Bicyclo [1.1. 0] butanone compound and synthesis method thereof

Abstract

The invention relates to a bicyclo [1.1. 0] butanone compound and a synthesis method thereof, the structural formula of the compound is as follows: # imgabs0 # formula (I), R is any one of phenyl, p-tolyl, p-ethyl phenyl, p-isopropyl phenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3, 5-dimethylphenyl, 1-naphthyl, and 4-trimethylsilyl, and the structural formula of the compound is as follows: # imgabs0 # formula (I), and in the formula (I), R is any one of phenyl, p-tolyl, p-ethyl phenyl, p-isopropyl phenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3, 5-dimethylphenyl, 1-naphthyl, and 4-trimethylsilyl. The method is low in raw material cost and easy to obtain, simple and convenient in experimental operation, efficient in synthesis process and suitable for large-scale production. By using cheap and easily available reagents such as 4-dimethylaminopyridine, acetic anhydride, sodium hydride and the like, the target bicyclo [1.1. 0] butanone compound can be obtained only through three-step reaction, and gram-scale production can be realized.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and particularly relates to a bicyclo[1.1.0]butanone compound and a synthesis method thereof. Background Art

[0002] The concept of “escaping the plane” has been widely adopted in the innovative design of new drugs. Its core strategy is to use sp-rich 3 Three-dimensional framework constructed by hybrid carbon replaces sp in traditional drugs 2 Hybridized aromatic two-dimensional skeletons can achieve optimized replacement as bioisosteres. Among them, bicyclo[n.1.1]alkanes, due to their unique structural characteristics, show excellent three-dimensional bioisostere functions of aromatics and heteroaromatics, which can significantly enhance the water solubility, lipid solubility and metabolic stability of drug molecules while improving drug activity, bringing multiple advantages to drug research and development.

[0003] At present, the synthesis of bicyclo[n.1.1]alkanes mainly relies on the ring expansion reaction of bicyclo[1.1.0]butane, such as the construction of bicyclo[1.1.1]pentane (BCPs), bicyclo[2.1.1]hexanes (BCHs) and bicyclo[3.1.1]heptanes (BCHeps) through [n+3] cycloaddition reaction. Among them, bicyclo[1.1.0]butanone, as a key bicyclo[1.1.0]butane derivative, plays an important role in the ring expansion reaction. However, the two existing methods for synthesizing bicyclo[1.1.0]butanone each have significant limitations, which to some extent restricts its application potential in drug design and synthesis.

[0004] The method for synthesizing bicyclo[1.1.0]butanone has been reported as follows:

[0005]

[0006] Method 1 has the following defects: 1) The first step requires three days of reaction, resulting in high time cost; 2) The synthetic intermediate is unstable and needs to be stored in a nitrogen atmosphere in a -20°C refrigerator and kept away from light, which increases the complexity of the experimental operation; 3) The dangerous reagent tert-butyl lithium is used, which can easily lead to the risk of fire or explosion; 4) The reaction temperature needs to be controlled at -78°C, and the experimental operation is complicated; 5) It cannot be prepared on a gram scale.

[0007] Method 2:

[0008]

[0009] Method 2 has the following defects: 1) The steps are cumbersome, and the synthesis path is as long as 6 steps, which increases the complexity and time cost of the synthesis process. 2) The environmental impact is significant. If the dichlorothionyl involved in the synthesis process decomposes in water, it will release toxic sulfur dioxide and hydrogen chloride, which is contrary to the principle of green environmental protection.

[0010] Therefore, developing a more efficient, safe, simple and large-scale synthesis method for bicyclo[1.1.0]butanone is of great significance for promoting the application of this type of compound in drug design and synthesis. Summary of the invention

[0011] In view of the problems existing in the above background technology, the purpose of the present invention is to provide a bicyclo[1.1.0]butanone compound and a synthesis method, which are specifically achieved by the following technical scheme:

[0012] A bicyclo[1.1.0]butanone compound, characterized in that the compound has the following structural formula:

[0013]

[0014] In formula (I), R is any one of phenyl, p-tolyl, p-ethylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3,5-dimethylphenyl, 1-naphthyl and 4-trimethylsilyl.

[0015] The synthesis method of the above-mentioned bicyclo[1.1.0]butanone compound has the following reaction formula:

[0016]

[0017] Among them, R in formula (III) is any one of phenyl, p-tolyl, p-ethylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3,5-dimethylphenyl, 1-naphthyl, and 4-trimethylsilyl.

[0018] The above-mentioned method for synthesizing a bicyclo[1.1.0]butanone compound comprises the following specific steps:

[0019] 1) dissolving 3-oxocyclobutane-1-carboxylic acid represented by formula (II) in tetrahydrofuran solution, adding into Grignard reagent represented by formula (III), and reacting overnight to obtain cis-γ-tertiary alcohol cyclobutyl ketone represented by formula (IV);

[0020] 2) cis-γ-tertiary alcohol cyclobutyl ketone, 4-dimethylaminopyridine and acetic anhydride are reacted in tetrahydrofuran at room temperature to prepare a compound represented by formula (V);

[0021] 3) The compound represented by formula (V) is reacted with sodium hydride in methyl tert-butyl ether at 60°C to obtain the bicyclo[1.1.0]butanone compound represented by formula (I).

[0022] Further, the operation of step 1) is as follows:

[0023] 1-1) A constant pressure dropping funnel and a reflux condenser are placed on a three-necked flask, magnesium powder is added to the three-necked flask, argon is replaced three times, and heat is applied with a heat drying gun for 30 minutes under evacuation, R-Br is added to the constant pressure dropping funnel, and tetrahydrofuran is added to dilute, 5 mL of tetrahydrofuran is added to a 50 mL three-necked flask, a small grain of iodine is added, 2-3 drops of a dilute solution of a halogenated hydrocarbon are dripped into the constant pressure dropping funnel, and the solution turns yellow, and the solution is heated to reflux with a heat drying gun until the yellow color fades, the reaction starts, and heating is stopped;

[0024] 1-2) Place the entire system in an ice bath at 0°C, slowly drip the remaining halogenated hydrocarbon solution into the three-necked flask, and after the addition is complete, heat and reflux in a 70°C oil bath for about two hours to complete the reaction, thereby obtaining a Grignard reagent tetrahydrofuran solution;

[0025] 1-3) Place the entire system in an ice bath at 0°C, dissolve 3-oxocyclobutane-1-carboxylic acid in tetrahydrofuran solution, slowly add it dropwise to the Grignard reagent tetrahydrofuran solution, and react overnight;

[0026] 1-4) After the reaction is completed, 1M dilute hydrochloric acid is added to quench the reaction, the magnetic particle is removed, the organic phase is extracted and separated, the aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, the organic phases are back-extracted with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, the filtrate is concentrated and drained, the magnetic particle is removed, the reaction solution is subjected to silica gel column chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 as eluent, the elution rate is 5-15mL / min, preferably 10mL / min, and TLC monitoring is performed with petroleum ether and ethyl acetate in a volume ratio of 4:1 as a developing solvent, and R f The effluent with a value of 0.4-0.5 is evaporated to dryness under reduced pressure to obtain a cis-γ-tertiary alcohol cyclobutyl ketone compound represented by formula (IV).

[0027] Further, the operation of step 2) is as follows:

[0028] 2-1) At room temperature, a cis-γ-tertiary alcohol cyclobutyl ketone compound and tetrahydrofuran are mixed and stirred to mix well, and then 4-dimethylaminopyridine and acetic anhydride are added and stirred overnight;

[0029] 2-2) After the reaction is completed, the mixture is concentrated and evaporated to dryness, and silica gel column chromatography is performed with petroleum ether and ethyl acetate in a volume ratio of 20:1 as eluent, and the elution rate is 5-15 mL / min, preferably 10 mL / min, and TLC monitoring is performed with petroleum ether and ethyl acetate in a volume ratio of 10:1 as developing solvent, and R f The effluent with a value of 0.4-0.5 was evaporated to dryness under reduced pressure to obtain a compound represented by formula (V).

[0030] Further, the operation of step 3) is as follows: a reflux condenser is arranged on a two-necked flask, a compound represented by formula (V) is added to the two-necked flask, argon is replaced three times, methyl tert-butyl ether is added, and then sodium hydride is added, and the mixture is heated to reflux in an oil bath at 60° C. for 2 h. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate, concentrated and evaporated to dryness, and silica gel column chromatography is performed with a volume ratio of 40:1 of petroleum ether and ethyl acetate as an eluent, at an elution rate of 5-15 mL / min, preferably 10 mL / min, and TLC monitoring is performed with a volume ratio of 10:1 of petroleum ether and ethyl acetate as a developing solvent, and R f The effluent with a value of 0.5-0.6 is evaporated to dryness under reduced pressure to obtain a bicyclo[1.1.0]butanone compound represented by formula (I).

[0031] The synthesis method of the present invention has the advantages of cheap and readily available raw materials, simple experimental operation, efficient synthesis process, and scalable preparation. By using cheap and readily available reagents such as 4-dimethylaminopyridine, acetic anhydride, and sodium hydride, the final bicyclo[1.1.0]butanone compound can be obtained in only three steps, and gram-scale preparation can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The compound Ⅰ-1 of the present invention 1 H NMR spectra;

[0033] Figure 2 The compound Ⅰ-1 of the present invention 13 C NMR spectra;

[0034] Figure 3 The compound IV-1 of the present invention 1 H NMR spectra;

[0035] Figure 4 The compound IV-1 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0036] The present invention is further described below in conjunction with specific embodiments to facilitate a better understanding of the present technical solution.

[0037] Example 1

[0038] Preparation of phenyl (-3-phenylbicyclo [1.1.0] butyl) ketone (I-1):

[0039] 1) On a 50mL three-necked flask, a constant pressure dropping funnel and a reflux condenser are arranged. Magnesium powder (230.4mg, 9.6mmol) is added to the three-necked flask, and argon gas is replaced three times. Under the state of evacuation, heat with a hot drying gun for 30 minutes, add bromobenzene (0.84mL, 8mmol) to the constant pressure dropping funnel, and then add 5mL tetrahydrofuran to dilute. Add 2.16mL tetrahydrofuran to the 50mL three-necked flask, add a small grain of iodine, and drip 2-3 drops of the diluted bromobenzene solution through the constant pressure dropping funnel. It turns yellow. Heat with a hot drying gun to reflux until the yellow fades, the reaction starts, and stop heating. Put the whole system in an ice bath system at 0℃, and slowly drip the remaining diluted bromobenzene solution into the 50mL three-necked flask. The dripping speed is suitable to maintain the steady boiling of the reaction solution. After the addition is completed, heat and reflux in a 70°C oil bath for about two hours to complete the reaction, and obtain a Grignard reagent tetrahydrofuran solution. Place the entire system in an ice bath system at 0°C, dissolve 3-oxocyclobutane-1-carboxylic acid (VI, 228 mg, 2 mmol) in 5 mL of tetrahydrofuran solution, and slowly drop it into the Grignard reagent tetrahydrofuran solution to react overnight. After the reaction is completed, add 1M dilute hydrochloric acid to quench the reaction, remove the magnetic particle, extract and separate the organic phase, and extract the aqueous phase three times with ethyl acetate. Combine the organic phases, back-extract the organic phase with sodium bicarbonate solution and saturated brine, dry it with anhydrous magnesium sulfate, filter it, concentrate and drain the filtrate, and perform silica gel column chromatography on the reaction solution with a volume ratio of 10:1 petroleum ether and ethyl acetate as the eluent, and the elution rate is 10 mL / min. Use a volume ratio of 4:1 petroleum ether and ethyl acetate as the developing solvent for TLC monitoring, and collect R f The effluent with a value of 0.5 was evaporated to dryness under reduced pressure to obtain 262 mg of a white solid, namely (3-hydroxy-3-phenylcyclobutyl)(phenyl)methanone (IV-1), with a yield of 52%. 1 H NMR Figure 3 , 13 C NMR Figure 4 .

[0040] 2) At room temperature, (3-hydroxy-3-phenylcyclobutyl)(phenyl)methanone (252 mg, 1.0 mmol) and 10 mL of tetrahydrofuran were mixed and stirred, followed by addition of 4-dimethylaminopyridine (122 mg, 1.0 mmol) and acetic anhydride (113 uL, 1.2 mmol), and stirring overnight; monitored by TCL (developing solvent: petroleum ether: ethyl acetate = 10:1, v / v); after the reaction was completed, concentrated and evaporated to dryness, and silica gel column chromatography was performed with petroleum ether and ethyl acetate in a volume ratio of 20:1 as eluent, the elution rate was 10 mL / min, and TLC monitoring was performed with petroleum ether and ethyl acetate in a volume ratio of 10:1 as developing solvent, and the effluent with an Rf value of 0.4-0.5 was collected, and vacuum evaporated to dryness, and directly proceeded to the next step.

[0041] 3) Place a reflux condenser on a two-necked flask. Add the product of the previous step to the two-necked flask, replace the argon three times, add 10 mL of methyl tert-butyl ether, then add sodium hydride (40 mg, 1.0 mmol), and heat to reflux in an oil bath at 60°C for 2 h. After the reaction is completed, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous magnesium sulfate, concentrate and evaporate to dryness, perform silica gel column chromatography with a volume ratio of 40:1 petroleum ether and ethyl acetate as eluents, and the elution rate is 10 mL / min. Perform TLC monitoring with a volume ratio of 10:1 petroleum ether and ethyl acetate as developing solvents, collect the effluent with an Rf value of 0.5-0.6, and evaporate to dryness under reduced pressure to obtain 65.3 mg of phenyl (-3-phenylbicyclo [1.1.0] butyl) ketone (Ⅰ-1), and the two-step yield is 28%. 1 H NMR Figure 1 , 13 C NMR Figure 2 .

[0042] Example 2

[0043] Gram-scale preparation of p-methylphenyl-3-(p-methylphenyl)bicyclo[1.1.0]butan-1-ylmethanone (I-2):

[0044] 1) On a 250mL three-necked flask, a constant pressure dropping funnel and a reflux condenser are arranged. Magnesium powder (2304mg, 96mmol) is placed in the three-necked flask, argon is replaced three times, and it is heated with a hot drying gun for 30 minutes under the state of evacuation. P-methylbromobenzene (13.7g, 80mmol) is added to the constant pressure dropping funnel, and then 70mL of tetrahydrofuran is added to dilute it. 10mL of tetrahydrofuran is added to the 250mL three-necked flask, and a small grain of iodine is added. 2-3 drops of the diluted solution of p-methylbromobenzene are dripped into the constant pressure dropping funnel through the control of the constant pressure dropping funnel. It turns yellow. Heat and reflux with a hot drying gun until the yellow fades, and the reaction begins. Stop heating. The whole system is placed in an ice bath system at 0℃, and the remaining diluted p-methylbromobenzene solution is slowly dripped into the 250mL three-necked flask. The dripping speed is suitable to maintain the steady boiling of the reaction solution. After the addition, heat and reflux in a 70℃ oil bath for about two hours to complete the reaction, and obtain a tetrahydrofuran solution of the Grignard reagent. Place the entire system in an ice bath system at 0℃, dissolve 3-oxocyclobutane-1-carboxylic acid (VI, 2280mg, 20mmol) in the tetrahydrofuran solution, and slowly drop it into the tetrahydrofuran solution of the Grignard reagent, and react overnight. After the reaction is completed, add 1M dilute hydrochloric acid to quench the reaction, remove the magnetic particle, extract and separate the organic phase, and extract the aqueous phase three times with ethyl acetate. Combine the organic phases, extract the organic phase with sodium bicarbonate solution and saturated brine, dry it with anhydrous magnesium sulfate, filter it, concentrate and drain the filtrate, and perform silica gel column chromatography on the reaction solution with a volume ratio of 10:1 petroleum ether and ethyl acetate as the eluent, and the elution rate is 15mL / min. Use a volume ratio of 4:1 petroleum ether and ethyl acetate as the developing solvent for TLC monitoring, collect the effluent with an Rf value of 0.5, and evaporate it to dryness under reduced pressure to obtain 3.2g of the product, which is directly used for the next step.

[0045] 2) At room temperature, the product of the previous step was mixed with 20 mL of tetrahydrofuran, stirred to mix, and then 4-dimethylaminopyridine (1.4 g, 11.6 mmol) and acetic anhydride (1.3 mL, 11.6 mmol) were added and stirred overnight; monitored by TLC (developing solvent was petroleum ether: ethyl acetate = 10:1, v / v). After the reaction was completed, the mixture was concentrated and evaporated to dryness, and silica gel column chromatography was performed with petroleum ether and ethyl acetate in a volume ratio of 20:1 as eluent, and the elution rate was 15 mL / min. TLC monitoring was performed with petroleum ether and ethyl acetate in a volume ratio of 10:1 as developing solvent, and the effluent with an Rf value of 0.4-0.5 was collected, and vacuum evaporated to dryness, and directly proceeded to the next step.

[0046] 3) Place a reflux condenser on a two-necked flask. Add the product of the previous step to the two-necked flask, replace the argon three times, add 10 mL of methyl tert-butyl ether, and then add sodium hydride (464 mg, 11.6 mmol), and heat to reflux in an oil bath at 60°C for 4 h. After the reaction is completed, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous magnesium sulfate, concentrate and evaporate to dryness, perform silica gel column chromatography with a volume ratio of 40:1 petroleum ether and ethyl acetate as the eluent, and the elution rate is 15 mL / min. Perform TLC monitoring with a volume ratio of 10:1 petroleum ether and ethyl acetate as the developing solvent, and collect R f The effluent with a value of 0.5-0.6 was evaporated to dryness under reduced pressure to obtain 1.1 g of p-methylphenyl-3-(p-methylphenyl)bicyclo[1.1.0]butan-1-ylmethanone (Ⅰ-2), with a three-step yield of 22%.

[0047] Examples 3 to 11 adopt the same method, except that the corresponding substituents are replaced during the synthesis process, to obtain intermediate products IV-3 to IV-11, whose structural data are shown in Table 1, and I-1 to I-11, whose structural data are shown in Table 2.

[0048] Table 1 Structural data of compounds IV-1-IV-11

[0049]

[0050]

[0051]

[0052]

[0053] Table 2 Structural data of compounds Ⅰ-1-Ⅰ-11

[0054]

[0055]

[0056]

[0057]

[0058] The room temperature in the above embodiments refers to 25-30° C. Unless otherwise specified, the reagents and methods involved in the above embodiments are all commonly used reagents and methods in the art.

Claims

1. A bicyclo[1.1.0]butanone compound, characterized in that The structural formula of the compound is as follows: In formula (I), R is any one of phenyl, p-tolyl, p-ethylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3,5-dimethylphenyl, 1-naphthyl and 4-trimethylsilyl.

2. The method for synthesizing a bicyclo[1.1.0]butanone compound according to claim 1, characterized in that: The reaction formula is as follows: Among them, R in formula (III) is any one of phenyl, p-tolyl, p-ethylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 3,5-dimethylphenyl, 1-naphthyl, and 4-trimethylsilyl.

3. The method for synthesizing a bicyclo[1.1.0]butanone compound according to claim 2, characterized in that: The specific steps are: 1) dissolving 3-oxocyclobutane-1-carboxylic acid represented by formula (II) in tetrahydrofuran solution, adding into Grignard reagent represented by formula (III), and reacting overnight to obtain cis-γ-tertiary alcohol cyclobutyl ketone represented by formula (IV); 2) cis-γ-tertiary alcohol cyclobutyl ketone, 4-dimethylaminopyridine and acetic anhydride are reacted in tetrahydrofuran at room temperature to prepare a compound represented by formula (V); 3) The compound represented by formula (V) is reacted with sodium hydride in methyl tert-butyl ether at 60°C to obtain the bicyclo[1.1.0]butanone compound represented by formula (I).

4. The method for synthesizing a bicyclo[1.1.0]butanone compound as claimed in claim 3, characterized in that: The operation of step 1) is as follows: 1-1) A constant pressure dropping funnel and a reflux condenser are placed on a three-necked flask, magnesium powder is added to the three-necked flask, argon is replaced three times, and heat is applied with a heat drying gun for 30 minutes under evacuation, R-Br is added to the constant pressure dropping funnel, and tetrahydrofuran is added to dilute, 5 mL of tetrahydrofuran is added to a 50 mL three-necked flask, a small grain of iodine is added, 2-3 drops of a dilute solution of a halogenated hydrocarbon are dripped into the constant pressure dropping funnel, and the solution turns yellow, and the solution is heated to reflux with a heat drying gun until the yellow color fades, the reaction starts, and heating is stopped; 1-2) Place the entire system in an ice bath at 0°C, slowly drip the remaining halogenated hydrocarbon solution into the three-necked flask, and after the addition is complete, heat and reflux in a 70°C oil bath for about two hours to complete the reaction, thereby obtaining a Grignard reagent tetrahydrofuran solution; 1-3) Place the entire system in an ice bath at 0°C, dissolve 3-oxocyclobutane-1-carboxylic acid in tetrahydrofuran solution, slowly add it dropwise to the Grignard reagent tetrahydrofuran solution, and react overnight; 1-4) After the reaction is completed, 1M dilute hydrochloric acid is added to quench the reaction, the magnetic particle is removed, the organic phase is extracted and separated, the aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, the organic phases are back-extracted with sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, the filtrate is concentrated and dried, the magnetic particle is removed, the reaction solution is subjected to silica gel column chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 as eluent, the elution rate is 5-15mL / min, and TLC monitoring is performed with petroleum ether and ethyl acetate in a volume ratio of 4:1 as a developing solvent, and R is collected. f The effluent with a value of 0.4-0.5 is evaporated to dryness under reduced pressure to obtain a cis-γ-tertiary alcohol cyclobutyl ketone compound represented by formula (IV).

5. The method for synthesizing a bicyclo[1.1.0]butanone compound according to claim 3, characterized in that: The operation of step 2) is as follows: 2-1) At room temperature, a cis-γ-tertiary alcohol cyclobutyl ketone compound and tetrahydrofuran are mixed and stirred to mix well, and then 4-dimethylaminopyridine and acetic anhydride are added and stirred overnight; 2-2) After the reaction, the mixture was concentrated and evaporated to dryness, and silica gel column chromatography was performed with petroleum ether and ethyl acetate in a volume ratio of 20:1 as the eluent, and the elution rate was 5-15 mL / min. TLC monitoring was performed with petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent, and R f The effluent with a value of 0.4-0.5 was evaporated to dryness under reduced pressure to obtain a compound represented by formula (V).

6. The method for synthesizing a bicyclo[1.1.0]butanone compound according to claim 3, characterized in that: The operation of step 3) is as follows: a two-necked flask is equipped with a reflux condenser, the compound represented by formula (V) is added to the two-necked flask, argon is replaced three times, methyl tert-butyl ether is added, and then sodium hydride is added, and the mixture is heated to reflux in an oil bath at 60° C. for 2 h. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and evaporated to dryness, and silica gel column chromatography is performed with a volume ratio of 40:1 of petroleum ether and ethyl acetate as an eluent at an elution rate of 5-15 mL / min, and TLC monitoring is performed with a volume ratio of 10:1 of petroleum ether and ethyl acetate as a developing solvent, and R f The effluent with a value of 0.5-0.6 is evaporated to dryness under reduced pressure to obtain a bicyclo[1.1.0]butanone compound represented by formula (I).

Images