CN108238913A - A kind of method for preparing azalaic acid - Google Patents
A kind of method for preparing azalaic acid Download PDFInfo
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- CN108238913A CN108238913A CN201611223328.5A CN201611223328A CN108238913A CN 108238913 A CN108238913 A CN 108238913A CN 201611223328 A CN201611223328 A CN 201611223328A CN 108238913 A CN108238913 A CN 108238913A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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Abstract
This method is related to a kind of method for preparing azalaic acid, it is proposed that new synthesis and purifying process, high income isolate and purify simply, there is very high economic benefit, suitable for industrial production.
Description
Technical field
This method is related to a kind of method for preparing azalaic acid (azelaic acid).
Technical background
Azalaic acid (Azelaic Acid), the entitled azelaic acid (nonanedioic acid) of chemistry, is naturally occurring
Saturated dicarboxylic acid containing nine carbon atoms.It is applied to clinical treatment Huang first early in Nazzaro-porro in 1979 etc.
Cutaneous diseases such as foxiness and acne, and achieve the effect of fabulous, but since the limitation of technology at that time can not obtain high-purity
Azelaic acid, therefore clinically find slightly have some adverse reactions.With the development of purification technique, nineteen ninety or so beginning, moral
The companies such as state Schering, U.S. Allergan release Azelaic Acid Cream one after another, for OTC drugs and cosmetics, China Zhejiang
Kang Enbei groups are also proposed 20% Azelaic Acid Cream.The adverse reaction of azelaic acid is generally all slighter and of short duration.1-5%'s
Patient medication just has itch, scorching hot, stimulation and tingling sensation.Other adverse reactions have erythema, dry skin, fash, furfur, thorn
Sharp, dermatitis and contact dermatitis etc., total incidence is less than 1%.This product has the Potential feasibility for causing allergy.Only a few
Report claims to cause asthma exacerbation, skin pigment reduction, hickie, crinosity, rubescent (sign of Darier's disease) when using this product
And recurrent lip bleb deteriorates.
Have the synthesis of numerous patent reports azalaic acid, as CN1127246, CN101244998, CN101679181,
CN102933538、CN101811954、CN102690183、CN104640833、CN104364377、CN103467273、
CN104447279、CN105198725、CN102725257、CN102712562、CN102344358、CN104093692、
CN102994402、CN103998410、CN104955799、CN1552687；CN101250101、CN101279909、
CN102325746、CN101696161、CN104797552、CN104854067、CN103965035、CN104418725；
US5380928, US5380931, US6660505, US7825277 etc..Wherein, most of method is by using oleic acid as raw material system
Standby azalaic acid；For example, CN101244998 is used to prepare azelaic acid using the method that ozone oxidation decomposes oleic acid.In addition, it also reports
Road some using other organic acids as the preparation process of raw material；Such as：CN102344358 systems by the way of tungoxyn cracking
Standby azelaic acid.Mostly using natural acid as raw material, material quality is difficult to control used method, reaction process by-product
It is more, the fat diacid impurity of more different chain length is also easy to produce, product quality is difficult to control.In this patent, we devise
Completely new synthesis route, and subsequent purification condition is explored, obtain the cuckoo of high-purity with higher yields
Spend acid
Invention content
The present invention is directed to invent a kind of easy, economic, efficient mode to prepare azalaic acid, it is proposed that completely new technique is closed
Into route and purifying process, have high income, isolate and purify it is simple, have good economic benefit, suitable for industrial production.
The synthetic route that this method uses is as follows：
Four acid compound of Formula II under the action of the suitable reagent suitable solvent or do not add under conditions of solvent in
Reaction prepares azelaic acid Formulas I at suitable temperature.
Wherein, suitable reagent is selected from sodium hydroxide, hydrochloric acid and sulfuric acid；Suitable solvent is selected from N, N- dimethyl formyls
Amine, N-Methyl pyrrolidone, glycol dimethyl ether, ethylene glycol diethyl ether, glycol dimethyl ether, diethylene glycol diethyl ether, 1,4-
Dioxane, toluene, chlorobenzene, dimethylbenzene, acetic acid and water；Suitable temperature is selected from 100-140 DEG C, preferably 120-130 DEG C.
The post processing mode of the reaction is：After the completion of reaction, it adds in suitable solvent, heat up stirring and dissolving, then delays
Slow cooling crystallization obtains solid.Wherein, suitable solvent is selected from water, diethylene glycol dimethyl ether, acetic acid, ethyl acetate, isopropyl acetate
Ester, acetonitrile and isopropanol.
Specific embodiment
Following embodiment illustrates the present invention, but not limits the present invention.
Embodiment 1：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) are added in reaction bulb 1.It is warming up to 120-130
DEG C, insulation reaction 16 hours.HPLC detections are added in acetonitrile (150ml), are warming up to 70-75 DEG C after the reaction was complete.Stirring is complete
After dissolving, 25-30 DEG C is slowly dropped to, heat preservation crystallization 3 hours.Filter to obtain off-white powder 11g, HPLC purity 99.51%.
MS(ESI)188.9(M+H+)；
1H NMR(400MHz,DMSO-d6) δ 11.90 (s, 2H), 2.15 (t, J=7.4Hz, 4H), 1.45 (p, J=
6.8Hz, 4H), 1.22 (d, J=4.4Hz, 6H)
Embodiment 2：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) are added in reaction bulb 1.It is warming up to 120-130
DEG C, insulation reaction 16 hours.HPLC detections are after the reaction was complete, add in drinking water (150ml), and 95-100 DEG C of insulated and stirred is to complete
Dissolving.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid be dried under reduced pressure to obtain crude product.By crude product plus
Enter in isopropyl acetate (150ml), be warming up to 70-75 DEG C.After stirring is completely dissolved, 25-30 DEG C is slowly dropped to, keeps the temperature crystallization 3
Hour.Filter to obtain off-white powder 10.4g, HPLC purity 99.53%.
MS(ESI)188.9(M+H+)；
Embodiment 3：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and diethylene glycol diformazan are added in reaction bulb 1
Ether (60mL).120-130 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in drinking water (150ml) after the reaction was complete,
95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid
It is dried under reduced pressure to obtain crude product.Crude product is added in acetonitrile (150ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, it is slowly dropped to
25-30 DEG C, heat preservation crystallization 3 hours.Filter to obtain off-white powder 9.8g, HPLC purity 99.53%.
MS(ESI)188.9(M+H+)；
Embodiment 4：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and acetic acid (15mL) are added in reaction bulb 1.
120-130 DEG C is warming up to, insulation reaction 16 hours.HPLC detections are after the reaction was complete, add in drinking water (150ml), 95-100 DEG C
Insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid be dried under reduced pressure
Obtain crude product.Crude product is added in acetonitrile (150ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, 25-30 DEG C is slowly dropped to,
Keep the temperature crystallization 3 hours.Filter to obtain off-white powder 10.1g, HPLC purity 99.63%.
MS(ESI)188.9(M+H+)；
Embodiment 5：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and drinking water are added in reaction bulb 1
(30mL).120-130 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in drinking water (150ml) after the reaction was complete,
95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid
It is dried under reduced pressure to obtain crude product.Crude product is added in ethyl acetate (150ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, slowly
25-30 DEG C is down to, heat preservation crystallization 3 hours.Filter to obtain off-white powder 10.4g, HPLC purity 99.58%.
MS(ESI)188.9(M+H+)；
Embodiment 6：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and N- crassitudes are added in reaction bulb 1
Ketone (15mL).120-130 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in drinking water (150ml) after the reaction was complete,
95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid
It is dried under reduced pressure to obtain crude product.Crude product is added in ethyl acetate (150ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, slowly
25-30 DEG C is down to, heat preservation crystallization 3 hours.Filter to obtain off-white powder 9.1g, HPLC purity 99.41%.
MS(ESI)188.9(M+H+)；
Embodiment 7：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and dimethylbenzene are added in reaction bulb 1
(15mL).120-130 DEG C is warming up to, insulation reaction 16 hours.HPLC detections are after the reaction was complete, slow uniform decrease in temperature to 25-30
DEG C, heat preservation crystallization 3 hours.Filtering, solid be dried under reduced pressure to obtain crude product.Crude product is added in into diethylene glycol dimethyl ether (60ml)
In, it is warming up to 70-75 DEG C.After stirring is completely dissolved, 0-5 DEG C is slowly dropped to, heat preservation crystallization 3 hours.Filter to obtain off-white powder
7.3g, HPLC purity 99.73%.
MS(ESI)188.9(M+H+)；
Embodiment 8：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) are added in reaction bulb 1.It is warming up to 120-130
DEG C, insulation reaction 16 hours.HPLC detections are after the reaction was complete, add in drinking water (150ml), and 95-100 DEG C of insulated and stirred is to complete
Dissolving.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid be dried under reduced pressure to obtain crude product.By crude product plus
Enter in isopropanol (60ml), be warming up to 70-75 DEG C.After stirring is completely dissolved, 0-5 DEG C is slowly dropped to, heat preservation crystallization 3 hours.It crosses
Filter to obtain off-white powder 7.5g, HPLC purity 99.69%.
MS(ESI)188.9(M+H+)；
Embodiment 9：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and 5% hydrochloric acid are added in reaction bulb 1
(30ml).110-120 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in drinking water (150ml) after the reaction was complete,
95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid
It is dried under reduced pressure to obtain crude product.Crude product is added in isopropanol (60ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, it is slowly dropped to
0-5 DEG C, heat preservation crystallization 3 hours.Filter to obtain off-white powder 9.3g, HPLC purity 99.71%.
Embodiment 10：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and 5% sulfuric acid are added in reaction bulb 1
(30ml).110-120 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in drinking water (150ml) after the reaction was complete,
95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, solid
It is dried under reduced pressure to obtain crude product.Crude product is added in isopropanol (60ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, it is slowly dropped to
0-5 DEG C, heat preservation crystallization 3 hours.Filter to obtain off-white powder 9.5g, HPLC purity 99.88%.
Embodiment 11：Heptane -1,1,7,7- tetrabasic carboxylic acids (30g, 0.11mol) and 5% hydroxide are added in reaction bulb 1
Sodium solution (30ml).110-120 DEG C is warming up to, insulation reaction 16 hours.HPLC detections add in 5% hydrochloric acid after the reaction was complete
(30ml), 95-100 DEG C of insulated and stirred is to being completely dissolved.Slow uniform decrease in temperature is to 25-30 DEG C, heat preservation crystallization 3 hours.Filtering, institute
Solid be dried under reduced pressure to obtain crude product.Crude product is added in isopropanol (60ml), is warming up to 70-75 DEG C.After stirring is completely dissolved, delay
It is slow to be down to 0-5 DEG C, heat preservation crystallization 3 hours.Filter to obtain off-white powder 8.1g, HPLC purity 99.91%.
Claims (5)
- A kind of 1. method of formula I azalaic acidsIts feature comprises the steps of：1) it does not add in suitable reagent or under the action of reagent in suitable solvent or does not add by four acid compound of Formula II Under conditions of solvent at suitable temperature reaction prepare azelaic acid Formulas I,2) crude product obtained by and in a suitable solvent crystallization purifying.
- 2. according to the method described in claim 1, it is characterized in that suitable solvent is independently chosen from N, N- dimethyl methyls in step 1) Amide, N-Methyl pyrrolidone, glycol dimethyl ether, ethylene glycol diethyl ether, glycol dimethyl ether, diethylene glycol diethyl ether, 1, 4- dioxane, toluene, chlorobenzene, dimethylbenzene, acetic acid and water, preferably water, acetic acid and diethylene glycol dimethyl ether.
- 3. according to the method described in claim 1, it is characterized in that suitable agent is independently chosen from sodium hydroxide, hydrochloric acid in step 1) And sulfuric acid.
- 4. according to the method described in claim 1, it is characterized in that suitable temperature is selected from 100-140 DEG C in step 1), preferably 120-130℃。
- 5. according to the method described in claim 1, it is characterized in that the suitable solvent in step 2) is selected from water, diethylene glycol diformazan Ether, acetic acid, ethyl acetate, isopropyl acetate, acetonitrile and isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611223328.5A CN108238913A (en) | 2016-12-27 | 2016-12-27 | A kind of method for preparing azalaic acid |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611223328.5A CN108238913A (en) | 2016-12-27 | 2016-12-27 | A kind of method for preparing azalaic acid |
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| CN108238913A true CN108238913A (en) | 2018-07-03 |
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| CN201611223328.5A Pending CN108238913A (en) | 2016-12-27 | 2016-12-27 | A kind of method for preparing azalaic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021027807A1 (en) * | 2019-08-12 | 2021-02-18 | 新钰生技股份有限公司 | Method for preparing azelaic acid |
| CN114478229A (en) * | 2022-02-16 | 2022-05-13 | 武汉华尔生物科技有限公司 | Preparation method of azelaic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101811954A (en) * | 2010-04-23 | 2010-08-25 | 浙江华诺化工有限公司 | Method for preparing azelaic acid by catalytic oxidation of oleic acid |
| CN105037138A (en) * | 2015-07-06 | 2015-11-11 | 上海应用技术学院 | Preparation method for 2,9-dibutyl sebacate |
-
2016
- 2016-12-27 CN CN201611223328.5A patent/CN108238913A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101811954A (en) * | 2010-04-23 | 2010-08-25 | 浙江华诺化工有限公司 | Method for preparing azelaic acid by catalytic oxidation of oleic acid |
| CN105037138A (en) * | 2015-07-06 | 2015-11-11 | 上海应用技术学院 | Preparation method for 2,9-dibutyl sebacate |
Non-Patent Citations (1)
| Title |
|---|
| 袁履冰: "《基础有机化学问答》", 28 February 1984, 上海科学技术出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021027807A1 (en) * | 2019-08-12 | 2021-02-18 | 新钰生技股份有限公司 | Method for preparing azelaic acid |
| TWI749674B (en) * | 2019-08-12 | 2021-12-11 | 新鈺生技股份有限公司 | A process for preparing azelaic acid |
| US11459288B2 (en) * | 2019-08-12 | 2022-10-04 | Corum Inc. | Process for preparing azelaic acid |
| CN114478229A (en) * | 2022-02-16 | 2022-05-13 | 武汉华尔生物科技有限公司 | Preparation method of azelaic acid |
| CN114478229B (en) * | 2022-02-16 | 2024-07-12 | 武汉华尔生物科技有限公司 | Preparation method of azelaic acid |
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