A method for continuously preparing vitamin E succinate polyethylene glycol ester

Abstract

This invention provides a continuous method for preparing vitamin E succinate polyethylene glycol ester (TPGS). It uses a strongly acidic cation exchange resin (such as the Amberlyst series) or a perfluorosulfonic acid resin (such as the Nafion series) as a heterogeneous catalyst, which is packed in a fixed bed to catalyze the esterification reaction between vitamin E succinate and polyethylene glycol. This method achieves precise proportioning of reactants, instantaneous mixing, isothermal reaction, and online dehydration, reducing the reaction time from several hours required by existing batch methods to tens of minutes. It allows for long-term stable use, requires no complex post-processing, and produces products with high yield, good purity, and light color. The preparation method of this invention solves the problems of difficult catalyst recovery, excessive waste, low efficiency, and unstable product quality in existing methods, making it particularly suitable for large-scale, continuous, and green production of TPGS.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical excipient synthesis technology, specifically relating to a method for the continuous preparation of vitamin E succinate polyethylene glycol ester (TPGS). Background Technology

[0002] Vitamin E succinate polyethylene glycol ester (TPGS) is a very important pharmaceutical excipient. Its current synthesis method is mainly a batch reactor reaction, using homogeneous catalysts such as concentrated sulfuric acid and p-toluenesulfonic acid. This method has problems such as equipment corrosion, large amounts of wastewater generated during post-processing, inability to recover the catalyst, long reaction time, and easy discoloration of the product.

[0003] Although existing studies have attempted to improve TPGS production methods using heterogeneous catalysts or solvent-free processes, most remain limited to batch operations. The reproducibility, cost, and scalability of these methods pose potential obstacles to industrialization, thus restricting further optimization of TPGS production methods. Therefore, developing a TPGS synthesis method based on readily available and stable heterogeneous catalysts, combined with a continuous flow process, is of great significance for promoting the green manufacturing and quality improvement of this product. Summary of the Invention

[0004] The purpose of this invention is to provide a continuous method for preparing vitamin E succinate polyethylene glycol ester (TPGS) based on existing technology. It adopts a clever combination of "commercial solid acid catalyst and continuous flow process", which greatly simplifies and greens the preparation method while ensuring excellent catalytic performance. It is easy to operate, cost-controllable, and easy to industrialize, with very significant advantages.

[0005] The technical solution of the present invention is as follows: A method for continuous preparation of vitamin E succinate polyethylene glycol ester includes the following steps: (1) A commercial solid acid catalyst is loaded into a fixed-bed reactor, and the reaction temperature is controlled at 120-150℃ and the reaction pressure is 0.5-1.5 MPa; (2) The material containing vitamin E succinate and polyethylene glycol 1000 is injected into the fixed bed reactor above, so that the residence time of the material in the fixed bed reactor is 10-60 minutes, and the target product is obtained.

[0006] The present invention provides a method for the continuous preparation of vitamin E succinate polyethylene glycol ester, which is carried out in a continuous flow reactor. A material comprising vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) is used. The material can be a mixed solution consisting of vitamin E succinate (VES), polyethylene glycol 1000 (PEG1000), and a solvent (e.g., toluene), or vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) can be melted separately and then mixed in a specific ratio to obtain a mixed melt. This mixture is then pumped through a precision pump, mixed in a mixer, and injected into a fixed-bed reactor packed with a commercial solid acid catalyst. The reaction temperature is controlled at 120-150°C, the reaction pressure at 0.5-1.5 MPa, and the material is held for 10-60 minutes to complete the esterification reaction, yielding the target product, vitamin E succinate polyethylene glycol ester (TPGS). The entire reaction apparatus includes an online dehydration unit (e.g., a molecular sieve packed column or a pervaporation membrane dehydrator). The reaction liquid enters the online dehydration unit to continuously remove the water generated in real time, thereby shifting the reaction equilibrium to the forward direction. The reaction products flow directly out from the outlet of the fixed-bed reactor. If a solvent is present, it can be removed by simple distillation to obtain high-purity vitamin E succinate polyethylene glycol ester (TPGS), in which the content of the byproduct polyethylene glycol diester is less than 1.0%. A commercial solid acid catalyst is packed in the fixed-bed reactor, allowing for long-term continuous operation and easy replacement after deactivation.

[0007] To achieve the above-described continuous preparation method, conventional continuous flow reactors in the art can be used. A typical apparatus flow may include: a feed unit for storing and transporting materials, a mixing unit for mixing materials, a fixed-bed reactor packed with a commercial solid acid catalyst, a temperature and pressure control unit for controlling reaction conditions, a dehydration unit for online removal of reaction-generated water, and a product collection unit. These units are connected in sequence via piping. Depending on the material form (e.g., whether a solvent is used), a solvent recovery unit may be added after the dehydration unit, or a preheating unit may be added after the mixing unit to accommodate high-viscosity materials; these are conventional choices for those skilled in the art.

[0008] In this invention, a commercial solid acid catalyst is packed in a fixed-bed reactor in the form of a packing material, and the fixed-bed reactor can be a tubular fixed-bed reactor.

[0009] In this invention, the commercial solid acid catalyst is a strongly acidic cation exchange resin or a perfluorosulfonic acid resin. The strongly acidic cation exchange resin is a sulfonated resin based on a styrene-divinylbenzene copolymer, such as DuPont's Amberlyst-15 or Amberlyst-36. These catalysts are highly acidic and relatively inexpensive. The perfluorosulfonic acid resin is a Nafion series resin or its supported form, such as Chemours' Nafion NR50 (granular) or Nafion SAC-13 (silicon-based supported type). These catalysts exhibit extremely strong acidity and thermal stability, making them particularly suitable for reactions sensitive to moisture or at high temperatures.

[0010] In this invention, in step (1), the reaction temperature is controlled at 120-150°C, which may be but is not limited to 120°C, 125°C, 130°C, 135°C, 140°C, 145°C or 150°C. Preferably, the reaction temperature is controlled at 130-145°C.

[0011] For the purposes of this invention, in step (1), the reaction pressure is controlled to be 0.5-1.5 MPa, which may be, but is not limited to, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa, 1.1 MPa, 1.2 MPa, 1.3 MPa, 1.4 MPa or 1.5 MPa. Preferably, the reaction pressure is controlled to be 1.0-1.2 MPa.

[0012] In this invention, in step (2), the material containing vitamin E succinate and polyethylene glycol 1000 is injected into the fixed bed reactor, such that the residence time of the material in the fixed bed reactor is 10-60 minutes. The residence time can be, but is not limited to, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes. Preferably, the residence time is 20-40 minutes, and more preferably, the residence time is 30 minutes.

[0013] For the purposes of this invention, in step (2), the molar ratio of vitamin E succinate to polyethylene glycol 1000 is 1:1.0-1.1, which may be, but is not limited to, 1:1.0, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09 or 1:1.1. Preferably, the molar ratio of vitamin E succinate to polyethylene glycol 1000 is 1:1.04-1.06; more preferably, the molar ratio of vitamin E succinate to polyethylene glycol 1000 is 1:1.05.

[0014] In practice, the amount of catalyst loaded (such as 50g and 30g in Examples 1-2) is determined by the reactor dimensions (inner diameter and length) to achieve the required catalyst bed height and residence time, which can be determined by those skilled in the art based on conventional engineering experience.

[0015] An apparatus for the continuous production of vitamin E succinate polyethylene glycol ester comprises, in sequence: a feed unit (e.g., a raw material storage tank) for storing and conveying materials; a mixing unit (e.g., a static mixer) for mixing materials; a fixed-bed reactor (e.g., a tubular fixed-bed reactor) packed with a commercial solid acid catalyst; a temperature control unit for controlling the reaction temperature; a pressure control unit (e.g., a back pressure valve) for maintaining the reaction pressure; an online dehydration unit (e.g., a molecular sieve dehydration column or a pervaporation membrane dehydrator) for removing reaction-generated water online; and a product collection unit (product storage tank) for collecting the final product. The feed unit, mixing unit, fixed-bed reactor, online dehydration unit, and product collection unit are connected in process sequence via piping. The online dehydration unit receives and processes the reaction liquid from the fixed-bed reactor to continuously remove water generated during the reaction process online; the temperature control unit and pressure control unit are associated with the fixed-bed reactor and are used to control the reaction temperature and reaction pressure.

[0016] The reaction apparatus of the present invention can be appropriately adjusted according to different reactants. If the reactants are a mixed solution composed of vitamin E succinate (VES), polyethylene glycol 1000 (PEG1000), and solvent (e.g., toluene), a falling film evaporator can be installed at the outlet of the fixed-bed reactor to recover the solvent. The outlet of the falling film evaporator is connected to a solvent collection unit (e.g., a solvent storage tank) for solvent recovery and a product collection unit (e.g., a product storage tank) for collecting the final product.

[0017] If no solvent is added to the reactants, and instead vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) are melted separately and then mixed in proportion to obtain a mixed melt, a high-temperature preheating mixer can be added to the mixing unit (e.g., static mixer) and the fixed-bed reactor (e.g., tubular fixed-bed reactor) to prevent blockage by high-viscosity materials, without the need for a falling film evaporator and a solvent collection unit (e.g., solvent storage tank) for solvent recovery.

[0018] The advantages of using the technical solution of this invention are as follows: (1) Catalysts are readily available and universal: mature commercial catalysts are directly used in the market, without the need for complicated self-preparation processes. The quality is stable and the supply is guaranteed, which greatly reduces the initial threshold for research and development and production.

[0019] (2) Truly green process: heterogeneous catalysis, no catalyst residue, and very little waste; continuous flow process is inherently safe and has low energy consumption.

[0020] (3) Excellent product quality: The reaction conditions are mild and precise, which effectively inhibits the oxidation of vitamin E succinate (VES) and the degradation of polyethylene glycol (PEG). The product has a light color (low APHA value) and the content of by-product polyethylene glycol (PEG) diester can be controlled below 1.0%.

[0021] (4) Excellent process operability: The catalyst can be operated for a long time after loading, without batch feeding and separation, and is very easy to achieve automated control and large-scale scale-up. Attached Figure Description

[0022] Figure 1 This is the gas phase spectrum of the product obtained in Example 1; Figure 2 This is the gas phase spectrum of the product obtained in Example 2. Detailed Implementation

[0023] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims. The following embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Those skilled in the art should understand that the present invention can be implemented using different conventional continuous flow equipment and connection methods without departing from the core of the method of the present invention. The specific device configurations and parameters (such as catalyst loading and reactor size) given in the embodiments are only one specific implementation method to achieve the stated effects and are not the only limitation of the present invention. The catalyst loading is determined by the reactor size to achieve the required catalyst bed height and residence time, which can be determined by those skilled in the art based on conventional engineering experience.

[0024] Example 1: Continuous flow synthesis using Amberlyst-15 catalyst The apparatus for the continuous preparation of vitamin E succinate polyethylene glycol ester in Example 1 includes a feed unit (material storage tank), a feed pump, a static mixer, a tubular fixed-bed reactor (20 mm inner diameter, 250 mm length) filled with Amberlyst-15 catalyst, a temperature control unit, a pressure control unit (back pressure valve), an online dehydration unit (molecular sieve dehydration column), a solvent recovery storage tank, a falling film evaporator, and a product collection unit (product receiving tank).

[0025] A method for continuous preparation of vitamin E succinate polyethylene glycol ester includes the following steps: (1) 50g of Amberlyst-15 catalyst (strong acid cation exchange resin with a particle size of 0.5-0.7mm) was loaded into a tubular fixed bed reactor (inner diameter 20mm, length 250mm), and the reaction temperature was controlled at 130℃ and the reaction pressure was 1.0MPa.

[0026] (2) Vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) were dissolved in toluene at a molar ratio of 1:1.05 to prepare a mixed solution with a total reactant concentration (VES and PEG1000) of 1.5 mol / L. This mixed solution was pumped into the above-mentioned tubular fixed-bed reactor packed with catalyst at a flow rate of 50 mL / min using a precision feed pump. The residence time of the material in the reactor was 30 minutes (calculated based on the reactor empty volume). The resulting effluent was directly fed into a falling film evaporator to evaporate and recover toluene (recovery rate >98%), yielding a light yellow waxy polyethylene glycol vitamin E succinate (TPGS). The molar ratio of vitamin E succinate (VES) to polyethylene glycol 1000 (PEG1000) was 1:1.05.

[0027] After 120 hours of continuous operation in a tubular fixed-bed reactor, the conversion rate of Amberlyst-15 catalyst remained above 99%. The average TPGS yield was >97%, as confirmed by gas chromatography (e.g., ...). Figure 1 As shown in the figure, the purity of the main product TPGS is >99%, and the content of the by-product PEG diester is <0.8%. The product color (APHA value) is significantly lower than that of Comparative Example 1.

[0028] Example 2 Solvent-free synthesis using Nafion NR50 catalyst The apparatus for the continuous preparation of vitamin E succinate polyethylene glycol ester in Example 2 is similar to that in Example 1, except that 30g of Nafion NR50 catalyst (granular, 0.5 mm in diameter) is packed into a tubular fixed-bed reactor. To prevent blockage by high-viscosity materials, a high-temperature preheating mixer is added before the tubular fixed-bed reactor.

[0029] A method for continuous preparation of vitamin E succinate polyethylene glycol ester includes the following steps: (1) 30g of Nafion NR50 catalyst (granular, with a particle size of 0.5 mm) was loaded into a tubular fixed bed reactor (inner diameter 10 mm, length 300 mm), and the reaction temperature was controlled at 145℃ and the reaction pressure was 1.2 MPa.

[0030] (2) Vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) were melted at 60°C. Two high-temperature metering pumps were used to precisely control the flow rate so that the melted vitamin E succinate (VES) and polyethylene glycol 1000 (PEG1000) were pumped into a high-temperature preheating mixer (set temperature 140°C) at a molar ratio of 1:1.05. The resulting mixed melt was then pumped into a tubular fixed bed reactor at a flow rate of 30 mL / min using a feed pump. The mixed melt was allowed to remain in the tubular fixed bed reactor for 30 minutes. The resulting effluent was cooled and solidified to obtain the product vitamin E succinate polyethylene glycol ester (TPGS), which did not require any solvent washing.

[0031] In Example 2, a solvent-free preparation method was used to prepare polyethylene glycol succinate (TPGS) of vitamin E. The product had extremely high purity, with an average TPGS yield >98%. Gas chromatography analysis (chromatogram shown) confirmed the high purity. Figure 2 As shown in the figure, the main product TPGS has a purity of >99.5%, an almost pure white color, and a PEG diester content of <0.5%, demonstrating the high efficiency and stability of the preparation method.

[0032] Comparative Example 1 (Existing concentrated sulfuric acid method) In a 500 mL three-necked flask equipped with a water separator and a condenser, 100 g (0.172 mol) of vitamin E succinate (VES), 181.6 g (0.181 mol) of polyethylene glycol 1000 (PEG1000, 1:1.05 molar ratio), and 150 mL of toluene were added. After stirring thoroughly, 2.82 g (1.0 wt% based on the total mass of VES and PEG1000) of concentrated sulfuric acid was added as a catalyst. The resulting reaction solution was heated to reflux (approximately 110 °C) for 6 hours, and the generated water was removed by azeotropic distillation using a water separator. After the reaction was completed, the reaction solution was cooled to 20-30 °C, neutralized with a 5% sodium carbonate aqueous solution, and washed three times with deionized water. The organic phase was dried over anhydrous sodium sulfate, and toluene was removed by vacuum distillation to obtain a deep yellow waxy product. Gas chromatography analysis showed that the VES conversion rate was approximately 98%, the TPGS yield was approximately 90%, the purity of the main product TPGS was approximately 95%, and the content of the byproduct PEG diester was approximately 3.5%. The post-treatment process was cumbersome and generated acidic wastewater.

[0033] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for continuous preparation of vitamin E succinate polyethylene glycol ester, characterized in that, Includes the following steps: (1) A commercial solid acid catalyst is loaded into a fixed-bed reactor, and the reaction temperature is controlled at 120-150℃ and the reaction pressure is 0.5-1.5 MPa; (2) The material containing vitamin E succinate and polyethylene glycol 1000 is injected into the fixed bed reactor, such that the residence time of the material in the fixed bed reactor is 10-60 minutes, to obtain the target product.

2. The preparation method according to claim 1, characterized in that, In step (1), the commercial solid acid catalyst is a strong acid cation exchange resin or a perfluorosulfonic acid resin.

3. The preparation method according to claim 2, characterized in that, In step (1), the strong acid cation exchange resin is a sulfonated resin based on a styrene-divinylbenzene copolymer matrix; preferably, the strong acid cation exchange resin is Amberlyst-15 or Amberlyst-36.

4. The preparation method according to claim 2, characterized in that, In step (1), the perfluorosulfonic acid resin is a Nafion series resin or its immobilized form; preferably, the perfluorosulfonic acid resin is Nafion NR50 or Nafion SAC-13.

5. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is 130-145℃ and the reaction pressure is 1.0-1.2 MPa.

6. The preparation method according to claim 1, characterized in that, In step (2), the dwell time is 20-40 minutes, preferably 30 minutes.

7. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of vitamin E succinate to polyethylene glycol 1000 is 1:1.0-1.1, preferably 1:1.04-1.06, and more preferably 1:1.

05.

8. The preparation method according to claim 1, characterized in that, The fixed-bed reactor is a tubular fixed-bed reactor.

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