CN104151167A - Preparation method for medicinal compound aspirin eugenol ester - Google Patents
Preparation method for medicinal compound aspirin eugenol ester Download PDFInfo
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- CN104151167A CN104151167A CN201310176925.7A CN201310176925A CN104151167A CN 104151167 A CN104151167 A CN 104151167A CN 201310176925 A CN201310176925 A CN 201310176925A CN 104151167 A CN104151167 A CN 104151167A
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- eugenol
- acetylsalicylic acid
- reaction
- preparation
- ester
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- 0 CC1(*c(cccc2)c2C([U])=[U])CC1 Chemical compound CC1(*c(cccc2)c2C([U])=[U])CC1 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method for a medicinal compound aspirin eugenol ester. In the preparation method, by utilization of a phase-transfer catalyst tetrabutylammonium bromide catalysis esterification reaction, white crystalline solid is obtained namely aspirin eugenol ester. Through the chemical reaction, irritation, easy oxidability and instability of aspirin and eugenol are lowered, in addition, the structural parts giving play to clinic effects are not changed, aspirin and eugenol are released under action of enzymes in a body, and the two original medicines have a synergistic effect, and have good pharmacological effects. The preparation method is advantaged by high yield, simple aftertreatment, green and environmental protection.
Description
Technical field
The present invention relates to the preparation method of the phase-transfer catalysis that a kind of medicinal compound acetylsalicylic acid eugenol ester is new.
Background technology
Inflammation is a kind of common disease and the frequently-occurring disease that threatens human and animal's health, and glucocorticoids steroidal anti-inflammatory medicine is infection control inflammation and non-infectious inflammation effectively, but life-time service easily causes the complication such as adrenocortical deterioration.And NSAID (non-steroidal anti-inflammatory drug) is conventionally much smaller than steroidal anti-inflammatory medicine toxic side effect, acetylsalicylic acid is exactly the NSAID (non-steroidal anti-inflammatory drug) representative with good anti-inflammatory and analgesic effect.In order effectively to control related inflammation disease, development of new, efficient, safe NSAID (non-steroidal anti-inflammatory drug) are the focuses of new drug development always.
Eugenol is the main component in Chinese medicine Myrtaceae platymiscium Flos Caryophylli volatile oil.Pharmacological experiments shows, it has the pharmacologically actives such as antipyretic, analgesia, anti-inflammatory, anti-oxidant, antithrombotic formation.But in Eugenol, contain phenolic hydroxyl group, have volatility and pungency, room temperature is placed also unstable, has affected its application.In addition, the long-term a large amount of use of acetylsalicylic acid also has damage to gi tract.
Chinese patent discloses a kind of " Eugenol acetylsalicylic acid ester pharmaceutical compound and preparation thereof and preparation method " (ZL2008 1 0017950.X), the method prepares its acyl chlorides by acetylsalicylic acid with thionyl chloride, then will after acyl chlorides dilution, under (benzene or trichloromethane) condition of ice bath, be added drop-wise in the aqueous solution of Eugenol, in this aqueous solution, contain sodium hydroxide and PEG-6000 (PEG-1000), dropwise rear continuation reaction 2-5h, stratification, organic phase concentrating under reduced pressure obtains solids, by recrystallizing methanol, can obtain compound acetylsalicylic acid eugenol ester.This reaction yield is low, and the reaction times is longer; The diluting solvent toxicity of selecting is larger; Phase-transfer catalyst PEG-1000 easily with organic solvent, the aqueous solution, reaction product formation mixture of viscous form, make aftertreatment loaded down with trivial details, cause productive rate not high, affect the application of acetylsalicylic acid eugenol ester.
Summary of the invention
In order to eliminate the side effect of Eugenol and acetylsalicylic acid, improve the productive rate of acetylsalicylic acid eugenol ester, the object of the present invention is to provide a kind of new preparation method of medicinal compound acetylsalicylic acid eugenol ester.The present invention utilizes principle of pro-drug, by chemical reaction, makes the combination of acetylsalicylic acid Eugenol, and shielding carboxyl and phenolic hydroxyl group, formed new medicinal compound acetylsalicylic acid eugenol ester.
The object of the invention is to adopt following technical scheme to reach:
A preparation method for medicinal compound acetylsalicylic acid eugenol ester, is characterized in that: in the round-bottomed flask that electric heating magnetic stirring apparatus, reflux are housed, add acetylsalicylic acid (acetylsalicylic acid), sulfur oxychloride (SOCl
2), splash into 10 N, dinethylformamide (DMF), slowly be heated to 70 ℃ of insulation reaction 2h, the sour gas discharging by sodium hydroxide (NaOH) aqueous solution neutralization reaction, decompression (0.08 Mpa) is steamed except unreacted sulfur oxychloride, the acyl chlorides of generation is diluted in the organic solvent tetrahydrofuran (THF) of new steaming stand-by; In three mouthfuls of round-bottomed flasks, add Eugenol, 5% phase-transfer catalyst Tetrabutyl amonium bromide (TBAB) and aqueous sodium hydroxide solution, stirring and evenly mixing, drips above-mentioned solution of acid chloride under condition of ice bath; Dropwise rear continuation and react 0.5 h, continuous hydrogen make-up aqueous solution of sodium oxide during dropping, the pH ≈ 10 of maintenance solution, makes reaction soln be alkalescence; Suction filtration obtains white solid after completion of the reaction, uses respectively aqueous sodium hydroxide solution and distilled water wash, finally by recrystallizing methanol, obtains white crystalline solid and is acetylsalicylic acid eugenol ester.
Its structural formula is as follows:
The acetylsalicylic acid eugenol ester making is white crystal in appearance, fusing point 71-72 ℃.Mass-spectrometric data is: ESI(+), and [M+H]
+=327.Proton nmr spectra: ((CD
3)
2sO, TMS, 400MH
z),
1hNMR, δ ppm: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).
Advantage of the present invention
1, the present invention prepares compound, pass through chemical reaction, reduce pungency, easily oxidizable and the unstable of acetylsalicylic acid and Eugenol, do not change the structure position of performance clinical effect simultaneously, under enzyme effect, discharge in vivo that two kinds of former medicines of acetylsalicylic acid and Eugenol are collaborative to play a role, there is better pharmacological action.
2, preparation method's mature and reliable of the present invention, has productive rate high, and aftertreatment is simple, is a kind of acetylsalicylic acid eugenol ester preparation method of environmental protection.
3, beneficial effect of the present invention becomes ester reaction to be explained by the committed step in orthogonal experimental design optimal preparation technology:
Table 1 reaction factor and level
Table 2 reaction orthogonal array
As can be seen from Table 2, becoming the secondary factors of the condition of ester reaction is the amount of sodium hydroxide ﹥ phase-transfer catalyst ﹥ reaction times, and best reaction conditions is A
3b
1c
1, but reaction times impact is little, and the final selective reaction time is 0.5h.Be best one-tenth ester reaction conditions for adding the Eugenol of 1eq in suitable reaction vessel, 5% phase-transfer catalyst TBAB and the NaOH aqueous solution of 1.2eq are appropriate, stirring and evenly mixing under condition of ice bath, the THF solution that drips the acyl chlorides making with 1eq acetylsalicylic acid, ice bath dropwises rear continuation and reacts 0.5 h.During dropping, constantly supplement NaOH(0.4eq) aqueous solution, make reaction soln keep alkalescence (pH ≈ 10).Suction filtration obtains white solid after completion of the reaction, uses respectively the NaOH aqueous solution and the distilled water wash of 0.1mol/L, finally by recrystallizing methanol, obtains white crystals and is acetylsalicylic acid eugenol ester.
Embodiment
According to technical scheme of the present invention, select best reaction conditions, carried out the preparation of medicinal compound acetylsalicylic acid eugenol ester.
(1) embodiment 1
The acetylsalicylic acid that adds 0.1mol in the 50ml round-bottomed flask of electric heating magnetic stirring apparatus, reflux is housed, the SOCl of 10ml
2, splash into 10 DMF, be slowly heated to 70 ℃ of insulation reaction 2h, the sour gas discharging by NaOH aqueous solution neutralization reaction.Decompression (0.08 Mpa) is steamed except unreacted SOCl
2, the acyl chlorides of generation is dissolved in to the new THF steaming of 20ml stand-by.The Eugenol that adds 0.1 mol in three mouthfuls of round-bottomed flasks of 500ml, the NaOH aqueous solution 300ml of 5% phase-transfer catalyst TBAB and 0.12mol, stirring and evenly mixing, drips (approximately 2 seconds one) above-mentioned solution of acid chloride under condition of ice bath.Dropwise rear continuation and react 0.5 h, during dropping, constantly supplement NaOH(0.04mol) aqueous solution, make reaction soln keep alkalescence (pH ≈ 10).Suction filtration obtains white solid after completion of the reaction, obtains white crude product respectively with the NaOH aqueous solution and the distilled water wash of 0.1mol/L.Crude product obtains white crystal 27.6g by recrystallizing methanol, productive rate 84.7% after drying.
(2) embodiment 2
The acetylsalicylic acid that adds 0.3mol in the 100ml round-bottomed flask of electric heating magnetic stirring apparatus, reflux is housed, the SOCl of 30ml
2, splash into 30 DMF, be heated to 70 ℃ of insulation reaction 2h, the sour gas discharging by NaOH aqueous solution neutralization reaction.Decompression (0.08 Mpa) is steamed except unreacted SOCl
2, the acyl chlorides of generation is dissolved in to the new THF steaming of 60ml stand-by.In the beaker of 1000ml, add the Eugenol of 0.3 mol, the NaOH aqueous solution 600ml of 5% phase-transfer catalyst TBAB and 0.36mol, stirring and evenly mixing, drips above-mentioned solution of acid chloride under condition of ice bath.Dropwise rear continuation and react 0.5 h, during dropping, constantly supplement NaOH(0.12mol) aqueous solution, make reaction soln keep alkalescence (pH ≈ 10).Suction filtration obtains white solid after completion of the reaction, obtains white crude product respectively with the NaOH aqueous solution and the distilled water wash of 0.1mol/L.Crude product obtains white crystal 82g by recrystallizing methanol, productive rate 83.8% after drying.
Claims (1)
1. the preparation method of a medicinal compound acetylsalicylic acid eugenol ester, it is characterized in that: in the round-bottomed flask that electric heating magnetic stirring apparatus, reflux are housed, add acetylsalicylic acid (acetylsalicylic acid), sulfur oxychloride, splash into 10 N, dinethylformamide, slowly be heated to 70 ℃ of insulation reaction 2h, the sour gas discharging by aqueous sodium hydroxide solution neutralization reaction, decompression (0.08 Mpa) is steamed except unreacted sulfur oxychloride, the acyl chlorides of generation is diluted in the organic solvent tetrahydrofuran (THF) of new steaming stand-by; In three mouthfuls of round-bottomed flasks, add Eugenol, 5% phase-transfer catalyst Tetrabutyl amonium bromide and aqueous sodium hydroxide solution, stirring and evenly mixing, drips above-mentioned solution of acid chloride under condition of ice bath; Dropwise rear continuation and react 0.5 h, continuous hydrogen make-up aqueous solution of sodium oxide during dropping, the pH ≈ 10 of maintenance solution, makes reaction soln be alkalescence; Suction filtration obtains white solid after completion of the reaction, then uses respectively aqueous sodium hydroxide solution and distilled water wash, finally by recrystallizing methanol, obtains white crystalline solid and is acetylsalicylic acid eugenol ester.
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|---|---|---|---|
| CN201310176925.7A CN104151167B (en) | 2013-05-14 | 2013-05-14 | A kind of preparation method of medicinal compound acetylsalicylic acid eugenol ester |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349076A (en) * | 2016-08-26 | 2017-01-25 | 中国农业科学院兰州畜牧与兽药研究所 | Crystal form B of aspirin eugenol ester and preparation method thereof |
| CN113387809A (en) * | 2020-03-11 | 2021-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester process impurity and preparation method thereof |
Citations (6)
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|---|---|---|---|---|
| EP0084678A1 (en) * | 1982-01-21 | 1983-08-03 | AUSONIA FARMACEUTICI S.r.l. | New compound having analgesic, antiinflammatory and mucoregulating activities, process for its production and relative pharmaceutical compositions |
| JPS59161335A (en) * | 1983-03-03 | 1984-09-12 | Ss Pharmaceut Co Ltd | Novel acetylsalicylic acid ester derivative and its preparation |
| CN1337391A (en) * | 2001-08-17 | 2002-02-27 | 重庆大学 | Phosgene process of synthesizing acetylsalicylate derivatives for medicine |
| CN101270052A (en) * | 2008-04-08 | 2008-09-24 | 中国农业科学院兰州畜牧与兽药研究所 | Eugenol aspirin ester pharmaceutical compound, preparation and preparing method |
| CN102659597A (en) * | 2012-05-18 | 2012-09-12 | 吉林大学 | Naproxen eugenol ester medicinal compound and preparation method of naproxen eugenol ester medicinal compound |
| CN102675112A (en) * | 2012-05-21 | 2012-09-19 | 山东凯盛新材料股份有限公司 | Synthetic method of diphenyl iso-phthalate |
-
2013
- 2013-05-14 CN CN201310176925.7A patent/CN104151167B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084678A1 (en) * | 1982-01-21 | 1983-08-03 | AUSONIA FARMACEUTICI S.r.l. | New compound having analgesic, antiinflammatory and mucoregulating activities, process for its production and relative pharmaceutical compositions |
| JPS59161335A (en) * | 1983-03-03 | 1984-09-12 | Ss Pharmaceut Co Ltd | Novel acetylsalicylic acid ester derivative and its preparation |
| CN1337391A (en) * | 2001-08-17 | 2002-02-27 | 重庆大学 | Phosgene process of synthesizing acetylsalicylate derivatives for medicine |
| CN101270052A (en) * | 2008-04-08 | 2008-09-24 | 中国农业科学院兰州畜牧与兽药研究所 | Eugenol aspirin ester pharmaceutical compound, preparation and preparing method |
| CN102659597A (en) * | 2012-05-18 | 2012-09-12 | 吉林大学 | Naproxen eugenol ester medicinal compound and preparation method of naproxen eugenol ester medicinal compound |
| CN102675112A (en) * | 2012-05-21 | 2012-09-19 | 山东凯盛新材料股份有限公司 | Synthetic method of diphenyl iso-phthalate |
Non-Patent Citations (1)
| Title |
|---|
| JIAN-YONG LI等: "Synthesis of aspirin eugenol ester and its biological activity", 《MED CHEM RES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349076A (en) * | 2016-08-26 | 2017-01-25 | 中国农业科学院兰州畜牧与兽药研究所 | Crystal form B of aspirin eugenol ester and preparation method thereof |
| CN113387809A (en) * | 2020-03-11 | 2021-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester process impurity and preparation method thereof |
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| CN104151167B (en) | 2016-04-20 |
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