CN103254051B - A kind of preparation method of dialkyl curcumin - Google Patents
A kind of preparation method of dialkyl curcumin Download PDFInfo
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- CN103254051B CN103254051B CN201310205777.7A CN201310205777A CN103254051B CN 103254051 B CN103254051 B CN 103254051B CN 201310205777 A CN201310205777 A CN 201310205777A CN 103254051 B CN103254051 B CN 103254051B
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Abstract
It is low that the present invention overcomes dialkyl curcumin yield in prior art, and be not suitable for the deficiency of suitability for industrialized production, a kind of preparation method of dialkyl curcumin is provided, by curcumine, organic solvent, phase-transfer catalyst, alkali and haloalkane or dialkyl sulfate mixing, reacts under nitrogenize protection, TLC tracking reaction process, after curcumine total overall reaction is complete, reaction terminates, and decompression steams organic solvent, add water, filter, washing, dry dialkyl curcumin crude product; Purifying: add organic solvent and heating activated carbon backflow in obtained dialkyl curcumin crude product, filter out gac, naturally cooling, filter to obtain dialkyl curcumin product.With under phase reforming catalyst catalysis, curcumine and haloalkane or dialkyl sulfate are in the presence of a base, carry out etherification reaction dialkyl curcumin, dialkyl curcumin product is obtained again by means re-crystallization. dialkyl curcumin product content is high, not demand pole chromatography, yield is high, is suitable for industrial mass manufacture.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to dialkyl curcumin.
Background technology
Turmeric is the dry rhizome of Zingiber curcuma Curcuma longa L., is per nnial herb, is the conventional Chinese medicine that " Chinese Pharmacopoeia " is collected; Its bitter is warm in nature, returns spleen, Liver Channel, has broken blood gas, inducing meastruation to relieve menalgia effect.Its primary bioactive components has curcumine, demethoxycurcumin, bisdemethoxycurcumin isoreactivity molecule, curcumine is the tautomeric structure of diketone structure and ketenes between phenyl ring, has antibacterial, anti-oxidant, reducing blood-fat, the pharmacological action such as antiviral, antitumor.Dialkyl curcumin is curcumin derivate, has various biological activity.
As: (1) antiandrogen active is used for castration refractory prostate cancer Castration-resistant prostate cancer (CRPC) (1. Guanhong Xu; Yanyan Chu; Nan Jiang et.al; The Three Dimensional QuantitativeStructure Activity Relationships (3D-QSAR) and Docking Studies of Curcumin Derivatives asAndrogen 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 CurcuminAnalogues 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 prostatecancer growth through degradation of full-length and splice variant androgen receptors.Neoplasia.2012Jan; 14 (1): 74-83.)),
(2) bladder cancer (Hsu JW is treated, Hsu I, Xu D, Miyamoto H, et.al.Decreased tumorigenesis andmortality from bladder cancer in mice lacking urothelial androgen receptor.Am J Pathol.2013,182 (5): 1811-20.)
(3) liver cancer (Wu MH is used for the treatment of, Ma WL, Hsu CL, Chen YL, et.al., Androgen receptor promoteshepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNAtranscription.Sci Transl Med.2010,2 (32), 32-35.)
Also have the biologic activity such as treating pulmonery tuberculosis, anti-trypanosome and leishmania, a large amount of preparation methods therefore developing dialkyl curcumin are significant.
The following preparation method of dialkyl curcumin bibliographical information: with methyl ethyl diketone 1, boron trioxide 2 and substituted alkyl phenyl aldehyde 3 for raw material, condensation under organic bases effect, obtain condensation product 4, condensation product 4 is hydrolyzed to obtain dialkyl curcumin 5 in acid condition, and its synthesis technique is as follows:
Bibliographical information is had to be that dialkyl curcumin (ChatchawanChangtam prepared by raw material by curcumine and haloalkane equally, Poonpilas Hongmanee, Apichart Suksamrarn, Isoxazole analogs of curcuminoids withhighly potent multidrug-resistant antimycobacterial activity, European Journal of MedicinalChemistry45 (2010) 4446-4457), its synthesis technique is as follows:
But above-mentioned two kinds of preparation methods, yield is not high, and (yield of Dimethylcurcumin is only 54%), all demand pole chromatography prepares dialkyl curcumin, is not suitable for preparation of industrialization.
Summary of the invention
It is low that the present invention overcomes dialkyl curcumin yield in prior art, and be not suitable for the deficiency of suitability for industrialized production, a kind of preparation method of dialkyl curcumin is provided, the present invention take curcumine as raw material, at organic solvent, under phase-transfer catalyst effect, the preparation method of haloalkane or dialkyl sulfate a large amount of preparation high purity dialkyl curcumin under alkali effect, technique is simple, easy and simple to handle, and 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 curcumin, and step is as follows:
(1) by curcumine, organic solvent, phase-transfer catalyst, alkali and haloalkane or dialkyl sulfate mixing, react under nitrogenize protection, TLC tracking reaction process, after curcumine total overall reaction is complete, reaction terminates, vacuum decompression steams except organic solvent, adds water, filter, washing, dry dialkyl curcumin crude product; Synthesis technique is as follows:
(2) purifying: add organic solvent and heating activated carbon backflow 10min-25min in the dialkyl curcumin crude product that step (1) is obtained, filter out gac, naturally cooling, filter to obtain dialkyl curcumin product.
As preferably, organic solvent described in step (1) comprises methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, N, one in dinethylformamide, methyl acetate, EtOAc, propyl acetate, ethanol butyl ester, methyl alcohol, ethanol or propyl alcohol, wherein organic solvent is 8 ~ 25mL/g with curcumine volume mass ratio.
As preferably, the phase-transfer catalyst described in step (1) comprises the one in Tetrabutyl amonium bromide, triethyl benzyl ammonia chloride or OPE catalyst series, and phase-transfer catalyst consumption is the 0.1-5% of curcumine quality.
As preferably, the alkali described in step (1) is that salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, triethylamine, pyridine or DIPEA are wherein a kind of, and wherein the mol ratio of alkali and curcumine is 2 ~ 5:1.
As preferably, the haloalkane described in step (1) or dialkyl sulfate wherein alkyl comprise-CH
3,-C
2h
5or-C
3h
7wherein a kind of, wherein haloalkane or dialkyl sulfate and curcumine mol ratio are 2 ~ 5:1.
As preferably, the temperature of reaction described in step (1) is 0 ~ 120 DEG C.
As preferably, the organic solvent described in step (2) comprises the one in methyl alcohol, ethanol or ethyl acetate; Wherein organic solvent is 8 ~ 25:1mL/g with dialkyl curcumin crude product volume mass ratio; Described activated carbon dosage is 2 ~ 5% of dialkyl curcumin crude product quality.
Beneficial effect of the present invention is as follows: with under phase reforming catalyst catalysis, curcumine and haloalkane or dialkyl sulfate are in the presence of a base, carry out etherification reaction dialkyl curcumin, dialkyl curcumin product is obtained again by means re-crystallization. dialkyl curcumin 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, demand pole chromatography does not prepare dialkyl curcumin, and yield is high, is suitable for industrial mass manufacture.
Embodiment
Below in conjunction with example, the present invention is illustrated:
Embodiment 1
Curcumine (110.4g is added in 2L reaction flask; 0.3mol); methylene dichloride (1200ml), salt of wormwood (91.1g; 0.66mol), methyl-sulfate (72.6g; 0.66mol) with Tetrabutyl amonium bromide (2.2g; 0.007mol); temperature is 0 DEG C of reaction 36 hours under nitrogen protection; TLC tracking reaction process, after curcumine total overall reaction is complete, reaction terminates; vacuum decompression steams except methylene dichloride; add water (500ml), (washing away the water-soluble substanceses such as inorganic salt), filter, washing, dry Dimethylcurcumin crude product (118g).
Above-mentioned Dimethylcurcumin crude product, ethyl acetate (1200ml) and gac (6g) reflux 10-25 minute is added in 2L reaction flask, filtered while hot removing filter residue, naturally cooling, obtain yellow crystals crystal, filter to obtain Dimethylcurcumin (105.9g), content more than 98%, yield 89.1%(is in curcumine), fusing point: 128-130 DEG C.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
Curcumine (110.4g is added in 2L reaction flask; 0.3mol); dioxane (880ml), N; N-diisopropylethylamine (193.9g; 1.5mol), ethyl sulfate (92.5g; 0.6mol) with Tetrabutyl amonium bromide (5.5g; 0.017mol); temperature is 100 DEG C of reactions 24 hours under nitrogen protection, and TLC follows the tracks of reaction, after curcumine total overall reaction is complete; reaction terminates; vacuum decompression steams except dioxane, and add water (500ml), filter, washing, dry diethyl curcumine crude product (106g).
Above-mentioned diethyl curcumine crude product, ethanol (850ml) and gac (5.3g) reflux 10-25 minute is added in 2L reaction flask, filtered while hot, naturally cooling, obtain yellow crystals crystal, filter to obtain diethyl curcumine (96.8g), content more than 98%, yield 76.0%, fusing point: 116-118 DEG C, 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
Curcumine (110.4g is added in 2L reaction flask; 0.3mol); tetrahydrofuran (THF) (2760ml), triethylamine (60.7g; 0.6mol), n-propyl bromide (184.5g; 1.5mol) with triethyl benzyl ammonia chloride (0.11g; 0.0005mol); temperature is 66 DEG C of reactions 24 hours under nitrogen protection; TLC follows the tracks of reaction; after curcumine total overall reaction is complete, reaction terminates, and vacuum decompression steams except organic solvent; add water (500ml), filter, washing, dry dipropyl curcumine crude product (123g).
Above-mentioned dipropyl curcumine crude product, ethanol (3100ml) and gac (2.5g) reflux 10-25 minute is added in 2L reaction flask, filtered while hot, naturally cooling, obtain yellow crystals crystal, filter to obtain dipropyl curcumine (96.8g), content more than 98%, yield 71.3%, fusing point: 126-127.5 DEG C.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 (6)
1. a preparation method for dialkyl curcumin, is characterized in that: step is as follows:
(1) by curcumine, organic solvent, phase-transfer catalyst, alkali and haloalkane or dialkyl sulfate mixing, react under nitrogenize protection, TLC tracking reaction process, after curcumine total overall reaction is complete, reaction terminates, vacuum decompression steams except organic solvent, adds water, filter, washing, dry dialkyl curcumin crude product; Described organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, N, one in dinethylformamide, methyl acetate, EtOAc, propyl acetate, ethanol butyl ester, methyl alcohol, ethanol or propyl alcohol, wherein organic solvent is 8 ~ 25mL/g with curcumine volume mass ratio;
(2) purifying: add organic solvent and heating activated carbon backflow 10min ~ 25min in the dialkyl curcumin crude product that step (1) is obtained, filter out gac, naturally cooling, filter to obtain dialkyl curcumin product.
2. the preparation method of dialkyl curcumin according to claim 1, it is characterized in that: the phase-transfer catalyst described in step (1) is the one in Tetrabutyl amonium bromide, triethyl benzyl ammonia chloride or OPE catalyst series, and phase-transfer catalyst consumption is 0.1 ~ 5% of curcumine quality.
3. the preparation method of dialkyl curcumin according to claim 1, it is characterized in that: the alkali described in step (1) is salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, triethylamine, pyridine or N, N-diisopropylethylamine is wherein a kind of, and wherein the mol ratio of alkali and curcumine is 2 ~ 5:1.
4. the preparation method of dialkyl curcumin according to claim 1, is characterized in that: the haloalkane described in step (1) or dialkyl sulfate wherein alkyl are-CH
3,-C
2h
5or-C
3h
7wherein a kind of, wherein haloalkane or dialkyl sulfate and curcumine mol ratio are 2 ~ 5:1.
5. the preparation method of dialkyl curcumin according to claim 1, is characterized in that: the temperature of reaction described in step (1) is 0 ~ 100 DEG C.
6. the preparation method of dialkyl curcumin according to claim 1, it is characterized in that: the organic solvent described in step (2) is the one in methyl alcohol, ethanol or ethyl acetate, wherein organic solvent is 8 ~ 25:1mL/g with dialkyl curcumin crude product volume mass ratio; Described activated carbon dosage is 2 ~ 5% of dialkyl curcumin crude product quality.
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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 |