CN108976187B - Substituted benzofuran derivative, preparation thereof and application thereof in preparation of antitumor drugs - Google Patents
Substituted benzofuran derivative, preparation thereof and application thereof in preparation of antitumor drugs Download PDFInfo
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- CN108976187B CN108976187B CN201710406193.4A CN201710406193A CN108976187B CN 108976187 B CN108976187 B CN 108976187B CN 201710406193 A CN201710406193 A CN 201710406193A CN 108976187 B CN108976187 B CN 108976187B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
The invention provides a substituted benzofuran derivative, which has a chemical structure shown as a general formula I; the invention also provides a preparation method of the formula I, which is shown in the following reaction formula:
Description
Technical Field
The invention relates to medicinal chemistry, in particular to a medicament and preparation thereof, and especially relates to a substituted benzofuran derivative, preparation thereof and application thereof in preparing antitumor medicaments.
Background
Malignant tumors are frequently encountered diseases and frequently encountered diseases that seriously jeopardize human life health. Globally, malignant tumors have become the second leading cause of death in humans, and the incidence is still on the rise. Current clinical applications of tumor therapy include: the chemotherapy is the mainstream treatment method among surgical treatment, radiotherapy, chemotherapy and biological treatment, but the existing chemotherapy drugs have the defects of limited antitumor activity, larger toxic and side effect, poor tolerance of patients, high price and the like. Therefore, the search for new, highly effective, low-toxicity antitumor compounds has become an important field of cancer chemoprevention research and is receiving general attention and research hotspots of various scientific communities around the world.
The functional vascular network of tumors can provide oxygen, nutrients and remove metabolites in time, and although tumors can obtain partial blood vessels by integrating with host blood vessels, the tumors still need to build their own vascular system by forming a new vascular network to keep growing and developing. The growth of solid tumors is hampered if the vascular system is not available for oxygen and nutrients (Microvasc Res,1977,14(1): 53-65). Therefore, tumor blood vessels have become an important target for tumor therapy. There are two approaches to the treatment of tumor vessels: one is the anti-angiogenesis, which adopts the methods of inhibiting basement membrane degradation, directly inhibiting endothelial cell proliferation, inhibiting activation of vascular growth factor, inhibiting endothelial cell specific integrin or survival signal, and the like, and some candidate drugs are tested in various clinical stages. The other is selective destruction of tumor vasculature, known as Vascular Targeting Agents (VTAs) or Vascular Disturbers (VDAs). In fact, these two effects may act synergistically in a drug molecule (Br J Radiol,1993,66(783): 181-. Generally speaking, the antineoplastic drugs acting on tumor vessels have the advantages of wide application range, quick response, difficult generation of drug resistance, high efficiency and the like, so the antineoplastic drugs are very concerned by medicinal chemists. For example, the natural antitumor compound cobupristin A-4(CA4) is already in phase III clinical research and is used for antitumor drug research, and the natural antitumor compound is a vascular interference agent type antitumor compound. BNC105 is a compound developed by Australian Bionomics company, and is a vascular interference agent type antitumor compound which is structurally modified from a natural antitumor compound, namely combretastatin A4, and can be combined with tubulin to selectively destroy tumor primary vessels and rapidly cut off the blood supply of tumors so as to cause the necrosis of the central area of the tumors. At the same time, BNC105 acts on the colchicine site of tubulin, interfering with mitosis and leading to apoptosis. Thus, BNC105 can exert a dual effect. Compared with the natural product combretastatin A4, which is already in phase III clinical study, BNC105 has 8 times of the ability of combretastatin A4 to inhibit the growth of blood vessels, can more powerfully inhibit the growth of tumor tissues, and has a wider treatment window. At present, the prodrug of BNC105 has entered phase II clinical trials for the treatment of breast, mesothelioma and renal cancers (Clin Cancer Res; 17 (15); 5152-. However, the literature shows that the half lethal value of BNC105 to mice is 60mg/kg, which indicates that the toxicity of BNC is still large, and the clinical application of BNC is limited, and further modification is necessary to reduce the toxicity of BNC.
Disclosure of Invention
The technical problem to be solved by the invention is to use substituted benzofuran as a parent nucleus structure to carry out structural modification and search the vascular disrupting agent antitumor drug with high activity, low toxicity and wider treatment application.
The invention provides a substituted benzofuran derivative, which has a chemical structure shown as a general formula I:
wherein R is hydrogen, deuterium, halogen, alkyl, alkoxycarbonyl or aryl;
the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; the alkyl group is C1–C6Is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl, preferably methyl; the aryl is phenyl or substituted phenyl;
r' is phosphoryl group shown in formula W, medicinal salt of phosphoryl group or phosphamide derivative;
the medicinal salt is a medicinal salt generated by reacting phosphoryl shown as a formula W with organic base or inorganic base in a compound I;
the phosphoramide derivative is generated by the reaction of phosphoryl represented by the formula W and amine or amino acid compounds in the compound I.
Another object of the present invention is to provide a process for the preparation of said substituted benzofuran derivatives.
The preparation method is shown in the following reaction formula I:
in the reaction formula: r is hydrogen, deuterium, halogen, alkyl, alkoxycarbonyl or aryl;
the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; the alkyl group is C1–C6Is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl, preferably methyl; the aryl is phenyl or substituted phenyl;
R1is methyl, ethyl, tert-butyl, benzyl or phenyl;
r' is phosphoryl, phosphoryl medicinal salt or phosphoramide derivative shown in formula W;
the medicinal salt is a medicinal salt generated by reacting phosphoryl shown as a formula W with organic base or inorganic base in a compound I;
the phosphoramide derivative is generated by the reaction of phosphoryl represented by the formula W and amine or amino acid compounds in the compound I.
Specifically, the preparation method comprises the following steps:
(a) nucleophilic addition reaction: the starting material 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (BNC-105, compound 2) reacts with nucleophilic reagent to obtain an addition product 3- [ 1-hydroxy-2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl ] -6-methoxy-2-methylbenzofuran-7-ol (compound 3);
(a') wittig reaction: the starting material 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (BNC-105, compound 2) and phosphorus ylide reagent react to obtain a product 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-ol (compound 4);
or (b) elimination reaction: the hydroxyl of tertiary alcohol in the addition product compound 3 and hydrogen atoms on ortho-position carbon atoms are subjected to elimination reaction to obtain 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-ol (compound 4);
(c) phosphorylation reaction: the free phenolic hydroxyl in the compound 4 is subjected to phosphorylation reaction to generate 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl dialkyl phosphate (compound 5);
(d) and (3) hydrolysis reaction: hydrolyzing phosphate bonds in the compound 5 to obtain 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl phosphate (compound 6);
(e) salt forming reaction: free hydroxyl of phosphate in the compound 6 reacts with organic base or inorganic base to generate pharmaceutically acceptable salt 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl phosphate (compound I).
The preparation method comprises the following steps of (a) nucleophilic addition reaction: in a proper solvent, under a certain temperature condition, the 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran compound 2 and a nucleophilic reagent organic metal compound generate addition reaction to generate a compound 3.
The solvent in the step (a) is an aprotic solvent, and is selected from dichloromethane, diethyl ether, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dichloroethane, chloroform, acetone or butanone, preferably dichloromethane, diethyl ether or tetrahydrofuran; the organic metal compound is a Grignard reagent or an organic lithium reagent and is selected from alkyl magnesium halide reagents or alkyl lithium reagents, the alkyl magnesium halide is alkyl magnesium iodide, alkyl magnesium bromide or alkyl magnesium chloride, and methyl magnesium iodide, ethyl magnesium iodide, isopropyl magnesium iodide or benzyl magnesium iodide is preferred; the molar ratio of the organometallic compound to compound 2 is 2:1 to 20:1, preferably 4:1 to 8: 1; the reaction temperature is-10-50 ℃, preferably-5-25 ℃, and particularly preferably 0-15 ℃; the reaction time is 0.5-5 h.
The preparation method of the invention comprises the following steps of (a') a wittig reaction: in a proper solvent, 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (compound 2) and phosphorus ylide reagent react to generate 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-phenol (compound 4) under a certain temperature condition.
The solvent in the step (a') is an aprotic solvent, and is selected from diethyl ether, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and the like, preferably diethyl ether or tetrahydrofuran; the phosphorus ylide reagent is prepared by the action of proper alkali on halogenated alkyl triphenylphosphine or phosphonate; the base is an organic or inorganic base selected from diethylamine, triethylamine, pyridine, piperidine, 1, 8-diazabicycloundec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), preferably 1, 8-diazabicycloundec-7-ene; the inorganic base is selected from hexamethyldisilazane lithium amide, hexamethyldisilazane sodium amide, hexamethyldisilazane potassium amide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium or tert-butyllithium, preferably potassium tert-butoxide or n-butyllithium; the molar ratio of the phosphorus ylide reagent to the compound 2 is 1:1-10:1, preferably 1.5:1-3: 1; the reaction temperature is-100-80 ℃, preferably-85-25 ℃; the reaction time is 1-24 h.
The preparation method comprises the following steps of (b) eliminating reaction: in a proper solvent and under a certain temperature condition, one molecule of water is eliminated in the presence of a dehydrating agent to generate a compound 3.
The solvent in the step (b) is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dichloromethane, dichloroethane, chloroform acetone or butanone, preferably dichloromethane, dichloroethane, diethyl ether or tetrahydrofuran; the dehydrating agent is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, thionyl chloride/organic base system, preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, thionyl chloride/pyridine or thionyl chloride/triethylamine; the molar ratio of the dehydrating agent to the compound 2 is 1:1 to 15:1, preferably 2.5: 1; the reaction temperature is-10-50 ℃, preferably-5-20 ℃, and particularly preferably-2-5 ℃; the reaction time is 0.5-5 h.
The preparation method comprises the following steps of (c) phosphorylation reaction: in a proper solvent, under the condition of a certain temperature and the existence of alkali, the free phenolic hydroxyl in the compound 4 reacts with halogenated dialkyl phosphate to generate a phosphate compound 5.
The solvent in step (c) is an aprotic solvent selected from dichloromethane, diethyl ether, toluene, acetonitrile, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dichloroethane, chloroform, acetone or butanone, preferably dichloromethane, acetonitrile, diethyl ether or tetrahydrofuran; the base is an organic or inorganic base selected from diethylamine, triethylamine, pyridine, piperidine, 4-Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIPEA), 1, 8-diazabicycloundec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), preferably triethylamine; the inorganic base is selected from sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate or potassium phosphate, preferably potassium carbonate; the halogenated dialkyl phosphate is halogenated dimethyl phosphate, halogenated diethyl phosphate, halogenated di-tert-butyl phosphate or halogenated dibenzyl phosphate, wherein halogen is chlorine, bromine or iodine; the reaction temperature is-20-60 ℃, preferably-5-30 ℃, and particularly preferably-0-15 ℃; the reaction time is 0.5-15 h.
The preparation method comprises the following steps of (d) hydrolysis reaction: removing phosphoryl from phosphate compound 5 in proper solvent under the catalysis of Lewis acid at certain temperature, and adding protecting group to produce compound 6.
The solvent in the step (d) is an aprotic solvent, and is selected from dichloromethane, diethyl ether, toluene, acetonitrile, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloroethane, chloroform, acetone or butanone, preferably dichloromethane, diethyl ether or tetrahydrofuran; the Lewis acid is selected from trifluoroacetic acid, trimethylbromosilane, trimethyliodosilane, trimethylaluminosilane, aluminum trichloride, aluminum triiodide, stannic chloride, boron tribromide or boron trichloride, preferably trimethyliodosilane or trimethylbromosilane. The reaction temperature is-20-60 ℃, preferably-15-35 ℃, and particularly preferably 0-20 ℃; the reaction time is 0.5-12 h.
The preparation method comprises the step (e) of salt forming reaction: the compound 6 reacts with alkali in a proper solvent under a certain temperature condition to generate a medicinal salt compound I.
The solvent is a protic solvent selected from methanol, ethanol, isopropanol or water, preferably methanol or water. The alkali is organic or inorganic alkali, and the inorganic alkali is selected from sodium methoxide, sodium acetate, potassium methoxide, potassium acetate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium phosphate or potassium phosphate, preferably potassium carbonate; the organic base is selected from basic amino acids, amines, ammonia, diethylamine, triethylamine, pyridine, piperidine, 4-Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIPEA), 1, 8-diazabicycloundec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), preferably basic amino acids. The reaction temperature is 0-80 ℃, preferably 15-25 ℃; the molar ratio of the base to the compound 5 is 4:1 to 50:1, preferably 8:1 to 15: 1; the reaction time is 0.5-5 h.
The pharmaceutically acceptable salt of the present invention is in the form of a salt which does not cause pharmacological side effects and is conventionally used, and is not particularly limited. The salt is selected from alkali metal salts of sodium, potassium or lithium; or an alkaline earth metal salt of calcium or magnesium; or a metal salt of aluminum, iron, zinc, copper, nickel or cobalt; or an inorganic or organic salt of ammonium; the ammonium salt includes, but is not limited to, basic amino acid salt selected from methylamine salt, ethylamine salt, dimethylamine salt, diethylamine salt, triethylamine salt, morpholine salt, guanidine salt, procaine salt, glucose ammonium salt, piperazine salt, benzylamine salt or phenethylamine salt. Preferably an alkali metal salt, ammonium salt or basic amino acid salt, more preferably a sodium salt, potassium salt, ammonium salt, lysine salt or arginine salt, most preferably a sodium salt, lysine salt or arginine salt.
Each of the phosphoryl groups in the pharmaceutically acceptable salts of water of the present invention forms a mono-or di-salt. That is, one or two acid radicals in each phosphoryl group react with organic base or inorganic base to form salt.
In a specific embodiment of the present invention, each of the phosphoryl groups in the pharmaceutically acceptable salts forms a mono-or di-salt with an alkali metal ion compound, ammonia water or a basic amino compound. The alkali metal ion compound is selected from the group consisting of basic compounds of lithium, sodium or potassium, including but not limited to sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate or potassium carbonate.
The basic amino compound of the present invention is a basic compound containing a nitrogen atom, wherein the nitrogen atom is trivalent and can exist in the form of primary amine, secondary amine and tertiary amine, and includes but is not limited to basic amino acid: lysine, arginine or histidine, such as morpholine, guanidine, procaine, dopamine, glucosamine, N-methylglucamine, dicyclohexylamine, piperazine, and also some alkaloids, such as ephedrine, pseudoephedrine, quinine, atropine, nicotine, hyoscyamine, and the like.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt comprises an alkali metal or ammonium salt, an amine salt of compound i. Selected from alkali metal salts, ammonium salts or amino acid salts; preferably a sodium, potassium, ammonium, lysine or arginine salt, most preferably a sodium, lysine or arginine salt.
The amine salt of the compound I is formed by combining acid radicals in phosphoryl groups with amino groups of amino compounds.
The basic amino acid salt of the compound I refers to a salt formed by reacting an acid radical in a phosphoryl group with a side chain amino group of a basic amino acid, and includes but is not limited to lysine or arginine salt.
In a particularly preferred embodiment of the invention, the substituted benzofuran derivative is a phosphate or phosphoramide derivative of compound i, preferably a substituted benzofuran phosphate, particularly preferably substituted disodium benzofuran phosphate.
The invention also provides application of the substituted benzofuran derivative in preparation of antitumor drugs.
The substituted benzofuran derivative is shown by in-vitro proliferation inhibition experiment research of human tumor cells: the substituted benzofuran derivative has a good inhibition effect on tumor cells such as human liver cancer cells HLF, human intestinal cancer cells HCT116, human breast cancer cells MDA-MB-231, human prostate cancer cells DU145, human melanoma cells A375, human colon cancer cells Lovo, human kidney cancer cells 786-o, human chronic myelogenous leukemia cells K562, human stomach cancer cells MGC-803, human pancreatic cancer cells PANC-1 and the like, so that the substituted benzofuran derivative can be used for preparing antitumor drugs.
The application of the substituted benzofuran derivatives in pharmacy is the application of substituted benzofuran phosphate or phosphoramide derivatives in preparing antitumor drugs, preferably the application of substituted benzofuran phosphate derivatives in preparing antitumor drugs, and particularly preferably the application of substituted benzofuran disodium phosphate in preparing antitumor drugs.
The medicament is a medicinal composition consisting of substituted benzofuran derivatives serving as active ingredients and medicinal auxiliary materials.
The medicament is a medicinal composition which is composed of active ingredients and pharmaceutical excipients, wherein the active ingredients are phosphate or phosphoramide derivatives of substituted benzofuran derivatives I.
Preferably, the medicament is a medicinal composition which is composed of substituted benzofuran derivative phosphate serving as an active ingredient and a medicinal auxiliary material.
Particularly preferably, the medicament is a medicinal composition which is composed of substituted benzofuran derivative disodium phosphate serving as an active ingredient and a medicinal auxiliary material.
The pharmaceutical composition is a freeze-dried powder injection, a tablet, a capsule, an orally disintegrating agent, a dropping pill, a spray, an aerosol or an injection, and preferably the injection or the freeze-dried powder injection.
The substituted benzofuran derivative phosphate derivative has excellent antitumor activity, low acute toxicity and excellent water solubility, may be prepared into injection or freeze dried powder for injection, provides new medicine for treating tumor diseases and has excellent clinical application foreground.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention.
Example 1 Synthesis of 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) allyl-2, 2-didehydro) -benzofuran-7-ol, Compound 4 shown in formula I
Placing deuterated methyl triphenyl phosphonium bromide (3.57g, 10mmol) in a three-neck flask, adding anhydrous tetrahydrofuran 30mL under the protection of argon, reducing the temperature to about-70 ℃, adding n-butyl lithium solution (5mL, 11mmol, 2.2M hexane solution) dropwise, adding BNC105(1.87g, 5mmol) anhydrous tetrahydrofuran solution 30mL after 1 hour, naturally returning to room temperature of 25 ℃, stirring until the raw material is completely consumed by TLC, reducing the temperature to about 0 ℃, adding 60mL ammonium chloride aqueous solution dropwise to quench, extracting the reaction solution twice (90 mL for 2 times) with 180 mL ethyl acetate, combining ethyl acetate organic phases, washing with 70 mL water once, drying with anhydrous sodium sulfate, filtering, reducing the vacuum degree of a rotary evaporator to 0.1MPa at 45 ℃, and reducing the vacuum degree of a rotary evaporatorThe mixture is concentrated under pressure, and the concentrated solution is recrystallized by 30ml of methanol to obtain 1.23g of white solid product 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) allyl-2, 2-dideuterio) -benzofuran-7-ol, the yield of which is 66%.1H NMR(500MHz,CDCl3)δ6.79(d,J＝8.5Hz,1H),6.66(d,J＝8.5Hz,1H),6.63(s,2H),5.68(s,1H),3.91(s,3H),3.88(s,3H)3.77(s,6H),2.35(s,3H)；ESI-MS:m/z 395.1[M+Na]+,371.1[M-H]-。
Example 2 Synthesis of 3- (2, 2-dichloro-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol, Compound 4 shown in formula I
Putting trichloromethyl diethyl phosphonate (2.56g, 10mmol) in a three-neck flask, adding anhydrous tetrahydrofuran (30 mL) under the protection of argon, cooling to about-80 ℃, dropwise adding n-butyl lithium solution (5mL, 11mmol, 2.2M hexane solution), dropwise adding anhydrous tetrahydrofuran solution (30 mL) of BNC105(3.72g, 10mmol) after 1 hour, naturally returning to room temperature of 25 ℃, heating to reflux until the raw materials are completely consumed, cooling to about 0 ℃, dropwise adding 60mL of ammonium chloride aqueous solution, quenching, extracting the reaction liquid twice (80 mL for 2 times) with 160 mL of ethyl acetate, combining ethyl acetate organic phases, washing with 60mL of water once, drying with anhydrous sodium sulfate, filtering, concentrating under the reduced pressure of a rotary evaporator with the vacuum degree of 0.1MPa at 45 ℃, recrystallizing the concentrated solution with 20mL of methanol to obtain a white solid product, namely 3- (2, 2-dichloro-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol 3.64g, yield 83%.1H NMR(500MHz,CDCl3)δ6.89(d,J＝8.5Hz,1H),6.75(d,J＝8.5Hz,1H),6.66(s,2H),3.89(s,3H),3.85(s,3H),3.73(s,6H),2.36(s,3H)；ESI-MS:m/z 461.2[M+Na]+,437.2[M-H]-。
Example 3 Synthesis of 3- (2, 2-dichloro-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol, Compound 4 shown in formula I
Placing benzyltriphenylphosphonium bromide (4.33g, 10mmol) in a three-neck flask, adding 30mL of anhydrous tetrahydrofuran under the protection of argon, cooling to about-70 ℃, adding n-butyllithium solution (5mL, 11mmol, 2.2M hexane solution) dropwise, adding 30mL of anhydrous tetrahydrofuran solution of BNC105(1.87g, 5mmol) dropwise after 1 hour, naturally returning to room temperature of 25 ℃, stirring until the raw material is completely consumed by TLC, cooling to about 0 ℃, adding 60mL of ammonium chloride aqueous solution dropwise to quench, extracting the reaction solution twice (60 mL for 2 times) with 120 mL of ethyl acetate, combining ethyl acetate organic phases, washing once with 50mL of water, drying with anhydrous sodium sulfate, filtering, concentrating under the vacuum degree of 0.1MPa by a rotary evaporator, recrystallizing the concentrated solution with 15 mL of methanol to obtain a white solid product, namely 3- (2, 2-dichloro-1- (3, 4), 5-Trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol 1.96g, yield 88%.1H NMR(500MHz,CDCl3)δ6.96(d,J＝8.5Hz,1H),6.91(d,J＝13Hz,1H),6.89(s,1H),6.86-6.76(m,3H),6.67(d,J＝8.5Hz,1H),6.66(s,2H),3.88(s,3H),3.83(s,3H),3.76(s,6H),2.35(s,3H)；ESI-MS:m/z 469.2[M+Na]+,445.2[M-H]-。
Example 4 Synthesis of methyl (E) -3- (7-hydroxy-6-methoxyethyl-2-methylbenzofuran) -3- (3,4, 5-trimethoxyphenyl) acrylate, Compound 4 shown in formula I
Have increased the description of such compounds
Placing triethyl phosphorylacetate (2.24g, 10mmol) in a three-neck flask, adding 30mL of anhydrous tetrahydrofuran under the protection of argon, reducing the temperature to about 0 ℃, adding sodium hydride (400mg, 10mmol, 60%) in batches, dropping 30mL of anhydrous tetrahydrofuran solution of BNC105(1.87g, 5mmol) after 1 hour, heating and refluxing until TLC shows that the raw material is completely consumed, reducing the temperature to about 0 ℃, dropping 50mL of ammonium chloride aqueous solution for quenching, extracting the reaction solution twice (80 mL for 2 times) by 160 mL of ethyl acetate, combining ethyl acetateThe organic phase of ester is washed once by 60ml of water, dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure by a rotary evaporator with the vacuum degree of 0.1MPa at 45 ℃, and the concentrated solution is recrystallized by 20ml of ethanol to obtain 1.95g of white solid product (E) -methyl 3- (7-hydroxy-6-methoxyethyl-2-methylbenzofuran) -3- (3,4, 5-trimethoxyphenyl) acrylate with the yield of 91 percent.1H NMR(500MHz,CDCl3)δ6.91(d,J＝8.5Hz,1H),6.81(s,1H),6.67(d,J＝8.5Hz,1H),6.61(s,2H),3.91(s,3H),3.85(s,3H),3.81(s,3H),3.72(s,6H),2.36(s,3H)；ESI-MS:m/z 451.1[M+Na]+,427.1[M-H]-。
Example 5 Synthesis of 3- (1-hydroxy-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol, Compound 3 shown in formula I
Placing 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (3.72g, 10mmol) in a three-neck flask, adding 60mL of anhydrous ether under the protection of argon, cooling to about 0 ℃, dropwise adding magnesium methyl iodide (20mL, 40mmol, 2M), naturally returning to room temperature (22 ℃) and stirring, TLC shows that the raw materials are completely consumed, then returning to about 0 ℃, dropwise adding 50mL of ammonium chloride aqueous solution and quenching, extracting the reaction solution twice (2 x 75mL) with 150 mL of ethyl acetate, combining ethyl acetate organic phases, washing with 60mL of water, drying with anhydrous sodium sulfate, filtering, concentrating under 45 ℃ and vacuum degree of a rotary evaporator of 0.1MPa, performing vacuum concentration, recrystallizing the concentrated solution with 20mL of 80% methanol to obtain a white solid product compound 3- (1-hydroxy-1- (3), 4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol 3.58g, yield 93%.1H NMR(500MHz,CDCl3)δ6.76(d,J＝8.5Hz,1H),6.68(d,J＝8.5Hz,1H),6.61(s,2H),3.87(s,3H),3.83(s,3H),3.77(s,6H),2.31(s,3H),1.92(s,3H)；13C NMR(126MHz,CDCl3)δ153.01,152.48,147.82,146.32,140.52,138.00,136.11,130.27,124.57,116.20,115.12,111.69,109.33,104.52,71.51,60.93,56.94,56.11,42.31,13.23；ESI-MS:m/z 389.1[M+H]+,387.1[M-H]-。
Example 6 Synthesis of the Compound 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol, Compound 4 shown in formula I
Dissolving 3- (1-hydroxy-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol (3.86g, 10mmol) in 50mL of anhydrous THF, cooling to about 0 ℃ in an ice-water bath under the protection of argon, adding pyridine (1.45mL, 18mmol) and thionyl chloride (1.1mL, 15mmol) dropwise, stirring for half an hour to 1 hour at the temperature, TLC shows that the raw materials are completely consumed, adding 20mL of ammonium chloride aqueous solution dropwise at 0 ℃ for quenching, extracting the reaction liquid twice (2X 75mL) with 150 mL of ethyl acetate, combining organic phases, washing once with 60mL of water, drying with anhydrous sodium sulfate, filtering, concentrating under 45 ℃ and a vacuum degree of 0.1MPa rotary evaporator under reduced pressure, recrystallizing the concentrated solution with 5mL of methanol to obtain a white solid product, namely 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol 3.25g, yield 88%.1H NMR(500MHz,CDCl3)δ6.77(d,J＝8.5Hz,1H),6.64(d,J＝8.5Hz,1H),6.61(s,2H),5.72(d,J＝1.5Hz,1H),5.67(s,1H),5.37(d,J＝1.5Hz,1H),3.92(s,3H),3.87(s,3H)3.78(s,6H),2.34(s,3H)；13C NMR(126MHz,CDCl3)δ153.13,153.04,143.43,141.73,140.32,138.07,135.98,130.73,124.97,116.29,115.41,110.23,107.63,104.48,60.94,57.25,56.14,13.24；ESI-MS:m/z 393.1[M+Na]+,369.1[M-H]-。
Example 7 Synthesis of Compound 6-disodium methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-dibenzyl phosphate, Compound I shown in formula I
6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol (3.7g, 10mmol), tetrabromoDissolving carbon (3.97g, 12mmol) in 22mL of anhydrous acetonitrile, cooling to about 0 ℃ in an ice-water bath under the protection of argon, sequentially adding dibenzyl phosphite (3.15g, 12mmol) and triethylamine (3.42mL, 24mmol), stirring for 2 hours at the temperature, TLC shows that the raw materials are completely consumed, and performing column chromatography (petroleum ether/ethyl acetate 2:1 elution) to obtain 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-dibenzyl phosphate 6.1g, wherein the yield is 97%.1H NMR(500MHz,CDCl3)δ7.32-7.44(m,10H),6.90(d,J＝8.5Hz,1H),6.81(d,J＝8.5Hz,1H),6.61(s,2H),5.71(d,J＝1.0Hz,1H),5.32-5.41(m,5H,overlapped),3.88(s,3H),3.84(s,3H),3.79(s,6H),2.25(s,3H)；13C NMR(126MHz,CDCl3)δ153.21,153.11,148.28,148.25,145.93,145.90,140.11,138.15,135.97,135.90,135.88,128.48,128.38,127.75,125.04,124.98,124.72,116.49,116.30,115.73,108.87,104.54,69.85,69.81,60.94,57.07,56.23,13.19；ESI-MS:m/z 653.2[M+Na]+.
6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-dibenzyl phosphate (6.3g, 10mmol) is dissolved in 80mL of anhydrous dichloromethane, cooled to about 0 ℃ in an ice-water bath under the protection of argon, and dropwise added with trimethyl bromosilane (4.8mL, 36mmol), and stirred at the temperature until TLC shows that the raw materials are reacted completely. Concentrating under reduced pressure at 40 deg.C under vacuum degree of 0.1MPa, adding methanol (25mL) into the concentrated solution, stirring for 15 min, concentrating under reduced pressure at 40 deg.C under vacuum degree of 0.1MPa, dissolving the residue with 30mL of methanol, adjusting pH to 7-8 with methanol solution of sodium methoxide, and adjusting pH to about 10 with small amount of sodium hydroxide methanol solution. Concentrating the obtained mixed solution to 30mL under a rotary evaporator with the vacuum degree of 0.1MPa at 40 ℃, slowly dropping acetone with the volume of 2.5 times (75mL) to separate out white crystalline solid, filtering, washing a filter cake with the acetone, and drying at 40 ℃ to obtain 4.1g of the product 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-dibenzyl disodium phosphate with the yield of 85%.1H NMR(500MHz,D2O)δ6.83(d,J＝8.5Hz,1H),6.72(s,3H),6.68(d,J＝8.5Hz,1H),5.75(s,1H),5.41(s,1H),3.79(s,3H)3.72(s,3H),3.71(s,6H),2.28(s,3H)；ESI-MS:m/z 449.2[M-2Na+H]-.
Example 8 Synthesis of 6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol, Compound 4 shown in formula I
Dissolving 3- (1-hydroxy-2-methyl-1- (3,4, 5-trimethoxyphenyl) propyl) -6-methoxy-2-methylbenzofuran-7-phenol (4.16g, 10mmol) in 50mL of anhydrous THF, cooling to about 0 ℃ in an ice water bath under the protection of argon, dripping pyridine (1.45mL, 18mmol) and thionyl chloride (1.1mL, 15mmol), stirring for half an hour at the temperature until the raw materials are completely consumed by TLC, dripping 20mL of ammonium chloride aqueous solution at 0 ℃ for quenching, extracting the reaction liquid twice (2 multiplied by 90mL) by 180 mL of ethyl acetate, combining organic phases, washing once by 70 mL of water, drying by anhydrous sodium sulfate, filtering, concentrating under the reduced pressure of a rotary evaporator with the vacuum degree of 0.1MPa, recrystallizing the concentrated solution by 30mL of methanol to obtain a white solid product, namely 6-methoxy-2-methyl-3- (2- Methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol 3.71g, yield 93%.1H NMR(500MHz,CDCl3)δ6.79(d,J＝8.5Hz,1H),6.69(d,J＝8.5Hz,1H),6.63(s,2H),3.93(s,3H),3.86(s,3H)3.75(s,6H),2.35(s,3H),1.85(s,6H)；ESI-MS:m/z 421.1[M+Na]+,397.1[M-H]-。
Example 9 Synthesis of 6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol, Compound 4 shown in formula I
Dissolving 3- (2-ethyl-1-hydroxy-1- (3,4, 5-trimethoxyphenyl) butyl) -6-methoxy-2-methylbenzofuran-7-ol (2.22g, 5mmol) in 25mL of anhydrous THF, cooling to about 0 ℃ in an ice-water bath under the protection of argon, adding pyridine (0.73mL, 9mmol) and thionyl chloride (0.56mL, 7.5mmol) dropwise, stirring at the temperature for half an hour to 1 hour, and TLC shows that the raw materials are not dissolved in the anhydrous THFThe materials are completely consumed, 20mL of ammonium chloride aqueous solution is dropped at the low temperature of 0 ℃ for quenching, the reaction solution is extracted twice (2X 80mL) by 160 mL of ethyl acetate, organic phases are combined, 60mL of water is washed once, anhydrous sodium sulfate is dried, filtration is carried out, decompression concentration is carried out by a rotary evaporator with the vacuum degree of 0.1MPa at the temperature of 40 ℃, the concentrated solution is recrystallized by 25mL of methanol to obtain a white solid product, namely 1.81g of 6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol, and the yield is 85%.1H NMR(500MHz,CDCl3)δ6.69(d,J＝8.5Hz,1H),6.59(d,J＝8.5Hz,1H),6.55(s,2H),3.91(s,3H),3.81(s,3H)3.71(s,6H),2.32(s,3H),2.13-1.94(m,4H),1.85(s,6H),0.95-0.85(m,6H)；ESI-MS:m/z 449.1[M+Na]+,425.1[M-H]-。
Example 10 Synthesis of 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol, Compound 4 shown in formula I
Dissolving 3- (1-hydroxy-1- (3,4, 5-trimethoxyphenyl) propyl) -6-methoxy-2-methylbenzofuran-7-phenol (4.07g, 10mmol) in 50mL of anhydrous THF, cooling to about 0 ℃ in an ice-water bath under the protection of argon, dripping pyridine (1.45mL, 18mmol) and thionyl chloride (1.1mL, 15mmol), stirring for half an hour to 1 hour at the temperature, TLC shows that the raw materials are completely consumed, dripping 20mL of ammonium chloride aqueous solution at 0 ℃ for quenching, extracting the reaction liquid twice (2X 75mL) by 150 mL of ethyl acetate, combining organic phases, washing once by 60mL of water, drying by anhydrous sodium sulfate, filtering, concentrating by a rotary evaporator at 40 ℃ under the vacuum degree of 0.1MPa, carrying out reduced pressure concentration by using 28 mL of methanol on the concentrated solution, and recrystallizing to obtain a white solid product, namely 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol 3.49g, yield 91%.1H NMR(500MHz,CDCl3)δ6.81(d,J＝8.5Hz,1H),6.71(d,J＝8.5Hz,1H),6.69(s,2H),6.11(q,J＝3.5Hz,1H),3.95(s,3H),3.82(s,3H)3.72(s,6H),2.38(s,3H),2.11(d,J＝4.5Hz,3H)；ESI-MS:m/z 407.1[M+Na]+,383.1[M-H]-。
Example 11 Synthesis of 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) butyl) benzofuran-7-ol, Compound 4 shown in formula I
Dissolving 3- (1-hydroxy-1- (3,4, 5-trimethoxyphenyl) butyl) -6-methoxy-2-methylbenzofuran-7-phenol (4.16g, 10mmol) in 50mL of anhydrous THF, cooling to about 0 ℃ in an ice-water bath under the protection of argon, dripping pyridine (1.45mL, 18mmol) and thionyl chloride (1.1mL, 15mmol), stirring for half an hour to 1 hour at the temperature, TLC shows that the raw materials are completely consumed, dripping 20mL of ammonium chloride aqueous solution at 0 ℃ for quenching, extracting the reaction liquid twice (2 × 90mL) by 180 mL of ethyl acetate, combining organic phases, washing once by 70 mL of anhydrous sodium sulfate, drying, filtering, concentrating by a rotary evaporator at 40 ℃ under the vacuum degree of 0.1MPa, recrystallizing the concentrated solution by 35 mL of methanol to obtain a white solid product, namely 6-methoxy-2-methyl-3- (1- (3,4, 5-trimethoxyphenyl) butyl) benzofuran-7-ol 3.71g (93% yield).1H NMR(500MHz,CDCl3)δ6.83(d,J＝8.5Hz,1H),6.73(d,J＝8.5Hz,1H),6.69(s,2H),6.02(t,J＝3.5Hz,1H),3.91(s,3H),3.83(s,3H)3.69(s,6H),2.41(s,3H),2.14(q,J＝4.75Hz,2H),0.81(t,J＝4.5Hz,3H)；ESI-MS:m/z 421.1[M+Na]+,397.1[M-H]-. EXAMPLE 12 Synthesis of disodium 3- (2, 2-dichloro-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-phosphate, Compound I shown in formula I
Synthesized in a similar manner to example 7 using 3- (2, 2-dichloro-1- (3,4, 5-trimethoxyphenyl) ethyl) -6-methoxy-2-methylbenzofuran-7-ol as a starting material, yield 85%.1H NMR(500MHz,D2O)δ6.85(d,J＝8.5Hz,1H),6.79(d,J＝8.5Hz,1H),6.61(s,2H),3.87(s,3H),3.82(s,3H),3.75(s,6H),2.37(s,3H)；ESI-MS:m/z 518.2[M-2Na+H]-。
EXAMPLE 13 Synthesis of disodium 6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-phosphate, Compound I shown in formula I
Synthesized in a similar manner to example 7 using 6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol as a starting material in a yield of 85%.1H NMR(500MHz,D2O)δ6.75(d,J＝8.5Hz,1H),6.67(d,J＝8.5Hz,1H),6.61(s,2H),3.91(s,3H),3.85(s,3H)3.74(s,6H),2.36(s,3H),1.81(s,6H)；ESI-MS:m/z 477.2[M-2Na+H]-。
EXAMPLE 14 Synthesis of disodium (E) -6-methoxy-2-methyl-3- (- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-phosphate, Compound I shown in formula I
Synthesized in a similar manner to example 7 using (E) -6-methoxy-2-methyl-3- (2-methyl-1- (3,4, 5-trimethoxyphenyl) propenyl) benzofuran-7-ol as a starting material with a yield of 87%.1H NMR(500MHz,D2O)δ6.87(d,J＝8.5Hz,1H),6.76(d,J＝8.5Hz,1H),6.68(s,2H),6.15(q,J＝3.5Hz,1H),3.91(s,3H),3.85(s,3H)3.73(s,6H),2.35(s,3H),2.13(d,J＝4.5Hz,3H)；ESI-MS:m/z 463.2[M-2Na+H]-。
Example 15 in vitro proliferation inhibition of human tumor cells by substituted benzofuran derivatives of the invention
All tumor cell lines of the present invention were purchased from Shanghai cell of Chinese academy of sciences.
The invention adopts an in vitro cytotoxicity test experiment, after all samples to be tested are dissolved into 10mM by dimethyl sulfoxide (purchased from Merck company), phosphate buffer solution is added to prepare 1000 mu M solution or uniform suspension, then phosphate buffer solution containing DMSO is used for dilution, and the samples are finally concentratedThe concentrations were 100. mu.M, 10. mu.M, 1. mu.M, 0.1. mu.M, 0.01. mu.M, and 0.001. mu.M. The test tumor cell lines included: HLF (human hepatoma cells), HCT116 (human intestinal cancer cells), MDA-MB-231 (human breast cancer cells), DU145 (human prostate cancer cells), A375 (human melanoma cells), Lovo (human colon cancer cells), 786-o (human renal cancer cells), MGC-803 (human gastric cancer cells), K562 (human chronic myeloid leukemia cells), PANC-1 (human pancreatic cancer cells). The Inhibitory Concentration (IC) at which the death rate (or survival rate) of each test compound per cancer cell was 50% was determined by MTT colorimetry50And 48 h). The test results are shown in Table 1.
TABLE 1 benzofuran derivatives in vitro antitumor Activity data
Example 16 the compound 6-methoxy-2-methyl-3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-
Acute toxicity evaluation of disodium dibenzyl phosphate (product of example 7)
(1) Test materials: 30 mice, the weight of which is 16-18 g, and the sex of which is half male and half female; the source is as follows: Xipul-Bikai laboratory animal, Inc. of Shanghai city, the license number of laboratory animal: SCXK (Shanghai) 2013-0016
(2) Test method
The administration route is as follows: the mice are in single tail vein, and fasting is not forbidden for 12h before administration;
dose capacity: administering the composition at a maximum dose volume of 40ml/kg body weight;
administration dose: mice were injected intravenously at the tail with 40ml/kg of disodium 6-methoxy-2-methyl-3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-dibenzylphosphate at 1.6mg/ml and 3.2mg/ml, respectively, i.e., at 60mg/kg and 120 mg/kg. The negative control group was given 40ml/kg body weight of 0.9% NaCl.
Observation indexes are as follows: mice were observed for toxicity and death within 14 days after administration, weighed on days 7 and 14, sacrificed after weighing on day 14, dissected, and examined for lesions in the major organs.
Statistical treatment: for weight data
Data are presented as SPSS16.0 software, tested using one-way ANOVA; significance level a ═ 0.05.
(4) Test results
A single tail vein injection of the disodium 6-methoxy-2-methyl-3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-dibenzylphosphate is given to the mice at a dose of 60mg/kg and 120mg/kg body weight, and after 14 days, the general behavior, diet, fur and other conditions of the mice are not abnormal and have no obvious toxic reaction. On both days 7 and 14 after the single administration, the body weight of the mice increased, and the body weight was not significantly different from that of the same sex negative control group, and the mice were not killed. Mice were sacrificed after weighing at day 14 after a single dose, gross dissection was performed, and no changes in volume, color, texture of the organs were observed visually. The results are shown in tables 2 and 3.
TABLE 2ICR mice Single tail vein 60mg/kg 6-methoxy-2-methyl
Weight Change after disodium (E) -3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-dibenzyl phosphate
Note: compared with the control group, P is more than 0.05
TABLE 3ICR mice Single Tail vein 120mg/kg 6-methoxy-2-methyl
Weight Change after disodium (E) -3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-dibenzyl phosphate
Note: compared with the control group, P is more than 0.05
(5) And (4) test conclusion: the MTD of the disodium 6-methoxy-2-methyl-3- [1- (3,4, 5-trimethoxyphenyl) propenyl ] benzofuran-7-dibenzyl phosphate in a single tail vein of a mouse is more than 120mg/kg, and is superior to the structural analogue BNC-105.
In conclusion, the test results show that: the substituted benzofuran derivative has excellent antitumor activity, low acute toxicity and good water solubility, is suitable for being prepared into injections or freeze-dried powder injections, and has great clinical application value.
Claims (32)
1. A substituted benzofuran derivative, wherein the chemical structure of said substituted benzofuran derivative is represented by formula i:
wherein R is hydrogen, deuterium, halogen, alkyl, alkoxycarbonyl or aryl;
the halogen is fluorine, chlorine, bromine or iodine; the alkyl group is C1–C6A straight or branched alkyl group of (a); the aryl group is phenyl;
r' is phosphoryl or a pharmaceutically acceptable salt of phosphoryl represented by formula W;
the medicinal salt is the medicinal salt generated by the reaction of phosphoryl represented by the formula W and organic base or inorganic base in the compound I.
2. A substituted benzofuran derivative according to claim 1, wherein said halogen is fluorine; the alkyl group is methyl, ethyl, propyl or isopropyl.
3. A substituted benzofuran derivative according to claim 2, wherein said alkyl group is a methyl group.
4. A process for the preparation of substituted benzofuran derivatives according to claim 1, wherein said process is represented by the following reaction scheme one:
in the reaction formula: r is hydrogen, deuterium, halogen, alkyl, alkoxycarbonyl or aryl;
the halogen is fluorine, chlorine, bromine or iodine; the alkyl group is C1–C6Linear or branched alkyl of (a); the aryl group is phenyl;
R1is methyl, ethyl, tert-butyl, benzyl or phenyl;
r' is phosphoryl or phosphoryl pharmaceutically acceptable salt shown as a formula W;
R〝〞is a phosphoryl pharmaceutically acceptable salt represented by formula W;
the medicinal salt is a medicinal salt generated by reacting phosphoryl shown as a formula W with organic base or inorganic base in a compound I;
the preparation method comprises the following steps:
(a) nucleophilic addition reaction: the starting material 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (BNC-105, compound 2) reacts with nucleophilic reagent to obtain an addition product 3- [ 1-hydroxy-2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl ] -6-methoxy-2-methylbenzofuran-7-ol (compound 3);
(a') wittig reaction: the starting material 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (BNC-105, compound 2) and phosphorus ylide reagent react to obtain a product 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-ol (compound 4);
or (b) elimination reaction: the hydroxyl of tertiary alcohol in the addition product compound 3 and hydrogen atoms on ortho-position carbon atoms are subjected to elimination reaction to obtain 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-ol (compound 4);
(c) phosphorylation reaction: the free phenolic hydroxyl in the compound 4 is subjected to phosphorylation reaction to generate 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl dialkyl phosphate (compound 5);
(d) and (3) hydrolysis reaction: hydrolyzing phosphate bonds in the compound 5 to obtain 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl phosphate (compound 6);
(e) salt forming reaction: free hydroxyl of phosphate in the compound 6 reacts with organic base or inorganic base to generate pharmaceutically acceptable salt 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-yl phosphate (compound 1).
5. The process for preparing substituted benzofuran derivative according to claim 4, wherein said halogen is fluorine; the alkyl group is methyl, ethyl, propyl or isopropyl.
6. The process for preparing substituted benzofuran derivative according to claim 5, wherein said alkyl group is a methyl group.
7. The process for preparing substituted benzofuran derivative according to claim 3, wherein step (a) comprises a nucleophilic addition reaction: in a proper solvent, under a certain temperature condition, 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran compound 2 and a nucleophilic reagent organic metal compound generate addition reaction to generate a compound 3; the solvent of step (a) is an aprotic solvent, and the organometallic compound is a Grignard reagent or an organolithium reagent; the molar ratio of the organometallic compound to the compound 2 is 2:1-20: 1; the reaction temperature is-10 ℃ to 50 ℃, and the reaction time is 0.5 to 5 hours.
8. The method for preparing substituted benzofuran derivative according to claim 7, wherein the solvent in step (a) is dichloromethane, diethyl ether, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dichloroethane, chloroform, acetone, or butanone; the Grignard reagent is alkyl magnesium halide; the molar ratio of the organometallic compound to the compound 2 is 4:1-8: 1; the reaction temperature is-5 ℃ to 25 ℃, and the reaction time is 0.5 h to 5 h.
9. The method for preparing substituted benzofuran derivative according to claim 8, wherein said alkyl magnesium halide in step (a) is alkyl magnesium iodide, alkyl magnesium bromide or alkyl magnesium chloride.
10. The method for preparing substituted benzofuran derivative according to claim 9, wherein said alkyl magnesium halide in step (a) is methyl magnesium iodide, ethyl magnesium iodide, isopropyl magnesium iodide, or benzyl magnesium iodide.
11. The process for preparing substituted benzofuran derivative according to claim 8, wherein the molar ratio of the organometallic compound of step (a) to compound 2 is 4:1 to 8: 1; the reaction temperature is 0-15 ℃.
12. The method for preparing a substituted benzofuran derivative according to claim 4, wherein the step (a') comprises a wittig reaction: reacting 2-methyl-3- (3,4, 5-trimethoxybenzoyl) -6-methoxy-7-hydroxybenzofuran (compound 2) with a phosphorus ylide reagent in a proper solvent at a certain temperature to generate 6-methoxy-2-methyl-3- [2, 2-disubstituted-1- (3,4, 5-trimethoxyphenyl) ethyl-1-alkenyl ] benzofuran-7-ol (compound 4); the solvent of step (a') is an aprotic solvent; the phosphorus ylide reagent is prepared by the action of proper alkali on halogenated alkyl triphenylphosphine or phosphonate; the alkali is organic alkali or inorganic alkali, and the molar ratio of the phosphorus ylide reagent to the compound 2 is 1:1-10: 1; the reaction temperature is-100-80 ℃; the reaction time is 1-24 h.
13. The method for preparing a substituted benzofuran derivative according to claim 12, wherein said step (a') comprises a wittig reaction: the solvent is diethyl ether, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran or ethyl acetate; the phosphorus ylide reagent is prepared by the action of proper alkali on halogenated alkyl triphenylphosphine or phosphonate; the organic base is diethylamine, triethylamine, pyridine, piperidine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, hexamethyldisilazane lithium amide, hexamethyldisilazane sodium amide, hexamethyldisilazane potassium amide, tert-butyl sodium amide, n-butyl lithium or tert-butyl lithium; the inorganic base is sodium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the molar ratio of the phosphorus ylide reagent to the compound 2 is 1.5:1-3: 1; the reaction temperature is-85-25 ℃.
14. The process for the preparation of substituted benzofuran derivatives according to claim 4, wherein said solvent of step (a') is diethyl ether or tetrahydrofuran, and said phosphorus ylide reagent is prepared by the action of a suitable base on halogenated alkyl triphenylphosphine or phosphonate; the organic base is potassium tert-butoxide, n-butyllithium or 1, 8-diazabicycloundecen-7-ene.
15. The process for preparing substituted benzofuran derivative according to claim 4, wherein step (b) comprises the elimination reaction: in a proper solvent, under a certain temperature condition, in the presence of a dehydrating agent, eliminating one molecule of water to generate a compound 4; the solvent in the step (b) is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dichloromethane, dichloroethane, chloroform acetone or butanone; the dehydrating agent is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid or a thionyl chloride/organic base system; the molar ratio of the dehydrating agent to the compound 2 is 1:1-15: 1; the reaction temperature is-10-50 ℃; the reaction time is 0.5-5 h.
16. The process for the preparation of substituted benzofuran derivatives according to claim 15, wherein step (b) comprises elimination: the solvent is dichloromethane, dichloroethane, diethyl ether or tetrahydrofuran; the dehydrating agent is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, thionyl chloride/pyridine or thionyl chloride/triethylamine; the molar ratio of the dehydrating agent to the compound 2 is 2.5: 1; the reaction temperature is-5 ℃ to 20 ℃.
17. The process for the preparation of substituted benzofuran derivatives according to claim 16, wherein step (b) comprises elimination: the solvent is dichloromethane, dichloroethane, diethyl ether or tetrahydrofuran; the dehydrating agent is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, thionyl chloride/pyridine or thionyl chloride/triethylamine; the reaction temperature is-2 ℃ to 5 ℃.
18. The process for preparing substituted benzofuran derivative according to claim 4, wherein step (c) comprises a phosphorylation reaction: in a proper solvent, under the conditions of a certain temperature and the existence of alkali, free phenolic hydroxyl in the compound 4 reacts with halogenated dialkyl phosphate to generate a phosphate compound 5; the solvent of step (c) is an aprotic solvent; the alkali is organic alkali or inorganic alkali; the halogenated dialkyl phosphate is halogenated dimethyl phosphate, halogenated diethyl phosphate, halogenated di-tert-butyl phosphate or halogenated dibenzyl phosphate, wherein halogen is chlorine, bromine or iodine; the reaction temperature is-20 ℃ to 60 ℃; the reaction time is 0.5-15 h.
19. The process for preparing substituted benzofuran derivative according to claim 18, wherein step (c) comprises a phosphorylation reaction: the solvent is dichloromethane, diethyl ether, toluene, acetonitrile, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dichloroethane, chloroform, acetone or butanone; the organic base is sodium acetate, potassium acetate, diethylamine, triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, N-diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium phosphate or potassium phosphate; the reaction temperature is-5 ℃ to 30 ℃.
20. The process for preparing substituted benzofuran derivative according to claim 19, wherein step (c) comprises a phosphorylation reaction: the solvent is dichloromethane, acetonitrile, diethyl ether or tetrahydrofuran; the organic base is triethylamine or potassium carbonate; the halogenated dialkyl phosphate is halogenated dimethyl phosphate, halogenated diethyl phosphate, halogenated di-tert-butyl phosphate or halogenated dibenzyl phosphate, wherein halogen is chlorine, bromine or iodine; the reaction temperature is 0-15 ℃.
21. The process for preparing substituted benzofuran derivative according to claim 4, wherein said step (d) comprises a hydrolysis reaction of: hydrolyzing a phosphate compound 5 in a proper solvent under the catalysis of Lewis acid at a certain temperature to generate a compound 6; the solvent of step (d) is an aprotic solvent; the Lewis acid is selected from trifluoroacetic acid, trimethyl bromosilane, trimethyl iodosilane, trimethyl aluminum silane, aluminum trichloride, aluminum triiodide, stannic chloride, boron tribromide or boron trichloride; the reaction temperature is-20 ℃ to 60 ℃; the reaction time is 0.5-12 h.
22. The process for preparing substituted benzofuran derivative according to claim 21, wherein said step (d) comprises a hydrolysis reaction of: the solvent is dichloromethane, diethyl ether, toluene, acetonitrile, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloroethane, chloroform, acetone or butanone; the Lewis acid is trimethyl iodosilane or trimethyl bromosilane, and the reaction temperature is-15-35 ℃.
23. The process for preparing substituted benzofuran derivative according to claim 22, wherein said step (d) comprises a hydrolysis reaction of: the solvent is dichloromethane, diethyl ether or tetrahydrofuran; the reaction temperature is 0-20 ℃.
24. The process for preparing substituted benzofuran derivative according to claim 4, wherein step (e) comprises a salt-forming reaction: reacting compound 6 with alkali in a proper solvent at a certain temperature to generate a medicinal salt of compound I; the solvent is a proton solvent selected from methanol, ethanol, isopropanol or water; the alkali is organic or inorganic alkali, and the inorganic alkali is selected from potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium phosphate or potassium phosphate; the organic base is selected from sodium methoxide, sodium acetate, potassium methoxide, potassium acetate, basic amino acids, ammonia, diethylamine, triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the reaction temperature is 0-80 ℃; the molar ratio of the base to the compound 5 is 4:1-50: 1; the reaction time is 0.5-5 h; each of said phosphoryl groups of said pharmaceutically acceptable salts forming a mono-or di-salt
25. The process for the preparation of substituted benzofuran derivatives according to claim 24, wherein step (e) comprises a salt formation reaction: the solvent is methanol or water; the organic base is basic amino acid; the reaction temperature is-15 ℃ to 25 ℃; the molar ratio of the base to the compound 5 is 8:1-15: 1; the reaction time is 0.5-5 h; each of the phosphoryl groups in the pharmaceutically acceptable salts forms a mono-or di-salt.
26. The process for preparing substituted benzofuran derivative according to claim 25, wherein said pharmaceutically acceptable salt is disodium substituted benzofuran phosphate.
27. Use of the substituted benzofuran derivative of claim 1 in the preparation of an anti-tumor medicament.
28. The use of substituted benzofuran derivatives as claimed in claim 27, wherein said medicament is a pharmaceutical composition comprising a benzofuran phosphate derivative as an active ingredient together with a pharmaceutically acceptable excipient.
29. The use of substituted benzofuran derivatives as claimed in claim 28, wherein said medicament is a pharmaceutical composition comprising substituted disodium benzofuran phosphate as an active ingredient together with pharmaceutical excipients.
30. The use of the substituted benzofuran derivative of claim 29 in the preparation of an anti-tumor medicament, wherein said pharmaceutical composition is a tablet, a capsule, an orally disintegrating formulation, a drop pill, a spray, an aerosol, or an injection.
31. The use of the substituted benzofuran derivative of claim 30 in the preparation of an anti-neoplastic drug, wherein said pharmaceutical composition is an injection.
32. The use of the substituted benzofuran derivative of claim 31 in the preparation of an anti-tumor medicament, wherein said injection is a lyophilized powder for injection.
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