* 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.
100 g of gallic acid and 150 g of ethanol were weighed into a reactor, 35 g of the brominated modified sulfonic acid resin obtained in Referential Example 2 was weighed, heated to 80 ° C for 5 h, filtered to obtain a filtrate, and bromine Modified sulfonic acid resin;the filtrate obtained in step (1) is distilled off excess alcohol to obtain crude product, and then recrystallization, dewatering and drying are carried out by deionized water to obtain ethyl gallate in 98percent yield and purity of 99.9percent .
92%
at 70℃; for 24 h;
To a 50 mL round bottom flask, the gallic acid (2.0 g, 11.8 mmol), ethanol (30 mL, 1.94 mol) and 10percent of concentrated sulfuric acid (0.2 mL) were vigorously stirred at 70°C in reflux apparatus. The reaction was monitored by TLC until end of reaction (24 h). The product was extracted using 20 mL of saturated solution of sodium bicarbonate (NaHCO3), 20 mL of distilled water and finally extracted for three times with 20 mL of ethyl acetate. The collected organic phase was evaporated and Na2SO4 anhydrous was added. After extraction ethyl gallate G was obtained already purified (92percent) and it was characterized by IR, GC-MS and NMR analyses.
70%
at 100℃; for 0.833333 h; Microwave irradiation
General procedure: A microwave vial was loaded with gallic acid 1 (0.3mmol, 50mg), the corresponding alcohol (0.9mmol), and concentrated H2SO4 (0.07mL). The reaction vessel was sealed and irradiated in a microwave reactor at 100°C for 50min. After cooling, volatiles were evaporated to dryness and the residue was dissolved in ethyl acetate (30mL) and washed successively with saturated solutions of NaHCO3 (3×20mL) and NaCl (1×20mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was then purified by column chromatography using hexane/EtOAc, (3:7) as the eluent. Melting points and characterization of compounds 2–7 were consistent with those found in the literature [25d]. In our case, the following yields were obtained: 2 (70percent), 3 (97percent), 4 (83percent), 5 (98percent), 6 (96percent), 7 (82percent).
69%
Stage #1: With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 1 h; Stage #2: With dmap In tetrahydrofuran at 0℃; for 6 h;
General procedure: To the solution containing gallic acid (250 mg, 1.47 mmol) in THF solvent at 0° C is added alcohol (2.94 mmol) and the DIC (0.34 mL, 2.205 mmol) as an activator. The reaction mixture was stirred for 1 h at 0° C, then added DMAP catalyst(18 mg, 0.147 mmol), and stirred again for the next 6 h at 0° C, then allowed to reach room temperature.The reaction was terminated when the TLC analysis showed no spot of the remaining gallic acid. After the reaction is complete, the reaction mixture is diluted with ether, filtered, evaporated,and purified by column silica gel chromatography. Pure compounds were analyzed by Thin Layer Chromatography (TLC), Nuclear Magnetic Resonance Spectrometer (NMR), and High Resolution Mass Spectrometer (HRMS)
51.5%
Reflux
General procedure: In 50 ml_ of the alcohol of interest, 3,4,5-trihydroxybenzoic acid (1 ) (1 .5 g, 8.85 mmol) was dissolved, followed by addition of 10 drops of sulfuric acid. The solution was refluxed overnight. Afterwards, the solution was allowed to cool to room temperature. The residual alcohol was evaporated, yielding the gallic acid ester derivatives 22, 23, 24 as a solid compound.
47.2%
for 40 h; Heating / reflux
In a flask was charged 15.1 g of 3,4,5-trihydroxybenzoic acid (1), and 160 ml of ethanol and 5 ml of sulfuric acid were added thereto in the order cited and heating with stirring was performed for 40 hours under reflux. Thereafter, the solvent was distilled off, the residue was extracted with ether and the organic layer was dried over magnesium sulfate. After the magnesium sulfate was filtered off, and the organic solvent was evaporated to afford a white solid (2) (yield of the reaction: 17.6 g, percent yield:47.2percent).
Reference：
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Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 17, p. 7975 - 7982
With brominated modified sulfonic acid resin at 80℃; for 5h;
5
100 g of gallic acid and 150 g of ethanol were weighed into a reactor, 35 g of the brominated modified sulfonic acid resin obtained in Referential Example 2 was weighed, heated to 80 ° C for 5 h, filtered to obtain a filtrate, and bromine Modified sulfonic acid resin;the filtrate obtained in step (1) is distilled off excess alcohol to obtain crude product, and then recrystallization, dewatering and drying are carried out by deionized water to obtain ethyl gallate in 98% yield and purity of 99.9% .
98%
Stage #1: ethanol; 3,4,5-trihydroxybenzoic acid With magnesium(II) chloride hexahydrate for 0.333333h; Green chemistry;
Stage #2: With sulfuric acid; sodium sulfate at 100℃; for 12h; Green chemistry;
3 [Example 3] Preparation of ethyl gallate using desalting and salt substitution
1. In a 1000mL round-bottom flask, add 500mL of EtOH and 119g of MgCl2-6H2O, dissolve, and then add 50g of Galiic acid-H2O.2. After stirring for 20 minutes, add Na2SO483g and then slowly add H2SO428mL.3. Keep the temperature at 100°C and stir for 12 hours.4. The reaction mixture is cooled to room temperature, filtered, and the filtrate is concentrated to obtain white solid ethyl gallate (52 g, 98%).
96%
With toluene-4-sulfonic acid at 88℃; for 0.133333h; Sealed tube; Microwave irradiation;
95%
With sulfuric acid at 70℃;
94%
With sulfuric acid for 3h; Reflux;
93%
With sulfuric acid at 90℃;
92%
With sulfuric acid at 70℃; for 24h;
1.4. Procedure for esterification of gallic acid
To a 50 mL round bottom flask, the gallic acid (2.0 g, 11.8 mmol), ethanol (30 mL, 1.94 mol) and 10% of concentrated sulfuric acid (0.2 mL) were vigorously stirred at 70°C in reflux apparatus. The reaction was monitored by TLC until end of reaction (24 h). The product was extracted using 20 mL of saturated solution of sodium bicarbonate (NaHCO3), 20 mL of distilled water and finally extracted for three times with 20 mL of ethyl acetate. The collected organic phase was evaporated and Na2SO4 anhydrous was added. After extraction ethyl gallate G was obtained already purified (92%) and it was characterized by IR, GC-MS and NMR analyses.
92.6%
With thionyl chloride at 35 - 65℃; for 1h;
1.1 Synthesis of gallic acid ethyl ester
400 g of ethanol and gallic acid 85 g (0.5 mol) were placed in the reaction flask, and 71.4 g ofthionyl chloridewas slowly added dropwise at room temperature tomaintain the temperature at 35-40 ° C. After the completion of the dropwise addition, the temperature was raised to 60-65 ° C for 1 hour. Whether the sampling test (HPLC) iscomplete, the ratio of product to raw material is 50:1 to determine the end point of the reaction. After the reaction is completed, it is concentrated to no liquid, and 400 g of water is added dropwise to room temperature for1 hour, filtered, and dried.91.7 g of product were obtained, HPLC: 97.9%, yield: 92.6%.
91%
With sulfuric acid Reflux;
90%
With sulfuric acid at 120℃; for 2h;
General Method 1
General procedure: 3,4,5-Trihydroxybenzoic acid (1 equiv) in alcohol (0.1 M) was added 10 μL of H2SO4. The mixture was stirred at 120 oC for 2 h. After completion (monitored by TLC), volatiles were evaporated. The reaction mixture was extracted with EtOAc and water. The combined organic layers were dried over MgSO4 and concentrated in vacuo.
89%
With sulfuric acid Reflux;
86%
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 10h;
Synthesis.
General procedure: To a solution of gallic acid (2.00 mM) and the corresponding alcohol (2.00 mM) in THF (10 mL) cooledat 0°C was added a solution of DCC (4.2 mM) in THF (10 mL). After stirring for 10 h, the solvent of the resulted mixture was removed under reduced pressure. The residue was extracted with ethyl acetate five times and filtered. The filter was washed successively with 4 M HCl solution, saturated NaHCO3 solution, and water, and then dried over Na2SO4 and evaporated.The crude products were purified by column chromatography on silica gel with petroleum ether-ethyl acetate (4:1) as eluent.The structures of the synthesized esters 1-15 were established by spectroscopic methods. Among them, 6, 8, and 12 are new compounds, and the others are known compounds.
80%
With sulfuric acid In toluene Heating;
80%
With sulfuric acid for 5h; Reflux;
80%
With sulfuric acid for 6h; Reflux;
4.2.1 Compound 1
Gallic acid (5g, 29mmol) was dissolved in 50mL alcohol, and 1mL of concentrated sulfuric acid was added dropwise. Then the reaction was refluxed for 6h. After the reaction was cooled to room temperature, the solvent was removed under reduced pressure. The solid was extracted with ethyl acetate and water, the organic layer was further washed with a saturated solution of NaHCO3. The organic phase was dried over Na2SO4 and was concentrated under reduced pressure to obtain the desired compound 1 (4.67g, 80% yield). 1H NMR (400MHz, DMSO-d6): δ=9.26 (s, 2H), 8.93 (s, 1H), 6.95 (s, 2H), 4.21 (d, J=7.1Hz, 2H), 1.28 (t, J=7.1Hz, 3H) (Fig.S1).
77%
With sulfuric acid for 6h; Reflux;
70%
With sulfuric acid at 100℃; for 0.833333h; Microwave irradiation;
4.1.1. Microwave assisted conditions for the synthesis of alkyl gallates 2-7
General procedure: A microwave vial was loaded with gallic acid 1 (0.3mmol, 50mg), the corresponding alcohol (0.9mmol), and concentrated H2SO4 (0.07mL). The reaction vessel was sealed and irradiated in a microwave reactor at 100°C for 50min. After cooling, volatiles were evaporated to dryness and the residue was dissolved in ethyl acetate (30mL) and washed successively with saturated solutions of NaHCO3 (3×20mL) and NaCl (1×20mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was then purified by column chromatography using hexane/EtOAc, (3:7) as the eluent. Melting points and characterization of compounds 2-7 were consistent with those found in the literature [25d]. In our case, the following yields were obtained: 2 (70%), 3 (97%), 4 (83%), 5 (98%), 6 (96%), 7 (82%).
70%
With sulfuric acid for 24h; Reflux;
69%
Stage #1: ethanol; 3,4,5-trihydroxybenzoic acid With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 1h;
Stage #2: With dmap In tetrahydrofuran at 0℃; for 6h;
General procedure of esterification of gallic acid
General procedure: To the solution containing gallic acid (250 mg, 1.47 mmol) in THF solvent at 0° C is added alcohol (2.94 mmol) and the DIC (0.34 mL, 2.205 mmol) as an activator. The reaction mixture was stirred for 1 h at 0° C, then added DMAP catalyst(18 mg, 0.147 mmol), and stirred again for the next 6 h at 0° C, then allowed to reach room temperature.The reaction was terminated when the TLC analysis showed no spot of the remaining gallic acid. After the reaction is complete, the reaction mixture is diluted with ether, filtered, evaporated,and purified by column silica gel chromatography. Pure compounds were analyzed by Thin Layer Chromatography (TLC), Nuclear Magnetic Resonance Spectrometer (NMR), and High Resolution Mass Spectrometer (HRMS)
51.5%
With sulfuric acid Reflux;
Synthetic procedure E
General procedure: In 50 ml_ of the alcohol of interest, 3,4,5-trihydroxybenzoic acid (1 ) (1 .5 g, 8.85 mmol) was dissolved, followed by addition of 10 drops of sulfuric acid. The solution was refluxed overnight. Afterwards, the solution was allowed to cool to room temperature. The residual alcohol was evaporated, yielding the gallic acid ester derivatives 22, 23, 24 as a solid compound.
47.2%
With sulfuric acid for 40h; Heating / reflux;
1.1 Example 1 Production method for cellulose tris[3',4',5'-tri(dodecan-1-yloxy)benzoate]-carried type filler and method of fabricating a column filled therewith; [1] Synthesis of ethyl 3,4,5-trihydroxybenzoate (2)
In a flask was charged 15.1 g of 3,4,5-trihydroxybenzoic acid (1), and 160 ml of ethanol and 5 ml of sulfuric acid were added thereto in the order cited and heating with stirring was performed for 40 hours under reflux. Thereafter, the solvent was distilled off, the residue was extracted with ether and the organic layer was dried over magnesium sulfate. After the magnesium sulfate was filtered off, and the organic solvent was evaporated to afford a white solid (2) (yield of the reaction: 17.6 g, percent yield:47.2%).
With hydrogenchloride
With sulfuric acid
With diethyl sulfate; benzene
With potassium pyrosulfate
With sulfuric acid Heating;
With acetyl chloride
With sulfuric acid for 3h; Heating;
With sulfuric acid for 15h; Reflux;
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h;
With sulfuric acid for 6h; Reflux;
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h;
With sulfuric acid at 100℃; for 0.116667h; Microwave irradiation;
2.3.1 General synthetic microwave esterification procedure
General procedure: Briefly, the acid (2 g) with the appropriate aromatic pattern, ethanol (2.5 mL) and H2SO4 (3 drops) were put together in a glass vial (2-5 mL) sealed with a cap and heated in the MW reactor cavity under mechanical stirring at 100 °C for 7 min. After cooling to room temperature, the solvent was removed and the compounds were purified by flash chromatography (silica gel; hexane with increasing ethyl acetate gradient) and recrystallized from diethyl ether/petroleum ether.
With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 20℃;
With sulfuric acid Inert atmosphere; Schlenk technique;
With sulfuric acid for 5h; Reflux;
Synthesis of Compounds 3a and 3b.
General procedure: Compounds 3a and 3b were synthesized using similar procedures. A representative example is described for compound 3a. A mixture of 4-hydroxybenzoic acid (5.0 g, 36.2 mmol), ethanol (50 mL),and a few drops of conc. H2SO4 was refluxed for 5 h. Excess solvent was removed in vacuo; the reaction mixture was poured into cold water and extracted repeatedly using methylenechloride. Combined organic extracts were washed with 10% NaHCO3, water, and brine, subsequently dried over anhydrous MgSO4, and concentrated to obtain a white solid (yield, 97%).
With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water
With sulfuric acid for 6h; Reflux;
Synthesis of Compounds 7a and b.
General procedure: Compounds 7a and b were synthesized using similar procedures. The procedure for the synthesis of 7a, used as an example, was performed as follows. 3,5-Hydroxybenzoic acid 6a (5.0 g, 32.5 mmol) was dissolved in anhydrous ethanol (50 mL). After addition of concentrated H2SO4 (0.5 mL), the solution was refluxed for 6 h. The ethanol was removed, and the mixture was extracted with dichloromethane and 10% NaHCO3 aqueous solution. Combined organic extracts were washed with water and brine, subsequently dried over anhydrous MgSO4, and concentrated to yield a white solid (yield, 95%).
With hydrazine hydrate monohydrate In ethanol at 20 - 95℃; for 9h;
57.81%
With hydrazine monohydrate In ethanol at 80℃; for 36h;
1.2 (2) preparation of 3, 4, 5 - trihydroxy benzoyl jing
The gallic thiourethane (3 g, 15.12 mmol) is dissolved in 35 ml ethanol, adding hydrazine hydrate (8.6 ml, 120.9 mmol), 80 °C reflux reaction for 36 hours, filtering, to obtain white solid, then the beating of ethyl acetate three times (3 × 15 ml), to obtain 1.6 g of white solid, yield 57.81%
With hydrazine hydrate monohydrate
90 % Turnov.
With hydrazine hydrate monohydrate In ethanol for 5h; Heating;
With hydrazine hydrate In ethanol for 36h; Reflux;
With hydrazine hydrate monohydrate In ethanol at 25℃; for 34h;
1.1; 2.1; 3.1
3,4,5-trihydroxybenzoic acid ethyl ester reacts with hydrazine hydrate to obtain 3,4,5-trihydroxybenzoic acid hydrazide; reaction solventIt is absolute ethanol, excess hydrazine hydrate, the molar ratio of ethyl 3,4,5-trihydroxybenzoate and hydrazine hydrate is 1:8, and the reaction temperature is 25°C, the reaction time is 34h
With sodium persulfate In acetic acid at 80℃; for 12h;
2 Example 2:
Weigh 200g of gallic acid ethyl ester,Placed in the reaction flask,Then add 5% CH3COOH 600mL,Stir and heat to 80 ° C to dissolve the methyl gallate,200 g of Na2S2O8 was added, and the reaction was stirred under reflux for 12 h to stop the reaction.The reaction solution was cooled and crystallized, filtered, and the filter cake was washed with hot water at 80 °C.The filter cake was dissolved in a 10% NaOH solution, and 20 g of activated carbon was charged.The mixture was decolorized by stirring at 25 ° C, filtered, and the filtrate was extracted three times with ethyl acetate.The filtrate was separated, and the aqueous phase was adjusted to pH 1.5 with 10% hydrochloric acid.Crystallization, filtration, vacuum drying to obtain pale yellow ellagic acid,The yield is 74% and the relative content is up to 93%.
With sodium carbonate
With ammonia; water durch Einleiten von Luft;
With Marshall's acid
Multi-step reaction with 2 steps
1: ammonium hydroxide / 12 h / 50 °C
2: 3-chloro-benzenecarboperoxoic acid / 10 h
With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; Schlenk technique;
96%
With tetrabutylammonium bromide; potassium carbonate In butanone Reflux;
95%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h;
95%
With potassium carbonate; sodium iodide In acetonitrile at 105℃; for 48h;
94%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h;
First, the compound shown in Chemical formula A was reacted with CH 3 (CH 2) 11 Br in the presence of K 2 CO 3 as a solvent with DMF at 80 ° C. for 6 hours to obtain the compound shown in Chemical formula B. The yield was 94%.
93%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 12h; Inert atmosphere;
90%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 17h; Inert atmosphere;
85%
With tetrabutylammonium bromide; potassium carbonate In acetonitrile for 72h; Reflux;
85%
With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere;
85%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 12h;
82%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere;
82%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃;
79%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;
75%
With potassium carbonate; potassium iodide In propan-2-one Heating;
69.5%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 70℃; for 40h;
1.2 [2] Synthesis of ethyl 3,4,5-tri(dodecan-1-yloxy)benzoate (3)
Under nitrogen atmosphere, 7.21 g of (2) and 9.45 g of anhydrous potassium carbonate were charged in a flask and 24 ml of bromododecane and 30 ml of N, N-dimethylformamide (DMF) were added thereto, followed by heating with stirring at 70°C for 40 hours. Thereafter, ice water was added thereto, the precipitate formed was recovered and recrystallized from acetone to afford a white solid (3) (yield: 16.1 g, percent yield: 69.5%).
67%
With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 12h;
4.2.2 Compound 2
Compound 1 (5g, 29mmol) and K2CO3 (12.22 g, 88.48 mmol) were dissolved in 40mL of DMF. 1-Bromododecane (16mL, 0.1mol) was added into the solution and the mixture was stirred at 95°C for 12h under argon. After completion of the reaction, the mixture was extracted with 40mL CH2Cl2 and 40mL water. The organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography on silica with CH2Cl2/petroleum ether=1:4 as the eluent, affording the desired compound 2 (12g, 67% yield). 1H NMR (600MHz, CDCl3): δ= 7.25 (s, 2H), 4.34 (q, J=7.2Hz, 2H), 4.01-4.02 (m, 6H), 1.72-1.84 (m, 6H), 1.44-1.51 (m, 6H), 1.26-1.40 (m, 51H), 0.87-0.89 (m, 9H) (Fig.S2).
64.8%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; Inert atmosphere;
48%
With potassium carbonate; potassium iodide In butanone for 72h; Inert atmosphere; Reflux;
41%
With potassium carbonate; potassium iodide In cyclohexanone at 140℃; for 7h;
With potassium carbonate In propan-2-one for 72h; Heating; Yield given;
With potassium carbonate In cyclohexanone
With potassium carbonate In acetonitrile for 20h; Heating;
38.67 g
Stage #1: ethyl 3,4,5-trihydroxybenzoate With potassium hydroxide; potassium iodide In ethanol Heating;
Stage #2: 1-dodecylbromide In ethanol for 6h; Heating; Further stages.;
With potassium carbonate; potassium iodide In propan-2-one Heating;
With potassium carbonate; sodium iodide In butanone for 144h; Reflux;
With potassium carbonate; sodium iodide In propan-2-one Reflux;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;
With potassium carbonate; potassium iodide In cyclohexanone for 24h; Reflux;
2.2. Alkylation of Di-/tri-hydroxybenzoates: Synthesis of Compounds (4)
General procedure: Alkylation of di-/tri-hydroxybenzoates was achieved by following a general procedure. Details of methyl 3,5-di-decyloxybenzoate are given here. While for 3,5-dialkoxy derivatives the methyl ester (methyl 3,5-di-hydroxybenzoate) was used, for 3,4-dialkoxy and 3,4,5-trialkoxy derivatives, ethyl 3,4-di-hydroxybenzoate and ethyl 3,4,5-tri-hydroxybenzoate were used, respectively. A mixture of methyl 3,5-di-hydroxybenzoate (9.2 g, 55 mmol), 1-bromodecane (24.8 g, 112 mmol), anhydrous potassium carbonate (23 g, 165 mmol), and catalytic amount of KI (ca. 1 g) in cyclohexanone (100 mL) was refluxed for 24 hours. Solvent was removed under reduced pressure and the residual mass was treated with water (75 mL), extracted with dichloromethane (4 ~ 30 mL), dried over anhydrous MgSO4, and evaporated in vacuo. Crystallization of the crude product from hexane/dichloromethane (2:1) gave the pure methyl 3,5-di-decyloxybenzoate as white solid. Yield: 90%. IR (KBr); ν, cm-1: 2923(s), 2851(m) (saturated, C-H), 1723(s) (C=O), 1601(m), (aromatic, C=C), 1472(w), 1443(m), 1393(w), 1325(m), 1240(m), 1165(s), 1129(w), 1055(m), 1007(w), 860(w), and 762(w). 1H-NMR (CDCl3); δ, ppm: 7.16 (2H, d, J = 2.2 Hz, C6H3), 6.63 (1H, dd, J =2.2 Hz, C6H3), 3.96 (4H, t, J = 6.5 Hz, -OCH2CH2-), 3.9 (3H, s, OCH3), 1.77 (4H, m, -OCH2CH2CH2), 1.44-1.26 (36H, m, -O(CH2)2(CH2)7CH3), and 0.88 (6H, t, J = 6.5 Hz, -O(CH2)9CH3).
With potassium carbonate In N,N-dimethyl-formamide for 12h; Reflux; Inert atmosphere;
Synthesis of Compounds 8a-d.
General procedure: Compounds 8a-d were synthesized using identical procedures. A representative synthesis is described for compound 8a. Compound 7a (500 mg, 2.75 mmol), K2CO3 (1.52 g, 11.0 mmol), and bromooctane (1.22 g, 6.33 mmol) were dissolved in DMF (40 mL) and refluxed for 12 h in an argon atmosphere. The mixture was cooled and the DMF was removed by vacuum distillation. The resulting mixture was extracted with dichloromethane and distilled water. The dichloromethane solution was collected, dried over anhydrous MgSO4, and filtered. The crude product was purified by column chromatography to yield 1.02 g (91%) of a viscous liquid.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;
With potassium carbonate; potassium iodide for 36h; Reflux;
With potassium carbonate In butanone for 72h; Reflux;
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 12h;
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 75℃; for 12h;
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 12h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 8h;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;
With potassium carbonate In acetonitrile Reflux;
GP2: Alkylation of benzoic esters
General procedure: The respective hydroxybenzoate with 1-3 hydroxy groups was suspended in a solvent (DMF,acetonitrile or dioxane) and an excess of potassium carbonate (1.3 eq per hydroxy group) ,alkyl bromide or alkyl iodide and in some cases one drop of aliquat 336 were added to thesuspension. The resulting mixture was stirred under reflux and the reaction monitored byTLC. After completion, the reaction was quenched with hydrochloric acid (2N), the phaseswere separated and the aqueous phase extracted three times with toluene or chloroform.The combined organic phases were dried with MgSO4 and the solvent was removed on therotary evaporator. The crude product was either recrystallized or chromatographed through acolumn.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;
72.3%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; Inert atmosphere;
1.1
Ethyl 3,4,5-trihydroxybenzoate (5.011 g, 25.286 mmol) and potassium carbonate (12.229 g, 88.484 mmol) were agitated in 40 ml of DMF in the presence of 1-bromoheptane (16.0 ml, 0.102 mol) under an argon atmosphere at temperatures from 90 to 100 °C. After the reacted product was extracted into an organic phase using chloroform-water, the organic phase was washed twice by water, further washed by saturated sodium thiosulfate solution, and dried by anhydrous magnesium sulfate. After the organic phase was filtrated, the filtrate was condensed. Thus obtained residue was purified by Silica Gel Column Chromatography (developing solvent: hexane → chloroform), thus, a desired compound (ethyl 3,4,5-tris(heptyloxy)benzoate, OR in the formula [A] is heptyloxy) (oily material, 9.006 g, yield 72.3 %) was obtained. 1HNMR and 13CNMR of the obtained compound were measured and the following data was obtained. 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 0.87-0.91 (m, 9H, CH3), 1.30-1.40 (m, 21H, CH3+CH2), 1.44-1.51 (m, 6H, CH2), 1.71-1.85 (m, 6H, CH2), 4.00-4.03 (m, 6H, ArOCH2), 4.355 (q, J=7.1 Hz, 2H, CH3CH2O), 7.255 (s, 2H, arom. H). 13 C NMR (100.4 MHz, CDCl3): δ (ppm) 14.075, 14.09, 14.39, 22.60, 22.65, 25.98, 26.02, 29.04, 29.20, 29.29, 30.30, 31.80, 31.89 (aliphatic), 60.95, 69.13, 73.46 (ether), 107.92, 125.01, 142.25, 152.77 (aromatic), 166.47 (carbonyl).
72.3%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; Inert atmosphere;
70%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;
With potassium carbonate In cyclohexanone
With potassium carbonate In acetonitrile for 20h; Heating;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;
3 EXAMPLE 3
EXAMPLE 3 To a reactor were fed 39.6 g (0.2 mol) of gallic acid ethyl ester (hereinafter referred to as 'GE'), 226.4 g (0.58 mol) of β-PAG, and 530 g of mixed xylenes, and then 4.4 g (15 mole percent relative to the GM) of boron trifluoride diethyl etherate was added. The reaction was performed at a temperature of 43°C to 47°C under a pressure of 4.0 kPa to 3.6 kPa (30 mmHg to 27 mmHg). After 10 hours, the analysis of the resulting mixture indicated that the yield of gallic acid methyl ester-3,5-bis(2,3,4,6-tetra-O-acetylglucoside) was 80.5% based on the GE. The concentration of acetic acid was 0.70 percent to 0.74 percent by weight during the reaction.
Stage #1: 1,5-difluoro-2,4-dinitrobenzene; 2,4-diaminodiphenylamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 2h;
Stage #2: Ethyl gallate In N,N-dimethyl-formamide at 60℃; for 2h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere;
9.1
Ethyl 3,4,5-trihydroxybenzoate (5.003 g, 25.245 mmol) and potassium carbonate (12.245 g, 88.600 mmol) were agitated in DMF (35 ml) in the presence of 1-bromopentadecane (25.5 ml, 87.972 mmol) under an argon atmosphere at 90 °C. After the reacted product was extracted into an organic phase using chloroform-water, the organic phase was washed twice by water, further washed by saturated sodium thiosulfate solution, and dried by anhydrous magnesium sulfate. After the organic phase was filtrated, the filtrate was condensed. Thus obtained residue was recrystalized twice by dichloromethane-methanol, thus, a desired compound (ethyl 3,4,5-tris(pentadecyloxy)benzoate, OR in the formula [A] is pentadecyloxy) (white powder, 18.758 g, yield 89.6 %) was obtained. 1HNMR, 13CNMR and MALDI-TOF-MS of the obtained compound were measured and the following data was obtained. 1 H NMR (400 MHz, CDCl3, TMS): δ(ppm) 0.86-0.895 (m, 9H, CH3), 1.26-1.40 (m, 69H, CH3+CH2), 1.43-1.51 (m, 6H, CH2), 1.70-1.84 (m, 6H, CH2), 3.99-4.03 (m, 6H, ArOCH2), 4.35 (q, J=7.1 Hz, 2H, CH3CH2O), 7.25 (s, 2H, arom. H). 13 C NMR (100.4 MHz, CDCl3): δ(ppm) 14.10, 14.12, 14.40, 22.685, 22.705, 26.06, 26.08, 29.315, 29.32, 29.36, 29.365, 29.37, 29.40, 29.565, 29.57, 29.63, 29.64, 29.66, 29.68, 29.70, 29.705, 29.71, 29.73, 29.74, 29.75, 30.32, 30.325, 31.92, 31.93 (aliphatic), 60.94, 69.18, 73.475 (ether), 108.00, 125.03, 142.33, 152.79 (aromatic), 166.47 (carbonyl). MALDI-TOF-MS (matrix: 2,5-dihydroxybenzoic acid): m/z=829.01 (M+), 852.03 ([M+Na]+)
89.6%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; Inert atmosphere;
General procedure: A mixture of 0.216g of ethyl gallate (2) (0.001M) and 0.138g of anhydrous potassium carbonate (0.001M) were stirred for 30min in dry acetone (30mL), to this 0.253g of 6-methyl 4-bromomethyl coumarin (1) was added and stirring was continued for 24h, the reaction was monitored using TLC. After completion, the reaction mixture was quenched in crushed ice. The separated solid was filtered and washed with 1:1 HCl. The compound was dried and crystallized from methanol.
dasatinib-ethyl gallate co-crystal (3/1)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ca. 124 mg
In methanol at 60℃; for 0.5h;
3 Preparation of the Co-Crystal with Ethyl Gallate (Molar Ratio 3:1)
127.3mg of dasatinib (monohydrate form) and 16.7 mg of ethyl gallate (Aldrich No. 48640) are dissolved in 10 mL ofmethanol at 60°C. and stirred for 0.5 hour at 60°C. The solvent is evaporated using a dry nitrogen flow at 60° C. within approximately 1.5 hours and the dried sample is held at 60° C. for 1 hout The sample is cooled and stored overnight at room temperature. Yield: approximately 124 mg. H-NMR spectroscopy indicates a molar ratio of dasatinib to ethyl gallate of 3:1. The solid material is further characterized by PXRD and TG-FTIR. Thermogravimetry coupled with FT infrared spectroscopy shows that the obtained material is neither a solvate, nor a hydrate. This result shows that the obtained co-crystal is a non-solvated solid form showing a PXRD pattern as in FIG. 3 with peak locations as indicated in table 4.
ethyl 8-hydroxy-4-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In ethanol; at 65℃; for 0.5h;Green chemistry;
General procedure: To a 5 mL vial flask type ethyl gallate G (50 mg, 0.253 mmol), ethylenediamine A1 (51 muL, 0.842 mmol) and ethanol (2 mL) were added. The resulting mixture was magnetically stirred (400 rpm) at 65C. The reaction was periodically monitored by thin layer chromatography (TLC) until completion of the reaction (30 minutes). The reaction was extracted after 30 min using 20 mL of distilled water and 20 mL of ethyl acetate for three times. After extraction, was observed by TLC and GC-MS analyses that purification by column chromatography were not necessary. Quinoxaline G-A1 was characterized by GC-MS, NMR and IR analyses. The same procedure was used for the synthesis of Quinoxaline G-A2, and Quinoxaline G-A3 using diethylenetriamine A2 (80 muL, 0.775 mmol), and <strong>[111-41-1]aminoethylethanolamine</strong> A3 (77 muL, 0.736 mmol) respectively.
Weigh 50g of gallic acid ethyl ester,Pour into a 500 ml three-necked flask after drying,Then add 25% concentrated ammonia 250ml,Plug the bottle with a stopper,Stir in a constant temperature water bath at 50 C for 12 h.The reaction solution was then poured into a 1000 ml dry three-necked flask.Inject 100 g of potassium persulfate,Reaction for 5h.After completion of the reaction, the reaction solution was filtered, and the filter cake was dissolved in a 15% NaOH solution, and 250 g of activated carbon was added thereto, and decolorization and purification were carried out at 30 C, and the filtrate was extracted three times with ethyl acetate. The filtrate was separated, and the aqueous phase was adjusted with 15% hydrochloric acid. The pH of the extract is 1.5, crystallization, filtration,Dry light yellow ellagic acid amorphous powder,The yield was 81%.
With tris(pentafluorophenyl)borate; In toluene;Reflux;
To the reaction flask into n-octanol 27.4 g (0.21 mol), ethyl gallate 39.6g (0.2mol), tris (pentafluoro-phenyl) borane 4g (0.008mol) and 350 g of toluene, with heating, the system became For clarification, the reflux reaction was further slowly increased for 5 to 6hours, and the raw material was The added refluxing materials sulfhydryl silica gel 7g performedfor capture of heavy metals, hot filtered, the filtrate was concentrated to recover the solvent and then added dropwise to 150g room temperature water slurried, filtered and dried to give electricalsub-level gallate Octyl 53.1g, HPLC: 98.7 %, yield: 94.1%.
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