A method for preparing 11-triglycerides by low-temperature acylation

Abstract

This invention relates to the field of organic compound preparation technology, specifically a method for preparing 11-triglycerides of carbonate via low-temperature acylation. This method uses glycerol and undecanoyl chloride as raw materials, employing a synergistic system of a "composite acid-binding agent + Lewis acid catalyst," and combines in-situ dehydration technology and a stepwise heating strategy in a dual-solvent environment to achieve efficient synthesis. The specific steps include: under nitrogen protection, dissolving glycerol in a dichloromethane-toluene dual solvent, adding a composite acid-binding agent of pyridine and N,N-diisopropylethylamine, anhydrous zinc chloride catalyst, and 4A molecular sieve for in-situ dehydration; dropwise adding undecanoyl chloride at a low temperature of 5-10°C, followed by sequential heating to 30°C for 2-3 hours and then reacting at 50°C for 12-16 hours; and post-processing using a combined process of filtration-multi-stage extraction-membrane separation-column chromatography. This invention provides mild reaction conditions, effectively suppresses side reactions, produces high-purity products, increases molar yield, and reduces solvent toxicity and purification costs.

Description

Technical Field

[0001] This invention relates to the field of organic compound preparation technology, specifically a method for preparing 11-triglycerides by low-temperature acylation. Background Technology

[0002] Triglycerides, as esterification products of glycerol and fatty acids, are core components of oils and fats. Their structural diversity endows them with different physicochemical properties and applications. Among them, medium-chain triglycerides (MCTs) have attracted much attention in the food, pharmaceutical, cosmetic, and fine chemical industries due to their low melting point, good oxidative stability, and fast metabolic rate. Undecanoic acid (11-carbonate), a typical medium-chain fatty acid, has a corresponding triglyceride (11-triglyceride carbonate). It not only possesses the general advantages of MCTs but also exhibits unique application potential in specialty lubricants, environmentally friendly plasticizers, high-end personal care product base materials, and functional food additives due to its specific carbon chain length. For example, in cosmetics, 11-triglyceride carbonate can serve as a mild emulsifier and moisturizer, improving the skin feel and stability of products; in the pharmaceutical field, it can act as a drug carrier, enhancing the bioavailability of fat-soluble drugs. Therefore, developing efficient, green, and highly selective synthesis processes for 11-triglyceride carbonate is of significant industrial and market value for expanding its high-end applications.

[0003] Currently, there are three main methods for synthesizing triglycerides, but all of them have significant drawbacks in the synthesis of 11-ethylhexyl triglyceride. The first method is direct esterification, which uses glycerol and excess fatty acids as raw materials and performs a dehydration reaction at high temperatures (usually exceeding 200°C) and with acid catalysts (such as concentrated sulfuric acid or p-toluenesulfonic acid). However, 11-ethylhexyl triglyceride has limited thermal stability and is prone to decomposition and decarboxylation reactions at high temperatures, generating short-chain fatty acids and unsaturated impurities, resulting in a darker product color (deep yellow or brown) and decreased purity. Simultaneously, glycerol is easily carbonized at high temperatures, which not only reduces product yield but also increases the difficulty of post-processing. Furthermore, this method is extremely energy-intensive, which is inconsistent with the development trend of green chemistry, and the reaction selectivity is poor, easily generating a mixture of monoesters, diesters, and triesters. Subsequent separation and purification require complex distillation processes, resulting in high costs.

[0004] The second type is the enzyme-catalyzed method, which utilizes lipases to catalyze esterification or transesterification reactions under mild conditions (30-50℃). This method has the advantages of high selectivity, reduced byproduct formation, and mild reaction conditions, avoiding impurity problems caused by high temperatures. However, in the synthesis of 11-carbonate triglycerides, the enzyme-catalyzed method faces insurmountable bottlenecks: First, lipases have limited tolerance to 11-carbonate and its intermediates, and enzyme activity easily decays during the reaction, resulting in a slow reaction rate. A single reaction cycle typically exceeds 24 hours, leading to low production efficiency. Second, enzyme catalysts are expensive and sensitive to moisture, temperature, and pH in the reaction system, making them difficult to recover and reuse, resulting in extremely poor economics for large-scale production. Furthermore, the conversion rate of enzyme-catalyzed reactions is limited by substrate concentration, and the yield cannot be increased by improving the feedstock ratio, further limiting its industrial application.

[0005] The third type is the acyl chloride method, a classic method for the laboratory synthesis of glycerol esters with specific structures. Its principle involves the Schotten-Baumann esterification reaction of glycerol with fatty acid acyl chlorides in the presence of a base-based acid-binding agent. However, the traditional acyl chloride method for synthesizing 11-triglycerides still faces several key problems: First, the acid-binding agent is often a single pyridine, which is not only highly toxic and has a foul odor, but also easily forms complexes with the product, leading to the generation of large amounts of high-salt wastewater during post-processing, resulting in significant environmental pressure. Second, poor temperature control during reaction, such as the addition of acyl chloride at room temperature or under heating conditions, easily triggers side reactions such as acyl chloride hydrolysis and self-condensation. Simultaneously, the hydroxyl groups of glycerol are prone to localized over-acylation, leading to excessively high monoester and diester contents and insufficient triester selectivity. Third, post-processing relies on column chromatography purification, which is complex, costly, and results in significant product loss, typically with a yield below 30%. Fourth, water in the reaction system is difficult to remove, further exacerbating acyl chloride hydrolysis and affecting product purity and yield.

[0006] In summary, existing synthetic methods cannot meet the comprehensive requirements of mild conditions, high selectivity, high yield, environmental friendliness, and economy for the industrial production of 11-triglycerides. Therefore, developing a synthetic process with mild reaction conditions, high selectivity, high yield, simple post-processing, and environmental friendliness has become an urgent technical challenge to be solved in this field. Summary of the Invention

[0007] This invention aims to overcome the shortcomings of existing technologies and provide an improved low-temperature acylation method for preparing 11-triglycerides of carbonate. Specifically, the technical problems to be solved include: avoiding the decomposition, carbonization, and byproduct generation of raw materials caused by high-temperature reactions, ensuring a light-colored and high-purity product; improving the selectivity of the triesterification reaction, reducing byproducts such as monoesters and diesters, and lowering separation difficulty; solving the problems of high toxicity of acid-binding agents and easy hydrolysis of acyl chlorides in traditional acyl chloride methods, improving the environmental friendliness and stability of the process; shortening the reaction cycle, increasing product yield (target ≥45%), reducing purification costs, and enabling large-scale application of the process; enhancing the universality of the process, providing a reference for the synthesis of other temperature-sensitive medium- and long-chain fatty acid glycerides.

[0008] The technical solution adopted by this invention to solve its technical problem is: a method for preparing 11-triglycerides by low-temperature acylation, comprising the following steps: Under nitrogen protection, glycerol was dissolved in a dichloromethane-toluene dual solvent, and a composite acid-binding agent, Lewis acid catalyst and 4A molecular sieve were added and stirred to form a homogeneous system. Control the internal temperature at 5-10℃, slowly add undecanoyl chloride, and after the addition is complete, first raise the temperature to 30℃ and keep it at that temperature for 2-3 hours, then raise the temperature to 45-55℃ and react for 12-16 hours. After the reaction was completed, 11-triglycerides of carbonate were obtained by filtration, multi-stage extraction, membrane separation purification, column chromatography purification and concentration and drying. The composite acid-binding agent is a mixture of pyridine and N,N-diisopropylethylamine in a mass ratio of 2:1-3:1. The Lewis acid catalyst is anhydrous zinc chloride or anhydrous ferric chloride. The volume ratio of dichloromethane to toluene in the dual solvents is 3:1-4:1. The molar ratio of glycerol, undecanoyl chloride, composite acid-binding agent, and catalyst is 1:3.0-3.2:3.5-4.0:0.05-0.1.

[0009] Specifically, the internal temperature of the low-temperature drop addition is controlled at 6-8℃, and the dropping rate of undecanoyl chloride is 0.5-1.0 mL / min.

[0010] Specifically, the amount of 4A molecular sieve added is 10%-15% of the mass of glycerol, and it is activated at 300°C for 2 hours before use.

[0011] Specifically, the total amount of the two solvents is 30-40 times the mass of glycerol, wherein the volume ratio of dichloromethane to toluene is 3.5:1.

[0012] Specifically, the Lewis acid catalyst is anhydrous zinc chloride, and its molar ratio with glycerol is 0.08:1.

[0013] Specifically, the multi-stage extraction process consists of washing twice with saturated sodium chloride solution, once with 5% sodium bicarbonate solution, once with 0.1 mol / L hydrochloric acid solution, and once with saturated sodium chloride solution, with the volume ratio of washing solution to total volume of dual solvents being 3:1 each time.

[0014] Specifically, the membrane separation uses a ceramic ultrafiltration membrane with a pore size of 50-100 nm, an operating pressure of 0.2-0.3 MPa, and a molecular weight cutoff of 500-1000 Da.

[0015] Specifically, the eluent for column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 12:1 to 15:1.

[0016] Specifically, the molar ratio of glycerol, undecanoyl chloride, and the composite acid binder is 1:3.1:3.8.

[0017] Specifically, the temperature to which the temperature is raised to 45-55°C is 50°C, and the reaction time is 14 hours.

[0018] The beneficial effects of this invention are: The reaction conditions are mild and controllable: the core acylation step is carried out at a low temperature of 5-10℃, and the temperature is raised to 30℃ and 45-55℃ in steps thereafter. High temperatures are avoided throughout the process, which effectively inhibits side reactions such as raw material decomposition, carbonization and hydrolysis of acyl chloride. The product has a light color (pale yellow) and a purity of ≥99%. Significantly improved selectivity and yield: The combined acid-binding agent enhances acid-binding efficiency and reduces local over-acylation; Lewis acid catalyst accelerates the reaction rate and shortens the reaction cycle to 14-19 hours; in-situ dehydration technology inhibits acyl chloride hydrolysis. The three factors work together to improve the selectivity of triesterification, and the molar yield is increased to 45%-52%, which is much higher than the traditional acyl chloride method (≤30%). Improved environmental friendliness and economy: The addition of DIPEA to the compound acid binder reduces the amount of pyridine used (toxicity reduced by more than 30%), and the salt content of the wastewater generated in the post-treatment is reduced by 25%; the dual solvent system improves the solubility of raw materials, membrane separation replaces part of column chromatography, purification costs are reduced by 40%, and product loss is reduced by 15%-20%; The process exhibits strong stability and versatility: nitrogen protection, in-situ dehydration, and stepwise heating strategies improve process repeatability, with yield fluctuations of ≤3% in multiple parallel experiments; this method can be extended to the esterification reaction of 8-14 carbon medium-long chain fatty acid acyl chlorides with glycerol, and is suitable for the synthesis of various temperature-sensitive glycerides. Attached Figure Description

[0019] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0020] Figure 1A schematic diagram of the esterification reaction process of glycerol and undecanoyl chloride in a low-temperature acylation method for preparing triglycerides of 11-carbonate provided by the present invention; Figure 2 The nuclear magnetic resonance spectrum of a method for preparing 11-triglycerides by low-temperature acylation provided by the present invention; Figure 3 The flowchart of a method for preparing 11-triglycerides by low-temperature acylation provided by the present invention is shown. Detailed Implementation

[0021] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0022] like Figures 1-3 As shown, the method for preparing triglycerides 11-carbonate by low-temperature acylation according to the present invention includes steps such as raw material preparation, reaction system construction, low-temperature dropwise addition reaction, stepwise heating reaction, post-treatment purification, and product characterization. Specific details are as follows: 1. Raw materials and reagents Glycerol: Purity ≥ 99.5%, industrial grade; Undecanoyl chloride: purity ≥98%, industrial grade; Composite acid-binding agent: Pyridine (purity ≥99%) and N,N-diisopropylethylamine (DIPEA, purity ≥99%) are mixed in a mass ratio of 2:1-3:1; Lewis acid catalyst: anhydrous zinc chloride or anhydrous ferric chloride, purity ≥98%; Dual solvents: dichloromethane (purity ≥99.5%) and toluene (purity ≥99.5%) are mixed in a volume ratio of 3:1 to 4:1; Auxiliary reagents: 4A molecular sieve (particle size 3-5μm, activated at 300℃ for 2 hours), saturated sodium chloride solution, 5% sodium bicarbonate solution, 0.1mol / L hydrochloric acid solution, anhydrous sodium sulfate, silica gel (for column chromatography, 200-300 mesh). Membrane separation component: ceramic ultrafiltration membrane (pore size 50-100nm, molecular weight cutoff 500-1000Da).

[0023] 2. Raw material ratio The molar ratio of glycerol, undecanoyl chloride, composite acid binder, and Lewis acid catalyst is 1:3.0-3.2:3.5-4.0:0.05-0.1; the total amount of the two solvents is 30-40 times the mass of glycerol; and the amount of 4A molecular sieve added is 10%-15% of the mass of glycerol.

[0024] 3. Reaction steps Reaction system construction: In a 250mL three-necked flask, add measured amounts of glycerol, dual solvents, composite acid-binding agent, Lewis acid catalyst, and 4A molecular sieve in sequence. Install a mechanical stirrer, a constant pressure dropping funnel, and a nitrogen delivery tube. Purge the air in the system with nitrogen for 3-5 minutes, maintaining a slight positive pressure protection with nitrogen. Control the stirring rate at 300-400r / min and stir for 10-15 minutes until a colorless, clear, homogeneous solution is formed.

[0025] Low-temperature dropwise addition reaction: Dissolve the measured amount of undecanoyl chloride in a dual solvent (1 / 5 of the total solvent volume) and transfer it to a constant-pressure dropping funnel; turn on the low-temperature bath and cool the internal temperature of the reaction system to 5-10℃, control the dropping rate to 0.5-1.0 mL / min, and slowly add the undecanoyl chloride solution; continuously monitor the internal temperature during the dropping process to ensure that it does not exceed 10℃, and a white solid (acid-binding agent hydrochloride) gradually precipitates out of the system in the later stage of the dropping.

[0026] Stepwise heating reaction: After the addition is complete, close the low-temperature bath and allow the system to heat naturally to 30°C. Maintain the temperature for 2-3 hours to promote the conversion of the intermediate product diester to the trimer. Then, heat to 45-55°C and continue stirring for 12-16 hours. Monitor the reaction progress using TLC with petroleum ether:ethyl acetate = 10:1 as the developing solvent and phosphomolybdic acid as the colorimetric reagent. When the spot of the raw material glycerol (Rf≈0.1) disappears or almost disappears, and the spot of the target product (Rf≈0.6) becomes clear, the reaction is considered complete.

[0027] Post-processing purification: Filtration: After the reaction is stopped, cool the system to room temperature, filter to remove 4A molecular sieve and acid-binding agent hydrochloride solid, wash the filter cake 2-3 times with two solvents (1 / 10 of the total solvent), and combine the filtrate and washing liquid; Multistage extraction: Transfer the combined liquid to a separatory funnel and wash twice with saturated sodium chloride solution (1.5 times the volume of the filtrate), once with 5% sodium bicarbonate solution (1.5 times the volume of the filtrate) (to neutralize residual acid), once with 0.1 mol / L hydrochloric acid solution (1.5 times the volume of the filtrate) (to neutralize residual alkali), and once with saturated sodium chloride solution (1.5 times the volume of the filtrate) (to remove salt). After each wash, allow the liquid to stand and separate into layers, and collect the organic phase. Drying and concentration: Add anhydrous sodium sulfate (5%-8% of the organic phase mass) to the organic phase, stir and dry for 2-3 hours, filter to remove anhydrous sodium sulfate, place the filtrate in a rotary evaporator, and concentrate to dryness at 40-50℃ and a vacuum of 0.09-0.1MPa to obtain a yellow oily crude product. Membrane separation and purification: Dissolve the crude product in a small amount of dichloromethane (twice the mass of the crude product), pass it through a ceramic ultrafiltration membrane module, control the operating pressure at 0.2-0.3 MPa and the flow rate at 10-15 mL / min, retain macromolecular impurities, and collect the permeate; Column chromatography purification: The permeate was concentrated and loaded onto a silica gel column (column diameter: column height = 1:10). Gradient elution was performed using petroleum ether: ethyl acetate = 12:1-15:1 as the eluent. The target product fraction was collected and concentrated to dryness to obtain a pale yellow oily pure product.

[0028] 4. Product Characterization Appearance: Pale yellow, transparent, oily liquid; Purity: Determined by TLC and high performance liquid chromatography (HPLC), purity ≥99%; Structural confirmation: through infrared spectroscopy (IR) and proton nuclear magnetic resonance spectroscopy (NMR). 1 HNMR and carbon spectroscopy (HNMR) 13 The product was characterized by CNMR and confirmed to be 11-triglyceride carbonate.

[0029] Example 1: Preparation of 11-triglycerides of glycerol carbonate using a composite acid-binding agent + Lewis acid catalyst + dual solvent system 1. Experimental materials and proportions Glycerol: 2.0 g (0.022 mol); Undecanoyl chloride: 14.0 g (0.068 mol), molar ratio of glycerol to undecanoyl chloride 1:3.09; Composite acid-binding agent: pyridine 3.5g (0.044mol) + DIPEA 1.8g (0.014mol), total molar amount 0.058mol, molar ratio with glycerol 2.64:1; Lewis acid catalyst: 0.15 g (0.0011 mol) of anhydrous zinc chloride, with a molar ratio of 0.05:1 to glycerol; Dual solvents: 49.5 mL dichloromethane + 16.5 mL toluene (volume ratio 3:1), total volume 66 mL, which is 33 times the mass of glycerol; 4A molecular sieve: 0.2g (10% of the mass of glycerol); Other auxiliary reagents: saturated sodium chloride solution, 5% sodium bicarbonate solution, 0.1 mol / L hydrochloric acid solution, anhydrous sodium sulfate, silica gel (200-300 mesh).

[0030] 2. Experimental equipment 250mL three-necked flask, mechanical stirrer, constant pressure dropping funnel, nitrogen cylinder, low temperature bath, electric heating mantle, rotary evaporator, separatory funnel, ceramic ultrafiltration membrane module (pore size 50nm), silica gel column (column diameter 2cm, column height 20cm), TLC chromatography plate, high performance liquid chromatograph, infrared spectrometer, nuclear magnetic resonance spectrometer.

[0031] 3. Experimental Procedure Reaction system construction: Fix a 250mL three-necked flask on the experimental platform, add 2.0g glycerol, 49.5mL dichloromethane, and 16.5mL toluene in sequence, turn on mechanical stirring (350r / min), add 3.5g pyridine and 1.8g DIPEA, stir for 5 minutes, then add 0.15g anhydrous zinc chloride and 0.2g activated 4A molecular sieve, install a constant pressure dropping funnel and nitrogen delivery tube, purge the air in the system with nitrogen for 4 minutes, maintain a slight positive pressure of nitrogen (approximately 0.01MPa), continue stirring for 12 minutes, and the system forms a colorless, clear, homogeneous solution.

[0032] Low-temperature dropping reaction: Weigh 14.0 g of undecanoyl chloride and dissolve it in 13.2 mL of a dual solvent (9.9 mL of dichloromethane + 3.3 mL of toluene), and transfer it to a constant-pressure dropping funnel; turn on the low-temperature bath and set the temperature to 7 °C. When the internal temperature of the reaction system stabilizes at 7 °C, open the stopcock of the dropping funnel and control the dropping rate at 0.8 mL / min, slowly adding the undecanoyl chloride solution; monitor the internal temperature in real time with a thermometer during the dropping process. When the internal temperature approaches 9 °C, appropriately reduce the dropping rate to 0.6 mL / min to ensure that the internal temperature does not exceed 10 °C; the dropping continues for about 25 minutes. In the later stage of the dropping, a white flocculent solid (a mixture of pyridine hydrochloride and DIPEA hydrochloride) gradually precipitates in the system. During the stirring process, the solid is uniformly dispersed in the system.

[0033] Stepwise heating reaction: After the addition was complete, the low-temperature bath was closed and removed, allowing the system to naturally heat up to 30°C (about 30 minutes). The stirring rate was maintained at 350 r / min, and the reaction was kept at this temperature for 2.5 hours. Then, the heating mantle was turned on, and the system was slowly heated to 50°C (heating rate 2°C / min). The reaction was continued at 50°C with stirring for 14 hours. During the reaction, samples were taken every 2 hours, quenched with alkali (5% sodium bicarbonate solution), neutralized with acid (0.1 mol / L hydrochloric acid solution), and then spotted onto a TLC plate. Petroleum ether:ethyl acetate = 10:1 was used as the developing solvent, and phosphomolybdic acid was used for color development. After 14 hours of reaction, TLC detection showed that the glycerol spot (Rf≈0.1) of the raw material had basically disappeared, and the spot of the target product (Rf≈0.6) was clear and free of impurities, indicating that the reaction was complete.

[0034] Post-processing purification: Filtration: Turn off the heating mantle and wait for the system to cool to room temperature (about 1 hour). Filter with a Buchner funnel to remove the 4A molecular sieve and the white solid acid-binding agent hydrochloride. Wash the filter cake three times with 13.2 mL of dual solvent (9.9 mL of dichloromethane + 3.3 mL of toluene). Filter for 1 minute after each wash. Combine the filtrate and washing liquid to obtain about 95 mL of pale yellow clear organic phase.

[0035] Multistage extraction: Transfer the organic phase to a 250 mL separatory funnel, add 142.5 mL of saturated sodium chloride solution (1.5 times the volume of the organic phase), shake for 3 minutes, allow to stand for 15 minutes to separate the layers, and collect the lower organic phase; repeat the washing with saturated sodium chloride solution once and collect the organic phase; add 142.5 mL of 5% sodium bicarbonate solution to the organic phase, shake for 2 minutes (avoid vigorous shaking to prevent emulsification), allow to stand for 20 minutes to separate the layers, and collect the lower organic phase; add 142.5 mL of 0.1 mol / L hydrochloric acid solution, shake for 2 minutes, allow to stand for 15 minutes to separate the layers, and collect the lower organic phase; finally, add 142.5 mL of saturated sodium chloride solution, shake for 2 minutes, allow to stand for 15 minutes to separate the layers, and collect the lower organic phase, yielding approximately 88 mL of organic phase.

[0036] Drying and concentration: Add 4.4g of anhydrous sodium sulfate (approximately 88g of organic phase, 5% of the amount) to the collected organic phase, stir and dry for 2.5 hours, filter with qualitative filter paper to remove anhydrous sodium sulfate, transfer the filtrate to a rotary evaporator flask, set the water bath temperature to 45℃ and the vacuum degree to 0.095MPa, concentrate for 1.5 hours to obtain 12.3g of yellow oily crude product.

[0037] Membrane separation and purification: 12.3g of crude product was dissolved in 24.6mL of dichloromethane. After stirring and dissolving, the solution was passed through a ceramic ultrafiltration membrane module. The operating pressure was set to 0.25MPa and the flow rate to 12mL / min. Approximately 23.8mL of permeate was collected, and approximately 1.2g of retentate (macromolecule impurities) was retained.

[0038] Column chromatography purification: The permeate was transferred to a rotary evaporator and concentrated to dryness to obtain 11.1 g of pale yellow oily intermediate; the intermediate was loaded onto a silica gel column (pre-equilibrated with petroleum ether) and eluted with petroleum ether:ethyl acetate = 15:1. The first 100 mL of eluent was impurity, and the subsequent 150 mL of eluent was collected and concentrated to dryness to obtain 10.2 g of pale yellow transparent oily product.

[0039] 4. Product Characterization and Results Appearance: Pale yellow, transparent, oily liquid, odorless; TLC detection: Single spot, Rf≈0.6, no other spots; HPLC analysis: Purity 99.2%; IR characterization: 3000-2850cm-1 (CH stretching vibration), 1740cm -1 (C=O stretching vibration of ester carbonyl group), 1170 cm⁻¹ -1 (COC stretching vibration), no hydroxyl absorption peak (3400 cm⁻¹) -1 (nearby), conforming to the structural characteristics of triglyceride 11; 1 HNMR characterization (CDCl3 as solvent): δ=0.88 (t, 9H, -CH3), δ=1.26 (m, 48H, -(CH2)8-), δ=1.62 (m, 6H, -CH2CO-), δ=2.34 (t, 6H, -CH2COO-), δ=4.12 (m, 6H, -OCH2-), δ=5.28 (m, 1H, -OCHO-), perfectly matching the structure of 11-triglyceride carbonate; Molar yield: 10.2g of product corresponds to 0.010mol of moles. Based on glycerol (0.022mol), the molar yield is 45.5%.

[0040] Example 2: Preparation of 11-triglycerides by composite acid-binding agent + Lewis acid catalyst + dual solvents + stepwise heating 1. Experimental materials and proportions Glycerol: 2.0 g (0.022 mol); Undecanoyl chloride: 14.2 g (0.069 mol), molar ratio of glycerol to undecanoyl chloride 1:3.14; Composite acid-binding agent: pyridine 3.8g (0.048mol) + DIPEA 1.9g (0.015mol), total moles 0.063mol, molar ratio with glycerol 2.86:1; Lewis acid catalyst: 0.22 g (0.0016 mol) of anhydrous zinc chloride, with a molar ratio of 0.07:1 to glycerol; Dual solvents: 52.8 mL dichloromethane + 13.2 mL toluene (volume ratio 4:1), total volume 66 mL, which is 33 times the mass of glycerol; 4A molecular sieve: 0.25g (12.5% ​​of the mass of glycerol); Other auxiliary reagents are the same as in Example 1.

[0041] 2. Experimental equipment Consistent with Example 1.

[0042] 3. Experimental Procedure Construction of the reaction system: The operation procedure is the same as in Example 1. 2.0 g glycerol, 52.8 mL dichloromethane, 13.2 mL toluene, 3.8 g pyridine, 1.9 g DIPEA, 0.22 g anhydrous zinc chloride and 0.25 g 4A molecular sieve were added sequentially. Nitrogen gas was purged for 5 minutes, and the mixture was stirred for 15 minutes to form a colorless, clear, homogeneous solution at a stirring rate of 380 r / min.

[0043] Low-temperature dropwise addition reaction: Dissolve 14.2 g of undecanoyl chloride in 13.2 mL of a dual solvent (10.6 mL of dichloromethane + 2.6 mL of toluene) and transfer the solution to a constant-pressure dropping funnel. Set the temperature of the low-temperature bath to 6 °C. When the internal temperature of the system stabilizes at 6 °C, add the acyl chloride solution dropwise at a rate of 0.7 mL / min. During the dropwise addition, control the internal temperature at 6-8 °C. The dropwise addition continues for about 28 minutes. A white solid precipitates in the system. Stir the solution until homogeneous.

[0044] Stepwise heating reaction: After the addition was complete, the temperature was naturally raised to 30°C and kept at this temperature for 3 hours (stirring rate 380 r / min); then the temperature was raised to 52°C at a rate of 2°C / min and stirred at this temperature for 13 hours; TLC monitoring showed that the spot of the raw material completely disappeared after 13 hours of reaction, and the spot of the target product was pure.

[0045] Post-processing purification: Filtration: After cooling to room temperature, filter by suction. Wash the filter cake three times with 13.2 mL of dual solvent. Combine the filtrate and washing liquid to obtain approximately 97 mL of organic phase.

[0046] Multistage extraction: Wash twice with 145.5 mL saturated sodium chloride solution, once with 145.5 mL 5% sodium bicarbonate solution, once with 145.5 mL 0.1 mol / L hydrochloric acid solution, and once with 145.5 mL saturated sodium chloride solution. Collect approximately 90 mL of organic phase.

[0047] Drying and concentration: Add 4.5g of anhydrous sodium sulfate, dry for 2 hours, filter and concentrate to obtain 12.8g of yellow oily crude product.

[0048] Membrane separation and purification: The crude product was dissolved in 25.6 mL of dichloromethane and passed through a ceramic ultrafiltration membrane module (operating pressure 0.28 MPa, flow rate 14 mL / min). About 24.5 mL of permeate was collected, and 1.3 g of impurities were retained.

[0049] Column chromatography purification: After concentration of the permeate, the sample was loaded onto the eluent, which was petroleum ether: ethyl acetate = 14:1. The target fraction was collected and concentrated to dryness to obtain 10.8 g of pale yellow transparent oily product.

[0050] 4. Product Characterization and Results Appearance: Pale yellow, transparent, oily liquid with good fluidity; TLC detection: Single spot, excellent purity; HPLC analysis: Purity 99.4%; IR and 1 1H NMR characterization: Completely matches the structure of 11-triglyceride carbonate; Molar yield: 10.8g of product corresponds to 0.011mol of moles, and the molar yield is 50.0% based on glycerol.

[0051] Example 3: Optimization of the entire system (composite acid-binding agent + catalyst + dual solvents + stepwise heating + in-situ dehydration + membrane separation) for the preparation of 11-triglycerides of carbonate 1. Experimental materials and proportions Glycerol: 2.0 g (0.022 mol); Undecanoyl chloride: 14.4 g (0.070 mol), molar ratio of glycerol to undecanoyl chloride 1:3.18; Composite acid-binding agent: pyridine 4.0g (0.051mol) + DIPEA 2.0g (0.015mol), total moles 0.066mol, molar ratio with glycerol 3.0:1; Lewis acid catalyst: 0.30 g (0.0022 mol) of anhydrous zinc chloride, with a molar ratio of 0.1:1 to glycerol; Two solvents: 51.0 mL dichloromethane + 15.0 mL toluene (volume ratio 3.4:1), total volume 66 mL, which is 33 times the mass of glycerol; 4A molecular sieve: 0.3g (15% of the mass of glycerol); Other auxiliary reagents are the same as in Example 1.

[0052] 2. Experimental equipment Consistent with Example 1.

[0053] 3. Experimental Procedure Construction of the reaction system: The operation procedure is the same as in Example 1. 2.0 g glycerol, 51.0 mL dichloromethane, 15.0 mL toluene, 4.0 g pyridine, 2.0 g DIPEA, 0.30 g anhydrous zinc chloride, and 0.3 g 4A molecular sieve are added sequentially. Nitrogen gas is purged for 5 minutes, and the mixture is stirred for 15 minutes to form a colorless, clear, and homogeneous solution. The stirring rate is 400 r / min to ensure uniform dispersion of the 4A molecular sieve.

[0054] Low-temperature dropwise addition reaction: Dissolve 14.4 g of undecanoyl chloride in 13.2 mL of a dual solvent (10.0 mL of dichloromethane + 3.2 mL of toluene) and transfer the solution to a constant-pressure dropping funnel. Set the temperature of the low-temperature bath to 5 °C. When the internal temperature of the system stabilizes at 5 °C, slowly add the acyl chloride solution at a rate of 0.5 mL / min. During the addition process, strictly control the internal temperature at 5-7 °C. The addition continues for about 33 minutes. A uniform white solid precipitates from the system without clumping.

[0055] Stepwise heating reaction: After the addition was complete, the temperature was naturally raised to 30°C and kept at that temperature for 2 hours (stirring rate 400 r / min); then the temperature was raised to 50°C at a rate of 2°C / min and the reaction was continued with stirring for 12 hours; TLC monitoring showed that the spot of the raw material completely disappeared after 12 hours of reaction, and the spot of the target product had no impurity peaks.

[0056] Post-processing purification: Filtration: After cooling to room temperature, filter by suction. Wash the filter cake three times with 13.2 mL of dual solvent. Combine the filtrate and washing liquid to obtain approximately 98 mL of organic phase.

[0057] Multistage extraction: Wash twice with 147 mL saturated sodium chloride solution, once with 147 mL 5% sodium bicarbonate solution, once with 147 mL 0.1 mol / L hydrochloric acid solution, and once with 147 mL saturated sodium chloride solution. Collect approximately 92 mL of organic phase.

[0058] Drying and concentration: Add 4.6g of anhydrous sodium sulfate, dry for 3 hours, filter and concentrate to obtain 13.2g of yellow oily crude product.

[0059] Membrane separation and purification: The crude product was dissolved in 26.4 mL of dichloromethane and passed through a ceramic ultrafiltration membrane module (operating pressure 0.3 MPa, flow rate 15 mL / min). About 25.2 mL of permeate was collected, and 1.1 g of impurities were retained.

[0060] Column chromatography purification: After concentration of the permeate, the sample was loaded onto the column. The eluent was petroleum ether: ethyl acetate = 13:1. Gradient elution was performed, the target fraction was collected, and concentrated to dryness to obtain 11.5g of pale yellow transparent oily product.

[0061] 4. Product Characterization and Results Appearance: Pale yellow, transparent, oily liquid, lighter in color; TLC analysis: Single, pure spot; HPLC analysis: Purity 99.6%; IR and 1 HNMR characterization: Completely matches the structure of 11-triglyceride carbonate; Molar yield: 11.5g of product corresponds to 0.012mol of moles, and the molar yield is 52.3% based on glycerol.

[0062] Comparative Example 1: Preparation of 11-triglycerides by direct esterification in the prior art Raw materials: 2.0 g (0.022 mol) glycerol, 30.0 g (0.165 mol) 11 carbonic acid, 0.3 g (catalyst) p-toluenesulfonic acid; Reaction steps: Add the raw materials to a 250mL round-bottom flask, install a water separator and a reflux condenser, heat to 220℃, and reflux for 8 hours, during which the water separator separates the generated water; Post-treatment: After cooling, neutralize with 5% sodium hydroxide solution, wash with water until neutral, dry with anhydrous sodium sulfate, and purify by vacuum distillation (180℃ / 0.001MPa); Results: The product was a dark yellow oily liquid with an HPLC purity of 82.5% and a molar yield of 28.3%, containing monoesters, diesters, and fatty acid decomposition products.

[0063] Comparative Example 2: Preparation of 11-triglycerides using the conventional acyl chloride method (single acid-binding agent + no catalyst + no in-situ dehydration) Raw materials: glycerol 2.0g (0.022mol), undecanoyl chloride 14.0g (0.068mol), pyridine 5.3g (single acid-binding agent), dichloromethane 66mL (single solvent); Reaction steps: Referring to the traditional acyl chloride method in the background art, undecanoyl chloride was added dropwise at room temperature, and the reaction was carried out at 50°C for 14 hours without a catalyst or molecular sieve. The post-treatment was acid washing, water washing, drying, and column chromatography. Results: The product was a yellow oily liquid with an HPLC purity of 90.2% and a molar yield of 23.1%. The product contained approximately 5% diester impurities, and the post-treatment wastewater had a high salt content.

[0064] Comparative Example 3: Preparation method of the composite acid-binding agent (single pyridine) of the present invention The raw materials are the same as in Example 1, but the composite acid binder is replaced with 5.3g of single pyridine; The reaction steps are the same as in Example 1; Results: The product was a yellow oily liquid with an HPLC purity of 95.8% and a molar yield of 35.7%. The toxicity of the post-treatment wastewater was higher than that of Example 1, and the product contained approximately 3% diester impurities.

[0065] This invention significantly improves the synthesis process of 11-triglycerides of carbonate through the synergistic effect of multiple innovative technologies, including a composite acid-binding agent, a Lewis acid catalyst, a dual-solvent system, stepwise heating, in-situ dehydration, and membrane separation purification. The molar yields of Examples 1-3 reached 45.5%, 50.0%, and 52.3%, respectively, with purities all ≥99.2%, far superior to the yields and purities of the control examples. Simultaneously, the environmental friendliness, stability, and versatility of the process are greatly improved, addressing many pain points of existing technologies and demonstrating promising prospects for industrial application.

[0066] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of protection claimed by the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for the production of 11 carbonic acid triglyceride by a low temperature acylation process, characterized in that, The method comprises the following steps: Under nitrogen protection, glycerol is dissolved in dichloromethane-toluene double solvent, a composite acid binding agent, a Lewis acid catalyst and 4A molecular sieve are added, and stirring is performed to form a homogeneous system; The internal temperature is controlled at 5-10℃, and undecanoyl chloride is slowly added dropwise; after the dropwise addition is completed, the temperature is first increased to 30℃ for 2-3 hours, and then increased to 45-55℃ for 12-16 hours of reaction; After the reaction is completed, filtration, multi-stage extraction, membrane separation and purification, column chromatography refining and concentration drying are performed to obtain 11 carbonic acid triglyceride; The composite acid binding agent is a mixture of pyridine and N,N-diisopropyl ethylamine in a mass ratio of 2:1-3:1, the Lewis acid catalyst is anhydrous zinc chloride or anhydrous ferric chloride, the volume ratio of dichloromethane to toluene in the double solvent is 3:1-4:1, and the molar ratio of glycerol, undecanoyl chloride, the composite acid binding agent and the catalyst is 1:3.0-3.2:3.5-4.0:0.05-0.

1.

2. A process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1, wherein: The internal temperature control of the low-temperature dropwise addition is 6-8℃, and the dropwise addition rate of undecanoyl chloride is 0.5-1.0 mL / min.

3. A process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1, wherein: The 4A molecular sieve is added in an amount of 10%-15% of the mass of glycerol, and is activated at 300℃ for 2 hours before use.

4. The process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1, wherein: The total amount of the double solvent is 30-40 times the mass of glycerol, and the volume ratio of dichloromethane to toluene is 3.5:

1.

5. The process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1, wherein: The Lewis acid catalyst is anhydrous zinc chloride, and the molar ratio of the catalyst to glycerol is 0.08:

1.

6. The process for the preparation of 11 carbonic acid triglyceride according to claim 1, characterized in that: The multi-stage extraction is in the following order: saturated sodium chloride solution washing 2 times, 5% sodium bicarbonate solution washing 1 time, 0.1 mol / L hydrochloric acid solution washing 1 time, and saturated sodium chloride solution washing 1 time, and the volume ratio of the amount of each washing liquid to the total amount of the double solvent is 3:

1.

7. A process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1, wherein: The membrane separation adopts a ceramic ultrafiltration membrane, the membrane pore size is 50-100 nm, the operating pressure is 0.2-0.3 MPa, and the molecular weight cut-off is 500-1000 Da.

8. A process for the preparation of 11 carbonic acid triglyceride by low temperature acylation as claimed in claim 1 wherein: The eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 12:1-15:

1.

9. The process for the preparation of 11 carbonic acid triglyceride according to claim 1, characterized in that: The molar ratio of glycerol, undecanoyl chloride and the composite acid binding agent is 1:3.1:3.

8.

10. The process for the preparation of 11 carbonic acid triglyceride by low temperature acylation method as claimed in claim 1, wherein: The specific temperature of the temperature increase to 45-55℃ is 50℃, and the reaction time is 14 hours.

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