A method for synthesizing benzocyclone compounds with dichloro substitution at the α-position

Abstract

The present invention discloses a method for synthesizing benzocyclone compounds with dichloro substitution at the α-position. The starting compound is added to an organic solvent in the presence of a catalyst, followed by a chlorination reaction with NCS, thereby introducing two chlorine atoms at the α-position of the carbonyl group to obtain the target compound. The method utilizes NCS, a commonly used, economical, and safe chlorination reagent, for the reaction. The resulting product has the advantages of simple operation, low chlorination reagent usage, and a low-cost catalyst usage.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of benzocyclone compounds with dichloro substitution at the α-position. Background Art

[0002] α-Chlorinated carbonyl compounds are important intermediates in organic synthesis because they can be transformed into a wide variety of molecules and can also serve as more metabolically stable replacements for hydrogen and methyl functional groups in pharmaceuticals without losing therapeutic efficacy. These advantages have sparked significant interest in chlorination catalysis.

[0003] Although several related reactions for dichloro substitution of the α-position of benzocyclohexanones have been reported, the chlorination reagents used, such as PhICl2, copper chloride, lithium chloride, and even highly toxic chlorine gas, are uneconomical, environmentally unfriendly, and unsafe. Complete conversion is difficult to achieve under typical conditions, and the addition of two chlorines can easily lead to the formation of byproducts under harsh conditions. Benzooxa-, aza-, and thiacyclohexanone-based compounds are also relatively uncommon in the reported reactions. Summary of the Invention

[0004] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0005] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0006] One of the purposes of the present invention is to provide a method for synthesizing benzocyclone compounds with dichloro substitution at the α-position. The raw materials can be completely chlorinated by NCS, and there are two chlorine atoms at the α-position of the carbonyl group. The reaction operation is simple and the reaction yield is high.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions: a method for synthesizing benzocyclone compounds with dichloro substitution at the α position, comprising:

[0008] The compound represented by structural formula I is added to the compound represented by structural formula II in an organic solvent in the presence of a catalyst to carry out a chlorination reaction, thereby introducing two chlorine atoms at the α position of the carbonyl group to obtain the compound represented by structural formula III;

[0009]

[0010]

[0011] Wherein, R is one of hydrogen, halogen, methyl, ethyl, methoxy, and nitro; X ​​is one of CH2, O, S, and NR'; R' is one of hydrogen, methyl, and tert-butyloxycarbonyl; and n is one of 0, 1, and 2.

[0012] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the catalyst comprises one of ferric chloride, cupric chloride, zinc chloride, hydrochloric acid, sulfuric acid, formic acid, and p-toluenesulfonic acid.

[0013] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the molar ratio of the catalyst to the compound represented by formula I is 0.01 to 0.1:1.

[0014] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the molar ratio of the compound represented by formula I to the compound represented by formula II is 1:2-4.

[0015] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the organic solvent comprises one of acetonitrile, acetone, ethyl acetate, ethanol, methanol, tetrahydrofuran, and dichloromethane.

[0016] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the chlorination reaction is carried out at a temperature of 40 to 100° C. and a reaction time of 1 to 8 hours.

[0017] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the chlorination reaction is carried out at a temperature of 100° C. and a reaction time of 4 hours.

[0018] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the compound represented by structural formula I is selected from one of the following compounds:

[0019]

[0020] Wherein, R is one of hydrogen, halogen, methyl, ethyl, methoxy, and nitro; and R' is one of hydrogen, methyl, and tert-butyloxycarbonyl.

[0021] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the compound represented by structural formula I is selected from one of the following compounds:

[0022]

[0023] Among them, R1 is one of hydrogen, halogen, methyl, methoxy, and nitro; R2 is one of hydrogen and chlorine; R3 is hydrogen; R4 is one of hydrogen, fluorine, and methoxy; R5 is hydrogen; R' is one of hydrogen, methyl, and tert-butyloxycarbonyl.

[0024] As a preferred embodiment of the synthesis method of the α-position dichloro-substituted benzocyclone compound of the present invention, the method further comprises the step of purifying the reaction product.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The present invention uses NCS, a commonly used, economical, and safe chlorination reagent, to carry out the reaction. Only a catalytic amount of the reaction catalyst is required. The raw material is completely chlorinated by NCS, resulting in two chlorine atoms at the α-position of the carbonyl group. The product can be used as an intermediate for various drug molecules. The product obtained by this synthesis method has the advantages of simple operation, low chlorination reagent usage, and low catalyst usage. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0028] Figure 1 This is the H NMR spectrum of product II-a in Example 1 of the present invention;

[0029] Figure 2 This is the H NMR spectrum of product II-g in Example 2 of the present invention;

[0030] Figure 3 This is the H NMR spectrum of product II-i in Example 3 of the present invention;

[0031] Figure 4 This is the H NMR spectrum of product II-aa in Example 8 of the present invention;

[0032] Figure 5 This is the H NMR spectrum of product II-ab in Example 9 of the present invention;

[0033] Figure 6 Schematic diagram of the synthesis steps in Example 15 of the present invention. DETAILED DESCRIPTION

[0034] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0035] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0037] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0038] Example 1

[0039] 4-chromanone Ia (0.5mmol, 74mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to the reaction flask, heated to reflux for 4h, cooled to room temperature, the solvent was spin-dried, water was added to dissolve the product, and it was extracted three times with ethyl acetate (20mLx 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product II-a, which was subsequently separated and purified by column chromatography to obtain a clean product II-a. Product yield = 99%, white solid. The nuclear magnetic hydrogen spectrum of product II-a is as follows Figure 1 shown. 1 H NMR (500MHz, CDCl3) δ8.00 (dd, J=7.9, 1.7Hz, 1H), 7.58 (ddd, J=8.7, 7.2, 1.8Hz, 1H), 7.15 (ddd, J=8.1, 7.2, 1.1Hz, 1H), 7.05 (dd, J=8.4, 1.0Hz, 1H), 4.67 (s, 2H).

[0040] The reaction formula is:

[0041]

[0042] Example 2

[0043] 6-bromo-4-chromanone Ig (0.5mmol, 113mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to the reaction flask, heated to reflux for 4h, cooled to room temperature, the solvent was spin-dried, water was added to dissolve the product, and it was extracted three times with ethyl acetate (20mLx 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product II-g, which was subsequently separated and purified by column chromatography to obtain a clean product II-g. Product yield = 96%, white solid. The nuclear magnetic hydrogen spectrum of product II-g is as follows Figure 2 shown. 1 HNMR (500MHz, CDCl3) δ8.11(d,J=2.5Hz,1H),7.66(dd,J=8.9,2.5Hz,1H),6.97(d,J=8.8Hz,1H),4.68(s,2H).

[0044] The reaction formula is:

[0045]

[0046] Example 3

[0047] 6-nitro-4-chromanone Ii (0.5mmol, 97mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to the reaction flask, heated to reflux for 4h, cooled to room temperature, the solvent was spin-dried, water was added to dissolve the product, and it was extracted three times with ethyl acetate (20mLx 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product II-i, which was subsequently separated and purified by column chromatography to obtain a clean product II-i. Product yield = 95%, white solid. The nuclear magnetic hydrogen spectrum of product II-i is as follows Figure 3 shown. 1 HNMR (500MHz, CDCl3) δ8.91(d,J=2.8Hz,1H),8.44(dd,J=9.2,2.8Hz,1H),7.23(d,J=9.2Hz,1H),4.80(s,2H).

[0048] The reaction formula is:

[0049]

[0050] Example 4

[0051] 1-tetralinone II (0.5 mmol, 75 mg), 10% p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL), and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to a reaction flask and heated under reflux for 4 h. The mixture was cooled to room temperature, the solvent was dried, and water was added to dissolve the product. The product was extracted three times with ethyl acetate (20 mL x 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product II-1. The crude product II-1 was subsequently separated and purified by column chromatography to obtain a clean product II-1. The product yield = 99% as a white solid. 1 H NMR (500MHz, CDCl3) δ7.92 (dd, J=8.2, 2.1Hz, 1H), 7.42 (ddd, J=7.9, 7.0, 2.1Hz, 1H), 7.37 (ddd, J=7.2,6.9,Hz,1H),7.35(dd,J=7.2,7.0,Hz,1H),3.03(t,J=5.1Hz,2H),2.73(t,J=5.1Hz,2H).

[0052] The reaction formula is:

[0053]

[0054] Example 5

[0055] A reaction flask was charged with 1-methyl-1,2,3,4-tetrahydroquinolin-4-one Iv (0.5 mmol, 75 mg), 10% p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL), and N-chlorosuccinimide (1.25 mmol, 167 mg). The mixture was heated at reflux for 4 h, cooled to room temperature, and the solvent was evaporated. The product was dissolved in water and extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product II-v. The crude product II-v was subsequently separated and purified by column chromatography to obtain the clean product II-v. The product yield = 95% as a white solid. 1 H NMR (500MHz, CDCl3) δ7.90 (dd, J=7.5, 1.7Hz, 1H), 7.38 (ddd, J=8.5, 7.0, 1.5Hz, 1H), 6. 85(ddd,J=7.3,7.0,1.1Hz,1H),6.75(dd,J=8.4,1.5Hz,1H),4.50(s,2H),3.10(s,2H).

[0056] The reaction formula is:

[0057]

[0058] Example 6

[0059] Thiochroman-4-one Iw (0.5mmol, 75mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to a reaction flask and heated under reflux for 4h. The mixture was cooled to room temperature, the solvent was dried, water was added to dissolve the product, and the product was extracted three times with ethyl acetate (20mL x 3). The organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, II-w. The crude product II-w was subsequently separated and purified by column chromatography to obtain a clean product II-w. The product yield = 90%, a white solid. 1 H NMR (500MHz, CDCl3) δ7.98 (dd, J=7.9, 1.5Hz, 1H), 7.58 (ddd, J=8.1, 7.0, 1.5Hz, 1 H), 7.05 (ddd, J=7.8, 7.0, 1.3Hz, 1H), 6.89 (dd, J=8.0, 1.5Hz, 1.2H), 4.60 (s, 2H).

[0060] The reaction formula is:

[0061]

[0062] Example 7

[0063] 1-Benzocycloheptanone Iy (0.5 mmol, 75 mg), 10% p-toluenesulfonic acid (0.05 mmol, 9 mg), acetonitrile (5 mL), and N-chlorosuccinimide (1.25 mmol, 167 mg) were added to a reaction flask and heated under reflux for 4 h. The mixture was cooled to room temperature, the solvent was dried, and water was added to dissolve the product. The product was extracted three times with ethyl acetate (20 mL x 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product II-y. The crude product II-y was subsequently separated and purified by column chromatography to obtain a clean product II-y. The product yield = 93% as a white solid. 1 H NMR (500MHz, CDCl3) δ7.49(dd,J=7.5,1.3Hz,1H),7.43(dd,J=7.5,1.8Hz,1H),7.34(dd,J=7.5,0.9Hz,1H),7.17( d, J=7.5Hz, 1H), 2.85 (dd, J=7.0, 6.3Hz, 2H), 2.68 (dd, J=6.6, 5.7Hz, 2H), 2.08 (dddd, J=7.0, 6.6, 6.2, 5.7Hz, 2H).

[0064] The reaction formula is:

[0065]

[0066] Example 8

[0067] 5-methoxy-1-indanone I-aa (0.5mmol, 81mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to the reaction flask, heated to reflux for 4h, cooled to room temperature, the solvent was spin-dried, water was added to dissolve the product, and it was extracted three times with ethyl acetate (20mLx 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product II-aa, which was subsequently separated and purified by column chromatography to obtain a clean product II-aa. Product yield = 93%, white solid. The nuclear magnetic hydrogen spectrum of product II-aa is as follows Figure 4 shown. 1 H NMR (500MHz, CDCl3) δ7.85 (d, J=8.6Hz, 1H), 7.01 (dd, J=8.6, 2.3Hz, 1H), 6.86–6.80 (m, 1H), 4.00 (s, 2H), 3.92 (s, 3H).

[0068] The reaction formula is:

[0069]

[0070] Example 9

[0071] 5-fluoro-1-indanone I-ab (0.5mmol, 75mg), 10% p-toluenesulfonic acid (0.05mmol, 9mg), acetonitrile (5mL), N-chlorosuccinimide (1.25mmol, 167mg) were added to the reaction flask, heated to reflux for 4h, cooled to room temperature, the solvent was spin-dried, water was added to dissolve the product, and it was extracted three times with ethyl acetate (20mLx 3), and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product II-ab, which was subsequently separated and purified by column chromatography to obtain a clean product II-ab. Product yield = 98%, white solid. The nuclear magnetic hydrogen spectrum of product II-ab is as follows Figure 5 shown. 1 H NMR (500MHz, CDCl3) δ7.95 (dd, J=8.5, 5.2Hz, 1H), 7.21 (td, J=8.7, 2.1Hz, 1H), 7.13–7.09 (m, 1H), 4.04 (s, 2H).

[0072] The reaction formula is:

[0073]

[0074] Example 10

[0075] Example 10 is basically the same as Example 1, except that the solvents are different, as shown in Table 1 below:

[0076] Table 1

[0077]

[0078]

[0079] As can be seen from Table 1, under the same reaction conditions, the target product can be obtained in all organic solvents; and the yield is higher in acetonitrile (MeCN), tetrahydrofuran (THF), and 2-methyltetrahydrofuran (2-MeTHF).

[0080] Example 11

[0081] Example 11 is basically the same as Example 1, except that the catalyst is different, as shown in Table 2 below:

[0082] Table 2

[0083] catalyst Addition amount Yield (%) Ferric chloride 10％ 80％ Copper chloride 10％ 50％ zinc chloride 10％ 51％ hydrochloric acid 10％ 62％ sulfuric acid 10％ 77％ Formic acid 10％ 74％ p-Toluenesulfonic acid 1％ 80％ p-Toluenesulfonic acid 2％ 88％ p-Toluenesulfonic acid 5％ 97％ p-Toluenesulfonic acid 10％ 99％

[0084] As can be seen from Table 2, under the same reaction conditions (10% addition), the target product can be obtained using ferric chloride, cupric chloride, zinc chloride, hydrochloric acid, sulfuric acid, formic acid, and p-toluenesulfonic acid catalysts. The highest yield was achieved using p-toluenesulfonic acid. As the addition of p-toluenesulfonic acid catalyst was reduced, the yield gradually decreased.

[0085] Example 12

[0086] Example 12 is basically the same as Example 1, except that the reaction temperature and reaction time are different, as shown in Table 3 below:

[0087] Table 3

[0088] temperature time Yield (%) 40℃ 4h 77％ 60℃ 4h 82％ 80℃ 4h 92％ 100℃ 4h 99％

[0089] As can be seen from Table 3, under the same reaction conditions, the reaction temperature has a certain effect on the yield, among which the yield is highest when the reaction temperature is 100°C and the reaction time is 4h.

[0090] Example 13

[0091] Example 13 is basically the same as Example 1, except that the chlorination reagent is different, as shown in Table 4 below:

[0092] Table 4

[0093] Chlorination reagents Addition amount (equiv.) Yield (%) NCS 2.0 62％ NCS 2.1 71％ NCS 2.2 76％ NCS 2.3 85％ NCS 2.4 92％ NCS 2.5 99％ NCS 2.6 99％

[0094] As can be seen from Table 4, under the same reaction conditions, the yield increased with the increase in the amount of NCS added, reaching a maximum yield of 99% at 2.5 equiv.

[0095] Example 14

[0096] Example 14 is basically the same as Example 1, except that the reaction raw materials are different, as shown in Table 5 below:

[0097] Table 5

[0098]

[0099]

[0100]

[0101]

[0102] Example 15

[0103] Examples 1 to 14 prepared a series of 2,2-dichlorobenzocyclone compounds, which are important organic synthesis intermediates and can be further structurally modified and chemically converted into various compounds.

[0104] Taking the 2,2-dichlorobenzocyclone compound II-z prepared in the embodiment as an example, a two-step synthesis can be performed to obtain the compound V with TRPML channel activity. The synthesis process is as follows: Figure 6 shown.

[0105] The specific steps are:

[0106] (1) Synthesis steps of compound III:

[0107] Add II-z (1.0 mmol, 200 mg), concentrated sulfuric acid (3.0 mmol, 300 mg), and tetrahydrofuran (5 mL) to the reaction flask, heat under reflux for 8 h, cool to room temperature, and spin-dry the solvent to obtain the crude product III, which was used directly in the next reaction without further purification.

[0108] (2) Synthesis steps of compound IV:

[0109] 1-(2-nitrophenyl)piperazine (1.0 mmol, 177 mg) and triethylamine (304 mg, 3.0 mmol) were added to a reaction flask, dissolved in dichloromethane (5 mL), and placed in an ice bath. Pivaloyl chloride (181 mg, 1.5 mmol) was slowly added dropwise, returned to room temperature, and stirred for 8 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain crude product IV. This was subsequently purified by column chromatography to obtain the clean product IV. The product yield = 98%, 256 mg, as a white solid.

[0110] (3) Synthesis steps of compound V:

[0111] Add crude product III (0.5mmol, 140mg) to the reaction flask and place it in an ice bath. Phosphorus oxychloride (307mg, 2.0mmol) is slowly added thereto and stirred for 30min after the addition is complete. Then add compound IV (183mg, 0.7mmol) and pyridine (158mg, 2mmol) to the reaction flask, return to room temperature, stir for 4h, quench with water after completion of the reaction, extract three times with ethyl acetate (20mLx 3), and collect the organic phase. The organic phase is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product to obtain crude product V, which is subsequently separated and purified by column chromatography to obtain clean product V. Product yield = 78%, 204mg, white solid.

[0112] The present invention uses NCS, a commonly used, economical, and safe chlorination reagent, to carry out the reaction. Only a catalytic amount of the reaction catalyst is required. The raw material is completely chlorinated by NCS, resulting in two chlorine atoms at the α-position of the carbonyl group. The product can be used as an intermediate for various drug molecules. The product obtained by this synthesis method has the advantages of simple operation, low chlorination reagent usage, and low catalyst usage.

[0113] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing a benzocyclone compound with dichloro substitution at the α position, characterized in that: include, The compound represented by structural formula I is added to the compound represented by structural formula II in an organic solvent in the presence of a catalyst to carry out a chlorination reaction, thereby introducing two chlorine atoms at the α position of the carbonyl group to obtain the compound represented by structural formula III; (Formula I); (Formula II); (Formula III); Wherein, R is one of hydrogen, halogen, methyl, ethyl, methoxy, and nitro; X ​​is one of CH2, O, S, and NR'; R' is one of hydrogen, methyl, and tert-butyloxycarbonyl; n is one of 0, 1, and 2; The catalyst is selected from one of ferric chloride, sulfuric acid, formic acid and p-toluenesulfonic acid; The organic solvent is selected from one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and dimethylformamide.

2. The method for synthesizing a benzocyclone compound with dichloro substitution at the α position according to claim 1, wherein: The molar ratio of the catalyst to the compound represented by formula I is 0.01-0.1:

1.

3. The method for synthesizing a benzocyclone compound with dichloro substitution at the α position according to claim 1, wherein: The molar ratio of the compound represented by formula I to the compound represented by formula II is 1:2-4.

4. The method for synthesizing a benzocyclone compound having dichloro substitution at the α-position as claimed in any one of claims 1 to 3, wherein: The chlorination reaction is carried out at a temperature of 40-100° C. and a reaction time of 1-8 hours.

5. The method for synthesizing a benzocyclone compound with dichloro substitution at the α position according to claim 4, wherein: The chlorination reaction was carried out at a temperature of 100° C. and a reaction time of 4 hours.

6. The method for synthesizing a benzocyclone compound having dichloro substitution at the α position as claimed in any one of claims 1 to 3 and 5, characterized in that: The compound represented by structural formula I is selected from one of the following compounds: 、 、 、 、 ； Wherein, R is one of hydrogen, halogen, methyl, ethyl, methoxy, and nitro; and R' is one of hydrogen, methyl, and tert-butyloxycarbonyl.

7. The method for synthesizing a benzocyclone compound with dichloro substitution at the α position according to claim 6, wherein: The compound represented by structural formula I is selected from one of the following compounds: 、 、 、 、 ； Among them, R1 is one of hydrogen, halogen, methyl, methoxy, and nitro; R2 is one of hydrogen and chlorine; R3 is hydrogen; R4 is one of hydrogen, fluorine, and methoxy; R5 is hydrogen; R' is one of hydrogen, methyl, and tert-butyloxycarbonyl.

8. The method for synthesizing a benzocyclone compound having dichloro substitution at the α position as claimed in any one of claims 1 to 3, 5 and 7, wherein: The method also includes the step of purifying the reaction product.

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