CN105037100A - Synthetic method of oxyresveratrol - Google Patents
Synthetic method of oxyresveratrol Download PDFInfo
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- CN105037100A CN105037100A CN201510348083.8A CN201510348083A CN105037100A CN 105037100 A CN105037100 A CN 105037100A CN 201510348083 A CN201510348083 A CN 201510348083A CN 105037100 A CN105037100 A CN 105037100A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
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Abstract
The invention relates to a synthetic method of oxyresveratrol. The synthetic method specifically comprises the following steps: carrying out Heck reaction on 4-idodine m-dihydroxybenzene and acrylic acid under the action of a palladium catalyst; then carrying out decarboxylation to generate an intermediate 2, 4-dyhydroxyl styrene without purification; enabling the unpurified 2, 4-dyhydroxyl styrene and 5-idodine m-dihydroxybenzene to directly react under the action of the palladium catalyst to obtain the oxyresveratrol. The synthetic method is simple in raw materials, high in the operability of the reaction condition, few in steps, short in reaction time and high in yield.
Description
Technical field
The present invention relates to a kind of method of synthesizing stilbene compound, a kind of especially method of efficient synthesis Oxyresveratrol.
Background technology
Oxyresveratrol, is oxidized resveratrol again, English name Oxyresveratrol, E-2,3', 4,5'-tetrahydroxystilbene, systematic naming method is: 2,4,3', 5'-tetrahydroxystilbene, CAS:29700-22-9, be the 2'-position hydroxylation growth of poly-hydroxy trans-styryl class resvertrol, color is faint yellow, and shape is amorphous solid, fusing point: 199 ~ 201 DEG C, relative density: 1.468g/cm
3, the easy moisture absorption, in water soluble, methyl alcohol, ethanol, propyl alcohol equal solvent.There are some researches show, Oxyresveratrol has the active and skin pigmentation effect of efficient restraint of tyrosinase, can resist bleb, defend against computer virus, alleviate oxidation, patron saint's warp and reduce apoptotic effect when the situation of generation cerebral ischemia.Because the hypotoxicity of this compound and higher water-soluble, there are the potentiality of excellent drug development, as anti-oxidant, anti-inflammatory, antithrombotic, anti-cancer, anticancer, lipidemia disease, antibacterial etc.Along with deepening continuously of research and development, Oxyresveratrol is expected to obtain widespread use in fields such as healthcare products, medical science and preserving fruit and vegetable utilizings.At occurring in nature, Oxyresveratrol is present in Jack-fruit genus, Morus, orange Morus in Moraceae, and smilax, Veratrum add that in the plants such as the Gnetum of Gnetaceae, content is very low, and its natural origin is very limited in addition.Therefore, preparing Oxyresveratrol by the method for chemosynthesis is the effective way solving its source.But the Oxyresveratrol method of synthesis at present rarely has report.2004, SunYeouKim etc. set out from 3,5-dimethoxy-benzyl bromine, after reacting with triphenylphosphine, there is Wittig with 2,4-dimethoxy benzaldehyde to react, generate the alkene of transconfiguration under the effect of iodine after, under the effect of Grignard reagent, demethylating obtains target product (SangYoonChoi, BiochemicalPharmacology, 67,2004,707).Zou Yong in 2010 etc. are with 3,5-resacetophenone is raw material, through to methylate and Willgerodt-Kindler rearrangement reaction and Perkin reaction build toluylene skeleton, target product (Zhang Hongyi, Zou Yong etc., the synthesis of oxidized resveratrol is obtained again through decarboxylation, demethylation isomerization, organic chemistry, 2010,30,1574).Methyl Grignard such as Zheng Qun happy grade in 2013 carries out demethylating reaction to 2,3,4,5-tetramethoxy toluylene and obtains target product (Zheng Qunyi etc., CN103172499B).The shortcomings such as it is long that but this several method exists synthetic route, and total recovery is lower, and operational danger is large.Therefore, invent a kind of method that is efficient, that simply prepare Oxyresveratrol to have very important significance.。
Summary of the invention
The object of this invention is to provide a kind of novel method of efficient synthesis Oxyresveratrol.The method not only raw material is simple, and step is few, and the reaction times is short, and reacts workable, and productive rate is high, is easy to realize industrialization.Reaction equation is as follows:
To achieve these goals, technical scheme of the present invention is:
The synthetic method of Oxyresveratrol, from 4-iodine Resorcinol (or obtaining under the effect of iodination reagent from Resorcinol), under the effect of palladium catalyst, there is Heck with vinylformic acid to react, and then decarboxylation, the intermediate 2 generated, 4-dihydroxy-benzene ethene do not need purifying directly under the effect of palladium catalyst with 5-iodine resorcin reaction, obtain the crude product of Oxyresveratrol.Just Oxyresveratrol can be obtained through simple column chromatography.
Palladium catalyst used is tetrakis triphenylphosphine palladium.
The consumption first time Heck reaction of palladium catalyst and decarboxylic reaction are 4%, and second time Heck reaction is 3%.
Alkali first time Heck reaction used and decarboxylic reaction are potassium hydroxide, and second time Heck reaction is piperidines.
The consumption first time Heck reaction of additive lithium chloride and decarboxylic reaction are 8%, and second time Heck reaction is 3%.
Preferred temperature of reaction first time Heck reaction and decarboxylic reaction occur at 85 DEG C, and second time Heck reaction is 140 DEG C of generations.
The solvent first time Heck reaction of reaction and decarboxylation are water, and second time Heck reaction is N,N-DIMETHYLACETAMIDE.
After reaction terminates, thick product column chromatography carrys out the mixed solvent that purifying solvent used is ethyl acetate and sherwood oil.
The invention provides a kind of synthetic method of synthesis Oxyresveratrol newly, this invention reactions steps is few, and the reaction times is short, and reacts workable, and productive rate is high, is easy to realize industrialization.
Embodiment
The present invention will be further explained to use embodiment below.
embodiment 1:the synthesis of Oxyresveratrol
In 50mL round-bottomed flask, add 0.014g lithium chloride, 0.200g tetrakis triphenylphosphine palladium, 0.324g potassium hydroxide, 0.880g4-iodine Resorcinol, 0.300g vinylformic acid successively, then add 3mL distilled water, heated and stirred reaction 3h in the oil bath of 85 DEG C.Reaction system is cooled to room temperature.Add 0.005g lithium chloride, 0.145g tetrakis triphenylphosphine palladium, 0.900g5-iodine Resorcinol again, 0.82mL piperidines, 12mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 14h in 140 DEG C of oil baths.After having reacted, system is cooled to room temperature, filters.Filtrate adds dilute hydrochloric acid to be made in acid (pH=5).Pour in separating funnel, be extracted with ethyl acetate (20mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 0.521g, yield is 57.1%.
1HNMR(DMSO-
d 6,400MHz):6.06(t,
J=2.0Hz,1H),6.23(dd,
J=2.4Hz,8.4Hz,1H),6.31(d,
J=2.0Hz,1H,1H),6.33(d,
J=1.6Hz,2H),6.76(d,
J=16.4Hz,1H),7.14(d,
J=16.4Hz,1H),7.34(d,
J=8.8Hz,1H),9.17(s,2H),9.41(s,1H),9.60(s,1H).
13CNMR(DMSO-
d 6,100MHz)101.46,102.76,104.65,107.61,116.44,123.51,125.46,127.40,140.80,156.00,158.19,158.64.ESI-MS:245(MS+H).
embodiment 2:the synthesis of Oxyresveratrol
0.140g lithium chloride, 2.000g tetrakis triphenylphosphine palladium, 3.240g potassium hydroxide, 8.800g4-iodine Resorcinol, 3.000g vinylformic acid is added successively in 500mL round-bottomed flask, add 30mL distilled water again, heated and stirred reaction 3.5h in the oil bath pan of 85 DEG C.Reaction system is cooled to room temperature.Add 0.050g lithium chloride, 1.450g tetrakis triphenylphosphine palladium, 9.000g5-iodine Resorcinol again, 8.20mL piperidines, 120mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 15h in 140 DEG C of oil bath pans.After having reacted, system is cooled to room temperature, filters.Filtrate adds dilute hydrochloric acid to be made in acid (pH=5).Pour in separating funnel, be extracted with ethyl acetate (200mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 5.399g, yield is 59.2%.
embodiment 3: the synthesis of Oxyresveratrol
Under nitrogen protection; 0.014g lithium chloride, 0.200g tetrakis triphenylphosphine palladium, 0.324g potassium hydroxide, 0.880g4-iodine Resorcinol, 0.300g vinylformic acid is added successively in 50mL round-bottomed flask; add 3mL distilled water again, heated and stirred reaction 3h in the oil bath of 85 DEG C.Reaction system is cooled to room temperature.Add 0.005g lithium chloride, 0.145g tetrakis triphenylphosphine palladium, 0.900g5-iodine Resorcinol again, 0.82mL piperidines, 12mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 14h in 140 DEG C of oil baths.After having reacted, system is cooled to room temperature, filters.Adding dilute hydrochloric acid makes filtrate be acid (pH=5).Pour in separating funnel, ethyl acetate carries out extracting (25mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 0.552g, yield is 60.5%.
embodiment 4:the synthesis of Oxyresveratrol
Under nitrogen protection; 0.014g lithium chloride, 0.100g tetrakis triphenylphosphine palladium, 0.324g potassium hydroxide, 0.880g4-iodine Resorcinol, 0.300g vinylformic acid is added successively in 50mL round-bottomed flask; add 3mL distilled water again, heated and stirred reaction 3h in the oil bath pan of 85 DEG C.Reaction system is cooled to room temperature.Add 0.005g lithium chloride, 0.073g tetrakis triphenylphosphine palladium, 0.900g5-iodine Resorcinol again, 0.82mL piperidines, 12mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 14h in 140 DEG C of oil bath pans.After having reacted, system is cooled to room temperature, filters.Adding dilute hydrochloric acid makes filtrate be acid (pH=5).Pour in separating funnel, ethyl acetate carries out extracting (25mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 0.513g, yield is 56.3%.
embodiment 5: the synthesis of Oxyresveratrol
In 50mL round-bottomed flask, add 0.014g lithium chloride, 0.200g tetrakis triphenylphosphine palladium, 0.324g potassium hydroxide, 0.880g4-iodine Resorcinol, 0.300g vinylformic acid successively, then add 3mL distilled water, heated and stirred reaction 3h in the oil bath of 85 DEG C.Reaction system is cooled to room temperature.Add 0.005g lithium chloride, 0.145g tetrakis triphenylphosphine palladium, 0.900g5-iodine Resorcinol again, 0.82mL piperidines, 12mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 8h in 140 DEG C of oil baths.After having reacted, system is cooled to room temperature, filters.Adding dilute hydrochloric acid makes filtrate be acid (pH=5).Pour in separating funnel, ethyl acetate carries out extracting (25mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 0.440g, yield is 48.3%.
embodiment 6: the synthesis of Oxyresveratrol
In 50mL round-bottomed flask, add 0.014g lithium chloride, 0.200g tetrakis triphenylphosphine palladium, 0.324g potassium hydroxide, 0.880g4-iodine Resorcinol, 0.300g vinylformic acid successively, then add 3mL distilled water, heated and stirred reaction 3h in the oil bath of 85 DEG C.Reaction system is cooled to room temperature.Add 0.005g lithium chloride, 0.145g tetrakis triphenylphosphine palladium, 0.900g5-iodine Resorcinol again, 0.82mL piperidines, 12mL
n,N-N,N-DIMETHYLACETAMIDE, reacting by heating 14h in 100 DEG C of oil baths.After having reacted, system is cooled to room temperature, filters.Adding dilute hydrochloric acid makes filtrate be acid (pH=5).Pour in separating funnel, ethyl acetate carries out extracting (25mL*3).Merge organic phase, organic over anhydrous dried over sodium sulfate, filter, revolve and desolventize.Thick product is after column chromatography is purified, and obtain light yellow solid 0.386g, yield is 42.3%.
Above-mentioned 6 embodiments are summarized as follows table:
| Reaction atmosphere | Catalyst levels | Molar weight | Temperature of reaction | Reaction times | Productive rate | |
| Embodiment 1 | In air | 7.0% | 3.74 mmol | 140 ℃ | 14 h | 57.1% |
| Embodiment 2 | In air | 7.0% | 37.4 mmol | 140 ℃ | 14 h | 59.2% |
| Embodiment 3 | In nitrogen | 7.0% | 3.74 mmol | 140 ℃ | 14 h | 60.5% |
| Embodiment 4 | In nitrogen | 3.5% | 3.74 mmol | 140 ℃ | 14 h | 56.3% |
| Embodiment 5 | In air | 7.0% | 37.4 mmol | 140 ℃ | 8 h | 48.3% |
| Embodiment 6 | In air | 7.0% | 37.4 mmol | 100 ℃ | 14 h | 42.3% |
Above-described embodiment, just preferred embodiment of the present invention, be not used for limiting practical range of the present invention, and the modification done with the feature described in the claims in the present invention and principle Gu all or change, all should within application claims scope.
Claims (8)
1. one kind is efficiently synthesized the method for Oxyresveratrol, it is characterized in that, Heck is there is and reacts and decarboxylic reaction in 4-iodine Resorcinol and vinylformic acid under the existence of palladium catalyst, alkali and additive, and then with 5-iodine Resorcinol, Heck occurs under the existence of palladium catalyst, alkali and additive and react, obtain Oxyresveratrol efficiently.
2. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that palladium catalyst used can be Palladous chloride, palladium, trifluoromethanesulfonic acid palladium and tetrakis triphenylphosphine palladium, wherein best with tetrakis triphenylphosphine palladium effect.
3. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that alkali used can be triethylamine, salt of wormwood, potassium hydroxide, sodium formiate, piperidines etc., wherein best with piperidines effect.
4. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that additive used can be lithium chloride, silver carbonate, cesium carbonate etc., wherein best with lithium chloride effect.
5. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that solvent used in this reaction can be
n,N-dimethyl formamide,
n,N-N,N-DIMETHYLACETAMIDE, water, toluene, PEG200,
n-methyl-2-pyrrolidone etc., wherein with
n, N-when N,N-DIMETHYLACETAMIDE is solvent, effect is best.
6. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that this reaction can be carried out in atmosphere, also can carry out under nitrogen protection, wherein better effects if under nitrogen protection.
7. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that second step Heck temperature of reaction can be carried out at 100-140 DEG C, wherein best with effect at 140 DEG C.
8. the synthetic method of the Oxyresveratrol according to claims 1, is characterized in that the second step Heck reaction times can be 10-14h, wherein best to react 14h effect.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001060774A1 (en) * | 2000-02-16 | 2001-08-23 | Brigham Young University | Synthesis of resveratrol |
| US7253324B1 (en) * | 2007-01-23 | 2007-08-07 | Sami Labs Limited | Process for the synthesis of biologically active oxygenated compounds by dealkylation of the corresponding alkylethers |
| WO2010113005A2 (en) * | 2009-03-27 | 2010-10-07 | Council Of Scientific & Industrial Research | One pot multicomponent synthesis of some novel hydroxy stilbene derivatives with alpha, beta-carbonyl conjugation under microwave irradiation |
| CN102050705A (en) * | 2010-11-02 | 2011-05-11 | 北京赛科药业有限责任公司 | Novel method for preparing resveratrol and derivative thereof through decarbonylation heck reaction |
| CN103917511A (en) * | 2011-12-01 | 2014-07-09 | 劳拉斯实验室私人有限公司 | Process for the preparation of polyhydroxystilbene compounds by deprotection of the corresponding ethers |
-
2015
- 2015-06-23 CN CN201510348083.8A patent/CN105037100A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001060774A1 (en) * | 2000-02-16 | 2001-08-23 | Brigham Young University | Synthesis of resveratrol |
| US7253324B1 (en) * | 2007-01-23 | 2007-08-07 | Sami Labs Limited | Process for the synthesis of biologically active oxygenated compounds by dealkylation of the corresponding alkylethers |
| WO2010113005A2 (en) * | 2009-03-27 | 2010-10-07 | Council Of Scientific & Industrial Research | One pot multicomponent synthesis of some novel hydroxy stilbene derivatives with alpha, beta-carbonyl conjugation under microwave irradiation |
| CN102050705A (en) * | 2010-11-02 | 2011-05-11 | 北京赛科药业有限责任公司 | Novel method for preparing resveratrol and derivative thereof through decarbonylation heck reaction |
| CN103917511A (en) * | 2011-12-01 | 2014-07-09 | 劳拉斯实验室私人有限公司 | Process for the preparation of polyhydroxystilbene compounds by deprotection of the corresponding ethers |
Non-Patent Citations (1)
| Title |
|---|
| AMIT SHARD等: "Tandem Heck/Decarboxylation/Heck Strategy: Protecting-Group-Free Synthesis of Symmetric and Unsymmetric Hydroxylated Stilbenoids", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 * |
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