Method for producing 1, 2-cyclopentanedicarboximide by using water-insoluble solid powder as reaction medium

Abstract

The invention discloses a method for producing 1, 2-cyclopentanedicarboximide by using non-water-soluble solid powder as a reaction medium, which comprises the following steps: mixing the non-water-soluble solid powder as the reaction medium and 1, 2-cyclopentanedicarboximide or a salt thereof as a raw material, heating, stirring and reacting, cooling after the reaction is finished, adding deionized water into the reaction system, stirring, extracting and filtering to obtain the 1, 2-cyclopentanedicarboximide. And concentrating the filtrate, cooling and crystallizing to obtain a 1, 2-cyclopentadicarboximide product. The adopted water-insoluble solid powder is large in heat conductivity coefficient, matched with the raw materials in density and particle size, good in heat stability and chemical stability, not only serves as a dispersion medium of the raw materials, but also serves as a heat-conducting medium of the reaction in the reaction, and does not generate oxidation, decomposition, polymerization and other reactions in the high-temperature reaction process; and chemical reaction with raw materials and products is avoided. After the reaction is finished, the product and the solid reaction medium can be conveniently separated through water extraction, and the solid reaction medium can be recycled after being dried.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for producing 1,2-cyclopentanedicarboximide by using water-insoluble solid powder as a reaction medium. Background Art

[0002] 1,2-Cyclopentanedicarboximide is an important intermediate for the preparation of gliclazide and a building block compound for other organic syntheses.

[0003] 1,2-cyclopentanedicarboximide is mainly synthesized by removing one molecule of ammonia through intramolecular cyclization of 1,2-cyclopentanedicarboxamide or its salt at high temperature. The reaction of cyclization of 1,2-cyclopentanedicarboxamide or its salt to generate 1,2-cyclopentanedicarboximide requires a temperature of 200-350°C. Conventional organic solvents (such as water, ethanol, tetrahydrofuran, acetone, petroleum ether, hexane, etc.) often used as reaction media in organic synthesis cannot meet the needs of high-temperature cyclization due to their low boiling points. Therefore, there are currently three specific operating methods for high-temperature cyclization:

[0004] 1) Direct high-temperature cyclization without medium.

[0005] 2) High temperature cyclization using heat transfer oil as the reaction medium,

[0006] 3) High temperature cyclization using ionic liquid as reaction medium.

[0007] Chinese patent CN104387313A mentions that high-temperature cyclization without a medium needs to be carried out at above 300°C. The reaction temperature is high, the coking phenomenon is serious, and the product yield is less than 50%. The main reason for this phenomenon is that the raw material 1,2-cyclopentanedicarboxamide or its salt is solid at the cyclization temperature. In the absence of a medium, the heat input is mainly conducted through the solid raw material. As we all know, the thermal conductivity of solids is small. In addition, there is gas between solids, and the thermal conductivity of gas is even smaller. The large heat transfer resistance causes a large temperature gradient inside the reaction system, and the temperature distribution is very uneven. The temperature inside the material is much lower than the material temperature at the heating surface. In order to increase the temperature inside the material to reach the required temperature for cyclization, the heating surface temperature must be increased, so that the direct high-temperature cyclization without a medium requires a higher temperature. The raw material temperature at the heating surface is generally above 300°C. This part of the material is coked and carbonized at high temperature. The low temperature of the internal material will cause a low cyclization conversion rate. The combined effect of the two makes the high-temperature cyclization product yield and product purity low in the absence of a medium. To solve this problem, CN201811074979.1 discloses a synthesis method using heat transfer oil as a reaction solvent, and CN202111610231.0 uses an ionic liquid as a reaction solvent.

[0008] With high-boiling-point liquids such as heat transfer oil or ionic liquids as the reaction medium, the heat transfer between the material and the heating surface is accelerated by convection, and the temperature inside the material is more uniform. However, there are the following problems: 1) Heat transfer oil is easy to smoke at high temperatures and has poor safety; ionic liquids are expensive and have high production costs; 2) Heat transfer oil and ionic liquids have high viscosity and low convection heat transfer coefficient; 3) Heat transfer oil and ionic liquids not only have high viscosity, but also have a large difference in polarity from the raw materials. The raw materials suspended in heat transfer oil or ionic liquids are easy to agglomerate, so the dispersion of the raw materials in heat transfer oil or ionic liquids is poor; 4) After the reaction is completed, there is a problem of difficulty in separating the product from the reaction medium (heat transfer oil or ionic liquid). Not only are there many separation steps and low production efficiency, but in order to improve the purity of the product, it is necessary to recrystallize through hazardous chemical solvents such as benzene and toluene, and the environmental friendliness of the production process is poor. Summary of the invention

[0009] In view of the above-mentioned shortcomings, the present invention provides a method for producing 1,2-cyclopentanedicarboximide by using water-insoluble solid powder as a reaction medium.

[0010] The invention adopts water-insoluble solid powder as a reaction medium, selects water-insoluble solid with large thermal conductivity and specific heat capacity, small particle size, density similar to that of raw material, and high thermal stability and chemical stability, mixes with raw materials under nitrogen protection, heats to reaction temperature to carry out cyclization reaction to prepare 1,2-cyclopentanedicarboximide, cools down after the reaction, adds deionized water to the reaction system, stirs for extraction, filters, concentrates the filtrate, cools down for crystallization, obtains 1,2-cyclopentanedicarboximide product, and the water-insoluble solid powder after removing the filtrate is dried and recycled as a reaction medium for high-temperature cyclization reaction.

[0011] The reaction equation of the cyclization reaction of the present invention is as follows:

[0012]

[0013] The reaction medium described in the method of the present invention is a water-insoluble solid powder with high temperature resistance and good chemical stability, which plays a dispersing and heat-conducting role and has the following characteristics: a melting point higher than 300°C, a density of 0.5-4g / cm 3 , specific heat capacity greater than or equal to 0.7J / (g﹒K), thermal conductivity higher than 30W / (m﹒K), particle size passing through 800-5000 mesh sieve.

[0014] Furthermore, the water-insoluble solid powder includes, but is not limited to, one or a mixture of graphite, alumina, and silicon carbide, preferably graphite.

[0015] The raw material described in the method of the present invention is 1,2-cyclopentanedicarboxamide or a salt thereof formed with an acid.

[0016] Furthermore, the salt formed by 1,2-cyclopentanedicarboxamide and acid includes, but is not limited to, 1,2-cyclopentanedicarboxamide sulfate or 1,2-cyclopentanedicarboxamide phosphate.

[0017] Furthermore, a method for producing 1,2-cyclopentanedicarboximide using a water-insoluble solid powder as a reaction medium comprises the following steps:

[0018] (1) Add a washed and dried solid reaction medium into a reactor, fully replace it with nitrogen, heat and stir, and after the reaction medium reaches a specified temperature, add the reaction raw materials, maintain the temperature for cyclization reaction, absorb the ammonia released by the reaction with water, and stop heating when the reaction is completed.

[0019] (2) After the reaction system is cooled to room temperature, deionized water is added thereto to extract 1,2-cyclopentanedicarboximide multiple times.

[0020] (3) filtering, concentrating the aqueous solution obtained by extraction by rotary evaporation, cooling, crystallizing 1,2-cyclopentanedicarboximide, filtering, and drying to obtain a finished product.

[0021] (4) The filtered solid powder is dried and recycled for high-temperature cyclization reaction.

[0022] Furthermore, in step (1), the ratio of the mass of the raw material to the volume of the water-insoluble solid powder is (0.5-10) g:50 mL, preferably (2-6) g:50 mL.

[0023] Furthermore, in step (1), the cyclization reaction temperature is 200-300°C, preferably 240-270°C; and the cyclization reaction time is 0.5-5h, preferably 1.5-3h.

[0024] Furthermore, in step (3), the crystallization temperature is 2-5°C.

[0025] The beneficial effects of the present invention are:

[0026] (1) The reaction medium used in the present invention is a water-insoluble solid powder. Since the reaction medium is insoluble in water, the 1,2-cyclopentanedicarboximide generated by the reaction is soluble in water. Therefore, after the reaction is completed, the 1,2-cyclopentanedicarboximide product can be easily extracted from the solid reaction medium with water. No organic solvent is used in the whole process of reaction and separation. This is an efficient and clean production method, which can be applied to the industrial production of 1,2-cyclopentanedicarboximide. The used solid medium can be dried and recycled for high-temperature cyclization reaction.

[0027] (2) The solid powder used as the reaction medium of the present invention has high thermal conductivity and specific heat capacity. Its thermal conductivity is higher than 30W / (m﹒K), which is similar to the thermal conductivity of metals, and its specific heat capacity is greater than or equal to 0.7J / (g﹒K). Good thermal conductivity reduces the thermal resistance and makes the temperature of the reaction system more uniform, while the large specific heat capacity can also ensure that the system temperature is not affected by the environment and the reaction process, further maintaining the uniformity of the system temperature.

[0028] (3) The solid powder used as the reaction medium of the present invention has a very fine particle size, which is not only easy to stir, but also has small gaps between particles and low gas content between particles, further ensuring a high heat transfer rate and temperature uniformity of the system.

[0029] (4) The solid powder used as the reaction medium of the present invention not only has a very fine particle size, but also has a density close to that of the raw material, thereby ensuring high dispersibility of the raw material in the solid medium.

[0030] (5) Due to the use of a solid medium having the characteristics described in the present invention, the reaction system not only has a uniform temperature, but also has good dispersion of the raw materials in the medium, so that the reaction can be carried out under relatively mild conditions (the reaction temperature is lower than the direct cyclization temperature without a medium and is close to the reaction temperature using a liquid reaction medium), thereby reducing the degree of carbonization and coking, and improving the product yield and product quality.

[0031] (6) The solid powder used as the reaction medium of the present invention has good temperature and chemical stability, will not chemically react with the raw materials and products during the reaction, and will not cause problems such as sintering, oxidation, and decomposition. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Shown is the liquid chromatogram of the finished product of Example 1;

[0033] Figure 2 Shown is the liquid chromatogram of the finished product of Example 2;

[0034] Figure 3 Shown is the liquid chromatogram of the finished product of Example 3;

[0035] Figure 4 Shown is the liquid chromatogram of the finished product of Comparative Example 1. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail below by way of examples, but the present invention is not limited thereto.

[0037] Example 1

[0038] Add 50mL of 5000-mesh graphite to the reactor, replace it with nitrogen three times, start stirring, adjust the stirring speed to 600rpm, heat to 270℃, add 4g of 1,2-cyclopentanedicarboxamide, keep warm for reaction, absorb the ammonia released by the reaction with water, stop heating after 2.5h, cool down, wait for the reactor to cool to room temperature, add 84mL of deionized water three times to extract 1,2-cyclopentanedicarboximide, filter, combine the filtrates, concentrate to 5mL, cool to 5℃, keep warm for crystallization, filter and dry to obtain the finished product, and perform liquid chromatography analysis on the finished product ( Figure 1 As shown), the purity of 1,2-cyclopentanedicarboximide is 98.2% and the yield is 90.4%.

[0039] The liquid chromatography analysis conditions for the finished product of 1,2-cyclopentanedicarboximide are as follows: the chromatographic column used is a C18 column (column diameter 4.6 mm, column length 150 mm, particle diameter 5 um), the column temperature is 40°C; the detector is an ultraviolet detector, the detection wavelength is 255 nm; the mobile phase is an acetonitrile aqueous solution (the volume ratio of acetonitrile to water is 5:3), the flow rate is 0.8 mL / min; the injection volume is 20 uL. The retention time of the product 1,2-cyclopentanedicarboximide in the chromatogram is about 3.4 minutes.

[0040] Example 2-Example 13

[0041] The operation process of Examples 2-13 is the same as that of Example 1, except that the operation parameters are changed. The corresponding changed operation parameters and experimental results are summarized in Table 2.

[0042] The difference between Example 2-3 and Example 1 is only the type of reaction medium.

[0043] Examples 1, 4 and 5 compare the effects of the raw material form (under respective optimized conditions). It can be seen that using 1,2-cyclopentanedicarboxamide as the experimental raw material achieves better reaction results.

[0044] The difference between Examples 6, 7 and 8 is that the amounts of the reaction raw materials are different.

[0045] The difference between Examples 7, 9 and 10 lies in the difference in cyclization temperature.

[0046] The difference between Examples 1, 9 and 11 lies in the difference in cyclization time.

[0047] Examples 1, 12 and 13 compare the effect of the particle size of the solid reaction medium used.

[0048] The physical properties of the solid powder used as the reaction medium in Examples 1-13 are shown in Table 1.

[0049] Comparative Example 1 (solvent-free direct high-temperature cyclization):

[0050] 2 g of 1,2-cyclopentanedicarboxamide was put into a 250 mL three-necked flask, the reaction temperature was set at 280°C, and the reaction was kept warm for 2 hours to obtain a black and white solid mixture. Samples were taken for liquid chromatography analysis, and the purity of 1,2-cyclopentanedicarboximide in the product was 39.1%, and the yield was 20.3%.

[0051] The liquid chromatograms of the liquid chromatographic analysis of the finished 1,2-cyclopentanedicarboximide obtained in Examples 2-3 and Comparative Example 1 are shown in Figure 2 , Figure 3 and Figure 4 .

[0052] Table 1 Physical properties of the solid reaction medium used in the examples

[0053]

[0054] The mesh size of the particle size in Table 1 refers to the particle size passing through a sieve of the corresponding mesh size. For example, the particle size of graphite 1 is passing through a 5000 mesh sieve.

[0055] Table 2

[0056]

Claims

1. A method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium, characterized in that: Using 1,2-cyclopentanedicarboxamide or its salt formed with acid as raw material, under nitrogen protection, stirring and heating the non-water-soluble solid powder to the reaction temperature, adding the raw material, carrying out cyclization reaction, cooling after the reaction, adding deionized water to the reaction system, stirring and extracting, filtering, concentrating the filtrate, cooling and crystallizing, and drying to obtain 1,2-cyclopentanedicarboximide product; the non-water-soluble solid powder used has a melting point higher than 300°C and a density of 0.5-4 g / cm 3 , specific heat capacity greater than or equal to 0.7 J / (g﹒K), thermal conductivity higher than 30 W / (m﹒K), particle size passing through 800-5000 mesh sieve, and having good thermal stability and chemical stability; the water-insoluble solid powder obtained after filtration is dried and recycled for the next cyclization reaction.

2. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The water-insoluble solid powder includes one or a mixture of graphite, aluminum oxide, and silicon carbide, preferably graphite.

3. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The ratio of the mass of the raw material to the volume of the water-insoluble solid powder is (0.5-10) g: 50 mL, preferably (2-6) g: 50 mL.

4. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The cyclization reaction temperature is 200-300°C, preferably 240-270°C.

5. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The cyclization reaction time is 0.5-5 h, preferably 1.5-3 h.

6. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The salt formed by 1,2-cyclopentanedicarboxamide and an acid includes 1,2-cyclopentanedicarboxamide sulfate or 1,2-cyclopentanedicarboxamide phosphate.

7. The method for producing 1,2-cyclopentanedicarboximide using water-insoluble solid powder as a reaction medium according to claim 1, characterized in that: The ammonia released by the cyclization reaction is absorbed by water.

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