Calcium dibutyrylcyclic adenosine phosphate and its continuous preparation method and application

Abstract

The present invention relates to calcium dibutyryladenosine cyclophosphate, its continuous preparation method and application. The continuous preparation method of calcium dibutyryladenosine cyclophosphate comprises the following steps: S1. An acid-binding agent, adenosine cyclophosphate, a catalyst and butyric anhydride are subjected to an acylation reaction in a microchannel reactor to obtain dibutyryladenosine cyclophosphate; S2. The dibutyryladenosine cyclophosphate obtained in step S1 and a calcium salt are subjected to a salt-forming reaction in another microchannel reactor to obtain a crude product of calcium dibutyryladenosine cyclophosphate; S3. The crude product of calcium dibutyryladenosine cyclophosphate obtained in step S2 is post-treated to obtain calcium dibutyryladenosine cyclophosphate, wherein adenosine cyclophosphate is added in the form of a solution, the catalyst includes pyridine and / or 4-dimethylaminopyridine, the time of the acylation reaction is 3 min - 100 min, and the salt-forming reaction is directly carried out after the acylation reaction is completed. The continuous preparation method of calcium dibutyryladenosine cyclophosphate has the advantages of uniform heating, short reaction time, continuous reaction, high product yield and high purity.

Description

Technical Field

[0001] The present invention relates to calcium dibutyryl adenosine cyclophosphate, a continuous preparation method thereof, and an application thereof. Background Art

[0002] Calcium dibutyryl adenosine cyclophosphate is a protein kinase activator. It 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 compound structure is as follows:

[0003]

[0004] At present, the continuous preparation method of calcium dibutyryl adenosine cyclophosphate disclosed in patent document CN105566424A uses adenosine cyclophosphate as a raw material. After mixing triethylamine salt with water and then with adenosine cyclophosphate, adenosine cyclophosphate triethylamine salt is prepared. Then, using butyric anhydride as an acylating agent, an acylation reaction lasting for 20 - 36 hours is carried out, followed by hydrolysis. After hydrolysis, the solvent is removed by reduced pressure concentration or reduced pressure distillation to obtain dibutyryl adenosine cyclophosphate, and then a salification reaction is carried out. Finally, a calcium dibutyryl adenosine cyclophosphate product is obtained through an intermittent second purification step. However, since the acylation reaction of this method is carried out in a 1000 ml three-necked flask, the reactor has a large liquid holdup and uneven heating, which in turn leads to uneven reaction and long reaction time. Moreover, since this method requires hydrolysis and solvent evaporation steps, the preparation of calcium dibutyryl adenosine cyclophosphate is difficult to be carried out continuously, and a large amount of hydrolysis impurities are easily generated during the subsequent solvent evaporation process. This method also has problems such as a large amount of post-treatment solvent consumption, high energy consumption, low product yield, and poor purity. Summary of the Invention

[0005] In order to solve the problems in the prior art that the continuous preparation method of calcium dibutyryl adenosine cyclophosphate has uneven reaction, long reaction time, discontinuous reaction, low yield, and poor purity, the present invention provides calcium dibutyryl adenosine cyclophosphate, a continuous preparation method thereof, and an application thereof. The continuous preparation method of calcium dibutyryl adenosine cyclophosphate provided by the present invention has the advantages of uniform heating, short reaction time, continuous reaction, high product yield, and high purity.

[0006] In order to achieve the above object, the present invention provides a continuous preparation method of calcium dibutyryl adenosine cyclophosphate, which comprises the following steps:

[0007] S1. An acylation reaction is carried out on an acid-binding agent, adenosine cyclophosphate, a catalyst, and butyric anhydride in a microchannel reactor to obtain dibutyryl adenosine cyclophosphate;

[0008] S2. The dibutyryl adenosine cyclophosphate prepared in step S1 and a calcium salt are continuously subjected to a salification reaction in another microchannel reactor to obtain a crude product of calcium dibutyryl adenosine cyclophosphate;

[0009] S3. The crude calcium dibutyryl adenosine cyclophosphate obtained in step S2 is post-treated to obtain calcium dibutyryl adenosine cyclophosphate;

[0010] The adenosine cyclophosphate 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;

[0011] The catalyst includes pyridine and / or 4-dimethylaminopyridine;

[0012] The time of the acylation reaction is 3 min - 100 min;

[0013] After the acylation reaction is completed, the salt formation reaction is directly carried out.

[0014] The continuous preparation method of calcium dibutyryl adenosine cyclophosphate provided by the present invention adopts a microchannel reactor. Due to the good heat exchange effect and safe pressurization method of the microchannel, the reaction is faster, the reaction is uniform and the reaction time is shortened, avoiding the problems of uneven reaction and long reaction time caused by large liquid holdup and uneven heating in the prior art, and improving the production efficiency of calcium dibutyryl adenosine cyclophosphate; on the other hand, after the acylation reaction is completed, the salt formation reaction is directly carried out, without the intermediate hydrolysis and solvent evaporation processes. The acylation reaction and the salt formation reaction in the microchannel reactor can be carried out continuously, realizing the continuous production of the acylation reaction and the salt formation reaction in the continuous preparation process of calcium dibutyryl adenosine cyclophosphate, and finally realizing the continuous production of calcium dibutyryl adenosine cyclophosphate; this method does not require the steps of hydrolysis and solvent evaporation, avoiding the generation of a large amount of hydrolysis impurities during the solvent evaporation process, and improving the yield and purity of calcium dibutyryl adenosine cyclophosphate.

[0015] Preferably, the temperature of the acylation reaction is 60 - 180 °C, more preferably 120 °C - 150 °C. A high acylation reaction temperature is beneficial to shortening the reaction time and improving the production efficiency of calcium dibutyryl adenosine cyclophosphate.

[0016] Preferably, the pressure of the acylation reaction is 0 - 5 Mpa, more preferably 0 MPa - 3 MPa. Under pressurized conditions, the solvent can obtain a higher boiling point, and the microchannel reactor can pressurize the reaction more safely, so that the acylation reaction can be carried out at a higher temperature, and the acylation time can be greatly reduced.

[0017] Preferably, the temperature of the salt formation reaction is 0 - 80 °C, more preferably 20 °C - 60 °C.

[0018] Preferably, the time of the acylation reaction is 3 min - 50 min.

[0019] Preferably, the time of the salt formation reaction is 5 min - 10 min.

[0020] Preferably, the acid-binding agent is one or more of calcium carbonate, sodium carbonate, calcium bicarbonate, sodium bicarbonate, and triethylamine.

[0021] Preferably, the catalyst is 4-dimethylaminopyridine. By optimizing the type of catalyst and combining it with the microchannel reactor, the time of the acylation reaction can be greatly shortened.

[0022] Preferably, the solvent for the adenosine cyclic phosphate is not water. By using a water-free solvent, the generation of hydrolysis impurities caused by the large amount of water used is avoided, and the yield and purity of calcium dibutyryl adenosine cyclic phosphate are improved.

[0023] Preferably, the calcium salt is calcium chloride.

[0024] Preferably, the calcium salt is added in the form of a solution, and the solvent includes one or more of ethanol, water, and methanol.

[0025] Preferably, during the acylation reaction, the amount of the solvent used per gram of adenosine cyclic phosphate is 2 ml - 100 ml.

[0026] Preferably, the molar ratio of the adenosine cyclic phosphate to the acid-binding agent is 1:(0.5 - 10.0), and more preferably 1:(0.5 - 2.0).

[0027] Preferably, the molar ratio of the adenosine cyclic phosphate to the butyric anhydride is 1:(0.9 - 20.0), and more preferably 1:(1.5 - 10).

[0028] Preferably, the molar ratio of the adenosine cyclic phosphate to the calcium salt is 1:(0.3 - 2.0), and more preferably 1:(0.5 - 1.0).

[0029] Preferably, the molar ratio of the adenosine cyclic phosphate to the catalyst is 1:(0.003 - 0.1), and more preferably 1:(0.003 - 0.05).

[0030] Preferably, the post-treatment step includes a direct crystallization step after the salt formation reaction. Since the continuous preparation method of calcium dibutyryl adenosine cyclic phosphate provided by the present invention selects a suitable solvent, the post-treatment can directly obtain calcium dibutyryl adenosine cyclic phosphate by crystallization, without the need for post-treatment methods such as extraction and distillation. This avoids problems such as product hydrolysis or alcoholysis caused by extraction and distillation, resulting in a decrease in product purity and yield. Therefore, by directly crystallizing after the salt formation reaction, calcium dibutyryl adenosine cyclic phosphate can be obtained quantitatively, with less loss, high purity, and high yield during the post-treatment process.

[0031] Preferably, 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, n-hexane, acetonitrile, toluene, isopropyl ether, and methyl tert-butyl ether. Preferably, it is methyl tert-butyl ether and / or ethanol.

[0032] Preferably, the post-treatment step further includes suction filtration.

[0033] The present invention also provides calcium dibutyryladenosine cyclophosphate prepared by the above preparation method.

[0034] The present invention also provides the application of calcium dibutyryladenosine cyclophosphate prepared by the above preparation method in drugs.

[0035] The positive and progressive effects of the present invention are as follows: Compared with the traditional batch reaction, the technical solution of the present invention uses a microchannel reactor and selects appropriate catalyst types, which can make the reaction uniform and shorten the reaction time during the preparation of calcium dibutyryladenosine cyclophosphate, improving the production efficiency of calcium dibutyryladenosine cyclophosphate; by using appropriate solvents, reaction time and direct crystallization post-treatment process, the generation of impurities is avoided, and the purity and yield of calcium dibutyryladenosine cyclophosphate are improved. Detailed Embodiments

[0036] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0037] It should be noted that, without conflict, the features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below with reference to the embodiments.

[0038] Example 1:

[0039] At room temperature, 20.04 Kg of adenosine cyclophosphate was dissolved in 200 L of acetonitrile, 7.90 Kg of triethylamine was added dropwise, and 23.5 g of 4-dimethylaminopyridine was added. After stirring evenly, the adenosine cyclophosphate triethylamine salt solution was obtained and denoted as solution A; 130 L of butyric anhydride was denoted as solution B; 5.44 Kg of calcium chloride was dissolved in 40 L of ethanol, and the solution was denoted as solution C; Solutions A and B were continuously fed into the microchannel reactor by pumps respectively. The temperature of the acylation reaction section was controlled at 80 °C by a temperature control system, the pressure was 0.5 MPa - 3 MPa, and the residence time was 30 min; after the acylation was completed, solution C was continuously fed into another microchannel reactor for salt formation. The temperature of the salt formation section was controlled at 15 °C by a temperature control system, and the residence time was 5 min.

[0040] After the reaction was completed, the reaction solution was collected in the reaction kettle and pumped into 400 L of n-hexane for crystallization. After filtration, the crude product of the target product was obtained. The crude product was dissolved in 200 L of ethanol, heated to 80 °C and stirred until dissolved completely. After complete dissolution, it was kept warm for 1 h. It was slowly cooled to room temperature for crystallization to obtain 27.8 Kg of calcium dibutyryl adenosine cyclophosphate solid of the target product, with a total yield of 93% and a content of 99.3%.

[0041] Example 2:

[0042] At room temperature, 20.04 Kg of adenosine cyclophosphate was dissolved in 200 L of methanol, 7.90 Kg of triethylamine was added dropwise, and 66.3 g of pyridine was added. After stirring evenly, the adenosine cyclophosphate triethylamine salt solution was obtained, denoted as solution A; 130 L of butyric anhydride was denoted as solution B; 5.44 Kg of calcium chloride was dissolved in 40 L of methanol, and the solution was denoted as C; Solution A and solution B were continuously fed into the microchannel reactor by pumps respectively. The temperature of the acylation reaction section was controlled at 80 °C by the temperature control system, the pressure was 0.5 MPa - 3 MPa, and the residence time was 30 min; After the acylation was completed, solution C was continuously fed into another microchannel reactor for salt formation. The temperature of the salt formation section was controlled at 15 °C by the temperature control system, and the residence time was 5 min.

[0043] After the reaction was completed, the reaction solution was collected in the reaction kettle and pumped into 400 L of acetone for crystallization. After filtration, the crude product of the target product was obtained. The crude product was dissolved in 200 L of ethanol, heated to 80 °C and stirred until dissolved completely. After complete dissolution, it was kept warm for 1 h. It was slowly cooled to -5 °C for crystallization to obtain 25.8 Kg of calcium dibutyryl adenosine cyclophosphate solid of the target product, with a total yield of 86% and a content of 97.4%.

[0044] Example 3:

[0045] At room temperature, 20.04 Kg of adenosine cyclophosphate was dissolved in 200 L of methanol, 7.90 Kg of triethylamine was added dropwise, and 66.3 g of pyridine was added. After stirring evenly, the adenosine cyclophosphate triethylamine salt solution was obtained, denoted as solution A; 130 L of butyric anhydride was denoted as solution B; 5.44 Kg of calcium chloride was dissolved in 40 L of methanol, and the solution was denoted as C; Solution A and solution B were continuously fed into the microchannel reactor by pumps respectively. The temperature of the acylation reaction section was controlled at 80 °C by the temperature control system, the pressure was 0.5 MPa - 3 MPa, and the residence time was 100 min; After the acylation was completed, solution C was continuously fed into another microchannel reactor for salt formation. The temperature of the salt formation section was controlled at 15 °C by the temperature control system, and the residence time was 5 min.

[0046] After the reaction was completed, the reaction solution was collected in the reaction kettle and pumped into 400 L of acetone for crystallization. After filtration, the crude product of the target product was obtained. The crude product was dissolved in 200 L of ethanol, heated to 80 °C and stirred until dissolved completely. After complete dissolution, it was kept warm for 1 h. It was slowly cooled to -5 °C for crystallization to obtain 23.7 Kg of calcium dibutyryl adenosine cyclophosphate solid of the target product, with a total yield of 79% and a content of 95.4%.

[0047] Example 4:

[0048] At room temperature, 20.04 Kg of adenosine cyclic phosphate was dissolved in 200 L of methanol, 7.90 Kg of triethylamine was added dropwise, and 23.5 g of 4-dimethylaminopyridine was added. After stirring evenly, a solution of adenosine cyclic phosphate triethylamine salt was obtained, denoted as solution A; 130 L of butyric anhydride was denoted as solution B; 5.44 Kg of calcium chloride was dissolved in 40 L of water, and the solution was denoted as solution C; Solution A and solution B were continuously fed into a microchannel reactor by pumps respectively. The temperature of the acylation reaction section was controlled at 80 °C by a temperature control system, the pressure was 0.5 MPa - 3 MPa, and the residence time was 30 min; After the acylation was completed, solution C was continuously fed into another microchannel reactor to form a salt. The temperature of the salt-forming section was controlled at 15 °C by a temperature control system, and the residence time was 10 min.

[0049] After the reaction was completed, the reaction solution was collected in a reaction kettle, pumped into 400 L of petroleum ether for crystallization by a pump, and the crude product of the target product was obtained after suction filtration. The crude product was dissolved in 200 L of methanol, heated to 65 °C and stirred for dissolution. After complete dissolution, it was kept warm for 1 h. Slowly cooled to -5 °C for crystallization to obtain 24.0 Kg of the solid of calcium dibutyryl adenosine cyclic phosphate, with a total yield of 80.3% and a content of 98.4%.

[0050] Comparative Example 1:

[0051] 10 g of adenosine cyclic phosphate was taken and dissolved in an aqueous solution of 80 g of purified water and 4 g of triethylamine, stirred evenly, concentrated completely at 50 °C, and the residual solid was added with 86 g of pyridine solvent. After complete dissolution, it was concentrated under reduced pressure to form a solid, and 13 g of adenosine cyclic phosphate triethylamine salt was obtained.

[0052] 13 g of adenosine cyclic phosphate triethylamine salt was placed in a 1000 mL three-necked flask, 600 mL of tetrahydrofuran was added and stirred for dissolution, then 50 mL of butyric anhydride was added, and the reaction was carried out in the dark at 30 °C for 36 hours. The temperature was lowered to room temperature, and water was added for hydrolysis for 1 hour, and the pressure was reduced at 25 °C.

[0053] The tetrahydrofuran was concentrated and removed, water was added to 500 mL, the aqueous phase was washed twice with methyl tert-butyl ether, 100 mL each time. The aqueous phase was distilled under reduced pressure at 60 °C, and the remaining aqueous phase was extracted 3 times with dichloromethane, 100 mL each time. The organic phases were combined and the dichloromethane was removed under reduced pressure to obtain 8 g of a slightly viscous pale yellow solid of calcium dibutyryl adenosine cyclic phosphate, with a yield of 80% and a purity of 98.4%.

[0054] Dissolve 8 g of the above dibutyryl cyclic adenosine phosphate in 80 mL of ethanol; dissolve 2.4 g of anhydrous calcium chloride in a mixed solution of 10 mL of butanol and 2 mL of water; mix the two solutions, react at room temperature for 10 minutes, filter, remove ethanol and water under reduced pressure, dissolve with 80 mL of ethanol, add 200 mL of methyl tert-butyl ether at 0 °C, and white solid will precipitate out. Filter to obtain 7.5 g of white powder, with a yield of 94% and a purity of 98.2%.

[0055] The total yield of the three steps is 75%.

Claims

1. A continuous preparation method of calcium dibutyrylcyclic adenosine monophosphate, characterized in that, It includes the following steps: S1. An acid-binding agent, adenosine cyclic phosphate, a catalyst and butyric anhydride are subjected to an acylation reaction in a microchannel reactor to obtain dibutyryl adenosine cyclic phosphate; S2. The dibutyryl adenosine cyclic phosphate obtained in step S1 and a calcium salt are subjected to a salt-forming reaction in another microchannel reactor to obtain a crude product of calcium dibutyryl adenosine cyclic phosphate; S3. The crude product of calcium dibutyryl adenosine cyclic phosphate obtained in step S2 is post-treated to obtain calcium dibutyryl adenosine cyclic phosphate; The adenosine cyclic phosphate is added in the form of a solution, and the solvent is methanol and / or acetonitrile; The catalyst is 4-dimethylaminopyridine; the acid-binding agent is one or more of calcium carbonate, sodium carbonate, calcium bicarbonate, sodium bicarbonate, and triethylamine; the calcium salt is added in the form of a solution, and the solvent is ethanol and / or methanol; The time of the acylation reaction is 3 min - 100 min; The salt-forming reaction is directly carried out after the acylation reaction ends.

2. The continuous preparation method of calcium dibutyryladenosine cyclophosphate according to claim 1, characterized in that, The molar ratio of the adenosine cyclic phosphate to the acid-binding agent is 1:(0.5 - 10.0); and / or, the molar ratio of the adenosine cyclic phosphate to the butyric anhydride is 1:(0.9 - 20.0); and / or, the molar ratio of the adenosine cyclic phosphate to the calcium salt is 1:(0.3 - 2.0); and / or, the molar ratio of the adenosine cyclic phosphate to the catalyst is 1:(0.003 - 0.1).

3. The continuous preparation method of calcium dibutyrylcyclic adenosine phosphate according to claim 1, characterized in that, The molar ratio of the adenosine cyclic phosphate to the acid-binding agent is 1:(0.5 - 2.0); and / or, the molar ratio of the adenosine cyclic phosphate to the butyric anhydride is 1:(1.5 - 10); and / or, the molar ratio of the adenosine cyclic phosphate to the calcium salt is 1:(0.5 - 1.0); and / or, the molar ratio of the adenosine cyclic phosphate to the catalyst is 1:(0.003 - 0.05).

4. The continuous preparation method of calcium dibutyrylcyclic adenosine phosphate according to claim 1, characterized in that, The temperature of the acylation reaction is 60 - 180 °C; and / or, the temperature of the salt-forming reaction is 0 - 80 °C; and / or, the pressure of the acylation reaction is 0 - 5 Mpa; and / or, the time of the acylation reaction is 3 min - 50 min; and / or, the time of the salt-forming reaction is 5 min - 10 min.

5. The continuous preparation method of calcium dibutyrylcyclic adenosine phosphate according to claim 1, characterized in that, The temperature of the acylation reaction is 120 °C - 150 °C; and / or, the temperature of the salt-forming reaction is 20 °C - 60 °C; and / or, the pressure of the acylation reaction is 0 MPa - 3 Mpa.

6. The continuous preparation method of calcium dibutyryladenosine cyclophosphate according to claim 1, characterized in that, The calcium salt is calcium chloride; and / or, during the acylation reaction, the dosage of the solvent relative to each gram of the adenosine cyclic phosphate is 2 mL - 100 mL.

7. The continuous preparation method of calcium dibutyryladenosine cyclophosphate according to claim 1, characterized in that, The steps of the post-treatment include a direct crystallization step after the salt-forming reaction ends.

8. The continuous preparation method of calcium dibutyryladenosine cyclophosphate according to claim 7, characterized in that, The solvent used for crystallization is one or more of petroleum ether, acetone and n-hexane.

9. The continuous preparation method of calcium dibutyryladenosine cyclophosphate according to claim 7, characterized in that, The steps of the post-treatment further include suction filtration.

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