A method for synthesizing 2-(3-hydroxypropyl)-cyclododecanone

Abstract

The application provides a synthesis method of 2-(3-hydroxypropyl)-cyclododecanone, which is as follows: under the action of an alkali catalyst, cyclododecanone and epichlorohydrin are reacted to obtain 2-epoxypropylcyclododecanone, and then hydrogen reduction is carried out to obtain 2-(3-hydroxypropyl)-cyclododecanone. The synthesis route is novel, the reagent such as epichlorohydrin is used for alkylation reaction, the epoxypropyl group can be introduced at the 2 position of cyclododecanone with high efficiency, compared with the alkylation reagents such as allyl alcohol and allyl acetate used in the traditional process, the method does not need a free radical initiator, and the monoalkylated product can be obtained with high selectivity, without double alkylation, multiple alkylation by-products, and the reaction yield is significantly improved. Secondly, the hydrogenation method can selectively obtain 2-(3-hydroxypropyl)-cyclododecanone, the reaction yield is high, and the selectivity is good. The method has good application prospect.

Description

Technical Field

[0001] This invention belongs to the fields of fine chemicals and fragrances, and specifically relates to a method for synthesizing 2-(3-hydroxypropyl)-cyclododecanone from cyclododecanone and epichlorohydrin through a two-step reaction including alkylation and hydrogenation reduction. Background Technology

[0002] Natural musk is originally an aromatic substance derived from musk deer, secreted by glands in the musk sac on the lower abdomen of male musk deer. It possesses a deep, warm, and long-lasting aroma, playing a vital role in perfumery and providing a soft and gentle sensory experience with a lingering fragrance. However, natural animal musk is not only limited in its source but also expensive, failing to meet the growing demand. Furthermore, with the musk deer facing extinction, the modern fragrance and flavor industry has largely abandoned the use of natural musk. To compensate for the scarcity of natural musk, chemists and fragrance synthesis experts began the artificial synthesis of musk fragrances long ago. After years of effort, a series of synthetic musk fragrances have been developed. Synthetic musk fragrances can be broadly classified according to their structure and properties into nitro musk, polycyclic musk, macrocyclic musk, and linear musk, etc. These musk fragrances are widely used in various products: shampoos, detergents, soaps, creams, and perfumes of all grades.

[0003] Nitro musk is banned due to its poor biodegradability and increasing bioaccumulation in nature and the human body. Cyclic musk has a more elegant and noble aroma than nitro musk, and some polycyclic musk varieties are very close to the scent of natural musk. Therefore, it has won the fragrance market due to its elegant aroma, low price, temperature stability, and colorfastness. However, according to the latest research, polycyclic musk is difficult for the human body to metabolize and exhibits bioaccumulation. Macrocyclic musk is a series of analogues of natural musk, environmentally friendly and harmless to humans, and its aroma and scent are closest to natural musk. Cyclopentadene lactone and cyclopentadene lactone are the most representative products of macrocyclic musk. Alicyclic and fatty musk fragrances are often simply referred to as "linear" musk fragrances. These fragrances, in addition to the characteristics of musk, often have fruity or pear-like notes and can influence the aroma in the top notes. Macrocyclic and linear musk represent the future development trend.

[0004] 2-(3-hydroxypropyl)-cyclododecanone is a key intermediate in the synthesis of cyclopentadecanolone. Currently, its main synthetic routes are as follows: The first route involves the reaction of cyclododecanone with dimethyl carbonate to introduce an ethoxycarbonyl group to enhance the acidity at the α-position. The resulting ketoester intermediate can efficiently undergo an addition reaction with acrolein. Finally, the aldehyde group is reduced, and the ethoxycarbonyl group is hydrolyzed to obtain 2-(3-hydroxypropyl)-cyclododecanone. This method has a good overall yield, but poor atom economy and a long synthetic process. The second route involves the radical addition reaction of cyclododecanone with allyl alcohol under the initiation of a peroxide initiator, yielding 2-(3-hydroxypropyl)-cyclododecanone in one step. Although this method has fewer synthetic steps, it requires a large amount of peroxide initiator, and the reaction yield is very poor, reportedly only around 50% in relevant literature (US3907831, US7098347). Another literature (CN108203426) reported that allyl ester was used instead of allyl alcohol and cyclododecanone in the reaction, and then hydrolyzed to obtain 2-(3-hydroxypropyl)-cyclododecanone, which improved the yield, but the effect was not very obvious, and it also increased the number of synthesis steps.

[0005]

[0006] In summary, 2-(3-hydroxypropyl)-cyclododecanone is a key intermediate in the synthesis of macrocyclic thymol-decadecanolactone and cyclopentadecanolactone. Currently, the main synthetic method involves alkylation of cyclododecanone with allyl alcohol or acrolein. However, current synthetic methods are either lengthy or have poor yields, resulting in high costs.

[0007] To prepare products such as cyclopentadecanolactone and cyclopentadecanolactone more economically and cost-effectively, it is urgent to develop novel synthetic routes for 2-(3-hydroxypropyl)-cyclododecanone, improve the synthesis yield, and reduce production costs. Summary of the Invention

[0008] The purpose of this invention is to provide a simple synthetic method for 2-(3-hydroxypropyl)-cyclododecane, using readily available and inexpensive cyclododecane and epichlorohydrin as raw materials, through alkylation and hydrogenation reactions to obtain 2-(3-hydroxypropyl)-cyclododecane. This invention features a novel synthetic route, using epichlorohydrin for alkylation to efficiently introduce an epioxypropyl group at the α-position of cyclododecane. Compared to traditional processes using alkylating agents such as allyl alcohol and allyl acetate, this method does not require a large amount of free radical initiator and can selectively yield monoalkylated products without dialkylation or polyalkylation byproducts, significantly improving the yield. Furthermore, the hydrogenation method selectively yields 2-(3-hydroxypropyl)-cyclododecane with high reaction yield and good selectivity.

[0009] To achieve the above objectives and technical effects, the present invention adopts the following technical solution:

[0010] A method for synthesizing 2-(3-hydroxypropyl)-cyclododecanone, specifically comprising:

[0011] S1, under the action of an alkaline catalyst, cyclododecone and epichlorohydrin undergo an alkylation reaction to give 2-epoxypropylcyclododecone intermediate;

[0012] S2,2-epoxypropylcyclododecanoate was hydrogenated and reduced to 2-(3-hydroxypropyl)-cyclododecanoate under the action of a hydrogenation catalyst and a Lewis acid catalyst.

[0013] The reaction route is shown below:

[0014]

[0015] In this invention, in step S1, the amount of epichlorohydrin used is 110-150 mol% of cyclododecanone.

[0016] In this invention, the alkaline catalyst in S1 can be one or more of the following: metal hydroxides, metal hydrides, metal carbonates, metal phosphates, amino salts, alkyl alkoxides, guanidines, amidines, and phosphazenes. Preferably, it consists of metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), metal hydrides (e.g., sodium hydride, potassium hydride, calcium hydride), amino salts (e.g., lithium diisopropylamino, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino), sodium alkyl alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), and phosphazenes (e.g., phosphazene base P4-tert-butyl, phosphazene base P4-tert-octyl). Preferably, the amount of alkaline catalyst used is 120-160 mol of cyclododecanone.

[0017] In this invention, a polar aprotic solvent is preferably used in S1, which may be, but is not limited to, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, xylene, etc.; the amount of solvent used is preferably 4.0 to 8.0 times the mass of cyclododecone.

[0018] In this invention, the reaction time of S1 is 2 to 7 hours; and / or the reaction temperature is -20 to 30°C.

[0019] In this invention, the S2 hydrogenation catalyst can be a conventional hydrogenation catalyst in the art, such as including but not limited to palladium on carbon, palladium alumina, palladium silicon oxide, palladium calcium carbonate, palladium barium sulfate, etc., wherein the palladium content is 2-10 wt%, preferably 4-8 wt%; preferably, the amount of the hydrogenation catalyst is 0.5-5.0 wt% of the 2-epoxypropylcyclododecanoate intermediate.

[0020] In this invention, the Lewis acid in S2 can be, but is not limited to, tin octoate, lithium chloride, zinc chloride, zinc bromide, magnesium chloride, zinc acetate, scandium trifluoromethanesulfonate, ferric chloride, etc.; preferably, the amount of the Lewis acid is 0.5-2.0 mol of 2-epoxypropylcyclododecanoate.

[0021] In this invention, the hydrogen used in the S2 hydrogenation reaction contains a certain proportion of carbon monoxide, preferably the proportion of carbon monoxide to hydrogen is 0.5 to 5.0 vol%; the pressure of the hydrogenation reaction can be 2.0 to 6.0 MPa, preferably 4.0 to 6.0 MPa.

[0022] In this invention, the solvent used in the S2 hydrogenation reaction can be, but is not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, toluene, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-butyl acetate, etc.; the amount of solvent used is preferably 3.0 to 7.0 times the mass of 2-epoxypropylcyclododecanoate.

[0023] The reaction time of S2 is 2 to 6 hours; and / or the reaction temperature is 80 to 120°C.

[0024] The present invention, by adopting the above technical solution, has the following positive effects:

[0025] 1. The synthetic route used in this method is novel. It uses epichlorohydrin as an alkylating agent to achieve monoalkylation of cyclododecone with high selectivity, without dialkylation or polyalkylation byproducts. This significantly improves the synthetic yield of the target product 2-(3-hydroxypropyl)-cyclododecone and is expected to reduce the production cost of macrocyclic thymol.

[0026] 2. Adding a catalytic amount of Lewis acid co-catalyst to the hydrogenation reaction, along with a certain amount of carbon monoxide in the hydrogen gas, can effectively control the hydrogenation reduction of 2-epoxypropyl and selectively obtain the primary alcohol product, namely 2-(3-hydroxypropyl)-cyclododecone; at the same time, the reaction conditions are mild and the product yield is high. Detailed Implementation

[0027] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0028] The main raw material information is as follows:

[0029] Cyclododecone, epichlorohydrin, Wanhua, 99%;

[0030] Sodium hydride and potassium hydride, dispersed in minerals, with a content of 60 wt%, Aladdin reagent;

[0031] Potassium tert-butoxide, sodium carbonate, sodium chloride, AR, Bailingwei reagent;

[0032] Glacial acetic acid, AR, Sinopharm Reagent;

[0033] Sodium sulfate, AR, Xilong reagent;

[0034] Diisopropylaminolithium solution (2M), bis(trimethylsilyl)aminolithium (2M), Bailingwei reagent;

[0035] Anhydrous tetrahydrofuran, ethylene glycol dimethyl ether, toluene, diethylene glycol dimethyl ether, chromatographic grade, Bailingwei reagent;

[0036] Anhydrous methyl tert-butyl ether, 2-methyltetrahydrofuran, Alfa Esa, chromatographic grade.

[0037] 5% Pd / C, 5% Palladium alumina, 2% Palladium silicate; Connor catalyst;

[0038] Zinc chloride, lithium chloride, zinc acetate, Inokai reagent, 99% purity;

[0039] Scandium trifluoromethanesulfonate, zinc bromide, Bailingwei reagent, purity 98%;

[0040] Ethyl acetate and butyl acetate, chromatographic grade, from Guoyao Reagent.

[0041] Hydrogen, 99.9%, Wanhua.

[0042] The gas chromatography test conditions of this invention are as follows:

[0043] Instrument model: Agilent 7890B; Column: HP-3 capillary column (30m × 0.30mm × 0.25μm); Initial temperature 80℃, increased to 100℃ at a rate of 5℃ / min; then increased to 220℃ at a rate of 10℃ / min and held for 5.0 min. Carrier gas: high-purity nitrogen, split ratio 30:1, split flow rate 42mL / min. Carrier gas saving: 19mL / min, initial waiting time 5.0 min. Injection temperature 250℃, detector: FID, detector temperature 250℃, air flow rate 350mL / min, hydrogen flow rate 30mL / min, make-up gas flow rate 60mL / min, injection volume 0.2μL.

[0044] Example 1:

[0045] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0046] At room temperature, a 500 mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath. After nitrogen purging, tetrahydrofuran (191.4 g), cyclododecanone (38.28 g, 0.21 mol), and epichlorohydrin (21.37 g, 0.231 mol) were added to the flask, and stirring was started to completely dissolve the cyclododecanone. Then, sodium hydride powder (dispersed in minerals, 60% content, 10.08 g, 0.252 mol) was added in batches to the flask. The reaction solution temperature was kept stable during the addition of sodium hydride, and the generated hydrogen gas was vented through a condenser and bubbler. After the sodium hydride was completely added, the reaction solution was kept at 0°C, and the reaction continued for 4 hours with rapid stirring. Samples were taken, and GC analysis showed that the cyclododecanone substrate had essentially reacted completely.

[0047] Post-processing: The reaction was quenched by adding 20 mL of deionized water to the reaction solution. The solvent tetrahydrofuran in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in 200 mL of ethyl acetate, washed twice with 10 mL of dilute acetic acid (1 M / L), and once each with 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of saturated brine. After drying the organic phase with anhydrous sodium sulfate, 47.45 g of the target 2-epoxypropylcyclododecanoate intermediate was obtained by vacuum distillation, with a yield of 94.0%. High-resolution mass spectrometry (HRMS-EI M) was used to analyze the product. + calcd C 15 H 26 O2:238.1933,found 238.1934. 1 H NMR (400MHz) δ1.30-2.51(m,23H),2.53(m,1H),2.63(q,1H),2.87(q,1H).

[0048] Example 2:

[0049] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0050] At room temperature, a 500 mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath. After nitrogen purging, tetrahydrofuran (328.1 g), cyclododecanone (54.69 g, 0.30 mol), and epichlorohydrin (33.31 g, 0.36 mol) were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, sodium hydride powder (dispersed in minerals, 60% content, 15.60 g, 0.39 mol) was added in batches to the flask. The temperature of the reaction solution was kept stable during the addition of sodium hydride, and the generated hydrogen gas was discharged through a condenser and a bubbler. After the sodium hydride was completely added, the reaction solution was kept at 0°C, and the reaction was continued for 7 hours with rapid stirring. Samples were taken, and GC analysis showed that the cyclododecanone substrate had basically reacted completely.

[0051] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent tetrahydrofuran in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 68.73 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 95.3%.

[0052] Example 3:

[0053] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0054] A 500 mL three-necked flask equipped with a magnetic stirrer was placed in a -20 °C cryogenic bath at room temperature. After nitrogen purging, tetrahydrofuran (196.9 g), cyclododecanone (49.22 g, 0.27 mol), and epichlorohydrin (37.47 g, 0.405 mol) were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, sodium hydride powder (dispersed in minerals, 60% content, 17.28 g, 0.432 mol) was added in batches to the flask. The temperature of the reaction solution was kept stable during the addition of sodium hydride, and the generated hydrogen gas was discharged through a condenser and a bubbler. After the sodium hydride was completely added, the reaction solution was kept at -20 °C, and the reaction was continued for 4 hours with rapid stirring. Samples were taken, and GC analysis showed that the cyclododecanone substrate had basically reacted completely.

[0055] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent tetrahydrofuran in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 63.61 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 98.0%.

[0056] Example 4:

[0057] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0058] A 500 mL three-necked flask equipped with a magnetic stirrer was placed in a 10°C water bath at room temperature. After nitrogen purging, ethylene glycol dimethyl ether (204.2 g), cyclododecanone (25.52 g, 0.14 mol), and epichlorohydrin (15.54 g, 0.168 mol) were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, potassium tert-butoxide (20.42 g, 0.182 mol) powder was added to the flask in batches, maintaining a stable reaction temperature throughout the addition. After the potassium tert-butoxide was completely added, the reaction mixture was kept at 10°C and stirred rapidly for another 3 hours. Samples were taken for GC analysis, which showed that the cyclododecanone substrate had essentially reacted completely.

[0059] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent ethylene glycol dimethyl ether in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 31.50 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 93.6%.

[0060] Example 5:

[0061] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0062] A 500mL three-necked flask equipped with a magnetic stirrer was placed in a 10℃ cold water bath at room temperature. After nitrogen purging, toluene (209.7g), cyclododecanone (41.93g, 0.23mol), and epichlorohydrin (25.54g, 0.276mol) were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, potassium hydride powder (dispersed in minerals, 60% content, 23.06g, 0.345mol) was added in batches to the flask. The temperature of the reaction solution was kept stable during the addition of potassium hydride, and the generated hydrogen gas was discharged through a condenser and a bubbler. After the potassium hydride was completely added, the reaction solution was kept at 10℃ and the reaction was continued for 3 hours with rapid stirring. Samples were taken and GC analysis showed that the cyclododecanone substrate had basically reacted completely.

[0063] In the post-treatment, deionized water (20 mL) was added to the reaction solution to quench the reaction, and then the solution was washed twice with dilute acetic acid (10 mL, 1 M / L), and once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated saline solution (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 53.30 g of the target 2-epoxypropylcyclododecyl intermediate, with a yield of 96.4%.

[0064] Example 6:

[0065] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0066] A 500 mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath at room temperature. After nitrogen purging, diethylene glycol dimethyl ether (207.8 g), cyclododecanone (34.64 g, 0.19 mol), and epichlorohydrin (21.10 g, 0.228 mol) were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, a tetrahydrofuran solution of lithium diisopropylaminonitrate (0.247 mol, 2 M) was slowly added to the flask. After the lithium diisopropylaminonitrate was completely added, the reaction mixture was kept at 0°C and the reaction was continued for 3 hours with rapid stirring. Samples were taken and analyzed by GC. The cyclododecanone substrate was found to be essentially completely reacted.

[0067] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent diethylene glycol dimethyl ether in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 41.43 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 90.7%.

[0068] Example 7:

[0069] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0070] A 500 mL three-necked flask equipped with a magnetic stirrer was placed in a -20 °C cryogenic bath at room temperature. After nitrogen purging, 255.2 g of methyl tert-butyl ether solvent, 51.04 g (0.28 mol) of cyclododecanone substrate, and 31.09 g (0.336 mol) of epichlorohydrin were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, a tetrahydrofuran solution (0.364 mol, 2 M) of lithium di(trimethylsilyl)aminoacetate was slowly added to the flask. After the lithium di(trimethylsilyl)aminoacetate was completely added, the reaction mixture was kept at -20 °C and the reaction was continued for 3 hours with rapid stirring. Samples were taken and GC analysis showed that the cyclododecanone substrate had reacted almost completely.

[0071] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent methyl tert-butyl ether in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 64.61 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 96.0%.

[0072] Example 8:

[0073] Preparation of 2-epoxypropylcyclododecanone intermediate from cyclododecanone and epichlorohydrin

[0074] A 500 mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath at room temperature. After nitrogen purging, 246.1 g of solvent 2-methyltetrahydrofuran, 49.22 g (0.27 mol) of substrate cyclododecanone, and 30.00 g (0.324 mol) of epichlorohydrin were added to the flask. Stirring was started to completely dissolve the cyclododecanone. Then, sodium hydride powder (dispersed in minerals, 60% content, 16.20 g, 0.405 mol) was added to the flask in batches and multiple times. The temperature of the reaction solution was kept stable during the addition of sodium hydride, and the generated hydrogen gas was discharged through a condenser and a bubbler. After the sodium hydride was completely added, the reaction solution was kept at 0°C, and the reaction was continued for 2 hours with rapid stirring. Samples were taken, and GC analysis showed that the substrate cyclododecanone had basically reacted completely.

[0075] In the post-processing stage, deionized water (20 mL) was added to the reaction solution to quench the reaction. The solvent 2-methyltetrahydrofuran in the crude reaction solution was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (200 mL), washed twice with dilute acetic acid (10 mL, 1 M / L), and washed once each with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was separated by vacuum distillation to obtain 61.79 g of the target 2-epoxypropylcyclododecanoate intermediate, with a yield of 95.2%.

[0076] Example 9:

[0077] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0078] At room temperature, a magnetic stir bar was first added to a 250 mL autoclave, followed by the addition of 31.25 g (0.13 mol) of 2-epoxypropylcyclododecanoate intermediate, 125.0 g of tetrahydrofuran solvent, 0.62 g of 5% Pd / C catalyst, and finally 90 mg (0.7 mmol) of Lewis acid auxiliaries. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 0.5 vol% carbon monoxide to control the total pressure inside the autoclave at 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 100 °C. The reaction was maintained at this temperature and pressure for 3 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 98.1%. High-resolution mass spectrometry (HRMS-EI M) of the product + calcd C 15 H 28 O2:240.2089, found 240.2087. 1 H NMR (400MHz) δ1.30-2.46(m,25H),3.32(brs,1H),3.50(t,2H).

[0079] Example 10:

[0080] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0081] At room temperature, a magnetic stir bar was first added to a 500 mL autoclave, followed by the addition of 2-epoxypropylcyclododecanoate intermediate (28.85 g, 0.12 mol), solvent tetrahydrofuran (201.9 g), catalyst 5% Pd / C (0.15 g), and finally Lewis acid auxiliary zinc chloride (160 mg, 1.2 mmol). After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 2.0 vol% carbon monoxide to control the total pressure inside the autoclave at 6.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 80 °C. The reaction was maintained at this temperature and pressure for 6 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 99.3%.

[0082] Example 11:

[0083] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0084] At room temperature, a magnetic stir bar was first added to a 250 mL autoclave, followed by the addition of 33.65 g (0.14 mol) of 2-epoxypropylcyclododecanoate intermediate, 134.6 g of tetrahydrofuran solvent, 1.68 g of 5% Pd / C catalyst, and finally 380 mg (2.8 mmol) of Lewis acid auxiliaries zinc chloride. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 1.0 vol% carbon monoxide to control the total pressure inside the autoclave at 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 120 °C. The reaction was maintained at this temperature and pressure for 2 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 98.5%.

[0085] Example 12:

[0086] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0087] At room temperature, a magnetic stir bar was first added to a 500 mL autoclave, followed by the addition of 40.86 g (0.17 mol) of 2-epoxypropylcyclododecanoate intermediate, 204.3 g of tetrahydrofuran solvent, 0.41 g of 5% palladium alumina catalyst, and finally, 140 mg (3.4 mmol) of Lewis acid auxiliaries. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 5.0 vol% carbon monoxide to maintain a total pressure of 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 100 °C. The reaction was maintained at this temperature and pressure for 4 hours. After the reaction, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed using gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 99.4%.

[0088] Example 13:

[0089] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0090] At room temperature, a magnetic stir bar was first added to a 250 mL autoclave, followed by the addition of 38.46 g (0.16 mol) of 2-epoxypropylcyclododecanoate intermediate, 115.4 g of butyl acetate solvent, 1.15 g of 2% palladium silicate catalyst, and finally scandium trifluoromethanesulfonate (1.57 g, 3.2 mmol) as a Lewis acid auxiliary. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 1.0 vol% carbon monoxide to control the total pressure inside the autoclave at 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 100 °C. The reaction was maintained at this temperature and pressure for 4 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 98.5%.

[0091] Example 14:

[0092] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0093] At room temperature, a magnetic stir bar was first added to a 250 mL autoclave, followed by the addition of 36.06 g (0.15 mol) of 2-epoxypropylcyclododecanoate intermediate, 144.2 g of solvent 2-methyltetrahydrofuran, 0.36 g of catalyst (5% Pd / C), and finally 0.55 g (3.0 mmol) of Lewis acid auxiliary zinc acetate. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 1.0 vol% carbon monoxide to control the total pressure inside the autoclave at 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 100 °C. The reaction was maintained at this temperature and pressure for 6 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 98.6%.

[0094] Example 15:

[0095] Hydrogenation of 2-epoxypropylcyclododecanone intermediate to prepare 2-(3-hydroxypropyl)-cyclododecanone

[0096] At room temperature, a magnetic stir bar was first added to a 250 mL autoclave, followed by the addition of 33.65 g (0.14 mol) of 2-epoxypropylcyclododecanoate intermediate, 134.6 g of methyl tert-butyl ether solvent, 0.34 g of 5% Pd / C catalyst, and finally 0.32 g (1.4 mmol) of Lewis acid auxiliary zinc bromide. After all materials were added, the autoclave was sealed, purged three times with nitrogen and three times with hydrogen, and then purged with hydrogen gas containing 1.0 vol% carbon monoxide to control the total pressure inside the autoclave at 5.0 MPa. The autoclave was placed in an oil bath, stirred, and then heated to 100 °C. The reaction was maintained at this temperature and pressure for 4 hours. After the reaction was completed, the autoclave was cooled, and the catalyst was separated by filtration before sampling and analysis. Quantitative analysis of the resulting reaction solution was performed by gas chromatography. The conversion rate of 2-epoxypropylcyclododecanoate was >99%, and the selectivity of the target product 2-(3-hydroxypropyl)-cyclododecanoate was 98.7%.

[0097] It is readily understood that the above embodiments are merely illustrative examples for clear explanation and do not imply that the invention is limited thereto. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing 2-(3-hydroxypropyl)-cyclododecanone, the method comprising the following steps: S1, under the action of an alkaline catalyst, cyclododecone reacts with epichlorohydrin to give 2-epoxypropylcyclododecone; S2,2-epoxypropylcyclododecanoate is hydrogenated and reduced to 2-(3-hydroxypropyl)-cyclododecanoate.

2. The method according to claim 1, characterized in that, The amount of epichlorohydrin used in S1 is 110-150 mol of cyclododecanone.

3. The method according to claim 1, characterized in that, The alkaline catalyst in S1 includes one or more of the following: metal hydroxide, metal hydride, metal carbonate, metal phosphate, amino salt, sodium alkyl alkoxide, guanidine, amidine, and phosphazene.

4. The method according to claim 3, characterized in that, The amount of the base catalyst in S1 is 120-160 mol of cyclododecanone.

5. The method according to claim 1, characterized in that, The polar aprotic solvent used in S1 includes at least one of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, and xylene.

6. The method according to claim 5, characterized in that, The amount of solvent used in S1 is 4.0 to 8.0 times the mass of cyclododecanone.

7. The method according to any one of claims 1-4, characterized in that, The reaction time of S1 is 2 to 7 hours; and / or the reaction temperature is -20 to 30°C.

8. The method according to claim 1, characterized in that, The S2 uses a hydrogenation catalyst, including at least one of palladium on carbon, palladium aluminum oxide, palladium silicon oxide, palladium calcium carbonate, and palladium barium sulfate.

9. The method according to claim 8, characterized in that, In step S2, the amount of the hydrogenation catalyst is 0.5-5.0 wt% of 2-epoxypropylcyclododecanoate.

10. The method according to claim 1, characterized in that, The S2 hydrogenation reaction requires the addition of a Lewis acid, which includes at least one of the following: tin octoate, lithium chloride, zinc chloride, zinc bromide, magnesium chloride, zinc acetate, scandium trifluoromethanesulfonate, and ferric chloride.

11. The method according to claim 10, characterized in that, In step S2, the amount of the Lewis acid used is 0.5-2.0 mol% of 2-epoxypropylcyclododecanoate.

12. The method according to any one of claims 1 and 8-11, characterized in that, The hydrogen gas used in the S2 hydrogenation reaction contains carbon monoxide; The pressure of the S2 hydrogenation reaction is 2.0–6.0 MPa.

13. The method according to claim 12, characterized in that, The hydrogen used in the S2 hydrogenation reaction contains carbon monoxide, and the proportion of carbon monoxide in the hydrogen is 0.5 to 5.0 vol%. The pressure of the S2 hydrogenation reaction is 4.0–6.0 MPa.

14. The method according to claim 1, characterized in that, The solvent in the S2 hydrogenation reaction includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, toluene, ethanol, isopropanol, acetone, butanone, ethyl acetate, and n-butyl acetate.

15. The method according to claim 14, characterized in that, In step S2, the amount of solvent used is 3.0 to 7.0 times the mass of 2-epoxypropylcyclododecanoate.

16. The method according to any one of claims 1 and 8-11, characterized in that, The reaction time of S2 is 2 to 6 hours; and / or the reaction temperature is 80 to 120°C.

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