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CAS No. : | 501-36-0 | MDL No. : | MFCD00133799 |
Formula : | C14H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LUKBXSAWLPMMSZ-OWOJBTEDSA-N |
M.W : | 228.24 | Pubchem ID : | 445154 |
Synonyms : |
trans-Resveratrol;SRT501;Vineatrol 20M.;Resvida;CA1201;RM1812;(E)-Resveratrol
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 67.88 |
TPSA : | 60.69 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.47 cm/s |
Log Po/w (iLOGP) : | 1.71 |
Log Po/w (XLOGP3) : | 3.13 |
Log Po/w (WLOGP) : | 2.76 |
Log Po/w (MLOGP) : | 2.26 |
Log Po/w (SILICOS-IT) : | 2.57 |
Consensus Log Po/w : | 2.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.62 |
Solubility : | 0.0551 mg/ml ; 0.000241 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.07 |
Solubility : | 0.0193 mg/ml ; 0.0000844 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.29 |
Solubility : | 0.118 mg/ml ; 0.000516 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.02 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; diethyl ether at 10℃; for 24h; | |
In diethyl ether | ||
In diethyl ether at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.82% | With 5%-palladium/activated carbon; hydrogen; In methanol; at 20℃; under 2250.23 Torr; for 3.0h; | In a 300 ml glass autoclave, 20 g of resveratrol, 130 g of methanol, and 0.2 g of 5% Pd / C were charged, nitrogen substitution was performed three times, and hydrogen substitution was performed three times. Under stirring, the reaction was carried out at room temperature under a hydrogen pressure of 3 kg / cm 2 for 3 hours. After the reaction, the reaction solution is filtered to remove Pd / C.Then, methanol was distilled off under reduced pressure to obtain 19.74 g (yield 97.82%) of hydrogenated resveratrol. |
95% | With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; under 3800.26 Torr; for 8.0h; | The molecular formula of dihydro-resveratrol was established as C,4H,403, which was obtained as white powders through hydrogenation of trans-resveratrol. A solution of trans-resveratrol (10 g, 43.8 mmol) in anhydrous EtOH (150 ml) was stirred at room temperature under 5 atm H2 pressure in the presence of 10% Pd/C (0.2 g). The reaction was quenched afier 8 hours (h), by filtering off the catalyst. The filtrate was evaporated in vacuum and the residue was subjected to silica gel chromatographic separation eluting with petroleum ether and ethyl acetate (1:1) to afford dihydro-resveratrol as white amorphous powder (9.6 g, 95% yield): HR-ESIMS ([M+1]+ mlz 231.1026, calcd 231.1016 for C,4H,503); ?H NMR (methanol-d4, 400 MHz) o 6.96 (2H,ABd, J=8.3 Hz), 6.67 (2H,ABd, J=8.4 Hz), 6.13 (2H, brd, J=2.2 Hz), 6.09 (1H, brt, J=2.2 Hz), 2.74 (2H, brdd, J=8.5, 5.6), 2.67 (2H, brdd, J=8.3, 5.2); ?3C NMR(methanol-d4, 100 MHz) 0 159.2 (2C, s), 156.3 (1C, s),145.6 (1C, s), 134.1 (1C, s), 130.3 (2C, d), 116.0 (2C, d),108.1 (2C, d), 101.1 (1C, d), 39.6 (2C, t), 38.0 (2C, t). |
92% | With 5%-palladium/activated carbon; hydrogen; In methanol; at 20℃; under 2250.23 Torr; for 3.0h;Autoclave; | In a 300 ml glass autoclave, 20 g resveratrol,130 g of methanol,5% Pd / C 0.2g is charged,Nitrogen replacement was performed 3 times and hydrogen replacement was performed 3 times.The mixture was reacted at room temperature with stirring under a hydrogen pressure of 3 kg / cm 2 for 3 hours.After the reaction, the reaction solution was filtered to remove Pd / C, and 100 g of methanol was distilled off under reduced pressure.This concentrated solution was added to 120 g of purified water to precipitate crystals and stirred at room temperature for 1 hour.The crystals were collected by filtration, washed with purified water, and dried under reduced pressure to obtain 18.56 g (yield 92.0%) of hydrogenated resveratrol. |
38% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 1.0h; | To a solution of the resveratrol (500 mg, 2.2 mmol) in methanol (1 mL) was added 10% palladium on carbon (200 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1 h. The reaction mixture was filtered with celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40% ethylacetate in hexane) to give the desire compound 4f as a white solid (190 mg, 38%). 1H-NMR (400 MHz, CD3OD) delta 2.62-2.76 (4H, m), 6.08 (1H, t, J = 2.3 Hz), 6.12 (2H, d, J = 2.3 Hz), 6.66 (2H, d, J = 8.7), 6.96 (2H, d, J = 8.7 Hz) ; ESI-MS (negative ion): calcd for C14H13O3 ([M-H]-) 229.0870 ; found 229.0846 HPLC Purity >99% (R.T. = 3.0 min, under gradient conditions as below). |
With palladium 10% on activated carbon; hydrogen; In ethanol; for 3.0h; | General procedure: Dihydro derivatives of compounds 7, 9, 11, 13, 15, 17, 19, 21, and 23 were prepared by hydrogenation of corresponding stilbenes. A standard protocol was followed,32 with minor modifications. Solutions of each stilbene (10mg) in absolute EtOH (5ml) were stirred under H2 for 3h in the presence of 10% Pd/C. The reaction mixtures were filtered over Celite to remove the catalyst, and evaporated to dryness. The resulting residues were purified by flash column chromatography, using a hexane/EtOAc gradient, to afford target compounds 8, 10, 12, 14, 16, 18, 20, 22, and 24, respectively, in yields of 85-95%. The spectroscopic data of compounds were in agreement with the literature, except for compound 24, for which no report was found (1H NMR spectrum is provided as Supporting information).32-41 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron tribromide In dichloromethane at 0 - 30℃; | |
99% | With boron tribromide In dichloromethane at 0 - 20℃; | |
98% | With aluminum (III) chloride; sodium sulfate; triethylamine In chlorobenzene at 0 - 115℃; for 6.5h; Inert atmosphere; | 1.1; 2.1; 3.1 1) Add 90ml of chlorobenzene to a 500ml dry four-necked flask, and add 39.5g of anhydrous aluminium trichloride, after adding, nitrogen replacement twice,After that, nitrogen gas was continuously introduced, the temperature was controlled at 0-30 ° C, and 36 g of triethylamine was slowly added dropwise.Add triethylamine dropwise to control the temperature from 0-30 ° C. After dripping, keep for 30 minutes.16g of anhydrous sodium sulfate and 20g of 3,4’,5-trimethoxystilbene were added. After the addition was completed, nitrogen was replaced twice, and then nitrogen was continuously passed through.The temperature of the reaction solution was raised to 110-115 ° C, and the temperature was maintained for 6 hours.After the reaction is completed, the reaction solution is cooled to 30-40 degrees and added to ice water.Control the temperature of the water phase system ≤ 30 ° C. After the addition, stir for 2 hours and filter.After drying, 16.5 g of resveratrol was obtained with a yield of 98%. |
96% | With boron tribromide In dichloromethane at -78 - 20℃; | |
95% | With boron tribromide In dichloromethane at -30 - 20℃; | |
92% | With boron tribromide In dichloromethane at -78℃; for 2h; | 3 4.3. (E)-5-(4-Hydroxystyryl)benzene-1,3-diol (resveratrol, 1) To a solution of 4 (270 mg 1 mmol) in 20 mL of anhydrous dichloromethane at -78 °C, 4.5 mL of a solution 1M of boron tribromide in dichloromethane was added dropwise. 37 The resulting solution was magnetically stirred at -78 °C for 2 h. After this time, the solution was let to reach room temperature, and then it was poured onto brine. The organic phase was separated and the aqueous phase was extracted with acetonitrile (4*30 mL). The combined organic phases were dried with anhydrous MgSO4, filtered and the solvent was removed at reduced pressure. The resulting product was purified by medium pressure column chromatography (Combiflash) using a silica gel column and a mixture hexane/ethyl acetate 1:1 as eluent, leading to a colourless solid (210 mg, 92%) characterised by NMR; 38, 39 [Found C 73.35 H 5.36 requires C, 73.67, H, 5.30]; GC conditions: Agilent J&W CG ColumnHP-5 30 m*25 mm*0.25 mm, helium as carrier gas, 230 °C injector T, 250 °C detector T, 20 psi head column pressure, 2 mL min-1 flux, oven temperature program 70 °C (1 min), 20 °C min-1, 250 °C (7.5 min), retention time 12.9 min; δH (400 MHz, acetone-d6) 7.30-7.27 (m, 2H), 6.88 (d, 1H, J=16.3 Hz), 6.75 (d, 1H, J=16.3 Hz), 6.71-6.69 (m, 2H), 6.41 (d, 2H, J=2.2 Hz), 6.14 (d, 1H, J=2.2 Hz), 3.64 (s, 1H), 2.88 (s, 2H); δC (100.6 MHz, acetone-d6, APT) 159.0 (C), 158.2 (C), 140.9 (C), 130.0 (C), 129.1 (CH), 128.7 (CH), 126.6 (CH), 116.4 (CH), 105.7 (CH), 102.7 (CH); m/z (EI) 228 (M+). |
91% | With boron tribromide In dichloromethane at 20℃; Inert atmosphere; Cooling; | |
90% | With boron tribromide In dichloromethane at 20℃; for 2h; | |
90% | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; triethylamine In chlorobenzene at 0 - 80℃; for 10h; Stage #2: With water In chlorobenzene at 0℃; for 1h; | 1 56.2 g of triethylamine (555.4 mmol) are introduced into 20 ml of chlorobenzene in a three-necked round-bottomed flask. A nitrogen atmosphere is applied, the reaction medium is cooled to 0-50C and 45 g of anhydrous aluminium chloride (337.5 mmol) are added in small fractions over 30 min. The medium is maintained at ambient temperature for 30 min with stirring and is then brought to 600C, where this temperature is maintained for 1 h. 10 g of (E)-3,5,4'-trimethoxystilbene (37 mmol) dissolved in 20 ml of chlorobenzene are subsequently added in 1 h. The mixture is maintained at 600C with stirring for 4 h and then at 800C for 4 h. It is brought back to ambient temperature, separation by settling is carried out and the upper chlorobenzene phase is recovered. The lower phase is slowly added to 100 g of a 50/50 ice/water mixture. The medium is kept stirred for 1 h and is extracted several times with ethyl acetate.The combined organic phases are washed with water and concentrated to result in 7.6 g of (E)-resveratrol, i.e. a crude yield of 90%. The crude product is dissolved in ethanol at 600C and resveratrol is precipitated by addition of water in order to obtain 6 g of precipitate exhibiting a melting point of 262-264°C.The proton and 13C NMR spectra are in agreement with the structure of (E)-resveratrol. |
86% | With boron tribromide In dichloromethane at -78℃; for 0.5h; | |
86% | With boron tribromide In dichloromethane at -78℃; for 0.5h; | 1 To a solution of 4-methoxy-benzylthphenylphosphonium bromide (12.5 g) in anhydrous tetrahydrofuran (200 ml_) at -78 0C was added n-butyllithium (2.44 M, 1.0 equiv), and the resulting red solution was stirred under argon for 2-4 h. A solution of 3,5-dimethoxybenzaldehyde (4.5 g) in tetrahydrofuran was added dropwise over 30 min and the mixture stirred for 6-15 h. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil. The oil was separated by flash column chromatography (49:1 hexane/ethyl acetate). The cis-stilbene eluted first as a clear oil followed by the trans isomer as a colorless solid or oil. Overall yield: 91 %. To a solution of the trans isomer (3.1.g) in anhydrous dichloromethane (150 mL) at -78 0C was added (dropwise) boron tribromide (1.0 M, 34.5 mL), and the resulting red solution was stirred under argon for 30 min. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil, which was separated by flash column chromatography (1 :1 hexane/ethyl acetate) to afford a colorless solid (2.26 g, 86%): mp 260 0C. |
85% | With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at 0℃; for 6h; | |
85% | With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at 0℃; | |
85% | With aluminum (III) chloride; diisopropylamine In toluene at 110℃; for 4h; Inert atmosphere; | |
84% | With boron tribromide | |
83% | With boron tribromide In dichloromethane at -10 - 20℃; for 3h; Inert atmosphere; | 2. General procedure for demethylation of stilbene 4 General procedure: In 6 mL of anhydrous methylene chloride, 200 mg of methoxy-stilbene 4 (0.74 mmol) was dissolved and cooled to -10 °C under argon. BBr3 (0.6 mL, 6.3 mmol, 17% in dichloromethane) in anhydrous methylene chloride (5 mL) was added slowly, and the mixture was allowed to reach to room temperature for 3-24 h. Water was added to destroy the excess BBr3, and the mixture was extracted twice with ethyl acetate. The organic extracts were washed with water and brine and dried, and the solvent evaporated. The crude product was purified by column chromatography on silica gel (20% EtOAc in hexane) yielding resveratrol and derivatives 1.2.1. 5-[(E)-2-(4-Hydroxyphenyl)ethenyl]benzene-1,3-diol (resveratrol, 1a).16Pale brown solid; yield: 141 mg (83%); mp 259-260 °C (lit.16 256-259 °C) ; Rf = 0.2 (hexanes-EtOAc, 1:1); 1H NMR (400 MHz, acetone-d6): δ=8.56 (s, 1H, OH), 8.28 (s, 2H, OH), 7.40 (d, 2H, J=8.5 Hz, H-2’, H-6’), 7.00 (d, 1H, J=16.3 Hz, H-β), 6.86 (d, 1H, J=16.3 Hz, H-α), 6.82 (d, 2H, J=8.5 Hz, H-3’, H-5’), 6.52 (d, 2H, J=2.0 Hz, H-2, H-6), 6.25(s, 1H, H-4); 13C NMR (100 MHz, acetone-d6): δ=159.6, 158.1, 140.8, 129.9, 129.0, 128.7, 126.8, 116.4, 105.6, 102.6. |
83% | With boron tribromide In dichloromethane at -78℃; for 1h; Schlenk technique; Inert atmosphere; | |
82% | With boron tribromide In dichloromethane at 0 - 20℃; | |
80% | With boron tribromide In dichloromethane at -30 - 20℃; for 2h; Inert atmosphere; | |
75% | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; tributyl-amine at 20 - 100℃; for 8h; Stage #2: With water at 0 - 5℃; for 3h; | 2 4.5 g of anhydrous aluminium chloride (33.7 mmol) are introduced, under a nitrogen atmosphere, at ambient temperature and with stirring, into 10.37 g of tributylamine (56 mmol) in a three-necked round-bottomed flask. The medium is brought to 600C and is maintained at this value for 4 h. 1 g of (E)-3,5,4'-trimethoxystilbene (3.7 mmol) is then introduced and the reaction medium is brought to 800C for 2 h and to 1000C for 2 h. It is brought back to ambient temperature and then 10 g of a 50/50 water/ice mixture are added. It is maintained at 0-50C with stirring for 3 h and extracted 4 to 5 times with 10 ml of methyl ethyl ketone. The combined organic phases are washed with 10 ml of a saturated aqueous sodium bicarbonate solution and then with 10 ml of water. After concentrating the organic phase, an HPLC quantitative determination (external calibration) gives an (E)-resveratrol yield of 75%. |
74% | With boron tribromide In dichloromethane at -30 - 28℃; Schlenk technique; | |
73.4% | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; triethylamine at 50 - 100℃; for 4.5h; Stage #2: With water In ethanol at 20 - 75℃; for 3.5h; | 5 5 g of (E)-3,5,4'-trimethoxystilbene (18.5 mmol) are introduced into 20 g of triethylamine (197.6 mmol) in a 100 ml three-necked round-bottomed flask. The mixture is heated to 500C under a nitrogen atmosphere and 16 g of anhydrous aluminium chloride (120 mmol) are added in small fractions over 30 min at this temperature. The reaction medium is then brought to 800C for 2 h and then to 1000C for 2 h. It is cooled to approximately 75°C, 10 ml of anhydrous ethanol are slowly added and then, at this temperature of 75°C, 50 ml of water are added in 30 min. The reaction medium is then cooled to ambient temperature, at which it is maintained for 3 h, and the medium is extracted with 1 times 35 ml and 3 times 30 ml of methyl ethyl ketone. The combined organic phases are washed with 30 ml of water, then with 30 ml of a saturated sodium bicarbonate solution and with 30 ml of water. After concentrating the organic phases, 15 ml of absolute ethanol are added, the mixture is heated to reflux and then 46 g of water are added over approximately 1 h, still at reflux. The mixture is cooled down to ambient temperature and left stirring for 3 h. The precipitate is filtered off and washed on the filter with 9 g of a water/ethanol mixture (80/20 by weight).After drying at 400C under vacuum for 24 h, 3.1 g of (E)-resveratrol are obtained, i.e. a yield of 73.4%.The HPLC and NMR analyses are in agreement with the structure of (E)-resveratrol. |
70% | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In toluene at 70 - 80℃; for 2h; Stage #2: With hydrogenchloride; water In toluene at 20℃; | 14 EXAMPLE 14; General procedure for the preparation of Stilbenols: Poly methoxystilbenes were prepared by Emmons-Horner coupling of the corresponding methoxybenzyl phosphonate with methoxyaryl aldehyde. Poly methoxylstilbenes were demethylated using a general procedure. The following procedure involving 3,4',5-trimethoxystilbene is applicable to all similar substrates. N,N-Dimethylaniline (27 g, 0.223 mol) was taken in a 250 mL round bottomed flask under dry nitrogen atmosphere. Anhydrous aluminium chloride (30 g, 0.225 mol) was added slowly with stirring. Dry toluene (25 mL) was added and stirred for 10 min. This was heated to 70-80° C. 3,4',5-tirmethoxystilbene (10 g, 0.037 mol) dissolved in toluene (50 mL) was dropped into the reaction mixture over a period of 5-10 min. The reaction mixture was stirred at 70-80° C. for 2 h. This was cooled to room temperature and dropped into ice water (100 mL) slowly with stirring. Toluene layer was separated. The aq. layer was acidified with 10% hydrochloric acid, and extracted with ethyl acetate (3×100 mL), which was dried over anhy. sodium sulfate, filtered, and the solvents stripped off under vacuum to get the crude resveratrol. This was purified by column chromatography on silica gel using ethyl acetate-hexane as eluent to get pure resveratrol (5.9 g, 70% yield) as white solid. The physical and spectral data for the starting material 3,4',5-trimethoxystilbene:Mpt: 42.0-44.0° C.(Solvent CDCl3, 300 MHz proton):δ 3.83 (s, 6H), 3.86 (s, 3H), 6.39 (t, J=2.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 2H), 6.88-6.94 (m, 3H), 7.05 (d, J=16.2 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H)13C NMR(75 MHz, CDCl3): δ 55.56, 55.59, 99.83, 104.55, 114.38, 126.78, 128.06, 128.97, 130.14, 139.93, 159.63, 161.20LC-MS: m/e 271 (M++1)The physical and spectral data for the product Resveratrol:Mpt: 265.5-267.9° C.(Solvent Acetone-d6, 300 MHz Proton): δ 6.28 (t, J=2.1 Hz, 1H), 6.55 (d, J=2.1 Hz, 2H), 6.83-6.92 (m, 3H), 7.03 (d, J=16.5 Hz, 1H), 7.43 (d, J=8.7 Hz, 2H), 8.3 (br s, 3H, -OH).13C NMR (75 MHz, Acetone-d6): δ 102.60, 105.62, 116.38, 126.75, 128.72, 129.07, 129.88, 140.86, 158.14, 159.54).LC-MS: m/e 227 (M+-1). |
70% | With boron tribromide In dichloromethane at 0 - 20℃; for 5h; | |
70% | With boron tribromide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; | |
70% | With boron tribromide In dichloromethane at 0℃; for 5h; | (E)-3',4,5'-trihydroxy-stilbene (1): BBr3 (1.38 g, 5.52 mmol) wasadded dropwise into methylated stilbene (6) (190 mg,0.745 mmol) in dry CH2Cl2 (20 mL) at 0 C, then stirred for 5 hand left at room temperature over 1 h. The mixture was pouredonto ice, and the organic layer was separated and the aqueouslayer extracted with CH2Cl2 (2 10 mL). The combined organiclayer was washed with saturated NaCl, dried over anhydroussodium sulfate and evaporated under reduced pressure to dryness.The solid was recrystallized from MeOH-CH2Cl2, to afford pureResveratrol (1) (112 mg, 70% yield) as an off-white powder; mp258-260 C. |
70% | With boron tribromide In dichloromethane for 5h; Inert atmosphere; Schlenk technique; | |
65% | With methyl magnesium iodide In diethyl ether at 100 - 160℃; | |
60% | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With boron tribromide In tetrahydrofuran at -20℃; Inert atmosphere; Stage #2: With methanol; sodium hydroxide for 4h; Inert atmosphere; Reflux; regioselective reaction; | |
56% | With methyl magnesium iodide at 100℃; for 0.5h; | |
56% | With boron tribromide In dichloromethane at -5 - 20℃; | |
54% | With methyl magnesium iodide In diethyl ether at 100℃; for 0.5h; | |
45% | With pyridine hydrochloride | |
45% | With pyridine hydrochloride at 190℃; for 4h; | |
42% | With pyridine hydrochloride at 190℃; for 4h; | |
20% | With pyridine hydrochloride for 2h; Inert atmosphere; Reflux; | |
20% | With pyridine hydrochloride for 2h; Reflux; Inert atmosphere; | trans-3,4',5-Trihydroxystilbene (Resveratrol) To a 250 mL round-bottomed flask equipped with a magnetic stir bar was added 8 (2.7 g, 10 mmol) and pyridine hydrochloride (10.4 g, 90 mmol, 9 equiv). A reflux condenser was equipped and the reaction mixture was refluxed for 2 h under an N2 atmosphere. Afterwards, the mixture was allowed to cool to ˜90° C. and quenched into H2O (200 mL) whereupon a purplish colored solid precipitated. The mixture was extracted with EtOAc (50 mL*3). The extracts were collected and diluted with hexanes (100 mL) and then filtered through a thin pad of silica gel to remove dark colored, polar impurities. The filtrate was evaporated in vacuo leaving an off-white solid. The crude product was slurried with HOAc and filtered to give resveratrol as a tan microcrystalline powder (450 mg, 20%), mp. 258-261° C., lit. 261° C. 1H NMR (DMSO): δ 9.59 (s, OH), 9.23 (s, 20H), 7.41 (d, J=8.9 Hz, 2H), 6.95 (d, Jab=16.3 Hz, 1H), 6.82 (d, Jab=16.3 Hz, 1H), 6.76 (d, J=8.9 Hz, 2H), 6.39 (d, J=2.0 Hz, 2H), 6.13 (t, J=2.1 Hz, 1H); 13C NMR (DMSO): δ 158.58, 157.28, 139.36, 128.15, 127.96, 127.92, 125.74, 115.61, 104.41, 101.87. Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.40; H, 5.44. |
With hydrogenchloride In methanol at 20℃; for 36h; | ||
With boron tribromide In dichloromethane at 25 - 35℃; for 3h; | ||
With boron tribromide In dichloromethane at 20℃; for 1.5h; | 24 Example 24; Synthesis of (E)-resveratrol:; 37.9 ml of boron tribromide (approximately 100 g, 400 mmol) are introduced into 100 ml of methylene chloride under a nitrogen atmosphere in a three-necked round- bottomed flask. The medium is cooled to approximately -200C and 10.8 g (approximately 40 mmol) of (E)-trimethylresveratrol dissolved in 20 ml of methylene chloride are introduced at this temperature over 1 h 30. The medium is allowed to return to ambient temperature with stirring and is left stirring at this temperature for 4 hours. The reaction medium is then slowly poured onto 800 g of an ice/water mixture. The medium is extracted with 325 ml and then 200 ml of MTBE and the organic phases are washed with 2 times 75 ml of a saturated sodium bicarbonate solution and then with 75 ml of water. The combined organic phases are concentrated on a rotary evaporator. The solid residue is taken up in 100 ml of methylene chloride, filtered off and dried to result in 8.1 g of crude resveratrol.The precipitate is dissolved in ethanol at 600C and precipitated by addition of water to result in resveratrol with a melting point of 262-264°C. The proton and C13 NMR spectra correspond to the expected product. | |
Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; triethylamine In dichloromethane; chlorobenzene at 0 - 80℃; for 11.25h; Stage #2: With water In dichloromethane; chlorobenzene at 0 - 5℃; for 1h; | 6 5.6 g of triethylamine (55.5 mmol) are introduced into 4 ml of methylene chloride. The medium is cooled to 0-5°C and 4.5 g of anhydrous aluminium chloride (33.5 mmol) are added in small fractions over 15 min with stirring and under a nitrogen atmosphere. The reaction medium is subsequently brought to 50°C for 4 h. It is cooled and the solvent and the excess amine are concentrated at ambient temperature in order to obtain approximately 8.5 g of a slightly fuming pinkish solid formed of AICI3/triethylamine complex. 2 ml of chlorobenzene are added to the solid and the mixture is brought to 60°C. 1 g of 3,5,4'-trimethoxystilbene (3.7 mmol) dissolved in 2 ml of chlorobenzene is added at this temperature over one hour. The mixture is maintained at 600C for 4 h and then at 800C for 2 h. The reaction medium is brought back to ambient temperature and then hydrolysed by addition of 10 g of a water/ice (50/50) mixture. The temperature is maintained at 0-50C for 1 h and the medium is extracted several times with ethyl acetate. After concentrating the organic phases, the precipitate obtained is washed with 6 ml of chlorobenzene and dried under vacuum to result in 0.6 g of crude (E)-resveratrol. | |
With pyridine hydrochloride at 180 - 200℃; Inert atmosphere; | ||
47.5 g | Stage #1: 3,5,4'-trimethoxy-trans-stilbene With aluminum (III) chloride; diisopropylamine In toluene at 25 - 120℃; for 4h; Stage #2: With water In toluene at 45℃; for 0.5h; | 1 Preparation of Resveratrol Using Diisopropyl Amine: Aluminium Chloride To a clean 3-necked 2 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged di-isopropyl amine (168.5 gms) at 25° to 35° C. To the solution aluminium chloride (222 gms) was added in lots at 25° C. to 35° C. and heated to 110° C. Reaction solution was stirred for 30 minutes and then resveratrol methyl ether solution (75 gms of resveratrol methyl ether in 300 ml of toluene) was added at 100° C. to 110° C. Reaction mass was stirred for 4 hours at 110° C. to 120° C. and then allowed to cool to 80° C. to 90° C. The reaction mass was quenched into chilled water (1050 ml) at below 45° C. and stirred for 30 minutes at same temperature. Precipitated material was filtered and washed with water (150 ml). The wet product (160 gms) was taken into a 3-necked 2 L round bottom flask and water (1125 ml) was charged at 25° to 35° C. To the mass sodium hydroxide solution (188 ml; 33.5 gms of sodium hydroxide dissolved in 188 ml water) was added and then reaction solution was washed with toluene (2×195 ml). The aqueous layer was separated out and pH was adjusted to 2 with Con HCl (71.25 ml) at 25° to 30° C. and stirred for 60 minutes at same temperature. Precipitated product was filtered and washed with water (150 ml) and the wet cake was slurred in water (750 ml) at temperature 80° to 85° C. followed by filtered and dried at 75° to 85° C. to provide the title compound. Yield: 47.5 gms. HPLC purity: 99.49% |
With pyridine hydrochloride at 190℃; for 0.833333h; | 16.2gC plus 69.3g pyridine hydrochloride, react at 190 ° C for 50 minutes, pour 200ml of ice water, stir, extract with 1L ethyl acetate, separate layers, wash with water, dry with sodium sulfate, recover ethyl acetate, recrystallize with ethanol to obtain white Resveratrol. | |
With magnesium; methyl iodide In diethyl ether at 45 - 190℃; Inert atmosphere; | ||
With boron tribromide In dichloromethane at -78℃; for 1h; | 1 Deprotection of trimethyl resveratrol We followed a published with some modification.4 ()-l,3-dimethoxy-5-(4- methoxystyryl)benzene (92 mg, 340 pmol, 1.0 equiv) was dissolved in CH2CI2 (15 mL) and a solution of BBr3 (1.0 M in CH2CI2, 3.3 mmol, 3.3 mL, 9.0 equiv) was added at -78 °C. The mixture was stirred for 1 h at -78 °C. Then the reaction was allowed to warm to room temperature, H2O (25 mL) was added and the mixture was poured into H2O (25 mL). Extraction with EtOAc (3 c 25 mL), washing of the combined organic layers with H2O (25 mL), brine (25 mL), drying over MgSCb and concentration under reduced pressure gave the crude product which was purified by flash column chromatography using hexanes and ethyl acetate (v/v = 9:1) as the eluent. The target compound of resveratrol was obtained as a white solid (74 mg, 96%). NMR (600 MHz, DMSO-rfe): d 9.53 (s, 1H), 9.17 (s, 2H), 7.39 (m, 2H), 6.92 (d, J= 16.3 Hz, 1H), 6.81 (d, J= 16.3 Hz, 1H), 6.75 (m, 2H), 6.37 (d, .7= 2.1 Hz, 2H), 6.11 (t, .7= 2.1 Hz, 1H) ppm. 13C NMR (201 MHz, DMSO-rfe): d 158.5, 157.2, 139.2, 128.1, 127.8, 127.8,125.6, 115.5, 104.3, 101.7 ppm. | |
With boron tribromide In dichloromethane at -78℃; for 1h; | 1 Deprotection of trimethyl resveratrol We followed a published with some modification.4 ()-l,3-dimethoxy-5-(4- methoxystyryl)benzene (92 mg, 340 pmol, 1.0 equiv) was dissolved in CH2CI2 (15 mL) and a solution of BBr3 (1.0 M in CH2CI2, 3.3 mmol, 3.3 mL, 9.0 equiv) was added at -78 °C. The mixture was stirred for 1 h at -78 °C. Then the reaction was allowed to warm to room temperature, H2O (25 mL) was added and the mixture was poured into H2O (25 mL). Extraction with EtOAc (3 c 25 mL), washing of the combined organic layers with H2O (25 mL), brine (25 mL), drying over MgSCb and concentration under reduced pressure gave the crude product which was purified by flash column chromatography using hexanes and ethyl acetate (v/v = 9:1) as the eluent. The target compound of resveratrol was obtained as a white solid (74 mg, 96%). NMR (600 MHz, DMSO-rfe): d 9.53 (s, 1H), 9.17 (s, 2H), 7.39 (m, 2H), 6.92 (d, J= 16.3 Hz, 1H), 6.81 (d, J= 16.3 Hz, 1H), 6.75 (m, 2H), 6.37 (d, .7= 2.1 Hz, 2H), 6.11 (t, .7= 2.1 Hz, 1H) ppm. 13C NMR (201 MHz, DMSO-rfe): d 158.5, 157.2, 139.2, 128.1, 127.8, 127.8,125.6, 115.5, 104.3, 101.7 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; at 20 - 80℃; | a) Preparation of 3,5,4'-resveratrol triacetate(Res(AC)3); Pyridine (10 eq) is added dropwise whilst stirring at ambient temperature to a solution of resveratrol (156 g with a purity of 96%, 0.66 mole) in acetic anhydride (372 ml, 6 eq). The reaction medium is heated to 80 C. for 1 hour. The product is obtained after precipitation in 3 l of water, filtration and two successive washings with water. Resveratrol triacetate is obtained with a quantitative yield and a HPLC purity of 99% (300 nm) and molar purity measured by NMR of the proton of 98%.Melting point=120-121 C.NMR 1H (DMSO/HMDS; 300 MHz): 2.21 (s, 3H); 2.23 (s, 6H); 6.85 (t, 2.2 Hz, 1H); 7.10 (d, 8.5 Hz, 2H); 7.15 (d, 16.5 Hz, 1H); 7.23 (d, 2.2 Hz, 2H); 7.28 (d, 16.5 Hz, 1H); 7.57 (d, 8.5 Hz, 2H). |
95% | With sodium hydroxide; In dichloromethane; water; at 20℃;Large scale; | Resveratrol (2.28kg, 10mol), sodium hydroxide (1.32kg, 33mol) was added to the dissolution tank, and deionized water was added to determine the volume to 10L and stirred to dissolve.An aqueous solution having a resveratrol concentration of 1.0 mol/L was prepared and used.3.67 kg of anhydrous acetic anhydride (36 moL, density 1.08 g/mL) was added to the dissolution tank.The volume was adjusted to 10 L with methylene chloride and stirred uniformly to prepare a dichloromethane solution having an acetic anhydride concentration of 3.6 mol/L, which was used.The resveratrol/sodium hydroxide aqueous solution and the acetic anhydride dichloromethane solution are respectively sent to the microreactor through the metering pump 1 and the metering pump 2,Control the microreactor temperature to 20 C, control resveratrol by adjusting the metering pump flow:The molar flow ratio of acetic anhydride was 1:3.6, and the residence time of the reaction liquid in the microreactor was 2 minutes.After the reaction is completed, the reaction liquid enters the liquid-liquid separator, the water layer enters the wastewater receiving tank, and the organic phase is sequentially saturated with sodium hydrogencarbonate solution.Wash with deionized water until neutral, and the organic phase is dried over anhydrous sodium sulfate to recover the solvent.Obtaining white or light yellow solid resveratrol triacetate 3.36kg, melting point 113-114 C, yield 95%, content 98.5%, |
89% | With pyridine; at 20℃; for 3h;Cooling with ice; Inert atmosphere; | To a solution of resveratrol (300 mg, 1.31 mmol) in acetic anhydride (2.5 mL, 26.2 mmol) was added pyridine (2.7 mL, 32.8 mmol) dropwise under ice-cooling and nitrogen atmosphere. The mixture was stirred at ambient temperature for 3 h. 1N HCl was added dropwise to the reaction mixture under ice-cooling. After stirring at ambient temperature, the resulting precipitates were collected by filtration. The precipitates were washed with water and dried in vacuo, then recrystallized with acetone (2.5 mL) to give the desired compound 4a (414 mg, 89%) as colorless powder. 1H-NMR (400MHz, DMSO-d6) delta 2.28 (3H, s), 2.29 (6H, s), 6.91 (1H, t, J = 2.1 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.23 (1H, d, J = 16.5 Hz), 7.30 (2H, d, J = 1.8 Hz), 7.35 (1H, d, J = 16.5 Hz), 7.64 (2H, d, J = 8.2 Hz) ; ESI-HRMS (positive ion): calcd for C20H18NaO6 ([M+Na]+) 377.1001 ; found 377.1018. HPLC Purity >99% (R.T. = 13.6 min, under gradient conditions as below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With proteolytic enzymes; at 0 - 15℃;Enzymatic reaction; | A cosmetic composition comprising a protease as a precursor material and a protease as a hydrolase was stored and stored at a temperature of 0 C to 15 C. Resveratrol was produced by the following reaction in the cosmetic composition of Experimental Example 3. In Comparative Example 3, the amount of resveratrol over time was measured in a product containing resveratrol (0.5%), and the resveratrol content in Experimental Example 3 was measured and the antioxidant activity was summarized in Table 3 and FIG. | |
With recombinant beta-glucosidase from Thermotoga maritima; In aq. phosphate buffer; dimethyl sulfoxide; at 90℃;pH 5.8;Enzymatic reaction;Kinetics; | To evaluate the hydrolysis of TmBglA towards <strong>[27208-80-6]polydatin</strong> and arctiin, 0.2 mug of purified TmBglA was added to the 1mL of <strong>[27208-80-6]polydatin</strong> (400 mg L1) and arctiin (540 mg L1) in 50mM SPB (pH 5.8 for <strong>[27208-80-6]polydatin</strong> and 6.2 for arctiin) respectively, and allowed to react at 80 C for 60 min. The reaction mixtures were left for 2min, 5min, 10 min, 20 min, 40 min, and 60 min, and then were stopped by cooled in ice bar before analysis and centrifuged at 12,000 rpm and 4 C for 5min to get the supernatant for analyzing by HPLC to monitor the enzymatic hydrolysis process. An Agilent Zorbax SBC18 column (4.6150 mm, 5 lm) was used for isocratic separation with a gradient sequence using methanol (A) and 0.05% phosphoric acid solution (B) in the following proportions: 40% A (9min) and 80% B (5min) at a flow rate of 1mL min1 for enzymatic transformation of <strong>[27208-80-6]polydatin</strong> to resveratrol, and a gradient sequence using acetonitrile (A) and water (B) in the following proportions: 25% A (15 min), 70% A (12 min), 70% A(10 min), and 25% A (6min) at a flow rate of 1mL min1 for enzymatic transformation of arctiin to arctigenin. The injection volume was 10 lL and detection was accomplished at 303nm for <strong>[27208-80-6]polydatin</strong>, and at 280nm for arctiin |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydroxide at 40℃; for 2h; | |
76% | With sodium hydroxide In water for 2h; | |
59% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (E)-1-(4-(benzyloxy)phenyl)-2-(3,5-bis(benzyloxy)phenyl)-ethene With aluminum (III) chloride; triethylamine In chlorobenzene at 0 - 80℃; for 10h; Stage #2: With water In chlorobenzene at 0℃; for 2h; | 3 4 ml of chlorobenzene and 6 g of triethylamine (59.3 mmol) are introduced into a three- necked round-bottomed flask. A nitrogen atmosphere is applied, the mixture is cooled to 0-50C and 4.9 g of anhydrous aluminium chloride (36.7 mmol) are introduced in small fractions at this temperature. The medium is brought to 500C and is maintained at this temperature for 1 h, and then 2 g of (E)-3,5,4'-tribenzyloxystilbene (4 mmol) dissolved in 5 ml of chlorobenzene are added in 1 h at this temperature. This temperature is maintained for 4 h and then a temperature of 80°C is maintained for 4 h. The mixture is brought back to ambient temperature, separation by settling is carried out and the heavy phase is recovered and poured onto 20 ml of a 50/50 ice/water mixture. The medium is kept stirred for 2 h and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and then with water and then concentrated to result in 0.93 g of crude (E)-resveratrol, i.e. a practically quantitative yield with respect to the starting tribenzylresveratrol. |
90% | With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline at 40 - 50℃; | 2 EXAMPLE 2; Preparation of (E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl) ethene of the Formula (III) Into a 3 lit. round-bottomed flask equipped with a thermometer were added aluminum chloride (390.35 gm) and N,N-dimethylaniline (413.10 gm) maintaining the temperature at 40-50° C. To this solution, a solution of (E)-1-(4-(benzyloxy)phenyl)-2-(3,5-bis(benzyloxy)phenyl)ethene (243 gm) prepared according to example 1 in dichloromethane was added and stirred well. After the reaction was over, the reaction mixture was acidified, extracted into ethyl acetate and concentrated to get pure (E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene (E-Resveratrol) in the exclusive E-form in 90% yield. 1H NMR (DMSO-d6, Bruker 400 MHz Avance): δ6.11 (t, J=1.8 Hz), 6.38 (d, J=1.8 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.82 (d, J=16.3 Hz, 1H), 6.92 (d, J=16.3 Hz), 7.39 (d, J=8.4 Hz, 2H); Mass mn/e: 228.2. |
87% | With hydrogen In dichloromethane at 20℃; for 5h; | 1 Take 24.9g of resveratrol tribenzylate,Was dissolved in 180 mL of CH2C12,Then, 15.57 g of a catalyst having a Pd loading of 5% was added,The reaction was carried out at room temperature for 5 hours. After the reaction was completed, the catalyst RS001 was recovered by filtration and the filtrate was steamed to recover the reaction solvent. The crude product was recrystallized from ethanol to obtain 9.9 g of resveratrol. The yield was 87%. |
80% | With boron tribromide | |
76% | With palladium 10% on activated carbon; ammonium formate In methanol; 1,2-dichloro-ethane at 40℃; for 0.75h; | 4 Embodiment 4 Weighing 0 . 10 g of formula II - 3 shown (E)-1-(4-benzyloxyphenyl)-2-(3,5-dibenzyloxyphenyl)ethylene and 0 . 076 g ammonium formate in 3 ml mixed solvent (1, 2 - dichloroethane/methanol=1/2) in heating to 40 °C, stirring 15 minutes, the raw material is dissolved. The insulation by adding 0 . 018 g 10% palladium-carbon catalyst, thermal insulation stirring TLC monitoring until the reaction is complete, about 30 minutes. Filtering to remove the palladium-carbon, reducing pressure of the mother liquor solvent, residue by column chromatography separation to obtain the target product I - 3 is shown in the 5-[(1E)-2-(4-hydroxyphenyl)vinyl]-1,3-benzenediol 0.035g, yield 76%. |
69% | With aluminium trichloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0℃; | |
39% | With boron tribromide; isoascorbic acid In dichloromethane at -78 - 20℃; Inert atmosphere; | |
36% | With aluminium trichloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | |
93% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With potassium carbonate In acetone at 25℃; for 0.0833333h; Inert atmosphere; Stage #2: methyl iodide In acetone at 25℃; for 12h; Inert atmosphere; | |
93% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With potassium carbonate In acetone at 25℃; for 0.0833333h; Inert atmosphere; Stage #2: methyl iodide In acetone at 25℃; for 12h; Inert atmosphere; | 4 Permethylated Resveratrol (8) Paucifloral F was synthesized according to the scheme shown in Figure 3 (modification of the procedures described by Snyder et al . [5]) . Isopaucifloral F is synthesized according to the scheme shown in Figure 4 (modification of the procedures described by Snyder et al . [5] ) . Permethylated Resveratrol (8) Resveratrol (1.00 g, 4.38 mmol, 1.0 equiv) was dissolved in acetone (20 mL) and K2CO3 (5.45 g, 39.4 mmol, 9.0 equiv) was added in a single portion at 25 °C. After stirring the resultant slurry for 5 min at 25 °C, Mel (2.45 mL, 39.4 mmol, 9.0 equiv) was added slowly over the course of 5 min by syringe. The reaction mixture was stirred for 12 h at 25 °C. Upon completion, the reaction contents were quenched with saturated aqueous NH4C1 (25 mL) , poured into water (10 mL) , and extracted with EtOAc (3 χ 30 mL) . The combined organic extracts were then washed with water (30 mL) and brine (30 mL) , dried (MgS04) , filtered, and concentrated. The resultant crude, yellow oil was purified by flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to afford permethylated resveratrol (8, 1.10 g, 93% yield) as a white solid. |
88% | With sodium hydroxide at 40℃; | |
83% | With potassium carbonate In acetone for 8h; Heating; | |
76% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Cooling with ice; Inert atmosphere; | Preparation of (E)-1,3-Dimethoxy-5-(4-methoxystyryl)benzene (Compound 4b) To a solution of 1 (200 mg, 0.876 mmol) in DMF (2 mL) were added potassium carbonate (296 mg, 2.14 mmol) and iodomethane (0.402 mL, 6.43 mmol) under ice-cooling and nitrogen atmosphere. The resultant mixture was raised at ambient temperature and was allowed to be stirred for 24 h. Water was added to the reaction mixture under ice-cooling and stirred. The aqueous layer was extracted with ethyl acetate for three times. The combined organic layers were washed with water and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (7% ethyl acetate in n-hexane) to give the desired compound 4b (179 mg, 76%) as pale yellow solid. (1H-NMR (400MHz, CDCl3) δ 3.82 (9H, s), 6.37 (1H, t, J = 2.1 Hz), 6.65 (2H, d, J = 2.1 Hz), 6.89 (2H, d, J = 8.7 Hz), 6.89 (1H, d, J = 16.5 Hz), 7.04 (1H, d, J = 16.5 Hz), 7.44 (2H, d, J = 8.7 Hz); ESI-HRMS (positive ion): calcd for C17H18NaO3 ([M+Na]+) 293.1148 ; found 293.1143 HPLC Purity 92% (R.T. = 12.1 min, under gradient conditions as below). |
68.6% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With potassium carbonate In acetone for 0.5h; Stage #2: methyl iodide In acetone at 40℃; for 12h; Darkness; | 5.1.2 Synthesis of permethylated resveratrol 7 To a solution of resveratrol (1.00g, 4.38mmol, 1.0 equiv) in dry acetone (25mL) was added K2CO3 (5.45g, 39.4mmol, 9.0 equiv). After stirring the reaction mixture for 30min, CH3I (2.45mL, 39.4mmol, 9.0 equiv) was added dropwise by syringe. Then the reaction mixture was stirred at 40°C in the dark for 12h. The reaction mixtures were monitored by TLC until completion. After being quenched with saturated aqueous NH4C1 (25mL), the reaction contents were poured into water (10mL), extracted with EtOAc (3×30mL). The combined organic extracts were then washed with water (30mL) and brine (30mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel (hexanes/EtOAc=8:1) to afford the permethylated Resveratrol 7 (white solid, 0.81g, 68.6%). |
58% | With potassium carbonate In acetone for 24h; | |
46% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 5h; Inert atmosphere; | |
With potassium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | The synthesis was conducted under an argon gas atmosphere. Potassium hydroxide (22 mg,0.3922 mmol) was dissolved in methanol (3.0 mL) and this solution added to a suspension of(E)-3,4?,5-triacetoxystilbene (113 mg, 0.319 mmol) in methanol (10 mL). The solid immediately dissolvedand the clear solution was gently heated to reflux for 60 min, with an associated progressive darkeningin colouration. The volume was then reduced to half by rotary evaporation and the remaining solutionacidified (pH 2) with 1 M aq. HCl. Ethyl acetate (150 mL) was added and the reaction washed withsaturated brine (3 × 20 mL), dried and evaporated to return a dark red solid. Purification with columnchromatography (isocratically eluted with 100% EtOAc) gave (E)-resveratrol (58 mg, 79%) as a palebeige coloured solid. Rf 0.65 (EtOAc); mp 261.0-263.0 C (lit. [18] mp 255-260 C); deltaH (CD3OD)6.13 (pseudo t, 1H, J = 2.2 Hz, 4-H), 6.41-6.42 (m, 2H, 2-H, 6-H), 6.71-6.79 (m, 3H, Htrans, 3?-H, 5?-H),6.93 (d, 1H, J = 16.3 Hz, Htrans) and 7.29-7.36 (m, 2H, Jortho = 8.6 Hz, 2?-H, 6?-H); deltaC (CD3OD) 100.30,103.47, 114.12, 124.64, 126.43, 127.06, 128.07, 138.97, 155.89 and 157.20; m/z (ESI) 229 ([M + H]+,100%), 230 (23%). | |
With potassium hydroxide; In methanol; ethyl acetate; | Example 27 (E)-5-(4-hydroxystyryl)benzene-1,3-diol (27). Potassium hydroxide dissolved in methanol was added to <strong>[42206-94-0](E)-5-(4-acetoxystyryl)-1,3-phenylene diacetate</strong> suspended in methanol and heated to 65 C. under a nitrogen atmosphere for 1 hour. The volume was reduced by rotary evaporation and the solution then acidified to pH 3 with 1 M HCl. Ethyl acetate was added and the solution then washed three times with saturated brine, then dried, filtered and rotary evaporated to give a dark red solid. Purification by isocratic elution from column chromatography (0,040-0,063 mm SiO2) with EtOAc gave (E)-5-(4-hydroxystyryl)benzene-1,3-diol as a pale beige coloured solid. Rf 0.65 (EtOAc); 1H NMR (CD3OD): delta 6.13 (pseudo t, 1H, J=2.2 Hz, 4), 6.41-6.42 (m, 2H, 2,6), 6.71-6.79 (m, 3H, Htrans, 3'5'), 6.93 (d, 1H, J=16.3 Hz, Htrans), 7.29-7.36 (m, 2H, trans, Jortho=8.6 Hz, 2',6'). 13C JMOD NMR (CD3OD): delta. LRESI positive ion mass spectrum; m/z 229 (MH+, 100%), 230 (23%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With novozyme 435 from Candida antarctica In tert-Amyl alcohol at 40℃; for 120h; Enzymatic reaction; regioselective reaction; | |
85% | With lipase Candida Antarctica In tert-Amyl alcohol at 40℃; for 96h; Darkness; | 1 (E)-4-(3,5-dihydroxystyryl)phenyl acetate (compound 1): resveratrol (2,88 g, 12.61 mmol) was dissolved in 2-methylbutan-2-ol (280 mL) and vinyl acetate (72.40 mL, 756.70 mmol) in presence of the supported lipase Candida Antarctica (Novozyme 435, CalB, 14.40 g). The mixture was stirred with a rotary evaporator at 40°C during 4 days, protected from sunlight by aluminium foil. The lipase was then filtered off and washed with AcOEt (10x50 mL) and diethyl ether (2x50 mL). The filtrate obtained was concentrated under reduced pressure and the residue obtained was purified by chromatography on silica gel using solid deposit (CH2Cl2/MeOH 99/1 to 98/2) to give the 4'-O-acetyl resveratrol 1 (2.89 mg, 85%) as white solid. Rf (CH2Cl2/MeOH 95/5) 0.3; 1H NMR (500 MHz; CD3OD) δH 7.54 (d, J = 7.6 Hz, 2H, H2' and H6'), 7.07 (d, J = 7.6 Hz, 2H, H3' and H5'), 7.04 (d, J = 16.2 Hz, 1H, H8), 6.97 (d, J = 16.2 Hz, 1H, H7), 6.49 (s, 2H, H2, H6), 6.21-6.19 (m, 1H, H4), 2.27 (s, 3H, CH3(OAc)); 13C NMR (125 MHz; MeOD) δC 171.1, 159.7(2C), 151.5, 140.6, 136.6, 130.2, 128.3, 128.3, 122.9 (2C), 122.9 106.1(2C), 103.2, 20.9. (E)-4-(3,5-bis((triisopropylsilyl)oxy)styryl)phenyl acetate (compound 2): |
57% | With supported Candida antarctica lipase B In tert-Amyl alcohol at 40℃; for 96h; Enzymatic reaction; regioselective reaction; |
57% | With lipase Candida antarctica In tert-Amyl alcohol at 40℃; for 96h; Enzymatic reaction; | 3 (E)-4-(3,5-dihydroxystyryl)phenyl acetate 16 Resveratrol (200 mg, 0.88 mmol) was dissolved in 2-methylbutan-2-ol (20 ml_) and vinyl acetate (5 ml_) in presence of the supported lipase Candida Antarctica (Novozyme 435, CalB, 1 g). The mixture was stirred with a rotary evaporator at 40°C during 4 days. The lipase was filtered off and washed with AcOEt twice and diethyl ether. The filtrate obtained was concentrated under reduced pressure and the residue obtained was purified by chromatography on silica gel (CH2CI2/MeOH 99/1 to 90/10) to give the 4'-0-acetyl resveratrol 16 (135 mg, 57%) as white solid. 27% of starting material were recovered after purification (5 mg). (0334) Rf (CH2CI2/MeOH 95/5) 0.30; 1 H NMR (500 MHz; CD3OD) δΗ 7.54 (d, J = 7.6 Hz, 2H, H2and H6 ), 7.07 (d, J = 7.6 Hz, 2H, H3 and H5 ), 7.04 (d, J = 16.2 Hz, 1 H, H8), 6.97 (d, J = 16.2 Hz, 1 H, H7), 6.49 (s, 2H, H2, H6), 6.21 -6.19 (m, 1 H, H4), 2.27 (s, 3H, CH3(oAc)) ; 13C NMR (125 MHz; MeOD) 5C 171 .1 , 159.7, 151 .5, 140.6, 136.58, 130.24, 128.3, 128.3, 122.9, 106.1 , 103.2, 20.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C16H1504 271 .0964; found 271 .0972. |
43% | With Candida antarctica lipase In tert-Amyl alcohol at 40℃; for 90h; | |
In 2-methyl-2-butanol at 40℃; Enzymatic reaction; regioselective reaction; | ||
With Candida antarctica lipase In tert-Amyl alcohol at 40℃; for 90h; Enzymatic reaction; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With dmap; triethylamine In dichloromethane at 10℃; Stage #2: n-octanoic acid chloride In dichloromethane at 10℃; for 1h; | (E)-5-(4-(Octanoyloxy)styryl)-1,3-phenylene dioctanoate (3d) Resveratrol (1) (5.0 g, 21.9 mmol) wasdissolved in CH2Cl2 (40 mL) and kept cool at 10 °C. TEA (7.1 g, 70.1 mmol) and DMAP (0.26 g, 2.2 mmol)were added to the reaction mixture. After stirring at 10 °C, octanoyl chloride (11.0 g, 67.9 mmol) wasadded carefully and the reaction was kept for 1 h at 10 °C. After adding distilled water (40 mL) to reactionmixture, the CH2Cl2 fraction was extracted. The CH2Cl2 layer were dried over anhydrous MgSO4 andevaporated under vacuum. The crude product was purified by silica gel column chromatography withn-hexane-EtOAc (30:1) as an eluent to give compound 3d (12.9 g, 96.7% yield). Compound 3d: IRνmax cm-1: 1758, 1644, 1367, 1267; 1H-NMR (500 MHz, CDCl3) δ 7.51 (2H, d, J = 8.5 Hz), 7.11 (4H, m),7.08 (1H, J = 16.0 Hz), 6.99 (1H, d, J = 16.0 Hz), 6.82 (1H, d, J = 2.0 Hz), 2.58 (6H, m), 1.79 (6H, m),1.34-1.42 (24H, m), 0.94 (12H, m); 13C-NMR (100 MHz, CDCl3) δ 172.2, 171.8, 151.4, 150.5, 139.4,134.3, 129.6, 127.6, 127.2, 121.9, 116.8, 114.4, 34.4, 34.4, 31.6, 29.0, 28.9, 24.9, 24.8, 22.6, 14.0;ESI-MS (positive mode) m/z: 629 [M + Na]+, HRESIMS: m/z 645.3550 (calcd. for C38H54KO6, 645.3551). |
20% | With potassium carbonate In acetonitrile at 25℃; for 20h; | 1 Compound 1 1 : [4-[(E)-2-[3,5-di(octanoyloxy)phenyl]vinyl]phenyl] octanoate To a mixture of 5-[(E)-2-(4-hydroxyphenyl)vinyl]benzene-1 ,3-diol (1 g) and K2CO3 (1 .8 g) in ACN (30 mL) was added octanoyl chloride (2.14 g) at 25°C. The mixture was stirred at 25°C for 10 hours. Additional octanoyl chloride (1 .42 g) was added and the mixture was stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase prep-HPLC (C18, water(0.05%HCI)-ACN gradient) to give compound 1 1 (0.53 g, 20%) as colorless oil. 1 H NMR (400 MHz, CDCI3). 7.481 (m, 2H), 7.107 - 6.956 (m,6H),6.809, (m,1 H), 2.564 (m,6H), (0760) 1 .781 (m,6H),1 .383 (m, 24H), 0.894 (m,9H). |
With pyridine |
With pyridine at 20℃; | ||
With potassium carbonate In acetonitrile at 25℃; for 20h; | 69 Example 69: [4-[(E)-2-[3,5-di(octanoyloxy)phenyl]vi nyl]phenyl] octanoate To a mixture of 5-[(E)-2-(4-hydroxyphenyl)vinyl]benzene-1 ,3-diol (1 g) and K2003 (1 .8 g) inacetonitrile (30 mL) was added octanoyl chloride (2.14 g) at 25°C. The mixture was stirred at 25°C for 10hours. Additional octanoyl chloride (1 .42 g) was added and the mixture was stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase prep-HPLC (Cl 8, water(0.05%HCI)-acetonitrile gradient) to give [4-[(E)-2-[3,5- di(octanoyloxy)phenyl]vinyl]phenyl] octanoate (0.53 g, 20%) as colorless oil. 1H NMR (400 MHz, CDCI3):O 7.481 (m, 2H), 7.107 - 6.956 (m, 6H), 6.809, (m, 1 H), 2.564 (m, 6H), 1.781 (m, 6H), 1.383 (m, 24H),0.894 (m, 9H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 89% 2: 8% | With potassium carbonate In acetone for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3,5,4'-trimethoxystilbene With boron tribromide In toluene at 0 - 20℃; for 2.03333h; Stage #2: With water; sodium hydrogencarbonate In toluene at 0℃; for 0.333333h; | 5 Example 5 Example 5 E-3,5,4'-trihydroxystilbene (Resveratrol) To a solution of the product of Example 4 (0.5g, 1.85mmol) in dry toluene (5ml) at 0°C under N2 was added BBr3 (0.58ml, 5.55mmol) dropwise over 2 mins. The reaction mixture was then allowed to stir at 0°C for 0.5h and room temperature for 1.5h. Progress of the reaction was monitored by thin layer chromatography (methanol:dichloromethane 1:9). The reaction was then cooled to 0°C before the careful addition of saturated aq. NaHCO3 (15ml). This mixture was allowed to stir for 20mins before addition of ethyl acetate (25ml). Stirring was continued for 15mins before separation of the layers. The organic portion was washed further with brine (2 x 15ml) before drying (Na2SO4), filtration and concentration in vacuo yielding an off-white solid. This was slurried in diethylether:hexane (1:1) (20ml), filtered and air-dried yielding resveratrol as a beige solid (0.39g, 92%). |
90% | With aluminum (III) chloride; triethylamine In chlorobenzene at 60 - 70℃; for 0.5h; Inert atmosphere; | |
Multi-step reaction with 2 steps 1: BBr3 2: diphenyl disulphide / tetrahydrofuran / Heating |
With pyridine hydrochloride at 190 - 195℃; for 4h; | ||
Stage #1: 3,5,4'-trimethoxystilbene With iodine In hexane for 48h; Reflux; Stage #2: With boron tribromide In dichloromethane at 0 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With methanol; potassium hydroxide; at 65℃; for 0.5h;Product distribution / selectivity; | Example 10 50 MG (0.14 MMOL) OF (E) -3, 4 , 5-TRIACETOXYSTILBENE WAS DISSOLVED IN 3 ML METHANOL AND degassed with argon. 8 mg (0.14 mmol) of potassium hydroxide in 0.5 ml methanol were added dropwise under a slight argon stream and the mixture was heated for 30 minutes to 65C. The obtained solution was neutralized with 1 N hydrochloric acid, poured into 10 ml of ethyl acetate and extracted 3 x against 5 ML of brine. The organic phase was dried over MGS04 and the solvent removed in vacuo giving 30 mg of resveratrol (0.13 mmol, 92%). |
With potassium hydroxide; In methanol; ethyl acetate; | Alkene 1; (E)-Resveratrol The reaction was conducted under an argon gas atmosphere. Potassium hydroxide (22 mg, 0.3922 mmol) dissolved in methanol (3.0 mL) was added to a suspension of (E)-3,4',5-triacetoxystilbene (113 mg, 0.319 mmol) in methanol (10 mL). The solid immediately dissolved and the clear solution was gently heated to reflux for 60 minutes and a marked darkening in colouration noted. The volume was then reduced to half with rotary evaporation and the remaining solution acidified (pH 2) with 1M aq. HCl. Ethyl acetate (150 mL) was added and the reaction washed with sat. brine (3*20 mL), dried and evaporated to return a dark red solid. Purification with column chromatography (isocratically eluted with 100% EtOAc) gave (E)-resveratrol (58 mg, 79%) as a pale beige coloured solid. Rf 0.65 (EtOAc); mp 261.0-263.0 C. (lit mp 255-260 C.); deltaH(CD3OD) 6.13 (pseudo t, 1H, J 2.2, 4-H), 6.41-6.42 (m, 2H, 2-H, 6-H), 6.71-6.79 (m, 3H, Htrans, 3'-H, 5'-H), 6.93 (d, 1H, J 16.3, Htrans) and 7.29-7.36 (m, 2H, Jortho 8.6, 2'-H, 6'-H); deltaC(CD3OD) 100.30, 103.47, 114.12, 124.64, 126.43, 127.06, 128.07, 138.97, 155.89 and 157.20; m/z (ESI) 229 (MH+, 100%), 230 (23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,4,6-trimethyl-pyridine; silver carbonate In dichloromethane; acetonitrile at 25℃; for 72h; Under anhydrous N2; | 20 Preparation of a Resveratrol Galactoside Conjugate Resveratrol (77 mg, 0.337 mmole) was dissolved in anhydrous dichloromethane (20 mL) and anhydrous acetonitrile (5 mL) containing 3A molecular sieves (1 gram). Sym-collidine (134 μL, 1.01 mmole), dry silver carbonate (140 mg, 0.51 mmole) and acetobromogalactose (416 mg, 1.01 mmole) were added sequentially under anhydrous conditions, and this mixture allowed to stir under anhydrous nitrogen gas, in the dark, for 72 hours at 25° C. T.l.c. analysis (SiO2 plate; irrigant=9:1 chloroform:methanol) showed the production of three products (Rf=0.53, 0.29, 0.09 respectively). The reaction mixture was filtered through a Celite or diatomaceous earth pad and the precipitate washed with fresh chloroform (5×10 mL). The combined filtrates were extracted with water, 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, 2% aqueous ammonium hydroxide solution and water (1×50 mL each). The combined organic layers were dried over anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo. The crude sample was applied to a column of Silicagel G (70-230 mesh, 20 grams) and eluted with chloroform:methanol (19:1). The second major product to elute from the column was combined, evaporated, and dried in vacuo to give a glass (48 mg, 22% theoretical yield). 1H-n.m.r. analysis (CDCl3) indicated production of a mono-galactoside product. The per-acetate from above (40 mg, 0.07 mmole) is suspended in anhydrous methanol and sodium methoxide/methanol (25% w/v) added (0.5 mL). This mixture is allowed to stir at 0° C. for 2 hours and at room temperature for 16 hours. The reaction is neutralized with washed, dry IRC50(H+) resin, the resin filtered and washed with methanol (6×10 mL) and the filtrate evaporated to a white solid, homogeneous by t.l.c. (SiO2: irrigant=7:3 ethylacetate:methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With laccase In acetone at 27℃; for 24h; Enzymatic reaction; | |
20% | With silver(I) acetate In methanol at 50℃; for 1h; | Synthesis of α-viniferin (2a) After stirring of resveratrol (1a, 0.44 mmol) and32 AgOAc (0.66 mmol) in MeOH (5 mL) at 50°C for 1 h, the resultant solution was33 concentrated in vacuo. The residue was purified using silica gel column chromatography34 eluted with CHCl3/MeOH (10/1) and HPLC (40% MeCN elution), to afford 2a.35 -Viniferin (2a): 20% yield. IR (ATR): νmax 3270, 2958, 2921, 2851, 1594, 1143 cm-1;36 1H NMR (400 MHz, Acetone-d6): δ 7.43 (1H, dd, J = 8.7 and 1.6 Hz, H-6), 7.26 (1H, s,37 H-4), 7.24 (2H, d, J = 8.7 Hz, Ar), 7.06 (1H, d, J = 16.5 Hz, -CH=CH-), 6.91 (1H, d, J =38 17.0 Hz, -CH=CH-), 6.88 (1H, d, J = 8.7 Hz, H-7), 6.86 (2H, d, J = 9.16 Hz, Ar), 6.5439 (2H, d, J = 2.3 Hz, Ar), 6.29 (1H, t, J = 2.1 Hz, Ar), 6.26 (1H, t, J = 2.3 Hz, Ar), 6.20 (2H,40 d, J = 2.3 Hz, Ar), 5.45 (1H, d, J = 8.2 Hz, H-2), 4.47 (1H, d, J = 8.2 Hz, H-3); 13C NMR41 (100 MHz, Acetone-d6): δ 159.0, 158.9, 158.7, 157.6, 144.4, 140.0, 131.7, 131.3, 130.9,42 128.3, 127.9, 127.8, 126.4, 123.1, 115.3, 109.3, 106.6, 104.9, 101.9, 101.5, 93.2,43 57.0HRESITOFMS: m/z 455.1489 [M+H]+ (calcd. for C28H23O6, 455.1495). |
With copper(II) sulfate In acetonitrile at 20℃; |
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium hexacyanoferrate(III) / methanol; water / 20 °C 1.2: 24 h / 20 °C 2.1: potassium carbonate / methanol; water / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol; N,N-dimethyl-formamide With trichlorophosphate In acetonitrile at 20℃; for 2.5h; Cooling with ice; Stage #2: With water In acetonitrile at 50℃; for 3h; | 4.2. Synthesis method for (E)-2,4-dihydroxy-6-(4-hydroxystyryl)benzaldehyde (A) To a solution of resveratrol (2.28 g, 0.01 mol) in 50 mL of CH3CN and DMF (0.73 g, 0.01 mol), POCl3 (2.30 g, 0.015 mol) was added dropwise while cooling with an ice/water bath for 0.5 h. The reaction mixture was stirred for another 2 h at room temperature. Then, the solution was added to cold water (300 mL). The yellow solution was stirred under 50 °C for 3 h, and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel afforded (A) as yellow powder in 96% yield. Mp: 210-212 °C. 1H NMR (DMSO-d6): 6.21 (s, 1H), 6.62 (s, 1H), 6.78 (d, 2H, J = 8.4 Hz), 7.02 (d, 1H, J = 16.0 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.70 (d, 1H, J = 16.2 Hz), 9.71 (s, 1H), 10.27 (s, 1H), 10.76 (s, 1H), 12.12 (s, 1H). MS (ESI): 257.3 (C15H12O4, [M+H]+). Anal. Calcd for C15H12O4: C, 51.05; H, 3.86. Found: C, 50.91; H, 3.87. |
96% | With trichlorophosphate In N,N-dimethyl-formamide; acetonitrile at 20℃; for 2.5h; Cooling with ice; | Synthesis method for (E)-2, 4-dihydroxy-6-(4-hydroxystyryl)benzaldehyde (A) To a solution of resveratrol (2.28 g, 0.01 mol) in 50 mLof CH3CN and DMF (0.73 g, 0.01 mol), POCl3 (2.30 g,0.015 mol) was added dropwise while cooling with anice/water bath for 0.5 h. The reaction mixture was stirred for another 2 h at room temperature. Then, the solution was added to cold water (300 mL). The yellow solution was stirred under 50 oC for 3 h, and extracted with EtOAc (100mL 3). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel afforded (A) as yellow powder in 96% yield. Mp: 210-212 oC. 1H NMR (DMSOd6): 6.21 (s, 1H),6.62 (s, 1H), 6.78 (d, 2H, J = 8.4 Hz), 7.02(d, 1H, J = 16.0 Hz), 7.49(d, 2H, J = 8.4 Hz), 7.70 (d, 1H, J= 16.2 Hz), 9.71 (s, 1H), 10.27(s, 1H), 10.76 (s, 1H), 12.12(s, 1H). MS (ESI): 257.3 (C15H12O4, [M+H]+). Anal. Calcdfor C15H12O4: C, 51.05; H, 3.86. Found: C, 50.17; H, 3.86%. |
95% | With trichlorophosphate at 20℃; for 3h; Cooling with ice; | 1.1 1) Synthesis of aldehyde resveratrol (1): Weigh 1 g (4.4 mmol) of resveratrol in a round bottom flask and dissolve it in 5 ml of DMF; 2.5 mL of POCl3 was dissolved in 5 mL of DMF, and slowly add dropwise to the round bottom flask in an ice water bath. After the dropwise addition, stir at room temperature for 1 h until a viscous solution was formed. 30 ml of water was then added dropwise to the solution in an ice-water bath. Stir the yellow solution for 2h,After filtration and vacuum drying at 80 ° C, a yellow powder product (aldehyde resveratrol (1)) was obtained with a yield of 95%. |
95% | Stage #1: N,N-dimethyl-formamide With trichlorophosphate Stage #2: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol at 20℃; for 1h; Cooling with ice; | |
62% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol; N,N-dimethyl-formamide With trichlorophosphate In acetonitrile at -5℃; for 3h; Stage #2: With water In acetonitrile at 55℃; for 2h; | |
16% | With trichlorophosphate In acetonitrile at 20℃; for 1h; Cooling with ice; | (2,4-dihydroxy-6-((E)-2-(4-hydroxyphenyl)) benzaldehyde) Freshly distilled POCl3 (0.6 ml, 6 mmol) was added drop by drop to a solution of resveratrol(912 mg, 4 mmole) and DMF (464 ml, 6 mmol) in 20 ml of MeCN that was sitting in an icewaterbath. The mixture was stirred for 1 h at room temperature. Then, the solution was addedto a mixture of ice and water, and the yellow mixture was stirred at 40°C in a water bathand extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with water,dried over Na2SO4, filtered and evaporated. Purification by flash chromatography yieldedproduct 2 162 mg (yield 16%). 1H NMR (200 MHz, MeOD, ppm): δ 6.17 (d, J = 2.2 Hz, 1H),6.56 (d, J = 2.2 Hz, 1H), 6.76-6.81 (m, 2H), 6.92-6.99 (m, 1H), 7.39-7.47 (m, 3H), 10.19 (s,1H). 13C NMR (200 MHz, MeOD, ppm): δ 102.3, 107.5, 116.6, 120.9, 125.9, 129.5, (CH), 135.9,144.5, 147.0, 159.2, 168.9 (C), 194.3 (CHO). 1H NMR and 13C NMR spectra of RA wereobtained with a 200-MHz Bruker NMR spectrometer (Bruker Biospin GmbH, Rheinstetten,Germany). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.5% | With potassium carbonate In acetonitrile at 20℃; for 4h; | 4. General synthetic procedures for RLA8 and compounds 9. (compound 9 as example) General procedure: 1. (E)-2-(2-fluoro-4-((3-methoxy-5-(4-methoxystyryl)phenoxy)methyl)phenoxy)acetic acid (compound 9) To a solution of 10a (0.5 g, 2.19 mmol) in acetonitrile was added K2CO3 (0.91 g, 6.57 mmol) at room temperature. Then the solution of methyl iodide in acetonitrile was dropwise added at room temperature with stirring for 4 h. Then the reaction mixture was filtrated and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford a white solid 11a 0.3 g (yield: 53.5%). |
53.5% | With potassium carbonate In acetonitrile at 20℃; for 4h; | 4. General synthetic procedures for RLA8 and compounds 9. (compound 9 as example) General procedure: 1. (E)-2-(2-fluoro-4-((3-methoxy-5-(4-methoxystyryl)phenoxy)methyl)phenoxy)acetic acid (compound 9) To a solution of 10a (0.5 g, 2.19 mmol) in acetonitrile was added K2CO3 (0.91 g, 6.57 mmol) at room temperature. Then the solution of methyl iodide in acetonitrile was dropwise added at room temperature with stirring for 4 h. Then the reaction mixture was filtrated and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a mixture of petroleum ether/ethyl acetate (10:1, v/v) as eluent to afford a white solid 11a 0.3 g (yield: 53.5%). |
48% | With potassium carbonate In acetone at 20℃; | 1 Resveratrol 10.16g (44.51mmol) was dissolved in 100ml dry acetone (acetone),Added 18.75g (135.66mmol) of potassium carbonate and mix well. The 6ml (97.31mmol) of methyl iodide was dissolved in 50ml of anhydrous acetone and uniformly mixed at room temperature was slowly added dropwise to the reaction system. Completion of the dropwise addition, stirred at room temperature. The reaction was monitored by TLC. After completion of the reaction, potassium carbonate was removed by suction, the filter cake was rinsed with anhydrous acetone, the filtrate was collected, the solvent evaporated under reduced pressure to give a brown oil, brown oil was subjected to column 200-300 mesh silica gel layer separated by decantation with petroleum ether ethyl acetate (volume ratio 41) to give 3,4'-dimethoxy-5-hydroxy - (E) - stilbene (i-1) of a yellow solid 5.48g, yield: 48.0%. |
32% | With potassium carbonate In acetone for 12h; Reflux; | |
4.9 g | With potassium carbonate In acetone for 10h; Reflux; Inert atmosphere; | 1.1.1 Reference Example 1.1 3,4'-Dimethoxy-5-hydroxy-(E)-stilbene (i-1) Dissolve 20g resveratrol in 400mL acetone,Add 30.3g K2CO3 and 6.66mL CH3I successively,Heat and reflux for 10 hours under the protection of nitrogen, stop heating, filter after cooling, and wash the filter cake with acetone;Combine the filtrate and washing liquid, concentrate and separate with 200-300 mesh silica gel column chromatography,Elute with a mixed solvent of petroleum ether: ethyl acetate: acetic acid (8.5: 1.5: 0.16),4.9 g of 3,4'-dimethoxy-5-hydroxy-(E)-stilbene (i-1) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.5% | With iron(III) chloride hexahydrate In methanol; water at 20℃; for 60h; | 3.2. Synthesis of Compoud 2 The solution of FeCl3*6H2O (380 g, 1.43 mol) in H2O (100 mL) was added to a solution of 1(300 g, 1.32 mol) in methanol (500 mL) under stirring at room temperature, and the mixture was stirredfor 60 h at room temperature. After removing of methanol in vacuo, water was added to the mixture,and the mixture was extracted with EtOAc. Subsequently, the obtained organic layer was washed withbrine and water, dried over anhydrous Na2SO4 for 24 h, then concentrated in vacuo to give a residue,which was further chromatographed on silica gel column with CHCl3-MeOH (15:1, ν/ν) as eluent toprovide unreacted resveratrol 130 g and product 2 (23 g, yield 13.5%).Compound 2: grey amorphous powder. 1H-NMR(CD3COCD3, 500 MHz) δ: 8.41 (OH), 8.38 (OH),8.33 (OH), 8.17 (2H, 2 x OH), 7.20 (2H, d, J = 9.0 Hz, H-2a, 6a), 7.16 (2H, d, J = 8.5 H, H-2b, 6b),6.90 (1H, d, J = 16.0 Hz, H-7b), 6.82 (2H, d, J = 9.0 Hz, H-3a, 5a), 6.73 (2H, d, J = 8.5 Hz, H-3b, 5b),6.72 (2H, d, J = 2.0 Hz, H-10a, 14a), 6.70 (1H, d, J = 16.0 Hz, H-8b), 6.32 (1H, d, J = 2.0 Hz, H-12b),6.23 (2H, br s, H-12a, 14b), 5.41 (1H, d, J = 5.5 Hz, H-7a), 4.47 (1H, d, J = 5.5 Hz, H-8a); (+)-ESI m/z:477 [M + Na]+. |
10.2% | With iron(III) chloride hexahydrate In methanol; water at 20℃; for 72h; | 1 5- [2- (4-hydroxyphenyl) -4- [2- (4-hydroxyphenyl) vinyl-6-hydroxy] -2,3-dihydro-3-benzofuranyl] -1, 3-benzenediol (1) 100 g of resveratrol (438.6 mmol) was dissolved in 1000 mL of anhydrous methanol, and an aqueous FeCl3 solution [116.7 g of FeCl3 · 6H2O (432.619 mmol) was dissolved in 67 mL of water was added dropwise with stirring]. The reaction solution was stirred at room temperature for 3 days and the reaction was stopped. The solvent was evaporated under reduced pressure to obtain a black extract. The extract was subjected to silica gel (100-200 mesh) column chromatography using petroleum ether: acetone = 6: 3 to obtain 30.5 g (67.181 mmol) of a gray solid compound with a yield of 10.2%. |
With iron(III) chloride In methanol |
With ruthenium(III) trichloride hydrate In methanol; water at 0 - 35℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With streptomyces avermilitis tyrosinase; benzene-1,2-diol; In aq. buffer; for 3h;pH 8.0;Enzymatic reaction; | When cultured according to the above-described expression method 1,The SAV-derived tyrosinase-expressing cells were washed without cell disruption, and then resuspended in 0.1 mM resveratrol,(NADH, L-ascorbic acid, glutathione, cysteine, hydroquinone, 1-naphthol, p-coumaric acid, curcumin, catechol, pyrogallol or ferulic acid)Was added to produce fichethanol.After the reaction, the product was extracted with the same amount of ethylacetate (EA) or nonpolar solvent, and quantitatively analyzed by high performance liquid chromatography to compare the production efficiency of physisathenol by the addition of reducing agent. |
100% | With ascorbic acid; In aq. phosphate buffer; dimethyl sulfoxide; at 30℃;pH 6.0; | The reaction was normally carried out in 2.0 mL phosphate buffer(50 mM, pH 6.0) containing 20.0mM Res, 40.0mM L-ascorbic acid and25% (v/v) DMSO (for pre-dissolving Res) in a shaking incubator withagitation of 220 rpm at 30 C. 10.0 mg of tyrosinase CLEAs was added tostart the reaction, and every one hour a 0.1 mL sample was taken,which was then 20 times diluted with 50% (v/v) acetonitrile aqueoussolution before being subjected to HPLC analysis as described below. |
With water; In aq. phosphate buffer; dimethyl sulfoxide; glycerol; at 30℃; for 12h;pH 7.5; | The reaction was performed in a 500-mL flask that contained cells of the transformed E. coli strain (32 g of dry cell weight per liter), resveratrol(30 mM), dimethylsulfoxide (4% v/v), and potassium phosphate buffer (200 mM, pH7.5) containing glycerol (10% v/v) in a volume of 20 mL. The reaction mixture was supplemented with Tween 80 (1% v/v) when required. The reactions were carried out at 30 C with reciprocal shaking at a speed of 240 rpm. |
With Streptomyces sp. strain SB-14; In aq. phosphate buffer; dimethyl sulfoxide; at 28℃; for 24h;pH 7.2;Enzymatic reaction; | The cells harvested from a culture broth of Streptomyces sp. Strain SB-14 were washed twice with apotassium phosphate buffer (50 mM, pH 7.2). After centrifugation (13,000 g, 10 min), 100 mg of cells(wet wt.) was added in 900 muL of a potassium phosphate buffer (100 mM, pH 7.2) with 100 muL ofresveratrol (0.5 mM in DMSO). The total reaction volume was 1 mL and shaken for 24 h at 28 C. After 12 h, the reactant was extracted with ethylacetate (JUNSEI, Kyoto, Japan). The extracted sample was evaporated in a centrifugal vacuum concentrator (BioTron, Puchon, Korea) and dissolved in methanol (MERCK, Darmstadt, Germany). | |
With D-glucose 6-phosphate; Bacillus megaterium cytochrome P450 BM3, CYP102A1, wild-type; yeast glucose 6-phosphate; NADP; In aq. phosphate buffer; at 37℃; for 0.166667h;pH 7.4;Enzymatic reaction;Kinetics; | Oxidation of trans-resveratrol, a substrate of human CYP1A2, by CYP102A1 was identified. Typical steady-state reactions for trans-resveratrol hydroxylation included 50 pmol P450 BM3 in 0.25 ml of a 100 mM potassium phosphate buffer (pH 7.4) were performed along with a specified amount of a substrate. To determine the kinetic parameter of several CYP102A1 mutants, 2 to 100 muM of trans-resveratrol was used. An NADPH-generating system was used to initiate reaction solutions (final concentrations: 10 mM glucose 6-phosphate, 0.5 mM NADP+, and 1 IU yeast glucose 6-phosphate per ml). Trans-resveratrol stocks (20 mM) were prepared in DMSO and diluted into the enzyme reactions with the final organic solvent concentration <1% (v/v). Reactions were generally incubated for 10 min at 37 C., and terminated with 105 mul of ice-cold acetic acid/methanol (95/5, v/v). | |
With beta-nicotinamide adenine dinucleotide 2?-phosphate reduced tetrasodium salt; ascorbic acid; In aq. phosphate buffer; dimethyl sulfoxide; at 37℃; for 1h;pH 7.4;Darkness; Enzymatic reaction; | Crude protein extracts were prepared from elicited V. vinifera cv. Gamay cell cultures as described in [6]. Resveratrol hydroxylation reaction was assayed as described in [39,53]. The reaction mixture contained 0.2 mM of trans-R delivered in DMSO (Fluka Chemika-Sigma Aldrich, St. Louis, MO, USA),1 mM ascorbic acid, 1 mM NADPH, and 100 mM potassium phosphate buffer, pH 7.4, and started by adding 50 L of protein extract to complete a final volume of 1 mL. The reaction mixture was incubated for 1 h at 37 C in the dark and terminated by the addition of 0.5 mL ethyl acetate to extract stilbenoids twice. The solvent was evaporated in a Speed-vac (Eppendorff, Hamburg, Germany) and the solid residue resuspended in 0.2 mL 80% methanol. One L of reaction medium extract was injected for UHPLC-MS MRM analysis under the optimized conditions. Absolute concentration of stilbenes in real samples of cell extracts and enzymatic reactionextract was determined using an external calibration curve performed with three levels of standards in duplicate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydride In tetrahydrofuran; mineral oil Stage #2: chloromethyl methyl ether In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 25℃; | |
30% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: chloromethyl methyl ether In tetrahydrofuran; mineral oil at 20℃; for 24h; | |
27% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16.5h; Cooling with ice; | Preparation of (E)-1,3-Bis(methoxymethoxy)-5-(4-(methoxymethoxy)styryl)benzene (Compound 4e) To a solution of 1 (100 mg, 0,44 mmol) in DMF(1 mL) was added N,N-diisopropylethylamine (283 mg, 2.2 mmol) and methoxymethylchloride (282 mg, 3.5 mmol) under ice cooling. The mixture was stirred at ambient temperature for 16.5 h. The reaction mixture was added to water under ice cooling, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was suspended in ethyl acetate and crystallized with n-hexane. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (20% ethyl acetate in n-hexane) to give the desire compound 4e as a white solid (42 mg, 27%). 1H-NMR (400MHz, CDCl3) δ 3.49 (3H, s), 3.50 (6H, s), 5.19 (6H, s), 6.64 (1H, t, J = 2.3 Hz), 6.85 (2H, d, J = 2.3 Hz), 6.91 (1H, d, J = 16.0 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.04 (1H, d, J = 16.0 Hz), 7.43 (2H, d, J = 8.7 Hz); ESI-MS (positive ion): calcd for C20H24NaO6 ([M+Na]+) 383.1465; found 383.1475 HPLC Purity >99% (R.T. =11.6 min, under gradient conditions as below). |
23% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide; mineral oil at 25℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 78% 2: 28% | With triethylamine In dichloromethane at 0 - 20℃; for 2.5h; | |
1: 65% 2: 28% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 1 [0185] Resveratrol (Res) was reacted with 1.2 equivalents of acetylsalicyloyl chloride under basic conditions to generate two resveratrol aspirinate isomers: RAS (yield: 65%) and RAS-1 (yield: 28%). The compound structures were determined by 1H NMR and MS analysis. [0186] RAS: white solid; 1H NMR (600 MHz, CD3OD) δ 6.89 (1H, s, H-2), 6.51 (1H, t, J=2.0 Hz, H-4), 6.84 (1H, s, H-6), 7.09 (1H, d, J=16.3 Hz, H-7), 6.93 (1H, d, J=16.3 Hz, H-8), 7.41 (2H, d, J=8.6 Hz, H-10/14), 6.79 (2H, d, J=8.6 Hz, H-11/13), 7.26 (1H, d, J=8.0 Hz, H-4′), 7.74 (1H, dt, J=8.0, 1.6 Hz, H-5′), 7.47 (1H, t, J=8.0 Hz, H-6′), 8.20 (1H, dd, J=8.0, 1.6 Hz, H-7′), and 2.30 (3H, s, CH3C═O); 13C NMR (125 MHz, CD3OD); positive APCIMS, m/z 391 [M+H]+. [0187] RAS-1: white solid; 1H NMR (600 MHz, CD3OD) δ 6.53 (2H, d, J=2.0 Hz, H-2/6), 6.24 (1H, t, J=2.0 Hz, H-4), 7.09 (1H, d, J=16.3 Hz, H-7), 7.03 (1H, d, J=16.3 Hz, H-8), 7.61 (2H, d, J=8.6 Hz, H-10/14), 7.18 (2H, d, J=8.6 Hz, H-11/13), 7.26 (1H, d, J=8.0 Hz, H-4′), 7.73 (1H, dt, J=8.0, 1.6 Hz, H-5′), 7.47 (1H, t, J=8.0 Hz, H-6′), 8.21 (1H, dd, J=8.0, 1.6 Hz, H-7′), and 2.29 (3H, s, CH3C═O); positive APCIMS, m/z 391 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | Resveratrol (1) (5.0 g, 21.9 mmol) was dissolvedin CH2Cl2 (40 mL) and kept cool at 10 C. TEA (7.1 g, 70.1 mmol) and DMAP (0.26 g, 2.19 mmol)were added to the reaction mixture at 10 C. Acetyl chloride (5.3 g, 67.9 mmol) was added carefully andthe reaction was kept for 1 h at 10 C. After adding distilled water (40 mL) to the reaction mixture, theCH2Cl2 fraction was extracted. The CH2Cl2 layers were dried over anhydrous MgSO4 and evaporated undervacuum. The crude product was purified by silica gel column chromatography with n-hexane-EtOAc (30:1)as an eluent to give compound 3a (6.9 g, 88.2% yield). Compound 3a: IR numax cm-1: 1759, 1707, 1532,1124; 1H-NMR (500 MHz, CDCl3) delta 7.54 (2H, d, J = 8.5 Hz), 7.12 (4H, m), 7.08 (1H, J = 16.0 Hz),6.98 (1H, d, J = 16.0 Hz), 6.85 (1H, d, J = 2.0 Hz), 2.33 (9H, s); 13C-NMR (100 MHz, CDCl3) delta 169.3,169.0, 151.3, 150.4, 139.5, 134.4, 129.6, 127.6, 127.2, 121.9, 116.9, 114.4, 21.1; ESI-MS (positive mode)m/z: 377 [M + Na]+, HRESIMS: m/z 393.0734 (calcd. for C20H18KO6, 393.0734). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; In dimethyl sulfoxide; at 60℃; for 1h; | General procedure: For the identification of resveratrol metabolite, produced by P450 BM3 mutants, GC-MS analysis was done by comparing GC-profiles and fragmentation patterns of piceatannol and resveratrol. An oxidation reaction of trans-resveratrol by P450 BM3 mutants was done. The aqueous samples were extracted with ethyl acetate. After centrifugation, the organic phase was dried under nitrogen as well as the standard trans-resveratrol and piceatannol solutions (10 mM in DMSO). Then, trimethylsilyl (TMS) derivatives were prepared as follows. 100 mul of a solution of BSTFA/TMCS (99/1, v/v) (Supelco) was added to the dry residue or standard trans-resveratrol and piceatannol, and then the mixture was left for 60 min at 60 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydroxide In N,N-dimethyl-formamide for 0.166667h; Stage #2: ethyl bromide In N,N-dimethyl-formamide at 40℃; for 24h; | (E)-1,3-Diethoxy-5-(4-ethoxystyryl)benzene (2a) Resveratrol (1) (15.0 g, 65.7 mmol) was dissolved ina solution of DMF (150 mL) and NaOH (8.9 g), and stirred for 10 min. Then, 1-bromoethane (25.8 g,236.6 mmol) was added and the reaction was kept for 24 h at 40 °C. After the removal of DMF byevaporation under vacuum, the reaction mixture was extracted with toluene (45 mL × 2). The combinedorganic layer were dried over anhydrous MgSO4 and evaporated under vacuum. The crude product waspurified by silica gel column chromatography with n-hexane-EtOAc (95:5) as an eluent to givecompound 2a (15.4 g, 75.0% yield). Compound 2a: IR νmax cm-1: 1587, 1509, 1247; 1H-NMR(400 MHz, CDCl3) δ 7.45 (2H, d, J = 8.4 Hz), 7.05 (1H, d, J = 16.4 Hz), 6.91 (2H, J = 8.4 Hz), 6.92 (1H, d, J = 16.0 Hz), 6.66 (2H, d, J = 2.4 Hz), 6.39 (1H, t, J = 2.0 Hz), 4.08 (6H, m), 1.45 (9H, m);13C-NMR (100 MHz, CDCl3) δ 160.3, 158.8, 139.6, 129.8, 128.6, 127.8, 126.6, 114.7, 104.9, 100.5,63.5, 14.9, 14.8; ESI-MS (positive mode) m/z: 313 [M + H]+, HRESIMS: m/z 313.1798 (calcd. forC20H25O3, 313.1798). |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; Cooling with ice; Inert atmosphere; | Preparation of (E)-1,3-Dimethoxy-5-(4-methoxystyryl)benzene (Compound 4b) General procedure: To a solution of 1 (200 mg, 0.876 mmol) in DMF (2 mL) were added potassium carbonate (296 mg, 2.14 mmol) and iodomethane (0.402 mL, 6.43 mmol) under ice-cooling and nitrogen atmosphere. The resultant mixture was raised at ambient temperature and was allowed to be stirred for 24 h. Water was added to the reaction mixture under ice-cooling and stirred. The aqueous layer was extracted with ethyl acetate for three times. The combined organic layers were washed with water and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (7% ethyl acetate in n-hexane) to give the desired compound 4b (179 mg, 76%) as pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydroxide In N,N-dimethyl-formamide for 0.166667h; Stage #2: 1-bromo-butane In N,N-dimethyl-formamide at 40℃; for 24h; | (E)-1,3-Dibutoxy-5-(4-butoxystyryl)benzene (2b) Resveratrol (1) (15.0 g, 65.7 mmol) was dissolved ina solution of DMF (150 mL) and NaOH (8.9 g), and stirred for 10 min. Then, 1-bromobuthane (30.6 g,223.5 mmol) was added and the reaction was kept for 24 h at 40 °C. After the removal of DMF byevaporation under vacuum, the reaction mixture was extracted with toluene (45 mL × 2). The combinedorganic layer were dried over anhydrous MgSO4 and evaporated under vacuum. The crude product waspurified by silica gel column chromatography with n-hexane-EtOAc (95:5) as an eluent to givecompound 2b (21.2 g, 81.5% yield). Compound 2b: IR νmax cm-1: 1589, 1509, 1385, 1294; 1H-NMR(400 MHz, CDCl3) δ 7.45 (2H, d, J = 8.4 Hz), 7.08 (1H, d, J = 16.4 Hz), 6.93 (2H, J = 8.4 Hz), 6.94(1H, d, J = 16.0 Hz), 6.69 (2H, d, J = 2.4 Hz), 6.43 (1H, t, J = 2.0 Hz), 4.02 (6H, m), 1.83 (6H, m), 1.57(6H, m), 1.05 (9H, m); 13C-NMR (100 MHz, CDCl3) δ 160.5, 159.0, 139.6, 129.8, 128.6, 127.7, 126.6,114.7, 104.9, 100.5, 67.7, 31.5, 31.4, 19.4, 19.3, 13.9; ESI-MS (positive mode) m/z: 397 [M + H]+,HRESIMS: m/z 435.2296 (calcd. for C26H36KO3, 435.2296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With potassium iodide; sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 1-Bromopentane In N,N-dimethyl-formamide at 45℃; for 12h; | (E)-1,3-Bis(pentyloxy)-5-(4-(pentyloxy)styryl)benzene (2c) Resveratrol (1) (50.0 g, 219.1 mmol) wasdissolved in a solution of DMF (200 mL). After adding NaOH (28.0 g) and KI (1.8 g), the reactionmixture was stirred for 5 min at RT. Then, 1-bromopentane (109.2 g, 223.5 mmol) was added and thereaction was kept for 12 h at 45 °C. After the removal of DMF by evaporation under vacuum, the reactionmixture was extracted with toluene (45 mL × 2). The combined organic layer were dried over anhydrousMgSO4 and evaporated under vacuum. The crude product was purified by silica gel column chromatographywith n-hexane-EtOAc (95:5) as an eluent to give compound 2b (21.2 g, 81.5% yield). Compound 2c:IR νmax cm-1: 1692, 1385, 1344; 1H-NMR (400 MHz, CDCl3) δ 7.47 (2H, d, J = 8.4 Hz), 7.07 (1H, d,J = 16.4 Hz), 6.93 (2H, J = 8.4 Hz), 6.94 (1H, d, J = 16.0 Hz), 6.68 (2H, d, J = 2.4 Hz), 6.42 (1H, brs),4.00 (6H, m), 1.85 (6H, m), 1.48 (12H, m), 0.99 (9H, m); 13C-NMR (100 MHz, CDCl3) δ 160.5, 159.0,139.6, 129.8, 128.6, 127.7, 126.6, 114.7, 104.9, 100.5, 68.0, 29.1, 29.0, 28.3, 28.2, 22.5, 14.1; ESI-MS(positive mode) m/z: 439 [M + H]+, HRESIMS: m/z 477.2761 (calcd. for C29H42KO3, 477.2765). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydroxide In N,N-dimethyl-formamide for 0.166667h; Stage #2: 1-bromo-hexane In N,N-dimethyl-formamide at 40℃; for 24h; | (E)-1,3-Bis(hexyloxy)-5-(4-(hexyloxy)styryl)benzene (2d) Resveratrol (1) (10.0 g, 43.8 mmol) was dissolvedin a solution of DMF (100 mL) and NaOH (5.96 g), and stirred for 10 min. Then, 1-bromohexane(25.8 g, 236.6 mmol) was added and the reaction was kept for 24 h at 40 °C. After the removal of DMFby evaporation under vacuum, the reaction mixture was extracted with toluene (45 mL × 2). The combinedorganic layer were dried over anhydrous MgSO4 and evaporated under vacuum. The crude product waspurified by silica gel column chromatography with n-hexane-EtOAc (95:5) as an eluent to give compound2d (16.3 g, 77.3% yield). Compound 2d: IR νmax cm-1: 1698, 1593, 1457, 1162; 1H-NMR (400 MHz, CDCl3)δ 7.45 (2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 16.4 Hz), 6.91 (2H, J = 8.4 Hz), 6.92 (1H, d, J = 16.0 Hz),6.67 (2H, d, J = 2.4 Hz), 6.42 (1H, t, J = 2.0 Hz), 4.00 (6H, m), 1.82 (6H, m), 1.52 (6H, m), 1.39 (12H,m), 0.97 (9H, m); 13C-NMR (100 MHz, CDCl3) δ 160.5, 158.9, 139.6, 129.8, 128.6, 127.7, 126.6, 114.7, 104.8, 100.5, 68.0, 31.6, 29.4, 29.3, 25.8, 25.7, 22.6, 14.0; ESI-MS (positive mode) m/z: 481 [M + H]+,HRESIMS: m/z 519.3235 (calcd. for C32H48KO3, 519.3235). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With sodium hydroxide In N,N-dimethyl-formamide for 0.166667h; Stage #2: 1-bromo-octane In N,N-dimethyl-formamide at 40℃; for 24h; | (E)-1,3-Bis(octyloxy)-5-(4-(octyloxy)styryl)benzene (2e) Resveratrol (1) (10.0 g, 43.8 mmol) was dissolvedin a solution of DMF (100 mL) and NaOH (5.9 g), and stirred for 10 min. Then, 1-bromooctane (25.8 g,236.59 mmol) was added and the reaction was kept for 24 h at 40 °C. After the removal of DMF byevaporation under vacuum, the reaction mixture was extracted with toluene (45 mL × 2). The combinedorganic layer were dried over anhydrous MgSO4 and evaporated under vacuum. The crude product waspurified by silica gel column chromatography with n-hexane-EtOAc (95:5) as an eluent to give compound2e (21.0 g, 84.7% yield). Compound 2e: IR νmax cm-1: 1694, 1507, 1383, 1298; 1H-NMR (400 MHz, CDCl3)δ 7.45 (2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 16.4 Hz), 6.91 (2H, J = 8.4 Hz), 6.92 (1H, d, J = 16.0 Hz),6.66 (2H, d, J = 2.4 Hz), 6.40 (1H, t, J = 2.0 Hz), 4.00 (6H, m), 1.83 (6H, m), 1.50 (6H, m), 1.36 (24H, m),0.94 (9H, m); 13C-NMR (100 MHz, CDCl3) δ 160.5, 158.9, 139.6, 129.8, 128.6, 127.7, 126.5, 114.7,104.8, 100.5, 68.0, 31.8, 29.4, 29.3, 29.2, 26.1, 26.0, 22.6, 14.1; ESI-MS (positive mode) m/z: 565 [M + H]+,HRESIMS: m/z 603.4176 (calcd. for C38H60KO3, 603.4174). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With dmap; triethylamine In dichloromethane at 10℃; Stage #2: 3,3-Dimethylacryloyl chloride In dichloromethane at 10℃; for 1h; | (E)-5-(4-(3-Methylbut-2-enoyloxy)styryl)-1,3-phenylene bis(3-methylbut-2-enoate) (3b) Resveratrol (1)(5.0 g, 21.9 mmol) was dissolved in CH2Cl2 (40 mL) and kept cool at 10 °C. TEA (7.3 g, 72.3 mmol)and DMAP (0.26 g, 2.2 mmol) were added to the reaction mixture at 10 °C. 3,3-Dimethylacroyl chloride(8.3 g, 70.1 mmol) was added carefully and the reaction was kept for 1 h at 10 °C. After adding distilledwater (50 mL) to reaction mixture, the CH2Cl2 fraction was extracted. The CH2Cl2 layers were driedover anhydrous MgSO4 and evaporated under vacuum. The crude product was purified by silica gelcolumn chromatography with n-hexane-EtOAc (95:5) as an eluent to give compound 3b (6.9 g, 92.5%yield). Compound 3b: IR νmax cm-1: 1738, 1645, 1379, 1343; 1H-NMR (400 MHz, CDCl3) δ 7.50 (2H,dd, J = 7.2, 2.0 Hz), 7.11 (4H, m), 7.01 (1H, d, J = 16.4 Hz), 6.86 (1H, t, J = 2.0 Hz), 2.26 (9H, d,J = 1.2 Hz), 2.02 (9H, s); 13C-NMR (100 MHz, CDCl3) δ 164.7, 164.4, 160.4, 160.1, 151.4, 150.4, 139.3,134.3, 129.4, 127.5, 127.2, 122.0, 116.8, 115.1, 115.0, 114.8, 27.7, 27.6, 20.6, 20.5; ESI-MS (positivemode) m/z: 497 [M + Na]+, HRESIMS: m/z 513.1672 (calcd. for C29H30KO6, 513.1673). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With dmap; triethylamine In dichloromethane at 10℃; Stage #2: 2-ethylhexanoic acid chloride In dichloromethane at 10℃; for 1h; | (E)-5-(4-(2-Ethylhexanoyloxy)styryl)-1,3-phenylene bis(2-ethylhexanoate) (3c) Resveratrol (1) (10.0 g,43.8 mmol) was dissolved in CH2Cl2 (50 mL) and kept to cool at 10 °C. TEA (7.3 g, 72.3 mmol) and DMAP (0.54 g, 4.4 mmol) were added to the reaction mixture. After stirring at 10 °C, 2-ethylnexanoylchloride (22.8 g, 140.2 mmol) was added carefully and the reaction was kept for 1 h at 10 °C. Afteradding distilled water (50 mL) to reaction mixture, the CH2Cl2 fraction was extracted. The CH2Cl2 layerswere dried over anhydrous MgSO4 and evaporated under vacuum. The crude product was purified bysilica gel column chromatography with n-hexane-EtOAc (50:1) as an eluent to give compound 3c(25.2 g, 94.8% yield). Compound 3c: IR νmax cm-1: 1754, 1644, 1376, 1201; 1H-NMR (500 MHz, CDCl3)δ 7.52 (2H, d, J = 8.5 Hz), 7.11 (4H, m), 7.03 (1H, J = 16.0 Hz), 6.98 (1H, d, J = 16.0 Hz), 6.78 (1H, d,J = 2.0 Hz), 2.56 (3H, m), 1.87 (6H, m), 1.76 (8H, m), 1.07 (9H, m), 0.97 (12H, m); 13C-NMR(100 MHz, CDCl3) δ174.7, 174.4, 151.5, 150.5, 139.4, 134.3, 129.6, 127.6, 127.2, 121.9, 116.8, 114.3,47.4, 47.3, 31.7, 31.6, 29.6, 25.5, 25.4, 22.6, 13.9, 11.9; ESI-MS (positive mode) m/z : 629 [M + Na]+,HRESIMS: m/z 645.3550 (calcd. for C38H54KO6, 645.3551). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap In acetonitrile at 50℃; for 24h; | 3.4.5. General Procedure for the Preparation of 3,4′,5-N-Monosubstituted-methoxy-oligo(ethyleneglycol) Resveratrol Carbamate Esters (2-4) General procedure: A solution of resveratrol (0.24 g, 1.1 mmol, 1.0 eq.) and DMAP (0.52 g, 4.2 mmol, 4.0 eq.) in ACN(15 mL) was added to a solution of the activated 4-nitrophenyl methoxy-oligo(ethylene glycol)urethane (2c-4c) (4.8 mmol, 4.5 eq) in ACN (5 mL) and the resulting mixture was allowed to react under vigorous stirring at 50 °C for 24 h. The reaction mixture was diluted with DCM (150 mL) and washed with 0.5 N HCl (100 mL). The aqueous layer was washed with DCM (5 × 75 mL) and all the organic fractions were collected, dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography. (E)-5-(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethyl)carbamate)-1,3-phenylene bis((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate) (2). Purified by flash chromatography using DCM/Acetone = 6.5:3.5 aseluent. 75% yield as a pale yellow oil. 1H-NMR (250 MHz, CDCl3) δ (ppm): 3.08 (m, 9 H, 3 × -O-CH3),3.39 (s, 9H, 3 × -O-CH3) 3.42-3.69 (m, 36H, 6 × -O-CH2-CH2-O- + 3 × -O-CH2-CH2-NH-), 5.80(m, 3H, 3 × -NH-), 6.86 (t, 1H, 4JH-H = 2.0 Hz, H-4), 6.90-7.12 (m, 6H, H-2, H-3′, H-5′, H-6, H-7,H-8), 7.45 (d, 2H, 3JH-H = 8.75 Hz, H-2′, H-6′); 13C-NMR (62.9 MHz, CDCl3) δ (ppm): 154.6, 154.3,151.6, 150.7, 139.1, 133.9, 129.2, 127.4, 127.1, 121.8, 116.3, 114.3, 71.8, 70.5, 70.2, 70.2, 69.8, 59.0,40.9; ESI-MS (ion trap): m/z 818 [M + Na]+. HRMS (ESI+): m/z 796.3873 [M + H]+, calcd forC38H58N3O15: 796.3868. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap In acetonitrile at 50℃; for 24h; | 3.4.5. General Procedure for the Preparation of 3,4′,5-N-Monosubstituted-methoxy-oligo(ethyleneglycol) Resveratrol Carbamate Esters (2-4) General procedure: A solution of resveratrol (0.24 g, 1.1 mmol, 1.0 eq.) and DMAP (0.52 g, 4.2 mmol, 4.0 eq.) in ACN(15 mL) was added to a solution of the activated 4-nitrophenyl methoxy-oligo(ethylene glycol)urethane (2c-4c) (4.8 mmol, 4.5 eq) in ACN (5 mL) and the resulting mixture was allowed to react under vigorous stirring at 50 °C for 24 h. The reaction mixture was diluted with DCM (150 mL) and washed with 0.5 N HCl (100 mL). The aqueous layer was washed with DCM (5 × 75 mL) and all the organic fractions were collected, dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap In acetonitrile at 50℃; for 24h; | 3.4.5. General Procedure for the Preparation of 3,4′,5-N-Monosubstituted-methoxy-oligo(ethyleneglycol) Resveratrol Carbamate Esters (2-4) General procedure: A solution of resveratrol (0.24 g, 1.1 mmol, 1.0 eq.) and DMAP (0.52 g, 4.2 mmol, 4.0 eq.) in ACN(15 mL) was added to a solution of the activated 4-nitrophenyl methoxy-oligo(ethylene glycol)urethane (2c-4c) (4.8 mmol, 4.5 eq) in ACN (5 mL) and the resulting mixture was allowed to react under vigorous stirring at 50 °C for 24 h. The reaction mixture was diluted with DCM (150 mL) and washed with 0.5 N HCl (100 mL). The aqueous layer was washed with DCM (5 × 75 mL) and all the organic fractions were collected, dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In dichloromethane at 0 - 20℃; | 9.1; 15 Step 1: A solution of trifluoromethanesulfonic anhydride (d 1.487, 3.7 mL, 19.5 mmol) in CH2C12 (5.0 mL) was added dropwise to a solution of pyridine (d, 0.9819, 1.96 mL, 24.3 mmol) and the corresponding phenol (1.2 g, 5.3 mmol) in anhydrous CH2C12 (10 mL) at 0 °C. After complete addition, the mixture was warmed to room temperature and allowed to stir overnight. The mixture was then diluted with ethyl acetate, quenched with brine. The organic layer was separated. The aqueous solution was extracted with ethyl acetate. The combined organic solution was dried over MgS04. After drying, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give the triflates (3.3 g) quantatively. -NMR (CDC13, 300 MHz): 7.63 (d,/ = 8.7 Hz, 2H), 7.46 (d J = 1.5 Hz, 2H), 7.33 (d J = 8.4 Hz, 2H), 7.21-7.04 (m, 3H). "C-NMR (CDC13, 75 MHz): 149.8, 149.6, 141.3, 136.0, 131.6, 128.7, 126.7, 122.0, 119.3, 118.8 (qj = 319 Hz), 118.7 (qj = 319 Hz), 114.1. |
83% | With pyridine In dichloromethane at -30 - 20℃; | 1 Synthesis of resveratrol tristriflate: To a solution of 11.41 g resveratrol (50 mmol) and 21 mL pyridine (260 mmol, 5 eq) in 300 mL CH2Cl2 cooled to -30° C. was added 30 mL (178 mmol, 3.5 eq) triflic anhydride. The reaction was warmed and stirred overnight at ambient temperature. The reaction was then washed with water, 4 N HCl and 4 M NaOH, dried over MgSO4 and concentrated to yield 29.24 g of a tan solid (94%). The material was recrystallized from 200 mL EtOH to afford 25.92 g of a yellow crystalline solid in 83% yield. Mp 98-99° C. 1H NMR (CDCl3): 7.62 (d, 2H, J=8.9 Hz), 7.46 (d, 2H, J=7.3 Hz), 7.33 (d, 2H, J=8.9 Hz), 7.21-7.03 (m, 3H). 13C NMR (CDCl3): 149.79, 149.54, 141.26, 135.97, 131.53, 128.67, 126.71, 121.95, 119.22 118.74 (q, J=321 Hz) 118.68 (q, J=321 Hz), 114.04. Calc for C17H9F9O9S3: C 32.70%, H 1.28%, F 27.24%, S 15.40%. Found C 32.81%, H 1.28%, F 27.24%, S 15.30%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;Inert atmosphere; | General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;Inert atmosphere; | General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;Inert atmosphere; | General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.9 g | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; | Resveratrol 5.00g (21.91mmol) was dissolved in 30ml of anhydrous DMF, was added 9.0g (65.12mmol) of potassium carbonate and mix well. The 7.25g (32.81mmol) 5- chloro-2,2-dimethyl butyl isovalerate dissolved 20mL of anhydrous DMF, mixed evenly, an oil bath at 90 slowly dropped to the reaction system. Completion of the dropwise addition, heating was continued with stirring. The reaction was monitored by TLC. After completion of the reaction, the system was cooled to room temperature, potassium carbonate was removed by suction, the filter cake rinsed with ethyl acetate, collectedThe filtrate 50mL ethyl acetate added to the filtrate, after mixing, 2mol / LHCl washed 2 times 100mL, collect the organic phase, the aqueous stripping phase, the organic phases were combined, dried over anhydrous sodium sulfate. After completion of the drying, the solvent was evaporated under reduced pressure to give a brown oil which was chromatographed on a silica gel column (volume ratio 41) eluting with ethyl acetate petroleum ether , respectively, to give 3,5-dihydroxy-4 ' - (4-methyl-4-carboxy-pentyloxy) - (the E) - stilbene (iv-1) of a yellow solid 1.90g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In dimethyl sulfoxide; at 25℃; | (1) take 228mg of resveratrol dissolved in 2mLDMSO added 354mg of resveratrol triacetate and 138mg K2CO3, the reaction was stirred at 25 , and the reaction monitored by TLC. After completion of the reaction, the reaction solution was poured into 20mL1NHCl, and extracted three times with 20mL ethyl acetate, washed three times with distilled water 20mL, 20mL and washed twice with saturated brine, dried over anhydrous sodium sulfate overnight, filtration, and the filtrate was spin-dried samples .(2) separating purified by silica gel column chromatography, with dichloromethane: methanol = 98 was eluted. Collection target component, spin dried to obtain 3,5 -O- acetylated resveratrol 442mg, yield 76% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; | 3.1 Preparation of compound 4 The following are placed in a three-necked flask: resveratrol (1.0 g, 4.4 mmol) N,N-dimethylformamide (15 ml)benzyl bromide (3.4 g, 19.7 mmol, 4.5 eq.) potassium carbonate (3.6 g, 26.3 mmol, 6 eq.).The reaction mixture is stirred at room temperature for 16 hours and then poured into 20 mL of water. The solid thus formed is filtered off and washed with water and then with petroleum ether. It is dried under vacuum to give a white powder corresponding to the protected resveratrol (m = 2.1 g, 95% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In dimethyl sulfoxide at 80℃; Inert atmosphere; | 1 EXAMPLE 1 EXAMPLE 1 Synthesis of resveratrol phthalonitrile in one reaction pot-To a 1000 mL, three-necked flask fitted with a thermometer and a nitrogen inlet were added resveratrol (20.0 g, 87.6 mmol), 4-nitrophthalonitrile (47.0 g, 272 mmol), powdered anhydrous K2CO3 (50.0 g, 362 mol), and dimethylsulfoxide (DMSO) (1000 mL). The resulting mixture was degassed with nitrogen at ambient temperature and heated at 80° C. under a nitrogen atmosphere for 8-16 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the amorphous resveratrol phthalonitrile (52.4 g, 99% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine In toluene at 20℃; | 2 Preparation of Resveratrol Tris(Butyl Carbonate) (2, R=n-Bu) Resveratrol (10.0 g; 43.8 mmol) was dissolved in 50 mL (618 mmol; 14.1 equiv) of pyridine. The mixture was diluted with toluene (75 mL) and treated with n-butyl chloroformate (19.15 g; 140 mmol; 3.2 equiv) dissolved in 25 mL of toluene. An exotherm was noted during the addition, and cooling was applied (maximum temperature was 37° C.). The resulting white stirrable slurry was stirred overnight at ambient temperature, at which point HPLC analysis indicated one major product but several minor peaks (assumed to be mono- and di-carbonates). An additional 20% of butyl chloroformate (3.8 g) was added and the mixture was stirred overnight, at which point HPLC analysis indicated >94% of a single peak. The mixture was partitioned between 150 mL of ethyl acetate and 100 mL of water, and the water layer was decanted. The organic layer was washed with 3 M HCl (200 mL) and 5% sodium bicarbonate (100 mL), dried (MgSO4), then concentrated in vacuo with moderate heating to afford 22.96 g (99%) of Formula 2, R=n-Bu.1H NMR was consistent with the anticipated structure and HPLC analysis indicated 97.1% purity with 0.7% resveratrol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Phytolacca americana glucosyltransferase; In aq. phosphate buffer; at 35℃; for 24h;pH 7.2;Enzymatic reaction; | General procedure: Glucosylation reactions were performed at 35 C for 24 h in 5 mL of 50 mM potassium phosphate buffer (pH 7.2) supplemented with 50 muM substrate, 100 muM UDP-glucose, and 5 muM enzyme. The incubation was stopped by adding 1.5% trifluoroacetic acid; and the reaction mixture was analyzed by high performance liquid chromatography (HPLC). The reaction mixture was extracted with n-BuOH. The n-BuOH fraction was concentrated by evaporation and the residue was dissolved in water. The water fraction was applied to Diaion HP20, washed with water, and eluted with methanol. The methanol solution was subjected to preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.1% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 85℃; for 120h; | 13 Resveratrol 1310 (350 mg, 1.53 mmol) and a brominated branched alkyl RBr (4.0 g, 11.1 mmol) were reacted for 120 hours (5 days) at 85° C. in DMF (10 ml) in the presence of potassium carbonate (5.0 g, 36.2 mmol) and potassium iodide (0.5 g, 3.01 mmol). Chloroform and water were employed for partitioning, the organic phase was extracted from the reaction mixture, dried over sodium sulfate and thereafter the solvent was evaporated under reduced pressure. A silica gel column chromatography (n-hexane followed by n-hexane/chloroform, 2:1) was employed for purification, and a colorless transparent liquid was obtained (1.26 g, yield: 77.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With fluorosulfonyl fluoride; triethylamine In dimethyl sulfoxide at 20℃; for 12h; Stage #2: With formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In dimethyl sulfoxide at 20℃; | 2.4 Procedure for the synthesis of 3x A mixture of 1x (0.3 mmol), Et3N (3.6 eq, 1.08 mmol, 109.1 mg), DMSO (1 mL) was stirred with a SO2F2 balloon at room temperature for 12 hours, and then, Pd(OAc)2 (5 mol%, 3.36 mg), dppp (6 mol%, 7.42 mg), Et3N (12 eq, 3.6 mmol, 364.0 mg), HCOOH (12 eq, 3.6 mmol, 165.6 mg) were added into the reaction mixture to react overnight at room temperature. The reaction mixture was extracted with dichloromethane (3 × 20 mL) and the extracts were washed with water, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using hexane as eluents to give the desired product (3x). |
56% | Stage #1: (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol With fluorosulfonyl fluoride; triethylamine In dimethyl sulfoxide Stage #2: With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; acetic acid; triethylamine In dimethyl sulfoxide at 20℃; | 4 Example 4: Resveratrol (20 mmol, 4.56 g) was dissolved in dimethylsulfoxide, Et3N (3.6 eq) was added,Cover with salt water plug, insert a balloon filled with sulfuryl fluoride gas,The reaction was monitored by a TLC plate, the sulfuryl fluoride balloon was removed after the conversion of starting material, and then reactedPd (OAc) 2 (5 mol%), dppp (6 mol%), Et3N (12 eq) and HCOOH (12 eq) were added to the solution and the reaction was continued at room temperature.TCL plate detection, when the reaction is completed, quenched with water, extracted with dichloromethane three times, the combined organic phase, and then washed three times with water, plusDrying over anhydrous sodium sulphate, dichloromethane was removed in vacuo at low temperature, and the residue was purified by column chromatography on silica gel to give a white solid (2.0 g). Isolated yield56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 3h; | General procedure: To a mixture of compound 1 (1.0 equiv) and DMAP (0.1 equiv) into DMF and DCM in a100 ml round-bottom flask, were added EDCI·HCl (1.0 equiv) and compound 2a-c (1.0equiv), and the reaction mixture was subjected to heat at 60 C for 3 h. After the completionof reaction, the solvent DCM was removed under reduced pressure. Then the mixture wasextracted with ethyl acetate and the organic layer was washed with saturated brine, driedover anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed(silica gel, petroleum ether/ethyl acetate = 3:2) to afford compounds 4a-j.4.2.1. (E)-3-Hydroxy-5-(4-hydroxystyryl)phenyl 2-(1H-imidazol-1-yl)acetate (4a)90% Yield, light yellow solid. mp 167.8-168.4 C; 1H NMR (500 MHz, DMSO-d6) delta 9.85(s, 1H), 9.07 (s, 1H), 7.76 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.12(d, J = 7.5 Hz, 1H), 6.92 (d, J = 15.2 Hz, 1H), 6.82 (d, J = 15.2 Hz, 1H), 6.77 (s, 1H), 6.75(d, J = 7.5, 2H), 6.64 (s, 1H), 6.47 (s, 1H), 4.97 (t, J = 2.0 Hz, 2H); 13C NMR (125 MHz,DMSO-d6) delta 165.3, 159.8, 158.2, 152.2, 140.7, 138.9, 130.1, 128.7, 128.6 (two carbons),128.3, 126.9, 120.9, 116.4 (two carbons), 114.2, 107.9, 104.9, 46.1. HRESIMS: m/z 337.1194[M + H]+ (calcd for C19H17N2O4, 337.1188). Elemental analysis: Found: C, 67.82%; H, 4.80%;N, 8.35%; O, 19.02%; calcd for C19H16N2O4: C, 67.85%; H, 4.79%; N, 8.33%; O, 19.03%. |
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 3h; | General procedure: Compound 1 (1.0 equiv) and DMAP (0.1 equiv)were mixed in a 100 mL round-bottom flask and dissolved by DMF and DCM. Then EDCI·HCl (1.0 equiv) and compounds 2g-2i (1.0 equiv) were separately added, and the reaction mixture was subjected to heating at 60C for 3 h. After the completion of the reaction, the solvent DCM was removed under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography using a mixture of petroleum ether and EtOAc (3:2) to get compounds 3q-3u. (E)-3-Hydroxy-5-(4-hydroxystyryl)phenyl-2-(1H-imidazol-1-yl)acetate (3q). C19H16N2O4, light yellow solid, yield 90%; mp 167.8-168.4C. 1H NMR (500 MHz, DMSO-d6, delta, ppm, J/Hz): 9.86 (1H, s, 4?-OH), 9.07 (1H, s, 3-OH), 7.77(1H, s, H-1??), 7.41-7.35 (2H, m, H-2?, 6?), 7.06 (1H, d, J = 7.5, H-3??), 7.02 (1H, d, J = 7.5, H-2??), 6.92 (1H, d, J = 15.2, H-alpha),6.82 (1H, d, J = 15.1, H-beta), 6.78-6.75 (2H, m, H-3?, 5?), 6.74 (1H, s, H-2), 6.68-6.66 (1H, m, H-6), 6.56 (1H, t, J = 2.0, H-4),5.33 (1H, s, H-8a), 5.03 (1H, s, H-8b). 13C NMR (125 MHz, DMSO-d6, delta, ppm): 165.30 (C-7), 159.82 (C-3), 158.16 (C-4?),152.19 (C-5), 140.68 (C-1), 138.87 (C-1??), 130.07 (C-2?, 6?), 128.70 (C-1?), 128.61 (C-3??), 128.33 (C-alpha), 126.89 (C-beta),120.90 (C-3??), 116.37 (C-3?, 5?), 114.22 (C-6), 107.85 (C-2), 104.86 (C-4), 46.07 (C-8). HR-ESI-MS m/z 337.1188 [M + H]+(calcd for C19H17N2O4, 337.1194). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Then 1 mole of (A) is reacted with 3 moles of (B) in the presence of trimethylamine and tetrahydrofuran at room temperature for 12-72 hours to form acyl protected tartaric acid which is then reacted with K2CO3 (10 molar), methanol, OC-RT for at least 1 hour, to form resveratrol tartrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With silver trifluoroacetate In N,N-dimethyl-formamide at -10℃; for 10h; | |
65.4% | With silver trifluoroacetate In N,N-dimethyl-formamide at -10℃; for 10h; | 2.2 2. Synthesis of intermediate compound S6 Weigh out 580 mg (1 mmol) of 4- (S)-(benzylthio) -epigallocatechin gallate (S5) in a 100 mL eggplant-shaped bottle, then add 30 mL DMF, stir and dissolve at -10 ° C. After adding 1140 mg (5 mmol) of resveratrol and 1100 mg (5 mmol) of AgOOCCF3 in this order, the reaction was stirred at -10 ° C for 10 h, and the reaction was monitored by HPLC.After the precipitate was filtered off, 50 mL of distilled water was added to the reaction solution to terminate the reaction. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate column, evaporated to dryness under pressure, and prepared under high pressure. (MeOH / H2O = 45%), product S6 was obtained in 65.4% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 30℃; for 288h; | 1.4 Fermentation Procedures The strain A12 was cultured on the PDA solid medium at 30oC for 2 days to form spores. These spores were transferred into a 250-mL Erlenmeyer flask containing 100 mL of the culture and then incubated on a rotary shaker at 30oC (200 rpm) for two days to get seed broth. One hundred milliliters of the 2-day-old fermented seed broth were inoculated in a 10L-fermentation cylinder containing 6 L of the media and then incubated at 30oC for 2 days. Four hundred milligrams of resveratrol (1) were dissolved in 10 mL of ethanol. The resulting solution was inoculated in a fermentation cylinder and the fermentation broth was incubated for another 12 days. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 5%-palladium/activated carbon; hydrogen In acetonitrile for 48h; | 2.6 6) Preparation of 5-[(1E)-2-(4-hydroxyphenyl)vinyl]-1,3-benzenediol (Compound 7) 5 g of 5-[(1E)-2-(phenylbenzyloxy)vinyl-1,3-cyclohexanedione,1 g of 5% pd/C is dissolved in 120 ml of acetonitrile solution, and an inert gas is introduced, and the reaction is carried out at 3 atm for about 48 hours.Palladium carbon is recovered by suction filtration, the solvent is distilled off, and the product is obtained by column chromatography.5-[(1E)-2-(4-hydroxyphenyl)vinyl]-1,3-benzenediol, the yield is above 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.76% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 10h; | A solution of (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1 -yl) nona-2,4,6,8-tetraenoic acid (1 g, 3.33 mmol, 1 equiv.), 5-[(E)-2-(4-hydroxyphenyl) vinyl]benzene-1 ,3-diol (151 .94 mg,665.70 mmol, 0.2 equiv.), N,Ndicyclohexylcarbodiimide (686.76 mg, 3.33 mmol, 673.30 mL, 1 equiv.), and 4-dimethylaminopyridine (40.66 mg, 332.85 mmol, 0.1 equiv.) in CH2CI2 (40 mL) was stirred at 20C for 10 h. The solvent was removed in vacuo, and the crude product was purified by silica gel chromatography using Petroleum ether/Ethyl acetate20:1-5:1 as a mobile phase. The title product (0.6557.88 mmol, 16.76% yield) was obtained as yellow solid. 1H NMR: (400 MHz, CDCI3): O 7.4 (m, 2H),7.03-7.1 (m, 12H), 6.07-6.1 (m, 5H), 6.27-6.33 (m, 5H), 5.9 (br s, 3H), 2.35 (brs, 8H), 1.93-1.97 (m, 15H),1.65 (m, 8H), 1.54-1.55 (m, 8H), 1.39- 1.42 (m, 6H) 0.9-1.0 (m, 18H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
367 mg | With potassium carbonate; In acetonitrile; at 20℃; for 10h; | To a solution of 5-[(E)-2-(4-hydroxyphenyl)vinyl]benzene-1 ,3-diol (0.278 g, 1 .22 mmol, 1 equiv.) and K2003 (420.89 mg, 3.05 mmol, 2.5 equiv.) in acetonitrile (30 mL) was added 4-phenylbutanoylchloride (1 .00 g, 5.48 mmol, 4.5 equiv.). The mixture was stirred at 20 C for 10 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was combined with another batch and purified by column chromatography (5i02, Petroleum ether/Ethyl acetate20/1 to 8:1) to afford [4-[(E)-2-[3, 5-bis (4-phenylbutanoyloxy) phenyl] vinyl] phenyl] 4- phenylbutanoate (367mg, 93.51% purity) as a white solid. LC/MS (M÷NH4j: 684.3 |
367 mg | With potassium carbonate; In acetonitrile; at 20℃; for 10h; | To a solution of 5-[(E)-2-(4-hydroxyphenyl)vinyl]benzene-1 ,3-diol (0.278 g,1 .22 mmol) and K2CO3 (420.89 mg,3.05 mmol) in acetonitrile (30 mL) was added <strong>[18496-54-3]4-phenylbutanoyl chloride</strong> (1 .00 g, 5.48 mmol). The mixture was stirred at 20 C for 10 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was combined with another batch and purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=20/1 to 8:1 ) to afford compound 2 (367mg) as a white solid. LC/MS (M+NfV): 684.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 67.4% 2: 30.5% | With potassium carbonate In acetone at 25℃; for 24h; | 3.4. Semi-synthesis of methylated derivatives General procedure: Compounds 15, 16, 17, 18 and 19 were prepared by using the reported procedures(Chao et al. 2010) with minor revisions. The procedure for semi-synthesis of methylstilbene derivatives is summarized in Figure S1. Briefly, to a solution of 1 equivalent ofcompound 1 (20 mg, 0.077 mMol), 2 (15 mg, 0.066 mMol) or 3 (100 mg, 0.41 mMol), indry acetone (3 mL), was added, a dry potassium carbonate (26.6 mg) or (14 mg) or(113 mg), respectively. In each case, a solution of methyl iodide (54.58 mg, 5 equiv.) or(28.00 mg, 3 equiv.) or (232.6 mg, 4 equiv.), respectively, in 1mL dry acetone, wasadded dropwise. The reaction mixture was stirred for 24 h at room temperature andthen the reaction was worked up by addition of water, evaporation of acetone, extractionwith CH2Cl2 (33mL), drying over MgSO4 and analysis using TLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With RS004 catalyst In ethanol at 20℃; for 6h; | 1-10 Example 1 Add 100g to a 500ml three-neck bottle3,5-dihydroxybenzaldehyde, 156g p-hydroxybenzylTrimethyl phosphate, 1 g of RS004 (5%) and 300 ml of ethanol were stirred at room temperature for 6 hours. Filtration, filter cake washed with 20g water, washed with 5g ethanol, dried and recycled for use;The filtrate was desolvated at -0.01 MPa. at 30 ° C. After evaporation, it was recrystallized by adding 400 g of ethanol, and cooled to 0 ° C for 2 hours to obtain a resveratrol wet product, which was dried at -0.01 MPa. at 30 ° C. 12 hours,Resveratrol refined 160g, yield 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap In acetonitrile at 60℃; for 24h; | 3.34 Embodiment 34 The obtained intermediate product F 0.005 mol (1.4817 g), resveratrol 0.001 mol (0.2287 g) and 4-dimethylaminopyridine (DMAP) 0.5 g were added to 100 ml of acetonitrile, and the reaction was thoroughly stirred at 60 ° C for 24 hours. After completion, the reaction liquid was first washed with 500 ml of dilute hydrochloric acid, then extracted with 500 ml of dichloromethane, and the extracted phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the product P7 0.00085 mol (0.6573 g).The yield reached 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In propan-2-one at 60℃; for 72h; Inert atmosphere; | 1-5 Synthesis of Resveratrol Propargyl Ether Monomer Under a nitrogen atmosphere, resveratrol (10.00 g, 43.81 mmol), acetone (100 mL), anhydrous K2CO3(20.00 g, 144.57 mmol) and 3-bromopropyne (17.20 g) were added to a 250 mL three-necked flask, 144.57 mmol).The mixture was stirred at 60°C for 72 hours and then cooled to room temperature.The solid was removed by filtration, the filter cake was washed with acetone, the filtrates were combined, and the solvent was concentrated by distillation under reduced pressure.The obtained crude product was recrystallized from methanol to obtain a pale yellow solid with a yield of 63%. |
63% | With potassium carbonate In propan-2-one at 60℃; for 72h; | 2.3. Synthesis of RSV-P A mixture of resveratrol (10.00 g, 43.81 mmol), acetone (100 mL), anhydrous K2CO3 (20.00 g, 144.57 mmol), and 3-bromopropyne (17.20 g, 144.57 mmol) was stirred at 60 C for 3 days, and then cooled to room temperature. The solid was filtered and washed with acetone. The filtrate was combined, and the solvent was removed under reduced pressure. The obtained crude product was recrystallized from methanol to yield a yellowish solid in a yield of 63%. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 7.08-6.85 (m, 4H), 6.74 (d, J 2.1 Hz, 2H), 6.52 (t, J 2.1 Hz, 1H), 4.71 (t, J 5.6 Hz, 6H), 2.54 (dt, J 5.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.98, 157.53, 139.83, 130.74, 129.05, 127.79, 126.66, 115.18, 106.11, 101.46, 78.52, 75.83, 55.93. Anal. Calcd. for [C23H18O3]: C, 80.67%; H, 5.30%. Found: C, 80.42%; H, 5.37%. HRMS (MALDI-FT, m/z) Calcd. for (M H) C23H19O3: 343.1329, Found 343.1330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogen; water-d2 at 120℃; for 72h; Autoclave; | General procedure for the deuteration reactions. General procedure: In a 4 ml vial fitted with a magnetic stir bar and septum cap, iron catalyst (60 mg, 20 mol%) and substrate (0.25 mmol) were added. Then, a needle was inserted in the septum, allowing gaseous reagents to enter. After adding the solvent deuterium oxide (1.5 ml), the vials (up to eight) were set in an alloy plate and then placed into a 300 ml steel Parr autoclave. The autoclave was flushed with hydrogen six times at 10 bar and finally pressurized to the desired value (20 bar). Then, it was placed into an aluminium block and heated to the desired temperature. At the end of the reaction, the autoclave was quickly cooled down to r.t. with an ice bath and vented. Finally, the samples were removed from the autoclave, and ethyl acetate was added to the crude mixture. This mixture was centrifuged, and the organic layer was removed from the vials (three times). After removal of all volatiles in vacuo, the desired products were obtained. In case of anilines with deuterium labelling on the nitrogen, 1 ml H2O was added during work up and N-D was replaced by N-H. |
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Code | Phrase |
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Code | Phrase |
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
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P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
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Code | Phrase |
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P306 | IF ON CLOTHING: |
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P322 | |
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P372 | Explosion risk in case of fire. |
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P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
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P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
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P401 | |
P402 | Store in a dry place. |
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P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
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Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
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H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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