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An industrial preparation process of tetrasodium P<1>,P<4>-di(uridine-5')tetraphosphate

A technology of tetraphosphate and uridine, applied in the field of P1, can solve problems such as difficult product preparation and product degradation

Inactive Publication Date: 2018-06-15
GUANGDONG ZHONGSHENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the above patent documents, the reaction solution for preparing the compound of formula I needs to be concentrated before subsequent operations can be performed after adding water to quench the reaction solution. The well-known solvents used in the reaction are N,N-dimethylformamide, N,N-dimethylacetamide, Dimethyl sulfoxide and others are high-boiling solvents with boiling points higher than 150°C. Concentrating the above solvents requires high vacuum and high temperature, which inevitably leads to product degradation and makes it difficult to prepare products that meet medicinal requirements.

Method used

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  • An industrial preparation process of tetrasodium P&lt;1&gt;,P&lt;4&gt;-di(uridine-5')tetraphosphate
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  • An industrial preparation process of tetrasodium P&lt;1&gt;,P&lt;4&gt;-di(uridine-5')tetraphosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: UMP-2Bu 3 NH preparation

[0059] 3875g (10.52mol) of disodium salt of UMP was added to 25L of water and stirred to dissolve, the aqueous solution was added to the cation exchange resin (hydrogen type), soaked for 2h, rinsed with water until no UMP flowed out, combined the effluent, and added 3997g (21.57mol) of tributylamine mol), stirred at room temperature for 1 h, concentrated to dryness under reduced pressure at 60°C, concentrated to dryness with 5 L of dioxane with azeotropic water, and dissolved in 50 L of N,N dimethylformamide for later use.

Embodiment 2

[0060] Example 2: UTP-3Bu 3 NH preparation

[0061] Add 2894g (5.26mol) of trisodium salt of UTP to 12.5L of water and stir to dissolve, add the aqueous solution to the cation exchange resin (hydrogen type), rinse with water until no UTP flows out, combine the effluents, and add 3948g (21.3mol) of tributylamine , stirred at room temperature for 2 hours, concentrated to dryness under reduced pressure at 55°C, concentrated to dryness with 5L of dioxane azeotropically with water, and dissolved in 25L of N,N dimethylformamide for later use. Example 3: P 1 , P 4 - Preparation of di(uridine-5'-tetraphosphate)

Embodiment 3

[0062] UTP-3Bu 3 NH in N,N dimethylformamide solution, add N,N diisopropylcarbodiimide 1991g (15.78mol) under stirring, react at 25°C for 2h, add UMP-2Bu respectively 3 NH N,N dimethylformamide solution and 1002g (10.52mol) magnesium chloride were reacted at 25°C for 3h. After the reaction was complete, 10L of water was added to quench.

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Abstract

An industrial preparation process of tetrasodium P<1>,P<4>-di(uridine-5')tetraphosphate is provided. The process includes preparing cyclic triphosphoric acid from a tributylamine salt of UTP by utilizing a carbodiimide type condensating agent; reacting the cyclic triphosphoric acid with a tributylamine salt of UMP to synthesize P<1>,P<4>-di(uridine-5')tetraphosphoric acid; directly salifying the reaction solution, without concentration, with a salt of an organic acid; performing crystallization; performing gradient elution with anion exchange resin after dissociation; subjecting the eluate, without the need of water concentration, to salt removing and water removing through membrane filtration; and then salifying to obtain the high-purity tetrasodium P<1>,P<4>-di(uridine-5')tetraphosphate.The tetrasodium P<1>,P<4>-di(uridine-5')tetraphosphate meeting officinal requirements can be prepared in a large scale by the process.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a P 1 , P 4 -The industrialized preparation method of di(uridine-5'-tetraphosphate) sodium salt. Background technique [0002] Diquafosol Sodium Eye Drops is the first P2Y2 receptor agonist eye drops approved for marketing in the world. It acts on the P2Y2 receptors on the conjunctival epithelium and goblet cell membrane, and promotes moisture retention by up-regulating the intracellular calcium ion concentration. And the secretion of mucin, thereby improving the symptoms of dry eye disease, making the tear film closer to normal. In addition, this product is a compound expected to be developed as an expectorant having an effect of inducing expectoration or a drug for treating pneumonia. This product was developed by Santen Pharmaceutical Co., Ltd. after obtaining authorization from Inspire Pharmaceuticals (a subsidiary of Merck), and was launched in Japan in December 2010. T...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00C07H1/06B01D61/02B01D9/02
CPCB01D9/02B01D61/027C07H1/00C07H1/06C07H19/10
Inventor 邓军
Owner GUANGDONG ZHONGSHENG PHARMA
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