CN103214354A - Preparation method of trans-stilbene compound and water-soluble derivative of compound - Google Patents
Preparation method of trans-stilbene compound and water-soluble derivative of compound Download PDFInfo
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Abstract
The invention relates to a preparation method of a trans-stilbene compound and a water-soluble derivative of the compound. The preparation method comprises the following step of: utilizing an on-water Wittig reaction by using substitutional benzyl triphenyl phosphonium bromide as reaction phosphonium salt and using sodium (potassium) hydroxide as alkali to react with aromatic aldehyde of various phenol-containing hydroxyls to synthesize the trans-stilbene compound. According to the preparation method of the trans-stilbene compound and the water-soluble derivative of the compound, water is used as reaction medium for substituting the strict anhydrous operation of the classical Wittig reaction and severe conditions of organic alkali action, so that the reaction is green and simple, and the separation-purification is easy. Besides, the preparation method is suitable for synthesizing various trans-stilbene compounds with physiological activities.
Description
Technical field
The present invention relates to a kind of preparation method with compound and soluble derivative thereof of toluylene skeleton.The preparation method of particularly a kind of trans diphenylethylene compounds and soluble derivative thereof.
Technical background
Trans toluylene (trans-Stilbene) compounds, as resveratrol, the white skin China fir of Piceatannol(alcohol), Combretastatin A etc. have multiple important biological functions such as anti-senile dementia, anticancer, antibiotic, anti-oxidant, blood fat reducing.Because the continual renovation of new drug target, the pharmaceutical chemistry of this compounds makes much progress, and has formed the frontier of trans diphenylethylene compounds, is the very promising compound of a class.Since the drug effect of trans diphenylethylene compounds uniqueness, the research and development focus that oneself is very powerful and exceedingly arrogant in becoming pharmacy field.
The natural origin of trans diphenylethylene compounds is very limited, make it is carried out bioactivity research and application and development is subjected to certain limitation, therefore synthetic route and the method research to trans toluylene seems very important, becomes the focus that people pay close attention to.Studies confirm that this compounds of chemosynthesis and the product of natural extract have same biological activity.There is the raw materials cost height in the method for present most of synthesis of trans diphenylethylene compounds, severe reaction conditions, and shortcomings such as trivial operations can only be as laboratory scale preparation method.Therefore, the synthetic method of trans toluylene is furtherd investigate, sought a kind of reaction conditions gentleness, raw materials cost is low, and the simple relatively synthetic method of operation has crucial meaning.
The development of " (on water) waterborne " organic reaction is a breakthrough in the green building-up reactions research field of water.The heterogeneous nature of system is the essential characteristic of " waterborne " reaction.Water is not only important green reaction medium, and can both observe water in great majority " waterborne " organic reaction has tangible castering action to the speed and the selectivity of reacting.Adopt the condition of " waterborne " reaction, the scale of reaction is enlarged, help separation, the purifying of product.
Summary of the invention
One of the present invention ground purpose is to provide the preparation method of a kind of trans diphenylethylene compounds and soluble derivative thereof.
" (on water) waterborne " organic reaction is developed into the Wittig reaction, find to utilize ' ' (On Water) waterborne ' ' the Wittig reaction, trans toluylene product almost completely optionally generated.This method is with the benzyl three phenyl phosphonium bromides that the replace phosphonium salt as the Wittig reaction, with sodium hydroxide (potassium) as alkali, under the water strong mixing and the aromatic aldehyde reaction, the synthesis of trans diphenylethylene compounds.Or, can obtain corresponding water-soluble diphenylethylene compounds with the aromatic aldehyde that sodium phosphate salt is modified.This method is a reaction medium with water, has replaced the strict waterless operation of classical Wittig reaction and the severe condition of organic alkali effect, reacts green, easy, separation and purification is easy.Be fit to synthetic various trans diphenylethylene compounds, as Combretastatin category-A compound and sodium phosphate salt prodrug thereof, trans-resveratrol, the white skin China fir of Piceatannol(alcohol with physiologically active) etc.
For achieving the above object, reaction mechanism of the present invention is:
Wherein, R wherein
1, R
2, R
3, R
1', R
2' be: hydrogen, alkyl, alkoxyl group ,-XH (X=O, N, S), nitro, halogen.
According to above-mentioned mechanism, the present invention adopts following technical scheme:
A kind of preparation method of trans diphenylethylene compounds, it is characterized in that this method is with the benzyl three phenyl phosphonium bromides that the replace phosphonium salt as reaction, adopt sodium hydroxide (potassium) as alkali, utilize ' ' (On Water) waterborne ' ' the Wittig reaction, at water, with the aromatic aldehyde reaction synthesis of trans diphenylethylene compounds of various phenolic hydroxy groups, the structural formula of the benzyl three phenyl phosphonium bromides of wherein said replacement is:
; The structural formula of the aromatic aldehyde of described phenolic hydroxy group is:
; R wherein
1, R
2, R
3, R
1', R
2' be: hydrogen, alkyl, alkoxyl group ,-XH (X=O, N, S), nitro, halogen.
Above-mentioned R
1, R
2, R
3, R
1', R
2' be hydrogen, hydroxyl or methoxyl group.
The concrete grammar of last method is: a. is in the sodium hydroxide or potassium hydroxide aqueous solution of 5 mmol/L ~ 10 mmol/L, by the benzyl three phenyl phosphonium bromides of 1: 1 ~ 1: 0.6 mol ratio input replacement and the aromatic aldehyde of phenolic hydroxy group; Under 500 ~ 2000 rev/mins stirring velocitys and 60 ~ 80 ° of C temperature, reaction is to reacting completely; Conditioned reaction system pH to 7 uses ethyl acetate extraction, washing, and drying, suction filtration revolves to steam to remove and desolvates; Resistates promptly obtains trans diphenylethylene compounds through separation and purification.
A kind of preparation method who prepares above-mentioned trans diphenylethylene compounds soluble derivative, the concrete steps that it is characterized in that this method are: the hydroxyl phosphoric acid reagent in the aromatic aldehyde of above-mentioned phenolic hydroxy group is changed into sodium phosphate salt, promptly obtain the soluble derivative of trans diphenylethylene compounds.
Above-mentioned phosphorylation agent is preferably: dibenzyl phosphite or tetra-sodium four benzyl esters.
The inventive method is a reaction medium with water, has replaced the strict waterless operation of classical Wittig reaction and the severe condition of organic alkali effect, reacts green, easy, separation and purification is easy.Be fit to synthetic various trans diphenylethylene compounds with physiologically active.
Embodiment
Following examples only are used to illustrate the present invention, are not qualification of the present invention.
Embodiment one: synthesis of trans Combretastatin A-4;
In 250 milliliters of three-necked flasks of high speed shear mulser are housed, add (3,4,5-trimethoxy benzyl) three phenyl phosphonium bromides, 21 gram (40.1mmol) and 3-hydroxyls-4-methoxybenzaldehyde (isovanillin) 6 gram (39.4 mmol) and 80 milliliters of 5mol/L aqueous sodium hydroxide solutions.Start the high speed shear mulser, rotating speed is controlled at about 600 rev/mins,, system is yellow suspension liquid.Heat in 80 ° of C oil baths, follow the tracks of reaction with TLC, after about 8 hours, stop heating, reaction solution is brown suspension liquid.After the cooling,, use ethyl acetate extraction with 8 % hydrochloric acid conditioned reaction system pH to 7, washing, drying, suction filtration revolves to steam to remove and desolvates.Resistates uses column chromatography, and gradient elution, eluent are ethyl acetate: 1: 4 ~ 1:2 of sherwood oil, obtaining white solid is trans Combretastatin A-4 6.5 grams, productive rate: 52.2 %.
1 H-NMR (500 MHz, d
6-DMSO): d ( ppm) 3.88 (3H, s), 3.94 (9H, s), 5.63 (1H, s), 6.73 (2H, s), 6.86 (1H, d, J=8.3), 6.89 (1H, d, J=16.2), 6.95 (1H, d, J=16.2), 6.99 (1H, dd, J=8.3, 1.9), 7.16 (1H, d, J= 1.9)。
Embodiment two: synthesizing resveratrol;
In 250 milliliters of three-necked flasks of high speed shear mulser are housed, add (3, the 5-dimethoxy-benzyl) three phenyl phosphonium bromides, 19.7 grams (39.9mmol) and 4-methoxybenzaldehyde (aubepine) 5.3 gram (38.9 mmol) and 80 milliliter of 5 mol/L aqueous sodium hydroxide solution.Start the high speed shear mulser, rotating speed is controlled at about 600 rev/mins,, system is yellow suspension liquid.Heat in 80 ° of C oil baths, follow the tracks of reaction with TLC, after about 8 hours, stop heating, reaction solution is brown suspension liquid.After the cooling,, use ethyl acetate extraction with 8 % hydrochloric acid conditioned reaction system pH to 7, washing, drying, suction filtration revolves to steam to remove and desolvates.Resistates uses column chromatography, and gradient elution, eluent are ethyl acetate: 1: 4 ~ 1:2 of sherwood oil, it is promptly trans-3,5 to obtain pale solid, 4 '-trimethoxy toluylene, 5.9 grams, productive rate: 56.2 %.
In 500 milliliters of three-necked flasks, add above-mentioned trans-3,5,4 '-trimethoxy toluylene 5.9 gram (21.8 mmol) and 300 milliliters of dry methylene chloride under 15 ° of C, splash into 75 milliliters of (boron tribromides of 3 mol/L), after being added dropwise to complete, TLC follows the tracks of reaction, the reaction finish after with frozen water, use dichloromethane extraction, washing, drying is revolved to steam to remove and is desolvated, getting the off-white color crystal with recrystallization from ethyl acetate/petroleum ether is trans-resveratrol 4.3 grams, productive rate: 86.5%.
1 H-NMR (500 MHz,CDCl
3): δ (ppm) 6.12 (t, J=2.1, 1H), 6.42 (d, J=2.1, 2H), 6.75 (d, J=16.2, 1H), 6.76 (d, J=7.8, 2H ), 6.98 (d, J=16.2, 1H), 7.28 (d, J=7.8, 2H)。
Embodiment three: synthetic white skin shirt alcohol;
In 250 milliliters of three-necked flasks of high speed shear mulser are housed, add (3, the 5-dimethoxy-benzyl) three phenyl phosphonium bromides 21.5 gram (43.5mmol) and 4-methoxyl groups-3-hydroxy benzaldehyde (isovanillin) 5.5 gram (40.5 mmol) and 80 milliliters of 5mol/L aqueous sodium hydroxide solutions.Start the high speed shear mulser, rotating speed is controlled at about 600 rev/mins,, system is yellow suspension liquid.Heat in 80 ° of C oil baths, follow the tracks of reaction with TLC, after about 8 hours, stop heating, reaction solution is brown suspension liquid.After the cooling,, use ethyl acetate extraction with 8 % hydrochloric acid conditioned reaction system pH to 7, washing, drying, suction filtration revolves to steam to remove and desolvates.Resistates uses column chromatography, and gradient elution, eluent are ethyl acetate: 1: 4 ~ 1:2 of sherwood oil, it is promptly trans-3,5 to obtain pale solid, 4 '-trimethoxy-3 '-hydroxy stibene 6.1 grams, productive rate: 52.7 %.
In 500 milliliters of three-necked flasks, add above-mentioned trans-3,5,4 '-trimethoxy-3 '-hydroxy stibene, 6.1 grams (21.3mmol) and 300 milliliters of dry methylene chloride under 15 ° of C, splash into 75 milliliters of (boron tribromides of 3 mol/L), after being added dropwise to complete, TLC follows the tracks of reaction, the reaction finish after with frozen water, use dichloromethane extraction, washing, drying is revolved to steam to remove and is desolvated, getting the off-white color crystal with recrystallization from ethyl acetate/petroleum ether is white skin China fir alcohol 4.9 grams, productive rate: 94.3%.
1 H-NMR (500 MHz, DMSO-d
6): δ (ppm) 9.12(b, 2H); 9.02(b, 1H);8.89(b, 1H); 7.15(d, J=2.1, 1H); 6.93(d, J=16.2, 1H); 6.75(d, J=16.2, 1H); 6.58(dd, J=7.8, J=2.1, 1H); 6.50(d, J=7.8, 1H); 6.38(d, J=2.1, 2H); 6.10(t, J=2.1, 1H)。
Embodiment four: synthesis of trans Combretastatin A-4 phosphate disodium salt predrug;
In exsiccant 250 mL three-necked bottles, add 3-hydroxyl-4-methoxybenzaldehyde (1.520 g, 10.0 mmol), with the dissolving of 200 mL anhydrous acetonitriles, solution is transparent slightly yellow.Add potassium tert.-butoxide (1.18 g, 10.5 mmol, 1.05 eq), it is yellow muddy that system is.Be heated to 70 ° of C, stir after 15 minutes, be the yellow-green colour muddiness.(5.918 g, 11.0 mmol 1.1eq), stir a moment, generate a large amount of white solids, the system muddiness that is white in color to add tetra-sodium four benzyl esters.Continue to stir after 1 hour, stop heating, naturally cool to room temperature.Add 100 mL sherwood oils, stir a moment, remove by filter insoluble white solid, filtrate is revolved to steam to remove and is desolvated, and obtains brown liquid.Thick product gets the light yellow solid compound through column chromatography for separation (300-400 order silica gel, gradient elution, PE:EA=3:1 to PE:EA=1:1)
a(3.049 g, 7.40 mmol).Productive rate: 74.8 %.
1 H-NMR (DMSO- d
6, 500 MHz): d (ppm) 9.83 (s, 1H, -CHO), 7.82 (dd, J
1= 8.0 Hz, J
2= 1.5 Hz, 1H, H-4), 7.81 (d, J= 1.5 Hz, 1H, H-2), 7.39- 7.35 (m, 10H, -Ph-H), 7.34 (d, J= 8.0 Hz, 1H, H-5), 5.20 (s, 2H, -CH
2-), 5.19 (s, 2H, -CH
2-), 3.89 (s, 3H, -OCH
3)。
In exsiccant 50 mL three-necked bottles, add compound
a(0.721 g, 1.75 mmol), with the dissolving of 5 mL anhydrous acetonitriles, solution is the light brown muddiness, cools off in ice-water bath.Under argon shield, add (the CH that steams through heavily
3)
3SiBr (0.51 mL, 0.592 g, 3.87 mmol, 2.2 eq), the system color deepens immediately.Stir after 2 hours, add the methanol solution of 5 % sodium methylates, transfer to system PH 10, liquid becomes the light brown clarification.Stir after 30 minutes, add 10 mL acetone, the adularescent precipitation generates immediately.Remove ice-water bath, stirring is spent the night, and adds 10 mL acetone once more, no considerable change.Leach solid and dry, get milky thick product, about 0.570 g.Be dissolved in water in thick product to saturated, it is faint yellow that system is, and a little brown suspended substance is arranged.The methanol solution that adds 5 % sodium methylates transfers to system PH 11, and the elimination insolubles is faint yellow clarification.Filtrate adds 10 mL acetone after washing with 2 Χ, 5 mL ethyl acetate, and system becomes white opacity.Stir after 2 hours, add 10 mL acetone once more, precipitation increases.Stirring is spent the night, and adds 10 mL acetone, no considerable change.Stir after 1 hour, leach solid and dry, get the white solid compound
b(0.338 g, 1.22 mmol), productive rate: 70 %.
1 H-NMR (D
2O, 500 MHz): d (ppm) 9.69 (s, 1H, -CHO), 7.74 (s, 1H, H-2), 7.71 (d, J= 8.5 Hz, 1H, H-4), 7.19 (d, J= 8.5 Hz, 1H, H-5), 3.92 (s, 3H, -OCH
3)。
In 5 mL round-bottomed flasks, add compound
b(1.380 g, 5.00 mmol) and (3,4,5-trimethoxy benzyl) triphenyl bromide phosphines (4.190 g, 8.01 mmol, 1.60 eq), 3.50 mL, 2.5 mol/L aqueous sodium hydroxide solutions (8.75 mmol, 1.75 eq), it is yellow muddy that system is.In 80 ° of C oil baths, heat.Stir after 8 hours, reaction solution is brown muddiness, and yellow mercury oxide is arranged, and stops heating, after the cooling, adds 20 mL water, transfers to system PH 11 with the methanol solution of 5 % sodium methylates.Wash with 3 Χ, 20 mL ethyl acetate.In water layer, add 60 mL acetone, have yellow mercury oxide to generate.Leach solid and dry, get thick product.Be dissolved in water in thick product to saturated, it is faint yellow that system is, and a little suspended substance is arranged.The methanol solution that adds 5 % sodium methylates transfers to system PH 11, and the elimination insolubles is faint yellow clarification.Filtrate adds 20 mL acetone after washing with 2 Χ, 20 mL ethyl acetate, and system becomes white opacity.Stir after 2 hours, add 20 mL acetone once more, precipitation increases.Stirring is spent the night, and adds 20 mL acetone, no considerable change.Stir after 1 hour, leach solid and dry, get the trans Combretastatin A-4 of white solid phosphate disodium salt predrug (1.852 g, 2.88 mmol), productive rate: 57.6 %.
1 H-NMR (D
2O, 500 MHz): d (ppm) 7.81 (d, J= 8.0 Hz, 1H, H-6’), 7.54 (d, J= 18.0 Hz, 1H, -CH=CH-), 7.41 (d, J= 18.0 Hz, 1H, -CH=CH-), 7.05 (d, J= 8.0 Hz, 1H, H-5’), 7.03 (s, 1H, H-2’), 7.02 (s, 2H, H-2’’, H-6’’), 3.95 (s, 6H, -OCH
3), 3.89 (s, 3H, -OCH
3), 3.85 (s, 3H, -OCH
3)。
Claims (5)
1. the preparation method of a trans diphenylethylene compounds, it is characterized in that this method is with the benzyl three phenyl phosphonium bromides that the replace phosphonium salt as reaction, adopt sodium hydroxide (potassium) as alkali, utilize ' ' (On Water) waterborne ' ' the Wittig reaction, at water, with the aromatic aldehyde reaction synthesis of trans diphenylethylene compounds of various phenolic hydroxy groups, the structural formula of the benzyl three phenyl phosphonium bromides of wherein said replacement is:
The structural formula of the aromatic aldehyde of described phenolic hydroxy group is:
R wherein
1, R
2, R
3, R
1', R
2' be: hydrogen, alkyl, alkoxyl group ,-XH, X=O, N, S, nitro or halogen.
2. the preparation method of trans diphenylethylene compounds according to claim 1 is characterized in that described R
1, R
2, R
3, R
1', R
2' be hydrogen, hydroxyl or methoxyl group.
3. the preparation method of trans diphenylethylene compounds according to claim 1 and 2, the concrete grammar that it is characterized in that this method is: a. is in the sodium hydroxide or potassium hydroxide aqueous solution of 5 mmol/L ~ 10 mmol/L, by the benzyl three phenyl phosphonium bromides of 1: 1 ~ 1: 0.6 mol ratio input replacement and the aromatic aldehyde of phenolic hydroxy group; Under 500 ~ 2000 rev/mins stirring velocitys and 60 ~ 80 ° of C temperature, reaction is to reacting completely; Conditioned reaction system pH to 7 uses ethyl acetate extraction, washing, and drying, suction filtration revolves to steam to remove and desolvates; Resistates promptly obtains trans diphenylethylene compounds through separation and purification.
4. preparation method who prepares trans diphenylethylene compounds soluble derivative according to claim 1, the concrete steps that it is characterized in that this method are: the hydroxyl phosphoric acid reagent in the aromatic aldehyde of above-mentioned phenolic hydroxy group is changed into sodium phosphate salt, promptly obtain the soluble derivative of trans diphenylethylene compounds.
5. method according to claim 4 is characterized in that described phosphorylation agent is preferably: dibenzyl phosphite or tetra-sodium four benzyl esters.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675918A (en) * | 2018-05-29 | 2018-10-19 | 常州大学 | A kind of synthetic method of piceatannol |
| WO2021051271A1 (en) * | 2019-09-17 | 2021-03-25 | 深圳大学 | Use of piceatannol in preparing a drug for preventing and treating neurodegenerative diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050167A (en) * | 2007-05-10 | 2007-10-10 | 天津大学 | Method for synthesizing anticancer compound CA4 |
| CN102731565A (en) * | 2011-04-07 | 2012-10-17 | 复旦大学 | Water-soluble derivative of diphenylethene compounds, preparation method and usage thereof |
-
2013
- 2013-04-28 CN CN2013101533282A patent/CN103214354A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050167A (en) * | 2007-05-10 | 2007-10-10 | 天津大学 | Method for synthesizing anticancer compound CA4 |
| CN102731565A (en) * | 2011-04-07 | 2012-10-17 | 复旦大学 | Water-soluble derivative of diphenylethene compounds, preparation method and usage thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675918A (en) * | 2018-05-29 | 2018-10-19 | 常州大学 | A kind of synthetic method of piceatannol |
| CN108675918B (en) * | 2018-05-29 | 2020-06-26 | 常州大学 | Synthesis method of piceatannol |
| WO2021051271A1 (en) * | 2019-09-17 | 2021-03-25 | 深圳大学 | Use of piceatannol in preparing a drug for preventing and treating neurodegenerative diseases |
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Application publication date: 20130724 |