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CN102603692A - Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives - Google Patents

Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives Download PDF

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CN102603692A
CN102603692A CN2012100458773A CN201210045877A CN102603692A CN 102603692 A CN102603692 A CN 102603692A CN 2012100458773 A CN2012100458773 A CN 2012100458773A CN 201210045877 A CN201210045877 A CN 201210045877A CN 102603692 A CN102603692 A CN 102603692A
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dimethoxy
chroman
chromene
hydrogen
trimethoxyphenyl
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CN102603692B (en
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万升标
周铭祥
苑建
黄丽琼
江涛
李学敏
张晓瑜
孙东魁
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Ocean University of China
Hong Kong Polytechnic University HKPU
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Hong Kong Polytechnic University HKPU
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Abstract

The invention provides chroman and chromene derivatives as tumor multidrug resistance inhibitors as well as a preparation method of the chroman and chromene derivatives. The chroman and chromene derivatives are represented by the following general formulae I and II respectively, wherein R is one or more of hydrogen, hydroxy, alkoxy, alkyl amino, alkyl acylamino, halogen, fluorine-containing alkyl or benzoyl; the benzoyl contains one or more of substituent groups of hydroxy, alkoxy, alkyl amino, alkyl acylamino, halogen or fluorine-containing alkyl; the alkyls in the alkoxy, the alkyl amino, the fluorine-containing alkyl and the alkyl acylamino are linear-chain or branch-chain alkyls with 1-10 carbon atoms; X is hydrogen or oxygen; and Y is oxygen or nitrogen. The chroman and chromene derivatives have low toxicity and good tumor multidrug resistance inhibiting activities, and can be used for preparing drugs for treating breast cancer, colon cancer, prostate cancer, leukemia, myeloma, pancreatic cancer and the like.

Description

A kind of artitumor multi-medicine-resistant suppressor factor chroman and chromene derivative
Technical field
The invention belongs to medical technical field, be specifically related to a kind of chroman and chromene derivative and preparation method thereof and as the application of artitumor multi-medicine-resistant suppressor factor.
Background technology
Chemotherapy is one of main method of treatment tumour, and the multidrug resistance of tumour cell (MDR) is the major cause of chemotherapy of tumors failure and tumor recurrence and transfer, makes chemotherapy face severe challenge.P-gp is the antitumor drug efflux pump of the dependent wide spectrum of ATP.
The P-gp suppressor factor has roughly been developed three generations [Ramalingam, et al:Clin Lung Cancer 2005; 7:773].The first-generation suppresses ingestion of medicines originally as the P-gp substrate, effluxes the medicine ability but suppress P-gp, and toxic side effect is big, has seriously limited its clinical application.Represent medicine such as verapamil, it is the multidrug resistant reversal agent of finding early.The s-generation is representative with Valspodar (PSC-833), Biricodar (VX-710) and Dofequidar fumarate (MS-209) etc., and inhibition P-gp ability is 3～100 times of the first-generation, and toxic side effect decreases.But, because of while competitive inhibition cytochrome P-450 enzyme, change chemotherapeutics pharmacokinetics characteristic, increased toxicity, thereby restriction chemotherapeutics using dosage.Third generation suppressor factor comprise Tariquidar (XR-9576) and Ontogen (ONT-093, OC1442093), and Zosuquidar trihydrochloride (LY-335979); Laniquidar (R-101933); Elacridar (GF-120918) etc., its characteristic feature is that selectivity suppresses P-gp, and longer duration; Can the multiple chemotherapeutics of enhanced sensitivity, toxic side effect is little.XR-9576 is carrying out the anti-breast cancer phase iii clinical trial, and [Zhang Yan etc.: medicine estimates 2006 to demonstrate the excellent development prospect; 3:264].
L-Epicatechin gallate and catechin and gallate are a kind of natural polyphenol compounds that contains the chroman skeleton of low toxicity; Can combine and reverse the resistance of drug-resistant tumor cells such as CHRC5 and PS833 to antitumor drugs such as many gentle Mi Xing and Zorubicins with tumor drug resistance albumen P-gp (P-gp); The resistance multiple is up to 1.8 times of [Wan Yong Feng, Current Drug Metabolism, 2006; 7,755-809.].The natural flavone that contains the chromene skeleton of low toxicity comprises also come to light [the Di Pietro that has the artitumor multi-medicine-resistant activity such as Quercetin and poplar mycin in addition; A. wait Cell Mol Life Sci 2002; 59; 307-322.], and suppress tumor drug resistance albumen P-gp and mammary cancer drug-resistant protein (BCRP) and reach the artitumor multi-medicine-resistant effect.But it is low that the catechin compounds that contains the chroman skeleton and the chromocor compound that contains the chromene skeleton have the artitumor multi-medicine-resistant activity, and shortcomings such as chemistry and biological metabolism instability are arranged, so influenced it greatly as the application in the artitumor multi-medicine-resistant.
Summary of the invention
The present invention is directed to the catechin compounds that contains the chroman skeleton in the prior art and the chromocor compound that contains the chromene skeleton, to have the artitumor multi-medicine-resistant activity low; And shortcomings such as chemistry and biological metabolism instability; A kind of chroman and chromene derivative and preparation method thereof are provided; Said chroman and chromene derivative and NVP-XAA 723 and flavones have the same bone shelf structure, but chroman and chromene derivative be low toxicity and to have more a good resistance tumor multi-medicine drug-resistant active.The present invention also provides a kind of chroman and the purposes of chromene derivative in artitumor multi-medicine-resistant with general formula I and II structure.
For realizing the foregoing invention purpose, the present invention adopts following technical proposals to be achieved:
A kind of artitumor multi-medicine-resistant suppressor factor chroman and chromene derivative, said chroman derivative are represented that by general formula I said chromene derivative is represented by general formula I I:
Figure BDA0000138497300000031
R is hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, halogen, contains in fluoroalkyl or the benzoyl-one or more among general formula I and the general formula I I; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl or the halogenic substituent one or more, wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl; X is hydrogen or oxygen in the formula; Y is oxygen or nitrogen in the formula; Carbon in the general formula I-2 chirality is R type or S type, and carbon in the general formula I-3 chirality is R type or S type;
L is the linking group that contains the straight or branched of 1-10 carbon atom among general formula I and the general formula I I, and said linking group also contains aerobic, nitrogen, halogen or sulphur atom; Or L is hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contains in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl, fluorine, the chlorine or bromine one or more in the general formula I;
Q is hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contains in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl or the halogen one or more among general formula I and the general formula I I; Or Q is represented by following general formula I II, IV or V:
Figure BDA0000138497300000041
R among general formula III, IV and the V 1For hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, halogen or the benzoyl-one or more; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, the halogenic substituent one or more; Wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl, n is 1-5; Or said R 1Group is hydrogeneous, hydroxyl, alkoxyl group, alkylamino, contain in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl, alkylamidoalkyl or the halogen one or more; Or said R 1Group is represented by formula VI or VII:
Figure BDA0000138497300000042
R in the formula 2For hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, halogen or the benzoyl-one or more; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, contain in fluoroalkyl, alkylamidoalkyl or the fluoro substituents one or more; Wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl, m is 1-5.
Said compound of Formula I be (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-5,7-dimethoxy chroman-3-alcohol; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy benzoyloxy)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-triethoxy benzoyloxy)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-three allyloxy benzoyloxys)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-dimethylin-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-acetamido-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxyl group cinnamoyloxy group)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl) acetoxyl group))-5,7-dimethoxy chroman;
Said general formula I I compound is 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (7); 2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; 2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzyloxy)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; 2-(3, the 4-Dimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl)-2-oxo oxyethyl group))-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; 2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy cinnamoyloxy group) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; 2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy benzoyloxy) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; 2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxy benzoyloxy) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone; Or 2-(3, the 4-Dimethoxyphenyl)-3-(2-(4-methoxybenzoyl oxygen base) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone.
Said compound of Formula I prepares as follows: with methylene dichloride, chloroform or N is solvent, at the triethylamine of 1-5 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine; Make respectively (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-and 3-hydroxyl-5,7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5; 7-dimethoxy-4 '-hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the Benzoyl chloride 99min., phenyllacetyl chloride or the cinnamyl chloride that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone and 1-5 mol ratio is 0 ℃-25 ℃ reactions 0.5-24 hour down; Prepare described chroman derivative; The mol ratio of said use reagent with respect to use respectively (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-3-hydroxyl-5; 7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone or 2-(3; The 4-Dimethoxyphenyl)-and 3-(2-hydroxyl-oxethyl)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone.
Said general formula I or general formula I I compound also can prepare as follows: with methylene dichloride, chloroform or N is solvent, at the triethylamine of 1-5 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine; The 1-5 mol ratio under the N '-carbonyl dimidazoles catalysts such as (CDI), makes (2R to dimethyl aminopyridine (DMAP), 1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI) or N respectively; 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5; 7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone or 2-(3; The 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5; The phenylformic acid, toluylic acid or the styracin that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone and 1-5 mol ratio prepare described chroman and chromene derivative 0 ℃-25 ℃ following reactions 0.5-24 hour, and the mol ratio of said use reagent is with respect to using (2R respectively; 3R)-2-(3; 4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman, 2-(3; The 4-Dimethoxyphenyl)-3-hydroxyl-5; 7-dimethoxy-4 '-hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone.
Said general formula I I compound prepares as follows: with methylene dichloride, chloroform or N is solvent; At the salt of wormwood of 1-5 mol ratio, yellow soda ash, Pottasium Hydroxide, sodium hydroxide sodium hydride, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N; Under the existence of N-dimethyl aminopyridine; Make 2-(3; The 4-Dimethoxyphenyl)-3-hydroxyl-5; The benzyl bromine, benzyl methanesulfonates, benzyl p-toluenesulfonic esters, 2-bromoacetophenone or the 2-chloroacetophenone that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone and 1-5 mol ratio prepare described chromene derivative 0 ℃-100 ℃ following reactions 0.5-24 hour, and the mol ratio of said use reagent is with respect to 2-(3; The 4-Dimethoxyphenyl)-and 3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone.
Further again, described chroman and chromene derivative are used for treating the application of the medicine of mammary cancer, colorectal carcinoma, prostate cancer, white blood disease, myelomatosis and carcinoma of the pancreas in preparation.
Wherein, said chroman and chromene derivative are as oral medication or parenteral medication; Said oral medication is tablet, capsule or seed dressing agent, and said parenteral drug formulation is injection or suppository.
Can further describe the synthetic route of general formula I chroman derivative of the present invention in conjunction with following structure iron:
Reagent and reaction conditions:
(a): saturated hydrogen chloride methanol solution, room temperature, 12 hours.
(b): salt of wormwood/methyl-sulfate/acetone/glycol dimethyl ether, reflux 24 hours.
(c): salt of wormwood/methyl alcohol/glycol dimethyl ether, room temperature, 2 hours.
(d): 3-methoxybenzoic acid, 4-methoxybenzoic acid, 3,4-dimethoxybenzoic acid, 3,4; 5-triethoxy phenylformic acid, 3; 4,5-triolefin propoxy benzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid, 3-dimethylin-4-fluorobenzoic acid or 3-acetamido-4-fluorobenzoic acid are to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride; Room temperature, 12 hours.
(e): 3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoic acid or 3-(3,4; 5-trimethoxy-benzamide base)-the 4-fluorobenzoic acid; To dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
(f): 4-methoxy cinnamic acid, 3,4-dimethoxy-cinnamic acid or 3,4, the 5-trimethoxy cinnamic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
(g): 3, the 4-dimethoxyphenylacetic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
Can further describe the synthetic route of general formula I I chromene derivative of the present invention in conjunction with following structure iron:
Figure BDA0000138497300000091
Reagent and reaction conditions:
(h): 3,4, the 5-trimethoxybenzoic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
(i): 3,4,5-trimethoxy phenylcarbinol methanesulfonates, N/salt of wormwood, room temperature, 12 hours.
(j): 2-bromo-1-(3, the 4-Dimethoxyphenyl) ethyl ketone, N/salt of wormwood, room temperature, 12 hours.
(k): 3,4, the 5-trimethoxy cinnamic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
(l): 3,4, the 5-trimethoxybenzoic acid, 3,4-dimethoxybenzoic acid or 4-methoxybenzoic acid are to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI)/methylene dichloride, room temperature, 12 hours.
Compared with prior art; Advantage of the present invention with positively effect is: the chroman of said general formula I of the present invention and general formula I I is compared with Valspodar (PSC-833) etc. with existing artitumor multi-medicine-resistant suppressor factor such as verapamil with chromene derivative, and the artitumor multi-medicine-resistant effect is strong and toxic side effect is little.The chroman derivative of said general formula I of the present invention demonstrates the selectivity of better inhibition P-gp.The chromene derivative of said general formula I I of the present invention demonstrates the activity of better inhibition P-gp and BCRP.
The chroman of said general formula I of the present invention and general formula I I and chromene derivative be low toxicity and have the good resistance tumor multi-medicine drug-resistant active, said chroman and chromene derivative can be used to prepare treats the medicine that is used to treat mammary cancer, colorectal carcinoma, prostate cancer, white blood disease, myelomatosis and carcinoma of the pancreas etc.
Embodiment
Below in conjunction with embodiment technical scheme of the present invention is done further detailed explanation.Embodiment 1: and preparation (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5,7-dimethoxy chroman (compound 3 shown in the synthetic route structure iron)
In the saturated hydrogen chloride methanol solution of 50mL, add full acetylated NVP-XAA 723 2.0g, 2.5mmol, solid slowly dissolves, and it is faint yellow that solution shows.Stirring at room reaction 12h, solution colour is deepened gradually, finally becomes wine red, and the TLC detection reaction is complete.The reaction solution rotary evaporation is removed methyl alcohol and is obtained NVP-XAA 723 (EGCG).EGCG continues to add glycol dimethyl ether-acetone mixed solvent 100mL without being further purified, and makes it whole dissolvings, adds 7.5g salt of wormwood afterwards, the 10mL methyl-sulfate.Reflux 48h, evaporate to dryness.Saturated sodium carbonate solution is washed 3 times, ethyl acetate extraction.Combining extraction liquid, anhydrous magnesium sulfate drying spends the night.Filtering and concentrating, silica gel column chromatography (ETHYLE ACETATE: sherwood oil=1: 2) get white solid, petroleum ether-ethyl acetate recrystallization; White solid (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5; 7-dimethoxy chroman 0.6g, productive rate: 42.8%.mp?90-92℃。
1H?NMR(CDCl 3，600MHz)δ(ppm)：7.16(s，2H)，6.69(s，2H)，6.24(d，J＝1.2Hz，1H)，6.12(d，J＝1.2Hz，1H)，5.66-5.64(m，1H)，5.08(bs，1H)，3.85-3.78(m，24H)，3.05-3.01(m，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：165.2，159.9，158.9，155.6，153.2，153.0，142.6，138.0，133.5，128.4，125.2，107.3，104.0，100.2，93.3，92.0，77.9，77.8，68.7，61.0，60.9，60.8，60.5，56.4，56.3，56.1，56.1，55.5，26.0。
Embodiment 2: and preparation (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman (compound 4 shown in the synthetic route structure iron)
With embodiment 1 preparation (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5; (0.50g 0.86mmol) is dissolved in the mixed solvent of 10mL methyl alcohol and 10mL glycol dimethyl ether 7-dimethoxy chroman, adds 0.2g K again 2CO 3, stirring at room reaction, TLC detection reaction progress.Behind the 1h, raw material disappears.Evaporate to dryness gets white solid, adds 20mL ETHYLE ACETATE, filters insolubles, and rotary evaporation concentrates; Silica gel column chromatography separate (ETHYLE ACETATE: sherwood oil=1: 4), product (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-and 3-hydroxyl-5,7-dimethoxy chroman 0.28g, productive rate: 87%.
mp?157-159℃； 1H?NMR(CDCl 3，500MHz)δ(ppm)：6.70(s，2H)，6.31(d，J＝8.0Hz，1H)，6.13(d，J＝8.0Hz，1H)，6.59-6.57(m，1H)，5.03-5.01(m，1H)，4.11-4.09(m，1H)，3.87-3.78(m，15H)，2.99-2.97(m，2H). 13C?NMR(CDCl 3，125MHz)δ(ppm)：160.1，158.8，155.0，153.3，132.9，103.6，103.5，99.6，93.3，92.3，77.3，77.1，76.8，67.7，60.8，56.2，55.5，55.4，26.0。
Embodiment 3: and preparation (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman (compound 5 shown in the synthetic route structure iron)
Get the 4-methoxybenzoic acid (0.18g, 1.18mmol) with (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman (200mg, 0.53mmol); Add again to dimethylamino pyridine (0.26g, 2.15mmol) with 1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (0.29g, 2.15mmol); Under the nitrogen protection, be dissolved in the 20ml anhydrous methylene chloride, stirring at room 24h reacts completely.Saturated sodium bicarbonate solution is given a baby a bath on the third day after its birth inferior, collects organic phase, anhydrous magnesium sulfate drying 4h; Revolve dried bullion, post separates (petrol ether/ethyl acetate=3/1v/v), make pure product (2R; 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxybenzoyl oxygen base)-5; 7-dimethoxy chroman 0.18g, productive rate 68%.mp?67-69℃。
1H?NMR(CDCl 3，500MHz)δ(ppm)：7.56-7.55(m，1H)，7.54(s，1H)，7.26(d，J＝16Hz，1H)，7.04(d，J＝8Hz，1H)，6.71(s，1H)，6.25(s，1H)，6.12(s，1H)，5.65-5.63(m，1H)，5.07-5.05(m，1H)，3.80-3.72(m，18H)，3.06-3.02(m，2H). 13C?NMR(CDCl 3，125MHz)δ(ppm)：165.4，159.7，159.5，158.9，155.5，153.1，133.4，131.4，129.3，122.0，119.1，114.7，103.9，100.2，93.5，92.0，77.9，68.7，60.8，55.9，55.4，26.0。
Embodiment 4: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman (in the synthetic route structure iron shown in 6)
With the 3-methoxybenzoic acid is raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-methoxybenzoyl oxygen base)-5, the productive rate of 7-dimethoxy chroman is 67%; Mp 132-134 ℃.
1H?NMR(CDCl 3，500MHz)δ(ppm)：7.26(d，J＝16Hz，2H)，6.89(d，J＝16Hz，2H)，6.71(s，2H)，6.25(s，1H)，6.12(s，1H)，5.65-5.63(m，1H)，5.07-5.06(m，1H)，3.80-3.72(m，18H)，3.06-3.02(m，2H). 13C?NMR(CDCl 3，125MHz)δ(ppm)：165.3，164.2，159.7，159.5，158.9，155.5，153.1，133.3，130.1，129.3，122.0，93.5，92.0，77.9，68.7，60.7，56.0，55.4，26.1。
Embodiment 5: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy benzoyloxy)-5,7-dimethoxy chroman (compound 7 shown in the synthetic route structure iron)
With 3, the 4-dimethoxybenzoic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy benzoyloxy)-5, the productive rate of 7-dimethoxy chroman is 71%; Mp 46-48 ℃.
1H?NMR(CDCl 3，600MHz)δ(ppm)：7.58-7.56(m，1H)，7.42(s，1H)，7.11-7.09(m，1H)，6.70-6.68(m，2H)，6.24(s，1H)，6.11(s，1H)，5.65-5.63(m，1H)，5.06-5.04(m，1H)，3.88-3.71(m，21H)，3.03-3.00(m，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：165.4，159.7，159.0，155.6，148.7，137.9，133.5，123.8，122.6，112.3，110.2，104.0，100.3，93.4，92.0，78.1，68.3，60.9，60.5，58.5，56.1，56.1，55.5，26.2。
Embodiment 6: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-triethoxy benzoyloxy)-5,7-dimethoxy chroman (compound 8 shown in the synthetic route structure iron)
With 3,4,5-triethoxy phenylformic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-triethoxy benzoyloxy)-5, the productive rate 65% of 7-dimethoxy chroman; Mp 49-51 ℃.
1H?NMR(CDCl 3，600MHz)δ7.13(s，2H)，6.68(s，2H)，6.23(d，J＝1.1Hz，1H)，6.10(s，1H)，5.62(s，1H)，5.06(s，1H)，4.08-4.04(q，J＝7.1，6.6Hz，2H)，4.01-3.97(q，J＝6.6，7.1Hz，4H)，3.78-3.69(m，15H)，3.02(d，J＝2.76Hz，2H)，1.38-1.35(t，J＝7.14，6.6Hz，6H)，1.32-1.29(t，J＝7.14，7.14Hz，3H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：165.3，159.8，159.0，155.6，153.2，152.7，142.5，137.9，133.5，124.9，108.7，104.0，100.3，93.3，91.9，69.0，68.6，64.9，60.9，56.0，56.0，55.5，26.0。
Embodiment 7: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-three allyloxy benzoyloxys)-5,7-dimethoxy chroman (compound 9 shown in the synthetic route structure iron)
With 3,4,5-triolefin propoxy benzoic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron; (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3; 4,5-three allyloxy benzoyloxys)-5, the productive rate of 7-dimethoxy chroman (oily matter) is 73%.
1H?NMR(CDCl 3，600MHz)δ7.17(s，2H)，6.67(s，2H)，6.24(d，J＝2.76Hz，1H)，6.12(s，1H)，6.07-5.94(m，3H)，5.65(t，J＝2.22，1.08Hz，1H)，5.37(d，J＝1.08Hz，1H)，5.34(d，J＝1.62Hz，1H)，5.29-5.26(d，m，J＝15.76，1H)，5.25(d，J＝1.08Hz，1H)，5.23(d，J＝1.08Hz，1H)，5.16-5.14(d，J＝10.44Hz，1H)，5.06(s，1H)，4.57-4.56(d，J＝6.06Hz，2H)，4.52-4.51(dd，J＝1.38，5.22Hz，4H)，3.79-3.68(m，15H)，3.02(d，J＝2.76Hz，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：164.9，159.8，158.9，158.9，155.5，153.2，152.2，142.1，142.1，138.1，134.1，133.4，133.0，133.0，125.0，118.0，109.2，109.1，104.1，100.2，93.4，92.0，91.9，77.8，74.0，74.0，70.0，70.0，69.9，68.5，56.0，55.4，55.3，26.0。
Embodiment 8: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman (compound 10 shown in the synthetic route structure iron)
With the 3-fluorobenzoic acid is raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-fluorobenzoyl oxygen base)-5, the productive rate of 7-dimethoxy chroman is 70%; Mp 60-62 ℃.
1H?NMR(CDCl 3，600MHz)δ7.96-7.93(m，J＝5.52，8.82Hz，2H)，7.03-7.00(t，J＝8.82，8.22Hz，2H)，6.69(s，2H)，6.25(d，J＝2.16Hz，1H)，6.11(d，J＝1.62Hz，1H)，5.67(s，1H)，5.06(s，1H)，3.78-3.71(m，15H)，3.04(d，J＝2.76Hz，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：166.6，164.9，164.5，159.7，158.9，155.5，153.2，137.9，133.3，132.2，126.3，115.5，115.4，100.1，93.5，92.0，77.8，68.7，60.7，55.9，55.4，26.1。
Embodiment 9: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman (compound 11 shown in the synthetic route structure iron)
The 4-fluorobenzoic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-fluorobenzoyl oxygen base)-5, the productive rate of 7-dimethoxy chroman is 72%; Mp 55-57 ℃.
1H?NMR(CDCl 3，600MHz)δ7.74-7.73(d，J＝7.68Hz，1H)，7.63-7.61(dd，J＝1.62，9.36Hz，1H)，7.36-7.32(m，1H)，7.22-7.19(td，J＝2.22，8.22Hz，1H)，6.70(s，2H)，6.26(d，J＝2.22Hz，1H)，6.12(d，J＝2.16Hz，1H)，5.66-5.65(t，J＝2.22，3.30Hz，1H)，5.07(s，1H)，3.81-3.74(m，15H)，3.07(d，J＝3.30Hz，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：163.3，161.6，159.8，158.9，155.5，153.2，138.0，133.3，132.3，132.2，132.2，130.0，129.9，125.5，120.2，120.0，116.6，116.5，103.8，100.0，93.6，92.1，77.8，69.1，60.8，56.0，55.4，55.4，26.0。
Embodiment 10: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-dimethylin-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman (compound 12 shown in the synthetic route structure iron)
With 3-dimethylin-4-fluorobenzoic acid is raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-dimethylin-4-fluorobenzoyl oxygen base)-5, the productive rate of 7-dimethoxy chroman is 73%; Mp 56-58 ℃.
1H?NMR(CDCl 3，600MHz)δ7.47-7.45(m，2H)，6.96-6.92(m，1H)，6.69(s，1H)，6.24(d，J＝2.22Hz，1H)，6.11(d，J＝2.16Hz，1H)，5.65-5.64(t，J＝3.30，2.76Hz，1H)，5.06(s，1H)，3.79-3.71(m，15H)，3.03(d，J＝3.3Hz，2H)，2.80(s，6H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：165.1，159.8，159.0，158.8，155.6，153.2，140.9，140.8，137.9，133.5，126.4，122.9，122.8，119.9，116.1，115.9，103.9，100.2，93.4，92.0，78.0，68.6，60.9，56.0，55.5，42.6，42.6，26.1。
Embodiment 11: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-N-acetamido-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman (compound 13 shown in the synthetic route structure iron)
With 3-N-ethanoyl-4-fluorobenzoic acid is raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R; 3R)-2-(3; 4, the 5-trimethoxyphenyl)-3-(3-N-acetamido-4-fluorobenzoyl oxygen base)-5, the productive rate of 7-dimethoxy chroman is 78%; Mp 94-96 ℃.
1H?NMR(CDCl 3，600MHz)δ8.84-8.82(d，J＝6.6Hz，1H)，7.67(s，1H)，7.33(s，1H)，7.06-7.03(t，J＝8.82，9.9Hz，1H)，6.72(s，2H)，6.27(d，J＝2.16Hz，1H)，6.11(d，J＝2.22Hz，1H)，5.64(s，1H)，5.07(s，1H)，3.80-3.75(m，15H)，3.05(t，J＝3.3Hz，2H)，2.19(s，3H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：168.6，164.5，159.7，158.9，156.5，155.5，153.1，137.7，133.4，126.6，126.4，124.4，114.9，114.8，103.9，100.1，93.6，92.0，77.7，69.0，60.7，56.0，55.3，25.9，24.0。
Embodiment 12: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman (compound 14 shown in the synthetic route structure iron)
(3,4,5-trimethoxy-benzamide base)-the 4-fluorobenzoic acid is a raw material with 3-; Compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3; 4, the 5-trimethoxyphenyl)-(3-(3,4 for 3-; 5-trimethoxy-benzamide base)-4-fluorobenzoyl oxygen base))-5, the productive rate of 7-dimethoxy chroman is 76%; Mp 111-113 ℃.
1H?NMR(CDCl 3，600MHz)δ8.96-8.95(dd，J＝1.68，7.68Hz，1H)，7.94(d，J＝2.76Hz，1H)，7.71-7.69(m，1H)，7.47(d，J＝1.62Hz，1H)，7.39-7.37(dd，J＝1.68，8.22Hz，1H)，7.11-7.08(dd，J＝8.22，9.90Hz，1H)，6.91-6.90(d，J＝8.22Hz，1H)，6.74(s，2H)，6.27(d，J＝2.22Hz，1H)，6.11(d，J＝2.58Hz，1H)，5.66-5.65(t，J＝2.88，3.18Hz，1H)，5.08(s，1H)，3.95-3.73(m，24H)，3.06(d，J＝3.30Hz，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：165.2，164.5，159.7，158.9，155.6，153.5，153.2，141.8，137.7，133.4，129.6，127.0，126.8，126.7，124.2，115.1，115.0，104.6，103.8，100.0，93.6，92.1，77.3，77.1，76.9，69.1，60.9，56.5，56.1，26.1。
Embodiment 13: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman (compound 15 shown in the synthetic route structure iron)
(3,4-dimethoxy benzoylamino)-the 4-fluorobenzoic acid is a raw material with 3-, and compound 5 is identical in preparation method and the synthetic route structure iron; (2R; 3R)-(3,4, the 5-trimethoxyphenyl)-(3-(3 for 3-for 2-; 4-dimethoxy benzoylamino)-4-fluorobenzoyl oxygen base))-5, the productive rate of 7-dimethoxy chroman is 71%; Mp 77-79 ℃.
1H?NMR(CDCl 3，600MHz)δ8.91-8.90(d，J＝6.00Hz，1H)，7.96(s，1H)，7.75-7.73(m，1H)，7.14-7.11(t，J＝9.90，8.82Hz，1H)，7.09(s，2H)，6.76(s，2H)，6.29(s，1H)，6.13(s，1H)，5.68(s，1H)，5.10(s，1H)，3.91-3.75(m，24H)，3.05(S，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：164.9，164.6，159.7，158.9，155.6，154.9，153.2，152.5，149.4，137.7，133.4，127.0，126.7，126.5，124.0，119.7，115.0，114.8，110.8，110.5，103.8，100.2，93.6，92.1，77.9，69.1，60.9，56.2，56.1，26.1。
Embodiment 14: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxyl group cinnamoyloxy group)-5,7-dimethoxy chroman (compound 16 shown in the synthetic route structure iron)
With the 4-methoxy cinnamic acid is raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxyl group cinnamoyloxy group)-5, the productive rate of 7-dimethoxy chroman is 78%; Mp 79-81 ℃.
1H?NMR(CDCl 3，600MHz)δ7.55-7.52(d，J＝15.96Hz，1H)，7.39-7.37(d，J＝8.82Hz，2H)，6.86-6.84(d，J＝8.22Hz，2H)，6.73(s，2H)，6.25-6.22(d，J＝15.96Hz，1H)，6.24(s，1H)，6.12(s，1H)，5.61(s，1H)，5.03(s，1H)，3.82-3.78(m，18H)，2.99(m，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：166.5，161.6，159.7，159.0，155.5，153.2，145.1，137.9，133.4，129.8，127.0，115.3，114.4，104.0，100.4，93.5，92.1，77.9，67.6，60.9，56.2，55.5，55.4，26.2。
Embodiment 15: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman (compound 17 shown in the synthetic route structure iron)
With 3, the 4-dimethoxy-cinnamic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy cinnamoyloxy group)-5, the productive rate of 7-dimethoxy chroman is 65%; Mp 103-105 ℃.
1H?NMR(CDCl 3，600MHz)δ7.52(d，J＝15.6Hz，1H)，7.26(s，1H)，7.02(dd，J＝1.8Hz，8.4Hz，1H)，6.96(d，J＝1.8Hz，1H)，6.73(s，2H)，6.25-6.24(m，2H)，5.76(d，J＝12.6Hz，1H)，5.64-5.62(m，1H)，5.04-5.02(m，1H)，3.89-3.80(m，21H)，3.01-2.99(m，2H). 13C?NMR(CDCl 3，150MHz)δ166.3，159.6，158.9，155.3，153.1，151.2，149.1，145.2，137.8，133.2，127.1，122.7，115.4，110.9，109.3，103.8，100.3，93.3，92.0，77.8，67.4，60.8，56.1，55.9，55.8，55.4，55.3，26.1。
Embodiment 16: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman (compound 18 shown in the synthetic route structure iron)
With 3,4, the 5-trimethoxy cinnamic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron, (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy cinnamoyloxy group)-5, the productive rate of 7-dimethoxy chroman is 65%; Mp 98-100 ℃.
1H?NMR(CDCl 3，600MHz)δ7.50-7.46(d，J＝15.96Hz，1H)，6.72(s，2H)，6.66(s，2H)，6.29-6.26(dd，J＝1.08，15.96Hz，1H)，6.25(s，1H)，6.13(s，1H)，5.66(s，1H)，5.05(s，1H)，3.85-3.79(m，24H)，3.00(m，2H). 13C?NMR(CDCl 3，150MHz)δ(ppm)：166.2，159.8，159.1，155.4，153.5，153.3，145.4，140.3，137.8，133.3，129.8，117.1，105.3，104.0，100.4，93.5，92.1，77.8，67.6，61.0，60.9，56.2，55.5，55.5，26.2。
Embodiment 17: (2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl) acetoxyl group))-5,7-dimethoxy chroman (compound 19 shown in the synthetic route structure iron)
With 3, the 4-dimethoxyphenylacetic acid is a raw material, and compound 5 is identical in preparation method and the synthetic route structure iron; (2R, 3R)-2-(3,4; The 5-trimethoxyphenyl)-and 3-(2-(3, the 4-Dimethoxyphenyl) acetoxyl group))-5, the productive rate of 7-dimethoxy chroman is 72%.
1H?NMR(CDCl 3，500MHz)δ(ppm)：6.80-6.79(m，1H)，6.69-6.68(m，1H)，6.67-6.66(m，1H)，6.43(s，2H)，6.21(s，1H)，6.04(s，1H)，5.57-5.55(m，1H)，5.09-5.08(m，1H)，3.85-3.64(m，21H)，3.35(s，2H)，3.08-3.05(m，2H). 13C?NMR(CDCl 3，125MHz)δ(ppm)：171.3，159.4，156.7，152.9，150.1，149.2，134.9，127.5，122.7，113.6，112.4，102.5，100.7，78.2，69.9，61.3，59.3，56.9，56.8，42.2，26.0。
Embodiment 18,2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 20 shown in the synthetic route structure iron)
Get 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (200mg; 0.56mmol), 3,4,5-trimethoxybenzoic acid (178mg; 0.84mmol), 1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCHCl, 161mg, 0.84mmol), to dimethylamino pyridine (DMAP; 102mg 0.84mmol) is dissolved in the 20mL anhydrous methylene chloride stirred overnight at room temperature.Reaction solution is through 10% aqueous sodium carbonate and saturated common salt washing, again through anhydrous magnesium sulfate drying.Boil off solvent, silica gel column chromatography (ETHYLE ACETATE: sherwood oil=1: 2) get white solid 2-(3, the 4-Dimethoxyphenyl)-3-(3; 4; 5-trimethoxy benzoyloxy)-5 .mp108-110 ℃ of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone (264mg, yield 85.4%).
1H?NMR(CDCl 3，600MHz)δ：7.52(dd，J＝2.22，8.82Hz，1H)，7.45(s，1H)，7.41(d，J＝1.68Hz，1H)，6.91(d，J＝8.82Hz，1H)，6.54(d，J＝2.22Hz，1H)，6.35(d，J＝2.22Hz，1H)，3.92，3.90，3.89，3.88，3.79(5s，21H，7×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：170.6，164.4，163.9，161.3，159.2，153.3，153.0，151.3，148.8，142.9，134.0，123.9，122.4，121.7，110.9，110.7，108.8，107.8，96.1，92.7，61.0，56.3，56.0，55.9。
Embodiment 19,2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzyloxy)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 21 shown in the synthetic route structure iron)
Get 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (200mg; 0.54mmol), 3,4,5-trimethoxy phenylcarbinol methanesulfonates (232mg; 0; 81mmol), (149mg 1.1mmol) places the 10mL N to salt of wormwood, stirring at room 12 hours.Reaction is finished, and in the reaction solution impouring frozen water, filters.Gained solid silicone column chromatography (ETHYLE ACETATE: sherwood oil=1: 2) get white solid 2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzyloxy)-5 .mp 90-92 ℃ of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone (252mg, yield 86.7%).
1H?NMR(CDCl 3，600MHz)δ：7.64(d，J＝2.22Hz，1H)，7.58(dd，J＝2.16，8.76Hz，1H)，6.89(d，J＝8.82Hz，1H)，6.57(s，2H)，6.46(d，J＝2.22Hz，1H)，6.31(d，J＝2.16Hz，1H)，4.99(s，2H)，3.94，3.90，3.86，3.77，3.75，3.71(6s，21H，7×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：174.1，163.9，158.9，153.3，153.0，150.7，148.4，139.5，137.7，132.7，123.5，121.8，111.9，110.5，109.4，106.1，106.0，95.8，92.5，74.2，60.8，56.5，56.0，55.8。
Embodiment 20,2-(3, the 4-Dimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl)-2-oxo oxyethyl group))-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 22 shown in the synthetic route structure iron)
Get 2-(3; The 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (200mg, 0.56mmol), 2-bromo-1-(3; The 4-Dimethoxyphenyl) ethyl ketone (217mg; 0.84mmol), (154.6mg 1.12mmol) places 10mL N, stirred overnight at room temperature to salt of wormwood.Reaction is finished, and in the reaction solution impouring frozen water, filters.Gained solid silicone column chromatography (ETHYLE ACETATE: sherwood oil=1: 2) get white solid 2-(3; The 4-Dimethoxyphenyl)-(2-(3 for 3-; The 4-Dimethoxyphenyl)-2-oxo oxyethyl group))-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (231mg, 76.8%yield) .mp 222-224 ℃.
1H?NMR(CDCl 3，600MHz)δ：7.88(s，1H)，7.74(dd，J＝8.22，20.34Hz，2H)，7.54(s，1H)，6.92(d，J＝8.22Hz，1H)，6.84(d，J＝8.82Hz，1H)，6.50(s，1H)，6.33(s，1H)，5.44(s，2H)，3.94，3.91，3.89(3s，18H，6×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：193.1，173.9，164.0，160.9，158.8，153.6，152.7，151.0，149.1，148.6，139.5，127.9，123.3，123.0，121.7，111.8，110.6，110.2，110.1，109.2，95.9，92.5，73.9，56.5，56.2，56.1，55.9，55.9。
Embodiment 21,2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 23 shown in the synthetic route structure iron)
Get 2-(3; The 4-Dimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (1.00g, 2.80mmol), ethylene bromohyrin (600mg; 4.20mmol), Anhydrous potassium carbonate (773mg; 5.60mmol) (100mg 0.60mmol) places the 20mL N to the and potassiumiodide, 60 ℃ of stirred overnight.Add 100mL water in the reaction solution, use ethyl acetate extraction.Organic phase is used anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent; Silica gel column chromatography (ETHYLE ACETATE: sherwood oil=1: 2) get white solid, get white solid 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5; .mp 120-122 ℃ of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone (974mg, productive rate 86.5%).
1H?NMR(CDCl 3，600MHz)δ：7.71-7.69(m，2H)，6.98(d，J＝8.8Hz，1H，H)，6.52(d，J＝2.2Hz，1H)，6.37(d，J＝2.2Hz，1H)，4.65(br?s，1H，-OH)，3.98(t，J＝3.8Hz，2H)，3.97，3.96，3.95，3.91(4s，12H，4×OCH 3)，3.79(t，J＝3.8Hz，2H)； 13C?NMR(CDCl 3，150MHz)δ：174.9，164.3，161.0，158.9，153.7，151.1，148.9，139.8，129.9，121.8，111.1，110.9，109.0，96.1，92.5，75.0，61.7，56.5，55.9
Embodiment 22,2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy cinnamoyloxy group) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 24 shown in the synthetic route structure iron)
Get 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, and 7-dimethoxy-4 '-hydrogen-chromene-4-ketone (200mg, 0.48mmol); 3,4,5-trimethoxy cinnamic acid (229mg; 0.96mmol), 1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCHCl, 184mg, 0.96mmol), to dimethylamino pyridine (DMAP; 117mg 0.96mmol) is dissolved in the 20mL anhydrous methylene chloride stirred overnight at room temperature.Reaction solution is through 10% aqueous sodium carbonate and saturated common salt washing, again through anhydrous magnesium sulfate drying.Boil off solvent, (ETHYLE ACETATE: (3, the 4-Dimethoxyphenyl)-(2-(3 for 3-sherwood oil=1: 2) to get white solid 2-for silica gel column chromatography; 4; 5-trimethoxy cinnamoyloxy group) oxyethyl group)-5 .mp 152-154 ℃ of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone (261mg, yield 87.5%).
1H?NMR(CDCl 3，600MHz)δ：7.72(d，J＝2.22Hz，1H)，7.66(dd，J＝2.22，8.82Hz，1H)，7.44(d，J＝16.96，1H)，6.83(d，J＝8.76Hz，1H)，6.71(s，2H)，6.49(d，J＝2.16Hz，1H)，6.33(d，J＝2.22Hz，1H)，6.16(d，J＝15.96，1H)，4.42(s，4H)，3.95，3.92，3.90，3.88，3.87，3.71(6s，21H，7×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：173.9，166.7，164.0，161.0，158.9，153.4，153.1，150.9，148.4，144.8，140.1，139.5，129.9，123.2，121.9，116.9，112.0，110.6，109.3，105.3，95.9，92.5，70.10，63.68，61.0，56.4，56.2，56.1。
Embodiment 23,2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy benzoyloxy) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 25 shown in the synthetic route structure iron)
With 3,4, the 5-trimethoxybenzoic acid is a raw material; Compound 24 is identical in preparation method and the synthetic route structure iron, and (3, the 4-Dimethoxyphenyl)-(2-(3 for 3-for 2-; 4,5-trimethoxy benzoyloxy) oxyethyl group)-5, the productive rate of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone is 85.0%; Mp 80-82 ℃.
1H?NMR(CDCl 3，600MHz)δ：7.63(d，J＝8.28Hz，1H)，7.53(s，1H)，7.17(s，2H)，6.61(d，J＝8.82Hz，1H)，6.43(s，1H)，6.28(s，1H)，4.51(s，2H)，4.43(s，2H)，3.89，3.85，3.84，3.82，3.81，3.74(6s，21H，7×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：173.8，165.9，164.0，160.9，158.7，152.8，152.8，150.8，148.4，142.1，139.7，125.0，123.0，122.0，111.1，110.5，109.3，106.9，95.8，92.4，69.9，64.3，60.9，56.4，56.2，55.9，55.8，55.7。
Embodiment 24,2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxy benzoyloxy) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 26 shown in the synthetic route structure iron)
With 3, the 4-dimethoxybenzoic acid is a raw material, and compound 24 is identical in preparation method and the synthetic route structure iron; 2-(3; The 4-Dimethoxyphenyl)-and 3-(2-(3,4-dimethoxy benzoyloxy) oxyethyl group)-5, the productive rate of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone is 84.2%; Mp 181-183 ℃.
1H?NMR(CDCl 3，600MHz)δ：7.67(dd，J＝1.62，8.22Hz，1H)，7.58(d，2.16Hz，1H)，7.45-7.43(m，2H)，6.78(d，J＝8.82Hz，1H)，6.66(d，J＝8.76Hz，1H)，6.47(d，J＝2.22Hz，1H)，6.33(d，J＝2.22Hz，1H)，4.52-4.47(AB，J＝14.88，5.52Hz，4H)，3.95，3.92，3.89，3.87，3.85，3.78(6s，18H，6×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：173.9，166.1，164.0，161.0，158.8，152.9，150.7，148.5，139.7，123.7，123.2，122.5，122.1，112.0，111.3，110.5，110.1，95.8，92.5，70.0，64.0，56.4，56.1，56.0，55.8，55.7。
Embodiment 25,2-(3, the 4-Dimethoxyphenyl)-3-(2-(4-methoxybenzoyl oxygen base) oxyethyl group)-5,7-dimethoxy-4 '-hydrogen-chromene-4-ketone (compound 27 shown in the synthetic route structure iron)
With the 4-methoxybenzoic acid is raw material, and compound 24 is identical in preparation method and the synthetic route structure iron, 2-(3, the 4-Dimethoxyphenyl)-3-(2-(4-methoxybenzoyl oxygen base) oxyethyl group)-5, and the productive rate of 7-dimethoxy-4 '-hydrogen-chromene-4-ketone is 83.4%; Mp 107-109 ℃.
1H?NMR(CDCl 3，600MHz)δ：7.76(d，J＝8.76，2H)，7.68(dd，J＝1.62，8.22Hz，1H)，7.58(d，J＝1.62Hz，1H)，6.81(d，J＝8.82Hz，2H)，6.67(d，J＝8.82Hz，1H)，6.47(d，J＝2.22Hz，1H)，6.33(d，J＝2.16Hz，1H)，4.48(s，4H)，3.95，3.88，3.85，3.83，3.78(5s，15H，5×OCH 3)； 13C?NMR(CDCl 3，150MHz)δ：174.0，166.1，164.0，163.3，161.0，158.8，150.7，148.5，139.6，131.6，123.2，122.3，122.2，113.4，111.3，110.5，109.4，95.8，92.5，70.1，63.8，56.4，56.0，55.8，55.7，55.4。
The antitumor mdr cell experiment of embodiment 26, chroman and chromene derivative
The method of present embodiment TP and bibliographical information identical (Zhang Pu YongJ Med Chem.2010,53:5108-5120).1 μ M general formula I of the present invention and the described chroman of general formula I I and chromene derivative act on P-gp high expression level mammary cancer drug-resistant cell strain MDA435LCC6 with the taxol (Paclitaxel) of 1nM, 5nM, 10nM, 50nM, 100nM or 183.2nM respectively; Record respectively MDA435LCC6 mammary cancer drug-resistant cell strain inhibiting rate, calculate the half-inhibition concentration (IC of taxol 50), and calculate chroman and chromene derivative reverse multiple (RF); Simultaneously 1 μ M general formula I of the present invention and the described chroman of general formula I I and chromene derivative act on BCRP high expression level human embryonic kidney cell drug-resistant cell strain HEK293/R2 with the TPT (topotecan) of 1nM, 5nM, 10nM, 50nM, 100nM or 486.9nM respectively; Record respectively HEK293/R2 cell strain inhibiting rate, calculate the half-inhibition concentration (IC of TPT 50), and calculate chroman and chromene derivative reverse multiple (RF); Simultaneously 1 μ M general formula I of the present invention and the described chroman of general formula I I and chromene derivative act on the BCRP high expression level to the drug-fast mammary cancer drug-resistant cell strain of mitoxantrone MCF7-MX100 with the TPT (topotecan) of 1nM, 5nM, 10nM, 50nM, 100nM or 320nM respectively; Record 100 cell strain inhibiting rates respectively, calculate the half-inhibition concentration (IC of TPT MCF7-MX 50), and calculate chroman and chromene derivative reverse multiple (RF).
Antitumor mdr cell experimental result such as table 1.
Antitumor drug half-inhibition concentration during the compound of antitumor drug half-inhibition concentration when reversing the compound of multiple (RF) formula=nothing associating use/have associating use.
Table 1,1 μ M chroman and chromene derivative artitumor multi-medicine-resistant are active
Figure BDA0000138497300000261
Figure BDA0000138497300000271
Table 1 result show in chroman of the present invention and the chromene derivative compound 3,7,9,12,13,14,15,16,17,18,21,24,26 and 27 and the Paclitaxel acting in conjunction when P-gp high expression level MDA435LCC6 mammary cancer drug-resistant cell strain; The reversing drug resistance multiple is equal to or greater than verapamil, is strong multidrug-resistance reversal agent of imitating.And the reversing drug resistance multiple of compound 4,5,6,8,10,11,19,20,22 and 25 is the multidrug-resistance reversal agent of poor efficiency all less than verapamil; In chroman of the present invention and the chromene derivative compound 21,24 and 27 and the topotecan acting in conjunction when B CRP crosses expression HEK293/R2 drug-resistant cell strain; The reversing drug resistance multiple is all greater than 10 times; Be strong multidrug-resistance reversal agent of imitating, and other compound is active for the stronger anti-multidrug resistance of performance; In chroman of the present invention and the chromene derivative compound 20,24 and 27 and the topotecan acting in conjunction when BCRP crosses expression HEK293/R2 drug-resistant cell strain; The reversing drug resistance multiple is all greater than 7 times; Be strong multidrug-resistance reversal agent of imitating, and other compound is active for the stronger anti-multidrug resistance of performance.
Embodiment 27, chroman and chromene derivative toxotest
Detect new synthetic compound inhibiting rate to tumour cell MDA435LCC6, drug-resistant tumor cell MDA435LCC6MDR and l cell L929 etc. when 1 μ M, 5 μ M, 10 μ M, 50 μ M and the 100 μ M, calculation of half inhibitory concentration respectively with MTS proliferation assay method.Toxotest result such as table 2.
Table 2, chroman and chromene derivative are to LCC6 breast cancer cell, LCC6MDR breast cancer cell mdr cell and L929 l cell half-inhibition concentration (IC 50, μ M)
Figure BDA0000138497300000281
Figure BDA0000138497300000291
Table 2 result show chroman of the present invention and chromene derivative except that compound 22 to the half-inhibition concentration of tumour cell MDA435LCC6, drug-resistant tumor cell MDA435LCC6MDR and l cell L929 all greater than 75 μ M, prove that chroman of the present invention and chromene derivative are the multidrug-resistance reversal agent of safety.
Chroman of the present invention and chromene derivative can be used as oral medication or non-enterally administer.As oral medication can be tablet, capsule or seed dressing agent, and the parenteral drug formulation has injection and suppository etc.These preparations all can be according to the method preparation that those skilled in the art knew.For making tablet, capsule, the used auxiliary material of seed dressing agent is the auxiliary agent of conventional usefulness, for example starch, gelatin, gum arabic, silica or polyoxyethylene glycol; The used solvent of liquid dosage form is water, ethanol, Ucar 35, plant oil such as Semen Maydis oil, peanut oil or olive wet goods for example.Containing in the preparation of The compounds of this invention also can have other auxiliary agents, for example tensio-active agent, lubricant, disintegrating agent, sanitas, correctives or pigment etc.
Above embodiment is only in order to explaining technical scheme of the present invention, but not limits it; Although the present invention has been carried out detailed explanation with reference to previous embodiment, for the person of ordinary skill of the art, still can make amendment to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of relevant art scheme break away from the spirit and the scope of the present invention's technical scheme required for protection.

Claims (7)

1. artitumor multi-medicine-resistant suppressor factor chroman and chromene derivative is characterized in that said chroman derivative represented that by general formula I said chromene derivative is represented by general formula I I:
Figure 619285DEST_PATH_IMAGE001
R is hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, halogen, contains in fluoroalkyl or the benzoyl-one or more among general formula I and the general formula I I; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl or the halogenic substituent one or more, wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl; X is hydrogen or oxygen in the formula; Y is oxygen or nitrogen in the formula; Carbon in the general formula I-2 chirality is R type or S type, and carbon in the general formula I-3 chirality is R type or S type;
L is the linking group that contains the straight or branched of 1-10 carbon atom among general formula I and the general formula I I, and said linking group also contains aerobic, nitrogen, halogen or sulphur atom; Or L is hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contains in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl, fluorine, the chlorine or bromine one or more in the general formula I;
Q is hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contains in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl or the halogen one or more among general formula I and the general formula I I; Or Q is represented by following general formula I II, IV or V:
Figure 399022DEST_PATH_IMAGE002
R among general formula III, IV and the V 1For hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, halogen or the benzoyl-one or more; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, the halogenic substituent one or more; Wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl, n is 1-5; Or said R 1Group is hydrogeneous, hydroxyl, alkoxyl group, alkylamino, contain in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole, chroman or the chromene in fluoroalkyl, alkylamidoalkyl or the halogen one or more; Or said R 1Group is represented by formula VI or VII:
Figure 856549DEST_PATH_IMAGE003
R in the formula 2For hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, contain in fluoroalkyl, halogen or the benzoyl-one or more; Said benzoyl-contains hydroxyl, alkoxyl group, alkylamino, contain in fluoroalkyl, alkylamidoalkyl or the fluoro substituents one or more; Wherein alkoxyl group, alkylamino, contain that alkyl is the alkyl with straight or branched of 1-10 carbon atom in fluoroalkyl and the alkylamidoalkyl, m is 1-5.
2. a kind of chroman according to claim 1 and chromene derivative, it is characterized in that said compound of Formula I for ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-5,7-dimethoxy chroman-3-alcohol;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxybenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy benzoyloxy)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-triethoxy benzoyloxy)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-three allyloxy benzoyloxys)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-dimethylin-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-acetamido-4-fluorobenzoyl oxygen base)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoyl oxygen base))-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(4-methoxyl group cinnamoyloxy group)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4-dimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman;
( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(3,4,5-trimethoxy cinnamoyloxy group)-5,7-dimethoxy chroman;
Or ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl) acetoxyl group))-5,7-dimethoxy chroman;
Said general formula I I compound is 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone (7);
2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzoyloxy)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone;
2-(3, the 4-Dimethoxyphenyl)-3-(3,4,5-trimethoxy benzyloxy)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone;
2-(3, the 4-Dimethoxyphenyl)-3-(2-(3, the 4-Dimethoxyphenyl)-2-oxo oxyethyl group))-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone
2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy cinnamoyloxy group) oxyethyl group)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone
2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4,5-trimethoxy benzoyloxy) oxyethyl group)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone
2-(3, the 4-Dimethoxyphenyl)-3-(2-(3,4-dimethoxy benzoyloxy) oxyethyl group)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone;
Or 2-(3, the 4-Dimethoxyphenyl)-3-(2-(4-methoxybenzoyl oxygen base) oxyethyl group)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone
3. the preparation method of chroman according to claim 1 and 2 and chromene derivative; It is characterized in that said compound of Formula I prepares as follows: with methylene dichloride, chloroform or N is solvent; At the triethylamine of 1-10 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N; Under the existence of N-dimethyl aminopyridine, make respectively ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the 7-dimethoxy-4 '- HydrogenThe Benzoyl chloride 99min., phenyllacetyl chloride or the cinnamyl chloride that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of-chromene-4-ketone and 1-10 mol ratio is 0 ℃-25 ℃ reactions 0.5-24 hour down; Prepare described chroman derivative, the mol ratio of said use reagent with respect to use respectively ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone.
4. the preparation method of chroman according to claim 1 and 2 and chromene derivative; It is characterized in that said general formula I or general formula I I compound prepare as follows: with methylene dichloride, chloroform or N is solvent; At the triethylamine of 1-10 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N; Under the existence of N-dimethyl aminopyridine; The 1-10 mol ratio is to dimethyl aminopyridine (DMAP), 1-ethyl-(3-dimethyl amido propyl group) carbodiimide hydrochloride (EDCI) or N, under the N'-carbonyl dimidazoles catalysts such as (CDI), make respectively ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the 7-dimethoxy-4 '- HydrogenThe phenylformic acid, toluylic acid or the styracin that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of-chromene-4-ketone and 1-10 mol ratio is 0 ℃-25 ℃ reactions 0.5-24 hour down; Prepare described chroman and chromene derivative, the mol ratio of said use reagent with respect to use respectively ( 2R, 3R)-2-(3,4, the 5-trimethoxyphenyl)-3-hydroxyl-5,7-dimethoxy chroman, 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone or 2-(3, the 4-Dimethoxyphenyl)-3-(2-hydroxyl-oxethyl)-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone.
5. the preparation method of chroman according to claim 1 and 2 and chromene derivative; It is characterized in that said general formula I I compound prepares as follows: with methylene dichloride, chloroform or N is solvent; At the salt of wormwood of 1-10 mol ratio, yellow soda ash, Pottasium Hydroxide, sodium hydroxide sodium hydride, triethylamine, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N; Under the existence of N-dimethyl aminopyridine; Make 2-(3, the 4-Dimethoxyphenyl)-3-hydroxyl-5, the 7-dimethoxy-4 '- HydrogenThe benzyl bromine, benzyl methanesulfonates, benzyl p-toluenesulfonic esters, 2-bromoacetophenone or the 2-chloroacetophenone that contain methoxyl group, oxyethyl group, allyloxy, fluorine, kharophen, dimethylin or contain the methoxy benzamide base of-chromene-4-ketone and 1-10 mol ratio is 0 ℃-100 ℃ reactions 0.5-24 hour down; Prepare described chromene derivative; The mol ratio of said use reagent is with respect to 2-(3; The 4-Dimethoxyphenyl)-and 3-hydroxyl-5, the 7-dimethoxy-4 '- Hydrogen-chromene-4-ketone.
6. claim 1 or 2 described chromans and chromene derivative are used for treating the application of the medicine of mammary cancer, colorectal carcinoma, prostate cancer, white blood disease, myelomatosis and carcinoma of the pancreas in preparation.
7. the application of chroman according to claim 6 and chromene derivative is characterized in that said chroman and chromene derivative are as oral medication or parenteral medication; Said oral medication is tablet, capsule or seed dressing agent, and said parenteral drug formulation is injection or suppository.
CN201210045877.3A 2011-03-04 2012-02-27 Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives Expired - Fee Related CN102603692B (en)

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