Preparation method of 1-(5-methoxy-2, 3-dihydro-1, 4-benzodioxane-8-yl) ethanone
By using cuprous cyanide and methyl Grignard reagent to prepare 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone, the safety hazards and highly toxic reagents of existing methods are solved, and high-yield and isotopically labeled synthesis is achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-25
- Publication Date
- 2026-03-31
AI Technical Summary
Existing methods for synthesizing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone use unfriendly chemical reagents, posing safety hazards. Furthermore, methods with high yields use easily explosive or highly toxic reagents, resulting in high safety risks in both laboratory and industrial production.
Using cuprous cyanide and 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin as raw materials, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone was prepared by nitrogen purging, reaction, extraction, water washing, drying and filtration, followed by nucleophilic addition and hydrolysis using methyl Grignard reagents such as methyl magnesium bromide. This method is suitable for isotope labeling.
This provides a safe and stable synthesis method with high yield and the ability to easily introduce isotope labeling, avoiding the safety risks of using easily explosive and highly toxic reagents in traditional methods.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone. Background Technology
[0002] The description of the background art in this invention pertains to related technologies and is used merely for illustration and to facilitate understanding of the invention. It should not be construed as the applicant explicitly believing or presuming that the invention was prior art on the filing date of the first application.
[0003] 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone is an important benzodioxane constituent group. As an aromatic heterocyclic moiety, it provides molecular stability and specific chemical reactivity, making it an important functional group for organic synthetic drugs. Benzodioxanes possess antibacterial, anti-inflammatory, and antitumor biological activities and are a common drug structural unit, frequently found in various pharmacologically active compounds, such as anti-inflammatory drugs and neuroprotective agents. Due to their high efficiency and low toxicity, an increasing number of benzodioxane-containing derivatives are being discovered and synthesized in drug molecules. Utilizing the principle of synergistic activity, these derivatives are widely used in pharmaceutical intermediates and various fine chemicals and advanced chemical materials.
[0004] Currently, the methods for synthesizing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone include: 1: Acetylation
[0005] The yield is 81%, which is high, but it requires the use of volatile and fuming reagent acetyl chloride and easily explosive hazardous chemical nitromethane, which is extremely unfriendly to synthesis personnel and poses safety hazards in production.
[0006] CN110862398,2020,A Organic Process Research and Development, 2010, vol.14, #5, P.1182-1187; 2: Methylation The yield is 80%, and the required dimethyl sulfate is also a highly toxic hazardous chemical.
[0007] US4368199, 1983, A While the two commonly used methods mentioned above have high yields, the reagents used are not environmentally friendly and pose safety hazards to the environment and synthesis personnel. Against this backdrop, finding a method with high yield, stable process, and the use of common, readily available, and safe chemical reagents is an urgent need for safe production. Summary of the Invention
[0008] While current known synthetic methods achieve yields exceeding 80%, the reagents used are often unsafe (dimethyl sulfate is a highly toxic hazardous chemical, nitromethane is an easily explosive hazardous chemical, etc.). These methods pose risks to laboratory and industrial personnel. However, for safety management in chemical synthesis, to prevent and reduce laboratory accidents, ensure personal safety, and avoid property damage, the chemical reagents used in the process should be as safe and non-toxic as possible. Therefore, the process route of this invention was developed. Furthermore, according to the method of this invention, isotope labeling can be performed quickly (…). 13 C, 14 C). This enriches the synthesis of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone and also applies it to the field of isotope chemical labeling.
[0009] A method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone, comprising the following steps: Cuprous cyanide and the starting material were added to N,N-dimethylformamide and purged with nitrogen. The starting material was 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin or 5-chloro-8-methoxy-2,3-dihydro-benzo[1,4]dioxin. After reacting at 110°C, the temperature was lowered, ammonia was added, and the mixture was extracted and combined with the organic phases. After washing with water, drying and filtering the organic phases, the 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
[0010] Further steps include the following:
[0011] Cuprous cyanide and 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin were added to N,N-dimethylformamide and purified with nitrogen. The reaction was carried out at 110°C and then cooled. Ammonia was added and the mixture was extracted and the organic phases were combined. After washing with water, drying and filtering the organic phases, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
[0012] Furthermore, the methyl Grignard reagent is methyl magnesium bromide reagent, methyl magnesium iodide, or methyl magnesium chloride.
[0013] Further steps include the following: Cuprous cyanide (90.0 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (270.0 mg, 1.1 mmol), N,N-dimethylformamide (3 ml), and pure water (1.5 ml) were added to a 25 ml single-necked flask. The mixture was purged with nitrogen three times and stirred at 110 °C for 20 h. Heating was stopped, and the mixture was cooled to room temperature. Ammonia (30 ml) was added, and the mixture was extracted with dichloromethane (40 ml × 3). The organic phases were combined. The organic phases were washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35 °C, and purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1).
[0014] Under nitrogen protection, add 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1) (163.0 mg, 0.85 mmol) and anhydrous tetrahydrofuran (10 ml) to a 50 ml two-necked flask; stir and cool to below -10 °C; maintain the temperature between -10 and 0 °C, and add a tetrahydrofuran solution of methyl magnesium bromide (0.34 ml, 1.02 mmol) dropwise. After the addition is complete, raise the temperature to 80 °C. At ℃, stirred for 12 h, and spotted onto a TLC plate for control. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1) was detected, indicating complete reaction. 1 mol / L hydrochloric acid (20 ml) was added, and the reaction system was stirred at room temperature for 1 h. Dichloromethane (30 ml × 3) was added for extraction three times, and the mixture was concentrated and purified by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl) ethyl ketone.
[0015] Furthermore, adopt 14C is marked; this includes the following steps:
[0016] Add cuprous cyanide to a 25ml single-necked flask ( 14 C) (91.6 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (270.0 mg, 1.1 mmol), N,N-dimethylformamide (3 ml), pure water (1.5 ml), nitrogen purging three times, stirring at 110 °C for 20 h; heating stopped, cooled to room temperature, ammonia (30 ml), dichloromethane extraction (40 ml × 3), organic phases combined; organic phase washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, silica gel added, concentrated under reduced pressure at 35 °C, purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- 14 C; Under nitrogen protection, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- was added to a 50 ml two-necked flask. 14 C (156.5 mg, 0.81 mmol) and anhydrous tetrahydrofuran (12 ml); stir and cool to below -15 °C; control the temperature from -15 to 0 °C, add methyl magnesium bromide tetrahydrofuran solution (0.32 ml, 0.97 mmol) dropwise, after the addition is complete, raise the temperature to 80 °C, stir for 10 h, and check the TLC plate. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was observed. 14 C. After the reaction is complete, add 1 mol / L hydrochloric acid (25 ml) and stir the reaction system at room temperature for 1 h; extract three times with dichloromethane (30 ml × 3), combine the organic phases, concentrate to dryness with silica gel, and purify by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone- 14 C.
[0017] Furthermore, adopt 13 C is marked; this includes the following steps:
[0018] Add cuprous cyanide to a 25ml single-necked flask. 13C (181.1 mg, 2 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (539.2 mg, 2.2 mmol), N,N-dimethylformamide (5 ml), pure water (2.5 ml), nitrogen purging three times, stirring at 110 °C for 22 h; heating stopped, cooled to room temperature, ammonia (50 ml), dichloromethane extraction (60 ml × 3), organic phases combined; organic phase washed twice with water (40 ml × 2), washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, silica gel added, concentrated under reduced pressure at 35 °C, purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- 13 C; Under nitrogen protection, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was added to the dried reaction flask. 13 C (319.0 mg, 1.66 mmol) and anhydrous tetrahydrofuran (18 ml); stir and cool to below -10 °C; control the temperature at -10 to 0 °C, add methyl magnesium bromide tetrahydrofuran solution (0.66 ml, 1.99 mmol) dropwise, after the addition is complete, raise the temperature to 80 °C, stir for 10 h, and check the TLC plate. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was observed. 13 C. After the reaction is complete, add 1 mol / L hydrochloric acid (40 ml) and stir the reaction system at room temperature for 1 h; extract three times with dichloromethane (50 ml × 3), combine the organic phases, and purify by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. 13 C.
[0019] The embodiments of the present invention have the following beneficial effects: This patent introduces a novel synthetic method, which has not been previously reported. The method uses 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin as a starting material, with cyano substitution, followed by nucleophilic addition and hydrolysis to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. The starting materials are simple and readily available, the process is stable, and the operation is straightforward. Furthermore, it can be applied to the isotopic labeling synthesis of C13 and C14 compounds.
[0020] This patented method expands the synthesis of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone, and crucially, it allows for the simple and convenient introduction of isotope labeling. Detailed Implementation
[0021] The present application will be further described below with reference to the embodiments.
[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, in the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Different embodiments can be substituted or combined, and for those skilled in the art, other implementation methods can be obtained based on these embodiments without creative effort.
[0023] A method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone, comprising the following steps: Cuprous cyanide and the starting material were added to N,N-dimethylformamide and purged with nitrogen. The starting material was 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin or 5-chloro-8-methoxy-2,3-dihydro-benzo[1,4]dioxin. After reacting at 110°C, the temperature was lowered, ammonia was added, and the mixture was extracted and combined with the organic phases. After washing with water, drying and filtering the organic phases, the 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
[0024] In some embodiments of the present invention, a method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone includes the following steps:
[0025] Cuprous cyanide and 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin were added to N,N-dimethylformamide and purified with nitrogen. The reaction was carried out at 110°C and then cooled. Ammonia was added and the mixture was extracted and the organic phases were combined. After washing with water, drying and filtering the organic phases, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
[0026] In some embodiments of the present invention, the methyl Grignard reagent is methyl magnesium bromide reagent, methyl magnesium iodide or methyl magnesium chloride.
[0027] Example 1. 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone
[0028] Cuprous cyanide (90.0 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (270.0 mg, 1.1 mmol), and N,N-dimethylformamide (3 ml) were added to a 25 ml single-necked flask. Then, pure water (1.5 ml) was added, and the mixture was purged with nitrogen three times. The mixture was stirred at 110 °C for 20 h. Heating was stopped, and the mixture was cooled to room temperature. Ammonia (30 ml) was added, and the mixture was extracted with dichloromethane (40 ml × 3). The organic phases were combined. The organic phase was washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35 °C, and purified by column chromatography using silica gel to obtain 163.0 mg of 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1). (Yield: 85.0%) Under nitrogen protection, IM-1 (163.0 mg, 0.85 mmol) and anhydrous tetrahydrofuran (10 ml) were added to a 50 ml two-necked flask. The mixture was stirred and cooled to below -10 °C. The temperature was maintained between -10 and 0 °C, and a tetrahydrofuran solution of methyl magnesium bromide (0.34 ml, 1.02 mmol) was added dropwise. After the addition was complete, the temperature was raised to 80 °C, and the mixture was stirred for 12 h. A TLC test showed no IM-1, indicating complete reaction. 20 ml of 1 mol / L hydrochloric acid was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was extracted three times with dichloromethane (30 ml × 3), concentrated to dryness, and purified by column chromatography to obtain 161.1 mg of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone (TM) (yield: 91.0%). Example 2. Synthesis of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone 14 C
[0029] Add cuprous cyanide to a 25ml single-necked flask ( 14C) (91.6 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (270.0 mg, 1.1 mmol), N,N-dimethylformamide (3 ml), pure water (1.5 ml), nitrogen purging three times, stirring at 110 °C for 20 h. Heating was stopped, and the mixture was cooled to room temperature. Ammonia (30 ml) was added, and the mixture was extracted with dichloromethane (40 ml × 3). The organic phases were combined. The organic phase was washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography at 35 °C under reduced pressure to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin. 14 C(IM-2) total 156.5 mg. (Yield: 81.0%) Under nitrogen protection, IM-2 (156.5 mg, 0.81 mmol) and anhydrous tetrahydrofuran (12 ml) were added to a 50 ml two-necked flask. The mixture was stirred and cooled to below -15 °C. The temperature was maintained between -15 and 0 °C, and a tetrahydrofuran solution of methyl magnesium bromide (0.32 ml, 0.97 mmol) was added dropwise. After the addition was complete, the temperature was raised to 80 °C, and the mixture was stirred for 10 h. A TLC test showed no IM-2, indicating complete reaction. 1 mol / L hydrochloric acid (25 ml) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was extracted three times with dichloromethane (30 ml × 3), and the organic phases were combined. The solution was concentrated to dryness using silica gel and purified by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. 14 C(TM- 14 C) Total 151.5 mg (Yield: 89.0%) Example 3. Synthesis of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone 13 C
[0030] Add cuprous cyanide to a 25ml single-necked flask. 13 C (181.1 mg, 2 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (539.2 mg, 2.2 mmol), N,N-dimethylformamide (5 ml), pure water (2.5 ml), nitrogen purging three times, stirring at 110 °C for 22 h. Heating was stopped, and the mixture was cooled to room temperature. Ammonia (50 ml) was added, and the mixture was extracted with dichloromethane (60 ml × 3). The organic phases were combined. The organic phase was washed twice with water (40 ml × 2), washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 35 °C. The purified product was obtained by column chromatography to 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin. 13Total C(IM-3) content: 319.0 mg. (Yield: 83.0%) Under nitrogen protection, IM-3 (319.0 mg, 1.66 mmol) and anhydrous tetrahydrofuran (18 ml) were added to a dried reaction flask. The mixture was stirred and cooled to below -10°C. The temperature was maintained between -10°C and 0°C, and a tetrahydrofuran solution of methyl magnesium bromide (0.66 ml, 1.99 mmol) was added dropwise. After the addition was complete, the temperature was raised to 80°C, and the mixture was stirred for 10 h. A TLC test showed no IM-3, indicating the reaction was complete. 1 mol / L hydrochloric acid (40 ml) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was extracted three times with dichloromethane (50 ml × 3), and the organic phases were combined and purified by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. 13 C(TM- 13 C) Total 305.6 mg (Yield: 88.0%) This invention is also applicable to the isotope-labeled synthesis of 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. 13 C / 14 Synthesis of C.
[0031] It should be noted that the above embodiments can be freely combined as needed. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone, characterized in that, Includes the following steps: Cuprous cyanide and the starting material were added to N,N-dimethylformamide and purged with nitrogen. The starting material was 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin or 5-chloro-8-methoxy-2,3-dihydro-benzo[1,4]dioxin. After reacting at 110°C, the temperature was lowered, ammonia was added, and the mixture was extracted and combined with the organic phases. After washing with water, drying and filtering the organic phases, the 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
2. The method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone according to claim 1, characterized in that, Includes the following steps: Cuprous cyanide and 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin were added to N,N-dimethylformamide and purified with nitrogen. The reaction was carried out at 110°C and then cooled. Ammonia was added and the mixture was extracted and the organic phases were combined. After washing with water, drying and filtering the organic phases, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was obtained. 5-Cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was reacted with anhydrous tetrahydrofuran and a tetrahydrofuran solution containing methyl Grignard reagent was added dropwise until no 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was detected. After extraction, concentration and purification, 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone was obtained.
3. The method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone according to claim 1, characterized in that, The methyl Grignard reagent is methyl magnesium bromide reagent, methyl magnesium iodide, or methyl magnesium chloride.
4. The method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone according to claim 1, characterized in that, Includes the following steps: Cuprous cyanide (90.0 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (270.0 mg, 1.1 mmol), N,N-dimethylformamide (3 ml), and pure water (1.5 ml) were added to a 25 ml single-necked flask. The mixture was purged with nitrogen three times and stirred at 110 °C for 20 h. Heating was stopped, and the mixture was cooled to room temperature. Ammonia (30 ml) was added, and the mixture was extracted with dichloromethane (40 ml × 3). The organic phases were combined. The organic phases were washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35 °C, and purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1). Under nitrogen protection, add 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1) (163.0 mg, 0.85 mmol) and anhydrous tetrahydrofuran (10 ml) to a 50 ml two-necked flask; stir and cool to below -10 °C; maintain the temperature between -10 and 0 °C, and add a tetrahydrofuran solution of methyl magnesium bromide (0.34 ml, 1.02 mmol) dropwise. After the addition is complete, raise the temperature to 80 °C. At ℃, stirred for 12 h, and spotted onto a TLC plate for control. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (IM-1) was detected, indicating complete reaction. 1 mol / L hydrochloric acid (20 ml) was added, and the reaction system was stirred at room temperature for 1 h. Dichloromethane (30 ml × 3) was added for extraction three times, and the mixture was concentrated and purified by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl) ethyl ketone.
5. The method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone according to claim 1, characterized in that, use 14 C is marked; this includes the following steps: Add cuprous cyanide to a 25ml single-necked flask ( 14 C) (91.6 mg, 1 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (270.0 mg, 1.1 mmol), N,N-dimethylformamide (3 ml), pure water (1.5 ml), nitrogen purging three times, stirring at 110 °C for 20 h; heating stopped, cooled to room temperature, ammonia (30 ml), dichloromethane extraction (40 ml × 3), organic phases combined; organic phase washed twice with water (30 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, silica gel added, concentrated under reduced pressure at 35 °C, purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- 14 C; Under nitrogen protection, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- was added to a 50 ml two-necked flask. 14 C (156.5 mg, 0.81 mmol) and anhydrous tetrahydrofuran (12 ml); stir and cool to below -15 °C; control the temperature from -15 to 0 °C, add methyl magnesium bromide tetrahydrofuran solution (0.32 ml, 0.97 mmol) dropwise, after the addition is complete, raise the temperature to 80 °C, stir for 10 h, and check the TLC plate. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was observed. 14 C. After the reaction is complete, add 1 mol / L hydrochloric acid (25 ml) and stir the reaction system at room temperature for 1 h; extract three times with dichloromethane (30 ml × 3), combine the organic phases, concentrate to dryness with silica gel, and purify by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone- 14 C.
6. The method for preparing 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)ethyl ketone according to claim 1, characterized in that, use 13 C is marked; this includes the following steps: Add cuprous cyanide to a 25ml single-necked flask. 13 C (181.1 mg, 2 mmol), 5-bromo-8-methoxy-2,3-dihydro-benzo[1,4]dioxin (SM-1) (539.2 mg, 2.2 mmol), N,N-dimethylformamide (5 ml), pure water (2.5 ml), nitrogen purging three times, stirring at 110 °C for 22 h; heating stopped, cooled to room temperature, ammonia (50 ml), dichloromethane extraction (60 ml × 3), organic phases combined; organic phase washed twice with water (40 ml × 2), washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, silica gel added, concentrated under reduced pressure at 35 °C, purified by column chromatography to obtain 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin- 13 C; Under nitrogen protection, 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was added to the dried reaction flask. 13 C (319.0 mg, 1.66 mmol) and anhydrous tetrahydrofuran (18 ml); stir and cool to below -10 °C; control the temperature at -10 to 0 °C, add methyl magnesium bromide tetrahydrofuran solution (0.66 ml, 1.99 mmol) dropwise, after the addition is complete, raise the temperature to 80 °C, stir for 10 h, and check the TLC plate. No 5-cyano-8-methoxy-2,3-dihydro-benzo[1,4]dioxin was observed. 13 C. After the reaction is complete, add 1 mol / L hydrochloric acid (40 ml) and stir the reaction system at room temperature for 1 h; extract three times with dichloromethane (50 ml × 3), combine the organic phases, and purify by column chromatography to obtain 1-(5-methoxy-2,3-dihydro-1,4-benzodioxane-8-yl)acetone. 13 C.