A synthesis and detection method of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

Abstract

A method for synthesizing and detecting 1,2,4,5-cyclohexanetetracarboxylic dianhydride belongs to the field of pharmaceutical intermediates. The method uses 1,2,4,5-cyclohexanetetracarboxylic ester to carry out ester exchange and hydrolysis reaction in a specific ratio of organic acid aqueous solution by catalysis of a small amount of concentrated hydrochloric acid, and the obtained intermediate is dehydrated and cyclized in acetic anhydride to obtain high-purity chair-form 1,2,4,5-cyclohexanetetracarboxylic dianhydride, and a methylamine derivatization method is used to obtain fast and convenient conformational differentiation and accurate quantitative results in high-performance liquid chromatography. The present invention is a synthetic method for directional control of conformation, and the obtained product is a chair-form conformation with a content of ≥99.5%, which can provide high-purity raw materials with stable advantageous conformations for the downstream polyimide material field.

Description

Technical Field

[0001] The invention relates to a synthesis and detection method of 1,2,4,5-cyclohexanetetracarboxylic dianhydride mainly in chair conformation, belonging to the technical field of pharmaceutical intermediates. Technical Background

[0002] 1,2,4,5-cyclohexanetetracarboxylic dianhydride is the upstream raw material of polyimide. Since the cyclohexane skeleton has boat, twisted boat and chair conformations, correspondingly, after the polymerization of polyimide, due to the different conformations of the polymerized monomers, the final polymerization degree and corresponding material properties are also different: the thermal properties of cyclohexane anhydride with boat conformation as the main one after polymerization are excellent, but the polymerization degree is not stable enough, while the chair conformation as the dominant conformation shows excellent electrical properties and higher polymerization degree.

[0003] At present, there are many known reports on the synthesis of 1,2,4,5-cyclohexanetetracarboxylic dianhydride: direct hydrogenation method (JP2003286222), esterification hydrolysis method (CN 104926649, JP2006045166) and transesterification method (CN 108069978). The obtained products are characterized by conformation, and most of them are boat conformation or mixed conformation of boat conformation and twisted boat conformation. There is no synthesis method for 1,2,4,5-cyclohexanetetracarboxylic dianhydride with chair conformation as the main conformation.

[0004] The analytical detection methods for the application of this compound in the reaction control process and product content quantification are mainly based on time-consuming thermal analysis, complex derivatization methods or less used normal phase chromatography systems. It is difficult to promote and apply them in the production process, and there is a lack of quick and simple methods that can simultaneously perform conformational differentiation and accurate quantitative detection. Summary of the invention

[0005] The purpose of the present invention is to provide a synthesis and detection method of 1,2,4,5-cyclohexanetetracarboxylic dianhydride with a chair conformation as the main component. The present invention uses cyclohexane carboxylic acid ester as a raw material, uses a specific ratio of organic acid-water for reaction and solvent, and experiments show that after adding a small amount of hydrochloric acid as a catalyst and activating at reflux temperature for a period of time, the compound can simultaneously undergo ester exchange and hydrolysis reactions to obtain high-purity chair conformation cyclohexanetetracarboxylic acid; after drying, the intermediate is dehydrated in acetic anhydride, cooled and crystallized, and after drying, 1,2,4,5-cyclohexanetetracarboxylic dianhydride with a chair conformation as the main component can be obtained.

[0006] Among them, the addition of water is important. During the experiment, it was found that neither hydrolysis nor ester exchange reaction alone could obtain a large amount of chair conformation. The carboxylic acid ester needs to undergo partial ester exchange with the organic acid in a specific solvent environment to obtain the diacid diester and triacid monoester, which are then transferred to the aqueous phase for further acid hydrolysis. Finally, white crystals are precipitated in the organic acid-water mixed solvent system to complete the locking of the chair conformation.

[0007] In the process of reaction control and product conformation differentiation and content determination, a low-concentration methylamine aqueous solution is used in acetonitrile to quickly derivatize the control reaction liquid or product. Methylamine and anhydride structures can generate imines with the same conformation without destroying the ring structure, and the qualitative and quantitative operations of reversed-phase chromatography can be directly performed. The operation is simple and fast, the differentiation is good, and the quantification is accurate, which is conducive to popularization and application.

[0008] To achieve the above technical solution, the synthesis and detection method of 1,2,4,5-cyclohexanetetracarboxylic dianhydride comprises the following steps:

[0009] 1) heating 1,2,4,5-cyclohexanetetracarboxylic acid ester, organic acid, water and concentrated hydrochloric acid to reflux for activation, performing ester exchange and hydrolysis reaction by distilling off low boiling point components, concentrating, cooling and crystallizing, and drying to obtain 1,2,4,5-cyclohexanetetracarboxylic acid with chair conformation as the main component;

[0010] 2) subjecting 1,2,4,5-cyclohexanetetracarboxylic acid and acetic anhydride to dehydration reaction under reflux, cooling for crystallization, and drying to obtain 1,2,4,5-cyclohexanetetracarboxylic dianhydride having a chair conformation as the main component;

[0011] 3) Using a pre-configured methylamine derivatization reagent, 1,2,4,5-cyclohexanetetracarboxylic dianhydride is derivatized to perform conformational differentiation and content detection in high performance liquid chromatography.

[0012] Furthermore, in the above technical solution, the specific operating steps and reaction conditions are as follows:

[0013] 1) The first step, synthesis of 1,2,4,5-cyclohexanetetracarboxylic acid

[0014] After mixing 1,2,4,5-cyclohexanetetracarboxylic acid ester with organic acid, water and concentrated hydrochloric acid, stirring is started, and the temperature is raised to 100-102°C and refluxed for about 2 hours; the temperature in the kettle drops, and a distillation device is used to distill out low-boiling point components and simultaneously carry out ester exchange and hydrolysis reactions, and the fractions with a temperature below 100°C in the kettle are removed as much as possible to maintain the temperature in the kettle at about 100°C and no longer drop, and the temperature is further raised and concentrated; when the water content of the distillate is less than 10%, the temperature is lowered for crystallization, and drying is performed to obtain 1,2,4,5-cyclohexanetetracarboxylic acid with a chair conformation as the main component.

[0015] In the above technical solution, the 1,2,4,5-cyclohexanetetracarboxylic acid ester is selected from 1,2,4,5-cyclohexanetetracarboxylic acid methyl ester, 1,2,4,5-cyclohexanetetracarboxylic acid ethyl ester or 1,2,4,5-cyclohexanetetracarboxylic acid isopropyl ester.

[0016] In the above technical solution, the organic acid is selected from formic acid or acetic acid.

[0017] In the above technical scheme, the molar ratio of 1,2,4,5-cyclohexanetetracarboxylic acid ester to organic acid is 1:4-10, preferably 1:6-8; the amount of water used is 40%-85% by weight of the organic acid, preferably 50%-80%; the amount of concentrated hydrochloric acid used is 0.1%-0.8% by weight of the raw material cyclohexanecarboxylic acid ester, preferably 0.15%-0.5%.

[0018] In the above technical scheme, after the reaction is completed, the 1,2,4,5-cyclohexanetetracarboxylic acid obtained after concentration, cooling, crystallization and drying is mainly a chair conformation.

[0019] 2) The second step, synthesis of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0020] The 1,2,4,5-cyclohexanetetracarboxylic acid and acetic anhydride are heated to reflux for dehydration reaction, and after the reaction is completed, the temperature is lowered for crystallization, and the 1,2,4,5-cyclohexanetetracarboxylic dianhydride having a chair conformation as the main component is obtained by drying;

[0021] In the above technical solution, the molar ratio of 1,2,4,5-cyclohexanetetracarboxylic acid to acetic anhydride is 1:4-10, preferably 1:6-8.

[0022] In the above technical scheme, after the reaction is completed, the 1,2,4,5-cyclohexanetetracarboxylic dianhydride obtained after cooling, crystallization and drying has a chair conformation as the main stereo conformation.

[0023] 3) The third step, detection of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0024] 1,2,4,5-cyclohexanetetracarboxylic dianhydride was derivatized using a pre-configured methylamine derivatization reagent to perform conformational differentiation and content detection in HPLC.

[0025] In the above technical scheme, the preparation method and storage method of the methylamine derivatization reagent are as follows: 150 g of acetonitrile (HPLC grade) is added to 50 g of a commercially available 25% methylamine aqueous solution (GR grade), mixed evenly, filtered through a 0.22 μm nylon membrane, and placed at -4°C for use (valid for 7 days).

[0026] In the above technical scheme, the pretreatment method of the sample to be tested is as follows: add 5 mL of pre-prepared derivatization reagent to 0.5 g of the product obtained in step 2, shake for a few seconds, and after all the solids in the test tube are dissolved, transfer to a 25.00 mL volumetric flask, dilute to the scale with deionized water, take 2 mL of 0.22 μm polyethersulfone membrane to filter, and test.

[0027] In the above technical scheme, the chromatographic column should be Agilent Extend-C18 chromatographic column, column length 250mm, inner diameter 4.6mm, particle size 5um, or equivalent chromatographic column. The mobile phase is acetonitrile and 0.05% disodium hydrogen phosphate aqueous solution, the ratio is acetonitrile / 0.05% disodium hydrogen phosphate-water = 15 / 85. Flow rate: 1mL / min, detection wavelength 205nm, injection volume 10μL, and quantification by normalization method.

[0028] Beneficial effects of the present invention

[0029] 1. Using a specific organic acid-water reaction method catalyzed by hydrochloric acid, cyclohexanecarboxylate undergoes transesterification and hydrolysis reaction. The resulting intermediate is precipitated from the organic acid-water mixed solvent environment, and the stereo conformation of the product can be directionally controlled to be a chair conformation.

[0030] 2. Using the chair conformation intermediate in a specific proportion of acetic anhydride for refluxing and further dehydration reaction without destroying the main conformation, high-purity 1,2,4,5-cyclohexanetetracarboxylic dianhydride with chair conformation as the main component can be obtained to meet the downstream product demand for the dominant conformation.

[0031] 3. It provides an analytical approach: Regarding the stereo conformational structural characterization of this type of solid acid anhydride, the destruction of the conformation should be avoided during the derivatization process, so that conformational differentiation and quantitative detection can be achieved at the same time, which is convenient and fast, and has high promotion and applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is the DSC spectrum of 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 1;

[0033] Figure 2 This is the liquid phase spectrum after derivatization with 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 1;

[0034] Figure 3 is the DSC spectrum of 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 2;

[0035] Figure 4 This is the liquid phase spectrum after derivatization with 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 2;

[0036] Figure 5 is the DSC spectrum of 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 3;

[0037] Figure 6 This is the liquid phase spectrum after derivatization with 1,2,4,5-cyclohexanetetracarboxylic dianhydride in Example 3; DETAILED DESCRIPTION

[0038] Example 1

[0039] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic acid

[0040] In a 250mL four-necked bottle equipped with a thermometer, a reflux condenser, and mechanical stirring, add 31.9g of 1,2,4,5-cyclohexanetetracarboxylic acid methyl ester (0.1mol, content 99%), 36g of acetic acid (0.6mol), 28mL of deionized water, and 0.05ml of concentrated hydrochloric acid, start stirring, and heat to 100-102°C and reflux for about 2h. When the reflux temperature in the kettle begins to drop, switch to the distillation device to start distillation, remove as much as possible the fraction below 100°C in the kettle, and keep the bottom temperature at 100°C and no longer drop. Continue to heat up and distill until the water content of the distilled liquid is less than 10%, cool down and crystallize, and dry to obtain 22.8g of 1,2,4,5-cyclohexanetetracarboxylic acid (yield 87%, content 99%).

[0041] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0042] In a 250mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer, add 22.8g of 1,2,4,5-cyclohexanetetracarboxylic acid (0.087mol, content 99%) and 53.2g of acetic anhydride (0.52mol), start stirring and heat to 142°C for reflux for about 1h. Cool down and crystallize, dry, and obtain 17.2g of 1,2,4,5-pyromellitic tetracarboxylic dianhydride (yield 88%, content 99.5%). The stereostructure is chair conformation as characterized by DSC, see attached Figure 1 .

[0043] Content detection of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0044] Preparation of derivatization reagent: Add 150 g of acetonitrile (HPLC grade) to 50 g of commercially available 25% methylamine aqueous solution (GR grade), mix well, pass through a 0.22 μm nylon membrane, and place at -4°C for use (valid for 7 days).

[0045] Sample pretreatment: Add 5 mL of pre-prepared derivatization reagent to 0.5 g of the product obtained in step 2, shake for a few seconds, and after all the solid in the test tube is dissolved, transfer to a 25.00 mL volumetric flask, dilute to the mark with deionized water, and take 2 mL to pass through a 0.22 μm polyethersulfone membrane for testing.

[0046] The chromatographic column selected was Agilent Extend-C18 chromatographic column, and acetonitrile and 0.05% sodium dihydrogen phosphate aqueous solution were used as the system mobile phase. The mobile phase ratio was pre-adjusted to acetonitrile / 0.05% sodium dihydrogen phosphate-water = 15 / 85. The system was flushed isocratically at a flow rate of 1 mL / min. After the baseline was stable, the injection was started. The detection wavelength was 205 nm, the injection volume was 10 μL, and the normalization method was used for quantification. It can be seen that the retention time of the analyte (chair conformation) after derivatization was 3.745 min, and the content was 99.49%. The other two impurities were derivatives of the boat conformation and the twisted boat conformation, respectively. The spectra are shown in the attached Figure 2 .

[0047] Example 2

[0048] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic acid

[0049] Add 37.6g of 1,2,4,5-cyclohexanetetracarboxylic acid ethyl ester (0.1mol, content 99%), 48g of acetic acid (0.8mol), 24mL of deionized water, and 0.15mL of concentrated hydrochloric acid to a 250mL four-necked bottle equipped with a thermometer, a reflux condenser, and mechanical stirring, turn on stirring, heat to 100-102°C and reflux for about 3h. When the reflux temperature in the kettle begins to drop, switch to the distillation device to start distillation, remove as much as possible the fraction below 100°C in the kettle, and keep the bottom temperature at 100°C and no longer drop. Continue to heat and distill until the water content of the distilled liquid is less than 10%, cool and crystallize, and dry to obtain 21.3g of 1,2,4,5-cyclohexanetetracarboxylic acid (yield 81%, content 99%).

[0050] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0051] In a 250mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer, add 21.3g of 1,2,4,5-cyclohexanetetracarboxylic acid (0.081mol, content 99%) and 66.1g of acetic anhydride (0.648mol), start stirring and heat to 142°C for reflux for 0.5h. Cool down and crystallize, dry, and obtain 14.4g of 1,2,4,5-pyromellitic tetracarboxylic dianhydride (yield 79%, content 99.5%). The stereostructure is chair conformation as characterized by DSC, see attached Figure 3 .

[0052] Content detection of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0053] Preparation of derivatization reagent: Add 150 g of acetonitrile (HPLC grade) to 50 g of commercially available 25% methylamine aqueous solution (GR grade), mix well, pass through a 0.22 μm nylon membrane, and place at -4°C for use (valid for 7 days).

[0054] Sample pretreatment: Add 5 mL of pre-prepared derivatization reagent to 0.5 g of the product obtained in step 2, shake for a few seconds, and after all the solid in the test tube is dissolved, transfer to a 25.00 mL volumetric flask, dilute to the mark with deionized water, and take 2 mL to pass through a 0.22 μm polyethersulfone membrane for testing.

[0055] The chromatographic column selected was Agilent Extend-C18 chromatographic column, and acetonitrile and 0.05% sodium dihydrogen phosphate aqueous solution were used as the system mobile phase. The mobile phase ratio was pre-adjusted to acetonitrile / 0.05% sodium dihydrogen phosphate-water = 15 / 85. The system was flushed isocratically at a flow rate of 1 mL / min. After the baseline was stable, the injection was started. The detection wavelength was 205 nm, the injection volume was 10 μL, and the normalization method was used for quantification. It can be seen that the retention time of the analyte (chair conformation) after derivatization was 3.746 min, and the content was 99.53%. The other two impurities were boat-type and twisted boat-type conformation derivatives, and the spectra are shown in the attached Figure 4 .

[0056] Example 3

[0057] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic acid

[0058] In a 250mL four-necked bottle equipped with a thermometer, a reflux condenser, and a mechanical stirrer, add 43.3g of 1,2,4,5-cyclohexanetetracarboxylic acid isopropyl ester (0.1mol, content 99%), 36.8g of formic acid (0.8mol), 28mL of deionized water, and 0.2mL of concentrated hydrochloric acid, start stirring, heat to 100-102°C and reflux for about 2h. When the reflux temperature in the kettle begins to drop, switch to the distillation device to start distillation, remove as much as possible the fraction below 100°C in the kettle, and keep the bottom temperature at 100°C and no longer drop. Continue to heat up and distill until the water content of the distilled liquid is less than 10%, cool down and crystallize, and dry to obtain 22g of 1,2,4,5-cyclohexanetetracarboxylic acid (yield 84%, content 99%).

[0059] Synthesis of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0060] In a 250mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer, add 22g of 1,2,4,5-cyclohexanetetracarboxylic acid (0.084mol, content 99%) and 60g of acetic anhydride (0.59mol), start stirring and heat to 142°C for 1h. Cool down and crystallize, dry, and obtain 16.1g of 1,2,4,5-pyromellitic tetracarboxylic dianhydride (yield 85%, content 99.5%). The stereostructure is chair conformation as characterized by DSC, see attached Figure 5 .

[0061] Content detection of 1,2,4,5-cyclohexanetetracarboxylic dianhydride

[0062] Preparation of derivatization reagent: Add 150 g of acetonitrile (HPLC grade) to 50 g of commercially available 25% methylamine aqueous solution (GR grade), mix well, pass through a 0.22 μm nylon membrane, and place at -4°C for use (valid for 7 days).

[0063] Sample pretreatment: Add 5 mL of pre-prepared derivatization reagent to 0.5 g of the product obtained in step 2, shake for a few seconds, and after all the solid in the test tube is dissolved, transfer to a 25.00 mL volumetric flask, dilute to the mark with deionized water, and take 2 mL to pass through a 0.22 μm polyethersulfone membrane for testing.

[0064] The chromatographic column selected was an Agilent Extend-C18 chromatographic column, and acetonitrile and 0.05% disodium hydrogen phosphate aqueous solution were used as the system mobile phases. The mobile phase ratio was pre-adjusted to acetonitrile / 0.05% disodium hydrogen phosphate-water=15 / 85.

[0065] The system was flushed isocratically at a flow rate of 1 mL / min. After the baseline was stable, the sample was injected. The detection wavelength was 205 nm and the injection volume was 10 μL. The normalization method was used for quantification. It was found that the retention time of the analyte (chair conformation) after derivatization was 3.745 min and the content was 99.49%. The other two impurities were boat-type and twisted boat-type derivatives, respectively. The spectra are shown in the attached Figure 6 .

[0066] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing 1,2,4,5-cyclohexanetetracarboxylic dianhydride, characterized in that: The steps include: 1) heating 1,2,4,5-cyclohexanetetracarboxylic acid ester, organic acid, water and concentrated hydrochloric acid to reflux for activation, performing ester exchange and hydrolysis reaction by distilling off low boiling point components, concentrating, cooling and crystallizing, and drying to obtain 1,2,4,5-cyclohexanetetracarboxylic acid with chair conformation as the main component; the organic acid is selected from formic acid or acetic acid; the molar ratio of 1,2,4,5-cyclohexanetetracarboxylic acid ester to organic acid is 1:6-8; the amount of water used is 50-80% of the weight of the organic acid; the amount of concentrated hydrochloric acid used is 0.15-0.5% of the raw material cyclohexanecarboxylic acid ester; 2) subjecting 1,2,4,5-cyclohexanetetracarboxylic acid and acetic anhydride to dehydration reaction under reflux, cooling for crystallization, and drying to obtain 1,2,4,5-cyclohexanetetracarboxylic dianhydride having a chair conformation as the main component; the molar ratio of the 1,2,4,5-cyclohexanetetracarboxylic acid to the acetic anhydride is 1:6-8; 3) Using a pre-configured methylamine derivatization reagent, 1,2,4,5-cyclohexanetetracarboxylic dianhydride is derivatized to perform conformational differentiation and content detection in high performance liquid chromatography.

2. The method for synthesizing 1,2,4,5-cyclohexanetetracarboxylic dianhydride according to claim 1, characterized in that: In step 1), the 1,2,4,5-cyclohexanetetracarboxylic acid ester is selected from 1,2,4,5-cyclohexanetetracarboxylic acid methyl ester, 1,2,4,5-cyclohexanetetracarboxylic acid ethyl ester or 1,2,4,5-cyclohexanetetracarboxylic acid isopropyl ester.

3. The method for synthesizing 1,2,4,5-cyclohexanetetracarboxylic dianhydride according to claim 1, characterized in that: Step 3) Preparation and storage of the methylamine derivatization reagent: Add 150 g of HPLC grade acetonitrile to 50 g of commercially available GR grade 25% methylamine aqueous solution, mix well and filter through a 0.22 μm nylon membrane, and store at -4°C. The shelf life is 7 days.

4. The method for synthesizing 1,2,4,5-cyclohexanetetracarboxylic dianhydride according to claim 3, characterized in that: In step 3), acetonitrile and 0.05% sodium dihydrogen phosphate are used as mobile phases for the high performance liquid chromatography detection, and an Agilent Extend C-18 column or an equivalent column thereof is used as the chromatographic column.

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