CN102093258B - Aromatic diamidine compound and synthesis method thereof - Google Patents
Aromatic diamidine compound and synthesis method thereof Download PDFInfo
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- CN102093258B CN102093258B CN201010594633.1A CN201010594633A CN102093258B CN 102093258 B CN102093258 B CN 102093258B CN 201010594633 A CN201010594633 A CN 201010594633A CN 102093258 B CN102093258 B CN 102093258B
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Abstract
The invention relates to an aromatic diamidine compound and a synthesis method thereof. The aromatic diamidine compound has the following structure, wherein R is an alkyl group or hydrogen. The synthesis method comprises the following steps: carrying out nitrile alcoholysis reaction on aromatic dinitrile used as the raw material and alcohol; introducing ammonia or amine to carry out alkoxy substitution reaction, thereby obtaining a saturated water solution of the crude product; properly adding excessive sodium hydroxide solution to the saturated water solution of the crude product, and vigorously stirring at low temperature until a great deal of solid precipitates; and filtering, washing with cold water, drying the solid, and purifying by recrystallization to obtain the aromatic diamidine compound. The aromatic diamidine compound provided by the invention has a novel chemical structure and unique chemical properties, can interact with biomacromolecules to be applied to the field of medicines, especially has the anti-tumor potential, and is hopeful to be converted into an important pharmaceutical intermediate. In addition, the synthesis method of the aromatic diamidine compound has the advantages of convenience, high efficiency, low cost, high yield (higher than 60%) and high purity (up to 98%), and is easy to implement.
Description
Technical field
The present invention relates to a kind of fragrant two amidine compounds, particularly a kind of fragrant two amidine compounds and synthetic method thereof with novel chemical structure.
Background technology
Amidine is the carboxylic acid analogue that nitrogen replaces, and some amidine compound is some fragments with the material of physiologically active.Simultaneously in organic synthesis or important intermediate, amidine is very important compound, is widely used in microbiotic, diuretic(s), antiphlogistic drug, wormer and wide spectrum miticide.For the preparation of nitrogen heterocyclic, amidine or useful synthon.The amino of amidine and imino-can transform mutually, form tautomer.The classical synthetic method of amidine is amide acetals method, the ammonolysis process of nitrile and ortho-formiate method, and newer synthetic method has improved Pinner method, the reduction method of oxime, Sm/TMSCl/H
2o (trace) system method, amino reduction method, catalysis synthesis process, ester synthesis method etc.However, the productive rate of amidine and purification are problem places for synthetic amidine always, often in synthetic a large amount of amidine compounds, there is raw material, inorganic salt and follow reaction and the impurity such as by product that produces, thereby effectively and easily method of purification of exploration, obtain the more amidine of high yield and purity, become the new problem of the synthesis technique aspect of amidine.
Summary of the invention
The object of the present invention is to provide a kind of fragrant two amidine compounds, there is novel chemical structure and unique chemical property, can be applied to interaction of biomacromolecules field of medicaments.
The synthetic method that another object of the present invention is to provide a kind of above-mentioned fragrant two amidine compounds, the method is simple and direct, and raw material is cheap and easy to get, and can obtain highly purified fragrant two amidine compounds of high yield.
For achieving the above object, the invention provides a kind of fragrant two amidine compounds, it has following structure:
Wherein, R is alkyl or hydrogen.
The invention provides another kind of fragrant two amidine compounds, it has following structure:
Wherein, R is alkyl or hydrogen.
Further, the invention provides a kind of synthetic method of above-mentioned fragrant two amidine compounds, this synthetic method is taking hydrogenchloride as catalyzer, taking fragrant dintrile as raw material with the alcoholysis reaction of alcohol generation nitrile, then pass into the reaction that ammonia or amine carry out substituted alkoxy, in reaction, keeping temperature is 0～-20 DEG C, make the saturated aqueous solution of crude product, add suitably excessive sodium hydroxide solution, vigorous stirring at 0～5 DEG C of low temperature, until a large amount of solids are separated out, filter and use cold water flush, recrystallization purifying will be carried out after solid drying, obtain fragrant two amidine compounds.
Wherein, described alcohol, hydrogenchloride, ammonia or amine are all excessive; The reaction conditions of the alcoholysis reaction of described nitrile is :-20 DEG C～-5 DEG C/4-6 hour.
Described alcohol is methyl alcohol, ethanol or other alcoholic solvents; When described recrystallization, adopt polar solvent to carry out recrystallization, as adopted dimethyl formamide etc.
Described synthetic method, taking terephthalonitrile as raw material, can make benzene two amidine compounds.
The present invention also provides the synthetic method of another kind of above-mentioned fragrant two amidine compounds, this synthetic method is taking dihalo aromatic hydrocarbon as raw material, added in organic solvent, taking lithium alkylide as coupling agent, taking tetramethyl quadrol as stablizer, obtain active carbanion by halogen-lithium exchange reactions, then obtain crude product with carbodiimide addition, by extraction and column chromatography, recrystallization or chromatographic purification, obtain fragrant two amidine compounds again.
Wherein, carbodiimide: R-N=C=N-R ' (R can be alkyl or hydrogen).
The reaction conditions of described halogen-lithium exchange reactions is :-35 DEG C/12 hours; Described organic solvent adopts the organic solvent through super-dry, is ethanol, methyl alcohol, dimethyl formamide, tetrahydrofuran (THF), ether, normal hexane, tetramethyl quadrol, chloroform or ethyl acetate.
When described column chromatography, adopt medium polar solvent and intensive polar solvent to carry out gradient elution, taking aluminum oxide as stationary phase, wherein medium polar solvent is ethyl acetate or chloroform, and intensive polar solvent is ethanol; When described recrystallization, adopt dimethyl formamide or other intensive polar solvents to carry out recrystallization; The solvent that chromatographic purification is used is medium polar solvent.
Described synthetic method is with 4,4 '-diiodobiphenyl or 4, and 4 '-'-dibromobiphenyl is raw material, can make biphenyl two amidine compounds.
The invention has the beneficial effects as follows: fragrant two amidine compounds of the present invention, there is novel chemical structure and unique chemical property, can be applied to interaction of biomacromolecules field of medicaments, especially have antineoplastic potential quality, it is expected to be converted into important pharmaceutical intermediate; In addition the synthetic method of fragrant two amidine compounds of the present invention is simple and direct efficient, with low cost, easy to implement, and productive rate and purity high, productive rate can reach more than 60%, purity 98%.
In order further to understand feature of the present invention and technology contents, refer to following about detailed description of the present invention and accompanying drawing, but accompanying drawing only provide with reference to and explanation use, be not used for the present invention to be limited.
Brief description of the drawings
In accompanying drawing,
Fig. 1 is the ESI analysis chart to benzene two amidine compounds of the embodiment of the present invention 1;
Fig. 2 be the embodiment of the present invention 1 to benzene two amidine compounds
1h-NMR (400MHz, 25 DEG C) analysis chart;
Fig. 3 is the N of the embodiment of the present invention 2, N ', N ", N " '-hexyl biphenyl base-4, Fourth Ring, the ESI analysis chart of 4 '-bis-amidine compounds;
Fig. 4 is the N of the embodiment of the present invention 2, N ', N ", N " '-hexyl biphenyl base-4, Fourth Ring, 4 '-bis-amidine compounds
1h-NMR (400MHz, 25 DEG C) analysis chart.
Embodiment
The invention provides a kind of fragrant two amidine compounds, it has following structure:
Wherein, R is alkyl or hydrogen.
The synthetic method of above-mentioned these fragrant two amidine compounds of the present invention, it is taking hydrogenchloride as catalyzer, taking fragrant dintrile as raw material, with the alcoholysis reaction of alcohol generation nitrile, reaction conditions is :-20 DEG C～-5 DEG C/4-6 hour; Then pass into the reaction that ammonia or amine carry out substituted alkoxy, in reaction, keeping temperature is 0～-20 DEG C, make the saturated aqueous solution of crude product, add suitably excessive sodium hydroxide solution, vigorous stirring at 0～5 DEG C of low temperature, until a large amount of solid is separated out, filters and uses cold water flush, to after solid drying, carry out recrystallization purifying, obtain fragrant two amidine compounds.Wherein, described alcohol, hydrogenchloride, ammonia or amine are all excessive; Described alcohol is methyl alcohol, ethanol or other alcoholic solvents; When described recrystallization, adopt polar solvent to carry out recrystallization, as adopted dimethyl formamide (DMF) etc.
Described synthetic method can make benzene two amidine compounds during taking terephthalonitrile as raw material.
The invention provides another kind of fragrant two amidine compounds, it has following structure:
Wherein, R is alkyl or hydrogen.
The synthetic method of above-mentioned these fragrant two amidine compounds of the present invention, taking dihalo aromatic hydrocarbon as raw material, added in organic solvent, taking lithium alkylide as coupling agent, taking tetramethyl quadrol as stablizer, obtain active carbanion by halogen-lithium exchange reactions, then obtain crude product with carbodiimide: R-N=C=N-R ' (R can be alkyl or hydrogen) addition, by extraction and column chromatography, recrystallization or chromatographic purification, obtain fragrant two amidine compounds again.
Wherein, the reaction conditions of described halogen-lithium exchange reactions is :-35 DEG C/12 hours; Described organic solvent adopts the organic solvent through super-dry, is ethanol, methyl alcohol, dimethyl formamide, tetrahydrofuran (THF), ether, normal hexane, tetramethyl quadrol, chloroform or ethyl acetate.When described column chromatography, adopt medium polar solvent and intensive polar solvent to carry out gradient elution, taking aluminum oxide as stationary phase, wherein medium polar solvent is ethyl acetate or chloroform, and intensive polar solvent is ethanol; When described recrystallization, adopt dimethyl formamide or other intensive polar solvents to carry out recrystallization; The solvent that chromatographic purification is used is medium polar solvent.
Described synthetic method is with 4, and 4 '-diiodobiphenyl or 4, can make biphenyl two amidine compounds when 4 '-'-dibromobiphenyl is raw material.
Below by specific embodiment, the present invention is described in detail, but the present invention is not confined to scope of embodiments.
Embodiment 1: terephthalonitrile is converted into the reaction to benzene two amidines
In terephthalonitrile, add ethanol, at-5～-15 DEG C, stir, pass into hydrogen chloride gas, until system no longer increases weight, removal of solvent under reduced pressure, again add ethanol, at-5～-15 DEG C, stir, pass into ammonia, until solids disappeared, removal of solvent under reduced pressure, adds sodium hydroxide solution to filter and obtains, to benzene two amidine compound crude products, purifying through DMF recrystallization.Gained is to the structural formula of benzene two amidine compounds (reactant: to benzene two amidines) as follows:
The analysis chart of its ESI and H-NMR (the hydrogen spectrum of nucleus magnetic resonance) is distinguished as shown in Figure 1-2:
Fig. 1 MS (m/z) 163.2 (M
+), 164.2 (M
2+), 165.1 (M
3+)
Fig. 2
1h-NMR (δ, 400MHz, DMSO-d
6) ppm:6.42 (br, 6H, NH), 7.78 (s, 4H, phenyl)
Embodiment 2:4,4 '-diiodobiphenyl is converted into the reaction to benzene two amidines
4, in 4 '-diiodobiphenyl, add tetrahydrofuran (THF), at-35～-60 DEG C, add butyllithium and tetramethyl quadrol, after reaction for some time, add N, the tetrahydrofuran solution of N '-dicyclohexylcarbodiimide, after reacting completely under room temperature, add a small amount of shrend reaction of going out, with after extracted with diethyl ether, with n-hexane dissolution, purify and obtain N through column chromatography, N ', N ", N " '-hexyl biphenyl base-4, Fourth Ring, 4 '-bis-amidine compounds, its structural formula as follows (reactant: N, N ', N "; N " hexyl biphenyl base-4, '-Fourth Ring, 4 '-bis-amidines):
The analysis chart of its ESI and H-NMR is distinguished as shown in Figure 1-2:
Fig. 3 MS (m/z) 567.5 (M
+), 568.5 (M
2+), 569.5 (M
3+), 570.6 (M
4+).
Fig. 4
1h-NMR (δ, 400MHz, DMSO-d
6) ppm:8.02 (d, 4H, phenyl), 7.71 (d, 4H, phenyl), 3.95 (br, 2H), 3.01 (br, 2H)
In sum, fragrant two amidine compounds of the present invention, have novel chemical structure and unique chemical property, can be applied to interaction of biomacromolecules field of medicaments, especially have antineoplastic potential quality, and it is expected to be converted into important pharmaceutical intermediate; In addition the synthetic method of fragrant two amidine compounds of the present invention is simple and direct efficient, with low cost, easy to implement, and productive rate and purity high, productive rate can reach more than 60%, purity 98%.
The above; for the person of ordinary skill of the art; can make other various corresponding changes and distortion according to technical scheme of the present invention and technical conceive, and all these changes and distortion all should belong to the protection domain of the accompanying claim of the present invention.
Claims (2)
1. the synthetic method of fragrant two amidine compounds, it is characterized in that, this synthetic method is taking hydrogenchloride as catalyzer, taking fragrant dintrile as raw material with the alcoholysis reaction of alcohol generation nitrile, then pass into the reaction that ammonia or amine carry out substituted alkoxy, in reaction, keeping temperature is 0～-20 DEG C, make the saturated aqueous solution of crude product, add suitably excessive sodium hydroxide solution, vigorous stirring at 0～5 DEG C of low temperature, until a large amount of solid is separated out, filters and uses cold water flush, to after solid drying, carry out recrystallization purifying, obtain fragrant two amidine compounds;
Described fragrant dintrile is benzene dinitrile;
Described fragrant two amidine compounds are that it has following structure to benzene two amidine compounds:
Wherein, R is alkyl or hydrogen;
The reaction conditions of the alcoholysis reaction of described nitrile is :-20 DEG C～-5 DEG C/4-6 hour; Described alcohol, hydrogenchloride, ammonia or amine are all excessive.
2. the synthetic method of fragrant two amidine compounds as claimed in claim 1, is characterized in that, described alcohol is methyl alcohol, ethanol or other alcoholic solvents; When described recrystallization, adopt polar solvent to carry out recrystallization.
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| CN107216455B (en) * | 2017-06-15 | 2019-06-28 | 华中科技大学 | A kind of organic microporous polymer and preparation method thereof containing triazine ring structure |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042902A (en) * | 1988-10-25 | 1990-06-13 | 理查德·R·蒂德威尔 | The method of treatment and prevention pneumocystis carinii pneumonia and other disease and used compound and prescription |
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| GB1197929A (en) * | 1966-10-31 | 1970-07-08 | Toyo Jozo Kk | Process for the Manufacture of Substituted Bis-AmidinoCompounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042902A (en) * | 1988-10-25 | 1990-06-13 | 理查德·R·蒂德威尔 | The method of treatment and prevention pneumocystis carinii pneumonia and other disease and used compound and prescription |
Non-Patent Citations (6)
| Title |
|---|
| Benzdiamidine;Milan Jokic, et al;《Acta Crystallographica Section C Crystal Structure Communications》;20011231;第C57卷;1354-1355 * |
| Milan Jokic, et al.Benzdiamidine.《Acta Crystallographica Section C Crystal Structure Communications》.2001,第C57卷1354-1355. |
| 从对-苯二甲腈合成聚苯基不对称三嗪;卢凤才 等;《高分子通讯》;19800831(第4期);193-197 * |
| 卢凤才 等.从对-苯二甲腈合成聚苯基不对称三嗪.《高分子通讯》.1980,(第4期),193-197. |
| 廉应江 等.芳香二脒类化合物合成及抑菌活性的初步研究.《西北农林科技大学学报(自然科学版)》.2005,第33卷(第7期),45-48. |
| 芳香二脒类化合物合成及抑菌活性的初步研究;廉应江 等;《西北农林科技大学学报(自然科学版)》;20050731;第33卷(第7期);45-48 * |
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