A kind of synthetic method of dibutyryl adenosine sodium cyclophosphate
By reacting halogenated butyryl and cyclophosphate adenosine sodium under the action of phase transfer catalyst and recrystallization with acetone, the problems of excessive use of butyric anhydride and complex purification processes in the existing process are solved, achieving high purity and low cost. Butyryl cyclophosphate adenosine sodium production meets the needs of medicinal and industrialization.
Patent Information
- Application Number
- CN202311393348.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-25
- Publication Date
- 2024-12-27
- Estimated Expiration
- 2043-10-25
AI Technical Summary
In the existing synthesis process of dibutyryl cyclophosphate adenosine sodium, the use of a large amount of butyric anhydride leads to complex subsequent purification processes, low yields, increased impurities, and low exchange capacity and high cost of ion exchange resins, which cannot meet the requirements of pharmaceutical purity and industrial production.
Halogenated butyryl and cyclophosphate adenosine sodium are reacted under the action of phase transfer catalyst to produce dibutyryl cyclophosphate adenosine sodium, reducing the generation of butyric acid by-products, and improving product purity through acetone recrystallization and simplifying the process flow.
It reduces production costs, improves the chemical purity and stability of the product, simplifies the process flow, and meets the requirements of pharmaceutical purity and industrial production.
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Figure CN117645643B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing sodium dibutyryl adenosine cyclophosphate. Background Art
[0002] Sodium dibutyryladenosine cyclophosphate is a drug first applied for listing in Japan by Daiichi Sankyo Company Limited in 1984. There is no report of the drug being marketed in China. Sodium dibutyryladenosine cyclophosphate for injection can treat postoperative shock and severe heart failure, and the sodium salt in the form of an ointment is mainly used to treat skin diseases such as bedsores. The original research route developed by the company uses cycloadenosine as the starting material, which is reacted with butyric anhydride after triethylamine salt formation to obtain crude dibutyryladenosine cyclophosphate, and then dibutyryladenosine cyclophosphate sodium is obtained through cation exchange resin. This process uses a large amount of butyric acid glycoside as a butyrylation agent, which will complicate the subsequent purification process, resulting in a decrease in product yield, an increase in impurities, and an impact on the stability of product quality; and the ion exchange resin used has low exchange capacity, low yield, and high cost, which is not conducive to industrial production.
[0003] At present, there are few reports in domestic literature on the synthesis method of sodium dibutyryladenosine cyclophosphate, which are mainly about the synthesis method of calcium dibutyryladenosine cyclophosphate, that is, based on the synthesis process of sodium dibutyryladenosine cyclophosphate, the sodium used for salt formation is replaced by calcium chloride to obtain calcium dibutyryladenosine cyclophosphate. However, the chemical purity of the product obtained by the process operation reported in the current literature cannot meet the pharmaceutical requirements; although there are also literature reports that separation and purification technologies such as spray drying and column chromatography can be used to obtain a final product with a purity of 99.0%, this type of purification process is complicated to operate, labor-intensive, has high requirements on equipment, and is costly, and cannot meet the requirements of enterprise production.
[0004] Therefore, it is of great practical significance to find a production process for sodium dibutyryladenosine cyclophosphate with lower production cost, less impurities and higher chemical purity. Summary of the invention
[0005] Aiming at the technical problem of complex post-treatment of sodium dibutyryl adenosine cyclophosphate, the present invention provides a method for synthesizing sodium dibutyryl adenosine cyclophosphate.
[0006] The technical solution of the present invention is as follows:
[0007] A method for synthesizing sodium dibutyryl adenosine cyclophosphate, the reaction route is as follows:
[0008] ;
[0009] Wherein X is Cl or Br;
[0010] The synthesis method comprises at least the following steps:
[0011] Under the action of a phase transfer catalyst, sodium adenosine cyclophosphate reacts with butyryl halide to generate sodium dibutyryl adenosine cyclophosphate, the butyryl halide is selected from n-butyryl chloride and / or n-butyryl bromide, and the phase transfer catalyst is selected from cyclic crown ethers, quaternary ammonium salts, tertiary amines and / or quaternary phosphonium salts.
[0012] Furthermore, based on the amount of sodium cyclophosphate adenosine added, the amount of halogenated butyryl added is 2-3 equivalents.
[0013] Further, sodium cycloadenosine monophosphate is added to the solvent, and then halogenated butyryl, triethylamine and a phase transfer catalyst are added, and the reaction is carried out under a protective atmosphere at a reaction temperature of 85-90° C. After HPLC shows that the raw material is completely converted, the reaction is stopped, and the solvent is distilled under reduced pressure until no solvent is produced to obtain a brown viscous solid. The reaction solvent is distilled out by reduced pressure distillation, thereby reducing the generation of butyric acid by-products.
[0014] Further, acetone is added to the brown viscous solid obtained by the reaction and stirred to precipitate crystals, which are filtered and the filter cake is collected and dried to obtain a crude product of sodium dibutyryl adenosine cyclophosphate.
[0015] Furthermore, the synthesis method also includes recrystallization of the crude dibutyryl adenosine sodium cyclophosphate, and the specific method is as follows:
[0016] Acetone is added to the crude sodium dibutyryladenosine cyclophosphate to completely dissolve the sodium dibutyryladenosine cyclophosphate, and then activated carbon is added. After stirring, the mixture is filtered. Acetone is added to the filtrate again to precipitate crystals. The crystals are filtered, and the filter cake is collected and washed with acetone, and dried to obtain the product.
[0017] Furthermore, the solvent is toluene.
[0018] Furthermore, the amount of triethylamine added is 2-3 equivalents based on the amount of sodium cyclophosphate added.
[0019] Furthermore, based on the amount of sodium cyclophosphate added, the amount of the phase transfer catalyst added is 0.05-0.1 equivalent.
[0020] Furthermore, the protective atmosphere is at least one of a nitrogen atmosphere, a helium atmosphere or an argon atmosphere.
[0021] Further, sodium cyclic adenosine phosphate is prepared by reacting cyclic adenosine phosphate with sodium hydroxide, and the specific method is as follows:
[0022] Add cyclic adenosine monophosphate into water and stir evenly, then add sodium hydroxide and stir to react until cyclic adenosine monophosphate is completely dissolved, add anhydrous ethanol and stir to crystallize, centrifuge, collect the filter cake, and dry to obtain sodium cyclic adenosine monophosphate.
[0023] Furthermore, based on the amount of cyclic adenosine monophosphate added, the amount of sodium hydroxide added is 1-1.2 equivalents.
[0024] The beneficial effects of the present invention are:
[0025] Sodium adenosine cyclophosphate is converted into dibutyryl sodium adenosine cyclophosphate by butyrylation. The difficulty is that the reactant sodium adenosine cyclophosphate has a very low solubility in organic solvents, and a large amount of butyric anhydride is usually required as a solvent, which will result in the generation of a large amount of butyric acid byproducts in post-processing, and will also cause the generation of monobutyryl sodium adenosine cyclophosphate impurities, which is not conducive to the purification of the product. The present invention uses halogenated butyryl to replace butyric anhydride to react with sodium adenosine cyclophosphate to prepare dibutyryl sodium adenosine cyclophosphate, reduces the amount of acylating agent used, simplifies the post-processing process of the reaction, improves yield, and improves product quality and stability. At the same time, for the problem of poor solubility of sodium adenosine cyclophosphate, the present invention adopts a phase transfer catalyst to accelerate the effective collision of substrates in a heterogeneous system, provides reaction efficiency, and shortens the reaction time. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.
[0027] Figure 1 This is the H NMR spectrum of the sodium dibutyryl adenosine cyclophosphate product prepared in Example 1. DETAILED DESCRIPTION
[0028] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.
[0029] Example 1
[0030] A method for synthesizing sodium dibutyryl adenosine cyclophosphate, the reaction route is as follows:
[0031] ;
[0032] The specific steps are as follows:
[0033] (1) Reaction of cyclic adenosine phosphate with sodium hydroxide: Weigh 100 g of cyclic adenosine phosphate, add 25 g of water, stir well, then slowly add 40% NaOH and stir to react until it is completely dissolved, add anhydrous ethanol and stir to crystallize, centrifuge, collect the filter cake, and vacuum dry at 50°C for 6 hours to obtain sodium cyclic adenosine phosphate.
[0034] (2) Reaction of sodium adenosine cyclophosphate with butyryl chloride: 65 g of n-butyryl chloride and 58 g of triethylamine were added to 0.5 L of toluene, and 100 g of sodium adenosine cyclophosphate was added in batches. Then, 1.5 g of pyridine was added and the mixture was reacted at 85 °C for about 6 h under N2 protection. The reaction was stopped after HPLC showed that the raw materials were completely converted. The mixture was distilled under reduced pressure until no solvent was discharged to obtain a brown viscous solid.
[0035] (3) Purification: The brown viscous solid obtained in multiple batches of step (2) was combined into a batch, and 2 L of 80% (V / V) acetone aqueous solution was added. After stirring for 30 minutes, 5 L of acetone was added to precipitate crystals. The crystals were filtered and the filter cake was directly dried at 50°C for 12 h to obtain 112 g of crude sodium dibutyryladenosine cyclophosphate with a yield of 80%. The purity of the crude product was 99.3% as determined by HPLC.
[0036] (4) Recrystallization: To 112 g of the crude sodium dibutyryl adenosine cyclophosphate obtained in step (3), 1 L of 80% (V / V) acetone aqueous solution was added dropwise to completely dissolve the crude sodium dibutyryl adenosine cyclophosphate. Then, 1 g of needle-shaped activated carbon was added. The mixture was stirred for 30 minutes and filtered. 3 L of acetone was added to the filtrate to precipitate crystals. The crystals were filtered and the filter cake was collected and washed with 5 L of acetone. The mixture was dried at 50° C. for 12 h to obtain 106 g of sodium dibutyryl adenosine cyclophosphate with a yield of 95%.
[0037] The prepared dibutyryl adenosine sodium cyclophosphate was subjected to nuclear magnetic resonance detection. 1 H NMR (D2O , 600 MHz): δ 8.70 (s,1H), 8.48 (s, 1H), 6.41 (s, 1H), 5.74 (d, J = 6.0Hz, 1H), 5.20 (m, 1H), 4.54-4.50 (m, 1H), 4.38-4.32 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 2.54 (q, J = 7.2 Hz,2H), 1.79-1.75 (m, 2H), 1.70-1.66 (m, 2H), 1.01 (t, J = 6.0 Hz, 3H), 0.97 (t, J =6.0 Hz, 3H).
[0038] Example 2
[0039] A method for synthesizing sodium dibutyryl adenosine cyclophosphate, the reaction route is as follows:
[0040] ;
[0041] The specific steps are as follows:
[0042] (1) Reaction of cyclic adenosine phosphate with sodium hydroxide: Weigh 100 g of cyclic adenosine phosphate, add 25 g of water, stir well, then slowly add 40% NaOH and stir to react until it is completely dissolved, add anhydrous ethanol and stir to crystallize, centrifuge, collect the filter cake, and vacuum dry at 50°C for 6 hours to obtain sodium cyclic adenosine phosphate.
[0043] (2) Reaction of sodium adenosine cyclophosphate with butyryl chloride: 65 g of n-butyryl chloride and 58 g of triethylamine were added to 0.5 L of toluene, and then 100 g of sodium adenosine cyclophosphate was added in batches, followed by 5 g of 18-crown ether-6. The mixture was reacted at 85 °C for about 6 h under N2 protection. The reaction was stopped after HPLC showed that the raw materials were completely converted, and the mixture was distilled under reduced pressure until no solvent was discharged to obtain a brown viscous solid.
[0044] (3) Purification: The brown viscous solid obtained in multiple batches of step (2) was combined into a batch, and 2 L of 80% (V / V) acetone aqueous solution was added. After stirring for 30 minutes, 5 L of acetone was added to precipitate crystals. The crystals were filtered and the filter cake was directly dried at 50°C for 12 h to obtain 110 g of crude sodium dibutyryladenosine cyclophosphate with a yield of 79%. The purity of the crude product was 99.2% as determined by HPLC.
[0045] (4) Recrystallization: To 110 g of the crude sodium dibutyryl adenosine cyclophosphate obtained in step (3), 1 L of 80% (V / V) acetone aqueous solution was added dropwise to completely dissolve the crude sodium dibutyryl adenosine cyclophosphate. Then, 1 g of needle-shaped activated carbon was added. The mixture was stirred for 30 minutes and filtered. 3 L of acetone was added to the filtrate to precipitate crystals. The crystals were filtered and the filter cake was collected and washed with 5 L of acetone. The mixture was dried at 50° C. for 12 h to obtain 102 g of sodium dibutyryl adenosine cyclophosphate with a yield of 93%.
[0046] Example 3
[0047] (1) Reaction of cyclic adenosine phosphate with sodium hydroxide: Weigh 100 g of cyclic adenosine phosphate, add 25 g of water, stir well, then slowly add 40% NaOH and stir to react until it is completely dissolved, add anhydrous ethanol and stir to crystallize, centrifuge, collect the filter cake, and vacuum dry at 50°C for 6 hours to obtain sodium cyclic adenosine phosphate.
[0048] (2) Reaction of sodium adenosine cyclophosphate with butyryl bromide: 92 g of n-butyryl bromide and 58 g of triethylamine were added to 0.5 L of toluene, and 100 g of sodium adenosine cyclophosphate was added in batches. Then, 1.5 g of pyridine was added and the mixture was reacted at 85 °C for about 6 h under N2 protection. The reaction was stopped after HPLC showed that the raw materials were completely converted. The mixture was distilled under reduced pressure until no solvent was discharged to obtain a brown viscous solid.
[0049] (3) Purification: The brown viscous solid obtained in multiple batches of step (2) was combined into a batch, and 2 L of 80% (V / V) acetone aqueous solution was added. After stirring for 30 minutes, 5 L of acetone was added to precipitate crystals. The crystals were filtered and the filter cake was directly dried at 50°C for 12 h to obtain 114 g of crude sodium dibutyryladenosine cyclophosphate with a yield of 82%. The purity of the crude product was 99.4% as determined by HPLC.
[0050] (4) Recrystallization: To 114 g of the crude sodium dibutyryladenosine cyclophosphate obtained in step (3), 1 L of 80% (V / V) acetone aqueous solution was added dropwise to completely dissolve the crude sodium dibutyryladenosine cyclophosphate. Then, 1 g of needle-shaped activated carbon was added. The mixture was stirred for 30 minutes and filtered. 3 L of acetone was added to the filtrate to precipitate crystals. The crystals were filtered and the filter cake was collected and washed with 5 L of acetone. The mixture was dried at 50° C. for 12 h to obtain 108 g of sodium dibutyryladenosine cyclophosphate with a yield of 95%.
[0051] Although the present invention has been described in detail with reference to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention.
Claims
1. A method for synthesizing sodium dibutyryl adenosine cyclophosphate, characterized in that: The reaction route is as follows: ； Wherein X is Cl or Br; The synthesis method comprises at least the following steps: Under the action of a phase transfer catalyst, sodium adenosine cyclophosphate reacts with butyryl halide to generate sodium dibutyryl adenosine cyclophosphate, the butyryl halide is selected from n-butyryl chloride and / or n-butyryl bromide, and the phase transfer catalyst is selected from cyclic crown ethers, quaternary ammonium salts, tertiary amines and / or quaternary phosphonium salts; The reaction temperature is 85-90°C; The amount of butyryl halide added is 2-3 equivalents based on the amount of sodium cyclophosphate added; The amount of the phase transfer catalyst added is 0.05-0.1 equivalents based on the amount of sodium cyclophosphate added.
2. The synthesis method according to claim 1, characterized in that The synthesis method specifically comprises the following steps: adding butyryl halide and triethylamine to a solvent, and then adding sodium cyclophosphate adenosine and pyridine, reacting under a protective atmosphere at a reaction temperature of 85-90° C., stopping the reaction after HPLC shows that the raw materials are completely converted, and performing reduced pressure distillation until no solvent is discharged to obtain a brown viscous solid.
3. The synthesis method according to claim 2, characterized in that Acetone was added to the brown viscous solid obtained by the reaction and stirred to precipitate crystals, which were filtered and the filter cake was collected and dried to obtain a crude product of sodium dibutyryl cyclophosphate.
4. The synthesis method according to claim 3, characterized in that The synthesis method also includes recrystallization of the crude dibutyryl adenosine sodium cyclophosphate, and the specific method is as follows: Acetone is added to the crude sodium dibutyryladenosine cyclophosphate to completely dissolve the sodium dibutyryladenosine cyclophosphate, and then activated carbon is added. After stirring, the mixture is filtered. Acetone is added to the filtrate again to precipitate crystals. The crystals are filtered, and the filter cake is collected and washed with acetone, and dried to obtain the product.
5. The synthesis method according to any one of claims 2 to 4, characterized in that The solvent is toluene.
6. The synthesis method according to any one of claims 2 to 4, characterized in that The amount of triethylamine added is 2-3 equivalents.
7. The synthesis method according to claim 1, characterized in that Cyclic adenosine sodium is prepared by the reaction of cyclic adenosine monophosphate with sodium hydroxide.