Preparation method of phosphate ester

Abstract

The invention discloses a preparation method of phosphate ester, and relates to the technical field of pharmaceutical chemicals. Uridine monophosphate or salt thereof and a pyrophosphoric acid activecompound are used, and under the action of a metal ion catalyst Ca<2+>, Mn<2+> or Mg<2+>, high-purity U2P4 can be obtained with high yield in large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical engineering, in particular to a method for preparing phosphoric acid ester. Background technique [0002] Dry eye syndrome is a kind of disease that causes ocular discomfort symptoms due to the abnormal tear film quantity or quality caused by the tear film instability and ocular surface damage. The main direct cause of dry eye is that when people focus on work and study, the number of eye blinks decreases, which affects the function of the tear film and causes dry eyes. In addition, factors such as wearing contact lenses, dust pollution, dry air, and use of sedative drugs can easily induce dry eye syndrome. If dry eye syndrome is not treated in time, it will cause serious consequences such as corneal opacity, ulcers, vision loss, and even blindness. [0003] Document CN1147502C (1998), discloses a kind of preparation U 2 P 4 The synthetic method of the method, the steps are as fo...

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[0003] Document CN1147502C (1998), discloses a kind of preparation U 2 P 4 The synthetic method of the method, the steps are as follows: the method uses uridine monophosphate (UMP), or uridine diphosphate (UDP), or uridine triphosphate (UTP) as raw material, reacts with the activation group, and makes the active group The uridine phosphate compound of the group is reacted with UMP, UDP, UTP or pyrophosphoric acid (PPi) respectively, and is obtained through separation and purification. This method contains a large amount of by-products and reaction raw materials, and separation and purification are difficult;

[0004] Bioorganic & Medicinal Chemistry Letters, 11(2001), 157-160, the literature introduces a preparation of U 2 P 4 The synthesis method, the steps are as follows: use UMP or UDP to react with carbonyldiimidazole to generate UMP imidazole or UDP imidazole, then UMP imidazole reacts with UTP or UDP imidazole reacts with UDP to generate U 2 P 4 , the method has many by-products and is difficult to separate, so it cannot be suitable for industrialized production;

[0005] CN101495497B (2007), discloses a kind of preparation U 2 P 4 The synthetic method of the method, the steps are as follows: the method uses UTP as the starting raw material, generates cyclic triphosphoric anhydride (c-UTP) under the action of carbodiimide dehydrating agent, and c-UTP is catalyzed by magnesium, manganese or iron metal salt Under the reaction with UMP, U 2 P 4 , the method UTP raw material is expensive, and free UTP is a very unstable substance, and the feasibility of a large amount of industrialized production is relatively poor;

[0006] Org.Biomol.chem, 2011, No.9, 730-738, the literature introduces a preparation of U 2 P 4 The synthesis method, the steps are as follows: pyrophosphoric acid is activated with imidazole to prepare diimidazole pyrophosphate, and condensed with UMP under the catalysis of zinc chloride to obtain U 2 P 4 , the reaction yield is low under the catalysis of zinc chloride, which cannot be suitable for industrialized production;

[0007] CN105026414B (2013), discloses a kind of preparation U 2 P 4 A synthetic method, the steps are as follows: the method uses phosphoric acid active compounds, in the presence of metal ions iron, aluminum, lanthanum or cerium, in water or hydrophilic organic solvents with phosphoric acid compounds of UMP, UDP, UTP or pyrophosphoric acid or their Salt reaction, the phosphoric acid active compound is condensed by UMP, UDP, UTP or pyrophosphoric acid and a compound selected from imidazole, benzimidazole or 1,2,4-triazole with substituents, the method uses UDP as the starting Yield can reach 94% when starting raw material, but UDP raw material price is more expensive and this reaction time is longer, needs more than 20 hours, in addition, when using UMP as starting raw material, the yield of reaction is lower again, only has 45%~51 %

[0008] CN106928269A (2017), provides a kind of preparation method of phosphoric acid ester, comprises the following steps: pyrophosphoric acid active compound shown in formula II, and uridine monophosphate or its salt shown in formula III, in double metal ion composite catalyst Under the action, the reaction is carried out in a hydrophilic solvent to obtain P1, P4-di(5'-uridine base) tetraphosphate shown in formula I; but the use of a bimetallic catalytic system requires control of the bimetallic molar ratio 1: 1. In the specific embodiment, the metal ion catalyst equivalent is large, the temperature range is small, and the preparation conditions are relatively strict. Even if the yield and purity of the preparation are high, it is necessary to strictly control the input amount of the reactant and the catalyst and the reaction temperature. Large-scale production is unfavorable, and in the preparation of pyrophosphate active compounds, n-butylamine pyrophosphate uses n-tributylamine as one of the raw materials, and n-tributylamine is highly toxic and not environmentally friendly

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