BACKGROUND

The disclosure relates to a polysubstituted benzene, preparation method thereof, and method of using the same.

The benzene ring is one of the most important structural units in organic chemistry, of which six hydrogen atoms can be replaced by different elements or groups, thus producing benzene derivatives which can be used in the fields of medicine, pesticide, plastics and organic electronic devices, etc.

The polysubstituted benzene is synthesized by substitution reactions, including electrophilic substitution (such as Friedel-Crafts alkylation and Friedel-Crafts acylation), nucleophilic substitution and coupling reactions. These reactions involve harsh reaction conditions, expensive reagents, toxic metal catalysts, and low regioselectivity.

SUMMARY

The disclosure provides a polysubstituted benzene compound, having a formula I or I′:



In formula I, R4, R7, X, the carbon atoms connected thereto, and the benzene ring form a fused benzo compound.

In formula I′, R4, R7, X, the carbon atoms connected thereto, and the benzene ring form a benzyl compound, benzyl ether compound or benzyl sulfide compound.

The formula I comprises a dotted line referring to R4connected to X through a group comprising carbon, or no bond and atom connected between R4and X.

The formula I′ comprises a first dotted line referring to a single bond or a double bond between C1and X, and a second dotted line referring to R4connected to X through a group comprising carbon, or no bond and atom connected between R4and X.

Specifically, the fused benzo compound has one of the following two formulas:



The dotted line in the two formulas means R4is connected to C2through a group comprising carbon, or no bond and atom connected between R4and C2.

The benzyl compound has the following formula:



The dotted line between C1and C2refers to a single bond or a double bond between C1and C2; the dotted line between R4and C2means R4is connected to C2through a group comprising carbon, or no bond and atom connected between R4and C2.

The benzyl ether compound has the following formula:



The benzyl sulfide compound has the following formula:



In the formulas, X represents carbon, sulfur, or oxygen;

R1represents a C1-16alkyl, C2-16alkenyl, or C2-10alkynyl;

R2represents hydrogen, halogen, C1-16alkyl, C2-16alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, C1-26alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, amino, nitro, cyano group, aldehyde group and ester group; or a heteroaryl group or a substituted heteroaryl group by 1-5 groups selected from halogen, C1-26alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, amino, nitro, cyano group, aldehyde group and ester group;

the heteroaryl group is a 3-10-membered heteroaryl group comprising N, S, O, or a combination thereof;

R3represents C1-6aldehyde group, C2-6acyl group, —COOH, hydroxyl-substituted C1-6alkyl, —CH2O—C1-6alkyl or —CO2—C1-6alkyl;

R4and R7, at each occurrence, represent hydrogen, a C1-20alkyl, C2-36alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, C1-3halogenated alkyl, O—C1-3alkyl, C1-25alkyl, hydroxyl, amino, nitro, cyano group, aldehyde group and ester group;

R5and R6, at each occurrence, represent hydrogen, C1-6alkyl or C1-6silicon.

Particularly, X represents carbon, sulfur, or oxygen;

R1represents a C1-4alkyl, C2-4alkenyl, or C3-7alkynyl;

R2represents hydrogen, halogen, C1-4alkyl, C2-4alkenyl, or C3-7alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, C1-26alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group; or a heteroaryl group or a substituted heteroaryl group by 1-5 groups selected from halogen, C1-6alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group;

R3represents C1-6aldehyde group, C2-6acyl group, —COOH, hydroxyl-substituted C1-4alkyl, —CH2O—C1-4alkyl or —CO2—C1-6alkyl;

R4and R7, at each occurrence, represent hydrogen, C1-20alkyl, C2-36alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, C1-3halogenated alkyl, O—C1-3alkyl, C1-25alkyl, hydroxyl, amino, nitro, cyano group, aldehyde group and ester group; and

R5and R6, at each occurrence, represent hydrogen or C1-4alkyl.

Particularly, X represents carbon, sulfur, or oxygen;

R1represents a C1-3alkyl, allyl, or C3-4alkynyl;

R2represents hydrogen, halogen, C1-4alkyl, allyl, or C3-7alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methyl, methoxyl, C2-26alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group; or a heteroaryl group or a substituted heteroaryl group by 1-5 groups selected from halogen, C1-6alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group;

the heteroaryl group is a 5-6-membered heteroaryl group comprising N, S, O, or a combination thereof;

R3represents a C1-3aldehyde group, C2-4acyl group, —COOH, hydroxyl-substituted C1-4alkyl, —CH2O—C1-4alkyl or —CO2—C1-4alkyl;

R4and R7, at each occurrence, represent hydrogen, a C1-17alkyl, C2-36alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methoxyl, C1-25alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group; and

R5and R6, at each occurrence, represent hydrogen or methyl.

Particularly, X represents carbon, sulfur, or oxygen;

R1represents a C1-3alkyl, allyl, or C3-4alkynyl;

R2represents hydrogen, halogen, C1-4alkyl, allyl, or C3-7alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methyl, methoxyl, C2-26alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group;

R3represents C1-3aldehyde group, acetyl group, —COOH, hydroxyl-substituted C1-4alkyl, —CH2O—C1-4alkyl or —CO2—C1-4alkyl;

R4and R7, at each occurrence, represent hydrogen, C1-17alkyl, C2-36alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methoxyl, C1-25alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group; and

R5and R6, at each occurrence, represent hydrogen or methyl.

Particularly, X represents carbon, sulfur, or oxygen;

R1represents a C1-3alkyl, allyl, or C3-4alkynyl;

R2represents hydrogen, halogen, C1-4alkyl, allyl, or C3-7alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methyl, methoxyl, C2-26alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group; or a heteroaryl group or a substituted heteroaryl group by 1-5 groups selected from halogen, C1-6alkyl, C1-3halogenated alkyl, O—C1-3alkyl, hydroxyl, nitro, cyano group, aldehyde group and ester group;

the heteroaryl group is a 5-6-membered heteroaryl group comprising N, S, O, or a combination thereof;

R3represents formyl, acetyl, —COOH, hydroxyl-substituted C1-2alkyl, —CH2O—C1-2 alkyl or —CO2—C1-4alkyl;

R4and R7, at each occurrence, represent hydrogen, C1-17alkyl, C2-36alkenyl, or C2-10alkynyl; or an aryl group or a substituted aryl group by 1-5 groups selected from halogen, methoxyl, C1-25alkyl, hydroxyl, nitro, cyano group, aldehyde group and an ester group; and

R5and R6, at each occurrence, represent hydrogen or methyl.

Particularly, the polysubstituted benzene is one of the following compounds:



Hereinafter are the definitions of related groups of the abovementioned formulas:

Alkyl: a linear, branched or cyclic alkyl having 1-26 carbon atoms, comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, sec-butyl, amyl, new amyl, hexyl, heptyl, octyl, cyclopropyl or cyclohexyl, particularly a linear or branched alkyl having 1-4 carbon atoms, particularly, methyl, ethyl, or isopropyl.

Halogen: fluorine, chlorine, bromine or iodine.

Halogenated alkyl refers to an alkyl substituted by one or more halogens, for example, monohalogenated alkyl, polyhalogenated alkyl, and fully halogenated alkyl; the monohalogenated alkyl refers to an alkyl having only one halogen atom; the polyhalogenated alkyl refers to an alkyl having two or more halogen atoms, including and not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

C2-16alkenyl: linear or branched alkyl group having 2-16 carbon atoms and comprising at least one carbon-carbon double bond, including and but not limited to vinyl, allyl, butenyl, and hexenyl group.

C2-10alkynyl: linear or branched alkyl group having 2-10 carbon atoms and comprising at least one carbon-carbon triple bond, including and but not limited to ethynyl, propargyl, butynyl and pentynyl.

C1-6aldehyde group: linear or branched alkyl group having 1-6 carbon atoms and comprising at least one formyl group, including but not limited to formaldehyde group, acetaldehyde group and hexaldehyde group.

Aryl group: single or bicyclic aromatic hydrocarbons with 6-14 carbon atoms in the ring part, or aromatic ring comprising non-aromatic hydrocarbon, including but not limited to phenyl, indanyl, naphthyl and 1,2,3,4-tetrahydronaphthalyl.

Heteroaryl group: 3-10-membered heteroaryl group comprising N, S, O, or a combination thereof, including saturated, partially saturated, or unsaturated aromatic groups, monocyclic ring, fused-ring, and bridged-ring, and including but not limited to furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiapyran, tetrahydropyran, 1,4-dioxane, 1,4-oxothiocyclohexane, indazole, quinoline, indole, 8-aza-bicyclo (3.2.1) octane, 2,3-dihydrobenzofuran and 2,3-dihydrobenzothiazole.

Alkoxy: linear or branched chains having 1-6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy or hexyloxy, particularly linear or branched alkoxy having 1-4 carbon atoms, and more particularly, methoxy.

The bioactive polysubstituted benzene comprises one or more amino and carboxyl groups, or the like, so an acid and/or alkali salt thereof is formed, for example, a pharmaceutical salt having the biological effectiveness and properties of the bioactive polysubstituted benzene compound.

Also provided is a method for preparing the bioactive polysubstituted benzene compound. The preparation process is as follows:



where: Y is halogen, particularly bromine; R8represents hydrogen or C1-6alkyl;

when X represents carbon, the compound II is an alkyl alkene, aryl alkene, arene, substituted arene, heteroarene or substituted heteroarene, comprising styrene, alkyl substituted styrene, halogen substituted styrene, diphenylethylene, naphthalene ethylene, 1-phenyl-1,3-butadiene, benzene, naphthalene, toluene, ethylbenzene, anisole, phenetole, 2,4,6-trimethoxybenzene, 1,2,4-trimethoxybenzene, 1,5-dimethoxynaphthalene, furan, pyran, thiophene, estrone derived alkene, and cholesterol derived alkene;

when X represents sulfur, the compound II is a mercaptan compound selected from methylmercaptan, ethanethiol, isoamyl mercaptan or benzyl mercaptan;

when X represents oxygen, the compound II is an alcoholic compound selected from methanol, ethanol, isopropanol, butanol, allyl alcohol, propargyl alcohol, isoamyl alcohol, benzyl alcohol, substituted benzyl alcohol, 2-bromo-2-propene-1-ol, 1-vinyl-phenylethanol, geraniol or dehydroepiandrosterone.

Specifically, the compound VII reacts with the compound VI to yield the compound V; the compound V further reacts with the compound IV to yield the compound III; thereafter, the carbon rearrangement of the compound V or compound III is captured by the compound II, thereby yielding the compound I or I′.

Specifically, the method comprises:

1) adding 1 equivalent of compound VII, 1-5 equivalents of a base, and 1-3 equivalents of a compound VI to an organic solvent, thereby yielding a first mixture; heating and stirring the first mixture; filtering the first mixture and evaporating the organic solvent to yield a first product, separating and purifying the first product, thereby yielding a first intermediate product V;

2) adding 1 equivalent of the first intermediate product V, 1-3 equivalents of a compound IV, 5% equivalent of copper iodide, 30% equivalent of bis(triphenylphosphine)palladium chloride, and 0.5 equivalent of sodium iodide to the organic solvent, thereby yielding a second mixture; stirring the second mixture, thereby yielding a second intermediate product III; and

3) dissolving the first intermediate product V or the second intermediate product III, and a compound II in the organic solvent, thereby yielding a third mixture; heating the third mixture; evaporating the organic solvent to yield a third product, separating and purifying the third product, thereby yielding a compound I or I′.

Particularly, in 1) and 2), the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, dipotassium phosphate, cesium carbonate, lithium carbonate, pyridine, triethylamine, tributylamine, or a mixture thereof.

Particularly, in 1) and 2), the base is lithium hydroxide or potassium tert-butoxide.

Particularly, in 1), the reaction temperature of the compound VII and the compound VI is 30-80° C. for 5-24 hours.

Particularly, in 2), the first intermediate product V reacts with the compound IV at room temperature for 5-24 hours.

Particularly, in 3), the carbon arrangement of the first intermediate product V and the second intermediate product III occurs at 80-180° C. for 5-24 hours.

Particularly, in 1)-3), the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, cyclohexane, toluene, xylene, ethylbenzene, chlorobenzene, bromobenzene, dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, acetonitrile, acetone, N, N-dimethylacetamide, N, N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof.

Particularly, in 1)-3), the organic solvent is chlorobenzene or acetonitrile.

The operations of separation and purification comprise silica gel column chromatography, recrystallization, thin layer chromatography, preparative chromatography or distillation.

The disclosure also provides a use of the polysubstituted benzene for preparation of an antitumor pharmaceutical composition, and a use of the polysubstituted benzene for preparation of a pharmaceutical composition for treatment of gastric cancer, ovarian cancer, lung cancer, or prostate cancer.

Compared with the technology in the prior art, advantages of the polysubstituted benzene according to embodiments of the disclosure are summarized as follows:

(1) The compound of the disclosure has good biological activity, has the activity of inhibiting the proliferation of tumor cells, and the inhibitory effect on tumor cells is better than or equal to that of the natural product gossypol I-A9. The compound can be used for the research and development of new drugs, for the preparation of anti-tumor drugs, gastric cancer drugs, ovarian cancer drugs, lung cancer drugs or prostate cancer drugs.

(2) The preparation method is easy to operate, the raw materials involved therein are easily available, and the method has step economy, mild reaction conditions, low cost, and can be easily scaled-up to an industrial process.

