Preparation and purification method of crystal form of p-xylylene dicamphor sulfonate

Abstract

The invention provides a preparation and purification method of a p-xylylene dicamphor sulfonate crystal form, which comprises the following steps: carrying out condensation polymerization on camphorsulfonic acid and terephthalaldehyde under the action of organic alkali to prepare p-xylylene dicamphor sulfonate, carrying out post-treatment, dissolving, clarifying and layering, dropwise adding ethanol, and sequentially carrying out first crystal growing and second crystal growing to obtain the p-xylylene dicamphor sulfonate crystal form. The preparation method comprises the following steps: dissolving p-xylylene dicamphor sulfonate in water to obtain a crude product of the p-xylylene dicamphor sulfonate crystal form, decolorizing the crude product, and carrying out gradient cooling crystallization, so that the high-purity p-xylylene dicamphor sulfonate crystal form product with high yield can be prepared, the content of impurities in the product is effectively controlled, the irritation of the impurities to the skin is reduced, and the safety of the product is improved. Meanwhile, the product has a crystal form, the moisture absorption of the product can be improved, and storage is easy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of fine chemicals preparation, and relates to a preparation and purification method of a p-xylylene dicamphor sulfonic acid salt crystal form. BACKGROUND

[0002] When ultraviolet rays excessively irradiate on the skin, it will promote the formation of erythema or the production of melanin in skin cells, thus causing spots and blemishes. In addition, ultraviolet rays react with sebum secreted by the epidermis of the skin to produce lipid peroxide, which not only causes skin problems, but can even cause skin cancer in severe cases. Therefore, for sunscreens applied to the skin, countries have strictly limited their stability and irritation. The role of sunscreen is to absorb ultraviolet rays to prevent them from contacting the skin, thus cutting off the damage of ultraviolet rays to the skin and playing a protective role. In cosmetic products, the evaluation of stability and irritation of impurities generated during synthesis is also strengthened, and impurities are required to be removed to improve the purity of the product. If this trend cannot be met, some raw materials may be excluded from the scope of use.

[0003] Ultraviolet blockers are mainly used to prevent damage to the skin caused by ultraviolet rays, which can be roughly divided into chemical ultraviolet blockers and physical ultraviolet blockers. Chemical ultraviolet blockers block ultraviolet rays through chemical absorption, and common ones include cinnamic acid, salicylic acid and benzophenone; physical ultraviolet blockers rely on physical scattering and shielding mechanisms to resist ultraviolet rays, and inorganic ultraviolet blockers such as titanium dioxide and zinc oxide are typical representatives. In addition, p-xylylene dicamphor sulfonic acid, as an organic ultraviolet blocker, can effectively block ultraviolet A and part of ultraviolet B, thus having excellent ultraviolet blocking performance and antioxidant capacity.

[0004] P-xylylene dicamphor sulfonic acid has been approved by the US FDA for use in sunscreen due to its good cutting performance for UVA-A in the wavelength range of 320-400 nm. With the growing demand for cutting ultraviolet rays, its market continues to expand, not only widely used in the field of cosmetics, but also showing a broad application prospect in hair conditioner, medicine and other fields. However, using traditional synthesis technology, it is difficult to remove charged organic impurities, phosphorus chlorides, sulfate ions, chloride ions, heavy metals, sodium and other impurities in the synthesis process of p-xylylene dicamphor sulfonic acid. P-xylylene dicamphor sulfonic acid is obtained by polymerization reaction of 2 moles of 10-dl-camphor sulfonic acid and 1 mole of p-xylene formaldehyde in the presence of a base.

[0005] However, the existing preparation method of the terephthalylidene dicamphor sulfonic acid salt has some problems: the product has low purity, is easy to absorb moisture, and has a deep color. A large amount of organic impurities are generated during synthesis, resulting in a chemical purity of only 72%. Among them, two main impurities A (liquid phase retention time 3.76 min) and impurity B (liquid phase retention time 9.23 min) have high content (the HPLC spectrum of the product is shown in Figure 1 ).

[0006] In summary, a preparation and purification method of a terephthalylidene dicamphor sulfonic acid salt crystal form is provided to make the content of impurities A and B in the terephthalylidene dicamphor sulfonic acid salt meet the safety standard, and have a good crystal form. SUMMARY

[0007] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation and purification method of a terephthalylidene dicamphor sulfonic acid salt crystal form, which can obtain a high-purity product with high yield, effectively control the content of impurities, reduce the irritation of impurities to the skin, improve the safety of the product, and at the same time, the crystal form of the product meets the stability of long-term storage and improves the moisture absorption of the product.

[0008] To achieve the purpose of the present application, the following technical solutions are adopted:

[0009] The present application provides a preparation and purification method of a terephthalylidene dicamphor sulfonic acid salt crystal form, which comprises the following steps:

[0010] (1) mixing camphor sulfonic acid, an organic base and a first solvent, adding a terephthaldehyde solution thereto, and performing a polymerization reaction to obtain a reaction mixture;

[0011] (2) after the reaction mixture of step (1) is subjected to a cooling treatment, an acid solution and a third solvent are sequentially added thereto, a first temperature rise is performed, a solid-liquid separation is performed, a second temperature rise is performed on the obtained filtrate after the separation, a fourth solvent is added thereto, and then a first crystal growth and a second crystal growth are sequentially performed to obtain a terephthalylidene dicamphor sulfonic acid salt crystal form crude product;

[0012] (3) mixing the third solvent and the terephthalylidene dicamphor sulfonic acid salt crystal form crude product of step (2), sequentially performing a decolorization treatment and a gradient cooling crystallization to obtain a purified terephthalylidene dicamphor sulfonic acid salt crystal form product.

[0013] The preparation and purification method provided by the application is as follows: camphorsulfonic acid and p-xylene glycol are subjected to polycondensation reaction under the action of an organic base to prepare p-xylene glycol camphorsulfonate, after post-treatment, dissolution, layering, dropwise addition of a fourth solvent, first and second crystal growth, a crude product of p-xylene glycol camphorsulfonate crystal form is obtained, after decolorization of the crude product, high-purity p-xylene glycol camphorsulfonate crystal form product can be prepared at a high yield by gradient cooling crystallization. The preparation and purification method can effectively control the content of impurities in the product, reduce the irritation of impurities to the skin, improve the safety of the product, and at the same time, the product has a crystal form, can improve the hygroscopicity of the product, and is easy to store.

[0014] It should be noted that dropwise addition of ethanol to the reaction filtrate is conducive to product precipitation, and then first and second crystal growth, which is conducive to product precipitation and no longer sticky, easy to filter, improve production efficiency, and finally use water-soluble crude product combined with gradient cooling crystallization, so that the product has high purity and has a crystal form.

[0015] As a preferred technical solution of the application, the mixing method of step (1) comprises: mixing camphorsulfonic acid and a first solvent under stirring in a protective atmosphere, cooling to 5-10℃, dropwise adding an organic base to the mixture, and controlling the temperature of the mixture to be 10-30℃.

[0016] Preferably, the organic base of step (1) comprises sodium methoxide and / or sodium ethoxide.

[0017] Preferably, the p-xylene glycol solution of step (1) comprises p-xylene glycol and a second solvent.

[0018] Preferably, the solid-liquid ratio of p-xylene glycol and the second solvent in step (1) is (4-10):1 kg / L, for example, it can be 5:1 kg / L, 6:1 kg / L, 7:1 kg / L, 8:1 kg / L or 9:1 kg / L, etc., but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0019] Preferably, the first solvent and the second solvent of step (1) are both a mixture of methanol and toluene.

[0020] It should be noted that the first solvent and the second solvent in the reaction system are the same type of solvent, which avoids the reaction being a heterogeneous reaction, solves the problems of low reaction yield, many side reactions, and difficult purification, and solves a series of key problems restricting the industrial production of the product.

[0021] Preferably, the solid-liquid ratio of camphorsulfonic acid and the first solvent in step (1) is (4-8):1 kg / L, for example, it can be 4.5:1 kg / L, 5:1 kg / L, 5.5:1 kg / L, 6:1 kg / L, 6.5:1 kg / L, 7:1 kg / L or 7.5:1 kg / L, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0022] Preferably, the molar ratio of camphorsulfonic acid and p-xylylene in step (1) is (1.5-3):1, for example, it can be 1.6:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.6:1 or 2.8:1, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0023] Preferably, the molar ratio of camphorsulfonic acid and organic base in step (1) is (0.2-0.5):1, for example, it can be 0.25:1, 0.3:1, 0.35:1, 0.4:1 or 0.45:1, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0024] As a preferred technical solution of the present application, the polymerization reaction in step (1) is carried out in a protective atmosphere.

[0025] In the present application, the protective atmosphere includes nitrogen.

[0026] Preferably, the temperature of the polymerization reaction in step (1) is 30-80℃, for example, it can be 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃ or 75℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable, preferably 50-80℃.

[0027] Preferably, the end point of the polymerization reaction in step (1) is 20-40min after the p-xylylene solution is completely added, for example, it can be 22min, 25min, 26min, 28min, 30min, 32min, 35min, 36min or 38min, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0028] In the present application, the temperature of the p-xylylene solution should be kept >50℃ during the dropwise addition process to avoid crystallization.

[0029] As a preferred technical solution of the present application, the end point temperature of the cooling treatment in step (2) is <10℃, for example, it can be 8℃, 6℃, 5℃, 4C or 2℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0030] In the present application, the skilled in the art can confirm whether to carry out the decolorization treatment according to the color of the reaction mixture after the cooling treatment, which is not specifically limited here.

[0031] Preferably, the acid solution in step (2) comprises hydrochloric acid.

[0032] Preferably, the mass ratio of the acid solution to the reaction mixture in step (2) is (0.1-0.5):1, for example, it can be 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1 or 0.45:1, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0033] Preferably, the third solvent in step (2) comprises water.

[0034] Preferably, the mass ratio of the third solvent to the acid solution in step (2) is (2-5):1, for example, it can be 2.2:1, 2.5:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.6:1 or 4.8:1, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0035] As a preferred technical solution of the present application, the end temperature of the first temperature rise in step (2) is 50-60℃, for example, it can be 51℃, 52℃, 53℃, 54℃, 55℃, 56℃, 57℃, 58℃ or 59℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0036] Preferably, the end temperature of the second temperature rise in step (2) is 50-55℃, for example, it can be 51℃, 52℃, 53℃, 54℃ or 54.5℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0037] Preferably, the fourth solvent in step (2) comprises ethanol.

[0038] Preferably, the mass ratio of the fourth solvent to the third solvent in step (2) is (2-10):1, for example, it can be 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1, etc., but not limited to the listed values, other values not listed in the value range are also applicable, preferably (2-5):1.

[0039] In the present application, by controlling the mass ratio of the fourth solvent to the third solvent, the crystallization during the dropwise addition of anhydrous ethanol is ensured, and the gradient cooling and crystal growth treatment is carried out after the dropwise addition is completed.

[0040] As a preferred technical solution of the present application, the temperature of the first crystallization in step (2) is 40-45℃, for example, it can be 41℃, 42℃, 43℃, 44℃ or 44.5℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0041] It should be noted that by controlling the temperature range of the first crystallization, the specific crystal form needs to be formed at a specific temperature, which is beneficial to the formation of the optimal crystal form.

[0042] Preferably, the time of the first crystallization in step (2) is 1-3h, for example, it can be 1.2h, 1.5h, 1.6h, 1.8h, 2h, 2.2h, 2.5h, 2.6h or 2.8h, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0043] Preferably, the cooling rate of the second crystallization in step (2) is 3-10℃ / h, for example, it can be 4℃ / h, 5℃ / h, 6℃ / h, 7℃ / h, 8℃ / h or 9℃ / h, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0044] Preferably, the temperature of the second crystallization in step (2) is 5-10℃, for example, it can be 6℃, 7℃, 8℃, 9℃ or 9.5℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0045] It should be noted that by gradient cooling to the end temperature of the second crystallization, combined with controlling the temperature range of the second crystallization, it is beneficial to obtain high-purity products under specific crystal forms.

[0046] Preferably, the time of the second crystallization in step (2) is 1-3h, for example, it can be 1.2h, 1.5h, 1.6h, 1.8h, 2h, 2.2h, 2.5h, 2.6h or 2.8h, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0047] Preferably, after the second crystallization in step (2), solid-liquid separation, washing and drying are sequentially performed.

[0048] As a preferred technical solution of the present application, the temperature of the mixing in step (3) is 55-65℃, for example, it can be 56℃, 57℃, 58℃, 59℃, 60℃, 61℃, 62℃, 63℃ or 64℃, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0049] Preferably, the mass ratio of the third solvent to the crude terephthalylidene dicamphor sulfonic acid salt crystal form in step (3) is (1-6):1, which can be 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1 or 5:1, etc., but is not limited to the listed values, and other values not listed in the value range are also applicable, preferably (2-3):1.

[0050] As a preferred technical solution of the present application, the decoloring agent for the decoloring treatment in step (3) comprises activated carbon.

[0051] Preferably, the amount of the decoloring agent added in step (3) is 2% to 5% of the mass of the crude terephthalylidene dicamphor sulfonic acid salt crystal form, which can be 2.2%, 2.5%, 2.6%, 2.8%, 3%, 3.2%, 3.5%, 3.6%, 3.8%, 4%, 4.2%, 4.5%, 4.6% or 4.8%, etc., but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0052] Preferably, after the decoloring treatment in step (3), stirring, solid-liquid separation and concentration are sequentially performed before gradient cooling crystallization.

[0053] Preferably, the stirring time is 20-40min, which can be 22min, 25min, 26min, 28min, 30min, 32min, 35min, 36min or 38min, etc., but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0054] Preferably, the concentration method comprises: concentrating the separated filtrate under reduced pressure to 30%-35% of the volume of the filtrate at a temperature of 50-60℃, which can be 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34% or 34.5%, etc., but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0055] As a preferred technical solution of the present application, the gradient cooling crystallization in step (3) comprises: first cooling to 10-20℃ and incubating for 1-3h, and then second cooling to 0-5℃ and incubating for 20-40min after crystallization.

[0056] It should be noted that by performing two-gradient cooling crystallization on the concentrated solution, different cooling gradients are set for each section, and by adjusting the appropriate temperature range and appropriate incubation time, the best crystallization effect is achieved, and the yield and purity of the product are improved.

[0057] In the present application, the end temperature of the first cooling is 10-20℃, for example, it can be 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃ or 19℃, etc., the holding time of the first cooling is 1-3h, for example, it can be 1.2h, 1.5h, 1.6h, 1.8h, 2h, 2.2h, 2.5h, 2.6h or 2.8h, etc., the end temperature of the second cooling is 0-5℃, for example, it can be 0.5℃, 1℃, 1.5℃, 2℃, 2.5℃, 3℃, 3.5℃, 4℃ or 4.5℃, etc., the holding time of the second cooling is 20-40min, for example, it can be 22min, 25min, 26min, 28min, 30min, 32min, 35min, 36min or 38min, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0058] Preferably, after the gradient cooling crystallization of step (3), solid-liquid separation, washing and drying are sequentially performed.

[0059] As a preferred technical solution of the present application, the purity of the p-phenylene-bis-alsulphonic acid salt crystal product of step (3) is ≥99.5%, for example, it can be 99.5%, 99.6%, 99.7% or 99.8%, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0060] Preferably, in the X-ray powder diffraction pattern of the p-phenylene-bis-alsulphonic acid salt crystal product of step (3), there are characteristic diffraction peaks at 2θ angles of 4.8±0.2°, 7.0±0.2°, 7.7±0.2°, 12.7±0.2°, 14.1±0.2°, 14.6±0.2°, 17.7±0.2°, 25.3±0.2°.

[0061] Preferably, the high performance liquid chromatography method is used to determine that there is no impurity peak before and after the main peak retention time of the p-phenylene-bis-alsulphonic acid salt crystal product; if impurity peaks appear before and after, the sum of the relative percentage contents calculated by the peak area normalization method is <0.5%, for example, it can be 0.4%, 0.3%, 0.2% or 0.1%, etc., but not limited to the listed values, other values not listed in the value range are also applicable.

[0062] In the present application, the determination conditions of high performance liquid chromatography (HPLC) are as follows:

[0063] Chromatographic column: Waters XBridge C18, 3.5μm, 150mm×4.6mm;

[0064] Mobile phase: A phase 5mmol / L potassium phosphate dibasic aqueous solution: B phase acetonitrile, gradient as shown in Table 1;

[0065] Flow rate: 1 mL / min; UV detection wavelength: 311 nm; column temperature: 30℃; injection volume: 10 μL, analysis time: 35 min.

[0066] Table 1

[0067] Time (min) 5 mmol / L aqueous dibasic potassium phosphate (%) acetonitrile (%) 0 92 8 5 80 20 20 60 40 25 10 90 25.1 92 8 35 92 8

[0068] Compared with the prior art, the present application has the following beneficial effects:

[0069] (1) The preparation and purification method provided by the present application, camphorsulfonic acid and p-xylylene are subjected to polycondensation reaction under the action of an organic base to prepare p-xylylenedi camphorsulfonic acid salt, after post-treatment, dissolution, layering, dropwise addition of ethanol, and then first crystal growth and second crystal growth in sequence, a crude product of p-xylylenedi camphorsulfonic acid salt is obtained, after decolorization of the crude product, high-purity p-xylylenedi camphorsulfonic acid salt crystal product can be prepared in high yield through gradient cooling crystallization, the content of impurities in the product is effectively controlled, the irritation of impurities to the skin is reduced, and the safety of the product is improved; wherein the purity of the product is ≥ 99.5%;

[0070] (2) The preparation and purification method provided by the present application, the prepared product has a crystal form, good particle size, is easy to industrialize, and is not easy to absorb moisture, and is easy to store. BRIEF DESCRIPTION OF DRAWINGS

[0071] Figure 1 is an HPLC spectrum of a p-xylylenedi camphorsulfonic acid salt product prepared by a conventional synthesis method.

[0072] Figure 2 is an HPLC spectrum of a p-xylylenedi camphorsulfonic acid salt product prepared by Example 1 of the present application.

[0073] Figure 3 is a powder diffraction pattern of a p-xylylenedi camphorsulfonic acid salt product prepared by Example 1 of the present application.

[0074] Figure 4 is an HPLC spectrum of a p-xylylenedi camphorsulfonic acid salt product prepared by Comparative Example 4 of the present application.

[0075] Figure 5 is a powder diffraction pattern of a p-xylylenedi camphorsulfonic acid salt product prepared by Comparative Example 4 of the present application.

[0076] wherein, Figure 5The characteristic diffraction peaks that overlap are 13.533°, 13.713°, 14.089°, 14.442°, 14.765°, 15.341°, 15.809°, 16.105°, 16.307°, 16.671°, and 21.722°, 22.313°. DETAILED DESCRIPTION

[0077] The technical solutions of the present application are further illustrated below by means of specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations on the present application.

[0078] In the following examples and comparative examples, the activated carbon is selected from commercially available Bailv Z activated carbon.

[0079] Example 1

[0080] The present embodiment provides a preparation and purification method of a terephthalylidene dicamphor sulfonic acid salt crystal form, which comprises the following steps:

[0081] (1) Under nitrogen protection, 100 L of a reaction kettle is added with a first solvent and 5.5 kg of camphor sulfonic acid, and stirred to reduce the temperature to 8℃, and then 8.2 kg of sodium methoxide (containing 30.41%) is added dropwise, the dropping time of sodium methoxide is controlled to be 1.2 h, and the temperature of the mixed solution is controlled to be 15℃; 1.5 kg of p-xylylformaldehyde is dissolved in a second solvent under nitrogen protection; then the reaction kettle is heated to 80℃ under nitrogen protection to reflux for polymerization reaction, and p-xylylformaldehyde solution is added dropwise, the dropping time of the p-xylylformaldehyde solution is controlled to be 1 h, and the temperature of the p-xylylformaldehyde solution is controlled to be > 50℃, and after the p-xylylformaldehyde solution is completely added, the reaction is continued for 30 min to obtain a reaction mixture;

[0082] The first solvent is a mixture of 30 L of toluene and 600 mL of methanol; the second solvent is a mixture of 8.4 L of toluene and 600 mL of methanol;

[0083] (2) After the reaction mixture in step (1) is cooled to 5℃, 7.8 kg of 6N hydrochloric acid and 23 kg of a third solvent are added dropwise, and after the first temperature is raised to 58℃, it is allowed to stand for separation, and then the filtrate obtained after separation is subjected to the second temperature raising to 52℃, and 80 L of a fourth solvent is added dropwise, and after the dropping is completed, the first crystal growth and the second crystal growth are carried out in sequence, and then filtration, cold anhydrous ethanol washing and drying are carried out in sequence to obtain a terephthalylidene dicamphor sulfonic acid salt crystal form crude product;

[0084] The third solvent is water; the fourth solvent is ethanol;

[0085] The temperature of the first crystallization is 42℃, the holding time is 2h; the cooling rate of the second crystallization is 5℃ / h, the end temperature is 8℃, the holding time is 2h;

[0086] (3) adding a third solvent to the crude terephthalylidene dicamphor sulfonic acid salt crystal form of step (2) at a temperature of 60℃, adding activated carbon to decolorize, stirring for 30min, then filtering, and then concentrating the filtrate under reduced pressure at a temperature of 55℃ to 33% of the volume of the filtrate, then gradient cooling crystallization, and finally centrifuging, washing with anhydrous ethanol, and drying in sequence to obtain the purified terephthalylidene dicamphor sulfonic acid salt crystal form product;

[0087] The mass ratio of the third solvent to the crude terephthalylidene dicamphor sulfonic acid salt crystal form is 2:1; the activated carbon is added in an amount of 2.5% of the mass of the crude terephthalylidene dicamphor sulfonic acid salt crystal form;

[0088] The gradient cooling crystallization includes: first cooling to 15℃ and holding for 2h, then second cooling to 2℃ and holding for 30min after crystallization.

[0089] In this embodiment, the HPLC spectrum and the powder diffraction pattern of the product obtained are shown in Figures 2-3 and Figure 2 It can be seen that there is no impurity peak before and after the main peak retention time of the terephthalylidene dicamphor sulfonic acid salt crystal form product, indicating that the preparation and purification method can effectively control the content of impurities A and B in the product, and the product has high purity. As shown in Figure 3 , the terephthalylidene dicamphor sulfonic acid salt crystal form product has characteristic diffraction peaks at 2θ angles of 4.8±0.2°, 7.0±0.2°, 7.7±0.2°, 12.7±0.2°, 14.1±0.2°, 14.6±0.2°, 17.7±0.2°, and 25.3±0.2° in the X-ray powder diffraction pattern; the product has a crystal form, thereby improving the hygroscopicity of the product and enabling long-term storage.

[0090] Example 2

[0091] This embodiment provides a preparation and purification method of terephthalylidene dicamphor sulfonic acid salt crystal form, step (1) is performed according to example 1, and steps (2) and (3) are adjusted as follows:

[0092] (2) after the reaction mixture of step (1) is subjected to cooling treatment to 2℃, 7.8 kg of 6N hydrochloric acid and 23 kg of the third solvent are sequentially added dropwise thereto, after being subjected to first temperature increase to 55℃, it is subjected to standing separation, the filtrate obtained after the separation is subjected to second temperature increase to 50℃, and 60 L of the fourth solvent is added dropwise thereto, after the dripping is completed, it is sequentially subjected to first crystal growth and second crystal growth, and then is sequentially subjected to filtration, cold anhydrous ethanol washing and drying, to obtain crude p-xylylene dicanthrol sulfonate salt crystal form;

[0093] The third solvent is water, and the fourth solvent is ethanol.

[0094] The temperature of the first crystal growth is 40℃, and the temperature holding time is 2h; the cooling rate of the second crystal growth is 6℃ / h, the terminal temperature is 5℃, and the temperature holding time is 2h.

[0095] (3) under the condition of 55℃, the third solvent is added to the crude p-xylylene dicanthrol sulfonate salt crystal form of step (2), and is subjected to vacuum concentration until the ethanol is completely volatilized, activated carbon is added for decolorization treatment, after stirring for 30 min, it is subjected to filtration, and then the filtrate is subjected to vacuum concentration at 60℃ until the volume of the filtrate is 35%, and then is subjected to gradient cooling crystallization, and finally is sequentially subjected to centrifugation, anhydrous ethanol washing and drying, to obtain purified p-xylylene dicanthrol sulfonate salt crystal form product.

[0096] The mass ratio of the third solvent to the crude p-xylylene dicanthrol sulfonate salt crystal form is 2:1; and the added amount of the activated carbon is 2.5% of the mass of the crude p-xylylene dicanthrol sulfonate salt crystal form.

[0097] The gradient cooling crystallization includes: first cooling to 15℃ and temperature holding for 2h, and then second cooling to 0℃ and temperature holding for 30 min after crystallization.

[0098] Example 3

[0099] The present embodiment provides a preparation and purification method of p-xylylene dicanthrol sulfonate salt crystal form, except that the added amount of the fourth solvent in step (2) is 40L, and other conditions are the same as those in Example 1.

[0100] Example 4

[0101] The present embodiment provides a preparation and purification method of p-xylylene dicanthrol sulfonate salt crystal form, except that the temperature of the first crystal growth in step (2) is 30℃, and other conditions are the same as those in Example 1.

[0102] Example 5

[0103] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the temperature of the first crystallization in step (2) is 55℃.

[0104] Example 6

[0105] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the temperature of the second crystallization in step (2) is 0℃.

[0106] Example 7

[0107] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the temperature of the second crystallization in step (2) is 15℃.

[0108] Example 8

[0109] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the end point temperature of the first temperature reduction in step (3) gradient temperature reduction crystallization is 6℃.

[0110] Example 9

[0111] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the end point temperature of the first temperature reduction in step (3) gradient temperature reduction crystallization is 30℃.

[0112] Example 10

[0113] This example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that the end point temperature of the second temperature reduction in step (3) gradient temperature reduction crystallization is 8℃.

[0114] Comparative Example 1

[0115] This comparative example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that only the first crystallization in step (2) is performed.

[0116] Comparative Example 2

[0117] This comparative example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form, which is the same as example 1 except that only the second crystallization in step (2) is performed.

[0118] Comparative Example 3

[0119] The comparative example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form. In step (3), the gradient cooling crystallization is adjusted to direct cooling to 2°C and incubation for 30 min, and other conditions are the same as in Example 1.

[0120] Comparative Example 4

[0121] The comparative example provides a preparation and purification method of the terephthalylidene dicamphor sulfonic acid salt crystal form. In step (3), the gradient cooling crystallization is adjusted to direct cooling to 2°C and incubation for 30 min, and other conditions are the same as in Example 1.

[0122] The third solvent and the terephthalylidene dicamphor sulfonic acid salt crystal form crude product have a mass ratio of 2:1; the activated carbon is added in an amount of 2.5% of the mass of the terephthalylidene dicamphor sulfonic acid salt crystal form crude product; and the acetone and the terephthalylidene dicamphor sulfonic acid salt crystal form crude product have a mass ratio of 2:1.

[0123] Other conditions are the same as in Example 1.

[0124] In the comparative example, the HPLC spectrum and the powder diffraction pattern of the product obtained are shown in Figures 4-5 and Figure 4 It can be seen that there are impurity peaks before and after the main peak retention time of the terephthalylidene dicamphor sulfonic acid salt crystal form product, and the sum of the relative percentage contents calculated by the peak area normalization method is 5.6%, the impurity content is high, resulting in a product purity of only 92.9%, which affects the safety of the product. Figure 5 It can be seen that the terephthalylidene dicamphor sulfonic acid salt crystal form product has characteristic diffraction peaks at 2θ angles of 4.9±0.2°, 11.4±0.2°, 15.3±0.2°, and 17.3±0.2° in the X-ray powder diffraction pattern, and the peak intensity is weak, indicating that the crystal form of the product is poor, which is not conducive to improving the hygroscopicity of the product and thus cannot be stored for a long time.

[0125] The products obtained in the above examples and comparative examples are subjected to yield calculation, and the purity of the products is determined by high performance liquid chromatography, wherein the determination method of high performance liquid chromatography is carried out according to the conditions given in the specification. The above results are shown in Table 2.

[0126] Table 2

[0127]

[0128]

[0129] From Table 2, it can be seen that:

[0130] (1) The preparation and purification method provided in Embodiment 1-2 can obtain high-purity p-xylylenedi-methylene d-camphorsulfonic acid salt crystal product in high yield by the cooperation of polymerization reaction, first crystallization, second crystallization and gradient temperature reduction crystallization, and the content of impurities in the product is effectively controlled, and the product has a crystal form; wherein the yield of the product is ≥ 50%, and the purity is ≥ 99.5%.

[0131] (2) It can be seen from the comparison of Embodiment 1 and Embodiment 3 that if the dropwise addition amount of ethanol in step (2) is too low, the alcohol degree is too low, which significantly reduces the yield of the product.

[0132] (3) It can be seen from the comparison of Embodiment 1 and Embodiments 4-7 that if the temperature of the first crystallization in step (2) is too low or too high, the crystallization temperature is not suitable, which not only leads to inconsistent crystal forms, but also leads to low yield and low purity of the product; if the temperature of the second crystallization in step (2) is too low or too high, the product forms a crystal solid and is sticky, which is difficult to effectively filter, resulting in low yield and low purity of the product.

[0133] (4) It can be seen from the comparison of Embodiment 1 and Embodiments 8-10 that if the end point temperature of the first temperature reduction in the gradient temperature reduction crystallization in step (3) is too low or too high, the yield and purity of the product will decrease; if the end point temperature of the second temperature reduction in the gradient temperature reduction crystallization in step (3) is too high, the solubility increases due to the high temperature, which reduces the yield of the product.

[0134] (5) It can be seen from the comparison of Embodiment 1 and Comparative Examples 1-2 that if only the first crystallization or the second crystallization is performed in step (2), the holding time is insufficient and the temperature is not suitable, which reduces the yield and purity of the product.

[0135] (6) It can be seen from the comparison of Embodiment 1 and Comparative Examples 3-4 that if one-step temperature reduction crystallization is used in step (3), the product yield and purity are reduced due to the lack of a good crystallization process; if water and acetone system is used in step (3) and one-step temperature reduction crystallization is used, the product purity is greatly reduced due to inconsistent crystal forms.

[0136] The applicant declares that the above description is only a specific embodiment of the present application, but the protection scope of the present application is not limited thereto. It should be understood by those skilled in the art that any changes or replacements within the technical scope disclosed by the present application can be easily thought of by those skilled in the art, and all fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for preparing and purifying a crystalline form of terephthalylidene dicamphorsulfonate, characterized in that: The preparation and purification method comprises the following steps: (1) mixing camphorsulfonic acid, an organic base, and a first solvent, adding a terephthalaldehyde solution thereto, and performing a polymerization reaction to obtain a reaction mixture; (2) cooling the reaction mixture of step (1), sequentially adding an acid solution and a third solvent thereto, performing solid-liquid separation after a first heating, heating the filtrate obtained after the separation for a second time, adding a fourth solvent thereto, and then sequentially performing a first crystal growing and a second crystal growing to obtain a crude crystalline product of terephthalate dicamphorsulfonate; (3) mixing the third solvent and the crude crystalline product of terephthalate dicamphor sulfonate obtained in step (2), and sequentially performing decolorization treatment and gradient cooling crystallization to obtain a purified crystalline product of terephthalate dicamphor sulfonate.

2. The preparation and purification method according to claim 1, characterized in that The mixing method in step (1) comprises: stirring and mixing camphorsulfonic acid and the first solvent under a protective atmosphere, cooling the mixture to 5-10° C., adding an organic base dropwise thereto, and controlling the temperature of the mixed solution to be 10-30° C.; Preferably, the organic base in step (1) comprises sodium methoxide and / or sodium ethoxide; Preferably, the terephthalaldehyde solution in step (1) comprises terephthalaldehyde and a second solvent; Preferably, the solid-to-liquid ratio of the terephthalaldehyde and the second solvent in step (1) is (4-10): 1 kg / L; Preferably, in step (1), the first solvent and the second solvent are both a mixture of methanol and toluene; Preferably, the solid-to-liquid ratio of the camphorsulfonic acid and the first solvent in step (1) is (4-8): 1 kg / L; Preferably, the molar ratio of camphorsulfonic acid to terephthalaldehyde in step (1) is (1.5-3):1; Preferably, the molar ratio of camphorsulfonic acid to the organic base in step (1) is (0.2-0.5):

1.

3. The preparation and purification method according to claim 1 or 2, characterized in that: The polymerization reaction in step (1) is carried out under a protective atmosphere; Preferably, the polymerization reaction temperature in step (1) is 30-80°C, preferably 50-80°C; Preferably, the endpoint of the polymerization reaction in step (1) is to continue the reaction for 20-40 minutes after the complete addition of the terephthalaldehyde solution.

4. The preparation and purification method according to any one of claims 1 to 3, characterized in that The terminal temperature of the cooling treatment in step (2) is less than 10°C; Preferably, the acid solution in step (2) comprises hydrochloric acid; Preferably, the mass ratio of the acid solution to the reaction mixture in step (2) is (0.1-0.5):1; Preferably, the third solvent in step (2) comprises water; Preferably, the mass ratio of the third solvent to the acid solution in step (2) is (2-5):

1.

5. The preparation and purification method according to any one of claims 1 to 4, characterized in that The terminal temperature of the first heating in step (2) is 50-60°C; Preferably, the terminal temperature of the second heating in step (2) is 50-55°C; Preferably, the fourth solvent in step (2) comprises ethanol; Preferably, the mass ratio of the fourth solvent to the third solvent in step (2) is (2-10):1, preferably (2-5):

1.

6. The preparation and purification method according to any one of claims 1 to 5, characterized in that Step (2) the temperature of the first growing crystal is 40-45°C; Preferably, the first crystal growing time in step (2) is 1-3 hours; Preferably, the cooling rate of the second crystal growing in step (2) is 3-10°C / h; Preferably, the temperature of the second growing crystal in step (2) is 5-10°C; Preferably, the second crystal growing time in step (2) is 1-3 hours; Preferably, in step (2), solid-liquid separation, washing and drying are sequentially performed after the second crystal growing.

7. The preparation and purification method according to any one of claims 1 to 6, characterized in that The mixing temperature in step (3) is 55-65° C. Preferably, the mass ratio of the third solvent in step (3) to the crude crystalline form of terephthalate dicamphorsulfonate is (1-6):1, preferably (2-3):

1.

8. The preparation and purification method according to any one of claims 1 to 7, characterized in that The decolorizing agent in the decolorizing treatment in step (3) includes activated carbon; Preferably, the amount of the decolorizing agent added in step (3) is 2% to 5% of the crude crystalline form of terephthalate dicamphorsulfonate; Preferably, after the decolorization treatment in step (3), stirring, solid-liquid separation and concentration are sequentially performed before the gradient cooling crystallization; Preferably, the stirring time is 20-40 min; Preferably, the concentration method comprises: concentrating the separated filtrate under reduced pressure at a temperature of 50-60° C. to 30%-35% of the volume of the filtrate.

9. The preparation and purification method according to any one of claims 1 to 8, characterized in that: The gradient cooling crystallization method in step (3) includes: first cooling to 10-20°C and keeping warm for 1-3 hours, and then cooling to 0-5°C and keeping warm for 20-40 minutes after crystallization; Preferably, the gradient cooling crystallization in step (3) is followed by solid-liquid separation, washing and drying.

10. The preparation and purification method according to any one of claims 1 to 9, characterized in that: The purity of the terephthalate dicamphorsulfonate crystalline product in step (3) is ≥99.5%; Preferably, the terephthalate dicamphorsulfonate crystalline product in step (3) has characteristic diffraction peaks at 2θ angles of 4.8±0.2°, 7.0±0.2°, 7.7±0.2°, 12.7±0.2°, 14.1±0.2°, 14.6±0.2°, 17.7±0.2°, and 25.3±0.2° in the X-ray powder diffraction pattern; Preferably, high performance liquid chromatography is used to determine that there are no impurity peaks before and after the retention time of the main peak of the terephthalate dicamphorsulfonate crystalline product; if impurity peaks appear before and after, the sum of the relative percentages calculated by peak area normalization method is less than 0.5%.

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