A CAM preparation process and its application

Abstract

The invention relates to the field of C07C233 / 08, and specifically relates to a CAM preparation process and application thereof. Acetic anhydride is used as a dehydrating agent, 1,1-cyclohexanediacetic acid is dehydrated to form 1,1-cyclohexanediacetic anhydride, and the 1,1-cyclohexanediacetic anhydride is added dropwise into ammonia water to obtain the CAM. The production process is simple, the labor cost is greatly reduced, the production efficiency is improved, the generation of side reactions is reduced, and the product quality is improved. The CAM finished product has good crystallization and no agglomeration, the liquid phase content is higher than 99.9%, and the yield reaches 96%, reaching the international leading level in the same industry.

Description

Technical Field

[0001] The present invention relates to the field of C07C233 / 08, and in particular to a CAM preparation process and application thereof. Background Art

[0002] Gabapentin has different pharmacological effects from existing anticonvulsant drugs, and has shown effects in various animal models to prevent epilepsy. In addition, it also shows effects in animal models of spasm, analgesia and amyotrophic lateral sclerosis. Compared with other anticonvulsant drugs, gabapentin has fewer behavioral and cardiovascular side effects. CAM (1,1-cyclohexanediacetic acid monoamide), as an important intermediate of gabapentin, has attracted much attention.

[0003] Chinese patent CN 103333081A discloses a method for preparing 1,1-cyclohexyldiacetic acid monoamide, using 1,1-cyclohexyl dicyanoacetate, 1,1-cyclohexyldiacetic acid and 1,1-cyclohexyldiacetic anhydride as main raw materials to prepare 1,1-cyclohexyldiacetic acid monoamide with high purity and yield. However, the purity of the product after crystallization with deionized water needs to be improved, and the production process is complicated, the labor cost is high, and the production efficiency is very low. Chinese patent CN 104402744 A discloses a method for preparing gabapentin, wherein 1,1-cyclohexanediacetic acid monoamide is prepared to prepare 3,3-pentylidenebutyrolactam and then gabapentin is prepared, dichlorotoluene and / or tetrahydrofuran are used as inert solvents, 1,1'-cyclohexanediacetic anhydride is reacted with ammonia water and an acid-binding agent triethylamine, and no post-treatment process is performed. The purity and yield of the 1,1-cyclohexanediacetic acid monoamide product are insufficient, and the yield and quality of the 1,1-cyclohexanediacetic acid monoamide product directly affect the purity and yield of gabapentin.

[0004] In view of the above problems, the present invention provides a CAM preparation process, which has a simple production process, greatly reduces labor costs and improves production efficiency, reduces the occurrence of side reactions, and improves product quality. The CAM finished product has good crystallization and no agglomeration, the liquid phase content is higher than 99.9%, and the yield reaches 96%, reaching the international leading level in the same industry. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a CAM preparation process, which uses acetic anhydride as a dehydrating agent, dehydrates 1,1-cyclohexanediacetic acid to form 1,1-cyclohexanediacetic anhydride, and then adds 1,1-cyclohexanediacetic anhydride dropwise into ammonia water to obtain CAM.

[0006] As a preferred technical solution, the CAM preparation process includes at least the following steps:

[0007] (1) Anhydrification: 1,1-cyclohexanediacetic acid and acetic anhydride are added into a reaction kettle, heated to reflux, and distilled under reduced pressure to obtain anhydride material, and the anhydride material is cooled to 50-80°C;

[0008] (2) Amination: adding the anhydride material dropwise into aqueous ammonia to carry out an amination reaction to obtain an ammoniated material;

[0009] (3) Acidification: Sulfuric acid is added dropwise to the aminated material for acidification, followed by heat preservation and filtration to obtain a filter cake;

[0010] (4) Post-treatment: The filter cake is dissolved in an alcohol solution, filtered while hot, and the filtrate is cooled and recrystallized. The CAM product is obtained after filtration, water washing, and vacuum drying.

[0011] As a preferred technical solution, the mass ratio of 1,1-cyclohexanediacetic acid and acetic anhydride in step (1) is (1.5-5): (0.8-2); preferably, the mass ratio of 1,1-cyclohexanediacetic acid and acetic anhydride in step (1) is (1.8-2.5): 1 Preferably, the heating and reflux in step (1) is specifically: gradually heating to 100-170°C, and maintaining the reflux cycle for 100-150min. Based on the system of the present invention, 1,1-cyclohexanediacetic acid and acetic anhydride are fully reacted by heating and reflux, and then the unreacted acetic acid and acetic anhydride are distilled out by reduced pressure distillation, and then the anhydride material is cooled to 50-80°C to ensure that the anhydride material is effectively used for subsequent ammoniation, and avoid agglomeration of the anhydride material due to the low temperature of the anhydride material, which affects the subsequent ammoniation reaction; at the same time, the ammoniation reaction rate is appropriately increased, and the anhydride material dropwise addition time is shortened, which helps to improve production efficiency.

[0012] As a preferred technical solution, the ammoniation in step (2) is specifically as follows: at room temperature, the anhydride material is added dropwise into ammonia water for 4-6 hours. After the addition is completed, the reaction is stirred for 1-3 hours, and then activated carbon is added for decolorization, and the mixture is kept warm at room temperature for 20-40 minutes to obtain the ammoniation material;

[0013] Preferably, the concentration of the ammonia water is 8-20wt%, and the mass ratio of the anhydride material to the ammonia water is (3-6):1; preferably, the concentration of the ammonia water is 10-15wt%, and the mass ratio of the anhydride material to the ammonia water is (4-5):1. Preferably, the mass ratio of the activated carbon to the ammonia water is (0.8-1.2):1000. Preferably, the dripping time of the anhydride material is 4h, and the stirring reaction time is 2h; by designing that the anhydride material is stirred for 2h after the dripping is completed in 4h during the ammoniation process, the anhydride material and the ammoniation material with a concentration of 10-15wt% are fully ammoniated, while avoiding the use of high-concentration ammonia water to affect the health of workers and pollute the environment.

[0014] As a preferred technical solution, the acidification in step (3) is specifically as follows: at room temperature, the stirring speed is controlled to be 40-60 r / min, sulfuric acid is added dropwise to the aminated material until the pH value of the material is 1-5, and then filtered to obtain a filter cake.

[0015] As a preferred technical solution, the sulfuric acid in step (3) is a sulfuric acid aqueous solution with a mass fraction of 40-60%, and the sulfuric acid is added dropwise for 50-70 minutes.

[0016] Based on the system of the present invention, by controlling the mass ratio of 1,1-cyclohexanediacetic acid and acetic anhydride to be (1.5-5): (0.8-2), especially the mass ratio of (1.8-2.5): 1,1-cyclohexanediacetic acid and acetic anhydride to react, the raw material purity of the anhydride material is guaranteed, the purity of the ammoniated material prepared by the subsequent amination reaction is guaranteed, the amount of activated carbon used is reduced, and the quality of CAM products is guaranteed while reducing the production cost. The inventor analyzed that the reason may be: at this mass ratio, 1,1-cyclohexanediacetic acid and acetic anhydride react fully, ensuring the yield of the anhydride material while reducing the generation of by-products, when the anhydride material with higher purity reacts with ammonia water with a concentration of 10-15wt%, the competitive reaction between impurities and ammonia water has little effect on the main reaction, thereby improving the purity of the ammoniated material, and the low amount of activated carbon added in the system can effectively remove impurities in the anhydride material, reduce the cost of activated carbon, and at the same time contribute to the stability of the subsequent acidification reaction, greatly shorten the sulfuric acid addition time, and improve production efficiency.

[0017] As a preferred technical solution, the temperature of the alcohol solution in step (4) is 50-70°C;

[0018] Preferably, the alcohol solution is one or a combination of methanol aqueous solution, ethanol aqueous solution, isopropanol aqueous solution, and ethylene glycol aqueous solution;

[0019] Preferably, the alcohol solution is an ethanol aqueous solution, and the mass concentration of ethanol in the ethanol aqueous solution is 20-50%.

[0020] The inventors found in the actual production and development process that in the traditional production process of CAM, the generation of by-products can be reduced by controlling the sulfuric acid addition time, but the acidification reaction process is as long as more than 8 hours, which seriously affects the production efficiency, and the crystallinity of the CAM finished product needs to be improved. This may be due to the inclusion of impurities during crystallization, which affects the purity of the crystal. The applicant unexpectedly found in the actual production and development process that by controlling the acidification time of the ammoniated material prepared by step (2) to be shortened to 50-70 minutes, and post-treating the filter cake obtained after acidification, especially placing the filter cake in an ethanol aqueous solution with a mass concentration of 20-50% at a temperature of 50-70°C for recrystallization, the purity of the CAM product is increased to more than 99.9% without losing the CAM product, and the yield is more than 96%, reaching the international leading level in the same industry; at the same time, the production efficiency is greatly improved. The inventors analyzed that the reasons may be: on the one hand, at this concentration and temperature, the ethanol aqueous solution can effectively dissolve the filter cake, and the solubility of the CAM product in the filter cake is much lower than the solubility of the impurities in the filter cake, so that the impurities in the filter cake are filtered out during hot filtration, effectively improving the purity of the CAM product, and the CAM product is well crystallized and does not agglomerate. On the other hand, at this concentration, the CAM product will not precipitate, ensuring the product yield. If the concentration of the ethanol aqueous solution is too high or the temperature is too high, the CAM product will precipitate, resulting in a decrease in the product yield. If the concentration of the ethanol aqueous solution is too low or the temperature is too low, the impurities in the filter cake cannot be effectively removed, the product purity is reduced, and the subsequent recrystallization is affected, resulting in a decrease in product quality.

[0021] The second aspect of the present invention provides an application of a CAM preparation process, which is applied to the preparation of high-purity 1,1-cyclohexyldiacetic acid monoacetyl.

[0022] Beneficial Effects

[0023] 1. The present invention provides a CAM preparation process, which has a simple production process, greatly reduces labor costs and improves production efficiency, reduces the occurrence of side reactions, and improves product quality. The CAM finished product has good crystallization and no agglomeration, the liquid content is higher than 99.9%, and the yield reaches 96%, reaching the international leading level in the same industry.

[0024] 2. Based on the system of the present invention, 1,1-cyclohexyldiacetic acid and acetic anhydride are fully reacted by heating and refluxing, and then the unreacted acetic acid and acetic anhydride are evaporated by reduced pressure distillation, and then the anhydride material is cooled to 50-80°C to ensure that the anhydride material is effectively used for subsequent amination, and to avoid agglomeration of the anhydride material due to the low temperature of the anhydride material, which affects the subsequent amination reaction; at the same time, the amination reaction rate is appropriately increased, and the anhydride material addition time is shortened, which helps to improve production efficiency.

[0025] 3. Based on the system of the present invention, by controlling the mass ratio of 1,1-cyclohexanediacetic acid and acetic anhydride to be (1.5-5):(0.8-2), especially reacting 1,1-cyclohexanediacetic acid and acetic anhydride in a mass ratio of (1.8-2.5):1, the raw material purity of the anhydride material is ensured, the purity of the aminated material prepared by the subsequent ammoniation reaction is ensured, the use amount of activated carbon is reduced, the quality of CAM products is ensured, and the production cost is reduced.

[0026] 4. Based on the CAM preparation process designed by the present invention, the acidification time of the aminated material prepared in step (2) is shortened to 50-70 min, and the filter cake obtained after acidification is post-treated, especially the filter cake is placed in an ethanol aqueous solution with a mass concentration of 20-50% at a temperature of 50-70° C. for recrystallization. Under the premise of not losing the CAM product, the purity of the CAM product is increased to more than 99.9%, and the yield is achieved to more than 96%; at the same time, the production efficiency is greatly improved. DETAILED DESCRIPTION

[0027] Example 1

[0028] Embodiment 1 of the present invention provides a CAM preparation process, comprising the following steps:

[0029] (1) Anhydrification: 1,1-cyclohexanediacetic acid and acetic anhydride are added into a reaction kettle, heated to reflux, and distilled under reduced pressure to obtain an anhydride material, and the anhydride material is cooled to 75° C.;

[0030] (2) Amination: adding the anhydride material dropwise into aqueous ammonia to carry out an amination reaction to obtain an ammoniated material;

[0031] (3) Acidification: Sulfuric acid is added dropwise to the aminated material for acidification, followed by heat preservation and filtration to obtain a filter cake;

[0032] (4) Post-treatment: The filter cake is dissolved in an alcohol solution, filtered while hot, and the filtrate is cooled and recrystallized. The CAM product is obtained after filtration, water washing, and vacuum drying.

[0033] The mass ratio of 1,1-cyclohexanediacetic acid to acetic anhydride in step (1) is 2:1, and the mass of 1,1-cyclohexanediacetic acid in step (1) is 4000g. The heating and reflux in step (1) is specifically: gradually heating to 130°C and maintaining the reflux cycle for 120min. The mass of the anhydride material is 2175g.

[0034] The ammoniation in step (2) is specifically as follows: at 25° C., the anhydride material is added dropwise into ammonia water for 4 hours. After the addition is completed, the reaction is stirred for 2 hours, and then activated carbon is added for decolorization. The mixture is kept warm at room temperature for 30 minutes to obtain the ammoniation material;

[0035] The concentration of the ammonia water is 12wt%, the mass ratio of the anhydride material to the ammonia water is 4.6:1, and the mass ratio of the activated carbon to the ammonia water is 1:1000.

[0036] The acidification in step (3) is specifically as follows: at 25° C., the stirring speed is controlled to be 50 r / min, sulfuric acid is added dropwise to the aminated material until the pH value of the material is 2, and then filtered to obtain a filter cake.

[0037] The sulfuric acid in step (3) is a sulfuric acid aqueous solution with a mass fraction of 50%, and the sulfuric acid is added dropwise for 60 minutes.

[0038] The temperature of the alcohol solution in step (4) is 60°C; the mass ratio of the alcohol solution to the filter cake is 10:1.

[0039] The alcohol solution is an ethanol aqueous solution, and the mass concentration of ethanol in the ethanol aqueous solution is 30%.

[0040] The purity of the CAM product is 99.95%, and the mass yield is 98%.

[0041] The second aspect of Example 1 of the present invention provides an application of a CAM preparation process, which is applied to the preparation of high-purity 1,1-cyclohexanediacetic acid monoacetyl.

[0042] Example 2

[0043] Embodiment 2 of the present invention provides a CAM preparation process, and the specific implementation method is the same as that of embodiment 1, except that the temperature of the alcohol solution in step (4) is 70°C; the mass ratio of the alcohol solution to the filter cake is 15:1; the mass concentration of ethanol in the ethanol aqueous solution is 20%. The purity of the CAM product is 99.93%, and the mass yield is 98%.

[0044] Example 3

[0045] Embodiment 3 of the present invention provides a CAM preparation process, and the specific implementation method is the same as that of embodiment 1, except that the temperature of the alcohol solution in step (4) is 50°C; the mass ratio of the alcohol solution to the filter cake is 8:1; the mass concentration of ethanol in the ethanol aqueous solution is 50%. The purity of the CAM product is 99.92%, and the mass yield is 96%.

[0046] Comparative Example 1

[0047] Comparative Example 1 of the present invention provides a CAM preparation process, and the specific implementation method is the same as that of Example 1, except that the alcohol solution in step (4) is replaced by an equal amount of deionized water. The purity of the CAM product is 99.80%, and the mass yield is 95%.

[0048] Comparative Example 2

[0049] Comparative Example 2 of the present invention provides a CAM preparation process, and the specific implementation method is the same as that of Example 1, except that the temperature of the alcohol solution in step (4) is 80°C; the mass ratio of the alcohol solution to the filter cake is; the mass concentration of ethanol in the ethanol aqueous solution is 10%. The purity of the CAM product is 99.85%, and the mass yield is 95.8%.

[0050] Comparative Example 3

[0051] Comparative Example 3 of the present invention provides a CAM preparation process, and the specific implementation method is the same as that of Example 1, except that the temperature of the alcohol solution in step (4) is 40°C; the mass ratio of the alcohol solution to the filter cake is; the mass concentration of ethanol in the ethanol aqueous solution is 70%. The purity of the CAM product is 99.88%, and the mass yield is 95.2%.

[0052] Performance Testing Methods

[0053] 1. Product purity: The purity of the CAM products prepared in the examples and comparative examples was determined by liquid chromatography.

[0054] 2. Product mass yield: The mass yield of the CAM products prepared in the examples and comparative examples was calculated by the following formula.

[0055] Product quality yield = actual CAM quality generated / theoretical CAM quality generated (theoretical CAM quality generated = m(CDA) / 200*199).

Claims

1. A CAM preparation process, characterized in that: The following steps are involved: (1) Anhydrification: 1,1-cyclohexanediacetic acid and acetic anhydride are added into a reaction kettle, heated to reflux, and distilled under reduced pressure to obtain an anhydride material, and the anhydride material is cooled to 75° C.; (2) Amination: adding the anhydride material dropwise into aqueous ammonia to carry out an amination reaction to obtain an ammoniated material; (3) Acidification: Sulfuric acid is added dropwise to the aminated material for acidification, followed by heat preservation and filtration to obtain a filter cake; (4) Post-treatment: dissolve the filter cake in an alcohol solution, filter it while hot, cool the filtrate and recrystallize it, filter, wash with water, and vacuum dry to obtain the CAM product; In the step (1), the mass ratio of 1,1-cyclohexanediacetic acid to acetic anhydride is 2:1, and the mass of 1,1-cyclohexanediacetic acid in the step (1) is 4000 g; the heating and reflux in the step (1) is specifically: gradually heating to 130° C. and maintaining the reflux cycle for 120 min; the mass of the anhydride material is 2175 g; The ammoniation in step (2) is specifically as follows: at 25° C., the anhydride material is added dropwise into ammonia water for 4 hours. After the addition is completed, the reaction is stirred for 2 hours, and then activated carbon is added for decolorization. The mixture is kept warm at room temperature for 30 minutes to obtain the ammoniation material; The concentration of the ammonia water is 12wt%, the mass ratio of the anhydride material to the ammonia water is 4.6:1; the mass ratio of the activated carbon to the ammonia water is 1:1000; The acidification in step (3) is specifically as follows: at 25° C., controlling the stirring speed to 50 r / min, adding sulfuric acid dropwise to the aminated material until the pH value of the material is 2, and then filtering to obtain a filter cake; In the step (3), the sulfuric acid is a 50% sulfuric acid aqueous solution, and the sulfuric acid is added dropwise for 60 minutes; The temperature of the alcohol solution in step (4) is 60° C.; the mass ratio of the alcohol solution to the filter cake is 10:

1. The alcohol solution is an ethanol aqueous solution, and the mass concentration of ethanol in the ethanol aqueous solution is 30%; The purity of the CAM product is 99.95%, and the mass yield is 98%.

2. An application of the CAM preparation process according to claim 1, characterized in that: It is used in the preparation of high-purity 1,1-cyclohexyldiacetic acid monoacetyl.