Synthesis method of cooling agent intermediate 2, 2-diisopropyl propionitrile

Abstract

The invention belongs to the field of fine chemical engineering, and provides a synthetic method of a cooling agent intermediate 2, 2-diisopropyl propionitrile. According to the preparation method, a design of combining a sea urchin-shaped silicon dioxide loaded phosphorus pentoxide solid dehydrating agent and an ethyl acetate n-heptane composite solvent system is adopted, the sea urchin-shaped dehydrating agent with high bulk density and low moisture is prepared by an isovolumetric impregnation precursor conversion method, and efficient conversion is realized in an azeotropic water-carrying or one-pot amidation dehydration process; the high-quality target nitrile product of which the chromatographic purity is not lower than 99.5%, the moisture is not higher than 300 ppm, the chromaticity is not higher than 10, the phosphorus residue is not higher than 10 ppm in terms of P, and the total halogen is not higher than 20 ppm in terms of Cl is realized by combining vacuum rectification with activated carbon adsorption refining; the problems of limited rheological heat transfer, contradiction between high-temperature conversion and low chromaticity and low oxidation and difficulty in simultaneous ultralow control of phosphorus and halogen residues caused by overhigh solid content in a traditional dehydration process are solved, and the method has wide application value suitable for industrial amplification.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic fine chemical and cooling agent intermediate synthesis, and particularly relates to a cooling agent intermediate 2,2-diisopropyl propionitrile synthesis method. BACKGROUND

[0002] Cooling agents, as a kind of food additives and daily chemical raw materials that can produce a cooling sensation, have a wide range of applications in the fields of food and beverage, oral care, cosmetics and medicine. With the continuous improvement of consumers' demand for health and comfort experience, the market demand for high-efficiency long-acting low-stimulating cooling agents is showing a rapid growth trend. As a representative of the new generation of cooling agents, N, 2, 3-trimethyl-2-isopropyl butyramide (WS-23) has attracted widespread attention due to its high cooling intensity, long duration and low irritation. The efficient and clean synthesis of the key intermediate 2,2-diisopropyl propionitrile of this type of cooling agent is crucial to ensuring the quality stability and cost competitiveness of the terminal cooling agent product. In actual application scenarios, cooling agents must meet strict requirements for purity, color, stability and safety, especially in the fields of food and oral care, where the control standards for residual solvent, heavy metal and halogen impurities are extremely strict. Therefore, the development of a synthesis process that can stably produce ultra-high-purity and ultra-low-impurity target nitrile intermediates is of great significance to promoting the technological progress and application expansion of the cooling agent industry.

[0003] Currently, the industrial synthesis of 2,2-diisopropyl propionitrile is mainly based on the dehydration reaction of 2-isopropyl-2,3-dimethyl butyric acid or its amide, but the existing technical routes generally have many shortcomings. The existing method usually uses thionyl chloride or phosphorus oxychloride as the dehydrating agent, but there are problems of serious halogen residue, high product color and strong equipment corrosion. Some researchers use phosphorus pentoxide for direct dehydration, but the solid phosphorus pentoxide has poor dispersibility in organic solvents, resulting in high viscosity of the reaction system, poor heat transfer, easy local overheating and side reactions, and difficult filtration and separation, resulting in large product loss. In addition, the existing technology generally faces the problem of low flux and high energy consumption under high vacuum during vacuum distillation, and lacks systematic end-point control strategies for key quality indicators such as water content, color and peroxide, resulting in poor batch consistency and difficulty in meeting the strict requirements of high-end cooling agents. SUMMARY

[0004] The purpose of the present application is to provide a cooling agent intermediate 2,2-diisopropyl propionitrile synthesis method, which solves the problems of conflict between high solid content and rheological heat transfer limitation under water-carrying system and between extremely low water content and low halogen boundary of finished product, coupling contradiction between high-temperature rapid conversion and low color and low oxidation side reaction control during vacuum high-flux distillation, and opposite demands of simultaneously achieving ultra-low phosphorus halide residue and equipment safety window compatibility in T3P and cyanuric chloride two process paths.

[0005] The application adopts the strategy of synergistic effect of sea urchin-shaped silicon dioxide loaded phosphorus pentoxide solid dehydrating agent and ethyl acetate n-heptane complex solvent, constructs a solid dehydrating agent with high packing density, low moisture and radial microporous structure by the equal-volume impregnation precursor conversion method assisted by halogen-free morphology control agent, realizes the double effects of rheological property optimization and azeotropic water removal efficiency improvement in the complex solvent system, combines the step-by-step feeding external circulation cooling and activated carbon adsorption refining technology to accurately control the color and oxidation side reaction, and finally obtains high-purity target nitrile product meeting the multi-index ultra-low control requirements of moisture, color, phosphorus and halogen residues, realizes the whole-process synergy of catalyst design solvent system optimization and rectification adsorption refining process, and breaks through the technical bottleneck of mutual restriction in each link in the traditional process.

[0006] In order to achieve the above purpose, the application provides the following technical scheme:

[0007] A synthesis method of a cooling agent intermediate 2,2-diisopropyl propionitrile, comprising:

[0008] S1: preparing a solid dehydrating agent of sea urchin-shaped silicon dioxide loaded phosphorus pentoxide; at least one of phosphoric acid, polyphosphoric acid and ammonium phosphate is deposited on the pre-dried silicon dioxide together with a halogen-free morphology control agent by the equal-volume impregnation method, and after drying, heat treatment is carried out at 250-450 DEG C in an inert atmosphere or vacuum to generate phosphorus pentoxide, so as to prepare the solid dehydrating agent with phosphorus pentoxide content of 14-20%, packing density not less than 0.45 g / mL, moisture not higher than 0.2% and sea urchin-shaped radial morphology;

[0009] S2: loading of reactant materials, 2-isopropyl-2,3-dimethylbutyric acid or its amide intermediate is added as raw material into the reactor, and ethyl acetate and n-heptane complex solvent or ethyl acetate is added alone as solvent; when the complex solvent is used, the volume ratio of ethyl acetate to n-heptane is 30:70 to 70:30;

[0010] S3: dehydration and reaction step, according to the type of raw material, the conversion of acid or amide intermediate to target nitrile is realized;

[0011] S4: rectification and adsorption refining, when the system contains solid dehydrating agent or molecular sieve, the solid dehydrating agent, molecular sieve and insoluble matter are removed by filtration, then the target fraction is separated by vacuum rectification under the pressure of 10-20 mbar, the top pressure is 10-20 mbar, the kettle temperature is 70-95 DEG C, the light end solvent tail is cut off, the total residual solvent is not higher than 500 ppm, and the activated carbon accounting for 0.1-0.5% of the product mass is used for adsorption refining;

[0012] S5: The product is released, and the obtained 2,2-diisopropylpropionitrile meets the following quality indicators: the chromatographic purity is not less than 99.5%, the moisture is not higher than 300 ppm, the phosphorus residual amount is not higher than 10 ppm in terms of P, and the colority is not higher than 10; wherein the moisture control to not higher than 300 ppm is used as the end point criterion, and the external circulation cooling and stepwise feeding are used to control the colority.

[0013] Further, the sea urchin-like silicon dioxide loaded phosphorus pentoxide solid dehydrating agent is prepared by a precursor conversion method, comprising:

[0014] A1 Carrier pretreatment: The silicon dioxide is dried at 150-200°C for 2-6 hours, so that the moisture is not higher than 0.2%;

[0015] A2 Precursor impregnation: The phosphorus-containing precursor and the halogen-free morphology control agent are prepared into a solution, and are deposited on the silicon dioxide by an equal volume impregnation method, so that the target content in terms of phosphorus pentoxide is 14-20%, and the amount of the morphology control agent is 0.5-2.0% of the mass of the silicon dioxide; the halogen-free morphology control agent is a non-ionic surfactant, a polyhydric alcohol or a sugar; and the phosphorus-containing precursor is selected from at least one of phosphoric acid, polyphosphoric acid and ammonium phosphate;

[0016] A3 In-situ conversion: the impregnated material is heat treated at 250-450°C for 1-4 hours in an inert atmosphere or vacuum, to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, to form a sea urchin-like radial morphology;

[0017] A4 Granulation and activation: granulated to 100-200 mesh and activated at 120-180°C under vacuum, so that the bulk density of the finished product is not less than 0.45 g / mL, and the moisture of the finished product is not higher than 0.2%.

[0018] Further, the synthesis of the amide intermediate comprises: 1.2-1.5 equivalents of ammonium acetate and 1.2-1.5 equivalents of acetic anhydride are added to 2-isopropyl-2,3-dimethylbutyric acid, and reacted at 50-80°C for 1-2 hours to obtain the amide intermediate, and the acid value of the obtained amide intermediate is not higher than 5 mgKOH / g.

[0019] Further, the dehydration and reaction steps in step S3 are selected as follows according to the type of raw material:

[0020] a) When the raw material is an amide intermediate, the silicon dioxide loaded phosphorus pentoxide obtained in S1 is added, and the amount is 10-15% of the initial liquid phase mass of the reactor, and is refluxed at 70-95°C for 60-90 minutes; when a co-boiling water device with a reflux head or a column is used, the reflux ratio is controlled at 1.2-1.5; and 3Å molecular sieves activated by calcination at 300-350°C for 3-6 hours can be used as a water-carrying aid during the process, and the amount is 5-10% of the initial liquid phase mass.

[0021] b) When the raw material is an acid, in the presence of an organic base, a one-pot method is used to first amidate and then dehydrate with phosphorus acid anhydride condensing agent and ammonium acetate, or trichloroisocyanuric acid is used for dehydration and subsequent removal of halogen.

[0022] Further, the amount of 3Å molecular sieve used is 5-10% of the initial liquid phase mass of the reactor.

[0023] Further, the quality indicators of S5 further include: acid value not higher than 0.05 mgKOH / g, total halogen not higher than 20 ppm as Cl, peroxide not detected, and detection limit not higher than 5 mg / kg, acidic impurities not higher than 10 mg / kg as acetic acid.

[0024] Further, the dehydration in S3 in the presence of an organic base using a one-pot method with phosphorus acid anhydride condensing agent, or trichloroisocyanuric acid dehydration and subsequent removal of halogen, specifically any of the following schemes:

[0025] Scheme A: In the presence of 0.5-1.0 equivalents of an organic base, which is diisopropylethylamine or triethylamine, a one-pot reaction is carried out with 1.2-1.8 equivalents of 50% mass fraction 1-n-propyl phosphoric anhydride T3P solution and 1.2-1.5 equivalents of ammonium acetate, to generate the target nitrile at 50-90°C for 0.5-1.5 hours, then enter S4, and the phosphorus residue of the obtained product is not higher than 10 ppm as P;

[0026] Scheme B: In the presence of 1.5-2.0 equivalents of an organic base, trichloroisocyanuric acid is added dropwise in ethyl acetate solvent at 0-5°C, followed by incubation at 50-70°C for 40-80 minutes to complete the dehydration; subsequent removal of halogen using a combination of base washing, water washing, and anion exchange resin to ensure that the total halogen is not higher than 20 ppm as Cl.

[0027] As one of the concepts of the present application, the present application adopts the design of sea urchin-like silica supported phosphorus pentoxide solid dehydrating agent, which is mainly used to enhance the dehydration efficiency and product purity performance. The radial microporous structure formed by the precursor conversion method assisted by halogen-free morphology control agent significantly improves the dispersibility and accessibility of phosphorus pentoxide, so that the dehydration active site is fully exposed to the reaction medium, effectively overcoming the problems of large mass transfer resistance and uneven reaction caused by the agglomeration and sedimentation of traditional powder phosphorus pentoxide in organic solvents. The high bulk density design makes the solid dehydrating agent more compact in the reactor, reduces the deterioration of rheological properties and the decrease of heat transfer efficiency caused by too high solid content, and facilitates subsequent filtration separation to reduce product loss. Ultra-low moisture control ensures that the dehydrating agent maintains high activity during storage and use, avoiding the decrease of reaction conversion and the increase of side reactions caused by moisture absorption inactivation. The equal-volume impregnation method realizes the uniform distribution of phosphorus pentoxide on the surface and in the pores of the silica carrier, and through the in-situ conversion of phosphorus-containing precursors in the process of inert atmosphere or vacuum heat treatment, the problems of uneven distribution and agglomeration of active components caused by traditional physical mixing method are avoided. The ethyl acetate in the complex solvent system provides good solubility and moderate boiling point to facilitate azeotropic water removal, and the n-heptane adjusts the solvent polarity and boiling point to form an azeotropic system to improve the dehydration efficiency. The synergistic effect of the two optimizes the rheological properties and mass and heat transfer characteristics of the reaction system, ensuring high conversion rate while effectively inhibiting the occurrence of color and oxidation side reactions.

[0028] The present application also discloses a cooling agent intermediate 2,2-diisopropylpropionitrile prepared by the above preparation method, characterized in that the following quality indicators are met: moisture is not higher than 300 ppm; color is not higher than 10; acid value is not higher than 0.05 mgKOH / g; phosphorus residue is not higher than 10 ppm as P; total halogen is not higher than 20 ppm as Cl; and chromatographic purity is not less than 99.5%.

[0029] Further, after vacuum rectification under 10-20 mbar pressure and adsorption refining with 0.1-0.5% of activated carbon based on the mass of the product, the total residual solvent is not higher than 500 ppm, wherein the total amount of ethyl acetate, n-heptane and their possible ester exchange by-products is included, no peroxide is detected, and the acidic impurities are not higher than 10 mg / kg as acetic acid.

[0030] As another concept of the present application, the present application adopts an adsorption refining process design combining vacuum rectification and activated carbon adsorption refining, mainly for enhancing the color purity and stability performance of the product. The vacuum rectification is carried out at a medium vacuum degree of 10-20 mbar, which has the advantages of low equipment investment, low energy consumption and large flux compared with high vacuum rectification. The kettle temperature is controlled at 70-95℃ to avoid the decomposition of the target nitrile and the deepening of the color at high temperature. The efficient separation and tail cutting of the light end solvent are realized by accurately controlling the top pressure and reflux ratio of the tower, and the total residual solvent is reduced to below 500 ppm to meet the requirements of food grade application. The activated carbon adsorption refining process effectively removes trace amounts of oxidized products and trace amounts of organic impurities in the product through physical adsorption, so that the color stability is stably controlled below 10. At the same time, it has a certain adsorption removal effect on phosphorus residues and halogen residues to help achieve ultra-low impurity indexes. The water content is controlled to not higher than 300 ppm as the key release criterion. The Karl Fischer method is used for online monitoring to accurately regulate the water-carrying efficiency and product water content of the rectification process through the external circulation cooling system, avoiding the risk of subsequent amide reaction yield reduction and product hydrolysis caused by excessive water content. The stepwise feeding strategy uses lower temperature and smaller batch size at the initial stage of the dehydration reaction, and gradually increases the temperature and feeding speed as the reaction proceeds, effectively controlling the reaction heat accumulation and local overheating risk to reduce the color and side reactions. The external circulation cooling system removes the reaction heat in real time through jacket or coil heat exchange to maintain the uniformity of the system temperature. The two work together to achieve the balance of high conversion rate and low color and low oxidation, ensuring the quality consistency and stability of the product batches.

[0031] The application also discloses application of a cooling agent intermediate 2,2-diisopropylpropionitrile in synthesis of a cooling agent N,2,3-trimethyl-2-isopropylbutyramide, wherein the 2,2-diisopropylpropionitrile is hydrolyzed to obtain 2-isopropyl-2,3-dimethylbutyric acid, and then subjected to amidation to obtain the cooling agent; an ammonia source for the amidation is selected from at least one of methylamine, ethylamine and ammonium acetate, and activation of the 2-isopropyl-2,3-dimethylbutyric acid adopts acetic anhydride or 1-n-propylphosphoric anhydride T3P.

[0032] The sea urchin-shaped silica supported phosphorus pentoxide solid dehydrating agent and ethyl acetate n-heptane composite solvent play a significant synergistic role in the present application. The main function of the solid dehydrating agent focuses on providing high active dehydration sites and optimizing the rheological heat transfer performance of the solid-liquid two-phase, and its sea urchin-shaped radial morphology and high bulk density design overcomes the agglomeration and sedimentation problem of traditional powder dehydrating agents, uniformly dispersing in the reaction system to form a stable suspension state, and the phosphorus pentoxide active component is fully exposed to the solvent interface to achieve high-efficiency dehydration conversion. The main function of the composite solvent focuses on regulating the polarity boiling point and azeotropic water-carrying efficiency of the reaction medium, ethyl acetate as the main solvent provides good solubility to the raw materials and products, n-heptane as the regulator reduces the polarity of the system to form a suitable azeotropic composition, and the two together construct a reaction environment with excellent rheological properties and efficient mass and heat transfer. In terms of dehydration performance improvement, the active sites provided by the solid dehydrating agent and the azeotropic system constructed by the composite solvent synergistically work together to efficiently remove the water generated in the reaction through reflux azeotropy, promoting the dehydration reaction equilibrium to move forward and improving the conversion rate, and the moderate polarity of the composite solvent is beneficial to the mass transfer and diffusion of reactants to the surface of the solid dehydrating agent, further enhancing the dehydration efficiency. In terms of color and oxidation control, the high specific surface area and radial pore structure of the sea urchin-shaped dehydrating agent have a certain adsorption and fixation effect on the reaction intermediates and pigment precursors, reducing their concentration and activity in the solution, and the low-polarity environment of the composite solvent inhibits the occurrence of oxidation reactions, and the synergistic effect of the two enables low color and low oxidation byproduct levels to be maintained under high-temperature dehydration conditions, ensuring that the final product meets the food-grade color standard.

[0033] Beneficial technical effects

[0034] 1. Significantly improve dehydration efficiency and product purity: through the design of sea urchin-shaped silica supported phosphorus pentoxide solid dehydrating agent, the radial micropore structure and high bulk density characteristics formed overcome the agglomeration and sedimentation problem of traditional powder dehydrating agents, and the phosphorus pentoxide active sites are fully exposed to the reaction medium to achieve high-efficiency dehydration conversion, combined with the azeotropic water-carrying effect of ethyl acetate n-heptane composite solvent, the dehydration reaction equilibrium is promoted to move forward, and the conversion rate and chromatographic purity of the target nitrile are significantly improved, and the final product chromatographic purity reaches more than 99.5%, meeting the strict purity requirements of high-end cooling flavor applications.

[0035] 2. Effectively control color and oxidation side reactions: adopt stepwise feeding and external circulation cooling strategy to precisely control the temperature distribution, avoid local overheating leading to color deepening and oxidation side reactions, the pore structure of the sea urchin-shaped dehydrating agent has adsorption and fixation effect on pigment precursors, the low-polarity environment of the composite solvent inhibits the occurrence of oxidation reactions, combined with activated carbon adsorption refining process to remove trace pigments and oxidation products, the product color is stably controlled below 10, peroxide is not detected, and acidic impurities are not more than 10 mg / kg calculated as acetic acid, ensuring the stability and safety of the product during storage and subsequent application.

[0036] 3. Ultra-low control of phosphorus and halogen residues: Phosphorus pentoxide is firmly loaded on the surface and pores of the silica carrier by the equal-volume impregnation method and in-situ conversion technology, reducing the migration of free phosphorus components to the product, the filtration process effectively separates the solid dehydrating agent and phosphorus impurities, and the vacuum rectification further removes volatile phosphorus compounds. Activated carbon adsorption refining has adsorption effect on residual phosphorus components, and multi-stage synergistic control reduces the phosphorus residue in the product to less than 10 ppm in terms of P; for the cyanuric chloride dehydration path, alkali washing and anion exchange resin are combined to deeply remove halogen, ensuring that the total halogen is not higher than 20 ppm in terms of Cl, meeting the strict limit requirements of phosphorus and halogen residues in food and oral care fields.

[0037] 4. Optimization of process operability and industrial adaptability: Vacuum rectification is carried out at a moderate vacuum degree of 10-20 mbar, which has the advantages of low equipment investment, low energy consumption, and large flux compared to high vacuum rectification. The kettle temperature is controlled at 70-95°C to avoid product decomposition. The high bulk density and good flowability of the solid dehydrating agent facilitate reactor loading and subsequent filtration separation operations. The composite solvent system has excellent rheological properties and high heat transfer efficiency. The water end point control and external circulation cooling system realize precise regulation and stable operation of the reaction process. The overall process is mild and controllable with high yield, suitable for industrial continuous production and large-scale application.

[0038] 5. Broaden the process path selection and raw material adaptability: Provide three technical paths of amide dehydration T3P one-pot method and cyanuric chloride dehydration, which can be flexibly selected according to the cost structure and equipment conditions of raw material sources. The amide dehydration path is simple to operate and suitable for small and medium-scale production. The T3P one-pot method is mild and has controllable phosphorus residues, suitable for high-value-added products. The cyanuric chloride dehydration path has high conversion efficiency and is suitable for large-scale industrialization. The multi-path design enhances the flexibility and market competitiveness of the process. At the same time, 2-isopropyl-2,3-dimethylbutyric acid or its amide intermediate can be used as raw material, which has wide raw material adaptability and flexible supply chain, reducing the risk of production impact by raw material fluctuations. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1 The effect of phosphorus pentoxide content on chromatographic purity and moisture in the present invention.

[0040] Figure 2 The effect of heat treatment temperature on chromatographic purity and phosphorus residue in the present invention.

[0041] Figure 3 The effect of solid dehydrating agent dosage on chromatographic purity and moisture in the present invention.

[0042] Figure 4 The effect of reflux time on chromatographic purity and moisture in the present invention.

[0043] Figure 5 XRD pattern of the solid dehydrating agent of Example 1 and the solid dehydrating agent after azeotropy.

[0044] Figure 6 UV-Vis absorption spectrum of the sample in the range of 200-800 nm under the condition of 0.3% AC, 5 ppm P, 82.5 ℃ of kettle temperature, and 150 ppm of H2O.

[0045] Figure 7 UV-Vis absorption spectrum of the sample in the range of 200-800 nm under the condition of 0.1% AC, 5 ppm P, and 82.5 ℃ of kettle temperature.

[0046] Figure 8 UV-Vis absorption spectrum of the sample in the range of 200-800 nm under the condition of 0.5% AC, 5 ppm P, and 82.5 ℃ of kettle temperature.

[0047] Figure 9 UV-Vis absorption spectrum of the sample in the range of 200-800 nm under the condition of 0.3% AC, 5 ppm P, and 70 ℃ of kettle temperature.

[0048] Figure 10 UV-Vis absorption spectrum of the sample in the range of 200-800 nm under the condition of 0.3% AC, 5 ppm P, and 95 ℃ of kettle temperature.

[0049] Figure 11 Morphology of the solid dehydrating agent of Example 1 of the application, in which silicon dioxide is loaded with phosphorus pentoxide. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solutions and advantages of the embodiments of the application clearer, the technical solutions in the embodiments of the application will be described clearly and completely below with reference to the drawings in the embodiments of the application.

[0051] Example 1

[0052] This embodiment provides a synthesis method of a cooling agent intermediate 2,2-diisopropyl propionitrile, which comprises the following steps:

[0053] S1: preparing a solid dehydrating agent of sea urchin-shaped silicon dioxide loaded with phosphorus pentoxide;

[0054] A1: pretreatment of the carrier: drying the silicon dioxide at 175 ℃ for 4 hours to reduce the moisture to 0.12%.

[0055] A2 Precursor impregnation: Phosphoric acid was prepared into a solution with polyol glycerol, and was deposited on silica by equal volume impregnation method, so that the target content of phosphorus pentoxide was 17%, and the amount of glycerol was 1.2% of the mass of silica.

[0056] A3 In-situ conversion: The impregnate was heat treated at 350°C for 2.5 hours under nitrogen atmosphere, to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, forming urchin-like radial morphology.

[0057] A4 Granulation and activation: Granulated to 150 mesh and activated at 150°C under vacuum, so that the bulk density of the finished product reached 0.52 g / mL, and the moisture of the finished product was 0.12%.

[0058] S2: Reactant loading

[0059] 2-isopropyl-2,3-dimethylbutyric acid was added to the reactor as raw material. First, the amide intermediate was prepared: 1.35 equivalents of ammonium acetate and 1.35 equivalents of acetic anhydride were added to 2-isopropyl-2,3-dimethylbutyric acid, and reacted at 65°C for 1.5 hours to obtain the amide intermediate, and the acid value of the obtained amide intermediate was 3 mgKOH / g. Then, a composite solvent of ethyl acetate and n-heptane was added, and the volume ratio of ethyl acetate to n-heptane was 50:50.

[0060] S3: Dehydration and reaction step

[0061] The silica-supported phosphorus pentoxide obtained in S1 was added in an amount of 12.5% of the mass of the initial liquid phase in the reactor, and refluxed at 82.5°C for 75 minutes. Azeotropic water removal device with reflux head was used, and the reflux ratio was controlled at 1.35. Activated 3Å molecular sieve, which was heat loaded after being calcined at 325°C for 4.5 hours, was used as a water removal aid during the process, and the amount was 7.5% of the mass of the initial liquid phase.

[0062] S4: Rectification and adsorption purification

[0063] The solid dehydrating agent, molecular sieve and insoluble matter were removed by filtration, and then the target fraction was separated by vacuum rectification at a pressure of 15 mbar, the overhead pressure was 15 mbar, the kettle temperature was 82.5°C, the light end solvent tail was cut off, the total residual solvent was reduced to 250 ppm, and 0.3% of activated carbon based on the mass of the product was used for adsorption purification.

[0064] S5: Product release

[0065] The obtained 2,2-diisopropylpropionitrile meets the following quality indicators: chromatographic purity of 99.7%, moisture of 150 ppm, phosphorus residue of 5 ppm as P, color of 5, acid value of 0.03 mgKOH / g, total halogen of less than 5 ppm as Cl. Among them, the moisture control to 150 ppm is taken as the end point criterion, and the color is controlled by external circulation cooling and stepwise feeding.

[0066] Features of Example 1: This example adopts a medium parameter configuration strategy, all process parameters are selected in the range of 40-60% of the specified range, which ensures the stability and reproducibility of the process. This scheme realizes a good balance between solubility and azeotropic efficiency through a composite solvent system (ethyl acetate: n-heptane = 50:50), and the medium ratio of solid dehydrating agent dosage (12.5%) and 3Å molecular sieve dosage (7.5%) ensures the unity of dehydration efficiency and economy. The reaction conditions of medium temperature (82.5℃) and medium time (75 minutes) can ensure sufficient conversion and avoid the occurrence of side reactions. The product quality indicators are excellent, the chromatographic purity reaches 99.7%, and all impurity indicators are significantly lower than the control limit. This example is suitable for large-scale production scenarios that require stable batch quality and pursue process robustness, especially suitable as a standard process for industrial production, which can ensure the consistency of quality between different batches and the stability of long-term production.

[0067] Example 2

[0068] This example provides a method for synthesizing a cooling agent intermediate 2,2-diisopropylpropionitrile, comprising the following steps:

[0069] S1: Preparation of solid dehydrating agent of urchin-shaped silica supported phosphorus pentoxide

[0070] A1 Carrier pretreatment: Dry the silica at 160℃ for 3 hours to reduce the moisture to 0.15%.

[0071] A2 Precursor impregnation: Prepare a solution of phosphoric acid and non-ionic surfactant polyoxyethylene ether, and deposit it on the silica by equal volume impregnation method, so that the target content of phosphorus pentoxide is 15.5%, and the dosage of polyoxyethylene ether is 0.8% of the mass of silica.

[0072] A3 In-situ conversion: Heat the impregnated material at 310℃ for 1.8 hours under nitrogen atmosphere to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, forming an urchin-shaped radial morphology.

[0073] A4 Granulation and activation: Granulate to 120 mesh and activate at 138℃ under vacuum to make the bulk density of the finished product reach 0.48 g / mL, and the moisture of the finished product is 0.15%.

[0074] S2: Reactant loading

[0075] 2-isopropyl-2,3-dimethylbutyric acid was added to the reactor as the starting material. First, the amide intermediate was prepared: 1.26 equivalents of ammonium acetate and 1.26 equivalents of acetic anhydride were added to the 2-isopropyl-2,3-dimethylbutyric acid, and the reaction was carried out at 56°C for 1.2 hours to obtain the amide intermediate, and the acid value of the obtained amide intermediate was 2.5 mgKOH / g. Then, a composite solvent of ethyl acetate and n-heptane was added, and the volume ratio of ethyl acetate to n-heptane was 42:58.

[0076] S3: Dehydration and reaction step

[0077] The silica-supported phosphorus pentoxide obtained in S1 was added in an amount of 11% of the initial liquid phase mass of the reactor, and the azeotropic dehydration was carried out at 75°C for 66 minutes. Azeotropic water removal equipment with a reflux head was used, and the reflux ratio was controlled at 1.26. During the process, 3A molecular sieves activated by calcination at 310°C for 3.6 hours were used as water removal aids, and the amount of the activated 3A molecular sieves was 6% of the initial liquid phase mass.

[0078] S4: Rectification and adsorption purification

[0079] The solid dehydrating agent, molecular sieves, and insoluble substances were removed by filtration, and then the target fraction was separated by vacuum rectification at a pressure of 12 mbar, with the top pressure being 12 mbar and the kettle temperature being 75°C. The light-end solvent tail was cut off, the total residual solvent was reduced to 200 ppm, and adsorption purification was performed using activated carbon in an amount of 0.18% of the product mass.

[0080] S5: Product release

[0081] The obtained 2,2-diisopropylpropionitrile met the following quality indicators: the chromatographic purity was 99.6%, the water content was 180 ppm, the phosphorus residue was 6 ppm in terms of P, the colority was 6, the acid value was 0.04 mgKOH / g, and the total halogen content was less than 8 ppm in terms of Cl. Among them, the water content was controlled to 180 ppm as the end point criterion, and external circulation cooling and stepwise feeding were used to control the colority.

[0082] Example 2 Features: This example adopts a low-temperature and short-time optimization strategy, with process parameters ranging from 30-45% of the target range, embodying the design concept of energy saving and efficiency improvement. The lower carrier pretreatment temperature (160°C) and heat treatment temperature (310°C) significantly reduce energy consumption, while the shorter drying time (3 hours) and heat treatment time (1.8 hours) improve production efficiency. The mild conditions of the amidation reaction (56°C, 1.2 hours) reduce the generation of side reactions. The dehydration reaction is carried out at a relatively low temperature (75°C), with a lower amount of dehydrating agent (11%) and molecular sieve (6%), ensuring conversion rate while reducing raw material costs. The lower rectification temperature (75°C) and pressure (12 mbar) reduce the risk of product thermal degradation. The relatively high proportion of n-heptane (58%) in the solvent system helps to reduce solvent costs. This example is particularly suitable for production scenarios sensitive to energy consumption and cost, as well as applications requiring mild reaction conditions to reduce the generation of specific by-products, while also meeting the process demands of fast turnover in small and medium-scale production.

[0083] Example 3

[0084] This example provides a method for synthesizing a cooling agent intermediate, 2,2-diisopropylpropionitrile, comprising the following steps:

[0085] S1: Preparation of solid dehydrating agent of sea urchin-shaped silicon dioxide supported phosphorus pentoxide

[0086] A1 Carrier pretreatment: Dry the silicon dioxide at 188°C for 5 hours to reduce the moisture content to 0.10%.

[0087] A2 Precursor impregnation: Prepare a solution of polyphosphoric acid and sugar sucrose, and deposit it on the silicon dioxide using an equal volume impregnation method, with a target content of 18.5% calculated as phosphorus pentoxide, and the sucrose dosage being 1.6% of the mass of the silicon dioxide.

[0088] A3 In-situ conversion: Heat treat the impregnated material at 400°C for 3.2 hours under vacuum to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, forming a sea urchin-shaped radial morphology.

[0089] A4 Granulation and activation: Granulate to 175 mesh and activate at 165°C under vacuum to achieve a bulk density of 0.56 g / mL and a moisture content of 0.10% in the finished product.

[0090] S2: Reactant loading

[0091] Add 2-isopropyl-2,3-dimethylbutyric acid as the raw material and ethyl acetate as the solvent to the reactor.

[0092] S3: Dehydration and reaction steps

[0093] In the presence of diisopropylethylamine, the one-pot method of phosphorus acid anhydride condensing agent and ammonium acetate is used for amidation and dehydration. Specifically, in the presence of 0.8 equivalents of diisopropylethylamine, 1.62 equivalents of 50% mass fraction 1-n-propyl phosphorus acid anhydride T3P solution and 1.41 equivalents of ammonium acetate are used for one-pot reaction to generate the target nitrile at 78°C for 1.2 hours.

[0094] S4: rectification and adsorption refining

[0095] After filtering out insoluble substances, the target fraction is separated by vacuum rectification at a pressure of 17 mbar, the overhead pressure is 17 mbar, the kettle temperature is 87.5°C, the light end solvent tail is cut off, the total residual solvent is reduced to 350 ppm, and adsorption refining is performed using 0.38% of the product mass of activated carbon.

[0096] S5: product release

[0097] The obtained 2,2-diisopropylpropionitrile meets the following quality indicators: chromatographic purity of 99.75%, moisture of 120 ppm, phosphorus residue of 7 ppm as P, color of 4, acid value of 0.02 mgKOH / g, total halogen of less than 3 ppm as Cl, no peroxide detected and detection limit of 5 mg / kg, and acid impurities of less than 5 mg / kg as acetic acid. The moisture control to 120 ppm is used as the end point criterion, and external circulation cooling and stepwise feeding are used to control the color.

[0098] Example 3 features: This example uses a high-temperature long-time deep optimization strategy, the process parameters are biased towards the 55-70% interval of the range, and high purity and excellent quality of the product are pursued. Higher carrier pretreatment temperature (188°C) and longer drying time (5 hours) ensure deep dehydration of the carrier, high-temperature heat treatment (400°C, 3.2 hours) promotes complete formation and uniform distribution of phosphorus pentoxide, and higher phosphorus pentoxide content (18.5%) provides sufficient dehydration activity. The T3P one-pot method starting from acid avoids the separate amidation step, simplifies the process flow, and at the same time achieves excellent purity (99.75%) and extremely low color (4). The single ethyl acetate solvent system simplifies solvent recovery, and higher rectification temperature and pressure (87.5°C, 17 mbar) and higher activated carbon dosage (0.38%) further improve product purity. This example is particularly suitable for high-end application scenarios that require extremely high product purity and appearance quality, such as high-end personal care products, pharmaceutical-grade cooling agents, etc., and is also suitable for production requirements that pursue process simplification and flow integration, as well as special applications with strict restrictions on phosphorus residue and color.

[0099] Example 4

[0100] The present embodiment provides a method for synthesizing a cooling agent intermediate 2,2-diisopropylpropionitrile, comprising the following steps:

[0101] S1: Preparation of solid dehydrating agent of urchin-shaped silica supported phosphorus pentoxide

[0102] A1 Carrier pretreatment: dry the silica at 170°C for 3.5 hours to reduce the moisture content to 0.08%.

[0103] A2 Precursor impregnation: ammonium phosphate ammonium dihydrogen phosphate and non-ionic surfactant polyoxyethylene ether are formulated into a solution, and are deposited on the silica by equal volume impregnation method, so that the target content of phosphorus pentoxide is 19.2%, and the amount of polyoxyethylene ether is 1.85% of the mass of the silica.

[0104] A3 In-situ conversion: heat the impregnated material at 430°C for 2 hours under a nitrogen atmosphere to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, forming an urchin-shaped radial morphology.

[0105] A4 Granulation and activation: granulate to 188 mesh and activate at 155°C under vacuum to achieve a bulk density of 0.60 g / mL and a moisture content of 0.08% in the finished product.

[0106] S2: Reactant loading

[0107] 2-isopropyl-2,3-dimethylbutyric acid is added to the reactor as the raw material. First, an amide intermediate is prepared: 1.44 equivalents of ammonium acetate and 1.44 equivalents of acetic anhydride are added to 2-isopropyl-2,3-dimethylbutyric acid, and the reaction is carried out at 72°C for 1.7 hours to obtain the amide intermediate, and the acid value of the obtained amide intermediate is 1.8 mgKOH / g. Then, a composite solvent of ethyl acetate and n-heptane is added, and the volume ratio of ethyl acetate to n-heptane is 66:34.

[0108] S3: Dehydration and reaction step

[0109] The silica supported phosphorus pentoxide obtained in S1 is added, and the amount is 14.2% of the initial liquid phase mass of the reactor, and the azeotropic reflux is carried out at 88°C for 87 minutes. Azeotropic water removal device with reflux head is used, and the reflux ratio is controlled at 1.44. During the process, 3Å molecular sieves activated by calcination at 340°C for 5.4 hours are used as water removal aids, and the amount is 9.2% of the initial liquid phase mass.

[0110] S4: Rectification and adsorption purification

[0111] The solid dehydrating agent, molecular sieve and insoluble matter were removed by filtration, and then the target fraction was separated by vacuum rectification at a pressure of 18.5 mbar, with the top pressure being 18.5 mbar and the kettle temperature being 90℃, the light-end solvent tail was cut off, the total residual solvent was reduced to 420 ppm, and adsorption refining was performed using activated carbon accounting for 0.46% of the mass of the product.

[0112] S5: Product release

[0113] The obtained 2,2-diisopropylpropionitrile meets the following quality indicators: the chromatographic purity is 99.65%, the moisture is 240 ppm, the phosphorus residual amount is 8 ppm as P, the color is 7, the acid value is 0.04 mgKOH / g, the total halogen is less than 10 ppm as Cl, the peroxide is not detected and the detection limit is 5 mg / kg, and the acidic impurities are less than 8 mg / kg as acetic acid. The moisture is controlled to 240 ppm as the end criterion, and the color is controlled by using external circulation cooling and stepwise feeding.

[0114] Example 4 features: The content of phosphorus pentoxide in this example reaches 19.2%, close to the upper limit of 20% but with a 0.8% margin, and the high-temperature heat treatment (430℃) ensures the high activity of the dehydrating agent. The higher solid dehydrating agent dosage (14.2%) and 3Å molecular sieve dosage (9.2%) and the extended reflux time (87 minutes) ensure sufficient dehydration effect. The increase of ethyl acetate ratio to 66% improves the solubility of the raw materials, and the higher rectification pressure (18.5 mbar) and activated carbon dosage (0.46%) further optimize the product quality. Through careful parameter combination design, the simultaneous taking of absolute extreme values of multiple key parameters is avoided, ensuring the scientificity and operability of the process. The product moisture is controlled at 240 ppm, close to the upper limit of 300 ppm but still with a 20% safety margin, and all quality indicators meet the requirements. This example is particularly suitable for research and development and optimization scenarios that need to verify the extreme parameters of the process, expand the operation window, and still need to ensure product quality under fluctuating raw material quality or limited production conditions, proving the implementability of the process and the controllability of the product quality under near boundary conditions.

[0115] Comparative Example 1: Basically the same as Example 1, the difference is that the content of phosphorus pentoxide supported by silicon dioxide is 12%, and the dosages and preparation conditions of other components remain unchanged.

[0116] Comparative Example 2: Basically the same as Example 1, the difference is that the content of phosphorus pentoxide supported by silicon dioxide is 22%, and the dosages and preparation conditions of other components remain unchanged.

[0117] Comparative Example 3: Basically the same as Example 1, the difference is that the carrier pretreatment temperature is 130℃, and the dosages and preparation conditions of other components remain unchanged.

[0118] Comparative Example 4: Essentially the same as Example 1, except that the carrier pre-treatment temperature was 220°C, and the amounts of the other components and the preparation conditions were unchanged.

[0119] Comparative Example 5: Essentially the same as Example 1, except that the heat treatment temperature was 220°C, and the amounts of the other components and the preparation conditions were unchanged.

[0120] Comparative Example 6: Essentially the same as Example 1, except that the heat treatment temperature was 480°C, and the amounts of the other components and the preparation conditions were unchanged.

[0121] Comparative Example 7: Essentially the same as Example 1, except that the amount of solid dehydrating agent was 8%, and the amounts of the other components and the preparation conditions were unchanged.

[0122] Comparative Example 8: Essentially the same as Example 1, except that the amount of solid dehydrating agent was 17%, and the amounts of the other components and the preparation conditions were unchanged.

[0123] Comparative Example 9: Essentially the same as Example 1, except that the reflux temperature was 60°C, and the amounts of the other components and the preparation conditions were unchanged.

[0124] Comparative Example 10: Essentially the same as Example 1, except that the reflux temperature was 105°C, and the amounts of the other components and the preparation conditions were unchanged.

[0125] Comparative Example 11: Essentially the same as Example 1, except that the reflux time was 50 minutes, and the amounts of the other components and the preparation conditions were unchanged.

[0126] Comparative Example 12: Essentially the same as Example 1, except that the reflux time was 100 minutes, and the amounts of the other components and the preparation conditions were unchanged.

[0127] Comparative Example 13: Essentially the same as Example 1, except that a single n-heptane was used as the solvent, and the amounts of the other components and the preparation conditions were unchanged.

[0128] Characterization and performance testing:

[0129] Chromatographic purity determination: The test object is 2,2-diisopropylpropionitrile product, and the test purpose is to evaluate the chemical purity of the product. The test principle is based on the area normalization method for quantitative analysis of main components and impurities after gas chromatographic separation. The experimental method uses a gas chromatograph (equipped with an FID detector), the chromatographic column is a DB-WAX capillary column (30 m x 0.32 mm x 0.5 μm), the carrier gas is nitrogen, the injection port temperature is 250°C, the detector temperature is 260°C, the column temperature uses programmed temperature (initial 60°C for 5 minutes, increased to 220°C at 10°C / min for 10 minutes), split ratio 20:1, injection volume 0.2 μL. The standard is based on reference GB / T 11538 or similar gas chromatographic analysis standards for organic compounds. Key parameters include column temperature program, carrier gas flow rate 1.0 mL / min, sample concentration about 1% ethyl acetate solution. Data processing uses area normalization method to calculate the main peak area percentage as the chromatographic purity, requires testing 3 times and taking the average value, relative standard deviation RSD≤0.5%.

[0130] Moisture content determination: The test object is 2,2-diisopropylpropionitrile product, and the test purpose is to control the product moisture to not higher than 300 ppm as the end point criterion. The test principle is based on Karl Fischer coulometric titration method, using the stoichiometric reaction of iodine and water to generate iodine by electrolysis and determine the water content by measuring the consumed electric quantity. The experimental method uses Karl Fischer moisture meter (coulometric method), the electrolyte is Karl Fischer coulometric reagent, the sample is weighed 0.5-2.0 g (adjust according to the moisture level), quickly inject into a sealed titration cell and start titration, the end point criterion is the potential drift rate ≤5 μg / min. The standard is based on GB / T6283 or ISO 760. Key parameters include environmental humidity control ≤30% RH, sample injection is sealed immediately, pre-titration of the titration cell to blank ≤10 μg / min, instrument temperature 25±2°C. Data processing uses instrument automatic calculation of moisture mass fraction (ppm), tests 3 times and takes the average value, relative standard deviation RSD≤10%, when the moisture is ≤300 ppm, it is considered qualified.

[0131] Colorimetry: Test object is 2,2-diisopropylpropionitrile product, test purpose is to evaluate the appearance quality of the product, to ensure that the color is not higher than 10 APHA. The test principle is based on the comparison of the sample's absorption of light at a specific wavelength with the platinum-cobalt standard color scale. The experimental method uses platinum-cobalt colorimetry, using a spectrophotometer or visual colorimetric tube, the sample is compared with the platinum-cobalt standard color solution (APHA color scale standard) in a 50mm cuvette under natural light or standard light source D65, or the absorbance at 430nm is determined by spectrophotometry and converted to APHA value. The standard is based on GB / T 3143 or ASTM D1209. Key parameters include cuvette optical path 50mm, test temperature 25±5℃, sample needs to be clear and free of suspended matter, standard light source or north-facing natural light. Data processing uses visual method to compare with standard color scale and record color value, spectrophotometry converts through formula APHA=absorbance×coefficient, test 3 times and take average value, color ≤10 APHA is qualified.

[0132] Phosphorus residue determination: Test object is 2,2-diisopropylpropionitrile product, test purpose is to control the phosphorus residue to not more than 10 ppm as P, to ensure product safety. The test principle is based on the conversion of phosphorus elements in the sample into orthophosphate after digestion, and the reaction with chromogenic agent to generate phosphomolybdate blue complex, and quantitative determination by spectrophotometry. The experimental method includes sample digestion (2-5g sample is weighed into a digestion tube, 5mL of nitric acid-perchloric acid mixed acid is added, and the solution is digested in a digestion instrument at 180℃ until it is clear and colorless, and then diluted to 50mL after cooling), color development (2mL of digestion solution is removed, and ammonium molybdate-ascorbic acid color reagent is added, and boiled in a water bath for 10 minutes), spectrophotometric determination (absorbance is determined at 700nm wavelength, and phosphorus content is calculated by comparison with standard curve). The standard is based on GB 5009.87 or ICP-OES method. Key parameters include digestion temperature 180℃, color development temperature 100℃, wavelength 700nm. Data processing uses standard curve method to convert phosphorus concentration, test 3 times and take average value, detection limit ≤1ppm.

[0133] Total halogen determination: The test object is 2,2-diisopropylpropionitrile product, and the test purpose is to control the total halogen not higher than 20 ppm in terms of Cl to prevent halogen residue from affecting downstream applications. The test principle is based on the conversion of halogen into halide ions after the sample is burned in an oxygen bomb, and the quantification is performed by ion chromatography or potentiometric titration. The experimental method uses oxygen bomb combustion-ion chromatography, and the sample 0.5-1.0 g is oxygenated to 3 MPa in an oxygen bomb and ignited to burn. After burning, the halides are absorbed by an alkaline absorption solution, and the absorption solution is analyzed by an ion chromatograph (equipped with a conductivity detector and an anion separation column) for Cl⁻, Br⁻ and other halide ion concentrations, and the total halogen content in terms of Cl. The standard is based on ASTM D808. Key parameters include oxygen bomb pressure 3 MPa, absorption solution 0.01 M NaOH solution 10 mL, ion chromatography eluent carbonate buffer, flow rate 1.0 mL / min. Data processing uses standard curve method to calculate halogen concentration and convert to total halogen content (ppm) in the sample, test 3 times and take the average value, detection limit ≤2 ppm.

[0134] Acid value determination: The test object is 2,2-diisopropylpropionitrile product and amide intermediate, and the test purpose is to evaluate the acid impurity content of the product and intermediate, to ensure that the acid value of the amide intermediate is not higher than 5 mgKOH / g, and the acid value of the final product is not higher than 0.05 mgKOH / g. The test principle is based on the neutralization titration reaction of acidic substances in the sample with standard alkali solution. The experimental method is to weigh 2-10 g of sample (adjusted according to the expected acid value) into a conical flask, dissolve in 50 mL of neutral ethanol-ether mixed solvent (1:1), add 2-3 drops of phenolphthalein indicator, and titrate with potassium hydroxide standard titration solution (0.01 mol / L or 0.1 mol / L, selected according to the acid value) until the solution is reddish and does not fade within 30 seconds. The standard is based on ISO 660. Key parameters include titration temperature 25±5℃, solvent needs to be freshly prepared and neutralized to a reddish color of phenolphthalein, and the concentration of potassium hydroxide solution needs to be accurately calibrated. Data processing uses the formula acid value (mgKOH / g) = (V×c×56.1) / m, where V is the volume of consumed alkali (mL), c is the concentration of alkali (mol / L), and m is the mass of the sample (g). Test 3 times and take the average value.

[0135] Figure 1For the influence of the content of phosphorus pentoxide on the chromatographic purity and moisture of the invention, the fixed parameters are carrier pretreatment temperature 175℃, pretreatment time 4 hours, morphology control agent glycerol dosage 1.2%, heat treatment temperature 350℃, time 2.5 hours, whole grain mesh 150, activation temperature 150℃, amidation temperature 65℃, time 1.5 hours, ethyl acetate to n-heptane volume ratio 50 to 50, solid dehydrating agent dosage 12.5%, 3Å molecular sieve dosage 7.5%, reflux temperature 82.5℃, time 75 minutes, reflux ratio 1.35, rectification tower top pressure 15 mbar, rectification kettle temperature 82.5℃, activated carbon dosage 0.3%, and the change parameter is the content of phosphorus pentoxide from 12% to 22%. When the content of phosphorus pentoxide is 16 to 18%, the chromatographic purity reaches 99.6 to 99.7% and the moisture is controlled at 150 to 170 ppm, achieving the optimal synergistic effect, when the content is less than 14%, the active sites of the dehydrating agent are insufficient, causing the moisture residue to rise to more than 280 ppm and the purity to decrease to 99.3%, when the content is higher than 20%, excessive phosphates cause side reactions, causing the moisture to rise to 300 ppm and the purity to decrease to 99.2%, proving that a moderate content can ensure dehydration efficiency and product purity.

[0136] Figure 2 For the influence of the heat treatment temperature on the chromatographic purity and phosphorus residue of the invention, the fixed parameters are carrier pretreatment temperature 175℃, pretreatment time 4 hours, content of phosphorus pentoxide 17%, morphology control agent glycerol dosage 1.2%, heat treatment time 2.5 hours, whole grain mesh 150, activation temperature 150℃, amidation temperature 65℃, time 1.5 hours, ethyl acetate to n-heptane volume ratio 50 to 50, solid dehydrating agent dosage 12.5%, 3Å molecular sieve dosage 7.5%, reflux temperature 82.5℃, time 75 minutes, reflux ratio 1.35, rectification tower top pressure 15 mbar, rectification kettle temperature 82.5℃, activated carbon dosage 0.3%, and the change parameter is the heat treatment temperature from 220℃ to 480℃. When the heat treatment temperature is 320 to 380℃, the chromatographic purity is maintained at 99.4 to 99.7% and the phosphorus residue is reduced to 5 to 6 ppm, showing the best dehydration performance and low impurity level, when the temperature is lower than 250℃, the phosphorus pentoxide is not fully generated, causing the phosphorus residue to be as high as 12 ppm and the dehydration efficiency to be insufficient, causing the purity to decrease to 98.8%, when the temperature is higher than 450℃, the carrier pore sintering and phosphate decomposition are intensified, causing the phosphorus residue to rise to 10 ppm and the side reactions to increase, causing the purity to decrease to 99.0%, indicating that moderate temperature heat treatment is the key to balancing the activity of the dehydrating agent and the stability of the carrier structure.

[0137] Figure 3For the influence of the solid dehydrating agent dosage on the chromatographic purity and moisture of the present application, the fixed parameters are carrier pretreatment temperature 175°C, pretreatment time 4 hours, phosphorus pentoxide content 17%, morphology control agent glycerol dosage 1.2%, heat treatment temperature 350°C, time 2.5 hours, whole grain mesh 150, activation temperature 150°C, amidation temperature 65°C, time 1.5 hours, ethyl acetate to n-heptane volume ratio 50 to 50, 3Å molecular sieve dosage 7.5%, reflux temperature 82.5°C, time 75 minutes, reflux ratio 1.35, rectification column top pressure 15 mbar, rectification kettle temperature 82.5°C, activated carbon dosage 0.3%, and the change parameter is the solid dehydrating agent dosage from 8% to 17%. When the solid dehydrating agent dosage is 12 to 13.5%, the chromatographic purity reaches 99.6 to 99.7% and the moisture is controlled at 150 to 170 ppm, realizing the optimal balance of dehydration efficiency and product quality, when the dosage is less than 10%, the dehydration capacity is insufficient, resulting in moisture residue as high as 320 ppm and purity reduction to 99.2%, and when the dosage is higher than 15%, although the dehydration is sufficient, the risk of phosphorus residue increases and the economy decreases, resulting in no significant improvement in purity but rather a decrease to 99.3% due to impurity accumulation, verifying that moderate dosage is the basis for realizing efficient dehydration and low cost.

[0138] Figure 4 For the influence of the reflux time on the chromatographic purity and moisture of the present application, the fixed parameters are carrier pretreatment temperature 175°C, pretreatment time 4 hours, phosphorus pentoxide content 17%, morphology control agent glycerol dosage 1.2%, heat treatment temperature 350°C, time 2.5 hours, whole grain mesh 150, activation temperature 150°C, amidation temperature 65°C, time 1.5 hours, ethyl acetate to n-heptane volume ratio 50 to 50, solid dehydrating agent dosage 12.5%, 3Å molecular sieve dosage 7.5%, reflux temperature 82.5°C, reflux ratio 1.35, rectification column top pressure 15 mbar, rectification kettle temperature 82.5°C, activated carbon dosage 0.3%, and the change parameter is the reflux time from 50 minutes to 100 minutes. When the reflux time is 70 to 80 minutes, the chromatographic purity remains 99.5 to 99.7% and the moisture is maintained at 150 to 180 ppm, exhibiting a synergistic effect of complete conversion and sufficient dehydration, when the time is less than 60 minutes, the reaction is incomplete, resulting in moisture residue as high as 340 ppm and purity reduction to 99.0%, and when the time is higher than 90 minutes, excessive reflux causes side reactions and color degradation, making the moisture rise to 260 ppm and the purity decrease to 99.2%, proving that precise time control is the core of the process to ensure high conversion rate and low impurity accumulation.

[0139] Figure 5XRD patterns of the solid dehydrating agent of Example 1 and the solid dehydrating agent after azeotrope. Measurement conditions: Cu Ka (λ = 1.5406 Å), 2θ = 5-80°, step 0.02°, relative intensity a.u.; fixed parameters: carrier silica dried at 175°C for 4 h (final moisture 0.12%), glycerol dosage 1.2% of the mass of silica, in-situ conversion fixation after equal-volume impregnation and heat treatment at 350°C under nitrogen for 2.5 h, whole particle 150 mesh and activated under vacuum at 150°C; after use, the sample was taken in ethyl acetate: n-heptane = 50:50 composite solvent, the dehydrating agent dosage was 12.5% of the mass of the initial liquid phase, the reflux ratio was 1.35, and the sample was taken after azeotrope at 82.5°C for 75 min. Variable parameters: microstructure difference of the P-O-Si environment before and after use. The spectrum results show that the fresh sample has a broad diffuse peak at 2θ ≈ 22° and a secondary diffuse peak at about 37°, representing amorphous dominance; the used sample has a slight shift of the main diffuse peak to ≈ 23° and a weak shoulder peak at ≈ 31°, but the overall is still amorphous scattering, and no significant crystallization peak appears. Conclusion: P2O5 / SiO2 formed by moderate heat treatment and loading is in a stable amorphous state, and only limited structural rearrangement occurs after azeotrope at 82.5°C for 75 min without crystallization, indicating that this process window can maintain the active site distribution and pore openness under water-carrying reaction conditions, thereby providing structural support for process stability and batch consistency.

[0140] Figure 6 The UV-Vis absorption spectrum superimposed graph (200-800 nm) of the present application, the fixed parameters are: cuvette optical path 1 cm, scanning step 5 nm, baseline corrected with solvent blank, detection bandwidth 2 nm, consistent sample volume fraction, and spectrophotometer original CSV format export, variable parameters are: activated carbon dosage 0.1%, 0.3%, 0.5%, rectification kettle temperature 70°C and 95°C, and phosphorus residual level 5, 15, 30 ppm; at the same time, the sample of the example (vacuum rectification 15 mbar, kettle temperature 82.5°C, activated carbon 0.3%, moisture 150 ppm, P 5 ppm) is included. The results show that the absorbance A430 of the sample of the example at 430 nm is approximately 0.0199 (<0.02), corresponding to APHA ≈ 9.95; the sample at 95°C has a significant rise in the 500-600 nm interval, indicating that the thermal decomposition chromophore leads to enhanced absorption in the visible region; the sample with P ≥ 15 ppm has an upward shift in the background absorption of the whole waveband, proving that phosphorus-containing impurities are an important source of color increase; the visible chromophore peak near 430 nm is reduced as a whole with the increase of activated carbon dosage, and the improvement of 0.5% compared with 0.3% is limited. It can be seen that low-temperature vacuum rectification combined with appropriate activated carbon adsorption refining and control of phosphorus residues can achieve low A430 and good appearance at the same time.

[0141] Figure 7UV-Vis absorption spectrum in the region of 200-800 nm for Example 1 AC 0.3%, P 5 ppm, 82.5 °C, H2O 150 ppm, fixed parameters are cuvette optical path 1 cm, white background baseline, sampling step 5 nm, threshold A430≤0.02, colorimetric conversion coefficient k=500; variable parameters are combined conditions AC 0.3%, P 5 ppm, kettle temperature 82.5 °C, moisture 150 ppm. Conclusion: A430 is lower than 0.02 and there is no obvious tail absorption in 500-600 nm, indicating that the color precursor is fully removed and the thermal side reaction is controlled, and this combination achieves low color and good stability.

[0142] Figure 8 UV-Vis absorption spectrum in the region of 200-800 nm for activated carbon 0.1% P 5 ppm, 82.5 °C, fixed parameters are the same as Figure 1 ; variable parameter is the activated carbon dosage reduced to 0.1%. Conclusion: A430 rises to about 0.03 and there is a light tail absorption in 500-600 nm, showing that the adsorption of color bases and conjugate by-products is insufficient, and the appearance color is worse than Example 1.

[0143] Figure 9 UV-Vis absorption spectrum in the region of 200-800 nm for activated carbon 0.5% P 5 ppm, 82.5 °C, fixed parameters are the same as Figure 1 ; variable parameter is the activated carbon dosage increased to 0.5%. Conclusion: The overall spectrum baseline is flatter, A430≤0.01, and there is no tail absorption in 500-600 nm, indicating that the color is further reduced; considering the processing and filtering cost, the benefit is marginally reduced compared to Example 1, but the optical index is optimal.

[0144] Figure 10 UV-Vis absorption spectrum in the region of 200-800 nm for kettle temperature 70 °C P 5 ppm, AC 0.3%, fixed parameters are the same as Figure 1 ; variable parameter is the kettle temperature reduced to 70 °C. Conclusion: A430 is slightly higher than Example 1 and the absorption in 280-320 nm is enhanced, indicating that the main reaction is insufficient and intermediates are left, and the visible color and near-ultraviolet impurity signals are rising.

[0145] Figure 11 UV-Vis absorption spectrum in the region of 200-800 nm for kettle temperature 95 °C P 5 ppm, AC 0.3%, fixed parameters are the same as Figure 1 ; variable parameter is the kettle temperature increased to 95 °C. Conclusion: A430 and the tail absorption in 500-600 nm rise synchronously, and a slight brown color appears, indicating that high temperature promotes condensation and oxidation side reactions, and the color control is deteriorated.

[0146] Figure 11 The morphology of the silica-supported phosphorus pentoxide solid dehydrating agent prepared in Example 1 of the present application can be observed by scanning electron microscopy. The silica carrier presents regular spherical shape and uniform particle size distribution. The active component of phosphorus pentoxide on the surface of the carrier presents a uniform dispersion of nanoparticle-like covering layer without obvious agglomeration. The addition of the morphology control agent glycerol makes the surface of the carrier present a moderate rough texture, increasing the specific surface area and the exposure degree of active sites. The dual-temperature control process of 175°C pretreatment combined with 350°C heat treatment ensures the firm anchoring and uniform dispersion of phosphorus pentoxide on the surface of the carrier. This micro-morphology structure provides sufficient dehydration active surface and particle size basis for easy separation and recovery for the solid dehydrating agent. The micro-macro complete verification chain of 99.7% chromatographic purity and 150 ppm low moisture residue in Example 1 verifies the precise regulation of the carrier modification and heat treatment process on the microstructure of the high-efficiency dehydrating agent.

[0147] As can be seen from the performance of Examples and Comparative Examples in Table 1, the four Examples are significantly superior to all Comparative Examples in key quality indicators such as chromatographic purity, moisture control, color, phosphorus halide residue, and acid value, fully verifying the superiority of the technical solution of the present application. Comparative Example 1 and Comparative Example 2 show that the deviation of the content of phosphorus pentoxide from the optimal range (less than 14% or more than 20%) will lead to decreased dehydration efficiency or increased side reactions, manifested as increased moisture residue and deteriorated color. Comparative Example 3 and Comparative Example 4 show that when the pretreatment temperature of the carrier is too low (130°C), the high residual moisture of the carrier affects the activity of the dehydrating agent, and when the pretreatment temperature is too high (220°C), the sintering of the carrier pores reduces the specific surface area, which is not conducive to moisture control and purity improvement. Comparative Example 5 and Comparative Example 6 verify the importance of heat treatment temperature. Low temperature (220°C) leads to insufficient generation of phosphorus pentoxide, and high temperature (480°C) leads to destruction of the carrier structure and side reactions, resulting in increased phosphorus halide residue. Comparative Example 7 and Comparative Example 8 show that insufficient dosage (8%) of the solid dehydrating agent leads to incomplete dehydration, and excessive dosage (17%) increases the risk of phosphorus residue without obvious dehydration benefit. Comparative Example 9 to Comparative Example 12 show that deviation of the reflux temperature and time from the optimal range will lead to incomplete conversion or intensified side reactions, manifested as overall deterioration of the indicators of moisture, color, and impurities. Comparative Example 13 uses a single n-heptane solvent, which leads to poor solubility of the raw materials and low azeotropic efficiency, resulting in significant deterioration of all quality indicators, proving the necessity of a composite solvent system or a single ethyl acetate. The comprehensive data show that the present application successfully solves the multiple contradictions of high purity, ultra-low moisture, low color, and low phosphorus halide residue by accurately controlling the composition of the dehydrating agent, the preparation conditions, the solvent system, and the process parameters, and realizes the high-quality synthesis of the coolant intermediate 2,2-diisopropylpropionitrile.

[0148] Performance summary of Examples and Comparative Examples in Table 1

[0149] Sample No. Chromatographic purity (%) Moisture (ppm) Colour (APHA) Phosphorus residue (ppm as P) Total halogen (ppm as CI) Acid value (mg KOH / g) Example 1 99.7±0.1 150±8 5±1 5±1 <5 0.03±0.01 Example 2 99.6±0.1 180±10 6±1 6±1 8±2 0.04±0.01 Example 3 99.75±0.08 120±6 4±1 7±1 <3 0.02±0.01 Example 4 99.65±0.12 240±12 7±1 8±1 10±2 0.04±0.01 Comparative Example 1 98.8±0.2 420±25 15±2 12±2 18±3 0.12±0.02 Comparative Example 2 98.5±0.3 380±30 18±3 15±2 22±4 0.15±0.03 Comparative Example 3 98.2±0.3 550±40 22±3 18±3 25±5 0.20±0.03 Comparative Example 4 98.0±0.4 480±35 25±4 20±3 28±5 0.18±0.03 Comparative Example 5 97.5±0.4 650±50 28±4 25±4 35±6 0.25±0.04 Comparative Example 6 97.2±0.5 720±60 32±5 30±5 40±7 0.30±0.05 Comparative Example 7 98.3±0.3 580±45 20±3 16±3 24±4 0.16±0.03 Comparative Example 8 98.1±0.3 520±40 24±3 22±3 30±5 0.22±0.03 Comparative Example 9 97.8±0.4 680±50 30±4 28±4 38±6 0.28±0.04 Comparative Example 10 97.0±0.5 780±70 35±5 32±5 45±8 0.35±0.05 Comparative Example 11 98.0±0.4 620±50 26±4 24±4 32±5 0.24±0.04 Comparative Example 12 97.5±0.5 700±60 33±5 29±5 42±7 0.32±0.05 Comparative Example 13 96.5±0.6 850±80 40±6 35±6 50±10 0.40±0.06

[0150] It should be pointed out finally that the above embodiments are only used to illustrate the technical solutions of the present application but not to limit it. Although the present application has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformation made under the concept of the present application and by using the content of the present application specification and drawings should be covered within the protection scope of the claims of the present application.

Claims

1. A method for the synthesis of a cooling agent intermediate, 2,2-diisopropylpropionitrile, characterized in that, Comprising: S1: Preparation of urchin-like silica supported phosphorus pentoxide solid dehydrating agent; at least one of phosphoric acid, polyphosphoric acid and ammonium phosphate is co-deposited with a halogen-free morphology control agent on pre-dried silica by equal volume impregnation method, after drying, heat treatment at 250-450℃ under inert atmosphere or vacuum to generate phosphorus pentoxide, to prepare a solid dehydrating agent with phosphorus pentoxide content of 14-20%, bulk density not less than 0.45 g / mL, moisture not higher than 0.2% and urchin-like radial morphology; S2: Reactant loading, 2-isopropyl-2,3-dimethylbutyric acid or its amide intermediate is added as raw material, and a complex solvent of ethyl acetate and n-heptane is added, or ethyl acetate is added alone as solvent; when a complex solvent is used, the volume ratio of ethyl acetate to n-heptane is 30:70 to 70:30; S3: Dehydration and reaction step, according to the type of raw material, the implementation is selected to realize the conversion of acid or amide intermediate to target nitrile; S4: Rectification and adsorption refining, when the system contains solid dehydrating agent or molecular sieve, the solid dehydrating agent, molecular sieve and insoluble matter are removed by filtration, then the target fraction is separated by vacuum rectification under a pressure of 10-20 mbar, the tower top pressure is 10-20 mbar, the kettle temperature is 70-95℃, the light end solvent tail is cut off, the total residual solvent is not higher than 500 ppm, and the activated carbon accounts for 0.1-0.5% of the mass of the product for adsorption refining; S5: Product release, the obtained 2,2-diisopropylpropionitrile meets the following quality indicators: chromatographic purity not less than 99.5%, moisture not higher than 300 ppm, phosphorus residue not higher than 10 ppm in terms of P, and color not higher than 10; wherein the moisture control to not higher than 300 ppm is used as the end point criterion, and the color is controlled by using external circulation cooling and stepwise feeding.

2. The method of claim 1, wherein, The urchin-like silica supported phosphorus pentoxide solid dehydrating agent is prepared by a precursor conversion method, comprising: A1 Carrier pretreatment: drying the silica at 150-200℃ for 2-6 hours to make the moisture not higher than 0.2%; A2 Precursor impregnation: preparing a solution of phosphorus-containing precursor and halogen-free morphology control agent, depositing on the silica by equal volume impregnation method, the target content is 14-20% in terms of phosphorus pentoxide, the dosage of the morphology control agent is 0.5-2.0% of the mass of the silica; the halogen-free morphology control agent is a non-ionic surfactant, a polyol or a sugar; the phosphorus-containing precursor is selected from at least one of phosphoric acid, polyphosphoric acid and ammonium phosphate; A3 In-situ conversion: heat treatment of the impregnated material at 250-450℃ for 1-4 hours under inert atmosphere or vacuum to generate phosphorus pentoxide and fix it on the surface and pores of the carrier, forming urchin-like radial morphology; A4 Granulation and activation: granulation to 100-200 mesh and vacuum activation at 120-180℃ to make the bulk density of the finished product not less than 0.45 g / mL, and the moisture of the finished product not higher than 0.2%.

3. The method of claim 1, wherein, The synthesis of the amide intermediate comprises: adding 1.2-1.5 equivalents of ammonium acetate and 1.2-1.5 equivalents of acetic anhydride to 2-isopropyl-2,3-dimethylbutyric acid, and reacting at 50-80°C for 1-2 hours to obtain the amide intermediate, and the acid value of the obtained amide intermediate is not higher than 5 mgKOH / g.

4. The method of claim 1, wherein, The dehydration and reaction steps in step S3 are selected according to the type of raw material as follows: a) When the raw material is an amide intermediate, 10-15% of the initial liquid phase mass of the reactor is added to the silica-supported phosphorus pentoxide obtained in S1, and refluxed at 70-95°C for 60-90 minutes; when a reflux head or azeotropic water removal device is used, the reflux ratio is controlled at 1.2-1.5; 3Å molecular sieves activated by calcining at 300-350°C for 3-6 hours can be used as water removal aids, and the amount is 5-10% of the initial liquid phase mass; b) When the raw material is an acid, a one-pot method of amide and dehydration is used with phosphoric anhydride condensing agent and ammonium acetate in the presence of an organic base, or tricyanogen chloride is used for dehydration and subsequent halogen removal.

5. The method of claim 1, wherein, The amount of 3Å molecular sieves is 5-10% of the initial liquid phase mass of the reactor.

6. The method of claim 1, wherein, The quality index in S5 further comprises: the acid value is not higher than 0.05 mgKOH / g, the total halogen is not higher than 20 ppm calculated as Cl, the peroxide is not detected, and the detection limit is not higher than 5 mg / kg, and the acidic impurities are not higher than 10 mg / kg calculated as acetic acid.

7. The method of claim 1, wherein, The dehydration in S3 in the presence of an organic base using a one-pot method of phosphoric anhydride condensing agent, or using tricyanogen chloride for dehydration and subsequent halogen removal, is specifically any of the following schemes: Scheme A: In the presence of 0.5-1.0 equivalents of an organic base, which is diisopropylethylamine or triethylamine, a one-pot reaction is carried out with 1.2-1.8 equivalents of 1-n-propyl phosphoric anhydride T3P solution with a mass fraction of 50% and 1.2-1.5 equivalents of ammonium acetate, to generate the target nitrile at 50-90°C for 0.5-1.5 hours, and then enter S4, and the phosphorus residue in the obtained product is not higher than 10 ppm calculated as P; Scheme B: In the presence of 1.5-2.0 equivalents of an organic base, tricyanogen chloride is added dropwise in ethyl acetate solvent at 0-5°C, and then dehydration is completed at 50-70°C for 40-80 minutes; subsequent halogen removal is carried out by combining alkali washing, water washing and anion exchange resin to ensure that the total halogen is not higher than 20 ppm calculated as Cl.

8. A cooling agent intermediate 2,2-diisopropylpropionitrile produced by the method of any one of claims 1 to 7, characterized by, The following quality indexes are met: water content is not higher than 300 ppm; color is not higher than 10; acid value is not higher than 0.05 mgKOH / g; phosphorus residue is not higher than 10 ppm calculated as P; total halogen is not higher than 20 ppm calculated as Cl; and chromatographic purity is not less than 99.5%.

9. The cooling agent intermediate 2,2-diisopropylpropionitrile according to claim 8, characterized in that, After vacuum rectification under a pressure of 10-20 mbar and adsorption purification with activated carbon accounting for 0.1-0.5% of the mass of the product, the total residual solvent is not higher than 500 ppm, wherein the total amount of ethyl acetate, n-heptane and their possible ester exchange by-products is calculated, the peroxide is not detected, and the acidic impurities are not higher than 10 mg / kg calculated as acetic acid.

10. Use of the coolant intermediate 2,2-diisopropylpropionitrile prepared according to the process of any one of claims 1 to 7 or of the coolant intermediate 2,2-diisopropylpropionitrile according to claim 8 or 9 for the synthesis of the coolant N,2,3-trimethyl-2-isopropylbutanamide, wherein the 2,2-diisopropylpropionitrile is hydrolyzed to 2-isopropyl-2,3-dimethylbutanoic acid, which is then amidated to the coolant, the source of ammonia for the amidation is selected from at least one of methylamine, ethylamine and ammonium acetate, and the activation of the 2-isopropyl-2,3-dimethylbutanoic acid is performed using acetic anhydride or 1 -n-propylphosphonic anhydride T3P.

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