Method of preparing phosphate

A technology of phosphate ester and pyrophosphoric acid, which is applied in the field of medicine and chemical industry, can solve the problems of poor feasibility of industrial production, poor stability of UTP, poor reaction yield, etc., and achieve the effect of easy industrial production, less operation steps and low cost of raw materials

Active Publication Date: 2017-07-07
CHANGCHUN PUHUA PHARMA
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  • Abstract
  • Description
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Problems solved by technology

This method UTP raw material price is more expensive than UMP, in addition, in the preparation of cyclic triphosphoric anhydride (c-UTP), need to carry out salt conversion to UTP sodium salt, be prepared into UTP amine salt, need long-time distilled water in this process , the stability of UTP is poor, it will degrade, and the reaction yield is poor, and the feasibility of mass industrial production is poor

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preparation example Construction

[0028] The present invention provides a preparation method of phosphate ester, which comprises the following steps:

[0029] The pyrophosphate active compound represented by formula II reacts with the uridine monophosphate or its salt represented by formula III in a hydrophilic solvent under the action of a double metal ion composite catalyst to obtain P represented by formula I 1 ,P 4 -Bis(5'-uridine) tetraphosphate;

[0030]

[0031] In formula II, X is imidazolyl, N-methylimidazolyl or 1,2,4-triazolyl;

[0032] The double metal ion in the double metal ion composite catalyst is Zn 2+ , Mn 2+ , Mg 2+ , Fe 2+ , Fe 3+ And Al 3+ A combination of any two of them.

[0033] The preparation method provided by the invention has the advantages of easy availability of raw materials, low raw material cost, few operation steps, simple process, high reaction yield (product separation yield of more than 80%), high product purity (HPLC purity more than 99.9%), and easy The advantages of industrial ...

Embodiment 1

[0060] Example 1 Preparation of n-butylamine pyrophosphate (PPi-TBA)

[0061]

[0062] Tetrasodium pyrophosphate (26.6g, 0.1mol) was dissolved in deionized water (500mL), the aqueous solution was passed through a strong ion exchange column (pk216 proton type), the fractions containing pyrophosphate were combined, and tributylamine (37.1g , 0.2mol) to form a salt, the eluate is concentrated into an oily substance by a rotary evaporator. The oil was charged with water through 1,4-dioxane (100 mL), and the water was repeated 3 times to obtain the oily n-butylamine pyrophosphate (quantitative).

Embodiment 2

[0063] Example 2 Preparation of imidazole pyrophosphate (II)

[0064]

[0065] In a DMF (150 mL) solution of n-butylamine pyrophosphate (54.8 g, 0.1 mol), 1,1-carbonyldiimidazole (37.7 g, 0.3 mol) was added as an activator under nitrogen protection, and the mixture was stirred at room temperature for 2 hours. Methanol (3.2g, 0.1mol) was added to the reaction solution, stirred at room temperature for 10 minutes, and then pumped under a vacuum of 5 mmHg column, and stirred for 10 minutes. A DMF solution of imidazole pyrophosphate (II) is obtained.

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Abstract

The invention provides a method of preparing a phosphate. The method comprises the following step: enabling a pyrophosphate active compound expressed by formula II to react with uridine monophosphate expressed by a formula III or a salt thereof in a hydrophilic solvent under the action of a bimetallic ion composite catalyst to obtain P1,P4-bis (5'-uridine group) tetraphosphate expressed by formula I. In the formula II, X is imidazolyl, N-methyl imidazolyl, or 1, 2, 4-triazolyl; and the bimetallic ions in the bimetallic ion composite catalyst are a combination of any two of Zn2+, Mn2+, Mg2+, Fe2+, Fe3+ and Al3+. The method of preparing a phosphate employs a bimetallic catalytic system and can achieve high-efficiency and easy separation preparation of diquafosol.

Description

Technical field [0001] The present invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of phosphoric acid ester. Background technique [0002] Diquafoxol (P 1 ,P 4 -Di(5'-uridine) tetraphosphate tetrasodium salt) (Formula I) was developed by Ins Bayer (USA) and introduced by Santen Pharmaceutical Co., Ltd., and used eye drops for the treatment of dry eye Research and development, in April 2010, Diquafoxol eye drops (3%) was approved for marketing in Japan. [0003] [0004] The literature methods used in the prior art to prepare the compound represented by formula I mainly include: [0005] Document 1: Originally researched the synthesis route of the patent of Indias Bayer (CN1147502C, application date: 19980724). This method uses uridine monophosphate (UMP), or uridine diphosphate (UDP), or uridine triphosphate (UTP) as raw materials, and reacts with an activated group to prepare a uridine phosphate compound with an act...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09
CPCC07F9/098
Inventor 黄林青朱峡王尊来林子琦戈楠
Owner CHANGCHUN PUHUA PHARMA
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