Preparation method of (2S, 4R, 7R, 8R)-3, 3, 7, 11-tetramethyl tricyclo [6.3. 0. 02. 4] undec-1 (11)-ene

Abstract

The invention provides a preparation method of (2S, 4R, 7R, 8R)-3, 3, 7, 11-tetramethyl tricyclo [6.3. 0. 02. 4] undec-1 (11)-ene, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: mixing (1R, 2S, 8R, 11R)-7-methylene-3, 3, 11-trimethyltricyclo [6.3. 0. 02. 4] undecane with a catalyst, and carrying out an isomerization reaction under the conditions of hydrogen and pressurization to obtain (2S, 4R, 7R, 8R)-3, 3, 7, 11-tetramethyltricyclo [6.3. 0. 02. 4] undec-1 (11)-ene. A chemical synthesis method is adopted for preparation, the problem that a target product can only be extracted from natural plants is solved, and the method is environmentally friendly, efficient and free of three industrial wastes.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene. Background Technology

[0002] (2S,4R,7R,8R)-3,3,7,11-Tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene exists in the volatile oils of natural plants. This substance has a unique methyl cyclic terpene structure. By regulating the crosstalk between the Notch and Wnt / β-catenin transmembrane signaling pathways in epidermal stem cells, it prolongs the S phase of keratinocytes, thereby promoting an increased rate of collagen fiber remodeling. According to a report in the international journal *Natural Product Research*, it has important biochemical functions, including enhancing the catalytic activity index of superoxide dismutase, directly targeting and scavenging HO· free radical chain reactions, forming stable quinone-like structures, and inhibiting mitochondrial membrane potential imbalance.

[0003] The existing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene can only be extracted from plants, and there are currently no reported cases of its artificial synthesis. Currently, the content of (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene in natural plant oils is limited, accounting for only 0.2~0.3% of the effective components of volatile oils, mainly derived from plant volatile oils or resins. There are currently two main extraction methods: one is steam distillation, where the evaporated oil is collected by heating the plant material containing it, and then cooled to obtain liquid oil. The other method uses organic solvents (such as hexane or ethanol) to dissolve the ene in the plant material, and then recovers it by evaporating the solvent. However, the products obtained by these two methods also contain other components with similar properties, making separation difficult and resulting in low purity of the target product, only 30~35%. Furthermore, repeated distillation and extraction purification methods lead to decreased yield and increased industrial waste emissions, which is inconsistent with the concept of green environmental protection. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene. This invention uses a molecular isomerization pathway to prepare (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, which has the advantages of being environmentally friendly and highly efficient.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, comprising the following steps: (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane was mixed with a catalyst and subjected to isomerization under hydrogen and pressure to obtain (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene.

[0006] Preferably, the catalyst includes one or more of ruthenium / alumina catalyst, palladium / silica catalyst, and palladium on carbon catalyst.

[0007] Preferably, the ruthenium content in the ruthenium / alumina catalyst is 3-6% by mass; and the palladium content in the palladium / silica catalyst is 3-6% by mass.

[0008] Preferably, the mass ratio of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane to the catalyst is 100:1.2~1.8.

[0009] Preferably, the temperature of the isomerization reaction is 145~170℃.

[0010] Preferably, the pressure of the isomerization reaction is 0.5~0.7 MPa.

[0011] Preferably, the isomerization reaction takes 8 to 12 hours.

[0012] Preferably, after the isomerization reaction, the method further includes post-processing of the obtained isomerization product, the post-processing including the following steps: The isomerization reaction product is subjected to solid-liquid separation, and the resulting liquid phase is subjected to vacuum fractionation.

[0013] Preferably, the vacuum degree of the reduced pressure fractionation is 3 mmHg, and the fraction with a top temperature of 76~77°C is heated and collected.

[0014] This invention provides a method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, comprising the following steps: mixing (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane with a catalyst, and carrying out an isomerization reaction under hydrogen and pressure to obtain (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene. This invention uses a molecular structural isomerization method for preparation, solving the problem that (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene can only be extracted from natural plants. The raw material (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane is commercially available at a low cost. Its main source is plant extraction, and its content in plants is relatively high, more than 10 times that of (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene. This invention obtains the target product from (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane through a one-step isomerization reaction. The preparation method provided by this invention is environmentally friendly and efficient, and produces no industrial waste. The resulting (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene has a high yield and purity, with a yield of up to 89.06% and a purity of up to 71.2%.

[0015] Furthermore, the physicochemical properties of the isomerization reaction products obtained by this invention are consistent with those of the products obtained from natural extraction. Detailed Implementation

[0016] This invention provides a method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, comprising the following steps: (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane was mixed with a catalyst and subjected to isomerization under hydrogen and pressure to obtain (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene.

[0017] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0018] In this invention, the catalyst preferably comprises one or more of ruthenium / alumina catalyst, palladium / silica catalyst, and palladium on carbon catalyst. In this invention, the ruthenium / alumina catalyst and the palladium / silica catalyst are preferably supported catalysts. The ruthenium content in the ruthenium / alumina catalyst is preferably 3-6% by mass, more preferably 4-5%, and the palladium content in the palladium / silica catalyst is preferably 3-6% by mass, more preferably 4-5%.

[0019] In this invention, the mass ratio of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane to the catalyst is preferably 100:1.2~1.8, more preferably 100:1.3~1.6, and even more preferably 100:1.4~1.5.

[0020] In this invention, the mixing is preferably carried out in a reaction vessel. There are no special requirements for the mixing method; any mixing method well-known to those skilled in the art can be used, such as stirring. After mixing, this invention preferably introduces nitrogen gas into the reaction vessel for protection, and then introduces hydrogen gas under anaerobic conditions to remove the nitrogen gas.

[0021] In this invention, the temperature of the isomerization reaction is preferably 145~170℃, more preferably 150~165℃, even more preferably 155~160℃, and the time is preferably 8~12h, more preferably 9~10h; the pressure of the isomerization reaction is preferably 0.5~0.7MPa, more preferably 0.5MPa. In this invention, the preferred method for increasing the temperature and pressure of the isomerization reaction is: At room temperature, the hydrogen pressure is first increased to 0.3 MPa, then the temperature is increased to 100°C, then the pressure is increased to the isomerization reaction pressure, and finally the temperature is increased to the isomerization reaction temperature. This invention improves reaction safety and reduces byproduct production by controlling the temperature and pressure increase process.

[0022] In this invention, the reaction formula for the isomerization reaction is shown in Formula A: Formula A.

[0023] In this invention, after the isomerization reaction, it is preferable to further perform post-processing on the obtained isomerization reaction product, the post-processing including the following steps: The isomerization reaction product is subjected to solid-liquid separation, and the resulting liquid phase is subjected to vacuum fractionation.

[0024] In this invention, the solid-liquid separation method is preferably filtration; the vacuum fractionation is preferably carried out in a glass fractionation apparatus containing a fractionation column. In this invention, the vacuum degree of the vacuum fractionation is preferably 3 mmHg, and the fraction with a top temperature of 76~77°C is heated and collected.

[0025] The structural formula of the obtained (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene is as follows: .

[0026] The preparation method of (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene provided by the present invention will be described in detail below with reference to the embodiments. However, these embodiments should not be construed as limiting the scope of protection of the present invention.

[0027] Example 1 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 7.5g of ruthenium / alumina catalyst with a ruthenium loading of 5%. Pass nitrogen gas through and measure the air concentration. Then, under anaerobic conditions, pass hydrogen gas through to replace the nitrogen gas in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 145°C. The reaction time is maintained for 8 hours. (3) After the reaction is completed, the temperature inside the reactor is cooled to room temperature, hydrogen is discharged and the filtrate is obtained by filtration. The filtrate is collected for later use and put into the fractionation equipment of the glass instrument. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is collected. This fraction is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, and the product mass is 445.3g.

[0028] The molecular formula of the product obtained is: C 15 H 24 Molecular weight: 204.35, density: 0.948 g / cm³ 3 Boiling point: 263.9℃ at 760mmHg, flash point: 110℃.

[0029] Example 2 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 8g of ruthenium / alumina catalyst with a ruthenium loading of 5%. Pass nitrogen gas through and measure the air concentration. Then, under anaerobic conditions, pass hydrogen gas through to replace the nitrogen gas in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 145°C. The reaction time is maintained for 12 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 436.5g.

[0030] Example 3 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 6g of ruthenium / alumina catalyst with a ruthenium loading of 3%. Purge with nitrogen and measure the air concentration. Purge with hydrogen under anaerobic conditions to replace the nitrogen in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 150°C. The reaction time is maintained for 10 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 436.5g.

[0031] Example 4 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 7.5g of palladium / silica catalyst with a palladium loading of 5%. Purge with nitrogen and measure the air concentration. Purge with hydrogen under anaerobic conditions to replace the nitrogen in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 158°C. The reaction time is maintained for 10 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 360.6g.

[0032] Example 5 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 8g of palladium / silica catalyst with a palladium loading of 6%. Purge with nitrogen and measure the air concentration. Purge with hydrogen under anaerobic conditions to replace the nitrogen in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 160°C. The reaction time is maintained for 12 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 374.7g.

[0033] Example 6 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 6g of palladium / silica catalyst with a palladium loading of 3%. Purge with nitrogen and measure the air concentration. Purge with hydrogen under anaerobic conditions to replace the nitrogen in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 100°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 158°C. The reaction time is maintained for 12 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 351.8g.

[0034] Example 7 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 8g of palladium-carbon catalyst with a palladium loading of 6%. Pass nitrogen gas through and measure the air concentration. Then, under anaerobic conditions, pass hydrogen gas through to replace the nitrogen gas in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 90°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 165°C. The reaction time is maintained for 8 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, heated and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a product mass of 293.3g.

[0035] Example 8 (1) Take 500g of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane and place it in a laboratory high-pressure reactor. Add 7g of palladium catalyst with a palladium loading of 3%. Pass nitrogen gas through and measure the air concentration. Then, under anaerobic conditions, pass hydrogen gas through to replace the nitrogen gas in the reactor. (2) Under room temperature conditions, the hydrogen pressure in the pressurized reactor is 0.3 MPa. The temperature is slowly increased to 90°C. Then the hydrogen pressure in the reactor is adjusted to 0.5 MPa and the temperature in the reactor is increased to 165°C. The reaction time is maintained for 12 hours. (3) After the reaction is complete, the temperature inside the reactor is cooled to room temperature, hydrogen gas is discharged, and the filtrate is obtained by filtration. The obtained filtrate is collected for later use and put into a glass fractionation apparatus. The pressure is reduced to 3 mmHg, and the fraction with a top temperature of 76~77℃ is (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, with a yield of 276.8g.

[0036] Comparative Example 1 Compared with Example 1, the difference is that the reaction temperature was changed to 120°C and the pressure was changed to 0.2 MPa.

[0037] Comparative Example 2 Compared with Example 1, the difference is that the reaction temperature was changed to 180°C and the pressure was changed to 0.8 MPa.

[0038] The purity and yield of (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene obtained in Examples 1-8 and Comparative Examples 1-2 are shown in Table 1: Table 1. Yields and purity of Examples 1-8 and Comparative Examples 1-2

[0039] The above description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene, characterized in that, Includes the following steps: (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane was mixed with a catalyst and subjected to isomerization under hydrogen and pressure to obtain (2S,4R,7R,8R)-3,3,7,11-tetramethyltricyclo[6.3.0.02.4]undec-1(11)-ene.

2. The preparation method according to claim 1, characterized in that, The catalyst includes one or more of the following: ruthenium / alumina catalyst, palladium / silica catalyst, and palladium on carbon catalyst.

3. The preparation method according to claim 2, characterized in that, The ruthenium / alumina catalyst contains 3-6% ruthenium by mass; the palladium / silica catalyst contains 3-6% palladium by mass.

4. The preparation method according to claim 1 or 2, characterized in that, The mass ratio of (1R,2S,8R,11R)-7-methylene-3,3,11-trimethyltricyclo[6.3.0.02.4]undecane to the catalyst is 100:1.2~1.

8.

5. The preparation method according to claim 1, characterized in that, The isomerization reaction is carried out at a temperature of 145~170℃.

6. The preparation method according to claim 1 or 5, characterized in that, The pressure of the isomerization reaction is 0.5~0.7 MPa.

7. The preparation method according to claim 1 or 5, characterized in that, The isomerization reaction takes 8 to 12 hours.

8. The preparation method according to claim 1, characterized in that, Following the isomerization reaction, the method further includes post-processing of the resulting isomerization product, which includes the following steps: The isomerization reaction product is subjected to solid-liquid separation, and the resulting liquid phase is subjected to vacuum fractionation.

9. The preparation method according to claim 8, characterized in that, The vacuum degree of the reduced pressure fractionation is 3 mmHg, and the fraction with a top temperature of 76~77°C is heated and collected.

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