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Preparation method of benorilate

A technology for the reaction of Benodate and Mitsunobu is applied in the field of preparation of Benodate, which can solve the problems of high price, low yield, large solvent consumption, etc., and achieve the effects of reducing synthesis cost, mild synthesis conditions and easy control of reaction.

Active Publication Date: 2020-04-24
GUANGXI UNIVERSITY OF TECHNOLOGY
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Problems solved by technology

[0003] The problem that the synthetic method of beinolate exists at present: beinolate synthesis is generally divided into two kinds of methods, and a kind of method is to be raw material with aspirin, without acyl chloride, directly with acetaminophen ester under specific solvent and condition change
Although this method can be synthesized in one step, the reaction temperature should be kept below 0°C in the reaction conditions, and the reaction time should be more than 10 hours, and the condensation agent N,N-dimethylchloromethylene ammonium chloride required for the reaction is expensive And unstable, so the application value of this process is relatively low
Another method is to carry out acid chlorination of aspirin first, and then esterify with acetaminophen, but aspirin acid chloride is unstable and easy to be hydrolyzed before esterification, resulting in low yield, and the whole reaction also consumes a large amount of solvent. And the final product is difficult to separate and purify quickly and effectively

Method used

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  • Preparation method of benorilate
  • Preparation method of benorilate
  • Preparation method of benorilate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Under ice-water bath conditions, in a 50mL flask, first add 0.3023g of acetaminophen and 0.6295g of triphenylphosphine, then add 20mL of dichloromethane, then add 0.552g of di-tert-butyl azodicarboxylate, and finally in 20min After adding 0.4324g of acetylsalicylic acid step by step, after keeping it in an ice-water bath for 20 minutes, return to normal temperature for reaction. The reaction time is 8.5 hours, and the yield is 63.0%. Crystallization and separation are carried out with 95% ethanol, and after three times of recrystallization, the obtained White beinolate crystals, the total yield is 52.6% based on acetaminophen. The product quality conforms to the 2005 edition of "Chinese Pharmacopoeia".

Embodiment 2

[0024] Under ice-water bath conditions, first add 0.3023g of acetaminophen and 0.6295g of triphenylphosphine into a 50ml flask, then add 20mL of tetrahydrofuran, then add 0.552g of di-tert-butyl azodicarboxylate, and finally add it step by step within 20min. After adding 0.4324g of acetylsalicylic acid, keep it in an ice-water bath for 20 minutes, then return to normal temperature for reaction, the reaction time is 8.5 hours, and the yield is 63.0%; use 95% ethanol to carry out crystallization and separation, and after three times of recrystallization, white Benoy is obtained Ester crystals, with a total yield of 46.3% based on acetaminophen. The product quality conforms to the 2005 edition of "Chinese Pharmacopoeia".

Embodiment 3

[0026] According to the measurement relationship, six parts of a certain amount of acetaminophen, acetylsalicylic acid, diethyl azodicarboxylate (DEAD) and triphenylphosphine were weighed.

[0027] Under the condition of ice-water bath, add acetaminophen and triphenylphosphine in turn to a 50mL round-bottomed flask; add 20mL of reaction solvent according to Table 1, and mix well. After the solution becomes clear, slowly add DEAD dropwise. Add acetylsalicylic acid in batches, keep in an ice-water bath for 20 minutes, heat to the reaction temperature according to Table 1, react for 8.5 hours, and calculate the yield.

[0028] As can be seen from Table 1, changing the reaction solvent and the reaction temperature affects the yield of the product beinolate; the yields of the three solvents are all higher than the yields of the high-temperature reaction at low temperatures, indicating that this reaction is optimal at room temperature. The boiling point of dichloromethane is too low...

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Abstract

The invention relates to a preparation method of benorilate, which relates to the technical field of medicine synthesis. According to the invention, acetylsalicylic acid and acetaminophen are used asraw materials to directly synthesize behenolate under the condition of common catalysis of azodicarboxylic acid ester compounds and triphenylphosphine. The preparation method comprises the following steps: adding acetaminophen and a light-delay reaction catalyst I triphenylphosphine into a reaction bottle, adding an organic solvent, adding a light-delay reaction catalyst II, and uniformly mixing;and adding acetylsalicylic acid in batches within 20 minutes, stirring in an ice bath for 20 minutes, heating to normal temperature, magnetically stirring, and reacting for 8.5 hours to obtain the benorilate. According to the present invention, the acetylsalicylic acid and the p-acetamidophenol are catalyzed by using a light delay reaction catalysis system so as to be esterified, such that the steps are simple, the drugs only need to be sequentially added, the process route is short, and the synthesis cost is effectively reduced.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of beinolate. Background technique [0002] Benorylate (Benorylate) chemical name: acetoxy benzoic acid p-acetamidophenyl ester, also known as acetaminophen, benrolai, is a non-steroidal antipyretic analgesic, an esterification product of aspirin and paracetamol, mainly For anti-inflammatory, antipyretic, analgesic, treatment of rheumatism. The adverse reaction is less than that of aspirin, and it is easy for patients to tolerate. [0003] The problem that the synthetic method of beinolate exists at present: beinolate synthesis is generally divided into two kinds of methods, and a kind of method is to be raw material with aspirin, without acyl chloride, directly with acetaminophen ester under specific solvent and condition change. Although this method can be synthesized in one step, the reaction temperature should be kept below 0°C in the reaction c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/25
CPCC07C231/12C07C233/25Y02P20/584
Inventor 黄晓程张宝栋粟晖林汉宝
Owner GUANGXI UNIVERSITY OF TECHNOLOGY
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