A method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and analogs thereof. The method uses 2-fluoro-5-bromobenzonitrile as a raw material, introduces a cyclopropyl group through cyclopropylmagnesium bromide, then introduces a cyano group through a Van Leusen reaction, then hydrolyzes to obtain a carboxylic acid, and finally methylates to obtain a target product. The method has simple and safe reaction operations in each step, high yield, good repeatability, and is a method suitable for industrialized scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and specifically relates to a method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and analogs thereof. Background Art

[0002] There is no documented synthesis method for the compound 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester. There are two methods for synthesizing analogues, which were tried separately: the first method uses 5-bromo-2-fluorophenylacetic acid as a raw material, deprotonates it through lithium diisopropylazide (LDA), and then introduces the cyclopropyl group through bromocyclopropane, but fails to obtain the target product; the second method uses 5-bromo-2-fluorophenylacetic acid as a raw material, introduces a diazo group at the ortho position of the carbonyl group through p-toluenesulfonyl azide, and then reacts with cyclopropylboronic acid under light, but also fails to obtain the target product.

[0003] Therefore, there is an urgent need to provide a method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs, which has simple and safe operation in each step, high yield, good reproducibility and is suitable for industrial synthesis. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs, wherein each step of the reaction is simple and safe to operate, the yield is high, and the repeatability is good, and the method is suitable for industrialized scale-up production.

[0005] The objective of the present invention is achieved through the following technical solutions:

[0006] The present invention provides a method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs, comprising the following steps:

[0007] (1) Add tetrahydrofuran and compound 1 to a reaction vessel, and under nitrogen protection, slowly drop cyclopropylmagnesium bromide after cooling, stir, and heat to room temperature for reaction. After the reaction is completed, add hydrochloric acid dropwise under ice bath, dropwise, and react at room temperature overnight. Then extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and perform column chromatography to obtain compound 2;

[0008] (2) Add ethylene glycol dimethyl ether and potassium tert-butoxide to a reaction vessel, and under nitrogen protection, after cooling, add p-toluenesulfonylmethyl isocyanide dropwise, and carry out a primary reaction. Then, add compound 2 dropwise, and carry out a secondary reaction. Then, add methanol dropwise, and carry out a reflux reaction. Then, add water, stir, adjust the pH with hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 3.

[0009] (3) Add concentrated hydrochloric acid, compound 3 and 1,4-dioxane to a reaction vessel for reaction. After the reaction is completed, cool down, add ice water, extract with methyl tert-butyl ether in sequence, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and slurry with petroleum ether to obtain compound 4;

[0010] (4) Methanol and compound 4 were added to a reaction vessel, and thionyl chloride was added dropwise under nitrogen protection after cooling. After the addition was completed, the reaction was allowed to proceed, and the temperature was then cooled, concentrated, and saturated aqueous sodium bicarbonate solution was added with stirring, extracted with methyl tert-butyl ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5;

[0011] Wherein, when the compound 1 is 2-fluoro-5-bromobenzonitrile, the final compound 5 obtained is methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate;

[0012] When the compound 1 is 2,5-dichlorobenzonitrile, the final compound 5 is a 2-(5-bromo-2-fluorophenyl-2-cyclopropylacetic acid methyl ester analog.

[0013] Furthermore, in step (1), the amount of tetrahydrofuran added is 1500-2000 mL; the amount of compound 1 added is 0.4-0.58 mol; and the amount of cyclopropylmagnesium bromide added is 1-1.45 mol.

[0014] Furthermore, in step (1), the cooling is to -73°C to -83°C, the stirring time is 1.5-2.5h, the heating time to room temperature is 0.3-0.8h, and the ethyl acetate extraction is performed twice with 800-1200mL of ethyl acetate.

[0015] Furthermore, in step (2), the amount of ethylene glycol dimethyl ether added is 300-800 mL; the amount of potassium tert-butoxide added is 0.6-0.62 mol; the amount of p-toluenesulfonylmethyl isocyanide added is 0.36-0.37 mol; and the amount of compound 2 added is 0.24-0.247 mol.

[0016] Furthermore, in step (2), the cooling is to -50°C to -60°C, the primary reaction is to react at -60°C to -70°C for 15-25 min, the secondary reaction is to react at -60°C to -30°C for 0.5-1.5 h, the reflux reaction time is 1-2 h, the water addition and stirring time is 15-20 min, and the hydrochloric acid is used to adjust the pH to 4-5.

[0017] Furthermore, in step (3), the amount of concentrated hydrochloric acid added is 200-400 mL; the amount of compound 3 added is 0.1-0.15 mol; the amount of 1,4-dioxane added is 300-400 mL; and the amount of ice water added is 1500 mL.

[0018] Furthermore, in step (3), the reaction is carried out at 90-110° C. for 40-50 hours, and the methyl tert-butyl ether extraction is carried out twice using 200-400 mL of methyl tert-butyl ether.

[0019] Furthermore, in step (4), the amount of methanol added is 210-250 mL; the amount of compound 4 added is 0.077-0.09 mol; the amount of thionyl chloride added is 0.165-0.18 mol; and the amount of saturated sodium bicarbonate aqueous solution added is 200-400 mL.

[0020] Furthermore, in step (4), the cooling is to 0-20°C, the reaction is carried out at 60-70°C for 1.5-2.5h, and the methyl tert-butyl ether extraction is performed once with 200-500mL of methyl tert-butyl ether.

[0021] The present invention also provides 2-(5-bromo-2-fluorophenyl-2-cyclopropylacetic acid methyl ester and its analogs synthesized by the synthesis method.

[0022] The beneficial effects of the present invention are:

[0023] The invention uses 2-fluoro-5-bromobenzonitrile as a raw material, introduces a cyclopropyl group through cyclopropylmagnesium bromide, then introduces a cyano group through a Van Leusen reaction, then hydrolyzes to obtain a carboxylic acid, and finally methylates to obtain a target product. The synthesis method has simple and safe operations in each step, high yield, good repeatability, is suitable for the synthesis of various derivatives, and is a synthesis method suitable for industrialized scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0025] Figure 1 The reaction flow chart for preparing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate of the present invention;

[0026] Figure 2The following is a reaction flow chart for preparing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate analogs of the present invention. DETAILED DESCRIPTION

[0027] The embodiments of the present invention are described in detail below, and the embodiments are intended to explain the present invention and should not be construed as limiting the present invention. If specific techniques or conditions are not specified in the embodiments, they are carried out according to the techniques or conditions described in the literature in this area or according to the product specifications. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0028] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

[0029] The synthesis method of methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs in the present invention is carried out in 4 steps, and its reaction flow chart is as follows: Figure 1 As shown, the specific steps include:

[0030] (1) Add tetrahydrofuran and compound 1 to a three-necked flask, cool to -73 to -83°C under nitrogen protection, slowly drop cyclopropylmagnesium bromide, stir at -73 to -83°C for 1.5 to 2.5 hours, warm to room temperature for 0.3 to 0.8 hours, drop hydrochloric acid under ice bath, keep the temperature below 20°C, react at room temperature overnight, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, mix and column chromatography to obtain yellow liquid compound 2;

[0031] Wherein, when the synthetic product is 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester, compound 1 is 2-fluoro-5-bromobenzonitrile; when the synthetic product is a 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester analog, compound 1 is 2,5-dichlorobenzonitrile, the amount of tetrahydrofuran added is 1500-2000mL; the amount of compound 1 added is 0.4-0.58mol; the amount of cyclopropylmagnesium bromide added is 1-1.45moL; the amount of hydrochloric acid added is 1900mL-2200mL 2.5M-3M; ethyl acetate extraction is to use 800-1200mL ethyl acetate for 2 times;

[0032] (2) Add ethylene glycol dimethyl ether and potassium tert-butoxide to a three-necked flask, cool to -50--60°C under nitrogen protection, add a solution of ethylene glycol dimethyl ether containing p-toluenesulfonylmethyl isocyanide dropwise, react at -60°C--70°C for 15-25 min, add compound 2 dropwise, react at -60°C--30°C for 0.5-1.5 h, add methanol dropwise, reflux for 1-2 h, add water and stir for 15-20 min, adjust the pH to 4-5 with hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, mix and column chromatography to obtain a yellow liquid compound 3;

[0033] Among them, the amount of ethylene glycol dimethyl ether added is 300-800mL; the amount of potassium tert-butoxide added is 0.6-0.62mol; the amount of p-toluenesulfonylmethyl isocyanide added is 0.36-0.37mol; the amount of compound 2 added is 0.24-0.247mol; the amount of methanol added is 400mL;

[0034] (3) Add concentrated hydrochloric acid, compound 3 and 1,4-dioxane to a three-necked flask, react at 90-110° C. for 40-50 h, cool, add ice water, extract with methyl tert-butyl ether, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and slurry with petroleum ether to obtain a white solid compound 4;

[0035] The amount of concentrated hydrochloric acid added is 200-400 mL; the amount of compound 3 added is 0.1-0.15 mol; the amount of 1,4-dioxane added is 300-400 mL; the amount of ice water added is 1500 mL; the methyl tert-butyl ether extraction is performed by extracting twice with 200-400 mL of methyl tert-butyl ether;

[0036] (4) Methanol and compound 4 were added to a three-necked flask, and the temperature was lowered to 0-20° C. under nitrogen protection, and thionyl chloride was added dropwise. After the addition was completed, the reaction was carried out at 60-70° C. for 1.5-2.5 h, the temperature was lowered, the mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred. The mixture was extracted with methyl tert-butyl ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid compound 5, which is methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate;

[0037] The amount of methanol added is 210-250 mL; the amount of compound 4 added is 0.077-0.09 mol; the amount of thionyl chloride added is 0.165-0.18 mol; the amount of saturated sodium bicarbonate aqueous solution added is 200-400 mL; and the methyl tert-butyl ether extraction is performed by using 200-500 mL of methyl tert-butyl ether for one extraction.

[0038] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention.

[0039] Example 1

[0040] The synthesis method of 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester in Example 1 of the present invention is as follows Figure 1 As shown, the specific steps include:

[0041] (1) 1500 mL of tetrahydrofuran and 81.6 g of compound 1-1 (0.4 mol, 1.0 eq) were added to a 5 L three-necked flask. The temperature was lowered to -78°C under nitrogen protection, and 1000 mL of cyclopropylmagnesium bromide (1 M tetrahydrofuran solution, 1.0 mol, 2.5 eq) was slowly added dropwise. After the addition was completed, the mixture was stirred at -78°C for 2 hours, and the temperature was raised to room temperature for reaction for 30 minutes. 1900 mL of 2.5 M hydrochloric acid was added dropwise under an ice bath, and the temperature was controlled to be less than 20°C. After the addition was completed, the mixture was reacted at room temperature overnight, and extracted with ethyl acetate (1000 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 60.0 g of yellow liquid compound 1-2 with a yield of 61.7%.

[0042] (2) 500 mL of ethylene glycol dimethyl ether and 69.4 g of potassium tert-butoxide (0.62 mol, 2.5 eq) were added to a 2 L three-necked flask. The temperature was lowered to -60°C under nitrogen protection. A solution of 72.2 g of p-methylbenzenesulfonylmethyl isocyanide (0.37 mol, 1.5 eq) in 500 mL of ethylene glycol dimethyl ether was added dropwise. After the addition was completed, the mixture was reacted at -65°C for 20 minutes. 60.0 g of compound 1-2 (0.247 mol, 1.0 eq) was added dropwise. ) was added with 100 mL of ethylene glycol dimethyl ether solution, and the mixture was reacted at -60°C to -30°C for 1 hour. 400 mL of methanol was added dropwise, and the mixture was refluxed for 1.5 hours. 2000 mL of water was added and stirred for 15 minutes. 2M hydrochloric acid was used to adjust the pH to 4-5. The mixture was extracted with ethyl acetate (1000 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 32.1 g of yellow liquid compound 1-3 with a yield of 50.6%.

[0043] (3) 300 mL of concentrated hydrochloric acid, 32.1 g of compound 1-3 (0.13 mol, 1.0 eq), and 300 mL of 1,4-dioxane were added to a 1 L three-necked flask, reacted at 100° C. for 48 hours, cooled, added with 1500 mL of ice water, extracted with methyl tert-butyl ether (300 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried with petroleum ether to obtain 21.0 g of white solid compound 1-4, with a yield of 59.2%.

[0044] (4) 210 mL of methanol and 21.0 g of compound 1-4 (0.077 mol, 1.0 eq) were added to a 500 mL three-necked flask under nitrogen protection. The temperature was lowered to 10° C. 19.6 g of thionyl chloride (0.165 mol, 2.14 eq) was added dropwise. After the addition was completed, the mixture was reacted at 65° C. for 2 hours. The mixture was cooled and concentrated. 300 mL of saturated aqueous sodium bicarbonate solution was added and stirred. The mixture was extracted with methyl tert-butyl ether (300 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 20.0 g of yellow liquid 1-5. The yield was 90.5%.

[0045] 1H-NMR (400MHz, CDCl3): δ=7.62-7.64(1H, m), δ=7.26-7.27(1H, m), δ=6.90-7.05(1H , m), δ=3.71 (3H, s), δ=3.08-3.11 (1H, d), δ=1.36-1.41 (1H, m), δ=0.32-0.85 (4H, m).

[0046] Example 2

[0047] The synthetic method of 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester analogue in Example 2 of the present invention is as follows Figure 2 As shown, the specific steps include:

[0048] (1) 2000 mL of tetrahydrofuran and 100.0 g of compound 2-1 (0.58 mol, 1.0 eq) were added to a 10 L three-necked flask. The mixture was cooled to -78°C under nitrogen protection and 1450 mL of cyclopropylmagnesium bromide (1 M tetrahydrofuran solution, 1.45 mol, 2.5 eq) was slowly added dropwise. After the addition was completed, the mixture was stirred at -78°C for 2 hours, and the mixture was heated to room temperature for reaction for 30 minutes. 2200 mL of 3 M hydrochloric acid was added dropwise under an ice bath, and the temperature was controlled to be less than 20°C. After the addition was completed, the mixture was reacted at room temperature overnight, and extracted with ethyl acetate (1000 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 52.0 g of yellow liquid compound 2-2 with a yield of 41.4%.

[0049] (2) 500 mL of ethylene glycol dimethyl ether and 67.3 g of potassium tert-butoxide (0.6 mol, 2.5 eq) were added to a 2 L three-necked flask. The temperature was lowered to -60 °C under nitrogen protection. A solution of 70.3 g of p-methylbenzenesulfonylmethyl isocyanide (0.36 mol, 1.5 eq) in 500 mL of ethylene glycol dimethyl ether was added dropwise. After the addition was completed, the mixture was reacted at -65 °C for 20 minutes. 52.0 g of compound 2-2 (0.24 mol, 1.0 eq) was added dropwise. ) was added with 100 mL of ethylene glycol dimethyl ether solution, and the mixture was reacted at -60°C to -30°C for 1 hour. 400 mL of methanol was added dropwise, and the mixture was refluxed for 1.5 hours. 2000 mL of water was added and stirred for 15 minutes. 2M hydrochloric acid was used to adjust the pH to 4-5. The mixture was extracted with ethyl acetate (1000 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 40.7 g of yellow liquid compound 2-3 with a yield of 75%.

[0050] (3) 400 mL of concentrated hydrochloric acid, 40.7 g of compound 2-3 (0.13 mol, 1.0 eq), and 400 mL of 1,4-dioxane were added to a 2 L three-necked flask, reacted at 100 ° C for 48 hours, cooled, added with 1500 mL of ice water, extracted with methyl tert-butyl ether (300 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried with petroleum ether to obtain 22.6 g of off-white solid compound 2-4, with a yield of 50%.

[0051] (4) 250 mL of methanol and 22.6 g of compound 2-4 (0.09 mol, 1.0 eq) were added to a 500 mL three-necked flask under nitrogen protection. The temperature was lowered to 10° C. 21.9 g of thionyl chloride (0.18 mol, 2.0 eq) was added dropwise. After the addition was completed, the mixture was reacted at 65° C. for 2 hours. The temperature was lowered, concentrated, and 300 mL of saturated aqueous sodium bicarbonate solution was added with stirring. The mixture was extracted with methyl tert-butyl ether (400 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 21.6 g of yellow liquid 2-5. The yield was 88.9%.

[0052] 1H-NMR (400MHz, CDCl3): δ=7.59-7.60(1H, s), δ=7.28-7.32(1H, t), δ=7.20-7.22(1H , dd), δ=3.73 (3H, s), δ=3.31-3.33 (1H, d), δ=1.37-1.43 (1H, m), δ=0.33-0.82 (4H, m).

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. 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 solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be covered by the scope of the claims of the present invention.

Claims

1. A method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs, characterized in that: The following steps are involved: (1) Tetrahydrofuran and compound 1 were added to a reaction vessel. Under nitrogen protection, cyclopropylmagnesium bromide was slowly added dropwise after cooling. After the addition was completed, the temperature was raised to room temperature after stirring. After the reaction was completed, hydrochloric acid was added dropwise under ice bath. After the addition was completed, the reaction was allowed to proceed overnight at room temperature. The mixture was then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 2. (2) Add ethylene glycol dimethyl ether and potassium tert-butoxide to a reaction vessel, and under nitrogen protection, after cooling, add p-toluenesulfonylmethyl isocyanide dropwise, and carry out a primary reaction. Then, add compound 2 dropwise, and carry out a secondary reaction. Then, add methanol dropwise, and carry out a reflux reaction. Then, add water, stir, adjust the pH with hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 3. (3) Add concentrated hydrochloric acid to the reaction vessel, and react compound 3 and 1,4-dioxane. After the reaction is completed, cool down, add ice water, extract with methyl tert-butyl ether in turn, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and slurry with petroleum ether to obtain compound 4; (4) Methanol and compound 4 were added to a reaction vessel. Under nitrogen protection, thionyl chloride was added dropwise after cooling. After the addition was completed, the reaction was allowed to proceed. The temperature was then cooled, concentrated, saturated aqueous sodium bicarbonate solution was added, stirred, extracted with methyl tert-butyl ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5. Wherein, when the compound 1 is 2-fluoro-5-bromobenzonitrile, the final compound 5 obtained is methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate; When the compound 1 is 2,5-dichlorobenzonitrile, the final compound 5 is a 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetic acid methyl ester analog.

2. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (1), the amount of tetrahydrofuran added is 1500-2000 mL; the amount of compound 1 added is 0.4-0.58 mol; and the amount of cyclopropylmagnesium bromide added is 1-1.45 mol.

3. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (1), the cooling is to -73°C to -83°C, the stirring time is 1.5-2.5h, the heating time to room temperature is 0.3-0.8h, and the ethyl acetate extraction is performed twice with 800-1200mL of ethyl acetate.

4. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (2), the amount of ethylene glycol dimethyl ether added is 300-800 mL; the amount of potassium tert-butoxide added is 0.6-0.62 mol; the amount of p-toluenesulfonylmethyl isocyanide added is 0.36-0.37 mol; and the amount of compound 2 added is 0.24-0.247 mol.

5. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (2), the cooling is to -50°C~-60°C, the primary reaction is to react at -60°C~-70°C for 15-25 min, the secondary reaction is to react at -60°C~-30°C for 0.5-1.5 h, the reflux reaction time is 1-2 h, the water addition and stirring time is 15-20 min, and the hydrochloric acid is used to adjust the pH to 4~5.

6. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (3), the amount of concentrated hydrochloric acid added is 200-400 mL; the amount of compound 3 added is 0.1-0.15 mol; the amount of 1,4-dioxane added is 300-400 mL; and the amount of ice water added is 1500 mL.

7. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (3), the reaction is carried out at 90-110° C. for 40-50 hours, and the methyl tert-butyl ether extraction is carried out twice using 200-400 mL of methyl tert-butyl ether.

8. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (4), the amount of methanol added is 210-250 mL; the amount of compound 4 added is 0.077-0.09 mol; the amount of thionyl chloride added is 0.165-0.18 mol; and the amount of saturated sodium bicarbonate aqueous solution added is 200-400 mL.

9. The method for synthesizing methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs as claimed in claim 1, characterized in that: In step (4), the cooling is to 0-20°C, the reaction is carried out at 60-70°C for 1.5-2.5h, and the methyl tert-butyl ether extraction is performed once with 200-500mL of methyl tert-butyl ether.

10. Methyl 2-(5-bromo-2-fluorophenyl)-2-cyclopropylacetate and its analogs synthesized by the synthesis method according to any one of claims 1 to 9.

Images