Calcium dibutyrylcyclic adenosine phosphate and its preparation method

Abstract

The present invention discloses calcium dibutyryl adenosine cyclophosphate and a preparation method thereof. The preparation method of calcium dibutyryl adenosine cyclophosphate comprises the following steps: (1) reacting adenosine cyclophosphate with an acid-binding agent to obtain adenosine cyclophosphate triethylamine salt; (2) carrying out an acylation reaction on the adenosine cyclophosphate triethylamine salt obtained in step (1), a catalyst and butyric anhydride to obtain dibutyryl adenosine cyclophosphate triethylamine salt; (3) carrying out a salt-forming reaction on the dibutyryl adenosine cyclophosphate triethylamine salt obtained in step (2) and a calcium salt; after the salt-forming reaction, directly crystallizing to obtain a crude product of calcium dibutyryl adenosine cyclophosphate; (4) refining the crude product of calcium dibutyryl adenosine cyclophosphate obtained in step (3) to obtain calcium dibutyryl adenosine cyclophosphate. The preparation method of calcium dibutyryl adenosine cyclophosphate in the present invention has a short production cycle, is beneficial to industrial production, and has great application value; moreover, the obtained calcium dibutyryl adenosine cyclophosphate has high yield and high purity.

Description

Technical Field

[0001] The present invention relates to calcium dibutyrylcyclic adenosine phosphate and a preparation method thereof. Background Art

[0002] Calcium dibutyrylcyclic adenosine phosphate is a product obtained by acylating cyclic adenosine monophosphate (cAMP) and then salifying. Calcium dibutyrylcyclic adenosine phosphate belongs to a protein kinase activator and can be used for the adjuvant treatment of angina pectoris and acute myocardial infarction, and can also be used for myocarditis, cardiogenic shock, subarachnoid hemorrhage after surgery, and psoriasis, and can be used in combination with other anticancer drugs to treat leukemia. The chemical structure is as follows:

[0003]

[0004] Currently, the main method for synthesizing calcium dibutyrylcyclic adenosine phosphate industrially is as described in CN 105566424B. Using cyclic adenosine monophosphate as a raw material, reacting with triethylamine in an aprotic solvent to prepare cyclic adenosine monophosphate triethylamine salt, and then using butyric anhydride as an acylating agent to synthesize calcium dibutyrylcyclic adenosine phosphate in an organic aprotic solvent, and then obtaining the calcium dibutyrylcyclic adenosine product through continuous washing and reverse extraction. The production cycle is 3 - 4 days, the crude product yield is 78% - 82%, the total product yield is 70% - 75%, and the product purity is 98% - 98.5%. However, this process is prone to hydrolysis after repeated extraction in water, and has a long acylation reaction time, low reaction yield, complex post-treatment, and low product purity.

[0005] Therefore, there is an urgent need to provide a preparation method for calcium dibutyrylcyclic adenosine phosphate with a short production cycle, which is conducive to industrial production, and the yield and purity of calcium dibutyrylcyclic adenosine phosphate are both relatively high. Summary of the Invention

[0006] The present invention mainly aims to overcome the defects in the preparation method of calcium dibutyrylcyclic adenosine phosphate in the prior art, such as long production cycle, being not conducive to industrial production, and being unable to achieve both high yield and high purity simultaneously, and provides calcium dibutyrylcyclic adenosine phosphate and a preparation method thereof. The preparation method for calcium dibutyrylcyclic adenosine phosphate provided by the present invention not only has a short production cycle and is conducive to industrial production, but also can achieve the effects of both high product yield and high purity.

[0007] The present invention mainly solves the above technical problems through the following technical solutions.

[0008] One of the technical solutions of the present invention is: a preparation method for calcium dibutyrylcyclic adenosine phosphate. The preparation method for calcium dibutyrylcyclic adenosine phosphate includes the following steps:

[0009] (1) Reacting cyclic adenosine monophosphate with an acid-binding agent to obtain cyclic adenosine monophosphate triethylamine salt;

[0010] Wherein, the acid-binding agent is triethylamine;

[0011] The cyclic adenosine monophosphate is added in the form of a solution, and the solvent includes one or more of methanol, ethanol, acetone, dichloromethane, petroleum ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, toluene, isopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, dimethyl sulfoxide, isopropanol, pyridine, and cyclohexane;

[0012] (2) The cyclic adenosine monophosphate triethylamine salt, catalyst, and n-butyric anhydride obtained in step (1) are subjected to an acylation reaction to obtain dibutyryl cyclic adenosine monophosphate triethylamine salt;

[0013] Among them, the molar ratio of the cyclic adenosine monophosphate to the catalyst is 1:(0.003 - 0.1);

[0014] (3) The dibutyryl cyclic adenosine monophosphate triethylamine salt obtained in step (2) and the calcium salt are subjected to a salt formation reaction; after the salt formation reaction, direct crystallization is carried out to obtain the crude product of calcium dibutyryl cyclic adenosine monophosphate;

[0015] (4) The crude product of calcium dibutyryl cyclic adenosine monophosphate obtained in step (3) is refined to obtain calcium dibutyryl cyclic adenosine monophosphate.

[0016] In step (1) of the present invention, the cyclic adenosine monophosphate is added in the form of a solution, and the solvent preferably includes methanol, ethanol, or acetonitrile.

[0017] More preferably, the solvent does not include water. Using a solvent that does not include water is beneficial for direct crystallization with a poor solvent during the post-treatment process, eliminating the need for relatively complex post-treatment processes such as extraction, distillation, and pH adjustment, effectively avoiding the generation of hydrolysis impurities due to the large amount of water used, and improving the yield and purity of calcium dibutyryl cyclic adenosine monophosphate.

[0018] In step (1) of the present invention, preferably, after the cyclic adenosine monophosphate and the acid-binding agent are mixed evenly, the reaction is carried out under heating conditions. The heating temperature can be conventional in the art, for example, 40°C to 90°C.

[0019] In step (1) of the present invention, the molar ratio of the cyclic adenosine monophosphate to the acid-binding agent can be conventional in the art, for example, 1:(0.5 - 10.0), preferably 1:(1 - 5), for example, 1:(1.1 - 2).

[0020] In step (2) of the present invention, the molar ratio of the cyclic adenosine monophosphate to the catalyst is preferably 1:(0.005 - 0.02), for example, 1:0.016.

[0021] In step (2) of the present invention, the molar ratio of the cyclic adenosine monophosphate to the n-butyric anhydride can be 1:(0.9 - 20.0), preferably 1:(6 - 14), more preferably 1:(7 - 13), for example, 1:12.14.

[0022] In step (2) of the present invention, the catalyst may be pyridine and / or 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine.

[0023] In step (2) of the present invention, the acylation reaction is preferably carried out by dropping the catalyst and the butyric anhydride into the triethylamine salt.

[0024] In step (2) of the present invention, the temperature of the acylation reaction may be 60°C - 110°C; preferably 80°C - 90°C.

[0025] In step (2) of the present invention, the time of the acylation reaction may be 2 h - 8 h, for example 5 h.

[0026] In step (2) of the present invention, the acylation reaction may be conventional in the art, for example, carried out under stirring conditions. Preferably, it is carried out under pressure. The pressure of the pressurization may be 0 MPa - 5 MPa; preferably 1 MPa - 3 MPa.

[0027] In step (2) of the present invention, those skilled in the art can understand that the butyric anhydride is generally a liquid at room temperature. Preferably, the butyric anhydride is added in the form of a solution, and the solvent of the solution is as described in step (1).

[0028] More preferably, the types of solvents in step (1) and step (2) are the same.

[0029] More preferably, during the acylation reaction, the amount of the solvent of the solution per gram of adenosine cyclic phosphate is 2 mL - 100 mL.

[0030] In step (3) of the present invention, the molar ratio of adenosine cyclic phosphate to the calcium salt is 1:(0.3 - 2.0).

[0031] In step (3) of the present invention, the calcium salt is added in the form of a solution, and the solvent of the solution is one or more of ethanol, water, and methanol.

[0032] In step (3) of the present invention, the calcium salt may be conventional in the art, preferably calcium chloride.

[0033] In step (3) of the present invention, the temperature of the salt formation reaction may be 0°C - 80°C, preferably 20°C - 80°C, more preferably 20°C - 60°C.

[0034] In step (3) of the present invention, the time of the salt formation reaction may be 1 h - 2 h, preferably 1.5 h.

[0035] In step (3) of the present invention, the salt formation reaction may be conventional in the art, for example, carried out under stirring conditions.

[0036] In step (3) of the present invention, the crystallization can be conventional in the art, for example, carried out under stirring conditions.

[0037] In step (3) of the present invention, the solvent used for crystallization can be one or more of dichloromethane, petroleum ether, tetrahydrofuran, dioxane, ethyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, isopropanol, cyclohexane, acetonitrile, toluene, isopropyl ether, methyl tert-butyl ether, and methanol; preferably methyl tert-butyl ether, methanol, acetone, toluene, or petroleum ether.

[0038] In step (3) of the present invention, according to the routine in the art, after the crystallization, generally filtration is also included. The filtration can adopt the conventional operations and conditions in the art. After the filtration, the crude product of calcium dibutyryladenosine cyclophosphate can be obtained.

[0039] In step (4) of the present invention, the method of purification can be conventional in the art. For example, the crude product of calcium dibutyryladenosine cyclophosphate is dissolved, and after complete dissolution, it is kept warm and then cooled to crystallize.

[0040] Among them, the temperature for dissolution can be conventional in the art, preferably 60°C - 80°C, more preferably 65°C - 75°C.

[0041] Among them, the solvent used for dissolution can be conventional in the art, such as methanol and / or ethanol.

[0042] Among them, the time for keeping warm can be conventional in the art, such as 0.5 h - 2 h, preferably 1 h.

[0043] Among them, the temperature after cooling can be below the conventional room temperature (25°C - 30°C) in the art, such as -5°C.

[0044] Among them, the solvent used for crystallization is as described in the previous step (3).

[0045] In the present invention, in step (4), when the crude product of calcium dibutyryladenosine cyclophosphate is completely dissolved by ethanol and crystallized by dropwise adding methyl tert-butyl ether to obtain purified calcium dibutyryladenosine cyclophosphate, the synthesis route is as follows:

[0046]

[0047] In the present invention, according to the routine in the art, those skilled in the art can understand that the preparation method of calcium dibutyryladenosine cyclophosphate is an intermittent synthesis method.

[0048] In the present invention, due to the selection of appropriate solvents in steps (1) to (2), after the salt formation reaction in step (3), calcium dibutyryl adenosine cyclophosphate can be directly crystallized out, without the need for complex post-treatment processes such as extraction and distillation. This avoids product hydrolysis or alcoholysis caused by methods such as extraction and distillation, thereby reducing the purity and yield of the product. Therefore, by directly crystallizing after the salt formation reaction, calcium dibutyryl adenosine cyclophosphate can be obtained quantitatively, with less loss, high purity, and high yield during the post-treatment process.

[0049] The second technical solution of the present invention is: a calcium dibutyryl adenosine cyclophosphate, which is prepared by the method for preparing calcium dibutyryl adenosine cyclophosphate as described above.

[0050] On the basis of conforming to common general knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0051] The reagents and raw materials used in the present invention are all commercially available.

[0052] The positive and progressive effects of the present invention are as follows:

[0053] In the present invention, the preparation method of calcium dibutyryl adenosine cyclophosphate uses adenosine cyclophosphate as the starting material, and after acylation and salt formation, a crude product of calcium dibutyryl adenosine cyclophosphate is prepared, and then through crystallization, a fine product of calcium dibutyryl adenosine cyclophosphate is obtained. This preparation method has the advantages of stability, mild reaction conditions, safe and controllable reaction process, simple post-treatment operation, easy product separation, etc. It not only greatly reduces the production cost, but also has a relatively high total yield (more than 84%) and purity (more than 97%) of the obtained product compared with the previous synthesis processes, and is suitable for industrial production. Specific Embodiments

[0054] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0055] Example 1

[0056] At room temperature, 75 L of methanol, adenosine cyclic phosphate (17.28 Kg, 1.0 eq), and triethylamine (5.84 Kg, 1.1 eq) were added to the reactor, stirred evenly, and heated after the solution was homogeneous. After the solution was heated to 80 °C and pressurized to 1.0 Mpa, 4-dimethylaminopyridine (21.0 g, 0.003 eq) was added and a solution of butyric anhydride (97.5 L, 12.14 eq) was added dropwise. The addition was carried out slowly for 3 h. After the addition was completed in 3 h, stirring was continued for reaction for 2 h. After the reaction was completed, the solution was cooled to room temperature, calcium chloride (4.08 Kg, 0.64 eq) was dissolved in 3.6 L of aqueous solution and added to the reactor, and stirring was continued for 1.5 h. After the reaction was completed, 75 L of acetone was added, stirred for crystallization, and the crude product of the target product was obtained by suction filtration. The crude product was dissolved in 15 L of methanol, heated to 65 °C and stirred for dissolution. After complete dissolution, it was kept warm for 1 h. It was slowly cooled to -5 °C for crystallization to obtain 20.0 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate as the target product, with a yield of 89% and a liquid phase purity of 99%.

[0057] Example 2

[0058] At room temperature, 75 L of acetonitrile, adenosine cyclic phosphate (17.28 Kg, 1.0 eq), and triethylamine (5.84 Kg, 1.1 eq) were added to the reactor, stirred evenly, and heated after the solution was homogeneous. After the solution was heated to 80 °C, pyridine (68.0 g, 0.016 eq) was added and a solution of butyric anhydride (97.5 L, 12.14 eq) was added dropwise. The addition was carried out slowly for 3 h. After the addition was completed in 3 h, stirring was continued for reaction for 2 h. After the reaction was completed, the solution was cooled to room temperature, calcium chloride (4.08 Kg, 0.64 eq) was dissolved in 2.5 L of aqueous solution and added to the reactor, and stirring was continued for 1.5 h. After the reaction was completed, 75 L of toluene was added, stirred for crystallization, and the crude product of the target product was obtained by suction filtration. The crude product was dissolved in 15 L of ethanol, heated to 75 °C and stirred for dissolution. After complete dissolution, it was kept warm for 1 h. It was slowly cooled to -5 °C for crystallization to obtain 19.3 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate as the target product, with a yield of 85.8% and a liquid phase purity of 98.5%.

[0059] Example 3

[0060] At room temperature, 75 L of methanol, adenosine cyclic phosphate (17.28 Kg, 1.0 eq), and triethylamine (5.84 Kg, 1.1 eq) were added to the reactor, stirred evenly, and heated after the solution became uniform. After the solution was heated to 110 °C and pressurized to 1.5 Mpa, 4-dimethylaminopyridine (21.0 g, 0.003 eq) was added, and the solution of butyric anhydride (97.5 L, 12.14 eq) was added dropwise. The addition was carried out slowly for 3 h. After the addition was completed in 3 h, stirring was continued for 2 h. After the reaction was completed, the solution was cooled to room temperature, calcium chloride (4.08 Kg, 0.64 eq) dissolved in 3.6 L of ethanol solution was added to the reactor, and stirring was continued for 1.5 h. After the reaction was completed, 75 L of petroleum ether was added, and crystals were precipitated by stirring. The crude product of the target product was obtained by suction filtration. The crude product was dissolved in 15 L of ethanol, heated to 75 °C and stirred until dissolved completely, and then kept warm for 1 h. The temperature was slowly lowered to room temperature to precipitate crystals, and 19.0 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate, the target product, was obtained, with a yield of 84.6% and a liquid phase purity of 97.5%.

[0061] Example 4

[0062] Compared with Example 1, in Example 4, calcium chloride was dissolved in ethanol, and methyl tert-butyl ether was added after the salt formation reaction; others were the same as in Example 1.

[0063] In Example 4, 19.76 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate, the target product, was obtained, with a yield of 88% and a liquid phase purity of 98.4%.

[0064] Example 5

[0065] Compared with Example 1, in Example 5, the acylation reaction time was 8 h; others were the same as in Example 1.

[0066] In Example 5, 19.54 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate, the target product, was obtained, with a yield of 87% and a liquid phase purity of 97.4%.

[0067] Example 6

[0068] Compared with Example 1, in Example 6, the acylation reaction temperature was 130 °C and the acylation reaction time was 2 h; others were the same as in Example 1.

[0069] In Example 6, 19.98 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate, the target product, was obtained, with a yield of 89% and a liquid phase purity of 98.3%.

[0070] As can be seen from Examples 1 to 6, the products obtained by the preparation method of calcium dibutyryl adenosine cyclic phosphate in the present invention have relatively high total yields and purities.

Claims

1. A preparation method of calcium dibutyryl adenosine cyclophosphate, characterized in that, it comprises the following steps: (1) Cyclic adenosine monophosphate reacts with an acid-binding agent to obtain cyclic adenosine monophosphate triethylamine salt; wherein, the acid-binding agent is triethylamine; the cyclic adenosine monophosphate is added in the form of a solution, and the solvent is selected from methanol, ethanol or acetonitrile; (2) The cyclic adenosine monophosphate triethylamine salt, a catalyst and butyric anhydride obtained in step (1) are subjected to an acylation reaction to obtain calcium dibutyryl adenosine cyclophosphate triethylamine salt; the acylation reaction is carried out by dropping the catalyst and the butyric anhydride into the cyclic adenosine monophosphate triethylamine salt; wherein, the molar ratio of the cyclic adenosine monophosphate to the catalyst is 1:(0.003 - 0.1); the catalyst is pyridine and / or 4-dimethylaminopyridine; the temperature of the acylation reaction is 60°C - 110°C; the time of the acylation reaction is 2h - 8h; (3) The calcium dibutyryl adenosine cyclophosphate triethylamine salt obtained in step (2) and a calcium salt are subjected to a salt-forming reaction; after the salt-forming reaction, direct crystallization is carried out to obtain a crude product of calcium dibutyryl adenosine cyclophosphate; the calcium salt is added in the form of a solution, and the solvent of the solution is one or more of ethanol, water, and methanol; (4) The crude product of calcium dibutyryl adenosine cyclophosphate obtained in step (3) is refined to obtain calcium dibutyryl adenosine cyclophosphate.

2. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 1, characterized in that, in step (1), the molar ratio of the cyclic adenosine monophosphate to the acid-binding agent is 1:(0.5 - 10.0).

3. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 2, characterized in that, in step (1), the molar ratio of the cyclic adenosine monophosphate to the acid-binding agent is 1:(1 - 5).

4. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 3, characterized in that, in step (1), the molar ratio of the cyclic adenosine monophosphate to the acid-binding agent is 1:(1.1 - 2).

5. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 1, characterized in that, the preparation method of calcium dibutyryl adenosine cyclophosphate satisfies one or both of the following conditions a~b: a. In step (2), the molar ratio of the cyclic adenosine monophosphate to the catalyst is 1:(0.005 - 0.02); b. In step (2), the molar ratio of the cyclic adenosine monophosphate to the butyric anhydride is 1:(0.9 - 20.0).

6. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 5, characterized in that, in step (2), the molar ratio of the cyclic adenosine monophosphate to the catalyst is 1:0.

016.

7. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 5, characterized in that, in step (2), the molar ratio of the cyclic adenosine monophosphate to the butyric anhydride is 1:(6 - 14).

8. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 7, characterized in that, in step (2), the molar ratio of the cyclic adenosine monophosphate to the butyric anhydride is 1:(7 - 13).

9. The preparation method of calcium dibutyryl adenosine cyclophosphate according to claim 8, characterized in that, In step (2), the molar ratio of the adenosine cyclic phosphate to the butyric anhydride is 1:12.

14.

10. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 5, characterized in that in step (2), the catalyst is 4-dimethylaminopyridine.

11. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 1, characterized in that in step (2), the pressure of the acylation reaction is 0 MPa - 5 MPa.

12. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 1, characterized in that in step (2), the temperature of the acylation reaction is 80°C - 90°C.

13. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 11, characterized in that in step (2), the pressure of the acylation reaction is 1 MPa - 3 MPa.

14. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 1, characterized in that in step (2), the butyric anhydride is added in the form of a solution.

15. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 14, characterized in that during the acylation reaction, the dosage of the solvent of the solution per gram of adenosine cyclic phosphate is 2 mL - 100 mL.

16. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 1, characterized in that the method for preparing calcium dibutyryl adenosine cyclic phosphate satisfies one or more of the following conditions i to iv: i. In step (3), the molar ratio of the adenosine cyclic phosphate to the calcium salt is 1:(0.3 - 2.0); ii. In step (3), the calcium salt is calcium chloride; iii. In step (3), the temperature of the salt-forming reaction is 0°C - 80°C; iv. In step (3), the time of the salt-forming reaction is 1 h - 2 h.

17. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 16, characterized in that in step (3), the temperature of the salt-forming reaction is 20°C - 80°C.

18. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 17, characterized in that in step (3), the temperature of the salt-forming reaction is 20°C - 60°C.

19. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 16, characterized in that the time of the salt-forming reaction is 1.5 h.

20. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 1, characterized in that in step (3), the solvent used for crystallization is one or more of dichloromethane, petroleum ether, tetrahydrofuran, dioxane, ethyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, isopropanol, cyclohexane, acetonitrile, toluene, isopropyl ether, methyl tert-butyl ether and methanol.

21. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 20, characterized in that in step (3), the solvent used for crystallization is methyl tert-butyl ether, methanol, acetone, toluene or petroleum ether.

22. The method for preparing calcium dibutyryl adenosine cyclic phosphate according to claim 20, characterized in that after crystallization in step (3), filtration by suction is further included.

23. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 1, characterized in that, in step (4), the refining method is to dissolve the crude calcium dibutyryladenosine cyclophosphate, and after complete dissolution, keep warm, then cool down, and crystallize to obtain the product.

24. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 23, characterized in that, the temperature of the dissolution is 60°C - 80°C.

25. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 24, characterized in that, the temperature of the dissolution is 65°C - 75°C.

26. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 24, characterized in that, the solvent used for the dissolution is methanol and / or ethanol.

27. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 24, characterized in that, the time for keeping warm is 0.5 h - 2 h.

28. The preparation method of calcium dibutyryladenosine cyclophosphate according to claim 27, characterized in that, the time for keeping warm is 1 h.

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