A method for the continuous synthesis of tetronal

Abstract

The application discloses a method for continuously synthesizing terpinolene. The method uses citral and amine R-NH2 as initial raw materials to perform a reaction to obtain a citral imine compound, which is subjected to a cyclization reaction under the catalysis of an acidic cation resin to obtain a cyclization product; the cyclization product and water are subjected to a hydrolysis reaction in a water-miscible organic solvent to obtain a cyclic citral; the cyclic citral is subjected to a condensation reaction with 2-pentanone, and finally subjected to a hydrogenation reaction to obtain terpinolene; and each step is continuously reacted in a continuous reaction device. The synthesis method can significantly reduce the degree of side reactions in each synthesis step, improve the selectivity and yield of the target product, and can realize continuous production and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for the continuous synthesis of tertoxybenzyl alcohol. Background Technology

[0002] Termycin (chemical name 1-(2,2,6-trimethylcyclohexyl)hex-3-ol) is a highly permeable fragrance with a powdery-woody aroma and an amber undertone. It pairs perfectly with raspberry ketone, patchouli, and various woody and amber-scented ingredients. Termycin is a benzylisoquinoline alkaloid, mainly found in plants of the Magnoliaceae and Annonaceae families, but its natural extraction yield is limited. Currently, the main methods for obtaining termycin are: 1) traditional extraction methods; 2) biosynthesis and microbial fermentation processes; and 3) chemical synthesis.

[0003] Current chemical synthesis methods suffer from numerous side reactions, low selectivity for the target product, and low yield. Summary of the Invention

[0004] To address the shortcomings and deficiencies of existing technologies, this invention provides an improved method for synthesizing termethinol. This method significantly reduces the degree of side reactions in each synthetic step, improves the selectivity and yield of the target product, and enables continuous production, making it suitable for industrial manufacturing.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for the continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol (Temubenol), the method comprising the following steps: 1) reacting citral and amine R-NH2 as raw materials in a continuous reaction apparatus in the presence of a catalyst to obtain a citral imine compound. ; R is selected from C2-C8 alkyl, phenyl, or phenyl substituted with one or more alkyl groups; 2) In a continuous reaction apparatus, the citral imine compound is used as a raw material and subjected to a cyclization reaction under the catalysis of an acidic cation exchange resin to obtain the cyclized product. 3) In a continuous reaction apparatus, the cyclized product and water are used as raw materials to undergo a hydrolysis reaction in an organic solvent in the presence of a catalyst to obtain cyclocitral; the organic solvent is miscible with water; the mass of the organic solvent accounts for 40%-90% of the total mass of the cyclized product, water, and organic solvent; 4) In a continuous reaction apparatus, the cyclocitral and 2-pentanone are used as raw materials to undergo a condensation reaction in the presence of a catalyst to obtain compound 7. ;5) In a continuous reaction apparatus, the compound 7 and hydrogen are used as raw materials and hydrogenation is carried out in the presence of a catalyst to obtain the 1-(2,2,6-trimethylcyclohexyl)hex-3-ol (Temubeol).

[0006] In steps 1)-5) above, the types of continuous reaction apparatus used in each step can be the same or different. In this invention, acidic cation exchange resin refers to a cation exchange resin with an acidic functional group structure.

[0007] In some embodiments, in step 1), the continuous reaction apparatus is a continuous reactive distillation apparatus, and the method controls the removal of water generated in the reaction during this step. The reaction between citral and amine compounds is a reversible reaction, and water is generated during the reaction. This application removes the water generated during the reaction, which helps to shift the equilibrium of the reversible reaction to the right and improve the conversion rate of citral.

[0008] In some embodiments, the continuous reactive distillation apparatus includes a combination of a reactor and a distillation column, i.e., it employs reactive distillation.

[0009] In some embodiments, the upper part of the continuous reactive distillation apparatus is a distillation zone, and the lower part is a reaction zone; the distillation zone is filled with distillation packing or fitted with distillation trays; the reaction zone is filled with the catalyst used in this step; the citral and amine R-NH2 are fed from the middle of the continuous reactive distillation apparatus. In this invention, the middle is not strictly the geometric middle, but rather approximately around the top, that is, roughly at the uppermost end of the reaction zone. The distillation zone, by adjusting the reflux ratio, collects the water generated in the reaction at the top of the column and refluxes the amine compounds and products back to the reactor in the lower part, thereby promoting the reaction.

[0010] In some embodiments, the temperature of the distillation zone is 40~140 °C.

[0011] In some embodiments, the temperature of the reaction zone is 10~80 °C.

[0012] In some embodiments, the vacuum level of the reactor is 0~760 mmHg.

[0013] In some embodiments, in step 1), the catalyst is selected from molecular sieves or alumina. Preferably, the molecular sieve is selected from one or more combinations of ZSM-5, H-Beta, HY, TS-1, and Ti-MWW. All of the above catalysts are acidic catalysts, which are beneficial for the adsorption of citral and amine compounds, thereby increasing the reaction rate.

[0014] In some embodiments, the molar ratio of citral to amine R-NH2 is 0.6 to 1.5:1.

[0015] In some embodiments, the mass hourly space velocity (MSV) of the mixed feed of citral and amine, calculated based on the catalyst loading amount, is 0.1–20 h⁻¹. -1 .

[0016] In some embodiments, the acidity of the acidic cation exchange resin is 4~20 mmol / g; In step 2), the raw material citral imine compound (the product of step 1) is unstable. Continuous production can reduce the residence time of this substance in the reactor. Furthermore, this step uses an acidic cation exchange resin as a catalyst, so the product after the reaction does not need post-treatment and can immediately proceed to the next reaction. The synergistic effect of both reduces the existence time of the citral imine compound and improves the reaction yield.

[0017] In some embodiments, the average pore size of the acidic cation exchange resin is 20-500 nm. For example, it can be 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm, 400 nm, or 500 nm.

[0018] In some embodiments, the acidic group of the acidic cation exchange resin is selected from one or more combinations of sulfonic acid group, carboxylic acid group, phosphate group, and acidic phenolic hydroxyl group.

[0019] In some embodiments, in step 3), the organic solvent is selected from one or more combinations of methanol, ethanol, isopropanol, and acetone.

[0020] In some embodiments, R is selected from C4-C8 alkyl or phenyl groups; preferably, R is selected from pentyl, hexyl, heptyl, octyl, or phenyl groups.

[0021] In some implementations, the continuous reaction device in steps 2)-5) is a fixed-bed reactor.

[0022] In some embodiments, in step 2), the temperature of the cyclization reaction is 10~100 °C.

[0023] In some embodiments, in step 2), the cyclization reaction is carried out at atmospheric pressure.

[0024] In some embodiments, in step 2), the continuous reaction apparatus is a fixed-bed reactor, and the mass hourly space velocity of the citral imine compound, calculated based on the cationic resin loading, is 0.1–5 h⁻¹. -1 .

[0025] In step 3), the cyclization product is unstable and immiscible with water. Without adding a solvent miscible with the raw material water, the reaction system is two-phase, resulting in a slow reaction rate and easy decomposition of the cyclization product. In this invention, an organic solvent miscible with water is added as a solvent in this step, which makes the reaction system a homogeneous solution system, which is beneficial to improving the reaction rate, reaction conversion rate, and selectivity. At the same time, the continuous hydrolysis method reduces the residence time of the cyclization product in the reactor.

[0026] In some embodiments, in step 3), the catalyst is selected from zinc oxide or supported zinc oxide.

[0027] In some embodiments, the support for the supported zinc oxide is selected from one or more combinations of silica, alumina, molecular sieves, and carbon. The molecular sieve can be ZSM-5 molecular sieve, etc.

[0028] In some embodiments, the loading of zinc oxide in the supported zinc oxide is 1wt%-50wt%.

[0029] In some embodiments, in step 3), the cyclized product, water, and organic solvent are mixed before feeding. This can make the reaction system more homogeneous.

[0030] In some embodiments, in step 3), the molar ratio of the cyclization product to water is 0.1 to 1.2:1.

[0031] In some embodiments, in step 3), the temperature of the hydrolysis reaction is 10~100 °C.

[0032] In some embodiments, in step 3), the hydrolysis reaction is carried out at atmospheric pressure.

[0033] In some embodiments, in step 3), the continuous reaction device is a fixed-bed reactor, and the mass hourly space velocity of the cyclization product calculated based on the catalyst loading is 0.1~5 h⁻¹. -1 .

[0034] In some embodiments, in step 4), the catalyst is selected from one or more combinations of titanium dioxide, zirconium oxide, and cerium oxide.

[0035] In some embodiments, in step 4), the molar ratio of cyclocitral to 2-pentanone is 1.5 to 0.5:1.

[0036] In some embodiments, the temperature of the condensation reaction is 60~180 °C.

[0037] In some embodiments, the pressure of the condensation reaction is 0.1~1 MPa.

[0038] In some embodiments, in step 4), the continuous reaction device is a fixed-bed reactor, and the mass hourly space velocity of cyclic citral calculated based on the catalyst loading is 0.1~5 h⁻¹. -1 .

[0039] In step 4), 2-pentanone has two active α-H groups, and the condensation product also has a carbonyl group and an active α-H group. This will cause the condensation product and the starting material 2-pentanone to continue to undergo cross-condensation. However, this application adopts a continuous condensation method, which will reduce the residence time of both in the reactor and thus reduce the occurrence of side reactions.

[0040] In some embodiments, in step 5), the catalyst is a supported metal catalyst, which includes an active metal and a support; the active metal is selected from one or more combinations of ruthenium, nickel, palladium, platinum, cobalt, and copper; the support is selected from one or more combinations of silica, alumina, carbon, and molecular sieves.

[0041] In some embodiments, the molar ratio of hydrogen to compound 7 is 100 to 2.5:1.

[0042] In some embodiments, in step 5), the continuous reaction device is a fixed-bed reactor, and the mass hourly space velocity of compound 7, calculated based on the catalyst loading, is 0.1~5 h⁻¹. -1 .

[0043] In some embodiments, the temperature of the hydrogenation reaction is 80~200 °C.

[0044] In some embodiments, the pressure of the hydrogenation reaction is 0.5 to 4 MPa.

[0045] Compared with the prior art, the present invention has the following advantages: 1. The synthesis method of this application can significantly reduce the degree of side reactions in each synthesis step, improve the selectivity and yield of the target product termobilol, and can realize continuous production, making it suitable for industrial production.

[0046] 2. Steps 2) and 3) of this application adopt a continuous cyclization and hydrolysis method, which reduces the residence time of unstable citral imine compounds, helps to improve product yield, avoids post-processing, and reduces waste.

[0047] 3. Step 4) of this application adopts a continuous condensation method, which reduces the cross-condensation between the condensation product and 2-pentanone and improves product selectivity.

[0048] 4. The entire process of the method in this application is continuous, the yield of the target product termolybdenum is high, the safety risks of the reaction process are reduced, and the discharge of waste is reduced. Attached Figure Description

[0049] Figure 1 This is a gas chromatography result diagram of the reaction system after the reaction in Example 2 was completed; Figure 2This is a gas chromatography result diagram of the reaction system after the reaction in Example 3 was completed; Figure 3 This is a gas chromatography result of the reaction system after the reaction was completed in the comparative preparation example 2. Detailed Implementation

[0050] Existing technologies for preparing termethinol via chemical synthesis suffer from numerous side reactions, low selectivity for the target product, and low yield.

[0051] In this regard, the present invention adopts a continuous production method for each step of the synthesis of termethinol, which can shorten the residence time of materials, avoid the decomposition of unstable reaction intermediates, and avoid side reactions such as cross-condensation, thus greatly improving the yield of the target product.

[0052] Secondly, in step 1), this invention employs a continuous reactive distillation apparatus, with the upper part being the distillation zone and the lower part the reaction zone. The distillation zone is filled with distillation packing or fitted with distillation trays; the reaction zone is filled with the reaction catalyst for this step. In the distillation zone, by adjusting the reflux ratio, the water generated during the reaction is collected at the top of the column, and the amine compounds and products are refluxed to the reactor at the bottom, thereby promoting the reaction. The reaction in step 1) is a reversible reaction, and water is generated during the reaction. This application removes the water generated during the reaction, which helps to shift the equilibrium of the reversible reaction to the right and improve the conversion rate of citral.

[0053] Furthermore, steps 2) and 3) of this application employ continuous cyclization and hydrolysis, reducing the residence time of unstable citral imine compounds and contributing to improved product yield. In step 2), a cationic resin is innovatively used as a catalyst. Using this catalyst improves both the conversion rate and selectivity of this step because the selected cationic resin is highly acidic and has a large pore size, facilitating the diffusion of citral imine and timely reaction at acidic sites. Simultaneously, the product can be promptly removed from the catalyst, both synergistically promoting conversion and selectivity. On the other hand, the reaction product from this step can proceed immediately to the next reaction without post-treatment, further reducing the residence time of citral imine compounds and improving reaction selectivity.

[0054] Finally, in the hydrolysis reaction system of step 3), the present invention adds an additional water-miscible organic solvent as a solvent, which makes the reaction system a homogeneous solution system, which is beneficial to improving the reaction rate, reaction conversion rate, and selectivity. In this step, the cyclization product of the reaction raw material is unstable and immiscible with water. Without adding a solvent miscible with the water of the raw material, the reaction system is two-phase, the reaction rate is slow, and the cyclization product is easily decomposed.

[0055] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0056] The following embodiments utilize the following reaction pathway: Example 1: Preparation of compound 3 The upper part of the reactive distillation apparatus (50 mm inner diameter) was packed with 30 cm of packing material (model: Tianda CY700), the temperature was set at 100 ℃, the vacuum was controlled at 10~20 mm Hg, and the reflux ratio was set at 20:5; the lower part was packed with 300 g of HY molecular sieve (cloverleaf type, 3 mm diameter) as reaction catalyst; the feed was fed in the middle at a flow rate of 3 kg / h, and the reactants were citral and octylamine, with a molar ratio of citral to octylamine of 0.95. The reaction section temperature was set at 50 ℃. After the feed was stabilized, samples were taken from the bottom of the reactive distillation apparatus for analysis, and the reaction products were detected by gas chromatography (gas chromatograph model: Agilent 7820A). The conversion rate of citral and the selectivity of compound 3 were calculated, as shown in Table 1 below.

[0057] In the above implementation process, the reaction catalyst HY molecular sieve can be replaced with ZSM-5, H-Beta, TS-1, Ti-MWW, and alumina. The corresponding reaction effects are shown in Table 1. It can be seen that all of the above molecular sieves can achieve a citral conversion rate >98% and a citral imine compound selectivity >98%.

[0058] Table 1: Different catalysts In addition, during the above implementation process, octylamine can be replaced with one of pentylamine, hexylamine, heptaamine, or aniline. The results are shown in Table 2, and the corresponding conversion rate and selectivity are excellent.

[0059] Table 2: Different amine substrates Example 2: Preparation of compound 4 Compound 4 was synthesized from compound 3 through a cyclization reaction: The cyclization reaction was carried out in a fixed-bed reactor (32 mm inner diameter) by loading 500 g (0.315-1.25 mm diameter) of macroporous cation exchange resin (average pore size approximately 38-45 nm, acidic groups being sulfonic acid groups, acidity 12 mmol / g (determined by NH3-TPD); Dandong Mingzhu Special Resin, D005 series) as catalyst. The temperature was set at 50 ℃, with top feeding and a feed flow rate of 1 kg / h for citral imine compound (compound 3). After stable feeding, samples were taken from the bottom of the apparatus for analysis, and the reaction products were analyzed by gas chromatography (Gas Chromatograph: Agilent 7820A). The results showed that the feed conversion rate for this step was 99.5%, and the product selectivity was 95.3%.

[0060] In the above implementation process, the types of macroporous cation exchange resins can be replaced with those in Table 3, and the corresponding conversion rates and selectivity are shown in Table 3.

[0061] Table 3: Different macroporous cation exchange resins It is evident that when compound 3 undergoes a cyclization reaction to synthesize compound 4, using a macroporous cationic resin with acidic groups of sulfonic acid or phosphoric acid as a catalyst can achieve a high conversion rate of compound 3 and a high selectivity for the target product compound 4. However, when using a carboxylic acid or acidic phenolic hydroxyl resin, the conversion rate of compound 3 may be slightly reduced. This is because the acidity of the catalyst is slightly weaker, resulting in a slightly lower intensity of the active sites.

[0062] Comparative Preparation Example 1: Preparation of Compound 4 600 g of citral imine compound (compound 3) and 30 g of concentrated sulfuric acid were added to a 1 L Mitsui flask, and the mixture was stirred and reacted for 12 hours. Samples were then taken for analysis. The results showed that the reactant conversion rate was 85% and the product selectivity was 78%.

[0063] It is evident that when using traditional concentrated sulfuric acid as a catalyst, the conversion rate and selectivity of this step are significantly reduced. Furthermore, using concentrated sulfuric acid as a catalyst results in complex post-reaction treatment, requiring the addition of alkali for neutralization, and generating substantial amounts of wastewater and waste salts.

[0064] Example 3: Preparation of compound 5 Compound 4 was hydrolyzed in a fixed-bed reactor (32 mm inner diameter) to prepare compound 5. The reactor was loaded with 500 g of zinc oxide catalyst (3 mm diameter), the temperature was set at 35 °C, and the feed (a mixture of compound 4, water, and solvent) was top-feeded at a flow rate of 3 kg / h. Isopropanol was used as the solvent, with a mass fraction of 60% isopropanol in the feed mixture, and the molar ratio of compound 4 to water was 0.5. After the feed stabilized, samples were taken from the bottom of the apparatus for analysis, and the reaction products were detected by gas chromatography (Gas Chromatograph: Agilent 7820A). The conversion and selectivity of this step are shown in Table 4.

[0065] In the above implementation process, the zinc oxide catalyst can be replaced with ZnO / SiO2, ZnO / Al2O3, ZnO / ZSM-5, and ZnO / C, where the mass percentage of zinc oxide in the catalyst is 25%. The reaction results are shown in Table 4. It can be seen that each catalyst in this step can achieve a conversion rate >98% and a selectivity >93%.

[0066] Table 4: Different catalysts In the above implementation process, adjusting the mass percentage of isopropanol in the feed mixture to 40% resulted in a conversion rate of 99.5% and a selectivity of 96.2%. Adjusting the mass percentage of isopropanol in the feed mixture to 90% resulted in a conversion rate of 99.3% and a selectivity of 98.4%.

[0067] Comparative Preparation Example 2: Preparation of Compound 5 The procedure was essentially the same as in Example 3, except that isopropanol was not added to the top feed, i.e., no additional solvent was added. As a result, the conversion rate in this step was 4.6%, and the selectivity was 76.4%.

[0068] Comparative Preparation Example 3: Preparation of Compound 5 The procedure was essentially the same as in Example 3, except that in the top feed, the mass percentage of isopropanol in the mixture was adjusted to 30%, while the molar ratio of compound 4 to water remained unchanged. As a result, the conversion rate in this step was 45.6%, and the selectivity was 90.7%.

[0069] As can be seen from the comparison between Example 3 and Comparative Preparation Examples 2 and 3, this application achieves a significantly improved conversion rate and target product selectivity in the hydrolysis reaction of compound 4 by adding a specific amount of alcohol solvent. This is because the starting material citral imine compound is unstable and immiscible with water. If no solvent is added or the amount of solvent is insufficient, the reaction will be two-phase, the reaction rate will be slow, and the citral imine compound will decompose. Therefore, this step uses the method of adding solvent to make it a homogeneous solution. At the same time, the continuous hydrolysis method reduces the residence time of the citral imine compound in the reactor.

[0070] Example 4: Preparation of compound 7 The condensation reaction of cyclocitral and 2-pentanone was carried out in a fixed-bed reactor (32 mm inner diameter) loaded with 500 g of titanium dioxide catalyst (3 mm diameter). The set temperature was 120 °C, the set pressure was 0.5 MPa, the feed was top-feeded at a flow rate of 0.8 kg / h, and the molar ratio of cyclocitral to 2-pentanone was 1.05. After the feed stabilized, samples were taken from the bottom of the apparatus for analysis, and the reaction products were detected by gas chromatography (Gas Chromatograph: Agilent 7820A). The results showed that the conversion rate of 2-pentanone in this step was 97.3%, and the selectivity was 94.9%.

[0071] Example 5: Preparation of compound 8 The hydrogenation reaction of compound 7 was carried out in a fixed-bed reactor (32 mm inner diameter) loaded with 500 g of Ru / Al₂O₃ (cloverleaf type, 3 mm diameter) catalyst. The set temperature was 100 °C, the set pressure was 2 MPa, the feed was top-feeded, the feed flow rate was 0.5 kg / h, and the molar ratio of hydrogen to compound 7 was 5. After the feed stabilized, samples were taken from the bottom of the unit for analysis, and the reaction products were analyzed by gas chromatography (Gas Chromatograph: Agilent 7820A). The results showed that in this step, the conversion rate of compound 7 was 99.7%, and the selectivity was 98.9%.

[0072] Comparative Preparation Example 4: Batch Reaction Compound 3 was synthesized by adding 600 g of a mixture of citral and octylamine (molar ratio of citral to octylamine was 0.95) and 30 g of HY molecular sieve catalyst to a 1 L Mitsui flask, stirring, and reacting for 12 hours. Samples were then taken for analysis. The results showed a conversion rate of 78.4% and a selectivity of 86.2% in this step.

[0073] Synthesized compound 4: Same as comparative example 1.

[0074] Synthesis of Compound 5: 600 g of Compound 4, a mixture of water and isopropanol, and 30 g of zinc oxide were added to a 1 L Mitsui flask. The mass percentage of isopropanol in the mixture was 60%, and the molar ratio of Compound 4 to water was 0.5. Stirring was then started, and the reaction was carried out for 12 hours. Samples were taken for analysis. The results showed that the conversion rate in this step was 97.4%, and the selectivity was 83.4%.

[0075] Compound 7 was synthesized by adding 600 g of cyclocitral and 2-pentanone (molar ratio of cyclocitral to 2-pentanone was 1.05) and 30 g of titanium dioxide to a 1 L Mitsui flask, stirring, and reacting for 12 hours. Samples were then taken for analysis. The results showed that the conversion rate was 81.3% and the selectivity was 76.5% in this step.

[0076] Synthesis of Compound 8: 600 g of Compound 7 and 10 g of Ru / Al2O3 catalyst were added to a 1 L high-pressure reactor. After nitrogen purging, hydrogen gas was introduced, the temperature was raised to 100 °C, and the pressure inside the reactor was maintained at 2 MPa for 12 hours. Samples were taken for analysis. The results showed that the conversion rate in this step was 99.5%, and the selectivity was 89.4%.

[0077] It is evident that when a batch reaction is used to prepare the target product of this application, the conversion rate and target product selectivity of each step are significantly reduced.

[0078] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0079] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for the continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol, characterized in that: The method includes the following steps: 1) In a continuous reaction apparatus, citral and amine R-NH2 are reacted in the presence of a catalyst to obtain a citral imine compound. ; R is selected from C2-C8 alkyl, phenyl, or phenyl substituted with one or more alkyl groups; 2) In a continuous reaction apparatus, the citral imine compound is used as a raw material and subjected to a cyclization reaction under the catalysis of an acidic cation exchange resin to obtain the cyclized product. 3) In a continuous reaction apparatus, the cyclized product and water are used as raw materials to undergo a hydrolysis reaction in an organic solvent in the presence of a catalyst to obtain cyclocitral; the organic solvent is miscible with water; the mass of the organic solvent accounts for 40%-90% of the total mass of the cyclized product, water, and organic solvent; 4) In a continuous reaction apparatus, the cyclocitral and 2-pentanone are used as raw materials to undergo a condensation reaction in the presence of a catalyst to obtain compound 7. ;5) In a continuous reaction apparatus, using compound 7 and hydrogen as raw materials, a hydrogenation reaction is carried out in the presence of a catalyst to obtain 1-(2,2,6-trimethylcyclohexyl)hex-3-ol.

2. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 1), the continuous reaction apparatus is a continuous reactive distillation apparatus, and the method controls the removal of water generated in the reaction during this step; preferably, the continuous reactive distillation apparatus includes a combination of a reactor and a distillation column; and / or, the molar ratio of citral to amine R-NH2 is 0.6~1.5:1; and / or, the mass hourly space velocity (MSV) of the mixed feed of citral and amine, calculated based on the catalyst loading, is 0.1~20 h⁻¹. -1 ; and / or, in step 1), the catalyst is selected from molecular sieves or alumina.

3. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 2, characterized in that: The upper part of the continuous reactive distillation apparatus is a distillation zone, and the lower part is a reaction zone; the distillation zone is filled with distillation packing or equipped with distillation trays; the reaction zone is filled with the catalyst of this step; the citral and amine R-NH2 are fed from the middle of the continuous reactive distillation apparatus; preferably, the temperature of the distillation zone is 40~140 ℃; and / or, the temperature of the reaction zone is 10~80 ℃; and / or, the vacuum degree of the reactor is 0~760 mmHg.

4. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: The acidity of the acidic cation exchange resin is 4~20 mmol / g; and / or the average pore size of the acidic cation exchange resin is 20~500 nm.

5. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: The acidic group of the acidic cation exchange resin is selected from one or more combinations of sulfonic acid group, carboxylic acid group, phosphate group, and acidic phenolic hydroxyl group.

6. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 3), the organic solvent is selected from one or more combinations of methanol, ethanol, isopropanol, and acetone.

7. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: The R is selected from C4-C8 alkyl or phenyl groups; preferably, the R is selected from pentyl, hexyl, heptyl, octyl or phenyl groups.

8. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In steps 2)-5), the continuous reaction devices are all fixed-bed reactors.

9. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 2), the cyclization reaction is carried out at a temperature of 10–100 °C; and / or, in step 2), the cyclization reaction is carried out at atmospheric pressure; and / or, in step 2), the continuous reaction apparatus is a fixed-bed reactor, and the mass hourly space velocity of the citral imine compound, calculated based on the cationic resin loading, is 0.1–5 h⁻¹. -1 .

10. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 3), the catalyst is selected from zinc oxide or supported zinc oxide; preferably, the support for the supported zinc oxide is selected from one or more combinations of silica, alumina, molecular sieve, and carbon; and / or, the loading of zinc oxide in the supported zinc oxide is 1wt%-50wt%.

11. The method for continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 3), the cyclization product, water, and organic solvent are mixed before feeding; and / or, in step 3), the molar ratio of the cyclization product to water is 0.1~1.2:

1.

12. The method for the continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 3), the hydrolysis reaction is carried out at a temperature of 10–100 °C; and / or, in step 3), the hydrolysis reaction is carried out at atmospheric pressure; and / or, in step 3), the continuous reaction apparatus is a fixed-bed reactor, and the mass hourly space velocity of the cyclization product calculated based on the catalyst loading is 0.1–5 h⁻¹. -1 .

13. The method for the continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 4), the catalyst is selected from one or more combinations of titanium dioxide, zirconium oxide, and cerium oxide; and / or, in step 4), the molar ratio of cyclocitral to 2-pentanone is 1.5~0.5:1; and / or, the temperature of the condensation reaction is 60~180℃; and / or, the pressure of the condensation reaction is 0.1~1 MPa; and / or, in step 4), the continuous reaction device is a fixed-bed reactor, and the mass hourly space velocity of cyclocitral calculated based on the catalyst loading is 0.1~5 h⁻¹. -1 .

14. The method for the continuous synthesis of 1-(2,2,6-trimethylcyclohexyl)hex-3-ol according to claim 1, characterized in that: In step 5), the catalyst is a supported metal catalyst, comprising an active metal and a support; the active metal is selected from one or more combinations of ruthenium, nickel, palladium, platinum, cobalt, and copper; the support is selected from one or more combinations of silica, alumina, carbon, and molecular sieves; and / or, the molar ratio of hydrogen to compound 7 is 100~2.5:1; and / or, in step 5), the continuous reaction device is a fixed-bed reactor, and the mass hourly space velocity of compound 7 calculated based on the catalyst loading is 0.1~5 h⁻¹. -1 ; and / or, the temperature of the hydrogenation reaction is 80~200 °C; and / or, the pressure of the hydrogenation reaction is 0.5~4 MPa.

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