Calcium chlorogenic acid anhydrate, its preparation method and application

Abstract

This application relates to the technical field of pharmaceutical chemistry, and specifically discloses a calcium chlorogenate anhydrate, its preparation method and application. The X-ray powder diffraction pattern of the calcium chlorogenate anhydrate includes the following characteristic peaks: 4.756°, 14.972°, 15.538°, 17.636°, 18.782°, 20.673°, with an error of ±0.2°. The X-ray powder diffraction pattern of the calcium chlorogenate anhydrate is shown in Figure 1. By adopting a new preparation method, this application has prepared a new calcium chlorogenate salt with higher purity, better stability and lower solubility, which can be used as the active ingredient of depot-type injection. The preparation method provided by this application is simple and easy to operate, and the obtained calcium chlorogenate anhydrate has high yield and purity, and the reaction conditions are mild, which is suitable for large-scale production.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical chemistry. More specifically, it relates to calcium chlorogenate anhydrous, its preparation method and application. Background Art

[0002] Chlorogenic acid, also known as caffeotannic acid or caffeic tannic acid, is a phenolic acid formed by the condensation of caffeic acid and quinic acid (quinic acid), and is a product of the aerobic respiration metabolism of plants. The chemical name of chlorogenic acid is 5-O-caffeoylquinic acid, molecular formula: C 16 H 18 O9, molecular weight: 354.31, and the structural formula is shown as follows.

[0003]

[0004] Chlorogenic acid is an important bioactive substance, and its various uses have been disclosed in related technologies:

[0005] 1. Anti-tumor: such as preventing and treating nasopharyngeal carcinoma (CN200610021897.1); preventing and treating small cell lung cancer (CN200710140602.7); preventing and treating bladder cancer (CN201210086313.4); preventing and treating ependymoma (CN201410468334.1); preventing and treating oligodendroglioma (CN201410468312.5); preventing and treating cervical cancer (CN200610021591.6); preventing and treating female organ tumors (CN200610021909.0); preventing and treating pulmonary blastoma (CN201510078820.7); preventing and treating primary cutaneous T-cell lymphoma (CN201510079639.8); treating melanoma (CN201510079033.4); treating yolk sac tumor (CN201510053341.X); treating choriocarcinoma (CN201510080133.9); CN201710719094.1, CN201710714132.4, CN201810206147.4, CN201710719622.3, etc. also disclose that the combined use of chlorogenic acid and other drugs has anti-tumor, anti-cancer, and treatment of tumor multi-drug resistance effects.

[0006] 2. Treatment of autoimmune diseases: CN201510568417.2 discloses that chlorogenic acid can activate the immune-related signaling pathways of the body; it also has functions such as treating lupus erythematosus (CN201510078874.3); enhancing immune function (CN200510088025.2); treating vitiligo (CN201410778100.7); treating psoriasis (CN201410490695.6), etc.

[0007] 3. Antioxidant, anti-aging, anti-musculoskeletal aging: such as anti-hypoxia (ZL200710128491.8); treating and / or preventing eye inflammation (CN201710051216.4); muscular dystrophy (CN201510580291.0); treating progeria (CN201510072776.9), etc.

[0008] 4. Protecting the cardiovascular system: treating cardiomyopathy (CN201510078634.3), etc.

[0009] 5. Other uses: CN200680024175.X discloses that chlorogenic acid has the effect of increasing bone marrow cells; CN200910246627.4 discloses that chlorogenic acid has the effects of treating thrombocytopenia and anemia; CN200910246134.0 discloses that chlorogenic acid has a protective and reparative effect on spleen hematopoietic stem cell damage; CN200910246630.6 discloses that chlorogenic acid has the effect of treating myelofibrosis; CN201510078953.4 discloses that chlorogenic acid can treat urticaria; CN201510063970.0 discloses that chlorogenic acid has the effect of treating osteopetrosis; CN201510568285.3 discloses that chlorogenic acid can activate the WNT signaling pathway of the body; CN201510123289.0 discloses that chlorogenic acid has the effect of promoting fibroblast proliferation; CN201110386854.4, CN201310210438.8, CN200510088023.3, etc. disclose that chlorogenic acid has a hepatoprotective effect; CN200610021590.1 discloses that chlorogenic acid has estrogen-like or estrogen-promoting effects; CN201510078629.2 discloses that chlorogenic acid has the effect of treating pathologic jaundice; CN201510079127.1 discloses that chlorogenic acid can be used to treat epilepsy; CN200910246133.6 discloses that chlorogenic acid can treat bone marrow infection; CN201510078986.9 discloses that chlorogenic acid can treat amyotrophic lateral sclerosis; CN201510079049.5 discloses that chlorogenic acid can treat Parkinson's disease; CN201610149050.5 discloses that chlorogenic acid can inhibit the LAG-3 target, etc.

[0010] Although chlorogenic acid has good pharmacological activities, due to factors such as poor oral absorption, large first-pass effect in the gastrointestinal tract, short half-life, and easy degradation by intestinal flora, its bioavailability is extremely low (<1%), making it difficult to formulate oral preparations to exert its efficacy. Parenteral administration, especially injection, can solve the problem of low bioavailability, but due to its short half-life and short duration of drug effect, multiple administrations are required within a day, and the blood drug concentration is not stable, which also affects the exertion of its efficacy. Moreover, CN201410680646.9 mentions that chlorogenic acid has obvious inhibitory effects on Lewis lung cancer, H22 liver cancer, EMT-6 breast cancer, and mouse xenografts of human glioma, but the antitumor effect is not positively correlated with the dose. On the contrary, after reaching a certain dose, as the dose increases, the drug effect gradually decreases. Therefore, when the blood drug concentration in the body is too high, the antitumor effect of the drug may instead decrease. Therefore, maintaining the blood drug concentration within a certain range is more conducive to the exertion of the drug effect.

[0011] To fully exert the application value of chlorogenic acid, it is necessary to find an injection delivery system that can achieve once-daily and sustained release. However, due to reasons such as low drug loading and high industrialization technical difficulty of new sustained-release injection preparations (sustained-release microspheres, implants, etc.), their druggability is limited. Suspension intramuscular / subcutaneous administration without excipients as a drug depot has become the most preferred administration plan. The drug in the depot can slowly dissolve and release into the blood circulation to maintain a stable blood drug concentration in the body, avoiding the sharp fluctuations in blood drug concentration during injection (the blood drug concentration is too high in the initial stage, and due to the short half-life of the drug, the blood drug concentration rapidly decreases), thereby better exerting the inhibitory effect of chlorogenic acid on tumors.

[0012] However, due to the relatively good solubility of chlorogenic acid and its salts / coordination compounds themselves (both are greater than about 10 mg / ml), the possibility of formulating them into a suspension injection delivery system is limited. A calcium chlorogenate sesquihydrate is disclosed in related technologies, which has good stability, low solubility, and low irritation, and can be used as the active ingredient of a depot-type injection. Polymorphism of compounds is a common phenomenon, and the optimization of the properties such as stability, hygroscopicity, and solubility of crystal forms is a long-term pursuit. Summary of the Invention

[0013] The present application provides an anhydrous calcium chlorogenate, its preparation method and application. By adopting a new preparation method, a new calcium chlorogenate salt is obtained, which has higher purity, better stability, and lower solubility, and can be used as the active ingredient of a depot-type injection.

[0014] In the first aspect, an anhydrous calcium chlorogenate provided by the present application adopts the following technical solution:

[0015] An anhydrous calcium chlorogenate, the structural formula of the anhydrous calcium chlorogenate is as follows:

[0016]

[0017] The X-ray powder diffraction pattern of the anhydrous calcium chlorogenate includes the following characteristic peaks: 4.756°, 14.972°, 15.538°, 17.636°, 18.782°, 20.673°, with an error of ±0.2°.

[0018] Preferably, the X-ray powder diffraction pattern of the anhydrous calcium chlorogenate includes the following characteristic peaks: 4.756°, 14.368°, 14.972°, 15.538°, 16.429°, 17.636°, 18.782°, 20.673°, 22.404°, 23.720°, with an error of ±0.2°.

[0019] Preferably, the X-ray powder diffraction pattern of the anhydrous calcium chlorogenate is as Figure 1 shown.

[0020] Preferably, the anhydrous calcium chlorogenate has no crystal water.

[0021] Preferably, the DSC spectrum of the anhydrous calcium chlorogenate is as Figure 2 shown.

[0022] Preferably, the TG spectrum of the anhydrous calcium chlorogenate is as Figure 3 shown.

[0023] In a second aspect, the present application provides a method for preparing the above-mentioned anhydrous calcium chlorogenate, adopting the following technical solution:

[0024] A method for preparing the above-mentioned anhydrous calcium chlorogenate, the preparation method specifically includes the following steps:

[0025] Add chlorogenic acid to water, dropwise add an aqueous sodium bicarbonate solution and stir to react, and raise the temperature and stir;

[0026] Then dropwise add a calcium chloride solution to the system and continue to stir, cool down, crystallize, filter, wash with water, to obtain an off-white solid;

[0027] Add the obtained white solid to water, raise the temperature, stir and make a slurry, cool down, stir and crystallize, filter, wash with water, and vacuum dry to obtain anhydrous calcium chlorogenate.

[0028] The preparation method provided by the present application is simple and easy to operate, and the yield and purity of the obtained anhydrous calcium chlorogenate are both high, the reaction conditions are mild, and it is suitable for large-scale production.

[0029] Preferably, the molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is (0.8-1.2):(0.8-1.2):(0.4-0.6).

[0030] Preferably, the molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is (0.9 - 1.1):(0.9 - 1.1):0.5.

[0031] Preferably, the molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is 1:1:0.5.

[0032] Preferably, the temperature for adding calcium chloride is 40 - 70 °C.

[0033] Preferably, the temperature for adding calcium chloride is 50 - 60 °C.

[0034] Preferably, the temperature for adding calcium chloride is 55 °C.

[0035] Preferably, the time for adding calcium chloride and stirring for reaction is 10 - 30 min.

[0036] Preferably, the time for adding calcium chloride and stirring for reaction is 10 - 20 min.

[0037] Preferably, the time for adding calcium chloride and stirring for reaction is 10 min.

[0038] Preferably, the temperature for beating is 40 - 70 °C.

[0039] Preferably, the temperature for beating is 50 - 60 °C.

[0040] Preferably, the temperature for beating is 55 °C.

[0041] Preferably, the time for beating is 0.5 - 5 h.

[0042] Preferably, the time for beating is 1 - 3 h.

[0043] Preferably, the time for beating is 2 h.

[0044] Preferably, the crystallization time for beating is 0.5 - 5 h.

[0045] Preferably, the crystallization time for beating is 1 - 3 h.

[0046] Preferably, the crystallization time for beating is 2 h.

[0047] Preferably, the temperature for vacuum drying is 30 - 70 °C.

[0048] Preferably, the temperature for vacuum drying is 40 - 60 °C.

[0049] Preferably, the temperature for vacuum drying is 60 °C.

[0050] In a third aspect, the present application provides a use of the above anhydrous chlorogenic acid calcium in the preparation of a drug for treating and / or preventing tumors, inflammatory diseases, autoimmune diseases, antioxidation, anti-aging, anti-musculoskeletal aging or protecting the cardiovascular system.

[0051] In a fourth aspect, the present application provides a pharmaceutical composition comprising the above anhydrous chlorogenic acid calcium.

[0052] In summary, the present application has the following beneficial effects:

[0053] The solubility of the anhydrous chlorogenic acid calcium provided by the present application is lower than that of chlorogenic acid calcium sesquihydrate and chlorogenic acid, and it can be used to prepare a sustained-release injection preparation to improve the activity of the drug. In addition, the anhydrous chlorogenic acid calcium of the present application has good stability under high temperature, high humidity and light conditions. Description of the Drawings

[0054] Figure 1 is the X-ray powder diffraction pattern of the anhydrous chlorogenic acid calcium of the present application.

[0055] Figure 2 is the differential scanning calorimetry (DSC) diagram of the anhydrous chlorogenic acid calcium of the present application.

[0056] Figure 3 is the thermogravimetric (TG) analysis spectrum of the anhydrous chlorogenic acid calcium of the present application.

[0057] Figure 4 is the X-ray powder diffraction pattern of chlorogenic acid calcium sesquihydrate.

[0058] Figure 5 is the thermogravimetric (TG) analysis spectrum of chlorogenic acid calcium sesquihydrate.

[0059] Figure 6 is the X-ray powder diffraction pattern of the anhydrous chlorogenic acid calcium of the present application after being placed at 40 °C for 10 days.

[0060] Figure 7 is the X-ray powder diffraction pattern of the anhydrous chlorogenic acid calcium of the present application after being placed at 60 °C for 10 days.

[0061] Figure 8 is the X-ray powder diffraction pattern of the anhydrous chlorogenic acid calcium of the present application after being irradiated with light for 10 days.

[0062] Figure 9 is the X-ray powder diffraction pattern of the anhydrous chlorogenic acid calcium of the present application after being placed at RH 75% for 10 days. Detailed Embodiments

[0063] The present application has prepared a chlorogenic acid calcium salt by using a new preparation method.

[0064] Specifically, the calcium salt of chlorogenic acid is anhydrous calcium chlorogenate, and its preparation method specifically includes the following steps:

[0065] (1) Add chlorogenic acid to water, dropwise add an aqueous solution of sodium bicarbonate and carry out a stirring reaction, and raise the temperature for stirring.

[0066] (2) Then, dropwise add a calcium chloride solution to the system under the condition of 40 - 70 °C and carry out a stirring reaction for 10 - 30 min, cool down, crystallize, filter, wash with water, and obtain a white solid.

[0067] Among them, the molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is (0.8 - 1.2):(0.8 - 1.2):(0.4 - 0.6).

[0068] (3) Add the obtained white solid to water, raise the temperature to 40 - 70 °C, and carry out stirring and pulping for 0.5 - 5 h; cool down, stir and crystallize for 0.5 - 5 h, filter, wash with water, and carry out vacuum drying under the condition of 30 - 70 °C to obtain anhydrous calcium chlorogenate.

[0069] Specifically, the structural formula of the calcium salt of chlorogenic acid is as follows:

[0070]

[0071] The specific analysis of the anhydrous calcium chlorogenate is as follows:

[0072] The X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ ± 0.2° includes the following characteristic peaks: 4.756°, 14.368°, 14.972°, 15.538°, 16.429°, 17.636°, 18.782°, 20.673°, 22.404°, 23.720°, with an error of ±0.2°. Among them, the X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ ± 0.2° is as Figure 1 shown. This X-ray powder diffraction pattern was measured using Cu-Kα radiation.

[0073] The DSC spectrum measured using a thermal analyzer is as Figure 2 shown.

[0074] The TG spectrum measured using a thermogravimetric analyzer is as Figure 3 shown.

[0075] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below in conjunction with the accompanying drawings. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without making creative efforts fall within the scope of protection of this application.

[0076] The detection equipment used in this application is as follows:

[0077] 1. Powder X-ray diffraction analysis: Rigaku D / max-2550 powder X-ray diffractometer made in Japan; Test conditions: CuKα radiation, tube current 150 mA, tube voltage 40 kV, scanning speed 8° / min, step size 0.02°.

[0078] 2. Differential scanning calorimetry (DSC): Mettler DSC1 thermal analyzer made in Switzerland; Parameter settings:

[0079] Initial temperature 30°C; Final temperature 300°C; Heating rate 10 K / min.

[0080] 3. Thermogravimetric analysis (TG): Mettler TGA / DSC1 thermal analyzer made in Switzerland; Parameter settings: Initial temperature 30°C; Final temperature 500°C; Heating rate 5 K / min.

[0081] Examples

[0082] Example 1

[0083] This application provides a calcium chlorogenic acid sesquihydrate. The preparation method of the calcium chlorogenic acid sesquihydrate is as follows:

[0084] Add 40.0 g of chlorogenic acid (113 mmol) and 600 mL of purified water into the reaction flask, slowly dropwise add 113 mL of sodium bicarbonate aqueous solution (1 mol / L) at 20°C. After dropping, stir at the same temperature for 30 min.

[0085] Then slowly dropwise add 57 ml of calcium chloride solution (1 mol / L) into the system, stir at 20°C for 1 h, filter, wash the filter cake with a small amount of purified water, and vacuum dry at 55°C for 20 h to obtain 40.97 g of off-white solid calcium chlorogenic acid sesquihydrate, with a yield of 90.6%.

[0086] The test results are as follows:

[0087] The thermogravimetric analysis results show that the weight loss is 7.079% at 150°C, which is the characteristic weight loss of 1.5 molecules of water.

[0088] The X-ray powder diffraction pattern is as Figure 4 shown, and the thermogravimetric (TG) analysis pattern is as Figure 5 shown.

[0089] Example 2

[0090] This application provides an anhydrous calcium chlorogenic acid. The preparation method of the anhydrous calcium chlorogenic acid is as follows:

[0091] Add 100.0 g of chlorogenic acid (283 mmol) and 1500 mL of purified water into the reaction flask. Slowly add 283 mL of sodium bicarbonate aqueous solution (1 mol / L) dropwise at 20 °C. After the addition is complete, stir the reaction for 30 min, then raise the temperature to 55 °C and stir at this temperature for 10 min.

[0092] Then slowly add 141.5 mL of calcium chloride aqueous solution (1 mol / L) to the system, stir at this temperature for 10 min, turn off the heating, and let the system cool naturally to room temperature. A large amount of off-white solid precipitates. Filter, and wash the filter cake with a small amount of purified water to obtain the off-white solid.

[0093] Add the above-mentioned off-white solid and 1500.0 mL of purified water into the reaction flask, raise the temperature to 55 °C, and stir and slurry at this temperature for 2 h. Cool to room temperature and continue to stir for 2 h. A large amount of off-white solid precipitates. Filter, wash the filter cake with a small amount of purified water, and dry it under vacuum at 60 °C to constant weight. Finally, 85.1 g of off-white solid is obtained, with a yield of 80.7%, which is anhydrous calcium chlorogenate.

[0094] The test results are as follows:

[0095] The X-ray powder diffraction pattern is as Figure 1 shown.

[0096] The differential scanning calorimetry (DSC) diagram is as Figure 2 shown.

[0097] The moisture test result is 0.67%. The thermogravimetric analysis result shows that this calcium salt does not contain crystal water. The thermogravimetric (TG) analysis pattern is as Figure 3 shown.

[0098] Example 3

[0099] This application provides an anhydrous calcium chlorogenate. The preparation method of this anhydrous calcium chlorogenate is as follows:

[0100] Add 40.0 g of chlorogenic acid (113 mmol) and 600 mL of purified water into the reaction flask. Slowly add 113 mL of sodium bicarbonate aqueous solution (1 mol / L) dropwise at 20 °C. After the addition is complete, stir the reaction for 30 min, then raise the temperature to 55 °C and stir at this temperature for 10 min.

[0101] Then slowly add 57 mL of calcium chloride aqueous solution (1 mol / L) to the system, stir at this temperature for 10 min, turn off the heating, and let the system cool naturally to room temperature. A large amount of off-white solid precipitates. Filter, and wash the filter cake with a small amount of purified water to obtain the off-white solid.

[0102] Add the above off-white solid and 750.0 mL of purified water into a reaction flask, heat up to 55 °C, keep warm and stir for pulping for 2 h. Cool down to room temperature, stir for 2 h, and a large amount of off-white solid precipitates. Filter, wash the filter cake with a small amount of purified water, and dry it under vacuum at 60 °C until constant weight. Finally, 41.30 g of off-white solid is obtained, with a yield of 78.3%, which is anhydrous calcium chlorogenic acid.

[0103] The test results are as follows:

[0104] The corresponding X-ray powder diffraction pattern and thermogravimetric (TG) analysis pattern are the same as those in Example 2.

[0105] The moisture test result is 0.65%. The thermogravimetric analysis result shows that this calcium salt does not contain crystal water.

[0106] Detection test

[0107] I. Stability test

[0108] The detection objects are the calcium chlorogenic acid sesquihydrate prepared in Example 1 and the anhydrous calcium chlorogenic acid prepared in Example 2.

[0109] The detection conditions are shown in Table 1 and Table 2.

[0110] Table 1 Detection condition 1

[0111] Condition Parameter / Type Chromatographic column Agilent Eclipse Plus C18 (4.6×250mm, 5μm) C18-96 Column temperature 30℃ Flow rate 1.0 ml / min Injection volume 10ul Detection wavelength 325 nm Mobile phase A 0.1% formic acid aqueous solution Mobile phase B Acetonitrile

[0112] Table 2 Detection condition 2 - Mobile phase gradient

[0113] Time (min) Mobile phase A (%) Mobile phase B (%) 0.01 95 5 10 90 10 20 90 10 30 80 20 40 80 20 40.01 95 5 50 Stop

[0114] The detection results are shown in Table 3 and Table 4 (RH relative humidity).

[0115] Table 3 Detection results of anhydrous calcium chlorogenic acid placed for 10 days under corresponding conditions

[0116]

[0117] Table 4 Detection results of calcium chlorogenic acid sesquihydrate placed for 10 days under corresponding conditions

[0118]

[0119]

[0120] As can be seen from Table 3, anhydrous calcium chlorogenic acid has basically no change after being placed for 10 days under high temperature, high humidity and light conditions, and has good stability. Impurity 1 is an impurity brought in by the raw material, and its structure is an impurity with one less hydroxyl group on the right side. The structural formula is as follows:

[0121]

[0122] Compared with Table 4 and the test results of calcium caffeate sesquihydrate placed under the same conditions for 10 days, it can be seen that the calcium caffeate anhydrous provided by this application has a higher purity and fewer types of impurities.

[0123] In addition, the X-ray powder diffraction patterns of the calcium caffeate anhydrous provided by this application after being placed at 40 °C for 10 days, at 60 °C for 10 days, under light for 10 days, and at RH 75% for 10 days are respectively as Figure 5 - Figure 9 shown. From the above test results, it can be seen that the calcium caffeate anhydrous provided by this application has no obvious change under various test conditions. This indicates that the calcium caffeate anhydrous provided by this application has better stability.

[0124] II. Solubility Test

[0125] The test objects are the calcium caffeate sesquihydrate prepared in Example 1, the calcium caffeate anhydrous prepared in Example 2, and other salts of caffeic acid.

[0126] The solubility of the above substances in water was detected. The test results are shown in Table 5.

[0127] Table 5 Solubility Test Results

[0128]

[0129]

[0130] As can be seen from Table 5, the solubility of the calcium caffeate anhydrous provided by this application is only 1.32 mg / ml, which is lower than that of the calcium caffeate sesquihydrate, and is reduced by 2.23 times based on the solubility of the calcium caffeate sesquihydrate. At the same time, the solubility of the calcium caffeate anhydrous provided by this application is much lower than that of caffeic acid and other salts.

[0131] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, rather than to limit it; although this application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of this application.

Claims

1. Calcium caffeate anhydride, characterized in that, The structural formula of the anhydrous calcium chlorogenic acid is as follows: The X-ray powder diffraction pattern of the anhydrous calcium chlorogenic acid includes the following characteristic peaks: 4.756°, 14.972°, 15.538°, 17.636°, 18.782°, 20.673°, with an error of ±0.2°.

2. The calcium caffeate anhydride according to claim 1, wherein The X-ray powder diffraction pattern of the anhydrous calcium chlorogenic acid includes the following characteristic peaks: 4.756°, 14.368°, 14.972°, 15.538°, 16.429°, 17.636°, 18.782°, 20.673°, 22.404°, 23.720°, with an error of ±0.2°.

3. The calcium chlorogenate anhydride according to claim 1, wherein The X-ray powder diffraction pattern of the anhydrous calcium chlorogenic acid is shown in Figure 1.

4. The anhydrous chlorogenic acid calcium according to claim 1, characterized in that, The anhydrous calcium chlorogenic acid has no crystal water.

5. The calcium chlorogenate anhydride according to claim 1, characterized in that, The DSC spectrum of the anhydrous calcium chlorogenic acid is shown in Figure 2.

6. The calcium chlorogenate anhydride according to claim 1, wherein The TG spectrum of the anhydrous calcium chlorogenic acid is shown in Figure 3.

7. A method for preparing anhydrous chlorogenic acid calcium according to any one of claims 1-6, characterized in that, The preparation method specifically includes the following steps: Add chlorogenic acid to water, dropwise add an aqueous sodium bicarbonate solution and carry out a stirring reaction, and raise the temperature and stir; Then dropwise add a calcium chloride solution to the system and continue stirring, lower the temperature, crystallize, filter, wash with water, and obtain an off-white solid; Add the obtained white solid to water, raise the temperature, stir and make a slurry, lower the temperature, stir and crystallize, filter, wash with water, and dry under vacuum to obtain anhydrous calcium chlorogenic acid.

8. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is (0.8 - 1.2):(0.8 - 1.2):(0.4 - 0.6).

9. The preparation method of anhydrous calcium chlorogenate according to claim 8, characterized in that, The molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is (0.9 - 1.1):(0.9 - 1.1):0.

5.

10. The preparation method of anhydrous chlorogenic acid calcium according to claim 9, characterized in that, The molar ratio of chlorogenic acid, sodium bicarbonate, and calcium chloride is 1:1:0.

5.

11. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The temperature for adding calcium chloride is 40 - 70°C.

12. The preparation method of anhydrous chlorogenic acid calcium according to claim 11, characterized in that, The temperature for adding calcium chloride is 50-60℃。 13. The method for preparing anhydrous chlorogenic acid calcium according to claim 12, wherein The temperature for adding calcium chloride is 55°C.

14. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The time for adding calcium chloride and carrying out a stirring reaction is 10 - 30 min.

15. The preparation method of anhydrous chlorogenic acid calcium according to claim 14, characterized in that, The time for adding calcium chloride and carrying out a stirring reaction is 10 - 20 min.

16. The preparation method of anhydrous chlorogenic acid calcium according to claim 15, characterized in that, The time for adding calcium chloride and carrying out a stirring reaction is 10 min.

17. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The temperature of the slurry-making is 40 - 70°C.

18. The preparation method of anhydrous chlorogenic acid calcium according to claim 17, characterized in that, The temperature of the slurry-making is 50 - 60°C.

19. The method for preparing anhydrous chlorogenic acid calcium according to claim 18, characterized in that, The temperature of the slurry-making is 55°C.

20. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The time of the slurry-making is 0.5 - 5 h.

21. The method for preparing anhydrous chlorogenic acid calcium according to claim 20, characterized in that, The time of the slurry-making is 1 - 3 h.

22. The preparation method of anhydrous chlorogenic acid calcium according to claim 21, characterized in that, The time of the slurry-making is 2 h.

23. The preparation method of anhydrous chlorogenic acid calcium according to claim 7, characterized in that, The crystallization time during the slurry-making is 0.5 - 5 h.

24. The preparation method of anhydrous chlorogenic acid calcium according to claim 23, characterized in that, The crystallization time during the slurry-making is 1 - 3 h.

25. The preparation method of anhydrous chlorogenic acid calcium according to claim 24, characterized in that, The crystallization time during the slurry-making is 2 h.

26. Use of the anhydrous calcium chlorogenic acid according to any one of claims 1 - 6 in the preparation of a drug for treating and / or preventing tumors, inflammatory diseases, autoimmune diseases, antioxidant, anti-aging, anti-musculoskeletal aging, or protecting the cardiovascular system.

27. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes the anhydrous calcium chlorogenic acid according to any one of claims 1 - 6.

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