CN103254051A - Preparation method of dialkyl curcumin - Google Patents
Preparation method of dialkyl curcumin Download PDFInfo
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- CN103254051A CN103254051A CN2013102057777A CN201310205777A CN103254051A CN 103254051 A CN103254051 A CN 103254051A CN 2013102057777 A CN2013102057777 A CN 2013102057777A CN 201310205777 A CN201310205777 A CN 201310205777A CN 103254051 A CN103254051 A CN 103254051A
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- curcumine
- curcumin
- dialkyl
- dialkyl group
- organic solvent
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Abstract
The invention overcomes the shortcomings of low yield of dialkyl curcumin and unsuitability for industrial production in the prior art, and provides a preparation method of dialkyl curcumin. The preparation method comprises the following steps of: mixing curcumin with an organic solvent, a phase transfer catalyst, an alkali and alkyl halide or dialkyl sulfate for reacting under nitrogen protection, tracking the reaction process by TLC (Thin Layer Chromatography), when the curcumin is completely reacted and the reaction is ended, performing decompression evaporation to separate out the organic solvent, and then adding water to the left material, and carrying out filtering, water washing and drying to obtain the crude product of curcumin; and purifying the obtained crude product of curcumin by the steps of adding an organic solvent and active carbon to the obtained crude product of curcumin, heating and refluxing, filtering out the active carbon, cooling naturally, and then carrying out filtering, thereby obtaining the dialkyl curcumin product. An etherification reaction is performed between curcumin and alkyl halide or dialkyl sulfate under catalysis of the phase transfer catalyst in the presence of the alkali to obtain dialkyl curcumin; and finally, the final dialkyl curcumin product is obtained in a recrystallization way. Therefore, the dialkyl curcumin product is high in content, free of column chromatography, high in yield and suitable for industrial batch production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate in particular to the dialkyl group curcumine.
Background technology
Turmeric is the dry rhizome of Zingiber curcuma Curcuma longa L., is per nnial herb, is " the conventional Chinese medicine of Chinese pharmacopoeia collection; Its bitter is warm in nature, returns spleen, Liver Channel, and broken blood promoting the circulation of qi, inducing meastruation to relieve menalgia effect are arranged.Its main bioactive ingredients has curcumine, demethoxycurcumin, bisdemethoxycurcumin isoreactivity molecule, curcumine is the tautomeric structure of diketone structure and ketenes between phenyl ring, has antibiotic, anti-oxidant, reducing blood-fat, pharmacological action such as antiviral, antitumor.The dialkyl group curcumine is curcumin derivate, has the various biological activity.
As the active intractable prostate cancer Castration-resistant prostate of castration cancer (CRPC) (the 1. Guanhong Xu that is used for of: (1) androgen antagonist, Yanyan Chu, Nan Jiang et.al, The Three Dimensional Quantitative Structure Activity Relationships (3D-QSAR) and Docking Studies of Curcumin Derivatives as Androgen Receptor Antagonists.Int.J.Mol.Sci.2012,13,6138-6155; 2. Li Lin, Qian Shi, Alexander K.Nyark.et.al., Antitumor Agents.250.
Design and Synthesis of New Curcumin Analogues as Potential Anti-Prostate Cancer Agents, J.Med.Chem.2006,49,39633972. 3. Yamashita S, Lai KP, Chuang KL, Xu D, et.al., ASC-J9suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors.Neoplasia.2012Jan; 14 (1): 74-83.)),
(2) treatment bladder cancer (Hsu JW, Hsu I, Xu D, Miyamoto H, et.al.Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor.Am J Pathol.2013,182 (5): 1811-20.)
(3) be used for the treatment of liver cancer (Wu MH, Ma WL, Hsu CL, Chen YL, et.al., Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription.Sci Transl Med.2010,2 (32), 32-35.)
Also have biologic activity such as treating pulmonery tuberculosis, anti-trypanosome and leishmania, a large amount of preparation methods that therefore develop the dialkyl group curcumine are significant.
Dialkyl group curcumine bibliographical information is prepared as follows method: be raw material with methyl ethyl diketone 1, boron trioxide 2 and substituted alkyl phenyl aldehyde 3, condensation under the organic bases effect, get condensation product 4, condensation product 4 hydrolysis under acidic conditions gets dialkyl group curcumine 5, and its synthesis technique is as follows:
It can be feedstock production dialkyl group curcumine (Chatchawan Changtam by curcumine and haloalkane that bibliographical information is arranged equally, Poonpilas Hongmanee, Apichart Suksamrarn, Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity, European Journal of Medicinal Chemistry45 (2010) 4446-4457), its synthesis technique is as follows:
But above-mentioned two kinds of preparation methods, yield is not high, (yield of dimethyl curcumine only is 54%), all the demand pole chromatography prepares the dialkyl group curcumine, is not suitable for preparation of industrialization.
Summary of the invention
It is low that the present invention overcomes in the prior art dialkyl group curcumine yield, and be not suitable for the deficiency of suitability for industrialized production, a kind of preparation method of dialkyl group curcumine is provided, the present invention is raw material with the curcumine, at organic solvent, under the phase-transfer catalyst effect, the preparation methods of haloalkane or sulfuric acid dialkyl a large amount of preparation high purity dialkyl group curcumines under the alkali effect, technology is simple, easy and simple to handle, cost is low.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows: a kind of preparation method of dialkyl group curcumine, and step is as follows:
(1) curcumine, organic solvent, phase-transfer catalyst, alkali and haloalkane or sulfuric acid dialkyl are mixed, under the nitrogenize protection, react, the TLC tracking reaction process, after the curcumine total overall reaction is intact, reaction finishes, vacuum decompression steams except organic solvent, adds water, filtration, washing, the dry dialkyl group curcumine crude product that gets; Synthesis technique is as follows:
(2) purifying: add organic solvent and gac reflux 10min-25min in the dialkyl group curcumine crude product that makes to step (1), filter out gac, naturally cooling, filter dialkyl group curcumine product.
As preferably, the described organic solvent of step (1) comprises methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, N, a kind of in dinethylformamide, methyl acetate, ethyl ester ethyl ester, propyl acetate, ethanol butyl ester, methyl alcohol, ethanol or the propyl alcohol, wherein organic solvent is 8～25mL/g with curcumine volume mass ratio.
As preferably, the described phase-transfer catalyst of step (1) comprises a kind of in Tetrabutyl amonium bromide, triethyl benzyl ammonia chloride or the OPE catalyst series, and the phase-transfer catalyst consumption is the 0.1-5% of curcumine quality.
As preferably, the described alkali of step (1) is salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, sodium bicarbonate, triethylamine, pyridine or N, and the N-diisopropylethylamine is wherein a kind of, and wherein the mol ratio of alkali and curcumine is 2～5:1.
As preferably, the described haloalkane of step (1) or sulfuric acid dialkyl wherein alkyl comprise-CH
3,-C
2H
5Or-C
3H
7Wherein a kind of, wherein haloalkane or sulfuric acid dialkyl and curcumine mol ratio are 2～5:1.
As preferably, the described temperature of reaction of step (1) is 0～120 ℃.
As preferably, the described organic solvent of step (2) comprises a kind of in methyl alcohol, ethanol or the ethyl acetate; Wherein organic solvent is 8～25:1mL/g with dialkyl group curcumine crude product volume mass ratio; Described activated carbon dosage is 2～5% of dialkyl group curcumine crude product quality.
Beneficial effect of the present invention is as follows: under phase reforming catalyst catalysis, curcumine and haloalkane or sulfuric acid dialkyl are in the presence of alkali, carry out etherification reaction dialkyl group curcumine, obtaining dialkyl group curcumine product by means re-crystallization again. dialkyl group curcumine product content is all more than 98%, this techniqueflow is brief, workable, raw material is easy to get, wastewater flow rate is few, solvent consumption also can be recycled less, the demand pole chromatography does not prepare the dialkyl group curcumine, and the yield height is suitable for industrial mass manufacture.
Embodiment
Below in conjunction with example the present invention is done and to specify:
Embodiment 1
In the 2L reaction flask, add curcumine (110.4g; 0.3mol); methylene dichloride (1200ml), salt of wormwood (91.1g; 0.66mol), methyl-sulfate (72.6g; 0.66mol) and Tetrabutyl amonium bromide (2.2g; 0.007mol); temperature is 0 ℃ of reaction 36 hours under nitrogen protection; the TLC tracking reaction process, after the curcumine total overall reaction was intact, reaction finished; vacuum decompression steams except methylene dichloride; add water (500ml), water-soluble substanceses such as () flush away inorganic salt, filtration, washing, dry dimethyl curcumine crude product (118g).
In the 2L reaction flask, added above-mentioned dimethyl curcumine crude product, ethyl acetate (1200ml) and gac (6g) reflux 10-25 minute, filtered while hot is removed filter residue, naturally cooling, get the yellow crystals crystal, filter dimethyl curcumine (105.9g), content is more than 98%, and yield 89.1%(is in curcumine), fusing point: 128-130 ℃.H
1NMR:(400Hz,CDCl
3),δ(ppm),3.92(s,6H,2x?CH
3O),3.93(s,6H,2x?CH
3O),5.82(s,1H,=CHa-),6.45(d,J=15.6Hz,2H,2x-CHb=CHc-),6.86(m,6H,2x?C
6H
3-),7.57(d,J=15.6Hz,2H,2x-CHc=CHb-).
Embodiment 2
In the 2L reaction flask, add curcumine (110.4g; 0.3mol); dioxane (880ml), N; N-diisopropylethylamine (193.9g; 1.5mol), ethyl sulfate (92.5g; 0.6mol) and Tetrabutyl amonium bromide (5.5g; 0.017mol); temperature is 100 ℃ of reactions 24 hours under nitrogen protection, and TLC follows the tracks of reaction, after the curcumine total overall reaction is intact; reaction finishes; vacuum decompression steams except dioxane, adds water (500ml), filtration, washing, the dry diethyl curcumine crude product (106g) that gets.
In the 2L reaction flask, added above-mentioned diethyl curcumine crude product, ethanol (850ml) and gac (5.3g) reflux 10-25 minute, filtered while hot, naturally cooling, get the yellow crystals crystal, filter diethyl curcumine (96.8g), content is more than 98%, yield 76.0%, fusing point: 116-118 ℃, H
1NMR:(400Hz, CDCl
3), δ (ppm), 1.39 (t, J=6.9Hz, 6H, 2x CH
3CH
2), 2.45 (s, 2H, CH
2), 3.88 (q, J=7.2Hz, 4H, 2x CH
3CH
2), 3.96 (s, 6H, CH
3O-), 6.46-6.80 (m, 4H, 2x CH=CH), 7.01 (d, 2H, 2x C
6H
3-), 7.24 (d2x C
6H
3-), 7.64 (d, 2H, 2x C
6H
3-).
Embodiment 3
In the 2L reaction flask, add curcumine (110.4g; 0.3mol); tetrahydrofuran (THF) (2760ml), triethylamine (60.7g; 0.6mol), n-propyl bromide (184.5g; 1.5mol) and triethyl benzyl ammonia chloride (0.11g; 0.0005mol); temperature is 66 ℃ of reactions 24 hours under nitrogen protection; TLC follows the tracks of reaction; after the curcumine total overall reaction was intact, reaction finished, and vacuum decompression steams except organic solvent; add water (500ml), filtration, washing, the dry dipropyl curcumine crude product (123g) that gets.
In the 2L reaction flask, added above-mentioned dipropyl curcumine crude product, ethanol (3100ml) and gac (2.5g) reflux 10-25 minute, filtered while hot, naturally cooling, get the yellow crystals crystal, filter dipropyl curcumine (96.8g), content is more than 98%, yield 71.3%, fusing point: 126-127.5 ℃.H
1NMR:(400Hz,CDCl
3),δ(ppm),1.04(t,J=7.2Hz,6H,2x?CH
3),1.86(m,J=7.2Hz,4H,2x?CH
2),3.89(s,6H,CH
3O-),4.01(t,J=6.8Hz,4H,2xCH
2),5.79(s,1H,=CHa-),6.46(d,J=15.7Hz,2H,-CHb=CHc),6.84(d,J=8.6Hz,2H,-CHb=CHc-),7.07(d,2H,2x?C
6H
3-),7.14(d?J=8.4,2H,2x?C
6H
3-),7.58(d,J=15.7Hz,2H,2xC
6H
3-)。
Claims (7)
1. the preparation method of a dialkyl group curcumine, it is characterized in that: step is as follows:
(1) curcumine, organic solvent, phase-transfer catalyst, alkali and haloalkane or sulfuric acid dialkyl are mixed, under the nitrogenize protection, react, the TLC tracking reaction process, after the curcumine total overall reaction is intact, reaction finishes, vacuum decompression steams except organic solvent, adds water, filtration, washing, the dry dialkyl group curcumine crude product that gets;
(2) purifying: add organic solvent and gac reflux 10min～25min in the dialkyl group curcumine crude product that makes to step (1), filter out gac, naturally cooling, filter dialkyl group curcumine product.
2. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described organic solvent of step (1) comprises methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, N, a kind of in dinethylformamide, methyl acetate, ethyl ester ethyl ester, propyl acetate, ethanol butyl ester, methyl alcohol, ethanol or the propyl alcohol, wherein organic solvent is 8～25mL/g with curcumine volume mass ratio.
3. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described phase-transfer catalyst of step (1) comprises a kind of in Tetrabutyl amonium bromide, triethyl benzyl ammonia chloride or the OPE catalyst series, and the phase-transfer catalyst consumption is 0.1～5% of curcumine quality.
4. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described alkali of step (1) is salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, sodium bicarbonate, triethylamine, pyridine or N, the N-diisopropylethylamine is wherein a kind of, and wherein the mol ratio of alkali and curcumine is 2～5:1.
5. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described haloalkane of step (1) or sulfuric acid dialkyl wherein alkyl comprise-CH
3,-C
2H
5Or-C
3H
7Wherein a kind of, wherein haloalkane or sulfuric acid dialkyl and curcumine mol ratio are 2～5:1.
6. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described temperature of reaction of step (1) is 0～100 ℃.
7. the preparation method of dialkyl group curcumine according to claim 1, it is characterized in that: the described organic solvent of step (2) comprises a kind of in methyl alcohol, ethanol or the ethyl acetate, and wherein organic solvent is 8～25:1mL/g with dialkyl group curcumine crude product volume mass ratio; Described activated carbon dosage is 2～5% of dialkyl group curcumine crude product quality.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113754525A (en) * | 2021-08-31 | 2021-12-07 | 天津大学 | Method for improving bulk density and fluidity of curcumin crystal |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| SATYENDRA MISHRA,ET AL.: ""Synthesis and exploration of novel curcumin analogues as anti-malarial agents"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 戴汉松等: ""姜黄素的提取及其甲基化研究"", 《天然产物研究与开发》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113754525A (en) * | 2021-08-31 | 2021-12-07 | 天津大学 | Method for improving bulk density and fluidity of curcumin crystal |
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Effective date of registration: 20210120 Address after: 318000 No. 218-1 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province Patentee after: Taizhou Yunong Biotechnology Co.,Ltd. Address before: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1 Patentee before: CHANGZHOU University |
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