WO2016086674A1 - Method for preparing halogenated 4-chromanone derivative - Google Patents

Abstract

Disclosed is a method for preparing a chemical medicine, which particularly relates to a method for preparing a halogenated 4-chromanone derivative. In the present invention, a compound represented by formula (II) and a compound represented by formula (III) are used as initial raw materials to perform an esterification reaction, then perform a rearrangement reaction, and finally perform a cyclization reaction, so as to obtain the halogenated 4-chromanone derivative. The present invention has the advantages of low production cost, high yield, simple operation and short cycle, and is a brand-new preparation process suitable for industrial production.

Description

Preparation method of halogenated 4-chromanone derivative Technical field

The invention relates to a preparation method of a chemical medicine, in particular to a preparation method of a halogenated 4-chromanone derivative.

Background technique

4-chromanone is a kind of natural compound with a wide range of biological activities. It exists in many forms in nature and has a wide range of biological activities such as anti-inflammatory and anti-allergic activity, anti-cancer activity, anti-platelet aggregation and excellent antibacterial activity. Activity, which is also an active ingredient in many traditional Chinese medicines, is of great significance in drug synthesis. The introduction of such compounds into pharmaceutical synthesis has found that many of the chromanone and its derivatives have important physiological activities and pharmacological effects. Five kinds of 3-arylmethyl-4-chromanone compounds isolated from Mucscari comoum by Loggia et al. Experiments showed that all compounds have significant inhibitory effects on croton oil-induced ear swelling in mice; Bikker et al synthesized some 7-[2-(Imidazolyl)ethoxy]-4-chromone compound and 7-[2-(imidazolyl)ethoxy]-4-chromanone compound and their anticancer activity Studies have shown that these compounds have inhibitory farnesyltransferase activity, among which 7-[2-(imidazolyl)ethoxy]-4-chromone and 7-[2-(imidazolyl)ethoxy]- The IC50 of the 4 ^- chromanone ^- inhibiting farnesyltransferase was 2.6, 4.4 μmol·L ^-1 , respectively. Kataoka et al. synthesized some 8-position amide 4-chromanone derivatives and tested their inhibition of acetyl-CoA activity in rabbit small intestine and total cholesterol in rat serum.

Background technique

There are many synthetic methods for chromanone compounds, and the following two are commonly used:

According to HETEROCY CLES, 1994, 28(9): 2099-114, Acta Chim Hung, 1988, 125(2): 303-12 and J Med Chem, 1969, 12(2): 277-9. Acrylic acid and acryloyl chloride are used as raw materials and substituted phenol in the presence of sodium methoxide, and the addition reaction is carried out to obtain methyl phenoxypropionate, which is then hydrolyzed to obtain a chromone, wherein the addition reaction has a long reaction time and a low yield. And the isomers are present in the ring, the separation is difficult, the operation is complicated, and there is no industrial prospect.

According to WO2008043019; Bioorganic & Medicinal Chemistry 14 (2006): 2545-2551, it is reported in detail that sodium aryloxypropionate is obtained by heating and refluxing phenol and halopropionic acid under basic conditions to condense. The product is acidified with hydrochloric acid to obtain aryloxypropionic acid, which is then dehydrated by concentrated sulfuric acid at room temperature to obtain a chromanone. This process uses concentrated sulfuric acid as a cyclization reagent, which is highly polluting to the environment. Or according to J Am Chem Soc. 1954, 76(20): 5065-5069; J Indian Chem Soc, 1958, 35(2): 95-8; Tetrahedron Letters 44 (2003) 4007-4010, using oxalyl chloride as the acyl group The reagent is further subjected to intramolecular Friedel-Crafts acylation using aluminum trichloride to obtain a 4-chroman ketone compound. Such a method has the disadvantages of serious three wastes, high catalyst, long process cycle and low yield. In addition, the cyclization catalyzed by concentrated sulfuric acid must be controlled at room temperature, and carbonization is likely to occur when the temperature is too high, but there is also a production of rearranged isomers. The yield is lowered.

Therefore, it is necessary to provide a preparation method of a halogenated 4-chromanone derivative which is simple in process, low in waste, and low in cost.

Summary of the invention

The invention overcomes the shortcomings of the prior art, has complicated operation and low yield, and provides a novel preparation process with low cost, high yield, simple operation, short cycle and suitable for industrial production.

In order to achieve the above object, the solution adopted by the present invention is:

Step 1: Esterification reaction

Starting from a compound of the formula (II) and a compound of the formula (III) to give a compound of the formula (IV), the reaction can be carried out in a solvent-free or stable inert solvent, the selected solvent comprising: a halogenated aliphatic hydrocarbon such as dichloro Methane, chloroform, dichloroethane, esters such as ethyl acetate, acetonitrile, ketones such as acetone, ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, aromatic hydrocarbons and their derivatives such as toluene, xylene, Chlorobenzene, dichlorobenzene, Nitrobenzene or the like, an alkane such as petroleum ether, etc., wherein the preferred solvent is nitrobenzene;

The compound of the formula (III) is selected in an amount of from 1:0.9 to 1.5, preferably 1:1.1;

The reaction temperature of the step may vary within a wide range depending on the solvent selected, for example, the reaction temperature is between -20 ° C and 100 ° C, preferably between -5 ° C and 50 ° C, more preferably between 20 and 35 ° C;

When R ₅ is a halogen, the acid binding agent selected in the step includes hydroxides of alkali metals and alkaline earth metals thereof, such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc., carbonates, Bicarbonate such as potassium carbonate, sodium carbonate, etc., potassium hydrogencarbonate, sodium hydrogencarbonate, etc., alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., preferably sodium hydroxide, organic amines such as trimethylamine, triethylamine, Pyridine or the like and derivatives thereof, preferably triethylamine;

When R ₅ is -OH, the catalyst selected for this step includes a strong protic acid such as concentrated sulfuric acid, dry hydrogen halide, p-toluenesulfonic acid, etc.; anhydrous acid salt such as AlCl ₃ , FeCl ₃ , potassium hydrogen sulfate, Sodium acetate or the like; some special oxides such as alumina, silica, zinc oxide, titanium dioxide, tetrabutyl titanate, etc.; strongly acidic cation exchange resins and molecular sieves, preferably concentrated sulfuric acid.

This step reaction generally has an excellent yield, and the compound of the formula (IV) typically has a yield of more than 95% or even 100%. Step 2: Rearrangement reaction

The resulting compound of formula (IV) is rearranged under Lewis acid catalyst to give a compound of formula (V) in an aromatic hydrocarbon and its derivatives such as toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene or halogen. A hydrocarbon-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the like, an alkane such as petroleum ether or the like, preferably a solvent of nitrobenzene; or a solventless system.

As described above, the solvent is used in an amount of 2 to 7 times by weight, preferably 2 to 4 times by weight, based on the compound (IV).

The Lewis acid catalyst selected includes aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride and triflate, such as aluminum triflate. Lanthanum triflate, calcium triflate, trifluoromethanesulfonate, ruthenium triflate, etc., and protonic acids such as hydrogen fluoride or methanesulfonic acid, preferably aluminum trichloride, ferric chloride and tetra Titanium chloride, the amount of the catalyst is 1:0.5-2 (molar ratio), preferably 1-0.9:1.5 (molar ratio);

The reaction temperature of this step may vary within a wide range depending on the solvent selected, for example, the reaction temperature is between 60 ° C and 200 ° C, preferably between 90 ° C and 150 ° C, more preferably between 115 and 135 ° C; When a solvent having a low boiling point is used, the solvent is distilled off to reach the reaction temperature required for the reaction.

The typical yield of the compound of formula (V) in this step is over 80%.

Step 3: Cyclization reaction

The obtained compound of the formula (V) is cyclized under basic conditions to give a compound of the formula (I), which is a halogenated aliphatic hydrocarbon such as dichloromethane, chloroform, dichloroethane, an ester such as ethyl acetate, acetonitrile or ketone. Such as acetone, etc., ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, etc., aromatic hydrocarbons such as toluene, xylene, etc., halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, alkanes such as petroleum ether, etc., preferably petroleum ether; The solvent is used in an amount of 4 to 10 times by weight, preferably 4 to 6 times by weight, based on the compound (IV).

The reaction temperature of the step may vary within a wide range depending on the solvent selected, for example, the reaction temperature is between -5 ° C and 100 ° C, preferably between 40 and 70 ° C;

The base selected for the cyclization includes: hydroxides of alkali metals and alkaline earth metals thereof, such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc.; carbonates, hydrogencarbonates such as potassium carbonate, carbonic acid Sodium or the like, potassium hydrogencarbonate, sodium hydrogencarbonate or the like; alkoxides, including sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., preferably sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, sodium hydrogencarbonate.

Advantageous Effects: Compared with the prior art, the invention has a novel production process with low production cost, high yield, simple operation, short cycle and suitable for industrial production.

detailed description

The implementation of the present invention will be specifically described below:

Example 1

(1) 112.1 g of 2-fluorophenol of the compound of the formula (II), ie, 1.0 mol, 119 g of 3-chloropropionic acid, ie 1.1 mol, was introduced into a 2 L four-necked flask equipped with a condenser and mechanical stirring under a nitrogen atmosphere, and 102g of aluminum oxide, heated to 100 ° C, water separation, the reaction is finished, washed with water, washed with saturated sodium bicarbonate until neutral, dried, directly used for the next reaction;

(2) 33.9 g of boron trifluoride, that is, 0.5 mol, was added to the reactant within 1 hour, maintaining the reaction temperature at 120 ° C, and the generated hydrogen chloride gas was absorbed by a sodium hydroxide solution, and reacted for 5 hours. The HPLC was followed until the reaction was over. After the reaction is completed, the solvent is distilled off;

(3) 1.2 kg of ethyl acetate was added to the product obtained above, and 250 g of ice and 600 ml of concentrated hydrochloric acid were stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phase was combined, 150 g of ice water and 40 g of sodium hydroxide were added and stirred for 1 hour, and the solvent was evaporated to give 4-fluoro-chroman-4-one crude product which was recrystallized to give white 4-fluoro-chroman-4-one. 134.5 g, purity 99%, total yield 81%.

Example 2

Preparation (5-fluoro-chroman-4-one):

(1) Under a nitrogen atmosphere, 112.1 g of 3-fluorophenol of the compound of formula (II), ie 1.0 mol, was added to a 2 L four-necked flask equipped with a condenser and mechanically stirred, and 97.4 g of 3-chloropropionic acid was added, ie 0.9 mol. 400 g of tetrahydrofuran was added, 147 g of concentrated sulfuric acid was added, and the reaction temperature was maintained at -5 °C. The reaction is completed, washed with water, washed with saturated sodium hydrogencarbonate until neutral, dried and used directly for the next reaction;

(2) 113.8 g of titanium tetrachloride, ie 0.6 mol, was added to the reactant within 1 hour, maintaining the reaction temperature at 60 ° C, and the generated hydrogen chloride gas was absorbed with a sodium hydroxide solution, and reacted for 5 hours. The HPLC was followed until the reaction was over. After the reaction is completed, the solvent is distilled off;

(3) 2.2 kg of petroleum ether, 250 g of ice and 600 ml of concentrated hydrochloric acid were added to the product obtained above, and the mixture was stirred for 30 minutes, and the organic phase was separated, and the aqueous phase was extracted twice with petroleum ether. The organic phase was combined, 150 g of ice water and 67.2 g of potassium hydroxide were added and stirred for 1 hour, and the solvent was evaporated to give 4-fluoro-chroman-4-one crude product which was recrystallized to give white 4-fluoro-chroman-4- The ketone was 136.3 g, and the purity was 99%, which was 82.1% in total.

Example 3

Preparation (6-bromo-chroman-4-one):

(1) In a nitrogen atmosphere, 173 g of compound 3-bromophenol, ie, 1.0 mol, and 780 g of dry toluene were charged into a 2 L four-necked flask equipped with a condenser and mechanically stirred. After completely dissolved by heating, 3-chloropropionyl chloride 127.3 g was charged. , that is, 1.0 mol and 172.3 g of sodium t-butoxide, the control temperature does not exceed 25 ° C, the reaction is finished, washed with water, washed with saturated sodium hydrogencarbonate until neutral, dried, directly used for the next reaction;

(2) 113.5 g of ferric chloride, that is, 0.7 mol, was added to the reactant within 1 hour, and the mixture was heated under reflux, and the generated hydrogen chloride gas was absorbed with a sodium hydroxide solution, reacted for 5 hours, and traced by HPLC until The reaction is over. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 1.3 kg of diisopropyl ether, 250 g of ice and 600 ml of concentrated hydrochloric acid were added, and the mixture was stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted twice with diisopropyl ether. The organic phase was combined, 150 g of ice water and 192 g of sodium ethoxide were added and stirred for 1 hour, and the solvent was evaporated to give 5,7-difluoro-chroman-4-one crude product, which was recrystallized to give white 6-bromo-chromane-4. - 186.2 g of ketone, purity 99%, total yield 82%.

Example 4

Preparation of (5,6-difluoro-chroman-4-one):

(1) In a nitrogen atmosphere, a compound of formula (II), 130.1 g of 3,4-difluorophenol, 1.0 mol, 1 kg of solvent petroleum ether, was charged into a 2 L four-necked flask equipped with a condenser and heated to dissolve. , join 3 227.9 g of bromopropionic acid, ie 1.5 mol, 223.9 g of p-toluenesulfonic acid was added, heated to 35 ° C, water was separated, the reaction was completed, washed with water, washed with saturated sodium bicarbonate until neutral, dried and used directly for the next reaction. ;

(2) 120 g of trifluoromethanesulfonic acid, i.e., 0.8 mol, was added in portions to the above-mentioned reactants, maintaining the reaction temperature at 75 ° C, and the generated hydrogen chloride gas was absorbed with a sodium hydroxide solution, reacted for 5 hours, and traced by HPLC. Until the end of the reaction. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 800 g of dichloromethane, 250 g of ice and 600 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phase was combined, 150 g of ice water and 229.5 g of potassium hydrogencarbonate were added and stirred for 1 hour, and the solvent was distilled off to obtain crude 5,6-difluoro-chroman-4-one, which was recrystallized to give white 5,6-difluoro. - Color full-4-ketone 156.6 g, purity 99%, total yield 85.1%. Example 5

Preparation of (6-bromo-4-fluoro-chroman-4-one)

(1) Under a nitrogen atmosphere, 191 g of 4-bromo-2-fluorophenol of the compound of formula (II), ie 1.0 mol, 1.6 kg of solvent nitrobenzene, was charged into a 2 L four-necked flask equipped with a condenser and mechanically stirred, and heated to After dissolution, add 182.3 g of 3-bromopropionic acid, ie 1.2 mol, and 122.1 g of zinc oxide, heat to 100 ° C, separate the water, the reaction is finished, wash with water, wash with saturated sodium bicarbonate until neutral, dry, directly used Next reaction;

(2) 204.5 g of zinc chloride, i.e., 1.5 mol, was added to the above reactants in portions, maintaining the reaction temperature at 200 ° C, and the generated hydrogen chloride gas was absorbed with a sodium hydroxide solution, reacted for 5 hours, and traced by HPLC until The reaction is over. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 1.3 kg of dichloromethane, 250 g of ice and 600 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phase was combined, 150 g of ice water and 212 g of sodium carbonate were added, and the mixture was stirred for 1 hour, and the solvent was evaporated to give 6-bromo-4-fluoro-chroman-4-one crude product which was crystallized to give white 6-bromo-4- Fluorine-chroman-4-one 205.6 g product, purity 99%, total yield 83.9%.

Example 6

Preparation of (4-chloro-6-fluoro-chroman-4-one):

(1) Under a nitrogen atmosphere, put 146.6 g of compound 2-chloro-6-fluorophenol into a 2 L four-necked flask equipped with a condenser and mechanically stirred, that is, 1.0 mol, dry chloroform (1.3 kg), completely dissolved by heating, and then put into 3 - chloropropionyl chloride 140g, ie 1.1mol and 138.2g of potassium carbonate, heated to reflux, after the reaction is completed, washed with saturated sodium bicarbonate solution to neutral, dried, directly used for the next reaction;

(2) 105.7 g of methanesulfonic acid, that is, 1.1 mol, was added to the reactant within 1 hour, and heated under reflux. The hydrogen chloride gas generated during the reaction was absorbed with a sodium hydroxide solution, reacted for 5 hours, and traced by HPLC. Until the end of the reaction. After the reaction is completed, the solvent is distilled off;

(3) 1.8 kg of petroleum ether was added to the product obtained above, and 250 g of ice and 600 ml of concentrated hydrochloric acid were stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted three times with petroleum ether. The organic phase was combined, 150 g of ice water and 276.4 g of potassium carbonate were added, and the mixture was stirred for 1 hour, and the solvent was evaporated to give 4-chloro-6-fluoro-chroman-4-one as a crude product. - Color full-4-ketone 166.5 g, purity 99%, total yield 79%.

Example 7

Preparation of (4,6-difluoro-chroman-4-one):

(1) In a nitrogen atmosphere, a compound 2,4-difluorophenol (130.1 g, ie, 1.0 mol, 1.5 kg of dry chlorobenzene) was placed in a 2 L four-necked flask equipped with a condenser and mechanically stirred, and heated to complete dissolution. 178.2 g of 3-chloropropionyl chloride, i.e., 1.4 mol and 117.6 g of sodium hydrogencarbonate, and the reaction temperature was 30 ° C, and the reaction was monitored. After the reaction is completed, it is washed with a saturated sodium hydrogencarbonate solution until neutral, dried, and used directly for the next reaction;

(2) 160g of aluminum trichloride, ie 1.2mol, was added to the reactant within 1 hour, heated to 90 ° C, hydrogen chloride gas generated during the reaction was absorbed with sodium hydroxide solution, reacted for 5 hours, using HPLC Track until the reaction is over. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 900 g of chloroform, 250 g of ice and 600 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted twice with chloroform. The organic phases were combined, and 150 g of ice water and 81 g of sodium methoxide were added, and the mixture was stirred for 1 hour, and the solvent was evaporated to give 4,6-difluoro-chroman-4-one crude product which was recrystallized to give white product 4, 6- Difluoro-chroman-4-one 158.8 g, purity 99%, total yield 86.3%.

Example 8

Preparation of (4,5,7-trifluoro-chroman-4-one):

(1) Under a nitrogen atmosphere, 148.1 g of 1,2,4-trifluorophenol (1,2,4-trifluorophenol) of the compound of formula (II), 1.0 mol, 1.0 kg of ethyl acetate, was charged into a 2 L four-necked flask equipped with a condenser and mechanically stirred. After heating to dissolve, add 180.8 g of 3-iodopropionic acid, ie 1.3 mol, and add 98.4 g of sodium acetate, heat to 50 ° C, and separate the water. After the reaction is finished, wash with water and wash with saturated sodium bicarbonate solution until neutral. , dried, used directly in the next reaction;

(2) 284.5 g of titanium tetrachloride, that is, 1.5 mol, was added in portions to the above-mentioned reactants, and the reaction temperature was maintained at 70 ° C. The generated hydrogen chloride gas was absorbed by a sodium hydroxide solution, and reacted for 5 hours, followed by HPLC. Trace until the end of the reaction. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 1.65 kg of dichloroethane was added, and 250 g of ice and 600 ml of concentrated hydrochloric acid were stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted three times with dichloroethane. The organic phases were combined, 150 g of ice water and 159 g of sodium carbonate were added, and the mixture was stirred for 1 hour, and the solvent was evaporated to give 4,5,7-trifluoro-chroman-4-one crude product which was recrystallized to give the pure product 4, 5. 7-Trifluoro-chroman-4-one 171.2 g, purity 99%, total yield 84.7%.

Example 9

Preparation of (4-bromo-6,7-difluoro-chroman-4-one):

(1) Under a nitrogen atmosphere, 207.9 g of 2-bromo-4,5-difluorophenol of the compound of formula (II), ie 1.0 mol, was added to a 2 L four-necked flask equipped with a condenser and mechanical stirring, and 3-chloro was added dropwise. Propyl chloride 114.5g, that is, 0.9mol, 111.3g of triethylamine was added, the temperature was 35 ° C, the reaction was completed, washed with water, washed with a saturated sodium hydrogen carbonate solution until neutral, dried, directly used for the next reaction;

(2) 324.4 g of ferric chloride, ie 2.0 mol, was added to the reactant within 1 hour, maintaining the reaction temperature at 150 ° C, and the generated hydrogen chloride gas was absorbed by a sodium hydroxide solution, and reacted for 5 hours. The HPLC was followed until the reaction was over. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 2 kg of toluene, 250 g of ice and 600 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, the organic phase was separated, and the aqueous phase was extracted three times with petroleum ether. The organic phase was combined, and 150 g of ice water and 40 g of sodium hydroxide were added and stirred for 1 hour, and the solvent was distilled off to obtain a crude 5,7-difluoro-chroman-4-one, which was recrystallized to give white 5,7-difluoro. - Color full-4-ketone 198.2 g, purity 99%, total yield 93.3%.

Example 10

Preparation of (5-chloro-6,7-difluoro-chroman-4-one):

(1) Under a nitrogen atmosphere, a compound of formula (II), 3-4.5 mg of 3-chloro-4,5-difluorophenol, is added to a 2 L four-necked flask equipped with a condensing tube and mechanically stirred, ie, 1.0 mol, dry dichloroethane. 1.1kg of alkane solvent, adding 235.2g of 3-bromopropionyl bromide, ie 1.1mol, adding 84.2g of potassium hydroxide solid, the temperature is 75 ° C, the reaction is finished, washed with water, washed with saturated sodium bicarbonate solution to neutral, dry , the product obtained by removing the solvent is directly used for the next reaction;

(2) 474.2 g of aluminum trifluoromethanesulfonate, i.e., 1.0 mol, was added to the reactant within 1 hour, and heated under reflux. The hydrogen chloride gas generated was absorbed with a sodium hydroxide solution, reacted for 5 hours, and traced by HPLC. Until the reaction is over. After the reaction is completed, the solvent is distilled off;

(3) To the product obtained above, 2 kg of chlorobenzene, 250 g of ice and 600 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, and the organic phase was separated, and the aqueous phase was extracted three times with chlorobenzene. The organic phases were combined, and 150 g of ice water and 336.6 g of potassium t-butoxide were added and stirred for 1 hour, and the solvent was evaporated to give 5-chloro-6,7-difluoro-chroman-4-one as a crude product. 5-chloro-6,7-difluoro-chroman-4-one 181.1 g, purity 99%, total yield 82.9%.

Claims (9)

A method for preparing a halogenated 4-chromanone derivative, wherein the halogenated 4-chromanone derivative has the formula (I),

among them: R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and bromine, and R ₁ -R _{4 are} not hydrogen at the same time; R ₆ and R ₇ are hydrogen, C ₁ -C ₆ alkyl, alkenyl, alkynyl and derivatives thereof; It is characterized by the following steps: (1) Compound of formula (II)

Reacting with a compound of formula (III);

Wherein, in the formula (II), R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, fluorine, chlorine and bromine, and R _{1 to} R _{4 are} not hydrogen at the same time; Wherein, in the formula (III), R ₆ , R ₇ are hydrogen, C ₁ -C ₆ alkyl, alkenyl, alkynyl and derivatives thereof; R ₅ is OH, Cl, Br, I; X is -Cl, - Br,-I; The above reaction is carried out between -20 ° C and 100 ° C to obtain a compound of the formula (IV):

Wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and bromine, and R ₁ -R _{4 are} not hydrogen at the same time; R ₆ and R ₇ are hydrogen, C ₁ -C ₆ alkyl, alkenyl, alkynyl and derivatives thereof; X is -Cl, -Br, -I; (2) The compound of the formula (IV) thus obtained is rearranged under the catalysis of a Lewis acid catalyst to give a compound of the formula (V):

Wherein R ₁ , R ₂ , R ₃ and R ₄ in the formula (V) are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and bromine, and R _{1 -} R _{4 are} not simultaneously hydrogen; and R ₆ and R ₇ are hydrogen. , C ₁ -C ₆ alkyl, alkenyl, alkynyl and derivatives thereof; X is -Cl, -Br, -I; (3) The obtained compound of the formula (V) is cyclized under basic conditions to give a compound of the formula (I):

The cyclization reaction is carried out in a halogenated aliphatic hydrocarbon, an ester, a ketone, an ether, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, or an alkane solvent; the basic conditions are an alkali metal and an alkaline earth metal thereof, sodium alkoxide. The process according to claim 1, wherein the reaction of the compound of the formula (II) with the compound of the formula (III) in the step (1) is carried out in the following solvent: the solvent is: dichloromethane, chloroform, dichloroethane , ethyl acetate, acetonitrile, acetone, diethyl ether, diisopropyl ether, tetrahydrofuran, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, or petroleum ether; The molar ratio of the compound of the formula (II) to the compound of the formula (III) is from 1:0.9 to 1.5, and the reaction temperature is controlled from 20 ° C to 35 ° C. The process according to claim 2, wherein the reaction of the compound of the formula (II) with the compound of the formula (III) in the step (1) is carried out in a nitrobenzene solvent; the compound of the formula (II) and the compound of the formula (III) The molar ratio is 1:1.1. The preparation method according to claim 1, wherein in the step (1), the compound of the formula (II) and the compound of the formula (III) include a catalyst in addition to the catalyst, and an acid binding agent is further added; The catalysts are: concentrated sulfuric acid, dry hydrogen halide, p-benzoic acid, AlCl ₃ , FeCl ₃ , potassium hydrogen sulfate, sodium acetate, aluminum oxide, silicon dioxide, zinc oxide, titanium dioxide, tetrabutyl titanate. a strong acid cation exchange resin, or one of molecular sieves; The acid binding agent is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, or organic amine. One type; Wherein, the ratio of the amount of the compound of the formula (II) to the molar amount of the catalyst is 1:1 to 1.5, and the molar ratio of the acid binding agent is 1:1 to 1.5. The preparation method according to claim 4, wherein the catalyst is: concentrated sulfuric acid; the acid binding agent is sodium hydroxide, trimethylamine, triethylamine, or pyridine. The method according to claim 1, wherein the Lewis acid catalyst in the rearrangement reaction of the compound of the formula (IV) in the step (2) is: aluminum trichloride, boron trifluoride, zinc chloride, chlorination. Iron, titanium tetrachloride, tin tetrachloride, trifluoromethanesulfonate, hydrogen fluoride, or methanesulfonic acid; and rearrangement reaction in toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, or petroleum ether In a solvent; The temperature of the rearrangement reaction is controlled at 60 ° C - 200 ° C; the molar ratio of the compound of the formula (IV) to the catalyst is 1:0.5-2; the solvent is used in an amount of 2-7 times the weight ratio of the compound (IV). The preparation method according to claim 6, wherein the catalyst in the step (2) is aluminum trichloride, ferric chloride or titanium tetrachloride, and the molar ratio of the catalyst is 1:0.9-1.5; The amount used is 2-4 times by weight of the compound (IV), and the reaction temperature is controlled to be 115-135 °C. The preparation method according to claim 1, wherein the solvent of the cyclization reaction of the formula (V) in the step (3) is: dichloromethane, chloroform, dichloroethane, ethyl acetate, acetonitrile, acetone, diethyl ether, Tetrahydrofuran, diisopropyl ether, toluene, xylene, chlorobenzene, dichlorobenzene, or petroleum ether; the solvent is used in an amount of 4-10 times by weight of the compound (IV); The temperature of the cyclization reaction of the compound of the formula (V) is controlled at -5 ° C - 100 ° C; the molar ratio of the compound of the formula (V) to the amount of the base is 1:1 - 3; the basic substance is potassium carbonate, sodium carbonate, potassium hydrogencarbonate , sodium bicarbonate, sodium methoxide, sodium ethoxide, or sodium t-butoxide. The preparation method according to claim 8, wherein the solvent is used in the step (3) in a weight ratio of 4-6 times the compound (IV); the temperature of the cyclization reaction is controlled at 40 ° C - 70 ° C; The basic substance selected is sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, or sodium hydrogencarbonate.