CN104151167B - A kind of preparation method of medicinal compound acetylsalicylic acid eugenol ester - Google Patents

Abstract

The invention discloses a preparation method of the medicinal compound aspirin eugenol ester. The invention adopts a phase-transfer catalyst tetrabutylammonium bromide to catalyze an ester-forming reaction to obtain a white crystalline solid that is aspirin eugenol ester. The present invention reduces the irritation, easy oxidation and instability of aspirin and eugenol through chemical reactions, and at the same time does not change the structural parts that exert clinical effects, and releases the two original drugs of aspirin and eugenol under the action of enzymes in the body to synergize Play a role and have better pharmacological effects. The preparation method has high yield and simple post-treatment, and is a green and environment-friendly preparation method of aspirin eugenol ester.

Description

A kind of preparation method of medicinal compound aspirin eugenol ester

technical field

The invention relates to a new phase-transfer catalyzed preparation method of the medicinal compound aspirin eugenol ester.

Background technique

Inflammation is a common and frequently-occurring disease that threatens the health of humans and animals. Glucocorticoid steroid anti-inflammatory drugs can effectively control infectious inflammation and non-infectious inflammation, but long-term use can easily cause complications such as adrenal cortical function decline . Non-steroidal anti-inflammatory drugs are usually much less toxic and side effects than steroidal anti-inflammatory drugs, and aspirin is a representative of non-steroidal anti-inflammatory drugs with excellent anti-inflammatory and analgesic effects. In order to effectively control related inflammatory diseases, the development of new, efficient and safe non-steroidal anti-inflammatory drugs has always been a hot spot in the research and development of new drugs.

Eugenol is the main component of the volatile oil of cloves, a traditional Chinese medicine plant in the family Myrtaceae. Pharmacological research results show that it has pharmacological activities such as antipyretic, analgesic, anti-inflammatory, anti-oxidation, and anti-thrombosis. However, eugenol contains phenolic hydroxyl groups, which are volatile and irritating, and unstable at room temperature, which affects its application. In addition, long-term and large-scale use of aspirin can also damage the gastrointestinal tract.

A Chinese patent discloses a "medicinal compound of eugenol aspirin ester and its preparation and preparation method" (ZL200810017950.X). In this method, acetylsalicylic acid is prepared with thionyl chloride to obtain its acid chloride, and then the acid chloride is diluted (benzene or trichloromethane) into the aqueous solution of eugenol under ice bath conditions, the aqueous solution contains sodium hydroxide and polyethylene glycol-1000 (PEG-1000), continue to react for 2-5h after the dropwise addition, and let stand Separate the layers, and concentrate the organic phase under reduced pressure to obtain a solid, which can be recrystallized from methanol to obtain the compound aspirin eugenol. The reaction yield is low and the reaction time is long; the selected diluent solvent is highly toxic; the phase transfer catalyst PEG-1000 is easy to form a viscous mixture with organic solvents, aqueous solutions, and reaction products, which makes post-processing cumbersome and leads to low yield , affecting the application of aspirin eugenol ester.

Contents of the invention

In order to eliminate the side effects of eugenol and aspirin and improve the yield of aspirin eugenol ester, the object of the present invention is to provide a new preparation method of the medicinal compound aspirin eugenol ester. The invention utilizes the principle of prodrug, combines aspirin eugenol through chemical reaction, shields carboxyl group and phenolic hydroxyl group, and forms a new medicinal compound aspirin eugenol ester.

The purpose of the invention is to adopt the following technical solutions to achieve:

A preparation method of medicinal compound aspirin eugenol, characterized in that: adding acetylsalicylic acid (aspirin) and thionyl chloride (SOCl ₂ ) into a round bottom flask equipped with an electric heating magnetic stirrer and a reflux device, Add 10 drops of N,N-dimethylformamide (DMF) dropwise, heat slowly to 70°C and keep it warm for 2 hours, neutralize the acid gas released by the reaction with aqueous sodium hydroxide (NaOH), evaporate under reduced pressure (-0.08Mpa) In addition to the unreacted thionyl chloride, dilute the generated acid chloride in the freshly steamed organic solvent tetrahydrofuran (THF) for use; add eugenol and 5% phase transfer catalyst tetrabutylammonium bromide to the three-neck round bottom flask (TBAB) and sodium hydroxide aqueous solution, stir and mix well, add the above acid chloride solution dropwise under ice bath conditions; continue to react for 0.5h after the dropwise addition, and continuously replenish sodium hydroxide aqueous solution during the dropwise addition to keep the pH of the solution ≈ 10, so that The reaction solution is alkaline; after the reaction is completed, a white solid is obtained by suction filtration, washed with aqueous sodium hydroxide solution and distilled water respectively, and finally recrystallized with methanol to obtain a white crystalline solid which is aspirin eugenol ester.

Its structural formula is as follows:

The obtained aspirin eugenol ester is white crystal in appearance and has a melting point of 71-72°C. The mass spectrum data is: ESI (+), [M+H] ⁺ =327. Proton NMR spectrum: ((CD ₃ ) ₂ SO, TMS, 400MH _Z ), ¹ HNMR, δppm: 8.126,7.750,7.471,7.306,7.071,6.992,6.813(6H,Ar-H);5.979(1H,- CH=); 5.090 (2H, =CH ₂ ); 3.736 (3H, OCH ₃ ); 3.387 (2H, -CH ₂ -); 2.215 (3H, CH ₃ ).

Advantages of the invention

1. The compound prepared by the present invention can reduce the irritation, easy oxidation and instability of aspirin and eugenol through chemical reaction, and at the same time, it does not change the structural part that plays a clinical role, and releases aspirin and eugenol under the action of enzyme in vivo The two original drugs act synergistically and have better pharmacological effects.

2. The preparation method of the present invention is mature and reliable, has high yield and simple post-treatment, and is a green and environment-friendly preparation method of aspirin eugenol ester.

3, the beneficial effect of the present invention is illustrated by the key step ester-forming reaction in the optimization preparation process of orthogonal test design:

Table 1 Response factors and levels

Table 2 Reactive Orthogonal Design Table

As can be seen from Table 2, the primary and secondary factors of the conditions of the ester-forming reaction are the amount of sodium hydroxide > phase transfer catalyst > reaction time, the best reaction conditions are A ₃ B ₁ C ₁ , but the reaction time has little influence, the final selection The reaction time is 0.5h. That is, the best ester-forming reaction condition is to add 1eq eugenol, 5% phase transfer catalyst TBAB and 1.2eq NaOH aqueous solution in a suitable reaction vessel, stir and mix well under ice bath conditions, add dropwise with 1eq acetyl The THF solution of acid chloride prepared from salicylic acid was added dropwise in ice bath and continued to react for 0.5h. During the dropwise addition, NaOH (0.4eq) aqueous solution was continuously added to keep the reaction solution alkaline (pH≈10). After the reaction was completed, a white solid was obtained by suction filtration, washed with 0.1 mol/L NaOH aqueous solution and distilled water respectively, and finally recrystallized with methanol to obtain white crystals which were aspirin eugenol ester.

detailed description

According to the technical scheme of the present invention, the best reaction conditions are selected to prepare the medicinal compound aspirin eugenol ester.

(1) Embodiment 1

Add 0.1mol of aspirin and 10ml of SOCl ₂ into a 50ml round bottom flask equipped with an electric heating magnetic stirrer and a reflux device, drop in 10 drops of DMF, slowly heat to 70°C and keep it warm for 2 hours, neutralize the released by the reaction with NaOH aqueous solution Acid gas. The unreacted SOCl ₂ was distilled off under reduced pressure (-0.08Mpa), and the generated acid chloride was dissolved in 20ml of freshly distilled THF for use. Add 0.1mol eugenol, 5% phase transfer catalyst TBAB and 0.12mol NaOH aqueous solution 300ml into a 500ml three-neck round bottom flask, stir and mix well, add dropwise (about 2 seconds per drop) the above acid chloride solution under ice bath conditions. Continue to react for 0.5h after the dropwise addition, and continuously replenish NaOH (0.04mol) aqueous solution during the dropwise addition to keep the reaction solution alkaline (pH≈10). After the reaction was completed, a white solid was obtained by suction filtration, and washed with 0.1 mol/L NaOH aqueous solution and distilled water respectively to obtain a white crude product. The crude product was recrystallized with methanol after drying to obtain 27.6 g of white crystals, with a yield of 84.7%.

(2) Embodiment 2

Add 0.3mol of aspirin and 30ml of SOCl ₂ into a 100ml round bottom flask equipped with an electric heating magnetic stirrer and a reflux device, drop in 30 drops of DMF, heat to 70°C and keep it warm for 2 hours, neutralize the acidity released by the reaction with NaOH aqueous solution gas. The unreacted SOCl ₂ was distilled off under reduced pressure (-0.08Mpa), and the resulting acid chloride was dissolved in 60ml of freshly distilled THF for use. Add 0.3 mol of eugenol, 5% phase transfer catalyst TBAB and 0.36 mol of NaOH aqueous solution 600 ml in a 1000 ml beaker, stir and mix, and add the above acid chloride solution dropwise under ice bath conditions. After the dropwise addition, the reaction was continued for 0.5 h, and NaOH (0.12 mol) aqueous solution was continuously added during the dropwise addition to keep the reaction solution alkaline (pH≈10). After the reaction was completed, a white solid was obtained by suction filtration, and washed with 0.1 mol/L NaOH aqueous solution and distilled water respectively to obtain a white crude product. The crude product was dried and recrystallized with methanol to obtain 82 g of white crystals, with a yield of 83.8%.

Claims (1)

1. A preparation method of medicinal compound aspirin eugenol ester is characterized in that: add acetylsalicylic acid (aspirin) in the round bottom flask equipped with electric heating magnetic stirrer, reflux device, thionyl chloride, drop into 10 drops of N,N-dimethylformamide, slowly heated to 70°C for 2 hours, neutralized the acid gas released by the reaction with aqueous sodium hydroxide solution, and distilled off the unreacted thionyl chloride under reduced pressure at -0.08Mpa. The generated acid chloride was diluted in freshly steamed organic solvent tetrahydrofuran (THF) for later use; eugenol, 5% phase transfer catalyst tetrabutylammonium bromide and aqueous sodium hydroxide solution were added to a three-neck round-bottomed flask, and stirred evenly. Add the above-mentioned acid chloride solution dropwise under ice bath conditions; continue to react for 0.5h after the dropwise addition, and continuously replenish aqueous sodium hydroxide solution during the dropwise addition to keep the pH of the solution = 10 to make the reaction solution alkaline; The solid was then washed with aqueous sodium hydroxide solution and distilled water, and finally recrystallized with methanol to obtain a white crystalline solid which was aspirin eugenol ester.