A new method for the synthesis and refinement of medicinal paeonol

A refining method and a technology for paeonol, applied in the field of drug synthesis, can solve the problems of difficulty in obtaining ideal purity and better crystal form, polluting the production environment, affecting production requirements, etc. The effect of partial oxidation

Active Publication Date: 2017-09-12
HEFEI LIFEON PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction system uses toluene as a solvent, which not only pollutes the production environment, but also contains C 3 - Possibility of methyl isomerization
The results of comparative experiments show that it is difficult to obtain products with ideal purity and better crystal form by adding n-heptane to the toluene solution to precipitate the product (see Example 7 for details), which in turn affects the stable and controllable industrialization Drug Production Requirements

Method used

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  • A new method for the synthesis and refinement of medicinal paeonol
  • A new method for the synthesis and refinement of medicinal paeonol
  • A new method for the synthesis and refinement of medicinal paeonol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1. Methylation reaction: 76.6g (0.5mol) 2,4-dihydroxyacetophenone, 250ml methyl Isobutyl ketone, 0.91g (0.0025mol) benzyltributylammonium bromide, 3.15g (0.025mol) sodium sulfite, 150ml purified water. Add 82.8 g (0.65 mol) of dimethyl sulfate at one time when the temperature of the water bath is raised to 45 °-50 °C under continuous stirring. After stirring evenly, add 25% potassium carbonate aqueous solution evenly dropwise into the reaction bottle from the constant pressure dropping funnel, and control the pH value of the reaction solution between 7.5 and 8.5 to carry out the methylation reaction. When the consumption of potassium carbonate reached 0.75 mol, regular samples were taken for TLC monitoring. If the raw material spots disappeared, it indicated that the reaction had reached the end point. Stop dripping and potassium carbonate solution, continue to stir for 15 minutes and then terminate the heating reaction, remove the water bath and cool down to below roo...

Embodiment 2

[0054] Embodiment 2 (the comparative example without reducing agent)

[0055] The reducing agent sodium sulfite in the methylation reaction of Example 1 was discarded, and all other processes and conditions were unchanged. The yield and quality results are shown in Table 2.

[0056] Table 2: Summary of output and quality results of each intermediate product and final product in Example 2

[0057]

[0058] The results of Example 2 suggest that after the reducing agent in the methylation reaction in Example 1 was discarded, the purity and yield of the methylated crude product and primary crystallized product decreased significantly. It needs to undergo secondary recrystallization to basically reach the current quality standard of this product.

Embodiment 3

[0059] Embodiment 3 (the control example that improves reaction pH value)

[0060] During the operation process of the methylation reaction in Example 1, the control range of the pH value of the methylation reaction process was increased to 8.5-10.5, and other reaction conditions remained unchanged. The quality and yield levels of the obtained crude product and primary and secondary refined products are listed in Table 3.

[0061] Table 3: Summary of output and quality levels of intermediate products and final products in Example 3

[0062]

[0063] The results of Example 3 suggest that if the pH range of the methylation reaction in Example 1 is increased to 8.5-10.5, the yield and purity of the methylation reaction will drop significantly, and two refinements are required to basically reach the current quality standard of this product. . Compared with Example 1, the consumption of alkalization and methylation reagent in the reaction process is greatly improved.

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Abstract

The invention discloses a new method for synthesizing and refining medicinal paeonol. Put 2,4-dihydroxyacetophenone and hydrophobic aliphatic ketone into the reaction bottle successively, after stirring and dissolving, add purified water containing reducing agent, phase transfer catalyst and dimethyl sulfate successively, and the water bath is heated to 45-65°C, under continuous stirring, add dropwise alkaline aqueous solution to keep the pH value in the range of 7.5-8.5 for methylation reaction. Then the organic layer was washed with alkali water containing a reducing agent, then neutralized with dilute acid, washed with saline and purified water, and dried with a desiccant, and then concentrated in vacuo to obtain a crude product that was recrystallized once with dilute ethanol containing a reducing agent. The target product is obtained. The method greatly improves the selectivity of 4-hydroxy methyl etherification, reduces the generation of by-products, simplifies the subsequent separation process, does not require traditional steam distillation, and meets the production requirements of safety, economy and environmental protection.

Description

technical field [0001] The invention relates to a new method for synthesizing and refining paeonol crude drug, which belongs to the field of drug synthesis. Background technique [0002] Paeonol is the main active ingredient of the root bark of peony and the root or whole plant of Xu Changqing. It has analgesic, anti-inflammatory, antipyretic and anti-allergic effects, and is widely used in medicine and cosmetics. Its chemical name is 2-hydroxy-4-methoxyacetophenone (2-hydroxy-4-methoxyacetophenone). Extracting the cortex of Moutan or the rhizome of Xu Changqing as a raw material, followed by steam distillation, was the main way to obtain medicinal paeonol in the past. Due to the low content of paeonol in plants, the distillation extraction process is energy-consuming and time-consuming, and consumes a lot of traditional Chinese medicine resources. In recent years, a preparation method of chemical synthesis has been developed. [0003] The chemical synthesis of paeonol mos...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/84C07C45/61C07C45/78C07C45/81
Inventor 季俊虬李孝常高美华陈军
Owner HEFEI LIFEON PHARMA
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