CN118638091A - A method for synthesizing an oxabenzo[3.2.2]bridged ring compound skeleton - Google Patents

Abstract

The invention provides a method for synthesizing an oxobenzo[3.2.2] bridged ring compound skeleton, the method comprising: rearranging 5,5-dimethyl-1,3-cyclohexanedione in acid catalysis to obtain compound I, hydrolyzing with alkali to obtain compound II, protecting phenolic hydroxyl group with dimethyl sulfate to obtain compound III, performing Michael addition with 2-cyclohexene-1-ketone in cuprous cyanide catalysis to obtain compound IV, selectively demethylating with sodium ethanethiolate to obtain compound V, brominating with phenyltrimethylammonium tribromide and then performing intramolecular S _N 2 reaction with alkali to obtain compound VI, i.e., an oxobenzo[3.2.2] bridged ring compound skeleton. The synthetic method overcomes the defects of expensive reagents and low yield in the prior art, is convenient for the mass production of related compounds of subsequent oxobenzo[3.2.2] bridged ring compound skeletons, and has good application prospects.

Description

A method for synthesizing an oxabenzo[3.2.2]bridged ring compound skeleton

Technical Field

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing an oxabenzo[3.2.2]bridged ring compound skeleton.

Background Art

The oxabenzo[3.2.2] bridge ring structure is a type of natural product that has been studied and paid more attention by scientists in recent years. Compounds containing this structure are widely distributed in the plant kingdom and have diverse and significant biological activities. Cannabispirketa, a natural product containing this skeleton, is isolated from hemp leaves. Hemp has the effects of anesthesia, antitussive and antiasthmatic, antispasmodic and analgesic, hemostatic and blood stasis, detoxification and fetal protection; at the same time, Cannabispirketa has good biological activities such as inhibiting the proliferation of breast cancer cells (MCF-7) and inducing apoptosis. It can be seen that the synthesis and development of [3.2.2] bridge ring molecular compounds have great potential in drug research and biology, and provide a new direction for later researchers to study how to synthesize related products.

We believe that there are more unknown activities and medicinal values waiting for human exploration and discovery. At present, a few research groups have completed the construction of [3.2.2] bridged ring compounds and the total synthesis of natural products containing this skeleton, but the research on the synthesis of oxybenzo[3.2.2] bridged ring compounds has not been reported.

Summary of the invention

The present invention mainly overcomes the shortcomings of the prior art and proposes a method for synthesizing an oxybenzo[3.2.2] bridged ring compound skeleton, which comprises: rearranging 5,5-dimethyl-1,3-cyclohexanedione under acid catalysis to obtain compound I, hydrolyzing it with alkali to obtain compound II, protecting the phenolic hydroxyl group with dimethyl sulfate to obtain compound III, performing Michael addition with 2-cyclohexene-1-one under cuprous cyanide catalysis to obtain compound IV, selectively demethylating it with sodium ethanethiolate to obtain compound V, brominating it with phenyltrimethylammonium tribromide and then performing intramolecular S _N 2 reaction with alkali to obtain compound VI, which is an oxybenzo[3.2.2] bridged ring compound skeleton. The synthesis method overcomes the defects of the prior art such as expensive reagents and low yield, facilitates the subsequent mass production of related compounds containing the oxybenzo[3.2.2] bridged ring compound skeleton, and has good application prospects.

In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

A method for synthesizing an oxabenzo[3.2.2]bridged ring compound skeleton, the synthesis route is as follows:

.

The synthesis method comprises steps 1 to 6:

Specific:

Step 1: Compound 5,5-dimethyl-1,3-cyclohexanedione is used as a starting material and rearranged under high temperature reflux conditions by acid catalysis to obtain compound I;

Step 2: Compound I is heated and hydrolyzed with sodium hydroxide aqueous solution to obtain compound II;

Step 3: The phenolic hydroxyl group of compound II is protected with dimethyl sulfate to obtain III;

Step 4: Compound III is subjected to Michael addition reaction with 2-cyclohexene-1-one under the catalysis of cuprous cyanide to obtain compound IV;

Step 5: Compound IV is treated with sodium ethanethiolate to selectively remove the methyl group of the phenol methyl ether adjacent to the methyl group to obtain compound V;

Step 6: Compound V is subjected to bromination reaction with phenyltrimethylammonium tribromide, and then the brominated substrate is subjected to intramolecular _SN2 reaction with sodium hydroxide aqueous solution to obtain compound VI, which is an oxabenzo[3.2.2] bridged ring compound skeleton;

The compound VI is an oxabenzo[3.2.2] bridged ring compound skeleton, and the structural formula is as follows:

.

Furthermore, the structural formulas of the compound 5,5-dimethyl-1,3-cyclohexanedione and compound I-IX are respectively as follows:

.

Furthermore, the specific synthesis method of step 1 is:

A water-free and oxygen-free reflux device is built at room temperature, 5,5-dimethyl-1,3-cyclohexanedione is added to the device, acetic anhydride is added as a solvent, concentrated sulfuric acid is slowly added, and then the mixture is heated to 139° C. - 150° C. and refluxed for 1-3 hours to remove acetic anhydride, followed by dilution with ice water, extraction, and washing with saturated sodium bicarbonate solution, distilled water, and saturated brine, and finally drying, removing the solvent, and separating and purifying to obtain compound I;

The molar ratio of the 5,5-dimethyl-1,3-cyclohexanedione to the concentrated sulfuric acid is 71.30-74.30:78.50-81.30.

Furthermore, the specific synthesis method of step 2 is:

Compound I is hydrolyzed with sodium hydroxide aqueous solution to obtain compound II, which specifically comprises:

Add compound I to the device at room temperature, then add solvent ethanol, then add sodium hydroxide aqueous solution in drops under an ice bath, then heat to 58°C-65°C and react at normal pressure for 1-3 hours; after the reaction, adjust the pH value, remove ethanol, then wash with saturated sodium bicarbonate solution, water and saturated brine in sequence, finally dry, remove the solvent, and separate and purify to obtain compound II;

The molar ratio of the compound I to sodium hydroxide is 60.30-63.30:17.18-20.18.

Furthermore, the specific synthesis method of step 3 is:

Compound II is subjected to dimethyl sulfate to methylate the phenolic hydroxyl group to obtain compound III, which specifically comprises:

Add compound II and anhydrous potassium carbonate into the reaction device at room temperature, and then add solvent acetone; then slowly add dimethyl sulfate dropwise, raise the temperature to 58°C-65°C and reflux for 10-14 hours. After the reaction is completed, filter out the potassium carbonate solid, wash with saturated sodium bicarbonate solution, water and saturated brine in sequence, and finally dry. After removing the solvent, separate and purify to obtain compound III;

The molar ratio of the compound II, anhydrous potassium carbonate and dimethyl sulfate is 44.88-47.88:128.19-131.19:134.62-137.62.

Furthermore, the specific synthesis method of step 4 is:

Compound III is subjected to Michael addition reaction with 2-cyclohexene-1-one to obtain compound IV, which specifically comprises:

At 0°C-5°C, add compound III and solvent tetrahydrofuran into the reaction device, then slowly drop n-butyl lithium into the reaction bottle, react for 10-20 minutes, then return to room temperature and react for 2.5-4 hours to obtain a lithium reagent;

Add cuprous cyanide and solvent tetrahydrofuran at room temperature, slowly dropwise add them into the lithium reagent at -78°C--80°C, then transfer to 0°C--5°C and stir for 10-20 minutes, then transfer to -78°C--80°C and react for 1-3 hours, and after completion, obtain a copper salt solution;

2-cyclohexen-1-one, boron trifluoride ether solution and ultra-dry tetrahydrofuran are mixed in a reaction bottle, slowly added dropwise into the copper salt solution at -78°C, and reacted at -78°C-80°C for 4-6 hours; saturated ammonium chloride aqueous solution is added to quench, and the mixture is washed with saturated sodium bicarbonate solution, water and saturated brine in sequence, and finally dried, and after removing the solvent, the mixture is separated and purified to obtain compound IV;

The molar ratio of the compound III, n-butyl lithium, cuprous cyanide, 2-cyclohexene-1-one and boron trifluoride etherate is 78.51-81.51: 82.44-85.44: 58.88-61.88: 39.26-42.26: 39.26-43.26.

Furthermore, the specific synthesis method of step 5 is:

Compound IV is selectively demethylated by sodium ethanethiolate to obtain compound V, specifically comprising:

Add compound IV and N,N-dimethylformamide to a reaction device at room temperature, then add sodium ethanethiolate solid under stirring, heat to 153°C-160°C and react for 6-10 hours at normal pressure; after the reaction, add dilute hydrochloric acid aqueous solution to quench, wash with saturated sodium bicarbonate solution, water and saturated brine in sequence, and finally dry, remove the solvent, separate and purify to obtain compound V;

The molar ratio of the compound IV to sodium ethanethiolate is: 4.27-7.27:13.67-16.67.

Furthermore, the specific synthesis method of step 6 is:

Compound V is brominated with phenyltrimethylammonium tribromide, and then subjected to an intramolecular _SN2 reaction with an aqueous sodium hydroxide solution to obtain VI, specifically comprising:

Add phenyltrimethylammonium tribromide and tetrahydrofuran to a reaction device at room temperature to prepare a solution; dissolve compound V in tetrahydrofuran at room temperature and place in a low-temperature bath at -78°C, then slowly add the tetrahydrofuran solution of phenyltrimethylammonium tribromide dropwise thereto, react at -78°C-80°C for 3-5 hours, then move to room temperature to react for 12-16 hours, and after the reaction is completed, filter the solid by suction, remove the solvent, and obtain a yellow solid for standby use;

The obtained yellow solid was dissolved with a solvent of dichloromethane and transferred to a reaction device, and a dilute sodium hydroxide solution was slowly added at 0°C, and the mixture was transferred to room temperature for reaction for 30-50 minutes. After the reaction, the mixture was washed with a saturated sodium bicarbonate solution, water and saturated brine in sequence, and finally dried. After removing the solvent, the compound VI was separated and purified;

The molar ratio of the compound V, phenyltrimethylammonium tribromide and NaOH is 2.02-5.02:6.25-9.25:0.02-0.05.

Beneficial Effects

Compared with the prior art, the present invention has the following advantages:

The present invention provides a method for synthesizing an oxybenzo[3.2.2] bridged ring compound skeleton, which comprises: rearranging 5,5-dimethyl-1,3-cyclohexanedione under acid catalysis to obtain compound I, hydrolyzing it with alkali to obtain compound II, protecting phenolic hydroxyl group with dimethyl sulfate to obtain compound III, performing Michael addition with 2-cyclohexene-1-one under cuprous cyanide catalysis to obtain compound IV, selectively demethylating with sodium ethanethiolate to obtain compound V, brominating with phenyltrimethylammonium tribromide and then performing intramolecular S _N 2 reaction with alkali to obtain compound VI, which is an oxybenzo[3.2.2] bridged ring compound skeleton. The synthesis method overcomes the defects of expensive reagents and low yield in the prior art, facilitates the subsequent mass production of related compounds containing the oxybenzo[3.2.2] bridged ring compound skeleton, and has good application prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a synthetic route diagram of the oxabenzo[3.2.2]bridged ring compound in an embodiment of the present invention;

FIG2 is the structural formula of compounds I to VI in the examples.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

According to the synthesis route shown in FIG1 , the compounds in the following examples were synthesized, and the structural formulas of the compounds involved are shown in FIG2 .

Embodiment 1:

Step 1:

Take a two-necked round-bottom flask and set up an anhydrous and oxygen-free reflux device, weigh 5,5-dimethyl-1,3-cyclohexanedione (10 g, 71.30 mmol, 1.0 equiv), add it into the two-necked flask, and replace the argon gas three times again. At room temperature, acetic anhydride (111 mL) was added to dilute the substrate, sulfuric acid (4.20 mL, 78.50 mmol, 1.1 equiv) was slowly added dropwise, the temperature was raised to 139 ° C and refluxed for 1 hour. After the reaction was completed, the system was cooled, concentrated under reduced pressure to remove acetic anhydride, ice water (200 mL) was added to dilute and stirred for 20 min, and extracted with dichloromethane (50 mL×3); then washed with saturated sodium bicarbonate solution (50 mL), distilled water (50 mL) and saturated brine (50 mL) in turn, and finally dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated and purified by column chromatography, the eluent volume ratio was (petroleum ether: ethyl acetate = 12: 1), and brown oily compound I (13.40 g, 84%) was obtained. R _f = 0.5 (petroleum ether: ethyl acetate = 4: 1).

Step 2:

Take a 250 mL double-necked round-bottom flask, dry it and replace argon three times, dissolve compound I (13.40 g, 60.30mmol, 1.0 equiv) in anhydrous ethanol (100 mL) and transfer it to a reaction bottle, slowly add sodium hydroxide (6.87 g, 17.18 mmol 2.85 equiv) in water (11-mL) dropwise at room temperature, heat to 60 ° C and react for 1 hour. After the reaction, wait for the system to cool, adjust the pH to neutral with 4 N hydrochloric acid solution, concentrate under reduced pressure to remove ethanol and filter, and the filtrate is washed with saturated sodium bicarbonate solution (50 mL), water (30 mL) and saturated brine (30 mL) in turn, and finally add an appropriate amount of anhydrous sodium sulfate to dry, concentrate under reduced pressure to remove the solvent, and separate and purify it by column chromatography. The eluent volume ratio is (petroleum ether: ethyl acetate = 4: 1) to obtain a light yellow solid compound II (6.20 g, 74%). R _f = 0.4 (petroleum ether:ethyl acetate = 2:1).

Step 3:

Take a 250 mL double-necked round-bottom flask and set up an anhydrous and oxygen-free reflux device. After drying and replacing argon three times, weigh compound II (6.20 g, 44.88 mmol, 1.0 equiv) and anhydrous potassium carbonate (15.51 g, 128.19mmol, 2.5 equiv) in turn, and then replace argon three times again. Add acetone (80 mL) at room temperature to dilute the substrate, then add dimethyl sulfate (12.74 mL, 134.62 mmol 3.0 equiv) dropwise, heat to 58 °C and reflux for 10 hours. After the reaction is completed, wait for the system to cool to room temperature, filter out the potassium carbonate solid, and rinse the filter cake with ethyl acetate. The collected filtrate was washed with saturated sodium bicarbonate solution (50 mL), water (30 mL) and saturated brine (30 mL) in turn, and finally dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated and purified by column chromatography, with the eluent volume ratio of (petroleum ether: ethyl acetate = 25: 1), to obtain a milky white oily compound III (5.84 g, 78%). R _f = 0.7 (petroleum ether: ethyl acetate = 4: 1).

Step 4:

Take a 250 mL single-mouth round-bottom flask and dry it. After replacing the argon three times, take 60 mL of ultra-dry tetrahydrofuran at room temperature to dissolve compound III (13.05 g, 78.51 mmol, 2.0 equiv) and transfer it to a single-mouth flask. Slowly add n-butyl lithium (32.99 mL, 82.44 mmol, 2.1 equiv, 2.5 M hexane solution) to the reaction flask at 0 °C. After the addition is complete, continue to react at this temperature for 10 minutes, then heat to room temperature for 2.5 hours to obtain the lithium reagent for use.

Take a 250mL two-necked round-bottom flask and dry it. Replace the argon three times, weigh cuprous cyanide (5.33g, 58.88mmol, 1.5equiv) and add it to the two-necked flask, replace the argon three times again, take 15mL of redistilled tetrahydrofuran and add it to the two-necked flask, at -78°C, extract the lithium reagent from the previous step and slowly add it dropwise to the reaction flask, then transfer it to 0°C and stir for 10 minutes, and then transfer it to -78°C to react for 1 hour to obtain a yellow copper salt solution.

Take a 25mL single-mouth round-bottom flask for use, strictly dry and replace argon three times, extract 10mL of redistilled tetrahydrofuran, 2-cyclohexene-1-one (3.78g, 39.26mmol, 1.0equiv), and boron trifluoride ether solution (4.95mL, 39.26mmol, 1.0equiv) in turn, add them to the single-mouth flask and mix them. At -78°C, extract the solution and slowly drop it into the reaction bottle of the previous step, react at -78°C for 4 hours, after the reaction is completed, quench with saturated ammonium chloride solution (10mL), extract with ethyl acetate (70mL×3); then wash with distilled water (50mL) and saturated brine (50mL) in turn, finally add an appropriate amount of anhydrous sodium sulfate to dry, concentrate under reduced pressure to remove the solvent, and separate and purify by column chromatography, the eluent volume ratio is (petroleum ether: ethyl acetate = 30:1→15:1), and obtain white solid compound IV (8.40g, 80.7%). R _f = 0.5 (petroleum ether: ethyl acetate = 4: 1); its structure was characterized by TLC thin layer chromatography and nuclear magnetic resonance data. Specifically as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ = 6.52 (s, 1H), 3.79 (s, 3H), 3.64 (s, 3H), 3.53 (tt, J = 12.4, 4.0 Hz, 1H), 3.23 (t, J = 13.2 Hz, 1H), 2.44-2.39 (m, 2H), 2.39–2.30 (m, 2H), 2.24 (s, 3H), 2.13 (s, 3H), 2.08 (dd, J = 5.6, 3.6 Hz, 1H), 1.77 (dd, J = 10.0, 4.4 Hz, 2H) ppm; ¹³ C NMR (100MHz, CDCl ₃ ): δ=212.2,156.6,156.6,136.7,122.2,121.8,109.1,61.2,55.2,45.8,41.3,36.0,29.3,25.8,20.3,12.0ppm.

Step 5:

Take a 100 mL two-necked round-bottom flask for standby use, connect it to a reflux device, dry and replace the argon, weigh compound IV (1.12 g, 4.27 mmol, 1.0 equiv), add it to the two-necked flask, and replace the argon again three times. At room temperature, ultra-dry N,N-dimethylformamide (35-mL) was added to dissolve the substrate, and sodium ethanethiolate (1.13 g, 13.67 mmol, 3.2 equiv) was weighed and added to the reaction bottle under stirring, and the temperature was raised to 153°C and refluxed for 6 hours. After the reaction was completed, the system was cooled, and 15 mL of 2M HCl was added to quench the reaction, and dichloromethane was extracted (15 mL); N,N-dimethylformamide was removed with distilled water (20 mL), and washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) in sequence, and finally added with an appropriate amount of anhydrous sodium sulfate to dry, concentrated under reduced pressure to remove the solvent, and separated and purified by column chromatography, the eluent volume ratio was (petroleum ether: ethyl acetate = 15:1), and white solid compound V (0.60 g, 56%) was obtained, R _f = 0.5 (petroleum ether: ethyl acetate = 4:1). Its structure was characterized by TLC thin layer chromatography and nuclear magnetic resonance data. The details are as follows: 1H NMR (400MHz, CDCl ₃ ): δ = 6.24 (s, 1H), 3.76 (s, 3H), 3.49 (t, J = 3.2Hz, 1H), 2.98 (s, 1H), 2.23 (s, 3H), 2.06 (s, 3H), 2.05-2.00 (m, 1H), 1.98 (dd, J = 1 2.4, 2.8Hz, 1H), 1.83-1.68 (m, 3H), 1.52 (tt, J＝12.4, 3.6Hz, 2H), 1.41-1.30 (m, 1H)ppm; ¹³ C NMR (100MHz, CDCl ₃ ): δ=154.0,153.6,135.4,114.9,110.8,103.5,98.3,55.4,39.1,36.3,29.7,28.6,20.3,19.4,11.2ppm.

Step 6:

Take a 100mL two-necked round-bottom flask, dry it and replace the argon three times. At room temperature, extract 15mL of redistilled tetrahydrofuran, dissolve compound V (500mg, 2.02mmol, 1.0equiv) and transfer it to a two-necked flask. Then slowly drop phenyltrimethylammonium tribromide (2.4g, 6.25mmol, 3.1equiv) dissolved in ultra-dry tetrahydrofuran (20mL) at -78°C, react for 3 hours at -78°C, move to room temperature and react for 12 hours. After the reaction is completed, filter with a sand core funnel, and concentrate the filtrate under reduced pressure to remove the solvent to obtain a yellow solid for use.

Take a 100mL double-mouthed round-bottomed flask for standby use. At room temperature, extract 5mL of dichloromethane, dissolve the yellow solid compound obtained by the bromination reaction and transfer it to a double-mouthed flask. Add 0.5M NaOH solution (0.8g NaOH solid dissolved in 40mL distilled water) at a rate of 2 drops per second at 0°C. After the addition is complete, transfer to room temperature for reaction for 0.5 hours. After the reaction is completed, extract with dichloromethane (10mL×3); then wash with distilled water (10mL) and saturated brine (10mL) in turn, and finally add an appropriate amount of anhydrous sodium sulfate to dry, concentrate under reduced pressure to remove the solvent, and separate and purify by column chromatography. The eluent volume ratio is (petroleum ether: ethyl acetate = 20:1→15:1), and a yellow solid compound VI (0.80g, 35.7%) is obtained, R _f = 0.5 (petroleum ether: ethyl acetate = 4:1). Its structure is characterized by TLC thin-layer chromatography and nuclear magnetic resonance data. The details are as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ = 4.45 (d, J = 8.0Hz, 1H), 3.77 (s, 3H), 3.74-3.71 (m, 1H), 2.94-2.86 (m, 1H), 2.76 (dd, J = 18.8, 6.0Hz, 1H), 2.53-2.47 (m, 1H) ), 2.37 (s, 3H), 2.26 (d, J = 2.4Hz, 1H), 2.14 (s, 3H), 2.11-2.04 (m, 1H), 1.97-1.88 (m, 1H)ppm; ¹³ C NMR (100MHz, CDCl ₃ ): δ=207.6,151.7,151.3,136.8,124.1,123.1,112.5,80.4,61.5,45.8,29.3,27.3,26.6,20.0,13.3ppm.

In summary, the present invention discloses a method for synthesizing an oxybenzo[3.2.2] bridged ring compound skeleton, which targets the oxybenzo[3.2.2] bridged ring skeleton, designs a series of common chemical reactions through chemical synthesis methods, and constructs the oxybenzo[3.2.2] bridged ring skeleton for the first time. The method is simple to operate, has cheap raw materials, and short steps, and lays a foundation for the subsequent synthesis of other types of compounds containing or involving the oxybenzo[3.2.2] bridged ring skeleton, embodies the superiority of the method, and has high practical value.

Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims (9)

1. A synthesis method of an oxabenzo [3.2.2] bridged ring compound skeleton, which is characterized in that the synthesis route is as follows:

。

2. A method of synthesizing an oxabenzo [3.2.2] bridged ring compound skeleton according to claim 1, wherein said method of synthesizing comprises steps 1 to 6:

Specific:

step 1: the compound 5, 5-dimethyl-1, 3-cyclohexanedione is used as a starting material, and is subjected to acid catalytic rearrangement under the condition of high-temperature reflux to obtain a compound I;

step 2: heating and hydrolyzing the compound I by using a sodium hydroxide aqueous solution to obtain a compound II;

step 3: protecting phenolic hydroxyl groups of the compound II by dimethyl sulfate to obtain III;

step 4: the compound III and 2-cyclohexene-1-one are subjected to Michael addition under the catalysis of cuprous cyanide to obtain a compound IV;

step 5: removing methyl on phenol methyl ether ortho to methyl selectively by using sodium ethanethiol to obtain a compound V;

Step 6: carrying out bromination reaction on the compound V by using phenyl trimethyl ammonium tribromide, and then carrying out intramolecular S _N 2 reaction on the brominated substrate by using sodium hydroxide aqueous solution to obtain a compound VI, namely an oxabenzo [3.2.2] bridged ring compound skeleton;

The compound VI is an oxabenzo [3.2.2] bridged ring compound skeleton, and has the structural formula as follows:

3. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound skeleton according to claim 1, wherein the structural formulas of the compound 5, 5-dimethyl-1, 3-cyclohexanedione and the compounds I to IX are respectively shown as follows:

。

4. the method for synthesizing an oxabenzo [3.2.2] bridged ring compound skeleton as recited in claim 1, wherein the specific synthetic method in step1 is as follows:

Setting up a water-free and oxygen-free reflux device at room temperature, adding 5, 5-dimethyl-1, 3-cyclohexanedione into the device, adding solvent acetic anhydride, slowly adding concentrated sulfuric acid, heating to 139-150 ℃ for reflux for 1-3 hours, removing acetic anhydride, sequentially diluting with ice water, extracting, sequentially washing with saturated sodium bicarbonate solution, distilled water and saturated saline water, finally drying, removing the solvent, and separating and purifying to obtain a compound I;

The molar ratio of the 5, 5-dimethyl-1, 3-cyclohexanedione to the concentrated sulfuric acid is 71.30-74.30:78.50-81.30.

5. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound as recited in claim 1, wherein the specific synthetic method of step 2 is as follows:

The compound I is hydrolyzed by sodium hydroxide aqueous solution to obtain a compound II, which comprises the following steps:

Adding a compound I into a device at normal temperature, adding ethanol serving as a solvent, dropwise adding a sodium hydroxide aqueous solution under ice bath, and then heating to 58-65 ℃ for normal pressure reaction for 1-3 hours; after the reaction is finished, regulating the pH value, removing ethanol, washing with saturated sodium bicarbonate solution, water and saturated saline water in sequence, finally drying, removing the solvent, and separating and purifying to obtain a compound II;

the molar ratio of the compound I to the sodium hydroxide is 60.3-63.3: 17.18-20.18.

6. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound as recited in claim 1, wherein the specific synthetic method of step 3 is as follows:

the compound II is subjected to dimethyl sulfate to carry out methylation on phenolic hydroxyl groups to obtain a compound III, and the method specifically comprises the following steps:

Adding a compound II and anhydrous potassium carbonate into a reaction device at normal temperature, and then adding a solvent acetone; slowly dripping dimethyl sulfate, heating to 58-65 ℃ and refluxing for 10-14 hours, filtering out potassium carbonate solid after the reaction is finished, washing with saturated sodium bicarbonate solution, water and saturated saline water in sequence, finally drying, removing solvent, and separating and purifying to obtain a compound III;

the molar ratio of the compound II to the anhydrous potassium carbonate to the dimethyl sulfate is 44.88-47.88:128.19-131.19:134.62-137.62.

7. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound as recited in claim 1, wherein the specific synthetic method of step 4 is as follows:

The compound III is prepared by Michael addition with 2-cyclohexene-1-ketone to obtain a compound IV, which specifically comprises the following steps:

Adding a compound III and tetrahydrofuran solvent into a reaction device at the temperature of 0-5 ℃, slowly dripping n-butyllithium into a reaction bottle, reacting for 10-20 minutes, and recovering to room temperature for reacting for 2.5-4 hours to obtain a lithium reagent;

adding cuprous cyanide and tetrahydrofuran solvent at normal temperature, slowly dripping the cuprous cyanide and tetrahydrofuran solvent into the lithium reagent at-78-80 ℃, then transferring the lithium reagent to 0-5 ℃ and stirring for 10-20 minutes, transferring the lithium reagent to-78-80 ℃ and reacting for 1-3 hours to obtain copper salt solution after the completion;

Uniformly mixing 2-cyclohexene-1-one, boron trifluoride diethyl etherate solution and ultra-dry tetrahydrofuran in a reaction bottle, slowly dropwise adding the mixture into copper salt solution at the temperature of minus 78 ℃ and reacting for 4-6 hours at the temperature of minus 78 ℃ to 80 ℃; adding saturated ammonium chloride water solution for quenching, washing with saturated sodium bicarbonate solution, water and saturated saline water in sequence, finally drying, removing the solvent, and separating and purifying to obtain a compound IV;

the molar ratio of the compound III, n-butyllithium, cuprous cyanide, 2-cyclohexene-1-one and boron trifluoride diethyl ether is 78.51-81.51:82.44-85.44:58.88-61.88:39.26-42.26:39.26-43.26.

8. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound as recited in claim 1, wherein the specific synthetic method in step 5 is as follows:

The compound IV is subjected to selective demethylation by sodium ethanethiol to obtain a compound V, which specifically comprises the following steps:

adding a compound IV and N, N-dimethylformamide into a reaction device at room temperature, then adding sodium ethanethiol solid under stirring, heating to 153-160 ℃ for reaction for 6-10 hours, and carrying out normal pressure; after the reaction is finished, adding a dilute hydrochloric acid aqueous solution for quenching, washing with a saturated sodium bicarbonate solution, water and saturated saline water in sequence, finally drying, removing a solvent, and separating and purifying to obtain a compound V;

The molar ratio of the compound IV to the sodium ethanethiol is as follows: 4.27-7.27:13.67-16.67.

9. The method for synthesizing an oxabenzo [3.2.2] bridged ring compound as recited in claim 1, wherein the specific synthetic method in step6 is as follows:

Brominating the compound V by using phenyl trimethyl ammonium tribromide, and then carrying out intramolecular S _N 2 reaction by using sodium hydroxide aqueous solution to obtain VI, wherein the method specifically comprises the following steps:

Adding phenyl trimethyl ammonium tribromide and tetrahydrofuran into a reaction device at room temperature to prepare a solution; dissolving a compound V in tetrahydrofuran at room temperature, placing the solution in a low-temperature bath at-78 ℃, slowly and dropwise adding a tetrahydrofuran solution of phenyl trimethyl ammonium tribromide into the solution, reacting for 3-5 hours at-78-80 ℃, then moving to room temperature for reacting for 12-16 hours, filtering the solid after the reaction is finished, and removing the solvent to obtain yellow solid for later use;

dissolving the obtained yellow solid with a solvent of dichloromethane, transferring the obtained yellow solid into a reaction device, slowly adding a dilute sodium hydroxide solution at the temperature of 0 ℃, transferring the solution to room temperature for reaction for 30-50 minutes, washing the reaction end with a saturated sodium bicarbonate solution, water and saturated saline water in sequence, finally drying, removing the solvent, and separating and purifying to obtain a compound VI;

The molar ratio of the compound V to the phenyltrimethylammonium tribromide to the NaOH is 2.02-5.02:6.25-9.25:0.02-0.05.