Synthesis method and purification method of DMI

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a synthesis method and a purification method of DMI (isosorbide dimethyl ether). The DMI synthesis step comprises the following steps: mixing isosorbide, alkali and a high-boiling-point solvent, then adding DMS (dimethyl sulfate) for reaction, and collecting an organic phase after the reaction is finished to obtain a reaction product containing the DMI; the molar weight ratio of the isosorbide to the DMS to the alkali is 1: (0.5-3): (2-5). According to the method, the isosorbide is used as a starting raw material of a DMI synthesis route, the utilization rate of the isosorbide is remarkably increased by optimizing synthesis reaction raw materials and process conditions, preferably selecting NaOH or an aqueous solution thereof as alkali and limiting a feeding sequence and a formula dosage, and a brand new thought is provided for batch production of the DMI by virtue of natural properties of the isosorbide.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for synthesizing and purifying DMI. Background Technology

[0002] In the current chemical and pharmaceutical industries, high-boiling-point solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and dimethylacetamide (DMAC) are widely used. However, these solvents generally suffer from high toxicity, high hazard, and easy decomposition, posing numerous hidden dangers to production safety, environmental protection, and human health.

[0003] DMI (Diethylstilbestrol) has become an ideal alternative to the aforementioned solvents due to its unique advantages. DMI is synthesized from the bio-based raw material sorbitol as a precursor, making it renewable. Furthermore, it possesses low toxicity and a high boiling point (246°C), effectively avoiding many problems associated with traditional high-boiling-point solvents. Based on these advantages, DMI has a wide range of applications. In the pharmaceutical field, DMI can be used as a pharmaceutical excipient, participating in drug formulations as an inactive ingredient to enhance the stability, solubility, and processing performance of drug formulations, and positively influencing the absorption, distribution, metabolism, and excretion (ADME) process. In the field of membrane preparation, DMI shows application potential in the preparation of sustainable ultrafiltration and microfiltration membranes, acting as an excipient, solvent, or permeation aid.

[0004] Currently, the synthesis of DMI mainly employs processes using DMS, dimethyl carbonate, and chloromethane as raw materials (e.g., US patents US4659846, US4322359, US patents US4700871, US patents US4435586, and PCT patent WO2007096511). The synthesis methods are relatively limited, and the technology is primarily controlled by foreign companies. The number of manufacturers is small, resulting in limited market supply and high DMI prices, failing to meet the growing market demand. Furthermore, commonly used solvents in DMI synthesis include tert-butanol, acetone, and dimethyl sulfoxide. These solvents have low boiling points and are highly volatile, leading to difficulties in solvent recovery, environmental pollution, and increased usage costs. Although existing technologies attempt to improve solvents, the high production costs still cannot meet the requirements for mass production of DMI.

[0005] Against this backdrop, it is imperative to provide a safe, environmentally friendly, feasible, and efficient synthetic method for converting isosorbide into DMI. Summary of the Invention

[0006] To address the aforementioned technical problems, the first aspect of this invention provides a method for synthesizing DMI, wherein the DMI synthesis steps include:

[0007] Isosorbide, a base, and a high-boiling-point solvent were mixed, and then DMS was added to react. After the reaction was completed, the organic phase was collected to obtain the reaction product containing DMS.

[0008] Optionally, the molar ratio of isosorbide, DMS, and base is 1:(0.5-3):(2-5).

[0009] In some embodiments, the synthesis step of the DMI specifically includes:

[0010] (1) Mix isosorbide, alkali and high-boiling-point solvent at 80-95℃;

[0011] (2) Add DMS at 85-135℃ and react for 0.5-5 hours;

[0012] (3) After the reaction is completed, cool the temperature to below 80°C, add water, separate the liquid and collect the organic phase to obtain the reaction product containing DMI.

[0013] Optionally, the boiling point of the high-boiling solvent is above 130°C.

[0014] Optionally, the high-boiling-point solvent is xylene, which has a boiling point of 137–140°C.

[0015] The present invention preferably uses xylene as a high-boiling-point solvent, which can solve the problems of difficult solvent separation and recovery. Using xylene as a reaction medium can promote the forward reaction, and after the reaction is completed, the product can be distilled to separate xylene from the reaction system, so as to obtain DMI product with high yield and high purity.

[0016] Optionally, the amount of the high-boiling-point solvent added, based on the molar amount of isosorbide, is 0.2-1 L / mol; examples include 0.2 L / mol, 0.25 L / mol, 0.3 L / mol, 0.35 L / mol, 0.4 L / mol, 0.5 L / mol, 0.6 L / mol, 0.7 L / mol, 0.8 L / mol, 0.9 L / mol, and 1 L / mol; further, it can be selected as 0.25 L / mol.

[0017] Examples of bases include NaOH, KOH, and NH3.

[0018] Optionally, the base is NaOH or an aqueous solution thereof.

[0019] Optionally, the concentration of the NaOH aqueous solution is 40-50%, and examples include 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, and 50%; more preferably, it is 45%.

[0020] This invention preferably uses NaOH or its aqueous solution as the alkali, which can promote the reaction and purification from multiple dimensions. Experimental investigations have shown that using NaOH in the synthesis reaction of DMI results in a higher yield and purity of the final product compared to KOH. The reasons are speculated to be: firstly, NaOH has sufficient solubility to maintain an effective concentration, ensuring the homogeneity of the reaction system; secondly, NaOH is less likely to be lost with the organic phase, and the solubility of the Na2SO4 generated after the reaction is moderate (approximately 40.8 g / 100 g water at 30°C), requiring less water for washing. After the reaction, high-temperature concentration and crystallization facilitate filtration and collection. Compared to NaOH, the high solubility of KOH may cause some alkali to enter the organic phase, creating a locally strongly alkaline environment that further exacerbates DMS hydrolysis; and the solubility of the K2SO4 generated is relatively low (approximately 13 g / 100 g water at 30°C), requiring more water for washing, which affects the DMI yield and increases the difficulty of post-processing. Meanwhile, DMS exhibits a higher tendency to hydrolyze in the KOH system, while its hydrolysis is slower in NaOH, thus improving the reaction conversion rate. Furthermore, in the high-temperature reaction system of this invention, the strong nucleophilicity of KOH may exacerbate side reactions, while the reaction rate of NaOH meets the reaction requirements and exhibits stronger reaction specificity and selectivity. From an industrial production perspective, the production cost of NaOH is lower (approximately 60% of the price of KOH), and it is easier to separate and process, whereas K₂SO₄ has poor water solubility and is difficult to remove. Additionally, NaOH has lower corrosiveness to the reactor, while the strong alkalinity of KOH accelerates the corrosion of stainless steel equipment. Therefore, considering product quality, process controllability, and equipment compatibility, NaOH is a better choice for large-scale industrial production of DMI.

[0021] In some embodiments, the alkali is an aqueous solution of NaOH, and in step (1), isosorbide and xylene are first mixed, and then the aqueous solution of NaOH is added and mixed evenly.

[0022] In some embodiments, the alkali is an aqueous solution of NaOH, and in step (1), isosorbide and the aqueous solution of NaOH are first mixed, and then xylene is added and mixed evenly.

[0023] In some embodiments, the alkali is NaOH (dried solid), and in step (1), isosorbide is first dissolved in water, then NaOH is added, and after mixing evenly, xylene is added and mixed evenly.

[0024] The feeding method of this invention is flexible. It can involve mixing isosorbide and xylene first, then adding an aqueous NaOH solution; or mixing isosorbide and NaOH solution first, then adding xylene; or dissolving isosorbide in water first, then adding NaOH, mixing thoroughly, and finally adding xylene. By constructing a two-phase system stepwise, it helps control the reaction interface and improve selectivity. Further investigation revealed that the timing of adding the alkaline solution (i.e., the aqueous NaOH solution) also has a certain impact on the synthesis quality of DMI. Mixing isosorbide and xylene first, then adding the alkaline solution, yields a higher quality DMI product. The reason is speculated to be that dissolving isosorbide in the alkaline aqueous phase inevitably triggers ring-opening and oxidation side reactions, leading to decreased yield, increased impurities, and increased post-processing difficulty, resulting in high risks in industrial implementation. Adding xylene first, then the alkaline solution, preferentially dissolves the organic phase, inhibits catalytic hydrolysis and oxidation by the alkali, and also eliminates metal salt residue (which easily forms complex salt precipitates during the reaction process, potentially clogging pipelines during post-processing), ensuring product purity and separation efficiency.

[0025] In some implementations, the DMS in step (2) is added by dripping, and the dripping time is controlled to be within 2 hours.

[0026] Optionally, water may be added in step (3) after the temperature has been lowered to 55-60°C.

[0027] Optionally, the amount of water added in step (3) is 0.1-1 L / mol, based on the molar amount of isosorbide;

[0028] Examples of possible values ​​include 0.1 L / mol, 0.2 L / mol, 0.3 L / mol, 0.4 L / mol, 0.5 L / mol, 0.6 L / mol, 0.7 L / mol, 0.8 L / mol, 0.9 L / mol, and 1 L / mol; a further option is 0.5 L / mol.

[0029] Furthermore, xylene is used to extract and wash the aqueous phase after separation in step (3), and the extracted organic phase is combined with the organic phase after water separation.

[0030] Based on the molar amount of isosorbide, the amount of xylene added in step (3) is 0.1-1 L / mol;

[0031] Examples of possible values ​​include 0.1 L / mol, 0.2 L / mol, 0.3 L / mol, 0.4 L / mol, 0.5 L / mol, 0.6 L / mol, 0.7 L / mol, 0.8 L / mol, 0.9 L / mol, and 1 L / mol; further options include 0.1 L / mol.

[0032] In some embodiments, after the reaction in step (2) is completed, alkali is added first, and then the temperature is raised to remove moisture.

[0033] In some embodiments, after the reaction in step (2) is completed, the temperature is raised to remove moisture, and then alkali is added.

[0034] Optionally, the temperature at which the moisture is removed by heating is below 135°C.

[0035] A second aspect of the present invention provides a method for purifying DMI, wherein the organic phase is purified to obtain a purified product.

[0036] The purification method is distillation; the xylene recovered by distillation can be directly reused in the synthesis of DMI.

[0037] Optionally, the distillation operation is as follows: the organic phase is placed in a water pump for distillation treatment, and the fraction at 50-100℃ is collected; the remaining liquid is placed in an oil pump for distillation treatment, and the fraction at 80-90℃ is collected to obtain a colorless oily purified product.

[0038] Optionally, the distillation operation is as follows: vacuum distillation is performed under a vacuum degree below -0.1 MPa, and the fraction at 50-120℃ is collected; the remaining liquid is placed under a vacuum degree below -0.001 MPa for vacuum distillation, and the fraction at 75-85℃ is collected to obtain a colorless oily purified product.

[0039] Further optionally, the distillation operation is as follows: vacuum distillation is performed at a vacuum degree of -0.097 MPa, and the fraction at 50-120°C is collected; the remaining liquid is placed under a vacuum degree of -0.00001 MPa for vacuum distillation, and the fraction at 75-85°C is collected to obtain a colorless oily liquid product DMI.

[0040] The temperature in the distillation scheme of this invention is the external temperature, that is, the temperature of the heating medium on the outer layer of the distillation apparatus.

[0041] During the research, it was found that the reaction products after the synthesis reaction inevitably contained monoethers (such as isosorbide monomethyl ether), and it was difficult to separate them from DMI regardless of whether direct distillation or rectification was used. Experimental investigations revealed that washing the organic phase with alkaline water after liquid-liquid separation could largely remove the main impurities. Distilling the filtrate after alkaline washing to remove the solvent and then distilling the product yielded a product with high purity. Furthermore, it was found that adding alkali directly to the filtrate before distillation could also reduce the impurity content in the product, further improving the yield and purity of DMI in the product.

[0042] In some embodiments, the purity of DMI in the purified product is 90% or higher; more preferably 99% or higher.

[0043] Beneficial effects:

[0044] This invention provides a method for synthesizing and purifying DMI, which has the following advantages:

[0045] (1) This invention uses isosorbide as the starting material for the synthesis route of DMI. By optimizing the raw materials and process conditions of the synthesis reaction, NaOH or its aqueous solution is preferred as the alkali, and the order of feeding and the amount of formulation are limited, the utilization rate of isosorbide is significantly improved. With the help of the natural properties of isosorbide, a new idea is provided for the mass production of DMI.

[0046] (2) The overall processing flow of the present invention is safe and environmentally friendly. The reaction products are purified by a specific post-treatment method. On the one hand, the water collected in the water removal stage and the pre-distillate collected in the distillation process can be recycled. On the other hand, no waste gas is generated during the reaction and purification process, and the amount of waste gas emissions is significantly reduced. At the same time, the present invention is a closed system with automated feeding reaction. There are no problems such as DMS causing danger to the safety of operators, and the safety is strong.

[0047] (3) The present invention has high reaction efficiency, and the overall preparation process only takes 5-6 hours. It solves the problems of low reactivity of isosorbide, insufficient conversion and slow reaction rate, and improves the production efficiency of DMI.

[0048] (4) By subjecting the purified aqueous phase to high-temperature dehydration treatment, the present invention can also separate high-purity sodium sulfate, further reducing the generation of waste brine; and the preparation process of the present invention generates less solid waste (the residue after each mole of raw material reaction is generally 1-3 grams), which can be accumulated in multiple batches for solid waste treatment, with flexible treatment methods and strong operability.

[0049] (5) The raw materials of this invention are readily available, easy to operate, have low implementation costs, and produce high-quality products, which can be widely promoted in the field of DMI synthesis technology. Detailed Implementation

[0050] The isosorbide used in the embodiments of this invention was self-made and sourced from Shanghai Donggeng Chemical Technology Co., Ltd. Note: Unless otherwise specified, the solvent used in the solutions involved in this invention is water; all concentrations mentioned are mass concentrations; the room temperature is 25°C; and all raw materials used are commercially available.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing and purifying DMI.

[0053] The synthesis steps of the DMI include:

[0054] (1) Preparatory stage: Weigh 148.0g of isosorbide (1mol, purity 99%) into a 1000mL four-necked flask, add 250mL of xylene, heat and stir at 90℃ until dissolved; add 184.5g of 45% NaOH aqueous solution (NaOH molar amount is 2.05mol), stir quickly and heat to 90℃;

[0055] (2) Reaction stage: 192.5g DMS (1.51mol of DMS with 99% purity) was added dropwise at 90℃, and the addition was completed in 1h. After the addition was completed, the temperature was lowered to 85℃, and 90.0g of 45% NaOH (1.01mol of NaOH) was added. The temperature was raised to 130℃ to remove water, and the reaction was maintained at this temperature for 0.5h.

[0056] (3) Collection stage: After the reaction is completed, the temperature is lowered to 60℃, 100mL of water is added, the mixture is kept warm and stirred, and after washing until no solid is present, the liquid is separated to obtain an aqueous phase and an organic phase; 50mL of xylene is added to the aqueous phase for extraction and washing, and the extracted organic phase is combined with the separated organic phase.

[0057] The purification method of the DMI is as follows: take the organic phase combined in step (3) and distill it.

[0058] The distillation process is as follows: vacuum distillation is performed at a vacuum degree of -0.097 MPa, and the fraction at 50-120℃ is collected; the remaining liquid is placed under a vacuum degree of -0.00001 MPa for vacuum distillation, and the fraction at 75-85℃ is collected to obtain a colorless oily purified product DMI.

[0059] Example 2

[0060] This embodiment provides a method for synthesizing and purifying DMI, and the specific implementation method is the same as that in embodiment 1; the difference is that in step (1), NaOH aqueous solution is added first, and then xylene is added.

[0061] Example 3

[0062] Example 3 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that the NaOH aqueous solution is added at once, specifically in step (1).

[0063] Example 4

[0064] Example 4 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that the amount of NaOH added in step (1) is 2 mol; the amount of NaOH added in step (2) is 0.26 mol; that is, the molar ratio of DMS, NaOH in step (1) and NaOH in step (2) is 1:1.33:0.17.

[0065] Example 5

[0066] Example 5 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that the amount of NaOH added in step (1) is 2 mol; the amount of NaOH added in step (2) is 1.77 mol; that is, the molar ratio of DMS, NaOH in step (1), and NaOH in step (2) is 1:1.33:1.17.

[0067] Example 6

[0068] Example 6 provides a method for synthesizing and purifying DMI, with the same specific implementation method as Example 1; the difference is that the molar ratio of isosorbide and DMS is 1:1; the operation keeps the amount of isosorbide added constant, and adjusts the amount of DMS added.

[0069] Example 7

[0070] Example 7 provides a method for synthesizing and purifying DMI, with the same specific implementation method as Example 1; the difference is that the molar ratio of isosorbide to DMS is 1:2; the operation keeps the amount of isosorbide added constant, and adjusts the amount of DMS added.

[0071] Example 8

[0072] Example 8 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that step (2) is maintained at 90°C.

[0073] Example 9

[0074] Example 9 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that in step (2), the temperature is raised to 140°C to remove water.

[0075] Example 10

[0076] Example 10 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that in step (2), the temperature is raised to 150°C to remove water.

[0077] Example 11

[0078] Example 11 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that the NaOH aqueous solution is replaced with a KOH aqueous solution.

[0079] Example 12

[0080] Example 12 provides a method for synthesizing and purifying DMI, with the specific implementation method being the same as in Example 1; the difference is that after the organic phases are combined, they are washed with alkaline water (45% NaOH aqueous solution) and then distilled.

[0081] Example 13

[0082] Example 13 provides a method for synthesizing and purifying DMI, with the same implementation method as Example 1; the difference is that 3g of dry NaOH solid is added to the organic phase before distillation in step (3).

[0083] Performance testing

[0084] The content and purity of DMI in the products prepared in the examples were determined by GC, and the mass of the residue at the bottom of the reactor after each reaction was determined; the results are recorded in Table 1.

[0085] Table 1

[0086] Serial Number content(%) Yield (%) Example 1 93.02 80.85 Example 2 91.66 73.29 Example 3 85.05 57.92 Example 4 88.17 63.28 Example 5 81.83 67.42 Example 6 89.15 73.25 Example 7 95.67 71.53 Example 8 68.72 46.95 Example 9 91.85 76.52 Example 10 92.36 75.98 Example 11 88.21 70.23 Example 12 99.12 75.57 Example 13 99.02 79.65

[0087] As can be seen from the data in Table 1, this invention uses isosorbide to react with DMS to synthesize DMI. By optimizing the raw materials and process conditions of the synthesis reaction, NaOH or its aqueous solution is preferred as the alkali, and the order of feeding and the amount of formulation are limited, the utilization rate of isosorbide is significantly improved. Furthermore, by washing the organic phase product after separation with alkaline water and then distilling, or by adding alkali and distilling, the yield and purity of the product can be further improved.

Claims

1. A method for the synthesis of DMI, characterized in that, The synthesis steps of the DMI include: mixing isosorbide, alkali and high-boiling solvent, then adding DMS for reaction, collecting organic phase after reaction to obtain reaction product containing DMI; The molar ratio of isosorbide, DMS and alkali is 1:(0.5-3):(2-5).

2. The method of claim 1, wherein the DMI is synthesized by the process comprising: The synthesis steps of the DMI include: (1) mixing isosorbide, alkali and high-boiling solvent at 80-95℃; (2) adding DMS for reaction at 85-135℃ for 0.5-5h; (3) cooling to below 80℃ after reaction, adding water, separating, collecting organic phase to obtain reaction product containing DMI.

3. The method of synthesis of DMI according to claim 1 or 2, characterized in that, The boiling point of the high-boiling solvent is above 130℃.

4. The method of claim 3, wherein the DMI is synthesized by the process comprising: The high-boiling solvent is xylene.

5. The method of synthesis of DMI according to claim 1 or 2, wherein, The addition amount of high-boiling solvent in step (1) is 0.2-1L / mol based on the molar amount of isosorbide.

6. The method of synthesis of DMI according to claim 1 or 2, wherein, The alkali is NaOH or its aqueous solution.

7. The method of purifying DMI according to claim 1, wherein, The organic phase is subjected to purification treatment to obtain purified product; The purification method is distillation; the xylene recovered by distillation can be directly reused for synthesis of DMI.

8. The method of purifying DMI according to claim 7, wherein, The operation of distillation is: distillation treatment of organic phase in water pump, collecting 50-100℃ fraction; distillation treatment of residual liquid in oil pump, collecting 80-90℃ fraction to obtain purified product.

9. The method of claim 7, wherein the DMI is purified by, The operation of distillation is: vacuum distillation under vacuum degree below-0.1MPa, collecting 50-120℃ fraction; vacuum distillation of residual liquid under vacuum degree below-0.001MPa, collecting 75-85℃ fraction to obtain purified product.

10. The method of purification of DMI according to claim 8 or 9, characterized in that, The purity of DMI in the purified product is above 90%.