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CAS No. : | 153-18-4 | MDL No. : | MFCD00006830 |
Formula : | C27H30O16 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IKGXIBQEEMLURG-NVPNHPEKSA-N |
M.W : | 610.52 | Pubchem ID : | 5280805 |
Synonyms : |
Quercetin 3-O-rutinoside;Rutoside;Yunxianggan;Venoruton;Sophorin;Paliuroside;Oxyritin;Eldrin;Birutan
|
Num. heavy atoms : | 43 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 16.0 |
Num. H-bond donors : | 10.0 |
Molar Refractivity : | 141.38 |
TPSA : | 269.43 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -10.26 cm/s |
Log Po/w (iLOGP) : | 0.46 |
Log Po/w (XLOGP3) : | -0.33 |
Log Po/w (WLOGP) : | -1.69 |
Log Po/w (MLOGP) : | -3.89 |
Log Po/w (SILICOS-IT) : | -2.11 |
Consensus Log Po/w : | -1.51 |
Lipinski : | 3.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 4.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -3.3 |
Solubility : | 0.308 mg/ml ; 0.000505 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.87 |
Solubility : | 0.0083 mg/ml ; 0.0000136 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -0.29 |
Solubility : | 315.0 mg/ml ; 0.515 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 6.52 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-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 |
---|---|---|
96% | With chitosan In methanol at 75℃; for 3 h; Autoclave | Weighing 30.53g (0.05 µM) Rutin, 2.42g (15mmol) catalyst natural alkaline high molecular compound chitosan, 100 ml methanol solvent and 15.4g (0.35 µM) ethylene oxide add to the sucking stirring in the autoclave, open the digital controller, the set temperature is 75 °C, the rotating speed of 1000r/min, stirring and heating to 75 °C, thermal insulation reaction 3h. After the reaction, the temperature rapidly in cold water, and the cessation of the stirring, the closing of the digital controller, open the reaction kettle, pouring the reaction solution. Pouring the reaction solution of hydrochloric acid for adjusting the pH 6, and filtering the catalyst, the reaction solution after filtering in a seed crystal standing crystallization, the obtained crystal 35.65g, yield 96percent, external standard content of 90.1percent. |
87.6% | With natural polymer sodium alginate In methanol at 70℃; for 4 h; Autoclave | Take 200 g of rutin obtained in (1) and 10.0 g Natural polymer sodium alginate added to 400 g of anhydrous methanol, and then pass 100 g of ethylene oxide, sealed autoclave, heating and stirring began, heated to 70 ° C, incubated for 4.0 h, HPLC test Trihydroxyethyl rutin When the ratio reached 86percent, the reaction was quenched rapidly to terminate the reaction. Hydrochloric acid was added to adjust the pH value of the reaction solution to 6.0. After standing for crystallization for 12 h, the mixture was suction filtered and dried to obtain 198.4 g of solid with a yield of 99.2percent. 3) to190 g of the solid obtained in (2) was added to 3200 mL of a mixed solution of anhydrous methanol and ethanol (anhydrous methanol and BThe volume ratio of alcohol is 1 : 1), heated to reflux completely dissolved, add needle activated carbon 8.0 g, continue to reflow 0.5 h, while Hot filtration, The filtrate was allowed to stand at room temperature crystallization 12h after, Suction filtration, drying The product 166.4 g, yield 87.6percent, total yield 83.2percent, content 98.7percent. |
116 g | Stage #1: With PAMAM dendrimer In methanol at 80℃; for 5 h; Stage #2: Reflux |
(2) Taking (1) obtained in the 145 g Rutin and 7.2 g 3 on behalf of the PAMAM dendritic polymer are added to the 580 g without water in methanol, then access 58 g ethylene oxide, sealing the high-pressure autoclave, the beginning of the heating and stirring, heated to 80 °C after, thermal insulation reaction 5.0 h, HPLC detection synthetizing Rutin proportion up to 86percent when, rapid cooling, the termination of the reaction, for adjusting the pH value of the reaction solution of hydrochloric acid for the 5.0, standing crystallization 12 h after, filtered, and dried to obtain a crystal 133 g, yield 91.7percent;(3) To the (2) obtained in the crystal 133 g by adding 2.5 L water-free methanol, heating to reflux to totally dissolve, adding active carbon 4.0 g, continue to reflux 1.0 h after, to take advantage of the heat filter, the filtrate is reduced to the room temperature is static devitrifying 12 h after, filtering, drying to obtain the product troxerutin 108 g, yield 81.2percent, total yield of 74.5percent, content 99.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 68℃; for 24 h; Inert atmosphere | The reaction solvent water was dried at room temperature at 2000 kgInto the reaction tank,Then put rutin 610kg,Under nitrogen protection, the catalyst potassium hydroxide solution (containing 79 kg of potassium hydroxide)And then slowly added under the liquid surface249 kg of chloroethanol,Heating up to 68 ° C,Constant temperature reaction 4 hours and then add potassium hydroxide solution (containing potassium hydroxide 42kg),The reaction was continued for 20 hours after sampling,After the reaction was complete,Ice bath to 18 ° C,Under nitrogen protection, hydrochloric acid adjusts the pH to 6.The resulting solution was distilled under reduced pressure to dryness, and 4 times the weight of the obtained solidified methanol was stirred and heated to 75 ° C for 45 minutes. The crystals were cooled to 24 ° C for 12 hours and centrifuged to obtain 3 ', 4', 7 ' Trihydroxyethyl rutin crude, the resulting mother liquor into the distillation tank distillation, after passing the test apply. 3 ', 4', 7 'trihydroxyethyl rutin crude and ethyl acetate in the mass ratio of 1: 4 into the reaction tank, add activated carbon heated to 82 ° C, reflux 1 hour after the stop, the thermal filtration of the mother liquor cooling To 20 ° C for 10 hours,And then centrifugal rejection filter,Drying to produce 3 ', 4', 7-trihydroxyethyl rutin yield of 90percent, content of 91percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; dmap at 20℃; for 12h; Inert atmosphere; | 2'',2''',3'',3''',4'',4'''-hexa-O-acetyl-3',4',5,7-tetra-O-methylrutin(30) To a stirred solution of rutin (1.22 g. 2.0mmol) in dry pyridine (10 mL) was added acetic anhydride (3.06 g, 30 mmol) andDMAP (24mg, 0.20 mmol). After stirred for 12 h at room temperature, the reactionmixture was poured into aqueous HCl (0.1 M) (60 mL). The precipitate wasfiltered to give rutin peracetate10a (1.86 g, 90%) as a white solid. |
90% | With pyridine; dmap at 20℃; for 12h; Inert atmosphere; | 2'',2''',3'',3''',4'',4'''-hexa-O-acetyl-3',4',5,7-tetra-O-methylrutin (34): To a stirred solution of rutin (1.22 g. 2.0 mmol) in dry pyridine (10mL) was added acetic anhydride (3.06 g, 30 mmol) and DMAP (24 mg, 0.20 mmol).After stirred for 12 h at room temperature, the reaction mixture was pouredinto aqueous HCl (0.1 M) (60 mL). The precipitate was filtered to give rutinperacetate (1.86 g, 90%) as a white solid. To a stirred solution ofrutin peracetate (1.55 g. 1.5 mmol) in CH3OH (10 mL) was addedimidazole (408 mg, 6.0 mmol) and the resulting mixture was stirred for 8 h atroom temperature. After the solvent was removed under reduced pressure, thecrude product was purified by column chromatography on silica (dichloromethane/ethylacetate 1:5) to afford 2'',2''',3'',3''',4'',4'''-hexa-O-acetylrutin (1.03 g,80%) as a yellow solid.To a stirred solution of 2'',2''',3'',3''',4'',4'''-hexa-O-acetylrutin(863 mg. 1.0 mmol) in dry DMF (5 mL) was added K2CO3 (828mg, 6 mmol) and CH3I (851 mg, 6.0 mmol). After the addition, themixture was stirred for 12 h at room temperature. The reaction mixture was thendiluted with CH2Cl2 (20 mL) and poured into aqueous HCl(0.1 M) (10 mL). The organic layer was separated, washed with H2O(3×10 mL) and dried over Mg2SO4. After concentrated todryness under reduced pressure, the crude product was purified by columnchromatography on silica (petroleum ether/ethyl acetate 1:12) to afford theknown compound 34 (762 mg, 83%) as a yellowsolid * MERGEFORMAT . Data for 34: 1HNMR (400 MHz, CDCl3):δ 7.69 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 1.7 Hz, 1H), 6.36 (d, J = 1.6 Hz, 1H), 5.83 (d, J = 7.9 Hz, 1H), 4.91-5.30 (m, 6H), 4.51(s, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.90 (s, 3H), 3.64-3.69 (m,2H), 3.58 (dd, J = 2.5, 11.6 Hz, 1H),3.38 (dd, J = 5.3, 11.6HZ, 1H), 2.10 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.98 (s,3H), 1.93 (s, 3H), 1.03 (d, J = 6.2Hz, 3H). |
84% | With dmap In pyridine at 20℃; for 18h; | 2.3. Synthesis of Decaacetylated Rutin (R-10-OAc) The decaacetylated rutin compound was obtained by the addition of 6 mL of acetic anhydride and (40 mg, 0.33 mmol) of 4-Dimethylaminopyridine (DMAP) into a stirred solution of (1.22 g, 1.97 mmol) rutin trihydrate powder in 10 mL pyridine. The reaction was stirred for 18 hours under room temperature. The mixture was then neutralized by the addition of about 50 mL of 1 M HCl slowly until full precipitation occurred, then filtered and dried in the oven. After that, the residue was purified by silica gel column chromatography (eluent: Ethyl acetate /Hexane, 2/1, v/v) giving R-10-OAc (84%) as a white powder (Rf : 0.32, EtOAC: Hex 2:1). 1H NMR (500 MHz, CDCl3): δ 7.90-7.84 (m, 3H, Ar), 7.28-7.24 (m, 2H, Ar), 5.36 (d, 1H, J = 7.3 Hz, OCHO), 5.22 (t, 1H, J = 8.3 Hz, OCHO), 5.13 (d, 1H, J = 9.3 Hz, CHOAc), 5.02 (d, 2H, J = 7.3 Hz, 2CHOAc), 4.87 (t, 3H, J = 9.3 Hz, 3CHOAc), 3.59-3.44 (m, 3H, OCH2, OCHCH3), 3.20 (dd, 1H, J = 10.8 Hz, J = 5.9 Hz, OCHCH2), 2.37-1.87 (m, 30H, 10OAc), 0.99 (d, 3H, J = 6.4 Hz, CH3). 13C NMR (100 MHz, CDCl3) : δ 172.1, 170.3, 170.2, 170.0, 169.9, 169.7, 169.4, 168.3, 168.2, 168.0, 167.9, 161.9, 156.8, 156.3, 155.9, 154.8, 154.1, 150.3, 144.3, 141.9, 137.1, 127.4, 124.8, 123.6, 115.2, 113.6, 109.2, 105.3, 101.3, 100.1, 99.7, 97.7, 73.3, 73.0, 72.7, 72.6, 71.6, 71.0, 69.7, 69.5, 69.2, 67.1, 66.5, 60.5, 21.3, 21.2, 21.0, 20.8, 17.3. |
78% | With dmap In N,N-dimethyl-formamide at 45℃; for 2h; | 3. General method for peracetylation of polyphenols: General procedure: Polyphenols, acetic or butyric anhydride (6.0 equivalents per -OH group) andDMAP (0.3 equivalent) were completely dissolved in DMF in a round bottom flask to afinal concentration of 15 mM polyphenols. The reaction was kept at 45°C under stirringand monitored by analytical TLC (hexanes:ethyl acetate 3:1). After 0.5 - 2 h, cold 10%NaCl (aq) was added, and soluble fractions were extracted at 3 20 mL with ethyl acetate.The pooled organic phase was then washed with 3 20 mL 10% NH4Cl(aq) and 3 20mL 10% NaHCO3(aq), dried over anhydrous Na2SO4 and evaporated under reducedpressure to yield peracetylated (1a-8a) or perbutyrylated (2b, 4b, 6b) products. Meltingpoints were measured for solid products and compared to data from the literature, ifavailable. Structures were confirmed by 1H NMR, 13C NMR and LCMS(ESI+). |
73% | at 130℃; for 4h; | Synthesis of rutin peracetate (5) Rutin (1, 0.3 g, 0.5 mmol) was added to acetic anhydride (12 mL) and the mixture was heated at 130 °C, for 4 h. The solution obtained was poured intoice and extracted with CH2Cl2. The organic layer was extracted with a saturated solution of NaHCO3, dried with anhydrous Na2SO4, filtered, and then evaporated under reduced pressure. The obtained oil was dissolved in ethyl acetate. A solid material was obtained by adding petroleum ether 60-80 °C corresponding to 2-(3,4-di-O-acetylphenyl)-5,7-di-O-acetyl-3-[3,4,5-tri-Oacetyl-α-L-rhamnopyranosyl-(16)-3,4,5-tri-O-acetyl-β-D-glucopyranosyloxy]-4H-chromen-4-one (5) (0.43 g, 0.41 mmol, 73 % yield); mp 119-120 °C (petroleum ether 60-80 °C). |
With pyridine Ambient temperature; overnight; | ||
With pyridine | ||
15.3 mg | With pyridine; dmap at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide at 68℃; for 24h; Inert atmosphere; | 3 The reaction solvent water was dried at room temperature at 2000 kgInto the reaction tank,Then put rutin 610kg,Under nitrogen protection, the catalyst potassium hydroxide solution (containing 79 kg of potassium hydroxide)And then slowly added under the liquid surface249 kg of chloroethanol,Heating up to 68 ° C,Constant temperature reaction 4 hours and then add potassium hydroxide solution (containing potassium hydroxide 42kg),The reaction was continued for 20 hours after sampling,After the reaction was complete,Ice bath to 18 ° C,Under nitrogen protection, hydrochloric acid adjusts the pH to 6.The resulting solution was distilled under reduced pressure to dryness, and 4 times the weight of the obtained solidified methanol was stirred and heated to 75 ° C for 45 minutes. The crystals were cooled to 24 ° C for 12 hours and centrifuged to obtain 3 ', 4', 7 ' Trihydroxyethyl rutin crude, the resulting mother liquor into the distillation tank distillation, after passing the test apply. 3 ', 4', 7 'trihydroxyethyl rutin crude and ethyl acetate in the mass ratio of 1: 4 into the reaction tank, add activated carbon heated to 82 ° C, reflux 1 hour after the stop, the thermal filtration of the mother liquor cooling To 20 ° C for 10 hours,And then centrifugal rejection filter,Drying to produce 3 ', 4', 7-trihydroxyethyl rutin yield of 90%, content of 91%. |
With potassium carbonate In N,N-dimethyl-formamide for 0.133333h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride; methanol for 3h; Heating; | |
95.6% | With sulfuric acid In lithium hydroxide monohydrate at 100℃; for 3h; | 2.5.2. Quercetin (2) A solution of the rutin (15 g, 24.57 mmol) in 6% H2SO4 /H2O (v/v,500 mL) and the reaction mixture was heated at 100 °C for 3 h. At the end of the reaction period, the solution was cooled and the precipitated solid was filtration and collection. The residue was dissolved in ethanol (40 mL) and reflux for 1 h. The reaction solution was cooled and poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Quercetin was obtained as a light green solid (7.1 g, 95.6%). 1H NMR (400 MHz, (CD3)2SO) δ 12.46 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, (CD3)2SO) δ 176.3, 164.3, 161.1, 156.6, 148.1, 147.3, 145.5, 136.2, 122.4, 120.5,116.1, 115.5, 103.5, 98.7, 93.8. |
95.6% | With sulfuric acid In lithium hydroxide monohydrate at 100℃; for 3h; | 2.5.2. Quercetin (2) A solution of the rutin (15 g, 24.57 mmol) in 6% H2SO4 /H2O (v/v,500 mL) and the reaction mixture was heated at 100 °C for 3 h. At the end of the reaction period, the solution was cooled and the precipitated solid was filtration and collection. The residue was dissolved in ethanol (40 mL) and reflux for 1 h. The reaction solution was cooled and poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Quercetin was obtained as a light green solid (7.1 g, 95.6%). 1H NMR (400 MHz, (CD3)2SO) δ 12.46 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, (CD3)2SO) δ 176.3, 164.3, 161.1, 156.6, 148.1, 147.3, 145.5, 136.2, 122.4, 120.5,116.1, 115.5, 103.5, 98.7, 93.8. |
90% | With lithium hydroxide monohydrate at 100℃; Ionic liquid; | |
89% | With sulfuric acid; lithium hydroxide monohydrate at 20℃; for 0.166667h; | Typical hydrolysis procedure General procedure: Sulfuric acid (2.0mL, 0.037mmol) was added dropwise to a beaker (100 mL) containing scutellarin (50 mg, 0.11 mmol). It was shaken or agitated by ultrasound agitated to dissolve the substrate in the acid at room temperature. Water (2.0 mL) was then added carefully dropwise. When the evolution of heat ceased (in 10 minutes), the mixture was added to water (15 mL) in one portion with stirring with a glass rod. The yellow crystals that were deposited were collected by suction filtration and washed by water (5 mL). In most cases, such products were pure enough for direct use. Moreover, it could be further purified by recrystallisation from aqueous methanol (70%, v/v) or column chromatography on silica gel (eluent:ethyl acetate/formic acid/water=100/4/3, v/v/v, Rfs of SCU and SCUE were 0.1 and 0.8 on silica gel GF254 respectively). Light yellow crystals were obtained after recrystallisation (28.5mg, 93% yield); m.p. 285-287°C (>300°C)27. IR (KBr, cm-1): νmax 3442, 3331, 3098, 1671, 1619, 1587, 1509. 1H NMR (500MHz, DMSO-d6): δ 12.80 (s, 1H, 5-OH), 10.48 (s, 1H, 7-OH), 10.33 (s, 1H, 4′-OH), 8.75 (s, 1H, 6-OH), 7.92 (d, 2H, J=8.6Hz, C2′, C6′-H), 6.92 (d, 2H, J=8.6Hz, C3′, C5′-H), 6.75 (s, 1H, C3-H), 6.58 (s, 1H, C8-H). HR-ESI-MS (m/z): 309.0363 for [M+Na]+, calcd 309.0370. |
6.788% | With sulfuric acid Reflux; | 1.3 Embodiment 1 3, was prepared from the resulting quercetin rutin Take half of the above step retained rutin filtrate was added 1mol / L sulfuric acid, in a water bath at reflux for 1 ~ 1.5h, until total hydrolysis of steam to ethanol, cooled, the precipitated quercetin, filtration.Quercetin precipitate after washing, after drained, dried, and weighed to give quercetin 6.788g, calculate the yield of 6.788%, and then recrystallized from ethanol to give yellow needles, quercetin boutique. |
With hydrogenchloride In hydrogenchloride for 1h; Heating; | ||
With phosphate buffer; β-glucosidase from rat small intestinal mucosa of duodenum; phenylmethylsulphonyl fluoride; 2-hydroxyethanethiol In lithium hydroxide monohydrate at 37℃; for 0.333333h; rate of hydrolysis in mol/hr/mg protein; other proteins; | ||
With sulfuric acid for 2h; | ||
With hydrogenchloride; ethanol for 4h; Heating; | ||
With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 2h; Reflux; | ||
With rutin hydrolyzing enzyme from fagopyrum tataricum In ethanol; lithium hydroxide monohydrate at 37℃; for 0.25h; | ||
With formic acid; α-L-rhamnosyl-β-D-glucosidase from Aspergillus niger K2 in Pichia pastoris In methanol; lithium hydroxide monohydrate; acetonitrile at 25℃; for 0.5h; | ||
With hydrogenchloride In lithium hydroxide monohydrate at 39.84 - 59.84℃; for 6h; | Forced studies of rutin For the determination of concentration changes of rutin in the presence of its impurities and degradation products (quercetin and isoquercetin) as a result of factors affecting action, changes in the absorption spectra of rutin were examined. The degradation of rutin was studied in aqueous solutions: in hydrochloric acid (pH = 0.3) at 333 K up to 360 min, sodium hydroxide (pH = 13.3) at 313 K up to 15 min and in hydrogen peroxide (10%) at 353 K up to 200 min. Samples were prepared by dissolving an accurately weighed 5.0 mg of rutin in 25.0 mL of the equilibrated solution to 313 K in glass stoppered flasks. At specified times, samples of the reaction solutions (1.0 mL) were collected and instantly cooled with a mixture of ice and water, neutralized with 0.8 ml of NaOH or HCl solutions of suitable concentrations and assayed. The ionic strength of all solutions was adjusted to 0.5 mol/L with a solution of sodium chloride (4 mol/L). | |
With hydrogenchloride In lithium hydroxide monohydrate for 0.5h; Reflux; | ||
With hydrogenchloride; potassium carbonate In lithium hydroxide monohydrate at 70℃; for 3h; | 7 Preparation of 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-benzopyran-4-one A clean and dry 500 mL round bottom flask was taken, and the analytical balance was weighed into rutin (6 g, 9.828 mmoL) and K2CO3 (20 g, 144.8 mmoL).Add 10% HCl solution to dissolve,Then a small amount of ethanol can be added to the inner wall of the flask.Dissolve the solid on the inner wall.After processing,Heated to 70 ° C for 3 h,hydrolysis,Getting a flocculent solid,Filtering,Get a rough product. | |
With lithium hydroxide monohydrate at 50℃; for 1h; Irradiation; Green chemistry; Enzymatic reaction; | ||
With rutinosidase from Aspergillus niger K2; lithium hydroxide monohydrate In dimethyl sulfoxide Enzymatic reaction; | ||
With Prunus dulcis beta-glucosidase at 59.84℃; Enzymatic reaction; | ||
With trifluoroacetic acid at 100℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dipotassium peroxodisulfate; <i>tert</i>-butyl alcohol In water Radiolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 33% 2: 17% 3: 32% | In methanol; diethyl ether at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water at 75℃; for 6h; | 1; 2; 3 EXAMPLE 1 [00035] 100 g rutin are treated under hot conditions, at about 75° C., with 28 g of ethylene oxide in 100 ml of water containing 1.1 g of sodium hydroxide, and the reaction mixture is kept stirring for about 6 hours. The reaction is monitored by HPLC chromatography, and the end of the reaction is detected when the relative proportions of di-, tri- and tetrahydroxyethyl rutoside derivatives are, respectively, 4%, 88% and 7 to 8%. The medium is then acidified by adding sulfuric acid to neutralize the alkali which is present. [00036] The aqueous medium is concentrated under reduced pressure (about 2×104 Pa) at a temperature of between 60 and 70° C., such that the water concentration is close to 2% in the final crystallization medium. [00037] The concentrate is taken up in 240 ml of methanol and is then filtered to remove the salts formed. 220 ml of isopropanol are added to the solution and, after checking the water content, crystallization is carried out over about 8 hours, the temperature being decreased from 65° C. to 25° C. over the first two hours and being maintained between 25 and 20° C. during the next 6 hours. [00038] 89.4 g (80% yield) of troxerutin with a titer of 92% of trisubstituted derivative, 4% of tetrasubstituted derivative and 3% of disubstituted derivative are thus obtained, the remainder consisting of the abovementioned hydroxyethyl derivatives of isoquercitrine-3-glucoside and of kaempferol-3-rutinoside.; EXAMPLE 2 [00039] The process is performed as in example 1, but the crystallization is carried out over about 3 to 4 hours, during which the temperature is decreased from 65° C. to 30° C. and is then maintained at between 30 and 25° C. over about 2 hours. [00040] 87.2 g (78% yield) of troxerutin with a titer of 93% of trisubstituted derivative, 3.5% of tetrasubstituted derivative and 2.5% of disubstituted derivative are thus obtained, the remainder consisting of the same derivatives as above.; EXAMPLE 3 [00041] The process is performed as in example 1, but the aqueous solution is passed over ion-exchange resins or strong cationic type, and then of strong anionic type, before filtration. The medium is then concentrated so as to bring the water content to a value equal to about 5.2% in the final medium. [00042] The concentrate is taken up in 800 ml of methanol and 30 ml of isopropanol solution are added. The crystallization is carried out as above, over about 2 hours, while maintaining the temperature at between 25 and 15° C. over about 1 hour at the end of crystallization. [00043] 84.2 g (75% yield) of troxerutin with a titer of 95% of trisubstituted derivative, 2.8% of tetrasubstituted derivative and 1.7% of disubstituted derivative are thus obtained, the remainder consisting of the same derivatives as above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Aspergillus niger crude enzyme extract In methanol at 60℃; for 4h; aq. piperazine-HCl buffer; Enzymatic reaction; | |
98.6% | With hesperidinase In aq. buffer at 40℃; for 0.666667h; Ionic liquid; Enzymatic reaction; | Hesperidinase-catalyzed synthesis of isoquercitrin in a continuous-flow microreactor Hesperidinase-catalyzed synthesis of isoquercitrin was carried out in a glass-PDMS microreactor with rectangular microchannels. The microreactor developed by the laser burn technology had one T-shaped inlet and one outlet channels. The main channel dimension was 200 μm wide, 50 μm deep and 2 m long (see Fig. 1). The reaction substrate (rutin at pH 9 in glycine-sodium hydroxide buffer) and an enzyme solution contain 10 % [Bmim][BF4] were both pumped into the microchannel by a two-channel syringe pump. The flow rates of the two phases were same |
98.6% | With hesperidinase from Aspergillus niger; water In aq. buffer at 40℃; for 0.666667h; Flow reactor; Enzymatic reaction; | Hesperidinase-catalyzed synthesis of isoquercitrin in a continuous-flow microreactor Hesperidinase-catalyzed synthesis of isoquercitrin was realized in a glass-PDMS microreactorwith rectangular microchannels. The microreactor developed by the laser burn technologyhad a T-shaped inlet and an outlet channel. The main channel dimension was 200 μmwide, 50 μm deep and 2 m long (Fig. 1). The reaction substrate (rutin at pH 9 in glycine-sodium hydroxide buffer) and an enzyme solution containing 10 % [Bmim][BF4] were bothpumped into the microchannel by a two-channel syringe pump. The flow rates of the twophases were the same. |
56.9% | With naringinase; water at 50℃; for 2h; | |
With pH adjustment agent In water at 72℃; for 24h; | 1 250 g flower buds from the Japanese pagoda tree (Saphora japonica), a member of the Fabaceae family, was soaked for 2 hours in 2500 mL hot water (at least 95° C.) and then filtered and the resulting filtrate was recovered and designated as the first extract. The filtered off residue was subjected to extraction by additional soaking in hot water to yield a second extract. The first and second extracts were combined, cooled to 30° C. or below; the precipitated component was filtered off; and the precipitate was washed with water, recrystallized, and dried to yield 22.8 g rutin with a purity of at least 95%.20 g of this rutin was dispersed in 400 mL water and the pH was adjusted to 4.9 using a pH adjustment agent. To this was added 0.12 g naringinase (Amano Enzyme Inc., product name: Naringinase “Amano”, 3,000 U/g) to start a reaction followed by holding for 24 hours at 72° C. The reaction solution was thereafter cooled to 20° C. and the precipitate produced by cooling was filtered off. The obtained precipitate (solid fraction) was washed with water and dried, yielding 13.4 g isoquercitrin (IQC). | |
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C / Inert atmosphere 2: hydrogenchloride / water / 2 h / 80 °C 3: potassium carbonate / N,N-dimethyl-formamide / 6 h / 20 °C 4: sodium methylate / methanol; tetrahydrofuran / 6 h / 20 °C 5: 10% Pd/C; hydrogen / tetrahydrofuran; ethanol / 2 h / 20 °C / 750.08 Torr | ||
Stage #1: rutin With hesperidinase; 1-butyl-3-methylimidazolium Tetrafluoroborate In aq. buffer at 40℃; Enzymatic reaction; Stage #2: With triacetylglycerol at 30℃; for 0.5h; | 1 Rutin was dissolved at pH 9.0 glycine-sodium hydroxide buffer solution at a concentration of 1g / L, were added to a solution of 10% by volume of ionic liquid [Bmim] [BF4] And 18% at a concentration of 0.01g / mL hesperidin enzyme solution constituting the reaction system at 40°C with shaking at a constant temperature to obtain rutin hydrolyzate, following every embodiment with reference to the preparation of rutin hydrolyzate.Ionic liquid cosolvent system rutin hydrolyzate of pH between 2.0 and 7.0; The 3 mL of rutin hydrolysate with a pH 2.0 was placed in a 100 mL Erlenmeyer flask then added 3 mL of Triacetin, 30°C, 130 r / min shaking water bath shaker in 30min, poured into a separatory funnel until the two phase equilibrium after, HPLC detection and phase extraction raffinate phase isoquercitrin extraction efficiency was calculated isoquercitrin of 60.27%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 4h; | |
61% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 4h; | |
Stage #1: rutin With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 60℃; for 3h; |
With potassium carbonate In N,N-dimethyl-formamide at 40℃; regioselective reaction; | ||
Stage #1: rutin With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 60℃; for 3h; Inert atmosphere; | 3.6. Synthesis of 7-(Benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3,5-dihydroxy-4H-chromen-4-one (9) A mixture of rutin (8, 5.00 g, 8.2 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in dry DMF (40 mL) was stirred under argon atmosphere for 0.5 h. Benzyl bromide (3.2 mL, 27.1 mmol) was then added dropwise. After stirring for 3 h at 60 °C, the mixture was acidified to pH 5 with 10% aqueous acetic acid solution, and the precipitate was collected by centrifugation. Ethanol (60 mL) was added to the precipitate and then conc. aqueous hydrochloric acid (9 mL) of was add in portions. This reaction mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the precipitate was filtered and washed with water. The crude product was recrystallized from CH2Cl2/EtOH to afford 9 as yellow powder in 85% yield, m.p. 186-188 °C. 1H-NMR (DMSO-d6) δ 7.90 (d, J = 2.0 Hz, 1H, -ArH), 7.84(dd, J = 8.8, 2.0 Hz, 1H, -ArH), 7.53-7.30 (m, 15H, -ArH), 7.25 (d, J = 8.8 Hz, 1H, -ArH), 6.86 (d,J = 2.0 Hz, 1H, -ArH) 6.45 (d, J = 2.0 Hz, 1H, -ArH), 5.24 (s, 4H, -CH2), 5.21 (s, 2H, -CH2); ESI-MS (m/z) 573.1 [M+H]+. | |
Stage #1: rutin With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; for 3h; Inert atmosphere; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60h; | 3 Reagents and reaction conditions: (i) BnBr, K2CO3, DMF, room temperature; (ii) ethanol, concentrated hydrochloric acid, 70 , 3h.Preparation steps: (i) said anhydrous rutin obtained (50g, 0.08mol) set 1000mL reaction flask was added 600mL of DMF anhydrous, stirred and dissolved was added anhydrous K2CO3 (56g, 0.41mol, 5eq) and benzyl bromide ( 36.9mL, 0.3mol, 3.8eq), the reaction 2.5 days at room temperature, thin layer chromatography (TLC) the reaction was complete, the reaction mixture was poured into ice-water bath with concentrated hydrochloric acid and adjusted to pH 6 to precipitate heavy precipitate was filtered, the filter cake is the crude intermediate M-07; (ii) the M-07 crude directly with anhydrous ethanol (600mL) was heated and dissolved, and then concentrated hydrochloric acid (200mL), the reaction was refluxed for 3h at 70 , until the reaction was complete, the precipitate was cooled to room temperature, poured into an ice-water bath, the precipitate was filtered, washed with water until neutral, earth cake was dried to obtain a yellow powdery solid intermediate M-08. The total two-step reaction in 80% yield. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; | Synthesis of 7,3’,4’-tri-O-benzylquercetin (6) A mixture of rutin (1.22 g, 2.0 mmol), BnBr (1.9 mL, 16.0 mmol)and K2CO3 (2.20 g, 16.0 mmol) in DMF (20 mL) was stirred at roomtemperature for 16 h. The reaction mixture was evaporated underreduced pressure. Ethanol (30 mL) and concentrated HCl (3 mL) wereadded to the residue, and the solution was refluxed for 2 h. The solution was cooled and filtered to give 6 as a yellow solid; yield 0.97 g (85%) | |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 18h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h; | 7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3,5-dihydroxy-4H-chromen-4-one (16) To a solution of rutin(610 mg, 1 mmol) in DMF (30 mL), BnBr (684 mg, 4 mmol) and K2CO3 (552 mg, 4 mmol) were added.The solution was stirred at 50 C for 3 h. Water (100 mL) was added, and the solution was cooled to0 C for overnight. The solid 15 was collected by suction filtration and dissolved in 95% alcohol (20mL), and hydrochloric acid (3 mL) was added. After stirring for 2 h at 70 C, solid was precipitated inthe solution. Then, compound 16 (740 mg, 84%) was collected by suction filtration after the solutionwas cooled to r.t. | |
With potassium carbonate In N,N-dimethyl-formamide at 40℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.8.57. 7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-5-hydroxy-3-(((2R,3S,4R,5R,6S)-3,4,5-trihydroxy-6-((((2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy) methyl)tetrahydro-2H-pyran-2-yl)oxy)-4H-chromen-4-one (51) To a solution of rutin 50 (2000 mg, 2.96 mmol) in DMF (20 mL) wereadded K2CO3 (1716 mg, 12.44 mmol) and benzoyl bromide (2.8 mL,23.68 mmol). The reaction mixture was stirred overnight at room temperature.Then it was diluted with EtOAc (60 mL). The organic phasewas divided, washed with water (2x50 mL), dried over MgSO4 andconcentrated under vacuum yielding of crude 51, which was usedwithout futher purification for the next step (2000 mg). UPLC/MS Rt =2.44 min (gradient 1), MS (ESI) m/z: 881.3 [M+H]+.[M+H]+ calculatedfor C48H49O16: 881.3. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-5-hydroxy-3-(((2R,3S, 4R,5R,6S)-3,4,5-trihydroxy-6-((((2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-4H-chromen-4-one (25) To a solution of rutin 24 (2000 mg, 2.96 mmol) in DMF (20 mL) were added K2CO3 (1716 mg, 12.44 mmol) and benzoyl bromide (2.8 mL, 23.68 mmol). The reaction mixture was stirred overnight at room temperature. Then it was diluted with EtOAc (60 mL). The organic phase was divided, washed with water (2x50 mL), dried over MgSO4 and concentrated under vacuum yielding of crude 25, which was used without further purification for the next step (2000 mg). UPLC/MS Rt = 2.44 min (gradient 1), MS (ESI) m/z: 881.3 [M+H]+.[M+H]+ calculated for C48H49O16: 881.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With laccase (EC 1.10.3.2) from Pycnoporus cinnabarinus In methanol; water at 24℃; for 0.25h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: benzyl bromide; rutin With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water at 70℃; for 2h; regioselective reaction; | 3.1.9. 2-(3,4-Bis(benzyloxy)phenyl)-7-(benzyloxy)-3,5-dihydroxy-4H-chromen-4-one (14) In order to take off the three crystal water, rutin (13) was dried under vacuum at 100 °C for 6 h. To a stirring mixture of rutin (13) (0.626 g, 1 mmol) and K2CO3 (0.58 g, 4.2 mmol, 4.2 equiv.) in DMF (30 ml) at room temperature was added benzyl bromide (0.42 ml, 3.5 mmol, 3.5 equiv.), then the reaction mixture was allowed to warm to 40 °C and the stirring was maintained for 3 h under argon. The resulting mixture was cooled to 0 °C and its pH was adjusted to 6 with 10% acetic acid, then the solid obtained was filtered, dissolved in 20 ml of 95% ethanol and reacted with 3 ml of 36% hydrochloric acid at 70 °C for 2 h. The reaction mixture was cooled to 0 °C, the solid obtained was filtered, washed with cold water and purified by column chromatography (25% ethyl acetate in petroleum ether) to give 14 (0.53 g, 92% yield) as a yellow solid [18]. Mp 190-191 °C (lit. [18] 188-190 °C). 1H NMR (DMSO-d6, 300 MHz) δ: 5.21 (s, 2H, -OCH2Ph), 5.25 (s, 4H, 2× -OCH2Ph), 6.45(d, J = 2.2 Hz, 1H, 6-H), 6.86 (d, J = 2.2 Hz, 1H, 8-H), 7.26 (d, J = 8.6 Hz, 1H, 5'-H), 7.33-7.51 (m, 15H), 7.84 (dd, J = 2.2, 8.6 Hz, 1H, 6'-H), 7.89 (d, J = 2.2 Hz, 1H, 2'-H), 9.66 (s, 1H, 3-OH), 12.41 (s, 1H, 5-OH). ESI-MS m/z: 573 [M + H]+, 595 [M + Na]+. |
81.2% | Stage #1: rutin With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 16h; Cooling with ice; | 2.1 The rutin was placed in a vacuum oven at 80 ° C for 10 hours to remove the crystal water, take 4.88g (8mmol) rutin dissolvedIn 40 ml of N, N-dimethylformamide (DMF)(28 mmol) of anhydrous K2CO3 was added and stirred at room temperature for 30 min. 3.4 ml (28 mmol) of benzyl bromide was added dropwise slowly in an ice bath and allowed to react at room temperature for 16 h. With glacial acetic acid to adjust the pH to 6-7, 200ml of distilled water, stirring 3h, to solid precipitation and clarify the water layer. The precipitated yellow precipitate was collected by filtration and washed with water. The crude product was recrystallized from chloroform / methanol to give 3.72 g of pure product 1 in a yield of 81.2%. |
80% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 60h; Inert atmosphere; | Synthesis of 3',4',7-tri-O-benzylquercetin(I) To a mixture of anhydrous rutin (50 g, 0.08 mol) andanhydrous K2CO3 (56 g, 0.41 mol, 5 eq.) in 600 mL of anhydrous N,N-dimethylformamide (DMF),benzyl bromide (BnBr, 36.9 mL, 0.3 mol, 3.8 eq.) was added under argon. After stirring at roomtemperature for 2.5 days, the reaction mixture was poured into ice water and its pH was adjusted to 6 withconcentrated hydrochloric acid, the resulting precipitate was filtered to afford a crude product which wasused for the next step without further purification. To a solution of the previous step’s product in 600 mLEtOH was added 200 mL concentrated hydrochloric acid. The mixture was stirred 70 C for 3 h, aftercooling to room temperature, the reaction mixture was poured into cold water and the resulting precipitatewas filtered and washed with cold water, the obtained residue was purified by column chromatography onsilica gel (1:2 EtOAc-petroleum ether) to give compound I (46.8 g, 80% yield over two steps) as ayellowish brown solid. ESI-MS m/z 595.2 [M + Na]+; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H),7.81 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.8, 1.9 Hz, 1H), 7.30-7.55 (m, 15H), 7.25 (d, J = 8.8 Hz, 1H),6.86 (d, J = 1.9 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.24 (s, 4H), 5.21 (s, 2H). |
43% | Stage #1: benzyl bromide; rutin With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; for 0.25h; Stage #2: With hydrogenchloride In ethanol; water; N,N-dimethyl-formamide at 78℃; for 2h; | 4 Preparation of 7,3',4'-tribenzyloxy quercetin. 34g of rutin, which was dehydrated and dried off in water, was dissolved in 260mL of anhydrous DMF,Then, 53.79 g of anhydrous potassium carbonate was added and the mixture was stirred at room temperature for 15 minutes.Then, 46 mL of benzyl bromide was added and the mixture was stirred for 3 to 4 hours at 50 ° C.After the reaction, the pH value was adjusted to 6 with 10% acetic acid and filtered to obtain a precipitate.The precipitate was dissolved in 800 mL of absolute ethanol, then 150 mL of concentrated hydrochloric acid was added.The mixture was refluxed at 78 ° C for 2 hours. After cooling to room temperature filtered to give a pale yellow solid.The resulting solid was recrystallized from methylene chloride / methanol to give 7,3 ', 4'-tribenzyloxy quercetin as a light yellow solid.Yield 43% |
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 2: hydrogenchloride / ethanol; water / 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: rutin; methyl iodide With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water at 70℃; for 2h; | 3.1.34. 2-(3,4-Dimethoxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chromen-4-one (33) To a stirring mixture of rutin (13) (0.626 g, 1 mmol) which has been taken off the three crystal water and K2CO3 (0.58 g, 4.2 mmol, 4.2 equiv.) in DMF (30 ml) at room temperature was added iodomethane (0.23 ml, 3.5 mmol, 3.5 equiv.), then the reaction mixture was allowed to warm to 40 °C and the stirring was maintained for 3 h under argon. The resulting mixture was cooled to 0 °C and its pH was adjusted to 6 with 10% acetic acid, then the solid obtained was filtered, dissolved in 20 ml of 95% ethanol and reacted with 3 ml of 36% hydrochloric acid at 70 °C for 2 h. The reaction mixture was cooled to 0 °C, the solid obtained was filtered, washed with cold water and purified by column chromatography (25% ethyl acetate in petroleum ether) to give 33 (0.313 g, 91% yield) as a yellow solid. Mp 176-177 °C. 1H NMR (CDCl3, 300 MHz) δ 3.89 (s, 3H, -OCH3), 3.97 (s, 3H, -OCH3), 3.99 (s, 3H, -OCH3), 6.38 (d, J = 2.2 Hz, 1H, 6-H), 6.50 (d, J = 2.2 Hz, 1H, 8-H), 7.00 (d, J = 8.6 Hz, 1H, 5'-H), 7.78 (d, J = 2.0 Hz, 1H, 2'-H), 7.83 (dd, J = 2.0, 8.6 Hz, 1H, 6'-H), 11.71 (s, 1H, 5-OH). ESI-MS m/z: 345 [M + H]+, 367 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With chitosan In methanol at 75℃; for 3h; Autoclave; | 4 Example 4 Weighing 30.53g (0.05 µM) Rutin, 2.42g (15mmol) catalyst natural alkaline high molecular compound chitosan, 100 ml methanol solvent and 15.4g (0.35 µM) ethylene oxide add to the sucking stirring in the autoclave, open the digital controller, the set temperature is 75 °C, the rotating speed of 1000r/min, stirring and heating to 75 °C, thermal insulation reaction 3h. After the reaction, the temperature rapidly in cold water, and the cessation of the stirring, the closing of the digital controller, open the reaction kettle, pouring the reaction solution. Pouring the reaction solution of hydrochloric acid for adjusting the pH 6, and filtering the catalyst, the reaction solution after filtering in a seed crystal standing crystallization, the obtained crystal 35.65g, yield 96%, external standard content of 90.1%. |
87.6% | With natural polymer sodium alginate In methanol at 70℃; for 4h; Autoclave; | 7.2 Take 200 g of rutin obtained in (1) and 10.0 g Natural polymer sodium alginate added to 400 g of anhydrous methanol, and then pass 100 g of ethylene oxide, sealed autoclave, heating and stirring began, heated to 70 ° C, incubated for 4.0 h, HPLC test Trihydroxyethyl rutin When the ratio reached 86%, the reaction was quenched rapidly to terminate the reaction. Hydrochloric acid was added to adjust the pH value of the reaction solution to 6.0. After standing for crystallization for 12 h, the mixture was suction filtered and dried to obtain 198.4 g of solid with a yield of 99.2%. 3) to190 g of the solid obtained in (2) was added to 3200 mL of a mixed solution of anhydrous methanol and ethanol (anhydrous methanol and BThe volume ratio of alcohol is 1 : 1), heated to reflux completely dissolved, add needle activated carbon 8.0 g, continue to reflow 0.5 h, while Hot filtration, The filtrate was allowed to stand at room temperature crystallization 12h after, Suction filtration, drying The product 166.4 g, yield 87.6%, total yield 83.2%, content 98.7%. |
Stage #1: oxirane; rutin With sodium hydroxide In water at 75℃; for 6h; Stage #2: With hydrogenchloride In water | Ethylene oxide (6.60 g, 150 mmol) and NaOH (0.28 g, 7 mmol) were added to a solution of rutin (12.21 g, 20 mmol) in H2O (100 mL) at room temperature. After stirring at 75 °C for 6 h, the pH value of the mixture was adjusted to 4.0 by concentrated hydrochloric acid. Then, the yellow solid was formed. The crude product was collected by filtration and washed with cold water. It was repeatedly recrystallized by methyl alcohol and the yellow powder, compound 1, was obtained. The purity was 99.84% tested by HPLC (CH3OH/H2O = 8:1; v/v) equipment (Shimadzu). |
Stage #1: rutin With pyridine In methanol for 0.5h; Inert atmosphere; Sealed tube; Stage #2: oxirane at 50℃; Inert atmosphere; Sealed tube; Sonication; | Close the reactor mouth, the metering accurate 300.0kg methanol vacuum pumped into the reactor, open the reactorMouth, stirring, from the reactor mouth slowly add rutin 80. 0kg crude, pyridine 2. 0kg, nitrogen 2 times, at a vacuum of 90. 64kPa. Sealed reactor mouth, catalytic 0.5h,Catalytic temperature is 10 ~ 25 ° C. 35kg of ethylene oxide will be accurately measured with a vacuum pumped into the reactor, after a cold stirring period of time, open the reactor heating steam valve heating, ultrasonic radiation time of 40 ~ 60min, the intensity of 40kHz blessing, to be reaction Dad on the pressure The table indicates the pressure reaches 0. 15MPa when the steam heating steam valve, until the pressure rose to 16MPa start timing, the pressure inside the kettle in the 0? 15 ~ 0.18MPa,Etherification temperature of 50 +5 ° C to maintain 0.5 ~ 1.0 h,After reaction 0.5h, the ophthalmic reaction solution was clear and transparent, and the fluidity was good. The reaction was complete and the etherification was completed. The exhaust gas was first vented to the ethylene oxide absorber and the pressure drop To 0. 05MPa, otherwise, continueReaction until the test qualified. Record the pressure once every 5 minutes and record the pressure adjustment. The reaction system was heated to (60 ± 5) ° C after adding hydrogen peroxide, and the reaction was continued for 20 min at constant temperature. The reaction solution was pressed into a decolorizer.To decolorization kettle by adding 1. 5kg activated carbon closed kettle mouth, the reaction of good material into the good pressure of the activated carbon decolorization tank,After about 1/3 of the liquid enters the decolorization kettle and opens the decolorization kettle and stirs. When the reaction liquid pressure is over, turn on the decolorization kettle feed valve and open the bleaching kettle heat steam valve until the temperature of the decolorization kettle rises to (70 ± 5) ° C , The pressure rose to 0.10 ~ 0.12MPa off when the decolorization kettle heat steam, keep this condition stirring bleaching 30min.From the storage tank to filter the liquid material to the crystallization tank on the crystallization tank, the crystallization tank temperature is not higher than 30 ° C)When the temperature of the liquid to be reduced to below 30 ° C, adjust the pH value with acetic acid to 5. 5 ~ 6. 5, add acid should be slowly dropping, and fully stirred. Calculate the amount of acid used to record. The crystallization was started after the completion of the acid-stirring step and centrifuged. Centrifuge lmin so that the filter bag close to the centrifuge wall, the crystallization of good material about 40kg into the centrifuge centrifuge for about 5min, when the centrifuge outlet liquid into the mother liquid drops, the closure of the centrifuge, Centrifuge centrifuge material into a clean plastic bag, each batch of about centrifugation 3 to 4 times, after weighing the finished centrifuge, fill in the intermediate Please check the single application for sample testing.After centrifugation, the troxerutin wet product was transferred to the dryer twice in the temperature range of 0. 06 ~0.08 MPa40 ~ 60 ° C under the conditions of drying 2. 5h. Check the dry quality of qualified, put the material weighing to pay crushing posts. The dried troxerutin is crushed by a crusher, and the crushed material is delivered to the intermediate station for sampling detection after the crushing. According to the mixed batch, the weight of the finished product is 500. 0kg. The mixed batch is determined to be added to the total mixing machine and rotated at 2r / min for 30 minutes. Packing materials in polyethylene bags, one in the packaging between the bag to adjust the amount of 25. 0 ± 0. lkg, sampling, sealing, set the second layer of bags, sealing bar, and then transfer from the transfer window To the outer packaging, outsourcing, labeling storage. | |
With sodium methylate In methanol at 70℃; for 4h; Autoclave; | 1 The Rutin (100g) and sodium methoxide (8g) after mixing is put in high pressure in the reactor, the ethylene oxide (32g) into 300 ml in methanol, putting into the high-pressure in the reactor, the closing of the high-pressure reactor, the elevated temperature to 70 °C, at this moment the high pressure reaction kettle pressure is 0.3 mpa left, reaction 4h to start sampling monitoring, HPLC detection synthetizing the highest content of stopping the reaction when the Rutin, the reaction liquid through the dilute hydrochloric acid for adjusting the pH 5 - 6. The filtrate average is divided into two parts, a stirring cooling crystallization, then filtered to obtain relatively higher product purity of troxerutin, another through the steaming and methanol, to obtain the weight relatively high troxerutin. | |
Stage #1: oxirane; rutin With sodium hydroxide In methanol; water at 65 - 75℃; for 1.2h; Inert atmosphere; Stage #2: With zinc(II) acetate dihydrate In methanol; water at 75 - 85℃; for 0.25h; Inert atmosphere; Stage #3: With sulfuric acid In methanol; water for 0.25h; Inert atmosphere; | 3 General procedure: S1: 3000 mL and equipped with Mettler acidity - thermometer,Airway, Outlet,Condenser and electric mixer reaction flask were sequentially charged 350mL of purified water and 3.96g of sodium hydroxide,After the solution was added 350mL of methanol,Nitrogen after 15min once added to the liquid phase purity of 96.2% refined rutin 317.5g (0.5mol)The water bath was heated to 65 ° C to stop the introduction of nitrogen,Ethylene oxide gas is slowly introduced into the reaction bottle through the airway to carry out an anterior etherification reaction.period,Maintain the internal temperature of 65 ~ 75 , pH of 8.3 to 8.6 conditions continued ventilation reaction, until the reaction solution becomes clear.Then timed sampling of tris (hydroxyethyl) rutin and its three hydroxyethyl isomers liquid phase purity test.When the tetrahydroxyethyl rutin peak area ratio reached 1.15%, immediately terminate the etherification reaction.At the same time with nitrogen to drive the reaction flask residual ethylene oxide gas.S2: continue to pass nitrogen, and control the internal temperature of 75 ~ 85 , intermittent dropping 5.0% sodium hydroxide solution to adjust the reactionLiquid PH is 8.3 to 8.8 from the dropping funnel to the reaction flask was uniformly added dropwise a mass concentration of 20% of magnesium acetate tetrahydrate(118 g, 0.55 mol) in water to chelate with rutin hydroxyethylate. Plus Bi, maintaining the pH of the reaction solution was 8.3 ~ 8.8, stirring was continued for 15min.S3:After the chelation reaction is completed, the temperature is lowered to 70 ° C and at 70 to 75 ° C,The pH of the reaction solution is 8.3 to 8.8Ethylene oxide was further introduced into the etherification reaction in the latter stage, and the purity of the trihydroxyethyl rutin in the reaction liquid was periodically sampled.Until the percentage area of the rutin peak reached 93.3%, and the latter etherification reaction was stopped immediately when it rose no further.At the same time with a water bath cooling, and nitrogen to fully drive the residual residual ethylene oxide gas.S4: When the internal temperature of the reaction solution dropped to 25 ° C, a solution of 12.5% by mass dilute sulfuric acid was added dropwise with stirring to PH1.05, plus Bi, continue stirring reaction 15min. Then a mass concentration of 10% sodium carbonate aqueous solution was added dropwise, and the pH of the reaction solution was adjusted back to 3.0.S5: The entire reaction mixture was transferred to a concentration flask, at a water bath temperature of 70-80 under vacuum rotary concentration to waterWhen the amount was 15.0%, 2350 mL of methanol was added and heating was continued to dissolve. Add 3.5g activated carbon, filtered hot filtered after reflow 30min. The filtrate was then allowed to cool to 40 ° C and allowed to stand for 2h before being vacuum filtered and the insoluble filter discarded.S6: The filtrate was slowly cooled to 6 ° C, slow stirring crystallization 4h vacuum suction filtration, and with a small amount of cold medium washingPolyester cake 3 times. The filter cake was dried in vacuo at 60 ° C to give 301 g of curcumin once refined. Liquid phase detection, three hydroxyethyl rutin liquid phase purity 96.26%, content 96.11%, the other indicators test results are shown in Table 1. Tricyclic ethyl rutin meter, etherification reaction, a total refining yield of 80.73%.S7: secondary refining: take a refined product 250g in 3000mL reaction flask, adding a volume concentration of 95% waterMethanol 2100mL, heated to boiling water bath with stirring, filtered hot filtered after refluxing 20min, the filtrate was transferred to a crystal bottle after a small amount of unsafe substance, the room temperature water was stirred and cooled to 35 then switched to cold water, ice water to continue slowly stirring Cooled to 7 ° C, and then slowly stirred crystallization 4h suction filtration, and the filter cake was washed with a small amount of cold medium three times, the filter cake was dried in vacuo at 60 ° C to give 232.5g Troxerutin second refined liquid detection of trihydric Ethyl rutin liquid phase purity: 98.37% (Troxerutin content of 98.23%), other indicators test data in Table 1. With trihydroxyethyl rutin, the total yield of secondary purification was 92.73%.S8: washing (three times refined): take secondary product 200g in 2000mL reaction flask, add 1600mL of methanol.The temperature of the water bath was raised to boiling with stirring, and the mixture was stirred and refluxed for 15 minutes. Washed, the first natural cooling, and then cold water and ice water to cool to 9 , stand 4h after filtration. The filter cake is washed twice with fresh methanol. Filter cake was dried at 60 ~ 62 in vacuo to give three times the refined product 190.3g. Trihydroxyethyl rutin phase purity of 99.41%, Troxerutin content: 99.30%. Other analytical data in Schedule 1. The three refining yield was 94.5%. Etherification reaction, the total yield of the three refining process was 70.74%. Example four This example is in the third embodiment of the feed size and process conditions based on zinc acetate dihydrate instead of four water vinegar Magnesium as a chelating agent. The molar ratio of refined rutin to zinc acetate dihydrate is 1: 1.1, the mass concentration of aqueous zinc acetate dihydrate solution is 20.0%, the feeding mode, the pH value of the complexation reaction, the temperature control range, and the subsequent acidification process uses dilute sulfuric acid mass concentration , PH value acidification, PH process callback using alkali concentration, callback endpoint PH value and other conditions are the same as in Example three. The etherification reaction, hydrolysis, concentration and the process conditions of the first, second and third refining processes in this embodiment are the same as those of the third embodiment. In terms of trihydroxyethyl rutin, the etherification reaction showed a total yield of 81.57% in the first refining process, a total yield of 92.46% in the second refining process and a yield of 94.73% in the third refining process. Etherification reaction, the total yield of three refining process was 71.45%. The third refined product testing data are shown in Table 2. | |
116 g | Stage #1: oxirane; rutin With PAMAM dendrimer In methanol at 80℃; for 5h; Stage #2: In methanol Reflux; | 3.2; 3.3 (2) Taking (1) obtained in the 145 g Rutin and 7.2 g 3 on behalf of the PAMAM dendritic polymer are added to the 580 g without water in methanol, then access 58 g ethylene oxide, sealing the high-pressure autoclave, the beginning of the heating and stirring, heated to 80 °C after, thermal insulation reaction 5.0 h, HPLC detection synthetizing Rutin proportion up to 86% when, rapid cooling, the termination of the reaction, for adjusting the pH value of the reaction solution of hydrochloric acid for the 5.0, standing crystallization 12 h after, filtered, and dried to obtain a crystal 133 g, yield 91.7%;(3) To the (2) obtained in the crystal 133 g by adding 2.5 L water-free methanol, heating to reflux to totally dissolve, adding active carbon 4.0 g, continue to reflux 1.0 h after, to take advantage of the heat filter, the filtrate is reduced to the room temperature is static devitrifying 12 h after, filtering, drying to obtain the product troxerutin 108 g, yield 81.2%, total yield of 74.5%, content 99.2%. |
2.41 kg | Stage #1: oxirane; rutin With sodium hydroxide In water at 60℃; for 3h; Inert atmosphere; Large scale; Stage #2: With hydrogenchloride In water Large scale; | 1; 3 Comparative Example 1 Preparation of troxerutin compound According to the existing preparation method route (1) mentioned in the background art, trochein is prepared.At 75 ° C, add 2.01Kg of rutin, 2.0Kg of water, and 1.64g of sodium hydroxide to the reaction kettle, pass nitrogen to expel oxygen; then pass ethylene oxide,Monitor the pH of the solution. When the pH of the reaction solution is 9.1,Reduce the reaction temperature to 60 ° C,JoinResin200g, continue to react until the pH of the reaction solution is 10.0,Stop adding ethylene oxide. Add a 1: 1 aqueous hydrochloric acid solution to adjust the pH of the solution to about 4.5.Hot filtration, concentration, and vacuum drying to obtain 2.41Kg rutin,Of which HPLC detectionThe 3 ', 4', 7-trihydroxyethylrutin content was 89.3%. |
238.4 kg | Stage #1: rutin With sodium carbonate In methanol Large scale; Stage #2: With magnesium acetate In methanol at 60 - 70℃; Large scale; Stage #3: oxirane With pyridine In methanol Heating; Large scale; | 3.1 3. Preparation of trihydroxyethyl rutin (Troxerutin) Implementation 1: Close the mouth of the reaction kettle, pump 600.0kg of methanol with accurate measurement into the reaction kettle 1 with vacuum, open the mouth of the reaction kettle, start stirring, slowly add 200.0kg of crude rutin from the mouth of the reaction kettle, and add 29.0kg of carbonic acid to the solution after the dissolution is complete Sodium, the pH value is between 8.8 and 9.9, stir for 30 to 80 minutes, then add 46.0kg of magnesium acetate to reflux for 240 to 260 minutes, the reaction temperature is 60 to 70°C, the stirring speed is 60 to 90r/min, and the temperature is lowered to 15 to 20 , pump 44.5kg of ethylene oxide with accurate measurement into the reaction kettle with vacuum, adjust the pH value to 9.0 with pyridine, open the heat carrying steam valve of the reaction kettle to heat, and turn off the heat carrying steam when the pressure indicated by the pressure gauge on the reaction kettle reaches 0.28MPa Steam valve, start timing when the pressure rises to 0.40MPa, keep the temperature in the kettle at 75-90°C for 130min, cool down to 30-40°C, add EDTA to the reaction kettle, and adjust to pH 13 with sodium hydroxide until the system If there is no turbidity, it is separated through the 400-mesh screen at the bottom of the reactor, and the filtered liquid is put into the reactor 2 filled with activated carbon. After about 1/3 of the feed liquid enters the reactor 2, start stirring. After the filtered hydraulic pressure is completed, Close the feed valve of reaction kettle 2, open the heat-carrying steam valve, and close the heat-carrying steam when the temperature of the reaction kettle rises to 80°C±2°C and the pressure rises to 0.12-0.14MPa, keep stirring and decolorizing for 30min under this condition, press filter, and the filtrate Move the liquid to the crystallization cylinder on the crystallization tank. When the temperature of the feed liquid drops below 30°C, adjust the pH value to 5-6 with concentrated hydrochloric acid. When adding the acid, add it dropwise slowly and stir thoroughly.After acid addition and stirring, start timing crystallization for 24 hours and then centrifuge. When the mother liquor at the centrifuge outlet becomes droplets, close the centrifuge and put the centrifuged material into a clean plastic bag. Put the centrifuged troxerutin wet product into the reaction kettle. Dissolve with a small amount of methanol, add chelating resin D403, stir for 30 minutes, filter, the filtrate crystallizes, filter with suction, transfer the filter cake to a dryer, use low temperature first and then high temperature, at vacuum degree - (0.06 ~ 0.08) MPa, temperature 30 ~ Dry at 40°C for 1.5-2.0h, then heat up to 50-60°C, and dry at a vacuum of -(0.06-0.08) MPa for 1.0-1.5h to obtain trihydroxyethylrutin (troxerudin) with a content of 93.8%. D) 238.4kg. |
Stage #1: rutin With sodium carbonate In methanol Large scale; Stage #2: With magnesium acetate In methanol at 60 - 70℃; Large scale; Stage #3: oxirane With pyridine; methanol at 75 - 90℃; Large scale; | 3.1-3.6 3. Preparation of trihydroxyethyl rutin (Troxerutin) Implementation 1: Close the mouth of the reaction kettle, pump 600.0kg of methanol with accurate measurement into the reaction kettle 1 with vacuum, open the mouth of the reaction kettle, start stirring, slowly add 200.0kg of crude rutin from the mouth of the reaction kettle, and add 29.0kg of carbonic acid to the solution after the dissolution is complete Sodium, the pH value is between 8.8 and 9.9, stir for 30 to 80 minutes, then add 46.0kg of magnesium acetate to reflux for 240 to 260 minutes, the reaction temperature is 60 to 70°C, the stirring speed is 60 to 90r/min, and the temperature is lowered to 15 to 20 , pump 44.5kg of ethylene oxide with accurate measurement into the reaction kettle with vacuum, adjust the pH value to 9.0 with pyridine, open the heat carrying steam valve of the reaction kettle to heat, and turn off the heat carrying steam when the pressure indicated by the pressure gauge on the reaction kettle reaches 0.28MPa Steam valve, start timing when the pressure rises to 0.40MPa, keep the temperature in the kettle at 75-90°C for 130min, cool down to 30-40°C, add EDTA to the reaction kettle, and adjust to pH 13 with sodium hydroxide until the system If there is no turbidity, it is separated through the 400-mesh screen at the bottom of the reactor, and the filtered liquid is put into the reactor 2 filled with activated carbon. After about 1/3 of the feed liquid enters the reactor 2, start stirring. After the filtered hydraulic pressure is completed, Close the feed valve of reaction kettle 2, open the heat-carrying steam valve, and close the heat-carrying steam when the temperature of the reaction kettle rises to 80°C±2°C and the pressure rises to 0.12-0.14MPa, keep stirring and decolorizing for 30min under this condition, press filter, and the filtrate Move the liquid to the crystallization cylinder on the crystallization tank. When the temperature of the feed liquid drops below 30°C, adjust the pH value to 5-6 with concentrated hydrochloric acid. When adding the acid, add it dropwise slowly and stir thoroughly.After acid addition and stirring, start timing crystallization for 24 hours and then centrifuge. When the mother liquor at the centrifuge outlet becomes droplets, close the centrifuge and put the centrifuged material into a clean plastic bag. Put the centrifuged troxerutin wet product into the reaction kettle. Dissolve with a small amount of methanol, add chelating resin D403, stir for 30 minutes, filter, the filtrate crystallizes, filter with suction, transfer the filter cake to a dryer, use low temperature first and then high temperature, at vacuum degree - (0.06 ~ 0.08) MPa, temperature 30 ~ Dry at 40°C for 1.5-2.0h, then heat up to 50-60°C, and dry at a vacuum of -(0.06-0.08) MPa for 1.0-1.5h to obtain trihydroxyethylrutin (troxerudin) with a content of 93.8%. D) 238.4kg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.45% | Stage #1: benzyl bromide; quercetin-3-O-rutinoside With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In methanol; lithium hydroxide monohydrate at 65℃; for 2h; | Example of synthesis of 5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3- hydroxy-4H-chromen-4-one: 7. Anhydrous K2C03 (1.81 g; 13.1 mmol) and benzyl bromide (2.24 g; 13.1 mmol) wereadded sequentially to a solution of 2-(3,4-dihydroxyphenyl)-4,5-dihydroxy-3-[3,4,5-trihydroxy-6-[(3, 4, 5-trihydroxy-6-m ethyl-oxan-2-yl)oxym ethyl]oxan-2-yl]oxy- chromen-7-one 6(1 g; 1.6 mmol) in DMF (12 ml). The reaction mixture is allowed to stir under argon atmosphere at room temperature. Upon completion (about 24 hours), the reaction mixture was diluted with EtOAc (40 ml) and washed with H20(2 x 30 ml). The organic phase was dried with anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue is added with a mixture of HCI (37 %)/MeOH = 2/98 v/v7 and heated to reflux (T°= 65°C) for 2 hours. Upon completion, the mixture is allowed to cool to room temperature, then filtered through a Buchner funnel, and finally the orange solid is washed with cold methanol.The final product 7 thus obtained does not require a further final purification (450 mg; 42.45 %). 1H NMR (400 MHz, CDCI3): 7.88 (5, 1H), 7.75 (d, 1H, J = 6.5 Hz), 7.65-7.25 (m,21 H, Ph), 7.01 (d, 2H), 6.56 (5, 1 H, J = 8.7 Hz), 6.45 (5, 1 H), 5.26 (5, 2H, CH2Ph),5.23 (5, 2H, CH2Ph), 5.21 (5, 2H, CH2Ph), 5.11 (5, 2H, CH2Ph);l3 NMR (100 MHz, CDCI3): 171.70, 163.19, 159.33, 158.63, 150.14, 148.58,141.83, 137.68, 137.13, 136.82, 136.15, 135.59, 128.74, 128.62, 128.53, 128.45,127.89, 127.85, 127.77, 127.62, 127.53, 127.18, 126.63, 124.26, 121.20, 114.17,106.68, 97.52, 93.66, 71.52, 70.93, 70.67, 70.53. |
42.45% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | To a solution of 2- (3,4-dihydroxyphenyl) -4,5-dihydroxy-3- [3,4,5-trihydroxy-6 -[(3,4,5-trihydroxy-6-methyl-oxane-2 -yl) oxymethyl] oxan-2-yl] oxy-cromen-7-one 6 (1 g; 1.6 mmol) in DMF (12 ml) anhydrous K2CO3 (1.81 g; 13.1 mmol) was added sequentially) and benzyl bromide (2.24 g; 13.1 mmoles). The reaction mixture is left under stirring in an argon atmosphere and at room temperature. On completion (approximately 24 hours), the reaction mixture was diluted with EtOAc (40 mL) and washed with H2O (2 x 30 mL). The organic phase was dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The residue is added with a mixture of HCI (37%) I MeOH = 2/98 v / v, and heated under reflux (T° = 65° C) for 2 hours.To complete, the mixture is allowed to cool down to room temperature, then filtered through a buchner funnel and finally, the orange solid is washed with cold methanol. The final product 7 thus obtained does not require a further final purification (450 mg; 42.45%). 1 H NMR (400 MHz, CDCI3): 7.88 (s, 1 H), 7.75 (d, 1 H, J = 6.5 Hz), 7.65-7.25 (m, 21 H, Ph), 7.01 (d, 2H), 6.56 (s, 1 H, J = 8.7 Hz), 6.45 (s, 1 H), 5.26 (s, 2H, CH2Ph), 5.23 (s, 2H, CH2Ph), 5.21 (s, 2H, CH2Ph), 5.1 1 (s, 2H, CH2Ph);13C NMR (100 MHz, CDCI3): 171.70, 163.19, 159.33, 158.63, 150.14, 148.58, 141.83, 137.68, 137.13, 136.82, 136.15, 135.59, 128.74, 128.62, 128.53, 128.45, 127.89, 127.85, 127.77, 127.62, 127.53, 127.18, 126.63, 124.26, 121.20, 1 14.17, 106.68, 97.52, 93.66, 71.52, 70.93, 70.67, 70.53. |
Stage #1: benzyl bromide; quercetin-3-O-rutinoside With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 80℃; for 2h; | 2.2.2 Synthesis of 3-O-methylquercetin (11) Rutin (5.00g, 8.19mmol), K2CO3 (9.04 g, 65.52 mmol), and BnBr (7.79 mL, 65.52 mmol) were added to 60 mL of dimethylformamide (DMF), and the mixture was stirred for 10 h under argon at room temperature. The resulting mixture was diluted with 150mL of ethyl acetate (EtOAc) and washed with water (2×150mL). The residue obtained after evaporation of the solvent was dissolved in 100 mL of 1N HCl, and the mixture was refluxed at 80°C for 2 h. |
Stage #1: benzyl bromide; quercetin-3-O-rutinoside With Cs2CO3 In N,N-dimethyl-formamide at 60 - 90℃; for 48h; Stage #2: With hydrogenchloride In ethanol for 2h; Reflux; | 1.1 Preparation of the reaction intermediate VI-1 2.0 g of rutin was placed in a round bottom flask, 4.8 g of cesium carbonate and 3.4 g of bromide were added, followed by stirring with 40 ml of dimethylformamide. Heated to 60-90 ° C. After 48 hours, the aqueous solution of acetic acid was added dropwise and the solid precipitated. After filtration, the filter cake was dissolved in hydrochloric acid in ethanol solution, heated to reflux for about 2 hours, After filtration, compound VI-1 was isolated. | |
In N,N-dimethyl-formamide at 0℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 6h; | 2.2.4 Synthesis of 4′-O-methylquercetin (15), 7-O-methylquercetin (16) and 4′, 7-O-dimethylquercetin (17) Rutin (200 mg, 0.328 mmol), K2CO3 (90.6 mg, 0.656 mmol), and dimethylsulfate (62.2 μL, 0.656 mmol) were added to 10 mL of DMF, and the mixture was stirred for 6 h at 65°C. The resulting mixture was added to 50 mL of 2.5 N HCl and refluxed at 80°C for 2 h. The reaction mixture was diluted with 150 mL of EtOAc and washed with water (2×150 mL). The reaction mixture was obtained by drying the EtOAc phase using Na2SO4. After evaporating the solvent, compounds 15, 16, and 17 were obtained by preparative HPLC with an ODS-3 column (20 mm φ×250 mm). Compounds were eluted with the linear gradient MeOH/0.05% aqueous solution of TFA (0 min, 60/40; 50 min, 100/0; 6 0min, 100/0) to obtain 15, 16 and 17 as yellowish powders with yields of 4.1%, 10.0%, and 7.7%, respectively. The structures of the synthesized compounds 15, 16, and 17 were confirmed using NMR, MALDI-TOFMS, UV and IR spectra, and by the measurements of specific optical rotation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: dimethyl sulfate; rutin With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 6h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 80℃; for 2h; | 2.2.4 Synthesis of 4′-O-methylquercetin (15), 7-O-methylquercetin (16) and 4′, 7-O-dimethylquercetin (17) Rutin (200 mg, 0.328 mmol), K2CO3 (90.6 mg, 0.656 mmol), and dimethylsulfate (62.2 μL, 0.656 mmol) were added to 10 mL of DMF, and the mixture was stirred for 6 h at 65°C. The resulting mixture was added to 50 mL of 2.5 N HCl and refluxed at 80°C for 2 h. The reaction mixture was diluted with 150 mL of EtOAc and washed with water (2×150 mL). The reaction mixture was obtained by drying the EtOAc phase using Na2SO4. After evaporating the solvent, compounds 15, 16, and 17 were obtained by preparative HPLC with an ODS-3 column (20 mm φ×250 mm). Compounds were eluted with the linear gradient MeOH/0.05% aqueous solution of TFA (0 min, 60/40; 50 min, 100/0; 6 0min, 100/0) to obtain 15, 16 and 17 as yellowish powders with yields of 4.1%, 10.0%, and 7.7%, respectively. The structures of the synthesized compounds 15, 16, and 17 were confirmed using NMR, MALDI-TOFMS, UV and IR spectra, and by the measurements of specific optical rotation. Compound 15: UV λmax 207, 254, 368nm; [α]25D -26.9° (c 0.20, MeOH); IR (KBr) νmax 3430, 1655, 1617, 1499, 1456cm-1; 1H NMR (dimethylsulfoxide-d6, 600MHz) δH 3.81 (3H, s, 4′-OCH3), 6.15 (1H, d, J=2.04Hz, H-6), 6.39 (1H, d, J=2.04Hz, H-8), 7.05 (1H, d, J=8.22Hz, H-5′), 7.62 (1H, dd, J=8.22, 2.76Hz, H-6′), 7.63 (1H, d, J=2.10Hz, H-2′); 13C NMR (dimethylsulfoxide-d6,150MHz) δC 56.1 (4′-OCH3), 93.9 (C-8), 98.7 (C-6), 103.6 (C-4a), 112.4 (C-5′), 115.1 (C-2′), 120.3 (C-6′), 123.9 (C-1′), 136.7 (C-3), 146.7 (C-3′), 146.8 (C-2), 149.9 (C-4′), 156.7 (C-8a), 161.3 (C-5), 164.5 (C-7), 176.5 (C-4); MALDI-TOFMS m/z 317.0494 [M+H]+. (0015) Compound 16: UV λmax 206, 255, 371nm; [α]25D -17.3° (c 0.20, THF); IR (KBr) νmax 3402, 1656, 1593, 1502, 1442, 1324cm-1; 1H NMR (dimethylsulfoxide-d6, 600MHz) δH 3.82 (3H, s, 7-OCH3), 6.31 (1H, d, J=2.04Hz, H-6), 6.60 (1H, d, J=1.38Hz, H-8), 6.86 (1H, d, J=8.22Hz, H-5′), 7.56 (1H, dd, J=8.22, 2.04Hz, H-6′), 7.69 (1H, d, J=2.04Hz, H-2′); 13C NMR (dimethylsulfoxide-d6,150MHz) δC 56.5 (7-OCH3), 92.4 (C-8), 98.0 (C-6), 104.5 (C-4a), 115.6 (C-2′), 116.1 (C-5′), 120.5 (C-6′), 122.4 (C-1′), 136.6 (C-3), 145.6 (C-3′), 147.8 (C-2), 148.4 (C-4′), 156.6 (C-8a), 160.9 (C-5), 165.4 (C-7), 176.5 (C-4); MALDI-TOFMS m/z 317.0274 [M+H]+. (0016) Compound 17: UV λmax 206, 254, 368nm; [α]25D -3.72° (c 0.23, THF); IR (KBr) νmax 3420, 1656, 1594, 1501, 1441, 1332cm-1; 1H NMR (dimethylsulfoxide-d6, 600MHz) δH 3.82 (3H, s, 7-OCH3), 3.83 (3H, s, 4′-OCH3), 6.32 (1H, d, J=2.10Hz, H-6), 6.68 (1H, d, J=2.04Hz, H-8), 7.05 (1H, d, J=8.94Hz, H-5′), 7.65 (1H, dd, J=8.94, 2.04Hz, H-6′), 7.69 (1H, d, J=2.04Hz, H-2′); 13C NMR (dimethylsulfoxide-d6,150MHz) δC 56.2 (4′-OCH3), 56.6 (7-OCH3), 92.5 (C-8), 98.0 (C-6), 104.6 (C-4a), 115.3 (C-2′), 112.3 (C-5′), 120.3 (C-6′), 123.8 (C-1′), 137.0 (C-3), 146.7 (C-3′), 147.3 (C-2), 150.0 (C-4′), 156.7 (C-8a), 160.9 (C-5), 165.5 (C-7), 176.6 (C-4); MALDI-TOFMS m/z 331.0608 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 0.5 h / 58 °C 1.2: 62 h / 20 - 100 °C 2.1: water; hydrogenchloride / 2 h / 100 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 60 h / Reflux 2: sulfuric acid / ethanol / 2 h / Reflux | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 24 h / 60 °C 2: hydrogenchloride / water / 3 h / 70 °C |
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 60 h / Reflux 2: sulfuric acid / ethanol / 4 h / Reflux | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 48 h / Reflux 2: water; hydrogenchloride / ethanol / 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | Stage #1: rutin With sodium tetraborate decahydrate In water at 40 - 45℃; Stage #2: oxirane In water at 40 - 45℃; for 6h; | 1.1; 1.2 1. Add 328 g, 0.86 mol of borax (Na2B4O7 · 10H2O) to 2000 ml of deionized water and dissolve with stirring, then add 605 g, 0.82 moles of rutin, stir until dissolved at 40-45 ° C, A routine-borax complex aqueous solution is obtained. The solution was maintained at 40 to 45 , and 88 g of 2 mol ethylene oxide was poured into the reaction solution under stirring. The reaction time was about 6 hours, and the reaction proceeded until the HPLC detection reaction was completely completed. , And the resin volume was 25 kg. After the addition of the sample was completed, the filtrate was washed with deionized water until the pH of the effluent became close to neutrality. First, 2000 ml of 10% ethanol After washing, the column was washed with 10000 ml of 60% ethanol and then thoroughly washed with 90% ethanol. The 60% ethanol effluent was collected, concentrated in vacuo until the alcohol odor disappeared and water was added to 12000 ml, The filtrate cake was washed with ice water to obtain 473 g of 7-monohydroxyethylrutoside (total weight 1440 g). The content calculated according to anhydrous was 99.3%, and the chromatogram purity was 99.3 %, And the yield is 89.3%.1440 g of the 7-monohydroxyethylrutoside water-containing solid obtained in 2.1 was taken, and 4750 ml of deionized water was added. The mixture was heated to 60 ° C under stirring, completely dissolved and filtered. The filtrate was washed with 3N hydrochloric acid The pH was adjusted to 2.0, and the mixture was allowed to stand overnight at 3 to 5 ° C. The solid obtained by suction filtration was dried at 40 to 50 ° C for 12 hours to obtain 463 g of 7-monohydroxyethylrutoside (moisture content: 8% ), The calculated content according to anhydride was 99.5%, the chromatographic purity was 99.5%, the yield was 90.1%, and the total yield was 80.5%. |
84.8% | Stage #1: rutin With sodium tetraborate decahydrate In water at 40 - 45℃; Stage #2: oxirane In water at 40 - 45℃; for 6h; | 1; 2 1. 328 g (0.86 mol) Borax (Na2B4O7.10H2O) is added into 2,500 ml deionized water, and dissolve with stirring. 605 g (0.82 mol) rutin is added and dissolve with stirring at 40-45° C. Clear and transparent solution of rutin-borax complex is obtained. Under 40-45° C., with stirring, 88 g (2.0 mol) ethylene oxide is gradually introduced into the reaction solution followed by a reaction for about 6 h. The reaction is complete based on HPLC analysis. The pH value of the solution is adjusted to 2.0 by using 5N HCl and further let stand for 12 h at 3-5° C. After filtration, the solid cake is obtained, in which contains 504 g 7-monohydroxyethyl rutoside and the yield is 95%. 2. 1,460 g 7-monohydroxyethyl rutoside obtained from 1 above is added into 4,750 ml deionized water and heated to 60° C. with stirring. When full dissolution reached, the solution is filtrated and the filtrate stands at 3-5° C. for overnight. The predicated solid is obtained by filtration and further dried at 40-50° C. for 12 h. 450g 7-monohydroxyethyl rutoside is obtained. The content by anhydrous count is 98.3%. The chromatographic purity is 98.6%. The yield is 89.3% and the total yield is 84.8%. |
94.5 % | Stage #1: rutin With sodium carbonate In methanol Stage #2: With zinc diacetate In methanol at 60 - 70℃; Stage #3: oxirane With pyridine; hydrogenchloride In methanol Heating; | 1.1 1. The preparation of a hydroxyethyl rutin (monorutin) Implementation 1: Add 600.0mL of methanol with accurate measurement into the reaction kettle, slowly add 200.0g of rutin from the mouth of the reaction kettle, start stirring, and dissolve completely, add 28.0g of sodium carbonate to the solution, the pH value is between 8.6 and 9.7, stir for 30~ 80min, then add 60.0g zinc acetate to reflux reaction for 240~260min, the reaction temperature is 60~70, the stirring speed is 200~400r/min, cool down to room temperature, use concentrated hydrochloric acid to adjust the pH value of the reaction solution to 7.0, and add accurately measured 14.5 Put ethylene oxide in the reaction kettle, adjust the pH value to 8.2 with pyridine, turn on the reaction kettle to heat, and turn off the heating when the pressure indicated by the pressure gauge on the reaction kettle reaches 0.28MPa, and keep the pressure in the kettle at 0.280.30MPa for 6090min .After the reaction, adjust the pH value of the reaction solution to 12, add EDTA to the reaction kettle, and adjust it to a pH value of 13 with sodium hydroxide, stir fully, produce a large amount of precipitation, filter, add 1.0g of activated carbon to the filtrate into the reaction kettle, close the mouth of the kettle, open Heating, until the temperature of the reactor rises to 80°C±2°C, and when the pressure rises to 0.12-0.14MPa, turn off the heating, keep stirring and decolorize for 30min under this condition.Release the pressure, filter the material, and move the filtered material liquid into the beaker. When the temperature of the material liquid drops below 30°C, adjust the pH value to 3-4 with concentrated hydrochloric acid. When adding the acid, it should be slowly added dropwise and fully stirred. , start counting from the end of adding acid and stir, crystallize for 24h, and vacuum filter. When the filtrate drops, wash with a small amount of methanol. After the filtrate is clear, release the pressure and close the vacuum. Norutin) is dropped into the reaction kettle, dissolved with a small amount of methanol, added chelating resin D751 and stirred for 30min, filtered, the filtrate crystallized, suction filtered, and the filter cake was transferred to a vacuum drying oven, using first low temperature and then high temperature, at a vacuum degree of -(0.06 ~0.08)MPa, dry at 30~40°C for 1.5~2.0h, then raise the temperature to 50~60°C, dry at vacuum -(0.06~0.08)MPa for 1.0~1.5h, and obtain monohydroxyl with a content of 94.5%. Ethyl rutin (monorutin) 206g. |
94.5 % | Stage #1: rutin With sodium carbonate In methanol Stage #2: With zinc diacetate In methanol at 60 - 70℃; Stage #3: oxirane With pyridine; hydrogenchloride; methanol; water Heating; | 1.1; 1.2; 1.3; 1.4 1. The preparation of a hydroxyethyl rutin (monorutin) Implementation 1: Add 600.0mL of methanol with accurate measurement into the reaction kettle, slowly add 200.0g of rutin from the mouth of the reaction kettle, start stirring, and dissolve completely, add 28.0g of sodium carbonate to the solution, the pH value is between 8.6 and 9.7, stir for 30~ 80min, then add 60.0g zinc acetate to reflux reaction for 240~260min, the reaction temperature is 60~70, the stirring speed is 200~400r/min, cool down to room temperature, use concentrated hydrochloric acid to adjust the pH value of the reaction solution to 7.0, and add accurately measured 14.5 Put ethylene oxide in the reaction kettle, adjust the pH value to 8.2 with pyridine, turn on the reaction kettle to heat, and turn off the heating when the pressure indicated by the pressure gauge on the reaction kettle reaches 0.28MPa, and keep the pressure in the kettle at 0.280.30MPa for 6090min .After the reaction, adjust the pH value of the reaction solution to 12, add EDTA to the reaction kettle, and adjust it to a pH value of 13 with sodium hydroxide, stir fully, produce a large amount of precipitation, filter, add 1.0g of activated carbon to the filtrate into the reaction kettle, close the mouth of the kettle, open Heating, until the temperature of the reactor rises to 80°C±2°C, and when the pressure rises to 0.12-0.14MPa, turn off the heating, keep stirring and decolorize for 30min under this condition.Release the pressure, filter the material, and move the filtered material liquid into the beaker. When the temperature of the material liquid drops below 30°C, adjust the pH value to 3-4 with concentrated hydrochloric acid. When adding the acid, it should be slowly added dropwise and fully stirred. , start counting from the end of adding acid and stir, crystallize for 24h, and vacuum filter. When the filtrate drops, wash with a small amount of methanol. After the filtrate is clear, release the pressure and close the vacuum. Norutin) is dropped into the reaction kettle, dissolved with a small amount of methanol, added chelating resin D751 and stirred for 30min, filtered, the filtrate crystallized, suction filtered, and the filter cake was transferred to a vacuum drying oven, using first low temperature and then high temperature, at a vacuum degree of -(0.06 ~0.08)MPa, dry at 30~40°C for 1.5~2.0h, then raise the temperature to 50~60°C, dry at vacuum -(0.06~0.08)MPa for 1.0~1.5h, and obtain monohydroxyl with a content of 94.5%. Ethyl rutin (monorutin) 206g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With α-L-rhamnosyl-β-D-glucosidase from Aspergillus niger In dimethyl sulfoxide at 35℃; for 8h; Enzymatic reaction; | 2.8. Biocatalyzed rutinosylation: compound 7 Rutin (2.5 g, 4.16 mmol) was added step by step (625 mg, 0.5 eq per time) within a reaction time of 8 h, to a solution of coniferyl alcohol (500 mg, 2.81 mmol, 0.128 M) and rutinosidase (0.037 U) in 22 mL of a 85:15 mixture of citrate-phosphate buffer (0.05 M, pH 5.0) and DMSO. The obtained suspension was incubated at 35°C and 1000 rpm. The reaction was monitored by TLC (MeOH: AcOEt:HCOOH; 2:8:0.1). When all the starting alcohol was consumed, the reaction mixture was cooled to room temperature, diluted tentimes with citrate-phosphate buffer and centrifuged, recoveringonly the supernatant. After changing the pH from 5.0 to 7.5-7.7,the aqueous layer was extracted twice with AcOEt and then, afterremoving the residual AcOEt via concentration in vacuo, subjectedto an XAD4 solid phase extraction (mobile phase H2O: MeOH, from 100:0 to 0:100), affording 7 (716 mg, 1.72 mmol, yellow solid, isolated yield: 60%). 1H NMR (400 MHz; MeOD): 7.04 (d, J = 2.0 Hz, 1H: H-3), 6.89(dd, J = 8.4, 2.0 Hz, 1H: H-5), 6.76 (d, J = 8.4 Hz, 1H: H-6), 6.60 (d,J = 16.0 Hz, 1H: Ha), 6.21 (ddd, J = 16.0, 6.8, 6.0 Hz, 1H: Hb), 4.80 (d,J = 1.6 Hz, 1H: H-14), 4.48 (ddd, J = 12.3, 6.0, 1.6 Hz, 1H: H-7A), 4.37(d, J = 7.6 Hz, 1H:H-8), 4.28 (ddd, J = 12.3, 6.8, 0.8 Hz, 1H: H-7B), 4.01(dd, J = 11.2, 1.6 Hz, 1H: H-13A), 3.88 (s, 3H: = OCH3), 3.73-3.64 (m,3H: H-13, H-16, H-18), 3.44-3.21 (m, 5H: H-9, H-10, H-11, H-12,H-17), 1.30 (d, J = 6.4 Hz, 3H: H-19). 13C NMR (101 MHz; MeOD): 147.7, 146.3, 133.1, 128.9, 122.1,120.0, 114.8, 109.2, 101.6, 100.9, 76.7, 75.5, 73.7, 72.6, 70.97, 70.83,70.3, 69.5, 68.4, 54.9, 16.7 . MS, m/z ESI = 511.3 Da [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.4% | With piperidine In N,N-dimethyl-formamide at 78℃; for 4h; | 12 Synthesis of quercetin penta(2,3-dichlorobenzoic acid) ester (12) Weigh 610 mg (1 mmol) of rutin and dissolve it in 20 ml of dimethylformamide (DMF).Add 5 ml of 2,3-dichlorobenzoyl chloride and stir with a magnetic stirrer for 0.5 h.After fully dissolving, 15 drops of piperidine were added, the temperature was controlled at 78 ° C, and refluxed for 4 h. The reaction was monitored by TLC plate to ensure the reaction was completed. 80 ml of distilled water was added and stirred for 2 hours, and a large amount of solid precipitated. The solid was precipitated and the water became clear and the water layer was clarified. The precipitate was washed with water until neutral, dissolved in 70 mL of ethyl acetate, and passed through a silica gel column, methyl acetate: dichloromethane (2:3), and the eluent was evaporated. Recrystallization from chloroform / methanol, white solid, yield 52.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.6% | With piperidine In N,N-dimethyl-formamide at 77℃; for 4h; | 13 Synthesis of quercetin penta(3,4-dichlorobenzoic acid) ester (13) Weigh 610 mg (1 mmol) of rutin, dissolve it in 20 ml of dimethylformamide (DMF), add 5 ml of 3,4-dichlorobenzoyl chloride, stir with a magnetic stirrer for 0.5 h, and dissolve it thoroughly.14 drops of piperidine were added, the temperature was controlled at 77 ° C, and refluxed for 4 h. The reaction was monitored by TLC plate to ensure the reaction was completed. 80 ml of distilled water was added and stirred for 2 hours, and a large amount of solid precipitated. To the solid precipitationThe water became clear and the water layer was clarified, the precipitate was washed with water until neutral, and 70 mL of ethyl acetate was added to dissolve.After passing through a silica gel column, methyl acetate: dichloromethane (3: 1.5), the eluent was collected and evaporated.Recrystallized from chloroform / methanol, white solid,The yield was 51.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.1% | With alpha-L-rhamnosidase from Aspergillus niger JMU-TS528; at 60.0℃; for 1.0h;pH 3 - 5;Enzymatic reaction;Kinetics; Catalytic behavior; | For the kinetics study, the reaction mixture was composedof 1980 mL of rutin solution at different concentrations and20 mL of enzyme (preinactivated enzyme for the blank) andimmediately incubated at 60 C for 15 min, followed by heatingat 100 C for 10 min to inactivate the enzyme. The initialconcentrations of rutin solutions were 0.04, 0.08, 0.16, 0.33,0.49, 0.66, and 0.82 mM. After denaturation of the enzyme,the reaction solutions were filtered through 0.22 mm membranesand then submitted to HPLC analysis. The chemicalscheme of a-L-rhamnosidase is shown in Fig. 2. The measuredrutin transformation was applied to calculate enzymaticactivity. One unit of enzyme activity was defined as theamount of enzyme required to hydrolyze 1 mg rutin perminute. A Lineweaver-Burk chart was plotted between 1/Sand 1/V, where S (mmol/mL) was the rutin concentration,and V (mmol/(minmg)) was the reaction rate at a givenrutin concentration. Then, the kinetic constants, i.e.,Michaelis constant (Km) and maximum velocity (Vmax)were calculated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With potassium carbonate In N,N-dimethyl-formamide at 80 - 85℃; | 1; 2 Example 2 Preparation of Troxerutin Compound (1) mixing 3280 g of dimethylformamide, 720 g of anhydrous potassium carbonate and 800 g of rutin,Heat to 80-85 , add 496g of 2-bromoethanol dropwise, keep the reaction until rutin disappears,The temperature was lowered to room temperature, 10,000 g of ethyl acetate was added dropwise, filtered, and dried at 50 to 60 ° C.Yellow solid trokCrude Rutin908.7g, yield 93.3%.(2)908.7 g of crude trochein was added to 2726 g of dimethylformamide and acetoneIn 4546g of the mixture, heat to 65-70 ° C, stir to dissolve, filter,Cool to room temperature and crystallize overnight, filter, wet the product with 3031g of acetone for 2 hours, filter,Dry at 50 60 ,Detrok RutinOnce refined865.1g, yield 95.2%.(3) Add 865.1g of trocheutin one-time refined product to isopropanolIn a mixture of 4326 g and 951.6 g of purified water, heat to 80 ° C and stir to dissolve.Reduce the temperature to room temperature, heat and stir for 6 hours, filter, and wash with anhydrous methanol 3 times.Dry at 50 60 to obtain 821g of rutin secondary refined product.Yield: 94.9%; content: 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: rutin With potassium hydroxide In water; acetone at 60℃; for 0.166667h; Stage #2: dimethyl sulfate In water; acetone | ||
Stage #1: dimethyl sulfate; rutin With potassium carbonate In acetone at 20℃; for 48h; Stage #2: With hydrogenchloride In ethanol; water for 2h; | 4.2.1 General procedure for the preparation of the compounds 1-2 General procedure: Dissolve the raw materials myricitrin (20mmol) and K2CO3 (300mmol) in acetone, reflux stirring for 0.5h, slowly add dimethyl sulfate (300mmol) and stir at room temperature for 48h. Filtered precipitate, dissolve in absolute ethanol (100mL), reflux, add concentrated hydrochloric acid dropwise (20mL), yellow solid precipitate, and continue the reaction for 2h, filtration Purification to give compound 1. Compound 1 (10mmol) was dissolved with K2CO3 (30mmol) in DMF and stirred at room temperature for 0.5h. 3-bromopropyne (30mmol) was slowly added and reacted at room temperature for 3h, disperse with water (150mL), precipitate white solid, filter and dry to obtain compound 2. | |
Stage #1: dimethyl sulfate; rutin With potassium carbonate In acetone at 20℃; for 48h; Stage #2: With hydrogenchloride In ethanol; water for 2h; | 4.2.1 General procedure for the preparation of the compounds 1-2 General procedure: Dissolve the raw materials myricitrin (20mmol) and K2CO3 (300mmol) in acetone, reflux stirring for 0.5h, slowly add dimethyl sulfate (300mmol) and stir at room temperature for 48h. Filtered precipitate, dissolve in absolute ethanol (100mL), reflux, add concentrated hydrochloric acid dropwise (20mL), yellow solid precipitate, and continue the reaction for 2h, filtration Purification to give compound 1. Compound 1 (10mmol) was dissolved with K2CO3 (30mmol) in DMF and stirred at room temperature for 0.5h. 3-bromopropyne (30mmol) was slowly added and reacted at room temperature for 3h, disperse with water (150mL), precipitate white solid, filter and dry to obtain compound 2. |
Tags: 153-18-4 synthesis path| 153-18-4 SDS| 153-18-4 COA| 153-18-4 purity| 153-18-4 application| 153-18-4 NMR| 153-18-4 COA| 153-18-4 structure
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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 |
Sorry,this product has been discontinued.
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