阅读说明：本技术 一种地夸磷索四钠的制备方法 (Preparation method of diquafosol tetrasodium ) 是由 刘磊 赵云德 张来平 朱林飞 薛晨 于 2021-09-22 设计创作，主要内容包括：本发明公开了治疗干眼病药物的生产技术领域的一种地夸磷索四钠的制备方法。该方法包括如下步骤：(1)成盐：在焦磷酸水溶液中通入无机氨,进行纳滤,纳滤浓缩液减压浓缩至粘稠状物,加入DMF,得到溶液A；(2)活化：向溶液A中补加DMF稀释,搅拌均匀,再分多次加入羰基二咪唑,得到溶液B；(3)催化缩合：溶液B中加入尿苷5’-单磷酸,搅拌均匀后,分多次加入催化剂,反应结束后,加入乙酸乙酯,析出固体,抽滤,固体干燥后得到地夸磷索粗品；(4)将地夸磷索粗品加入到蒸馏水中,搅拌下加入碳酸钠固体,至pH为8～10,抽滤,向滤液中加入95％乙醇,过滤,得地夸磷索四钠。本发明的优点是采用无机氨代替现有技术的有机胺,安全性高。(The invention discloses a preparation method of diquafosol tetrasodium, belonging to the technical field of production of medicaments for treating xerophthalmia. The method comprises the following steps: (1) salifying: inorganic ammonia is introduced into the pyrophosphoric acid aqueous solution for nanofiltration, nanofiltration concentrated solution is decompressed and concentrated to be sticky, and DMF is added to obtain solution A; (2) and (3) activation: adding DMF into the solution A for dilution, uniformly stirring, and then adding carbonyldiimidazole for multiple times to obtain a solution B; (3) catalytic condensation: adding uridine 5' -monophosphate into the solution B, stirring uniformly, adding a catalyst for multiple times, adding ethyl acetate after the reaction is finished, separating out a solid, performing suction filtration, and drying the solid to obtain a crude product of diquafosol; (4) and adding the crude product of diquafosol into distilled water, adding sodium carbonate solid under stirring until the pH value is 8-10, performing suction filtration, adding 95% ethanol into the filtrate, and filtering to obtain diquafosol tetrasodium. The invention has the advantages that inorganic ammonia is adopted to replace organic amine in the prior art, and the safety is high.)

1. The preparation method of diquafosol tetrasodium is characterized by comprising the following steps of:

(1) salifying: inorganic ammonia is introduced into the pyrophosphoric acid aqueous solution, the pyrophosphoric acid aqueous solution is stirred for 0.5 to 1.5 hours, nanofiltration is carried out, nanofiltration concentrated solution is subjected to reduced pressure concentration at the temperature of 45 to 50 ℃ to form a viscous substance, DMF is added, and the reduced pressure concentration is continued to remove water in the solution, so that solution A is obtained;

(2) and (3) activation: adding DMF (dimethyl formamide) into the solution A obtained in the step (1) for dilution, uniformly stirring, adding carbonyldiimidazole for multiple times, stirring for reacting for 1.5-2.5 hours after adding, and cooling the reaction solution to 0-15 ℃ to obtain a solution B;

(3) catalytic condensation: adding uridine 5' -monophosphate into the solution B obtained in the step (2), uniformly stirring, adding a catalyst for multiple times, keeping the temperature at 0-15 ℃ after the addition is finished, stirring for reacting for 1-2 hours, adding ethyl acetate after the reaction is finished, separating out a solid, performing suction filtration, and drying the solid to obtain a crude product of diqua fosol;

(4) and (3) adding the crude diquafosol obtained in the step (3) into distilled water, adding sodium carbonate solid under stirring until the pH value is 8-10, performing suction filtration, collecting filtrate, adding 95% ethanol into the filtrate, stirring for 10-12 hours, and filtering to obtain diquafosol tetrasodium.

2. The method for preparing diquafosol tetrasodium according to claim 1, characterized in that: the catalyst in the step (3) is a mixed catalyst of anhydrous ferric trichloride and anhydrous zinc chloride, and the weight ratio of the ferric trichloride to the zinc chloride is 1: 1-1.5.

3. The method for preparing diquafosol tetrasodium according to claim 1, characterized in that: the molar ratio of ammonia to pyrophosphoric acid in step (1) is 2-2.2: 1.

4. The method for preparing diquafosol tetrasodium according to claim 1, characterized in that: the molar ratio of the ammonium pyrophosphate to the carbonyldiimidazole is 1: 2-2.2.

5. The method for preparing diquafosol tetrasodium according to claim 1, characterized in that: the molar ratio of the ammonium pyrophosphate to the uridine 5' -monophosphate is 1: 2-2.2.

6. The method for preparing diquafosol tetrasodium according to claim 1, characterized in that: and (3) when nanofiltration is carried out in the step 1, carrying out reduced pressure concentration when the nanofiltration is concentrated to one fourth of the residual original volume.

Technical Field

The invention belongs to the technical field of production of medicaments for treating xerophthalmia, and particularly relates to a preparation method of diquafosol tetrasodium.

Background

Diquafossol tetrasodium is a P2Y2 receptor agonist, mainly acts on P2Y2 receptors on conjunctival epithelium and goblet cell membrane, and promotes the secretion of water and mucin by up-regulating the calcium ion concentration in cells, thereby improving the dry eye symptoms and being used for local treatment of the dry eye.

The medicine is developed after being authorized by Inspire pharmaceutical company (Merck corporation) of Shentian pharmacy, is first approved in Japan for treating xerophthalmia 10 months in 2010 and is sold under the trade name ofThe specification was 3% (5 mL). The product is imported in 2017 in 10 months and has the trade name of Lieisi. In clinical studies in japan, no serious ocular and systemic adverse reactions were found. Diquas are well tolerated and can be used for the long-term treatment of dry eye conditions. In 2018, the global sale of Diquas is 153.67 billion yen (equivalent to 10.02 billion yen). The public data shows that the drug has a sales amount of about 3500 ten thousand yuan for public medical institutions in 2019.

The synthesis route of diquafosol which can be researched by the literature at present is mainly three, (1) the diquafosol is synthesized by taking uridine 5 ' -monophosphate (uridine 5 ' -monophosphate) and uridine 5 ' -triphosphate (UTP) as raw materials through salification, activation and catalytic condensation; (2) uridine 5' -diphosphate (UDP) is used as a raw material, and diquafosol is synthesized through salification, activation and catalytic condensation; (3) tetrasodium pyrophosphate and uridine 5 '-monophosphate (uridine 5' -monophosphate) are used as raw materials, and are subjected to salt formation, activation and catalytic condensation to synthesize diquafosol. In the three synthesis routes, organic bases such as n-tributylamine or triethylamine are used for salifying, wherein the n-tributylamine is a highly toxic substance, and the triethylamine is a toxic substance and is all organic bases.

Disclosure of Invention

The invention aims to provide a preparation method of diquafosol tetrasodium with high safety.

In order to realize the technical purpose, the preparation method of the diquafosol tetrasodium adopts the following technical scheme:

a preparation method of diquafosol tetrasodium comprises the following steps:

(1) salifying: inorganic ammonia is introduced into the pyrophosphoric acid aqueous solution, the pyrophosphoric acid aqueous solution is stirred for 0.5 to 1.5 hours, nanofiltration is carried out, nanofiltration concentrated solution is subjected to reduced pressure concentration at the temperature of 45 to 50 ℃ to form a viscous substance, DMF is added, and the reduced pressure concentration is continued to remove water in the solution, so that solution A is obtained;

(2) and (3) activation: adding DMF (dimethyl formamide) into the solution A obtained in the step (1) for dilution, uniformly stirring, adding carbonyldiimidazole for multiple times, stirring for reacting for 1.5-2.5 hours after adding, and cooling the reaction solution to 0-15 ℃ to obtain a solution B;

(3) catalytic condensation: adding uridine 5' -monophosphate into the solution B obtained in the step (2), uniformly stirring, adding a catalyst for multiple times, keeping the temperature at 0-15 ℃ after the addition is finished, stirring for reacting for 1-2 hours, adding ethyl acetate after the reaction is finished, separating out a solid, performing suction filtration, and drying the solid to obtain a crude product of diqua fosol;

(4) and (3) adding the crude diquafosol obtained in the step (3) into distilled water, adding sodium carbonate solid under stirring until the pH value is 8-10, performing suction filtration, collecting filtrate, adding 95% ethanol into the filtrate, stirring for 10-12 hours, and filtering to obtain diquafosol tetrasodium.

Preferably, the catalyst in the step (3) is a mixed catalyst of anhydrous ferric trichloride and anhydrous zinc chloride, and the weight ratio of the ferric trichloride to the zinc chloride is 1: 1-1.5.

Preferably, the molar ratio of ammonia to pyrophosphoric acid in step (1) is 2-2.2: 1.

Preferably, the molar ratio of the ammonium pyrophosphate to the carbonyldiimidazole is 1: 2-2.2.

Preferably, the molar ratio of the ammonium pyrophosphate salt to the uridine 5' -monophosphate is 1: 2-2.2.

Preferably, when nanofiltration is performed in step 1, the nanofiltration is concentrated to one fourth of the original volume, and reduced pressure concentration is started.

The reaction formula of the diquafosol tetrasodium prepared by the invention is as follows:

compared with the prior art, the invention has the beneficial effects that:

the invention adopts inorganic ammonia to replace organic amine (n-tributylamine and triethylamine) in the prior art, thereby reducing the possibility of highly toxic residue in the finished product to zero, ensuring higher safety of the medicine for human raw material medicine and ensuring the life safety of production personnel in the production process of the medicine.

Detailed Description

The present invention is further illustrated by the following detailed description, which is to be construed as merely illustrative and not limitative of the remainder of the disclosure, and modifications and variations such as those ordinarily skilled in the art are intended to be included within the scope of the present invention as defined in the appended claims.

Example 1:

adding 600g of 30% pyrophosphoric acid aqueous solution into a reaction bottle, then slowly introducing 35g of ammonia gas, stirring for half an hour after the introduction, performing nanofiltration concentration, concentrating to one third of the original volume, continuously concentrating the nanofiltration concentrated solution at 45-50 ℃ under reduced pressure to obtain a viscous substance, adding 400ml of DMF, and continuously concentrating under reduced pressure to remove water until the water content is less than 0.1%.

Supplementing 200ml of DMF into the dehydrated DMF solution of ammonium pyrophosphate, uniformly stirring, adding 328g of carbonyldiimidazole by 5 times, after the addition is finished, stirring for reaction for 1.5h, cooling the reaction liquid to the internal temperature of 0-15 ℃, adding 655g of uridine 5' -monophosphate into the reaction liquid, after the uniform stirring, adding 15g of catalyst (7.5g of ferric trichloride and 7.5g of zinc chloride) by 3 times, after the addition is finished, keeping the temperature and stirring for reaction for 1h, after the reaction is finished, adding 1.5L of ethyl acetate, separating out solids, filtering, and drying to obtain a crude product of the quarto phosohol.

Adding the crude product of diquafosol into 600ml of water, slowly adding sodium carbonate solid into the water under stirring until the pH value is about 8-9, stirring for half an hour, filtering, collecting filtrate, performing nanofiltration on the filtrate until the volume of the filtrate is half of the original volume, adding 600ml of 95% ethanol, crystallizing, filtering, and drying the solid to obtain diquafosol tetrasodium.

Example 2:

adding 600g of 30% aqueous solution of pyrophosphoric acid into a reaction bottle, then dropwise adding 140g of 25% ammonia water, stirring for half an hour after the completion of the reaction, carrying out nanofiltration concentration, concentrating to one third of the original volume, continuously concentrating the nanofiltration concentrated solution at 45-50 ℃ under reduced pressure to obtain a viscous substance, adding 400ml of DMF, and continuously concentrating under reduced pressure to remove water until the water content is less than 0.1%.

Supplementing 200ml of DMF into the dehydrated DMF solution of ammonium pyrophosphate, uniformly stirring, adding 328g of carbonyldiimidazole by 5 times, after the addition is finished, stirring for reaction for 1.5h, cooling the reaction liquid to the internal temperature of 0-15 ℃, adding 655g of uridine 5' -monophosphate into the reaction liquid, after the uniform stirring, adding 15g of catalyst (7g of ferric trichloride and 8g of zinc chloride) by 3 times, after the addition is finished, keeping the temperature and stirring for reaction for 1h, after the reaction is finished, adding 1.5L of ethyl acetate, separating out a solid, filtering, and drying to obtain a crude product of diqua fosol.

Adding the crude product of diquafosol into 600ml of water, slowly adding sodium carbonate solid into the water under stirring until the pH value is about 8-9, stirring for half an hour, filtering, collecting filtrate, performing nanofiltration on the filtrate until the volume of the filtrate is half of the original volume, adding 600ml of 95% ethanol, crystallizing, filtering, and drying the solid to obtain diquafosol tetrasodium.

Example 3:

adding 600g of 30% aqueous solution of pyrophosphoric acid into a reaction bottle, then dropwise adding 154g of 25% ammonia water, stirring for half an hour after the completion of the reaction, carrying out nanofiltration concentration, concentrating to one third of the original volume, continuously concentrating the nanofiltration concentrated solution at 45-50 ℃ under reduced pressure to obtain a viscous substance, adding 400ml of DMF, and continuously concentrating under reduced pressure to remove water until the water content is less than 0.1%.

Supplementing 200ml of DMF into the dehydrated DMF solution of ammonium pyrophosphate, uniformly stirring, adding 360g of carbonyldiimidazole in 5 times, after the addition is finished, stirring for reaction for 1.5h, cooling the reaction liquid to the internal temperature of 0-15 ℃, adding 720g of uridine 5' -monophosphate into the reaction liquid, after the uniform stirring, adding 15g of catalyst (6g of ferric trichloride and 9g of zinc chloride) in 3 times, after the addition is finished, keeping the temperature and stirring for reaction for 1h, after the reaction is finished, adding 1.5L of ethyl acetate, separating out solids, filtering, and drying to obtain the crude product of diqua fosol.

Adding the crude product of diquafosol into 600ml of water, slowly adding sodium carbonate solid into the water under stirring until the pH value is about 8-9, stirring for half an hour, filtering, collecting filtrate, performing nanofiltration on the filtrate until the volume of the filtrate is half of the original volume, adding 600ml of 95% ethanol, crystallizing, filtering, and drying the solid to obtain diquafosol tetrasodium.