CN101602754A - A kind of flavanone derivatives and its production and use - Google Patents

A kind of flavanone derivatives and its production and use Download PDF

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CN101602754A
CN101602754A CNA2009100749512A CN200910074951A CN101602754A CN 101602754 A CN101602754 A CN 101602754A CN A2009100749512 A CNA2009100749512 A CN A2009100749512A CN 200910074951 A CN200910074951 A CN 200910074951A CN 101602754 A CN101602754 A CN 101602754A
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flavanone
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dihydroxyl
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CN101602754B (en
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李青山
石磊
韩玲革
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Abstract

The present invention relates to polyphenols and preparation method and use thereof, be specially a kind of flavanone derivatives and its production and use, solve the problem that existing natural flavanone kind composition is difficult to extract, is difficult to obtain, can't widespread use, structure is: (on seeing), and wherein: R 1, R 2, R 3Be selected from alkyl, halogen, the nitro of hydrogen, a 1-8 carbon, the alkoxyl group or the amino of a 1-8 carbon respectively; R 4, R 5Can be selected from the alkyl of 1-8 carbon, the alkoxyl group or the alkylene of a 1-8 carbon respectively, by compound 6-hydroxyl-2,4 hydroxy acetophenone class materials and aromatic aldehyde or heterocycle aldehyde material are in polyol solvent, obtain as catalyst reaction with high boiling point acid, can be applicable to prepare the medicine of antitumor drug and cardiovascular and cerebrovascular diseases.Activity with anti-tumor activity and inhibition cardiovascular and cerebrovascular diseases has been opened up new approach for the preparation said medicine, brings new breakthrough at field of medicaments, and this synthetic method mild condition, and is easy and simple to handle.

Description

A kind of flavanone derivatives and its production and use
Technical field
The present invention relates to polyphenols and preparation method and use thereof, be specially a kind of flavanone derivatives and its production and use.
Background technology
Flavanone kind composition is the polyphenols that a class extensively distributes at nature.Flavanone kind composition has wide biological activity and pharmacologically active.Studies show that in a large number flavanone kind composition has removes free radical, anti-oxidant, anti-mutation, antitumor, antibiotic, antiviral and regulate immunity, treatment of vascular sclerosis, function such as hypoglycemic, also has part to be proved to be the anti HIV-1 virus activity.Yet to be a class low-molecular-weight is distributed widely in botanic natural plant composition for flavanone kind composition, is the metabolite of plant polyphenol kind, is considered to class trace flavonoid, because it is relatively limited in distributed in nature.Therefore naturally occurring flavanone kind composition is difficult to extract, and is difficult to obtain, and can't be used widely.So people take artificial synthesis to obtain various flavanone kind compositions by big quantity research usually, but up to the present, do not appear in the newspapers for the flavanone kind composition and the synthetic method thereof of 5,7 dihydroxyl-6,8 alkyl or alkylene replacement.For the active rule of the flavanone of inquiring into this type of brand new, and, need more structural and active bonded example in order to find the active chemicals that better has the flavanone skeleton.
Summary of the invention
The problem that the present invention is difficult to extract in order to solve existing natural flavanone kind composition, is difficult to obtain, can't widespread use provides a kind of flavanone derivatives and its production and use.
The present invention adopts following technical scheme to realize: a kind of flavanone derivatives, and structure is as follows:
Figure G2009100749512D00021
Wherein: R 1, R 2, R 3Can be identical or different, be selected from alkyl, halogen, the nitro of hydrogen, a 1-8 carbon, the alkoxyl group or the amino of a 1-8 carbon respectively, R 1, R 2And/or R 3Can replace or unsubstituted fused ring compound with forming with phenyl ring is thick; R 4, R 5Can be identical or different, be selected from the alkyl of 1-8 carbon, the alkoxyl group or the alkylene of a 1-8 carbon respectively, the hydroxyl hydrogen on a ring can be the metal alkali (such as sodium salt, magnesium salts ion etc.) of hyoscine, and the b ring can be heterogeneous ring compound; In the said structure 2,3 steric configuration is respectively R configuration or S configuration, perhaps in the said structure 2,3 steric configuration is R configuration and S configuration simultaneously, the implication of these words is that institute of the present invention synthetic compound can be the single R configuration behind method purifying such as column chromatography, recrystallization or the optically active compound of S configuration, also can be not purified and comprises the mixture of the steric isomer of R configuration and S configuration when having same two dimensional structure.
Prepare the method for described flavanone derivatives, synthetic route is as follows:
Figure G2009100749512D00022
R wherein 1, R 2, R 3, R 4, R 5Definition such as claim 1
The concrete steps of said synthesis route are: with compound 6-hydroxyl-2,4 hydroxy acetophenone class materials are starting raw material, in polyol solvent, with high boiling point acid as catalyzer, obtain corresponding flavanone derivatives with aromatic aldehyde or heterocycle aldehydes substance reaction, above-mentioned temperature of reaction is 50-200 ℃, and the reaction times is 1-15 hour, the mol ratio of compound 6-hydroxyl-2,4 hydroxy acetophenone class material, aromatic aldehyde or heterocycle aldehyde material and catalyzer is 1: 1.0～5.0: 1.0～5.0.Described polyol solvent can be methyl alcohol, ethanol and ethylene glycol, and glycol ether, glycerine etc., described catalyzer can be boric acid, citric acid, tartrate etc.
Flavanone derivatives according to scheme preparation of the present invention has anti-tumor activity and suppresses the cardiovascular and cerebrovascular diseases activity, so institute of the present invention synthetic flavanone derivatives can be applied to prepare in the medicine of antitumor and cardiovascular and cerebrovascular diseases.When compound of the present invention or their mixture are used to prepare antitumor drug and cardiovascular and cerebrovascular diseases medicament, can make injection, tablet, capsule, suppository, film, pill according to the ordinary method of field of medicaments, drug form such as externally-applied liniment, ointment, this is that those of ordinary skill in the art is known.
The present invention utilize aforesaid method synthetic part preferred compound have:
Compound 1-a:6 ' hydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-b:4 ' chloro-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-c:6 ' chloro-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-d:4 ' nitro-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-e:6 ' nitro-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-f:4 ' hydroxyl 6 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-g:4 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-h:6 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-i:4 ', 6 ' dimethoxy-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-j:4 ', 6 ' dihydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-k:4 ', 5 ' dimethoxy-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-l:4 ', 5 ' dihydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-m:4 ', 6 ' two chloro-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-n:2-(furans-2-yl)-5,7-dihydroxyl-6,8-methyl-chromanone
Compound 1-o:4 ' hydroxyl-5,7 dihydroxyl-6,8-dimethoxy flavanone;
Amino-5,7 dihydroxyl-6 of compound 1-p:4 ', 8-dimethyl flavanone;
Compound 1-q:4 ' methyl-5,7 dihydroxyl-6,8-dimethyl flavanone;
Compound 1-r:5,7 dihydroxyl-6 methyl-8-allyl group flavanone;
Structural formula is as follows respectively:
Figure G2009100749512D00051
Figure G2009100749512D00061
The determination of pharmacological activity of the compound of the present invention's preparation:
Above-mentioned part flavanone kind composition of synthetic and salt thereof are carried out preliminary antitumor activity screening, measure the anti-tumor activity of this compounds by mtt assay, the result shows that this compounds has certain cytotoxic activity to different tumour cells, points out this compounds to have certain antitumor efficacy; Part of compounds has been carried out the Human umbilical vein endothelial cells proliferation experiment, shown that it has proliferation function preferably, shown that this type of medicine has certain protective role in to blood vessel injury; Part of compounds has been carried out the inhibition activity experiment of serum induction of vascular smooth muscle cell proliferation, shown that it just has very high inhibition activity, can effectively prevent and treat atherosclerotic formation.
(1) extracorporeal suppression tumor cell proliferation activity experiment
Adopt mtt assay to carry out experiment in vitro,, get nutrient solution and be made into the individual cells suspension with containing 10% tire calf serum with the HepG-2 liver cancer cell, with every hole 1000-10000 cell inoculation to 96 orifice plates, every pore volume 200ul.Cultivated 3-5 days, and added above-mentioned synthetic compound 1-b, cultivate after 1 day, every hole adds MTT solution 20ul. continued to hatch 4 hours, stop to cultivate, and careful the suction abandoned the culture supernatant hole in, for suspension cell need centrifugal after again suction abandon culture supernatant in the hole.Every hole adds 150ul DMSO, vibrates 10 minutes, and crystallisate is fully melted.Select the 490nm wavelength, measure each hole absorbance value on the enzyme linked immunological monitor, the record result is an X-coordinate with time, and light absorption value is that ordinate zou is drawn cell growth curve.Experimental result sees the following form 1:
Figure G2009100749512D00062
Figure G2009100749512D00071
Table 1-different concns compound 1-b suppresses the influence of HepG-2 hepatoma cell proliferation
Conclusion: compound 1-b has restraining effect to the HepG-2 liver cancer cell when concentration 12.5ug/ml, inhibiting rate reaches more than 50% when concentration 25ug/ml, illustrates that flavanone (is example with the compound 1-b) compound of such brand new has certain inhibition tumor cell proliferation activity.
(2) vitro human huve cell proliferation activity experiment
Adopt mtt assay to carry out experiment in vitro,, get nutrient solution and be made into the individual cells suspension with containing 10% tire calf serum with Human umbilical vein endothelial cells, with every hole 1000-10000 cell inoculation to 96 orifice plates, every pore volume 200ul.Cultivated 3-5 days, and added above-mentioned synthetic compound 1-n, cultivate after 1 day, every hole adds MTT solution 20ul. continued to hatch 4 hours, stop to cultivate, and careful the suction abandoned the culture supernatant hole in, for suspension cell need centrifugal after again suction abandon culture supernatant in the hole.Every hole adds 150ul DMSO, vibrates 10 minutes, and crystallisate is fully melted.Select the 490nm wavelength, measure each hole absorbance value on the enzyme linked immunological monitor, the record result is an X-coordinate with time, and light absorption value is that ordinate zou is drawn cell growth curve.Experimental result sees the following form 2:
Blank Negative control 50ug/ml 25ug/ml 12.5ug/ml 6.25ug/ml
Mean value 0.2975 0.251 0.3965 0.358375 0.35375 0.346875
The IC value -0.58 -0.428 -0.409 -0.382
The t check P＜0.01 P＜0.01 P＜0.01 P＜0.01
The influence of table 2-different concns compound 1-n Human umbilical vein endothelial cells propagation
Conclusion: compound 1-n has short proliferation function to Human umbilical vein endothelial cells HUVEC when concentration 6.25ug/ml, inhibiting rate reaches more than 50% when concentration 25ug/ml, illustrates that flavanone (is example with the compound 1-n) compound of such brand new has certain short proliferation function to Human umbilical vein endothelial cells HUVEC.
(3) the inhibition activity experiment of serum induction of vascular smooth muscle cell proliferation
(vascular smooth muscle cell, VSMC) propagation and phenotypic alternation are atherosclerotic main pathological basis to vascular smooth muscle cell.Increasing evidence shows that atherosclerosis is an excessive inflammatory response to blood 00 pipe damage.Behind the blood vessel injury, monocyte, thrombocyte and lymphocyte are attached to vessel wall, discharge a series of cytokines and peptide class somatomedin, combine with specific receptors, influence VSMC phenotype and growth signals, have therefore promoted the generation of fiber propagation pathology in late period.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.
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), adds compound 1-e and handle after 4 hours, add 10%FBS and cultivated 20 hours.Detect the propagation situation of cell with mtt assay.
Conclusion: compound 1-e can reach 50% to serum induction of vascular smooth muscle cell proliferation inhibiting rate when concentration 3.17ug/ml, and flavanone (is example with compound 1-e) the compound inhibition activity good to having of serum induction of vascular smooth muscle cell proliferation of such brand new is described.
Compared with prior art, the present invention is with compound 6-hydroxyl-2,4 hydroxy acetophenone class materials and aromatic aldehyde or heterocycle aldehydes substance reaction obtain corresponding flavanone derivatives, show that by above-mentioned pharmacological activity test institute of the present invention synthetic compound has the biological activity of anti-tumor activity and inhibition cardiovascular and cerebrovascular diseases, this compounds has the effect of the tumor cell proliferation of inhibition, also have short Human umbilical vein endothelial cells proliferation function, demonstrate the activity that has the super oxyradical of external removing, suppresses the lipoperoxide generation of free yl induction.Above activity shows that this compounds can be expected and is used for preparation prevention or medicine for treating tumor thing or drug combination, can be used for blood vessel injury protection medication and cardiovascular system diseases medication and caused or other physiological changes relevant with oxyradical or the medicine of disease by oxyradical.The present invention has opened up new approach for the preparation said medicine, brings new breakthrough at field of medicaments, and this synthetic method mild condition, and is easy and simple to handle.
Embodiment
Embodiment 1: compound 1-a:(6 ' hydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
With 200 milligrams of (0.001mol) 6-hydroxyl-2,4 hydroxyl-3,5 dimethyl acetophenones, 125 milligrams of (0.001mol) 2-hydroxy benzaldehydes, 61 milligrams of (0.001mol) boric acid are dissolved in a small amount of ethylene glycol, heat up in 100 ℃, and stirring reaction 1 hour is with the reactant dissolve with ethanol, get 30 milligrams of light green materials through column chromatography, yield 15%, HNMR (500MHz, DMSO), δ 7.02 (2H, d, J=8.4Hz, H-e), 6.75 (1H, d, J=8.5Hz, H-d), 6.65 (1H, d, J=8.5Hz, H-d), 5.58 (1H, dd, J=12.3,2.7Hz, H-c), 3.18 (1H, dd, J=17.0,12.5Hz, H-b 2), 2.86 (1H, dd, J=17.0,3.0Hz, H-b 1), 1.97 (6H, d, J=4.5Hz, H-a) ESI-MS (m/z): [M-1] -=299.
Embodiment 2: compound 1-b:(4 ' chloro-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
With 200 milligrams of (0.001mol) 6-hydroxyl-2,4 hydroxyl-3,5 dimethyl acetophenones, 700 milligrams of (0.005mol) 4-chlorobenzaldehydes, 270 milligrams of (0.005mol) citric acids are dissolved in the small amount of ethanol, heat up in 200 ℃, and stirring reaction 5 hours is with the reactant dissolve with ethanol, get 25 milligrams of light green materials through column chromatography, yield 12.5%, HNMR (500MHz, DMSO), δ 7.56 (2H, d, J=8.4Hz, H-e), 7.51 (2H, d, J=8.5Hz, H-d), 5.58 (1H, dd, J=12.3,2.7Hz, H-c), 3.18 (1H, dd, J=17.0,12.5Hz, H-b2), 2.86 (1H, dd, J=17.0,3.0Hz, H-b1), 1.97 (6H, d, J=4.5Hz, H-a) ESI-MS (m/z): [M-1]-=317.
Embodiment 3: and compound 1-n:2-(furans-2-yl)-5,7-dihydroxyl-6,8-methyl-chromanone
With 200 milligrams of (0.001mol) 6-hydroxyls-2,4 hydroxyls-3,5 dimethyl acetophenones, 0.3ml (0.0015mol) furfural, 250 milligrams of (0.004mol) tartrate are dissolved in a small amount of glyceryl alcohol, heat up in 50 ℃, stirring reaction 15 hours with the reactant dissolve with ethanol, gets 35 milligrams of faint yellow materials through column chromatography, yield 15%
HNMR(500MHz，DMSO)δ7.36(H，d，J＝8.4Hz，H-e)，6.26(H，d，J＝8.5Hz，H-d)，6.19(H，d，J＝8.5Hz，H-d)，5.74(1H，dd，J＝12.3，2.7Hz，H-c)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.85(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.99(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝257。
According to the synthetic following compounds of above-mentioned preparation method.
Embodiment 4: compound 1-c:(6 ' chloro-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)δ7.72(1H，d，J＝8.4Hz，H-d)，7.53(1H，d，J＝8.5Hz，H-d)，7.42(1H，d，J＝8.5Hz，H-d)，7.41(1H，dd，J＝7.6Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.96(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝317。
Embodiment 5: compound 1-d:(4 ' nitro-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ8.31(2H，d，J＝8.4Hz，H-e)，7.83(2H，d，J＝8.5Hz，H-d)，5.76(1H，dd，J＝12.3，2.7Hz，H-c)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.97(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.99(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝299
Embodiment 6: compound 1-e:(6 ' nitro-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation
HNMR(500MHz，DMSO)，δ8.02(1H，d，J＝8.4Hz，H-d)，7.89(1H，d，J＝8.5Hz，H-d)，7.85(1H，d，J＝8.5Hz，H-d)，7.70(1H，dd，J＝8.2Hz，H-d)，5.55(1H，dd，J＝12.3，2.7Hz，H-c)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.96(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝299。
Embodiment 7: compound 1-f:(4 ' hydroxyl 6 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.02(1H，d，J＝8.4Hz，H-d)，6.53(1H，d，J＝8.5Hz，H-d)，6.22(1H，d，s，H-d)5.52(1H，dd，J＝12.3，2.7Hz，H-c)，3.75(3H，d，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝329。
Embodiment 8: compound 1-g:(4 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.06(2H，d，J＝8.4Hz，H-e)，6.89(2H，d，J＝8.5Hz，H-d)，5.56(1H，dd，J＝12.3，2.7Hz，H-c)，3.75(3H，d，s，H-a)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.83(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝313
Embodiment 9: compound 1-h:(6 ' methoxyl group-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.12(1H，d，J＝8.4Hz，H-d)，7.05(1H，d，J＝8.5Hz，H-d)，6.85(1H，d，J＝8.5Hz，H-d)，6.78(1H，dd，J＝6.8Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)3.75(3H，d，s，H-a)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.96(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝313。
Embodiment 10: compound 1-i:(4 ', 6 ' dimethoxy-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.03(1H，d，J＝8.4Hz，H-e)，6.28(1H，d，J＝8.5Hz，H-d)，6.21(1H，d，s，H-d)，5.56(1H，dd，J＝12.3，2.7Hz，H-c)，3.75(6H，d，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝343。
Embodiment 11: compound 1-j:(4 ', 6 ' dihydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ6.89(1H，d，J＝8.4Hz，H-e)，6.26(1H，d，J＝8.5Hz，H-d)，6.20(1H，d，s，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝315
Embodiment 12: compound 1-k:(4 ', 5 ' dimethoxy-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ6.69(1H，d，J＝8.4Hz，H-e)，6.64(1H，d，s，H-d)，6.59(1H，d，J＝8.5Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.75(6H，d，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝343。
Embodiment 13: compound 1-l:(4 ', 5 ' dihydroxyl-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ6.89(1H，d，J＝8.4Hz，H-e)，6.67(1H，d，s，H-d)，6.61(1H，d，J＝8.5Hz，H-d)5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝315。
Embodiment 14: compound 1-m:(4 ', 6 ' two chloro-5,7 dihydroxyl-6,8-dimethyl flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.46(1H，d，J＝8.4Hz，H-e)，7.21(1H，d，J＝8.5Hz，H-d)，7.18(1H，d，s，H-d)5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝353
Embodiment 15: compound 1-o:(4 ' hydroxyl-5,7 dihydroxyl-6,8-dimethoxy flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.46(2H，d，J＝8.4Hz，H-e)，7.21(2H，d，J＝8.5Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.73(6H，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝331
Embodiment 16: amino-5,7 dihydroxyl-6 of compound 1-p:(4 ', 8-dimethoxy flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.46(2H，d，J＝8.4Hz，H-e)，7.21(2H，d，J＝8.5Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)，3.73(6H，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(6H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝331
Embodiment 17: compound 1-q:(4 ' methyl-5,7 dihydroxyl-6,8-dimethoxy flavanone) preparation:
HNMR(500MHz，DMSO)，δ6.82(2H，d，J＝8.4Hz，H-e)，6.34(2H，d，J＝8.5Hz，H-d)，5.58(1H，dd，J＝12.3，2.7Hz，H-c)，4.21(2H，s，H-f)，3.73(6H，s，H-a)3.18(1H，dd，J＝17.0，12.5Hz，H-b 2)，2.86(1H，dd，J＝17.0，3.0Hz，H-b 1)，1.97(9H，d，J＝4.5Hz，H-a)ESI-MS(m/z)：[M-1] -＝297
Embodiment 18: compound 1-r:(5,7 dihydroxyl-6 methyl-8-allyl group flavanone) preparation:
HNMR(500MHz，DMSO)，δ7.25(1H，s，H-j)，7.03(4H，d，J＝8.8Hz，H-i)，6.58(1H，s，，H-h)6.30(1H，d，J＝7.8Hz，H-g)5.58(1H，dd，J＝12.3，2.7Hz，H-f)，4.94(2H，s，H-e)，3.73(6H，s，H-d)3.22(2H，s，，H-b)，3.18(1H，dd，J＝17.0，12.5Hz，H-c2)，2.86(1H，dd，J＝17.0，3.0Hz，H-c1)，1.97(3H，s，，H-a)ESI-MS(m/z)：[M-1]-＝309

Claims (3)

1, a kind of flavanone derivatives is characterized in that structure is as follows:
Wherein: R 1, R 2, R 3Can be identical or different, be selected from alkyl, halogen, the nitro of hydrogen, a 1-8 carbon, the alkoxyl group or the amino of a 1-8 carbon respectively, R 1, R 2And/or R 3Can replace or unsubstituted fused ring compound with forming with phenyl ring is thick; R 4, R 5Can be identical or different, be selected from the alkyl of 1-8 carbon, the alkoxyl group or the alkylene of a 1-8 carbon respectively, the hydroxyl hydrogen on a ring can be the metal alkali of hyoscine, and the b ring can be heterogeneous ring compound; The steric configuration of prosposition is respectively R configuration or S configuration in the said structure, and perhaps the steric configuration of prosposition is R configuration and S configuration simultaneously in the said structure.
2, the method for preparation flavanone derivatives as claimed in claim 1 is characterized in that synthetic route is as follows:
Figure A2009100749510002C2
The concrete steps of said synthesis route are: with compound 6-hydroxyl-2,4 hydroxy acetophenone class materials are starting raw material, in polyol solvent, with high boiling point acid as catalyzer, obtain corresponding flavanone derivatives with aromatic aldehyde or heterocycle aldehydes substance reaction, above-mentioned temperature of reaction is 50-200 ℃, and the reaction times is 1-15 hour, the mol ratio of compound 6-hydroxyl-2,4 hydroxy acetophenone class material, aromatic aldehyde or heterocycle aldehyde material and catalyzer is 1: 1.0～5.0: 1.0～5.0.
3, a kind of flavanone derivatives is applied to prepare the medicine of antitumor drug and cardiovascular and cerebrovascular diseases.
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