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High-purity P1,P4-bis(uridine-5'-tetraphosphoric acid) salt preparation method

A technology of tetraphosphoric acid and uridine, applied in the field of P1, can solve problems such as difficult to reduce medicinal requirements

Inactive Publication Date: 2017-08-18
GUANGDONG ZHONGSHENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above impurities are difficult to reduce to the pharmaceutical requirements by solvent crystallization method or anion resin purification method

Method used

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  • High-purity P1,P4-bis(uridine-5'-tetraphosphoric acid) salt preparation method
  • High-purity P1,P4-bis(uridine-5'-tetraphosphoric acid) salt preparation method
  • High-purity P1,P4-bis(uridine-5'-tetraphosphoric acid) salt preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: UMP-2Bu 3 NH preparation

[0070] Add 208.5g (0.566g) of disodium salt of UMP to 1.25L of water and stir to dissolve, add the aqueous solution to the cation exchange resin (hydrogen type), soak for 2 hours, rinse with water until no UMP flows out, combine the effluents, and add 214.8g of tributylamine (1.159mol), stirred at room temperature for 1h, concentrated to dryness under reduced pressure at 60°C, concentrated to dryness with 500ml of dioxane with azeotropic water, dissolved in 2.5L of N,N dimethylformamide, and stored within 0°C for later use.

Embodiment 2

[0071] Example 2: UTP-3Bu 3 NH preparation

[0072] Add 289.4g (0.526mol) of trisodium salt of UTP to 1.25L 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 394.8g (2.13 mol), stirred at room temperature for 1 h, concentrated to dryness under reduced pressure at 50°C, concentrated to dryness with 500ml of dioxane with azeotropic water, dissolved in 2.5L of N,N dimethylformamide, and stored within 0°C for future use.

Embodiment 3-9

[0073] Example 3-9, P 1 , P 4 - Preparation of di(uridine-5'-tetraphosphate)

[0074] UTP-3Bu 3 NH N, N dimethylformamide solution 25.0ml (5.0mmol), 18.0ml (3.6mmol), 13.5ml (2.7mmol), 10.8ml (2.16mmol), 9.0ml (1.8mmol), 6.75ml (1.35 mmol), 5.4ml (1.08mmol), add N,N diisopropylcarbodiimide 1.04g under stirring, react at 25℃ for 2h, add UMP-2Bu 3 NH N, N dimethylformamide solution 25ml (5.4mmol) and 1.36g (10.0mmol) zinc chloride, reacted at 25°C for 3h, after the reaction was complete, added 20ml of water to quench, concentrated to dryness under reduced pressure at 65°C, added 100ml of water was stirred and crystallized for 30min, filtered, and the filtrate was collected to obtain P 1 , P 4 - tributylamine salt of di(uridine-5'-tetraphosphate). HPLC detects purity, and the result is as follows:

[0075] Table 2: Change list of related substances under different ratios of UMP:UTP

[0076]

[0077] It can be clearly seen from the above table that with the continuous i...

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Abstract

The invention provides a P1,P4-bis(uridine-5'-tetraphosphoric acid) salt preparation method. The method includes: subjecting tributylamine salt of UTP to action of carbodiimide condensing agents; subjecting synthesis with excessive tributylamine salt of UMP to obtain P1,P4-bis(uridine-5'-tetraphosphoric acid); performing anion exchange resin gradient elution without water concentration, diluting, performing anion exchange resin elution again, and salifying and refining to obtain P1,P4-bis(uridine-5'-tetraphosphoric acid) salt. The method has advantages that the production cycle can be shortened remarkably, and products in medicinal purity can be obtained by preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a P 1 , P 4 - Preparation method of di(uridine-5'-tetraphosphate) 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. The sales of diquafosol ey...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00C07H1/06
CPCC07H19/10C07H1/00C07H1/06
Inventor 谭珍友
Owner GUANGDONG ZHONGSHENG PHARMA
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