CN1749237A - Tetra substituted chalcone derivative and preparing method and use - Google Patents
Tetra substituted chalcone derivative and preparing method and use Download PDFInfo
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Abstract
The present invention provides 2-hydroxy-3-amino methylene-4, 6-dibubstituted chalcone derivative with the structural general expression as shown. The preparation process includes the following steps: Lewis acid catalyzed reaction of compound I and anhydrous methy1cyanide inside inert solvent to obtain intermediate trihydroxy acetophenone amide hydrochloride; further acid hydrolysis to obtain compound II; selective etherification with alkylation reagent under alkaline cddn to obtain compound III; condensation with aromatic aldehyde under alkaline condition to obtain compound IV; and reaction with secondary amine in the presence of acid and formaldehyde to produce destination compound V. The present invention provides completely new structure compounds with powerful tumor cell inhibiting effect and IC50 value up to 0.8 micron, and capable of being used in preparing antitumor medicine.
Description
Technical field
The invention belongs to the synthetic of organic compound, relate to the preparation method of tetra substituted chalcone derivative, relate in particular to 2-hydroxyl-3-amine methylene radical-4,6-two replaces the preparation method of chalcone derivative, and the application in the preparation antitumor drug.
Background technology
Chalcone derivative has antitumor action.Calendar year 2001 C.Pouget etc. has reported that a series of two replacements or trisubstituted 2-hydroxy-benzalacetophenone derivative have antitumor action, and wherein 2 ', 4 '-dihydroxyl phenyl styryl ketone and 2 '-hydroxyl-4 '-methoxyl group phenyl styryl ketone is effective to breast cancer cell MCF-7, its IC
50Value is respectively 16.3 and 18.3 μ M.The structure of the chalcone derivative that this article provided is comparatively common, do not have on the aromatic ring to replace or only have the oxygen of containing functional group (hydroxyl and methoxyl group) and replace, the author has only carried out the discussion of preliminary activity and structure activity relationship to these compounds simultaneously, and the mechanism of its antitumor action is not done further further investigation; Two of a series of boracics of report such as S.K.Kumar in 2003 replace or trisubstituted chalcone derivative also has antagonistic action to the human breast cancer cell strain, record IC through mtt assay
50The scope of value is 3.5-100 μ M.The author is on the basis of one of target spot of breast cancer treatment in MDM2 (the Mouse Double Minute 2) oncogene that forefathers propose, reported the chalcone derivative that contains carboxylic acid and the binding pattern of MDM2 in conjunction with forefathers, introduced isosteric notion, replaced the carboxylic acid group and synthesized a series of borated chalcone derivatives with boronate.Ceng Zuowei fluorescent probe before the boron-containing compound and be used for the detection of fluorine cpd and glucide, this article only report the activity of its anti-breast cancer, and further do not illustrate its mechanism of action.
Summary of the invention
The purpose of this invention is to provide the chalcone derivative that a class contains nitrogen-atoms, mainly refer to 2-hydroxyl-3-amine methylene radical-4,6-two replaces chalcone derivative, it is the chalcone derivative of a class formation novelty, the present invention is the structure that changes 2-hydroxy-benzalacetophenone derivative, on the 3-position, introduce different amine methylene radical structures, synthesized a series of 2-hydroxyl-3-amine methylene radical-4,6-two replaces chalcone derivative, 2-hydroxyl provided by the invention-3-amine methylene radical-4,6-two replace the chalcone derivative general structure and are:
Wherein
R
1Straight or branched alkane for hydrogen atom or 1 to 3 carbon atom;
Ar is for do not have replacing, singly replace, two replace or trisubstituted phenyl ring, and the substituting group on the phenyl ring can be hydrogen atom, halogen atom, hydroxyl, nitro, dimethylin, contain the alkyl of the straight or branched of 1 to 6 carbon atom, contain the alkoxyl group of the straight or branched of 1 to 3 carbon atom;
R
2Be open chain or cyclic tertiary amine structure NR
3R
4, R wherein
3And R
4Can be identical or different, they can be methyl, ethyl, contain the alkyl alcohol and the ester thereof of 1-4 carbon atom, contain the carboxylic acid and the ester thereof of 1-4 carbon atom, contain the alkylamine of 1-4 carbon atom, or R
3, R
4Become five yuan or six-ring with carbon, oxygen and nitrogen-atoms cyclization respectively.
Another object of the present invention provides 2-hydroxyl-3-amine methylene radical-4, and 6-two replaces the preparation method of chalcone derivative, realizes by following steps:
Synthetic route of the present invention:
(1) Compound I and anhydrous acetonitrile obtain intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate through Lewis acid (Lewis acid) catalysis in inert solvent, this reaction is usually with ether, methylene dichloride, chloroform, ethyl acetate etc. are solvent, used Lewis acid has zinc chloride, boron trifluoride ether solution etc., reaction can be carried out between 0-5 ℃, normally reacted 6-8 hour, intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate obtains Compound I I through acidic hydrolysis again, reaction can be carried out between 100-105 ℃, backflow 1-5 hour, normally refluxed 2 hours, products therefrom II need not purifying, can directly carry out next step reaction;
(2) Compound I I selective etherification through alkylating reagent under alkaline condition can obtain compound III, can get pure product through recrystallization.Reaction is carried out in polar solvent such as acetone usually, and alkaline matter commonly used has yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, and temperature of reaction can be carried out between 10-30 ℃, at room temperature carries out usually;
(3) compound III obtains compound IV with various aromatic aldehyde condensations under alkaline condition, and reaction is carried out in the protic mixed solvent usually, and as methanol-water, alcohol-water, Virahol-water etc., alkali commonly used has sodium hydroxide, potassium hydroxide, sodium hydride etc.Temperature of reaction can be carried out between 10-30 ℃, at room temperature carries out usually, obtains product and can get pure product by recrystallization;
(4) IV of gained is in protic solvent, in the presence of acid and formaldehyde, generate target compound V with various secondary amine reactions, used protic solvent is methyl alcohol, ethanol, Virahol etc., and used formaldehyde can be formalin, trioxymethylene and Paraformaldehyde 96 etc.Reaction is carried out between 50-90 ℃ usually.Products therefrom can get pure product through column chromatography.
Compound I can directly be bought, Compound I I can be by literature method (K.C.Gulati et al, Org Synth, Coll.Vol.II, 522) make, compound III can (K.Y.T.Juntend et al EP0292576) makes, and compound IV can be by literature method (Xiaoyong Bu et al by literature method, Synthesis, 1997,11,1246-1248) make.
Another purpose of the present invention is 2-hydroxyl-3-amine methylene radical-4, and 6-two replaces the application of chalcone derivative in the preparation antitumor drug.Preliminary pharmacological evaluation finds that they to various tumor cell strains, comprise Bel-7402, and PC-3, ECA-2, A549, MCF-7 etc. all have good in-vitro to suppress proliferation function, and wherein the Vb effect is comparatively outstanding, to the IC of above-mentioned 5 kinds of tumor cell lines
50Value shows that its antitumor spectra is wider between 1.7-3.1 μ M; Compound Vg is the highest to the inhibiting rate of Human Prostate Cancer Cells PC-3, its IC
50Value reaches 3nM, shows that its selectivity is higher.
Characteristics of the present invention are to be lead compound to have active 2-hydroxy-benzalacetophenone, at 2-hydroxyl-4, on the 6-dimethoxy phenyl styryl ketone parent nucleus, obtain 2-hydroxyl-3-amine methylene radical-4,6-dimethoxy chalcone derivative by the Mannich reaction.This is the brand-new compound of a class formation, and preliminary pharmacological activity screening experiment shows that these compounds all have better antitumor activity, and the antitumor spectra of some compound is very wide, and the selectivity of some compound is fine.The used starting material of the present invention are wide material sources not only, are easy to preparation, and the reaction conditions gentleness, and each goes on foot the yield height, and is simple to operate, and production cost is lower, is suitable for suitability for industrialized production.
Embodiment
Following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
Embodiment 1,2-hydroxyl-4,6-dimethoxy-methyl phenyl ketone (III): reference literature method (K.Y.T.Juntend et al, EP 0292576) makes.
M.p.77-78℃
1HNMR(δ，CDCl
3)：14.06(s，1H)，6.05(d，1H，J＝2.4Hz)，5.92(d，1H，J＝2.4Hz).3.90(s，3H)，3.62(s，3H)，2.63(s，3H)
Embodiment 2,2 '-hydroxyl-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (IV): the reference literature method (Xiaoyong Bu et al, Synthesis, 1997,11,1246-1248) make.
M.p.123-124℃
1HNMR(δ，CDCl
3)：14.20(s，1H)，8.12-8.16(d，1H，J＝15.6Hz)，7.85-7.89(d，1H，J＝15.2Hz)，7.68-7.70(m，1H)，7.42-7.44(m，1H)，7.26-7.31(m，2H)，6.10-6.11(d，1H，J＝2.4Hz)，5.95-5.96(d，1H，J＝2.4Hz)，3.90(s，3H)，3.84(s，3H).
Embodiment 3,2 '-hydroxyl-3 '-(4-methylpiperazine-1-base-methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Va):
Compound IV 1.59g (4.99mmol), formalin 1.24g (15.30mmol), N methyl piperazine 1.10g (10.98mmol), methyl alcohol 12.5ml and salt acid number are added dropwise in the reaction flask backflow 2h.Cooling, decompression and solvent recovery, thin up, alkalization, dichloromethane extraction, saturated sodium-chloride washing, anhydrous sodium sulfate drying, decompression and solvent recovery, column chromatography (eluent: sherwood oil: ethyl acetate: triethylamine=200ml: 400ml: 9.6ml), obtain yellow solid 1.17g, yield 56%.m.p.146-148℃。
1HNMR(δ，CDCl
3)：7.96-8.00(d，1H，J＝15.6Hz)，7.67-7.70(m，1H)，7.38-7.42(d，1H，J＝15.6Hz)，7.39-7.41(m，1H)，7.26-7.29(m，2H)，6.00(s，1H)，3.86(s，3H)，3.85(s，3H)，3.71(s，2H)，2.60-2.61(m，4H)，2.44-2.45(m，4H)，2.26(s，3H).
Embodiment 4,2 '-hydroxyl-3 '-(piperidines-1-base-methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vb):
Operating process just replaces N methyl piperazine with piperidines referring to embodiment 3.Obtain yellow crystal, yield 50%.m.p.159-162℃。
1HNMR(δ，CDCl
3)：7.92-7.96(d，1H，J＝16.0Hz)，7.66-7.69(m，1H)，7.36-7.38(m，1H)，7.24-7.26(m，2H)，7.20-7.23(d，1H，J＝16.0Hz)，5.99(s，1H)，3.82(s，3H)，3.81(s，3H)，3.66(s，2H)，2.40-2.50(m，4H)，1.55-1.59(m，4H)，1.40-1.42(m，2H).
Embodiment 5,2 '-hydroxyl-3 '-(pyrroles-1-base-methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vc):
Operating process just replaces N methyl piperazine with the pyrroles referring to embodiment 3.Obtain yellow crystal, yield 50%.m.p.125-127℃。
1HNMR(δ，CDCl
3)：8.03-8.07(d，1H，J＝15.6Hz)，7.68-7.70(m，1H)，7.52-7.56(d，1H，J＝15.6Hz)，7.40-7.43(m，1H)，7.28-7.30(m，2H)，6.02(s，1H)，3.94(s，2H)，3.93(s，3H)，3.91(s，32H)，2.86(brs，4H)，1.89(brs，4H).
Embodiment 6,2 '-hydroxyl-3 '-(morpholine-1-base-methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vd):
Operating process is just replaced N methyl piperazine with morpholino referring to embodiment 3.Obtain yellow crystal, yield 61%.m.p.162-164℃。
1HNMR(δ，CDCl
3)：8.02-8.06(d，1H，J＝15.6Hz)，7.68-7.70(m，1H)，7.55-7.59(d，1H，J＝15.6Hz)，7.41-7.43(m，1H)，7.28-7.30(m，2H)，6.02(s，1H)，3.91(s，3H)，3.89(s，3H)，3.70-3.72(t，4H，J
1＝8.8Hz，J
2＝4.4Hz)，3.67(s，2H)，2.55-2.57(t，4H，J
1＝8.8Hz，J
2＝4.4Hz).
Embodiment 7,2 '-hydroxyl-3 '-(N, N dimethylamine ylmethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Ve):
Operating process is just used N referring to embodiment 3, and N dimethylamine replaces N methyl piperazine.Obtain yellow crystal, yield 63%.m.p.188-190℃。
1HNMR(δ，CDCl
3)：8.03-7.99(d，1H，J＝15.6Hz)，7.65-7.68(m，1H)，7.50-7.54(d，1H，J＝16.0Hz)，7.38-7.40(m，1H)，7.25-7.27(m，2H)，5.99(s，1H)，3.88(s，3H)，3.87(s，3H)，3.58(s，2H)，2.30(s，6H).
Embodiment 8,2 '-hydroxyl-3 '-(N, N dimethylamine ylmethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vf):
Operating process is just used N referring to embodiment 3, and N dimethylamine replaces N methyl piperazine.Obtain yellow crystal, yield 71%.m.p.187-190℃。
1HNMR(δ，CDCl
3)：14.71(s，1H)，8.15-8.19(d，1H，J＝15.6Hz)，7.78-7.82(d，1H，J＝15.6Hz)，7.68-7.70(m，1H)，7.44-7.45(m，1H)，7.31-7.33(m，2H)，6.06(s，1H)，4.17(s，2H)，4.07(s，3H)，3.99(s，3H)，3.12(brs，4H)，1.45-1.49(t，6H，J
1＝14.0Hz，J
2＝6.8Hz).
Embodiment 9,2 '-hydroxyl-3 '-(N, N-thyl methyl amine ylmethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vg):
Operating process is just used N referring to embodiment 3, and N-methylethyl amine replaces N methyl piperazine.Obtain yellow crystal, yield 70%.m.p.187-190℃。
1HNMR(δ，CDCl
3)：14.71(s，1H)，8.17-8.21(d，1H，J＝15.6Hz)，7.81-7.85(d，1H，J＝15.2Hz)，7.69-7.72(m，1H)，7.45-7.47(m，1H)，7.33-7.35(m，2H)，6.09(s，1H)，4.22(s，2H)，4.07(s，3H)，4.04(s，3H)，3.16(brs，2H)，2.72(s，3H)，1.51-1.54(t，3H，J
1＝14.8Hz，J
2＝7.2Hz).
Embodiment 10,2 '-hydroxyl-3 '-(N-methyl-N-β-hydroxyethylamine methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vh):
Operating process just replaces N methyl piperazine with N-methyl-N-β-oxyethylamine referring to embodiment 3.Obtain yellow crystal, yield 74%.m.p.127-130℃。
1HNMR(δ，CDCl
3)：8.11-8.15(d，1H，J＝15.6Hz)，7.78-7.82(d，1H，J＝15.6Hz)，7.69-7.71(m，1H)，7.43-7.46(m，1H)，7.31-7.33(m，2H)，6.03(s，1H)，3.96(s，3H)，3.92(s，3H)，3.65-3.68(t，2H，J
1＝10.8Hz，J
2＝5.2Hz)，3.61(s，2H)，2.63-2.66(t，2H，J
1＝10.8Hz，J
2＝5.2Hz)，2.27(s，3H).
Embodiment 11,2 '-hydroxyl-3 '-(N-methyl-N-β-acetyl oxygen ethylamino-methyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vi):
Compound Vh2.03g (5.01mmol) is dissolved in CH
2Cl
2Among the 25ml, add aceticanhydride 0.55ml, stirring at room 2h.Decompression and solvent recovery is transferred pH to 8, dichloromethane extraction with dilute hydrochloric acid, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, decompression and solvent recovery, column chromatography (eluent: sherwood oil: ethyl acetate: triethylamine=400ml: 200ml: 8.4ml), obtain yellow solid 1.05g, yield 47%.m.p.97-99℃。
1HNMR(δ，CDCl
3)：8.02-8.06(d，1H，J＝15.6Hz)，7.67-7.70(m，1H)，7.57-7.61(d，1H，J＝15.6Hz)，7.40-7.42(m，1H)，7.29-7.30(m，2H)，6.01(s，1H)，4.23-4.26(t，2H，J
1＝11.2Hz，J
2＝5.6Hz)，3.91(s，3H)，3.88(s，3H)，3.68(s，2H)，2.74-2.76(t，2H，J
1＝11.2Hz，J
2＝5.6Hz)，2.34(s，3H)，2.04(s，3H).
Embodiment 12,2 '-hydroxyl-3 '-(N-methyl-N-carboxymethyl aminomethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vj):
Operating process such as example 3 just replace N methyl piperazine with sarkosine.Obtain yellow crystal, yield 54%.m.p.157-159℃。
1HNMR(δ，CDCl
3)：7.94-7.96(d，1H，J＝7.2Hz)，7.80-7.84(d，1H，J＝15.6Hz)，7.55-7.57(d，1H，J＝8.0Hz)，7.49-7.53(d，1H，J＝16.0Hz)，7.44-7.47(m，2H)，6.32(s，1H)，3.91(s，3H)，3.90(s，3H)，3.88(s，2H)，3.28(s，2H)，2.41(s，3H).
Embodiment 13,2 '-hydroxyl-3 '-(N-methyl-N-methoxycarbonyl methylamine ylmethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vk):
Operating process such as example 3 just replace N methyl piperazine with hydrochloride methyl sarcosnate.Obtain yellow crystal, yield 53%.m.p.115-117℃。
1HNMR(δ，CDCl
3)：13.88(brs，1H)，8.10-8.14(d，1H，J＝15.2Hz)，7.73-7.77(d，1H，J＝16.0Hz)，7.70-7.71(m，1H)，7.44-7.46(m，1H)，7.31-7.33(m，2H)，6.02(s，1H)，3.97(s，3H)，3.92(s，3H)，3.82(s，2H)，3.73(s，3H)，3.35(s，2H)，2.47(s，3H).
Embodiment 14,2 '-hydroxyl-3 '-(N-methyl-N ', N '-dimethyl propyl aminomethyl)-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (Vl):
Operating process such as example 3 are just used N, N ', and N '-trimethylammonium propylene diamine replaces N methyl piperazine.Obtain yellow crystal, yield 49%.m.p.86-87℃。
1HNMR(δ，CDCl
3)：7.90-7.94(d，1H，J＝15.6Hz)，7.59-7.61(m，1H)，7.34-7.38(d，1H，J＝15.2Hz)，7.44-7.46(m，1H)，7.31-7.33(m，2H)，6.02(s，1H)，3.97(s，3H)，3.92(s，3H)，3.82(s，2H)，3.73(s，3H)，3.35(s，2H)，2.47(s，3H).
Embodiment 15, anti-tumor biological testing method:
The tumour cell isolated culture:
Choose tumour cell Molt-4, PC-3, Bel-7402, A549, SGC-823, HL60, ECA-109, LS-174t is in 37 ℃, 5%CO
2Hatch in the cell culture incubator, go down to posterity when treating cell density length (attached cell is gone down to posterity after using Puck ' s EDTA digestion) to 70-90%, experiment is required after being used for.
Mtt assay is measured the vitro inhibition effect of chalcone derivative to different knurl strains:
Compound is dissolved dilution, tumour cell Bel-7402, PC-3, ECA-2 with DMSO, A549, MCF-7 plant on 96 orifice plates and go into 4000/200 μ l/ holes, and every hole adds compound 2 μ l, and final concentration is 12.0 μ M, 6.0 μ M, 3.0 μ M, 1.5 μ M are jointly in 37 ℃, 5%CO
2Hatching in the cell culture incubator 72 hours, is blank with DMSO (1%).After 72 hours, adding final concentration is the MTT of 0.25mg/ml, places 37 ℃, 5%CO
2In the cell culture incubator 4 hours, blot solvent afterwards, every hole adds 100 μ lDMSO, and in 570nm place mensuration absorbancy (OD value), the gained data are used to calculate IC with the enzyme linked immunological instrument
50Gained the results are shown in Table 1:
12 compounds of institute's synthetic are to the IC of different tumor cell lines
50(μ M) value
As can be seen from the above table, 12 1) all compounds all have certain inhibition activity to different tumor cell lines.2) the 3-position is hexa-atomic or five-membered ring compound Va, the Vb, Vc and the Vd that replace all have high inhibitory to 5 kinds of tumor cell lines, its IC
50Value is 1.7-22.7 μ m.3) activity of the compound that replaces for the open chain alkyl of 3-position is also higher, along with the minimizing of alkyl carbon atoms number, the inhibition activity of certain tumor cell line is strengthened greatly, and wherein compound Vg is the highest to the inhibiting rate of Human Prostate Cancer Cells PC-3, its IC
50Value reaches 3nM.4) in 12 compounds, the activity of having only compound Vj is the most weak.5) generally speaking, this compounds has the good antitumor application prospect, thereby the tool good commercial is worth.
Need not further to elaborate, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the embodiment of front is interpreted as only illustrating, but not limits the scope of the invention by any way.
Claims (6)
1.2-hydroxyl-3-amine methylene radical-4,6-two replaces chalcone derivative, and general structure is:
Wherein
R
1Straight or branched alkane for hydrogen atom or 1 to 3 carbon atom;
Ar is for do not have replacing, singly replace, two replace or trisubstituted phenyl ring, and the substituting group on the phenyl ring can be hydrogen atom, halogen atom, hydroxyl, nitro, dimethylin, contain the alkyl of the straight or branched of 1 to 6 carbon atom, contain the alkoxyl group of the straight or branched of 1 to 3 carbon atom;
R
2Be open chain or cyclic tertiary amine structure NR
3R
4, R wherein
3And R
4Identical or different, or methyl, ethyl, contain the alkyl alcohol and the ester thereof of 1-4 carbon atom, contain the carboxylic acid and the ester thereof of 1-4 carbon atom, contain the alkylamine of 1-4 carbon atom, or R
3, R
4Become five yuan or six-ring with carbon, oxygen and nitrogen-atoms cyclization respectively.
2. 2-hydroxyl according to claim 1-3-amine methylene radical-4,6-two replaces the preparation method of chalcone derivative, it is characterized in that realizing by following steps:
(1) Compound I and anhydrous acetonitrile obtain intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate through Lewis acid catalysis in inert solvent, temperature of reaction is 0-5 ℃, reacted 6-8 hour, intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate obtains Compound I I through acidic hydrolysis again, temperature of reaction is 100-105 ℃, backflow 1-5 hour;
(2) Compound I I selective etherification through alkylating reagent under alkaline condition can obtain compound III, can get pure product through recrystallization, is reflected in the polar solvent and carries out, and temperature of reaction is 10-30 ℃;
(3) compound III obtains compound IV with various aromatic aldehyde condensations under alkaline condition, is reflected in the protic mixed solvent and carries out, and temperature of reaction is 10-30 ℃, obtains product and can get pure product by recrystallization;
(4) compound IV of gained generates target compound V with various secondary amine reactions in the presence of acid and formaldehyde in protic solvent, and temperature of reaction is 50-90 ℃, and products therefrom can get pure product through column chromatography.
3. 2-hydroxyl according to claim 2-3-amine methylene radical 4,6-two replaces the preparation method of chalcone derivatives, it is characterized in that: select in methanol-water, alcohol-water or the Virahol-water any in the step (3) in the protic mixed solvent for use.
4. 2-hydroxyl according to claim 2-3-amine methylene radical-4,6-two replaces the preparation method of chalcone derivatives, it is characterized in that: used protic solvent is selected in methyl alcohol, ethanol or the Virahol any for use in the step (4).
5. 2-hydroxyl according to claim 2-3-amine methylene radical-4,6-two replaces the preparation method of chalcone derivatives, it is characterized in that: used formaldehyde is selected in formalin, trioxymethylene or the Paraformaldehyde 96 any for use in the step (4).
6. 2-hydroxyl according to claim 1-3-amine methylene radical-4,6-two replace the application of chalcone derivative in the preparation antitumor drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009143714A1 (en) * | 2008-05-27 | 2009-12-03 | 天津药物研究院 | 2,4-dihydroxyl chalcone derivative, process for preparing them and use thereof |
| CN102070429A (en) * | 2010-12-15 | 2011-05-25 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN101041646B (en) * | 2007-04-30 | 2011-07-20 | 浙江大学 | Preparation method and usage for nitrogen-containing chalcone derivatives |
| CN102863343A (en) * | 2012-10-20 | 2013-01-09 | 罗梅 | Preparation and synthesis method of chiral (R)-phenylglycinol hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IT1271301B (en) * | 1994-12-20 | 1997-05-27 | Indena Spa | NATURAL AND SYNTHETIC CALCONES AND THEIR ESTERS WITH ANTI-PROLIFERATIVE ACTIVITY IN CANCER OF THE UTERUS, OVARIAN AND BREAST AND FORMULATIONS CONTAINING THEM |
| GB9712966D0 (en) * | 1997-06-19 | 1997-08-27 | Indena Spa | Novel chalcones |
| GB9920910D0 (en) * | 1999-09-03 | 1999-11-10 | Indena Spa | Novel chalcones |
| JP2005516941A (en) * | 2001-12-19 | 2005-06-09 | アセロジエニクス・インコーポレイテツド | Chalcone derivatives and their use for treating diseases |
| WO2004031165A1 (en) * | 2002-10-01 | 2004-04-15 | Takara Bio Inc. | Remedies |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101041646B (en) * | 2007-04-30 | 2011-07-20 | 浙江大学 | Preparation method and usage for nitrogen-containing chalcone derivatives |
| WO2009143714A1 (en) * | 2008-05-27 | 2009-12-03 | 天津药物研究院 | 2,4-dihydroxyl chalcone derivative, process for preparing them and use thereof |
| CN101591230B (en) * | 2008-05-27 | 2013-10-30 | 天津药物研究院 | 2,4-dyhydroxyl chalcone derivative, preparation method and application thereof |
| CN102070429A (en) * | 2010-12-15 | 2011-05-25 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN102070429B (en) * | 2010-12-15 | 2013-03-13 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN102863343A (en) * | 2012-10-20 | 2013-01-09 | 罗梅 | Preparation and synthesis method of chiral (R)-phenylglycinol hydrochloride |
| CN102863343B (en) * | 2012-10-20 | 2013-10-09 | 罗梅 | Preparation and synthesis method of chiral (R)-phenylglycinol hydrochloride |
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