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p 1 ,p 4 The preparation method of two (uridine 5'-) tetraphosphate

A technology of uridine monophosphate triethylamine salt and tetraphosphate, which is applied in the field of P1, can solve problems such as difficulty in reaching medicinal standards, no research on metal ion residues, etc., and achieve high yield, high purity, and low metal ion residues. Effect

Active Publication Date: 2021-10-08
SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Chinese patent CN1151166C provides a kind of P1, P4 two (uridine 5,-) tetraphosphate purification method, adopts anion exchange chromatography and active carbon chromatography to purify successively to obtain P 1 , P 4 Di(uridine 5'-)tetraphosphate tetrasodium salt, with a purity of at least 95%, of which only the impurities UDP and UTP account for about 1%, which is difficult to meet the pharmaceutical standard of less than 1% of the total impurities in the finished product
[0012] At the same time, P 1 , P 4 Di(uridine 5'-) tetraphosphate sodium salt is used as an eye drop preparation, and the residual metal ions of its catalyst should be controlled at an extremely low level. The requirements for eye drops on the residue of heavy metal ions need to control the residue of manganese and zinc below 20ppm, and the prior art has not studied the residue of metal ions

Method used

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  • p <sup>1</sup> ,p <sup>4</sup> The preparation method of two (uridine 5'-) tetraphosphate
  • p <sup>1</sup> ,p <sup>4</sup> The preparation method of two (uridine 5'-) tetraphosphate
  • p <sup>1</sup> ,p <sup>4</sup> The preparation method of two (uridine 5'-) tetraphosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] a) Preparation of bistriethylamine pyrophosphate

[0058] Put the pretreated hydrogen-type cation exchange resin PK216 (2.4L) into the chromatography column, add disodium pyrophosphate (75.2g, 282.81mmol) into 1.8L water and stir to dissolve, add the aqueous solution to the hydrogen-type cation-exchange resin In PK216, after soaking for 1 hour, elute with purified water to pH 5.5-6.5, combine the eluents, and titrate the content of pyrophosphoric acid (43.2g, 242.24mmol) and add triethylamine (50.7g, 513.26mmol), Stir for 30min, concentrate under reduced pressure at 45-50°C until white semi-solid, add appropriate amount of N,N'-dimethylformamide (500mL) to the residue for azeotropic dehydration, after concentration is complete, add N,N'- Dimethylformamide, stir evenly to obtain N,N'-dimethylformamide suspension of bistriethylamine pyrophosphate.

[0059] b) Preparation of uridine triethylamine salt

[0060] Put the pretreated hydrogen-form cation exchange resin PK216 ...

Embodiment 2

[0068] a), b), c) steps are the same as in Example 1.

[0069] d)P 1 , P 4 Preparation of Di(uridine 5'-)tetraphosphate

[0070]Mix the N,N'-dimethylformamide solution of uridine acid triethylamine salt obtained in step b) and the N,N'-dimethylformamide solution of imidazole pyrophosphate triethylamine salt obtained in step c) , stirred evenly, added anhydrous manganese chloride (306.2g, 2.43mol) in batches, and controlled the reaction temperature between 25-35°C. After the addition is complete, the mixture is kept under the condition of 25-35° C. and stirred for 2 hours. HPLC detection.

[0071] e) The steps are the same as in Example 1.

Embodiment 3

[0073] a), b), c) steps are the same as in Example 1.

[0074] d)P 1 , P 4 Preparation of Di(uridine 5'-)tetraphosphate

[0075] Mix the N,N'-dimethylformamide solution of uridine acid triethylamine salt obtained in step b) and the N,N'-dimethylformamide solution of imidazole pyrophosphate triethylamine salt obtained in step c) , stirred evenly, added anhydrous manganese chloride (153.5g, 1.22mol) in batches, and controlled the reaction temperature between 25-35°C. After the addition was complete, the mixture was incubated and stirred for 4 hours under the condition of 25-35°C. HPLC detection.

[0076] e)P 1 , P 4 Purification of Di(uridine 5'-)tetraphosphate

[0077] After the reaction was completed, the reaction solution was stirred with 1.8L ethyl acetate, filtered, the solid was dissolved in 1000mL, solid sodium bicarbonate (102.5g, 1.22mol) and sodium carbonate (64.65g, 610mmol) were added, stirred for 2 hours, filtered, the filtrate Add concentrated hydrochloric ...

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Abstract

The present invention relates to P 1 , P 4 The preparation method of two (uridine 5'-) tetraphosphates, the method comprises the following steps: imidazole triethylamine pyrophosphate shown in formula I and uridine monophosphate triethylamine salt shown in formula II, on metal Under the effect of salt catalyst, react in N,N-dimethylformamide, obtain the P shown in formula III 1 , P 4 Bis(uridine 5’-)tetraphosphate

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a P 1 , P 4 The preparation method of di(uridine 5'-)tetraphosphate. Background technique [0002] Diquafosol Tetrasodium (Diquafosol Tetrasodium), the chemical name is P 1 ,P 4 -Di(uridine-5'-)sodium tetraphosphate has been jointly developed into 3% eye drops by Santen Pharmaceutical Company and inspire Pharmaceutical Company for the treatment of dry eye disease. It was launched in Japan in 2010 under the trade name Diquas, The structural formula is as follows: [0003] [0004] The prior art discloses P 1 , P 4 The preparation method of two (uridine 5'-) tetraphosphates, but these preparation methods mostly all will use highly toxic tributylamine, thereby the pollution to environment is bigger. The disclosed preparation methods are: [0005] 1) Uridine diphosphate tributylamine salt self-condenses in the presence of an activator to obtain P 1 , P 4 Di(uridine 5'-)...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H1/00C07H1/06
CPCC07H1/00C07H1/06C07H19/10
Inventor 俞雄戴德明袁西伦张袁伟
Owner SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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