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CAS No. : | 99-24-1 | MDL No. : | MFCD00002194 |
Formula : | C8H8O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FBSFWRHWHYMIOG-UHFFFAOYSA-N |
M.W : | 184.15 | Pubchem ID : | 7428 |
Synonyms : |
Gallincin;NSC 363001;Gallicin;Gallic acid methyl ester
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 43.79 |
TPSA : | 86.99 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.81 cm/s |
Log Po/w (iLOGP) : | 0.96 |
Log Po/w (XLOGP3) : | 0.86 |
Log Po/w (WLOGP) : | 0.59 |
Log Po/w (MLOGP) : | 0.18 |
Log Po/w (SILICOS-IT) : | 0.28 |
Consensus Log Po/w : | 0.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.73 |
Solubility : | 3.41 mg/ml ; 0.0185 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.27 |
Solubility : | 0.988 mg/ml ; 0.00537 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.75 |
Solubility : | 32.8 mg/ml ; 0.178 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H317-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 7 h; | Potassium carbonate (63.31 g, 400 mmol) and benzyl bromide (59.47 mL, 500 mmol) were added to a solution of 3,4,5-trihydroxybenzoate methyl ester (compound 60) (18.41 g, 100 mmol) in DMF (70 mL). This reaction mixture was stirred at 120°C for seven hours, and then poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The title compound 61 (3,4,5-tribenzyloxybenzoate methyl ester) (47.19 g) was obtained in a quantitative yield. The NMR spectrum of compound 61 is shown in Table 29. Table 29 NMR spectrum of compound 61400 MHz 1H NMR (CDCl3) δ 7.45-7.24 (17H, m, Ar-H), 5.14 (4H, s, ArCH2O), 5.11 (2H, s, ArCH2O), 3.89 (3H, s, CO2CH3). |
100% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 40℃; for 24 h; | A mixture of methyl gallate 9 (10 g, 53 mmol) and potassium carbonate (45 g, 320 mmol) in DMF (120 mL) was treated with benzyl bromide (210 mmol, 25.7 mL) and stirred at 40° C. under an argon atmosphere for 24 h. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in minimum amount of methylene chloride and diluted with an equal volume of hexanes and loaded onto a short silica gel pad in a sintered glass funnel. The silica was eluted with hexanes (300 mL) to remove excess benzyl bromide and the eluant discarded. The product was then eluted with methylene chloride: hexanes (1:1, 300 mL) followed by methylene chloride (500 mL) and the eluants combined and evaporated to afford pure benzyl product 10 as an off-white solid (100percent yield). 1H NMR (300 MHz, CDCl3): δ 3.88 (s, 3H, CH3), 5.11 and 5.13 (2s, 6H, OCH2), 7.35-7.41 (m, 17H, Ar-H). [0119] To a solution of 3,4,5-tribenzyl-methyl gallate 10 (10 g, 22 mmol) in dry tetrahydrofuran (75 mL) was added solid lithium aluminum hydride (1.25 g, 33 mmol) in small portions. The suspension was heated to reflux under argon for 2 h. The reaction was cooled to 0° C. and carefully quenched with the dropwise addition of water. The slurry was then extracted with ethylacetate/hexanes. The organic solution was dried with saturated brine, followed by anhydrous magnesium sulfate, filtered and evaporated to afford the pure alcohol 11 as a white solid (8.9 g, 95percent yield). 1H NMR (300 MHz, CDCl3): δ 4.6 (d, 2H, CH2), 5.04 and 5.11 (2s, 6H, OCH2), 6.67 (s, 2H, 2,6-Ar-H), 7.25-7.43 (m, 15H, Ar-H). [0120] To a solution of 3,4,5-tribenzyloxy-benzyl alcohol 11 (8.9 g, 21 mmol) in methylene chloride (200 mL) at 0° C. was added pyridinium chlorochromate (5.43 g, 25 mmol) in small portions with vigorous stirring. The cooling was discontinued and reaction stirred at room temperature for 4 h. The dark brown suspension was filtered over a long pad of silica gel in a sintered glass funnel, and eluted with methylene chloride, until all the pure product eluted out. The organic filtrate was evaporated down to give the pure product 12 as a soft white solid (8.1 g, 91.5percent yield). 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 6H, OCH2), 7.18 (s, 2H, 2,6-Ar-H), 7.26-7.41 (m, 15H, Ar-H), 9.80 (s, 1H, CHO). |
96% | With potassium carbonate In acetone for 24 h; Heating / reflux | Methyl 3,4,5-Tribenzyloxybenzoate. Benzyl bromide (10.6 mL, 89.7 mmol) was added to a solution of methyl 3,4,5-trihydroxybenzoate (5.0 g, 27 mmol) and potassium carbonate (oven dried, 12.4 g, 89.7 mmol) in 250 mL of acetone. This solution was heated to reflux under Ar for 24 h. The reaction mixture was cooled, treated with triethylamine (7.6 mL, 54 mmol), and extracted with EtOAc. The organic layer washed sequentially with 10percent H2SO4, H2O, and brine, and dried over Na2SO4. After filtration and concentration, 11.8 g (96percent) of methyl 3,4,5-tribenzyloxybenzoate was collected as an off white solid. |
95.4% | With potassium carbonate In N,N-dimethyl-formamide at 10 - 60℃; for 4 h; Large scale | 3,4,5-trihydroxybenzoate (9.6 kg, 1.0 eq.) and DMF (76.8 liters) are charged to a reactor at 10-25° C. 2. To the reactor is charged K2C03 (25.1 kg, 3.5 eq.) at the same temperature. 3. Benzyl bromide (28.4 kg, 3.2 eq.) is then added slowly to the mixture at a temperature of from 20-45° C and the mixture aged at about 60° C for about 4 hours. 4. Analysis of the reaction mixture shows that 5. The solids are filtered off and the cake washed with DMF twice (1 vol.). 6. The filtered solution and wash is added to water (115 liters) at 5° C and the mixture stirred for 2 hours at 5-15° C. 7. The resulting mixture was filtered and the cake washed with water. 8. The isolated solid was dried for 12 hours under vacuum at 45° C to obtain the product (22.6 kg as an off-white solid. 9. In this alternate process IIIa-13-1-1 is obtained as an off-white solid with 99.4percent purity in a 95.4percent yield. |
90% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 15 h; Inert atmosphere | To a stirred solution of methyl 3,4,5-trihydroxybenzoate 12 (0.94 g, 5.15 mmol) and potassium carbonate (6.56 g, 25.7 mmol)in DMF (20 mL), benzyl bromide (4.4 g, 25.7 mmol) was added. The reaction mixture was stirred at 60 °C under N2 atmosphere. After 15 h, water was added, and the whole was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum to obtain methyl 3,4,5-tri(benzyloxy)benzoate 13 (1.93g, 90percent). |
89% | With potassium carbonate In N,N-dimethyl-formamide for 6 h; | Compound 2 (1 g, 5.43 mmol) was taken in dry DMF (60 mL) and was stirred in presence of K2CO3 (10 g , 54.34 mmol). Benzyl bromide (4 mL, 16.70 mmol) was added to the stirred solution and stirring was continued for 6h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with EtOAc and washed with water. The organic layer was then dried over anhydrous Na2SO4, and the solvent was evaporated to get the crude product, which was purified by column chromatography using using 5percent EtOAc in petroleum ether as the eluent to get the pure product 3 as white powder (2.2 g, yield 89 percent). 1H NMR (CDCl3, 400 MHz): 7.37-7.35 (m, 4H), 7.33-7.24 (m, 10H), 7.20-7.17 (m, 3H), 5.06 (s, 4H), 5.04 (s, 2H), 3.82 (s, 3H); FTIR (KBr, cm-1 ): 3411, 3044, 3031, 2948, 2878, 1715, 1589, 1499, 1453, 1110 and 754 cm-1 ; mp. 94C |
85% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6 h; | General procedure: Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86percent yield)as white solid. This compound was used in the next stepreaction without further purification.Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86percent yield)as white solid. This compound was used in the next stepreaction without further purification.A mixture of methyl 2.114 g 3,4,5-tris(benzyloxy)benzoate(4.66 mmol), sodium hydroxide (96 mmol), 6 cm3MeOH, and 12 cm3 dioxane was heated at reflux for 4 h.The solvent was removed and the resulting residue waspartitioned between water and ethyl acetate. The combinedorganic layers were washed with brine, dried (Na2SO4),and concentrated at reduced pressure to give the titlecompound (1.984 g, 4.51 mmol, 97percent yield) as a whitesolid. Spectral data were in accordance with those previouslyreported |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In dimethyl sulfoxide at 20℃; | Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were mechanically stirred in dry DMSO (200 mL) at room temperature overnight. Water (200 mL) was added and the crude product isolated by filtration. Evaporation of residual solvents in a vacuum desiccator left a pale yellow solid which was essentially pure product. Yield: 128.2 g (94percent). |
90.5% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In 1,4-dioxane for 24 h; Reflux | Preparation of (AB)3G1-CH2OH (c) Lithium aluminum hydride (0.809 g, 0.0213 mole) was suspended in 40 mL of freshly distilled THF in a dry three-neck round-bottom flask under nitrogen atm. (AB)3 G1-COOCH3 (9 g, 0.0198 mole) was dissolved in 50 mL of freshly distilled THF and added drop wise to the lithium aluminum hydride solution. The reaction mixture was refluxed with stirring for 2 hours. The THF solution was cooled to room temperature and transferred to a beaker. Water was added drop wise to the vigorously stirred THF solution until the gray color of the lithium aluminum hydride was disappeared and a white solid was formed which is filtered and washed with THF. Excess solvent was removed under reduced pressure and the crude product was recrystallized from 95percent methanol/water mixture to get the pure product ((AB)3 G1-CH2OH) (7.6 g, 90percent); 1H NMR (400 MHz, CDCl3) δ: 4.6 (s, CH2OH, 2H), 5.09 (s, ArCH2O, 2H), 5.15 (s, ArCH2O, 4H), 6.72 (s, ArH, 2H), 7.30-7.48 (m, PhH, 15H); 13C NMR (100 MHz, CDCl3) δ: 65.42, 71.22, 75.26, 106.46, 127.45, 127.83, 127.90, 128.18, 128.52, 128.62, 136.66, 137.13, 137.81, 137.87, 153.02. |
89% | With potassium carbonate In acetone for 12 h; | Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g5 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), dry potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were stirred in refluxing dry acetone (600 mL) for 12 h. After cooling, the acetone was evaporated, and the solution was dissolved in water (250 mL). The water phase was extracted with diethyl ether (4 x 100 mL), the organic phase was washed with brine (2 x 50 mL), dried (MgSO4) and the solvent was removed in vacuo. Recrystallisation from petroleum ether and ethyl acetate gave the titled compound as white crystals, m.p. 102-103 0C. Yield: 121.4 g (89percent). Spectroscopic data were in accordance with the literature (J. Barbera, R. Iglesias, J. L. Serrano, T. Sierra, M. R. de Ia Fuente, B. Palacios, M. A. Perez- Jubindo, J. T. Vazquez, J. Am. Chem. Soc. 1998, 120, 2908). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: With sulfuric acid In methanol for 12 h; Reflux Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; |
To a mixture of potassium carbonate (4.002 g, 29 mmol), methyl gallate (6 g, 29.7mmol), in dry DCM and diiodomethane (2.8 mL, 34.8 mmol) was added at room temperatureunder nitrogen condition, allowed to stir for 5h at 120°C. The resulting mixture was poured in toice cooled water (500 mL) and was extracted with ethyl acetate. The combined organic extractswere washed with brine, then dried over Na2SO4, filtered and evaporated under reduced pressure.The residue was purified by column chromatography with 15percent EtOAc/hexane to affordcompound 9 (3.6 g, 58percent) as white amorphous powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium hydrogencarbonate In dimethyl sulfoxide at 60℃; for 1.5 h; Inert atmosphere | To a solution of compound A0061-1 (1 g,5.43 mmol) in dimethyl sulfoxide (DMSO) (25 ml) was added potassium hydrogen carbonate (KHCO3) (0.54 g, 5.43 mmol) followed by dibromomethane (0.4 ml) and the mixture was heated at 60 0C for 1.5 hours under nitrogen. The reaction was cooled and poured into water (50 ml) . The mixture was extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to yield a crude oil which was further purified by column chromatography on silica gel (petroleum etheriethyl acetate=5:l) to yield compound A0061-2. (580 mg, yield: 55percent, NMR confirmed) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid for 6h; Heating; | |
99% | With brominated modified sulfonic acid resin at 65℃; for 4h; | 2 100 g of gallic acid and 100 g of methanol were weighed into a reactor,40 g of the brominated modified sulfonic acid resin obtained in Reference Example 2 was added,Heating and heating to 65 DEG C for 4 hours, filtrating to obtain filtrate, recovering brominated modified sulfonic acid resin;the filtrate obtained in step (1) is distilled off excess alcohol to obtain crude product, and then recrystallization, dewatering and dewatering with deionized water to obtain methyl gallate in 99% yield and purity of 99.9% |
97% | With sulfuric acid for 1.5h; Heating / reflux; | 1.1 Galic acid(60g, 353mmol) was dissolved in methanol(600mlitre), conc. sulfuric acid(18mlitre) was added thereto, and the mixture was stirred under reflux for 1.5 hour. The reaction vessel was cooled down to room temperature and the reaction mixture was neutralized with saturated sodium bicarbonate solution at 0-5°C. Then, the organic solvent was removed under reduced pressure. The concentrated residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated to give methyl 3,4,5-trihydroxybenzoate(63g, Yield 97%) as an ivory solid. This compound was used in the next step reaction without further purification. |
96% | With sulfuric acid for 2h; Heating; | |
95% | With toluene-4-sulfonic acid for 2h; Heating; | |
95% | With sulfuric acid for 3h; Reflux; | |
95% | With toluene-4-sulfonic acid at 75℃; for 0.1h; Sealed tube; Microwave irradiation; | |
94% | With hydrogenchloride for 2h; | |
94% | With sulfuric acid for 4h; Reflux; Cooling; | |
94% | With sulfuric acid for 2h; Reflux; | |
93% | With sulfuric acid at 90℃; | |
93% | With sulfuric acid at 80℃; Inert atmosphere; Reflux; | 2.b-1.i Synthesis of Compound 2 gallic acid (1) (10 g, 58.8 mmol) was placed in an eggplant-shaped flask and thoroughly dried with a vacuum pump Replaced with N 2 gas. 100 mL methanol was added by a syringe, stirred at 0 ° C., and H 2 SO 4 (5 mL, 93.88 mmol) was added. Thereafter, the reaction solution was refluxed under N 2 gas at 80 ° C. overnight. The reaction was stopped by adding 15% NaOH aqueous solution (30 mL) to the reaction solution, and partitioning extraction was carried out using ethyl acetate. The organic layer was washed with NaHCO 3 and saturated brine, dried over magnesium sulfate, filtered and the filtrate obtained was concentrated to dryness with an evaporator to obtain a white solid compound 2 (yield: 10.1 g, yield: 93%) obtained. |
93.6% | With thionyl chloride at 35℃; for 1h; Reflux; Large scale; | 3.1 The First Step: Synthesis of methyl gallate 31Kg into methanol and gallic acid 7.65Kg (45mol, 1eq) to the 50L reactor was slowly added dropwise at room temperature for twochloride sulfoxide 5.85Kg (1.1eq), keeping the temperature at 35-40 deg.] C, After the addition, temperature was raised to After refluxing for 1 hour, the sampling test(HPLC) was complete. The ratio of the product to the raw material was 50:1 to determine the end point of the reaction. After the reaction was completed, it was concentrated to a non-slip liquid, and the mixture was droppedinto 28 kg of water at room temperature for 1 hour, filtered, and dried.8Kg of product was obtained, HPLC: 98.6%, yield: 96.6%. |
93% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 10h; | Synthesis. 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. |
92% | With sulfuric acid for 2h; Reflux; Inert atmosphere; | Compound (14) To a stirred solution of gallic acid 11 (1.0 g, 5.88 mmol) in methanol (6 mL), sulfuric acid (0.2 mL) was added. The reaction mixture was heated under reflux for 2 h and evaporated. The residual mass was taken in water (40 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain methyl 3,4,5-trihydroxybenzoate 12 as a white solid (0.94 g, 92%). |
92% | With sulfuric acid for 12h; Reflux; | 2.2.1. Preparation of solid 1 As described in a previous study [47], 4.25 g (25mmol) gallic acidwas dissolved in 50 mL MeOH, 1.5mL concentrated H2SO4 wasadded, and then the mixturewas heated to reflux for 12 h. After that,the solvent was removed under reduced pressure and the mixturewas extracted with ethyl acetate. The obtained mixture was washedtwice with water and saturated NaHCO3 solution, and dried overanhydrous Na2SO4. The crude product obtained was purified bycolumn chromatography on silica gel (eluent: petroleum ether/ethylacetate 2:1), and 4.25 g (23mmol) white solid 1 was obtainedwith a 92% yield and a melting point of 199.9-200.5 °C. |
91% | With thionyl chloride at 90℃; for 10h; Cooling; | 3,4,5-Tris-hydroxy-benzoic acid methyl ester (2): To a stirred solution of gallic acid (2 g, 11.11mmol) in dry MeOH (100 mL), SOCl2 (5 mL, 67.8 mmol) was added drop wise under cold condition. Then the mixture was heated to reflux for 10 h at 90 C. After completion of reaction, the solvent was evaporated to get an oily mass. The excess SOCl2 was removed by vacuum. The crude reaction mixture was purified by column chromatography using 50% ethyl acetatepetroleum ether as eluent to afford 2 (1.85 g, yield 91%) as a white solid mass |
91% | 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. |
91% | With sulfuric acid for 9h; Reflux; | |
90% | With thionyl chloride at 0 - 65℃; Inert atmosphere; | |
88% | With sulfuric acid for 6h; Reflux; | |
88% | With sulfuric acid for 48h; Reflux; | Methyl 3,4,5-Trihydroxybenzoate (10) To a 1 L round-bottomed flask charged with a solution of gallic acid (34.02 g, 0.2 mol) in dry methanol (400 mL) was added concentrated sulfuric acid (2 mL). The resulting solution was refluxed for 48 h. The reaction solution was cooled and neutralized with NaOH (2.0 N). After concentration, the residue was diluted with EtOAc (600 mL), washed with water (2 200 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was crystallized from EtOAc/petroleum ether to furnish methyl 3,4,5-trihydroxybenzoate (10). White solid; yield: 32.6 g (88%); mp 204.5-205.5 °C; Rf = 0.37 (EtOAc/ hexane, 1:1). IR (KBr disk): 3319 (br), 2957, 1677, 1612, 1541, 1465, 1438, 1308, 1263, 1205, 1036, 1004, 774 cm-1. 1H NMR (400 MHz, DMSO-d6): = 9.27 (s, 2 H), 8.94 (s, 1H), 6.94 (s, 2 H), 3.74 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): = 166.6, 145.8, 138.6, 119.6, 108.8, 51.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H9O5: 185.0450; found: 185.0436. |
86% | With sulfuric acid | |
86% | With sulfuric acid for 5h; Reflux; | 3,4,5-Tris(benzyloxy)benzoic acid (3a) General procedure: Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86% yield)as white solid. This compound was used in the next stepreaction without further purification.Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86% yield)as white solid. This compound was used in the next stepreaction without further purification.A mixture of methyl 2.114 g 3,4,5-tris(benzyloxy)benzoate(4.66 mmol), sodium hydroxide (96 mmol), 6 cm3MeOH, and 12 cm3 dioxane was heated at reflux for 4 h.The solvent was removed and the resulting residue waspartitioned between water and ethyl acetate. The combinedorganic layers were washed with brine, dried (Na2SO4),and concentrated at reduced pressure to give the titlecompound (1.984 g, 4.51 mmol, 97% yield) as a whitesolid. Spectral data were in accordance with those previouslyreported |
85% | With sulfuric acid for 12h; Reflux; | |
85% | With sulfuric acid for 12h; Reflux; | Methyl 3,4,5-trihydroxybenzoate General procedure: Gallic acid (850.6 mg, 5 mmol) and dissolved in MeOH (10 mL). Then, cone. H2S04 (272.7 L, 11 mmol) was added to the solution and was stirred at reflux for 12h (monitored by TLC). The solvent was concentrated under reduced pressure. After extraction with EtOAc (20 mL), the solution was washed with distilled water (3 x 10 mL) and saturated NaHC03 (20 mL), and dried over Na2SC>4. The solution was evaporated and purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :2) as eluent, to give methyl 3,4,5- trihydroxybenzoate as a white powder (782.6 mg, 85 %): NMR (300 MHz, MeOD) δ 7.06 (s, 2H), 4.98 (s, 3H), 3.82 (s, 3H); 13C NMR (75 MHz, DMSO) δ 166.76, 146.09, 146.02, 138.84, 119.73, 108.94, 52.04 |
83% | With sulfuric acid In methanol Reflux; | |
82% | With sulfuric acid for 8h; Reflux; | 2.2. Synthesis of gallic acid-benzylidenehydrazine hybrids The gallic acid 1 (10 g) was mixed with 50 mL methanol, and then 0.5 mL of concentrated H2SO4 was added. Afterwards, the reacting mixture was stirred at reflux for 8 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was then poured on crushed ice and the precipitate was collected by filtration to obtain methyl gallate 2 (yield = 82%) as a white solid. |
82% | With sulfuric acid for 8h; Reflux; | 2.2. Synthesis of gallic acid-benzylidenehydrazine hybrids The gallic acid 1 (10 g) was mixed with 50 mL methanol, and then 0.5 mL of concentrated H2SO4 was added. Afterwards, the reacting mixture was stirred at reflux for 8 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was then poured on crushed ice and the precipitate was collected by filtration to obtain methyl gallate 2 (yield = 82%) as a white solid. |
81% | With sulfuric acid | |
81% | With sulfuric acid Heating; | |
80% | With sulfuric acid for 120h; Reflux; | |
80% | With hydrogenchloride In lithium hydroxide monohydrate for 4h; Reflux; | |
79% | With sulfuric acid In toluene Heating; | |
75% | With sulfuric acid for 24h; Reflux; | |
75% | With toluene-4-sulfonic acid at 65℃; for 18h; | 1. Synthesis of methyl 3,4,5-trihydroxybenzoate (2) A solution of 17 g (0.1 mol) gallic acid and 0.002 g (0.01 mmol) of p-toluene sulphonic acid in 100 ml methanol was refluxed under stirring overnight. The mixture was cooled, the solvent was evaporated under vacuum and the residual was dissolved in EtOAc. Thereafter, the organic phase was shaken with 10% NaHCO3 solution, dried (Na2SO4) and evaporated to obtain 2 in 75% yield as buff solid m.p. 198°C [lit. [1]200 °C]. |
75% | With toluene-4-sulfonic acid Reflux; | 2.1.1. synthesis of methyl 3,4,5-trihydroxybenzoate (2) A solution of 17 g (0.1 mol) gallic acid and 0.002 g (0.01 mmol) of p-toluenesulfonic acid in 100 mL methanol was refluxed under stirring overnight. The mixture was cooled, the solvent was evaporated under vacuum and the residual was dissolved in EtOAc. There after, the organic phase was shaken with 10% NaHCO3 solution, dried (Na2SO4)and evaporated to obtain 2 in 75% yield as buff solid m.p. 198 °C [lit.(Mostafa et al., 2006) 200 °C]. |
74.8% | Stage #1: methanol; 3,4,5-trihydroxybenzoic acid for 1.5h; Reflux; Stage #2: With Sodium hydrogenocarbonate In methanol at 0℃; | To a solution of 3, 4, 5-trihydroxybenzoic acid (3 g, 17.6 mmol) in methanol (30 ml) was added concentrated sulfuric acid (0.9 ml) and the mixture was stirred under reflux for 1.5 hours. The reaction vessel was cooled to room temperature and the reaction mixture was neutralized with saturated sodium bicarbonate solution at 0 0C. The organic solvent was removed under reduced pressure. The concentrated residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous Na2SO4, concentrated and dried under vacuum to give compound A0061-1. (2.424 g, yield: 74.8%) as a white solid. |
74% | With samarium(III) trichloride at 80℃; for 130h; sealed tube; Inert atmosphere; | |
74% | With sulfuric acid for 48h; Reflux; | |
72% | Stage #1: methanol; 3,4,5-trihydroxybenzoic acid With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; Stage #2: With 4-dimethylaminopyridine 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) |
66% | With sulfuric acid | |
62% | With thionyl chloride at 0℃; for 2.16667h; Reflux; | |
60% | With sulfuric acid for 24h; Reflux; | |
53.5% | With sulfuric acid at 65℃; for 24h; | |
52.8% | With sulfuric acid Reflux; | 3.1 General procedure for the synthesis of compounds General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5%and water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives |
33% | With sulfuric acid for 6h; Reflux; | Methyl gallate (15) To a solution of gallic acid (10) (3.18 g, 18 mmol) in dry methanol (30 mL) was added sulfuric acid (0.3 mL). The mixture was heated at reflux for 6 hours, cooled to room temperature and the solvent removed in vacuo to afford the crude natural product (3.3 g, quant.). Recrystallization from water afforded methyl gallate (15) as white crystals (1.09 g, 33%). |
18% | With sulfuric acid for 24h; Reflux; | |
With hydrogenchloride | ||
With cationen-exchanger | ||
With sulfuric acid | ||
With hydrogenchloride | ||
With sulfuric acid Heating; | ||
With hydrogenchloride | ||
With acetyl chloride | ||
With toluene-4-sulfonic acid In toluene | ||
With sulfuric acid | ||
With sulfuric acid Heating; | ||
With sulfuric acid at 100℃; for 2h; | ||
With sulfuric acid at 100℃; for 2h; | ||
With sulfuric acid | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | 1.a Example 1 Example 1 [0046] Preparation method of nitrogen-containing biphenyl compound of the present invention can be generally summarized as follows: [0047] Compound 3 (0.1 mmol) and Compound 4 (0.2-0.5 mmol) were put in a 25 mL round-bottomed flask, followed by addition of Pd(OAc)2 (0.01-0.05 mmol), Bu4NBr (0.15 mmol), K2CO3 (0.3 mmol) and 3 mL THF-H2O (VTHF/VH2O=1). The mixture was heated to 70° C. and the reaction was carried out for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column to give compounds 5-8 in Example 2-5. [0048] Compound 4 is purchased from Acros or Sigma-Aldrich Company. [0049] Compound 3 is obtained by the following synthetic route: [0050] (a) Synthesis of Bromo Compound 3: [0051] Bromo Compound 3 was synthesized using gallic acid as a starting material, through esterification of carboxyl group, etherification of phenolic hydroxyl group, bromination of benzene ring, removal of benzyl protecting group, and final methyl etherification. [0052] (b) Synthesis of Iodo Compound 3: [0053] Iodo Compound 3 was synthesized using one intermediate compound obtained during the synthesis of bromo Compound 3 as a starting material, through removal of benzyl protecting group, methyl etherification, nitration of benzene ring, reduction of nitro group into amino group, and final Sandmeyer reaction (amino group was firstly converted to a diazonium salt in the presence of concentrated HCl+NaNO2, and then, after the addition of an aqueous solution of KI, the iodo compound was obtained). | |
With sulfuric acid for 14h; Reflux; Inert atmosphere; | ||
With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 20℃; | ||
With Amberlyst-15 for 72h; Reflux; | 3.1 Typical procedure for preparation of aryl hydrazides. Preparation Method I (see Scheme 2) Preparation of 3,4,5-trihydroxybenzohydrazide (H1-Supplemental material). A methanol (300ml) suspension of 3,4,5-trihydroxybenzoic acid and (17g; 0.1mol) and the strongly acidic ion-exchange resin Amberlyst-15 (5g) was stirred with refluxing for three days. The insoluble catalyst was separated by filtration, and washed with methanol (3×10ml). The combined methanol filtrates were mixed with hydrazine hydrate (20ml; 20.5g; 0.4mol) and refluxed for 3h. The volume of the reaction mixture was reduced to ∼30ml and left at room temperature for 1h and then at -5°C. The formed white precipitate was separated by filtration, washed with ice cold methanol (3×5ml), followed by ice cold ether (3×10ml) and dried on air to give pure product (17.1g; 93%). 1H NMR (DMSO-d6) δ 9.34 (1H, br s, NH), 6.79 (2H, s, 2-H), and 4.33 (2H, br s, NH2) ppm. 13C NMR (DMSO-d6) δ 167.1, 146.1, 136.9, 124.3, and 107.2ppm | |
With 1-hydroxy-pyrrolidine-2,5-dione; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride | ||
With thionyl chloride at 60℃; for 8h; Inert atmosphere; | 3,4,5-Tribenzyloxybenzoic acid (9c) To a solution of 8c (60.0 g, 0.318 mol) in MeOH (638 mL) was added SOCl2 (23.2 mL, 0.319 mol) fordropwise at 60 °C. The reaction mixture was stirred at 60 °C for 8 h. Then, the reaction mixture wasevaporated under reduced pressure. The crude mixture was applied to following reaction without furtherpurification.To a mixture of crude material (2.00 g, 10.9 mmol) and K2CO3 (6.78 g, 49.0 mmol) in DMF (36.0 mL)were added benzyl bromide (4.10 mL, 35.9 mmol) and TBAI (1.60 g, 4.33 mmol) at room temperature.The reaction mixture was stirred at room temperature for 11 h. Then, the reaction mixture was filteredthrough a pad of Celite, diluted with H2O, and extracted with CH2Cl2. The organic layer was washed withwater and brine, dried over anhydrous MgSO4, and evaporated under reduced pressure. The crude mixturewas applied to following reaction without further purification.To a stirred solution of crude residue in MeOH/THF (1/1, 36.3 mL) was added 4 M NaOH aq. (9.50 mL,38.0 mmol) at 80 °C. The reaction mixture was stirred at 80 °C for 1 h. Then, the reaction mixture wasquenched with 6 M HCl aq., and filtered. The filtrate was washed with H2O to give 9c (3.30 g, 7.49 mmol,68%) as a white solid.Spectral data for 9c were in good agreement with those reported in reference.16 | |
With sulfuric acid | ||
With sulfuric acid at 120℃; | ||
With sulfuric acid for 20h; Reflux; | ||
With thionyl chloride for 3.5h; Reflux; | ||
With thionyl chloride for 3.5h; Reflux; | 1.1 Example 1 Example 1 Preparation of the Compound of Formula (I) In general, the compound of formula (I) of the present disclosure, particularly, compounds 1, 4, 5, 9, and 11-15 were obtained from commercial sources as described in the "Materials and Methods" section. Compounds 2, 3, and 10 were synthesized in accordance with procedures described bellowed. 1.1 Methyl Gallate (Compound 2) To a stirred suspension of gallic acid monohydrate (4.09 g, 21.7 mmol) in methanol (16 mL) at 0° C. was added dropwisely thionyl chloride (2 mL, 27.6 mmol). The mixture was heated under reflux for 3.5 h. The reaction mixture was then poured into crushed ice. The resulted precipitate was filtered and washed thoroughly with water. The crude product was recrystallized from n-hexane-ethyl acetate (EA) to provide methyl gallate as white crystal, mp 199-201° C. 1H NMR (300 MHz, CD3OD) δ (ppm) 3.82 (s, 3H), 7.04 (s, 2H); 13C NMR (125 MHz, CD3OD) δ (ppm) 52.4, 110.2, 121.6, 139.9, 146.7, 169.2. | |
With thionyl chloride at 0 - 20℃; | 1.1 Step 1 To a suspension of 1 (5 gm, 29.41 mmol) in methanol (50 mL) was added thionyl chloride (4.19 gm, 35.29 mmol) at 0°C. The mixture was allowed to stir for 5 hr in at room temperature. After completion, the reaction mixture was evaporated to dryness under vacuum pressure. White solid 2 was used directly in Step 2. | |
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid at 100℃; for 2h; | 3.1 Step 1. General procedure: Add compound 1a (18mmol) to 19mL methanol MeOH solution, stir, and then add 0.45mL H2SO4 with a mass fraction of 98.3%. The reaction mixture is refluxed at 100°C for 2 hours, distilled under reduced pressure, and the residue is dissolved in water , And extracted with dichloromethane (DCM), the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1b (2.68g); | |
With sulfuric acid for 4h; Reflux; | 3.3 Synthesis of methyl 3, 4, 5-tris(hydroxyl) benzoate (1) To a stirred solution of 3,4,5-tris(hydroxyl)benzoic acid (5.0g, 32.4mmol) in anhydrous methanol (80mL), the catalytic amount of conc. H2SO4 (1.0mL) was added dropwise in the cold condition. Then, the reaction was refluxed for 4h with constant stirring, after completion of reaction (monitored by TLC), the resulting mixture was evaporated under reduced pressure. The resulted crude mass was extracted with ethyl-acetate, washed with aqueous NaHCO3 solution (2×50mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford targeted scaffold 1. The spectroscopic datas were matched those reported in the literature [18]. | |
With sulfuric acid for 5h; Cooling; Reflux; | 2.2. Synthetic Procedure of Methyl 3,4,5-Tris (Hydroxyl)Benzoate (2) [29] 3,4,5-Tris (hydroxyl) benzoic acid 1 (5.0 g,32.4 mmol) was dissolved in dry methanol (80 mL); thereafter,the catalytic amount of conc. H2SO4 (1.0 mL) wasadded dropwise in the cold condition. Furthermore, thereaction was set to reNux for 5 h. After the consumption ofthe starting material on TLC, the resulting reaction mixturewas condensed under in vacuo followed by extraction. Thus, ethyl acetate (100 mL) was added to the obtained crude massand washed with NaHCO3 solution (2 × 50 mL), dried overanhydrous Na2SO4, ltered, and again evaporated to furnishthe targeted sca9old 2 in good yield. +e physical data(NMR) of compound 2 were closely matched with the reportedliterature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 170℃; | |
92% | ||
91% | In neat (no solvent) at 170℃; for 0.25h; Inert atmosphere; | Methyl 7-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (11) A mixture of methyl 3,4,5-trihydroxybenzoate (10) (18.4 g, 0.1 mol) and dichlorodiphenyl methane (23.7 g, 0.1 mol) in a 100 mL roundbottomed flask under an argon atmosphere was heated to 170 °C using an oil bath. Stirring was maintained at this temperature for 10-15 min, during which the evolved HCl gas was trapped with water. The reaction flask was removed from the oil bath and was allowed to cool to ambient temperature. The obtained dark brown residue was diluted with warm toluene (200 mL) and any unreacted compound 10 was removed by filtration whilst the solution was hot. Upon dilution of the toluene filtrate with hexane (500-600 mL), a white solid precipitated. The product was collected by filtration and washed with warm water. Crystallization from methanol yielded methyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (11). Colorless crystals; yield: 31.6 g (91%); mp 165-166 °C; Rf = 0.56 (EtOAc/hexane, 1:1). IR (KBr disk): 3389 (br), 3034, 2954, 1699, 1654, 1611, 1518, 1446, 1387, 1328, 1261, 1074, 766, 698 cm-1. 1H NMR (400 MHz, CDCl3): = 7.58-7.56 (m, 4 H), 7.42 (d, J = 1.6 Hz, 1H), 7.39-7.32 (m, 6 H), 7.21 (d, J = 1.6 Hz, 1H), 6.55 (s, 1H), 3.85 (s, 3 H). 13C NMR (100 MHz, CDCl3): = 167.1, 148.3, 139.4, 139.2, 138.3, 129.3, 128.3, 126.2, 123.9, 118.6, 114.2, 103.2, 52.3. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H16O5Na: 371.0890; found: 371.0891. |
91% | In neat (no solvent) at 170℃; Inert atmosphere; | Methyl 7-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (11) A mixture of methyl 3,4,5-trihydroxybenzoate (10) (18.4 g, 0.1 mol) and dichlorodiphenyl methane (23.7 g, 0.1 mol) in a 100 mL roundbottomed flask under an argon atmosphere was heated to 170 °C using an oil bath. Stirring was maintained at this temperature for 10-15 min, during which the evolved HCl gas was trapped with water. The reaction flask was removed from the oil bath and was allowed to cool to ambient temperature. The obtained dark brown residue was diluted with warm toluene (200 mL) and any unreacted compound 10 was removed by filtration whilst the solution was hot. Upon dilution of the toluene filtrate with hexane (500-600 mL), a white solid precipitated. The product was collected by filtration and washed with warm water. Crystallization from methanol yielded methyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (11). Colorless crystals; yield: 31.6 g (91%); mp 165-166 °C; Rf = 0.56 (EtOAc/hexane, 1:1). IR (KBr disk): 3389 (br), 3034, 2954, 1699, 1654, 1611, 1518, 1446, 1387, 1328, 1261, 1074, 766, 698 cm-1. 1H NMR (400 MHz, CDCl3): = 7.58-7.56 (m, 4 H), 7.42 (d, J = 1.6 Hz, 1H), 7.39-7.32 (m, 6 H), 7.21 (d, J = 1.6 Hz, 1H), 6.55 (s, 1H), 3.85 (s, 3 H). 13C NMR (100 MHz, CDCl3): = 167.1, 148.3, 139.4, 139.2, 138.3, 129.3, 128.3, 126.2, 123.9, 118.6, 114.2, 103.2, 52.3. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H16O5Na: 371.0890; found: 371.0891. |
83% | at 180℃; | |
79% | at 170℃; | |
70% | With potassium carbonate at 170 - 180℃; for 0.166667h; | |
62% | With potassium carbonate In acetonitrile at 20℃; for 16h; | |
46% | With potassium carbonate In acetonitrile at 20℃; for 24h; Inert atmosphere; | |
With pyridine; propan-2-one | ||
at 180℃; | ||
33.6 g | at 170 - 180℃; for 0.0833333h; | |
at 175℃; | ||
With pyridine In propan-2-one at 20℃; for 24h; | Preparation of 13 A solution ofmethyl gallate (12, 10.0 g, 54 mmol)was treated with Ph2CCl2 (15.3 mL, 76.9 mmol) and anhydrouspyridine (13.1 mL, 162 mmol) in acetone (54 mL) at room temperature for 24 h. Afterthe reaction mixture was poured into aq satd NH4Cl, the whole wasextracted with EtOAc. The EtOAc extract was washed with aq satd NaCl and driedover MgSO4. Removal of the solvent from the EtOAc extract underreduced pressure gave a residue, which was purified by column chromatography(SiO2 750 g, n-hexane:EtOAc=5:1)to afford diphenylacetal (10.3 g, 55%). A solution of diphenylacetal (10.0 g,28.7 mmol) was treated with 1,3-dibromo-5,5-dimethylhydantoin (3.3 g, 11.5mmol) in anhydrous CHCl3 (200 mL) at room temperature for 10 min.After the reaction mixture was poured into aq satd NaCl, the whole wasextracted with EtOAc. The EtOAc extract was dried over Na2SO4.Removal of the solvent from the EtOAc extract under reduced pressure gave brominatedproduct 13 (10.5 g).Brominated product13; brown oil, IR nmax (KBr): 3250, 1715, 1580 cm-1; 1HNMR (500 MHz, CDCl3) d7.34-7.61 (10H, m), 7.18 (1H, s), 3.89 (3H, s); MS (FAB) m/z 427 [M+H]+; HRMS (FAB) m/z calcd for C21H1679BrO5:427.0181, found: 427.0183. | |
at 170 - 180℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; at 50℃; for 12.0h; | Weigh 50 g of gallic acid methyl ester,Pour into a 500 ml three-necked flask after drying,Then add 25% concentrated ammonia 250ml,Plug the bottle with a stopper,Put in a constant temperature water bath at 50 C, stir for 12 h,The reaction solution was then poured into a 1000 ml dry three-necked flask.Introduce air,Oxidation reaction for 24 h.After the reaction was completed, the reaction solution was filtered, and the filter cake was dissolved in a 25% NaOH solution.250 g of activated carbon was put in and stirred and decolored at 25 C.Filtration, the filtrate was extracted three times with dichloromethane, the filtrate was separated, and the aqueous phase was adjusted to pH 2 with 25% hydrochloric acid, crystallization, filtration,The pale yellow ellagic acid amorphous powder was dried in a yield of 72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With boron trifluoride diethyl etherate; bis-[(trifluoroacetoxy)iodo]benzene In dichloromethane at 20℃; for 24h; Inert atmosphere; | Ellagic acid (5) Method 1: To a solution of methyl gallate (15) (128 mg, 0.69 mmol) dissolved in methylene chloride (10 mL), was added PIFA (455 mg, 1.06 mmol) dissolved in boron trifluoride-diethyl etherate (1.5 mL). The reaction mixture was stirred at ambient temperature under nitrogen for 24 hours. Water (10 mL) was added to quench the reaction mixture. Extraction using n-butanol (4 10 mL), followed by purification via column chromatography (acetone-hexane 1:4), afforded the natural product 5 as a cream solid (87 mg, 83%). |
78% | With dipotassium peroxodisulfate In acetic acid at 80℃; for 12h; | 1 Example 1: Weigh 200 g of gallic acid methyl ester,Placed in the reaction flask, then added 600 mL of acetic acid,Stir and heat to 80 ° C to dissolve the methyl gallate,200 g of K2S2O8 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 added thereto, and the mixture was decolorized by stirring at 25 ° C, filtered, and the filtrate was extracted three times with ethyl acetate, and the filtrate was separated.The aqueous phase was adjusted to pH 1.5 with 10% hydrochloric acid, crystallization, filtration, and vacuum drying to obtain pale yellow ellagic acid.The yield is 78% and the relative content is up to 95%. |
With iron(III) chloride; acetic acid |
With methanol; barium dihydroxide Reagens 4: Wasser; Durchleiten von Luft; | ||
With methanol; sodium hydrogencarbonate Reagens 4: Wasser; Durchleiten von Luft; | ||
Multi-step reaction with 2 steps 1: ammonium hydroxide / 12 h / 50 °C 2: 3-chloro-benzenecarboperoxoic acid / 10 h | ||
0.74 g | Stage #1: methyl galloate With sodium hydrogencarbonate In water at 15 - 25℃; for 24h; Stage #2: With sodium tetraborate heptahydrate In water; acetonitrile at 80℃; | 21; 22; 23; 24; 25; 26; 27; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38 Example 21 Synthesis of Compound d-1 8.5 g of sodium hydrogencarbonate was dissolved in 200 ml of purified water,While performing air bubbling at a flow rate of 5 ml / min,A solution of 3.75 g of methyl gallate in 20 ml of methanol was added little by little,The reaction was carried out at an internal temperature of 15 to 25 ° C. for 24 hours.The green precipitate was filtered off, suspended for 1 hour with 200 ml of 5% aqueous sulfuric acid solution,Filtration, washing with water and drying under reduced pressure at 60 ° C. 2.69 g of a crude product of compound d-1 as a green solid target substance was obtained. The obtained crude product had a weight content of 75.4 wt% and a purity conversion yield of 66.0%.To 1.0 g of the obtained crude product, 25 ml of acetonitrile and 2.5 ml of purified water were added, and the mixture was stirred at an internal temperature of 20 ° C. for 30 minutes.Dust filtering was carried out to remove insoluble matter, and the obtained solution had pH 2. It was 0. To this solution, 20 ml of a 0.01 M aqueous solution of sodium tetraborate heptahydrate prepared in advance was added dropwise to adjust the pH to 6.0. Next, acetonitrile was distilled off under normal pressure at an internal temperature of about 80 ° C. After cooling to an internal temperature of 20 ° C., the mixture was stirred for 2 hours. Precipitated crystals were filtered, washed with 10 ml of purified water, and then dried at 60 ° C. under reduced pressure. 0.74 g of pale yellow crystals of the target compound d-1 was obtained. Weight content was 99.9 wt%, purity conversion yield was 64.6% |
Multi-step reaction with 5 steps 1: potassium iodide; potassium carbonate / acetone / Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 3: copper / N,N-dimethyl-formamide / Heating 4: palladium(II) hydroxide; hydrogen / ethyl acetate / 18 h 5: methanol; water / 4 h / 85 °C | ||
Multi-step reaction with 2 steps 1: [bis(acetoxy)iodo]benzene; boron trifluoride diethyl etherate / dichloromethane / 16 h / 20 °C / Inert atmosphere 2: water; methanol / 24 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With erythritol tetranitrate | |
98% | With triethylamine for 2h; Ambient temperature; | |
98% | With triethylamine at 4 - 20℃; for 2h; |
96% | With triethylamine at 0 - 20℃; for 2.25h; | |
93% | In pyridine at 0 - 20℃; for 2h; | |
93% | With pyridine at 20℃; for 12h; | |
92% | With sulfuric acid | |
78% | With pyridine Ambient temperature; | |
74% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 1.2 Step 2 To a suspension of 2 (4 gm, 21.72 mmol) in dichloromethane (DCM) (30 mL) was added triethylamine (6.6 gm, 65.16 mmol) and acetic anhydride (6.5 gm, 65.16 mmol) at 0°C. The mixture was allowed to stir for 2 hr room temperature. After completion, the reaction mixture was diluted with water and extracted by dichloromethane three times. The collected organic phase was dried over anhydrous Na2S04, concentrated and purified by column chromatography (12% EtOAc in Hexane) to obtain 3 (5 gm, 16.12 mmol, 74 % yield) as a white solid. 1H NMR (500 MHz, CDCb): (2H, s), 3.90 (3H, s), 2.30 (3H, s), 2.29 (3H, s). |
With sulfuric acid | ||
With sodium acetate | ||
With triethylamine | ||
With pyridine | ||
With pyridine at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate;potassium iodide; In dimethyl sulfoxide; at 20℃;Product distribution / selectivity; | Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were mechanically stirred in dry DMSO (200 mL) at room temperature overnight. Water (200 mL) was added and the crude product isolated by filtration. Evaporation of residual solvents in a vacuum desiccator left a pale yellow solid which was essentially pure product. Yield: 128.2 g (94%). |
90.5% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; for 24h;Reflux; | Preparation of (AB)3G1-CH2OH (c) Lithium aluminum hydride (0.809 g, 0.0213 mole) was suspended in 40 mL of freshly distilled THF in a dry three-neck round-bottom flask under nitrogen atm. (AB)3 G1-COOCH3 (9 g, 0.0198 mole) was dissolved in 50 mL of freshly distilled THF and added drop wise to the lithium aluminum hydride solution. The reaction mixture was refluxed with stirring for 2 hours. The THF solution was cooled to room temperature and transferred to a beaker. Water was added drop wise to the vigorously stirred THF solution until the gray color of the lithium aluminum hydride was disappeared and a white solid was formed which is filtered and washed with THF. Excess solvent was removed under reduced pressure and the crude product was recrystallized from 95% methanol/water mixture to get the pure product ((AB)3 G1-CH2OH) (7.6 g, 90%); 1H NMR (400 MHz, CDCl3) delta: 4.6 (s, CH2OH, 2H), 5.09 (s, ArCH2O, 2H), 5.15 (s, ArCH2O, 4H), 6.72 (s, ArH, 2H), 7.30-7.48 (m, PhH, 15H); 13C NMR (100 MHz, CDCl3) delta: 65.42, 71.22, 75.26, 106.46, 127.45, 127.83, 127.90, 128.18, 128.52, 128.62, 136.66, 137.13, 137.81, 137.87, 153.02. |
89% | With potassium carbonate;potassium iodide; In acetone; for 12h;Product distribution / selectivity; | Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g5 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), dry potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were stirred in refluxing dry acetone (600 mL) for 12 h. After cooling, the acetone was evaporated, and the solution was dissolved in water (250 mL). The water phase was extracted with diethyl ether (4 x 100 mL), the organic phase was washed with brine (2 x 50 mL), dried (MgSO4) and the solvent was removed in vacuo. Recrystallisation from petroleum ether and ethyl acetate gave the titled compound as white crystals, m.p. 102-103 0C. Yield: 121.4 g (89%). Spectroscopic data were in accordance with the literature (J. Barbera, R. Iglesias, J. L. Serrano, T. Sierra, M. R. de Ia Fuente, B. Palacios, M. A. Perez- Jubindo, J. T. Vazquez, J. Am. Chem. Soc. 1998, 120, 2908). |
88% | With t-butyl ammonium iodide; potassium carbonate; In 1,4-dioxane; for 24h;Inert atmosphere; Reflux; | As described in a previous study [48], 1.84 g (10 mmol) Methyl-3, 4, 5-trihydroxybenzoate and 5.52 g (40 mmol) potassium carbonate were dissolved in 30mL 1, 4-dioxane, than 3.78 g(30 mmol) benzyl chloride and trace amounts of tertiary butylammonium iodide were added, and then the mixturewas heated toreflux for 24 h. After that, the mixture was filtered and the solventwas removed under reduced pressure. The crude product wasrecrystallized from methanol, and 1.5 g (3.30 mmol) white solid 2was obtained with 88% yield and a melting point of 91.9 C.2.0 g (4.4 mmol) solid 2 and 11 mL (220 mmol) hydrazinemonohydrate were dissolved in 15 mL MeOH and 7mL THF, andthen the mixture was heated to 70 C for 12 h. After that, themixture was cooled to room temperature and the solvent wasremoved under reduced pressure. The residue was dissolved inCH2Cl2 and washed with water, and dried over anhydrous Na2SO4.The crude product obtained was purified by column chromatographyon silica gel (eluent: CH2Cl2/MeOH 95:5), and 1.82 g(4 mmol) white solid 3 was obtained with a 91% yield and a meltingpoint of 121.5-121.7 C. |
With potassium iodide; sodium carbonate; In water; acetone; | EXAMPLE 5a 3.4,5-Trisbenzyloxybenzoic Acid Methyl Ester 105 g (0.83 mol) of benzyl chloride are added dropwise at 56 C., under reflux, over a period of 10 minutes, to 18.4 g (0.1 mol) of 3,4,5-trihydroxybenzoic acid methyl ester, 50.0 g (0.48 mol) of sodium carbonate and 10.0 g (0.06 mol) of potassium iodide in 200 ml of acetone. After a further 20 hours at reflux, 500 ml of water are added at room temperature and the mixture is then extracted with ether. The crude product is worked up in customary manner, excess benzyl chloride is removed by distillation, and the residue is recrystallized from hexane/ethyl acetate. Colourless crystals, yield 45.0 g (98% of theory) 1H-NMR (CDCl3): 3.85 (s,3H, OCH3), 5.05 (s, 2H, OCH2), 5.10 (s, 4H, OCH2), 7.15-7.45 (m, 17H, arom. H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium iodate In water; acetone at 20℃; for 2.5h; | General Method 2 General procedure: KIO3 (0.5 M in H2O, 1 equiv) was added to 1,2-dihydroxybenzene derivative (1 equiv) and 3,4,5-trihydroxybenzoic acid derivative (1 equiv) in acetone / water (1.0 M, 1:4) dropwise at room temperature. After stirring at room temperature for indicated time, the reaction mixture was filtered, washed with 1 N HCl, and dried. The desired product was obtained as a solid. |
54% | With dihydrogen peroxide; horseradish peroxidase In aq. phosphate buffer; acetone | |
With potassium iodate; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 58h; | |
78% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; | 1. Synthesis of methyl 3,4,5-trimethoxybenzoate (3) To 300 ml of anhydrous DMF, methyl gallate (2) (12.5 g, 0.068 mol), iodomethane (12.6 ml, 0.204 mol), and potassium carbonate (28.2 g, 204mmol) were added, and they were stirred at 85 °C for 48 h. To the reaction mixture, iodomethane (6.30 mL, 102 mmol) was again added and it was further stirred at 85 °C for 10 h. The mixture was poured into water and the resulting colorless precipitates were filtered off. The filtered solid was recrystallized from ethanol to give 3 as white solid yield 78% m.p. 84°CC [lit. [2 ]85-87 °C]. |
With potassium carbonate; acetone |
With methanol; potassium hydroxide | ||
With potassium carbonate; potassium iodide In acetone Heating; | ||
With potassium carbonate In acetone for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | To a mixture of potassium carbonate (4.002 g, 29 mmol), methyl gallate (6 g, 29.7mmol), in dry DCM and diiodomethane (2.8 mL, 34.8 mmol) was added at room temperatureunder nitrogen condition, allowed to stir for 5h at 120C. The resulting mixture was poured in toice cooled water (500 mL) and was extracted with ethyl acetate. The combined organic extractswere washed with brine, then dried over Na2SO4, filtered and evaporated under reduced pressure.The residue was purified by column chromatography with 15% EtOAc/hexane to affordcompound 9 (3.6 g, 58%) as white amorphous powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; potassium iodide In acetone at 60℃; | 5 Example 5: Preparation and detection of compound LP-5 1.0 g (6.5 mmol) of methyl 3,4,5-trihydroxybenzoate and 2.8 g (20.2 mmol) of potassium carbonate and 60 mL of acetone were placed in a 100 mL three-necked flask and heated to reflux at 60 ° C.Further, 2.6 ml (20.9 mmol) of 1-bromopentane was added thereto,After the completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the mixture was evaporated, evaporated, evaporated, evaporated.Methyl 3,4,5-tripentyloxybenzoate 1.9 g (yield: 95%). |
90% | With potassium carbonate In acetonitrile for 72h; Heating; | |
70% | With tetrabutylammomium bromide; potassium carbonate In acetone for 48h; Inert atmosphere; Reflux; |
With potassium carbonate In acetone for 72h; Heating; Yield given; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Heating; | ||
With tetrabutylammomium bromide; potassium carbonate In acetone at 70℃; for 48h; Inert atmosphere; | 1.1 Preparation Example 1 Add 3.68 g (20 mmol) of methyl gallate and 9.365 g (62. Ommol) of bromopentane to a two-neck reaction tube, and then add 5.52 g (40.0 mmol) of K2C03, catalyst equivalent (20 mg) of TBAB, and then add 100 ml of acetone solvent, stirred uniformly under a nitrogen atmosphere, and reacted at 70 ° C for 48 h; after completion of the reaction, it was cooled to room temperature, and the acetone solvent was removed by rotary evaporation, extracted with dichloromethane and water, and the organic phase was concentrated, then purified by silica gel column. The product is recorded as al-C00CH3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere; | 9.1 Step 1: Methyl 3.4.5 -Tris(hexanyloxV)benzoate YZ -2-37:A 250 ml round -bottom flask equipped with a Teflon -coated magnetic stirring bar was charged with 150 ml of DMF and 60.0 g (363.48 mmol) of 1 -bromohexane. The mixture was sparged with nitrogen, and the 60.0 g of anhydrous K 2CO3 and 20 g (108.61 mmol) of methyl 3,4,5 -trihydroxybenzoate 1 were added as N2 sparging was continued. The mixture was heated at 80 0C for 24 h with stirring under a N 2 atmosphere. The re action was judged complete by TLC analysis. The reaction mixture was cooled to room temperature. Water (700 ml) was added, and the product was extracted with ether. The organic phase was washed with water. The organic phase was separated and dried over MgS O4. The solvent was evaporated, and then crude product was pass through a column of silica gel using Hexane: ethyl acetate (9.5:0.5) as eluent. The product was obtained a s yellow liquid in 44.4 g (93.6 %).1H-NMR (500 MHz, CDCl 3) δ: 7.27 (s, 2 H), 4.01 (m, 6 H, 3 x OCH 2), 3.89 (s, 3 H, COOCH3), 1.82 (m, 4 H, 2 x CH2), 1.75 (m, 2 H, CH2), 1.48 (m, 6 H, 3 x CH 2), 1.22 (m, 12 H, 6 x CH 2), 0.90 (m, 9 H, 3 x CH3) ppm. 13C-NMR (100 MHz, CDCI3) δ 166.90, 152.77, 142.26, 124.60, 107.87, 73.43, 69.09, 52.06, 31.69, 31.52, 30.23, 29.21, 25.74, 25.71, 25.67, 22.65, 22.59, 14.00 ppm. |
90% | With potassium carbonate In acetonitrile for 72h; Heating; | |
87% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 10h; Inert atmosphere; |
85% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 6h; | |
85.7% | With potassium carbonate at 65℃; for 48h; Inert atmosphere; | |
72.6% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h; | |
With potassium carbonate In acetone for 72h; Heating; Yield given; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide at 65℃; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Reflux; | ||
With potassium carbonate; potassium iodide In butanone Reflux; | ||
Stage #1: methyl galloate With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5h; Inert atmosphere; Stage #2: 1-bromo-hexane In N,N-dimethyl-formamide at 80℃; for 20h; Inert atmosphere; | ||
With tetrabutylammomium bromide; potassium carbonate In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 21h; Inert atmosphere; | |
93.3% | With potassium carbonate In N,N-dimethyl-formamide for 6h; Inert atmosphere; | |
93% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; Inert atmosphere; |
91% | Stage #1: methyl galloate With potassium carbonate In acetone at 60℃; Inert atmosphere; Stage #2: 1-bromo-octane In acetone for 24h; Inert atmosphere; Reflux; | |
90% | With potassium carbonate In acetonitrile for 72h; Heating; | |
89% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere; | Preparation of Methyl-3,4,5-Tris-octyloxy-benzoate Methyl-3,4,5-Trihydroxy benzoate (2 g, 10.8 mmol) was takenin a dry DMF (75 ml) under the inert atmosphere and it cooledto 0 °C, added K2CO3 (8.9 g, 65 mmol) to the above solutionand followed by 1-bromo octane (11 mL, 84 mmol) after additionover reaction mass comes to RT itself. The reaction masswas stirred for about 12 h at RT. Then the reaction mixture waspoured into ice-water and extracted with Ethyl acetate (2 times),organic layer was separated and washed with saturated brinesolution, dried over Na2SO4 and evaporated, The crude productwas purified by silica gel (60-120 mesh) column chromatographyusing ethyl acetate: pet-ether as an eluent. The pure productis a colorless solid, Yield is 5 g (89 %), mp: 45-46 °C, FTIR(KBr): (υO-C):1310 cm-1, υC=O 1720 cm-1; 1H NMR(300 MHz, CDCl3) (δ): 7.25(s, 2H), 4.03-3.99(t, J = 12 Hz6H), 3.89(s,3H), 1.86-1.72(m,6H), 1.49-1.43(m,6H), 1.31-1.28 (m, 24H), 0.90-0.86(t, J = 12 Hz, 9H); 13CNMR(75 MHz, CDCl3) δ = 166.8, 152.7, 124.6, 108.2, 73.4,69.2, 51.8, 31.7, 30.2, 29.3, 29.1, 25.8, 22.5. |
88% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 48h; Inert atmosphere; | |
88% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; | |
88% | With potassium carbonate at 80℃; for 48h; Inert atmosphere; | |
85% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; | |
84% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 10h; Inert atmosphere; | |
84.6% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; | 8.1 1) Synthesis of methyl 3,4,5-tris(n-octyloxy)benzoate Methyl gallate (5.00 g, 27.17 mmol) and potassium carbonate (38 g, 275.5 mmol) were weighed separately.Potassium iodide (0.45 g, 2.71 mmol) was placed in a 250 mL three-necked flask, and 120 mL of N,N-dimethylformamide and 21 mL of bromooctane were added.The system was reacted at 70 ° C for 24 h under N2 protection. After the TLC monitoring reaction was completed, it was cooled to room temperature. The filtrate obtained by suction filtration was washed with water and extracted with ethyl acetate.The crude product was purified on a silica gel column and then recrystallized from ethanol to give a white solid product.As will be seen from the test, the above white solid was methyl 3,4,5-tris(n-octyloxy)benzoate.The yield was 84.6%. |
80% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 48h; | |
65.6% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 48h; Inert atmosphere; | Compound 35-precursor: To a suspension of K2CO3 (20.88 g, 150.0 mmol) in DMF (100 mL) was added under argon methyl 3,4,5-trihydroxybenzoate (4.0 g, 21.6 mmol), and 1 -bromooctane (11.28 mL, 72.24 mmol). The mixture was heated at 80°C for 48 h under stirring. The reaction mixture was then allowed to cool to room temperature, before pouring into a large amount of water. The resulting mixture was then extracted with dietyl ether. The organic layers were washed with distilled water, combined, dried over MgSCL and filtered before removal of the solvent under reduced pressure. The expected product was obtained as a white solid (7.35 g, 65.5%). NMR (400 MHz, CD3CN) d 7.23 (s, 2H, ), 4.00-3.94 (m, 6H, ), 3.83 (s, 3H, OCH3), 1.78-1.72 (m, 6H, Hb ), 1.36-1.23 (m, 24H, -8 ), 0.90-0.86 (s, 9H, )· 13C NMR (100 MHz, CDCI3) d 167.1 (C02Me), 152.9 (C3 ), 142.5 (C4 ), 124.8 (Ci ), 108.1 (C2 ), 69.3 (Ca ), 52.2 (OCH3), 32.0, 30.5, 29.6, 29.4, 26.2, 22.8, 14.2 |
61% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; Inert atmosphere; | |
With potassium carbonate In acetone for 72h; Heating; Yield given; | ||
With potassium carbonate In various solvent(s) for 84h; Heating; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Heating; | ||
With potassium carbonate In acetonitrile Heating; | ||
With potassium carbonate; potassium iodide In acetone for 48h; Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate In N,N-dimethyl-formamide at 65℃; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In ethanol for 24h; Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide | ||
With tetrabutylammomium bromide; potassium carbonate In acetone | ||
With potassium carbonate In N,N-dimethyl-formamide Reflux; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | ||
Stage #1: methyl galloate With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; for 1h; Stage #2: 1-bromo-octane In N,N-dimethyl-formamide at 90℃; for 24h; | 2.a a. Add 500 mg of gallic acid methyl ester (92 g, 0.5 mol) to a 500 mL round bottom flask, add 200 mL of N,N-dimethylformamide and stir to dissolve, then add anhydrous potassium carbonate (276 g, 2 mol) and potassium iodide. (0.1 g), after heating to 90 °C and stirring for 1 hour, adding bromo n-octane (308.8 g, 1.6 mol), reacting at 90 °C for 24 hours, cooling to room temperature, pouring the reaction solution into 2 L of water, then Extracting three times with n-hexane, distilling off the n-hexane solvent under reduced pressure, and finally recrystallizing from methanol to give the product 3,4,5-tris(octyloxy)benzoic acid methyl ester. | |
With potassium carbonate; potassium iodide In butanone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide | |
91% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere; | |
90% | With potassium carbonate In acetonitrile for 72h; Heating; |
90% | Stage #1: methyl galloate With potassium carbonate In acetone at 60℃; Inert atmosphere; Stage #2: 1-bromo dodecane In acetone for 24h; Inert atmosphere; Reflux; | |
85% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 20h; | |
85% | With potassium carbonate; potassium iodide In acetonitrile for 24h; Reflux; | 4.2.10. Compound 17 A mixture of methyl gallate (16) (1.9 g, 10.4 mmol), decylbromide (8.9 g, 40.2 mmol), KI (2.11 g, 12.8 mmol), and anhydrous potassium carbonate (9.8 g, 70.8 mmol) in acetonitrile (40 mL) was heated under reflux for 24 h. After being cooled to room temperature, the solvent was removed with a rotavapor. To the resulting mixture, water (40 mL) was added and the aqueous phase was extracted with dichloromethane (3×40 mL). The combined organic phase was successively washed with water (2×40 mL) and brine (40 mL), and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (petroleum ether/dichloromethane 30:1) to give compound 17 as a pale yellow oil (2.0 g, 85%). 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J=6.4 Hz, 9H), 1.20-1.40 (m, 36H), 1.46-1.52 (m, 6H), 1.62-1.84 (m, 6H), 3.88 (s, 3H), 4.01 (t, J=6.1 Hz, 6H), 7.25 (s, 2H). MS (ESI): 605.4 [M+H]+. |
81% | With 18-crown-6 ether; potassium carbonate In butanone Heating; | |
80.5% | With potassium carbonate; potassium iodide In acetone for 72h; Reflux; | |
65% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h; | |
54% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 48h; Inert atmosphere; | |
46% | With potassium carbonate for 24h; Reflux; | |
With potassium carbonate | ||
With potassium carbonate In acetone for 72h; Heating; Yield given; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Heating; | ||
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 110℃; | ||
With potassium carbonate In N,N-dimethyl-formamide Heating; | ||
With potassium carbonate; potassium iodide In acetone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 65℃; | ||
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; Inert atmosphere; | ||
Stage #1: methyl galloate With potassium carbonate; potassium iodide In acetone for 0.5h; Reflux; Stage #2: 1-bromo dodecane In acetone for 48h; Reflux; | 4.2.3. Methyl-3,4,5-tris(dodecyloxy)benzoate (n=12). General procedure: The solutionof methyl-3,4,5-trihydroxybenzoate (10.0 g, 54.3 mmol), K2CO3(44.4 g, 325.8 mmol), and catalyst amount KI dissolved in 300 mL anhydrous acetone was mixed and the solution was then refluxed for 30 min. To this solution, 1-bromododecane (49.8 g,168.3mmol) was added and then refluxed for further 48 h. The solids were filtered offand the filtrate was concentrated to dryness. The product isolated as white powder was obtained after recrystallization from acetone/MeOH. Yield 95%. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=6.90 Hz,-CH3, 9H), 1.24-1.60 (m, -CH2, 54H), 1.67-1.83(m, -CH2, 6H), 3.86(s, -OCH3, 3H), 3.86-4.01 (m, -OCH2, 6H), 7.23 (s, Ar-H, 2H). 13C NMR (75MHz,CDCl3): δ 14.09, 22.67, 26.05, 29.28, 29.37, 29.62, 29.68,30.30, 31.91, 52.06, 69.12, 73.45,107.93,124.61,142.32,152.79,166.92. | |
With potassium carbonate In ethanol for 24h; Reflux; | ||
14.62 g | With potassium carbonate; potassium iodide In butanone for 72h; Reflux; | |
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 24h; | ||
With 18-crown-6 ether; potassium carbonate In acetone at 60℃; for 36h; | ||
With potassium carbonate; potassium iodide In acetone for 72h; Reflux; | ||
With potassium carbonate; potassium iodide In butanone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; | |
70% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; | |
1.065 g | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; |
With potassium carbonate 1) DMF; 2) DMF, 60 deg C, 8 h; Yield given. Multistep reaction; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | ||
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With [bis(acetoxy)iodo]benzene; boron trifluoride diethyl etherate In dichloromethane at 20℃; for 16h; Inert atmosphere; | General method for the oxidative dimerization using PIDA in BF3·OEt2, PIFA in BF3·OEt2and IBX in BF3·OEt2 General procedure: 1,2,4-Trimethoxynaphthalene (17) (0.5 mmol) was dissolved in dichloromethane (2 mL) at 0 oCto which the oxidant (0.75 mmol) dissolved in boron trifluoride·diethyl etherate (0.75 mmol) wasadded under nitrogen and the mixture stirred at room temperature for 16-36 hours, with the exception of IBX in BF3·OEt2 (Note 1). The reaction was quenched with saturated aqueous sodiumbicarbonate (3 mL) and extracted with dichloromethane (2 × 10 mL). The organic layers werecombined, dried over magnesium sulfate, and the crude material purified via flash columnchromatography (ethyl acetate-hexane 1:4).Note 1: The reaction with IBX in BF3·OEt2 was stirred at room temperature for 12 hours, thenheated to reflux for 24 hours. |
32% | With 2,2-diphenyl-1-picrylhydrazyl In methanol for 1h; Ambient temperature; | |
Multi-step reaction with 3 steps 1: 64 percent / o-chloranil / diethyl ether / 3 h / -40 - 20 °C 2: 73 percent / acetic acid; acetonitrile / 15 h / Ambient temperature 3: 79 percent / Na2S2O4 / tetrahydrofuran / 0.5 h / 0 °C |
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / acetone / Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 3: copper / N,N-dimethyl-formamide / Heating 4: palladium(II) hydroxide; hydrogen / ethyl acetate / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 7h; | Potassium carbonate (63.31 g, 400 mmol) and benzyl bromide (59.47 mL, 500 mmol) were added to a solution of 3,4,5-trihydroxybenzoate methyl ester (compound 60) (18.41 g, 100 mmol) in DMF (70 mL). This reaction mixture was stirred at 120C for seven hours, and then poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The title compound 61 (3,4,5-tribenzyloxybenzoate methyl ester) (47.19 g) was obtained in a quantitative yield. The NMR spectrum of compound 61 is shown in Table 29. Table 29 NMR spectrum of compound 61400 MHz 1H NMR (CDCl3) delta 7.45-7.24 (17H, m, Ar-H), 5.14 (4H, s, ArCH2O), 5.11 (2H, s, ArCH2O), 3.89 (3H, s, CO2CH3). |
100% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 24h; | A mixture of methyl gallate 9 (10 g, 53 mmol) and potassium carbonate (45 g, 320 mmol) in DMF (120 mL) was treated with benzyl bromide (210 mmol, 25.7 mL) and stirred at 40 C. under an argon atmosphere for 24 h. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in minimum amount of methylene chloride and diluted with an equal volume of hexanes and loaded onto a short silica gel pad in a sintered glass funnel. The silica was eluted with hexanes (300 mL) to remove excess benzyl bromide and the eluant discarded. The product was then eluted with methylene chloride: hexanes (1:1, 300 mL) followed by methylene chloride (500 mL) and the eluants combined and evaporated to afford pure benzyl product 10 as an off-white solid (100% yield). 1H NMR (300 MHz, CDCl3): delta 3.88 (s, 3H, CH3), 5.11 and 5.13 (2s, 6H, OCH2), 7.35-7.41 (m, 17H, Ar-H). [0119] To a solution of 3,4,5-tribenzyl-methyl gallate 10 (10 g, 22 mmol) in dry tetrahydrofuran (75 mL) was added solid lithium aluminum hydride (1.25 g, 33 mmol) in small portions. The suspension was heated to reflux under argon for 2 h. The reaction was cooled to 0 C. and carefully quenched with the dropwise addition of water. The slurry was then extracted with ethylacetate/hexanes. The organic solution was dried with saturated brine, followed by anhydrous magnesium sulfate, filtered and evaporated to afford the pure alcohol 11 as a white solid (8.9 g, 95% yield). 1H NMR (300 MHz, CDCl3): delta 4.6 (d, 2H, CH2), 5.04 and 5.11 (2s, 6H, OCH2), 6.67 (s, 2H, 2,6-Ar-H), 7.25-7.43 (m, 15H, Ar-H). [0120] To a solution of 3,4,5-tribenzyloxy-benzyl alcohol 11 (8.9 g, 21 mmol) in methylene chloride (200 mL) at 0 C. was added pyridinium chlorochromate (5.43 g, 25 mmol) in small portions with vigorous stirring. The cooling was discontinued and reaction stirred at room temperature for 4 h. The dark brown suspension was filtered over a long pad of silica gel in a sintered glass funnel, and eluted with methylene chloride, until all the pure product eluted out. The organic filtrate was evaporated down to give the pure product 12 as a soft white solid (8.1 g, 91.5% yield). 1H NMR (300 MHz, CDCl3): delta 5.16 (s, 6H, OCH2), 7.18 (s, 2H, 2,6-Ar-H), 7.26-7.41 (m, 15H, Ar-H), 9.80 (s, 1H, CHO). |
96% | With potassium carbonate; In acetone; for 24h;Heating / reflux; | Methyl 3,4,5-Tribenzyloxybenzoate. Benzyl bromide (10.6 mL, 89.7 mmol) was added to a solution of methyl 3,4,5-trihydroxybenzoate (5.0 g, 27 mmol) and potassium carbonate (oven dried, 12.4 g, 89.7 mmol) in 250 mL of acetone. This solution was heated to reflux under Ar for 24 h. The reaction mixture was cooled, treated with triethylamine (7.6 mL, 54 mmol), and extracted with EtOAc. The organic layer washed sequentially with 10% H2SO4, H2O, and brine, and dried over Na2SO4. After filtration and concentration, 11.8 g (96%) of methyl 3,4,5-tribenzyloxybenzoate was collected as an off white solid. |
95.4% | With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 60℃; for 4h;Large scale; | 3,4,5-trihydroxybenzoate (9.6 kg, 1.0 eq.) and DMF (76.8 liters) are charged to a reactor at 10-25 C. 2. To the reactor is charged K2C03 (25.1 kg, 3.5 eq.) at the same temperature. 3. Benzyl bromide (28.4 kg, 3.2 eq.) is then added slowly to the mixture at a temperature of from 20-45 C and the mixture aged at about 60 C for about 4 hours. 4. Analysis of the reaction mixture shows that 5. The solids are filtered off and the cake washed with DMF twice (1 vol.). 6. The filtered solution and wash is added to water (115 liters) at 5 C and the mixture stirred for 2 hours at 5-15 C. 7. The resulting mixture was filtered and the cake washed with water. 8. The isolated solid was dried for 12 hours under vacuum at 45 C to obtain the product (22.6 kg as an off-white solid. 9. In this alternate process IIIa-13-1-1 is obtained as an off-white solid with 99.4% purity in a 95.4% yield. |
94.2% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; | Step A: A solution containing methyl gallate (20.0g, 109mmol), potassium carbonate (90.1g, 652mmol), DMF (120mL), a mixture of benzyl (74.3g, 434mmol) bromide was stirred overnight at 40 ,After the addition of water (240 mL), EtOAc (EtOAc m. The solvent was distilled off under reduced pressure to give 3,4,5 - benzyloxy - benzoic acid methyl ester (68) (46.5g), yield 94.2%. |
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15h;Inert atmosphere; | To a stirred solution of methyl 3,4,5-trihydroxybenzoate 12 (0.94 g, 5.15 mmol) and potassium carbonate (6.56 g, 25.7 mmol)in DMF (20 mL), benzyl bromide (4.4 g, 25.7 mmol) was added. The reaction mixture was stirred at 60 C under N2 atmosphere. After 15 h, water was added, and the whole was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum to obtain methyl 3,4,5-tri(benzyloxy)benzoate 13 (1.93g, 90%). |
89% | With potassium carbonate; In N,N-dimethyl-formamide; for 6h; | Compound 2 (1 g, 5.43 mmol) was taken in dry DMF (60 mL) and was stirred in presence of K2CO3 (10 g , 54.34 mmol). Benzyl bromide (4 mL, 16.70 mmol) was added to the stirred solution and stirring was continued for 6h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with EtOAc and washed with water. The organic layer was then dried over anhydrous Na2SO4, and the solvent was evaporated to get the crude product, which was purified by column chromatography using using 5% EtOAc in petroleum ether as the eluent to get the pure product 3 as white powder (2.2 g, yield 89 %). 1H NMR (CDCl3, 400 MHz): 7.37-7.35 (m, 4H), 7.33-7.24 (m, 10H), 7.20-7.17 (m, 3H), 5.06 (s, 4H), 5.04 (s, 2H), 3.82 (s, 3H); FTIR (KBr, cm-1 ): 3411, 3044, 3031, 2948, 2878, 1715, 1589, 1499, 1453, 1110 and 754 cm-1 ; mp. 94C |
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h; | General procedure: Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86% yield)as white solid. This compound was used in the next stepreaction without further purification.Gallic acid (1.5 g,8.83 mmol) was dissolved in 9 cm3 methanol, conc.0.45 cm3 sulfuric acid was added thereto, and the mixturewas stirred under reflux for 5 h. The reaction vessel wascooled down to room temperature and the reaction mixturewas neutralized with saturated sodium bicarbonate solutionat 0 C. Then, the organic solvent was removed at reducedpressure, and the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated to give methyl1.39 g 3,4,5-trihydroxybenzoate (7.55 mmol, 86% yield)as white solid. This compound was used in the next stepreaction without further purification.A mixture of methyl 2.114 g 3,4,5-tris(benzyloxy)benzoate(4.66 mmol), sodium hydroxide (96 mmol), 6 cm3MeOH, and 12 cm3 dioxane was heated at reflux for 4 h.The solvent was removed and the resulting residue waspartitioned between water and ethyl acetate. The combinedorganic layers were washed with brine, dried (Na2SO4),and concentrated at reduced pressure to give the titlecompound (1.984 g, 4.51 mmol, 97% yield) as a whitesolid. Spectral data were in accordance with those previouslyreported |
With potassium carbonate; In acetone; | [00102] Scheme 1. Synthesis of the benzyloxybenzoyl chlorides 5 [00103] In terms of the core aromatic ring, pyrogallol 8 (present in 2a) and 3- methoxycatechol 6a (X = OMe, Y = H, present in la) were chosen. Two halogen substituted phenols, 6b (X = H, Y = CI) and 6c (X = F, Y = H) were chosen to provide a p-donor (similar to the methoxy group) but electron withdrawing group. An unsubstituted catechol 6d (X, Y = H) was included. As shown in Scheme 2, each of these phenols was then coupled to each of the acid chlorides 5a-f and several methoxy-substituted benzoyl chlorides. After coupling, the benzyloxy esters were deprotected via catalytic hydrogenation. The overall yields are shown in Table 2. | |
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 11h;Inert atmosphere; | To a solution of 8c (60.0 g, 0.318 mol) in MeOH (638 mL) was added SOCl2 (23.2 mL, 0.319 mol) fordropwise at 60 C. The reaction mixture was stirred at 60 C for 8 h. Then, the reaction mixture wasevaporated under reduced pressure. The crude mixture was applied to following reaction without furtherpurification.To a mixture of crude material (2.00 g, 10.9 mmol) and K2CO3 (6.78 g, 49.0 mmol) in DMF (36.0 mL)were added benzyl bromide (4.10 mL, 35.9 mmol) and TBAI (1.60 g, 4.33 mmol) at room temperature.The reaction mixture was stirred at room temperature for 11 h. Then, the reaction mixture was filteredthrough a pad of Celite, diluted with H2O, and extracted with CH2Cl2. The organic layer was washed withwater and brine, dried over anhydrous MgSO4, and evaporated under reduced pressure. The crude mixturewas applied to following reaction without further purification.To a stirred solution of crude residue in MeOH/THF (1/1, 36.3 mL) was added 4 M NaOH aq. (9.50 mL,38.0 mmol) at 80 C. The reaction mixture was stirred at 80 C for 1 h. Then, the reaction mixture wasquenched with 6 M HCl aq., and filtered. The filtrate was washed with H2O to give 9c (3.30 g, 7.49 mmol,68%) as a white solid.Spectral data for 9c were in good agreement with those reported in reference.16 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 96.0h;Inert atmosphere; | A solution of methyl gallate (20.0 g, 109 mmol), BnBr (14.2 mL, 119 mmol), KHC03 (32.4 g, 324 mmol) and KI (0.1 g, 0.60 mmol) in DMF (100 mL), is stirred during 4 days at room temperature. The reaction mixture is poured into 1 L of water and sulfuric acid is added until obtention of a neutral pH. The aqueous layer is then extracted 3 times with 150 mL of CH2C12. The combined organic layers are brought together, washed three times with 50 mL of brine, dried over MgS04, filtered and the volatiles are evaporated. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (98/2) to provide a yellow oil. The crude material was evaporated many times with dichloromethane. The obtained residue was filtered and washed petroleum ether to provide a white solid 28 in 70% yield. |
70% | With potassium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 30℃; for 96.0h; | A solution of methyl gallate (20.0 g, 108.6 mmol), benzyl bromide (14.2 mL, 119.0 mmol, 1.1 eq.), KHC03 (32.4 g, 324.0 mmol, 3.0 eq.) and KI (0.1 g, 0.60 mmol) in DMF (100 mL) was stirred during 4 days at 30C. The reaction mixture was poured into 1L of water and sulfuric acid was added until obtention of a neutral pH. The aqueous layer was then extracted 3 times with 150 mL of dichloromethane. The combined organic layers were brought together, washed three times with 50 mL of brine, dried over MgS04 and filtered. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (98/2) to provide an yellow oil. The crude material was evaporated many times with dichloromethane. The obtained residue was filtered and washed petroleum ether to provide compound 1 as a white solid in 70% yield. FontWeight="Bold" FontSize="10" H NMR (300 MHz, CD3OD-J) delta 7.52 (d, J = 7.5 Hz, 2H, Ar2-2,6-H), 7.31 (m, 3Eta, Ar2-3,4,5-H), 7.13 (s, 2Eta, Ar'-2,6-H), 5.18 (s, 2Eta, Ar2OCH2), 3.83 (s, 3Eta, COOCH3); 1 C NMR (75 MHz, CD3OD- d) delta 167.1, 150.5, 138.2, 137.2, 128.5, 128.0, 127.8, 125.0, 108.8, 73.8, 51.2. |
70% | With potassium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 96.0h; | A solution of methyl gallate (20.0 g, 109 mmol). BnBr (14.2 mL, 119 mmol), KHCO3 (32.4 g, 324 mmol) and KI (0.1 g, 0.60 mmol) in DMF (100 ml) was stirred for 4 days at room temperature. The reaction mixture was then poured into 1 L of water and sulfuric acid was added until neutral pH was obtained. The aqueous phase was then extracted 3 times with 150 ml of dichloromethane. The organic phases were combined, washed three times with 50 mL of brine, dried over MgSO4, filtered and the volatile substances were evaporated. The solvent was removed by evaporation and the residue was purified by silica gel chromatography, eluting with a CH2Cl2/MeOH mixture (98/2) to give a yellow oil. The residue was evaporated several times with dichloromethane. The residue obtained was filtered and washed with petroleum ether to give a white solid 34 in 70% yield. (0315) 1H NMR (300 MHz, CD3OD) delta 3.83 (s, 3H, COOCH3), 5.18 (s, 2H, Ar2OCH2), 7.13 (s, 2H, Ar1-2,6-H), 7.31 (m, 3H, Ar2-3,4,5-H), 7.52 (d, J=7.5 Hz, 2H, Ar2-2,6-H); 13C NMR (75 MHz, CD3OD) delta 51.2, 73.8, 108.8, 125.0, 127.8, 128.0, 128.5, 137.2, 138.2, 150.5, 167.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With borax; sodium hydroxide In water | |
79% | Stage #1: methyl galloate With borax In water for 1h; Stage #2: With sodium hydroxide In water for 0.166667h; Stage #3: dimethyl sulfate In water for 15h; | 1.2 Step 2) Step 2) Methyl 3,4,5-trihydroxybenzoate(50.0g, 270mmol) prepared in Step 1 and borax(54.0g, 140mmol) were dissolved in distilled water(1litre) and the mixture was stirred for 1 hour. To this solution was added sodium hydroxide(13g, 330mmol) dissolved in distilled water(100mlitre), and the resulting mixture was stirred for 10minutes. Dimethylsulfate(135mlitre, 370mmol) was added and the mixture was stirred again for 15 hours. The reaction solution was neutralized to pH 7-8 using conc. sulfuric acid, extracted with ethyl acetate and then subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane, 1/2, v/v) to give methyl 3,4-dihydroxy-5-methoxybenzoate(42.5g, Yield 79%) as a white solid. 1H NMR (300MHz, CDCl3): δ 3.81(s, 3H), 3.85(s, 3H), 5.70(bs, 2H), 7.15(d, 1H, J = 1.7Hz), 7.31(d, 1H, J = 1.7Hz) |
79% | Stage #1: methyl galloate With borax In water at 20℃; for 1h; Stage #2: With sodium hydroxide In water for 0.166667h; Stage #3: dimethyl sulfate In water for 15h; | Synthesis of methyl 3,4-dihydroxy-5-methoxybenzoate (5) Methyl 3,4,5-trihydroxybenzoate (50 g, 270 mmol) (2) and borax (54 g, 140 mmol) were dissolved in distilled water (1L) and stirred at room temperature for 1 hour. A solution of 13% NaOH was added and the solution was stirred for 10 minutes followed by addition of dimethylsulfate (135 ml, 370 mmol) and further stirred for 15 hours. The reaction was neutralized to pH 7-8 using 10% sulfuric acid, extracted with ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford compound 5 as a crude brown solid which was subjected to purification through column chromatography using petroleum ether (40-60): EtOAc 70:30 as mobile phase to |
79% | Stage #1: methyl galloate With borax In water at 20℃; for 1h; Stage #2: dimethyl sulfate With sodium hydroxide for 15h; | 2.1.2. synthesis of methyl 3,4-dihydroxy-5-methoxybenzoate (3) methyl 3,4,5-trihydroxybenzoate (50 g, 270 mmol) (2) and borax(54 g, 140 mmol) were dissolved in distilled water (1 L) and stirred at room temperature for 1 h. A solution of 13% NaOH was added and the solution was stirred for 10 min followed by addition of dimethylsulfate(135 mL, 370 mmol) and further stirred for 15 h. The reaction was neutralized to pH 7-8 using 10% sulfuric acid, extracted with ethylacetate, dried (Na2SO4) and evaporated in vacuo to afford compound 3 as a crude brown solid which was subjected to purification through column chromatography using petroleum ether (40-60): EtOAc 70:30as mobile phase to obtain methyl 3,4-dihydroxy-5-methoxybenzoate(42.5 g, yield 79%) as a white solid m.p. 112 °C [lit. (Pettit and Singh,1987) 110-111 °C]. |
73% | With borax; sodium hydroxide for 6h; | |
73% | Stage #1: methyl galloate With borax; sodium tetraborate decahydrate In water at 20℃; for 1h; Stage #2: dimethyl sulfate With sodium hydroxide In water at 20℃; for 12h; | |
72% | Stage #1: methyl galloate With sodium tetraborate decahydrate In ethanol; water for 1h; Stage #2: dimethyl sulfate With potassium carbonate In ethanol; water at 20℃; Stage #3: With hydrogenchloride; water In ethanol | |
65% | Stage #1: methyl galloate With sodium tetraborate decahydrate In water at 20℃; for 1h; Stage #2: dimethyl sulfate With sodium hydroxide In water at 20℃; for 24h; Stage #3: With sulfuric acid In water | |
47% | With borax; sodium hydroxide In water at 20℃; for 6h; | 10 To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0° C. The mixture was acidified to pH 2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification. |
47% | With borax; sodium hydroxide In water at 20℃; for 6h; | 10 3,4-Dihydroxy-5-methoxybenzoate To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0° C. The mixture was acidified to pH˜2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL*3). The combined organic layers were dried over anhydrous Na2SO4and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification. |
2.5 g | With borax; sodium hydroxide | |
With borax | ||
With borax; sulfuric acid | ||
With borax; sodium hydroxide In water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; | 6 Synthesis of Methyl 3,4,5-tri(octadecyloxy)benzoate 1-Bromooctadecane (64.0 g, 192 mmol), potassium carbonate (79.6 g, 576 mmol), 3,4,5-trihydroxymethylbenzoate (11.0 g, 60.0 mmol) were dissolved in N,N-dimethylformamide (600 mL), and the mixture was stirred at 90° C. for 16 hr. Completion of the reaction was confirmed by thin layer chromatography (hexane/dichloromethane (volume ratio)=2/1 and dichloromethane/methanol (volume ratio)=9/1), the reaction solution was poured into water (2.00 L), and the solid was precipitated, filtered and dried. The dry solid was dissolved in dichloromethane (500 mL), acetonitrile (1.50 L) was added to precipitate a solid. The solid was collected by filtration, and dried to give the object compound (56.7 g, 100%). 1H-NMR (400 MHz, CDCl3): δ=0.88 (t, 9H, J=6.8 Hz, -OCH2(CH2)16CH3), 1.21-1.51 (m, 90H, -O-CH2CH2 (CH2)15CH3) 1.70-, 6H, -O-CH2-CH2-(CH2)15-CH3), 3.89 (s, 3H, C(O)OCH3), 3.99-4.03 (m, 6H, Ar-OCH2), 4.99 (s, 2H, Ar-H), 7.25 (s, 2H, Ar-H) |
98% | With potassium carbonate In dimethyl sulfoxide; toluene at 60℃; for 24h; | |
98% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h; |
91% | With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 24h; | |
90% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; for 12h; | |
90% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; for 12h; | 1 Methyl 3,4,5-tris(octadecyloxy)benzoate (Compound 2a) was prepared according to the following general procedure, designated general procedure A. To a stirredsolution of methyl 3,4,5-trihydroxybenzoate Ia (5 g, 27.0 mmol) and 1-bromooctadecane (32.6 g, 97.8 mmol) in DMF (100 mL) was added K2C03 (14.9 g,108.0 mmol) and KI (0.45 g, 2.7 mmol) and the resulting mixture stirred at 90 °C for12h. The reaction mixture was cooled, diluted with CHCI3 (200 mL), washed withH20 (3 x 50 mL), dried over anhydrous Mg504, filtered and the filtrate concentratedunder reduced pressure. The residue was redissolved in smallest possible amountof warm CHCI3 and mixed with MeOH to induce the precipitation. The precipitate was collected by filtration and dried. The precipitation was repeated to obtain analytically pure methyl 3,4,5-tris(octadecyloxy)benzoate 2a (22.8 g, 90 %). White solid. 1H NMR (CDCI3) ö 7.25 (5, 2H), 4.06 - 3.96 (m, 6H), 3.88 (5, 3H), 1.86 - 1.78(m, 4H), 1.78 - 1 .70 (m, 2H), 1.53 - 1.43 (m, 6H), 1.35 - 1.23 (m, 84H), 0.88 (t, J =6.9 Hz, 9H); 130 NMR (CDCI3) ö 167.07, 152.96, 142.52, 124.79, 108.13, 73.62,69.31, 52.22, 32.09, 30.49, 29.92, 29.90, 29.88, 29.83, 29.80, 29.73, 29.56, 29.53,29.47, 26.24, 26.22, 22.85, 14.27. |
78% | With tetrabutylammomium bromide; potassium carbonate In acetone for 48h; Inert atmosphere; Reflux; | |
76% | With potassium carbonate; potassium iodide In acetone at 70℃; for 48h; | 4.2.1. Methyl 3,4,5-tris(octadecyloxy)benzoate (13) K2CO3 (54.0 g, 0.391 mol), 1-bromooctadecane (43.5 g, 0.130 mol), and potassium iodide (195 mg, 1.17 mmol) were added to a solution of methyl gallate (12) (8.0 g, 0.0434 mol) in dehydrated acetone (310 mL) at room temperature, and the reaction mixture was then warmed to 70 °C. After stirring for 48 h, the reaction mixture was cooled to room temperature and concentrated. The crude residue was then dissolved into CH2Cl2 (2.3 L) and washed with H2O (2.3 L). The organic layer was concentrated and redissolved into CH2Cl2 (400 mL), which was then recrystallized by the addition of EtOH (800 mL) to furnish pure 13 as a colorless powder (30.7 g, 76%). All physical data for 13 matched with the data in Tamiaki’s paper. |
72.1% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h; | |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 5h; | ||
In N,N-dimethyl-formamide at 100℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 5h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 17h; | ||
With desipramine; potassium carbonate | ||
With potassium carbonate In ethanol Reflux; | ||
48 g | Stage #1: methyl galloate With potassium carbonate at 80℃; for 0.5h; Stage #2: 1-Bromooctadecane at 80℃; for 12h; | 1.1 (1) Methyl benzoate substituted with three octadecyloxy groups (compound (E1)) [To methyl gallate (9.2 g) and potassium carbonate (103.7 g), 1,3-dimethyl-2-imidazolidinone (170 mL) wasadded, and the mixture was stirred at 80°C for 30 minutes. 1-Bromooctadecane (69.1 mL) was added thereto, and themixture was stirred at 80°C for 12 hours. 40°C hot water was added to the reaction liquid for suspension, then theprecipitate was collected by suction filtration, and then the obtained solid was washed with acetonitrile, acetone, andmethanol to quantitatively obtain the compound represented by E1 (48.0 g). 1H NMR (500 MHz, CDCl3) δ 7.25 (s, 2H), 3.99-4.03 (m, 6 H), 3.89 (s, 3 H), 1.78-1.84 (m, 4H), 1.71-1.77 (m,2H), 1.44-1.50 (m, 6H), 1.20-1.38 (m, 84H), 0.88 (t, J = 7.0 Hz, 9H) |
With potassium carbonate; potassium iodide In acetone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 90℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5h; | A mixture of methyl 3,4,5-trihydroxybenzoate (1.03 g, 5.59 mmol), 7 (11.4 g, 16.8 mmol), and K2CO3 (6.95 g, 50.3 mmol) was stirred in DMF (80 mL) for 5 h at 70 C. After the reaction mixture was poured into water, the resulting precipitate was collected by filtration and subjected to column chromatography (SiO2, CHCl3) to afford the product ester (10.7 g, 91%) as a colorless solid. 1H NMR (270 MHz, CDCl3) δ 0.88 (t, J=6.6 Hz, 27H, CH3), 1.17-1.52 (m, 162H), 1.62-1.82 (m, 18H), 3.75 (t, J=6.6 Hz, 4H, -OCH2-), 3.88 (s, 3H, -OCH3), 3.88 (t, J=6.6 Hz, 10H, -OCH2-), 3.93 (t, J=6.6 Hz, 4H, -OCH2-), 5.03 (s, 4H, ArCH2OR), 5.04 (s, 2H, ArCH2OR), 6.60 (s, 2H, ArH), 6.63 (s, 4H), 7.38 (s, 2H, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In various solvent(s) for 84h; Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate; potassium iodide In acetone for 48h; Heating; |
With potassium carbonate In N,N-dimethyl-formamide Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In propan-2-one for 1h; | |
94.4% | With potassium carbonate In acetonitrile for 48h; Reflux; | 2.1 4.2.1 Synthesis of 3,4,5-trimethoxybenzoic acid methyl ester (3)10 To a solution of methyl gallate 2 (2.95 g, 16.0 mmol) in CH3CN (120 ml) were added K2CO3 (19.2 g, 0.139 mol) and Me2SO4 (6.59 g, 52.2 mmol) and refluxed for 48 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was extracted with chloroform and water. After drying over anhyd Na2SO4, the organic layer was concentrated to give a yellow solid. The crude product was purified by column chromatography (silica gel, chloroform) to obtain 3 (3.41 g, 15.1 mmol, 94.4%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.31 (s, 2H), 3.92 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 166.66, 152.83, 141.94, 125.07, 106.59, 60.87, 56.14, 52.20. IR (KBr) cm-1: 3019.01, 2952.48, 2839.67, 1715.37, 1591.95, 1508.06, 1466.6, 1433.82, 1413.57, 1338.36, 1259.29, 1228.43, 1181.19, 1131.05, 993.16, 897.70, 864.92, 761.74, 736.67, 671.11, 440.66. Mp 85-86 °C (lit. 85 °C). 10b |
94.4% | With potassium carbonate In acetonitrile for 48h; Reflux; | 2.1 4.2.1 Synthesis of 3,4,5-trimethoxybenzoic acid methyl ester (3) 10 To a solution of methyl gallate 2 (2.95 g, 16.0 mmol) in CH3CN (120 ml) were added K2CO3 (19.2 g, 0.139 mol) and Me2SO4 (6.59 g, 52.2 mmol) and refluxed for 48 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was extracted with chloroform and water. After drying over anhyd Na2SO4, the organic layer was concentrated to give a yellow solid. The crude product was purified by column chromatography (silica gel, chloroform) to obtain 3 (3.41 g, 15.1 mmol, 94.4%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.31 (s, 2H), 3.92 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 166.66, 152.83, 141.94, 125.07, 106.59, 60.87, 56.14, 52.20. IR (KBr) cm-1: 3019.01, 2952.48, 2839.67, 1715.37, 1591.95, 1508.06, 1466.6, 1433.82, 1413.57, 1338.36, 1259.29, 1228.43, 1181.19, 1131.05, 993.16, 897.70, 864.92, 761.74, 736.67, 671.11, 440.66. Mp 85-86 °C (lit. 85 °C). 10b |
81% | With potassium carbonate In propan-2-one for 0.25h; microwave irradiation; | |
62.4% | With potassium carbonate In propan-2-one for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N,N,N-tributyl-1-butanaminium iodide; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 144h; Inert atmosphere; | |
69% | With Cs2CO3; sodium iodide In acetone at 65℃; | 4.1.1. Methyl 3,4,5-tris[2-(Boc-amino)-1-ethoxy]benzoate (2) A mixture of methyl 3,4,5-trihydroxybenzoate 1 (250 mg, 1.35 mmol), Cs2CO3 (1.75 g, 5.4 mmol),NaI (203 mg, 1.35 mmol) and 2-(Boc-amino)ethyl bromide (1.2 g, 5.4 mmol) in acetone (10 mL) wasrefluxed overnight at 65 °C and then evaporated to dryness. The residue was dissolved in ethyl acetate(20 mL) and washed with aqueous solutions of citric acid (10%) (3 20 mL) and brine (2 20 mL).The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residuewas purified on a Biotage HPFC (high performance flash chromotography) purification system ina reverse phase using water/acetonitrile (100:0 to 0:100) to afford 576 mg (69%) of 2 as a yellow foam.1H NMR (400 MHz, DMSO-d6) 7.20 (s, 2H, Ar), 6.96 (t, J = 5.7 Hz, 2H, NHCO), 6.63 (t, J = 5.7 Hz,1H, NHCO), 4.01 (t, J = 5.7 Hz, 4H, CH2O), 3.96 (t, J = 5.9 Hz, 2H, CH2O), 3.83 (s, 3H, CH3O),3.35 (m, 4H, CH2NH), 3.22 (m, 2H, CH2NH), 1.35 (s, 18H, Boc), 1.36 (s, 9H, Boc). HPLC (tR) [gradient:A:B, 10-100% of A in 10 min]: 9.54 min. |
52% | With potassium carbonate In N,N-dimethyl-formamide |
44% | With Cs2CO3 In acetonitrile at 80℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 74℃; for 4h; | |
81% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 18h; Inert atmosphere; | 5 Synthesis of Methyl 3,4,5-tris[3,4,5-tri(octadecyloxy)benzyloxy]benzoate Under an argon atmosphere, potassium carbonate (1.39 g, 10.1 mmol), methyl 3,5-hydroxybenzoate (181 mg, 1.00 mmol), 3,4,5-tri(octadecyloxy)benzylchloride (2.81 g, 3.01 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was stirred at 70° C. for 18 hr. Completion of the reaction was confirmed by thin layer chromatography, the reaction solution was poured into water (50 mL) to allow for precipitation to give a solid. The obtained solid was dissolved in dichloromethane (50 mL), and the solid was precipitated with acetonitrile (200 mL), collected by filtration, and dried to give a crude product of the object product. The obtained crude product was purified by silica gel column chromatography (dichloromethane/hexane (volume ratio)=1/2-1/1) to give the object compound (2.31 g, 81%). 1H-NMR (400 MHz, CDCl3): δ=0.88 (t, 9H, J=7.0 Hz, -O(CH2)17CH3), 1.25-1.74 (m, 291H, -OCH2 (CH2+N5-CH3)16CH3), 3.75 (m, 6H, -OCH2(CH2)16CH3), 3.90 (s, 3H, -C(O)OCH3), 3.86-3.94 (2m, 12H, -OCH2(CH2)16CH3), 5.02 (s, 6H, 3*-H2C-Ar), 6.59 (s, 2H, Ar-H), 6.62 (s, 4H, Ar-H), 7.38 (s, 2H, Ar-H) |
80.5% | With potassium carbonate In water; N,N-dimethyl-formamide; acetonitrile | R.7.1 (1) (1) Synthesis of methyl {3,4,5-tris[3,4,5-tris(octadecyloxy) Under an argon atmosphere, methyl gallate (182 mg, 1.00 mmol), 3,4,5-tris(octadecyloxy)benzyl chloride (2.81 g, 3.01 mmol) and potassium carbonate (1.39 g, 10.1 mmol) were added to dehydrating N,N-dimethylformamide (20 mL), and the mixture was stirred at 70° C. overnight. The reaction mixture was allowed to cool to room temperature, purified water (50 mL) was added, and the precipitated solid was collected by filtration. The obtained solid was slurry-washed in acetonitrile and filtered, and the obtained solid was purified by silica gel column chromatography (dichloromethane-hexane) to give the title compound (2.31 g, 80.5%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: methyl galloate With potassium carbonate at 80℃; for 0.5h; Stage #2: hexadecanyl bromide at 80℃; for 14h; | 6.1 (1) Synthesis of methyl benzoate substituted with three hexadecyloxy groups (compound (E35)) To methyl gallate (5.5 g) and potassium carbonate (62.2 g), 1,3-dimethyl-2-imidazolidinone (100 mL) wasadded, and the mixture was stirred at 80°C for 30 minutes. 1-Bromohexadecane (30.2 mL) was added thereto, and themixture was stirred at 80°C for 14 hours. Water (300 mL) was added to the reaction liquid for suspension, then theprecipitate was collected by suction filtration, and the obtained solid was washed with an aqueous solution of acetone(1:1). The obtained white solid was dissolved in dichloromethane (500 mL), methanol was added thereto, and theprecipitated solid was collected by suction filtration to obtain the compound represented by E35 (24.2 g, percent yield:94%). 1H NMR (500 MHz, CDCl3) δ 7.25 (2 H, s), 3.99-4.03 (6 H, m), 3.89 (3 H, s, COOMe), 1.71-1.84 (6 H, m),1.44-1.50 (6 H, m), 1.23-1.38 (72 H, br), 0.88 (9 H,t J = 7.0 Hz). |
88.3% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; | 9.1 1) Synthesis of methyl 3,4,5-tris(hexadecyloxy)benzoate Methyl gallate (5.00 g, 27.17 mmol), potassium carbonate (38 g, 275.5 mmol), potassium iodide (0.45 g, 2.71 mmol) in a 250 mL three-necked flask were weighed separately.120 mL of N,N-dimethylformamide and 27 mL of bromododecane were added. The system was reacted at 70 ° C for 24 h under N2 protection.After the TLC monitoring reaction was completed, it was cooled to room temperature. The filtrate obtained by suction filtration was washed with water and extracted with ethyl acetate.The crude product was purified on a silica gel column and then recrystallized from ethanol to give a white solid product.According to the test,The above white solid was methyl 3,4,5-tris(hexadecyloxy)benzoate in a yield of 88.3%. |
85% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 24h; Heating; |
78% | Stage #1: methyl galloate With potassium carbonate; potassium iodide In acetone at 60℃; for 2h; Stage #2: hexadecanyl bromide In acetone for 72h; Reflux; | 1 Synthesis of methyl 3,4,5-tris (hexadecyloxy) benzoate 0.92 g (5.0 mmol) of methyl gallate, 4.2 g (30.0 mmol) of anhydrous K2CO3, 1.20 g (7.0 mmol) of KI and 30 mL of acetone were added, heated to 60 ° C, refluxed for 2 h, and then 5.49 g (18.0 mmol) of 1-bromooctadecane was slowly added dropwise thereto and refluxed for 72 h.After completion of the reaction, the acetone was evaporated to dryness and CHCl was added3Extracted three times, filtered, the filtrate was washed once with distilled water, washed twice with 2% NaOH solution and then washed three times with saturated NaCl solution, and finally washed with anhydrous Na2SO4Dry, steamed to remove CHCl3To give the product 3,4,5-tris (hexadecyloxy) benzoate, yield: 3.34 g, yield 78%. |
75% | With 18-crown-6 ether; potassium carbonate; potassium iodide In acetone | |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 5h; | ||
With potassium carbonate In N,N-dimethyl-formamide Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate; potassium iodide In acetone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 65℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 17h; | ||
With potassium carbonate In acetone | ||
With potassium carbonate | ||
Stage #1: methyl galloate With potassium carbonate; potassium iodide In acetone for 0.5h; Reflux; Stage #2: hexadecanyl bromide In acetone for 48h; Reflux; | 4.2.3. Methyl-3,4,5-tris(dodecyloxy)benzoate (n=12). General procedure: The solutionof methyl-3,4,5-trihydroxybenzoate (10.0 g, 54.3 mmol), K2CO3(44.4 g, 325.8 mmol), and catalyst amount KI dissolved in 300 mL anhydrous acetone was mixed and the solution was then refluxed for 30 min. To this solution, 1-bromododecane (49.8 g,168.3mmol) was added and then refluxed for further 48 h. The solids were filtered offand the filtrate was concentrated to dryness. The product isolated as white powder was obtained after recrystallization from acetone/MeOH. Yield 95%. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=6.90 Hz,-CH3, 9H), 1.24-1.60 (m, -CH2, 54H), 1.67-1.83(m, -CH2, 6H), 3.86(s, -OCH3, 3H), 3.86-4.01 (m, -OCH2, 6H), 7.23 (s, Ar-H, 2H). 13C NMR (75MHz,CDCl3): δ 14.09, 22.67, 26.05, 29.28, 29.37, 29.62, 29.68,30.30, 31.91, 52.06, 69.12, 73.45,107.93,124.61,142.32,152.79,166.92. | |
With potassium carbonate In N,N-dimethyl-formamide Reflux; | ||
With potassium carbonate; potassium iodide In butanone for 72h; Reflux; | ||
With potassium carbonate In ethanol Reflux; | ||
With potassium carbonate; potassium iodide In acetone Reflux; | ||
With potassium carbonate; potassium iodide In butanone Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With phosphorus trichloride In toluene at 20℃; Reflux; | 4.1 Methyl 7-hydroxy-2,2-dimethylbenzo[d][1,3]dioxole-5-carboxylate (2a) To a suspension of the gallic acid methyl ester 1 (5.20 g, 28.2 mmol) in a mixture of toluene (20 mL) and acetone (13 mL), PCl3 (1.90 mL, 21.7 mmol) was added and the mixture was left stirring at room temperature overnight. The mixture was then quenched carefully with saturated aqueous NaHCO3 and the phases were separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with water and dried over MgSO4. After filtration, the solvent was removed under reduced pressure giving the title compound as an off-white solid (4.60 g, 73 % yield) that was used without any further purification. Mp 116-117°C (lit. [31] 114-115°C). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J =1.6Hz, 1H), 7.05 (d, J =1.5Hz, 1H), 3.87 (s, 3H), 1.70 (s, 6H). 13C NMR (100.6 MHz, CDCl3) δ 167.33, 148.59, 139.26, 138.71, 123.43, 120.29, 113.74, 103.21, 52.41, 25.97. Anal. calcd for C11H12O5: C, 58.93; H, 5.39; found: C, 59.05; H, 5.42. |
40% | With phosphorus pentoxide at 22℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | With Amberlyst 15E In benzene for 18h; Heating; | |
95% | In benzene for 16h; Reflux; Acidic conditions; | |
95% | With amberlyst15 In benzene for 48h; Reflux; Dean-Stark; |
91% | With Amberlyst-15 In toluene for 18h; Dean-Stark; Reflux; | |
89.9% | With Amberlyst 15 In benzene for 18h; Reflux; | |
88% | With Amberlyst-15(H) In toluene for 18h; Inert atmosphere; Reflux; | |
88% | With Amberlyst-15(H) In toluene for 18h; Dean-Stark; Reflux; | |
87% | With amberlyst-15(H) In toluene for 6h; Reflux; | |
79% | With Amberlyst 15 In benzene for 72h; Reflux; Inert atmosphere; Dean-Stark; | Methyl 2-ethoxy-7-hydroxybenzo[d][1,3]dioxole-5-carboxylate (16) Methyl gallate (8) (5.00 g, 27.1 mmol), ethyl orthoformate (13.4 mL, 81.3 mmol) and Amberlyst 15 ion-exchange resin (anhydrous) (150 mg) in benzene (400 mL) were refluxed for three days under a nitrogen atmosphere. During the reaction, solvent were reduced by a Dean-Stark apparatus until the solvent volume became a half of that of the starting condition. Amberlyst was removed and after solvent were evaporated. The residue was recrystallized from ethyl acetate-hexane mixture to give 5.13 g (79%) of 16 as white solid: 1H-NMR (400 MHz, CDCl3): δ 1.28 (3H, t, J = 7.1 Hz), 3.76 (2H, q, J = 7.1 Hz), 3.87 (3H ,s), 5.22 (1H, brs), 6.95 (1H, s), 7.20 (1H, d, J = 1.6 Hz), 7.34 (1H, d, J = 1.6 Hz); 13C-NMR (100 MHz, CDCl3): δ 14.69, 52.41, 59.68, 102.58, 114.01, 119.97, 123.86, 137.15, 138.82, 147.13, 167.13. |
62% | With amberlite IR 120 In toluene for 6.5h; Molecular sieve; Reflux; | |
61% | With toluene-4-sulfonic acid In toluene for 20h; Reflux; | Synthesis of compound 2 A mixture of gallic acid methyl ester 1 (2.50 g, 13.6 mmol), p-toluenesulfonic acid (2.34 g, 13.6 mmol) and triethyl orthoformate (6.03 g, 40.7 mmol) in 100 mL of toluene was refluxed for 20 h. After the reaction was completed, solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to afford compound 2 (2.0 g, yield 61%). |
61.3% | With toluene-4-sulfonic acid In toluene for 20h; Reflux; | 1.1 The synthetic route is as follows: (1) Methyl gallate (2·5g, 13.58mmol), p-Toluenesulfonic acid (2·336g, 13.58mmol) and triethyl orthoformate (6.03g, 40.74mmol) were dissolved in 100mL of toluene solution, heated to reflux, the reaction was completely monitored by TLC after 20 hours. The solvent was distilled off under reduced pressure, directly subjected to column chromatography, obtained transparent viscous liquid compound 3a (2.00g, yield 61.3%). |
57% | With Amberline-120 resin at 130℃; for 18h; | |
56% | With camphor-10-sulfonic acid In benzene at 90℃; for 6h; Inert atmosphere; | 2.b-1.ii Synthesis of Compound 3 Compound 2 (9.573 g, 52.02 mmol) and 10-camphorsulfonic acid (1.208 g, 5.202 mmol) were placed in an eggplant-shaped flask and sufficiently dried with a vacuum pump and then replaced with N 2 gas. 100 mL benzene and triethyl orthoformate (24.6 mL, 156.08 mmol) were added with a syringe. Thereafter, the reaction solution was refluxed under N 2 gas at 90 ° C. for 6 hours. After the reaction, filtration was carried out with Celite packed in the column, and elution was carried out with dimethyl chloride. The eluate was concentrated to dryness and then purified by silica gel column chromatography (developing solvent 5: 1 to 4: 1 hexane / ethyl acetate). The fraction containing the target product was recovered and concentrated to obtain an orthoester compound 3 (yield: 6.537 g, yield: 56%). |
With Amberlist 15E | 1.a Example 1 Example 1 [0046] Preparation method of nitrogen-containing biphenyl compound of the present invention can be generally summarized as follows: [0047] Compound 3 (0.1 mmol) and Compound 4 (0.2-0.5 mmol) were put in a 25 mL round-bottomed flask, followed by addition of Pd(OAc)2 (0.01-0.05 mmol), Bu4NBr (0.15 mmol), K2CO3 (0.3 mmol) and 3 mL THF-H2O (VTHF/VH2O=1). The mixture was heated to 70° C. and the reaction was carried out for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column to give compounds 5-8 in Example 2-5. [0048] Compound 4 is purchased from Acros or Sigma-Aldrich Company. [0049] Compound 3 is obtained by the following synthetic route: [0050] (a) Synthesis of Bromo Compound 3: [0051] Bromo Compound 3 was synthesized using gallic acid as a starting material, through esterification of carboxyl group, etherification of phenolic hydroxyl group, bromination of benzene ring, removal of benzyl protecting group, and final methyl etherification. [0052] (b) Synthesis of Iodo Compound 3: [0053] Iodo Compound 3 was synthesized using one intermediate compound obtained during the synthesis of bromo Compound 3 as a starting material, through removal of benzyl protecting group, methyl etherification, nitration of benzene ring, reduction of nitro group into amino group, and final Sandmeyer reaction (amino group was firstly converted to a diazonium salt in the presence of concentrated HCl+NaNO2, and then, after the addition of an aqueous solution of KI, the iodo compound was obtained). | |
With Armberlyst In toluene Reflux; | 19.A Example 19: Synthesis of 3,5,7-Trihydroxy-2-[3-hydroxy-4-methoxy-5-(5-methoxy-pyridin-2-ylmethoxy)phenyl]chroman- 4-ketone (57) Step A:Will contain methyl gallate (34.0g, 185mmol),Triethyl orthoformate (50.0 g, 337 mmol),A mixture of Armberlyst (2.2 g) and toluene (350 mL) was slowly stirred under reflux overnight in a reaction flask equipped with a water separator. During the reaction,Approximately 200 mL of solvent was dispensed. Cool to room temperature,The insoluble matter was removed by filtration through celite. Evaporate the solvent under reduced pressure.GotMethyl 2-ethoxy-7-hydroxy-benzo[1,3]dioxol-5-carboxylate (46) crude (60 g). This compound was used in the next reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 35℃; | 1 Example 1. Exemplary Benzoic Acid Syntheses While certain benzoic acids are commercially available, others may be synthesized using an esterification, etherification, and deprotection sequence as shown below. |
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate; potassium iodide In acetone for 48h; Heating; |
With potassium carbonate In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; Inert atmosphere; | |
88% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | |
77% | With potassium carbonate In acetone for 48h; Inert atmosphere; Reflux; |
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: methyl galloate With Cs2CO3 In 1,4-dioxane at 20℃; for 0.25h; Stage #2: iodomethane In 1,4-dioxane at 0 - 20℃; for 11h; | 1.1; 2.1; 3.1 General procedure: At room temperature, cesium carbonate (7.82 g, 1.2 equiv, 24 mmol) was added to a solution of methyl gallate (3.68 g, 1.0 equiv, 20 mmol) in 50 mL of 1,4-dioxane, and the mixture was stirred at room temperature for 15 min. The reaction flask was placed in an ice bath, and then iodomethane (1.25 mL, 1.0 equiv, 20 mmol) was slowly added dropwise to the reaction flask,After that, the reaction was naturally heated for 10 hours, and TLC showed that the reaction was complete.The cesium carbonate was removed by filtration through celite under reduced pressure. The resulting filtrate was concentrated under reduced pressure and then purified on a silica gel column (eluting gradient petroleum ether/ethyl acetate (v/v) 10/1-3/1),3.01 g of pure para-methylated methyl gallate was obtained (pale yellow oily transparent liquid, yield 76%). |
76% | Stage #1: methyl galloate With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 24h; | |
59.9% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 16h; Sealed tube; | 1 Embodiment 1:3, 5 - dihydroxy -4 - methoxybenzoic acid methyl ester (A - 12) synthesis of In 250 ml thick-walled glass sealing tube, the gallic acid methyl formate (A - 11) (90.0g, 0 . 49 µM) dissolved in 200 ml DMF, adding potassium carbonate (87.0g, 0 . 63 µM), iodomethane (69.0g, 0 . 49 µM), 40 °C stirring 16 hours, TLC detection after the reaction, by adding 150 ml water, for HCl (2 mol/L) in and to PH=4, the ethyl acetate extract (4 × 100 ml), the combined organic phase, saturated salt water (2 × 100 ml), dried with anhydrous sodium sulfate, concentrated, column chromatography (petroleum ether: ethyl acetate=10:1) to obtain white solid 58.0g, yield: 59.9%. |
58% | Stage #1: methyl galloate With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1h; Stage #2: iodomethane at 0 - 20℃; for 24.5h; | |
57% | With lithium carbonate In N,N-dimethyl-formamide | |
51.9% | Stage #1: methyl galloate With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 24.5h; Cooling with ice; | 16 methyl 3,5-dihydroxy-4-methoxybenzoate First, potassium carbonate (4.50 g, 32.6 mmol) was added to a dimethylformamide (DMF) solution (45 mL) with a methyl gallate (5.00 g, 27.2 mmol), and the solution was stirred for one hour at 85° C. Then, methyl iodide (4.00 g, 28.2 mmol) was gradually dropped and stirred for 30 minutes in an ice bath, and further stirred for 24 hours at room temperature. Reaction liquid was filtered, purified water was added, and extraction was performed with ethyl acetate. The separated ethyl acetate layer was washed with saturated saline and dehydrated by sodium sulfate. [0065] After concentration, the extract liquid was purified by silica gel column chromatography (solvent: chloroform→chloroform-ethyl acetate (3:1, v/v)) and obtained 4-methoxy form of 2.79 g (yield: 51.9%). |
40.92% | Stage #1: methyl galloate With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 24.5h; Cooling; | Next, in the container, a reducing agent is added to a solution of methyl gallate, for example, dimethylformamide or N, N-dimethylformamide, followed by stirring at about 85 ° C. for about 1 hour.Here, as the reducing agent, potassium carbonate can be mentioned. In this example, potassium carbonate (4.50 g, 32.6 mmol) was added to a dimethylformamide solution of methyl gallate (5.00 g, 27.2 mmol), and the mixture was stirred at about 85 ° C. for about 1 hour.Thereafter, the vessel is kept in a cooled state at about 0 ° C. by ice-bathing or the like, and methyl iodide (1.7 ml) is gradually added dropwise while stirring for about 30 minutes in that state, and then further stirred at room temperature for about 24 hours And reacted with stirring.Here, regarding the dropwise addition of methyl iodide, it is assumed that it is dropped little by little over time.Next, the reaction solution is filtered, purified water is added thereto, and stirring is performed by adding ethyl acetate and shaking in the vertical direction.then, it is separated into an aqueous layer and an ethyl acetate layer in a container. Clearly separate from the ethyl acetate layer on the upper side and the water layer on the lower side. Remove the water layer portion separated on the lower side and remove only the ethyl acetate layer in the container.Then, the solution of the ethyl acetate layer is washed by adding, for example, saturated saline solution to the solution having only the ethyl acetate layer. That is, saturated saline is added to remove impurities such as sulfuric acid dissolved in water and water. After that, it is dried by removing moisture with sodium sulfate, and it is concentrated. As a substitute for sodium sulfate, CaCl 2, MgSO 4, CaSO 4, Na 2 SO 4 or the like may be used. Further, the concentrated concentrate is filtered through a filter such as silica gel column chromatography(Solvent: chloroform or chloroform-ethyl acetate (3: 1, v / v)) to obtain the methoxy form at the 4-position of gallic acid, propyl gallate or methyl gallate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 15h; Inert atmosphere; | |
93% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 20h; | |
78% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 27h; Inert atmosphere; | 7 Methyl 3,4,5-tris(2-ethylhexyl)benzoate (5c) 4.7 Methyl 3,4,5-tris(2-ethylhexyl)benzoate (5c) To a solution of 1-bromo-2-ethylhexane (11.4 mL, 66 mmol) and 4 (3.68 g, 20.0 mmol) in dry DMF (100 mL) was added potassium carbonate (24.8 g, 180 mmol) under an argon atmosphere, and heated at 70 °C for 27 h. The reaction mixture was quenched by addition of water and neutralized with cold aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane, washed with water sufficiently, dried over anhydrous magnesium sulfate, and evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography (WAKO C300) eluting with hexane/dichloromethane (2:1, v/v) to give 5c in 78% (8.16 g, 15.67 mmol) as pale yellow oil: IR (NaCl, cm-1) 3100, 2958, 2928, 2873, 2860, 2731, 1722 (νC=O), 1588, 1460, 1432, 1334, 1217; 1108, 766; 1H NMR (CDCl3) δ 0.90 (t, J=7.3 Hz, 9H, CH3), 0.93 (t, J=7.3 Hz, 9H, CH3), 1.27-1.36 (m, 12H, CH2), 1.40-1.60 (m, 12H, CH2), 1.65-1.80 (m, 3H, CH), 3.85-3.95 (m, 6H, OCH2), 3.90 (s, 3H, COOMe), 7.25 (s, 2H, ArH); 13C NMR (CDCl3) δ 11.12, 11.20, 14.13, 14.17, 23.09, 23.14, 23.64, 23.81, 29.10, 29.29, 30.43, 30.50, 39.55, 40.60, 52.14 (COOCH3), 71.16, 75.88, 107.29, 124.50, 142.15, 153.0, 167.07 (C=O); FAB-MS (positive, NBA) m/z 520 (M+). Anal. Calcd for C32H56O5 (520.78): C, 73.80; H, 10.84. Found: C, 73.92; H, 10.71. |
76% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; Inert atmosphere; | |
76% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; Inert atmosphere; | Methyl 3,4,5-tris((2-ethylhexyl)oxy)benzoate (3f) Into a suspension of methyl 3,4,5-trihydroxybenzoate (10.00 g, 54.3 mmol) and K2C03 (45.03 g, 325.8 mmol) in degassed DMF (45 mL) was added 2-ethylhexyl bromide (34.61 g, 180.1 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was heated to 70 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and water was added. The product was extracted with ethyl acetate washed with water, brine and dried over MgS04. The crude mixture was concentrated and purified by column chromatography (Si02; 0 - 5% EtOAc:hexane) to give a yellowish oil as product (21.54 g, 76%). XH NMR (500 MHz, CDC13) δ 7.23 (s, 2H, ArH-2,6), 3.92 - 3.83 (m, 9Η, 3ArOCH2, OCH3), 1.73 (m, 2Η, 2ArOCH2CH), 1.67 (m, 1Η, ArOCH2CH), 1.60 - 1.36 (m, 12Η, 6CH2CH3), 1.34 - 1.25 (m, 12H, 3(CH2)2CH2CH3), 1.01 - 0.79 (m, 18H, 6CH3). 13C NMR (126 MHz, CDC13) δ 167.2 (C=0), 153.2 (ArC-3,5), 142.5 (ArC-4), 124.7 (ArC-1), 107.6 (ArC-2,6), 76.1 (ArOCH2), 71.4 (ArOCH2), 52.2 (OCH3), 40.8 (ArOCH2CH), 39.7 (ArOCH2CH), 30.7 (CH2CH2CH2CH3), 30.6 (CH2CH2CH2CH3), 29.4 (CH2CH2CH3), 29.3 (CH2CH2CH3), 24.0 (CH2CH3), 23.8 (CH2CH3), 23.3 (CH2CH3), 23.2 (CH2CH3), 14.3 (CH3), 14.2 (CH3), 1 1.3 (CH3), 1 1.2 (CH3). MALDI-TOF (m/z): [M]+ calcd for C32H5605, 520.41; found 520.99. |
45% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6.5h; Inert atmosphere; | |
15% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 48h; | |
With 18-crown-6 ether; potassium carbonate In acetone Reflux; | ||
33 g | With potassium carbonate In N,N-dimethyl-formamide at 20 - 120℃; for 12h; | 1 Example 14,4'-bis(2-(2-(3,4,5-tris(isooctyloxy)-benzamide)-ethoxy)-ethoxy)diphenylmethylamine(DPA-001)Synthesis Methyl 3,4,5-trihydroxybenzoate (18.4 g, 0.1 mol),Isooctyl bromide (2-ethyl-hexyl bromide)(63.7g, 0.33mol),Potassium carbonate (55.2 g, 0.4 mol) and DMF (150 ml) were mixed at room temperature.Heat to 110-120 ° C for 12 h. Cool to room temperature,Pour into a mixture of petroleum ether (150 ml) and water (150 ml) with stirring.Divided into the lower layer, the upper layer of petroleum ether solution with water(200ml × 2) wash,Concentrate to a crude oily intermediate 1-2.Intermediate 1-2 crude ester was dissolved in tetrahydrofuran (100 ml).Add methanol (50ml) and 30% NaOHaq (67g),The reaction was stirred for 3 h.Add petroleum ether (100 ml) and water (200 ml), stir for 10 min,The lower layer was separated; 2N hydrochloric acid (100 ml) was added and stirred for 10 min.Divide to the lower layer; wash the upper layer to pH 6-7,Concentrated to give 3,4,5-tris(isooctyloxy)-benzoic acid33.0g. |
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In acetone at 65℃; for 16h; | |
92% | With potassium carbonate In N,N-dimethyl-formamide at 65℃; | Next, the synthesis of the second and third generation dendron thiol examples 2, 3, 5 and 6 was performed. In order to use the common intermediate 26, while at the same time keeping to the convergent dendron synthesis methodology as much as possible, the first generation dendron bromides 31 and 32, were synthesised as shown in Scheme 4.Methyl 3,4,5-trihydroxybenzoate 17 and methyl 3,5-dihydroxybenzoate 18 were alkylated with 1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H-perfluorodecyl bromide 15 in DMF at 65° C. with K2CO3 as a base. Subsequent reduction using LiAlH4 afforded the benzyl alcohols 27 and 30 in excellent yields. Bromination using CBr4 and PPh3 in the presence of DIPEA in dichloromethane provided the first generation dendron bromides 31 and 32 as required. Similarly, the second generation dendron bromides 36 and 37 were synthesised as shown in Scheme 5. Alkylation of 3,5-dihydroxybenzyl alcohol 33 with bromides 31 and 32 followed by bromination yielded the second generation bromides 36 and 37 in moderate yields. Acetone was chosen as the solvent for alkylation instead of DMF due to its ease of removal. The final steps in the synthesis of the dendron thiol examples 2, 3, 5 and 6 involved the coupling of the intermediate 26 with the appropriate benzyl bromides. Scheme 6 shows the last stages in the preparation of second generation dendron thiols 2 and 5. Alkylation followed by acid deprotection afforded the thiols 2 and 5 in 10% and 12% respectively. Scheme 7 shows the final stages in the synthesis of the third generation thiols 3 and 6. The same reagents as before were used in these steps. The alkylation steps involved gave higher yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetonitrile for 1h; Reflux; | |
100% | With potassium carbonate In acetonitrile for 3h; Inert atmosphere; Reflux; | 1 3,4,5-tris(allylloxy)benzoic acid methyl ester (1) 3,4,5-tris(allylloxy)benzoic acid methyl ester (1) (see Figure 9). Methyl 3,4,5-trihydroxybenzoate (4.5 g, 25 mmol, 1.0 equiv) and K2C03 (16.4 g, 119 mmol, 4.8 equiv), were added to a round bottomed flask. Anhydrous acetonitrile (125 mL) and allyl bromide (21.0 g, 174 mmol, 7.0 equiv) were then added to the mixture under N2 atmosphere via syringe. The mixture was then heatedto reflux and stirred whilst protected from the light. After 3 hours 1H NMR showed completed conversion of the aromatic alcohol functionalities into their corresponding allyl ethers. Volatiles were then removed under reduce pressure. Toluene (200 mL) was added to the resulting residue, and the insoluble salts were filtered and washed with additional portions of toluene (3x100 mL). The toluene fractions were combined and the solvent removed under pressure togive the desired product (1) as an oil which was used for the next step without furtherpurification. Yield 7.5 g, 100 %. H NMR (400 MHz, CDCI3, 5, ppm): 7.28 (s, 2H, CHaromatic), 6.146.01 (m, 3Haiiyi), 5.47-5.16 (m, 6Haiiyi), 4.65-4.59 (m, 6H, OCH2), 3.88 (s, 3H, CH3O). 13C NMR (101MHz, CDCI3, 5, ppm): 166.7, 152.4, 142.0, 134.3, 133.1, 125.1, 118.0, 117.8, 108.9, 74.2, 70.0, 52.3. ESI-TOF mass spectrometry: expected m/z [M-H] theor. 305.13, found 305.12. FT-IR: 1715-1cm (u=). |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; Inert atmosphere; |
83% | With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 3h; | |
83% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; | Next, the synthesis of the first generation dendron thiol examples 1 and 4 was performed, as outlined in Scheme 2, below. Methyl 3,4,5-trihydroxybenzoate 17 and methyl 3,5-dihydroxybenzoate 18 were protected using allyl bromide in DMF at 60° C. using K2CO3 as a base. This afforded the protected methyl esters in yields of 83% and 98% respectively. The allyl group was chosen as the protecting group owing to its ease of attachment, stability over the required functional group manipulations, and ease of removal. Reduction of the methyl esters using LiAlH4 provided alcohols 19 and 20 in good yields of 96% and 99% respectively. The next step involved the formation of the ethers 21 and 22 by the alkylation of the alkoxides with dibromodecane followed by nucleophilic addition of thioacetate to allow the introduction of the thiol focal point, giving thioacetates 23 and 24 in good yield. The thiol focal point was introduced in a stepwise manner as shown. Finally, the removal of the allyl protecting groups from 23 and 24 using a palladium catalyst to isomerise the allyl group to an enol ether followed by acid hydrolysis occurred successfully to yield the common intermediates 25 and 26.The final steps in the synthesis of the first generation dendrons (Scheme 2) involved alkylation of phenolate anions derived from 25 and 26 followed by deprotection of the thiol group. Alkylation of thioacetates 25 and 26 with perfluorobromide 15 in refluxing acetone containing K2CO3 gave the esters in low yield. This is considered to be due to either the suppression of reactivity of the bromoalkane by the electron withdrawing fluorine atoms, as schematically illustrated in FIG. 3 and/or the unwanted premature cleavage of the thioester of the thiol derivative under the basic conditions. Acetone was chosen in preference to DMF as a solvent, as DMF gave a large number of side products as observed by TLC, most probably because of the more basic conditions provided by DMF as a result of deprotection of the thiol group. Since the final step in Scheme 2 involves a deprotection, it might be thought that deprotection during this alkylation step would be acceptable. However, once the thiol is revealed, it can react with the fluorinated bromide 15 to form a thioether. Therefore, it should preferably remain protected during the penultimate alkylation step. The final step involving the deprotection of the thiol derivatives under basic conditions provided the first generation dendron thiols 1 and 4. The basic conditions required short reaction times of approximately 10 min at room temperature. This method was preferred to acidic conditions, which require refluxing for over 12 h. It has been reported that basic conditions give disulphide side products but this was not observed in this case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 40℃; for 24h; | 4; a [0159] (a) Preparation of 3,4,5-tribenzyloxybenzaldehyde 6 from methyl gallate 3: [0160] A mixture of methyl gallate 3 (10 g, 53 mmol) and potassium carbonate (45 g, 320 mmol) in DMF (120 mL) was treated with benzyl bromide (210 mmol, 25.7 mL) and stirred at 40° C. under an argon atmosphere for 24 h. The reaction mixture was filtered and the filtrate evaporated to dryness . The residue was dissolved in minimum amount of methylene chloride and diluted with an equal volume of hexanes and loaded onto a short silica gel pad in a sintered glass funnel. The silica was eluted with hexanes (300 mL) to remove excess benzyl bromide and the eluant discarded. The product was then eluted with CH2Cl2:Hexanes (1:1, 300 mL) followed by methylene chloride (500 mL) and the eluants combined and evaporated to afford pure benzyl product 4 as an off-white solid (100% yield). 1H NMR (300 MHz, CDCl3): δ3.88 (s, 3H, CH3), 5.11 and 5.13 (2s, 6H, OCH2), 7.35-7.41 (m, 17H, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 48h; Inert atmosphere; | |
87% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere; | |
70% | Stage #1: methyl galloate With potassium carbonate In 1,4-dioxane at 20℃; for 1h; Stage #2: toluene-4-sulfonic acid 2-(2-methoxyethoxy)ethyl ester In 1,4-dioxane at 110℃; for 36h; | 8.2 (2) Preparation of methyl 3,4,5-tris(2-(2-methoxyethoxy)ethoxy)benzoate Methyl gallate (8.89 g, 0.048 mοl) and anhydrous potassium carbonate were sequentially added to a 500 mL single-mouth bottle.(39.99g, 0.290mmol) and 220mL of 1,4-dioxane, stirred at room temperature for 1h, then added -(2-methoxyethoxy)ethyl-4-methylbenzenesulfonate (51.63g, 0.188mol), reacted at 110 ° C for 36h, after the reaction is completed, it is filtered while hot, the filtrate is collected, and the crude product is obtained by rotary evaporation on a rotary evaporator, then purified by column separation. The selected eluent is dichloromethane. : Acetone (V: V = 15:1), the product was obtained by rotary evaporation to give 16.57 g of pale yellow liquid product, yield 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere; | |
83% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 24h; | 3.3 2.3.3. Methyl 3,4,5-tris(2-(2-(2-ethoxyethoxy)ethoxy)ethoxy)benzoate (3) A mixture of methyl gallate (2.76 g, 15 mmol), tosylated compound 1 (19.94 g, 60 mmol), KI (1.99 g, 12 mmol), and potassium carbonate (K2CO3) (20.73 g, 150 mmol) in dry DMF (100 mL) was stirred at 80 °C over 24 h. After removal of DMF in vacuo, the residue was dissolved in DCM and washed sequentially with saturated NaHCO3 and brine. After drying over MgSO4, purification by column chromatography with DCM/MeOH (20:1) afforded the product as colorless oil; yield: 83%. 1H NMR (CDCl3): δ = 1.15 (t, 9H, 3CH3), 3.45-3.87 (m, 39H, 18CH2 + CH3), 4.16 (t, 6H, 3CH2), 7.28 (s, 2H, Ar-H). MS (MALDI-TOF): m/z calc, 664.78; found, 687.35 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetone Reflux; | |
93% | With potassium carbonate In acetone; toluene for 12h; Reflux; Inert atmosphere; | |
92% | With potassium carbonate In N,N-dimethyl-formamide for 120h; |
81% | With 18-crown-6 ether; potassium carbonate In acetone for 24h; Reflux; Inert atmosphere; | |
74% | With 18-crown-6 ether; potassium carbonate In acetone at 80℃; for 12h; | 3.4 Synthetic procedure for the synthesis of methyl 3, 4, 5-tris (propargyloxy)benzoate (2) To a solution of compound 1 (5.0g, 27.1mmol) in anhydrous acetone, K2CO3 (26.30g, 190mmol, 8 equiv.) and 18-crown-6-ether (250μL) as co-catalyst were added, followed by the addition of propargyl bromide (16.46mL, 217mmol, 8.0 equiv.). Then, the reaction was refluxed for 12h, upon completion of reaction (monitored by TLC), resulting reaction mixture was evaporated under reduced pressure (below 50°C) to obtain the crude mass. The crude residue thus obtained was subjected to flash column chromatography (SiO2) to afford the desired compound 2 in 74% yield as white powder. The spectral datas were matched with the reported literature [18]. Yield (6.0g, 74%); Rf=0.5 (15% Ethyl acetate/n-hexane); 1H NMR (500MHz, CDCl3): δ 7.45 (s, 2H), 4.81-4.79 (m, 6H), 3.90-3.89 (m, 3H), 2.53-2.52 (m, 2H), 2.45-2.44 (m, 1H); 13C NMR (125MHz, CDCl3): δ 166.2, 151.2, 141.0, 125.7, 109.8, 78.6, 77.9, 76.1, 75.5, 60.2, 57.0, and 52.3ppm. |
68% | With 18-crown-6 ether; potassium carbonate In acetone for 12h; Heating; | |
67.9% | With potassium carbonate In acetonitrile at 85℃; | |
With potassium carbonate In acetone Inert atmosphere; | ||
With 18-crown-6 ether In acetone Reflux; | ||
With potassium carbonate In acetonitrile at 85℃; | ||
With 18-crown-6 ether; potassium carbonate In acetone at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium hydrogencarbonate; In dimethyl sulfoxide; at 60℃; for 1.5h;Inert atmosphere; | To a solution of compound A0061-1 (1 g,5.43 mmol) in dimethyl sulfoxide (DMSO) (25 ml) was added potassium hydrogen carbonate (KHCO3) (0.54 g, 5.43 mmol) followed by dibromomethane (0.4 ml) and the mixture was heated at 60 0C for 1.5 hours under nitrogen. The reaction was cooled and poured into water (50 ml) . The mixture was extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to yield a crude oil which was further purified by column chromatography on silica gel (petroleum etheriethyl acetate=5:l) to yield compound A0061-2. (580 mg, yield: 55%, NMR confirmed) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | To methyl gallate (5.5 g) and potassium carbonate (62.2 g), 1,3-dimethyl-2-imidazolidinone (140 mL) wasadded, then the mixture was stirred at 80C for 1 hour and then was cooled to 70C. <strong>[6938-66-5]1-Bromodocosane</strong> (38.6 g) wasadded thereto, and the mixture was stirred at 70C for 14 hours. Water (300 mL) was added to the reaction liquid, thesolution was stirred, then the precipitate was collected by suction filtration and washed with water (300 mL), acetonitrile(200 mL), acetone (500 mL), and dichloromethane (200 mL) to obtain the compound represented by E36 (28.6 g, percentyield: 86%). 1H NMR (500 MHz, CDCl3) delta 7.25 (2 H, s), 3.99-4.03 (6 H, m), 3.89 (3 H, s, COOMe), 1.71-1.84 (6 H, m), 1.47(6 H, m), 1.22-1.38 (108 H, br), 0.88 (9 H,t J = 9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; potassium iodide In acetonitrile Reflux; | 4.2.10. Compound 17 General procedure: A mixture of methyl gallate (16) (1.9 g, 10.4 mmol), decylbromide (8.9 g, 40.2 mmol), KI (2.11 g, 12.8 mmol), and anhydrous potassium carbonate (9.8 g, 70.8 mmol) in acetonitrile (40 mL) was heated under reflux for 24 h. After being cooled to room temperature, the solvent was removed with a rotavapor. To the resulting mixture, water (40 mL) was added and the aqueous phase was extracted with dichloromethane (3×40 mL). The combined organic phase was successively washed with water (2×40 mL) and brine (40 mL), and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (petroleum ether/dichloromethane 30:1) to give compound 17 as a pale yellow oil (2.0 g, 85%). |
95% | With potassium carbonate; potassium bromide In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | |
95% | With potassium carbonate; potassium bromide In acetonitrile at 80℃; |
95% | With potassium carbonate; potassium bromide In acetonitrile at 80℃; | |
95% | With potassium carbonate; potassium bromide In acetonitrile at 80℃; | |
94% | With potassium carbonate In acetone at 70℃; for 48h; | |
93% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Inert atmosphere; | |
92% | at 80℃; for 15h; | |
90% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | |
83% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; | |
80% | With potassium carbonate In acetone for 24h; Reflux; Inert atmosphere; | 2 Added to a solution of trihydroxybenzoate methyl ester (0.329 g: 1.79 mmol) in acetone (10 ml) are potassium carbonate (1.772 g: 0.018 mol: 3.5 equiv.) and monomethyl triethylene glycol monotosylate (2 g: 0.006 mol: 3.5 equiv.). The heterogeneous mixture is heated at reflux for 24 hours under nitrogen; the pink mixture obtained is then filtered in order to remove excess potassium carbonate. The acetone is then evaporated and the product is dissolved in dichloromethane (12 ml). Three washings follow with 10 ml of water, then 5 ml of 1M HCl and finally 10 ml of water, before evaporating the solvent of the organic phase. The product is then purified in a chromatography column (SiO2) with, as eluent, a 97/3 chloroform/methanol mixture.8 g (80%) of tris 3,4,5-tri(triethyleneoxy)benzoate methyl ester are then obtained.1H NMR (CDCL3, 250 MHz); δ ppm: 3.37 (s, CH3-O); 3.65 (m, CH2-O); 3.88 (s, CH3-O); 4.19 (s, CH2-O-Carom); 7.29 (s, CHarom). |
80% | Stage #1: methyl galloate With potassium carbonate In 1,4-dioxane at 20℃; for 1h; Stage #2: 2-(2-(2-methoxyethoxy)ethoxy)ethyl p-toluenesulfonate In 1,4-dioxane at 110℃; for 36h; | 1.2 (2) Preparation of methyl 3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzoate In a 500 mL single-mouth bottle, methyl gallate (5. 12 g, 0.0278 mol), anhydrous potassium carbonate (23. llg, 0.167 mmol) and 200 mL of 1,4-dioxane were sequentially added, and stirred at room temperature. After lh, 2-(2-(2-methoxyethoxy)ethoxy)ethyl-4-methylbenzenesulfonate (40.0 g, 0.126 mol) was added, and the reaction was completed at 110 ° C for 36 h. After hot filtration, the filtrate was collected, and the crude product was obtained by rotary evaporation on a rotary evaporator, and then purified by column separation. The selected eluent was ethyl acetate: acetone (V:V = 3:1), collected. After the product was rotary evaporated, 13.21 g of a pale yellow liquid product was obtained in a yield of 80%; |
80% | Stage #1: methyl galloate With potassium carbonate at 20℃; for 1h; Stage #2: 2-(2-(2-methoxyethoxy)ethoxy)ethyl p-toluenesulfonate at 110℃; for 36h; | |
79% | With potassium carbonate In acetone for 24h; Reflux; | |
75% | With potassium carbonate; potassium bromide In acetonitrile at 80℃; | |
71% | With potassium carbonate; sodium iodide In acetonitrile at 80℃; for 24h; | |
70% | With 18-crown-6 ether; potassium carbonate In acetone for 48h; Inert atmosphere; Reflux; | 1 To a solution of (2) (24.51 g, 76.9 mmol) in acetone (220 ml), methyl-3,4,5- trihydroxybenzoate (4.5 g, 24.4 mmol), anhydrous potassium carbonate (16.85 g, 122 mmol) and 18-crown-6 (1.3 g, (4.88 mmol) were added. The resulting slurry was stirred and refluxed under argon for 2 days. The resulting light-brown reaction mixture was filtered to remove the insoluble inorganics and concentrated under vacuum to give a brown residue. This was re-dissolved in chloroform (500 ml) and washed with satd. sodium carbonate solution (5 x 500 ml), satd. sodium bicarbonate solution (3 x 250 ml) and finally with brine (250 ml). The organic phase was separated, dried over Na2SO4 and evaporated to give the crude material as a light-brown oil. This was purified by column chromatography on silica eluting with 5% MeOH in chloroform (Rf 0.4) to give (3) as a slight yellow oil (10.6 g, 70%). 1NMR (400 MHz, CDCI3) δ: 7. 28 (s, 2H, Ar-H)1 4.23-4.17 (m, 6H, CH2), 3.89 (s, 3H, ArCO2CH3), 3.87, (t, J =4.9 Hz, 4H, OCH3), 3.80 (t, J =4.9 Hz, 2H, 0-CH3) 3.79-3.71 (m, 6H, CH2), 3.69-3.63 (m, 12H, CH2), 3.56-3.53 (m, 6H, CH2), 3.39 (s, 9H, 0-CH3). |
64% | With 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin; potassium carbonate In acetone for 18h; Reflux; | |
52% | With potassium carbonate; potassium iodide In acetone for 168h; Reflux; | |
41% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 26h; | |
With potassium carbonate In acetonitrile at 80℃; for 48h; | ||
With 18-crown-6 ether; potassium carbonate In acetone for 48h; Reflux; | ||
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 12h; | ||
With potassium carbonate; potassium bromide In N,N-dimethyl-formamide at 80℃; for 48h; | ||
With potassium carbonate In acetone Inert atmosphere; | ||
With potassium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; Inert atmosphere; | |
70% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; | 6 A suspension of finely ground dry K2CO3 (1.5 g, 0.01 mol) in dry DMF (50 mL) was added to a three-neck round bottom flask equipped with magnetic stirring, heating bath, condenser, and dropping funnel with pressure-equalization arm and degassed at 50° C. for 1 h, under stirring. Methyl 3,4,5-trihydroxybenzoate (0.22 g, 1.23 mmol) was added, while purging the system with N2. The 3,4,5-PPVE-CH2-Cl (3.22 g, 1.23 mmol) was dissolved in DMF (20 mL) and added to a dropping funnel and flushed with N2 for 30 min. Following the complete dissolution of the phenol in DMF, the chloride was added dropwise to the reaction mixture while the temperature was increased to 60° C. The suspension was stirred at 60° C. under N2 and monitored by TLC. After 4 h the reaction mixture was poured into ice-cold water (20 mL), and stirred for 5 rain, and then extracted five times with ethyl acetate (100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried on anhydrous MgSO4. Evaporation of the solvent yielded the crude product, which was purified by flash chromatography (basic alumina, hexane/ethyl acetate, 8/1). The pure fractions were collected, and after evaporation resulted in a viscous oil, 2.5 g, 70%. Purity (HPLC), 99+%; NMR (500 MHz, Freon113/CDCl3, TMS) d, δ=7.43 (s, 6H, Ar), 7.23 (s, 2H, Ar), 6.0 (m, CHF), 5.16 (s, 6H, -CH2-), 3.90 (s, 3H, -CH3); 13C NMR (126 MHz, CDCl3/HFB, TMS) d, δ=165.46, 151.72, 143.77, 143.40, 141.40, 132.44, 126.20, 120.50-104.33 (-CF2), 118.29, 108.71, 98.66-96.72 (-CHF), 69.29, 51.41; MALDI-TOF MS calc. for C52H20F60O16+Ag+: 3098.85; found m/z: 3099.20 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 50h; Inert atmosphere; | |
78% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 23℃; for 18h; Inert atmosphere; | |
78% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 23℃; for 18h; Inert atmosphere; | 1 In a dry two-neck round bottom flask containing methyl 3,4,5-trihydroxybenzoate (5.38 g, 0.03 mol) and potassium tert-butoxide (0.49 g, 8.76 mmol) dissolved in dry DMF (60 mL) was added perfluorovinyl ether (23.32 g, 0.08 mol) under N2. The reaction was stirred at 23° C. for 18 h. The reaction mixture was then poured into ice water containing hydrochloric acid (2 mL) and extracted three times with 100 mL of ether. The organic fractions were combined, washed with water, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product was purified on neutral alumina with hexane:ethyl acetate mixture (7:1) yielding 22.3 g of a clear liquid; (78%). Purity (HPLC), 99+%; 1HNMR (500 MHz, CDCl3/Freon113, TMS) d, δ=7.99 (s, 2H, Ar), 6.06 (d, 2J δ=53.5, 3H, -CHF), 3.96 (s, 3H, -CH3). 13C NMR (126 MHz, CDCl3/HFB, TMS) d δ=163.75, 143.39, 136.58, 130.20, 121.37, 120.42-104.22-CF2-), 98.50-96.56 (-CHF-), 52.78; MALDI-TOF MS calc. for C23H8F30O8+Na+: 1004.96; found m/z: 1005.20[M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; potassium iodide; In acetone; at 65℃; for 30h;Inert atmosphere; | A solution of 19 (6.5 g, 17.9mmol), MethylGallate (1 g, 5.4 mmol), K2C03 (3.7 g, 27.1 mmol) and KI (0.3 g, 1.63 mmol) in acetone (90 mL), is stirred during 30 h at 65C. The reaction mixture is filtered over Celite and the volatiles are evaporated. The resulting crude product is diluted in dichloromethane and washed twice with an aqueous saturated solution of NaHC03 and with brine. After drying over MgS04, filtration and evaporation of the solvent, the crude product is purified by chromatography over silica gel column (ethyl acetate/acetone 95/5 to 20/70) to afford 20 as a yellow oil in 83% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 18-crown-6 ether; potassium carbonate In acetone Inert atmosphere; Reflux; | |
89% | With potassium carbonate In acetone for 72h; Inert atmosphere; Reflux; | 2 Synthesis Example 2 Synthesis of Compound 2-1 [Show Image] [Show Image] Into a three-necked round-bottom flask equipped with a Dimroth condenser and a septum cover, 268 mg (1.5 mmol, 1.0 eq.) of methyl gallate, 3.0 g (0.51 mmol, 3.5 eq.) of heptadecafluoroundecyliodo, 115 mg (0.043 mmol, 0.3 eq.) of 18-crown 6-ether, and 760 mg of potassium carbonate were put, and the flask was deaerated and the atmosphere in the flask was replaced with argon. 20 ml of dehydrated acetone was added and the resulting mixture was refluxed for 3 days. After confirming that the raw material was dissipated by use of TLC (developing solvent: hexane/ethyl acetate = 5/1), the reactant was washed with distilled water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under a reduced pressure. Purification of the product was carried out through recrystallization (acetone). The yield of a compound 2-1 was 2.0 g (1.3 mmol, percent yield 89%). 1H NMR (CDCl3):δ = 7.28 (s, 2H), 4.11 (t, 3H), 4.05 (t, 2H), 3.89 (s, 3H), 2.33 (m, 6H), 2.15 (m, 4H), 2.08 (m, 2H) |
85% | With tetrabutylammomium bromide; potassium carbonate In 4-methyl-2-pentanone at 20℃; for 6h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dihydrogen peroxide; horseradish peroxidase In aq. phosphate buffer; acetone | |
46% | With potassium iodate In water; acetone at 20℃; for 1.5h; | General Method 2 General procedure: KIO3 (0.5 M in H2O, 1 equiv) was added to 1,2-dihydroxybenzene derivative (1 equiv) and 3,4,5-trihydroxybenzoic acid derivative (1 equiv) in acetone / water (1.0 M, 1:4) dropwise at room temperature. After stirring at room temperature for indicated time, the reaction mixture was filtered, washed with 1 N HCl, and dried. The desired product was obtained as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; water; isopropyl alcohol; at 20 - 60℃;Inert atmosphere; | Example 19: Preparation of the <strong>[641571-10-0]nilotinib</strong> hydrochloride - gallic acid methyl ester co- crystal A 0.02M stock solution of <strong>[641571-10-0]nilotinib</strong> hydrochloride is prepared by dissolving 538 mg of <strong>[641571-10-0]nilotinib</strong> free base in 50.0 ml methanol with 167muIota 6M HCI. 10 ml of this stock solution is mixed with 4.0 ml of a stock solution (0.05M) of gallic acid methyl ester (Fluka 48690) in methanol. Then the solvent is slowly evaporated under nitrogen at a flow of about 50 ml per minute at room temperature. After evaporation of the methanol 4.0 ml isopropanol is added, the mixture is sonicated and stirred at 60C, sonicated again, and then stirred at room temperature for several days before the crystalline product is separated by filtration. H-NMR spectroscopy indicates a ratio of <strong>[641571-10-0]nilotinib</strong> free base to gallic acid methyl ester of about 1 :0.7 and powder X-ray diffraction reveals a PXRD pattern as displayed in Fig. 17 which shows peaks at positions as indicated in Table 17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrazine hydrate monohydrate In ethanol for 18h; Reflux; | 3.4.5 -trihydroxybenzohydrazide (NED-2047) A solution of methyl gallate (4 g, 21.7 mmol) in ethanol (25 mL) was hydrazine hydrate (4.35 g, 86.9 mmol) and heated to a gentle reflux. After stirring for 18 h, the reaction mixture was cooled to room temperature, and the precipitated product was filtered and sequentially washed with water and ethanol and dried in a vacuum oven to give the title compound (3.85 g, 96%) as a white solid. 1H NMR (DMSO-D6) 9.29 (s, 1 H), 8.97 (br s, 2 H), 8.60 (br s, 1 H), 6.74 (s, 2 H), 4.28 (s, 2 H). LC-MS: m/z = 185[M+] |
85% | With hydrazine hydrate monohydrate In ethanol for 8h; Reflux; | |
75% | With hydrazine hydrate monohydrate In ethanol for 5h; Reflux; | 2.2. Synthesis of gallic acid-benzylidenehydrazine hybrids Hydrazine hydrate (50 mmol) was added to a solution of methyl gallate 2 (2.5 mmol) in 30 mL ethanol, and the reacting mixture was stirred in a reflux condenser for 5 h. After finish, the mixture was poured into water and the solid precipitate was collected by filtration to obtain galloyl hydrazide 3 (yield = 75%) as a white solid |
75% | With hydrazine hydrate monohydrate In ethanol for 5h; Reflux; | 2.2. Synthesis of gallic acid-benzylidenehydrazine hybrids Hydrazine hydrate (50 mmol) was added to a solution of methyl gallate 2 (2.5 mmol) in 30 mL ethanol, and the reacting mixture was stirred in a reflux condenser for 5 h. After finish, the mixture was poured into water and the solid precipitate was collected by filtration to obtain galloyl hydrazide 3 (yield = 75%) as a white solid |
74% | With hydrazine hydrate monohydrate In ethanol for 60h; Reflux; | 3.1.2. Galloyl hydrazide (3) Briefly, 80% hydrazine hydrate (1.8 mL, 48.2 mmol) was added to a solution of methyl gallate (2) (2.5 g, 2.97 mmol) that was previously prepared by esterification of commercial gallic acid (1) in ethanol (30 mL). This mixture was heated at reflux for 60 h, when TLC analysis indicated the end of the reaction. Then, the media was poured on ice, and the resulting precipitate was filtered, affording the title compound 3 (1.85 g, 74%) as pale white powder, mp 164-167 °C (MeOH); mp 167 °C [32]; IR (KBr) νmax (cm-1): 3365-3284 (O-H, N-H), 1623 (C=O), 1509-1303 (C=C), 1260 (C-O); 1H-NMR(DMSO-d6): δH 6.77 (s, 2H); 8.59 (NH); 9.32 (OH). 13C-NMR (DMSO-d6): δC 106.5, 123.9, 136.2,145.4, 166.4. MS m/z (%): 185 (MH+, 12), 153 (100), 126 (42). |
17.1 g | With hydrazine monohydrate In methanol for 3h; Reflux; | 3.1 Typical procedure for preparation of aryl hydrazides. Preparation Method I (see Scheme 2) Preparation of 3,4,5-trihydroxybenzohydrazide (H1-Supplemental material). A methanol (300ml) suspension of 3,4,5-trihydroxybenzoic acid and (17g; 0.1mol) and the strongly acidic ion-exchange resin Amberlyst-15 (5g) was stirred with refluxing for three days. The insoluble catalyst was separated by filtration, and washed with methanol (3×10ml). The combined methanol filtrates were mixed with hydrazine hydrate (20ml; 20.5g; 0.4mol) and refluxed for 3h. The volume of the reaction mixture was reduced to ∼30ml and left at room temperature for 1h and then at -5°C. The formed white precipitate was separated by filtration, washed with ice cold methanol (3×5ml), followed by ice cold ether (3×10ml) and dried on air to give pure product (17.1g; 93%). 1H NMR (DMSO-d6) δ 9.34 (1H, br s, NH), 6.79 (2H, s, 2-H), and 4.33 (2H, br s, NH2) ppm. 13C NMR (DMSO-d6) δ 167.1, 146.1, 136.9, 124.3, and 107.2ppm |
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux; | ||
With hydrazine hydrate monohydrate for 4h; Reflux; | 4.2.1. General procedure for the synthesis of hydrazides 2 General procedure: Hydrazides 2 were obtained in reaction of methyl esters 1 (1 mmol), which synthesized from corresponding acids [61], and hydrazine monohydrate (6 mmol) by heating under reflux for 4 h [62]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In N,N-dimethyl-formamide at 110℃; | 7 2,3-Dihydrophytyl bromide (40.6 g, 112 mmol), methyl gallate (5.90 g, 32.0 mmol) and potassium carbonate (22.14 g, 160 mmol) were suspended in DMF (400 ml), and the mixture was stirred at 110°C overnight. The reaction mixture was extracted with hexane (800 ml), washed with 1 mol/l hydrochloric acid (400 ml), 5% aqueous sodium hydrogen carbonate solution (400 ml) and 20% brine (400 ml), dried over sodium sulfate and the solvent in the filtrate was evaporated to give methyl 3,4,5-tri(2,3-dihydrophytyloxy)benzoate (29.3 g, yield 93%). The aforementioned methyl 3,4,5-tri(2,3-dihydrophytyloxy)benzoate (29.3 g, 30.0 mmol) was dissolved in THF (400 ml), and diisobutylaluminum hydride (DIBAL)(1.0 mol/l toluene solution, 96 ml, 96 mmol) was added dropwise over 30 min under a nitrogen atmosphere at 0°C. After stirring at room temperature overnight, 0.2 mol/l hydrochloric acid (50 ml) was added dropwise at 0°C to quench the reaction. The solvent was evaporated to about half, and the residue was dissolved in ethyl acetate (600 ml). The mixture was washed three times with 1 mol/l hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with 20% brine (300 ml), and dried over sodium sulfate. The solvent in the filtrate was evaporated to give 3,4,5-tri(2,3-dihydrophytyloxy)benzyl alcohol (26.8 g, yield 94%). |
93% | With potassium carbonate In N,N-dimethyl-formamide at 110℃; | 7 Synthesis of 3,4,5-tri(2,3-dihydrophytyloxy)benzyl alcohol Preparation Example 7 Synthesis of 3,4,5-tri(2,3-dihydrophytyloxy)benzyl alcohol 2,3-Dihydrophytyl bromide (40.6 g, 112 mmol), methyl gallate (5.90 g, 32.0 mmol) and potassium carbonate (22.14 g, 160 mmol) were suspended in DMF (400 ml), and the mixture was stirred at 110° C. overnight. The reaction mixture was extracted with hexane (800 ml), washed with 1 mol/l hydrochloric acid (400 ml), 5% aqueous sodium hydrogen carbonate solution (400 ml) and 20% brine (400 ml), dried over sodium sulfate and the solvent in the filtrate was evaporated to give methyl 3,4,5-tri(2,3-dihydrophytyloxy)benzoate (29.3 g, yield 93%). The aforementioned methyl 3,4,5-tri(2,3-dihydrophytyloxy)benzoate (29.3 g, 30.0 mmol) was dissolved in THF (400 ml), and diisobutylaluminum hydride (DIBAL)(1.0 mol/l toluene solution, 96 ml, 96 mmol) was added dropwise over 30 min under a nitrogen atmosphere at 0° C. After stirring at room temperature overnight, 0.2 mol/l hydrochloric acid (50 ml) was added dropwise at 0° C. to quench the reaction. The solvent was evaporated to about half, and the residue was dissolved in ethyl acetate (600 ml). The mixture was washed three times with 1 mol/l hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with 20% brine (300 ml), and dried over sodium sulfate. The solvent in the filtrate was evaporated to give 3,4,5-tri(2,3-dihydrophytyloxy)benzyl alcohol (26.8 g, yield 94%). |
93% | With potassium carbonate In N,N-dimethyl-formamide at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 123 mg | In methanol at 60℃; for 0.5h; | 6 Preparation of the Co-Crystal with Methyl Gallate (Molar Ratio 3:1) 127.3mg of dasatinib (monohydrate form) and 15.5mg of methyl gallate (Aldrich No. 274194) 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 hour. The sample is cooled and stored overnight at room temperature. Yield: approximately 123 mg. H-NMR spectroscopy indicates a molar ratio of dasatinib to methyl 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. 6 with peak locations as indicated intable 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | (1) Methyl gallate (3.68 g, 20 mmol) and anhydrous K2CO3 (24.8 g, 180 mmol) were added to 100 mL of CH3CN, and with stirring, the compound n-dodecyl bromide (28.7 mL, 120 mmol) was added. The mixture was heated to reflux and checked by TLC until the reaction was complete (about 24 h).Stop heating, cool naturally, suction filter to remove insoluble matter. The CH3CN was removed by rotary evaporation to give a yellow viscous material. 150 mL of CH3OH was added to dissolve it. Under stirring, aqueous NaOH (2.0 g, 50 mmol, 2 mol.L-1) was added, and the mixture was heated under reflux and detected by TLC until the reaction was complete (about 2 h). The reaction was stopped, and after cooling, CH3OH was removed by rotary evaporation, and dilute acid was added to adjust the pH to acidic. Then it was poured into crushed ice, cooled to precipitate a white solid, after suction filtration, washing (water: methanol = 1:1), drying to obtain the above synthetic route of compound 1a pure product, white solid 8.5g, yield 63%; | |
63% | With potassium carbonate; In acetonitrile; for 24h;Heating; | (1) Methyl gallate (3.68 g, 20 mmol) and anhydrous K2CO3(24.8g, 180mmol) was added to 100mL CH3CN,With stirring, the compound bromo-n-dodecane was added (28.7 mL, 120 mmol). Heating back, TLC testing, Until the reaction is complete (about 24 hours). Stop heating, cool naturally,Insoluble matter was removed by suction filtration. The CH3CN was removed by rotary evaporation to give a yellow viscous material.Add 150 mL of CH3OH to dissolve it, and stir it.Add NaOH aqueous solution (2.0 g, 50 mmol, 2 mol L-1),Heat to reflux and TLC detection until the reaction was complete (about 2 hours).The reaction was stopped, and after cooling, CH3OH was removed by steaming, and the pH was adjusted to be acidic with dilute acid.Then pour it into crushed ice, cool and precipitate a white solid, and suction filtration,Washing (water: methanol = 1:1), drying to obtain a pure compound 1,White solid 8.5g, yield 63% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In neat (no solvent, solid phase) at 20℃; for 0.75h; Green chemistry; | MOM Deprotection by pTSA General procedure: MOM ether (5 mmol) and pTSA.H2O (7.7 mmol) weretriturated well in a mortar for 5 min (in the case of entry 10trituration time was about 15 min), reaction mixture was leftat room temperature for another 30 min. After completion ofthe reaction (monitored by TLC), cold water (4oC) wasadded. The products were separated by centrifugation. Theyields of the products ranged from 85-98%. The purities andthe identities of the products were established by direct comparisonwith known compounds (TLC, Mp and IR). See supplementaryinformation for further details. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; Cooling with ice; | 10.A Step A: Methyl gallate (30.0 g, 163 mmol), N,N-diisopropylethylamine (126 g, 977 mmol) was dissolved in dichloromethane (120 mL), then chloromethylmethyl was added dropwise in an ice water bath Ether (52.5g, 652mmol), after the addition,Warm to room temperature and continue to stir for 1.5 hours.After adding water (240 mL), the layers were separated, and the aqueous layer was washed with methylene chloride (50mL×2), and the combined organic phase was washed with water (50mL×2) and saturated brine (50mL).Dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.The product is purified by column chromatography (200-300 mesh silica gel,Ethyl acetate:dichloromethane: petroleum ether = 1:1:10 to 1:1:6) eluted to give 3,4,5-tris-methoxymethoxy-benzoic acid methyl ester (56) ( 47.9 g), the yield was 93.0%. |
63% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 3,4,5-Tris(Methoxymethoxy)Benzoic Acid (7) To a cooled(0°C) mixture of methylgallate (500 mg, 2.71 mmol) and N,Ndiisopropylethylamine(1.6 ml, 8.96 mmol) in dichloromethane(20 ml) was added methoxymethyl (MOM)chloride (0.7 ml, 8.97 mmol).The reaction was stirred at 0°C for 20 minutes and then at roomtemperature overnight. The solvent was evaporated to dryness, andthe residue was dissolved in ethyl acetate (20 ml) and washedsuccessively with a saturated solution of ammonium chloride (3 20 ml) and water (3 20 ml). The organic layer was dried overanhydrous Na2SO4, filtered, and concentrated under vacuum. Theresidue was then purified by flash column chromatography usinghexane/EtOAc (6:1 to 2:1) as the eluent to give 543 mg (63%) of methyl3,4,5-tris(methoxymethoxy)benzoate as a white amorphous solid thatwas used for the next step. 1H-NMR (300 MHz, CD3Cl) d 7.51 (s, 2H,H-Ph), 5.24 (s, 4H, 2 CH2MOM), 5.13 (s, 2H, 1 CH2MOM), 3.83(s, 3H, OCH3), 3.51 (s, 3H, 1 CH3MOM), 3.41 (s, 6H, 2 CH3MOM). |
With potassium carbonate In acetone | MOM Derivatives; Selected Procedure for 1 General procedure: To the mixture (vanillin, 6.5mmol and K2CO3, 8mmol, inacetone), methoxymethyl chloride (8.1 mmol) was added andstirred for 1-2 hr. After completion of the reaction, (monitoredby TLC; solvent system-7:3 hexane and ethyl acetate)reaction mass filtered and the product (>95% yield) was obtainedon removal of the solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; | Tert-butyl(2-(2-(2-(3,4,5-tris(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)benzamido)ethoxy)ethoxy)ethyl)carbamate (8): A mixture of 6 (4.11 g, 12 mmol), methyl gallate (0.552 g, 3 mmol), and K2CO3 (7.35 g, 30 mmol) in DMF (30 mL) was heated at 80 °C for 24 h. Then, it was allowed to reach r.t. and partitioned between EtOAc (150 mL) and H2O (150 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (100 mL), then dried (Na2SO4) and concentrated to give a crude product that was purified by silica gel chromatography (ethyl acetate/petroleum ether, 4:1) to afford methyl 3,4,5-tris(2-(2-(2-(prop-2-yn-1-yloxy) ethoxy)ethoxy)ethoxy)benzoate (1.56 g, 75%) as a yellow oil. Aqueous KOH (5 mL, 1 M) was added to a solution of methyl 3,4,5-tris(2-(2-(2-(prop-2-yn-1-yloxy) ethoxy)ethoxy)ethoxy)benzoate (1.39 g, 2 mmol) in EtOH (50 mL). The resulting solution was heated at reflux for 2 h and then allowed to reach rt. Neutralization with Amberlite IR-120, followed by filtration and evaporation, afforded compound 8a (1.361 g, 100%) as a colorless oil. Thereafter, EDC·HCl (336 mg, 1 mmol) was added to a stirred solution of acid 8a (390 mg, 0.5 mmol) and 4 (248 mg, 1 mmol) in CH2Cl2 (6 mL). Stirring was continued under N2 for 24 h. Then, CH2Cl2 (20 mL) was added, and the reaction mixture was washed with brine (3×15 mL). The organic layer was dried (Na2SO4) and concentrated to give a crude product that was purified by silica gel chromatography (ethyl acetate/petroleum ether=9:1, v/v) to afford 8 (328.4 mg, 81%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetonitrile; for 0.25h;Cooling with ice; Reflux; | 0.83 g (4.5 mmol) of methyl gallate,3.13 g (22.7 mmol) of anhydrous potassium carbonate was dissolved in 50 mL of purified acetonitrile,Then, 4.96 g (18.1 mmol) of compound a was weighed and dissolved with 15 mL of purified acetonitrile,Poured into a constant pressure funnel slowly added dropwise to the above solution,Dropping continued for about 1.5 hours, dropping the ice bath was removed device, refluxed for 24 hours.After cooling, the solvent was spun, washed with water, extracted three times with dichloromethane, dried, filtered, concentrated,Purification by column chromatography (mass ratio of 1:20 ethyl acetate and dichloromethane as eluent)Compound 2a was obtained as a yellow oil, weighing 1.8 g, yield 70percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | With tris(pentafluorophenyl)borate; In toluene;Reflux; | To the reaction flask into n-octanol 27.4 g (0.21 mol), methyl gallate 36.8 g (0.2 mol), tris (pentafluoro-phenyl) borane 2g (0.004mol) and 350 g of toluene, with heating, the system became For clarification, the reflux reaction was further slowly increased for 3 to 4hours, and the raw material was To the material being refluxed, 6.7 g of sulfhydryl silica gel was addedto capture heavy metal, hot filtered, and the filtrate was concentrated and the solvent was recovered. Then, 150 g of water was added dropwise to room temperature, and the mixture was filtered and dried to obtainan electronic grade of octyl gallate 53 g. HPLC: 99.1 %, yield: 93.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide |
Tags: 99-24-1 synthesis path| 99-24-1 SDS| 99-24-1 COA| 99-24-1 purity| 99-24-1 application| 99-24-1 NMR| 99-24-1 COA| 99-24-1 structure
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P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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