CN107298666B

CN107298666B - Preparation method of flavonoid compound and intermediate thereof

Info

Publication number: CN107298666B
Application number: CN201610234791.3A
Authority: CN
Inventors: 孙青*; 孙青�; 张卫东; 袁虎
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Priority date: 2016-04-15
Filing date: 2016-04-15
Publication date: 2021-04-23
Anticipated expiration: 2036-04-15
Also published as: CN107298666A

Abstract

The invention discloses a preparation method of a flavonoid compound and an intermediate thereof, wherein the preparation method comprises the following steps: the compound 9 can be obtained by subjecting the compound 8 to ring-opening elimination reaction in a solvent in the presence of an acid. The preparation method has the advantages of easily available raw materials, high yield, simple post-treatment and no need of column chromatography.

Description

Preparation method of flavonoid compound and intermediate thereof

Technical Field

The invention relates to a preparation method of a flavonoid compound and an intermediate thereof.

Background

Flavonoids are a class of polyphenols that are widely distributed in nature. Hundreds of different types of flavonoids have been found to have a wide range of biological and pharmacological activities. A large number of researches show that the flavonoid compound has the functions of scavenging free radicals, resisting oxidation, resisting mutation, resisting tumors, resisting bacteria and viruses, regulating immunity, preventing and treating angiosclerosis, reducing blood sugar and the like. Many flavonoids have also been shown to be active against the HIV virus. In addition, with the development of food industry and the change of consumption concept, health food containing natural active ingredients becomes the pursuit of modern people, wherein the flavonoid compounds are increasingly concerned by people with the characteristics of pure nature, high activity, quick response, wide action and the like.

Norwogonin (5, 7, 8-trihydroxyflavone) is a flavone compound isolated from plants of the genus scutellaria of the family labiatae, which has insecticidal and bacteriostatic activity (j. ethnopharmacol.2014, 52, 183-: good insect antifeedant activity against Spodoptera litura (j. agric. food chem.2003, 51, 389393); has good inhibition effect on acinetobacter baumannii (Plos One 2013, 8(4), e 61594.). At a concentration of 91 μ g/mL, norwogonin has an inhibition rate of 28.7% on influenza virus sialidase and also shows a better inhibition effect on influenza virus (chem. pharm. Bull.1990, 38 (5)), 1329-; in addition, norwogonin also has NADH-oxidase inhibiting effect (IC)₅₀Protein Molecules 2010, 15, 7363-7377) and nerve growth promoting effect at 340nM/mg, and has strong antidepressant activity (J.Med.chem.2010, 53, 8274-8286)

Isoalpine baicalein and oxamin are hydroxylated analogs of 3-and 4' -positions of norwogonin, and isoalpine baicalein also has influenza virus sialidase inhibitory activity, shows good in vivo anti-influenza virus effect, and has low toxic and side effects. (chem.pharm.Burl.1990, 38(5), 1329-; the curatin has antioxidant and antitumor effects (Food science 2013, 34, 106-. In addition, the curatin exerts an anti-inflammatory effect by inhibiting the JNK and NF-. kappa.B signaling pathways induced by LPS, reducing the production of inflammatory cytokines and mediators (Eur.J. Ethnopharmacol.2014, 152, 183-189).

Wogonin (5, 7-dihydroxy-8-methoxyflavone) is also a natural flavonoid compound, and has antioxidant, antiinflammatory, neuroprotective, antitumor and antiviral activities, especially significant antitumor activity. Recent researches show that wogonin has the effects of enhancing the sensitivity of tumor cells to apoptosis induction, specifically inducing tumor cell apoptosis, inhibiting tumor angiogenesis, reversing the drug resistance of tumor cells, promoting the death of tumor cells by cooperating with anticancer agents and the like (Chinese university of medicine 2009, 40, 576 and 579; Chinese New medicine journal 2011, 20, 777 and 784). As a new anti-tumor national chemical class I medicine, wogonin smoothly passes through CFDA approval in 2014 12 months, and meanwhile, the national CFDAI and II clinical research batches are obtained.

The content of wogonin, norwogonin, isoalpine scutellarin and phytoxin in the raw medicinal materials is very low, and the extraction process is relatively complicated. The chemical synthesis method can avoid occupying farmland, is beneficial to improving the quality of the medicine and has lower cost.

At present, the synthesis of wogonin, norwogonin, isowogonin and curatin is less reported and mainly obtained by hydrolysis of corresponding natural product glycoside and chemical synthesis methods, mainly oxidation cyclization method or Baker-Venkataraman rearrangement method (chem.Pharm.Bull.2003, 51, 339-340; Acta phytochimic 1931, 5, 219-226; Indian.J.chem.B.1993, 32, 244-256; Proc.Ind.Acad.Sci.1946, 24, 243-252; Bull.chem.Soc.Jpn.1983, 56, 3773-3780; J.Med.chem.1986, 29, 6-2262; chem.Abstr.1949, 43, 638-639; Oreg.Prep.int.2009, 41-2009, 41-327, 9; hydroxyl-methoxy-introduced into these raw materials (hydroxyl-5, hydroxyl-2255) or hydroxyl-methoxy-5, and the original synthesis methods are reported, the synthesis of these starting materials is complicated, the overall yield is low, and some of the reaction conditions are severe. Therefore, the total yield of the synthetic route is low, and the large-scale production is difficult to realize.

Meanwhile, the search of our party finds that hydroxyl can be introduced into a benzene ring through the following three-step reaction, but the yield is low, and the method is not suitable for industrial production:

(1) iodination reaction: org, biomol, chem, 9, 70-73, yield 74%; bioorg.med.chem.lett.22, 6731-6734, yield 53%; synthetic Communications, 31, 3059-3068, yield 40% -100%; bioorganic and Medicinal Chemistry Letters; 17; p.3212-3216, yield 45%;

(2) boric acid esterification reaction: the yield of the double-frequency borane, heterocyles, 81, 1871-one 1879 is lower than 70 percent;

(3) and (3) oxidation reaction: sodium periodate, tetrahedron letters; 56; p.1524-1527, yield 58%; sodium perborate, WO2015/79251a1, yield 40% -80%.

Disclosure of Invention

The invention aims to overcome the defects of complex synthetic process, harsh reaction conditions and the like of raw materials used in the existing preparation method of the 8-hydroxy flavonoid compound, and provides a preparation method of the flavonoid compound and an intermediate thereof.

The invention provides a preparation method shown as a formula 9, which comprises the following steps: in a solvent, in the presence of acid, carrying out ring opening and elimination reaction on the compound 8 to obtain a compound 9;

wherein R is¹Is a hydroxyl protecting group (which may be a hydroxyl protecting group conventional in the art for such oxidation reactions, such as methyl, benzyl, acetyl, methoxymethyl, or p-methoxybenzyl); r²、R³、R⁵、R⁶、R⁷、R⁸And R⁹Independently of one another is hydrogen, C_1～6Alkyl (e.g. methyl or ethyl), C_1～6One OR more of acyl (e.g., formyl OR acetyl), 3-14 membered carbocyclic group, 3-14 membered heterocyclic group having "hetero atom O, S and N, hetero atom number of 1-6, carbon atom number of 1-13", OR-OR^x；R⁴Is hydrogen;

each R^xIndependently a hydroxyl protecting group (which may be a hydroxyl protecting group conventional in the art for such oxidation reactions, such as methyl, benzyl, acetyl, methoxymethyl, or p-methoxybenzyl).

In the preparation method of the compound 9, the compound 8 is preferably

In the preparation method of the compound 9, the solvent can be a solvent which is common in the field of ring opening and elimination reactions, as long as the solvent does not react with reactants or products, and can be an organic solvent and/or water; the organic solvent can be one or more of halogenated hydrocarbon solvents, ketone solvents, alcohol solvents and ether solvents, and the halogenated hydrocarbon solvents are particularly preferred in the invention. The halogenated hydrocarbon solvent can be a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent can be dichloromethane and/or dichloroethane; the ketone solvent can be acetone; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the ether solvent can be tetrahydrofuran and/or 2-methyltetrahydrofuran.

In the preparation method of the compound 9, the volume mol ratio of the solvent to the compound 8 can be a volume mol ratio which is conventional in the ring opening and elimination reaction in the field, for example, 100.0-200.0L/mol.

In the preparation method of the compound 9, the acid can be an acid which is conventional in the field of ring opening and elimination reactions of the type, and can be one or more of p-toluenesulfonic acid, formic acid, acetic acid, methanesulfonic acid and camphorsulfonic acid, and p-toluenesulfonic acid and/or camphorsulfonic acid are particularly preferred in the invention.

In the preparation method of the compound 9, the molar ratio of the acid to the compound 8 can be a molar ratio which is conventional in the ring-opening and elimination reaction in the field, such as 0.04-0.06.

In the preparation method of the compound 9, the temperature of the ring-opening elimination reaction may be a temperature conventional in the art for such ring-opening elimination reaction, for example, 15 to 25 ℃.

In the preparation method of the compound 9, the progress of the ring-opening and elimination reaction can be monitored by a conventional test method in the field (such as TLC, HPLC or NMR), and generally the end point is that the compound 8 is not reacted any more, and the reaction time can be 0.75 hours to 2 hours.

Preferably, the preparation method of the compound 9 further comprises the following steps: in a solvent, in the presence of alkali, carrying out oxidation reaction on the compound 3 and an oxidant to obtain the compound 8;

in the preparation method of the compound 8, the compound 3 is preferably

In the preparation method of the compound 8, the solvent can be a solvent which is conventional in the field of oxidation reactions of this type, as long as the solvent does not react with reactants or products, and can be an organic solvent and/or water; the organic solvent can be one or more of halogenated hydrocarbon solvents, ketone solvents, alcohol solvents and ether solvents, and the organic solvent is particularly preferably an ether solvent or a 'ketone solvent and halogenated hydrocarbon solvents (the volume ratio is 1: 1-2: 1)'. The halogenated hydrocarbon solvent can be a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent can be dichloromethane and/or dichloroethane; the ketone solvent can be acetone; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the ether solvent can be tetrahydrofuran and/or 2-methyltetrahydrofuran.

In the preparation method of the compound 8, the volume mol ratio of the solvent to the compound 3 can be a volume mol ratio which is conventional in the oxidation reaction of the type in the field, for example, 15.0-20.0L/mol.

In the preparation method of the compound 8, the base can be a base which is conventional in the oxidation reaction in the field and can be an inorganic base; such as one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, and lithium carbonate, with sodium bicarbonate being particularly preferred in the present invention.

In the preparation method of the compound 8, the molar ratio of the base to the compound 3 may be a molar ratio conventional in the oxidation reaction of this kind in the art, for example, 3 to 20 (e.g., 10).

In the preparation method of the compound 8, the oxidizing agent can be an oxidizing agent conventional in the field of such oxidation reactions, and dimethyl ketone peroxide (DMDO) is particularly preferred in the invention. When it is at homeWhen the solvent contains acetone, the oxidant can be potassium hydrogen peroxymonosulfate (2 KHSO)₅·KHSO₄·K₂SO₄) Which reacts with acetone to generate dimethyl ketone peroxide (DMDO) in situ.

In the preparation method of the compound 8, the molar ratio of the oxidant to the compound 3 can be a molar ratio conventional in the oxidation reaction of the type in the field, for example, 3.0 to 3.3.

In the process for the preparation of compound 8, the temperature of the oxidation reaction may be a temperature conventional in the art for such oxidation reactions, for example, 0 ℃ to 25 ℃ (e.g., 15 ℃).

In the preparation of compound 8, the progress of the oxidation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), generally ending when compound 3 is no longer reacted, and the reaction time can be from 12 hours to 13.5 hours (e.g., 13 hours).

Preferably, the preparation method of the compound 9 further comprises the following steps: in a solvent, in the presence of alkali, carrying out oxidation reaction on the compound 4 and an oxidant to obtain the compound 8;

in the preparation method of the compound 8, the compound 4 is preferably

In the preparation method of the compound 8, the solvent can be a solvent which is conventional in the field of oxidation reactions of this type, as long as the solvent does not react with reactants or products, and can be an organic solvent and/or water; the organic solvent can be one or more of halogenated hydrocarbon solvents, ketone solvents, alcohol solvents, water and ether solvents, and the invention particularly preferably selects ether solvents, or 'ketone solvents and halogenated hydrocarbon solvents (volume ratio is 1: 1-2: 1)'. The halogenated hydrocarbon solvent can be a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent can be dichloromethane and/or dichloroethane; the ketone solvent can be acetone; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the ether solvent can be tetrahydrofuran and/or 2-methyltetrahydrofuran.

In the preparation method of the compound 8, the volume mol ratio of the solvent to the compound 4 can be a volume mol ratio which is conventional in the oxidation reaction of the type in the field, for example, 15.0-20.0L/mol.

In the preparation method of the compound 8, the base can be a base which is conventional in the field of oxidation reactions and can be an inorganic base; such as one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, and lithium carbonate, with sodium bicarbonate being particularly preferred in the present invention.

In the preparation method of the compound 8, the molar ratio of the base to the compound 4 can be a molar ratio which is conventional in the oxidation reaction of the type in the field, for example, 10-20.

In the preparation method of the compound 8, the oxidizing agent can be an oxidizing agent conventional in the field of such oxidation reactions, and dimethyl ketone peroxide (DMDO) is particularly preferred in the invention. When the solvent contains acetone, the oxidant can be potassium hydrogen peroxymonosulfate complex salt (2 KHSO)₅·KHSO₄·K₂SO₄) Which reacts with acetone to generate dimethyl ketone peroxide (DMDO) in situ.

In the preparation method of the compound 8, the molar ratio of the oxidant to the compound 4 can be a molar ratio conventional in the oxidation reaction of the type in the field, for example, 3.0 to 3.3.

In the preparation of compound 8, the progress of the oxidation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), typically ending when compound 4 is no longer reacted, and the reaction time can be from 12 hours to 13.5 hours (e.g., 13 hours).

Preferably, the preparation method of the compound 9 further comprises the following steps: carrying out oxidation reaction on the compound 3 and an oxidant in a solvent to obtain a compound 4;

in the preparation method of the compound 4, the compound 3 is preferably

In the preparation method of the compound 4, the solvent can be a solvent which is conventional in the field of oxidation reactions of this type, as long as the solvent does not react with reactants or products, and can be an organic solvent and/or water; the organic solvent can be one or more of ketone solvent, alcohol solvent and ether solvent; the solvent is preferably an ether solvent and water, or an alcohol solvent and water (the volume ratio of the ether solvent to the water, or the alcohol solvent to the water may be 1: 1 to 2: 1). The ketone solvent can be acetone; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the ether solvent can be tetrahydrofuran and/or 2-methyltetrahydrofuran.

In the preparation method of the compound 4, the volume mol ratio of the solvent to the compound 3 can be a volume mol ratio conventional in the oxidation reaction of this type in the art, for example, 3.0 to 9.0L/mol (preferably 6.0L/mol).

In the preparation method of the compound 4, the oxidant can be an oxidant (but not dimethyl ketone peroxide; when the solvent contains acetone, the oxidant is not potassium hydrogen peroxymonosulfate complex salt) which is conventional in the field of oxidation reactions of this type, such as hydrogen peroxide, sodium perborate, sodium periodate (NaIO)₄) Hydrogen peroxymonosulfatePotassium complex salt (2 KHSO)₅·KHSO₄·K₂SO₄) And one or more of N-methylmorpholine oxide, preferably one or more of hydrogen peroxide, sodium periodate and sodium perborate, more preferably sodium periodate or sodium perborate.

In the preparation method of the compound 4, the molar ratio of the oxidant to the compound 3 can be a molar ratio conventional in the oxidation reaction of this type in the art, for example, 1.0 to 5.0 (preferably, 2.0 to 4.0).

In the process for preparing the compound 4, the temperature of the oxidation reaction may be a temperature conventional in the art for such oxidation reactions, for example, 0 ℃ to 60 ℃ (also, for example, 20 ℃ to 25 ℃).

In the preparation of compound 4, the progress of the oxidation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), generally ending when compound 3 is no longer reacted, and the reaction time can be 2 hours to 10 hours.

Preferably, the preparation method of the compound 9 further comprises the following steps: in a solvent, in the presence of alkali, a ligand and a catalyst, carrying out a boric acid esterification reaction on a compound 2 and a boron source to obtain a compound 3;

in the preparation method of the compound 3, the compound 2 is preferably

In the method for producing the compound 3, the boration reaction is preferably carried out in the presence of a protective gas. The shielding gas may be a shielding gas conventional in the art, such as nitrogen or argon.

In the preparation method of the compound 3, the solvent can be a solvent which is conventional in the boric acid esterification reaction in the field, and can be an organic solvent as long as the solvent does not react with reactants or products; the organic solvent may be one or more of amide solvents, nitrile solvents and ether solvents, preferably an ether solvent. The amide solvent can be N, N-dimethylformamide and/or N, N-dimethylacetamide; the nitrile solvent can be acetonitrile; the ether solvent may be one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.

In the preparation method of the compound 3, the volume mol ratio of the solvent to the compound 2 can be a volume mol ratio conventional in the boration reaction of this kind in the art, for example, 5.0 to 15.0L/mol (preferably 8.0 to 10.0L/mol).

In the preparation method of the compound 3, the base may be a base conventional in the art for such a boration reaction, such as an inorganic base and/or an organic base. The inorganic base may be an inorganic base conventional in the art for such boration reactions, such as one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, and potassium phosphate, preferably potassium acetate and/or potassium phosphate. The organic base may be an organic base conventional in the art for such boration reactions, such as one or more of diethylamine, triethylamine, pyridine, piperidine, DIPEA, DBU and DABCO, preferably triethylamine.

In the preparation method of the compound 3, the molar ratio of the base to the compound 2 can be a molar ratio conventional in the boration reaction of this kind in the art, for example, 1.0 to 5.0 (preferably, 2.0 to 3.0).

In the preparation method of the compound 3, the catalyst may be a catalyst conventional in the art for such a boration reaction, such as a palladium catalyst and/or a nickel catalyst. The palladium catalyst can be a palladium catalyst which is conventional in the boric acid esterification reaction in the field, such as palladium tetratriphenylphosphine and PdCl₂(dppf)、PdCl₂(PPh₃)₂One or more of palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium and palladium bromide, preferably palladium acetate, palladium chloride and bromineOne or more of palladium oxide. The nickel catalyst may be a nickel catalyst conventional in the art for such boration reactions, such as one or more of nickel acetate, nickel chloride and nickel bromide.

In the preparation method of the compound 3, the molar ratio of the catalyst to the compound 2 can be a molar ratio which is conventional in the boration reaction of this kind in the art, such as 0.01 to 0.1 (e.g. 0.05).

In the preparation method of the compound 3, the ligand may be a ligand conventional in the art for such a boration reaction, for example, a phosphine ligand. The phosphine ligand may be a phosphine ligand conventional in the art for such boration reactions, e.g., triphenylphosphine, tributylphosphine, P (o-Tol)₃One or more of 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl, 2-dicyclohexylphosphine-2 ', 4', 6 '-triisopropylbiphenyl, 2' -bis- (diphenylphosphino) -1, 1 '-binaphthyl, 1' -bisdiphenylphosphinoferrocene and 1, 3-bis (diphenylphosphino) propane, preferably P (o-Tol)₃。

In the preparation method of the compound 3, the catalyst and the ligand are preferably PdCl₂/PPh₃、PdBr₂/P(o-Tol)₃Or Pd (OAc)₂/P(o-Tol)₃。

In the preparation method of the compound 3, the molar ratio of the ligand to the compound 2 can be a molar ratio conventional in the boration reaction of this kind in the art, for example, 0.05 to 0.2 (preferably 0.1).

In the preparation method of the compound 3, the boron source can be a boron source conventional in the boration reaction in the field, such as bis-pinacol borate

And/or pinacolborane

Pinacolborane is preferred.

In the preparation method of the compound 3, the molar ratio of the boron source to the compound 2 can be a molar ratio conventional in the boration reaction of this kind in the art, for example, 1.0 to 1.5 (preferably 1.1).

In the preparation method of the compound 3, the temperature of the boration reaction can be a temperature conventional in the art for such boration reaction, such as 20 ℃ to 120 ℃, preferably 35 ℃ to 95 ℃, and more preferably 55 ℃ to 75 ℃ (for example, 60 ℃ to 70 ℃).

In the preparation of compound 3, the progress of the boration reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), generally ending when compound 2 is no longer reacted, and the reaction time can be 3 hours.

Preferably, the preparation method of the compound 9 further comprises the following steps: in a solvent, in the presence of iodine and silver salt or iodine and copper salt, carrying out iodination reaction on the compound 1 to obtain a compound 2;

in the preparation method of the compound 2, the compound 1 is preferably

In the preparation method of the compound 2, the iodination reaction may be performed in the presence of a protective gas. The shielding gas may be a shielding gas conventional in the art, such as nitrogen or argon.

In the preparation method of the compound 2, the solvent can be a solvent which is conventional in the field of iodination reaction and can be an organic solvent as long as the solvent does not react with reactants or products; the organic solvent can be halogenated hydrocarbon solvent and/or ether solvent. The halogenated hydrocarbon solvent can be a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent can be dichloromethane and/or dichloroethane; the ether solvent may be one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.

In the preparation method of the compound 2, the volume mol ratio of the solvent to the compound 1 can be a volume mol ratio which is conventional in the iodination reaction in the field, for example, 5.0 to 15.0L/mol (preferably 8.0 to 10.0L/mol).

In the preparation method of the compound 2, the silver salt can be a soluble silver salt which is conventional in the field of iodination reaction, such as one or more of silver trifluoroacetate, silver trifluoromethanesulfonate, silver acetate, silver carbonate, silver sulfate and silver nitrate, preferably silver trifluoroacetate and/or silver nitrate.

In the preparation method of the compound 2, the copper salt can be a soluble copper salt which is conventional in the field of iodination reaction, such as one or more of copper acetate, copper sulfate and copper nitrate.

In the preparation method of the compound 2, the molar ratio of the silver salt to the compound 2, or the molar ratio of the copper salt to the compound 2 may be a molar ratio that is conventional in the iodination reaction in the field, for example, 1.0 to 5.0.

In the preparation method of the compound 2, the molar ratio of the iodine to the compound 2 can be a molar ratio which is conventional in the iodination reaction in the field, for example, 1.0-2.0.

In the preparation method of the compound 2, the temperature of the iodination reaction may be a temperature conventional in the art for such iodination reactions, for example, 0 to 20 ℃.

In the preparation of compound 2, the progress of the iodination reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), typically ending when compound 1 is no longer reacted, and the reaction time can be 2 hours.

The invention also provides a preparation method shown as the formula 10, which comprises the following steps:

(1) preparing the compound 9 according to the preparation method of the compound 9;

(2) carrying out deprotection reaction on the compound 9 to obtain a compound 10;

wherein when R is²Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^2’Is the same as R²(ii) a When R is²is-OR^xWhen R is^2’is-OH;

when R is³Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^3’Is the same as R³(ii) a When R is³is-OR^xWhen R is^3’is-OH;

when R is⁴Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^4’Is the same as R⁴(ii) a When R is⁴is-OR^xWhen R is^4’is-OH;

when R is⁵Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^5’Is the same as R⁵(ii) a When R is⁵is-OR^xWhen R is^5’is-OH;

when R is⁶Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^6’Is the same as R⁶(ii) a When R is⁶is-OR^xWhen R is^6’is-OH;

when R is⁷Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^7’Is the same as R⁷(ii) a When R is⁷is-OR^xWhen R is^7’is-OH;

when R is⁸Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^8’Is the same as R⁸(ii) a When R is⁸is-OR^xWhen R is^8’is-OH;

when R is⁹Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^9’Is the same as R⁹(ii) a When R is⁹is-OR^xWhen R is^9’is-OH.

Preferably, R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least one of them is-OR^x(e.g., R)³And R⁷is-OR^x)。

Said compound 9 is preferably

The deprotection reaction conditions may be those conventional in the art, for example, "in a solvent (e.g., methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or acetone), under hydrogen in the presence of a palladium catalyst (e.g., palladium on carbon or palladium hydroxide) (when the hydroxyl protecting group is benzyl group), or" in a solvent (e.g., methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran or 2-methyltetrahydrofuran; particularly preferably methanol, ethanol or dichloromethane), in the presence of a Lewis acid (hydrochloric acid, sulfuric acid, nitric acid, formic acid, aluminum trichloride, aluminum triiodide, tin tetrachloride, boron tribromide or boron trichloride; particularly preferably hydrochloric acid, boron tribromide or boron trichloride) ".

The invention also provides a compound shown as the formula 8:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹The definitions of (A) and (B) are as described above.

The invention also provides a preparation method of the compound shown in the formula 8, which comprises the following steps: in a solvent, in the presence of alkali, carrying out oxidation reaction on the compound 3 and an oxidant to obtain a compound 8;

wherein the parameters of the oxidation reaction are as described above.

Preferably, the preparation method of the compound 8 further comprises the preparation method of the compound 3.

The invention also provides a preparation method of the compound shown in the formula 8, which comprises the following steps: in a solvent, in the presence of alkali, carrying out oxidation reaction on the compound 4 and an oxidant to obtain a compound 8;

wherein the parameters of the oxidation reaction are as described above.

Preferably, the preparation method of the compound 8 further comprises the preparation method of the compound 4.

The invention also provides a preparation method of the compound shown in the formula 4, which comprises the following steps: carrying out oxidation reaction on the compound 3 and an oxidant in a solvent to obtain a compound 4;

wherein R is¹Is a hydroxyl protecting group (which may be a hydroxyl protecting group conventional in the art for such oxidation reactions, such as methyl, benzyl, acetyl, methoxymethyl, or p-methoxybenzyl); r²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Independently of one another is hydrogen, C_1～6Alkyl (e.g. methyl or ethyl), C_1～6One OR more of acyl (e.g., formyl OR acetyl), 3-14 membered carbocyclic group, 3-14 membered heterocyclic group having "hetero atom O, S and N, hetero atom number of 1-6, carbon atom number of 1-13", OR-OR^x；

In the preparation method of the compound 4, the compound 3 is preferably

In the preparation method of the compound 4, the solvent can be a solvent which is conventional in the field of oxidation reactions of this type, as long as the solvent does not react with reactants or products, and can be an organic solvent and/or water; the organic solvent can be one or more of ketone solvent, alcohol solvent and ether solvent. The solvent is preferably an ether solvent and water, or an alcohol solvent and water (the volume ratio of the ether solvent to the water, or the alcohol solvent to the water may be 1: 1 to 2: 1). The ketone solvent can be acetone; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the ether solvent can be tetrahydrofuran and/or 2-methyltetrahydrofuran.

In the preparation method of the compound 4, the oxidant can be an oxidant (but not dimethyl ketone peroxide, and potassium hydrogen peroxymonosulfate complex salt and acetone) which is conventional in the field of oxidation reactions of the type, such as hydrogen peroxide, sodium perborate, sodium periodate (NaIO)₄) Potassium peroxymonosulfate complex salt (2 KHSO)₅·KHSO₄·K₂SO₄) And one or more of N-methylmorpholine oxide, preferably one or more of hydrogen peroxide, sodium periodate and sodium perborate, more preferably sodium periodate or sodium perborate.

Preferably, the preparation method of the compound 4 further comprises the following steps: in a solvent, in the presence of alkali, a ligand and a catalyst, carrying out a boric acid esterification reaction on a compound 2 and a boron source to obtain a compound 3;

in the preparation method of the compound 3, the compound 2 is preferably

In the preparation method of the compound 3, the catalyst may be a catalyst conventional in the art for such a boration reaction, such as a palladium catalyst and/or a nickel catalyst. The palladium catalyst can be a palladium catalyst which is conventional in the boric acid esterification reaction in the field, such as palladium tetratriphenylphosphine and PdCl₂(dppf)、PdCl₂(PPh₃)₂Palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium and/or palladium bromide, preferably one or more of palladium acetate, palladium chloride and palladium bromide. The nickel catalyst may be a nickel catalyst conventional in the art for such boration reactions, such as one or more of nickel acetate, nickel chloride and nickel bromide.

In the preparation method of the compound 3, the catalyst and the ligand are preferably PdCl₂/PPh₃、 PdBr₂/P(o-Tol)₃Or Pd (OAc)₂/P(o-Tol)₃。

And/or pinacolborane

Pinacolborane is preferred.

Preferably, the preparation method of the compound 4 further comprises the following steps: in a solvent, in the presence of iodine and silver salt or iodine and copper salt, carrying out iodination reaction on the compound 1 to obtain a compound 2;

in the preparation of the compound 2, the reactionCompound 1 is preferably

In the preparation method of the compound 2, the solvent can be a solvent which is conventional in the iodination reaction of the type in the field, and can be an organic solvent as long as the solvent does not react with reactants or products; the organic solvent can be halogenated hydrocarbon solvent and/or ether solvent. The halogenated hydrocarbon solvent can be a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent can be dichloromethane and/or dichloroethane; the ether solvent may be one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.

The invention also provides a preparation method shown in the formula 5, which comprises the following steps:

(1) preparing a compound 4 according to the preparation method of the compound 4;

(2) carrying out deprotection reaction on the compound 4 to obtain a compound 5;

when R is⁴Is hydrogen, C_1～6Alkyl of (C)_1～6The "hetero atom" is one or more of O, S and N, the number of hetero atoms is 1-6, and the number of carbon atomsWhen 1 to 13 of 3 to 14-membered heterocyclic groups are present, R^4’Is the same as R⁴(ii) a When R is⁴is-OR^xWhen R is^4’is-OH;

Said compound 4 is preferably

The invention also provides a preparation method shown in the formula 6, which comprises the following steps:

(2) carrying out methylation reaction on the compound 4 and a methylation reagent to obtain a compound 6;

said compound 4 is preferably

The methylation reaction conditions may be those conventional in the art, for example, "in a solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, N-dimethylformamide, acetone or butanone; particularly preferably acetone) in the presence of a base (which may be a base conventional in the art, e.g., an inorganic base; such as sodium hydrogen, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium phosphate or potassium phosphate, etc.; particularly preferably potassium carbonate).

The methylating agent may be any methylating agent conventional in the art, such as methyl iodide or dimethyl sulfate.

The temperature of the methylation reaction may be a temperature conventional in the art for such methylation reactions, for example, from 0 ℃ to 100 ℃; preferably 45 to 65 ℃.

The invention also provides a preparation method shown in the formula 7, which comprises the following steps:

(1) preparing a compound 6 according to the preparation method of the compound 6;

(2) carrying out deprotection reaction on the compound 6 to obtain a compound 7;

wherein when R is²Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^2’Is the same as R²(ii) a When R is²is-OR^xWhen R is^xIs benzyl, R^2’is-OH;

when R is³Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^3’Is the same as R³(ii) a When R is³is-OR^xWhen R is^xIs benzyl, R^3’is-OH;

when R is⁴Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^4’Is the same as R⁴(ii) a When R is⁴is-OR^xWhen R is^xIs benzyl, R^4’is-OH;

when R is⁵Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^5’Is the same as R⁵(ii) a When R is⁵is-OR^xWhen R is^xIs benzyl, R^5’is-OH;

when R is⁶Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^6’Is the same as R⁶(ii) a When R is⁶is-OR^xWhen R is^xIs benzyl, R^6’is-OH;

when R is⁷Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^7’Is the same as R⁷(ii) a When R is⁷is-OR^xWhen R is^xIs benzyl, R^7’is-OH;

when R is⁸Is hydrogen, C_1～6Alkyl of (C)_1～6When the group (a) is an acyl group, a 3-to 14-membered carbocyclic group, a 3-to 14-membered heterocyclic group having one or more of O, S as a hetero atom and N as a hetero atom, 1 to 6 as hetero atoms and 1 to 13 as carbon atoms^8’Is the same as R⁸(ii) a When R is⁸is-OR^xWhen R is^xIs benzyl, R^8’is-OH;

when R is⁹Is hydrogen, C_1～6Alkyl of (C)_1～6Acyl group of (2)3-14 membered carbocyclyl, 3-14 membered heterocyclic group containing O, S heteroatoms 1-6 and 1-13 carbon atoms^9’Is the same as R⁹(ii) a When R is⁹is-OR^xWhen R is^xIs benzyl, R^9’is-OH.

Preferably, R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹At least one of them is-OR^x(e.g., R)³is-OR^x)。

Said compound 6 is preferably

The deprotection reaction conditions may be those conventional in the art, which should not remove the methyl group in compound 6, but may remove the benzyl group, for example "in a solvent (e.g., methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, or acetone) under hydrogen in the presence of a palladium catalyst (e.g., palladium on carbon or palladium hydroxide)".

The invention also provides a compound shown as the formula 3:

The invention also provides a preparation method of the compound shown in the formula 3, which comprises the following steps: in a solvent, carrying out a boric acid esterification reaction on a compound 2 and a boron source in the presence of alkali, a ligand and a catalyst to obtain a compound 3;

the parameters of the boration reaction are the same as those described above.

Preferably, the preparation method of the compound 3 further comprises the following steps: in a solvent, in the presence of iodine and silver salt or iodine and copper salt, carrying out iodination reaction on the compound 1 to obtain a compound 2;

the parameters of the iodination reaction are as described above.

The invention also provides a preparation method of the compound shown in the formula 2, which comprises the following steps: in a solvent, carrying out iodination reaction on the compound 1 in the presence of iodine and silver salt or iodine and copper salt to obtain a compound 2;

The parameters of the iodination reaction are as described above.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the present invention, the term "carbocyclyl" refers to a ring system containing 3 to 14 carbon atoms, which may be saturated, partially saturated or aromatic (i.e., aryl), unless otherwise specified. Examples include, but are not limited to: phenyl, phenylene, benzenetriyl (benzylnaphthyl), indanyl, naphthyl, naphthylene, naphthalenetriyl (naphtalenetriyl), anthracenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicycloheptyl, bicyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, bicycloheptenyl, bicyclooctenyl.

In the present invention, the term "heterocyclyl" refers to a 3-to 14-membered heterocyclic ring system containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which may be saturated, partially saturated or aromatic (i.e. heteroaryl), unless otherwise specified. Examples of 3-14 membered heterocyclyl groups include, but are not limited to: furan, azetidine, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidone, pyridone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1, 4-dioxane, 1, 4-thiane, indazole, quinoline, quinazoline, quinoxaline, indole, indoline, thiazole, thiophene, isoquinoline, isoindole, isoindoline, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzofuran, dihydrobenzofuran, dihydroisobenzofuran, benzodioxole, benzimidazole, benzotriazole, pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, purine, naphthyridine, or tetrahydronaphthyridine.

Bn is benzyl.

MOM means methoxymethyl.

Pin refers to pinacol.

The positive progress effects of the invention are as follows: the preparation method has the advantages of easily available raw materials, high yield, simple post-treatment and no need of column chromatography.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, room temperature means 15 ℃ to 25 ℃.

Instruments and materials: 1D and 2D NMR were measured on a Bruker Avance 500 NMR spectrometer with TMS as internal standard. ESI-MS was measured on an Agilent LC/MSD Trap XCT mass spectrometer. Thin Layer Chromatography (TLC) silica gel plate type HSGF 254; developing with ultraviolet and iodine cylinder; the silica gel for the flash column chromatography is H-type (granularity: 10-40 mu, pH 6-7) silica gel (100-200, 300-400 mesh, thin-layer chromatography silica gel). The reagents used were purchased from ACROS, TCI, Alfa, alatin, carbofuran and Aldrich, and the remaining analytical reagents were all produced by the national drug group chemical reagents ltd.

1. Synthesis of Compound 2-1

Iodine/copper acetate method: taking flavone 1-1(

5.4g, 10mmol) and copper acetate (2.0g, 10mmol) were suspended in anhydrous THF (100 mL). A THF solution of iodine (2.54g, 10mmol) was added dropwise at 0 deg.C, stirring was continued for 2 hours, filtration was carried out, the cake was washed three times with DCM, the filtrate was concentrated to give the crude product, and recrystallization was carried out with DCM/PE to give an off-white crystalline solid (5.1g, 78%).

Iodine/silver nitrate method: collecting flavone 1-1(5.4g, 10mmol) and AgNO₃(1.7g, 10mmol) was suspended in anhydrous DCM (100 mL). A solution of iodine (2.54g, 10mmol) in DCM was added dropwise at 0 deg.C, stirring was continued for 2 hours, filtration was carried out, the cake was washed three times with DCM, the filtrate was concentrated to give the crude product, and DCM/PE was recrystallized to give an off-white crystalline solid (6.1g, 92%).

Iodine/silver trifluoroacetate process: flavone 1-1(5.4g, 10mmol) and AgOTf (2.2g, 10mmol) were suspended in anhydrous DCM (100 mL). A solution of iodine (2.54g, 10mmol) in DCM was added dropwise at 0 deg.C, stirring was continued for 2 hours, filtration was carried out, the cake was washed three times with DCM, the filtrate was concentrated to give the crude product, and the crude product was recrystallized from DCM/PE to give an off-white crystalline solid (6.4g, 96%). .

¹H NMR(500MHz，CDCl₃)δ7.92(dd，J＝9.0，2.0Hz，2H)，7.46(d，J＝7.5Hz，2H)，7.36-7.20(m，13H)，7.00(dd，J＝9.0，2.0Hz，2H)，6.60(s，1H)，6.37(s，1H)，5.14(s，2H)， 5.08(s，2H)，5.06(s，2H)；¹³C NMR(126MHz，CDCl₃)δ177.2，161.5，161.4，160.4，157.6，136.3，136.1，135.4，128.7，128.3，128.2，127.9，127.4，127.0，126.7，123.6，115.3，106.8，96.0，71.3，70.2，66.3；ESI-MS：m/z 689.3[M+Na]⁺.

NIS method: flavone 1-1(5.4g, 10mmol) and NIS (2.25g, 10mmol) were suspended in anhydrous THF (100 mL). Stirring for 6 hours at room temperature under the protection of argon, TLC shows that no product is generated, heating to 70 ℃ and refluxing overnight, the conversion rate of raw materials does not exceed 50%, more impurities appear in a reaction system, and a target product is few and is difficult to separate and purify.

Iodine chloride method: dissolving flavone 1-1(5.4g, 10mmol) in anhydrous DCM, adding ICl (1.65g, 10mmol) at 0 deg.C under argon protection, naturally returning to room temperature, stirring for 12 hr, concentrating, and performing column chromatography (EA/PE, 1: 1) to obtain product (3.1g, 46%) and di-iodo byproduct 2 g.

Comparative example 1 reference is made to Bioorganic and Medicinal Chemistry Letters; 17; p.3212-3216

Acetic acid (100mL),

(2.2g, 10mmol), iodine (2.54g, 10mmol) and copper acetate (2.0g, 10mmol) are mixed and reacted at 60 ℃ for 3 hours with a yield of 45 percent, the reaction time is prolonged to 24 hours, the conversion rate of the raw materials is not more than 70 percent, and the yield is 53 percent.

2. Synthesis of Compound 3-1

PdCl₂/PPh₃The method comprises the following steps: taking iodo substance 2-1(6.6g, 10mmol), PdCl₂(88mg，0.5mmol)、PPh₃(262mg, 1mmol) in a three-necked flaskAdding anhydrous dioxane (80mL), potassium phosphate (6.36g, 30mmol) and PinBH (1.4g, 11mmol) under the protection of Ar, heating to 70 ℃, stirring for 3 hours, cooling to room temperature, adding water for quenching, extracting DCM for three times, washing with saturated saline water, drying with anhydrous sodium sulfate, and recrystallizing the crude product (DCM/PE) to obtain the product (5.1g, 78%).

PdBr₂/P(o-Tol)₃The method comprises the following steps: taking iodo product 2-1(6.6g, 10mmol), PdBr₂(133mg，0.5mmol)、P(o-Tol)₃(340mg, 1mmol) and a three-necked flask, adding anhydrous THF (100mL), potassium acetate (2.94g, 30mmol) and PinBH (1.4g, 11mmol) under the protection of Ar, heating to 70 ℃, stirring for 3 hours, cooling to room temperature, adding water for quenching, DCM extracting for three times, washing with saturated saline, washing with water, drying with anhydrous sodium sulfate, and recrystallizing the crude product (DCM/PE) to obtain the product (5.6g, 85%).

Pd(OAc)₂/P(o-Tol)₃The method comprises the following steps: taking iodo substance 2-1(6.6g, 10mmol), Pd (OAc)₂(112mg，0.5mmol)、P(o-Tol)₃(340mg, 1mmol) in a three-necked flask, adding anhydrous THF (100mL), TEA (3mL), PinBH (1.4g, 11mmol) under Ar protection, heating to 60 ℃, stirring for 3 hours, cooling to room temperature, adding water for quenching, DCM extracting for three times, washing with saturated saline, drying over anhydrous sodium sulfate, and recrystallizing the crude product (DCM/PE) to obtain the product (6.3g, 95%).

¹H NMR(500MHz，CDCl₃)δ7.98(d，J＝9.0Hz，2H)，7.57(d，J＝7.5Hz，2H)，7.48(d，J＝9.0Hz，2H)，7.46-7.31(m，13H)，7.04(d，J＝9.0Hz，2H)，6.69(s，1H)，6.43(s，1H)，5.25(s，2H)，5.13(s，2H)，5.09(s，2H)，1.30(s，12H)；¹³C NMR(126MHz，CDCl₃)δ178.3，167.0，162.7，162.0，161.5，161.4，136.4，136.4，136.2，128.8，128.7，128.5，128.4，128.3，128.1，127.8，127.7，127.4，126.7，124.6，115.0，109.6，107.3，95.2，84.0，77.4，71.1，70.6，70.3，25.2；ESI-MS：m/z 689.3[M+Na]⁺.

3. Synthesis of Compound 4-1

Sodium periodate method: the boronic acid ester 3-1(3.33g, 5mmol) was dissolved in 30mL of methanol, sodium periodate (2.13g, 10mmol, 30mL of aqueous solution) was added under ice-water bath, and stirred at room temperature for about 10 hours, after TLC showed completion of the raw material reaction, most of methanol was distilled off, 100mL of ethyl acetate and water were added and stirred, the aqueous layer was separated, the organic layer was washed once with water, concentrated, and recrystallized (PE/EA ═ 3/1) to obtain an off-white solid product (2.3g, 83%).

Sodium perborate method: the boronic acid ester 3-1(3.33g, 5mmol) was dissolved in 30mL of tetrahydrofuran, sodium perborate tetrahydrate (3.1g, 20mmol, 30mL of an aqueous solution) was added under an ice-water bath, and stirred at room temperature for about two hours, after TLC showed completion of the reaction of the starting material, 100mL of ethyl acetate and water were added and stirred, the aqueous layer was separated, washed once with water, concentrated, and recrystallized (PE/EA ═ 3/1) to give an off-white solid product (2.7g, 96%).

¹H NMR(500MHz，CDCl₃)δ8.94(br s，1H)，8.04(d，J＝9.0Hz，2H)，7.57(d，J＝7.5Hz，2H)，7.49(d，J＝7.5Hz，2H)，7.46(d，J＝7.5Hz，2H)，7.41-7.29(m，9H)，7.18(d，J＝9.0Hz，2H)，6.88(s，1H)，6.63(s，1H)，5.29(s，2H)，5.20(s，2H)，5.13(s，2H)；¹³C NMR(126MHz，CDCl₃)δ176.6，161.3，160.2，151.1，150.9，147.7，137.7，137.0，137.0，129.5，128.9，128.9，128.7，128.5，128.4，128.3，128.2，127.9，127.6，123.9，115.7，109.6，106.6，98.6，71.3，70.8，69.9；ESI-MS：m/z 579.3[M+Na]⁺

4. Synthesis of Compound 5-1

Lewis acid method: dissolving the compound 4-2(418mg, 1.0mmol, 1.0eq) in 10mL of anhydrous DCM, and dropwise adding BCl under the protection of argon at 0 DEG C₃(3.3mL, 3.3mmol, 1M DCM solution), stirring at room temperature until the raw material is completely consumed, adding water for quenching, separating out an organic phase, extracting the aqueous phase DCM once, combining the organic phases, and washing twice with waterConcentrated and the crude product recrystallized from 70% methanol to give the product (0.26g, 91%).

Catalytic hydrogenation: weighing the compound 4-1(556mg, 1.0mmol, 1.0eq) and 10% palladium carbon (53mg, 0.05mol, 0.05eq) in a reaction bottle, adding 10mL of methanol, replacing air with hydrogen for 5 times, stirring at room temperature until the raw materials are completely consumed, filtering, concentrating, and recrystallizing the crude product with 70% of methanol to obtain the product (0.27g, 95%).

¹H NMR(500MHz，DMSO)δ12.27(s，1H)，10.34(s，1H)，10.22(s，1H)，8.63(s，1H)，7.90(d，J＝9.0Hz，2H)，6.82(dd，J＝9.0，2.0Hz，2H)，6.63(s，1H)，6.15(s，1H)；¹³C NMR(126MHz，DMSO)δ182.5，164.0，161.6，153.8，153.5，145.9，129.1，125.5，121.9，116.3，103.7，102.8，99.0；ESI-MS：m/z 285.1[M-H]^-.

5. Synthesis of Compound 7

Weighing the compound 4-3(900mg, 2mmol, 1.0eq) and dissolving in 20mL of anhydrous DMF, adding sodium hydrogen (240mg, 10mmol, 5.0eq) at 0 ℃, dropwise adding methyl iodide (1.42g, 10mmol, 5.0eq) after 15 minutes, stirring at room temperature for 6 hours, adding water for quenching, extracting with DCM for three times, washing with saturated saline water, drying with anhydrous sodium sulfate, and concentrating to obtain a methylated product (835mg, 90%). The methylated product was taken up in a reaction flask with palladium hydroxide (140mg, 1mol, 0.5eq), 20mL methanol and 10mL ethyl acetate were added, hydrogen replaced, stirred at room temperature until the starting material was consumed, filtered, concentrated and the crude product was recrystallized (DCM/PE) to give the product as a yellow solid (445mg, 87%).

Weighing the compound 4-3(900mg, 2mmol, 1.0eq) and potassium carbonate (552mg, 4mmol, 2.0eq) in 30mL of acetone, dropping dimethyl sulfate (504mg, 4mmol, 2.0eq), heating to 60 ℃, stirring for 4 hours, evaporating to remove acetone, adding water for dilution, extracting with DCM for three times, washing with saturated saline water, drying with anhydrous sodium sulfate, and concentrating to obtain a methylated product (925mg, 99%). The methylated product was taken up in a reaction flask with 10% palladium on carbon (106mg, 1mol, 0.5eq), 20mL methanol and 10mL ethyl acetate were added, hydrogen replaced, stirred at room temperature until the material was completely consumed, filtered, concentrated, and the crude product was recrystallized (DCM/PE) to give the product as a yellow solid (540mg, 95%).

¹H NMR(500MHz，DMSO)δ12.50(s，1H)，10.84(s，1H)，8.07(d，J＝7.0Hz，2H)，7.62-7.61(m，3H，)，7.00(s，1H)，6.31(s，1H)，3.85(s，3H)；¹³C NMR(126MHz，DMSO)δ182.1，163.1，157.4，156.3，149.6，132.1，130.9，129.3，127.8，126.3，105.1，103.8，99.2，61.1；ESI-MS：m/z 282.9[M-H]^-.

6. Synthesis of Compound 9-1

Boronic acid ester 3-1(0.66g, 1mmol) was dissolved in THF (15mL), 5M aqueous sodium bicarbonate solution was added to 2mL, and DMDO (3mmol, 3mL, 1M acetone solution) was slowly added dropwise over a period of about 20 minutes to the mixture at 0 deg.C with vigorous stirring. After the addition, the reaction was stirred at this temperature overnight, quenched by addition of dilute sodium sulfite solution, the aqueous phase extracted with DCM (2X 100mL), the organic phases combined, washed with brine and dried over anhydrous sodium sulfate. Filtering, adding 10mg camphorsulfonic acid into the filtrate, stirring for 45 minutes at room temperature, and concentrating to obtain a crude product. The crude product was dissolved in hot methanol solution and crystallized at room temperature to give pale yellow 3-hydroxyflavone (0.43g, 75%).

Dissolving borate 3-1(0.66g, 1mmol) in DCM/Acetone (2: 1, 15rnL), adding dropwise carbonate (sodium carbonate/sodium bicarbonate 160/126mg, 1.5mmol each) buffer solution 20mL at 0 deg.C-15 deg.C, slowly adding hydrogen peroxymonosulfate into the mixture under vigorous stirringPotassium complex salt (Oxone) solution (2.0g 2 KHSO)₅·KHSO₄·K₂SO₄20mL of aqueous solution, 3.3mmol), the dropping time is about 90 minutes. After dropping, the reaction was stirred at room temperature overnight, the organic layer was separated, the aqueous phase was extracted with DCM (2X 100mL), the organic phases were combined, washed with saturated sodium thiosulfate, brine and dried over anhydrous sodium sulfate. Filtering, adding 10mg of p-toluenesulfonic acid into the filtrate, stirring for 45 minutes at room temperature, and concentrating to obtain a crude product. The crude product was dissolved in hot methanol solution and crystallized at room temperature to give pale yellow 3-hydroxyflavone (0.5g, 88%).

¹H NMR(500MHz，DMSO)δ8.99(s，1H)，8.77(s，1H)，8.10(d，J＝9.0Hz，2H)，7.56(d， J＝7.5Hz，2H)，7.43(d，J＝7.0Hz，2H)，7.38(d，J＝7.0Hz，2H)，7.31-7.11(m，9H)，7.10(d，J＝9.0Hz，2H)，6.81(s，1H），5.23(s，2H)，5.09(s，2H)，5.08(s，2H)；¹³C NMR(126MHz，DMSO)δ172.2，159.6，150.9，150.8，147.0，142.5，138.1，137.7，137.2，137.1，129.4，129.0，128.9，128.7，128.5，128.4，128.3，127.8，127.3，124.5，115.3，107.6，97.4，71.0，69.8；ESI-MS：m/z595.2[M+Na]⁺

7. Synthesis of Compound 10

Weighing MOM protected 9-2(434mg, 1.0mmol, 1.0eq), dissolving in 10mM LEOH, and adding H dropwise₂SO₄(1mL, 4.0mmol, 4.0eq, 4M), stirring at 60 ℃ for 2 hours, neutralizing with 20mL of aqueous sodium bicarbonate solution, extracting with ethyl acetate three times, combining the organic phases, washing with water twice, concentrating to obtain a crude product, and recrystallizing with 70% methanol to obtain the product (0.23g, 76%).

The compound benzyl protected 9-1(572mg, 1.0mmol, 1.0eq) was weighed into a reaction flask, and 5mL of dichloromethane and ice were added under protection of ArBCl is dropped into the water bath₃(4mL, 4.0mmol, 4.0eq, 1M), naturally returning to room temperature, stirring for 2 hours, dropping 10mL of water into an ice water bath to quench the reaction, washing the organic phase with water once, concentrating to obtain a crude product, and recrystallizing with 70% methanol to obtain a product (0.28g, 93%).

¹H NMR(500MHz，CD₃OD)δ8.19(d，J＝9.0Hz，2H)，6.89(d，J＝9.0Hz，2H)，6.23(s，1H)；¹³C NMR(125MHz，CD₃OD)δ176.3，159.2，153.2，152.9，146.7，145.3，135.5，129.6，124.6，122.6，114.9，102.9，97.6；ESI-MS：m/z 301.1[M-H]^-。

Claims

1. A method for preparing a compound shown as a formula 4 comprises the following steps: carrying out oxidation reaction on the compound 3 and an oxidant in a solvent to obtain a compound 4; the oxidant is sodium perborate or sodium periodate;

wherein the solvent is an ether solvent and water, or an alcohol solvent and water; the ether solvent is tetrahydrofuran and/or 2-methyltetrahydrofuran, and the alcohol solvent is one or more of methanol, ethanol and isopropanol;

the compound 3 is

The compound 4 is

2. The method according to claim 1, wherein in the method for producing the compound 4, the volume molar ratio of the solvent to the compound 3 is 3.0 to 9.0L/mol;

and/or, in the preparation method of the compound 4, the molar ratio of the oxidant to the compound 3 is 1.0-5.0;

and/or, in the preparation method of the compound 4, the temperature of the oxidation reaction is 0-60 ℃;

and/or, in the preparation method of the compound 4, the progress of the oxidation reaction is ended when the compound 3 is not reacted any more.

3. The method according to claim 2, wherein in the method for producing the compound 4, the volume molar ratio of the solvent to the compound 3 is 3.0 to 6.0L/mol;

and/or, in the preparation method of the compound 4, the molar ratio of the oxidant to the compound 3 is 2.0-4.0;

and/or, in the preparation method of the compound 4, the temperature of the oxidation reaction is 20-25 ℃.

4. The method of claim 1, further comprising the steps of: in a solvent, in the presence of alkali, a ligand and a catalyst, carrying out a boric acid esterification reaction on a compound 2 and a boron source to obtain a compound 3;

the solvent is an organic solvent; the organic solvent is an ether solvent; the ether solvent is one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran;

the alkali is inorganic alkali or organic alkali; the inorganic alkali is one or more of sodium acetate, potassium acetate, sodium phosphate and potassium phosphate; the organic base is triethylamine;

the catalyst and the ligand are PdCl₂/PPh₃、PdBr₂/P(o-Tol)₃Or Pd (OAc)₂/P(o-Tol)₃；

The compound 2 is

The boron source is pinacol borane; the boric acid esterification reaction is carried out in the presence of protective gas.

5. The method according to claim 4, wherein in the method for producing the compound 3, the volume molar ratio of the solvent to the compound 2 is 5.0 to 15.0L/mol;

and/or, in the preparation method of the compound 3, the molar ratio of the alkali to the compound 2 is 1.0-5.0;

and/or, in the preparation method of the compound 3, the molar ratio of the catalyst to the compound 2 is 0.01-0.1;

and/or, in the preparation method of the compound 3, the molar ratio of the ligand to the compound 2 is 0.05-0.2;

and/or, in the preparation method of the compound 3, the molar ratio of the boron source to the compound 2 is 1.0-1.5;

and/or, in the preparation method of the compound 3, the temperature of the boric acid esterification reaction is 20-120 ℃;

and/or, in the preparation method of the compound 3, the progress of the boric acid esterification reaction is ended when the compound 2 is not reacted any more.

6. The method according to claim 5, wherein in the method for preparing the compound 3, the protective gas is nitrogen or argon;

and/or in the preparation method of the compound 3, the volume mol ratio of the solvent to the compound 2 is 8.0-10.0L/mol;

and/or, in the preparation method of the compound 3, the molar ratio of the alkali to the compound 2 is 2.0-3.0;

and/or, in the preparation method of the compound 3, the molar ratio of the ligand to the compound 2 is 0.05-0.1;

and/or, in the preparation method of the compound 3, the molar ratio of the boron source to the compound 2 is 1.1-1.5;

and/or, in the preparation method of the compound 3, the temperature of the boric acid esterification reaction is 55-75 ℃.

7. The method of claim 4, further comprising the steps of: in a solvent, in the presence of iodine and silver salt or iodine and copper salt, carrying out iodination reaction on the compound 1 to obtain a compound 2;

the solvent is an organic solvent; the organic solvent is a halogenated hydrocarbon solvent or an ether solvent; the halogenated hydrocarbon solvent is a chlorinated hydrocarbon solvent; the ether solvent is one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran;

the silver salt is silver trifluoroacetate and/or silver nitrate; the copper salt is copper acetate;

the compound 1 is

8. The method according to claim 7, wherein in the method for producing the compound 2, the iodination reaction is carried out in the presence of a protective gas;

and/or, in the preparation method of the compound 2, the volume mol ratio of the solvent to the compound 1 is 5.0-15.0L/mol;

and/or in the preparation method of the compound 2, the molar ratio of the silver salt to the compound 2 or the molar ratio of the copper salt to the compound 2 is 1.0-5.0;

and/or, in the preparation method of the compound 2, the molar ratio of the iodine to the compound 2 is 1.0-2.0;

and/or, in the preparation method of the compound 2, the temperature of the iodination reaction is 0-20 ℃;

and/or, in the preparation method of the compound 2, the progress of the iodination reaction is terminated when the compound 1 is no longer reacted.

9. The method according to claim 8, wherein in the method for preparing the compound 2, the shielding gas is nitrogen or argon;

and/or in the preparation method of the compound 2, the volume mol ratio of the solvent to the compound 1 is 8.0-10.0L/mol.

10. The process according to claim 9, wherein the chlorinated hydrocarbon solvent is dichloromethane and/or dichloroethane in the process for preparing the compound 2.

11. A preparation method of a compound shown as a formula 5 is characterized by comprising the following steps:

(1) preparing a compound 4 according to the method for preparing a compound 4 as claimed in any one of claims 1 to 10;

wherein, the compound 4 is

The compound 5 is

The deprotection reaction conditions are as follows: in methanol or ethanol, under hydrogen, in the presence of palladium on carbon.

12. A method for preparing a compound shown as a formula 6 comprises the following steps:

wherein, the compound 4 is

The compound 6 is

The methylation reaction conditions are as follows: in N, N-dimethylformamide or acetone in the presence of sodium hydrogen or potassium carbonate;

the methylating agent is methyl iodide or dimethyl sulfate.

13. A method for preparing a compound shown as a formula 7 comprises the following steps:

(1) the process for preparing compound 6 according to claim 12, to obtain compound 6;

wherein, the compound 6 is

The compound 7 is

The deprotection reaction conditions are as follows: in methanol or ethyl acetate under hydrogen in the presence of palladium on carbon or palladium hydroxide.

14. A compound of formula 3:

the compound 3 is

15. A method for preparing the compound represented by formula 3 according to claim 14, comprising the steps of: in a solvent, carrying out a boric acid esterification reaction on a compound 2 and a boron source in the presence of alkali, a ligand and a catalyst to obtain a compound 3;

the compound 2 is

The compound 3 is

Wherein the parameters of the boration reaction are as defined in any one of claims 4 to 6.

16. The method of claim 15, further comprising the steps of: in a solvent, in the presence of iodine and silver salt or iodine and copper salt, carrying out iodination reaction on the compound 1 to obtain a compound 2;

the compound 1 is

The compound 2 is

Wherein the parameters of the iodination reaction are defined in any one of claims 7 to 10.