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A method for preparing 5-amino-1,2-dihydropyrazol-3-one with orotic acid as raw material

A technology of dihydropyrazole and orotic acid, applied in organic chemistry and other directions, can solve the problems of strong alkaline environment, side reactions, low yield and the like, and achieve the effects of simple post-processing, easy amplification and simple operation

Active Publication Date: 2018-06-29
ANHUI UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a kind of synthetic method of 5-amino-1,2-dihydropyrazol-3-one with high efficiency and large-scale preparation value, in order to solve the problem of existing 5-amino-1,2-dihydropyrazole Technical problems such as side reactions, low yield, and strong alkaline environment in the preparation method of -3-ketone

Method used

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  • A method for preparing 5-amino-1,2-dihydropyrazol-3-one with orotic acid as raw material
  • A method for preparing 5-amino-1,2-dihydropyrazol-3-one with orotic acid as raw material

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Experimental program
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Effect test

Embodiment 1

[0026] (1) Add water (500mL) and hydrazine hydrate (50% aqueous solution, 300mL, 3.0mol, 3.0eq) into the reaction flask, and raise the temperature of the system to 60°C. Orotic acid (Compound 1, 156g, 1.0mol, 1.0eq.) was added in 3 portions, the reactant was gradually dissolved, stirred at this temperature for 3 hours, and cooled to room temperature. Add 500 mL of saturated ammonium chloride aqueous solution, and a white solid precipitates out. The precipitate was collected and dried to obtain 110.3 g of 5-hydroxypyrazole-4-carboxylic acid (86% yield).

[0027] (2) Tetrahydrofuran (500mL), triethylamine (104.0mL, 0.75mol, 1.5eq) and 5-hydroxypyrazole-4-carboxylic acid (64g, 0.5mol, 1.0eq) obtained in step (1) were added to the reaction In the bottle, the temperature of the system was raised to 50°C. Diphenylphosphoryl azide (DPPA, 130 mL, 0.6 mol, 1.2 eq.) was added in 3 portions, stirred at this temperature for 4 hours, and cooled to room temperature. The reaction solution...

Embodiment 2

[0029] (1) Add water (500mL) and hydrazine hydrate (50% aqueous solution, 500mL, 5.0mol, 5.0eq) into the reaction flask, and raise the temperature of the system to 90°C. Orotic acid (compound 1, 156g, 1.0mol, 1.0eq.) was added in 3 times, the reactants gradually dissolved, stirred at this temperature for 5 hours, and cooled to room temperature. Add 500 mL of saturated ammonium chloride aqueous solution, and a white solid precipitates out. The precipitate was collected and dried to obtain 121.5 g of 5-hydroxypyrazole-4-carboxylic acid (95% yield).

[0030] (2) Toluene (500mL), triethylamine (138.6mL, 1.0mol, 2.0eq) and 5-hydroxypyrazole-4-carboxylic acid (64g, 0.5mol, 1.0eq) obtained in step (1) were added to the reaction In the bottle, the temperature of the system was raised to 80°C. Diphenylphosphoryl azide (DPPA, 162.5 mL, 0.75 mol, 1.5 eq.) was added in 5 portions, stirred at this temperature for 5 hours, and cooled to room temperature. The reaction solution was concent...

Embodiment 3

[0032] (1) Add water (500mL) and hydrazine hydrate (50% aqueous solution, 450mL, 4.5mol, 4.5eq) into the reaction flask, and raise the temperature of the system to 100°C. Orotic acid (compound 1, 156g, 1.0mol, 1.0eq.) was added in 5 times, the reactants gradually dissolved, stirred at this temperature for 3.5 hours, and cooled to room temperature. Add 500 mL of saturated ammonium chloride aqueous solution, and a white solid precipitates out. The precipitate was collected and dried to obtain 116.2 g of 5-hydroxypyrazole-4-carboxylic acid (91% yield).

[0033] (2) Add n-hexane (500mL), triethylamine (104.0mL, 0.75mol, 1.5eq) and 5-hydroxypyrazole-4-carboxylic acid (64g, 0.5mol, 1.0eq) obtained in step (1) In the reaction flask, the temperature of the system was raised to 45°C. Diphenylphosphoryl azide (DPPA, 130 mL, 0.6 mol, 1.2 eq.) was added in 5 portions, stirred at this temperature for 4.5 hours, and cooled to room temperature. The reaction solution was concentrated, and ...

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Abstract

The invention discloses a method for preparing 5-amino-1,2-dihydropyrazole-3-one from orotic acid, belonging to the field of drug intermediate synthesis. The method comprises the following steps: reacting orotic acid serving as a raw material with hydrazine hydrate to generate 5-oxygen-2,5-dihydropyrazole-3-carboxylic acid; reacting 5-oxygen-2,5-dihydropyrazole-3-carboxylic acid with diphenylphosphoryl azide by taking triethylamine as alkali to cause Curtis rearrangement, and carrying out hydrolysis, so as to generate 5-amino-1,2-dihydropyrazole-3-one. According the method, the cheap and easily available natural substances are taken as the raw materials, no strong base is utilized, and by-products are safe; meanwhile, the process selection is reasonable, the facility requirement is low, the operation is simple, the yield is high, the total yield can reach 83%, and the production is easily enlarged; the method is applicable to the large-scale production of 5-amino-1,2-dihydropyrazole-3-one.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method for preparing 5-amino-1,2-dihydropyrazol-3-one from orotic acid. Background technique [0002] The chemical name of orotic acid is uracil-6-carboxylic acid, which is a biological endogenous substance. [0003] Amino-substituted pyrazole compounds are a class of very useful drug intermediates, and 5-amino-1,2-dihydropyrazol-3-ones are widely used in the synthesis of nitrogen-containing condensed ring aromatic compounds. Through the condensation cyclization reaction, the obtained compounds exhibit various biological activities and can be used in PET imaging in medicine (Bioorganic & Medicinal Chemistry Letters, 2013, 23(4), 1017-1021). In addition, 5-amino-1,2-dihydropyrazol-3-one is also an inhibitor of alanine racemase. [0004] 5-Amino-1,2-dihydropyrazol-3-one is usually prepared by cyclization reaction of cyanoacetylhydrazide under s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/52
CPCC07D231/52
Inventor 毕磊柯健方晟傅辰超
Owner ANHUI UNIVERSITY OF TECHNOLOGY