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Synthesis method of neostigmine bromide

A technology of neostigmine bromide and a synthetic method, applied in the field of pharmaceutical synthesis, can solve the problems of not easy to buy, high cost, high production difficulty, etc., and achieves the effects of satisfying industrial mass production, reducing costs, and having sufficient sources of raw materials

Active Publication Date: 2021-08-20
深圳市新浩瑞医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method is costly
Because the starting material m-dimethylaminophenol is expensive, the production is difficult, and there are few products on the market, it is not easy to buy this raw material

Method used

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  • Synthesis method of neostigmine bromide
  • Synthesis method of neostigmine bromide
  • Synthesis method of neostigmine bromide

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preparation example Construction

[0028] The present invention provides a kind of synthetic method of neostigmine bromide, the reaction route of described synthetic method comprises:

[0029]

[0030] Wherein, R is an alkali metal;

[0031] The synthetic method comprises the following steps:

[0032] 1) the m-aminophenol of formula (1) is selected to react with methyl halide to obtain the halogenated quaternary ammonium methyl ether of formula (2);

[0033] 2) the halogenated quaternary ammonium salt methyl ether of formula (2) adds catalyzer, and demethylation obtains the m-phenolic hydroxyl quaternary ammonium salt of formula (3);

[0034] 3) the m-phenolic hydroxyl quaternary ammonium salt of formula (3) forms the compound of formula (4) under strong alkali conditions;

[0035] 4) Esterification of the compound of formula (4) with dimethylcarbamoyl bromide to obtain neostigmine bromide of formula (5).

Embodiment 1

[0037] A synthetic method of neostigmine bromide, comprising the following steps:

[0038] 1) In a 10L three-necked flask, add 5L of acetone, 500g of m-aminophenol, and 790g of sodium carbonate, and stir at 25°C for 2 hours. Then, a mixed solution of 1.9 kg of methyl bromide and 1 L of acetone was added dropwise at 25° C., and the mixture was stirred at 25° C. for 4 hours. Concentrate under reduced pressure to recover acetone, add 5L of water for recrystallization. Filter and wash the filter cake with 300ml of ice water. The filter cake was dried under reduced pressure at 60-65° C. to obtain 915 g of quaternary ammonium bromide methyl ether. Purity: 98.3% (HPLC normalization method), yield: 80.0%.

[0039] 2) In a 10L three-necked flask, add 6L of dichloromethane and 800g of bromide quaternary ammonium methyl ether, stir to dissolve, cool to 5°C, slowly add 350g of anhydrous aluminum trichloride in batches, and control the feeding temperature to 25°C. After the addition, t...

Embodiment 2

[0044] A synthetic method of neostigmine bromide, comprising the following steps:

[0045] 1) In a 10L three-necked flask, add 5L of acetone, 500g of m-aminophenol, and then add 560g of sodium hydroxide, and stir at 30°C for 2 hours. Then, at 30°C, a mixed solution consisting of 2.0kg of fluoromethane and 1L of acetone was added dropwise, and the mixture was stirred at 30°C for 5 hours. Concentrate under reduced pressure to recover acetone, add 5L of water for recrystallization. Filter and wash the filter cake with 300ml of ice water. The filter cake was dried under reduced pressure at 65° C. to obtain 930 g of fluoroquaternary ammonium methyl ether. Purity 98.8% (HPLC normalization method), yield: 81.7%;

[0046]2) In a 10L three-necked flask, add 6L of dichloromethane and 800g of fluoroquaternary ammonium methyl ether, stir to dissolve, cool to 0°C, slowly add 350g of anhydrous aluminum trichloride in batches, and control the feeding temperature to 20°C. After the additi...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of neostigmine bromide. The synthesis method comprises the following steps of 1) selecting m-aminophenol of a formula (1) to react with halogenated methane to obtain halogenated quaternary ammonium salt methyl ether of a formula (2), 2) adding a catalyst into the halogenated quaternary ammonium salt methyl ether in the formula (2), and removing methyl ether to obtain m-phenolic hydroxyl quaternary ammonium salt in a formula (3), 3) forming a compound shown in a formula (4) from the m-phenolic hydroxyl quaternary ammonium salt shown in the formula (3) under a strong alkali condition, and 4) carrying out esterification reaction on the compound in the formula (4) and dimethyl carbamoyl bromide to obtain neostigmine bromide in a formula (5). According to the method, the m-aminophenol is adopted as the starting material, the price of the m-aminophenol is only one hundred of that of m-dimethylaminophenol, the cost of the neostigmine bromide can be greatly reduced when the m-aminophenol is used for synthesizing the neostigmine bromide, and mass production can be achieved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing bromyostigmine. Background technique [0002] Neostigmine bromide is an anticholinesterase drug. It is clinically used for myasthenia gravis, intestinal paralysis and urinary retention after abdominal surgery. Veterinary medicine is often used to promote gastrointestinal motility in animals and help animals such as cattle digest. Neostigmine bromide is a white crystalline powder; odorless, bitter. This product is easily soluble in water, melting point: 171-176°C, and decomposes at the same time when melting. [0003] The existing bromide neostigmine synthetic route is as follows: [0004] [0005] Specific method: using m-dimethylaminophenol as a raw material, first forming a sodium salt with a strong base, then forming an ester with dimethylcarbamoyl chloride, and then reacting with methyl bromide to form a bromide quaternary ammonium salt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/00C07C271/44C07C213/00C07C213/08C07C215/90C07C213/06C07C217/84
CPCC07C269/00C07C213/00C07C213/08C07C213/06C07C217/84C07C215/90C07C271/44
Inventor 金鹏
Owner 深圳市新浩瑞医药科技有限公司
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