CN101693642A - Method for synthesizing 1,2-diphenylethylene compounds - Google Patents
Method for synthesizing 1,2-diphenylethylene compounds Download PDFInfo
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- CN101693642A CN101693642A CN200910117520A CN200910117520A CN101693642A CN 101693642 A CN101693642 A CN 101693642A CN 200910117520 A CN200910117520 A CN 200910117520A CN 200910117520 A CN200910117520 A CN 200910117520A CN 101693642 A CN101693642 A CN 101693642A
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Abstract
The invention provides a new method for synthesizing 1,2-diphenylethylene compounds, which comprises the following steps: additively reacting aromatic aldehyde with a bisbenzyl zinc reagent in the molar ratio of 1:1-2.5:1 at the temperature of minus 80 DEG C to plus 80 DEG C for 2-16 hours in a non-protonic organic solvent under nitrogen protection by using Lewis acid as a catalyst, adding acid for quenching, and obtaining a target compound through separation. The invention adopts the bisbenzyl zinc reagent with higher reactive activity for replacing a benzyl zinc halide regent with lower reactive activity, thereby effectively increasing the reaction velocity and improving the reaction efficiency; the invention adopts the Lewis acid as the catalyst instead of a valuable transition metal complex catalyst, thereby lowering the synthetic cost and improving the yield of products.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to a kind of novel method of synthetic stilbene compounds.
Background technology
The stilbene compounds is the material that a class has important physiologically active, and they are very extensive in the distribution of occurring in nature.Its structure is as follows:
R
1Be hydrogen, alkyl, halogen, aromatic base, alkoxyl group, one or more in the nitro;
R
2Be hydrogen, alkyl, halogen, aromatic base, alkoxyl group, one or more in the nitro;
R
1Aromatic base be the ortho position, the group that a position or contraposition are replaced by halogen, alkoxyl group or alkyl;
R
2Aromatic base be the ortho position, the group that a position or contraposition are replaced by halogen, alkoxyl group or alkyl.
Wherein the most representative compound is a resveratrol compounds, this compound with toluylene parent nucleus found to have preventing heart disease afterwards, suppress platelet aggregation, regulation and control lipid and lipoprotein metabolism, anti-oxidant and to effect (Asia-Pacific traditional medicines such as tumor treatment, 2009,5,113).In addition, Combretastatin A-4 compounds has been proved to be has the effect that suppresses tumor-blood-vessel growth, is to have the antitumor drug that exploitation is worth most, has entered three phases clinical experiment (research and development of natural products, 2000,13,76) now.Given this compounds potential prospect in medicine and toluylene monomer structure are fairly simple, be easy to synthesize and carry out structure of modification, make this compounds become a class and have further investigation and the further lead compound that is worth of exploitation, so seek and find that the new diphenyl ethylene derivatives with higher physiologically active is one of drug research and hot of research and development in recent years.
Effect by Wittig reagent and aromatic aldehyde can be synthesized the stilbene compounds easily.But to be the productive rate of reaction lower and stereoselectivity reaction is not high for the deficiency of this method maximum, often can access the mixture of cis and trans stilbene, thereby bring very big difficulty for the purification of product separates.And the Heck linked reaction between the vinylbenzene of halobenzene that replaces and replacement is the synthetic method of another common stilbene.Although this synthetic method selectivity is higher, but, substituted phenylethylene need to use the noble metal complex compound catalyst to make raw materials cost too high in relative difficult and the reaction process owing to preparing, reaction conditions is relatively harsher, and overall yield is not high, is difficult to realize large-scale industrial production.Perkin condensation reaction between the toluylic acid that replaces and the aromatic aldehyde of replacement is the best method of synthesizing cis stilbene.But the problem that still exists the product carboxyl to be difficult for sloughing.2002, our reported first a kind of universal method (Angew.Chem.Int.Ed., 2002,41,2757) of utilizing addition reaction between benzyl halogenation zincon and the aromatic aldehyde to prepare the stilbene compounds.But after research in we exist speed of response slow when finding the stilbene compounds of this method at synthesis of polyhydroxy, productive rate is low, deficiencies such as severe reaction conditions.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of synthesis condition gentleness, the synthetic stilbene compounds that cost is low, speed of response is fast, productive rate is high.
The synthetic method of diphenylethylene compounds of the present invention; what adopt is in non-proton organic solvent; under nitrogen protection; under the katalysis of Lewis acid; with aromatic aldehyde and the mol ratio of two benzyl zincons with 1: 1～2.5: 1; addition reaction 2～16 (preferred 12～14) hour under the temperature of-80 ℃～80 ℃ (preferred-18 ℃～25 ℃) adds sour cancellation, separates promptly obtaining target compound.
Its reaction formula is as follows:
Described aromatic aldehyde is the phenyl aldehyde that ortho position, a position or contraposition are replaced by halogen, hydroxyl, nitro, alkoxyl group or alkyl.
Described pair of benzyl zincon is the halogenation benzyl that ortho position, a position or contraposition are replaced by halogen, hydroxyl, alkoxyl group or alkyl.Two benzyl zincons can directly be bought from market and obtain, and also can directly make through metal exchange reaction by benzyl magnesium halide and zinc halide reagent.
Described non-protonic solvent is ether, tetrahydrofuran (THF), n-butyl ether, methylene dichloride, toluene, 1,4-dioxane or glycol dimethyl ether.
Described Lewis acid is boron trifluoride diethyl etherate, trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE or tert-butyl diphenyl chlorosilane.
Described separating technology is: add sour cancellation after the addition reaction, standing demix is told organic phase, uses anhydrous magnesium sulfate drying, filters, boil off solvent after, use column chromatography target product.Wherein the used acid of cancellation reaction can hydrochloric acid, acid reagents commonly used such as sulfuric acid, nitric acid, phosphoric acid, acetate, trifluoroacetic acid.
The present invention compared with prior art has the following advantages:
1, the present invention adopts the higher two benzyl zincons of reactive behavior to replace the lower benzyl halogenation zincon of reactive behavior, has effectively accelerated speed of response, has improved reaction efficiency;
2, the present invention no longer adopts valuable transition metal complex catalyst with the Lewis acid as catalyst, has reduced synthetic cost, has improved the productive rate of product;
3, synthesis condition of the present invention is gentle more, generally at room temperature just can realize the synthetic of target compound, and technology is simpler, has made things convenient for operation.
Embodiment
Below by some typical embodiment the synthetic method of diphenylethylene compounds of the present invention is described further.
Embodiment 1: toluylene synthetic
(1) preparation of two benzyl zincons: under the atmosphere of nitrogen, (0.47g 19.2mmol) and in the round-bottomed flask of the 100ml of an iodine drips glycol dibromide (0.1ml) and tetrahydrofuran (THF) (10ml) in that magnesium is housed, be heated to 30 ℃～40 ℃, stirred 10 minutes.Then in cryosel is bathed, (2.20g 17.4mol) and the mixture of tetrahydrofuran (THF) (20ml), continues stirring and promptly gets benzyl halogenation azoviolet after two hours to add Benzyl Chloride.Under the atmosphere of nitrogen, benzyl halogenation azoviolet is added drop-wise to zinc chloride is housed (0.95g in round-bottomed flask 6.96mmol), stirs and makes two benzyl zincons after one hour.
(2) toluylene is synthetic: under the atmosphere of nitrogen, (0.1mmol, (2mmol, 0.2g) and tetrahydrofuran (THF) (2ml), reflux is after two minutes to add triethylamine in round-bottomed flask 0.03g) in that acetylacetonate nickel is housed.Cool to room temperature, add trimethylchlorosilane (0.76g, 6.96mmol), (0.37g 3.48mmol) and the mixture of tetrahydrofuran (THF) (10ml), stirs after 10 minutes two benzyl zincons that adding step (1) prepares to phenyl aldehyde.Behind the room temperature reaction 12 hours, the hydrochloric acid cancellation that adds 2mol/L (10ml), standing demix is told organic phase and water, the water ethyl acetate extraction of 20ml, merge organic phase, use anhydrous magnesium sulfate drying, filter, boil off solvent, use column chromatography product: toluylene 0.46g, productive rate are 73.5%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR (400MHz, CDCl
3): δ (ppm): 7.15 (s, 2H), 7.25-7.43 (m, 6H), 7.55 (d, J=8Hz, 4H).
Synthesizing of embodiment 2:4-methoxyl group toluylene
(1) preparation of two benzyl zincons: same with embodiment 1.
(2) 4-methoxyl group toluylene is synthetic: under the atmosphere of nitrogen, be equipped with acetylacetonate nickel (0.1mmol, add in round-bottomed flask 0.03g) triethylamine (2mmol, 0.2g) and the mixture of tetrahydrofuran (THF) (2ml), reflux two minutes.Cool to room temperature, add trimethylchlorosilane (0.76g, 6.96mmol), (0.64g 3.48mmol) and the mixture of tetrahydrofuran (THF) (10ml), stirs after 10 minutes two benzyl zincons that adding step (1) prepares to the 4-methoxybenzaldehyde.Behind the room temperature reaction 12 hours, the hydrochloric acid cancellation that adds 2mol/L (10ml), standing demix is told organic phase and water, the water ethyl acetate extraction of 20ml, merge organic phase, use anhydrous magnesium sulfate drying, filter, boil off solvent, use column chromatography product: tetramethoxy toluylene 0.55g, productive rate are 74.8%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 3H), 6.90 (d, J=8.6Hz, 2H), 7.02 (d, J=7.4Hz, 2H), 7.26-7.48 (m, 7H).
Embodiment 3,3,4,5-trimethoxy toluylene synthetic
(1) preparation of two benzyl zincons: same with embodiment 1.
(2) 3,4,5-trimethoxy toluylene synthetic: under the atmosphere of nitrogen, be equipped with acetylacetonate nickel (0.1mmol, add in round-bottomed flask 0.03g) triethylamine (2mmol, 0.2g) and the mixture of tetrahydrofuran (THF) (2ml), reflux two minutes.Cool to room temperature, (0.76g, 6.96mmol), 3,4, (0.85g 3.48mmol) and the mixture of tetrahydrofuran (THF) (10ml), stirs after 10 minutes two benzyl zincons that adding step (1) prepares to the 5-TMB to add trimethylchlorosilane.Behind the room temperature reaction 12 hours, add the hydrochloric acid cancellation of 2mol/L (10ml), standing demix, tell organic phase and water, water merges organic phase with the ethyl acetate extraction of 20ml, uses anhydrous magnesium sulfate drying, filter, boil off solvent, use column chromatography product: 3,4,5-trimethoxy toluylene 0.71g, productive rate is 75.6%.Its reaction formula is as follows:
Spectroscopic data:
1HNMR (400MHz, CDCl
3) δ (ppm): 3.86,3.91 (s, J=9.4Hz, 9H), 6.90 (d, J=8.6Hz, 2H), 7.22 (d, J=7.4Hz, 2H), 7.27 (d, J=3.6Hz, 1H), 7.36 (d, J=7.4Hz, 2H), 7.50 (d, J=3.6Hz, 2H).
Embodiment 4,3,4-di-methoxy-diphenylene synthetic
(1) preparation of two benzyl zincons
Same with embodiment 1.
Synthesizing of (2) 3,4-di-methoxy-diphenylenes
Under the atmosphere of nitrogen, be equipped with acetylacetonate nickel (0.1mmol, add in round-bottomed flask 0.03g) triethylamine (2mmol, 0.2g) and the mixture of tetrahydrofuran (THF) (2ml), reflux two minutes.Cool to room temperature, (0.76g, 6.96mmol), 3, (0.74g 3.48mmol) and the mixture of tetrahydrofuran (THF) (10ml), stirs after 10 minutes two benzyl zincons that adding step (1) prepares to the 4-dimethoxy benzaldehyde to add trimethylchlorosilane.Behind the room temperature reaction 8 hours, add the hydrochloric acid cancellation of 2mol/L (10ml), standing demix is told organic phase and water, the water ethyl acetate extraction of 20ml, merge organic phase, use anhydrous magnesium sulfate drying, filter, boil off solvent, use column chromatography product: 3,4-di-methoxy-diphenylene .55g, productive rate are 65.3%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR (400MHz, CDCl
3) δ (ppm): 3.95,3.90 (s, J=9.4Hz, 6H), 6.88 (t, J=8.6Hz, 1H), 7.03 (q, J=8.8Hz, 4H), 7.25 (t, J=3.6Hz, 1H), 7.35 (tt, J=7.2,1.6Hz, 2H), 7.50 (dt, J=9.6,1.6Hz, 2H).
Synthesizing of embodiment 5,3-methoxyl group-4-hydroxy stibene
(1) preparation of two benzyl zincons
Same with embodiment 1.
(2) 3-methoxyl group-4-hydroxyl-toluylene is synthetic
Under the atmosphere of nitrogen, be equipped with acetylacetonate nickel (0.1mmol, add in round-bottomed flask 0.03g) triethylamine (2mmol, 0.2g) and the mixture of tetrahydrofuran (THF) (2ml), reflux two minutes.Cool to room temperature, add trimethylchlorosilane (0.76g, 6.96mmol), (0.70g 3.48mmol) and the mixture of tetrahydrofuran (THF) (10ml), stirs after 10 minutes two benzyl zincons that adding step (1) prepares to 3-methoxyl group-4-hydroxy benzaldehyde.Behind the room temperature reaction 8 hours, the hydrochloric acid cancellation that adds 2mol/L (10ml), standing demix is told organic phase and water, the water ethyl acetate extraction of 20ml, merge organic phase, use anhydrous magnesium sulfate drying, filter, boil off solvent, use column chromatography product: 3-methoxyl group-4-hydroxy stibene 0.33g, productive rate is 42.3%.Its reaction formula is as follows:
Spectroscopic data:
1HNMR (400MHz, CDCl
3) δ (ppm): 3.94 (s, 3H), 5.67 (brs, 1H), 6.88-7.09 (m, 5H), 7.24 (tt, J=7.2,1.4Hz, 1H), 7.32 (tt, J=8.0,2.2Hz, 2H), 7.50 (dt, J=7.0,1.6Hz, 2H).
Claims (8)
1. synthesize 1; the method of 2-diphenylethylene compounds; what adopt is in non-proton organic solvent; under nitrogen protection; with Lewis acid is catalyzer, and with aromatic aldehyde and the mol ratio of two benzyl zincons with 1: 1～2.5: 1, addition reaction is 2～16 hours under-80 ℃～80 ℃ temperature; add sour cancellation, separate promptly obtaining target compound.
2. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described aromatic aldehyde is the phenyl aldehyde that ortho position, a position or contraposition are replaced by halogen, hydroxyl, nitro, alkoxyl group or alkyl.
3. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described pair of benzyl zincon is the halogenation benzyl that ortho position, a position or contraposition are replaced by halogen, hydroxyl, alkoxyl group or alkyl.
4. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described non-protonic solvent is ether, tetrahydrofuran (THF), n-butyl ether, methylene dichloride, toluene, 1,4-dioxane or glycol dimethyl ether.
5. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described catalyzer Lewis acid is boron trifluoride diethyl etherate, trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE or tert-butyl diphenyl chlorosilane.
6. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: the temperature of described addition reaction is-80 ℃～80 ℃, and the reaction times is 2～16 hours.
7. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described pair of benzyl zincon is directly to make through metal exchange reaction by benzyl magnesium halide and zinc halide reagent.
8. synthesize the method for stilbene compounds according to claim 1, it is characterized in that: described separating technology is to add sour cancellation after the addition reaction, standing demix is told organic phase, uses anhydrous magnesium sulfate drying, filter, boil off solvent after, use column chromatography target product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130592A (en) * | 2013-01-25 | 2013-06-05 | 重庆大学 | Synthetic method for diaryl methane derivatives |
| CN108586211A (en) * | 2018-06-08 | 2018-09-28 | 郑州德瑞医药科技有限公司 | A kind of synthetic method of 1,1- diarylethenes analog derivative |
| CN109970517A (en) * | 2019-04-28 | 2019-07-05 | 杭州瑞树生化有限公司 | A kind of preparation method of resveratrol compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195575B (en) * | 2006-12-08 | 2011-01-26 | 西北师范大学 | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene |
| CN101519342A (en) * | 2009-03-17 | 2009-09-02 | 西北师范大学 | Novel method for synthesizing Resveratrol by means of organic zinc halide reagent |
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- 2009-10-17 CN CN 200910117520 patent/CN101693642B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130592A (en) * | 2013-01-25 | 2013-06-05 | 重庆大学 | Synthetic method for diaryl methane derivatives |
| CN108586211A (en) * | 2018-06-08 | 2018-09-28 | 郑州德瑞医药科技有限公司 | A kind of synthetic method of 1,1- diarylethenes analog derivative |
| CN108586211B (en) * | 2018-06-08 | 2021-03-19 | 郑州德瑞医药科技有限公司 | Synthesis method of 1, 1-diarylethene derivatives |
| CN109970517A (en) * | 2019-04-28 | 2019-07-05 | 杭州瑞树生化有限公司 | A kind of preparation method of resveratrol compounds |
| CN109970517B (en) * | 2019-04-28 | 2021-09-17 | 杭州师范大学 | Preparation method of resveratrol compound |
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