Process for the synthesis of (trans, trans) -4-ethyl-4'- (2-propenyl) -1, 1'-bicyclohexane

Abstract

The application discloses a synthesis method of (anti, anti)-4-ethyl-4'-(2-propylene)-1,1'-bicyclohexane, which comprises the following steps: taking 4-ethyl bicyclohexyl ketone as raw material, condensing the 4-ethyl bicyclohexyl ketone with 2-oxo propyl dimethyl phosphate to synthesize anti-4-(2-oxo-propylene)-4'-ethyl-1,1'-bicyclohexane, then performing two-step hydrogenation to obtain anti 95% or more alpha-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol, then adding methylsulfonyl chloride to esterify, then adding anhydrous lithium bromide to perform bromine substitution, and finally adding potassium bis(trimethylsilyl) amide (KHMDS) as a base to remove hydrogen bromide, and through purification, the target product (anti, anti)-4-(2-bromo-propyl)-4'-ethyl-1,1'-bicyclohexane is obtained. The application comprises five mature reactions, and the total yield can reach 70% or more; the cost of the final product is generally much lower than that of the original method; and the post-treatment is simple, and the anti 95% or more target product can be obtained without isomerization.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for synthesizing 4-trans-alkylcyclohexylene, specifically a method for synthesizing (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane. Background Technology

[0002] (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane liquid crystal is one of the excellent liquid crystal monomers, characterized by high dielectric constant, low viscosity, and high thermal stability. Therefore, it is an excellent liquid crystal monomer in mixed liquid crystal materials. Over the past decade, the total global demand for this type of liquid crystal material has been growing rapidly.

[0003] (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane is an important liquid crystal monomer, used in large quantities in liquid crystal panels with high quality requirements. Therefore, its synthesis method also has high requirements. Finding a low-cost, highly atom-utilizing, and more environmentally friendly synthesis method is currently one of the most important research topics in the scientific research field.

[0004] Currently, the main synthetic production process uses trans-4-(trans-4'-n-propylcyclohexyl)cyclohexanone (3HHK) as a raw material. The target product is obtained through Wittig reaction, acid hydrolysis, isomerization under basic conditions, and another Wittig reaction. Most domestic manufacturers use this method, and the synthetic route is as follows:

[0005]

[0006] This method involves multiple Wittig reactions, resulting in low molecular utilization. Furthermore, the triphenylphosphine chloromethyl ether salt and triphenylphosphine bromoethane salt used are expensive and require large quantities, leading to high costs. Summary of the Invention

[0007] The purpose of this invention is to find a synthesis method that is more economical, environmentally friendly, and has higher atom utilization than current production processes.

[0008] To achieve the above objectives, the present invention provides a method for synthesizing 4-trans-alkylcyclohexylene, comprising:

[0009]

[0010] Step 1, Condensation: Using 4-ethylbicyclohexyl ketone as a raw material, it undergoes a condensation reaction with 2-oxopropyl dimethyl phosphate under alkaline conditions to generate trans-4-(2-oxopropylene)-4'-ethyl-1,1'-bicyclohexane.

[0011] Step 2, stepwise hydrogenation: trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane is first hydrogenated and reduced to the olefin bond, and then hydrogenated and reduced to the ketone group to generate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol;

[0012] Step 3, esterification: α-Methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol is esterified with methanesulfonyl chloride to generate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester;

[0013] Step 4, Halogenation: α-Methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester undergoes a halogenation reaction with anhydrous lithium bromide to generate (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane;

[0014] Step 5, removal of hydrogen bromide: (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane is dehydrogenated under strong base conditions to form the E-Zaytsev product (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane.

[0015] Optionally, in step 1, the molar ratio of 2-oxopropyl phosphate dimethyl ester to 4-ethylbicyclohexyl ketone is 1.2 to 1.5:1.

[0016] Optionally, in step 1, the alkaline condition refers to the addition of a strong base, wherein the amount of the strong base and dimethyl 2-oxopropyl phosphate is equal, and the strong base is potassium hydroxide or sodium hydroxide; and / or, the solvent is an aqueous methanol solution, wherein the volume ratio of methanol to water is 1 to 4:1.

[0017] Optionally, in step 2, the olefin hydrogenation reduction uses 3% palladium on carbon as a catalyst, and the solvent is a sterically hindered alcohol solvent, which is at least one of tert-butanol, tert-amyl alcohol, and isopropanol; the amount of catalyst used is 0.2-0.5% by weight of trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane.

[0018] Optionally, in step 2, yttrium chloride is added as a co-catalyst for the olefin hydrogenation reduction. The amount of the co-catalyst is 0.1-0.2% by weight of trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane. The process temperature for the olefin hydrogenation is 35-60°C, and the hydrogenation pressure is 0.02-0.05 MPa.

[0019] Optionally, in step 2, the ketone hydrogenation reduction uses 10% ruthenium carbon as a catalyst, with an amount of 1-3% by weight, based on the product of the alkene bond hydrogenation.

[0020] Optionally, in step 2, the process temperature for the hydrogenation reduction of the ketone group is 50-80℃; and the hydrogenation pressure is 0.2-0.5MPa.

[0021] Optionally, in step 3, the amount of methanesulfonyl chloride used is 1.1 to 1.25 times the amount of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A); and / or, an organic base is also added as an acid-binding agent, wherein the organic base is at least one of triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine.

[0022] Optionally, in step 4, the amount of anhydrous lithium bromide used is 2.5 to 3 times that of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester, by molar amount; and / or, the reaction temperature is 50-80°C.

[0023] Optionally, in step 5, the strong base has high steric hindrance and is at least one of potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, and sodium diisopropylamino; the amount of the strong base is 2-2.2 times the molar amount of (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane.

[0024] Compared with the prior art, the present invention has at least the following beneficial effects:

[0025] Although the hydrogenation of α,β-unsaturated ketones involves two steps, the intermediate only requires simple filtration before ketone hydrogenation can proceed. Specifically, this invention uses 3% palladium on carbon as a catalyst, yttrium chloride as a co-catalyst, and sterically hindered tert-butanol as a solvent to hydrogenate the alkene bond, yielding over 95% trans-product. After simple filtration to remove the catalyst, the filtrate is treated with 10% ruthenium on carbon, and the hydrogenation of the ketone group is completed at low temperature and medium pressure. This hydrogenation process is simple to operate and has a high trans-conversion rate.

[0026] This invention also selects a sterically hindered base and preferably a solvent to complete the dehydrobromide isomerization in one step, preparing highly regioselective trans-Zaitsev regular olefins with a high yield.

[0027] This invention involves a five-step reaction with an overall yield of over 70%, and the cost of the final product is generally much lower than that of the original method. Furthermore, the post-processing is relatively simple, requiring no isomerization to obtain the target product with over 95% trans content. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

[0029] The reaction route for synthesizing (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane according to the present invention is as follows:

[0030]

[0031] The specific steps are as follows:

[0032] In the first step, 4-ethylbicyclohexyl ketone is first condensed with 2-oxopropyl dimethyl phosphate under alkaline conditions to synthesize trans-4-(2-oxopropylidene)-4'-ethyl-1,1'-bicyclohexane (1A).

[0033] The molar ratio of 2-oxopropyl phosphate dimethyl ester to 4-ethylbicyclohexyl ketone is 1.2-1.5:1.

[0034] The alkaline conditions refer to the addition of a strong base, such as potassium hydroxide or sodium hydroxide. The amount of the strong base and the amount of dimethyl 2-oxopropyl phosphate are also considered.

[0035] The solvent is at least one of methanol and water. For example, it can be an aqueous methanol solution with a volume ratio of 1 to 4:1. When the amount of methanol is insufficient, the reaction system is a heterogeneous system and the reaction is slower. Therefore, a solvent with a methanol:water ratio of 4:1 (volume ratio) can be selected.

[0036] As an example, the procedure can be as follows: First, add 2-oxopropyl phosphate dimethyl ester and 4-ethyldicyclohexyl ketone to the reaction vessel, maintain the temperature at ≤5°C, and dropwise add a 6.3% potassium hydroxide aqueous solution in methanol (methanol:water = 4:1) in an amount (molarity) relative to 1.2-1.5 times that of 4-ethyldicyclohexyl ketone. As potassium hydroxide is added, the reaction solution gradually turns dark yellow. After the addition is complete, maintain the temperature between 20 and 35°C for 24-28 hours. Then, add 3-4V volumes of petroleum ether to the reaction solution for extraction. Separate the organic layer and wash it with water at a weight ratio of 0.5 (based on the mass of 4-ethyldicyclohexyl ketone), then wash it with 3% sodium bicarbonate at a weight ratio of 0.5, and finally wash it with water at a weight ratio of 0.5 until neutral. Concentrate to obtain product 1A, with a condensation reaction yield of 93-98%.

[0037] The second step involves stepwise hydrogenation: Product 1A from the first step is added to a sterically hindered alcohol solvent, with 3% palladium on carbon and yttrium chloride as catalysts. The double bond is first reduced by low-temperature, low-pressure stereoselective hydrogenation to prepare highly trans-(trans,trans)-4-(2-oxopropyl)-4'-ethyl-1,1'-bicyclohexane (2B). After filtration, 10% ruthenium on carbon is added, and hydrogenation is carried out at low temperature and medium pressure to α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A).

[0038] In available literature, the hydrogenation of α,β-unsaturated ketones to prepare saturated alcohols generally involves stepwise hydrogenation. First, the alkene bond is added, and hydrogenation of the alkene bond in cyclohexylmethylene mostly produces cis-formates. Then, the ketone group is reduced using hydrogen donors such as sodium borohydride or ammonium formate. Specifically, 3% palladium on carbon is used for alkene bond hydrogenation, which is generally cis-based, with cis being more common. Next, the ketone group is hydrogenated. Due to the steric hindrance of the ketone group, it is difficult for it to contact the catalyst, generally requiring high temperature and pressure, and the addition of a co-catalyst. Furthermore, the CO bond of the product undergoes further hydrogenolysis to form hydrocarbons. Common catalysts include platinum, rhodium, ruthenium, or chromium-copper oxide, as well as highly active W-6 type Raney nickel. However, Raney nickel has low activity and generally requires high temperatures of 70–100°C and high pressures of 5–10 MPa. Platinum is used as the catalyst, often with ferric chloride or tin chloride added as a co-catalyst.

[0039] This invention employs a two-step hydrogenation method for the trans-hydrogenation reduction of α,β-unsaturated ketene bonds. 1) Hydrogenation of the alkene bond is performed using palladium on carbon; to increase the content of the trans configuration, palladium on carbon and yttrium chloride are used as a composite catalyst, and sterically hindered alcohol solvents, such as tert-butanol, tert-amyl alcohol, and isopropanol, are used, with the solvent amount being 2-4 times the weight ratio of 1A. The co-catalyst yttrium chloride can increase the trans content of the alkene bond from 85% to 95%. Hydrogenation yields an alkene addition product (trans, trans)-4-(2-oxopropyl)-4'-ethyl-1,1'-bicyclohexane (2B) with a trans content exceeding 95%; the alkene bond hydrogenation yield is 100%. 2) Hydrogenation of α,β-unsaturated ketones: After simple filtration of the alkene hydrogenation product 2B to remove the catalyst, 10% ruthenium carbon (1-3% by weight of 2B) was added to the filtrate as a ketone hydrogenation catalyst; under low temperature and medium pressure, the ketone was hydrogenated to the alcohol α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A), with a crude hydrogenation product yield of 93-97%.

[0040] As an example, the stepwise hydrogenation step can be as follows: Add trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane (1A) to a reaction flask, add 2-3% tert-butanol by weight, 0.2-0.5% palladium on carbon by weight, and 0.1-0.2% yttrium chloride by weight, at 35-60°C, with a hydrogenation pressure of 0.02-0.05 MPa; hydrogenation yields a trans-4-(2-oxo-propylidene)-4' ... Propyl)-4'-ethyl-1,1'-bicyclohexane (2B) is filtered to remove 3% palladium on carbon and yttrium chloride co-catalyst, which can be recycled more than ten times; 1-3% by weight of 10% ruthenium on carbon is added to the filtrate as a ketone hydrogenation catalyst; the process temperature is 50-80℃ and the process pressure is 0.2-0.5MPa; after hydrogenation, tert-butanol is concentrated and recovered to obtain crude α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A), with a yield of 93-97%.

[0041] Step 3: Add methanesulfonyl chloride to product 2A to obtain intermediate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A).

[0042] This step involves esterifying the hydroxyl groups to facilitate subsequent halogenation. To accelerate the reaction, a base is added as an acid-binding agent to consume the generated acid. The base can be an organic base, such as at least one of triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine. The amount of alkali used is 1.05 to 1.15 times the molar ratio of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A); the amount of methanesulfonyl chloride used is 1.1 to 1.25 times the molar ratio of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A); the preferred reaction temperature is 15 to 45°C; the preferred reaction solvents are tetrahydrofuran, toluene, cyclopentyl methyl ether, etc., and the amount of solvent used is 2 to 4 times the weight ratio of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A); the yield of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A) is 93-98%.

[0043] As an example, the step could be: adding α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A) and 0.5-2 times the weight of tetrahydrofuran to a reaction flask, heating to 40-45°C until completely dissolved, cooling to 0-5°C, adding 1.05-1.15 times the molar amount of 2A (2A) of triethylamine, then adding 1.1-1.25 times the molar amount of 2A (2A) dropwise while controlling the temperature at 0-5°C, maintaining the temperature at 0-5°C for 1 hour, and then stirring at room temperature (10-45°C) for 0 hours. Hydrolyze the product by adding water at a ratio of 1 by weight dropwise over 5 hours at a controlled temperature of 0-10℃. Then concentrate the product under reduced pressure to recover tetrahydrofuran. Extract the product with dichloromethane at a ratio of 2-3 by weight, wash once with water at a ratio of 0.2-0.3 by weight, wash once with 3% sodium bicarbonate aqueous solution at a ratio of 0.2-0.3 by weight, and wash again with water at a ratio of 0.2-0.3 by weight. Repeat the washing process approximately twice until the product is neutral. Concentrate the product to obtain α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanolmethanesulfonyl ester (3A) (yield 93-98%).

[0044] Step 4: Add anhydrous lithium bromide to the crude product from Step 3 and reflux to give (trans,trans)-4-(2-bromo-propyl)-4'-ethyl-1,1'-bicyclohexane (4A).

[0045] The solvent can be tetrahydrofuran, toluene, cyclopentyl methyl ether, etc., in an amount of 3-5 times the weight of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A). Anhydrous lithium bromide is used as the brominating agent, in an amount of 2.5-3 times the molar ratio of 3A; the preferred reaction temperature is 50-80℃.

[0046] As an example, the step could be: Add α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester 3A to a reaction flask, add 3-5 times the weight of tetrahydrofuran, add 2.5-3 times the molar ratio of 3A of anhydrous lithium bromide, after which the mixture is purged twice with nitrogen, and the reaction is carried out at 50-80°C for 4 hours under nitrogen protection. The reaction solution is then cooled to 0-5°C, and 1-2 times the weight of water is added. Solution: After concentrating and recovering tetrahydrofuran, extract with 2-3 times the weight of dichloromethane, wash with 0.2-0.3 times the weight of water, wash once with 0.2-0.3 times the weight of 3% sodium bicarbonate solution, wash with 0.2-0.3 times the weight of water until neutral, concentrate and crystallize to obtain (trans,trans)-4-(2-bromo-propyl)-4'-ethyl-1,1'-bicyclohexane (4A), with a yield of 94-98%.

[0047] Step 5: Using product 4A as raw material, hydrogen bromide is removed using a strong steric hindrance base to prepare the highly selective, highly trans-Zaytsev product (trans, trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane (5A).

[0048] The sterically hindered strong base used for dehydrobromination is a base with significant steric hindrance, such as potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, sodium diisopropylamino, or bis(trimethylsilyl)-aminopotassium. The amount of this base is generally 1.1-1.5 times the molar ratio of (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane (4A). It has been reported that potassium tert-butoxide can isomerize the Hoffmann product to the Zaitsev product. This paper unexpectedly discovered that in the process of this invention, when bis(trimethylsilyl)-aminopotassium (KHMDS) is used as the strong base for dehydrobromination, the proportion of olefins in the Zaitsev product is higher, and due to the stronger basicity and greater steric hindrance of this base, the reaction rate is faster, and more than 95% of the E-Zaiitsev product is obtained. It is speculated that stronger basicity may facilitate transposition and increase steric hindrance. Furthermore, the present invention uses a polar aprotic solvent, which greatly increases the olefin content of E-Zaytsev products.

[0049] In some embodiments, the present invention uses a dehydrobromination reaction of bis(trimethylsilyl)-aminopotassium (KHMDS) at a molar ratio of at least 1.1; wherein, bis(trimethylsilyl)-aminopotassium (KHMDS) is used to dehydrobromide to form an alkene. This is because ① KHMDS is highly basic and readily attacks β-H, greatly increasing the reaction rate; ② the use of KHMDS ensures that the product is primarily a Zaitsev product with numerous substituents; and ③ due to the significant steric hindrance of bis(trimethylsilyl)-aminopotassium (KHMDS), the formed Zaitsev alkene is primarily an E-Zaiitsev alkene. The reaction process is as follows:

[0050]

[0051] ④ It was unexpectedly discovered that the use of KHMDS could gradually isomerize the olefins of the Hoffmann product to form the olefins of the Zaitsev product; resulting in a final Zaitsev product olefin conversion rate >99%; the olefin isomerization reaction process is as follows:

[0052]

[0053] In summary, this invention utilizes a sterically hindered strong base, bis(trimethylsilyl)-aminopotassium (KHMDS), for dehydrobromination. Due to the combined effect of the above four factors, the olefin content of the Hoffmann product in the product is less than 1%, and more than 95% of the target product (5A)E-Zaitsev product is obtained. The overall reaction process is as follows:

[0054]

[0055] This method yields a highly regioselective and high-purity E-Zaytsev product, (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane (5A), through a simple process.

[0056] The solvent used can be a polar aprotic solvent, such as dimethyl sulfoxide or dioxane; the reaction temperature can be 45-70℃.

[0057] As an example, the step could be as follows: Add 1.1-1.5 times the molar ratio of 4A (4A) of potassium bis(trimethylsilyl)amino (KHMDS) and 2-3 times the volume of 4A of DMSO sequentially to a reaction flask. After the addition is complete, purge with nitrogen, and then heat to 50-55°C under nitrogen protection. Add dropwise a 50% (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-dicyclohexane (4A) mixed with DMSO. Heat the reaction mixture to 45-70°C and stir for 12 hours. Then, under nitrogen protection, cool to 10-15°C and add dropwise 1-2 times the weight of 5% chloride. The ammonium aqueous solution was hydrolyzed, and the organic layer was extracted with 2-3 times its weight of petroleum ether. After separation, the mixture was washed once with 0.2-0.3 times its weight of water, and then washed approximately four times in total until neutral. The solution was then passed through a 20% by weight silica gel at a 60-100 mesh screen. After column chromatography, the product was concentrated to obtain (trans,trans)-4-ethyl-4'-(2-propenyl)-1,1'-bicyclohexane (crude product yield 90-95%). The product was then subjected to column chromatography, followed by crystallization with 2-3 times its weight of ethanol. After drying, the pure product (trans,trans)-4-ethyl-4'-(2-propenyl)-1,1'-bicyclohexane (5A) was obtained with a yield of 85-90%.

[0058] The raw materials and reagents used in the embodiments of the present invention are all commercially available.

[0059] Example

[0060] Step 1: Synthesis of trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane (1A) (95%)

[0061] Add 208g (1mol) of 4-ethylbicyclohexyl ketone and 226.5g (1.5mol) of 2-oxopropyl phosphate to the reaction flask. Under nitrogen protection, lower the temperature to 0-5℃. While maintaining the temperature below 5℃, add 1334g of a methanol-water solution of 6.3% potassium hydroxide (methanol:water = 4:1, volume ratio) dropwise. After the addition is complete, slowly raise the temperature to 20-35℃ and keep it at this temperature for 28h.

[0062] Extract the reaction mixture with 800 ml of petroleum ether, separate the layers, wash the organic layer once with 100 g of water, then wash once with 100 g of 3% sodium bicarbonate solution, and then wash with 100 g of water until neutral. Concentrate under reduced pressure at less than 100 °C to obtain 235.6 g of crude trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane (0.95 mol), yield 95%.

[0063] Step 2: Preparation of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (95%)

[0064] 1. Synthesis of (trans, trans)-4-(2-oxopropyl)-4'-ethyl-1,1'-bicyclohexane (2B) (100%)

[0065] 235.6 g (0.95 mol) of crude trans-4-(2-oxopropyl)-4'-ethyl-1,1'-bicyclohexane was added to a reaction flask. 500 g of tert-butanol was added as solvent, along with 1.18 g (0.5% by weight) of 3% palladium on carbon as catalyst and 0.1% (0.1% by weight) of yttrium chloride as co-catalyst. Hydrogenation was carried out at 0.02 MPa and 50-55 °C for 12 h, prior to olefin hydrogenation, to prepare (trans-,trans)-4-(2-oxopropyl)-4'-ethyl-1,1'-bicyclohexane (237.5 g, 100% yield) containing over 95%. The 3% palladium on carbon and yttrium chloride catalyst were recovered by filtration.

[0066] 2. Synthesis of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A) (95%)

[0067] Add 2.5% by weight (3g) of 10% ruthenium carbon to the above-mentioned filtrate, control the temperature at 60-80℃, and hydrogenate at 0.5MPa for 8 hours. After the hydrogenation is qualified, filter to recover 10% ruthenium carbon, which can be reused in this step of the reaction. Concentrate and recover tert-butanol, add petroleum ether solvent to obtain crude α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (227.4g, 0.9025mol, yield 95%).

[0068] Step 3: Synthesis of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A) (95%)

[0069] 239.4 g of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (0.9025 mol) and 180 g of tetrahydrofuran were added to a reaction flask. The mixture was heated to 40–45 °C, cooled by 0–5 °C, and 112 g of 1.1 mol (1.228 eq) triethylamine was added. Then, under nitrogen protection, 1.083 mol (1.2 eq) (124 g) methanesulfonyl chloride was added dropwise. After the addition was complete, the mixture was kept at 0–5 °C for 1 hour, then stirred at room temperature (20–35 °C) for 0.5 hours. 250 g of water was added dropwise for hydrolysis while maintaining the temperature at 0–10 °C. The mixture was concentrated under reduced pressure, and the crude product was extracted with 500 g of dichloromethane. After extraction, 100 g of water was added for washing once. Wash once with 3% sodium bicarbonate aqueous solution, then add 100g of water and wash again. Wash about twice until neutral. Concentrate to obtain 282.9g of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (0.8573mol, yield 95%).

[0070] Step 4: Synthesis of (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane (4A) (95%)

[0071] 282.9 g of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A) 0.8573 mol and 1410 g of tetrahydrofuran were added to a reaction flask. After stirring evenly, 212.2 g of anhydrous lithium bromide (2.44 mol 2.85 eq) was added. After the addition was complete, the mixture was purged twice with nitrogen. The temperature was raised to 70-75 °C under nitrogen protection and reacted for 4 hours. The reaction solution was cooled to 0-5 °C, and 400 g of water was added for hydrolysis. After concentrating the solvent, 1000 g of dichloromethane was added for extraction. The mixture was washed once with 100 g of water, once with 100 g of 3% sodium bicarbonate solution, and once with 100 g of water until neutral. The solution was concentrated and crystallized to obtain 256.4 g of 0.814 mol (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane, with a yield of 95%.

[0072] Step 5: Preparation of (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane (5A) Synthesis (87.4%)

[0073] In a three-necked flask, 211.1 g of bis(trimethylsilyl)-aminopotassium (KHMDS) (1.058 mol) and 500 ml of DMSO were added sequentially. After the addition was complete, the mixture was purged with nitrogen. Under nitrogen protection, the temperature was raised to 50–55 °C, and a 50% DMSO mixture of 512.8 g (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-dicyclohexane (0.814 mol crude product) was added dropwise. The reaction mixture was stirred at 50–55 °C for 12 hours. Then, under nitrogen protection, the temperature was lowered to 10–15 °C, and 200 g of DMSO was added dropwise. Hydrolysis was performed using a 5% ammonium chloride aqueous solution. The organic layer was extracted with 500g of petroleum ether, separated, and washed once with 100g of water each time, for a total of about four washes until neutral. The solution was then passed through a 35g silica gel column (60-100 mesh) and concentrated to obtain 175.2g of (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane (0.7326mol, crude product yield 92%). The solution was then purified by column chromatography, crystallized from ethanol, and dried to obtain 166.5g of pure product (crystallization yield 95%), with an overall yield of 87.4%.

[0074] In summary, this invention uses 4-ethylbicyclohexyl ketone as a raw material, first condensing it with dimethyl 2-oxopropyl phosphate to synthesize trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane (1A), then preparing it into α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol (2A) with more than 95% trans content through two stepwise hydrogenation processes. Then, it is esterified with methanesulfonyl chloride to generate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester (3A). After that, anhydrous lithium bromide is added for bromine substitution to obtain (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane (4A). Finally, bis(trimethylsilyl)-aminopotassium (KHMDS) was added as a base for dehydrobromination and isomerization, and the product was purified to obtain (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane (5A), which was then purified to obtain the final product. In the olefin hydrogenation step, a sterically hindered alcohol was used as the solvent, and a palladium-on-carbon + yttrium chloride composite catalyst (yttrium chloride as a co-catalyst) was employed, which facilitated the formation of the desired trans product. In the ketone reduction, 10% ruthenium-on-carbon was used to increase the catalyst activity, and low-temperature (50-80℃) and low-pressure hydrogenation reduced excessive hydrogenation of the ketone group to hydrocarbons, thus reducing the generation of byproducts. Furthermore, this invention selects a highly sterically hindered base, especially KHMDS, and uses a polar aprotic solvent to complete the dehydrobromination isomerization in one step, preparing highly regioselective trans-Zajtsev regular olefins with high yields.

[0075] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A method for synthesizing (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane, characterized in that, The method includes: Step 1, Condensation: Using 4-ethylbicyclohexyl ketone as a raw material, it undergoes a condensation reaction with 2-oxopropyl dimethyl phosphate under alkaline conditions to generate trans-4-(2-oxopropylene)-4'-ethyl-1,1'-bicyclohexane. Step 2, stepwise hydrogenation: trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane first undergoes hydrogenation reduction of the alkene bond, followed by hydrogenation reduction of the ketone group, to generate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol; the alkene bond hydrogenation reduction uses 3% palladium on carbon as a catalyst, yttrium chloride as a co-catalyst, and a sterically hindered alcohol solvent, which is at least one of tert-butanol, tert-amyl alcohol, and isopropanol; the ketone group hydrogenation reduction uses 10% ruthenium on carbon as a catalyst; Step 3, esterification: α-Methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol is esterified with methanesulfonyl chloride to generate α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester; Step 4, Halogenation: α-Methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester undergoes a halogenation reaction with anhydrous lithium bromide to generate (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane; Step 5, removal of hydrogen bromide: (trans,trans)-4-(2-bromopropyl)-4'-ethyl-1,1'-bicyclohexane is dehydrogenated under the action of a strong base to form the E-Zaytsev product (trans,trans)-4-ethyl-4'-(2-propene)-1,1'-bicyclohexane; the strong base is bis(trimethylsilyl)-aminopotassium.

2. The synthesis method according to claim 1, characterized in that, In step 1, the molar ratio of 2-oxopropyl phosphate dimethyl ester to 4-ethylbicyclohexyl ketone is 1.2~1.5:

1.

3. The synthesis method as described in claim 1, characterized in that, In step 1, the alkaline condition refers to the addition of a strong base, wherein the amount of the strong base and dimethyl 2-oxopropyl phosphate is equal, and the strong base is potassium hydroxide or sodium hydroxide; and / or, the solvent is an aqueous methanol solution, wherein the volume ratio of methanol to water is 1~4:

1.

4. The synthesis method according to claim 1, characterized in that, In step 2, the amount of catalyst used for the hydrogenation reduction of the olefin bond is 0.2-0.5% based on the weight of trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane.

5. The synthesis method as described in claim 4, characterized in that, In step 2, the amount of the co-catalyst is 0.1-0.2% of the weight of trans-4-(2-oxo-propylidene)-4'-ethyl-1,1'-bicyclohexane; the process temperature for hydrogenation of the olefin bond is 35-60℃; and the hydrogenation pressure is 0.02-0.05MPa.

6. The synthesis method according to claim 1, characterized in that, In step 2, the amount of catalyst used for the ketone hydrogenation reduction is 1-3% by weight, based on the weight of the product of the alkene hydrogenation.

7. The synthesis method according to claim 1, characterized in that, In step 2, the process temperature for the hydrogenation reduction of the ketone group is 50-80℃; the hydrogenation pressure is 0.2~0.5MPa.

8. The synthesis method according to claim 1, characterized in that, In step 3, the amount of methanesulfonyl chloride used is 1.1 to 1.25 times the amount of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol; and / or, an organic base is also added as an acid-binding agent, wherein the organic base is at least one of triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine.

9. The synthesis method according to claim 1, characterized in that, In step 4, the amount of anhydrous lithium bromide used is 2.5 to 3 times that of α-methyl-4'-ethyl-[1,1'-bicyclohexyl]-4-ethanol methanesulfonyl ester, by molar amount; and / or, the reaction temperature is 50-80°C.

10. The synthesis method according to claim 1, characterized in that, In step 5, the amount of the strong base used is 1.1-1.5 times the amount of (trans,trans)-4-(2-bromo-propyl)-4'-ethyl-1,1'-bicyclohexane.

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