CN111056968B

CN111056968B - Preparation method of benorilate

Info

Publication number: CN111056968B
Application number: CN201911329010.9A
Authority: CN
Inventors: 黄晓程; 张宝栋; 粟晖; 林汉宝
Original assignee: Guangxi University of Science and Technology
Current assignee: Guangxi University of Science and Technology
Priority date: 2019-12-20
Filing date: 2019-12-20
Publication date: 2023-04-14
Anticipated expiration: 2039-12-20
Also published as: CN111056968A

Abstract

The invention relates to a preparation method of benorilate, relating to the technical field of drug synthesis; the invention takes acetylsalicylic acid and acetaminophen as raw materials to directly synthesize benorilate under the co-catalysis condition of azodicarboxylic ester compounds and triphenylphosphine. Adding acetaminophen and a mitsunobu reaction catalyst I triphenylphosphine into a reaction bottle, then adding an organic solvent, adding a mitsunobu reaction catalyst II, and uniformly mixing; and adding acetylsalicylic acid in batches within 20min, stirring in an ice bath for 20min, then heating to normal temperature, stirring by magnetic force, and reacting for 8.5h to obtain the benorilate. The method uses a mitsunobu reaction catalytic system to catalyze the esterification of the acetylsalicylic acid and the paracetamol, has simple steps, only needs to add the medicines in sequence, has short process route, and effectively reduces the synthesis cost.

Description

Preparation method of benorilate

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of benorilate.

Background

Benorilate (benorilate) chemical name: acetyloxy benzoic acid p-acetamino phenyl ester, also called paracetamol and benraline, is a non-steroidal antipyretic and analgesic drug, is an esterification product of aspirin and paracetamol, and is mainly used for diminishing inflammation, relieving fever, relieving pain and treating rheumatism. Has less adverse reaction compared with aspirin, and is easy to be tolerated by patients.

The prior synthesis method of benorilate has the following problems: the synthesis of benorilate is generally divided into two methods, one method is that aspirin is used as a raw material, and the raw material is directly esterified with acetaminophen in a specific solvent and under a specific condition without acyl chlorination. Although the method can be synthesized in one step, the reaction temperature is kept below 0 ℃ in the reaction condition, the reaction time is more than 10 hours, and the condensation agent N, N-dimethyl chloromethylene ammonium chloride required by the reaction is expensive and unstable, so the application value of the process is low. Another method is to firstly perform acyl chlorination on aspirin and then esterify the aspirin with acetaminophen, but aspirin acyl chloride is unstable and is easy to hydrolyze before esterification, so that the yield is low, the whole reaction consumes a large amount of solvent, and the final product is difficult to separate and purify quickly and effectively.

Disclosure of Invention

In order to solve the problems, the invention aims to provide a method for preparing benorilate, which has the advantages of simple process, mild conditions, easy control of reaction and less environmental pollution.

11. In order to achieve the purpose, the technical scheme of the invention is as follows: a preparation method of benorilate comprises the steps of adding acetaminophen and a mitsunobu reaction catalyst I triphenylphosphine into a reaction bottle under the condition of ice-water bath, then adding an organic solvent, then adding a mitsunobu reaction catalyst II, uniformly mixing, adding acetylsalicylic acid in batches within 20min, stirring in an ice bath for 20min, then heating to normal temperature, stirring by magnetic force, and reacting to obtain benorilate, wherein the reaction equation is as follows:

further, the catalyst II for the mitsunobu-butyl azodicarboxylate, diethyl azodicarboxylate or diisopropyl azodicarboxylate is used.

Further, the mitsunobu-butyl azodicarboxylate is used as the mitsunobu-butyl azodicarboxylate.

Further, the organic solvent is tetrahydrofuran, acetonitrile or dichloromethane.

Further, the organic reagent is tetrahydrofuran.

Further, the rotating speed of the magnetic stirring is 400-500/s.

Further, the reaction time was 8.5 hours after the temperature was raised to room temperature.

Further, the mass ratio of acetylsalicylic acid to acetaminophen is 1.2.

Further, the ratio of the amount of the triphenylphosphine to the acetaminophen reaction mass is 1.2.

Further, the reaction ratio of the organic solvent to the acetaminophen is 20.

Compared with the prior art, the invention has the following beneficial effects:

1. the method uses a mitsunobu reaction catalytic system to catalyze the esterification of acetylsalicylic acid and paracetamol, has simple steps, only needs to add medicines in sequence, has short process route, and effectively reduces the synthesis cost.

2. The invention has mild synthesis conditions, only needs to keep the temperature between 0 and 5 ℃ during feeding, can keep the temperature at room temperature for the rest time, does not need a pressurizing or gas protecting device, and is easy to control the reaction.

3. The method uses tetrahydrofuran, acetonitrile or dichloromethane as a solvent, is convenient to recycle after the reaction is finished, cannot cause pollution to the outside, and can recycle the byproduct triphenylphosphine oxide of the mitsunobu reaction.

Detailed Description

The technical solution of the present invention will be further described with reference to the following specific examples.

Example 1

Under the condition of ice-water bath, firstly adding 0.3023g of acetaminophen and 0.6295g of triphenylphosphine into a 50mL flask, then adding 20mL of dichloromethane, then adding 0.552g of di-tert-butyl azodicarboxylate, finally adding 0.4324g of acetylsalicylic acid step by step within 20min, after keeping the ice-water bath for 20min, recovering to normal temperature reaction for 8.5h, wherein the yield is 63.0%; performing crystallization separation by using 95% ethanol, and performing recrystallization for three times to obtain white benorilate crystals, wherein the total yield is 52.6% calculated by using acetaminophen. The quality of the product accords with the Chinese pharmacopoeia of 2005 edition.

Example 2

Under the condition of ice-water bath, firstly adding 0.3023g of acetaminophen and 0.6295g of triphenylphosphine into a 50mL flask, then adding 20mL of tetrahydrofuran, then adding 0.552g of di-tert-butyl azodicarboxylate, finally adding 0.4324g of acetylsalicylic acid step by step within 20min, after keeping the ice-water bath for 20min, recovering to normal temperature reaction for 8.5h, wherein the yield is 63.0%; performing crystallization separation by using 95% ethanol, and performing recrystallization for three times to obtain white benorilate crystals, wherein the total yield is 46.3% by calculating the acetaminophen. The quality of the product conforms to the Chinese pharmacopoeia of 2005 edition.

Example 3

Weighing a certain amount of acetaminophen, acetylsalicylic acid, diethyl azodicarboxylate (DEAD) and triphenylphosphine according to the metering relation respectively.

Under the condition of ice-water bath, sequentially adding acetaminophen and triphenylphosphine into a 50mL round-bottom flask; respectively adding 20mL of reaction solvent according to the table 1, uniformly mixing, slowly dropwise adding DEAD after the solution becomes clear, adding acetylsalicylic acid in batches within 20min, keeping the solution in an ice-water bath for 20min, heating to the reaction temperature according to the table 1, reacting for 8.5h, and calculating the yield.

As can be seen from table 1, changing the reaction solvent and reaction temperature affects the yield of benorilate product; the yield of the three solvents is higher than that of the high-temperature reaction at low temperature, which shows that the reaction has the optimal normal temperature condition. The boiling point of dichloromethane was too low and the temperature was not well controlled, so this experiment was to compare room temperature with reflux to increase the dichloromethane room temperature.

TABLE 1 Effect of temperature on yield

Example 4

In order to verify the influence of different types of catalysts on the reaction, three different types of azodicarboxylic acid esters, namely diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and di-tert-butyl azodicarboxylate (DBAD), are combined for comparison.

The results are shown in table 2 below:

TABLE 2 Effect of different catalysts on reaction yield

It is stated that in the solvent acetonitrile DBAD is most effective in replacing DEAD with DBAD, while in the solvent dichloromethane DIAD and DBAD are most effective in replacing DEAD, and DBAD and triphenylphosphine are most effective as catalysts in general.

Example 5

The experiment investigates the influence of the reaction under the conditions of nitrogen protection and no inert gas protection on the yield.

According to the proportion of claim 8,9 and 10, a certain amount of acetaminophen, acetylsalicylic acid, DEAD and triphenylphosphine are weighed respectively.

Under the condition of ice-water bath, acetaminophen, triphenylphosphine and 20mL tetrahydrofuran solvent are respectively and sequentially added into two 50mL round-bottom flasks A and B, after uniform mixing, DEAD is dropwise added, and acetylsalicylic acid is added at one time.

After the addition of the substrate, the round-bottomed flask A was stoppered with a common wooden plug, and the round-bottomed flask B was evacuated and protected with nitrogen. And (3) keeping the ice water bath of the flasks A and B for 20min, then returning to normal temperature for reaction, and reacting for 16h with the magnetic stirring rotating speed of 400-500/s. The yield was calculated.

The reaction yield was 44.7% under nitrogen protection and 46.3% without nitrogen protection, indicating that the presence or absence of inert gas protection has no significant effect on the process.

Compared with the existing benorilate synthesis reaction, the method has the advantages that the steps are further simplified, only feeding materials are required to be added into a single reactor according to a fixed sequence, the temperature is controlled only when the feeding materials are fed, and the temperature is raised to the room temperature, so that the method is convenient and simple, and has low requirements on experimental devices.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited thereto, and any changes and substitutions without creative efforts shall be covered within the protection scope of the present invention, therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims

1. A preparation method of benorilate is characterized in that: under the condition of ice-water bath, adding acetaminophen and a mitsunobu reaction catalyst I triphenylphosphine into a reaction bottle, then adding an organic solvent, adding a mitsunobu reaction catalyst II, uniformly mixing, adding acetylsalicylic acid in batches within 20min, stirring for 20min in an ice bath, then heating to normal temperature, and carrying out magnetic stirring to obtain benorilate; the reaction equation is shown below:

the catalyst II for the mitsunobu-butyl azodicarboxylate, diethyl azodicarboxylate or diisopropyl azodicarboxylate.

2. The production method according to claim 1, characterized in that: the catalyst II for the mitsunobu-butyl azodicarboxylate is used.

3. The production method according to claim 1, characterized in that: the organic solvent is tetrahydrofuran, acetonitrile or dichloromethane.

4. The production method according to claim 3, characterized in that: the organic solvent is tetrahydrofuran.

5. The method of claim 1, wherein: the rotating speed of the magnetic stirring is 400-500/s.

6. The production method according to claim 1, characterized in that: the reaction time is 8.5h after the temperature is raised to the normal temperature.

7. The production method according to claim 1, characterized in that: the mass ratio of acetylsalicylic acid to acetaminophen is 1.2.

8. The method of claim 1, wherein: the ratio of the amount of triphenylphosphine to the amount of acetaminophen reaction mass was 1.2.

9. The method of claim 1, wherein: the reaction ratio of the organic solvent to the acetaminophen is 20.