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CAS No. : | 498-02-2 | MDL No. : | MFCD00008747 |
Formula : | C9H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DFYRUELUNQRZTB-UHFFFAOYSA-N |
M.W : | 166.17 | Pubchem ID : | 2214 |
Synonyms : |
Acetovanillone;Acetoguaiacone;NSC 209524;NSC 2146
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 45.15 |
TPSA : | 46.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.95 cm/s |
Log Po/w (iLOGP) : | 1.77 |
Log Po/w (XLOGP3) : | 0.51 |
Log Po/w (WLOGP) : | 1.6 |
Log Po/w (MLOGP) : | 0.83 |
Log Po/w (SILICOS-IT) : | 1.68 |
Consensus Log Po/w : | 1.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.43 |
Solubility : | 6.18 mg/ml ; 0.0372 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.06 |
Solubility : | 14.6 mg/ml ; 0.0876 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.28 |
Solubility : | 0.876 mg/ml ; 0.00527 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.36 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-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 |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 ML, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give 1- (4-BENZYLOXY-3- methoxyphenyl) ethanone (61 g, 99 percent). |
99% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give l-(4-benzyloxy-3- methoxyphenyl)ethanone (61 g, 99 percent). |
99% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 ML, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give 1- (4-BENZYLOXY-3- methoxyphenyl) ethanone (61 g, 99 percent). |
98% | With potassium carbonate In acetone for 48 h; Reflux | The mixture of 31.62 g (190 mmol) 1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36g (118mmol) potassium carbonate, 0.5g potassium iodide, 400ml acetone and 33.15 g (190 mmol) ml benzyl bromide were refluxed for 2 days. The solventULA-P03071WO21 Application was evaporated, the residue was taken up in 400 ml of water. The precipitate was filtered, washed with 100 ml of sodium carbonate saturated aqueous solution and 2 x100 ml of water, then dried on air to give 47.8 g of product [A]. Yield 98percent. |
98% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 5 h; | Step 1) 1-(4-Benzyloxy-3-methoxyphenyl)ethanone A mixture of 4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (34.1 mL, 260 mmol) and potassium carbonate (50.0 g, 360 mmol) in DMF (800 mL) was stirred at 40° C. for 5 hours. The reaction was cooled to room temperature and poured into a mixture of ice and water (2000 mL). The solid was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (60.66 g, 98percent). MS (ESI, pos. ion) m/z: 257.2 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.55-7.54 (d, J=2 Hz, 6H), 7.51-7.49 (dd, J=2.04 Hz, J=8.36 Hz, 1H), 7.45-7.43 (m, 2H), 7.40-7.36 (m, 2H), 7.34-7.32 (d, J=7.16 Hz, 1H), 6.90-6.88 (d, J=8.36 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H), 2.55 (s, 3H). |
97.7% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667 h; Stage #2: at 40℃; for 4 h; |
6.7g (40 mmol) of D1 are successively 16.6g(120mmol) of potassium carbonate, 30ml DMF was added to a 100ml pear-shaped bottle,After stirring at 40 degrees Celsius for 10 minutes, 5.2 ml (44 mmol) of D2 was added and the reaction was carried out at 40 degrees Celsius for 4 hours. Cool to room temperature, add ice water to the reaction flask, filter, wash,After drying, white powdery solid product D3 12g (39.1 mmol) was obtained with a yield of 97.7percent |
96% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2 h; | A 100 mL dry flask was charged with acetovanillone (4.16 g, 0.025 mol) and anhydrous DMF (10 mL). Sodium hydride (1.05 g, 0.0263 mol, 60percent in mineral oil) was added and the reaction mixture was stirred at room temperature followed by the dropwise addition of benzyl bromide (3.1 mL, 0.0263 mol). The reaction was carried out at room temperature for 2 h, then poured into water. Ethyl acetate (150 mL) was used to extract out the compound and the organic layer was washed with water (2x100 mL), brine, dried over sodium sulfate, and concentrated to give the benzyl intermediate (6.21 g, 96percent), which was subsequently used without further purification. |
96% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2 h; | A 100 mL dry flask was charged with acetovanillone (4.16 g, 0.025 mol) and anhydrous DMF (10 mL). Sodium hydride (1.05 g, 0.0263 mol, 60percent in mineral oil) was added and the reaction mixture was stirred at it followed by the dropwise addition of benzyl bromide (3.1 mL, 0.0263 mol). The reaction was carried out at rt for 2 h, then poured into water. Ethyl acetate (150 mL) was used to extract out the compound and the organic layer was washed with water (2×100 mL), brine, dried over sodium sulfate, and concentrated to give the benzyl intermediate (6.21 g, 96percent), which was subsequently used without further purification. |
96.5% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | A mixture of 109 (100.0 g, 601.68 mmol), benzyl bromide (79.0 mL, 649.81 mmol) and potassium carbonate (249.0 g, 1.8 mol) in N,N-dimethylformamide (2000 mL) was heated to 40° C. overnight. The solution was cooled to room temperature, poured into ice water (1500 mL) and stirred for 1 h. The resultant solid was filtered and washed by H2O (2×500 mL), dried to give 110 (148.8 g, yield=96.5percent) as a white solid. |
95.31% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.25 h; Microwave irradiation | 0.830 g (5 mmol) of acetovanillone (1), 1.026 g (6 mmol) of benzyl bromide, 0.828 g (6 mmol) of powdered potassium carbonate, and 10 mL of dimethyl formamide were added to a microwave accelerated reaction system (Milstone Ethos A, Italy). After reacting for 15 min at 80 °C, the reaction mixture was poured into 30 mL of water and white precipitates appeared. The precipitate was collected and washed with distilled water several times and then dried at room temperature under vacuum to give compound 2 in 95.31percent yield. 1H NMR (400 MHz, CDCl3): δ 2.57 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 5.25 (s, 2H, CH2), 6.90-7.57 (m, 8H, aromatics); 13C NMR (100 MHz, CDCl3): δ 26.3 (CH3), 56.1 (OCH3), 70.8 (CH2), 112.2-152.3 (C, aromatics), 197.0 (C=O). |
91% | Stage #1: With potassium carbonate In acetone at 20℃; for 0.5 h; Stage #2: at 60℃; for 21 h; |
In a 500 ml flask Solanaceae, 4-hydroxy-3-methoxy aminoacetophenone of 20. 8g (125mmol, 1. 0eq. ), 220 ml monohydroxyacetone, potassium carbonate 17. 4g (126mmol, 1. 0eq. ) Put, 30 minutes after stirring at room temperature, a benzyl bromide 18 ml (151mmol, 1. 2eq. ) Addition, reflux in time at 60 °C 21. After condensing, the purified water and adding 200 ml, extracted with chloroform (100 ml × 3), magnesium sulfate waterlessly org. layer by drying, filtering, concentrated, recrystallization (ethyl acetate 50 ml, Phenylbicyclohexane 1 ml, 60 °C), suction filtration, vacuum drying, a first crystal is obtained. Concentrating somas, recrystallization (ethyl acetate 5 ml, 60 °C), suction filtration, vacuum drying, a second crystal is obtained. The white crystal (compd. (I1)), yielding: 29. 2g (114mmol, 91percent)is obtained. |
70.3% | With potassium carbonate; potassium iodide In acetonitrile for 24 h; Reflux; Inert atmosphere | To a solution of acetovanillone (33) (4.70 g, 28.3 mmol) in MeCN (60 mL) was added K2CO3 (8.05 g, 58.3 mmol) and KI (0.20 g, 1.2 mmol). The mixture was stirred under N2 atmosphere and benzyl bromide (34) (4.0 mL, 34 mmol) was added dropwise. The reaction mixture was reflux for 24 h and then cooled to 25° C., then resulting precipitate was filtered off. The filtrate was evaporated and purified by column chromatography (SiO2, n-hexane: CH2Cl2=1:2) to give 30. White solid; yield: 70.3percent; mp 87-88° C.; 1H-NMR (CDCl3. 200 MHz): δ 2.51 (s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.86 (d, J=8.2 Hz, 1H), 7.21-7.55 (m, 7H); 13C-NMR (CDCl3, 50 MHz): δ 26.19, 56.05, 70.79, 110.53, 112.13, 123.07, 127.18, 128.10, 128.68, 130.72, 136.28, 149.49, 152.41, 196.80; Anal. calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.02; H, 6.25. |
594.5 g | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 20℃; for 4 h; |
At room temperature, 400.0 g (2.41 mol) of 3-methoxy-4-hydroxyacetophenone II was added to 2 L of DMF. 997.7 g (7.23 mol) of anhydrous potassium carbonate was added. After stirring for 15 min, a solution of 430.2 g (2.53 mol) of benzyl bromide was added dropwise. Drop finished. Stir at room temperature for 4 h. The reaction solution was poured into 10 L of ice water. Filter. Obtained 594.5 g of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6 h; | Compound 18 (8.3 g, 50 mmol) was dissolved in DMF (50 mL) and then anhydrous K2CO3 (2.5 g) and benzyl chloride (6.3 g, 50 mmol) were added. The reaction mixture was stirred at 80 °C for 6 h. The resulting crude was dissolved in H2O and extracted with EtOAc and then was purified by silica gel column chromatography to obtain 19 (12 g, 94percent) as a white powder, m.p. 82-84 °C; IR (neat) νmax 2873, 1670, 1585, 1512, 1458, 115, 1350, 1276, 1215, 1145, 1076, 991, 871, 798, 748 cm-1; 1HNMR (300 MHz, CDCl3) δ 7.57-7.33 (7H, m), 6.90 (1H, d, J = 9.0 Hz), 5.23 (2H, s), 3.95 (3H, s), 2.55 (3H, s); 13CNMR (75 MHz, CDCl3) δ 196.6, 152.2, 149.3, 136.1, 130.5, 128.5, 127.9, 127.0, 122.9, 111.9, 110.3, 70.6, 55.8, 26.0; EIMS m/z (rel. int.): 256 [M]+ (39), 92 (26), 91 (100), 65 (24); HREIMS calcd for C16H16O3 [M]+ 256.1099, found 256.1096. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In tetrahydrofuran at 20℃; for 3 h; | Reference Example 1. Preparat ion of intermedi ate (1) : 4-acetyl-2- methoxyphenyl acetate ( 1)<328>1<329><330> As shown in the above-descr ibed react ion formula, acetovani l lone(500mg , 3mM) di ssolved in 20 ml of THF was mixed wi th 0.5 ml of pyr idine and 0.6 ml of anhydrous acet ic acid. The mixture was st i rred for 3 hours at room <n="38"/>temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:l) to obtain white solid type of 4-acetyl-2-methoxyρhenyl acetate (1 ; 625mg).<331> <332> m.p.: 58.7 °C ;<333> 1H NMR (CDCl3) : δ ppm 7.60 (d, 1 H1 J = 1.8 Hz , H-3), 7.55 (dd, 1 H, J = 1.8, 8.2 Hz, H-5), 7.12 (d, 1 H, J = 8.2 Hz, H-6), 3.89 (s, 3 H, OCH3), 2.59 (s, 3 H, OCOCH3), 2.33 (s, 3 H, COCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.23% | With aluminum (III) chloride In nitrobenzene at 40℃; for 3h; Large scale; | 4-11 Example 4: Add ferric chloride (9.73g, 0.06mol) to 25ml of nitrobenzene and stir well.Add 2-methoxyphenyl acetate (5.0g, 0.03mol) dropwise and react at 60 for 8h,The system was cooled to room temperature, concentrated hydrochloric acid was added until the system was clear, and extracted with 25ml 1,2-dichloroethane,Combine the organic phases. The organic phase was washed with 25 ml of 2 mol / L sodium hydroxide, and the aqueous phase was collected.The aqueous phase was acidified with concentrated hydrochloric acid to pH = 2 ~ 3, and then extracted with 1,2-dichloroethane 20ml, the organic phases were combined and concentrated under reduced pressure,The crude product was recrystallized using 10 ml of ethanol. The purity by liquid chromatography was 99%, and the yield was 55%. |
75% | With methanesulfonic acid In dichloromethane Flow reactor; | |
67% | With methanesulfonic acid; phosphorus pentoxide at 90℃; for 5h; | 1-(4-Hydroxy-3-methoxyphenyl)ethanone (63) A mixture of 2-methoxyphenyl acetate 62 (7.08 g, 42.6 mmol) and Eaton’s reagent (3.18 g P2O5 in 21.48 mL CH3SO3H) was stirred vigorously at 90 °C for 5 h. The reaction mixture was diluted with water, neutralized with aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, and concentrated to leave a brown oil. Further purification by silica chromatography (CH2Cl2/MeOH 95/5) gave transposition product 63 (4.74 g, 67%) as an off-white solid; mp (CH2Cl2/MeOH) 114-115 °C (lit. 114-116 °C);44 1H NMR (CDCl3, 200 MHz) δ (ppm) 2.57 (s, 3H, COCH3), 3.96 (s, 3H, OCH3), 6.11 (s, 1H, ArOH), 3.98 (s, 3H, OCH3), 6.95 (d, J = 8.2 Hz, 1H, ArH), 7.51-7.55 (m, 2H, ArH). |
67% | With eaton’s reagent at 90℃; for 5h; | 1-(4-hydroxy-3-methoxyphenyl)ethanone (41)32 (Scheme 4). A mixture pf 2-methoxyphenyl acetate 40 (7.08 g, 42.6 mmol) and Eaton's reagent (3.18 g P2O5 in 21.48 mL CH3SO3H) was stirred vigorously at 90 °C for 5 h. The reaction mixture was diluted with water, neutralized with aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, and concentrated to leave a brown oil. Further purification by silica chromatography (CH2Cl2/MeOH 95/5) gave transposition product 41 (4.74 g, 67 %) as an off-white solid; mp (CH2Cl2/MeOH) 114-115 °C (lit. 114-116 °C);44 1H NMR (CDCl3, 200 MHz) δ (ppm) 2.57 (s, 3H, COCH3), 3.96 (s, 3H, OCH3), 6.11 (s, 1H, ArOH), 3.98 (s, 3H, OCH3), 6.95 (d, J=8.2 Hz, 1H, ArH), 7.51-7.55 (m, 2H, ArH). |
60% | With methanesulfonic acid; phosphorus pentoxide Inert atmosphere; | |
10% | With phosphorus pentoxide In methanesulfonic acid at 90℃; for 5h; Inert atmosphere; | 4-Hydroxy-3-methoxyacetophenone (37) A mixture of 2-methoxyphenyl acetate 36 (3.14 mL, 21.3 mmol), phosphorous pentoxide (1.60 g, 11.3 mmol) and methanesulfonic acid (11.0 mL, 170 mmol) was stirred vigorously at 90 °C for 5 h under nitrogen. The reaction mixture was diluted with H2O (50 mL), neutralized with aqueous NaHCO3 solution and extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, CH2Cl2) to afford acetophenone 37 (344 mg, 10%) as a pale yellow-white powdery solid. |
With zinc(II) chloride at 200℃; | ||
With aluminium trichloride; nitrobenzene | ||
4.4 g | With methanesulfonic acid; phosphorus pentoxide at 90℃; for 5h; | 1.4 Step 2 (Fries Phenol Ester Rearrangement): The product obtained in the previous step was dissolved in Eaton's reagent (3.18 g of phosphorus pentoxide dissolved in 21.48 ml of methanesulfonic acid solution) and stirred vigorously at a temperature of 90 ° C for 5 hours.Then, the reaction solution was quenched with water, and the reaction solution was neutralized to neutrality with a saturated sodium bicarbonate solution. 3 * 50ml dichloromethane extraction, mixed organic phase, dried over anhydrous sodium sulfate,Filtration and concentration under reduced pressure gave a crude brown oil.The crude product was crystallized from an ethyl acetate / n-hexane system to obtain 4.4 g (67% yield) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In methanol; water at 20℃; for 96h; Inert atmosphere; | (E)-1-(3,4-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one 12. To a stirred solution of KOH (1.14 g, 20.32 mmol) in water (4 mL) was added dropwise a solution of 3,4-dimethoxybenzaldehyde (1.70 g, 10.23 mmol) and apocynin (1.70 g, 10.23 mmol) in methanol (20 mL). The reaction mixture was stirred at room temperature for 96 h under N2. The mixture was poured into ice-water (10 mL), adjusted to pH 3-4 with hydrochloridric acid (10% solution), and then extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulphate and purified by flash chromatography using a 2:1 mixture of ethyl acetate:petroleum as eluent to give 12 as a yellow solid (2.72 g, 85%): |
With methanol; potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | General procedure for synthesis of 1-(4-phenoxyacetonitrile-3-methoxyphenyl)ethanone 2: To the stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone 1 (5 mmol) in DMFadded potassium carbonate (10 mmol) and chloroacetonitrile (5 mmol) at room temperaturefor about 3-4 h and on completion, as evident by TLC, reaction mixture quenched withcrushed ice and precipitated solid were collected by filtration and recrystallized from ethanolto give desired product as white crystals (mp 242-244°C). |
With potassium carbonate; acetone; potassium iodide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In ethanol at 70℃; | |
98% | With potassium carbonate In acetone at 20℃; for 24h; | 1 Step 1; Synthesis of 1-(4-allyloxy-3-methoxyphenyl)ethanone 4-Hydroxy-3-methoxyacetophenone (5.00 g, 30.1 mmol) was put into a 300 mL eggplant flask to be dissolved in acetone (50 mL), potassium carbonate (6.24 g, 45.1 mmol) was added thereto, the solution was stirred at room temperature for 5 minutes, allyl bromide (5.46 g, 45.1 mmol) was added thereto, and the resulting solution was stirred at room temperature for 24 hours. After concentration, ethyl acetate (50 mL×2) and pure water (50 mL) were added to the solution for extraction, and the organic layer was sequentially washed with a saturated sodium carbonate aqueous solution (50 mL×3) and saturated saline solution (50 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated, thereby obtaining 6.09 g (29.5 mmol, 98%) of pale yellow oil (intermediate compound 11; 1-(4-allyloxy-3-methoxyphenyl)ethanone). (0146) The identification result of the obtained intermediate compound 11 is described below. (0147) 1H NMR (CDCl3/TMS, 400 MHz): δ 2.57 (3H, s), 3.94 (3H, s), 4.69 (2H, dt, J=5.4, 1.5 Hz), 5.33 (1H, dq, J=11, 1.3 Hz), 5.43 (1H, dq, J=17, 1.5 Hz), 6.09 (1H, ddt, J=17, 11, 5.4 Hz), 6.89 (1H, d, J=9.0 Hz), 7.52-7.56 (2H, m). |
With potassium carbonate; acetone |
With potassium carbonate In acetone Reflux; | 4.2.9. Procedure for the synthesis of chalcones 27-32 via 8b-13b(Table 3, Scheme 4) General procedure: To a 250 mL round bottom flask containing substituted hydroxybenzaldehyde (5a or 6a or 7a or 8a or 9a or 10a) (1.9 mmol)in dry acetone (20 mL), allyl bromide (2.0 mmol) and anhydrous K2CO3 (3.8 mmol) were added. The remaining procedure was similar to that described for 1b. Compound 8b-13b obtained, respectively after column chromatography over silica gel with hexane-ethyl acetate (9:1) was treated with 4-chloroacetophenone (3 mmol) in methanol (20 mL) and 10% aqueous NaOH (4 mmol). The remaining procedure was similar to as described above. The desired compound 27-32 obtained after recrystallization from MeOH and water was characterized by 1H & 13C NMR and HRMS data. | |
With potassium carbonate In acetone for 3.16667h; Reflux; | 1-(4-(Allyloxy)-3-methoxyphenyl)butane-1,3-dione (14f) To a solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (0.20 g, 1.22 mmol) in dry acetone (20 mL) was added anhydrous K2CO3 (0.67 g, 4.88 mmol) over 10 min, followed by addition of allyl bromide (0.17 g,1.34 mmol), and the mixture was stirred under reflux for an additional 3 h. The mixture wascooled and evaporated, and the resulting slurry was dissolved in dichloromethane (30 mL),washed with water (2 × 15 mL), and dried over Na2SO4. Evaporation of the solvent gave 13f ascolourless oil. The intermediate 14f was obtained from 1-(4-(allyloxy)-3-methoxyphenyl)-ethanone 13f by following the procedure described above for 16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride;palladium; In ethanol; | (A) 4-ethyl-2-methoxyphenol Acetovanillone (Aldrich, 11.0 g, 0.066 mol) was dissolved in absolute ethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A few drops of concentrated hydrochloric acid were added and the mixture hydrogenated on a shaker at 42 psi. The reaction mixture was filtered through celite, and the filtrate was concentrated to afford 10.3 g of a golden liquid. This was diluted with water, extracted with diethyl ether and the organic phase was washed with water and sodium bicarbonate. The solvent was dried (MgSO4) and concentrated to afford 9.3 g of a slightly yellow liquid. | |
With hydrogenchloride;palladium; In ethanol; | (A) 4-ethyl-2-methoxyphenol Acetovanillone (Aldrich, 11.0 g, 66 mmol) was dissolved in absolute ethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A few drops of concentrated hydrochloric acid were added and the mixture hydrogenated on a shaker at 42 psi. The reaction mixture was filtered through Celite, and the filtrate was concentrated to afford 10.3 g of a golden liquid. This was diluted with water, extracted with diethyl ether and the organic phase was washed with water and sodium bicarbonate. The solvent was dried (MgSO4) and concentrated to afford 9.3 g of a slightly yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tetrahydroborate In ethanol for 3h; Ambient temperature; | |
65% | With iron(III) chloride; C6H13BN2 In dichloromethane at 20℃; | General procedure for reduction of ketones by NHC-BH3 9a-r General procedure: To a solution of ketone (0.25 mmol) in DCM (1 mL) was added NHC-BH3 4 (24-27 mg, 0.2-0.25 mmol) and anhydrous FeCl3 (0.125-0.25 mmol) at room temperature, the mixture was stirred for 30 min-1 h. The residue was dried in vacuo and purified by flash column chromatography (silica gel) to give the corresponding alcohols 9a-r. |
With sodium hydroxide; sodium tetrahydroborate |
With sodium tetrahydroborate | ||
Multi-step reaction with 2 steps 1: ethanolic NaOH 2: NaBH4; aqueous methanol. NaOH / Hydrieren des Reaktionsprodukts an Palladium/Kohle in Aethanol | ||
With [Ru(CO)H(κ1-P-PPh2Py)2(en)]BF4; isopropyl alcohol; potassium hydroxide at 80℃; for 24h; Inert atmosphere; | ||
8 %Chromat. | With sodium carbonate; isopropyl alcohol at 82℃; for 8h; Inert atmosphere; | |
27 %Spectr. | With methanol; borane-ammonia complex at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Glovebox; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With nitric acid; acetic acid at 0 - 20℃; for 3h; | |
91% | With nitric acid; acetic acid at 0 - 20℃; for 3h; | 1.1 (1) Synthesis of compound 2: Dissolve 8.3 g of 4-hydroxy-3-methoxyacetophenone (compound 1) in an acetic acid solvent, slowly add 4 mL of dilute nitric acid dropwise at 0°C, and stir for 3 hours at room temperature. After the completion of the reaction, the reaction solution was poured into ice water to separate out the precipitate, which was filtered and dried to obtain compound 2 with a yield of 91.0%. |
90% | With nitric acid In acetic acid at 20℃; for 4h; | 4.1.1. Synthesis of intermediate 3 and 4 The synthesis method of intermediates 3 and 4 were totallyprepared as our previously reported method [22]. The commerciallyavailable material compound 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one (1, 3.32 g, 20 mmol) was dissolvedwith 50 mL of AcOH, followed by adding 60% HNO3 (2 mL) andstirred at room temperature for 4 h. After the reaction wascompleted, which was monitored by thin layer chromatography(TLC), the ice was added to yield a large amount of yellow precipitation.The precipitation was filtered to obtain the product compound2 in the yield of 90% without further purification.To a suspension of compound 2 (2.11 g, 10 mmol) in 100 mL ofDMF, K2CO3 (3.45 g, 25 mmol) and tetrabutylammonium fluoride(2.61 g, 10 mmol) were in order added. The CH3I (2.13 g, 15 mmol)was added and the mixturewas stirred at 50 °C for 24 h. The reactionwas quenched by adding of icewater. Then, the mixturewas filteredand the obtained crude product was purified over silica gel (ethylacetate: petroleum 1:5) to obtain intermediate 3 as white solid.Yield 81%. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.72 (s, 1H), 4.04(s, 3H), 4.01 (s, 3H), 2.63 (s, 3H).13C NMR (101 MHz, CDCl3) d 195.01,154.01, 146.47, 144.14, 132.11, 116.80, 114.32, 61.99, 56.51, 26.18. |
83% | With nitric acid; acetic acid for 0.5h; | Preparation of 2-bromo-1-(4-hydroxy-3-methoxy-5-nitrophenyl)ethanone (3) 10041] 1 -(4-Hydroxy-3-methoxy-5-nitrophenyl)ethanone((a) L. E. Kiss, H. S. Ferreira, L. Torrio, M. J. Bonifcio, P. N.Palma, P Soares-da-Silva, D. A. Learnmonth, J. Med. Chem.,2010, 53, 3396-3411; (b) X. Lu, S. Wan, J. Jiang, X. Jiang, W.Yang, P. Yu, L. Xu, Z. Zhang, G. Zhang, L. Shan, Y. Wang, Eur. J. Med. Chem., 2011, 46, 2691-2698). To a solution of 4'-hydroxy-3'-methoxyacetophenone (10 g; 60.2 mmol) in acetic acid (140 ml) at AT, 70% HNO3 is added (4.2 ml; 66.3 mmol). The reaction mixture is stirred for 30 min and the yellow crystals are filtered, washed with ether and dried to arrive at 1-(4-Hydroxy-3-methoxy-5-nitrophenyl)ethanone (10.5 g; 83%), mp 158-159° C. (lit. 159-161° C., ethanol, X. Lu, S. Wan, J. Jiang, X. Jiang, W. Yang, P. Yu, L. Xu, Z. Zhang, G. Zhang, L. Shan, Y. Wang, Eur. J. Med. Chem., 2011, 46, 2691-2698). 1H NMR (CDCl3; 300 MHz) δ (ppm) 11.09 (1H; s), 8.30 (1H; d; J=1.5 Hz); 7.75 (1H; d; J=1.5 Hz); 4.01 (3H; s); 2.62 (3H; s). 13C NMR (CDCl3; 75 MHz) δ (ppm) 194.9; 150.4; 150.1; 133.0; 128.3; 117.7; 115.3; 56.9; 26.0. IR (neat) vmax cm-1 3228; 3091; 2988; 2925; 1676; 1612; 1535; 1413; 1378; 1350; 1329; 1218; 1136; 1047; 869; 735; 709; HRMS (DE) (m/z) [M-H]- calculated for C9H8NO5 210.0402. obtained 210.0404. |
83% | With nitric acid; acetic acid at 20℃; for 0.5h; | |
80% | With nitric acid; acetic acid at 20℃; for 0.5h; regioselective reaction; | |
78% | With nitric acid In acetic acid for 3h; Cooling with ice; | 1 Example 1: Synthesis of Compound Apo-NO2 Take apocynin (1.66g, 10mmol), add 10ml glacial acetic acid to dissolve, slowly add 67wt% concentrated nitric acid 1.5ml under ice bath, react for 30min, remove ice water, react at room temperature for 3h, add to the system after the reaction is over. Ice water was filtered under suction to give a yellow solid, which was crystallised from EtOAc (EtOAc) This compound is a known compound and is shown by mass spectrometry and nuclear magnetic spectroscopy to be consistent with the patterns described in the literature. |
75% | With nitric acid; acetic acid at 0 - 20℃; | 5.4. 1-(4-Hydroxy-3-methoxy-5-nitrophenyl)ethanone (4) Apocynin 1 (20 g, 120 mmol), dissolved in glacial acetic acid (300 ml), was cooled to 0 °C in an ice bath with stirring on. Nitric acid (65%, 14 ml, 224 mmol) was then added slowly through a dropping funnel. The reaction mixture was maintained at room temperature for 2 h and was then poured into ice water (250 ml) with stirring on for 10 min. After 30 min of standing, the reaction mixture was filtered through a Buchner funnel and the residue was washed with water, which was recrystallized in 95% ethanol to afford 19.1 g (75% yield) of 4 as a yellow needle crystal, mp: 159-161 °C. 1H NMR (CDCl3, 400 MHz): 11.13 (s, 1H, OH), 8.31 (d, 1H, J = 1.6 Hz, ArH), 7.77-7.76 (d, 1H, J = 1.6 Hz, ArH), 4.01 (s, 3H, OCH3), 2.63 (s, 3H, CH3CO). MS (ESI) m/z 212 [M + H]+. Analysis calculated for C9H9NO5·0.2H2O: C, 50.33; H, 4.41; N, 6.52. Found: C, 50.63; H, 4.23; N, 6.26. |
55% | With nitric acid; acetic acid at 20℃; | |
With diethyl ether; water; nitric acid; sodium nitrite | ||
With nitric acid | ||
24.0 g (75%) | With nitric acid In water | 18 4'-Hydroxy-3'-methoxy-5'-nitroacetophenone EXAMPLE 18 4'-Hydroxy-3'-methoxy-5'-nitroacetophenone To a solution containing 40 ml of nitric acid (d=1.41) and 40 ml of water was gradually added while cooling (below 7° C.) and stirring 25.0 g of 4'-hydroxy-3'-methoxyacetophenone. After stirring for 0.5 h at 0° C. the product was filtered, washed first with diluted nitric acid (1:1) and then with water. Yield 24.0 g (75%). The 1 H-NMR-spectrum of the product was in accordance with the structure alleged. |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With sulfuric acid In acetic acid at 5 - 10℃; for 0.166667h; Stage #2: With nitric acid In acetic acid at 20℃; for 2h; | ||
With nitric acid; acetic acid In water at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; | |
99% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | 18 A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give l-(4-benzyloxy-3- methoxyphenyl)ethanone (61 g, 99 %). |
99% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | 32 A solution of 4-hydroxy-3- methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 ML, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give 1- (4-BENZYLOXY-3- methoxyphenyl) ethanone (61 g, 99 %). |
98% | With potassium carbonate; potassium iodide In acetonitrile for 24h; Heating; | |
98% | With potassium carbonate In acetone for 48h; Reflux; | 1 The mixture of 31.62 g (190 mmol) 1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36g (118mmol) potassium carbonate, 0.5g potassium iodide, 400ml acetone and 33.15 g (190 mmol) ml benzyl bromide were refluxed for 2 days. The solventULA-P03071WO21 Application was evaporated, the residue was taken up in 400 ml of water. The precipitate was filtered, washed with 100 ml of sodium carbonate saturated aqueous solution and 2 x100 ml of water, then dried on air to give 47.8 g of product [A]. Yield 98%. |
98% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 5h; | 15.1 Step 1) 1-(4-Benzyloxy-3-methoxyphenyl)ethanone A mixture of 4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (34.1 mL, 260 mmol) and potassium carbonate (50.0 g, 360 mmol) in DMF (800 mL) was stirred at 40° C. for 5 hours. The reaction was cooled to room temperature and poured into a mixture of ice and water (2000 mL). The solid was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (60.66 g, 98%). MS (ESI, pos. ion) m/z: 257.2 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.55-7.54 (d, J=2 Hz, 6H), 7.51-7.49 (dd, J=2.04 Hz, J=8.36 Hz, 1H), 7.45-7.43 (m, 2H), 7.40-7.36 (m, 2H), 7.34-7.32 (d, J=7.16 Hz, 1H), 6.90-6.88 (d, J=8.36 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H), 2.55 (s, 3H). |
98% | With potassium carbonate; potassium iodide In acetonitrile for 24h; Reflux; | |
98% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 21h; | |
97.7% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; for 4h; | 1 6.7g (40 mmol) of D1 are successively 16.6g(120mmol) of potassium carbonate, 30ml DMF was added to a 100ml pear-shaped bottle,After stirring at 40 degrees Celsius for 10 minutes, 5.2 ml (44 mmol) of D2 was added and the reaction was carried out at 40 degrees Celsius for 4 hours. Cool to room temperature, add ice water to the reaction flask, filter, wash,After drying, white powdery solid product D3 12g (39.1 mmol) was obtained with a yield of 97.7% |
97.7% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; for 4h; | |
97.7% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; for 4h; | 1 6.7 g (40 mmol) of D1, 16.6 g (120 mmol) of potassium carbonate, 30 ml of DMF were added to a 100 ml pear-shaped bottle, and the mixture was stirred at 40 degrees Celsius for 10 minutes. Add 5.2ml (44mmol) D2, and react at 40 °C for 4h. Cool to room temperature, add ice water to the reaction flask, filter, wash with water, and dry to obtain 12 g (39.1 mmol) of white powdery solid product D3, yield 97.7% |
97% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 14h; Inert atmosphere; | 5 1 -(4-(benzyloxy)-3-methoxyphenyl)ethan-1 -one To a stirred solution of acetovanillone (6 g, 36.1 mmol) in DMF (120 ml.) at rt was added K2C03 (7.48 g, 54.15 mmol, 1.5 equiv.) followed by benzyl bromide dropwise (4.66 ml_, 38.99 mmol, 1.08 equiv.). The reaction mixture was stirred for 14 hrs at 40 °C before being cooled down to rt where it was poured into 1 L of water/ice mixture and stirred for 10 minutes. The suspension was then filtered using a Buchner funnel under vacuum, the solid rinsed with water (3 x 70 ml.) at 0°C, before being left under vacuum in the Buchner funnel for one hour. The solid was then transferred into a round bottom flask and dried to a constant weight on the high vacuum line giving 8.99g (97% yield) of the titled compound. (C. Miesch, T. Emrick, J. Colloid Interface Sci. 2014, 425, 152-8). (0345) 1H NMR (400 MHz, Chloroform-d) d 7.55 (d, J = 2.0 Hz, 1 H), 7.50 (dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (dd, J = 8.2, 1.4 Hz, 2H), 7.38 (m, 2H), 7.34 - 7.29 (m, 1 H), 6.91 - 6.87 (m, 1 H), 5.23 (s, 2H), 3.94 (s, 3H), 2.55 (s, 3H). |
96% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | 8 A 100 mL dry flask was charged with acetovanillone (4.16 g, 0.025 mol) and anhydrous DMF (10 mL). Sodium hydride (1.05 g, 0.0263 mol, 60% in mineral oil) was added and the reaction mixture was stirred at room temperature followed by the dropwise addition of benzyl bromide (3.1 mL, 0.0263 mol). The reaction was carried out at room temperature for 2 h, then poured into water. Ethyl acetate (150 mL) was used to extract out the compound and the organic layer was washed with water (2x100 mL), brine, dried over sodium sulfate, and concentrated to give the benzyl intermediate (6.21 g, 96%), which was subsequently used without further purification. |
96% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; | 9 A 100 mL dry flask was charged with acetovanillone (4.16 g, 0.025 mol) and anhydrous DMF (10 mL). Sodium hydride (1.05 g, 0.0263 mol, 60% in mineral oil) was added and the reaction mixture was stirred at it followed by the dropwise addition of benzyl bromide (3.1 mL, 0.0263 mol). The reaction was carried out at rt for 2 h, then poured into water. Ethyl acetate (150 mL) was used to extract out the compound and the organic layer was washed with water (2×100 mL), brine, dried over sodium sulfate, and concentrated to give the benzyl intermediate (6.21 g, 96%), which was subsequently used without further purification. |
96.5% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | 2 Compound 110 A mixture of 109 (100.0 g, 601.68 mmol), benzyl bromide (79.0 mL, 649.81 mmol) and potassium carbonate (249.0 g, 1.8 mol) in N,N-dimethylformamide (2000 mL) was heated to 40° C. overnight. The solution was cooled to room temperature, poured into ice water (1500 mL) and stirred for 1 h. The resultant solid was filtered and washed by H2O (2×500 mL), dried to give 110 (148.8 g, yield=96.5%) as a white solid. |
96% | With potassium carbonate In N,N-dimethyl-formamide | 4 Preparation method of robustine derivative-4-benzyloxy-3-methoxyacetophenone: 4.15 g (25 mmol) of apomatine was dissolved in 40 ml of DMF, 4 g of potassium carbonate and 5.85 g of iodoethane were added thereto, and stirred vigorously at room temperature. After 2 hours of reaction, TLC monitors that the raw materials have been completely reacted. It is poured into 150 ml of water, a large amount of solids are precipitated, and filtered to dry. 4-ethoxy-3-methoxyacetophenone was obtained in a yield of 96%. |
95.31% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.25h; Microwave irradiation; | 3 3-Methoxy-4-benzyloxyacetophenone (2) 0.830 g (5 mmol) of acetovanillone (1), 1.026 g (6 mmol) of benzyl bromide, 0.828 g (6 mmol) of powdered potassium carbonate, and 10 mL of dimethyl formamide were added to a microwave accelerated reaction system (Milstone Ethos A, Italy). After reacting for 15 min at 80 °C, the reaction mixture was poured into 30 mL of water and white precipitates appeared. The precipitate was collected and washed with distilled water several times and then dried at room temperature under vacuum to give compound 2 in 95.31% yield. 1H NMR (400 MHz, CDCl3): δ 2.57 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 5.25 (s, 2H, CH2), 6.90-7.57 (m, 8H, aromatics); 13C NMR (100 MHz, CDCl3): δ 26.3 (CH3), 56.1 (OCH3), 70.8 (CH2), 112.2-152.3 (C, aromatics), 197.0 (C=O). |
94% | With potassium carbonate In acetone Reflux; Inert atmosphere; | |
91% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: benzyl bromide In acetone at 60℃; for 21h; | 1 In a 500 ml flask Solanaceae, 4-hydroxy-3-methoxy aminoacetophenone of 20. 8g (125mmol, 1. 0eq. ), 220 ml monohydroxyacetone, potassium carbonate 17. 4g (126mmol, 1. 0eq. ) Put, 30 minutes after stirring at room temperature, a benzyl bromide 18 ml (151mmol, 1. 2eq. ) Addition, reflux in time at 60 °C 21. After condensing, the purified water and adding 200 ml, extracted with chloroform (100 ml × 3), magnesium sulfate waterlessly org. layer by drying, filtering, concentrated, recrystallization (ethyl acetate 50 ml, Phenylbicyclohexane 1 ml, 60 °C), suction filtration, vacuum drying, a first crystal is obtained. Concentrating somas, recrystallization (ethyl acetate 5 ml, 60 °C), suction filtration, vacuum drying, a second crystal is obtained. The white crystal (compd. (I1)), yielding: 29. 2g (114mmol, 91%)is obtained. |
91% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; Inert atmosphere; | |
90% | With potassium carbonate In N,N-dimethyl-formamide | |
89% | With potassium carbonate; potassium iodide In acetonitrile Inert atmosphere; Reflux; | |
87.98% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 12h; Reflux; | |
82% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In tetrahydrofuran; water at 80℃; for 10h; | |
70.3% | With potassium carbonate; potassium iodide In acetonitrile for 24h; Reflux; Inert atmosphere; | I.A.2.C To a solution of acetovanillone (33) (4.70 g, 28.3 mmol) in MeCN (60 mL) was added K2CO3 (8.05 g, 58.3 mmol) and KI (0.20 g, 1.2 mmol). The mixture was stirred under N2 atmosphere and benzyl bromide (34) (4.0 mL, 34 mmol) was added dropwise. The reaction mixture was reflux for 24 h and then cooled to 25° C., then resulting precipitate was filtered off. The filtrate was evaporated and purified by column chromatography (SiO2, n-hexane: CH2Cl2=1:2) to give 30. White solid; yield: 70.3%; mp 87-88° C.; 1H-NMR (CDCl3. 200 MHz): δ 2.51 (s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.86 (d, J=8.2 Hz, 1H), 7.21-7.55 (m, 7H); 13C-NMR (CDCl3, 50 MHz): δ 26.19, 56.05, 70.79, 110.53, 112.13, 123.07, 127.18, 128.10, 128.68, 130.72, 136.28, 149.49, 152.41, 196.80; Anal. calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.02; H, 6.25. |
With potassium carbonate In acetonitrile for 4h; Heating / reflux; | 9 Reference Example 9 30 g of 4-acetyl-2-methoxyphenol, 32 g of benzyl bromide, 28 g of potassium carbonate and 300 ml of acetonitrile were mixed and stirred under condition of reflux for 4 hours. Then the reaction mixture was cooled to room temperature. Ethyl acetate was added to it, and the solid was filtered off. The obtained organic layer was concentrated under reduced pressure. The residue was washed by hexane to obtain 46 g of 4-benzyloxy-3-methoxyacetophenone.1H-NMR (CDCl3, TMS) δ (ppm): 7.28-7.57 (7H, m), 6.89 (1H, d, J=8.3 Hz), 5.23 (2H, s), 3.94 (3H, s), 2.54 (3H, s) | |
With potassium carbonate In acetonitrile for 4h; Heating / reflux; | 11 Reference Example 11 Reference Example 11 30 g of 4-acetyl-2-methoxyphenol, 32 g of benzyl bromide, 28 g of potassium carbonate and 300 ml of acetonitrile were mixed and stirred under reflux for 4 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added and the mixture was filtered. The resulting filtrate was concentrated under reduced pressure. The residue was washed with hexane to obtain 46 g of 4-benzyloxy-3-methoxyacetophenone. 1H-NMR (CDCl3, TMS) δ (ppm): 7.28-7.57 (7H, m), 6.89 (1H, d, J = 8.3 Hz), 5.23 (2H, s), 3.94 (3H, s), 2.54 (3H, s) | |
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; | ||
594.5 g | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | 22.1 Step (1) 3-methoxy-4-benzyloxyacetophenone (XIV) At room temperature, 400.0 g (2.41 mol) of 3-methoxy-4-hydroxyacetophenone II was added to 2 L of DMF. 997.7 g (7.23 mol) of anhydrous potassium carbonate was added. After stirring for 15 min, a solution of 430.2 g (2.53 mol) of benzyl bromide was added dropwise. Drop finished. Stir at room temperature for 4 h. The reaction solution was poured into 10 L of ice water. Filter. Obtained 594.5 g of a white solid. |
With potassium carbonate; potassium iodide In acetonitrile at 80℃; for 12h; | A.A1 Step A1: 1- (4-Benzyloxy-5-methoxyphenyl) ethanone (A.1) 47.7 g (287 mmol) of 1- (4-hydroxy-5-methoxyphenyl) ethanone,47.5 g (344 mmol, 1.2 equiv.) Of K2CO3, 0.5 g of KI and 53.3 g(37.0 mL, 301 mmol, 1.05 eq.) Of benzyl bromide in 400 mL of acetonitrile was heated to 80 ° C for 12 hours. The reaction solution was cooled to room temperature, filtered through silica gel (50 g) and washed twice with ethyl acetate (100 mL).The filtrate was dried to give a white crystalline solid which was used directly in the next step. | |
With potassium carbonate In N,N-dimethyl-formamide at 50℃; | ||
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 1h; Inert atmosphere; | 1.1 Step 1: [068] To a stirred solution of 10.0 g (60.2 mmol) of 1-(4-hydroxy-3-methoxyphenyl)ethan-1 -one in 200 ml. of DMF were added 12.5 g (90.5 mmol) of K2CO3 and 1 1.3 g (66.07 mmol) of benzyl bromide. The reaction mixture was stirred at 40 °C for 1 h under N2 atmosphere. It was diluted with 500 ml. of water, and filtered; the filter cake was washed with water to obtain compound 1-1 , which was used in the next step without further purification. LC-MS: m/e = 257 [M+H]+. | |
297.3 g | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | 1.1 Step 1. Synthesis of 3-methoxy-4-benzyloxyacetophenone (Intermediate 1) At room temperature, vanillone (200.0g, 1.21mol) was added to 1L DMF, anhydrous potassium carbonate (498.9g, 3.62mol) was added, and after stirring for 15min, benzyl bromide (215.1g, 1.27mol) was added dropwise, after the dropping, the mixture was stirred at room temperature for 4h.The reaction solution was poured into 4L of ice water and filtered with suction to obtain 297.3 g of white solid. |
With potassium carbonate; potassium iodide In acetonitrile Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetonitrile at 20 - 80℃; for 3h; | |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; | 1 7.1.1 4-(3-Chloropropoxy)-3-methoxyacetophenone (10) To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00g, 36.1mmol) in DMF (25mL) was added K2CO3 and 1-bromo-3-chloropropane (6.98g, 50.6mmol). The reaction mixture was then stirred at rt for 10h. The mixture was then poured into cold water (100mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford the title compound 10 (8.27g) as a white solid, yield: 93.8%. Mp: 61-63°C (Lit.33 Mp: 57.5-58.5°C). MS (ESI) m/z: 242.2, 244.1 (M+). |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; |
93.8% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 25℃; for 10h; | 1.A Example 1 N-[3-fluoro-4-[6-methoxy-7-[3-(tetrahydropyrrol-1-yl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide Step A 1-[4-(3-chloropropyloxy)-3-methoxy]phenylethanone (II) 3-methoxy-4-hydroxyphenylethanone (600 g, 3.61 mol) and anhydrous potassium carbonate (698 g, 5.055 mol) were added to DMF (5v/w, 2500 mL). The mixture was stirred thoroughly at 25° C. for 30 min. Then 1,3-bromochloropane (795.9 g, 1.4 mol) was slowly added dropwise to the mixture. After the dropwise addition, the mixture was reacted under stirring at 25° C. for 10 h. After completion of the reaction, the mixture was filtered by suction. The filtered cake was washed with a small amount of DMF. The filtrate was collected, and slowly poured into ice-water. The mixture was violently stirred to separate out a white solid. The white solid was filtered by suction. The filtered cake was dried to produce a white solid (827.2 g) in a yield of 93.8%. |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 10h; | 1.A Step A: 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (intermediate II) Step A 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (intermediate II) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9g, 1.4 mol) while maintaining the temperature below 25°C. Then the resulted mixture was kept at 25°C for 10h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide.The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2g solid. Yield: 93.8%. |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 10h; | 1.A 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (Intermediate II) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9 g, 1.4 mol) while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2 g solid. Yield: 93.8%. |
93.8% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 30h; Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 25℃; for 10h; | 1.A Step A: 1-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (III) 1-(4-Hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Zhejiang Dongdong Pharmaceutical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) was added to 2500 mL of dry N,N-dimethylformamide. The mixture was stirred for 30 min at room temperature and then 1-bromo-3-chloropropane (795.9 g, 1.4 mol) was drop-wise added while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice-water slowly with vigorous stirring. Then the resulted mixture was stirred for 30 min. The precipitate was filtered, washed with water, and dried to give 827.2 g as white solid. Yield: 93.8%. |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; | 6.2. 4-(3-Chloropropoxy)-3-methoxyacetophenone (10) To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00 g,36.1 mmol) in DMF (25 mL) was added K2CO3 and 1-bromo-3-chloropropane (6.98 g, 50.6 mmol). The reaction mixture was thenstirred at rt for 10 h. The mixture was then poured into cold water(100 mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum toafford the title compound 10 (8.27 g) as a white solid, yield:93.8%. Mp: 61-63 C. MS (ESI) m/z: 242.2, 244.1 [M+H]+. |
92.5% | With potassium carbonate In acetone at 20℃; | 1 Experimental 7.1 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl) ethanone (24.9 g, 0.15 mol) and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was added dropwise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 mol, in 200 mL acetone) while maintaining the temperature below 25 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature for a whole night. The solid was removed by filtration, and the filtrate was poured slowly into 1 L ice water, which is stirred vigorously. A lot of precipitated white solid was filtered and dried in vacuo at 40 °C for 24 h to afford the target compound (69.5 g, yield: 92.5%). Mp 115-117 °C; MS (ESI) m/z (%): 264.8 [M+Na]+. |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | |
92.5% | With potassium carbonate In acetone at 20℃; | 1.2. 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone(14) Astirred solution of 1-(4-hydroxy-3-methoxyphenyl) ethanone (24.9 g, 0.15 mol)and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was addeddropwise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 molin 200mL acetone) while maintaining the temperature below 25. Uponcompletion of the addition, the reaction mixture was stirred at roomtemperature for a whole night. The solid was removed by filtration, and thefiltrate was poured slowly into 1L ice water, which is stirred vigorously. Alot of precipitated white solid was filtered and dried in vacuo at 40for 24 hours to afford the target compound (69.5 g, Yield: 92.5%) . M.p. 71-73;MS m/z (ESI): 264.8 [M+Na]+. |
92.5% | With potassium carbonate In acetone at 20℃; | 2 5.2 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (24.9 g, 0.15 mol) and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was added drop-wise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 mol, in 200 mL acetone) while maintaining the temperature below 25 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight. The solid was removed by filtration, and the filtrate was poured slowly into 1 L of ice water, which was stirred vigorously. A lot of precipitated white solid was filtered and dried in vacuo at 40 °C for 24 h to yield the target compound (69.5 g, yield: 92.5%). M.p. 71-73 °C; MS (ESI) m/z (%): 264.8 [M + Na]+. |
92.5% | With potassium carbonate In acetone at 20℃; | 1.A Step A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II) the 3- methoxy-4-hydroxyacetophenone (249g, 1. 5mol) and Anhydrous potassiumcarbonate (579 · 6g, 2.1mol) added into 125m ml of acetone, under temperature below 25 ° C gradually added 1-bromo-3-chloropropane(661.3g, 4.2mol)/ acetone (1200ml), completion of drop wise addition it wasstirred for overnight at room temperature. After the completion of the reaction, suction filtration, filtrate cake was washed using 100ml of acetone, combinedthe filter cake , filtrate was slowlypoured into 15ml of cold water meanwhile vigorously stirring of reaction, precipitatedlarge amount of white solid , suction filtration ,filter cake was dried invacuo at 40 ° C for 48h to obtain whitepowder 695 · 5g, yield 92. 5%, |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II) 3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579 g, 2.1 mol) were added to 1,250 mL of acetone at a temperature below 25 °C 1-bromo-3-chloropropane (661.3 g, 4.2 mol) in acetone (1200 mL) was added dropwise and stirred overnight at room temperature. After filtration, the filter cake was rinsed with 100mL acetone. The filter cake was slowly poured into 15L of ice water and stirred vigorously. A large amount of white solid was precipitated. The filter cake was vacuum dried at 40 ° C for 48h, A white powder of 695.5 g was obtained in a yield of 92.5% |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | 1.A Step A1- (4- (3- chloropropoxy) -3-methoxy) acetophenone (II) A mixture of 3-methoxy-4-hydroxyacetophenone (249g, 1.5moL) and anhydrous potassium carbonate (579.6g, 2.1mol) was added to1250mL of acetone was slowly added dropwise temperature below 25 -3-bromo-1- - chloropropane (661.3g, 4.2mol) / acetone (1200mL), a droppingwas completed, the mixture was stirred overnight at room temperature.After completion of the reaction, suction filtration, the filter cake was rinsed with 100mL of acetone, the combined filter cake, and the filtrate was slowly poured into15L of ice water with vigorous stirring, to precipitate a lot of white solid was suction filtered, the filter cake was dried in vacuo at 40 48 hours, a whitepowder 695.5g, yield: 92.5%. |
92.5% | With potassium carbonate In acetone at 25℃; | 1.A Step A Preparation of 1- (4- (3-chloropropoxy) -3-methoxy) acetophenone (II) 3-methoxy-4-hydroxyacetophenone(249 g, 1.5 mol) and anhydrous potassium carbonate(579.6 g, 2.1 mol) was added to 1,250 mL of acetone,A solution of 1-bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise at a temperature below 25 ° C,The mixture was stirred overnight at room temperature.After completion of the reaction,The filter cake was rinsed with 100 mL of acetone,The filter cake was combined and the filtrate was slowly poured into 15 L ice water,While vigorous stirring, precipitation of a large number of white solid,The filter cake is vacuum dried at 40 DEG C for 48 hours,A white powder of 695.5 g was obtained in a yield of 92.5%. |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | A Step A 1- (4- (3-Chloropropoxy) -3-methoxy) acetophenone (a) 3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) was added to 1250mL of acetone at a controlled temperature below 25 °C was slowly added dropwise 1-Bromo-3-chloropropane (661.3 g, 4.2 mol) in acetone (1200 mL) was added dropwise and the mixture was stirred at room temperature overnight. After completion of the reaction, suction filtration, the filter cake rinsed with 100mL acetone, the filter cake was combined, the filtrate slowly poured into 15L of ice water, while stirring vigorously, precipitated a large amount of white solid, suction filtration, the filter cake was vacuum dried at 40 °C 48h, White powder 695.5g, 92.5% |
92.5% | With potassium carbonate In acetone at 20℃; | A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II) 3-Methoxy-4-hydroxyacetophenone (249 g, 1.5 mol)And anhydrous potassium carbonate (579.6 g, 2.1 mol) were added to 1250 mL of acetone and 1-bromo-3-chloropropane (661.3 g, 4.2 mol) Stir overnight at room temperature.After the reaction was completed, suction filtration, the filter cake rinsed with 100mL acetone, the combined filter cake,The filtrate was slowly poured into 15L ice water, while vigorous stirring, precipitated a large number of white solid, suction filtration,The filter cake was vacuum dried at 40 ° C for 48 hours to give 695.5 g of white powder, yield: 92.5%. |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | 1.1 Step 1 Preparation of 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II) 3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.1 mol) were added In 1250mL acetone, the temperature control is below 25 °C.1-Bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, suction filtration, the filter cake was rinsed with 100 mL of acetone, and the filtrate was combined.The filtrate was slowly poured into 15 L of ice water while stirring vigorously to precipitate a large amount of white solid, which was suction filtered.The filter cake was dried under vacuum at 40 ° C for 48 hours.Obtained white powder 695.5g, yield: 92.5%; |
92.5% | With potassium carbonate In acetone at 20 - 25℃; | A Step A1-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (a) 3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.1 mol) were addedIn 1250 mL of acetone, 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) was slowly added dropwise under controlled temperature of 25 ° C or lower.After completion, stir at room temperature overnight. After the reaction was completed, suction filtration, the filter cake was rinsed with 100 mL of acetone, the filter cake was combined, and the filtrate was slowly poured.15L ice water, while stirring vigorously, a large amount of white solid was precipitated, suction filtration, and the filter cake was vacuum dried at 40 ° C for 48 h to obtain white powder.695.5 g, yield 92.5%, |
92.5% | With potassium carbonate In acetone at 25℃; | A Step A l-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (II) 3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.lmol)Add to 1250mL of acetone,1-bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise under controlled temperature of 25 ° C.After the drop,Stir at room temperature overnight.After the reaction is completed,Filtering,The filter cake was rinsed with 100 mL of acetone.Combine the filtrate,Slowly pour the filtrate into 15 L of ice water.Stirring at the same time,A large amount of white solid is precipitated,Filtering,The filter cake was dried under vacuum at 40 ° C for 48 h.White powder 695.5g,The yield was 92.5%. |
92.3% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: 1.3-chlorobromopropane In water; N,N-dimethyl-formamide at 20℃; for 5h; | 4.1.1. 4-(3-Chloropropoxy)-3-methoxyacetophenone (1) To a solution of 1-(4-hydroxy-3-methoxyphenyl)ethenone (49.8 g,0.30 mol) in DMF (300 mL), K2CO3 (82.8 g, 0.60 mol) was added andstirred for 30 min. Then 1-bromo-3-chloropropane (56.7 g, 0.36 mol)was added to the above suspension. The mixture was then poured into cold water (1 L) with vigorously agitating for 15 min after 5 h. Theresulting precipitate was filtered off, washed with water, and driedunder vacuum to obtained acetophenone 1 as white solid, yield: 92.3%(67.0 g). HRMS (ESI) m/z 243.0768 [M+H]+, Calcd. for 243.0788. |
92.5% | With potassium carbonate In acetone at 20℃; | 1.1 Preparation of 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (Intermediate II) Add 3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) to 1250mL of acetone and stir below 25°C.A solution of 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) was slowly added dropwise, and stirred at room temperature (25° C.) overnight. After the reaction is completed, filter with suction, wash the filter cake with acetone 3 times, combine the filtrate, slowly pour the filtrate into 15L ice water (0), stir, a large amount of white solid precipitates, filter with suction, and dry the filter cake at 35 for 20h , Get 695.5g of white powder, get intermediate II. Calculated yield: 92.5% |
91% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; | 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethan-1-one (19) A mixture of acetovanillone (250.0 g, 1.50 mol), 1-bromo-3-chloropropane (315.0 g, 2.0 mol), and K2CO3 (345.5 g, 2.50 mol) in DMF (1.5 kg) was stirred at 60 °C for 2 h then cooled to r.t., and poured slowly into ice-water (6 kg) while stirring constantly. The solid formed was filtered off, washed with cold water (2 × 0.8 kg), and dried at 45 °C for 6 h. The white product was stirred and heated with hexane-EtOAc (3:1, v/v, 0.8 kg) at 50 °C for 2 h then cooled to r.t. overnight. The resulting solid was filtered off, washed with hexane-EtOAc (3:1, v/v, 2 × 200 g), and dried at 40 °C for 4 h to afford 19 (331.3 g, 91%) as a white solid; mp 56.7-57.9 °C.1H NMR (400 MHz, CDCl3): δ = 2.34 (m, J = 6.4 Hz, 2 H), 2.58 (s, 3 H),3.79 (t, J = 6.4 Hz, 2 H), 3.93 (s, 3 H), 4.26 (t, J = 6.0 Hz, 2 H), 6.93 (d,J = 8.0 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 7.58 (dd, J = 2.0, 8.0 Hz, 1 H).13C NMR (100 MHz, CDCl3): δ = 26.3, 32.0, 41.4, 56.0, 65.4, 110.5,111.4, 123.2, 130.7, 149.3, 152.5, 196.8.MS (ESI): m/z = 243.2.0 [M + H]+. |
91.3% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: 1.3-chlorobromopropane In acetone at 0 - 25℃; for 20h; | 1.A Preparation of 4- (3-chloropropoxy) -3-methoxyacetophenone (A1) will3-methoxy-4-hydroxyacetophenone (16.6 g, 0.1 mol)Dissolved in 100mL acetone,Anhydrous potassium carbonate (19.3 g, 0.14 mol) was added,Stirred at room temperature for 0.5 h,A solution of 1-bromo-3-chloropropane was added dropwise at 0 ° C(21.9 g, 0.14 mol),During the dropwise addition, the control temperature is below 25 ° C.After completion of the reaction, the reaction was stirred at 25 ° C for about 20 hours. After completion of the reaction,The filtrate was slowly poured into 200 mL of ice water. After stirring for 15 min, the filtrate was filtered and the cake was dried to give 22.2 g of a white solid in 91.3% yield. |
91.9% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | 4.1.1 4-(3-Chloropropoxy)-3-methoxyacetophenone (1) Anhydrous K2CO3 (165.6g, 1.2mol) and 1-bromo-3-chloropropane (105.4g, 0.66mol) was added to a solution of 4-hydroxy-3-methoxy-acetophenone (100.0g, 0.60mol) in DMF (500mL). The reaction mixture was then stirred at rt for 6h. The mixture was then poured into cold water (1500mL) with vigorously agitating for 15min, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford 1 as white solid, yield: 91.9% (133.8g). MS (ESI) m/z 242.9 [M+H]+. |
91.2% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.1.3. Synthesis of 4-(3-Chloropropoxy)-3-methoxyaceto-phenone (1c) To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00 g,36.0 mmol) in DMF (25 mL) was added K2CO3 (7.45 g, 54.0 mmol) and 1-bromo-3-chloropropane (7.94 g, 50.6 mmol). The reaction mixture was then stirred at rt for overnight. The mixture was then poured into cold water (100 mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford the title compound 1c (7.94 g) as a white solid, yield: 91.2%. Mp:61-62 °C. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=2.0, 8.4 Hz, 1H),7.52 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4,23 (t, J=6.0 Hz,2H), 3.90 (s, 3H), 3.76 (t, J=6.4 Hz, 2H), 2.55 (s, 3H), 2.34-2.28 (m,2H). 13C NMR (100 MHz, CDCl3) δ 196.7, 152.4, 149.2, 130.6, 123.1,111.4, 110.4, 65.3, 55.9, 41.3, 31.9, 26.1. ESI-MS: m/z 243.0 [M+H]+. |
85.6% | With potassium carbonate In N,N-dimethyl-formamide at 25 - 30℃; Industrial scale; Green chemistry; | |
84% | With potassium carbonate In acetone for 24h; Heating; | |
In sodium hydroxide; di-isopropyl ether; water | 12 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone PREPARATION 12 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 liter of water heated to 86° C. was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80°-85° C. for 2.5 hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was heated to reflux in 15 gal of isopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg (36%). Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8°-58.5° C. analysis: Calculated for C12 H15 ClO3: C,59.39;H,6.23. Found: C,59.07;H,6.22. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 2 Reference Example (2): Process for preparing l-(4-(3-chloropropoxy)-3- methoxyphenvDethanoneTo a mixture of l-(4-hydroxy-3-methoxyphenyl)ethanone in dimethyl formamide were added potassium carbonate and l-bromo-3-chloropropane . The mixture was stirred at ambient temperature until completion of reaction. To the reaction mass was added purified water. The crystallized product was filtered, washed with water and dried to afford pure title compound. M.pt 63-66 °C. | |
With potassium carbonate In butanone at 78℃; for 1.5h; | 1 A mixture of Methyl ethyl ketone (300 ml), Benzyl triethylammonium chloride (5.0 g), Potassium Carbonate (83.2 g), 4-hydroxy-3-methoxy acetophenone (100 g) and 1-bromo-3-chloropropane (190 g) was heated at 78°C for 1.5 h. After completion of reaction, the reaction mixture was cooled to 30°C and DM Water (300 ml) was added to the reaction mixture and extracted. The organic phase was separated and washed with 5% sodium chloride solution. The organic phase was distilled out under vacuum at 50°C. Cyclohexane (500 ml) was added to the oily residue and stirred to give solid. The solid was filtered, washed with cyclohexane (100ml) and suck dried. The solid was dried in oven at 45°C to give the title product (133.0 g).[130] Dimer impurity content: 3.0%[131] Purity by HPLC: 97% | |
With potassium carbonate In acetonitrile at 75 - 80℃; | 2 Example 2 Example 2 synthesis of iloperidone Acetovanillone (50 g, 0.30 mol) is added to a suspension of potassium carbonate (60 g, 0.43 mol), acetonitrile (800 ml), N,N-dimethylformamide (200 ml) and 1-bromo-3-chloropropane (55.2 g, 0.35 mol). The mixture is heated at the temperature of 75-80°C and monitored by UPLC. After completion of the reaction, potassium carbonate (80 g, 0.58 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (90 g, 0.35 mol) and 100 ml of N,N-dimethylformamide are added. The mixture is heated at the temperature of 90-95°C and monitored by UPLC. After completion of the reaction, the resulting mixture is cooled to 55°C and the inorganic salts are filtered off. The clear solution obtained is concentrated under vacuum to a weight of 370 g, and cooled to 5°C. The resulting suspension is filtered. The solid isolated is dried under low pressure at 55°C to obtain iloperidone (97 g, 0.23 mol) as a white solid with a purity exceeding 99%. | |
In acetone at 0 - 20℃; for 12.5h; | ||
With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 75 - 80℃; | 2 Example 2 Synthesis of Iloperidone Example 2 Synthesis of Iloperidone [0049] Acetovanillone (50 g, 0.30 mol) is added to a suspension of potassium carbonate (60 g, 0.43 mol), acetonitrile (800 ml), N,N-dimethylformamide (200 ml) and 1-bromo-3-chloropropane (55.2 g, 0.35 mol). The mixture is heated at the temperature of 75-80° C. and monitored by UPLC. After completion of the reaction, potassium carbonate (80 g, 0.58 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (90 g, 0.35 mol) and 100 ml of N,N-dimethylformamide are added. The mixture is heated at the temperature of 90-95° C. and monitored by UPLC. After completion of the reaction, the resulting mixture is cooled to 55° C. and the inorganic salts are filtered off. The clear solution obtained is concentrated under vacuum to a weight of 370 g, and cooled to 5° C. The resulting suspension is filtered. The solid isolated is dried under low pressure at 55° C. to obtain iloperidone (97 g, 0.23 mol) as a white solid with a purity exceeding 99%. Molar yield from acetovanillone to iloperidone: 76%. | |
In acetone at 0 - 25℃; for 12.5h; | ||
In acetone at 0 - 20℃; for 12h; | ||
With potassium carbonate; acetone at 20℃; | ||
In acetone at 0 - 20℃; for 12.5h; | ||
692.2 g | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 20℃; for 6h; | 1.1 Step (1) 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) At room temperature, 500.0 g (3.01 mol) of 3-methoxy-4-hydroxyacetophenone II and 581.7 g (4.22 mol) of anhydrous potassium carbonate were added to 2 L of N,N-dimethylformamide (DMF). After sufficiently stirring for 30 min, 311.7 mL (3.16 mol) of 1-bromo-3-chloropropane was added dropwise. Drop finished, stir for 6 h at room temperature. The reaction solution was poured into 5 L of ice water. Filter. The filter cake was dried to give 692.2 g of a white solid. |
In acetone at 0 - 20℃; for 12.5h; | ||
In acetone at 0℃; for 12.5h; | ||
68.8 g | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6.5h; | 27.1 Step 1.1-[4-(3-Chloropropoxy)-3-methoxy]acetophenone (III-1) 50.0 g of 3-methoxy-4-hydroxyacetophenone and 58.2 g of anhydrous potassium carbonate were added to 200 mL of N at room temperature.After stirring for 30 minutes in N-dimethylformamide, 31.2 mL of 1,3-bromochloropropane was added dropwise, and the mixture was stirred at room temperature for 6 hours.The reaction solution was poured into 600 mL of ice water, suction filtered, and the filter cake was dried to give a white solid 68.8 g. |
In acetone at 0 - 25℃; for 12.5h; Alkaline conditions; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | ||
695.5 g | With potassium carbonate In acetone at 25℃; | 1.4 Step 4 Synthesis of 4-(3-chloropropoxy)-3-methoxyacetophenone Add 3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) to 1250mL of acetone, slowly add 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) dropwise at a temperature below 25°C., and then stir overnight at room temperature. After the reaction is complete, filter with suction, rinse the filter cake with 100 mL of acetone, combine the filter cakes, slowly pour the filtrate into 15 L of ice water, while stirring vigorously, and precipitate a large amount of white solid, which is filtered with suction.The filter cake was vacuum dried at 40°C for 48 hours to obtain 695.5 g of white powder. |
With potassium carbonate In acetone at 0 - 20℃; for 12.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(ll) bromide In ethanol at 70℃; for 1.5h; | 3.2.1; 3.2.2; 3.2.3 Synthesis of 2,4- (α-bromoacetyl) -guaiacol (1) 7.0 g of cupric bromide was dissolved in 70 mL of absolute ethanol and transferred to a constant pressure funnel;(2) Add 5.0 g of 4-acetyl guaiacol into a three-necked flask containing 60 mL of absolute ethanol;(3)(1) was added dropwise to (2) at 70 ° C,About half an hour drops finished, observed the reaction color has been dark green,toAt the end of the reaction, a white cuprous bromide was observed and the progress of the reaction was monitored by TLC. The reaction time was about1.5 hours. After the reaction was completed, the reaction mixture was filtered through a sand funnel and the filtrate was evaporated under reduced pressure to remove ethanol.Extract with methylene chloride and water and dry the methylene chloride extract over anhydrous methylene sulfate. DichloromethaneThe extract was evaporated under reduced pressure to remove methylene chloride, resulting in dark red crystals. The yield is about 80%. |
76% | With bromine In 1,4-dioxane; diethyl ether at 0℃; for 1h; | |
63% | With bromine In chloroform for 4h; Ambient temperature; |
56% | With copper(ll) bromide In ethyl acetate for 5h; Reflux; | 2 In succession, 2656 mg (16 mmol) of D1, 50 ml of ethyl acetate, 7.0g(28mmol) of copper bromide was added to a 100ml eggplant-shaped flask and stirred at reflux for 5h. The reaction was cooled and filtered through celite. The filtrate was washed successively with saturated sodium thiosulfate solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, evaporated to dryness under reduced pressure, and purified on a silica gel column to give 2.2 g of a white powder product D11. ,Yield 56%; |
56% | With copper(ll) bromide In ethyl acetate for 5h; Reflux; | 1 Preparation of compound D31 of the present invention In succession, 2656 mg (16 mmol) of D1, 50 ml of ethyl acetate,7.0g (28mmol) of copper bromide was added to a 100ml eggplant-shaped flask.After stirring and refluxing for 5 h, the reaction was cooled and filtered through Celite.The filtrate was successively saturated with sodium thiosulfate solution and saturated sodium bicarbonate solution.It is washed with saturated sodium chloride solution, evaporated to dryness under reduced pressure, and purified by silica gel column.Obtain 2.2g white powder product D11, yield 56%; |
56% | With copper(ll) bromide In ethyl acetate for 5h; Reflux; | |
56% | With copper(ll) bromide In ethyl acetate for 5h; Reflux; | 2 2656 mg (16 mmol) of D1, 50 ml of ethyl acetate, and 7.0 g (28 mmol) of copper bromide were added to a 100 ml eggplant-shaped bottle, followed by stirring and refluxing for 5 hours. After the reaction was cooled, it was filtered through diatomaceous earth. The filtrate was successively saturated sodium thiosulfate solution, saturated sodium bicarbonate solution,It was washed with saturated sodium chloride solution, evaporated to dryness under reduced pressure, and purified on a silica gel column to obtain 2.2 g of product D11 as a white powder in a yield of 56% |
50.9% | With bromine In chloroform; ethyl acetate | General procedure General procedure: (substituted) acetophenone or propiophenone(ACM) (1.0 eq) was dissolved in the mixture solvent of chloroform andethyl acetate (1:1) and then heated to 2re(1f.6u-x2,.0Ceuq)Brwasadded in portions. The reaction was monitored by HPLC (mobile phase:acetonitrile/H2O=40:60, 1 mL/min, 20 min, 254 nm). After reaction,the mixture was filtered and washed with solvent, the filtrate wasevaporated, and the residue was purified by flash column chromatographyon silica gel to give intermediates ACM-Br. |
47% | With copper(ll) bromide In chloroform; ethyl acetate at 20℃; for 4h; | |
With copper(ll) bromide In ethyl acetate for 2.5h; Heating; | ||
With copper(ll) bromide In ethyl acetate for 2h; Reflux; | 1.1 50 mL of ethyl acetate was added to 8.47 g (corresponding to 37.9 mmol) of cupric bromide to obtain a suspension, to which 3.00 g (corresponding to 18.1 mmol) of 4'-hydroxy-3'-methoxyacetophenone was added, Then, the resulting mixture was heated under reflux. After 2 hours, the reaction mixture was cooled down to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate = 4/1), to obtain 4.11 g (corresponding to 16.3 mmol) of 2-bromo-4'-hydroxy-3'-methoxyacetophenone (Fig. 1, Step 1). | |
With copper(ll) bromide In chloroform; ethyl acetate Reflux; | ||
With copper(I) bromide In ethanol | ||
With copper(ll) bromide In ethyl acetate Reflux; | ||
With copper(ll) bromide In dichloromethane; ethyl acetate at 60℃; Microwave irradiation; Sealed tube; | ||
With N-Bromosuccinimide; toluene-4-sulfonic acid In water; acetonitrile Reflux; | ||
With copper(ll) bromide In dichloromethane; ethyl acetate at 60℃; for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 19; Peparation of a mixture of 3-hydroxy-4-methoxyacetophenone (X) and 4-hydroxy-3- -methoxyacetophenone (XI) obtained in 1:1 molar ratio by demethylation of 3,4-dimethoxyacetophenone (XII) (X) (XII)1.06 g (8 mmol) of aluminium chloride and 300 mg (4 mmol) of thiourea are mixed, the resulting oily liquid is dissolved in 10 ml of dichloromethane. To this solution 0.36 g (2 mmol) of 3,4-dimefhoxyacetophenone (XII) dissolved in 5 ml of dichloromethane is added. The reaction mixture is stirred under reflux for 5 hours, then cooled to room temperature and 5 ml of 5 wt percent hydrochloric acid is added. EPO <DP n="24"/>The mixture is stirred for a few minutes, the phases are separated and the aqueous layer is extracted with 2 x 5 ml of dichloromethane. The combined organic phases are washed with 3 x 10 ml of 5 wt percent aqueous sodium hydroxide solution. The alkaline phases are combined, acidified with 18 wt percent hydrochloric acid solution and extracted with 3 x 10 ml of dichloromethane. The combined dichloromethane phases are washed with water, dried over sodium sulfate and evaporated.0.12 g oil is obtained which solidifies on standing, consisting of 3-hydroxy-4- methoxyacetophenone (X) and 4-hydroxy-3-methoxyacetophenone (XI) in 1:1 molar ratio (yield: 40 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The synthesis of E (Scheme 4) requires coupling of the carboxylic acid sulfosuccinimidyl ester 27, derived from 23, with 24 followed by the cleavage (TBAF, [HOAC,] THF) of the silyl protecting group . and subsequent conversion [(TSCL,.] pyr, Nal, acetone) of the alcohol into iodide 28, [ALKYLATION.] of the. phenoxide anion derived from 32 with iodide 28 gives rise to 33. Completion of the synthesis of E requires 1) reduction (NaBH4) of the methyl ketone functionality, 2) coupling of the resultant alcohol 34 with the new reagent 38 leading to 39 and 3) brief exposure of 39 to trimethyl silyl iodide, which leads, upon aqueous workup, to E. The required aromatic piece 32 is prepared from commercially available [ACETOVANILLONE] 29, as outlined in Scheme 5, using the protocol of [AKERBLOM] [(AKERBLOM,] E. [ <P>B. , ET AL., (1998) SIX NEW PHOTOLABILE LINKERS FOR SOLID-PHASE SYNTHESIS. 1. METHODS OF PREPARATION.] Mol. Divers., 3,137-148). The novel reagent 38 is prepared from the commercially available sulfo- NHS acetate 35 as detailed in Scheme 6. The methylation of sulfonate anions is well documented in the literature (Trujillo, J. L. and Gopalan, A. S. (2000) Facile [ESTERFICATION] of Sulfonic Acids and Carboxylic Acids with Triethylorthoacetate, Tetrahedron Letters 34,7355-7358), as well as the [ TREATMENT OF N-HYDROXYSUCCINIMIDE WITH BIS (BICHLOROMETHYL) CARBONATE (KONAKAHARA, T. , ET AL., (1993)] A Convenient Method for the Synthesis of Activated N-Methylcarbamates, Synthesis 103-106). | ||
With pyridine; In tetrahydrofuran; at 20.0℃; for 3.0h; | As shown in the above-described reaction formula, acetovanillone (500 mg, 3 mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridine and 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hours at room temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 4-acetyl-2-methoxyphenyl acetate (1; 625 mg).m.p: 58.7 C.;1H NMR (CDCl3): delta ppm 7.60 (d, 1H, J=1.8 Hz, H-3), 7.55 (dd, 1H, J=1.8, 8.2 Hz, H-5), 7.12 (d, 1H, J=8.2 Hz, H-6), 3.89 (s, 3H, OCH3), 2.59 (s, 3H, OCOCH3), 2.33 (s, 3H, COCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In acetonitrile at 20℃; | 1 1 -(3 -methoxy-4-(methoxymethoxy)phenyl)ethanone “29a”: To a solution of 4-hydroxy-3-methoxyacetophenone (2 g, 12 mmol) in anhydrous MeCN (2mL), were added K2C03 (5g, 36 mmol) and methoxymethyl chloride (1.83 mL, 24 mmol). The mixture was stirred overnight at rt. After removal of the solvent under reduced pressure, water was added to the residue and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to affording 2.4g(96% yield) of a clear oil.‘H NMR (400 MHz, CDC13) ö 7.55-7.52 (m, 2H), 7.18 (dd, 1H,J= 8.1, 2.5 Hz), 5.31 (s, 2H), 3.94 (s, 3H), 3.51 (s, 3H), 2.57 (s, 3H). ‘3C NMR (100 MHz, CDC13) ö 196.8, 150.8, 149.6,131.7, 123.0, 114.7, 114.5, 110.6, 95.2, 95.1, 56.4, 56.0, 26.3. |
62% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; | 10 4.1.9. Synthesis of 1-(4-methoxy-3-(methoxymethoxy)phenyl)ethanone (7a) General procedure: To an ice-cooled suspension of commercially available compound6a (1.66 g, 10.0 mmol) in 50 mL of DCM was added N,Ndiisopropylethylamine(3.53 mL, 20.0 mmol), then MOMCl(2.30 mL, 30.0 mmol) was added dropwise. The reaction was graduallyallowed to reach room temperature and was stirred for 6 h.Then, the mixture was quenched with saturated ammonium chloridesolution (20 mL) and was extracted with DCM. The organiclayers were combined, dried over sodium sulfate, filtered, andevaporated. The brownish residue was purified over silica gel toobtain a colorless oil (1.11 g, 53%). 1H NMR (400 MHz, CDCl3) d7.77 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 5.29(s, 2H), 3.96 (s, 3H), 3.54 (s, 3H), 2.57 (s, 3H). ESI-MS m/z: 211.1[M+H]+. |
With sodium hydride 1.) THF, DMF, RT, 3 h, 2.) THF, DMF, RT, 2 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 2h; | |
96% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | 3 Preparation method of robustine derivative-4-ethoxy-3-methoxyacetophenone: 4.15 g (25 mmol) of robustine in 40 ml of DMF,4 g of potassium carbonate and 6.42 g of benzyl bromide were added thereto, and stirred vigorously at room temperature.After 2 hours of reaction, TLC monitors that the raw materials have reacted completely. Put them into 150ml of water.A large amount of solids precipitated and were dried by filtration. Available 4-ethoxy-3-methoxyacetophenone,The yield was 96%. |
80% | With potassium carbonate In acetone for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; | 5 Acetovanillone (1) (3.8 g, 22.87 mmol), tert-butyl bromoacetate (4.68 g, 24.01 mmol) (Fisher Scientific), and K2CO3 (5.21 g, 37.70 mmol) were stirred in DMF (15 mL) at room temperature for 48 hours. The resulting solution was filtered, poured into dH2O, and extracted with EtOAc and saturated NaCl. The combined organic layer was dried with MgSO4 and concentrated by evaporation to yield (2): tert-butyl (4-acetyl-2-methoxyphenoxy)acetate (4.09 g, quantitative) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 2.56 (s, 3H), 3.94 (s, 3H), 4.66 (s, 2H), 6.77 (d, 1H), 7.53 (m, 2H) |
100% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With sodium hydroxide In methanol at 20℃; for 15h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In methanol for 15h; Reflux; | |
99% | With potassium carbonate In water; N,N-dimethyl-formamide at 0℃; | 4 Acetovanillone (10 g, 60.18 mmol) and potassium carbonate (13.3 lg, 96.29 mmol) were combined and dissolved in DMF (80ml). t-Butyl bromoacetate (14.09 g, 10.66 ml, 72.22 mmol) was added slowly at 0 °C. The resulting mixture was stirred overnight. The reaction was poured over water and the aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with sodium sulfate and evaporated to give 16.75 g (99%>) as a white solid. lH NMR (400 MHz, chloroform-d) δ 7.57-7.50 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 4.66 (s, 2H), 3.94 (s, 3H), 2.57 (s, 3H), 1.47 (s, 9H). |
99% | With potassium carbonate In N,N-dimethyl-formamide | |
98% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60h; Inert atmosphere; | 15 Compound 1 : DMNPE-ester or (4-Acetyl-2-methoxy-phenoxy)-acetic acid tert-butyl ester Compound 1 was synthesized by following the literature (Holmes, C. P. J. Org. Chem. 62 2370-2380 (1997)). Briefly, acetovanillone (2.63 g, 15.8 mmol), ferf-butyl bromoacetate (2.56 mL, 17.3 mmol) and potassium carbonate (3.60 g, 26.0 mmol) were mixed in 18.75 mL of solvent Ν,Ν-dimethylformamide (DMF). This slurry was stirred at room temperature under nitrogen for 60 hours. Salts were dissolved by adding 100 mL of water and the resultant white precipitate was further purified by partitioning between ethyl acetate and saturated sodium chloride solution. Combined organic layer was washed with saturated sodium chloride solution, dried using magnesium sulfate and evaporated to yield shiny white powder of DMNPE-ester. Yield 4.35 g (98%), Purity (>99% from NMR), TLC (EtOAc/MeOH, 75:25 v/v): Rf= 0.7; NMR (400 MHz, DMSO- 6): 5 7.53 ppm (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 6.89 (d, J= 8.8); 13C NMR (100 MHz, DMSO-i 6): δ 199.3, 165.8, 153.5, 147.8, 137.6, 132.1, 109.9, 108.7, 67.7, 56.6, 44.1, 30.0, 29.8, 23.3, 23.1 , 22.8, 21.3; UV/vis (DMSO): λχ (ελ) in DMSO: 262 nm (8037 M~' cm-1), 343 nm (4500 M"1 cm"1); MS (m/z): [MH]+ calcd for C15H20NO5, 281.1 ; found, 281.5; reversed phase HPLC-MS (flow rate 0.3 mL/min, runtime 30 minutes, injection volume 25 μΚ) solvent A (0.1% formic acid in H20), solvent B (0.1% formic acid in acetonitrile (ACN)), gradient 50% B to 100% B over 10 minutes, isocratic 100% B for 17 minutes, 100%) B to 0%> B over 3 minutes, C8 Hypersil column (5 μπι, 100 χ 4.6 mm, Varian): retention time (min) 17.21 ; ESI-MS (m/z): + calcd for Ci5H2oN05, 281.1 ; found, 281.5. |
98% | With potassium carbonate In acetonitrile for 24h; Inert atmosphere; Reflux; | |
89% | With potassium carbonate In acetonitrile for 24h; Inert atmosphere; Reflux; | |
17.80 g | With potassium carbonate In N,N-dimethyl-formamide for 48h; Ambient temperature; | |
With potassium carbonate | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; | 1; 4 Synthesis of Keto-ester 63.2 mmol (10.5 g) of acetovanillone, 69.2 mmol (13.5 g) tert- butylbromoacetate and 104 mmol (14.4 g) of potassium carbonate were added to 75 ml of dimethylformamide and stirred for 48 hours at room temperature. After 48 hours, water was added to the mixture until all salts were dissolved. This mixture was then partitioned between ethyl acetate and water. Pooled ethyl acetate fractions were washed with saturated NaCl, dried by addition of anhydrous magnesium sulfate. Ethyl acetate fraction was collected by filtration (to remove magnesium sulfate) and dried on a rotovap. This yields keto-ester as a white solid compound. Material was confirmed by MS and MR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ferrous(II) sulfate heptahydrate; sodium persulfate In water at 100℃; | |
92% | With laccase from Trametes versicolor; oxygen In acetone at 20℃; for 24h; Green chemistry; Enzymatic reaction; | General procedure for dimerization: synthesis of dimers 1-7 Diacetovanillon (3): MW = 330 g/mol, yield: 92%. 1H NMR (400 MHz, CDCl3, δ (ppm)): δ 7.49 (s, 4H, Ar), 3.93 (s, 6H, OCH3), 2.56 (s, 6H, C=OCH3). 13C NMR (400 MHz, CDCl3, δ (ppm)): δ 196.07 (OCH), 149.22 (Ar-C), 147.06 (Ar-C), 127.81 (Ar-C), 124.23 (Ar-C), 124.04 (Ar-C), 109.03 (Ar-C), 55.76 (OCH3), 26.25 (CH3). |
92% | With laccase from Trametes versicolor; oxygen In acetone at 20℃; for 24h; Enzymatic reaction; | 3 Example 3: Preparation of Compound (3) A solution of 1.5 g of compound of acetovanillone in 20 mL of 17 acetone was added to 180 mL of 18 NaOAc buffer (0.1 M, pH 5.0). The solution was saturated in 19 O2 for 5 min. Laccase from Trametes versicolor (20 U, 12.4 mg) was added and the reaction was stirred at room temperature for 24 hours. The precipitate was filtered, washed with water and dried under vacuum (at 100° C. overnight). Compound (20 3) is prepared from acetovanillone with a yield of 92%. Analyses: Mass: 330.1 (100%), 331.1 (18%), 332.2 (2%); 1H NMR: δ 7.49 (s, 4H, Ar), 3.93 (s, 6H, OCH3), 2.56 (s, 6H, C═OCH3); 13C NMR: δ 196.07 (OCH), 149.22 (Ar-C), 147.06 (Ar-C), 127.81 (Ar-C), 124.23 (Ar-C), 124.04 (Ar-C), 109.03 (Ar-C), 55.76 (OCH3), 26.25 (CH3). |
81% | With dipotassium peroxodisulfate; iron(II) sulfate In water; acetone at 20℃; for 48h; | |
80% | With dipotassium peroxodisulfate; iron(II) sulfate In water; acetone | |
66% | With dipotassium peroxodisulfate; ammonium iron(II) sulphate hexahydrate In water for 0.5h; | |
63% | With ferrous(II) sulfate heptahydrate In water at 90℃; for 0.5h; | |
63% | With ferrous(II) sulfate heptahydrate; dipotassium peroxodisulfate In water for 0.5h; Heating; | |
55% | With dihydrogen peroxide; horseradish peroxidase In ethanol; water for 10h; Enzymatic reaction; | |
43% | With [bis(acetoxy)iodo]benzene In acetonitrile at 25℃; for 24h; | |
1.1 g | With dipotassium peroxodisulfate; iron(II) sulfate In water; acetone at 20℃; for 168000h; stirring; modifying the method of Drumond, M. G. at al., Holzforschung 46 (1992) 127-134; | |
With sodium persulfate; iron(III) sulphate heptahydrate In water Reflux; | ||
With ferrous(II) sulfate heptahydrate; sodium persulfate In water at 100℃; for 0.0833333h; | ||
With ferrous(II) sulfate heptahydrate; sodium persulfate In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In dichloromethane at 0 - 20℃; | 10.1 To a solution of 4-1 (50.0 g, 301 mmol) andEt3N (210 mL) in 750 mL DCM was dropwisely added Tf2O (150 mL, 903 mmol) at 0 0C. After stirring at 0 0C for 1 h and then at r.t for 3 hrs, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc = 30:1 (v/v) to 5:1 (v/v)) to give 4-2 (56 g, 62% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, IH, J= 2.4 Hz), 7.57 (dd, IH, J= 1.6 Hz, 8.4 Hz), 7.32 (d, IH, J= 8.4 Hz), 3.99 (s, 3H), 2.63 (s, 3H). 19F NMR (376 MHz, CDCl3): δ -73.76 (s, 3F) ppm. LC-MS (ESI) m/z 299.0 [M+H]+. |
62% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; | 10.1 Example 10. Synthesis of 4-10, dimethyl (2S. TS)-l J ,-((2tS,2,^-2,2,-(5.5,-(2,2,-(5.5,- (6,7,9,10,12, 13-hexahydrodibenzo|"k,m] [ 1 ,4,7, 1 Oltetraoxacyclotetradecine-3 , 16-diyl)bis( 1H- imidazole-5 ,2-diyl))bis(pyrrolidine-2, 1 -diyl))bis(3 -methyl- 1 -oxobutane-2, 1 -diyDdicarbamate as shown in Scheme 4[00213] Step 1. Preparation of 4-2. To a solution of 4-1 (50.0 g, 301 mmol) andEt3N (210 mL) in 750 mL DCM was dropwisely added Tf20 (150 mL, 903 mmol) at 0 °C. After stirring at 0 °C for 1 h and then at r.t for 3 hrs, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc = 30/1 (v/v) to 5: 1 (v/v)) to give 4-2 (56 g, 62% yield) as a white solid. 1H NMR (400 MHz, CDC13): δ 7.66 (d, 1H, J= 2.4 Hz), 7.57 (dd, 1H, J= 1.6 Hz, 8.4 Hz), 7.32 (d, 1H, J= 8.4 Hz), 3.99 (s, 3H), 2.63 (s, 3H) ppm. 19F NMR (376 MHz, CDC13): δ -73.76 (s, 3F) ppm. LC-MS (ESI) m/z 299.0 [M+H]+. [00214] Step 2. Preparation of 4-3. Following general procedure E and replacing compound 1-9 with 4-2, compound 4-3 was obtained (10.5 g, 94% yield). LC-MS (ESI): m/z 277.2 [M+H]+. |
With 2,6-dimethylpyridine; dmap In dichloromethane at -78℃; |
4.57 g | With dmap In dichloromethane at 0℃; for 1h; | 168.1 Step 1: Synthesis of 4-acetyl-2-methoxyphenyl trifluoromethanesulfonate To a stirred solution of l-(4-hydroxy-3-methoxyphenyl) ethan-l-one 1 (3 g, 18 mmol) in DCM (60 mL) was added 4-dimethylaminopyridine (3.3 g, 27 mmol) at 0 °C. (2047) To the resulting reaction mixture was added triflic anhydride (6.1 g, 22 mmol) dropwise. Upon complete addition, the mixture was further stirred at 0°C for lh. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with IN HC1 (50 mL) and extracted with DCM (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography using 0-20% EA in hexane as eluent to afford the title compound (4.57 g). -NMK (400 MHz, CDCb) d 7.66 (d, J = 1.96 Hz, 1H), 7.57 (dd, ./ 1.96, 8.31 Hz, 1H), 7 32 (d, J= 8.31 Hz, 1H), (2048) 3.99 (s, 3H), 2.61-2.64 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine; copper diacetate In dichloromethane at 25 - 27℃; for 72h; Molecular sieve; | |
94% | With pyridine; copper diacetate at 25 - 27℃; for 72h; | |
94% | With pyridine; copper diacetate In dichloromethane at 25 - 27℃; for 72h; Molecular sieve; | 2.4. Experimental Procedure for the Synthesis of 1-(3methoxy-4-phenoxyphenyl)ethanone (4) To a stirred solution of 4-hydroxy-3-methoxyacetophenone(3 g, 18.05 mmol) in anhydrous dichloromethane(90 mL), activated molecular sieves (4A°, 3 g) was added.Phenylboronic acid (4.49 g, 36.82 mmol), copper (II) acetate(7.36 g, 40.58 mmol) and anhydrous pyridine (5.70 g, 72.15mmol, 5.82 mL) were added successively to the reaction mixture. The resulting suspension was stirred at 25-27°C.The progress of the reaction was monitored by TLC, using hexane: ethyl acetate (8:2). After the completion of reaction(72 h), the reaction mixture was diluted with dichloromethane(40 mL) and filtered through Buchner funnel under vacuum. The filtrate was washed with a dilute aqueous hydrochloricacid solution (2 M, 50 mL), followed by water (50mL), dried over anhydrous MgSO4 and evaporated under vacuum. The crude compound was purified by column chromatography over silica 100-200 using hexane: ethylacetate (8:2) as the mobile phase to afford the target compound as a white crystalline solid.Yield= 4.12 g (94%); mp = 82-84°C Rf = 0.9 (hexane:ethyl acetate = 8:2); λmax = 269.6 nm (MeOH); IR (KBr,cm1) = 3051, 2928, 1674, 1583, 1489, 1413, 1276, 1134; 1HNMR (400 MHz, DMSO-d6): 7.60 (d, J = 8 Hz, 2H), 7.36 (t,J = 7.8 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 8 Hz,1H), 6.94 (d, J = 8 Hz, 2H), 3.83 (s, 3H), 2.56 (s, 3H). |
81% | With pyridine; copper(II) acetate monohydrate In dichloromethane at 20℃; Molecular sieve; | |
79% | With pyridine; 4 A molecular sieve; copper (I) acetate In dichloromethane at 20℃; for 48h; | |
36% | With pyridine; copper diacetate In dichloromethane at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 3,4,5-trimethoxy-benzaldehyde; 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium hydroxide In methanol at 0℃; Stage #2: 3,4,5-trimethoxy-benzaldehyde In methanol at 0 - 40℃; | |
64% | With water; sodium hydroxide In ethanol at 5 - 25℃; Inert atmosphere; | 14 4.2.1 General procedure A: Synthesis of substituted chalcones (1-22) [46] General procedure: An aqueous solution of NaOH (20%, 5mL) was added dropwise to a previously cooled mixture of selected acetophenone (5mmol) and selected (hetero)aryl aldehydes (5mmol) in EtOH (25mL) under vigorous stirring. The mixture was stirred at RT for 24-72h. After completion of the reaction (as indicated by TLC), the mixture was poured onto crushed ice and acidified with dilute HCl. The precipitated product was filtered at suction and washed to neutral filtrate. The solid was recrystallized from EtOH to get crystalline product. |
64% | With sodium hydroxide In ethanol at 20℃; Inert atmosphere; | 2 General procedure A: synthesis of substituted chalcones (20-33) General procedure: A solution of NaOH (20%) (5mL) was added dropwise to a previously cooled mixture of 10mmol of substituted acetophenone and 10mmol of substituted carbaldehyde in 25mL ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dil. HCl. The precipitate obtained was filtered by suction and washed to neutral. The solid was recrystallized from ethanol/acetone to get crystalline chalcone. |
48% | With sodium hydroxide In ethanol at 0 - 20℃; | |
With potassium hydroxide In ethanol at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | 3'-methoxy-4'-tetrahydropyranylacetophenone (THP-C). In an oven-dried, 500 mL round bottom flask equipped with a stir bar and an addition funnel, p-toluenesulfonic acid monohydrate (156 mg, 0.82 mmol), pyridine (66 muL, 0.82 mmol), acetovanillone (6.10 g, 36.7 mmol), and CH2Cl2 (170 mL) were combined and rapidly stirred. Dihydropyran (10 mL, 110 mmol) was diluted with 40 mL of CH2Cl2, poured into the addition funnel, and added drop wise to the acetovanillone solution over a period of 2 h. The reaction was stirred for an additional 12 h at room temperature, after which it was washed with 200 mL of 1.0 N NaOH (2*). The organic phase was dried over Na2SO4, filtered, and concentrated to a clear oil under reduced pressure. The oil crystallized upon standing to afford 4.2 g of THP-C as a white solid (46% yield). The solid was used without further purification. TLC: Rf=0.19 (hexane/EtOAc 4:1); Melting point: 67-69 C.; 1H NMR: (300 MHz, CDCl3) delta 7.52 (s, 1H), 7.50 (d, J=10 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 5.50 (t, J=3 Hz, 1H), 3.90 (s, 3H), 3.89 (m, 1H), 3.59 (m, 1H), 2.54 (s, 3H), 1.95 (m, 3H), 1.63 (m, 1H); 13C NMR: (75 MHz, CDCl3) delta 197.08, 150.92, 150.12, 131.60, 123.18, 115.65, 111.29, 97.14, 62.31, 56.32, 30.33, 26.45, 25.31, 18.79; IR (ATR): 2966, 2936, 2880, 1672, 1585, 1510, 1462, 1442, 1413, 1390, 1352, 1290, 1272, 1243, 1221, 1201, 1172, 1153, 1120, 1110, 1051, 1032, 1020, 959 1046 cm-1; ESI-MS: expected, 250.1; observed, m/z 251.1 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In tetrahydrofuran; at 20.0℃; for 3.0h; | Reference Example 1. Preparat ion of intermedi ate (1) : 4-acetyl-2- methoxyphenyl acetate ( 1)<328>1<329><330> As shown in the above-descr ibed react ion formula, acetovani l lone(500mg , 3mM) di ssolved in 20 ml of THF was mixed wi th 0.5 ml of pyr idine and 0.6 ml of anhydrous acet ic acid. The mixture was st i rred for 3 hours at room <n="38"/>temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:l) to obtain white solid type of 4-acetyl-2-methoxyrhohenyl acetate (1 ; 625mg).<331> <332> m.p.: 58.7 C ;<333> 1H NMR (CDCl3) : delta ppm 7.60 (d, 1 H1 J = 1.8 Hz , H-3), 7.55 (dd, 1 H, J = 1.8, 8.2 Hz, H-5), 7.12 (d, 1 H, J = 8.2 Hz, H-6), 3.89 (s, 3 H, OCH3), 2.59 (s, 3 H, OCOCH3), 2.33 (s, 3 H, COCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With nitrobenzene; sodium hydroxide In water at 100℃; for 24h; | Compound 12 (4-hydroxy-3-methoxyphenyl)(oxo) acetic acid (or vanilglycolic acid) was synthesized at the Latvian State Institute of Wood Chemistry by the oxidation of compound 8 by nitrobenzene in alkaline medium at 100 °C, using the method reported by Mottern [56] with minor modifications. Compound 8 (35 g), nitrobenzene (27 g), and NaOH (25 g) were mixed in 75 mL water at 100 °C for 24 h. Aniline and small amount of nitrobenzene were distilled with water vapor; the cooled solution was acidified, treated with active oxygen and filtered. The solution was cooled and compound 12 was crystallized. The amount of compound 12 was 34 g (85%) (Tmelting = 133 °C) and itspurity was 85%, as checked chromatographically (GC, gas chromatography). |
Multi-step reaction with 3 steps 1: ethanolic sodium ethylate; copper 2: KMnO4; aqueous NaOH 3: aqueous HCl |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 70℃; for 15h; | To a N2 purged flask was added 2,4-bis-trifluorornethyl benzyl bromide(2.21 g, 7.20 mmol), acetovanillone (1.32 g, 7.92 mmol), and DMF (15 ml_). To the reaction solution was added fine mesh K2CO3 (3 equiv, 21.6 mrnol). The reaction was allowed to stir at 7O0C for 1 h, then at 600C for 14 h. The reaction solution was then diluted with EtOAc (150 mL), filtered through a Buchner funnel, washed with sat'd NH4CI (7OmL x 2) washed with sat NaCI (5OmL), dried over Na2SO4, and then filtered and concentrated in vacuo to provide a crude product (2.8g, 99% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 4.1.1.1 Preparation of ethyl 2-(4-acetyl-2-methoxyphenoxy)acetate (2a) To a solution of 4-hydroxy-3-methoxy-acetophenone (20.0g, 120.5mmol) in DMF (200mL) was added K2CO3 (17.4g, 126.5mmol) and ethyl 2-bromoacetate (20.9g, 126.5mmol). The reaction mixture was then stirred at 80°C for 3h. The mixture was then poured into cold water (500mL) with vigorously agitating, and the resulting precipitate was filtered-off, washed with water, and dried under vacuum to afford the title compound 2a (27.5g, 90.5%) as a white solid. MS (ESI) m/z: 253.15 [M+H] +. |
With potassium carbonate In <i>N</i>-methyl-acetamide; water | R.6 Reference Example 6 Reference Example 6 To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n-hexane-diethyl ether to give ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23.86 g). | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With hydrogenchloride; In ligroin; water; benzene; | PREPARATION 125 4-Ethyl-2-methoxyphenol A mixture of zinc powder, 150 ml of water and 49.9 g (0.3 mole) of acetovanillone was stirred and treated dropwise with 150 ml of concentrated hydrochloric acid. The solution was heated at reflux for 3.5 hr, during which time, after each hour, 10 ml of additional concentrated hydrochloric acid was added. After 3.5 hr the solution was diluted with ethyl alcohol and treated with aqueous ferric chloride solution. The mixture was cooled and filtered and the filter cake washed with water and the combined filtrates saturated with sodium chloride and extracted with ethyl ether (3*150 ml). The combined extracts were dried over sodium sulfate and concentrated to yield 1.4 g of a pink oil. The filter cake was washed with 250 ml of ethyl ether. The mixture was filtered and the filtrate dried over sodium sulfate and concentrated to a gum residue. The above obtained pink oil and gum residue were combined and chromatographed on a 750 g column of silica gel using 1:1 benzene:ligroin as the eluding solvent. Appropriate fractions were combined and concentrated to give 13.2 g (29% yield) of the title compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; | (b) 4-difluoromethoxy-3-methoxyacetophenone 20.8 g of 4-hydroxy-3-methoxyacetophenone are dissolved in 350 ml of dioxane and 350 ml of water by the addition of 30 g of sodium hydroxide, and the resulting solution is heated to 60. While stirring continuously, chlorodifluoromethane is passed into the solution until uptake of the gas stops (about 4 hours). The solution is cooled, and the resulting precipitate is filtered off with suction and washed three times with 40 ml of diethyl ether each time. The solution is diluted with water to twice its volume and likewise extracted three times with 100 ml of diethyl ether each time. The combined ether extracts are dried over magnesium sulfate and evaporated in vacuo; the residue is crystallized from petroleum ether (boiling point 50 to 70). 19 g (70.4% of theory) of 4-difluoromethoxy-3-methoxyacetophenone (M.P. 68) are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In N,N-dimethyl-formamide at 25℃; for 12h; | |
98% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16h; | |
98% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; | 1 Take a 50 ml flask called 4-methoxy-3-hydroxyacetophenone (3.32 g, 20 mmol, leq), add 15 ml of solvent DMF, add potassium carbonate (2.76 g, 20 mmol, leq) bromopropyne (2 · 38 g, 20 mmol, 1 eq) was then reacted at room temperature for 1 hour.After the end of the reaction, the solvent was evaporated to dryness and then evaporated to dichloromethaneThe organic phase is dried using anhydrous sodium sulfate.Evaporation of the dried white solid yield 6 (4.0 g 98%) |
97% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene; mineral oil at 20℃; for 48h; Inert atmosphere; | |
82% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 30℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 30℃; | |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide for 1h; Reflux; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 24h; | Synthesis of Compounds 2-5 General procedure: Acetylene derivatives 1 (0.010 mol) and potassium carbonate (0.015 mol) were refluxed in DMF for 1 h. The reaction mixture was cooled to room temperature and propargyl bromide (0.01 mol) was added and the mixture stirred at room temperature for 24 h. The reaction mixture was poured into 200 mL of ice-cold water. The solid obtained was washed with water and recrystallized from ethanol to afford the desired title compounds 2-5. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | ||
With potassium carbonate In acetone for 8h; Reflux; | 4.1. General procedure for the preparation of propargylatedcompounds 3b-14b General procedure: A mixture of appropriate phenolic compound (3a-14a, 1.0 eq.)and K2CO3 (1.2 eq.) in acetonewas stirred, Then, propargyl bromide(1.2 eq.) was added and the reaction was refluxed with stirring for8 h. After filtration and separation of suspended salts, the solvent offiltrate was evaporated to give the O-propargyated product (3b-14b). These intermediates were used for click reaction withoutfurther purification. | |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide for 16h; | 2.2. Synthesis of acetylinic napthaldehyde and acetophenone General procedure: In 5 ml DMF, 2-hydroxy naphthaldehyde was dissolved followed by the addition of anhydrous K 2 CO 3 . The resulting suspension was stirred for 30 min and the color change from brown to olive green was observed. To this, addition of propargyl bromide was done and the resultant mixture was again allowed to stir for 16 h. The workup was done by ice cold water leading to the formation of brown coloured precipitates of acetylinic napthaldehyde. Similar procedure was followed for preparation of acetylinic acetophenone. | |
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16h; | 2.1.1. General procedure for the synthesis of terminal alkynes (2a-2 g) General procedure: To a 50 mL round bottom flask, compounds (1a-1 g) (1 equiv.), propargylbromide (1.3 equiv.) and K 2 CO 3 (1.5 equiv.) was added into the 10 mL DMF solvent and then the solution was stired for 16 h at room temperature (rt). Aftertht the reaction mixture was poured into ice cold water that gave white colored precipitate of terminal alkynes ( 2a- 2 g). The precipitate thus obtained was fil- tered, washed with ethanol and then dried. Yield: 91%. | |
With potassium carbonate In N,N-dimethyl-formamide; toluene at 25℃; for 16h; | 2.1.1. General procedure for the synthesis of terminal alkynes (2a-2 g) General procedure: To a 50 mL round bottom flask, compounds (1a-1 g) (1 equiv.), propargylbromide (1.3 equiv.) and K 2 CO 3 (1.5 equiv.) was added into the 10 mL DMF solvent and then the solution was stired for 16 h at room temperature (rt). Aftertht the reaction mixture was poured into ice cold water that gave white colored precipitate of terminal alkynes ( 2a- 2 g). The precipitate thus obtained was fil- tered, washed with ethanol and then dried. Yield: 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.5% | Example 1: Preparation of l-[(4-acetyl-2-methoxyphenoxy)methyl]- N-benzyloxycarbonyl-1-aminocyclopropane; A 10 L reactor equipped with mechanical stirrer was loaded with triphenylphosphine (340.0 g, 1.296 mol) and THF (2 L) and the suspension was cooled with an ice bath. The stirred suspension was then slowly added with DIAD (264 g, 1.296 mol) over 30 minutes. After stirring for 30 min at 00C, the stirred suspension was added dropwise with a solution of 4-hydroxy- 3-methoxyacetofenone (180 g, 1.08 mol) and DIPEA (210 g, 1.62 mol) in THF (1500 mL). The suspension was left under stirring for 45 min at 00C, then added dropwise with a solution of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane (China Gateway) (240 g, 1.08 mol) in THF (1500 mL). After Ih, LC-MS analysis of a sample from the reaction mixture showed the complete disappearance of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane. The reaction mixture was evaporated and the crude product was recrystallized with EtOH 95% (4000 mL) to give l-[(4- acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl- 1 - aminocyclopropane (214 g, yield: 53.5%) as a white solid.1H-NMR (300 MHz, CDCl3): delta: 7.41-7.45 (m, 2 H), 7.26 (s, 5 H), 6.77 (d, 1 H), 5.43 (s, 1 H), 5.00 (s, 2 H), 4.04 (s, 2 H), 3.82 (s, 3 H), 2.49 (s, 3H), 0.92 (m, 4 H).LC-MS: M+H+: 370.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With N,N-phenylbistrifluoromethane-sulfonimide; potassium carbonate In tetrahydrofuran at 120℃; for 0.1h; Irradiation; Stage #2: 2-methoxypyridin-3-yl-boronic acid In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 120℃; for 0.166667h; | 19 (R)-N-{1-[3-Methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethyl}-2-trifluoromethoxy-benzenesulfonamide A mixture of acetovanillone (0.332 g, 2.0 mmol), N-phenyl-bis(trifluoromethane-sulfonimide) (710 mg, 2.0 mmol), potassium carbonate (830 mg, 6.0 mmol) and tetrahydrofuran (3.0 ml) was heated to 120° C. for 6 min in a microwave oven. 2-Methoxypyridine-3-boronic acid (611 mg, 4 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 100 μmol), N-methylpyrrolidinone (1 ml) were then added and the mixture heated in the microwave at 120° C. for 10 min. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated to give 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethanone in quantitative yield. Reductive amination with ammonium acetate (20 equivalents) in methanol (50 ml) containing sodium cyanoborohydride (1 equivalent) followed by aqueous work-up with saturated aqueous sodium bicarbonate and extraction into ethyl actetate gave, after solvent was evaporated 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine. To 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine was added 2-trifluoromethoxy-benzenesulfonyl chloride (1 equivalent) in dichloromethane, diisopropylethylamine (4 equivalents) and the mixture overnight. The racemic product was isolated by normal phase HPLC on silica gel eluting with heptane/ethyl acetate and the solvent evaporated to give a clear oily solid (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.9 (d, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3-7.2 (m, 2H), 7.05 (d, 1H), 6.9 (m, 1H), 6.75-6.65 (m, 2H), 5.0 (d, 1H), 4.55 (m, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 1.51 (d, 3H) ppm; MS (ESI) m/z: 483.3 [M+1]+. The racemate was resolved by chiral HPLC (CHIRALPAK-AS, eluting with 9:1 isohexane/ethanol) to give the title compound (11 mg) and its enantiomer (11) mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethanol; at 120℃; | General procedure: To a solution of hydroxy-substituted acetophenone and paraformaldehyde in EtOH (75 mL) was added 4-piperazinoacetophenone at rt as per reported earlier literature.[16], [17], [18] and [19] Then the resulting mixture was heated to reflux for 18-22 h at 120 C. On completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to yield the ortho substituted Mannich base in good yield (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With boron trifluoride diethyl etherate; In 1,4-dioxane; at 20℃; for 19h; | General procedure: Boron trifluoride-etherate (6.0 mmol) was added to a stirred solution of 4'-hydroxy-3'-methoxyacetophenone 1 (1.2 mmol) and benzaldehydes 2a-2g (2.4 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirring for 19 h, the resultant solution was partitioned with EtOAc, washed with 10% HCl aq, distilled water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using silica gel CC eluted with n-hexane/CHCl3 (2/1) to yield chalcones 3a-3g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With boron trifluoride diethyl etherate In 1,4-dioxane at 20℃; for 19h; | 4.4. Synthesis of chalcones 3a-3g General procedure: Boron trifluoride-etherate (6.0 mmol) was added to a stirred solution of 4'-hydroxy-3'-methoxyacetophenone 1 (1.2 mmol) and benzaldehydes 2a-2g (2.4 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirring for 19 h, the resultant solution was partitioned with EtOAc, washed with 10% HCl aq, distilled water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using silica gel CC eluted with n-hexane/CHCl3 (2/1) to yield chalcones 3a-3g. |
41.7% | With sodium hydroxide In ethanol; water at 20℃; for 48h; | |
41.7% | With ethanol; sodium hydroxide for 48h; | 2 Take 0.828g 4-hydroxy-3-methoxyacetophenone and 0.834g 3,4-dimethoxybenzaldehyde, dissolve in 40mL ethanol, add 1.5mL 50% NaOH solution dropwise, and react for 48h.After the pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, 1 times the amount of water was added to precipitate the precipitate, which was suction filtered to obtain a yellow solid, which was washed with a small amount of water.After drying and weighing, 0.655 g of light yellow 4'-hydroxy-3'-methoxy-3,4-dimethoxychalcone solid was obtained.The yield was 41.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With ammonia; hydrogen In methanol at 120℃; for 8h; Autoclave; | 42 Example 42: A method to catalyze the reductive amination of aldehydes and ketones to prepare primary amines, except for replacing "benzaldehyde" in step 2) of Example 1 with "4-hydroxy-3-methoxyacetophenone" and "90°C Except that "reaction 4h" was replaced with "120°C reaction 8h", the rest was exactly the same as in Example 1. The yield of 4-(1-aminoethyl)-2-methoxyphenol was 51%. |
Multi-step reaction with 2 steps 1: pyridine; hydroxylamine hydrochloride / dichloromethane / Reflux 2: hydrogenchloride; palladium on activated charcoal / methanol; water / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 40 °C 2.1: nitric acid; sulfuric acid / dichloromethane / 1 h / 0 °C / pH 7 - 8 3.1: ammonium formate; iron / toluene; water / 103 °C 4.1: sodium methylate / Dimethyl ether / 0.5 h / 20 °C 4.2: 8 h | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 40 °C 2.1: nitric acid; sulfuric acid / dichloromethane / 2.25 h / 0 °C 3.1: iron; ammonium acetate / toluene; water / 105 °C 4.1: sodium methylate / 1,2-dimethoxyethane / 0.5 h / Inert atmosphere 4.2: Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 12 h / 80 °C 2.1: acetic acid; nitric acid / 14 h / 0 - 20 °C 3.1: ammonium acetate; iron / toluene; water / 18 h / 88 °C 4.1: sodium methylate / 1,2-dimethoxyethane / 0.5 h 4.2: 15 h / 20 °C |
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 40 °C 2: sulfuric acid; nitric acid / dichloromethane; water / 1.33 h / 0 °C 3: ammonium formate; iron / water; toluene / Heating / reflux 4: sodium ethanolate / 1,2-dimethoxyethane / 0.5 h | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 40 °C 2: sulfuric acid; nitric acid / dichloromethane / 1.33 h / 0 °C 3: ammonium formate; iron / water; toluene / Heating / reflux 4: sodium methylate / 1,2-dimethoxyethane / 0.5 h | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 40 °C / Inert atmosphere 2: sulfuric acid; nitric acid / dichloromethane / 0 °C 3: iron; ammonium chloride / ethanol; water / 2 h / 90 °C / Inert atmosphere 4: sodium methylate / 1,2-dimethoxyethane / 20 °C | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.25 h / 20 °C 1.2: 4 h / 20 °C 2.1: nitric acid / dichloromethane / 4 h / -20 - -10 °C 3.1: iron; acetic acid / ethanol; water / 3 h / Reflux 4.1: sodium ethanolate / 1,2-dimethoxyethane / 0.5 h / 20 °C 4.2: 7 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium formate;palladium 10% on activated carbon; In water; ethyl acetate; at 80℃; for 2h; | Example 21: Generating ethyl 3-(4-hydroxyphenyl)propanoate and l-(4-hydroxy-3- methoxyphenyl)ethanone from ethyl 3-(4-(2-(4-hydroxy-3-methoxyphenyl)-2- oxoethoxy)phenyl) acrylate .Pd/C (10 mol%) is weighed into a reaction flask. A solvent mixture consisting of ethyl acetate and water (4: 1) and ammonium formate (2 equivalents) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80 C) for 2 minutes. Substrate ethyl 3-(4-(2-(4-hydroxy-3-methoxyphenyl)-2- oxoethoxy)phenyl)acrylate is added. The reaction is run for 120 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2S04. The products were purified by silica column to yield the products in above 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; potassium carbonate In acetonitrile at 80℃; Industry scale; | 1 Example 1: Preparation of l-[4-(3-chloro/bromo propoxy)-3-methoxyphenyl] ethanone (III)Acetonitrile (1L) was charged to 4-hydroxy-3-methoxy acetophenone (IV) (0.5 kg, 3.009 moles). l-Bromo-3-chloropropane (V) (1.89 Kg, 12.036 moles) was added to the reaction mixture and was stirred followed by addition of TBAB (0.030 Kg, 0.0903 moles ). Potassium carbonate (0.78 Kg, 5.657 moles) was added to the reaction mixture and heated to 80°C The mixture was cooled and filtered. The solid obtained was charged to dichloromethane (2 liters) and stirred. The reaction mixture was heated to 40-45 °C and distilled. The reaction mixture was cooled and methanol (0.5 liters ) was added followed by the addition of water (5 liters). The entire reaction mixture was added to chilled water and stirred. The reaction mixture was filtered and washed with water and dried. Yield: 0.779 Kg.Purity: 99.35% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water;HUSY (Si/Al=15); at 250℃; under 5250.53 Torr; for 2h;Inert atmosphere;Product distribution / selectivity; | In an autoclave (batch reactor) lignin (0.5 g), HUSY (Si/Al=15) (0.5 g) and mixture of water and organic solvent (30 g) were charged. After flushing the reactor with nitrogen gas for 3 times, nitrogen (7 bar) was charged. Reactor was heated up to 230° C. under the stirring (100 rpm). After attaining the desired temperature of 230° C. stirring was increased up to 500 rpm. Reaction was stopped after 30 minutes. Analysis of reaction mixture was done by GC, GC-MS. The lignin used in these examples were organosolv or dealkaline.Yield: >25percentMass balance: >90percent.The effect of reaction temperature and reaction time on depolymerization reaction is demonstrated by the results presented in Table 8 using SiO2-Al2O3 as catalyst*. TABLE 8 Exp. Time Lignin Product yield, Mass balance, No. (min.) conversion percentpercentNo. percent 1. 30 85 26 80 2. 60 85 41 86 3. 90 92 50 84 4. 120 95 70 85 Lignin, 0.5 g; HUSY (Si/Al = 15), 0.5 g; N2 Pressure, 7 bar (at)RT; Temperature, 250° C.No.Monomer and dimer products soluble in water/organic solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: acetic acid / 2 h / 60 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 20 - 25 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2 h / 60 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 2: nitric acid / dichloromethane / 2 h / -10 °C 3: toluene / 110 °C 4: iron / acetic acid / 2 h / 40 - 80 °C 5: acetonitrile / 8 h / 25 - 80 °C 6: trichlorophosphate / acetonitrile / 6 h / Reflux |
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 2: nitric acid / dichloromethane / 2 h / -10 °C 3: toluene / 110 °C 4: iron; acetic acid / 2 h / 40 - 80 °C 5: acetonitrile / 8 h / 25 - 85 °C 6: trichlorophosphate / acetonitrile / 6 h / Reflux | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: dimethyl amine; toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: nitric acid / toluene / 10 h / 110 °C 4: iron / acetic acid / 2 h / 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: acetic acid; iron / 2 h / 60 - 80 °C 5: acetonitrile / 10 h / 25 - 85 °C 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 25 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone; potassium carbonate / 20 °C 2: nitric acid / dichloromethane / -20 °C 3: toluene; dimethyl amine / 110 °C 4: acetic acid; iron / 85 °C 5: acetonitrile / Reflux 6: trichlorophosphate / acetonitrile / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene; N,N-dimethyl-formamide / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 2: nitric acid / dichloromethane / 2 h / 10 °C 3: toluene / 110 °C 4: iron; acetic acid / toluene / 2 h / 80 °C 5: acetonitrile / 8 h / 80 °C 6: trichlorophosphate / acetonitrile / 6 h / Reflux | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / water; dichloromethane / 4 h / 0 °C 3: N,N-dimethyl acetamide; toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: acetic acid; iron / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 6 h / 20 °C 2.1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 15 h / Reflux 4.1: iron; acetic acid / 2 h / 60 - 90 °C 5.1: acetonitrile / 12 h / Reflux 6.1: trichlorophosphate / acetonitrile / 6 h / Reflux | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 0.5 h / 20 °C 1.2: 20 h / 0 - 25 °C 2.1: nitric acid / dichloromethane / 8 h / -20 - -15 °C 3.1: toluene; N,N-dimethyl-formamide / 10 h / 113 °C 4.1: acetic acid; iron / 2 h / 20 - 80 °C 5.1: acetonitrile / 12 h / 80 °C 6.1: trichlorophosphate / acetonitrile / 5 h / 80 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: acetic acid; iron / 2.5 h / 20 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 20 - 25 °C 2.1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 3.1: toluene / 16 h / 110 °C 4.1: iron; acetic acid / 2 h / 40 - 80 °C 4.2: 0.01 h / 80 °C 5.1: acetonitrile / 8 h / Reflux 6.1: trichlorophosphate / acetonitrile / 6 h / 85 °C 6.2: pH 10 / Cooling with ice | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 0.5 h 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h 1.2: 5 h / 20 °C 2.1: nitric acid / dichloromethane / 6 h / -15 - -10 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 13 h / Reflux 4.1: acetic acid; iron / 2 h / 100 °C 5.1: acetonitrile / 20 °C 6.1: trichlorophosphate / Reflux | ||
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2: nitric acid / 0 - 20 °C 3: toluene / 110 °C 4: iron; acetic acid / 2 h / 80 °C 5: trichlorophosphate; N,N-dimethyl-formamide / 1 h / 110 °C 6: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 10 h / 85 °C | ||
Multi-step reaction with 6 steps 1: acetone / 12.5 h / 0 - 25 °C / Alkaline conditions 2: nitric acid / dichloromethane / -20 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2.5 h / 25 - 80 °C 5: acetonitrile / 10 h / 85 °C 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2: nitric acid / 0 °C 3: toluene / 10 h / Reflux 4: iron; acetic acid / 2 h / 80 °C 5: trichlorophosphate; N,N-dimethyl-formamide / 1 h / Reflux 6: sodium iodide / N,N-dimethyl-formamide / 10 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 25 °C 2: nitric acid / dichloromethane / 2 h / -20 - -10 °C 3: toluene / 16 h / 110 °C 4: acetic acid; iron / 2 h / 40 - 80 °C 5: acetonitrile / 8 h / Reflux 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 20 °C 2: nitric acid / dichloromethane / 3 h / -20 - -10 °C 3: toluene / 16 h / 100 °C 4: acetic acid; iron / 2 h / 40 - 80 °C 5: acetonitrile / 8 h / Reflux 6: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 12.5 h / 0 - 20 °C 2: nitric acid / dichloromethane / 4 h / 0 °C 3: toluene / 10 h / 110 °C 4: iron; acetic acid / 2 h / 80 °C 5: acetonitrile / 10 h / 80 °C 6: trichlorophosphate / 6 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With water; acetic acid; N,N,N',N'-tetramethylguanidine In tetrahydrofuran; acetonitrile at 20℃; | TMG Deprotection of Aryl Hydroxyl Groups in Solution. To a one dram vial equipped with a stir bar was added 50 mg (1 eq) of a TBDMS- or TIPS protected aryl hydroxyl, which was then dissolved in 500 μL of THF. In a separate vial was mixed 500 μL of ACN, 10 eq TMG, 11.5 eq glacial acetic acid, and 10 μL H2O. This cleavage cocktail was added to the protected hydroxyl and allowed to stir overnight at room temperature. The reaction was quenched with water (5 mL) and extracted three times with ethyl acetate (3×10 mL). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated to dryness. Purification was performed by silica gel chromatography with mixtures of ethyl acetate and hexanes or preparatory HPLC as described in general methods section. Deprotection of TIPS-2 to give acetovanillone (6). Yield=75%, 20 mg; 1H NMR (C4D8O, 400 MHz): δ=(bs, 1H), 7.59-7.51 (m, 2H), 6.85 (d, J=7.1 Hz, 1H), 3.94 (s, 3H), 2.50 (s, 3H); 13C NMR (C4D8O, 100 MHz): δ=195.3, 152.6, 148.4, 130.6, 124.2, 115.3, 111.1, 56.1, 25.9; HRESIMS m/z [M+H]+ 167.0702 (calcd for C9H11O3, 167.0703). |
63% | With acetic acid In tetrahydrofuran; water; acetonitrile at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium hydroxide In ethanol; water at 20℃; | General procedure for synthesis of chalcones via Claisen-Schmidt condensation General procedure: To a solution of 2,4,5-trimethoxy benzaldehyde (4mmol) and appropriate acetophenone (4mmol) in C2H5OH (25ml), 40% of aqueous KOH (2mmol) was added. The reaction mixture was stirred at r.t. till completion of reaction (monitored by TLC). Then the reaction mass was poured into ice water and neutralized with aqueous 10% HCl solution. The precipitate was filtered, washed with excess of water, dried and recrystallized from methanol to obtain pure chalcones. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; In methanol; at 20℃; for 24h;Inert atmosphere; | General procedure: To a methanol solution containing apocynin (300 mg,1.80 mmol) was added sodium hydroxide (7.20 mmol) followedby the addition of benzaldehydes (a-l) (1.90 mmol)and the contents were stirred at room temperature for 24h-72h. The reaction mixture was diluted with water and acidifiedto pH = 3 using 1N HCl and extracted with ethyl acetate.The organic layer was washed with water followed bybrine solution, dried over anhydrous sodium sulphate, filteredand concentrated under reduced pressure, to obtain thepure compounds. Yields of the products varied between 78and 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper(II) acetate monohydrate In tert-Amyl alcohol at 20 - 100℃; for 12.33h; Schlenk technique; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; at 100℃; for 20h; | General procedure: To a solution of aluminum chloride (2.08 g, 15.57 mmol) in dichlorobenzene was added a solution of 12 (1.2 g, 7.79 mmol) in dichlorobenzene at room temperature. The reaction was warmed to 100 C and further stirred for 20 h. After the reaction mixture was allowed to cool to room temperature, added with dichloromethane, and poured into 10% HCl cooled at 0 C. The aqueous layer was separated and extracted with CH2Cl2. The combined organic phases were washed with water, dried over Na2SO4. The filtrate was evaporated under vacuum, and the residue was purified by column chromatography (EtOAc/hexane, 1:4, v/v) to give a white solid (0.75 g, 62.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In methanol; for 14h;Cooling with ice; Reflux; | General procedure: 1,2-dimethoxy-4-vinylbenzene (DEVB) was synthesizedas follows: DMOAP (1.76 g) was added to absolute methanol(20 mL), then sodium borohydride (0.88 g) was addedslowly into the mixture and the solution was stirred for4 h under ice water bath. Then the reaction solution wasrefluxed for 10 h. The suspension gradually became a clearsolution, then it was adjusted to pH 3.0 with hydrochloricacid. The solvent was removed by vacuum distillationthen the reaction mixture was poured into iced water (20mL) and extracted with 1,2-dichloroethane. The extractwas eluted with the mixture of ethyl acetate and n-hexanein 1:1 (v/v) and then distilled to obtain the product DEVB.It was determined by elemental analysis and GC/MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium tetrahydroborate; palladium on activated charcoal In water; ethyl acetate at 80℃; for 14h; | |
1: 82% 2: 86% | With C32H25Cl2N6O2Rh2(1+)*Cl(1-); sodium hydroxide In water at 110℃; for 18h; Inert atmosphere; | 5 Embodiment 5 The 145 mg type e shown in lignin of β - O - 4 model compound, 4 mg double rhodium catalyst, 80 mg NaOH added 1 ml distilled water, under protection of argon 110 °C reaction 18 hours, to complete the lignin complete degradation, wherein the degradation product 3 - methoxy -4 - hydroxy acetophenone yield is 82%, O-methoxyphenol of yield is 86%. |
1: 82% 2: 86% | With C32H25Cl2N6O2Rh2(1+)*Cl(1-); sodium hydroxide In water at 110℃; for 18h; Inert atmosphere; Green chemistry; |
With C22H17Cl3N3ORh; sodium hydroxide In water for 60h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80%; 5%; 83% | With sulfuric acid; In methanol; at 80℃; for 1h; | 19 (11.3 mg, 0.021 mmol), conc H2SO4 (1.4 muL, 0.026 mmol) and MeOH (0.22 mL, 0.1M of substrate) was reflux at 80 C for 1 h. The product was extracted with dichloromethane. The organic layer was washed with the water, dried over MgSO4 and concentrated under vacuum. The products were separated by silica-gel column chromatography (EtOAc:hexane 2:8) to produce 28 (3.3 mg, 0.015 mmol, 80%), 13 (2.9 mg, 0.0175 mmol, 83%), 21 (0.35 gm, 0.001 mmol, 5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With ammonium formate In methanol at 70℃; for 4.5h; Inert atmosphere; Enzymatic reaction; Stage #2: ethyl 2-methoxyacetate With hydrogen; sodium carbonate In toluene at 70℃; | 8 example 8 A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd°-nanocatalyst (Pd°-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70°C for the time shown in table 4. Next, the solvent was evaporated and Pd°-Nanocatalyst (Pd°-AmP-MFC, 10.72 mg, 0.008 mmol, 8 wt%, 4 mol%), Novozyme- 435 (50 mg/mmol) and additive (mol. siev. 4 A (100 mg) or dry Na2C03 (20 mg)] were added to the vial with amine product. The vial was evacuated three times and refilled with H2. Dry toluene (0.6 mL) was added to the vial, and a balloon containing H2 was connected to the vial. The mixture was heated 70°C followed by addition of ethyl methoxyacetate (47 μ, 0.4 mmol) and stirred for the time shown in the Scheme. Next, the crude reaction mixture was filtrated through Celite using CHCb (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron tribromide In dichloromethane at -78℃; for 0.25h; Inert atmosphere; | 3, 4-Dihydroxy-acetophenone Boron tribromide (44.0 mL, 78.9 mmol) was added to a solution of 3-methoxy-4-hydroxyacetophenone (2.00 g, 13.1 mmol) in dryCH2Cl2 (108 mL) at -78 °C under nitrogenatmosphere. After 15 min, the reaction mixture was stirred at 0 °C, and diluted with H2O. The mixturewas added to brine and extracted with AcOEt. The obtained organic layer was washed with brine, driedover MgSO4, and concentrated in vacuo. The residue was purified with silica gel columnchromatography (1:1 = hexane:AcOEt) to afford 1 (2.00 g, 13.1 mmol, 100%) as brown oil. 1H NMR(600 MHz, DMSO-d6): δ 2.39 (s, 3H), 6.76 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.30(dd, J = 8.4, 1.8 Hz, 1H), 9.29 (s, 1H), 9.80 (s, 1H). |
97% | With aluminum triiodide; carbonic acid dimethyl ester In acetonitrile at 80℃; for 18h; | |
97% | With aluminum triiodide; carbonic acid dimethyl ester In acetonitrile at 80℃; for 18h; | 23-24 Example 24 (Demethylation of Vanilla Ethyl Ketone) Add acetonitrile (40ml), aluminum triiodide (2.242g, 5.5mmol) and dimethyl carbonate (0.495g, 5.5mmol) to a 100ml round bottom flask, stir at 80°C for 15min, add vanilla ethyl ketone (0.831 g, 5mmol), continue stirring at 80°C for 18h. After the reaction is complete, it is quenched with 2M dilute hydrochloric acid (10ml), and then extracted three times with ethyl acetate (50ml). The organic phases are combined, and then saturated aqueous sodium thiosulfate ( 10ml) was washed, then dried with anhydrous magnesium sulfate, filtered, the filtrate was removed from the solvent with a rotary evaporator, and the residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=1:1, volume ratio), Obtained 0.740 g of 3',4'-dihydroxyacetophenone (off-white solid, yield 97%). |
94% | With aluminum triiodide; calcium(II) oxide In acetonitrile at 80℃; for 18h; | 10 Example 10 (vanillone demethylation) To a 100 ml eggplant flask was added aluminum triiodide (2.242 g, 5.5 mmol), acetonitrile (40 ml),CaO (0.422 g, 7.5 mmol) and vanillone (0.833 g, 5.0 mmol) were heated to 80 °C,After 18 hours of reaction, stirring was stopped. After cooling to room temperature, 2 mol/L dilute hydrochloric acid (10 ml) was acidified in an eggplant-shaped flask.Extract with ethyl acetate (50ml x 3) and combine the organic phases and wash first with saturated aqueous sodium thiosulfate (10ml).It was washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether=1:2, volume ratio).0.720 g of 3,4-dihydroxyacetophenone (white solid, yield 94%) was obtained. |
94% | Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With Aluminum Chloride; sodium iodide; calcium(II) oxide In acetonitrile at 80℃; for 18h; Stage #2: With hydrogenchloride In water monomer; acetonitrile | 19 Example 19 (vanyl ethyl ketone demethylation) To a 100 ml round bottom flask was added acetonitrile (40 ml) followed by aluminum trichloride (0.766 g, 5.74 mmol,1.1 eq), sodium iodide (2.349 g, 15.67 mmol, 3 eq), calcium oxide (0.439 g, 7.83 mmol, 1.5 eq) and acetovanillone(0.867 g, 5.225 mmol), heated to 80 ° C, after 18 hours of reaction, stirring was stopped, and after cooling to room temperature, it was added to a round bottom flask.Acidified with 2mol/L dilute hydrochloric acid (10ml), extracted with ethyl acetate (50ml×3), combined with organic phase, first saturated with sodium thiosulfateWashed with aqueous solution (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfateThe product was evaporated to dryness, and the residue was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 4:1, volume ratio)0.751 g of 3,4-dihydroxyacetophenone (yellow solid, yield 94%). |
91% | With aluminum triiodide In dimethyl sulfoxide; acetonitrile at 80℃; for 18h; | 29 Example 29 (vanyl ethyl ketone demethylation) Add aluminum triiodide (2·240 g, 5 · 5 mmol), acetonitrile (40 ml) and DMSO (0.977 g, 12.5 mmol) to a 100 ml eggplant-shaped flask, and heat to 80 ° C with stirring, and stir for 0.5 hour. Then, vanillin (0.831 g, 5.0 mmol) was added, and the reaction was further stirred (80 ° C). After the reaction for 18 hours, the stirring was stopped. After cooling to room temperature, 2 mol/L of dilute hydrochloric acid (10 ml) was added to the eggplant bottle. The mixture was extracted with ethyl acetate (50 mL EtOAc). EtOAc (EtOAc m. It was evaporated to dryness by a rotary evaporator, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:4, volume ratio) to give 0.696 g of 4-acetyl catechol (yellow solid, Yield 91%). |
91% | With aluminum triiodide; dimethyl sulfoxide In acetonitrile at 80℃; for 18h; | Cleavage of Catechol Monoalkyl Ethers by Aluminum Triiodide- Dimethyl Sulfoxide; General Procedure General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in MeCN was added anhyd DMSO (0.430 g, 5.5 mmol, 1.1 equiv). After stirring for 0.5 h at 80 °C, the selected substrate (5 mmol) was added in one portion. The mixture was stirred overnight (18 h) at that temperature before quenching with aq 2 M HCl (10 mL). After extraction with EtOAc (3 50 mL), the organic phases were combined, washed with sat. aq Na2S2O3 and brine, and dried (MgSO4). The solvents were removed on a rotary evaporator, and the residue was purified by column chromatography to give the relevant catechol or phenol. |
86.37% | With water monomer; hydrogen bromide; acetic acid at 25 - 135℃; for 10.25h; | Method-1: To a stirred solution of 1-(4-hydroxy-3- methoxyphenyl)ethanone (I) (50 g, 0.030 mmol) in acetic acid (100 mL) was charged with 48% aqueous HBr (40.92 g, 0.051 mmol) at 25-30 C. The reaction contents were stirred at ambient temperature for 15 min and then slowly raised the temperature up to 130-135 C and maintained for 10 h. The reaction progress was monitored by TLC (chloroform:methanol, 4:1), then it was cooled to room temperature. The solvent acetic acid was distilled off on under reduced pressure at below 80 C to obtain residue, which was quenched into water (200 mL). The desired product was extracted with ethyl acetate (2 × 200 mL), the combined ethyl acetate layer was washed with water (100 mL). The ethyl acetate was removed by rotary evaporator at below 65 C under reduced pressure to obtain a residue and recrystallized from isopropyl alcohol (150 mL) under reflux and cooled to below 2 C. The desired product was obtained as a white crystalline wet solid. The wet product was dried in vacuum at 50-55 C for 1-2 h. Dry weight of compound 1 was 39.5 g, yield: 86.37%. |
75% | With pyridine; aluminum triiodide In acetonitrile at 80℃; for 18h; | General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 °C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%). |
65% | With aluminum triiodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | Hydroxychavicol (4-Allylbenzene-1,2-diol, 2); General Procedure General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
65% | With aluminum triiodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | 25 Example 25 (acetovanillone demethylation) To a 100 ml eggplant flask were added aluminum triiodide (2.250 g), acetonitrile (40 ml) DIC(0.378g) and acetovanillone (0.831g). After heating to 80 ° C, the mixture was stirred for 18 hours. After cooling to room temperature, 2 mol / L dilute hydrochloric acid (10 ml) was added to the eggplant flask, Ester (50 ml X) The organic phases were combined, washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), dried over saturated brine (10 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness on a rotary evaporator and the residue was purified by flash column chromatography (Eluent: ethyl acetate / petroleum ether = 3: 7, volume ratio) to give 0.496 g of 3,4-dihydroxyacetophenone (white solid in 65% yield). |
With 3-mercaptopropionic acid ethyl ester In aq. buffer at 30℃; for 24h; Inert atmosphere; Glovebox; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide In ethanol at 20℃; | 3.1. Synthesis of Cinnamylideneacetophenones General procedure: All starting reagents were purchased from Sigma-Aldrich. Compounds were synthesizedby Claisen-Schmidt condensation, according to the method reported by Weldon and co-authors,with minor modifications [20-22]. Cinnamaldehyde (6 mmol) was added to solution of respectiveacetophenone (5 mmol) in ethanol (5 mL). The solution was stirred at room temperature for 30 min,followed by dropwise addition of 5 mL ethanolic solution of NaOH (1.0 M). The progress of reactionwas checked by thin-layer chromatography (TLC) analyses. Reaction medium was poured intocrushed ice. Precipitated crude products were filtered, washed with cold water, and dried at roomtemperature. Soluble crude products were partitioned with ethyl acetate (3 25 mL). Organic phasewas concentrated under reduced pressure. Compounds 2, 7, 8 and 10-7 were recrystallized in ethanol.Compounds 3-6, 9 and 18 were recrystallized in mixtures of hexane and chloroform. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a solution of apocynin (6) (1.5 g, 9.02 mmol,1.0 eq) in 2-methyl tetrahydrofuran (25 mL) was added potassium carbonate (1.5 g, 10.82 mmol, 1.2 eq) at room temperature and stirred for 15 min. To the above reaction contents, compound 5 (1.88 g, 9.11 mmol, 1.01 eq) was added slowlyover a period of 15 min and heated to reflux for 1 h. After the completion of the reaction (checked by TLC), the reaction mixture was diluted with water (15 mL) and stirred for 15 min.The organic layer was washed with water (2 × 10 mL) followed by brine solution, separated, dried over Na2SO4 (5 g), filtered and evaporated under reduced pressure to obtain crude compound. The crude compound was titrated with n-hexane toobtain pure compound 7. Pale yellow solid; Yield: 3.65 g, 94 %;m.p.: 72-73 C; IR (KBr, nu max , cm -1 ): 3072 (-C-H stretch, aromatic),1681 (-C=O stretch), 1587 (-C=C-stretch), 1512 and 1338 (-NO 2stretch), 1084 (-C-O stretch); 1H NMR (400 MHz, DMSO-d6): delta 2.58 (s, 3H), 3.98 (s, 3H), 5.20 (s, 2 H), 6.56 (s, 1H),6.80 (s, 1H), 7.0 (d, J = 7.2 Hz, 1 H), 7.58 (s, 2 H); ESI-MS:m/z, 292.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84%; 6%; 4% | With lithium carbonate; In N,N-dimethyl-formamide; at 55℃; for 18h;Inert atmosphere; | General procedure: To a solution of the appropriate 4-acyl-1,2-dihydroxybenzene (9) (0.25 mol) and methyl iodide (71 g, 0.5 mol) in DMF (250 mL) was added Li2CO3, (37 g, 0.5 mol). The resulting suspension was stirred under argon at 55° C for 18 h. The reaction mixture was poured into water (1 L) containing conc. HCl (70 mL), extracted with ethyl acetate, chromatographed on silica gel (hexane/acetone, 20:1) to give products 10-12 and unreacted 4-acyl-1,2-dihydroxybenzenes (9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid In ethanol; water for 1h; Reflux; | Representative procedure for the synthesis of (1-12) General procedure: To a solution of phenyl/cyclohexyl/allyl thiosemicarbazide (0.0119 mol) in absolute ethanol (11 mL), water (22 mL) was added. To this solution, disubstituted aldehydes/ketones (0.0125 mol) and glacial acetic acid (0.55 mL) were added. This mixture was refluxed for an hour prior to cooling it down to room temperature. The precipitate was collected with filtration under vacuum and washed several times with cold water. The compounds were recrystallized from absolute ethanol after filtration of the precipitate in vacuum conditions and washing numerous times with cold water [21]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In acetone at 20℃; for 0.25h; Stage #2: 1-chloro-3,7-dimethylocta-2,6-diene In acetone | (E)-1-(4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-methoxyphenyl)ethan-1-one (3b) A mixture of 2.44 g (14.77 mmol) 3a, 3.04 g (22 mmol)K2CO3, in acetone (150 mL) was stirred at room temperaturefor 15 min, then 3.03 g (17.6 mmol) of geranyl chloridewas added and the mixture was stirred at reflux for 24 h.Upon completion of this time, the mixture was filtered andfinally the solvent removed under vacuum and the residualoil purified by column chromatography over silica gel(10 g/g crude, hexane/EtOAc, 9:1) to give 4.2 g (95 %) of 3b as a yellow oil, Rf 0.35 (Hexane/EtOAc, 8:2). IR: vmax1735, 1475, 1000, 1100 cm-1. 1H NMR (300 MHz, CDCl3)δ = 1.59 (s, 3H, CH=C(CH3)2), 1.66 (s, 3H, CH=C(CH3)2), 1.75 (s, 3H, CH=C(CH3)2), 2.05-2.17 (m, 4H, H-4″ andH-5″), 2.56 (s, 3H, C=OCH3), 3.91 (s, 3H, OCH3), 4.69(d, J = 6.4 Hz, 2H, H-1″), 5.02-5.11 (m, 1H, H-6″), 5.50(tt, J = 5.2, 2.7 Hz, 1H, H-2″), 6.88 (d, J = 8.2 Hz, 1H,H-5′), 7.52 (d, J = 1.9 Hz, 1H, H-2′), 7.45 (dd, J = 8.1,2.1 Hz, 1H, H-6′). 13C NMR (75.4 MHz, CDCl3) δ 16.63(CH=C(CH3)2), 17.59 (CH=C(CH3)2), 25.58 (CH=C(CH3)2), 26.07 (C=OCH3 and C-4″ or C-5″), 39.42 (C-4″ orC-5″”), 55.79 (OCH3), 65.76 (C-1″), 109.97 (C-2′), 111.16(C-5′), 118.91 (C-2″), 123.12 (C-6″), 123.61 (C-6′), 130.07(C-1′), 131.66 (C-7″), 141.25 (C-3″), 149.11 (C-3′), 152.50(C-4′), 196.74 (C-1). HRMS (EI) m/z [M+] calculated forC19H26O3: 302.1882. Found: 302.1881. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With potassium carbonate In N,N-dimethyl acetamide at 85℃; for 3h; | 1.1.1 Ethyl 7-(4-acetyl-2-methoxyphenyl)heptanoate (103) At room temperature, 20.0g (121mmol) of 3-methoxy-4-hydroxyacetophenone (101) was dissolved in 200mL of N,N-dimethylacetamide, 17.5 g (127 mmol) of anhydrous potassium carbonate and 30.0 g (127 mmol) of ethyl 7-bromoheptanoate (102) were added to the reaction solution. After the addition, the temperature was raised to 85° C. to react for 3 hours.After the reaction is complete, the reaction solution is cooled to room temperature, pour into 500mL ice water, stir at room temperature for 20min, filter with suction, the filter cake was washed with 200 mL of water, and 32.9 g of yellow solid was obtained after drying, with a yield of 84.5%. |
80.1% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h; | 4.1.1. Preparation of ethyl 7-(4-acetyl-2-methoxyphenoxy)heptanoate (2) To a solution of 4-hydroxy-3-methoxy-acetophenone (20.0 g,120.5 mmol) in DMF (200 mL) was added K2CO3 (17.4 g, 126.5 mmol)and ethyl 7-bromoheptanoate (30.0 g, 126.5 mmol). The reactionmixture was then stirred at 80 °C for 4 h. The mixture was then pouredinto cold water (500 mL) with vigorously agitating, the resulting precipitatewas filtered-off, washed with water, and dried under vacuum toafford the title compound 2 (31.3 g, 80.1%) as a white solid. MS (ESI)m/z: 323.05 [M+H] +. |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h; |
Tags: 498-02-2 synthesis path| 498-02-2 SDS| 498-02-2 COA| 498-02-2 purity| 498-02-2 application| 498-02-2 NMR| 498-02-2 COA| 498-02-2 structure
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