Preparation method for P<1>, P<4>-di(uridine5'-)tetraphosphate

A technology of tetraphosphate and uridine is applied in the field of preparation of P1,P4-ditetraphosphate, and can solve the problems such as the method that cannot be used in practice and the low yield of target product.

Pending Publication Date: 2019-09-10
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0005] No catalyzer is used in the preparation method disclosed by CN1147502C, but the

Method used

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  • Preparation method for P&lt;1&gt;, P&lt;4&gt;-di(uridine5'-)tetraphosphate
  • Preparation method for P&lt;1&gt;, P&lt;4&gt;-di(uridine5'-)tetraphosphate
  • Preparation method for P&lt;1&gt;, P&lt;4&gt;-di(uridine5'-)tetraphosphate

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Example Embodiment

[0029] Example 1 P 1 ,P 4 -Preparation of bis(uridine 5′-)tetraphosphate

[0030] Step 1. Preparation of intermediate compound represented by formula (Ⅱa) (UMP-TBA)

[0031] Add uridine-5′-monophosphate disodium salt (5.43mol, 2.0kg) and purified water (10.0kg) to a 20L plastic bucket, dissolve it under stirring and filter, and the filtrate is ready for use; convert 20.0L into hydrogen form The DOWEX IR100S resin is loaded into the chromatography column, rinsed with purified water (40.0kg), the resin is compacted, the bubbles are discharged, the washing liquid is drained, and the drain switch is turned off; the above filtrate is slowly introduced into the column to make the upper layer liquid The surface is just flooded with resin. After standing still, add purified water (95.0kg) to the column for column elution. When the pH of the eluate becomes 6.5-7.5, stop the elution. Combine the eluates and add them to the 200L reactor. Start stirring, add tri-n-butylamine (0.92kg) dropwise...

Example Embodiment

[0036] Example 2 P 1 ,P 4 -Preparation of bis(uridine 5′-)tetraphosphate

[0037] Take the prepared N,N-dimethylformamide solution of UTP-3TBA (UTP-3TBA 3.84g, 3.69mmol) into a 100ml three-necked flask, add diisopropylcarbodiimide (564mg, 4.44mmol) , N 2 After two replacements, react at 25-30°C for 5 hours. Add the N,N-dimethylformamide solution of UMP-TBA (UMP-TBA 2.23g, 4.43mmol) and anhydrous magnesium chloride (422mg, 4.43mmol) to the reaction solution, and then react at 25-30°C for 5 hours, Sampling HPLC detection, area normalization method to calculate UP4U content and large molecular weight impurity P 1 , P 5 Di(uridine 5′-)pentaphosphate (UP5U) and P 1 , P 6 -The content of bis(uridine 5'-)hexaphosphate (UP6U).

[0038] result:

[0039]

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Abstract

The invention provides a preparation method for P<1>, P<4>-di(uridine5'-)tetraphosphate. Specifically, the method has a high yield in an industrial production process, enables the amount of generationof large molecular weight impurities which are difficult to be removed to be significantly reduced, is easy in purification, and provides possibility for industrial production of the P<1>,P<4>-di(uridine5'-)tetraphosphate.

Description

technical field [0001] This application relates to a P 1 ,P 4 - Process for the preparation of bis(uridine 5'-)tetraphosphate (UP4U) salt. Background technique [0002] Diquafosol tetrasodium also known as P 1 ,P 4 -Di(uridine 5′-)tetraphosphate, the structure shown in (Ia), is a second-generation uridine nucleotide analogue, which is a P2Y2 receptor agonist and mucin secretion stimulator, Japan Santen Pharmaceutical Co., Ltd. has developed 3% diquafosol tetrasodium eye drops for the treatment of dry eye. In addition, it has the possibility of further development as an expectorant having an effect of inducing expectoration or a drug for treating pneumonia. [0003] [0004] About P 1 ,P 4- Synthesis of di(uridine 5'-)tetraphosphate, Chinese patent CN101495497B discloses a dehydration condensation reaction of uridine 5'-triphosphate (UTP) to prepare uridine 5'-cyclic triphosphate, and then react with urine A method for preparing glycoside 5'-monophosphate (UMP) by ...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/04
CPCC07H19/10C07H1/04
Inventor 蔡洪芳陈埔范刘春樊波薛州洋
Owner JIANGSU HENGRUI MEDICINE CO LTD
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