CN101602657A - Halogenated hydroxyl arone compounds and its production and use - Google Patents
Halogenated hydroxyl arone compounds and its production and use Download PDFInfo
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Abstract
The present invention relates to class new compound and its production and use, be specially a kind of halogenated hydroxyl arone compounds and its production and use, the problem that the halogenated hydroxyl arone class lead compound extraction cost of solution natural origin is too high, yield is low, be difficult to carry out follow-up study, structural formula is right formula, R
1' be the one or more hydroxyls or the hydrogen atom of optional position on the A ring, R
2' be the one or more hydroxyls or the hydrogen atom of optional position on the B ring; X is the one or more halogens or the hydrogen atom of optional position on the A ring or on the B ring, and this synthetic method has that reaction conditions is gentle, and raw material extensively is easy to get, and the preparation method is easy, and productive rate is higher, and low cost and other advantages is suitable for suitability for industrialized production.That synthetic halogenated hydroxyl arone compounds and atoxic salt thereof, ester, ether have is antibiotic, antitumor, anti-oxidant, anti-vascular endothelial cell damage and suppress the vascular smooth muscle cell proliferation activity.
Description
Technical field
The present invention relates to class new compound and its production and use, be specially a kind of halogenated hydroxyl arone compounds and its production and use.
Background technology
In recent years, the research of relevant marine alga active substance has caused extensive concern.Wherein, extracting the bromine phenolic compound obtain and have antitumor significantly, antibiotic, hypoglycemic, antithrombotic and anti-oxidant multiple biological activity (CN101177382A, CN1853618A, CN101283997A, CN101283998A) from marine alga, is the lead compound that has potentiality.Yet because the yield that extracts from marine alga is lower, cost is higher, can not satisfy the demand of new drug development and clinical application, can't widespread use.Therefore, seek a kind of synthetic method of halogenated hydroxyl arone compounds that can suitability for industrialized production and carry out rational structure optimization, help its further research and development and clinical application.
Summary of the invention
The problem that the present invention is too high for the halogenated hydroxyl arone class lead compound extraction cost that solves natural origin, yield is low, be difficult to carry out follow-up study provides a kind of novel halogenated hydroxyl arone compounds and its production and use.
The present invention adopts following technical scheme to realize: a kind of halogenated hydroxyl arone compounds, be the represented compound of structural formula I and salt, ester, the ether of this compound,
Wherein, R
1' be the one or more hydroxyls or the hydrogen atom of optional position on the A ring, R
2' be the one or more hydroxyls or the hydrogen atom of optional position on the B ring; X is the one or more halogens or the hydrogen atom of optional position on the A ring or on the B ring, and described halogen can be fluorine, chlorine, bromine, iodine; A ring, B ring represent that respectively phenyl ring or heterocycle, described heterocycle can be the various ring texturees that furans, thiophene, pyrroles, thiazole, imidazoles, pyridine, pyrazine, pyrimidine and indoles, quinoline, pteridine, acridine or other heteroatoms replace; Said n is represented the number of hydroxyl, hydrogen atom or halogen, n=0～5.
Prepare the method for described halogenated hydroxyl arone compounds, synthetic route may further comprise the steps:
Wherein, R
1', R
2', the definition such as the claim 1 of X, n, A ring and B ring, R
1Be the one or more alkoxyl groups or the hydrogen atom of optional position on the A ring, R
2One or more alkoxyl groups or hydrogen atom for optional position on the B ring;
Said synthesis route may further comprise the steps:
(1) as catalyzer and solvent, and temperature of reaction is 70～150 degrees centigrade to Compound I I at polyphosphoric acid, and the reaction times is under 1～12 hour the condition, to make compound IV with alkoxy benzene or alkoxyl group heterogeneous ring compound generation acylation reaction; Perhaps Compound I I obtains corresponding acyl chlorides III with reaction under chloride reagent and the catalyzer condition in inert solvent, acyl chlorides III and alkoxy benzene or alkoxyl group heterogeneous ring compound generation Friedel-Crafts reaction makes compound IV then, and the chloride reagent of described acyl chloride reaction is SOCl
2, phosphorus trichloride, phosphorus pentachloride or triphosgene, catalyzer is DMF, pyridine or Lewis base, temperature of reaction is 50～150 degrees centigrade, reaction times is 1～4 hour, the used catalyzer of Friedel-Crafts reaction is Lewis acid or protonic acid, temperature of reaction is subzero 15～20 degrees centigrade, and the reaction times is 1～4 hour; Perhaps also can be directly as starting raw material and alkoxy benzene or alkoxyl group heterogeneous ring compound the Friedel-Crafts reaction taking place by acyl chlorides III makes compound IV; (2) compound IV is carried out halogenating reaction with bromide reagent or chlorination reagent in inert solvent, the product that obtains is carried out aftertreatment with alkali lye obtain compound V, and the bromide reagent that described halogenating reaction adopts can be NBS or liquid bromine, and chlorination reagent can be SO
2Cl
2Or chlorine, the temperature of reaction of halogenating reaction is 0～100 degree centigrade, the reaction times is 1～24 hour; (3) compound V is in inert solvent and at Lewis acid or protonic acid under the condition as catalyzer; slough the alkoxyl group protecting group and obtain halogenated hydroxyl arone compounds I; the temperature of reaction of deprotection reaction is subzero 78～0 degrees centigrade, and the reaction times is 1～12 hour.
The non-toxic salt of structural formula I provided by the present invention, ester, ether also belong within the technology category of the present invention.The compounds of this invention and non-toxic salt thereof, ester, ether can be crystalline state or solvate (such as hydrate), and two states all belongs within the scope of the invention.This compound salify, one-tenth ester, one-tenth ether and solvation method are widely known by the people in the prior art simultaneously.
Used inert solvent is that in water, Glacial acetic acid, methylene dichloride, ethyl acetate, ether, tetrahydrofuran (THF), methyl alcohol, the ethanol one or more mix with arbitrary proportion in the above-mentioned reaction, and used alkali lye is ammoniacal liquor, carbonate, basic metal, alkaline-earth metal simple substance or its oxyhydroxide.Described Lewis acid or protonic acid can be trifluoromethanesulfonic acid, trifluoroacetic acid, AlCl
3, HF, SnCl
4, H
2SO
4, HCl.
The present invention also provides the salt of a kind of halogenated hydroxyl arone compounds and this compound, ester, ether, antibiotic in preparation, antitumor, anti-oxidant, the anti-vascular endothelial cell damage, suppress vascular smooth muscle cell proliferation medicine and sterilizing agent, antioxidant, application in the foodstuff additive, the arbitrary compound or the mixture of halogenated hydroxyl arone compounds and pharmaceutically acceptable derivates thereof can be mixed and made into injection with pharmaceutically acceptable pharmaceutical carrier simultaneously, tablet, capsule, oral liquid, suppository, film, aerosol, externally-applied liniment or ointment drug form.
The determination of pharmacological activity of the part of compounds of the present invention's preparation:
(1) anti tumor activity in vitro is measured
Adopting mtt assay to carry out anti tumor activity in vitro measures, the HepG-2 human hepatoma cell strain of taking the logarithm vegetative period, SGC-7901 human stomach cancer cell line and K562 human leukemia cell line, be made into the individual cells suspension with containing 10% tire calf serum nutrient solution respectively, control 1000 to 10000 cell inoculations in every hole to 96 orifice plates, every pore volume 200 μ l.At 37 ℃, 5%CO
2The conventional cultivation 3 to 5 days under the condition, the tire calf serum nutrient solution solution of the serial halogenated hydroxyl arone compounds of adding the present invention preparation, concentration is respectively 0.1,1,10,100 μ g/ml, every hole adds 10 μ l, and each concentration is all established 3 multiple holes.Establish the DMSO solvent contrast of respective concentration and the parallel blank of compound colour developing concentration simultaneously.Cultivate after 1 day, every hole adds MTT solution 20 μ l, continue to hatch 4 hours after, the careful suction abandoned the culture supernatant hole in, suspension cell need centrifugal after again suction abandon culture supernatant in the hole.Every hole adds DMSO150 μ l, vibrates 10 minutes, and crystallisate is fully dissolved.Measure each hole absorbance value (OD value) with enzyme linked immunological monitor 490nm wavelength, the record result calculates inhibiting rate, and with LOGIT method calculation of half inhibitory concentration (IC
50).Experimental result sees the following form 1:
Table 1 part halogenated hydroxyl arone compounds anti tumor activity in vitro test result
The result shows, the serial halogenated hydroxyl arone compounds of the present invention preparation all has in various degree restraining effect to HepG-2 human hepatoma cell strain, SGC-7901 human stomach cancer cell line and K562 human leukemia cell line, illustrate that this compounds has the activity that suppresses tumor cell proliferation, points out this compounds to have antitumor action.
(2) bacteriostatic activity is measured
Adopt the micro-broth dilution method bacteriostatic activity.Aseptic technique, the solution (128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml) that the serial halogenated hydroxyl arone compounds doubling dilution that the present invention is prepared is a different concns, be added to respectively in 96 orifice plates of sterilization, every hole 10 μ l, set blank simultaneously, seal behind the frost drying, preserve standby below-20 ℃.Select the fresh culture thing of ATCC reference culture streptococcus aureus, intestinal bacteria and Candida albicans for use, be prepared into concentration and be equivalent to the bacteria suspension of 0.5 Maxwell than turbid standard.After the dilution in 1: 1000 of MH meat soup, in 96 orifice plates, add in every hole in the rearmounted 35 ℃ of normal air incubators of 100 μ l sealing, hatch 24h.The result is MIC (the minimal inhibitory concentration minimum inhibitory concentration) value of this compound with the compound concentration of complete bacteria growing inhibiting in aperture.Experimental result sees the following form 2:
Table 2 part halogenated hydroxyl arone compounds bacteriostatic activity test result
The result shows that the serial halogenated hydroxyl arone compounds of the present invention's preparation all has bacteriostatic activity to gram-positive microorganism, Gram-negative bacteria and fungi, points out this compounds to have anti-microbial effect.
(3) to the mensuration of the provide protection of vascular endothelial cell damage
1, experimental principle
Vascular endothelial cell produces and expresses various adjusting molecules, and the adjusting to vascular function under physiology and pathological state plays a crucial role.Vascular endothelial cell damage is not only atherosclerotic initiating agent, and the generation and the development of diseases such as coronary heart disease, hypertension played an important role.Therefore research is the new way of control cardiovascular and cerebrovascular diseases to the protection of vascular endothelial cell damage.
Hydrogen peroxide can directly act on membrane lipid as a member in the active oxygen family, forms lipid peroxide, thereby MDA generates increase, and the plasma membrane permeability increases, and stream increases in the outer calcium, and LDH spills also and increases, the active decline of SOD simultaneously; But hydrogen peroxide coup injury endoplasmic reticulum, and can aggravate mitochondria dysfunction, make the oxidative phosphorylation disorder, cause endothelial cell damage even activate the apoptosis regulation gene, inspire apoptosis.Use H
2O
2Cause vascular endothelial cell damage, adopt mtt assay to measure the cell mitochondrial activity.According to the variation observation sample of optical density value to H
2O
2Due to the provide protection of vascular endothelial cell damage.
2, experiment material and method
Cell strain: the strain of CRL-1730 Human umbilical vein endothelial cells, available from ATCC Global BioresourceCenter.
Reagent: H
2O
2Available from the safe clinical reagent of Beijing northization company limited; Tetrazolium bromide (MTT) is available from Sigma company.
Instrument: microplate optical detecting instrument.
CRL-1730 Human umbilical vein endothelial cells counting is incubated at the flat culture plate in 96 holes, every hole 1 * 10
4Individual cell.After 24 hours, cell is used sample preparation 4 hours earlier, uses H then
2O
2(300 μ mol/L) handles and to cause the cellular oxidation damage model in 20 hours, measures the vascular endothelial cell mitochondria activity with mtt assay, with observation sample to H
2O
2Due to the provide protection of vascular endothelial cell oxidative damage.
3, data processing
Protection ratio (%)=(sample well OD-damages hole OD)/(normal hole OD-damage hole OD) * 100%
Positive judgement criteria: protection ratio carries out multiple sieve, and calculates EC greater than 50% sample
50Value.
4, experimental result sees the following form 3:
Table 3 part halogenated hydroxyl arone compounds is to the measurement result of the provide protection of vascular endothelial cell damage
The result shows that the serial halogenated hydroxyl arone compounds of the present invention's preparation is to H
2O
2Due to vascular endothelial cell damage have provide protection, point out this compounds have the control cardiovascular and cerebrovascular diseases effect.
(4) to the active mensuration of the inhibition of vascular smooth muscle cell proliferation
1, experimental principle
(vascular smooth muscle cell, VSMC) propagation and phenotypic alternation are atherosclerotic main pathological basis to vascular smooth muscle cell.VSMC is one of main cellular constituent that constitutes vessel wall, and in the atherosclerotic lesion of blood vessel, outgrowth VSMC is a topmost composition in the atheromatous plaque.Collagen in the extracellular matrix also affects propagation and the differentiation of VSMC except being the important composition composition in the atherosclerotic plaque, therefore also plays an important role in atherosclerosis formation and development process.
This experiment is set up serum (FBS) and is induced VSMC cell proliferation model, and further observation sample is induced VSMC inhibition of proliferation activity to FBS.
2, experiment material and method
Experiment material and method: DMEM (Dulbecco ' s Modified Eagle Medium) available from Gibco company; Tetrazolium bromide (MTT), trypsinase are all available from Sigma company; Standard foetal calf serum (FBS) is available from Hyclone company; Microplate optical detecting instrument; Microscope.
FBS induces the foundation and the screening of VSMC cell proliferation model: former pipe smooth muscle cell 0.125% trysinization of nourishing blood of being commissioned to train, be inoculated in 96 orifice plates, and cultivate 24 hours to subconfluence.Changing serum-free culture 24h into makes cell be tending towards static (G
0Phase), sample preparation added 10%FBS and cultivated 20 hours after 4 hours.Detect the propagation situation of cell with mtt assay.
3, data processing
Inhibiting rate (%)=(propagation hole OD-sample well OD)/normal hole OD*100%
Positive judgement criteria: inhibiting rate carries out multiple sieve, and calculates IC greater than 50% sample
50Value.
4, experimental result sees the following form 4:
Table 4 part halogenated hydroxyl arone compounds is to the active measurement result of the inhibition of vascular smooth muscle cell proliferation
The result shows that the serial halogenated hydroxyl arone compounds of the present invention's preparation has the activity of inhibition to the propagation of serum inductive vascular smooth muscle cell, points out this compounds to have the atherosclerotic effect of control.
(5) mensuration of anti-DPPH oxidation activity
1, experimental principle
Hexichol is a kind of more stable fat free love base for bitter taste diazanyl free radical DPPH, and a free electron is arranged on its N, and its ethanolic soln is purple, and maximum absorption peak is arranged at the 515nm place.Add after the antioxidant, DPPH catches an electronics and free electron pairing, and purple takes off, the material that becomes colorless, and the absorption at the 515nm place disappears, and its fading extent becomes quantitative relationship with the electronic number of its acceptance.Principle can be examined and determine sample hydrogen atom, the oxidation resistant ability of removing free radical are provided with the variation of spectrophotometer detection DPPH free radical and test liquid reaction back light absorption value according to this.
2, data processing
Sample is to fat free love base DPPH clearance rate (%)=(blank OD-sample OD)/blank OD * 100%
Positive judgement criteria: clearance rate is greater than 50%.
3, experimental result sees the following form:
The result shows that the serial halogenated hydroxyl arone compounds of the present invention's preparation has anti-DPPH oxidation activity, can be used for preparing antioxidant, sanitas and foodstuff additive.
In a word, reaction conditions of the present invention is relatively gentleer, and raw material is easy to get, and post-treating method is easy, and productive rate is higher, and synthetic cost is low, is suitable for suitability for industrialized production, in addition, applied range of the present invention, purposes is many.
Embodiment
The preparation of embodiment 1:4-chloro-3 ', 4 '-dihydroxy benaophenonel I
The preparation of (1) 3 ', 4 '-methylene-dioxy benzophenone IV
Take by weighing Benzoyl chloride III4.620g (33mmol) and 1,2-methylene dimethoxy benzene 3.660g (30mmol) places round-bottomed flask, add 20ml and newly steam anhydrous methylene chloride, after the stirring and dissolving, drip anhydrous stannic chloride 3ml under the condition of ice bath, drip the Bi Shengzhi room temperature reaction.The TLC monitoring reaction, 1h reacts completely.Add an amount of dilute hydrochloric acid cancellation reaction, with 50ml dichloromethane extraction three times, oil phase, is placed with anhydrous sodium sulfate drying and to be spent the night to neutral with the saturated common salt water washing, after being spin-dried for, filtration obtains white solid 4.746g with sherwood oil and recrystallizing methanol respectively, productive rate 70%.
1HNMR(500MHz，CDCl
3)δ：6.10(s，2H，CH
2)，6.90(d，1H，Ph)，7.41(d，2H，Ph)，7.60(t，1H，Ph)，7.65(t，2H，Ph)，7.77(d，2H，Ph)。ESI-MS(m/z)：227.0，228.1([M+H]
+)，249.2，250.3([M+Na]
+)。
(2) preparation of 4-chloro-3 ', 4 '-methylene-dioxy benzophenone V
Take by weighing 3 ', 4 '-methylene-dioxy benzophenone IV1.000g (4.4mmol), place round-bottomed flask, add 20ml and newly steam anhydrous methylene chloride, after the stirring and dissolving, the oil bath reflux conditions drips SULPHURYL CHLORIDE 0.608g (4.5mmol) down, drip complete back flow reaction, temperature of reaction is 100 degrees centigrade.The TLC monitoring reaction, 1h reacts completely.Revolve the steaming back and get white solid 0.815g with recrystallizing methanol, 120 ℃～123 ℃ of fusing points, productive rate 71%.
1HNMR(500MHz，CDCl
3)δ：6.10(s，2H，CH
2)，6.89(d，1H，Ph)，7.36(d，2H，Ph)，7.48(d，2H，Ph)，7.72(d，2H，Ph)。ESI-MS(m/z)：261.1，263.3([M+H]
+)，283.1，285.0([M+Na]
+)。
(3) preparation of 4-chloro-3 ', 4 '-dihydroxy benaophenonel I
Take by weighing 4-chloro-3 ', 4 '-methylene-dioxy benzophenone V100mg (0.4mmol), place round-bottomed flask, add the 10ml anhydrous methylene chloride, after the stirring and dissolving, under subzero 78 ℃ (dry ice acetone bath), drip the 5ml anhydrous methylene chloride solution of 301mg (1.2mmol) boron tribromide, drip the complete stirring at room that gradually is warming up to.The TLC monitoring reaction, 1h reacts completely.Add an amount of dilute hydrochloric acid cancellation reaction, with 30ml dichloromethane extraction twice, oil phase, spends the night with the anhydrous sodium sulfate drying placement to neutral with the saturated common salt water washing, obtains white solid 62mg, 171 ℃～173 ℃ of fusing points, productive rate 81% after filtration is spin-dried for.
1HNMR(500MHz，CDCl
3)δ：6.85(d，1H，Ph)，7.09(d，1H，Ph)，7.23(d，1H，Ph)，7.59(d，2H，Ph)，7.66(d，2H，Ph)，9.22-10.26(br，2H，OH)。ESI-MS(m/z)：247.0，249.1([M-H]
-)。
Embodiment 2:2,3-two bromo-4, the preparation of 5-dihydroxy benaophenonel I
The preparation of (1) 3,4-dimethoxy-benzophenone IV
Anhydrous methylene chloride 30ml places eggplant-shape bottle, under 202 degrees celsius, add 1,2-dimethoxy benzene 5ml (0.036mol), Benzoyl chloride III5.600g (0.040mol), slowly add aluminum chloride 5.800g (0.042mol) in batches, system becomes red-brown, 10min recession ice bath stirring at room, complete behind the TLC monitoring reaction 4h, with the frozen water termination reaction, with twice of 50ml dichloromethane extraction, collect oil phase and spend the night, revolve to steam to remove and desolvate, obtain white solid 7.138g with the anhydrous sodium sulfate drying placement, 100 ℃～102 ℃ of fusing points, productive rate 82%.
1HNMR(500MHz，CDCl
3)δ：3.984(d，6H，CH
3)，6.922(d，1H，Ph)，7.408(d，1H，Ph)，7.508(t，3H，Ph)，7.602(t，1H，Ph)，7.790(d，2H，Ph)。ESI-MS(m/z)：243.3([M+H]
+)，265.2([M+Na]
+)。
(2) 2,3-two bromo-4, the preparation of 5-dimethoxy-benzophenone V
Weighing 3,4-dimethoxy-benzophenone IV1.000g (4.132mmol) adds the 20ml glacial acetic acid in round-bottomed flask, after the stirring at room dissolving, drip the 10ml glacial acetic acid solution of 2.3ml liquid bromine, the zero degrees celsius reaction, TLC monitoring 24h afterreaction is complete.Reaction solution is slowly added in an amount of cold NaOH saturated aqueous solution, separate out the off-white color solid, suction filtration is with H
2The O washing leaching cake obtains off-white color solid 1.558g, 112 ℃～113 ℃ of fusing points, productive rate 94% to neutral after the drying.
1HNMR(500MHz，CDCl
3)δ：3.99(d，6H，CH
3)，6.87(s，1H，Ph)，7.48(d，2H，Ph)，7.55(d，1H，Ph)，7.82(d，2H，Ph)。ESI-MS(m/z)：398.7，401.0，402.6([M+H]
+)，420.9，423.0，425.0([M+Na]
+)。
(3) 2,3-two bromo-4, the preparation of 5-dihydroxy benaophenonel I
Take by weighing 2,3-two bromo-4,5-dimethoxy-benzophenone V100mg (0.25mmol), place round-bottomed flask, add the 10ml anhydrous methylene chloride, after the stirring and dissolving, drip the 5ml anhydrous methylene chloride solution of 181mg (0.72mmol) boron tribromide down in subzero 78 ℃ (dry ice acetone bath), drip the complete room temperature that is warming up to gradually, the TLC monitoring reaction is complete behind the stirring 12h.Add an amount of dilute hydrochloric acid cancellation reaction, with 20ml dichloromethane extraction twice, oil phase, spends the night with anhydrous sodium sulfate drying to neutral with the saturated common salt water washing, obtains white solid 83mg, productive rate 89% after filtration is spin-dried for.
1HNMR(500MHz，DMSO-d6)：δ：6.83(s，1H，Ph)，7.51-7.59(m，2H，Ph)，7.66-7.76(m，3H，Ph)，10.00-10.76(br，2H，OH)。ESI-MS(m/z)：368.9，370.9，372.9([M-H]
-)。
Embodiment 3:2,6-two bromo-3,3 ', 4,4 ', the preparation of 5-trihydroxybenzophenone I
(1) 3,3 ', 4,4 ', the preparation of 5-pentamethoxyl benzophenone IV
Add 1 in the eggplant-shape bottle, 2-dimethoxy benzene 5ml (36mmol), polyphosphoric acid 20ml, after the stirring and dissolving, add 3,4,5-trimethoxybenzoic acid II7.632 (36mmol), 150 ℃ of reactions of oil bath, complete behind the TLC monitoring reaction 4h, frozen water cancellation reaction, add 100ml distilled water, separate out gray solid, recrystallizing methanol gets white solid 6.520g, 115 ℃～117 ℃ of fusing points, productive rate 88%.
1HNMR(500MHz，CDCl
3)δ：3.908(s，6H，CH
3)，3.977(t，9H，CH
3)6.935(d，1H，Ph)，7.052(s，2H，Ph)，7.430(d，1H，Ph)，7.487(s，1H，Ph)。ESI-MS(m/z)：333.2([M+H]
+)，355.2([M+Na]
+)。
(2) 2,6-two bromo-3,3 ', 4,4 ', the preparation of 5-pentamethoxyl benzophenone V
Weighing 3,3 ', 4,4 ', 5-pentamethoxyl benzophenone IV1.000g (3mmol) adds the 20ml glacial acetic acid in round-bottomed flask, the stirring at room dissolving, the 10ml glacial acetic acid solution of dropping 2.0ml liquid bromine, room temperature reaction, the TLC monitoring reaction, the 12h afterreaction is complete.Reaction solution is slowly added in the proper ammonia, separate out the off-white color solid, suction filtration is with H
2The O washing leaching cake obtains off-white color solid 1.417g, 163 ℃～166 ℃ of fusing points, productive rate 96% to neutral after the drying.
1HNMR(500MHz，CDCl
3)δ：3.958(s，6H，CH
3)，3.997(t，9H，CH
3)，6.869(d，1H，Ph)，7.206(d，1H，Ph)，7.672(s，1H，Ph)。ESI-MS(m/z)：489.0，491.0，493.1([M+H]
+)。
(3) 2,6-two bromo-3,3 ', 4,4 ', the preparation of 5-pentahydroxybenzophenone I
Take by weighing 2,6-two bromo-3,3 ', 4,4 ', 5-pentamethoxyl benzophenone V100mg (0.20mmol) places round-bottomed flask, adds the 10ml anhydrous methylene chloride, after the stirring and dissolving, drip the 5ml anhydrous methylene chloride solution of 150mg (0.60mmol) boron tribromide under zero degrees celsius, drip the complete room temperature that is warming up to gradually, the TLC monitoring reaction is complete behind the stirring 6h.Add an amount of dilute hydrochloric acid cancellation reaction, with 20ml dichloromethane extraction twice, oil phase, spends the night with anhydrous sodium sulfate drying to neutral with the saturated common salt water washing, obtains white solid 75mg, 99 ℃～103 ℃ of fusing points, productive rate 88% after filtration is spin-dried for.
1HNMR(500MHz，DMSO-d6)：δ：6.869(d，1H，Ph)，7.266(d，1H，Ph)，7.681(s，1H，Ph)，10.01-10.80(br，5H，OH)。ESI-MS(m/z)：417.9，419.9，421.9([M-H]
-)。
The preparation of embodiment 4:4-bromo-3-(2-bromo-4,5-dihydroxy-benzene formyl radical) pyridine I
(1) preparation of 3-(4,5-dimethoxy benzoyl) pyridine IV
Anhydrous methylene chloride 30ml places eggplant-shape bottle, add 1 under the cryosel bath condition, 2-dimethoxy benzene 5ml (36mmol), nicotinoyl chlorine III5.680g (40mmol), slowly add aluminum chloride 5.800g (42mmol), system becomes red-brown in batches, 10min recession ice bath stirring at room, complete behind the TLC monitoring reaction 10h, with the frozen water termination reaction,, collect oil phase with 50ml dichloromethane extraction twice, with saturated sodium-chloride 20ml washed twice, spend the night with the anhydrous sodium sulfate drying placement, revolve to steam to remove and desolvate sherwood oil and re-crystallizing in ethyl acetate, obtain white solid 6.124g, productive rate 70%.
1HNMR(500MHz，CDCl
3)δ：3.953(d，6H，CH
3)，7.162(d，1H，Ph)，7.351(d，2H，Ph)，7.714(dd，1H，Ph)，8.250(d，1H，Ph)，8.811(d，1H，Ph)。ESI-MS(m/z)：244.1([M+H]
+)。
(2) preparation of 4-bromo-3-(2-bromo-4,5-dimethoxy benzoyl) pyridine V
Weighing 3-(4,5-dimethoxy benzoyl) pyridine IV1.000g (5mmol) adds the 20ml glacial acetic acid in round-bottomed flask, after the stirring and dissolving, drip the 10ml glacial acetic acid solution of 2.3ml liquid bromine, and temperature of reaction is 50 degrees centigrade, and TLC monitoring 20h afterreaction is complete.Reaction solution is slowly added in an amount of carbonate solution, separate out the off-white color solid, suction filtration is with H
2The O washing leaching cake obtains off-white color solid 1.386g, productive rate 84% to neutral after the drying.
1HNMR(500MHz，CDCl
3)δ：3.92(d，6H，CH
3)，7.29(s，1H，Ph)，7.40(s，1H，Ph)，8.20(d，1H，Ph)，8.82(d，1H，Ph)，8.90(s，1H，Ph)，7.82(d，2H，Ph)。ESI-MS(m/z)：398.9，400.6，402.9([M-H]
-)。
(3) preparation of 4-bromo-3-(2-bromo-4,5-dihydroxy-benzene formyl radical) pyridine I
Take by weighing 2,3-two bromo-4,5-dimethoxy-benzophenone V100mg (0.25mmol), place round-bottomed flask, add the 10ml anhydrous methylene chloride, after the stirring and dissolving, at subzero 50 ℃ of 5ml anhydrous methylene chloride solution that drip 181mg (0.72mmol) boron trifluoride down, drip the complete room temperature that is warming up to gradually, the TLC monitoring reaction is complete behind the stirring 5h.Add an amount of dilute hydrochloric acid cancellation reaction, with 20ml dichloromethane extraction twice, oil phase, spends the night with anhydrous sodium sulfate drying to neutral with the saturated common salt water washing, after filtration is spin-dried for, with first alcohol and water recrystallization, obtains white solid 79mg, productive rate 85%.
1HNMR(500MHz，DMSO-d6)：δ：7.012(s，1H，Ph)，7.153(s，1H，Ph)，8.203(d，1H，Ph)，8.826(d，1H，Ph)，8.920(s，1H，Ph)，9.60-9.96(br，2H，OH)。ESI-MS(m/z)：370.2，372.1，374.1([M-H]
-)。
Claims (5)
1, a kind of halogenated hydroxyl arone compounds is characterized in that being the represented compound of structural formula I and salt, ester, the ether of this compound,
Wherein, R
1' be the one or more hydroxyls or the hydrogen atom of optional position on the A ring, R
2' be the one or more hydroxyls or the hydrogen atom of optional position on the B ring; X is the one or more halogens or the hydrogen atom of optional position on the A ring or on the B ring, and described halogen can be fluorine, chlorine, bromine, iodine; A ring, B ring represent that respectively phenyl ring or heterocycle, described heterocycle can be the various ring texturees that furans, thiophene, pyrroles, thiazole, imidazoles, pyridine, pyrazine, pyrimidine and indoles, quinoline, pteridine, acridine or other heteroatoms replace; Said n is represented the number of hydroxyl, hydrogen atom or halogen, n=0～5.
2, prepare halogenated hydroxyl arone compounds as claimed in claim 1, it is characterized in that synthetic route may further comprise the steps:
Wherein, R
1', R
2', the definition such as the claim 1 of X, n, A ring and B ring, R
1Be the one or more alkoxyl groups or the hydrogen atom of optional position on the A ring, R
2One or more alkoxyl groups or hydrogen atom for optional position on the B ring;
Said synthesis route may further comprise the steps:
(1) as catalyzer and solvent, and temperature of reaction is 70～150 degrees centigrade to Compound I I at polyphosphoric acid, and the reaction times is under 1～12 hour the condition, to make compound IV with alkoxy benzene or alkoxyl group heterogeneous ring compound generation acylation reaction; Perhaps Compound I I obtains corresponding acyl chlorides III with reaction under chloride reagent and the catalyzer condition in inert solvent, acyl chlorides III and alkoxy benzene or alkoxyl group heterogeneous ring compound generation Friedel-Crafts reaction makes compound IV then, and the chloride reagent of described acyl chloride reaction is SOCl
2, phosphorus trichloride, phosphorus pentachloride or triphosgene, catalyzer is DMF, pyridine or Lewis base, temperature of reaction is 50～150 degrees centigrade, reaction times is 1～4 hour, the used catalyzer of Friedel-Crafts reaction is Lewis acid or protonic acid, temperature of reaction is subzero 15～20 degrees centigrade, and the reaction times is 1～4 hour;
(2) compound IV is carried out halogenating reaction with bromide reagent or chlorination reagent in inert solvent, the product that obtains is carried out aftertreatment with alkali lye obtain compound V, and the bromide reagent that described halogenating reaction adopts can be NBS or liquid bromine, and chlorination reagent can be SO
2Cl
2Or chlorine, the temperature of reaction of halogenating reaction is 0～100 degree centigrade, the reaction times is 1～24 hour;
(3) compound V is in inert solvent and at Lewis acid or protonic acid under the condition as catalyzer; slough the alkoxyl group protecting group and obtain halogenated hydroxyl arone compounds I; the temperature of reaction of deprotection reaction is subzero 78～0 degrees centigrade, and the reaction times is 1～12 hour.
3, the preparation method of a kind of halogenated hydroxyl arone compounds according to claim 2, it is characterized in that inert solvent used in the above-mentioned reaction is that in water, Glacial acetic acid, methylene dichloride, ethyl acetate, ether, tetrahydrofuran (THF), methyl alcohol, the ethanol one or more mix with arbitrary proportion, used alkali lye is ammoniacal liquor, carbonate, basic metal, alkaline-earth metal simple substance or its oxyhydroxide.
4, the salt of a kind of halogenated hydroxyl arone compounds and this compound, ester, ether are in the damage of antibiotic, antitumor, anti-oxidant, the anti-vascular endothelial cell of preparation, suppress the application in vascular smooth muscle cell proliferation medicine and sterilizing agent, antioxidant, the foodstuff additive.
5, the salt of a kind of halogenated hydroxyl arone compounds according to claim 4 and this compound, ester, ether, antibiotic in preparation, antitumor, anti-oxidant, the anti-vascular endothelial cell damage, suppress vascular smooth muscle cell proliferation medicine and sterilizing agent, antioxidant, application in the foodstuff additive is characterized in that arbitrary compound of halogenated hydroxyl arone compounds and pharmaceutically acceptable derivates thereof or mixture can be mixed and made into injection with pharmaceutically acceptable pharmaceutical carrier, tablet, capsule, oral liquid, suppository, film, aerosol, externally-applied liniment or ointment drug form.
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