CN105524032A - Method for producing isobenzofuran-1 (3H) -one compound - Google Patents

Abstract

A method for preparing isobenzofuran-1(3H)-one compounds having the following formula I, wherein R1, R2 and p are as defined in the specification.

Description

Method for preparing isobenzofuran-1(3H)-one series compound

technical field

The present invention relates to a method for preparing isobenzofuran-1(3H)-one series compounds; in particular to a method for preparing (Z)-3-butylene isobenzofuran-1(3H)-one ((Z) -3-butylideneisobenzofuran-1(3H)-one), namely (Z)-n-butylidenephthalide ((Z)-n-butylidenephthalide) method.

Background technique

3-Butylideneisobenzofuran-1(3H)-one (3-butylideneisobenzofuran-1(3H)-one) is a kind of monoterpene (mono-terpene) substance, molecular formula is C ₁₂ H ₁₂ O ₂ , molecular weight for 188.22. It can be used in the treatment of various tumors such as glioblastoma multiforme and breast cancer, see for example Tsai et al., Clin. Cancer Res. 2005, 11(9):3475-3484 and Tsai et al., JNeurochem. .2006, 99(4):1251-62. In the past, 3-butylene isobenzofuran-1(3H)-one was obtained by separating it from Angelica sinensis extract. However, the product isolated from the Angelica sinensis extract contains (Z)-3-butylene isobenzofuran-1(3H)-one and (E)-3-butylene isobenzofuran- Mixtures of 1(3H)-ketones. Therefore, the 3-butyleneisobenzofuran-1(3H)-one available on the market is generally (Z)-3-butyleneisobenzofuran-1(3H)-one and (E)-3 - A mixture of butylidene isobenzofuran-1(3H)-ones, the use of which in pharmaceuticals will be detrimental to the control and management of impurities.

In view of this, the present invention provides a method for synthesizing isobenzofuran-1(3H)-one series compounds, especially a method for synthesizing (Z)-3-butyleneisobenzofuran-1(3H)-one.

Contents of the invention

An object of the present invention is to provide a method for the preparation of compounds of the following formula I,

Include the following steps:

(1) reacting a halogenated carboxylic acid anhydride (halogenatedcarboxylicacidanhydride) with a compound of the following formula (1) at a first temperature of about 50° C. to about 140° C., to obtain a compound of the following formula (2):

;as well as

(II) reacting a compound of formula (2) with a compound of general formula R2(Mg)X at a second temperature of about -10°C to about 10°C to obtain a compound of formula I,

in,

Each R1 is independently C1 to C10 alkyl, C3 to C10 cycloalkyl or C6 to C20 aryl;

R2 is C1 to C20 alkyl;

X is Cl ^- , Br ^- or I ^- ; and

p is an integer of 0 to 3.

In some embodiments of the present invention, R2 is propyl and p is 0.

In some embodiments of the present invention, the first temperature is about 100°C to about 130°C.

In some embodiments of the present invention, the second temperature is about -5°C to about 5°C.

In some embodiments of the present invention, the halogenated carboxylic acid anhydride is selected from the following groups: monofluoroacetic anhydride, difluoroacetic anhydride, trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, perfluorovaleric anhydride, perfluoroacetic anhydride, Fluorohexanoic anhydride, chlorodifluoroacetic anhydride, monochloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, pentachloropropionic anhydride, heptachlorobutyric anhydride, perchlorovaleric anhydride, perchlorohexanoic anhydride and combinations thereof; Preferably, the halogenated carboxylic anhydride is trifluoroacetic anhydride.

In some embodiments of the present invention, the reaction of step (I) is carried out in toluene; and the reaction of step (II) is carried out in an inert solvent selected from the following groups: ether, tetrahydrofuran (tetrahydrofuran, THF), 2- Methyltetrahydrofuran and combinations thereof.

In some embodiments of the present invention, before performing step (II), the following purification operations are also included: extracting the reaction product of step (I) with ethyl acetate, and collecting the organic layer; and filtering the organic layer and concentrating the resulting filtrate , to obtain the compound of formula (2).

In some embodiments of the present invention, after the reaction of step (II), the following purification operation is also included: the reaction product of step (II) is mixed with ice water to provide a first pH value of about 5 to 7 mixture; extracting the first mixture with ethyl acetate, and collecting the organic layer; and filtering the organic layer and concentrating the resulting filtrate to obtain the compound of formula I.

In some embodiments of the present invention, the compound of formula (1) is provided as follows:

(I-1) react a compound of the following formula (3) with malonic acid in a tertiary amine and at a third temperature of about 50° C. to about 90° C. to obtain a compound of the following formula ( 4) Compounds:

;as well as

(I-2) reacting the compound of formula (4) with a brominating agent in a carboxylic acid at a fourth temperature of about 30°C to about 50°C to obtain the compound of formula (1).

The tertiary amine is preferably trialkylamine (such as triethylamine) or trialkoxyamine. The brominating agent is preferably selected from the following group: bromine, pyridinium bromide perbromide, N-bromosuccinimide and combinations thereof, especially pyridinium bromide perbromide. The carboxylic acid is preferably selected from the following group: formic acid, acetic acid, propionic acid, butyric acid and combinations thereof, especially acetic acid.

Preferably, before step (I-2), the following purification operations are carried out: extract the reaction product of step (I-1) with ethyl acetate, and collect the organic layer; filter the organic layer and concentrate the resulting filtrate; The concentrated filtrate is mixed with ethyl acetate and heated to a temperature of about 50° C. to about 60° C. to provide a second mixture; and the second mixture is cooled to room temperature and mixed with n-hexane to precipitate the compound of formula (4). More preferably, before extracting with ethyl acetate, the pH value of the reaction product of the step (I-1) is adjusted to about 5-7.

After step (I-2), the following purification operations are preferably carried out: extract the reaction product of step (I-2) with ethyl acetate, and collect the organic layer; and filter the organic layer and concentrate the resulting filtrate to obtain the A compound of formula (1).

In order to make the above-mentioned purpose, technical features and advantages of the present invention more comprehensible, some specific embodiments are described below in detail.

Description of drawings

Figure 1: Nuclear magnetic resonance (NMR) spectrum of 2-acetylbenzoic acid (2-acetylbenzoic acid).

Figure 2: NMR spectrum of 2-(2-bromoacetyl)benzoic acid.

Figure 3: NMR spectrum of (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one ((Z)-3-(bromomethylene)isobenzofuran-1(3H)-one.

Figure 4: NMR spectrum of (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one ((Z)-3-(bromomethylene)isobenzofuran-1(3H)-one.

detailed description

The following will specifically describe some specific embodiments according to the present invention; but without departing from the spirit of the present invention, the present invention can also be practiced in various forms of embodiments, and the protection scope of the present invention should not be construed as being limited to the specification. stated. Furthermore, as used in this specification (especially in the claims), "a", "the" and similar terms should be understood to include both singular and plural forms unless the context requires otherwise.

The present invention provides a method for preparing isobenzofuran-1(3H)-one series compounds. The method of the present invention is especially useful for preparing (Z)-3-butyleneisobenzofuran-1(3H)-one, for example. The difference between the method of the present invention and the existing method is that the method for obtaining 3-butylene isobenzofuran-1(3H)-one from the extract of Angelica sinensis can only obtain (Z)-3-butylene isobenzo Furan-1(3H)-ketone and (E)-3-butylene isobenzofuran-1(3H)-one mixture, the present invention can directly synthesize such as (Z)-3-butylene isobenzofuran Furan-1(3H)-one.

In particular, the present invention provides a process for the preparation of compounds of the following formula I,

Include the following steps:

(1) reacting a halogenated carboxylic acid anhydride with a compound of the following formula (1) at a first temperature to obtain a compound of the following formula (2):

;as well as

(II) reacting the compound of formula (2) with a compound of general formula R2(Mg)X at a second temperature to obtain the compound of formula I.

in,

Each R1 is independently selected from the following group: C1 to C10 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, neopentyl C3 to C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or C6 to C20 aryl, such as Phenyl, tolyl and xylyl;

R2 is C1 to C20 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, neopentyl, tertiary pentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-pentadecyl and n-eicosyl, with methyl, ethyl, n-propyl, isopropyl, tertiary butyl and tertiary pentyl better;

X is Cl ^- , Br ^- or I ^- ; and

p is an integer of 0 to 3.

In step (I), the halogenated carboxylic anhydride is reacted with the compound of formula (1) at a first temperature to obtain the compound of formula (2). The first temperature can be any temperature sufficient to react the halogenated carboxylic anhydride with the compound of formula (1). For example, when preparing (Z)-3-butyleneisobenzofuran-1(3H)-one (that is, in the compound of formula I, R2 is a propyl group and p is 0), the first The temperature may range from about 50°C to about 140°C, preferably from about 100°C to about 130°C, and more preferably from about 110°C to about 130°C. Studies have found that at a higher reaction temperature (eg, above 100° C.), the formation of by-products other than the compound of formula (2) can be greatly reduced, which is beneficial to the yield of the compound of formula I.

The halogenated carboxylic acid anhydride can be any anhydride compound that can react with the compound of formula (1). For example, the halogenated carboxylic anhydride can be selected from the group consisting of monofluoroacetic anhydride, difluoroacetic anhydride, trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, perfluorovaleric anhydride, perfluorohexanoic anhydride, chlorine Difluoroacetic anhydride, monochloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, pentachloropropionic anhydride, heptachlorobutyric anhydride, perchlorovaleric anhydride, perchlorohexanoic anhydride, and combinations thereof, but not limited thereto. In the following specific examples, the compound of formula (1) is 2-(2-bromoacetyl)benzoic acid, and the halogenated carboxylic acid anhydride is trifluoroacetic anhydride.

In step (II), the compound of formula (2) is reacted with the compound of general formula R2(Mg)X at a second temperature to obtain the compound of formula I. Without being limited by theory, the R2(Mg)X compound acts like a Grignardagent, replacing Br in formula (2) with R2 through coupling. Examples _of R2( _Mg )X _{compounds include CH3MgF} , _C2H5MgF , _C3H7MgF , _C4H9MgF , _CH3MgCl , _{C2H5MgCl , C3H7MgCl} , _{C4H 9} MgBr, CH ₃ MgBr, C ₂ H ₅ MgBr, C ₃ H ₇ MgBr, C ₄ H ₉ MgBr, CH ₃ MgI, C ₂ H ₅ MgI, C ₃ H ₇ MgI, and C ₄ H ₉ MgI, but not limited to this. The second temperature in step (II) can be any temperature that allows the above-mentioned coupling to proceed. For example, when preparing (Z)-3-butyleneisobenzofuran-1(3H)-one, the second temperature is preferably from about -10°C to about 10°C, more preferably from about -5°C to about 5°C. The inert solvent in step (II) can be any suitable solvent for the above-mentioned coupling, which can dissolve the compound of formula (2) and the compound of (R2)MgX, but does not react with it. Without violating the aforementioned principles, examples of the solvent may be diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran or any combination thereof. In the following embodiments, the (R2)MgX compound is C ₃ H ₇ MgCl, the second temperature is about 0° C., and the inert solvent is THF.

According to the method of the present invention, additional purification operations may be performed before and/or after step (II) to improve the purity of the product. The purification operation can be carried out before step (II) to purify the reaction product of step (I) and isolate the compound of formula (2); it can also be carried out after the reaction of step (II) to purify step (II) The reaction product of the compound of formula I was isolated. For example, the following purification operation may be performed before step (II): extract the reaction product of step (I) with ethyl acetate, and collect the organic layer; and filter the organic layer and concentrate the resulting filtrate to obtain formula (2) compound. After the reaction of step (II), the purification operation can be carried out by, for example, the following steps: the reaction product of step (II) is mixed with ice water to provide a pH value of about 5 to 7, preferably about 6 a mixture; extracting the first mixture with ethyl acetate, and collecting the organic layer; and filtering the organic layer and concentrating the resulting filtrate to obtain the compound of formula I. Without being bound by theory, this pH range contributes to increased yield. For the specific purification operation, please refer to the description of the following examples.

The compound of formula (1) used in step (I) can be obtained on the market, and can also be synthesized by the following method:

(I-1) A compound having the following formula (3) is reacted with malonic acid in a tertiary amine at a third temperature of about 50° C. to about 90° C. to obtain the compound having the following formula (4) )compound of:

;as well as

(I-2) reacting the compound of formula (4) with a brominating agent in a carboxylic acid at a fourth temperature of about 30°C to about 50°C, preferably about 35°C to about 45°C, To obtain the compound of formula (1).

In the step (I-1), the tertiary amine used is not particularly limited, and common examples include trialkylamines or trialkoxyamines, but are not limited thereto. In the following specific examples, triethylamine is used. In step (I-2), the brominating agent can be any reagent that can brominate the compound of formula (4) to provide the compound of formula (1). Examples of brominating agents are, for example, selected from the group consisting of bromine, pyridinium tribromide, N-bromosuccinimide, and any combination of the foregoing, but not limited thereto. As for the carboxylic acid, without limitation by theory, it can provide an acidic environment favorable for the bromination reaction. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, butyric acid or any combination thereof, but are not limited thereto. In the following specific examples, the third temperature is about 80° C., the fourth temperature is about 40° C., the brominating agent is pyridinium tribromide, and the carboxylic acid is acetic acid.

During the process of synthesizing the compound of formula (1), purification operations can also be performed before and/or after step (I-2), so as to improve the purity of the products of each reaction step. The purification operation can be carried out before step (I-2) to isolate the compound of formula (4) with the reaction product of purification step (I-1), or it can be carried out after step (I-2) to purify the reaction product of step (I-1). The reaction product of (I-2), the compound of formula (1) was isolated. For example, before the step (I-2), the purification operation can be carried out by the following steps: extract the reaction product of the step (I-1) with ethyl acetate, and collect the organic layer; filter the organic layer and concentrate the obtained filtrate; The concentrated filtrate is mixed with ethyl acetate and heated to a temperature of about 50° C. to about 60° C. to provide a second mixture; and the second mixture is cooled to room temperature and mixed with n-hexane to precipitate the compound of formula (4). Wherein, preferably before extracting with ethyl acetate, the pH value of the reaction product of this step (I-1) is adjusted to about 5 to 7, and without being limited by theory, this pH value range can help to produce rate increase. After step (I-2), the purification operation can be carried out by the following steps: extract the reaction product of step (I-2) with ethyl acetate, and collect the organic layer; and filter the organic layer and concentrate the resulting filtrate to obtain the formula (1) Compounds. For the specific purification operation mode, please refer to the description of the following examples.

Based on the above description, an embodiment of the present invention provides a method for preparing (Z)-3-butyleneisobenzofuran-1(3H)-one, the method comprising:

(I) reacting a halogenated carboxylic anhydride with 2-(2-bromoacetyl)benzoic acid at a first temperature to obtain (Z)-3-(bromomethylene)isobenzofuran-1(3H) - Keto: and

(II) reacting (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one with a compound of general formula (C ₃ H ₇ )MgX at a second temperature to obtain (Z)-3-Butylideneisobenzofuran-1(3H)-one,

Wherein, the first temperature, the second temperature and X are as defined above, and a purification operation may be further included before and/or after step (II) if necessary.

The present invention is now further illustrated by the following examples. Wherein, this embodiment is only provided as an illustration, but not intended to limit the protection scope of the present invention. The scope of protection of the present invention is defined in the claims.

Example: Preparation of (Z)-3-butyleneisobenzofuran-1(3H)-one

Step (I-1): Preparation of 2-acetylbenzoic acid (2-acetylbenzoic acid)

Take a 1-liter three-necked bottle as a reaction bottle, add phthalic anhydride (CASNO.85-44-9; 100 grams, 0.67 moles), part of malonic acid (CASNO. Equivalent, 21 g) and part of triethylamine (CASNO.121-44-8; 1.5 equivalent, 140 ml), heated until the temperature inside the bottle was maintained at 65°C, and reacted at 65°C for 20 minutes to obtain a yellow transparent homogeneous solution.

The remaining malonic acid (1 equivalent, 70 g) was slowly added to the reaction flask in three batches within 30 minutes, and the reactants on the reaction flask were washed into the reaction flask with the remaining triethylamine (0.5 equivalent, 50 ml). in solution. Then heat until the temperature in the reaction bottle is maintained at 80° C., and react at 80° C. for 20 hours (whether the reaction is complete or not is judged by NMR instrument analysis). The reaction process is as follows:

In the above formula, compound 1 is phthalic anhydride, compound 2 is 2-acetylbenzoic acid, and Et ₃ N is triethylamine.

After the reaction was completed, the reaction flask was cooled to room temperature, and 4N HCl (CASNO.7647-01-0) aqueous solution was slowly added into the reaction flask until the pH value of the mixture was about 5 to 6, followed by stirring for 30 minutes. Subsequently, the reaction product was extracted with ethyl acetate (CASNO.141-78-6; 100 ml×4) and the organic layer was collected, and the organic layer was washed with saturated brine (CASNO.: 7647-14-5) and saturated sodium bicarbonate ( CASNO.144-55-8) was washed with an aqueous solution until the pH value was about 7, then water was removed with anhydrous sodium sulfate (CASNO.7757-82-6), and the remaining substance was concentrated in vacuo to obtain a crude product.

The crude product was added to ethyl acetate (107 ml) and heated to 55°C to dissolve it to form a homogeneous solution. The homogeneous solution was slowly cooled to room temperature, and then n-hexane (107 ml) was added to make 2-acetyl Benzoic acid crystallized, and 43.6 g of 2-acetobenzoic acid was obtained by filtration, with a yield of about 39% (if the recovered unreacted starting material was deducted, the yield was about 60%). The nuclear magnetic resonance spectrum of gained 2-acetobenzoic acid is shown in Figure 1.

Step (I-2): Preparation of 2-(2-bromoacetyl)benzoic acid (2-(2-bromoacetyl)benzoic acid)

Get a 500 milliliter two-necked bottle as a reaction bottle, add 2-acetobenzoic acid (compound 2) (23.8 grams, 0.145 moles) and acetic acid (CASNO.64-19-7; 15 ml), and stirred at room temperature for 10 minutes. Then, pyridinium tribromide (CAS NO. 39416-48-3; 1.3 equivalents, 67 g) was added into the reaction flask and heated to 40° C. to obtain a red homogeneous solution. React at 40°C for 7 hours (whether the reaction is complete can be judged by NMR instrument analysis). The reaction process is as follows:

Among them, compound 3 is 2-(2-bromoacetyl)benzoic acid.

After the reaction was complete, the reaction solution was poured into ice water at 0°C, and the resulting mixture was stirred for 30 minutes. Then extract with ethyl acetate, and collect the organic layer, wash the organic layer with 5% sodium thiosulfate (CASNO.7772-98-7) aqueous solution and saturated brine, and finally remove the water with anhydrous sodium sulfate, and The remaining material was concentrated in vacuo to yield 32 g of 2-(2-bromoacetyl)benzoic acid (red-brown crystalline solid). The nuclear magnetic resonance spectrum of gained 2-(2-bromoacetyl)benzoic acid is shown in Figure 2.

Step (I): Preparation of (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one ((Z)-3-(bromomethylene)isobenzofuran-1(3H)-one)

Take a 25 ml round bottom flask as a reaction flask, dissolve 2-(2-bromoacetyl)benzoic acid (38.1 g, 0.156 mol) with toluene (CASNO.108-88-3; 313 ml, 0.5N) in the reaction flask (Compound 3), followed by adding trifluoroacetic anhydride (CAS NO. 407-25-0; 1.0 equivalent, 22.1 ml; TFAA for short). Then, the solution in the reaction flask was heated to 120° C. with a Dean-Stark reflux device and refluxed for 8 hours (whether the reaction was completed or not was judged by NMR instrument analysis). The reaction process is as follows:

Among them, compound 4 is (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one.

After the reaction was completed, the resulting product was concentrated and most of the toluene was removed, then ethyl acetate (100 ml×4) was added, and an equal amount of water was added for extraction. During the extraction process, the water layer was washed with a large amount of water until the water layer was roughly Neutral, and the organic layer was collected. The organic layer was dehydrated with anhydrous sodium sulfate, and the remaining material was concentrated in vacuo to obtain a crude product. The components of the crude product were treated with column chromatography (static phase: silica gel; eluent: n-hexane: ether = 10:1), and confirmed by thin layer chromatography to obtain 17.6 g of (Z)-3-(bromo Methylene)isobenzofuran-1(3H)-one (compound 4) (Rf value 0.3; static phase: silica gel; developing solvent: n-hexane:ether=10:1). The nuclear magnetic resonance spectrum of the obtained (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one is shown in FIG. 3 .

Step (II): Preparation of (Z)-3-butyleneisobenzofuran-1(3H)-one ((Z)-3-(bromomethylene)isobenzofuran-1(3H)-one)

Take a flask, bake the bottle under nitrogen, and dissolve (Z)-3-(bromomethylene)isobenzofuran-1(3H)-one (compound 4) (1.0 g, 4.44 mmol) in THF (CASNO .109-99-9; 5.6 ml) into the reaction bottle after dissolving. Then C ₂₇ H ₂₆ Cl ₂ NiP ₂ (CAS NO. 15629-92-2; 5 mol%, 130 mg) was added and reacted at 0°C for 20 minutes. Then, 2N C ₃ H ₇ MgCl (CAS NO. 2234-82-4; 1.54 equivalents, 1.3 ml) was slowly added dropwise at 0° C., and reacted for 10 minutes. The reaction process is as follows:

Among them, compound 5 is (Z)-3-butyleneisobenzofuran-1(3H)-one.

The reaction was traced by thin layer chromatography (static phase: silica gel; developer: n-hexane:ether=5:1; Rf value=0.5). After the reaction was complete, ice water was added to quench the reaction. After 20 minutes 2M HCl solution was added until the pH of the resulting mixture was approximately 6. Extracted with ethyl acetate (20 mL×3), and washed the organic layer with an equal amount of saturated brine, then collected the organic layer and removed water with anhydrous sodium sulfate, and concentrated the remaining material in vacuo to obtain a crude product. 543 mg of (Z)-3-butylene isobenzofuran-1(3H)-one ( Compound 5), yield 65%. The nuclear magnetic resonance spectrum of the obtained (Z)-3-butyleneisobenzofuran-1(3H)-one is shown in FIG. 4 .

The above-mentioned embodiments are only illustrative to illustrate the principles and effects of the present invention, and explain the technical features of the present invention, but are not intended to limit the protection scope of the present invention. Changes or arrangements that can be easily accomplished by those skilled in the art without violating the technical principle and spirit of the present invention all fall within the scope of the present invention. Therefore, the protection scope of the present invention shall prevail as defined in the claims.

Claims (19)

1. A method for preparing a compound of the following formula I, characterized in that: The method includes the following steps: (1) reacting a halogenated carboxylic acid anhydride with a compound of the following formula (1) at a first temperature of 50° C. to 140° C. to obtain a compound of the following formula (2): ;as well as (II) reacting the compound of formula (2) with a compound of general formula R2(Mg)X at a second temperature of -10°C to 10°C to obtain a compound of formula I, in, Each R1 is independently C1 to C10 alkyl, C3 to C10 cycloalkyl or C6 to C20 aryl; R2 is C1 to C20 alkyl; X is Cl ^- , Br ^- or I ^- ; and p is an integer of 0 to 3. 2. The method according to claim 1, characterized in that R2 is propyl and p is 0. 3. The method of claim 1, wherein the first temperature is 100°C to 130°C. 4. The method of claim 1, wherein the second temperature is -5°C to 5°C. 5. The method of claim 1, wherein the halogenated carboxylic acid anhydride is selected from the group consisting of monofluoroacetic anhydride, difluoroacetic anhydride, trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, perfluoroacetic anhydride, Valeric anhydride, perfluorohexanoic anhydride, chlorodifluoroacetic anhydride, monochloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, pentachloropropionic anhydride, heptachlorobutyric anhydride, perchlorovaleric anhydride, perchlorohexanoic anhydride and the foregoing The combination. 6. The method of claim 5, wherein the halogenated carboxylic acid anhydride is trifluoroacetic anhydride. 7. The method according to claim 1, characterized in that: the reaction of step (I) is carried out in toluene; and the reaction of step (II) is carried out in an inert solvent selected from the following groups: diethyl ether, tetrahydrofuran, 2-methyl Tetrahydrofuran and combinations thereof. 8. The method according to claim 1, characterized in that: before carrying out step (II), the following purification operations are also included: Extract the reaction product of step (I) with ethyl acetate, and collect the organic layer; And The organic layer is filtered and the resulting filtrate is concentrated to obtain the compound of formula (2). 9. the method for claim 1 is characterized in that: after carrying out the reaction of step (II), also comprise following purification operation: mixing the reaction product of step (II) with ice water to provide a first mixture with a pH value of 5 to 7; extracting the first mixture with ethyl acetate, and collecting the organic layer; and The organic layer is filtered and the resulting filtrate is concentrated to obtain the compound of formula I. 10. The method according to claim 1, characterized in that: the compound of the formula (1) is provided as follows: (I-1) react a compound of the following formula (3) with malonic acid in a tertiary amine and at a third temperature of 50°C to 90°C to obtain a compound of the following formula (4) compound of: ;as well as (I-2) reacting the compound of formula (4) with a brominating agent in a carboxylic acid at a fourth temperature of 30°C to 50°C to obtain the compound of formula (1). 11. The method according to claim 10, characterized in that the tertiary amine is a trialkylamine or a trialkoxyamine. 12. The method of claim 11, wherein the tertiary amine is triethylamine. 13. The method of claim 10, wherein the brominating agent is selected from the group consisting of bromine, pyridinium tribromide, N-bromosuccinimide and combinations thereof. 14. The method of claim 13, wherein the brominating agent is pyridinium tribromide. 15. The method of claim 10, wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, and combinations thereof. 16. The method of claim 15, wherein the carboxylic acid is acetic acid. 17. The method according to claim 10, characterized in that: before carrying out step (1-2), further carry out the following purification operation: Extract the reaction product of step (I-1) with ethyl acetate, and collect the organic layer; The organic layer was filtered and the resulting filtrate was concentrated; mixing the concentrated filtrate with ethyl acetate and heating to a temperature of 50°C to 60°C to provide a second mixture; and The second mixture was cooled to room temperature and mixed with n-hexane to precipitate the compound of formula (4). 18. The method according to claim 17, characterized in that: before extracting with ethyl acetate, the pH value of the reaction product of the step (I-1) is adjusted to 5-7. 19. The method according to claim 10, characterized in that: after step (1-2), the following purification operations are carried out: Extract the reaction product of step (1-2) with ethyl acetate, and collect the organic layer; And The organic layer is filtered and the resulting filtrate is concentrated to obtain the compound of formula (1).