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CAS No. : | 578-95-0 | MDL No. : | MFCD00005019 |
Formula : | C13H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FZEYVTFCMJSGMP-UHFFFAOYSA-N |
M.W : | 195.22 | Pubchem ID : | 2015 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 14 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.07 |
TPSA : | 32.86 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.38 cm/s |
Log Po/w (iLOGP) : | 1.94 |
Log Po/w (XLOGP3) : | 2.98 |
Log Po/w (WLOGP) : | 2.68 |
Log Po/w (MLOGP) : | 2.06 |
Log Po/w (SILICOS-IT) : | 3.63 |
Consensus Log Po/w : | 2.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.62 |
Solubility : | 0.047 mg/ml ; 0.000241 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.33 |
Solubility : | 0.0906 mg/ml ; 0.000464 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.29 |
Solubility : | 0.00101 mg/ml ; 0.00000516 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.45 |
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 |
---|---|---|
89% | for 12 h; Reflux; Inert atmosphere | A magnetically stirred solution of 9-acridanone (4.01 g, 21 mmol) in phosphorus oxychloride (105 mL, 1.13 mol) was brought to reflux for 12 h. The solution was cooled to rt, added slowly to cracked ice (650 g), and made slightly alkaline with concentrated ammoniumhydroxide. A light tan solid was collected by filtration, washed with water, and air dried for 24 h. Flash chromatography (silica gel/75percent hexane, 20percent THF, 5percent triethylamine) afforded 3.97 g (89percent yield)of 10 as fine yellow needles which was identical to material prepared by method A as judged by TLC, mp, and spectral data. |
86% | at 105℃; for 3 h; Inert atmosphere | Add 3 mmol of acridone to a two-necked flask equipped with a condenser and a stir bar, fill with N2, add 6 ml of P0C13 in a nitrogen atmosphere, and reflux at 105 ° C for 3 h. After the reaction is completed, cool to room temperature. The reaction solution was slowly dropped into ice water while stirring, and a mixture of ice, concentrated aqueous ammonia and chloroform (volume ratio 1:1:1) was added to the above liquid, and the chloroform layer was separated and dried (anhydrous magnesium sulfate). Filtration gave a pale yellow liquid, which was purified by column chromatography using ethyl acetate: petroleum ether.White needle crystals were obtained with strong fluorescence. Intermediate Compound 1, yield 86percent. |
47 g | With thionyl chloride In N,N-dimethyl-formamide | A mixture of 50 g (0.25 mol) of intermediate (d) and 35 g of thionyl chloride and 200 g of N, N-dimethylformamide,After completion of the reaction, the reaction mixture was poured into ice water, filtered and dried to obtain 47 g of a yellow solid powdery intermediate () |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | at 20 - 25℃; for 12 h; Ionic liquid | The synthesis method comprises the following steps:29.2 g of [Pmim] OH ionic liquid was added in a three-necked flask equipped with a condensing reflux at room temperature,19.5g acridone, stirring evenly after adding 11.3 g of chloroacetic acid, the control temperature of 25 stirring reaction 12h after standing at room temperatureThe residue was then washed with 25 ml of methanol and dried to give 24.2 g of acridone acetate (yield: 95.7percent). |
93.5% | With tetrabutylammomium bromide; sodium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 3 h; | 39percent acridone (2 mol),N-tetrabutylammonium bromide (TBAB) 19.34g (0.06mol),265 g (2.8 mol) of chloroacetic acid was added to a 1000 mL three-necked flask.Add 500 mL of organic solvent DMF and stir at 80 ° C to dissolve.Further, 100 mL of a 60 wtpercent NaOH aqueous solution was added, and after heating at 80 ° C for 3 hours,The reaction was stopped, allowed to cool to room temperature, and the reaction system was poured into 300 mL of ice water.A large amount of yellow solid precipitates were precipitated, allowed to stand overnight, suction filtered, and washed with ice water.That is, a wet intermediate is obtained; 500 mL of a 30 wtpercent NaOH aqueous solution is added to the wet intermediate,Dissolve and stir at room temperature, filter, and wash with 100 mL of 30 wtpercent NaOH aqueous solution.Combine the washing solution, add concentrated hydrochloric acid to adjust the pH value between 4 and 5.There is a large amount of yellow solid precipitates, Allow to stand overnight, suction filtration, wash with ice water,Drying, 474 g of acridinone acetate product was obtained, and the yield was 93.5percent.The purity by HPLC was 99.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sulfuric acid; at 70℃; for 1h; | Take 1gN- phenyl anthranilic acid was dissolved in 10ml of concentrated sulfuric acid, 70 for 1 hour.The reaction was added to ice water, suction filtered, washed with 5% sodium carbonate solution until neutral washing, filtration, drying the solid 0.81g, yield: 88% |
70% | With sulfuric acid; for 3h;Heating; | A mixture of aniline (0.65 g, 7 mmol), o-bromobenzoic acid (1 g,5 mmol), anhydrous potassium carbonate (0.82 g, 6 mmol), 0.1 g ofmetallic copper powder and 0.04 g of copper oxide was refluxed for4 h in 15 ml of amyl alcohol. The amyl alcohol was evaporated thenpoured into (100 ml) hot water, cooled to room temperature. Themedium pH was then adjusted to 4 by adding HCl (0.5 M). Compound1 was obtained as a white precipitate which was thenrecrystallized from ethanol. The N-phenylantranilic acid (1g,4.7 mmol) was taken in 4ml of concentrated sulphuric acid andheated on water bath for 3 h. Reaction mixture was added to hotwater and the resulting precipitates were filtered to get acridone.The sample of acridone 2 was recrystallized from acetic acid. Yield70%, m.p. > 330 C. IR (KBr, cm-1) 3275 (N- H), 3084 (C-H aromatic),1640 (C=O), 1570 (C=C). 1H NMR (DMSO-d6) delta (ppm): 11.74(s, 1H, NH), 8.23 (dd, J= 8.1, 1.2 Hz, 2H, H1-H8), 7.70 (td, J= 8.4,1.5 Hz, 2H, H3-H6), 7.53 (d, J= 8.1 Hz, 2H, H4-H5), 7.23 (td, J= 8.4,1.5 Hz, 2H, H2-H7). 13C NMR (300 MHz, DMSO-d6) delta (ppm): 177.29(C=O), 141.35 (C4a-C10a), 133.94 (C3-C6), 126.46 (C1-C8), 121.49(C4-C5), 120.91 (C8a-C9a), 117.80 (C2-C7). |
70% | With sulfuric acid; at 85℃; for 3h; | The N-phenylanthranilic acid (1 g, 4.7 mmol) was taken in 4 mL of concentrated sulfuric acid and heated on water bath for 3 h. Reaction mixture was added to hot water and the resulting precipitates were filtered to get acridone. The sample of acridone 2 was recrystallized from acetic acid. Yield 70%, Rf 0.71, mp > 330 C. IR (KBr) 3275 (N-H), 3084 (C-H aromatic),1640 (C=O), 1570 (C=C). 1H NMR (300 MHz, [D6]DMSO, 25 C, TMS): delta 11.74 (s, 1H, NH), 8.23 (dd, J = 8.1, 1.2 Hz, 2H, H1-H8), 7.70 (td, J = 8.4, 1.5 Hz, 2H, H3-H6), 7.53 (d, J = 8.1 Hz, 2H, H4-H5), 7.23 (td, J = 8.4, 1.5 Hz, 2H, H2-H7). 13C NMR (75 MHz, [D6]DMSO, 25 C, TMS) delta: 177.29, 141.35, 133.94, 126.46, 121.49, 120.91, 117.80. |
48% | With sulfuric acid; at 90 - 100℃; for 4h;Heating; | For the synthesis of compound 7, firstly 2- Chlorobenzoic acid ( 1 mmol) was dissolved in iso-amyl alcohol (50 ml) and treated with aniline (1 mmol) in the presence of K2CO3 (1.5 mmol) and CuO (0.25 mmol) and refluxed at 150 C for 36 h. After the completion of the reaction iso- amyl alcohol was evaporated under vacuum on rotary evaporator and hot water was added to the reaction mixture. Precipitates were obtained on acidification and filtered via suction and further treated with 10 mL conc. H2SO4 at 90-100 C for 4 h. Then the hot mixture was poured into cold water and the light yellow colored precipitates obtained were filtered followed by washings with water and then acetone to get the pure product 7. Light yellow solid; yield 48%, mp > 300 C.1H NMR (500 MHz, DMSO-d6) delta: 7.22-7.25 (m, 2H, ArH), 7.52 (d, J = 8.4 Hz, 2H, ArH), 7.69-7.73 (m, 2H, ArH), 8.21 (d, J = 8.05 Hz, 2H, ArH), 11.71 (s, NH); 13C NMR (125 MHz, normal/DEPT- 135) delta: 117.7 (+ve, ArCH), 120.9 (ArC), 121.4 (+ve, ArCH), 126.4 (+ve, ArCH), 133.9 (+ve, ArCH), 141.3 (ArC), 177.2 (C=O); HRMS (ESI) m/z for C13H9NO [M+H]+ calcd. 196.0756, found 196.0588. |
5.53 mmol | With Eaton's reagent; at 80℃; for 0.5h; | General procedure: To an oven dried round bottom flask equipped with magnetic stirrer, reflux condenser, CaCl2 guard tube, diarylamine 2-carboxylic acid (6.92 mmol) was taken. Eaton's reagent (P2O5-CH3SO3H) (8 mL) was added and the reaction mixture was heated at 80 C-100 C for 30 min-1 h until completion of reaction as indicated by TLC. The reaction mixture was allowed to come to room temperature and added slowly to the saturated aqueous NaHCO3 solution. Then, the solution was extracted with chloroform, dried over Na2SO4 and evaporated to dryness under vacuo. The crude residue was purified by silica gel column chromatography to afford the pure product. |
With polyphosphoric acid (PPA); at 100℃; for 3h; | General procedure: A mixture of 2-arylamino benzoic acids 3 (1mmol) and polyphosphoric acid (10mmol) was heated at 100C for 3h. The reaction run to completion when brown color of the reaction mixture faded to yellow. Then, it was poured into hot water (500ml) and made alkaline by liquor ammonia. Then, the obtained yellow precipitate was filtered off, washed with hot water, and purified using recrystallization from acetic acid to obtain pure products in 80-85% yield. | |
With polyphosphoric acid; at 100℃; for 3h; | General procedure: A mixture of appropriate 2-arylaminobenzoic acid 3 (1 mmol)and polyphosphoric acid (10 mmol) was heated at 100 C for 3 h. Upon completion, the reaction mixture was poured into hot water(50 ml). After cooling to room temperature, the mixture was madealkaline by ammonia solution. The obtained yellow precipitateswere filtered off, washed with hot water, and purified usingrecrystallization from acetic acid to obtain the pure products(80-85%). | |
76 g | With toluene-4-sulfonic acid; In toluene; at 100 - 110℃; | 1000 g of toluene were sequentially added to the reaction flask,Intermediate (c) 100 g (0.47 mol)And 80 g of p-toluenesulfonic acid,100 ~ 110 C under the reaction,TLC tracing showed that the reaction was complete and the temperature was reduced to 20-25 C. The resulting precipitate was filtered, washed and dried to obtain 76 g of a yellowish green solid powdery intermediate (d) |
With Eaton?s reagent; at 90℃; for 1h; | General procedure: To a solution of 2-bromo-benzoic acid 10a (1.29g, 6.4 mmol) andaniline 11a (0.6g, 6.4 mmol) in DMF (6 ml) at room temperature, wesubsequently added powdered Cu (0.05g), Cu2O (0.05g) and K2CO3(0.71g, 5.1 mmol) was added. The reaction mixture was heated at110 for 12 h. Upon removal of the solvents under a vacuum, the residuewas dissolved in 1 N NaOH solution(25 ml). The crude productwas obtained by precipitation upon acidification of the filtrate withconc.HCl. After drying, the crude 2-(phenylamino) benzoic acid wasadded to Eaton?s reagent (5 ml) at room temperature, then the mixturewas heated to 90 C for 1 h. The cooled reaction mixture was droppedinto the saturated aqueous NaHCO3 solution. The precipitate was filteredto collect the rough product. Purification of the residue by silicagel column chromatography provided compound 12a, an off-whitesolid. (0.47g, 37.6% yield). 1H NMR (400 MHz, DMSO-D 6) delta (ppm):11.75 (s, 1H), 8.28 - 8.20 (m, 2H), 7.74 (ddd, J = 8.4, 6.9, 1.5 Hz, 2H),7.55 (d, J = 8.3 Hz, 2H), 7.32 - 7.23 (m, 2H). 13C13C NMR (101 MHz,DMSO-D 6) delta (ppm): 177.30, 141.41 (2C), 133.99 (2C), 126.54 (2C),121.53 (2C), 121.01 (2C), 117.87 (2C). HRMS (ESI) m/z [M+H] + calculated for C13H9NO: 196.0762 found: 196.0757. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate for 0.0583333h; Irradiation; microwave; | |
80% | With sodium hydroxide In butanone at 70 - 75℃; for 1h; | |
70% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1-bromo-butane In N,N-dimethyl-formamide at 80℃; for 0.5h; | Preparation of compounds 2i and 3i. General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred suspension of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with propyl iodide (for 2i) or 1-bromobutane (for 3i) (5 mmol), and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled and then water was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. |
With potassium hydroxide | ||
at 150℃; for 2h; Microwave irradiation; | ||
With tetrabutylammomium bromide; sodium hydroxide In water; toluene for 10h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With phenylphosphane at 140℃; for 24h; | |
91% | With borane-THF In tetrahydrofuran for 1.5h; Inert atmosphere; Reflux; | |
88% | With borane-THF In tetrahydrofuran Reflux; Inert atmosphere; |
80% | With iodine; magnesium In methanol at 20℃; for 3h; | |
80% | With sodium In butan-1-ol at 110℃; | |
75% | Stage #1: 10H-acridin-9-one With borane-THF In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃; | |
72% | With sodium In pentan-1-ol Heating; | |
With sodium amalgam; ethanol | ||
With i-Amyl alcohol; sodium | ||
With borane-THF In tetrahydrofuran for 4h; Inert atmosphere; Reflux; | tert-Butyl Acridine-10(9H)-carboxylate General procedure: A two-necked 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with acridone 11 (195 mg, 1.00 mmol), and THF (2.5 mL). To the solution was added BH3*THF (1.08 M in THF, 1.3 mL, 1.4 mmol) at room temperature. The reaction mixture was heated at reflux for 4 h. The reaction was quenched with brine and 2 M aqueous NaOH, and the mixture was extracted with ether three times. The combined organic extracts were washed with saturated aqueous NaHCO3, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude dihydroacridine 12 as a colorless solid, which was used to the next reaction without further purification. A 50-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 12, Boc2O (766 mg, 3.51 mmol), and MeCN (3.3 mL). To the solution was added DMAP (203 mg, 1.66 mmol) at 0°C and stirring was continued for 11 h at room temperature. The reaction was diluted with ether. The mixture was washed with saturated aqueous NH4Cl and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography(hexanes-EtOAc= 9 : 1) to afford 13 (226 mg, 0.803 mmol, 80%). | |
With borane-THF In tetrahydrofuran for 4h; Reflux; | General procedure: A two-necked 20-mL round-bottomed flask equipped witha magnetic stirring bar was charged with acridone (195 mg, 1.00 mmol), and THF (2.5 mL). To thesolution was added BH3THF (1.08 M in THF, 1.3 mL, 1.4 mmol) at room temperature. The reactionmixture was heated to reflux for 4 h, after which time TLC (hexanes-EtOAc = 3:1) indicated completeconsumption of acridone. The reaction was quenched with brine and 2 M aqueous NaOH, and the mixturewas extracted with Et2O three times. The combined organic extracts were washed with saturated aqueousNaHCO3, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated underreduced pressure to afford the crude dihydroacridine as a colorless solid, which was used for the nextreaction without further purification. | |
With borane-THF In tetrahydrofuran for 4h; Reflux; Inert atmosphere; | ||
With borane-THF In tetrahydrofuran at 80℃; Inert atmosphere; | ||
With borane-THF In tetrahydrofuran for 4h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With trichlorophosphate; for 12h;Reflux; Inert atmosphere; | A magnetically stirred solution of 9-acridanone (4.01 g, 21 mmol) in phosphorus oxychloride (105 mL, 1.13 mol) was brought to reflux for 12 h. The solution was cooled to rt, added slowly to cracked ice (650 g), and made slightly alkaline with concentrated ammoniumhydroxide. A light tan solid was collected by filtration, washed with water, and air dried for 24 h. Flash chromatography (silica gel/75% hexane, 20% THF, 5% triethylamine) afforded 3.97 g (89% yield)of 10 as fine yellow needles which was identical to material prepared by method A as judged by TLC, mp, and spectral data. |
86% | With trichlorophosphate; at 105℃; for 3h;Inert atmosphere; | Add 3 mmol of acridone to a two-necked flask equipped with a condenser and a stir bar, fill with N2, add 6 ml of P0C13 in a nitrogen atmosphere, and reflux at 105 C for 3 h. After the reaction is completed, cool to room temperature. The reaction solution was slowly dropped into ice water while stirring, and a mixture of ice, concentrated aqueous ammonia and chloroform (volume ratio 1:1:1) was added to the above liquid, and the chloroform layer was separated and dried (anhydrous magnesium sulfate). Filtration gave a pale yellow liquid, which was purified by column chromatography using ethyl acetate: petroleum ether.White needle crystals were obtained with strong fluorescence. Intermediate Compound 1, yield 86%. |
86% | With thionyl chloride; at 105℃; for 3h;Inert atmosphere; | Add 3 mmol of acridone to a two-necked flask equipped with a condenser and a stir bar.Filled with N2, 6 ml of SOCl2 was added in a nitrogen atmosphere, and refluxed at 105 C for 3 h.After the reaction is completed, cool to room temperature.The reaction solution was slowly dropped into ice water while stirring, and ice, concentrated ammonia and chloroform were added.a mixture of (mass ratio 1:1:1) was added to the above liquid to separate the chloroform layer.Dry (anhydrous magnesium sulfate) and filter to give a pale yellow liquid.Purified by column chromatography with ethyl acetate: petroleum ether in a volume ratio of 1:3.White needle crystals were obtained with strong fluorescence. Intermediate compound I),The yield was 86%. |
86% | With thionyl chloride; at 80℃; for 3h;Inert atmosphere; | Add 3 mmol of acridone to a two-necked flask equipped with a condenser and a stir bar, fill with N2, add 6 ml of SOCl2 in a nitrogen atmosphere, and reflux at 80 C for 3 h. After the reaction is completed, the mixture is cooled to room temperature, and the reaction liquid is slowly dropped into ice water while stirring, and a mixture of ice, concentrated ammonia water and chloroform (mass ratio: 1:1:1) is added to the above liquid to separate chloroform. layer, Dry (anhydrous magnesium sulfate) and filter to give a pale yellow liquid. Purified by column chromatography with ethyl acetate: petroleum ether in a volume ratio of 1:3. The white needle crystals were obtained, and the intermediate compound I having strong fluorescence was obtained in a yield of 86%. |
47 g | With thionyl chloride; In N,N-dimethyl-formamide; | A mixture of 50 g (0.25 mol) of intermediate (d) and 35 g of thionyl chloride and 200 g of N, N-dimethylformamide,After completion of the reaction, the reaction mixture was poured into ice water, filtered and dried to obtain 47 g of a yellow solid powdery intermediate () |
[0005] Acridone(Acros) was mixed with POCI3 at 1:10 (W/V) and heated with reflux for lhr. After cooling, 30% aqueous ammonia was added drop-wise until the solution turned basic, at which point the mixture was extracted 3 times with chloroform. The organic layers were combined and dried with MgSO4, filtered, and then rotary evaporated. The resulting solid was then recrystallized overnight at -200C in chloroform/hexane, producing long, pale yellow crystals. The mother liquor was filtered away, the crystals were weighed and product was confirmed via Electrospray Mass Spectrometry (ES-MS) and Nuclear Magnetic Resonance spectroscopy (NMR). | ||
With trichlorophosphate; at 105℃; for 3h;Inert atmosphere; | Add 3 mmol of acridone to a double-necked flask equipped with a condenser and a stir bar, Charge N2, Add 6mL POCl3 in a nitrogen atmosphere, Reflux at 105 C for 3h, After the reaction is completed, cool to room temperature, slowly drop the reaction solution into ice water with stirring, add the mixture of concentrated ammonia and chloroform to the above liquid, separate the chloroform layer, dry (anhydrous magnesium sulfate), and filter to obtain A pale yellow liquid was purified through the column with (V ethyl acetate: V petroleum ether = 1: 3) to obtain white needle crystals of 9-chloroacridine. In a 100 mL round-bottom flask, dissolve 1 mmol of 9-chloroacridine in phenol at 70 C, add 2 mmol of ammonium carbonate, quickly warm to 120 C for 2 h, and pour into 10% NaOH at the end of the reaction, filter, Wash with 10% NaOH and water to obtain a pale yellow compound II (2- (4-bromophenyl) benzo [d] [1,3] selenazole) solid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With bromine; potassium carbonate In dichloromethane at 20℃; for 24h; Inert atmosphere; | 2.2 2 g (9.9 mmol) of acridone was dissolved in 50 mL of dichloromethane, 4.1 g (30 mmol) of potassium carbonate was added, and a nitrogen atmosphereNext, slowly add 2.5mL bromine, the reaction was stirred at room temperature for 24h. After completion of the reaction slowly added saturated sodium sulfite solution 50mL remove unreacted bromine. After separation, the organic layer was dried and concentrated to give a pale yellow crude product.The crude product is recrystallized from methanol to give 2.85 g of a white solid in 81% yield. |
70% | With benzyltriethylammonium tribromide In acetic acid at 80℃; for 8h; | |
61% | With benzyltriethylammonium tribromide In acetic acid at 80℃; for 8h; | 4 A mixture of 1.95 g (10 mmol) of acridone and 9.0 g (20 mmol, 2 eq.) of BTEABr3 obtained as in Example 3 was added with 500 ml of acetic acid, and stirred under a temperature condition of 80° C. for 8 hours. Then, the mixture was filtered without a cooling process, and a precipitate was collected to obtain 2,7-dibromoacridone (a yellow solid: a yield of 2.2 g and 61%) expressed by the general formula (79). The UV spectra of acridone and 2,7-dibromoacridone thus obtained are shown in FIGS. 16 and 17, respectively. Moreover, the 2,7-dibromoacridone thus obtained was subjected to 1H NMR measurement, and the obtained result is shown below.1H NMR (DMSO) δ12.09 (s, 1H), 8.27 (s, 2H), 7.88 (d, J=2.43 Hz, 2H), 7.52 (d, J=2.43 Hz, 2H). |
With bromine; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine; oxygen; copper(II) nitrate In dimethyl sulfoxide at 130℃; for 24h; | |
93% | With pyridine; oxygen; copper(II) trifluoroacetate In N,N-dimethyl-formamide at 130℃; for 48h; Schlenk technique; | |
91% | With copper In dimethyl sulfoxide at 100℃; |
86% | at 400℃; for 0.0833333h; | |
79% | With copper(l) iodide In dimethyl sulfoxide; chlorobenzene at 140℃; for 48h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate for 0.05h; Irradiation; microwave; | |
79% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; | |
With potassium hydroxide 1.) EtOH, 20 min, reflux, 2.) DMF, 1 h, reflux; Yield given. Multistep reaction; |
Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Schlenk technique; Inert atmosphere; Stage #2: benzyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃; Schlenk technique; Inert atmosphere; | |
90% | With sodium hydride; potassium iodide In N,N-dimethyl-formamide at 20℃; | |
79% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: benzyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; |
75.7% | With sodium hydroxide In butanone at 70 - 75℃; for 1h; | |
71% | With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; | |
12% | Stage #1: 10H-acridin-9-one With sodium hydride In mineral oil at 0 - 20℃; for 1h; Stage #2: benzyl chloride In mineral oil at 20℃; | |
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydride In N,N-dimethyl-formamide Ambient temperature; | |
71% | With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water; butanone at 75℃; for 10h; | N-Dodecylacridone Acridone (0.75 g, 3.84 mmol) and benzyltriethylammonium chloride (0.10 g, 0.44 mmol) were added in a mixture of butan-2-one (10 mL) and aqueous sodium hydroxide solution (1.0 M , 10 mL). Then, 1-bromododecane (0.93mL, 3.84 mmol) was added into the mixture. The reaction mixture was stirred at 75 °C for 10 h. After cooling down to room temperature, the reaction was quenched by water and extracted with CH2Cl2 (3 × 30 mL). The organic phase was dried over anhydrous MgSO4 and the solvent was removed. The yellow residue was chromatographed over a silica gel column eluting with ethyl acetate/hexane (1:2, v/v). The product was obtained asa yellow solid (1.0 g,71%). |
With tetrabutylammomium bromide; sodium hydroxide In water; toluene for 10h; Reflux; |
Stage #1: 10H-acridin-9-one With tetrabutylammomium bromide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: 1-dodecylbromide In N,N-dimethyl-formamide at 20 - 90℃; for 18h; | 2,7-dibromo-10-dodecylacridin-9(10H)-one (2) Acridone (2 g, 10 mmol), CsCO3 (0.326 g, 10 mmol) and tetrabutylammonium bromide (TBAB) (0.323 mg, 1 mmol) were dissolved in 50 mL DMF, stirred at room temperature for 3 h, and then added 1-bromododecane (3.738 g, 15 mmol) dropwise and slowly. The mixture was stirred at room temperature for 6 h, and then stirred at 90 °C for 12 h for reaction. The mixture was poured into 100 mL of saturate saline solution, filtered and dried powder, Solid 1. Solid 1 was dissolved in 30 mL of DMF, then added NBS (7.1 g, 40 mmol) and reacted in 90 °C for 12 h under dark. Then the mixture was placed in saturated brine, filtered, dried and purified by silica gel column chromatography (V (petroleum ether)/V (dichloromethane) = 4/1), yielding the product, Solid 2 as a yellow solid (2.56 g, 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide at 20℃; for 24h; | |
75% | With tetrabutylammomium bromide In N,N-dimethyl-formamide for 3h; Heating; Alkaline conditions; | 4.2.2. Ethyl 2-(9-oxoacridin-10(9H)-yl)acetate (3) To a mixture of acridone 2 (1 g, 5 mmol) and sodium hydride (90 mg, 7.2 mmol) in DMF (5 ml), ethyl 2-bromoacetate (1.2 g, 7.2 mmol) was added dropwise and the mixture was stirred at 60 °C for 3 h. After that, it was poured into crushed ice and the white yellow formed precipitate was recrystallized from ethanol-DMF. Yellow solide, yield 75%, m.p. = 187 °C. IR (KBr) 3107, 2984, 2932, 1751, 1631, 1594, 1495 1 H NMR (300 MHz, DMSO-d 6 , 25 °C, TMS): 8.36 (dd, J = 8.1, 1.5 Hz,2H, H1-H8), 7,95 (d, J = 8,7 Hz, 2H, H4, H5), 7.80 (td, J = 15.6, 6.9 1.5 Hz, 2H, H3, H6), 7.33 (t, J = 7.5 Hz, 2H, H2,H7), 5.75 (s, 2H, CH2), 4,33 (q, J = 7.2 Hz, 2H, CH2), 1,14 (t, J = 7.2 Hz, 3H,CH3). 13 C NMR (75 MHz, DMSO-d 6 , 25 °C, TMS):177.07, 168.64, 143.01, 142.23, 134.65, 127.13, 122.20, 122.00, 116.74, 61.89, 55.66, 15.12. |
60% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: ethyl bromoacetate With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 0 - 20℃; for 24h; |
55% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 60℃; for 0.25h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide for 3h; | Synthesis of 10-(carboxymethyl)-9(10H)acridone ethyl ester(1) To a stirred solution of 1.87 g of 9-acridone (9.57 mmol) in 10 mL of DMF at 60°C, 0.57 g (14.4 mmol) of NaH was added. The mixture was stirred for additional 15 min, and then 2.07 g (12.5 mmol) of ethyl bromoacetate was added. The reaction mixture was stirred for 3 h, cooled to room temperature, and poured in water. The obtained precipitate was filtered off and washed a few times with water. The obtained solid was recrystallized using ethanol as a solvent. Pale yellow solid. Yield, 1.48 g (55%).1H NMR (300 MHz, DMSO-d6) δ 1.20 (t,J= 7.1 Hz, 3H), 4.18 (q,J= 7.1 Hz, 2H), 5.40 (s, 2H), 7.33 (t,J= 7.4 Hz, 2H), 7.62 (d,J= 8.7 Hz, 2H), 7.78 (t,J= 8.7 Hz, 2H), 8.32 (dd,J= 8.0, 1.7 Hz, 2H). An NMR spectrum is in good agreement with a literature one [25]. |
With potassium hydroxide 1.) EtOH, 20 min, reflux, 2.) DMF, 1 h, reflux; Yield given. Multistep reaction; | ||
With sodium hydride In N,N-dimethyl-formamide for 3h; Heating; | 2.2.2. 2-(9-oxo-9,10-dihydroacridin-10-yl)acetohydrazide (3) General procedure: To a mixture of acridone 2 (0.5g, 2.5 mmol) and sodium hydride(45 mg, 3.6 mmol) in DMF (3 ml), ethyl 2-bromoacetate (0.6g,3.6 mmol) was added dropwise. The mixture was stirred at 60 °Cfor 3 h then poured into crushed ice. The ester precipitated as awhite yellow solid, it was recrystallized from ethanol-DMF. Hydrazinemonohydrate (5 mL) was added to a 2 ml solution of theester (0.56g, 2 mmol) in DMSO and the mixture was refluxed for24 h. Compound 3 was obtained as a solid after solvent evaporationand it was purified by recrystallization from DMF-ethanol. | |
Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 5 - 20℃; for 20h; | 4.1.30. 2-methoxy-5,6-dimethyl-10-(2-oxobutyl) acridin-9(10H)-one(13b) General procedure: To a solution of NaH (1.43 mmol) and compound 12b (0.33g,1.3 mmol) in DMF (5 ml) at room temperature was stirred for 1 h andthen cooled to 5-7. The ethyl bromoacetate (0.43 ml, 2.6 mmol) wasadded to the resulting mixture and continuously stirred at room temperaturefor 20 h. After completion of the reaction (TLC), the reactionmixture was poured into ice water (15 ml). The resulting precipitateswere filtered off, dried, and then extracted with chloroform.Evaporation of the solvent gave crude ester which was purified by recrystallization.As a green solid (0.33g) in yield of 76%. 1H NMR(400 MHz, DMSO-D6) δ 8.12 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 9.4 Hz,1H), 7.63 (d, J = 2.8 Hz, 1H), 7.50-7.43 (m, 2H), 5.05 (s, 2H), 4.25 (q,J = 7.1 Hz, 2H), 3.97 (s, 3H), 2.77 (s, 3H), 2.51 (s, 3H), 1.26 (d,J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-D 6) δ (ppm): 169.40,158.26, 156.85, 147.94, 146.48, 136.71, 133.75, 131.85, 129.78,125.47, 119.97, 119.40, 118.75, 98.58, 72.24, 61.45, 56.04, 20.84,14.58, 13.90. HRMS (ESI) m/z [M+H] + calculated for C20H21NO4:340.1549 found: 340.1543. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide for 5h; | General procedure for the synthesis of compounds 8-10 General procedure: To a suspension of 0.01 mol of acridone in 10 mL of DMF was added 0.012 mol of sodium hydride. The mixture was stirred for 30 min, then 0.011 mol of allyl bromide was added. After 5 h, the reaction mixture was poured into water, the precipitate was filtered off and dried. The resulting compounds were used without further purification. 10-Allylacridine-9(10H)-one (8). Yield 90 %, white powder, mp 132-134 °C. 1 NMR spectrum, δ, ppm (J,Hz): 4.92-5.02 m (2, 10H2), 5.23-5.38 m (2, 11H2),6.18-6.28 m (1, 10H), 7.35 t (2H, 2,7H, J = 7.4),7.54 d (2H, 4,5H, J = 8.7), 7.76-7.80 m (2H, 3,6H),8.37 d. d (2H, 1,8H, J = 8.0, 1.7). 13C NMR spectrum, δ, ppm: 54.08 (10), 115.79 (11), 116.54 (C4,5), 121.78(C2,7), 122.02 (C1,8), 126.92 (1,8), 133.67 (10a), 134.42(3,6), 142.94 (4,5), 165.20 (4), 177.20 (9). Mass spectrum, m/z (Irel, %): 235.2766 (100) [ + H]+. Found,%: C 81.65; H 5.56; N 5.97. C16H13NO. Calculated, %:C 81.68; H 5.57; N 5.95. |
79% | With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate for 0.0583333h; Irradiation; microwave; | |
74% | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water; butanone at 50℃; for 2.5h; |
71% | With dimethyl sulfoxide; potassium hydroxide at 70℃; for 12h; | |
70% | With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | 2.1.1 10-allylacridin-9(10H)-one (2) To a mixture of acridone (0.5g, 2.5mmol), potassium carbonate (0.5g, 3.6mmol) and Tetra-n-butylammonium bromide (TBAB) (0.5g, 2mmol) in DMF (5ml), allyl bromide (0.42g, 3.6mmol) was added and the mixture was stirred at room temperature for 6h. After that, it was poured into water and the white yellow formed precipitate was recrystallized from methanol-DMF. White crystals; yield: 70%, mp=133°C. IR (KBr): 3110, 3065, 1637, 1598, 1502, 1269cm-1. 1H NMR (300MHz, DMSO-d6, 25°C, TMS): 8.34 (dd, J=8.1, 1.7Hz, 2H, Ar-H), 7.85-7.81 (m, 4H, Ar-H), 7.38-7.32 (m, 2H, Ar-H), 5.96-5.83 (m, 1H, Ar-H), 5.21-5.19 (dd, J=7.6, 1.6Hz, 1H, CH2), 5.23-5.24 (m, 1H, CH2), 5.09-5.06 (m, 2H, CH2). 13C NMR (75MHz, DMSO-d6, 25°C, TMS) δ 177.09, 141.70, 134.76, 134.42, 127.18, 127.00, 122.37, 122.20, 117.44, 116.57, 116.57, 45.91. |
66% | With potassium hydroxide; cetyltrimethylammonim bromide In water; butanone for 2.5h; Heating; | |
46% | Stage #1: 10H-acridin-9-one With tetrabutylammomium bromide; potassium hydroxide In tetrahydrofuran; water at 20℃; for 0.5h; Stage #2: allyl bromide In tetrahydrofuran; water at 20℃; for 16h; | |
35% | With potassium carbonate In acetone for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide at 20℃; | |
92% | With sodium hydride In tetrahydrofuran at 40℃; for 4h; Inert atmosphere; | |
92% | With sodium hydride; potassium iodide In N,N-dimethyl-formamide at 20℃; for 3h; | 1.c Piperidone is prepared cN- propargyl acridine 0.85g acridone was dissolved 7mlDMF added 0.2gNaH and 0.14gKI, stirring at room temperature was added dropwise 0.7ml3- propargyl bromide and reaction was continued for 3 hours.To the reaction mixture was added 15ml water, crude filtration, active carbon and recrystallized from ethanol to give pale yellow needles 0.93g, yield: 92% mp = 207 (literature: 212-215 ) |
85% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; | General procedure for the synthesis of N-propargylderivatives 2f-2k. General procedure: A solution of azazerumbone (1e), azazerumbone oxide 1f or 1g, acridinone 1h,7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4(3H)-one (1i), or murrayafoline A (1j) (1 mmol) inanhydrous DMF (5 mL) was cooled to 0°C, sodiumhydride (1.2 equiv) and propargyl bromide (1.3 equiv)were added, and the mixture was stirred at room temperature until the reaction was complete (TLC). Themixture was quenched with cold water and extractedwith ethyl acetate (3×15 mL), and the combinedextracts were dried over anhydrous Na2SO4, filtered,and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using n-hexane-acetone as eluent. |
75% | With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide for 0.166667h; Microwave irradiation; | 2.2.1. 10-(Prop-2-yn-1-yl)acridone (1). To a mixture ofacridone (0.5 g, 2.5 mmol), potassium carbonate (0.55 g,3 mmol), and TBAB (0.5 g, 2.5 mmol) in DMF (7 ml),propargyl bromide (0.4 g, 3.6 mmol) was added, and themixture was then irradiated for 10 min. Microwave irradiationpower was set at 200W maximum. After that, it waspoured into water, and the white yellow formed precipitatewas recrystallized from methanol-DMF.White yellow solid; yield: 75%, mp 206-208°C. IR(KBr): 3208, 3010, 2210, 1638, and 1598 cm-1.-1H NMR(300 MHz, DMSO-d6, 25°C, TMS): / 8.34 (d, J 7.8 Hz,1H, Ar-H), 8.12 (s, 1H, Ar-H), 7.87-7.86 (m, 4H, Ar-H),7.37-7.38 (m, 2H, Ar-H), 5.32 (s, 2H, CH2), 2.41 (s, 1H,CH), 2.38 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6, 25°C,TMS) / 177.18, 141.78, 134.76, 134.47, 127.78, 127.07,123.37, 122.20, 118.44, 116.35, 79.12, 76.16, 36.12, and 20.18. |
75% | With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide for 6h; | 10-(Prop-2-yn-1-yl)acridone. (3) To a mixture of acridone (5 g, 25 mmol), potassium carbonate (5.5 g, 30 mmol) and TBAB (5 g, 25 mmol) in DMF (50 ml), propargyl bromide (4 g, 36 mmol) was added and the mixture was stirred at room temperature for 6 h. After that, it was poured into water and the white yellow formed precipitate was recrystallized from methanol-DMF. White yellow solid; yield: 75%, mp = 206 °C. IR (KBr): 3208, 3010, 2210, 1638, 1598 cm -1 . 1H NMR (300 MHz, DMSO-d 6 , 25 °C, TMS): δ= 8.34 (d, J = 7.8 Hz,1H, Ar-H), 8.12 (s,1H, Ar-H), 7.87- 7.86 (m, 4H, Ar-H), 7.37-7.38 (m, 2H, Ar-H), 5.32 (s, 2H, CH 2 ), 2.41 (s, 1H, CH), 2,38 (s, 3H, CH 3 ). 13C NMR (75 MHz, DMSO-d 6 , 25 °C, TMS) δ177.1 ( C = O ), 141.7, 134.7, 134.4, 127.7, 127.0, 123.3 (2C), 122.2, 118.4, 116.3 (2C), 79.1, 76. 1 (CH), 36.1 (CH 2 ). |
74% | With tetrabutylammomium bromide; sodium hydride In N,N-dimethyl-d<SUB>6</SUB>-formamide at 85℃; for 3h; | Synthesis of 10-(prop-2-yn-1-yl)acridone (3) To a mixture of acridone 2 (0.5 g, 2.5 mmol), sodium hydride (45 mg, 3.6 mmol) and TBAB (0.5 g, 2 mmol) in DMF (3 mL), propargyl bromide (0.38 g, 3.6 mmol) was added and the mixture was stirred at 85 °C for 3 h. After which, it was poured into crushed ice and the white yellow formed precipitate was recrystallized from ethanol-DMF. White solid; yield 74%, Rf 0.84, mp = 178 °C. IR (KBr): 3206, 3008, 2913, 1639, 1600, 1495 cm-1. 1H NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ 8.34 (d, 2H, H1-H8), 7.85-7.81 (m, 4H, H3-H6-H4-H5), 7.38-7.32 (m, 2H, H2-H7), 5.34 (s, 2H, CH2), 2.48 (s, 1H, CH); 13C NMR (75 MHz, [D6]DMSO, 25 °C, TMS) δ 177.08, 141.70, 134.76, 134.46, 127.18, 127.00, 122.37, 122.20, 117.44, 116.35, 79.12, 76.16, 36. |
59% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 50℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene at 50℃; for 6h; | |
51% | With potassium hydroxide; tetrabutylammomium bromide In toluene at 40℃; for 72h; | |
35% | With potassium carbonate In acetone for 24h; Heating; | |
With potassium <i>tert</i>-butylate 1.) DMF, 10 min, 2.) RT, 30 min; Yield given. Multistep reaction; | ||
With sodium hydride 1.) DMF, 50 deg C, 30 min, 2.) DMF, toluene, 25 deg C, 6 h; Yield given. Multistep reaction; | ||
With sodium hydride In tetrahydrofuran at 20℃; | ||
In tetrahydrofuran | ||
Stage #1: 10H-acridin-9-one With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: propargyl bromide In dimethyl sulfoxide at 20℃; for 3h; | 4.3 General procedure for the synthesis of 10-(prop-2-yn-1-yl)acridin-9-one derivatives 6 General procedure: A suspension of acridone derivative 4 (2.5mmol) and potassium tert-butoxide (3.6mmol) in DMSO (1.5ml) was stirred at room temperature for 30min. Then, it was added to a solution of propargyl bromide 5 (3.4mmol) in DMSO (5ml) drop wise and the reaction mixture was stirred at room temperature for 3h. After that it was poured into crushed ice and the aqueous solution was extracted with dichloromethane (3×20ml), washed with water, and dried over Na2SO4. The solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (9:1) to obtain pure products in 55-70% yield. | |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 3h; | ||
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; | ||
With sodium hydride In N,N-dimethyl-formamide at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 60℃; for 18h; | |
97% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 0 - 60℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 18h; Inert atmosphere; | |
96% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0℃; for 4h; | 10-Methylacridin-9(10H)-one (4d): A 30-mL flame-dried round-bottomed flask equipped with amagnetic stirring bar, a rubber septum, and a three-way stopcock was charged with acridone (398.0 mg,2.04 mmol) and anhydrous DMF (6.8 mL). To the solution was added NaH (164.0 mg, 4.10 mmol) at0 °C and the resulting mixture was stirred at room temperature for 30 min. To the resulting mixture was added MeI (255 μL, 4.10 mmol) dropwise at 0 °C. The resulting mixture was stirred for 4 h, after whichtime TLC (hexanes-EtOAc = 1:1) indicated complete consumption of acridone. The reaction mixture wasquenched with H2O, and the mixture was extracted with EtOAc three times. The combined organicextracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and filtered. The organicsolvents were removed under reduced pressure to give crude N-methylacridone 4d, which was purified byflash silica gel column chromatography (hexanes-EtOAc = 4:1) to afford N-methylacridone 4d (410.8 mg,1.96 mmol, 96%) as a pale yellow solid. The analytical data (IR, HRMS, 1H and 13C NMR) were identicalwith those reported in the literature.14 Rf = 0.44 (hexanes-EtOAc = 1:1). |
96% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Schlenk technique; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 16h; Schlenk technique; | |
96% | With benzyltrimethylammonium chloride; potassium hydroxide In tetrahydrofuran; water for 20h; | |
95% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 60℃; for 18h; | |
95% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 60℃; for 18h; | |
95% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 14h; | |
87% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 60℃; for 18h; | 5.2.3. 10-Methylacridin-9(10H)-one (4) Intermediate 3 (1.5g, 7.7mmol) was dissolved in DMF (40mL) and NaH (65% oil dispersion, 460mg, 19.2mmol) was added at 0°C. The suspension was stirred at 0°C for 30min and at 60°C for 30min, and then CH3I (2.7g, 19.2mmol) was added. The resultant solution was continuously stirred at 60°C for 18h. After cooling to room temperature, the reaction solution was quenched with water. The resulting solid was filtrated and dried in vacuo to afford the title compound as a yellow solid (1.4g, 87%). 1H NMR (400MHz, DMSO-d6) δ 8.36-8.33 (m, 2H), 7.88-7.81 (m, 4H), 7.34 (ddd, J=7.9, 6.4, 1.4Hz, 2H), 3.95 (s, 3H). MS (ESI) m/z calcd for C14H11NO [M+ H]+, 210.1, found: 210.3. |
84% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; | 3 Preparation of 10-methylacridin-9(10H)-one (4) Take the 9(10H)-acridone (1.5g, 7.7mmol) prepared in Example 2 above, dissolve it in DMF, and protect it with N2.Add NaH (0.55g, 23mmol) at 0°C, stir for 30min and then add iodomethane (1.64g, 11.5mmol) with a syringe,Then it was transferred to room temperature and stirred for 4 hours. TLC detected that the reaction was complete. Intermediate 4 was obtained, 1.35 g of yellow solid, 84% yield |
82.7% | With sodium hydroxide In butanone at 55 - 60℃; for 3h; | |
81% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 0 - 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 18h; | Acridinone A (10.0 g, 51.2 mmol) was dissolved in DMF (100 mL).Add NaH at 0 ° C (content: 60%, 5.12 g,128mmol),Stir at 60 ° C for 30 min,Add methyl iodide (8.0 mL, 128 mmol),Reaction at 60 ° C for 18 h,Cool to room temperature,Add water to quench the reaction,Filtering out solids,The filtrate was extracted with DCM (3×50 mL).Merge the DCM layer,Washed with saturated saline,Dry over anhydrous sodium sulfate,Concentrated under reduced pressure,The resulting residue is combined with the filter cake.Recrystallization of ethanol,Light yellow solid product,N-methyl-9-acridone B (8.7 g, 81% yield). |
80% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 60℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; Inert atmosphere; | |
73% | With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate for 0.0333333h; Irradiation; microwave; | |
71.1% | With aluminum oxide; tetrabutylammomium bromide; potassium carbonate; sodium hydroxide at 65℃; for 0.25h; Microwave irradiation; | 2.1.1 General procedure for the synthesis of N-alkyl-9(10H)-Acridone derivatives General procedure: The synthesis of the different N-alkyl acridone derivatives followed the synthetic procedure described by Wang et al. [38]. To a mixture of acridone (0.100g, 0.5mmol), K2CO3 (0.0071g, 0.18mmol), Al2O3 (0.0533g, 0.52mmol) NaOH (0.0071g, 0.18mmol) and TBAB (0.0017g, 0.005mmol) the proper alkyl halide, iodomethane, iodopentane or iodooctane, (2mL) was added on the 10mL microwave tube. The mixture was heated under microwave irradiation during 15minat 65°C with high speed stirring using a CEM (Discover SP) microwave oven. The reaction mixture was cooled at room temperature and the reaction product was purified by silica gel column chromatography using ethyl acetate and n-hexane (3:7) as eluent. |
With potassium hydroxide 1.) EtOH, 20 min, reflux, 2.) DMF, 1 h, reflux; Yield given. Multistep reaction; | ||
With sodium hydride 1.) DMF, 2.) DMF; Multistep reaction; | ||
Stage #1: 10H-acridin-9-one With potassium hydroxide In ethanol at 125℃; Stage #2: methyl iodide In N,N-dimethyl-formamide at 165℃; for 0.666667h; | ExamplePreparation of two-photon fluorescent probe 10-methyl-2-amino-acridone, as follows: Weigh 1.6277 g of potassium hydroxide, add 13 mL of absolute ethanol,Heating dissolves potassium hydroxide to form a mixture of potassium ethoxide. Add 0.4811 g acridone while hot,The temperature was raised to 125 ° C and ethanol was distilled off. Subsequently, 20 mL of N, N-dimethylformamide (DMF)The DMF was boiled at 165 ° C. Then slowly add 10 mL of methyl iodide, heat 40 min,While hot pour 50 mL ice water, after cooling yellow-green solid precipitation.Suction filtered, washed with 10 mL of ice water, dried at 70 , and further purified with absolute ethanol recrystallization.A yellow-green needle-like solid, ie 10-methyl-acridone. Precision weighed 0.2105 g10-Methyl-acridone In a three-necked flask, 6 mL of 99 wt% glacial acetic acid,And the temperature was raised to 40 ° C to dissolve the solid, followed by dropwise addition of 2 mL of concentrated nitric acid and 2 mL of 99 wt% glacial acetic acid,Stirring heated to 60 , the reaction 2 h. Pouring ice water while hot, golden yellow solid after cooling precipitation,Suction filtered, washed with 10 mL of ice water, the solid was placed in an oven, dried at 70 ° C to give a golden yellow solid, Ie 10-methyl-2-nitro-acridone.Precision Weigh 100 mg10-methyl-2-nitro-acridone in a round bottom flask,Add 5 mL ethanol and 2.5 mL Na2S solution (30 wt%), then add water to 50 mL,In the access to N2 conditions, heated to 130 ° C, the reaction 4 h. Pouring ice water while hot,After cooling there is yellowish solid precipitation. Suction filtered, washed with ice water, the solid placed in a vacuum oven,Dried at room temperature to give a khaki-colored solid, further purified by high performance liquid chromatography (HPLC)Obtained as a yellow needles solid 10-methyl-2-amino-acridone (MAA). | |
Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil | ||
With potassium hydroxide In ethanol; N,N-dimethyl-formamide at 110 - 165℃; for 0.666667h; | ||
With tetrabutylammomium bromide; sodium hydroxide In water; toluene for 10h; Reflux; | ||
In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | 1.1; 3.1 (1) In the reaction bottle, 100 mmol of raw material M is dissolved in DMF, under the protection of nitrogen, 100 mmol of methyl iodide is added, and the reaction is performed at room temperature for 3 hours; after the reaction is completed, water is added to the reaction solution.Stirred out solids, filtered, washed with water,Dry to get M1; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 10H-acridin-9-one With acetic acid for 1h; Stage #2: With benzyltriethylammonium tribromide at 20 - 80℃; for 1h; | 6.1 In a 500 mL round-bottom flask, 9-acridanone 5 g (25 mmol) was diluted in 200 mL of acetic acid, stirred for 1 hour, and then benzyltriethylammonium tribromide 11.5 g (25 mmol)Was added and stirred at room temperature for 5 hours, and then stirred at 80° C. for 1 hour.When the reaction was completed, the reaction solution was cooled to room temperature, and the resulting solid was filtered and washed with 200 mL of methanol to obtain 5.4 g (75% yield) of the compound represented by [Chemical Formula 50-a]. |
60% | With benzyltriethylammonium tribromide In acetic acid for 10h; Ambient temperature; | |
With acetic acid; benzyltriethylammonium tribromide at 20 - 80℃; | 3 A mixture of 9 (10H)-acridone (0.98 g, 5.0 mmol) and benzyltriethylammonium tribromide (2.3 g, 5.0 mmol) inAcOH (100 mL) was left to stir at room temperature overnight and at 80 C for 1 h. The mixture was cooled to room temperature, and filtered to provide crude 2-bromo-9 (10H)- acridon as a yellow solid. A mixture of crude 2-bromo-9 (10H)-acridone (1.2 g, 4.4 mmol) and DMF (40aL) in thionyl chloride(6 mL) was heated to80 C for 1 h, cooled to room temperature, and concentrated. The residue was poured intoNH40H solution in ice water, and the aqueous layer was extracted with CHC13(x 3). The combined organics were dried (Na2SO4) and concentrated to give crude 2-bromo-9- chloroacridine as a yellow solid. Utilizing the general procedure outlined in the synthesis ofN4-acridin-9-yl-N',Nl-diethylpentane-1, 4-diamine, 2-bromo-9-chloroacridine (0.42 g, 1.4 mmol),(S)-2-amino-5- diethylaminopentane (0.30 g, 1.9 mmol), phenol (0.40 g, 4.3 mmol), and triethylamine (0.50 mL, 3.6 mmol) reacted to give(4S)-N4-(2-bromoacridin-9-yl)-Nl, Nl-diethylpentane-1, 4-diamine as a yellow oil. 1H NMR(CDC13, 500 MHz)5 8.28 (s, 1H), 8.11 (d, 2H), 8.00 (d, 1H), 7.73 (m, 2H), 7.45 (t,1H), 4.92 (br s, 1H), 4.18 (br s, 1H), 2.52 (q, 4H), 2.44 (m, 2H), 1.60-1. 82 (m, 4H), 1.34 (d, 3H), 1.00 (t, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydride In N,N-dimethyl-formamide at 80℃; | |
78% | Stage #1: 10H-acridin-9-one With sodium hydride In tetrahydrofuran; mineral oil for 1.5h; Stage #2: 1 ,6-dibromohexane In tetrahydrofuran; water for 24h; Reflux; | 1.2 2. Preparation of compound 3a Take acridone 2a (5.12 mmol) in a dry tetrahydrofuran solution, ice bath,After adding sodium hydride (10.24 mmol, 60%) and stirring for 1.5 hours, 1,6-dibromohexane (30.73 mmol) was added dropwise, followed by heating under reflux for 24 hours. After the reaction is completed, cool to room temperature, add 15 mL of water, extract 3 times with dichloromethane, and dry the organic phase with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a concentrate, and the concentrate was separated by column chromatography to obtain the target compound 3a as a yellow solid with a yield of 78%. |
78% | Stage #1: 10H-acridin-9-one With sodium hydride In tetrahydrofuran at 0℃; for 1.5h; Stage #2: 1 ,6-dibromohexane In tetrahydrofuran at 0℃; for 24h; Reflux; | 4.3. General procedure for the synthesis of compounds 2a-2c General procedure: To a solution of 1 (5.12 mmol) in dry THF (20 mL) was added sodiumhydride (10.24 mmol, 60%) at 0 °C. After 1.5 h of stirring, dibromides(30.73 mmol) was added dropwise under the same condition.The reaction mixture was heated and kept refluxing for another 24 hand then allowed to cool to room temperature. The mixture was addedwater (15 mL), and then extracted by CH2Cl2. The organic phase wasseparated and dried overnight with MgSO4. The solvent was removedby evaporation, and the residue was purified by a flash silica gel columnchromatography to afford 2a-2c. 4.3.1. 10-(6-Bromohexyl) acridin-9(10H)-one (2a)The product was obtained as yellow solid in 78% yield. m.p.232-235 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=7.6 Hz, 2H), 7.71(t, J = 7.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H),4.32 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H), 1.93 (s, 4H), 1.59 (s,4H). 13C NMR (100 MHz, CDCl3) δ 177.9, 141.6, 133.9, 127.9, 122.4,121.2, 114.4, 45.9, 33.6, 32.5, 27.8, 26.9, 26.0. HRMS (ESI), m/z calcd.for C19H20BrNONa ([M+Na]+) 380.0620, found: 380.0636. |
70% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1 ,6-dibromohexane In N,N-dimethyl-formamide at 80℃; for 0.5h; | General procedure for the preparation of bromoalkyl acridones 2-5 General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred solution of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with the appropriate dibromoalkane (6 mmol) and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silicagel column chromatography. |
62% | With sodium hydride In N,N-dimethyl-formamide at 40℃; for 12h; | General procedure for the synthesis of compounds 8 (a-d) (A). General procedure: Compound 7 (1 mmol) was dissolved in dimethylformamide (15 mL) and poured into the reaction vessel containing NaH (2 mmol) for the generation of anion followed by the addition of dibromopropane/dibromobutane/dibromopentane/dibromohexane (1.5 mmol). The reaction continued for 4 h at 40 °C and monitored by TLC. After the completion, reaction was quenched by adding cold water (15 mL). The reaction mixture was extracted with ethyl acetate (4x25 mL). The combined organic part was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude products 8(a-d) obtained were then purified by column chromatography using ethyl acetate and hexane as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide for 24h; Reflux; | 1.3 Step S3: Acridinone (3.0 g, 15.4 mmol) and NaH (1.24 g, 30.8 mmol) were added to a round bottom flask containing 50 mL of anhydrous DMF, stirred at room temperature for 1.5 h and then added dropwise.1,3-dibromopropane (18.6 g, 92.4 mmol in 10 mL DMF), the reaction mixture was heated to reflux for 24 h then cooled to room temperature.Extract with ethyl acetate, separate the oil phase and dry over anhydrous magnesium sulfate.Filtered, concentrated,The crude product is separated and purified by column chromatography to obtain a yellow solid compound 5(4.0 g, yield 75%) |
66% | Stage #1: 10H-acridin-9-one With sodium hydride In tetrahydrofuran at 0℃; for 1.5h; Stage #2: 1,3-dibromo-propane In tetrahydrofuran at 0℃; for 24h; Reflux; | 4.3. General procedure for the synthesis of compounds 2a-2c General procedure: To a solution of 1 (5.12 mmol) in dry THF (20 mL) was added sodiumhydride (10.24 mmol, 60%) at 0 °C. After 1.5 h of stirring, dibromides(30.73 mmol) was added dropwise under the same condition.The reaction mixture was heated and kept refluxing for another 24 hand then allowed to cool to room temperature. The mixture was addedwater (15 mL), and then extracted by CH2Cl2. The organic phase wasseparated and dried overnight with MgSO4. The solvent was removedby evaporation, and the residue was purified by a flash silica gel columnchromatography to afford 2a-2c. |
59% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 80℃; for 24h; | 1.1 Step S1: using DMF as a solvent, a small amount of 9(10H)-acridone (98% by weight)(1 g about 5.1 mmol) was placed in a round bottom flask, placed on a thermostatic magnetic stirrer, and then added (0.41 g of about 10.2 mmol) of sodium hydride. The reaction was stirred at room temperature for about 1.5 h.Then, (3.1 mL, about 30.6 mmol) of 1.3-dibromopropane was added dropwise to the reaction system, and the mixture was placed in an oil bath at 80 ° C for about 24 hours, taken out, and the reaction system was cooled to room temperature, and extracted with ethyl acetate. After the reaction was completed by TLC dot plate, the organic phase was dried, and the mixture was stirred by rotary distillation, and the compound 1 acridine bromide (0.95 g, about 3 mmol, yield 59%) was obtained by column chromatography. |
40% | With sodium hydride In N,N-dimethyl-formamide at 40℃; for 12h; | General procedure for the synthesis of compounds 8 (a-d) (A). General procedure: Compound 7 (1 mmol) was dissolved in dimethylformamide (15 mL) and poured into the reaction vessel containing NaH (2 mmol) for the generation of anion followed by the addition of dibromopropane/dibromobutane/dibromopentane/dibromohexane (1.5 mmol). The reaction continued for 4 h at 40 °C and monitored by TLC. After the completion, reaction was quenched by adding cold water (15 mL). The reaction mixture was extracted with ethyl acetate (4x25 mL). The combined organic part was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude products 8(a-d) obtained were then purified by column chromatography using ethyl acetate and hexane as eluent. |
32% | With potassium hydroxide In dimethyl sulfoxide at 20℃; for 3h; | 2.1 Synthesis of 1-(3-bromopropyl)-6,11-dihydro-5H-benzo[a]carbazole (4) General procedure: To a solution of intermediate 3 (2.19g, 0.01mol) and 1,3-dibromopropane (8.08g, 0.04mol, 4equiv.) in DMSO (50mL) was added KOH (2.24g, 0.04mol, 4equiv.) and the mixture was allow to stir at ambient temperature for 3 h. Then, the reaction mixture was diluted with water (50mL) and extracted with diethyl ether (50mL×3). The combined organic layer was washed with brine (100mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc, 40:1, v/v) to give compound 4 as a white solid (1.31g, 38.5% yield). |
32% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 80℃; for 0.5h; | General procedure for the preparation of bromoalkyl acridones 2-5 General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred solution of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with the appropriate dibromoalkane (6 mmol) and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silicagel column chromatography. 10-(3′-N-Bromopropyl)acridone (2):21 (32%) yellowsolid, m.p. 113.5 °C-114.5 °C; FTIR, νmax (cm-1): 1631,1596, 1489, 1461, 1377, 1177, 752, 673; 1H NMR(400 MHz, CDCl3): δ 8.49 (dd, J = 8.0, 1.6 Hz, 2H),7.68-7.63 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.22 (t,J = 7.5 Hz, 2H), 4.48 (t, J = 7.7 Hz, 2H), 3.56 (t, J = 6.0 Hz,2H), 2.35-2.43 (m, 2H); 13C NMR (100 MHz, CDCl3): δ177.9, 141.6 (2C), 134.1 (2C), 128.1 (2C), 122.5 (2C),121.4 (2C), 114.2 (2C), 44.5, 30.2, 29.4; MS (EI): m/z (relativeintensity): 315 (M+, 20), 208 (100), 180 (26), 152 (13);HRMS (APCI): m/z calcd for C16H15NOBr [M + H]+:316.0332; found: 316.0339. |
20% | With sodium hydride In N,N-dimethyl-formamide at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-Methoxyethoxymethyl chloride In N,N-dimethyl-formamide at 20℃; for 2h; Further stages.; | |
77% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 20℃; for 0.75h; Schlenk technique; Inert atmosphere; Stage #2: 2-Methoxyethoxymethyl chloride | |
60.2% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; |
41% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Cooling with ice; Stage #2: 2-Methoxyethoxymethyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃; for 42h; | 1.i (I) Synthesis of MEM-acridone Drip funnel,In a 500 mL three-necked flask equipped with a nitrogen inlet tube, 9 (10H) -acridone (14.95 g, 77 mmol), sodium hydride (55% in oil, 5.05 g, 115 mmol), dehydrated N, N-dimethylformamide After adding 500 mL and stirring, the mixture was immersed in an ice bath after 30 minutes. Thereafter, 2-methoxyethoxymethyl chloride (13.8 ml, 121 mmol) was introduced into the system using a dropping funnel,Return to room temperature. 42 hours later,When the progress of the reaction was confirmed by TLC, consumption of the raw materials and spots that seemed to be the target product were confirmed, and the reaction was terminated.Pour the reaction solution into 4 L of water,The mixture was left for a while with stirring.Then, perform suction filtration using water,The residue was dried under reduced pressure. afterwards,Purified by column chromatography(Developing solvent ratio: dichloromethane: ethyl acetate = 10: 0 → 9: 1 → 1: 4 → 1: 9 → 1: 19)8.79 g (yield = 41%) of the target product was obtained. |
With sodium hydride In N,N-dimethyl-formamide for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With phosphorus tribromide at 0 - 100℃; for 24h; Inert atmosphere; | 5.2.6 9-Bromoacridine (7) PBr3 (19.5mL, 205mmol) was added dropwise to a 250mL round bottom flask containing 3 (4.0g, 20.5mmol) at 0°C under N2 atmosphere. After stirring at 110°C for 24h, the resultant solution was quenched by slow addition of H2O and an aqueous NaOH solution was added to the resultant mixture until pH=14. The crude product was extracted with CH2Cl2 (50mL×3). The combined organic extracts were washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure to obtain the title compound as a yellow solid (3.81g, 72%). 1H NMR (400MHz, Chloroform-d) δ 8.45 (d, J=8.8Hz, 2H), 8.27 (d, J=8.6Hz, 2H), 7.85-7.81 (m, 2H), 7.69-7.65 (m, 2H). MS (ESI) m/z calcd for C13H8BrN [M+ H]+, 258.0, found: 260.2. |
72% | With phosphorus tribromide at 0 - 110℃; for 24h; Inert atmosphere; | 3 Example 3: Preparation of 9-bromoacridine (4) Weigh out the intermediate 9(10H)-acridone (4.0 g, 20.5 mmol) prepared in Example 2 above and place it in a 250 mL round bottom flask. Under nitrogen protection at 0°C in an ice bath, phosphorus tribromide (19.5 mL, 205 mmol) was injected dropwise. After the addition, the reaction solution was moved to 110°C and stirred at this temperature for 24 hours. After the completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and then slowly added to water to quench the reaction. Then the pH of the filtrate was adjusted to 14 with sodium hydroxide solution, transferred to a separatory funnel, extracted with dichloromethane three times, the combined organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered with suction, and under reduced pressure Concentrated to obtain 3.81 g of yellow solid product, ie Intermediate 4, with a yield of 72%. |
64% | With phosphorus tribromide at 0 - 110℃; for 24h; Inert atmosphere; |
Multi-step reaction with 2 steps 1: 96 percent / CH2Cl2 / 1.5 h / 0 °C 2: 74 percent / 1.) NaBr, 2.) EtN(i-Pr)2 / acetonitrile / 1.) 1.5 h, 2.) 15 min | ||
Multi-step reaction with 2 steps 1: red phosphorus; sulfur / 200 °C 2: phosphorus; bromine / 100 - 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; | (a) A suspension of 1.44 g of sodium hydride in 100 ml of dimethylformamide is treated within 10 minutes with 9.75 g of 9-acridanone and held at 50 for 2 hours. At 120 there are then added 9.5 g of 4,4-diethoxybutyl chloride. After 16 hours, the mixture is cooled, poured into water and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated. The residue is extracted with hexane and crystallized twice from hexane. There is obtained 10-(4,4-diethoxybutyl)-9-acridanone of metling point 73-74.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; | EXAMPLE 9 A suspension of 58.6 g of 9-acridanone in 200 ml of dimethylformamide, heated to boiling under reflux, is treated portionwise with a total of 60 g of <strong>[25711-25-5]benzyl ethylenecarbamate</strong>. After 53 hours, the mixture is left to cool, the crystalline product is filtered and washed successively with dimethylformamide, acetone and ether. The mother liquor is treated with water, whereupon the precipitated product is filtered and washed as above. The combined material is crystallized from ethanol and there is obtained benzyl [2-(9-oxo-10(9H)-acridinyl)ethyl]carbamate of melting point 224-226. 9.31 g of this substance are suspended in 100 ml of dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; ethyl acetate; | (a) A mixture of 8.5 g of 9-acridanone, 180 ml of dimethylformamide and 3.3 g of sodium hydride is stirred for 0.5 hour, treated portionwise with 10.3 g of <strong>[5753-26-4]2-[1-(4-methyl)-piperazinyl]ethyl chloride dihydrochloride</strong>, stirred at 80 for 3 days and evaporated. The residue is treated with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated, whereupon the residue is recrystallized firstly from ether and then from ethyl acetate. There is obtained 10-[2-(4-methyl-1-piperazinyl)ethyl]-9-acridanone of melting point 156-157. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride In N,N-dimethyl-formamide at 40℃; for 12h; | General procedure for the synthesis of compounds 8 (a-d) (A). General procedure: Compound 7 (1 mmol) was dissolved in dimethylformamide (15 mL) and poured into the reaction vessel containing NaH (2 mmol) for the generation of anion followed by the addition of dibromopropane/dibromobutane/dibromopentane/dibromohexane (1.5 mmol). The reaction continued for 4 h at 40 °C and monitored by TLC. After the completion, reaction was quenched by adding cold water (15 mL). The reaction mixture was extracted with ethyl acetate (4x25 mL). The combined organic part was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude products 8(a-d) obtained were then purified by column chromatography using ethyl acetate and hexane as eluent. |
57% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1,4-dibromo-butane In N,N-dimethyl-formamide at 80℃; for 0.5h; | General procedure for the preparation of bromoalkyl acridones 2-5 General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred solution of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with the appropriate dibromoalkane (6 mmol) and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silicagel column chromatography. |
With sodium hydroxide; tetrabutylammomium bromide In water; benzene at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 10H-acridin-9-one With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: 1,3,5-trichloro-2,4,6-triazine In tetrahydrofuran at 20℃; for 18h; Heating / reflux; | 1.1 Acridone (10.0 g, 54. 6 mmol) was slowly added to a dried THF (tetrahydrofran) suspension (200 mL) of sodium hydride (60% in oil, 2.4 g, 60 mmol) under cooling in ice. After stirring at room temperature for 30 minutes, a dried THF solution (50 mL) of cyanuric chloride (2.50 g, 13. 8 mmol) was dropped. After stirring at room temperature for 12 hours, reflux for 6 hours was performed by heating. After that, about 100 mL of ethanol was added to the reaction mixture, and precipitated solid was filtered. After dissolving the obtained solid in warm chloroform, celite filtration was performed. The filtrate was condensed for recrystallization to obtain a light yellow compound with a yield of 77%. Measurement of the obtained compound by NMR (Nuclear Magnetic Resonance) could confirm that the compound was 1,3,5-tris(acridone-N-yl) triazine (abbreviation: ACT) represented by a structure formula (71). NMR (Nuclear Magnetic Resonance) spectrum data is shown below. 1H NMR (300 MHz, CDCl3) δ 7.37-7.51 (m, 12H), 7.67 (d, 6H, J=8.4 Hz), 8.35 (dd, 6H, J=1.8, 7.8 Hz) 13C NMR (75.5 MHz, CDCl3) 121.8, 124.9, 126.1, 127.1, 132.6, 136.4, 140.5, 179.7 In addition, the obtained compound was measured with a melting point measurement system (ATM-01 from AS ONE CORP.) to find that the melting point of the compound was 300° C. or more. Further, deposition of the obtained compound by evaporation and measurement with a photoelectron spectrometer (AC-2 from Riken Keiki Co., Ltd.) were performed to find that the ionization potential of the thin film compound was -5.6 eV In addition, an absorption spectrum of the thin film compound was measured with an ultraviolet-visible spectrophotometer (V-550 from JASCO Corporation) to find that the energy level of an absorption edge on the longer wavelength side of the absorption spectrum was 3.0 eV. From these results, it was determined that the HOMO level, the LUMO level, the energy gap between the HOMO level and the LUMO level of the material represented by the structure formula (71) are respectively -5.6 eV, -2.6 eV, and 3.0 eV. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile for 4h; | tert-Butyl 9-oxoacridine-10(9H)-carboxylate (4c): A 30-mL two-necked round-bottomed flaskequipped with a magnetic stirring bar, a rubber septum, and a three-way stopcock was charged withacridone (402.0 mg, 2.06 mmol) and anhydrous MeCN (6.8 mL). To the solution was added Boc2O(761.9 mg, 3.49 mmol), followed by DMAP (753.7 mg, 6.17 mmol). The resulting mixture was stirred for4 h, after which time TLC (hexanes-EtOAc = 4:1) indicated complete consumption of acridone. To theresulting mixture was added H2O, and the mixture was extracted with EtOAc three times. The combinedorganic extracts were washed with saturated aqueous NH4Cl and brine, dried over anhydrous sodiumsulfate, and filtered. The organic solvents were removed under reduced pressure to give crudeN-Boc-acridone 4c, which was purified by flash silica gel column chromatography (hexanes-EtOAc =4:1) to afford N-Boc-acridone 4c (565.3 mg, 1.91 mmol, 93%) as a colorless solid. The analytical data(HRMS, 1H and 13C NMR) were identical with those reported in the literature.13 Rf = 0.45(hexanes-EtOAc = 4:1); IR (neat, cm-1): 3446, 1743, 1636, 1604, 1488, 1459, 1369, 1360, 1246, 1178,1142, 1121, 937, 840, 749, 670, 610, 554. |
73% | With dmap In acetonitrile at 20 - 60℃; for 11h; | |
70% | With dmap In acetonitrile at 20 - 60℃; for 11h; |
63% | With dmap In acetonitrile at 60℃; for 3h; | Synthesis of ketone 5 N,N-dimethylpyridin-4-amine (1.83 g, 15 mmol) was added to a mixture of acridin-9(10H)-one (1.95 g, 10 mmol) and di-tert-butyl dicarbonate (3.27 g, 15 mmol) in acetonitrile (30 mL). The orange solution was stirred 3 h at 60 C. After removal of the solvent under reduced pressure, the solution was washed with 0.1 M aq. HCl (100 mL), brine (100 mL) and the mixture was extracted with EtOAc (3×100 mL), dried over Na2SO4 and the solvents evaporated at reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=50:1) affording 5 as white solid 2.06 g (yield: 63%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | With [Pmim]OH; at 20 - 25℃; for 12h;Ionic liquid; | The synthesis method comprises the following steps:29.2 g of [Pmim] OH ionic liquid was added in a three-necked flask equipped with a condensing reflux at room temperature,19.5g acridone, stirring evenly after adding 11.3 g of chloroacetic acid, the control temperature of 25 stirring reaction 12h after standing at room temperatureThe residue was then washed with 25 ml of methanol and dried to give 24.2 g of acridone acetate (yield: 95.7%). |
93.5% | With tetrabutylammomium bromide; sodium hydroxide; In water; N,N-dimethyl-formamide; at 80℃; for 3h; | 39% acridone (2 mol),N-tetrabutylammonium bromide (TBAB) 19.34g (0.06mol),265 g (2.8 mol) of chloroacetic acid was added to a 1000 mL three-necked flask.Add 500 mL of organic solvent DMF and stir at 80 C to dissolve.Further, 100 mL of a 60 wt% NaOH aqueous solution was added, and after heating at 80 C for 3 hours,The reaction was stopped, allowed to cool to room temperature, and the reaction system was poured into 300 mL of ice water.A large amount of yellow solid precipitates were precipitated, allowed to stand overnight, suction filtered, and washed with ice water.That is, a wet intermediate is obtained; 500 mL of a 30 wt% NaOH aqueous solution is added to the wet intermediate,Dissolve and stir at room temperature, filter, and wash with 100 mL of 30 wt% NaOH aqueous solution.Combine the washing solution, add concentrated hydrochloric acid to adjust the pH value between 4 and 5.There is a large amount of yellow solid precipitates, Allow to stand overnight, suction filtration, wash with ice water,Drying, 474 g of acridinone acetate product was obtained, and the yield was 93.5%.The purity by HPLC was 99.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 25℃; for 1h; Inert atmosphere; Stage #2: (3-chloropropyl)trimethylsilane In N,N-dimethyl-formamide; mineral oil at 50℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: bis(4-fluorophenyl)sulfoxide; 10H-acridin-9-one With methanesulfonic acid; phosphorus pentoxide In chlorobenzene at 50℃; for 2h; Inert atmosphere; Stage #2: lithium trifluoromethanesulfonate In dichloromethane for 1h; | 1-3 Example 1-3Synthesis of Compound No. 3A 200 ml four-necked flask was charged with 72.08 g (0.75 mol) of methanesulfonic acid and 7.10 g (0.05 mol) of phosphorous pentoxide. After purging with nitrogen, the contents were heated to 100° C. to dissolve. After cooling, 9.76 g (0.05 mol) of acridone was added thereto, and 11.91 g (0.05 mol) of bis(fluorophenyl) sulfoxide dissolved in 11.91 g of chlorobenzene was then added dropwise, followed by causing the system to react at 50° C. for 2 hours. The reaction mixture was poured into a mixture of 200 g of ice water, 80 g of methanol, and 200 g of toluene in a 1 L beaker, stirred for 1 hour, and left to stand. The upper layer was discarded. To the lower layer were added 200 g of methylene chloride and 9.36 g (0.06 mol) of lithium trifluoromethanesulfonate, followed by stirring for 1 hour. The methylene chloride layer was washed with three 300 ml portions of water and concentrated under reduced pressure to give 28.27 g of compound No. 3 of the invention composed of cation No. 19 and a nonafluorobutanesulfonate anion (yield: 100%; HPLC purity: 95.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium hydride In dimethyl sulfoxide at 25℃; Inert atmosphere; | (S)-(+)-10-[2-(6-Methoxynaphthalen-2-yl)propionyl]-10H-acridin-9-one (17) Sodium hydride (67 mg, 2.81 mmol) and 2-(4-isobutylphenyl)propionyl chloride (14; 2.56 mmol) were added to a solution of acridone 8 (500 mg, 2.56 mmol) in dry DMSO (10 mL) under an argon atmosphere. The reaction was allowed to proceed with stirring at 25 °C for 3 h at which time the reaction was complete. Water (10 mL) was added to the reaction mixture, and this mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine (20 mL), the organic fraction was dried (dry Na2SO4), and the solvent was removed in vacuo. The brown syrup obtained was purified on a Combiflash silica gold column using ethyl acetate-hexane (1:2, v/v) as eluent to give the title compound 16 in 51 % yield as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h; Stage #2: 2-chloro-N-(4-chlorophenyl)acetamide With potassium iodide In N,N-dimethyl-formamide; mineral oil at 0℃; Reflux; | 4.1. General synthetic procedure for 2-(9-oxoacridin-10(9H)-yl)-N-(substituted) phenyl acetamide (13a-o) General procedure: Acridone (10) (195mg, 1mmol) was added portion wise to a stirred suspension of NaH (56mg, 1.2mmol, 50% of mineral oil) in dry DMF (10ml) at 0°C. The reaction mixture was stirred for 2h. Afterward, 2-chloro-N-(substituted)phenyl acetamides 12a-o (2mmol) and KI (33.2mg, 0.2mmol) were added to the reaction mixture with stirring for different time intervals. After completion of the reaction (TLC), the reaction mixture was poured into crushed ice (50g) with constant stirring. The precipitated solid was collected and then extracted with chloroform. The combined organic extracts were washed with brine and water and finally dried with anhydrous sodium sulfate. Pure compounds were isolated after column chromatography and recrystallized from suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | General procedure: Acridone (10) (195mg, 1mmol) was added portion wise to a stirred suspension of NaH (56mg, 1.2mmol, 50% of mineral oil) in dry DMF (10ml) at 0C. The reaction mixture was stirred for 2h. Afterward, 2-chloro-N-(substituted)phenyl acetamides 12a-o (2mmol) and KI (33.2mg, 0.2mmol) were added to the reaction mixture with stirring for different time intervals. After completion of the reaction (TLC), the reaction mixture was poured into crushed ice (50g) with constant stirring. The precipitated solid was collected and then extracted with chloroform. The combined organic extracts were washed with brine and water and finally dried with anhydrous sodium sulfate. Pure compounds were isolated after column chromatography and recrystallized from suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h; Stage #2: 2-chloro-N-(2-fluorophenyl)acetamide With potassium iodide In N,N-dimethyl-formamide; mineral oil at 0℃; Reflux; | 4.1. General synthetic procedure for 2-(9-oxoacridin-10(9H)-yl)-N-(substituted) phenyl acetamide (13a-o) General procedure: Acridone (10) (195mg, 1mmol) was added portion wise to a stirred suspension of NaH (56mg, 1.2mmol, 50% of mineral oil) in dry DMF (10ml) at 0°C. The reaction mixture was stirred for 2h. Afterward, 2-chloro-N-(substituted)phenyl acetamides 12a-o (2mmol) and KI (33.2mg, 0.2mmol) were added to the reaction mixture with stirring for different time intervals. After completion of the reaction (TLC), the reaction mixture was poured into crushed ice (50g) with constant stirring. The precipitated solid was collected and then extracted with chloroform. The combined organic extracts were washed with brine and water and finally dried with anhydrous sodium sulfate. Pure compounds were isolated after column chromatography and recrystallized from suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: Acridone (10) (195mg, 1mmol) was added portion wise to a stirred suspension of NaH (56mg, 1.2mmol, 50% of mineral oil) in dry DMF (10ml) at 0C. The reaction mixture was stirred for 2h. Afterward, 2-chloro-N-(substituted)phenyl acetamides 12a-o (2mmol) and KI (33.2mg, 0.2mmol) were added to the reaction mixture with stirring for different time intervals. After completion of the reaction (TLC), the reaction mixture was poured into crushed ice (50g) with constant stirring. The precipitated solid was collected and then extracted with chloroform. The combined organic extracts were washed with brine and water and finally dried with anhydrous sodium sulfate. Pure compounds were isolated after column chromatography and recrystallized from suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 24h; Inert atmosphere; | |
87% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 24h; Inert atmosphere; Reflux; | |
79% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 120h; Reflux; |
65.3% | With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 12h; Inert atmosphere; | 7 Preparation of Compound 8: In a 500 mL three-necked flask,Bromobenzene (15.7 g, 0.1 mol) was added,Acridone (19.5 g, 0.1 mol),Xylene (300 g), under nitrogen,Sodium tert-butoxide (14.40 g, 0.15 mol) was added,Palladium acetate (0.148 g, 1% mol),Xantphos (0.696 g, 2% mol), heating,120 incubation reaction 12h,Cooled to 30 ° C,The reaction solution was washed with water,Liquid separation,Dried over anhydrous magnesium sulfate,Column chromatography was carried out on a 25 cm thick silica gel column,After the toluene was sufficiently rinsed,Combined with the column solvent desolvent,Toluene petroleum ether after recrystallization filtration,To give compound 8,Yellow solid 17.7 g,Yield 65.3%, MS |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-iodo-propane In N,N-dimethyl-formamide; mineral oil at 20℃; for 14h; Inert atmosphere; | |
74% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1-iodo-propane In N,N-dimethyl-formamide at 80℃; for 0.5h; | Preparation of compounds 2i and 3i. General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred suspension of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with propyl iodide (for 2i) or 1-bromobutane (for 3i) (5 mmol), and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled and then water was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 24h;Inert atmosphere; Reflux; | 2L reaction flask under a nitrogen stream to acridine money 10.0g(51.2mmol), the compound [78-1] 24.5g (61.5mmol), iodine Tues.Copper (CuI) 1g(5.1mmol), dimethylformamide, potassium carbonate 10.7g (76.9mmol), diepivalate Lloyd methane 0.2g (1.0mmol)Dissolved in 550mL the mixture was stirredunder reflux for 24 hours. After completion of the reaction slowly cooled toroom temperature, ethyl acetate and saturatedAnd extract with brine. Theorganic layer was separated, and dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. Concentrate CurlColumn usinga chromatographic method, to obtain the objective compound [78] was prepared in15.2g (58%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.3% | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 8h; Inert atmosphere; Reflux; | 1 (1) Synthesis of intermediate M-1 In a 1000 ml three-necked flask, under nitrogen protection, add 500 ml of toluene, 19.5 g (0.1 mol) of acridine-9(10H)-one, 23.3 g (0.1 mol) of 4-bromo-1,1'-biphenyl, 11.52 g (0·12 mol) sodium tert-butoxide, 0.575 g (0.01 mol) Pd (dba) 2 (bis(dibenzylideneacetone) palladium), 2.02 g (0.01 mol) tri-tert-butylphosphine 10% toluene solution of phosphine, heated to reflux for 8 hours, cooled, added with water, organic layer washed with water, dried over anhydrous magnesium sulfate, separated by silica gel column chromatography, petroleum ether: ethyl acetate = 1:1 (volume The yield of the compound of the formula M-1 was 29.16 g, and the yield was 84.3%. |
84.3% | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 8h; Reflux; Inert atmosphere; | 1 (1) Synthesis of intermediate M-1: In a 1000 ml three-necked flask, 500 ml of toluene was added under nitrogen protection.19.5 g (0.1 mol) of acridine-9(10H)-one,23.3 g (0.1 mol) of 4-bromo-1,1'-biphenyl, 11.52 g (0.12 mol) of sodium t-butoxide, 0.575 g (0.001 mol) of Pd(dba)2 (bis(dibenzylideneacetone)palladium ),2.02 g (0.001 mol)Tri-tert-butylphosphine10% toluene solution,Heat to reflux for 8 hours,Cooling, adding water, washing the organic layer, drying with anhydrous magnesium sulfate, silica gel column chromatographyfrom,Petroleum ether: ethyl acetate = 1:1 (volume ratio) eluted and separated to give 29.16 g of the compound of formula M-1, yield 84.3%. |
84% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 24h; Inert atmosphere; Reflux; |
167 g | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 48h; Heating; | A.A-1.1 Under a protective gas atmosphere the 100g (0.5mol) the 10H-acridine-9-one, 140g (0.6mol) of 4-bromobiphenyl, 9.6g (0.05mol) CuI of, 104.0g (0.75mol) the potassium carbonate and 22.0 ml (0.1mol) of 2,2,6,6-tetramethyl-3,5-heptanedione is dissolved in 600 ml of in dimethyl formamide. The reaction mixture is boiling under a protective gas atmosphere heating 48h. Then the water is added to the mixture. The solid filter for, water and ethanol washing and from toluene recrystallization. Yield: 167g (0.48mol), theoretical 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere; | General procedure: Under inert atmosphere, the sodium hydride (1.1 equiv.) was added to a solution of amine derivative 19-23 (1.1 equiv.) in DMF at 0 C. The benzyl bromide 15-18 (1 equiv.) was then added immediately and the reaction was stirred for 24 h. The mixture was then washed with water and extracted with methylene chloride. The organic phase was dried over MgSO4 and purified by flash chromatography (n-heptane/EtOAc, gradient from 100/0 to 0/100) to give pure compounds 5-14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 10H-acridin-9-one With sulfuryl dichloride In benzene Inert atmosphere; Reflux; Stage #2: phenol With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 84h; Inert atmosphere; | 9-Phenoxyacridine (2) 9-Phenoxyacridine (2)Dry benzene (450 mE) was added to 1.50 g acridone (1 equiv.) under N2-atmosphere. 50C12 (3.37 mE, 6 equiv.) was added and the reaction mixture was refluxed over night followed by removal of solvent by evaporation. Dry DMF (75 mL), phenol (2.17 g, 3 equiv.) and K2C03 (4.26 g, 3 equiv.) were added under N2. The reaction was stirred at 60° C. for 3.5 days. Afier filtration and evaporation the crude productwas purified using flash chromatography (CH2C12 to CH2C12:Et20, 6:1) giving 2.04 g of 2, 98% yield. ‘H NMR (CDC13):8.28 (5+4, br ddd, J=8.9, 1.1, 0.8 Hz, 2H), 8.11 (8+1, ddd, J=8.7, 1.3, 0.8 Hz, 2H), 7.79 (6+3, ddd, J=8.9, 6.6, 1.3 Hz, 2H), 7.47 (7+2, ddd, J=8.7, 6.6, 1.1 Hz, 2H), 7.28 (2’+4’, m, 2H), 7.06 (3’, m, 1H), 6.86 (1+5’, m, 2H). 3.40 (6, m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; for 5h; Inert atmosphere; | 1.1; 2.1 (1) Synthesis of Intermediate A 19.5 g (100 mmol, 1.0 eq.) of acridone and 20.4 g of iodobenzene (100 mmol, 1.0 eq.) were placed in a dry 2L three-necked flask, and dried and degassed 800 ml of toluene was added as a solvent, and nitrogen was purged for 15 minutes. . Then add 28.8g (300 mmol.3.0 eq.) sodium tert-butoxide, toluene solution of 1.8 g (2% mol) catalyst Pd2(dba)3 and 8.1 ml (4% mol) P(t-bu)3 (m/v, 10% ). Warm up to 100°C and react overnight for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, adsorbed on activated carbon, suction filtered, and the solvent was removed by spin-drying. Recrystallization from toluene and ethanol gave 22.5 g of Intermediate A in a yield of 83%. |
70% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide at 160℃; for 36h; Sealed tube; Inert atmosphere; | |
66.2% | With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide Reflux; Inert atmosphere; | 1.1 In a 500 mL round-bottom flask, 9-acridanone 10 g (51 mmol), iodobenzene 10.45 g (51 mmol), potassium carbonate 14.16 g (102 mmol), copper iodide 0.1 g (5 mmol),2,2,6,6-tetramethyl-3,5-pentadione 1.98 g (10 mmol) was diluted in 200 mL of dimethylformamide and then refluxed overnight in a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into 600 mL of cold water, extracted with 300 mL of toluene, washed three times with 500 mL of 3N hydrochloric acid, and then the solvent was removed and purified by column chromatography to form a compound represented by [Formula 3-a] 9.2g (yield 66.2%) was obtained. |
61% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 48h; Inert atmosphere; Reflux; | |
45% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide at 130℃; for 48h; Inert atmosphere; | |
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 8h; Inert atmosphere; | 2.1 (1) In the reaction flask, 100 mmol of raw material M is dissolved in DMF and protected by nitrogen,Add 100mmol of iodobenzene, cuprous iodide (1%), 1,10-phenanthroline (1%) and potassium carbonate 300mmol, react at 120 for 8h; after the reaction is complete, add water to the reaction solution,Stir out solids, filter, wash, dryGet M1; | |
In N,N-dimethyl-formamide at 120℃; for 3h; Inert atmosphere; | 6.1 (1) In the reaction flask, 100 mmol of raw material M is dissolved in DMF and protected by nitrogen,Add 100mmol of iodobenzene and react at 120 for 3h; after the reaction is complete, add water to the reaction solution,Stir out solids, filter, wash, dryGet M1; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | With 1-octyl-3-methylimidazole hexafluorophosphate; at 35.0℃; for 8.0h;Ionic liquid; | The synthesis method comprises the following steps:At room temperature, 69 g of [Omim] OH ionic liquid was added successively to a three-necked flask equipped with a condensing reflux apparatus, 19.5 gAcridine ketone, stir well after adding 17.4 g of sodium chloroacetate, the control temperature of 35 stirring 8h after standing at room temperature, filter,The filter cake was then washed with 30 ml of methanol and dried to give 27.2 g of sodium acridone acetate (yield: 94.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,10-Phenanthroline; oxygen; copper diacetate; palladium diacetate; silver carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | 2- (2-aminobenzoyl) benzoic acid (120 mg, 0.5 mmol)Anhydrous 1,10-phenanthroline (18 mg, 0.1 mmol)Copper acetate (22.8 mg, 0.1 mmol)Palladium acetate (11.2 mg, 0.05 mmol)Silver carbonate (27.6 mg, 0.1 mmol),Anhydrous DMF 2 mL in 10 ml of the reactor,The mixture was stirred at 120 C for 12 h,After completion of the reaction, an appropriate amount of water (20 ml x 3) and ethyl acetate (20 ml)The organic phase was washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, concentrated,And purified by column chromatography on silica gel, using petroleum ether / ethyl acetate volume ratio of 1 ~ 3: 1 as the eluent,The eluate containing the target compound was collected, the solvent was evaporated and dried to give 70.4 mg of product 9 (10H) acridone in a yield of75%The product was a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With di-tert-butyl peroxide; copper(II) dipivaloate; palladium dichloride In dimethyl sulfoxide at 100℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide for 1h; Stage #2: 2-chloro-4,6-diphenyl-1,3,5-triazine In N,N-dimethyl-formamide for 6h; | 5.1 To a 500 mL round-bottom flask, 10 g (51 mmol) of 9-acridanone and 100 mL of dimethylformamide were added, stirred, and 2.46 g (61 mmol) of 60% sodium hydride were added and stirred for 1 hour. [Chemical Formula 3-d] obtained from [Scheme 4] was dissolved in 200 mL of dimethylformamide, and then added to the reaction solution for 1 hour, followed by stirring for 5 hours. When the reaction was completed, the reaction solution was poured into 1000 mL of water and filtered to obtain 20 g (yield 91.6%) of the compound represented by [Chemical Formula 42-a]. |
66% | Stage #1: 10H-acridin-9-one With n-butyllithium In tetrahydrofuran for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: 2-chloro-4,6-diphenyl-1,3,5-triazine With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 80℃; | 1.2 (2) Synthesis of Precursor B Under an atmosphere of nitrogen, 2 g (10 mmol) of acridone was added into 30 mL of anhydrous tetrahydrofuran solution and dissolved with stirring. 7.5 mL (12 mmol) of 1.6M n-BuLi was slowly added dropwise under ice-cooling for 30 min and the resulting yellow suspension was slowly dripped Dissolved 3g (11mmol) diphenyl triazine,0.1 g (0.1 mmol) of tetrakistriphenylphosphine palladium in 20 mL of tetrahydrofuran was added and the reaction was heated overnight at 80 ° C. The reaction mixture was cooled to room temperature, 100 mL of saturated NaCl solution was added, and the organic phase was extracted with dichloromethane (30 mL × 3). After drying, the solvent was evaporated by evaporation and recrystallized from 100 mL of toluene to give 2.8 g of a white solid in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: C12H7Br2IO With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: 10H-acridin-9-one In tetrahydrofuran at -78 - 20℃; | 1.2; 2.2; 3.2; 4.2 (2) Synthesis of Intermediate-2 The experimental apparatus was sufficiently dried, and 35.9 g (79 mmol, 1.0 eq.) of intermediate-1 was added to a 3 L three-necked flask, 400 ml of dried tetrahydrofuran was added, dissolved, and the temperature was lowered to -78 ° C, and 37.9 ml of 2.5 M (94.8 mmol) was added dropwise. , 1.2 eq.) of n-BuLi. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then 300 ml of a THF solution containing 15.5 g (79 mmol, 1.0 eq.) of acridone was added dropwise at the same temperature, and the mixture was stirred at room temperature overnight.After the reaction was completed, the mixture was stirred for 1 hour with water, the mixture was allowed to stand for stratification, and the organic phase was washed three times with water. The filtrate was extracted with dichloromethane and washed with water. The organic phase was combined, dried, solvent was evaporated, dried, Among them, 800 ml of acetic acid and 200 ml of concentrated hydrochloric acid were added, the temperature was raised to 110 ° C, and refluxed for 16 hours overnight to terminate the reaction. After cooling to room temperature, an appropriate amount of water was added, stirred, and the solid was precipitated, suction filtered, washed with water, and then washed three times with ethanol, and finally dried to give 30.4 g of intermediate-2 in a yield of 76%. |
76% | Stage #1: C12H7Br2IO With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: 10H-acridin-9-one In tetrahydrofuran at 20℃; | 2.2; 3.2; 4.2 (2) Synthesis of intermediate-7 The experimental apparatus was sufficiently dried, and 35.9 g (79 mmol, 1.0 eq.) of intermediate-6 was added to a 3 L three-necked flask, 400 ml of dried tetrahydrofuran was added, dissolved, and the temperature was lowered to -78 ° C, and 37.9 ml of 2.5 M (94.8 mmol) was added dropwise. , 1.2 eq.) of n-BuLi. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then 300 ml of a THF solution containing 15.5 g (79 mmol, 1.0 eq.) of acridone was added dropwise at the same temperature, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was stirred for 1 hour with water, the mixture was allowed to stand for stratification, and the organic phase was washed three times with water. The filtrate was extracted with dichloromethane and washed with water. The organic phase was combined, dried, solvent was evaporated, dried, Among them, 800 ml of acetic acid and 200 ml of concentrated hydrochloric acid were added, the temperature was raised to 110 ° C, and refluxed for 16 hours overnight to terminate the reaction. After cooling to room temperature, an appropriate amount of water was added, stirred, and the solid was precipitated, suction filtered, washed with water, and then washed three times with ethanol, and finally dried to give 30.4 g of Intermediate-7 in a yield of 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.28% | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 8h; Reflux; Inert atmosphere; | 1 (1) Synthesis of intermediate M-1 In a 1000 ml three-necked flask, 500 ml of toluene was added under nitrogen protection. 19.5 g (0.1 mol) of acridine-9(10H)-one, 27.4 g (0.1 mol) of 3-bromo-N-ethylcarbazole, 11.52 g (0.12 mol) of sodium tert-butoxide, 0.575 g (0.001 mol) of Pd(dba) 2 (bis(dibenzylideneacetone)palladium), 2.02 g (0.001 mol) of a 10% toluene solution of tri-tert-butylphosphine, heated to reflux for 8 hours, cooled, added with water, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and separated by silica gel column chromatography, petroleum ether: Ethyl acetate = 1:1 (volume ratio) elution and separation gave 32.7 g of the compound of formula M-1, yield: 84.28%. |
84.28% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene for 8h; Inert atmosphere; Reflux; | 1 (1) Synthesis of intermediate M-1: In a 1000 ml three-necked flask, under nitrogen protection,Add 500 ml of toluene, 19.5 g (0.1 mol)Acridine-9(10H)-one, 27.4 g (0.1 mol) 3-bromo-N-ethylcarbazole, 11.52 g (0.12 mol) sodium tert-butoxide, 0.575 g(0.001 mol) Pd(dba) 2 (bis(dibenzylideneacetone)palladium), 2.02 g (0.001 mol) of 10% toluene of tri-tert-butylphosphineThe solution is heated to reflux for 8 hours, cooled, added with water, washed with organic layer, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatographySeparate and elute with petroleum ether: ethyl acetate = 1:1 (volume ratio) to obtain 32.7 g of the compound of formula M-1, yield: 84.28%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40 - 50℃; for 3h; | 3.1 Step 1. Preparation of acridone: 846.1 g (5 mol) of diphenylamine and 103 g (0.60 mol) of p-toluenesulfonic acid were added to the reaction kettle.Add 1000 mL of N,N-dimethylformamide and heat to 40-50 °C.Stirring (during keeping the gas path open, the gas path is open to the atmosphere),Pass carbon dioxide for 2 to 3 minutes (to drive away the air in the system),Then, the valve is closed and a low pressure of 0.65 MPa is formed in the system.Maintain a low pressure of 0.65MPa, continue to react for 3h, relieve pressure,Transfer the reaction mass to a 2000 mL round bottom flask and add 500 mL of water. Stirring reaction was continued for 0.5 h, filtered, and the filtrate was allowed to stand for separation into the aqueous phase.The organic phase was washed three times with 500 mL of water, distilled under reduced pressure and dried. Obtaining 913 g of a yellow solid powder, which is an acridone.The yield is 93.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: 1,5-dibromo-pentane In N,N-dimethyl-formamide at 80℃; for 0.5h; | General procedure for the preparation of bromoalkyl acridones 2-5 General procedure: A solution of acridone (1 mmol) in N,N-dimethylformamide (10 mL) was added to a stirred solution of sodium hydride (3 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated at 80 °C for 15 min, treated with the appropriate dibromoalkane (6 mmol) and heated at 80 °C for an additional 0.5 h. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silicagel column chromatography. |
60% | With sodium hydride In N,N-dimethyl-formamide at 40℃; for 12h; | General procedure for the synthesis of compounds 8 (a-d) (A). General procedure: Compound 7 (1 mmol) was dissolved in dimethylformamide (15 mL) and poured into the reaction vessel containing NaH (2 mmol) for the generation of anion followed by the addition of dibromopropane/dibromobutane/dibromopentane/dibromohexane (1.5 mmol). The reaction continued for 4 h at 40 °C and monitored by TLC. After the completion, reaction was quenched by adding cold water (15 mL). The reaction mixture was extracted with ethyl acetate (4x25 mL). The combined organic part was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude products 8(a-d) obtained were then purified by column chromatography using ethyl acetate and hexane as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tert.-butylhydroperoxide; 0.5C34H18N16(4-)*2H2O*2Cu(1+)*C3H7NO In water at 20℃; for 4h; Sonication; | |
93% | With tert.-butylhydroperoxide; 2C36H20N2O8(4-)*5Co(2+)*2HO(1-)*4H2O*6C3H7NO In water at 20℃; for 9h; Sonication; regioselective reaction; | |
92% | With tert.-butylnitrite; oxygen; acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone In 1,2-dichloro-ethane at 20℃; for 12h; Irradiation; |
62.2 %Chromat. | With oxygen In acetone for 12h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 110℃; for 12h; Inert atmosphere; | 28.1 Synthesis of Intermediate 5-1 Under nitrogen, was added 19.5g (100mmol) 9(10Η)-acridine-one (Compound A-1), 0.65g of palladium acetate (3mmol), 2.25g tri-tert-butylphosphine (11.0 mmol), 42.5 g of compound E-1 (110 mmol), 28.5 g of sodium t-butoxide,100 mL of toluene was reacted at 110 °C for 12 hours, cooled to room temperature, extracted with chloroform, and the solvent was evaporated to give 63.8 g of solid intermediate 5-1 (yield: 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 110℃; for 12h; Inert atmosphere; | 37.1 (1) Synthetic intermediate 5-1 Under nitrogen protection,Add 19.5 g (100 mmol) of 9 (10H)- acridone (a compound of formula A-1),0.65 g of palladium acetate (3 mmol),2.25 g of tri-tert-butylphosphine (11.0 mmol),30.0 g of the compound of formula E-1 (110 mmol),28.5 g of sodium t-butoxide,Toluene 100mL,Reaction at 110 ° C for 12 hours,After cooling to room temperature,Chloroform extraction,Rotating to remove the solvent,33.7 g of solid intermediate 5-1 was obtained through a silica gel column(yield 87%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Under nitrogen protection,24.6 g (100 mmol) of the compound of the formula F-1 was added,Tetrahydrofuran 500mL,At -78 C, 63 mL of n-butyl lithium (1.6 M) was added dropwise.Low temperature reaction for 30 minutes,The temperature was raised to 30 C for 3 hours.Cool down again to -78 C,Add 500mL9(10H)-acridone (Formula A-1The compound shown) (0.2 M 9.5 g (100 mmol)), slowly warmed to 30 C,After reacting for 15 hours, the reaction was quenched by the addition of aqueous ammonium chloride solution and extracted with chloroform.Rotating to remove the solvent,Pass through a silica gel column to obtain 20.3 g of solid intermediate 3-1(yield 56%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate In N,N-dimethyl-formamide for 24h; Inert atmosphere; Reflux; | |
68% | With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate In N,N-dimethyl-formamide at 155℃; for 48h; | 1 Synthetic intermediate A: General procedure: Add the raw materials (10mmol) and p-dibromobenzene (8mmol, log) into a 100mL two-neck flask, and add cuprous iodide (0.6mmol), potassium carbonate (10mmol), 1,10-phenanthroline ( 0.6mmol), 50mL of DMF, reacted at 155°C for 48 hours; the mixture was extracted three times with ethyl acetate; the extract was dried over MgSO4, filtered, concentrated and subjected to column chromatography (silica gel, from 100:1PE/CH2Cl2 to 5 :1PE/CH2Cl2 gradient elution) to obtain a white solid, that is, Intermediate A. The yield is shown in the following table: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 51% 2: 40% | With phosphorus; water; potassium hydroxide In dimethyl sulfoxide at 100℃; for 3h; Inert atmosphere; | Reaction of 9-chloroacridine with red phosphorus/KOH/DMSO(H2O) system A mixture of red phosphorus (0.65 g, 20.97 mmol), 9-chloroacridine(0.744 g, 3.49 mmol), KOH · 0.5H2O (1.50 g,11.77 mmol), and H2O (0.125 mL, 10.9 mmol) inDMSO (16 mL) was stirred for 3 h at 100°C in an argon atmosphere. The reaction mixture was cooled to ambient temperature, filtered using a Schott sintereddisc filter funnel, and DMSO was removed under reduced pressure. The resultant residue was washed with water (3 × 15-20 mL), and dried under reducedpressure to give 0.719 g of a mixture of products (dark brown powder). The powder was washed with chloroform(3 × 10 mL) and filtered off. The chloroform was removed to give 0.32 g (51%) of 9,10-dihydroacridine as a cream-colored powder, mp 169-170°C. 1H NMR (CDCl3, δ, ppm): 4.04 (s, 2H, CH2),5.93 (br s, 1H, NH), 6.65 (d, 2H, Ar), 6.83 (t, 2H, Ar),7.08 m (4H, Ar).13C NMR (CDCl3, δ, ppm): 31.3 (C9), 113.4 (C4,5),120.0 (C12), 120.6 (C2,7), 127.0 (C1,8), 128.6 (C3,6),140.2 (C11).For C13H11N anal. calcd. (%): C, 86.15; H 6.12.Found (%): C, 86.10; H, 6.23.Acridone (0.27 g, 40%) as a crystalline matter was isolated from the residue and characterized by GC-MS and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With palladium(II) acetate; tri-tert-butyl phosphine; sodium t-butanolate In toluene at 90℃; Inert atmosphere; | Synthesis of 10- [4-(2,5-Di-thiophen-2-ylpyrrol-1-yl)-phenyl]-10H-acridin- 9-one (TPAO). General procedure: DTP-Br (2 mM, 0.77 g), Phenothiazine(2 mM, 0.40 g), NaOtBu (2 mM, 0.2 g) and Pd(OAc)2(0.02 g), anhydrous toluene(20 mL) were added in a three-neck roundbottomed flask, then the mixture was degassed and processed under a nitrogen atmosphere, PtBu (2 mL) was injected with syringe. The mixture was stirred at 90C for overnight. After cooled to room temperature, the mixture was extracted with DCM and saturated brine, the organic phase was collected and removed under column pressure,and the crude product was processed by column chromatography on silica gel with petroleum: ethyl acetate (10:1) to give a pale power |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; for 12h;Inert atmosphere; Schlenk technique; Reflux; | Under the protection of nitrogen, the intermediate acridone (820 mg, 4.2 mmol), N-([1,1'-biphenyl] -4-yl) -N- (4-bromophenyl) were sequentially added to a 250 mL Schlenk bottle. )-[1,1'-biphenyl] -4-amine (2.4 g, 5 mmol), palladium acetate (18 mg, 0.08 mmol), tri-tert-butylphosphine tetrafluoroborate (73 mg, 0.25 mmol), tertiary The reaction was stirred at reflux for 12 hours with sodium butoxide (806 mg, 8.4 mmol) and 120 mL of toluene.After the reaction, the solvent was distilled off. The residue was dissolved in 200 mL of dichloromethane and 50 mL of water, washed with water, and the organic layer was separated. The aqueous layer was extracted twice with 15 mL of dichloromethane. The organic layers were combined, and the solvent was evaporated. The residue was passed through a column. Chromatographic separation (petroleum ether: dichloromethane = 1: 1 (V / V)), the solvent was distilled off, and after drying, 1.4 g of a pale yellow solid was obtained with a yield of 58%. |
58% | With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; for 12h;Inert atmosphere; Schlenk technique; Reflux; | Under the protection of nitrogen,In a 250mL Schlenk bottle, add the intermediate acridinone (820mg, 4.2mmol) and N-([1,1'-biphenyl] -4-yl) -N- (4-bromophenyl)-[1, 1'-biphenyl) -4-amine (2.4g, 5mmol), palladium acetate (18mg, 0.08mmol), tri-tert-butylphosphine tetrafluoroborate (73mg, 0.25mmol), sodium tert-butoxide (806mg , 8.4 mmol) and 120 mL of toluene, and the reaction was stirred under reflux for 12 hours. After the reaction was completed, the solvent was distilled off, the residue was dissolved with 200 mL of dichloromethane and 50 mL of water, washed with water, and the organic layer was separated. The aqueous layer was extracted twice with 15 mL of dichloromethane. The organic layers were combined. Chromatographic separation (petroleum ether: dichloromethane = 1: 1 (V / V)), the solvent was distilled off, and after drying, 1.4 g of pale yellow solid was obtained with a yield of 58%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(I) acetate In tetrahydrofuran at 80℃; for 10h; | |
75% | With silver hexafluoroantimonate; sodium hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(I) acetate In tetrahydrofuran at 80℃; for 10h; | 2 Synthesis of 2,3-diphenylpyrano[4,3,2-kl]acridine (II-a) (1) Combine acridone (39.1mg, 0.20mmol), diphenylacetylene (71.2mg, 0.40mmol), [Cp*RhCl2]2 (3.1mg, 5μmol, 2.5mol%), AgOAc (66.8mg, 0.40mmol) ), AgSbF6 (13.7mg, 40μmol, 20mol%), NaSbF6 (51.7mg, 0.20mmol) and tetrahydrofuran (1.0mL) were added to the reaction tube and stirred uniformly, heated to 80°C and reacted for 10 hours;(2) After the reaction is completed, cool the reaction tube to room temperature, add 10 mL of dichloromethane to dilute the reaction system,Then filter through diatomaceous earth and wash with 10-20 mL of dichloromethane, combine the filtrate,The solvent was removed under reduced pressure, and the residue was separated and purified by neutral aluminum oxide column chromatography (dichloromethane/ethyl acetate=10:1, v/v), and dried under vacuum to obtain the light yellow solid target product 2,3-diphenylpyrano[4,3,2-kl]acridine (II-a) 55.7mg, yield 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 10H-acridin-9-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-(2-morpholin-1-yl-ethoxy)benzyl chloride hydrochloride In N,N-dimethyl-formamide at 20℃; | 15,15.3 10-(4-(2-morpholinoethoxy)benzyl)acridin-9-(10H)-one Dissolve acridine-9-(10H)-one (1.0 equivalent) in anhydrous N,N-dimethylformamide, Sodium hydride (1.1 equivalent) was added, and the reaction solution was stirred at 0°C for 1 hour. Then 4-(2-(4-(chloromethyl)phenoxy)ethyl)morpholine hydrochloride was added and the reaction was transferred to room temperature. When TLC indicated that the reaction was complete, the reaction was quenched with ice water and extracted with ethyl acetate. After the organic phases were combined, they were further purified by flash column chromatography to obtain 10-(4-(2-morpholinoethoxy)benzyl)acridin-9-(10H)-one; the experimental data are as follows: 87%, brown solid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,2,6,6-tetramethylheptane-3,5-dione; potassium carbonate; copper(II) iodide In N,N-dimethyl-formamide at 70 - 150℃; for 48h; Inert atmosphere; | 3 Example 3: Synthesis of compound 3c: Under the protection of nitrogen, 2,6-dibromo-benzonitrile 1a (10.0mmol, 2.60g), acridinone 2c (10.0mmol, 1.95g), potassium carbonate (20.0mmol, 2.76g), cuprous iodide ( 2.0mmol, 0.38g), 2,2,6,6-tetramethyl-3,5-heptanedione (2.0mmol, 0.37g) were dissolved in DMF, reacted at 70 to 150°C for 48 hours, and cooled to room temperature , Washing with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then column chromatography to obtain 3c (8.61g, yield: 88%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 51% 2: 26% | With oxygen; 1-(2,2-diphenyl-2λ4,3λ4-[1,3,2]diazaborolo[4,5,1-ij]quinolin-1(2H)-yl)-3-phenylpropan-1-one In 1-methyl-pyrrolidin-2-one at 20℃; for 5h; Irradiation; Green chemistry; |
[ 71412-22-1 ]
2,3-Dihydroquinolin-4(1H)-one hydrochloride
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H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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