CN113620883A - Preparation method of semi-proton type compound, product and application thereof - Google Patents
Preparation method of semi-proton type compound, product and application thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of a semi-proton type compound, a product and application thereof, belonging to the technical field of compound preparation. The invention discloses a preparation method of a semi-proton type compound, which is characterized in that a heteroalkyl organic compound or a heterocyclic organic compound is reacted under the action of ammonium salt to prepare the semi-proton type compound. The synthetic method of the compound is shown as a general formula. The preparation method of the semi-proton type compound is simple, and the obtained semi-proton type compound has the biological activities of reducibility, antibiosis, tumor resistance and the like.
Description
Technical Field
The invention belongs to the technical field of compound preparation, and relates to a preparation method of a semi-proton type compound, and a product and application thereof.
Background
A semi-protic compound is a molecule that is protonated and interacts with another, unprotonated molecule via hydrogen bonds to form a stable semi-protonated structure. The structure of a semi-proton compound appears in a DNA repetitive fragment (i-motif structure) rich in Cytosine (C) base, and two C are N+-H…The N hydrogen bond being bound to C-C+The unique structure has the functions of regulating telomere length, gene expression and the like. However, no compounds with a semi-protonated structure have been identified in vitroThe report of the monomer synthesis and the functional research.
H in the semi-proton type compound can be used as an active proton donor for reduction reaction of other substances; meanwhile, biological function researches find that the synthesized semi-proton type compound has the biological activities of reducibility, antibiosis and tumor resistance.
Therefore, further studies on methods capable of synthesizing the semi-protic compound in vitro are needed.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for producing a semi-protic compound; the second purpose of the invention is to provide a semi-proton compound prepared by the preparation method of the semi-proton compound; the invention also aims to provide an application of the semi-proton type compound as an active proton donor in reduction reaction.
In order to achieve the purpose, the invention provides the following technical scheme:
1. a method of preparing a semi-protic compound, the method comprising: will contain R1And compounds containing R2Dissolving the compound in a solvent according to a molar ratio of 0.1-2: 1, adding an ammonium salt water solution, reacting, separating and removing impurities to obtain a semi-proton type compound;
said compound containing R1The compound of (a) is a heteroalkyl organic compound or a heterocyclic organic compound;
said compound containing R2The compound of (b) is a heteroalkyl organic compound or a heterocyclic organic compound.
Preferably, the solvent is any one or more of water, methanol, ethanol or acetonitrile.
Preferably, said compound contains R1In the compound of (1) wherein R1Comprising any one of N, O or S;
said compound containing R2In the compound of (1) wherein R1Including N, O or S.
Preferably, said compound contains R1The compound of (A) is triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine and bipyridinePurine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, betaine, matrine, histidine or tryptophan.
Preferably, said compound contains R1The compound of (a) is triethylamine derivative, imidazole derivative, pyrazole derivative, triazole derivative, oxazole derivative, thiazole derivative, phenanthroline derivative, furan derivative, pyran derivative, pyridine derivative, pyrrole derivative, indole derivative, thiophene derivative, purine derivative, pyrimidine derivative, pyrazine derivative, pyridazine derivative, thiazine derivative, phenazine derivative, quinoline derivative, isoquinoline derivative, guanidine derivative, matrine derivative, histidine derivative or tryptophan derivative.
Preferably, said compound contains R2The compound of (a) is any one of triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine, bipyridine, purine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, betaine, matrine, histidine or tryptophan.
Preferably, said compound contains R2The compound of (a) is triethylamine derivative, imidazole derivative, pyrazole derivative, triazole derivative, oxazole derivative, thiazole derivative, phenanthroline derivative, furan derivative, pyran derivative, pyridine derivative, pyrrole derivative, indole derivative, thiophene derivative, purine derivative, pyrimidine derivative, pyrazine derivative, pyridazine derivative, thiazine derivative, phenazine derivative, quinoline derivative, isoquinoline derivative, guanidine derivative, matrine derivative, histidine derivative or tryptophan derivative.
Preferably, the chemical formula of the ammonium salt is (NH)4)nR；
Wherein R is any one of phosphate radical, polyphosphate radical, nitrate radical, hexafluorophosphate radical, hexafluorosilicate radical, tetrafluoroborate radical, sulfate radical, persulfate radical, thiosulfate radical, molybdate radical, pyruvate radical, succinate radical, malate radical, tartrate radical, gallic acid, ferulate radical, benzoate radical, sulfamate radical, lignosulfonate radical, formate radical, acetate radical, salicylate radical, halogen radical or oxalate radical.
Preferably, the ammonium salt is any one of ammonium phosphate, ammonium polyphosphate, ammonium nitrate, ammonium hexafluorophosphate, ammonium hexafluorosilicate, ammonium tetrafluoroborate, ammonium sulfate, ammonium persulfate, ammonium thiosulfate, ammonium molybdate, ammonium pyruvate, ammonium succinate, ammonium malate, ammonium tartrate, ammonium bisabolonate, ammonium ferulate, ammonium benzoate, ammonium sulfamate, ammonium lignosulfonate, ammonium formate, ammonium acetate, ammonium salicylate, ammonium haloate, or ammonium oxalate.
Preferably, the ammonium salt and the compound containing R1The molar ratio of the compound (1) to the compound (3) is 1.2 to 3: 1.
2. The resulting semi-protic compound was prepared according to the above preparation method.
3. The use of the above-mentioned semi-protic compound as an active proton donor in reduction reactions.
The invention has the beneficial effects that:
the invention discloses a preparation method of a semi-proton type compound, which is characterized in that a heteroalkyl organic compound or a heterocyclic organic compound reacts under the action of ammonium salt, and the semi-proton type compound is prepared by molecular synthesis in vitro. The invention can provide compound molecules with new structures for the great health of life.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
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For the purposes of promoting a better understanding of the objects, aspects and advantages of the invention, reference will now be made to the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graph comparing the reduction effect of different compounds on oxidized glutathione (GSSG);
FIG. 2 shows the different compounds in pair H2O2The reduction effect of (2) is compared with the figure;
FIG. 3 is a graph showing the effect of a semi-proton type compound matrine-matrine hexafluorophosphate tumor cell.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention. It should be noted that the drawings provided in the following embodiments are only for illustrating the basic idea of the present invention in a schematic way, and the features in the following embodiments and examples may be combined with each other without conflict.
Example 1
The nitrate of the semi-proton type compound imidazole-imidazole is prepared by the following specific method:
1g of white imidazole was dissolved in 10mL of water, and then excess NH was added4NO3Aqueous solution (NH)4NO3The molar ratio to imidazole was 2: 1). Stirring and reacting for 12h at room temperature, freeze-drying, adding excessive chloroform to dissolve the product, and separating the product by column chromatography to obtain light brown semi-proton type imidazole-imidazole nitric acid with a melting point of 174-176 ℃.
1H NMR(400MHz,Deuterium Oxide)：δ7.68(s,2H),6.39(s,1H),3.59(t,J＝7.4Hz,1H),1.13(t,J＝7.1Hz,2H)。HRMS：[C6H9N4]NO3Molecular ion peak 137.2. The structure is as follows:
example 2
The preparation method of the semi-proton type compound thiophene-thiophene hexafluorophosphate comprises the following steps:
1g of thiophene was dissolved in 10mL of ethanol solution, and then excess NH was added4PF6Alcohol solution (wherein NH)4PF6The molar ratio of the thiophene to the thiophene is 1.5:1), uniformly mixing at room temperature, freeze-drying, adding a proper amount of acetonitrile to dissolve a product, filtering to obtain a supernatant, and drying to obtain a light yellow product, wherein the melting point of the light yellow product is 89-91 ℃.
1H NMR(400MHz,DMSO-d6)：δ8.33-8.23(m,5H),8.03-7.94(m,5H),7.23(s,1H),7.10(s,1H),6.98(s,1H)。HRMS：[C8H9S2]PF6Molecular ion peak 169.3. The structure is as follows:
example 3
The preparation method of the semi-proton type compound purine-pyrimidine hexafluorophosphate comprises the following steps:
dissolving 1g white purine and white pyrimidine (wherein molar ratio of purine to pyrimidine is 1:1) in 10mL water, respectively, stirring at room temperature for 2h, and adding NH with molar ratio of 3:14PF6Aqueous solution (wherein NH)4PF6The molar ratio of the product to purine is 3:1), adding a proper amount of acetonitrile to dissolve the product after freeze drying, filtering to obtain supernatant, and drying to obtain light yellow semi-proton purine-pyrimidine hexafluorophosphate with the melting point of 228-230 ℃.
1H NMR(400MHz,Deuterium Oxide)δ9.10(d,J＝1.9Hz,1H),8.92(s,1H),8.57(s,1H),4.74(s,8H),4.63(s,5H)。HRMS：[C9H9N6]PF6Molecular ion peak 201.2. The structure is as follows:
example 4
The acetate of a semi-proton type compound triethylamine-triethylamine is prepared by the following specific method:
1mL of triethylamine was dissolved in 10mL of ethanol, and CH was added3COONH4Solution (wherein CH3COONH4The molar ratio of the triethylamine to the triethylamine is 1.5:1), stirring and reacting for 12 hours at room temperature, adding excessive chloroform to dissolve a product after suction filtration, and separating the product by column chromatography to obtain white semi-proton type triethylamine-triethylamine acetic acid with the melting point of 41-43 ℃.
1H NMR(400MHz,Deuterium Oxide)：δ5.89(dd,J＝7.5,1.1Hz,1H),5.39(s,1H),5.25(s,1H),4.37(dd,J＝7.5,1.1Hz,1H)。HRMS：CH3COO[C4H19N2]Molecular ion peak 203.2. The structure is as follows:
example 5
The preparation method of the semi-proton type compound bipyridyl-bipyridyl hexafluorosilicic acid comprises the following steps:
1g of white 2,2' -bipyridine was dissolved in 10mL of ethanol solution, and NH was added at a molar ratio of 2:14SiF6Aqueous solution (wherein (NH)4)2SO4The molar ratio of the raw materials to 2,2' -bipyridyl is 2:1), evenly mixing the raw materials at room temperature, freeze-drying the mixture, adding a proper amount of acetonitrile to dissolve a product, filtering the mixture to obtain supernatant, and drying the supernatant to obtain an orange-red product. The melting point is 156-159 ℃.
1H NMR(400MHz,Acetonitrile-d3)：δ8.68(d,J＝5.7Hz,1H),7.96(t,J＝7.0Hz,1H),5.90(s,18H)。HRMS：[C20H17N4]2SiF6Molecular ion peak 313.4. The structure is as follows:
example 6
The preparation method of the semi-proton type compound matrine-matrine hexafluorophosphate comprises the following steps:
dissolving 1g white matrine in 10mL water, and adding NH4PF6The aqueous solution is stirred and reacted for 2h at room temperature (wherein NH)4PF6The molar ratio of the sodium chloride to the matrine is 1.5:1), freeze drying, adding a proper amount of acetonitrile to dissolve a product, filtering to obtain a supernatant, and drying to obtain a light brown product, wherein the melting point is 218-220 ℃.
1H NMR(400MHz,Chloroform-d)：δ7.18(s,5H),2.40–2.31(m,1H),2.27(s,1H),1.60(s,28H),1.29–1.20(m,7H),1.04(d,J＝17.4Hz,2H),0.92–0.81(m,3H),0.84(s,21H)。HRMS：[C30H49N4O2]PF6Molecular ion peak 497.7. The structure is as follows:
example 7
The preparation method of the semi-proton type compound quinoline-quinoline formic acid comprises the following steps:
1g of quinoline was dissolved in 10mL of methanol solution, and then excess NH was added4Aqueous COOH (wherein NH)4The molar ratio of COOH to quinoline is 1.6:1), stirring and reacting for 2 hours at room temperature, centrifuging, freeze-drying, adding a proper amount of acetonitrile to dissolve a product, filtering to obtain a supernatant, and drying to obtain a white product, wherein the melting point is 328-330 ℃.
1H NMR(400MHz,DMSO-d6)：δ9.66(s,1H),8.62(d,J＝6.1Hz,1H),8.37(dd,J＝8.3,1.1Hz,1H),8.27–8.16(m,2H),8.05(ddd,J＝8.3,6.9,1.3Hz,1H),7.91(ddd,J＝8.2,6.9,1.2Hz,1H),7.20(s,4H),7.08(s,4H)。HRMS：HCOO[C18H15N2]Molecular ion peak 259.3. The structure is as follows:
example 8
The semi-proton compound pyridazine-pyridazine hexafluorophosphate is prepared by the following specific method:
da 1gThe oxazine was dissolved in 10mL of ethanol and excess NH was added4PF6Aqueous solution (wherein NH)4PF6The molar ratio of the raw materials to pyridazine is 1.5:1), stirring and reacting for 2 hours at room temperature, freeze-drying, adding a proper amount of acetonitrile to dissolve a product, filtering, taking supernatant, and drying to obtain a white product, wherein the melting point is 260-262 ℃.
1H NMR(400MHz,Acetonitrile-d3)：δ9.17(t,J＝3.5Hz,1H),7.62(t,J＝3.5Hz,1H),5.96(s,6H)。HRMS：[C8H9N4]PF6Molecular ion peak 161.2. The structure is as follows:
example 9
The preparation method of the semi-proton type compound purine-purine hexafluorophosphate comprises the following steps:
dissolve 1g of purine in 10mL of water, then add NH4PF6Aqueous solution (wherein NH)4PF6The molar ratio of the purine to purine is 1.5:1), stirring and reacting for 2 hours at room temperature, adding a proper amount of acetonitrile to dissolve a product after freeze drying, filtering to obtain a supernatant, and drying to obtain a gray product, wherein the melting point is 249-251 ℃.
1H NMR(400MHz,Deuterium Oxide)：δ9.09(d,J＝2.7Hz,1H),8.91(s,1H),8.56(s,1H)。HRMS：[C10H9N8]PF6Molecular ion peak 241.2. The structure is as follows:
example 10
The semi-proton compound histidine-histidine hexafluorophosphate is prepared by the following specific method:
1g histidine was dissolved in 10mL water, then NH was added4PF6Aqueous solution (wherein NH)4PF6The mol ratio of the compound to histidine is 1.5:1), stirring and reacting for 2h at room temperature, freeze-drying, and adding a proper amount of acetonitrileDissolving the product, filtering to obtain supernatant, and drying to obtain a white product with a melting point of 259-261 ℃.
1H NMR(400MHz,Deuterium Oxide)：δ6.88(d,J＝1.4Hz,1H),5.67(s,1H),5.40(s,6H),5.35(s,1H),2.69(t,J＝6.7Hz,1H),1.78～1.61(m,2H),0.25(s,3H)。HRMS：[C12H19N6O4]PF6Molecular ion peak 311.3. The structure is as follows:
example 11
The semi-proton compound tryptophan-tryptophan hexafluorophosphate is prepared by the following specific method:
1g of tryptophan was dissolved in 10mL of water, and NH was added4PF6Aqueous solution (wherein NH)4PF6The molar ratio of the active component to tryptophan is 1.5:1), stirring and reacting for 2 hours at room temperature, freeze-drying, adding a proper amount of acetonitrile to dissolve a product, filtering, taking supernatant, and drying to obtain a white product, wherein the melting point of the white product is 238-240 ℃.
1H NMR(400MHz,DMSO-d6)：δ10.88(s,1H),7.56(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.20(d,J＝2.4Hz,1H),7.07(ddd,J＝8.1,6.9,1.2Hz,1H),7.01(s,9H),6.99(ddd,J＝8.0,6.9,1.1Hz,1H),3.43(dd,J＝9.0,4.0Hz,1H),3.35–3.26(m,1H),2.95(dd,J＝15.1,9.0Hz,1H)。HRMS：[C22H25N4O4]PF6Molecular ion peak 409.3. The structure is as follows:
example 12
The preparation method of the semi-proton type compound phenazine-phenazine hexafluorophosphate comprises the following steps:
1g of white phenazine is dissolved in 10mL of ethanol, and then excess NH is added4PF6Aqueous solution (wherein NH)4PF6The molar ratio to phenazine is 1.5:1),stirring and reacting for 2 hours at room temperature, adding a proper amount of acetonitrile to dissolve a product after freeze drying, filtering to obtain a supernatant, and drying to obtain a yellow product, wherein the melting point is 299-301 ℃.
1H NMR(400MHz,DMSO-d6)：δ10.88(s,1H),7.56(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.20(d,J＝2.4Hz,1H),7.07(ddd,J＝8.1,6.9,1.2Hz,1H),7.01(s,9H),6.99(ddd,J＝8.0,6.9,1.1Hz,1H),3.43(dd,J＝9.0,4.0Hz,1H),3.35～3.26(m,1H),2.95(dd,J＝15.1,9.0Hz,1H)。HRMS：[C24H17N4]PF6Molecular ion peak 461.4. The structure is as follows:
example 13
The preparation method of the semi-proton type compound adenosylmethionine-adenosylmethionine hexafluorophosphate comprises the following steps:
1g of ademetionine was dissolved in 10mL of ethanol, and NH was added4PF6Aqueous solution (wherein NH)4PF6The molar ratio of the N-acetylmethionine to the N-adenosylmethionine is 1.5:1), stirring and reacting for 2 hours at room temperature, adding a proper amount of acetonitrile to dissolve a product after freeze drying, filtering to obtain a supernatant, and drying to obtain a white product, wherein the melting point is 159-161 ℃.
1H NMR(400MHz,Deuterium Oxide)：δ7.69(s,1H),6.88(s,1H),3.10(d,J＝6.0Hz,1H),2.25(s,1H),2.04(dt,J＝18.2,9.6Hz,3H),1.79(dd,J＝19.8,10.4Hz,2H)。HRMS：[C30H43N12O10S2]PF6Molecular ion peak 797.5. The structure is as follows:
example 14
The method for preparing the semi-proton type compound phenanthroline-phenanthroline hexafluorosilicic acid comprises the following steps:
dissolving 1g of phenanthroline in 10mL of hydroalcoholic solution, and then adding NH4SiF6Aqueous solution (wherein NH)4SiF6The molar ratio of the phenanthroline to the phenanthroline is 1.5:1), stirring and reacting for 2 hours at room temperature, adding a proper amount of acetonitrile to dissolve a product after freeze drying, filtering to obtain a supernatant, and drying to obtain a pink product, wherein the melting point is 171-173 ℃.
1H NMR(400MHz,Acetonitrile-d3):δ8.98(dd,J＝4.4,1.7Hz,5H),8.39(dd,J＝8.1,1.8Hz,5H),7.89(s,5H),7.68(dd,J＝8.1,4.4Hz,5H),7.07(s,1H)。HRMS：[C24H17N4]2SiF6Molecular ion peak 361.4. The structure is as follows:
example 15
The semi-proton compound tryptophan-histidine hexafluorophosphate is prepared by the following specific method:
1g of tryptophan dissolved and equimolar histidine in 10mL of water, followed by excess NH4PF6Aqueous solution (wherein NH)4PF6The molar ratio of the tryptophan to the tryptophan is 1.5:1), stirring and reacting for 2 hours at room temperature, freeze-drying, adding a proper amount of acetic acid to dissolve a product, filtering, taking supernatant, and drying to obtain an off-white product, wherein the melting point is 228-230 ℃.
1H NMR(400MHz,DMSO-d6)：δ10.89(s,1H),7.56(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.20(d,J＝2.3Hz,1H),7.07(ddd,J＝8.1,6.9,1.2Hz,1H),6.88(d,J＝1.4Hz,1H),5.67(s,1H),5.40(s,6H),5.35(s,1H),3.45(dd,J＝9.0,4.0Hz,1H),2.96(dd,J＝15.1,8.9Hz,1H)，2.69(t,J＝6.7Hz,1H)。HRMS：[C17H22N5O4]PF6Molecular ion peak 360.3. The structure is as follows:
from the above examples, it can be seen that in the production method of the present invention, the reaction formula in the production process of the semi-protic compound is as follows:
wherein contains R1The compound of (a) is a heteroalkyl organic compound or a heterocyclic organic compound; containing R2The compound of (b) is a heteroalkyl organic compound or a heterocyclic organic compound.
When containing R1The compound of (a) is one of or a derivative of triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine, bipyridine, purine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, betaine, matrine, histidine or tryptophan, and contains R2The compound of (A) is one or more of triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine, bipyridine, purine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, betaine, matrine, histidine or tryptophan, or derivatives of the compounds, and is dissolved in one or more of water, methanol, ethanol or acetonitrile, and the compound has a chemical general formula of (NH)4)nR (any one of phosphate, polyphosphate, ammonium nitrate, ammonium hexafluorophosphate, ammonium hexafluorosilicate, ammonium hexafluoroborate, ammonium persulfate, ammonium tetrafluoroborate, ammonium persulfate, ammonium molybdate, ammonium ferulate, ammonium benzoate, ammonium sulfamate, ammonium lignosulfonate, ammonium formate, ammonium molybdate, ammonium pyruvate, ammonium succinate, ammonium malate, ammonium tartrate, ammonium bisabolate, ammonium ferulate, ammonium benzoate, ammonium sulfamate, ammonium lignosulfonate, ammonium formate, ammonium salicylate, a halogen ammonium salt or ammonium oxalate) under the action of a catalyst,the corresponding protic compound can be prepared in the same manner as in examples 1 to 15.
In the preparation of semi-protic compounds, when R is present1And compounds containing R2When the compounds are the same and can be respectively phenanthroline, pyrazole, piperazine, furan, thiazole and other slightly soluble or insoluble compounds in water, the compounds are dissolved in organic solvents such as ethanol, methanol, acetonitrile and the like during reaction, and then excessive ammonium salt water solution is added. If the precipitate is separated out, uniformly mixing the precipitate and the solvent until the precipitate is separated out, filtering to remove the solvent on the precipitate, washing off ammonium salt by using water, and drying; when containing R1And compounds containing R2When the compound (b) is a compound which is soluble or readily soluble in water, such as purine, pyrimidine or imidazole, the compound (b) is dissolved in an aqueous solution during the reaction, and then an excess amount of an aqueous ammonium salt solution is added thereto and the reaction is sufficiently stirred. Removing water when no free raw materials exist in the reaction liquid identified by thin layer chromatography, adding an organic solvent, separating the product by column chromatography, and drying.
In the general formula I, when containing R1And compounds containing R2When the compound (b) is a different molecule, it contains R1And compounds containing R2The compounds of (a) can be respectively different combinations of heterocyclic compounds such as purine, pyrimidine, pyridine, bipyridine, pyrazine, piperazine, phenazine, imidazole, thiazole, furan, matrine and the like.
When containing R1And compounds containing R2When the compounds are slightly soluble or insoluble in water, such as phenanthroline, pyrazole, piperazine, triethylamine and the like, dissolving the compounds in corresponding organic solvents during reaction, then adding excessive ammonium salt water solution, mixing uniformly until precipitation is finished if precipitation is precipitated, filtering to remove the solvent on the precipitation, washing ammonium salt with water, separating products by column chromatography, and drying; if no precipitate is separated out, removing water, adding an organic solvent, separating the product by column chromatography, and drying;
when containing R1And (or) a compound containing R2The compound is soluble in purine, pyrimidine, imidazole, adenosine, histidine, etcOr a compound which is easily soluble in water, they are dissolved in an aqueous solution at the time of reaction, and then an excess amount of an aqueous ammonium salt solution is added thereto, and the reaction is sufficiently stirred. And when no free raw materials exist in the reaction liquid identified by thin layer chromatography, removing water, adding an organic solvent, separating a product by column chromatography, and drying.
Example 6
Reduction performance of the semi-protic compounds prepared in the examples was examined:
1. the 24 test tubes were divided into four groups, an imidazole group, a thiophene group, a nitrate group of the semi-proton type compound imidazole-imidazole prepared in example 1, and a semi-proton type compound thiophene-thiophene hexafluorophosphate group prepared in example 2, each group consisting of 6 test tubes. In a test tube containing GSSG solution with the concentration of 1 mu mol/mL, 1 mu mol/mL of imidazole, thiophene, nitrate of semi-proton type compound imidazole-imidazole and semi-proton type compound thiophene-thiophene hexafluorophosphate are respectively added, then according to the instruction of the kit, reaction reagents are sequentially added, after incubation for 1 hour at room temperature, absorbance is detected at 412nm (the content of oxidized glutathione (GSSG) and prototype Glutathione (GSH) in the solution is detected by using a spectrophotometer method), and the content of GSSG and GSH is calculated, and the result is shown in figure 1. As can be seen from fig. 1, imidazole and thiophene did not reduce oxidized GSSG to GSH at a concentration of 1 μmol/mL, but the nitrate of the semi-protic compound imidazole-imidazole and the semi-protic compound thiophene-thiophene hexafluorophosphate reduced the GSSG content in solution while increasing the GSH content. It is demonstrated that the protic compounds prepared in examples 1 and 2 have good reducing ability, and are capable of reducing oxidized glutathione (GSSG) when used as a reducing agent.
2. The 18 test tubes were divided into three groups, purine group, pyrimidine group and purine-pyrimidine hexafluorophosphate group, which is a semi-proton type compound prepared in example 3, and 6 test tubes were each group. The hexafluorophosphates of purine, pyrimidine and purine-pyrimidine were added to the tubes at different concentrations, respectively, and then H was added to each tube at a concentration of 0.5g/L2O22mL of the solution was incubated at room temperature for 5 minutes, and then 3mol/L H was added2SO410rnL of solution and KMnO with concentration of no 0.01mol/L45mL of the solution was mixed, and absorbance was measured at 530nm (by measuring H in the solution using a spectrophotometer method)2O2Content of (d) according to a standard curve, H is calculated2O2The residual amount of (c). The results are shown in FIG. 2. As can be seen from FIG. 2, purines and pyrimidines do not have a hydrolysis H2O2However, the semi-protic purine-pyrimidine hexafluorophosphate compound can lower H dose-dependently2O2The content of (a). Thus, the semi-protic purine-pyrimidine hexafluorophosphate compound prepared in example 3 has reducibility and can be used as a reducing agent to reduce H2O2。
The semi-protic compound of the above examples 1, 2 and 3 can be used as a reducing agent for reduction reactions in vitro and in vivo, mainly due to the fact that R in the semi-protic compound prepared by the invention1And R2Are hydrogen bonded to form R1 +-R2It can be used as active proton donor, and has good reducibility when reacting with other oxidation type substances.
The semi-proton type compound prepared by other embodiments of the invention has the same structure, so the semi-proton type compound can be used as an active proton donor and has good reducibility when reacting with other oxidation type substances.
Example 7
Antimicrobial activity test of semi-protic compounds prepared in the examples:
the semi-proton type compounds triethylamine-triethylamine nitric acid and bipyridine-bipyridine hexafluorosilicic acid prepared in examples 4 and 5 were diluted with water to prepare a solution having a concentration of 1mg/mL, adding into culture medium containing gram-positive bacteria (Staphylococcus aureus), gram-negative bacteria (Escherichia coli) and fungi (Cryptococcus neoformans, Candida albicans, and Trichophyton rubrum) according to 96-well microdilution method, culturing at 37 deg.C for 12-72 hr, placing the culture plate on a shaker, shaking thoroughly, the Minimum Inhibitory Concentration (MIC) and minimum bactericidal concentration (MBC or MFC) of the semi-proton type compounds triethylamine-triethylamine nitric acid and bipyridine-bipyridine hexafluorosilicic acid against bacteria and fungi were measured by measuring absorbance at a wavelength of 600nm, and the results are shown in tables 1 and 2 below. As can be seen from the test results in tables 1 and 2, the semi-proton type compounds triethylamine-triethylamine nitric acid and bipyridine-bipyridine hexafluorosilicic acid prepared in examples 4 and 5 have good antibacterial effects on both bacteria and fungi, and show broad-spectrum antibacterial effects.
TABLE 1 antimicrobial Activity test of the semi-protic Compound Triethylamine-Triethylamine nitric acid
| μg/mL | Escherichia coli | Staphylococcus aureus | Cryptococcus neoformans | Candida albicans | Trichophyton rubrum |
| MIC | 0.065 | 0.065 | 0.25 | 0.5 | 1 |
| MBC | 0.5 | 0.5 | -- | -- | -- |
| MFC | -- | -- | 2 | 4 | 10 |
TABLE 2 semi-protic Compound bipyridine-bipyridine hexafluorosilicic acid antimicrobial Activity test
| μg/mL | Escherichia coli | Staphylococcus aureus | Cryptococcus neoformans | Candida albicans | Trichophyton rubrum |
| MIC | 0.125 | 0.25 | 0.125 | 0.25 | 0.25 |
| |
1 | 2 | -- | -- | -- |
| MFC | -- | -- | 1 | 2 | 4 |
Example 8
The effect of the proton-type compounds prepared in the examples on inhibiting the growth of human SH-SY5Y neuroblastoma and H22 hepatoma cells was tested:
the semi-proton type compound matrine-matrine hexafluorophosphate prepared in example 5 was added to 96-well cell culture plates cultured with human SH-SY5Y neuroblastoma and H22 hepatoma cells, respectively, and after incubation for 12H, the growth inhibitory effect of the semi-proton type matrine-matrine hexafluorophosphate on the above tumor cells was examined using CCK-8. The results are shown in FIG. 3. As can be seen from fig. 3, the semi-proton compound matrine-matrine hexafluorophosphate prepared in example 5 can significantly inhibit the growth of tumor cells, and the inhibition effect is dose-effect relationship. In addition, the half proton type compound matrine-matrine hexafluorophosphate has obviously stronger inhibition effect on two tumor cells than matrine with the same concentration.
In conclusion, the invention discloses a preparation method of a proton type compound, which is characterized in that a heteroalkyl organic compound or a heterocyclic organic compound reacts under the action of ammonium salt, and the proton type compound is prepared by molecular synthesis in vitro.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (10)
1. A method for preparing a semi-protic compound, the method comprising: will contain R1And compounds containing R2Dissolving the compound in water or an organic solvent according to a molar ratio of 0.1-2: 1, adding an ammonium salt aqueous solution, reacting, separating and removing impurities to obtain a semi-proton type compound;
said compound containing R1The compound of (a) is a heteroalkyl organic compound or a heterocyclic organic compound;
said compound containing R2The compound of (b) is a heteroalkyl organic compound or a heterocyclic organic compound.
2. The method according to claim 1, wherein said compound containing R1In the compound of (1) wherein R1Comprising any one of N, O or S;
said compound containing R2In the compound of (1) wherein R1Including N, O or S.
3. The method according to claim 2, wherein said compound containing R1The compound of (a) is any one of triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine, bipyridine, purine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, betaine, matrine, histidine or tryptophan.
4. The method according to claim 2, wherein said compound containing R1The compound of (a) is triethylamine derivative, imidazole derivative, pyrazole derivative, triazole derivative, oxazole derivative, thiazole derivative, phenanthroline derivative, furan derivative, pyran derivative, imidazole derivative, or imidazole derivative,Pyridine derivatives, pyrrole derivatives, indole derivatives, thiophene derivatives, purine derivatives, pyrimidine derivatives, pyrazine derivatives, pyridazine derivatives, thiazine derivatives, phenazine derivatives, quinoline derivatives, isoquinoline derivatives, guanidine derivatives, matrine derivatives, histidine derivatives, or tryptophan derivatives.
5. The method according to claim 2, wherein said compound containing R2The compound of (a) is any one of triethylamine, imidazole, pyrazole, triazole, oxazole, thiazole, phenanthroline, quinoline, pyridine, bipyridine, purine, pyrimidine, pyrazine, pyridazine, thiazine, phenazine, furan, pyran, pyrrole, indole, thiophene, isoquinoline, guanidine, matrine, histidine or tryptophan.
6. The method according to claim 2, wherein said compound containing R2The compound of (a) is triethylamine derivative, imidazole derivative, pyrazole derivative, triazole derivative, oxazole derivative, thiazole derivative, phenanthroline derivative, furan derivative, pyran derivative, pyridine derivative, pyrrole derivative, indole derivative, thiophene derivative, purine derivative, pyrimidine derivative, pyrazine derivative, pyridazine derivative, thiazine derivative, phenazine derivative, quinoline derivative, isoquinoline derivative, guanidine derivative, matrine derivative, histidine derivative or tryptophan derivative.
7. The method according to claim 1, wherein the ammonium salt has a chemical formula of (NH)4)nX；
Wherein X is any one of phosphate radical, polyphosphate radical, nitrate radical, hexafluorophosphate radical, hexafluorosilicate radical, tetrafluoroborate radical, sulfate radical, persulfate radical, thiosulfate radical, molybdate radical, pyruvate radical, succinate radical, malate radical, tartrate radical, gallic acid, ferulate radical, benzoate radical, sulfamate radical, lignosulfonate radical, formate radical, acetate radical, salicylate radical, halogen radical or oxalate radical.
8. The method according to claim 1, wherein the ammonium salt is a mixture of an ammonium salt and a compound containing R1The molar ratio of the compounds of (a) is greater than 1.
9. A semi-protic compound produced by the production method according to any one of claims 1 to 8.
10. Use of a semi-protic compound according to claim 9 as an active proton donor in a reduction reaction.
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| US4762631A (en) * | 1986-03-20 | 1988-08-09 | Nippon Chemi-Con Corporation | Electrolyte for electrolytic capacitor |
| US5112511A (en) * | 1985-12-28 | 1992-05-12 | Nippon Chemi-Con Corporation | Electrolyte for electrolytic capacitor |
| JP2014097934A (en) * | 2012-11-13 | 2014-05-29 | Ajinomoto Co Inc | Cosmetic composition containing acetate of amino acid compound |
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| US5112511A (en) * | 1985-12-28 | 1992-05-12 | Nippon Chemi-Con Corporation | Electrolyte for electrolytic capacitor |
| US4762631A (en) * | 1986-03-20 | 1988-08-09 | Nippon Chemi-Con Corporation | Electrolyte for electrolytic capacitor |
| JP2014097934A (en) * | 2012-11-13 | 2014-05-29 | Ajinomoto Co Inc | Cosmetic composition containing acetate of amino acid compound |
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