat la produsul reacţiei de nitrare. In the specialized literature, there are no methods of nitration of the imidazole nucleus with the use of metal nitrates and, in addition, the metal ion in the nitrate used must be coordinated to the product of the nitration reaction.
Problema pe care o rezolvă invenţia constă în elaborarea unui procedeu de sinteză a compuşilor coordinativi ai biometalelor tranziţionale 3d cu 2-nitro-4,5-difenilimidazol bazat pe nitrarea in situ a 4,5-difenilimidazolului în poziţia C2 cu nitraţii metalelor 3d respectivi şi coordinarea concomitentă a produsului reacţiei de nitrare cu ionii iniţiali de metal. The problem that the invention solves consists in the development of a process for the synthesis of the coordination compounds of 3d transition biometals with 2-nitro-4,5-diphenylimidazole based on the in situ nitration of 4,5-diphenylimidazole in the C2 position with nitrates of the respective 3d metals and simultaneous coordination of the product of the nitration reaction with the initial metal ions.
Esenţa invenţiei constă în aceea că se propune un procedeu de obţinere a compuşilor coordinativi ai unor biometale, aşa ca Co(II), Ni(II) şi Zn(II) cu 2-nitro-4,5-difenilimidazol la interacţiunea 4,5-difenilimidazolului cu nitraţii de Co(II), Ni(II) şi Zn(II), în metanol pur sau cu un conţinut mic de apă. În condiţii solvotermale (170ºC, 3 ore) nucleul heterociclic al 4,5-difenilimidazolului este nitrat în poziţia C2, iar ionii metalelor iniţiale se coordinează cu produsul nitrării prin chelatare, cu implicarea grupei nitro şi a unui atom de azot din nucleul heterociclic. Totodată solventul (metanolul) completează sfera de coordinare a ionului central. Efectuarea reacţiei în alte condiţii (160ºC sau 180ºC) duce la scăderea randamentului şi formarea altor compuşi. The essence of the invention is that a process is proposed for obtaining the coordination compounds of some biometals, such as Co(II), Ni(II) and Zn(II) with 2-nitro-4,5-diphenylimidazole at the interaction 4,5 -diphenylimidazole with Co(II), Ni(II) and Zn(II) nitrates, in pure methanol or with a small water content. In solvothermal conditions (170ºC, 3 hours) the heterocyclic nucleus of 4,5-diphenylimidazole is nitrated in the C2 position, and the initial metal ions coordinate with the nitration product by chelation, involving the nitro group and a nitrogen atom from the heterocyclic nucleus. At the same time, the solvent (methanol) completes the coordination sphere of the central ion. Carrying out the reaction under other conditions (160ºC or 180ºC) leads to a decrease in yield and the formation of other compounds.
Rezultatul invenţiei constă în aceea că în condiţiile solvotermale se produce concomitent nitrarea nucleului heterociclic şi coordinarea produsului reacţiei, nitraţii metalelor servind ca agenţi de nitrare neacizi şi ca sursă de ioni centrali pentru chelatarea cu nitroimidazolul rezultant. The result of the invention is that, under solvothermal conditions, nitration of the heterocyclic nucleus and coordination of the reaction product occur simultaneously, metal nitrates serving as non-acidic nitrating agents and as a source of central ions for chelation with the resulting nitroimidazole.
Reacţia de nitrare propusă are avantajul că nitraţii metalelor tranziţionale utilizate în calitate de agenţi de nitrare sunt mai inofensivi comparativ cu amestecurile de nitrare acide sau agenţii de nitrare pe suporturi minerale. The proposed nitration reaction has the advantage that the transition metal nitrates used as nitrating agents are more harmless compared to acidic nitrating mixtures or nitrating agents on mineral supports.
Invenţia se explică prin figură, care reprezintă structura complexului [Ni(4,5-Ph2ImNO2)2(CH3OH)2]. The invention is explained by the figure, which represents the structure of the complex [Ni(4,5-Ph2ImNO2)2(CH3OH)2].
Sinteza combinaţiilor complexe ale metalelor tranziţionale Ni2+, Zn2+, Co2+ cu 4,5-difenilimidazolul a fost efectuată, utilizând metoda solvotermală (v. schema): The synthesis of complex combinations of transition metals Ni2+, Zn2+, Co2+ with 4,5-diphenylimidazole was carried out, using the solvothermal method (see scheme):
Exemple de realizare a invenţiei Examples of realization of the invention
1. Sinteza compusului [Ni(4,5-Ph2ImNO2)2(CH3OH)2] (1) - bis(4,5-difenil-2-nitroimidazolil)bis(metanol)nichel(II) Amestecul format din Ni(NO3)2·6H2O - 92,8 mg (0,32 mmol) şi 4,5-difenilimidazol - 140,8 mg (0,64 mmol) dizolvat prin agitare în 9 mL metanol, a fost pus într-un vas de teflon cu capacitatea de 15 mL. Acest vas a fost plasat într-un reactor chimic ermetic de metal şi încălzit la 170°C timp de 3 ore, menţinându-se o temperatură constantă, apoi răcit până la temperatura camerei cu rata 0,06 °C/min. Cristalele brune aciforme obţinute au fost filtrate şi spălate de 3 ori cu câte 2 mL metanol pe filtru de hârtie, apoi uscate la aer. Masa produsului constituie 120 mg (randamentul calculat după sarea metalului este η = 58%). Compusul este solubil la încălzire în DMF, DMAA, etanol, izopropanol, acetonă, acetonitril şi insolubil în apă, metanol, toluen, cloroform. 1. Synthesis of the compound [Ni(4,5-Ph2ImNO2)2(CH3OH)2] (1) - bis(4,5-diphenyl-2-nitroimidazolyl)bis(methanol)nickel(II) The mixture consisting of Ni(NO3)2·6H2O - 92.8 mg (0.32 mmol) and 4,5-diphenylimidazole - 140.8 mg (0.64 mmol) dissolved by stirring in 9 mL of methanol, was placed in - a Teflon vessel with a capacity of 15 mL. This vessel was placed in a hermetic metal chemical reactor and heated to 170°C for 3 hours, maintaining a constant temperature, then cooled to room temperature at a rate of 0.06°C/min. The aciform brown crystals obtained were filtered and washed 3 times with 2 mL of methanol on filter paper, then dried in air. The mass of the product is 120 mg (the yield calculated according to the metal salt is η = 58%). The compound is soluble on heating in DMF, DMAA, ethanol, isopropanol, acetone, acetonitrile and insoluble in water, methanol, toluene, chloroform.
Datele analizei elementale, %: Elemental analysis data, %:
determinat - C 58,12; H 4,60; N 12,65; Ni 9,00; determined - C 58.12; H 4.60; N 12.65; Ni 9.00;
calculat pentru C32H28N6O6Ni - C 59,01; H 4,33; N 12,90; Ni 9,01. calculated for C32H28N6O6Ni - C 59.01; H 4.33; N 12.90; Nor 9.01.
Punctul de topire : ttop>355°C. Melting point: ttop>355°C.
Benzile în spectrul IR (cm-1): 3676(s), 2988(m), 2901(m), 2796(m), 1604(s), 1576(s), 1500(m), 1467(m), 1438(i), 1387(f.i), 1314(m), 1285(m), 1265(i), 1241(m), 1150(f.i), 1099(i), 1073(i), 1015(f.i), 976(i), 918(m), 835(m), 783(m), 772(m), 740(m), 733(m), 696(i), 679(m), 662(m). Bands in the IR spectrum (cm-1): 3676(s), 2988(m), 2901(m), 2796(m), 1604(s), 1576(s), 1500(m), 1467(m), 1438(i), 1387(f.i), 1314(m), 1285(m), 1265(i), 1241(m), 1150(f.i), 1099(i), 1073(i), 1015(f.i), 976(i), 918(m), 835(m), 783(m), 772(m), 740(m), 733(m), 696(i), 679(m), 662(m).
2. Sinteza compusului [Zn(4,5-Ph2ImNO2)2(CH3OH)2] (2) - bis(4,5-difenil-2-nitroimidazolil)bis(metanol)zinc(II) 2. Synthesis of the compound [Zn(4,5-Ph2ImNO2)2(CH3OH)2] (2) - bis(4,5-diphenyl-2-nitroimidazolyl)bis(methanol)zinc(II)
Folosind aceeaşi metodă ca în cazul (1) sinteza compusului (2) s-a efectuat cu următoarele cantităţi de substanţă: Zn(NO3)2·6H2O - 95 mg (0,32 mmol) şi 4,5-difenilimidazol - 140,8 mg (0,64 mmol). Au fost obţinute cristale aciforme oranj-deschis cu masa de 140 mg (randamentul calculat după sarea metalului η = 67%). Compusul este solubil la încălzire în DMF, DMAA, etanol, izopropanol, acetonă, acetonitril şi insolubil în apă, metanol, toluen, cloroform. Using the same method as in case (1), compound (2) was synthesized with the following amounts of substance: Zn(NO3)2·6H2O - 95 mg (0.32 mmol) and 4,5-diphenylimidazole - 140.8 mg ( 0.64 mmol). Light orange acicular crystals with a mass of 140 mg were obtained (calculated yield according to the metal salt η = 67%). The compound is soluble on heating in DMF, DMAA, ethanol, isopropanol, acetone, acetonitrile and insoluble in water, methanol, toluene, chloroform.
Datele analizei elementale, %: Elemental analysis data, %:
determinat - C 57,43; H 4,33; N 12,95; Zn 9,44; determined - C 57.43; H 4.33; N 12.95; Zn 9.44;
calculat pentru C32H28N6O6Zn - C 58,41; H 4,27; N 12,77; Zn 9,94. calculated for C32H28N6O6Zn - C 58.41; H 4.27; N 12.77; Zn 9.94.
Punctul de topire : ttop = 291…293°C. Melting point: ttop = 291...293°C.
Benzile în spectrul IR (cm-1): 3649(m), 2988(m), 2901(m), 2796(s), 1603(m), 1577(s), 1502(m), 1471(m), 1457(m), 1438(i), 1401(f.i), 1293(i), 1265(i), 1233(m), 1157(f.i), 1099(i), 1076(m), 1045(i), 1025(i), 975(i), 920(s), 833(m), 782(m), 770(i), 733(m), 695(i), 680(m), 657(s). Bands in the IR spectrum (cm-1): 3649(m), 2988(m), 2901(m), 2796(s), 1603(m), 1577(s), 1502(m), 1471(m), 1457(m), 1438(i), 1401(f.i), 1293(i), 1265(i), 1233(m), 1157(f.i), 1099(i), 1076(m), 1045(i), 1025(i), 975(i), 920(s), 833(m), 782(m), 770(i), 733(m), 695(i), 680(m), 657(s).
Benzile în spectrul 1H RMN (CD3COCD3): δ = 3, 00 ppm (singlet, 1H, OH); 3,31 şi 3,33 ppm (dublet, 3H, CH3); 3,85 ppm (singlet, 3H, CH3); 7,22…7,56 ppm (multiplet, 2OH, CHPh). Bands in the 1H NMR spectrum (CD3COCD3): δ = 3.00 ppm (singlet, 1H, OH); 3.31 and 3.33 ppm (doublet, 3H, CH3); 3.85 ppm (singlet, 3H, CH3); 7.22...7.56 ppm (multiplet, 2OH, CHPh).
3. Sinteza compusului [Co(4,5-Ph2ImNO2)2(CH3OH)2] (3) - bis(4,5-difenil-2-nitroimidazolil)bis(metanol)cobalt(II) 3. Synthesis of the compound [Co(4,5-Ph2ImNO2)2(CH3OH)2] (3) - bis(4,5-diphenyl-2-nitroimidazolyl)bis(methanol)cobalt(II)
Sinteza compusului [Co(4,5-Ph2ImNO2)2(CH3OH)2] (3) s-a realizat prin două metode: The synthesis of the compound [Co(4,5-Ph2ImNO2)2(CH3OH)2] (3) was carried out by two methods:
1) Folosind aceeaşi metodă ca în cazul (1) sinteza compusului (3) s-a efectuat cu următoarele cantităţi de substanţă: Co(NO3)2·6H2O - 93,5 mg (0,32 mmol) şi 4,5-difenilimidazol -140,8 mg (0,64 mmol). Au fost obţinute cristale aciforme roşii-închis cu masa 70 mg (randamentul calculat după sarea metalului η = 34%). Compusul este solubil la încălzire în DMF, DMAA, etanol, izopropanol, acetonă, acetonitril şi insolubil în apă, metanol, toluen, cloroform. 1) Using the same method as in case (1), compound (3) was synthesized with the following amounts of substance: Co(NO3)2·6H2O - 93.5 mg (0.32 mmol) and 4,5-diphenylimidazole -140 .8 mg (0.64 mmol). Dark red acicular crystals with a mass of 70 mg were obtained (calculated yield according to the metal salt η = 34%). The compound is soluble on heating in DMF, DMAA, ethanol, isopropanol, acetone, acetonitrile and insoluble in water, methanol, toluene, chloroform.
2) Sinteza se efectuează ca în pct. 1), însă în calitate de solvent se foloseşte amestecul metanol-apă (7 şi 2 mL respectiv). Au fost obţinute cristale aciforme roşii-închis cu masa 140 mg (randamentul calculat după sarea metalului η = 68%). Proprietăţile şi compoziţia chimică a produsului sunt similare cu cele obţinute conform metodei 1). 2) The synthesis is carried out as in point 1), but the methanol-water mixture (7 and 2 mL respectively) is used as solvent. Dark red acicular crystals with a mass of 140 mg were obtained (calculated yield according to the metal salt η = 68%). The properties and chemical composition of the product are similar to those obtained according to method 1).
Datele analizei elementale, %: Elemental analysis data, %:
determinat - C 58,07; H 4,60; N 12,40; Co 9,03; determined - C 58.07; H 4.60; N 12.40; Co 9:03;
calculat pentru C32H28N6O6Co - C 58,99; H 4,33; N 12,90; Co 9,05. calculated for C32H28N6O6Co - C 58.99; H 4.33; N 12.90; Co 9.05.
Punctul de topire : ttop>355°C. Melting point: ttop>355°C.
Benzile în spectrul IR (cm-1): 3657(s), 2989(m), 2902(m), 2772(m), 2542(m), 1605(s), 1577(s), 1523(s), 1499(i), 1468(m), 1437(f.i), 1388(f.i), 1314(m), 1286(m), 1269(i), 1241(m), 1150(f.i), 1099(i), 1073(m), 1032(m), 1018(f.i), 1009(f.i.), 976(i), 919(m), 833(m), 784(m), 772(m), 740(s), 734(m), 696(i), 680(m), 661(m). Bands in the IR spectrum (cm-1): 3657(s), 2989(m), 2902(m), 2772(m), 2542(m), 1605(s), 1577(s), 1523(s), 1499(i), 1468(m), 1437(f.i), 1388(f.i), 1314(m), 1286(m), 1269(i), 1241(m), 1150(f.i), 1099(i), 1073(m), 1032(m), 1018(f.i), 1009(f.i.), 976(i), 919(m), 833(m), 784(m), 772(m), 740(s), 734(m), 696(i), 680(m), 661(m).
Monocristalele compuşilor (1), (2) au fost studiate prin analiza cu raze X. Structura compusului [Ni(4,5-Ph2ImNO2)2(CH3OH)2] (1) este prezentată în figură. The single crystals of compounds (1), (2) were studied by X-ray analysis. The structure of the compound [Ni(4,5-Ph2ImNO2)2(CH3OH)2] (1) is presented in the figure.
Complecşii (2) şi (3) au o structură similară, confirmată prin datele analizei röentgenostructurale, precum şi prin alte analize (elementală, IR, termogravimetrică), dar există careva diferenţe în ceea ce priveşte unele unghiuri şi distanţe interatomice. Complexes (2) and (3) have a similar structure, confirmed by X-ray structural analysis data, as well as by other analyzes (elemental, IR, thermogravimetric), but there are some differences regarding some interatomic angles and distances.
Astfel, procedeul revendicat are la bază o nouă reacţie de nitrare directă a nucleului heterociclic din 4,5-difenilimidazol cu nitraţi ai biometalelor cu care concomitent se coordinează 2-nitroimidazolul rezultant împreună cu solventul utilizat. Este clar pentru un specialist în domeniu, că procedeul revendicat nu se poate limita doar la derivatul 4,5-difenilic al imidazolului, ci poate fi extins şi pentru imidazolii cu alţi substituenţi în poziţiile 4 şi 5. Thus, the claimed process is based on a new direct nitration reaction of the heterocyclic nucleus of 4,5-diphenylimidazole with nitrates of biometals with which the resulting 2-nitroimidazole is simultaneously coordinated together with the solvent used. It is clear to a specialist in the field, that the claimed process cannot be limited only to the 4,5-diphenyl derivative of imidazole, but can also be extended to imidazoles with other substituents in positions 4 and 5.
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