* 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.
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 ()
Reference:
[1] Pharmaceutical Sciences, 1997, vol. 3, # 5-6, p. 235 - 239
[2] European Journal of Inorganic Chemistry, 1999, # 3, p. 557 - 563
[3] Heterocycles, 2014, vol. 88, # 1, p. 535 - 546
[4] Patent: CN108640873, 2018, A, . Location in patent: Paragraph 0022; 0023
[5] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 926 - 935
[6] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 48
[7] Organic Syntheses, 1942, vol. 22, p. 5
[8] Chemische Berichte, 1900, vol. 33, p. 3770
[9] Patent: CN103755634, 2016, B, . Location in patent: Paragraph 0040
[10] Patent: WO2008/10984, 2008, A2, . Location in patent: Page/Page column 22
3
[ 91-40-7 ]
[ 1207-69-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
for 12 h; Reflux; Inert atmosphere
A magnetically stirred solution of N-phenylanthranilic acid (5.45 g,26 mmol) in phosphorus oxychloride (100 mL, 1.07 mol) was treated with concentrated sulfuric acid (0.5mL), then 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 ammonium hydroxide. A light tan solid was collected by filtration, washed with water, and air dried for 24 h. Flash chromatography (silica gel/75percent hexane, 20percentTHF, 5percent triethylamine) afforded 4.67 g (84percent yield) of 10 as fine yellow needles having one medium Rf spot by TLC; mp 117–119 °C (lit.15 mp 119–120 °C); 1H NMR (CDCl3): 8.50–8.10 (m, 4H),7.95–7.50 (m, 4H); IR (THF): 3075, 1622, 1562, 1438, 1404, 1324, 1287, 1014, 831, 767, 647, 608cm-1; Vis (CHCl3): λmax (") 360.5 nm (10,000); MS EI: m/e (relative intensity) 215 (33, M++2), 213(100, M+), 178 (21), 177 (16). Anal. Calcd for C13H8ClN: C, 73.07; H, 3.77; N, 6.55; Cl, 16.59. Found: C, 72.99; H, 3.80; N, 6.55; Cl, 16.58.
69%
Reflux
General procedure: The phenyl amino benzoic acid derivatives (47 mmol) (2a–c) were cyclized intra molecularly to 9-chloroacridine derivatives(3a–c) by refluxing them in 60 mL of POCl3 for 4 h and the reaction was monitored by TLC. After completion, the excess POCl3 was removed by rota evaporator under reduced pressure to the crude reaction mass crushed ice was added, pH was adjusted 7 by adding saturated bicarbonate solution. The solid separated was filtered,dried and purified by flash column chromatography using 5–10percent ethyl acetate: hexane as eluent in 60–120 mesh silica gelto get the corresponding 9-chloroacridine derivatives in good yield. These intermediates were confirmed by mass analysis (ESI mode) and proceed to next step.
56%
at 110℃; for 3 h;
In a 100ml eggplant type bottle,N-phenylanthranilic acid (5.0 g, 23.5 mmol) was added,Phosphorus oxychloride (50 ml, 537 mmol). Put it in a 110°C oil bath and stir for 3 hours.TLC (developer: dichloromethane/methanol=20/1) detects complete disappearance of compound III-14.Withdraw from the oil bath and naturally cool to room temperature.The reaction mixture was slowly added to 150 g of ice and stirred vigorously. After the heat is released,The pH was adjusted with saturated sodium bicarbonate solution until bubbles ceased to form.After filtration, the filter cake is washed with water 2 or 3 times and drained.This gave the solid, 9-chlorohydrazine, 2.8 g (brown solid, yield 56percent).
Reference:
[1] Journal of Physical Organic Chemistry, 2010, vol. 23, # 4, p. 382 - 389
[2] Journal of the American Chemical Society, 2010, vol. 132, # 40, p. 14006 - 14008
[3] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 5, p. 1405 - 1408
[4] Heterocycles, 2014, vol. 88, # 1, p. 535 - 546
[5] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 4, p. 748 - 754
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 877 - 885
[7] Electrochimica Acta, 2010, vol. 55, # 9, p. 3348 - 3354
[8] Patent: CN107721925, 2018, A, . Location in patent: Paragraph 0092; 0093
[9] Organic Syntheses, 1942, vol. 22, p. 5
[10] Journal of the Indian Chemical Society, 1998, vol. 75, # 10-12, p. 716 - 724
[11] European Journal of Medicinal Chemistry, 2010, vol. 45, # 2, p. 745 - 751
[12] Archiv der Pharmazie, 2009, vol. 342, # 12, p. 699 - 709
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 12, p. 3491 - 3494
[14] Heterocycles, 2010, vol. 80, # 2, p. 1047 - 1066
[15] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 217 - 224
[16] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4170 - 4177
[17] Tetrahedron Letters, 2014, vol. 55, # 22, p. 3308 - 3311
[18] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3014 - 3017
[19] Medicinal Chemistry, 2014, vol. 10, # 5, p. 506 - 511
[20] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 1021 - 1024
[21] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[22] Patent: CN103755634, 2016, B,
[23] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1135 - 1146
[24] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 926 - 935
[25] RSC Advances, 2018, vol. 8, # 68, p. 38995 - 39004
4
[ 260-94-6 ]
[ 1207-69-8 ]
Reference:
[1] Journal fuer Praktische Chemie (Leipzig), 1901, vol. <2> 64, p. 192
[2] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 48
[3] Chemische Berichte, 1900, vol. 33, p. 3770
[4] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 497 - 509
5
[ 118-91-2 ]
[ 1207-69-8 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 217 - 224
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4170 - 4177
[3] Medicinal Chemistry, 2014, vol. 10, # 5, p. 506 - 511
[4] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 1021 - 1024
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 877 - 885
[7] Patent: CN103755634, 2016, B,
[8] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1135 - 1146
[9] Patent: CN107721925, 2018, A,
6
[ 62-53-3 ]
[ 1207-69-8 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 217 - 224
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4170 - 4177
[3] Medicinal Chemistry, 2014, vol. 10, # 5, p. 506 - 511
[4] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 1021 - 1024
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 877 - 885
[7] Patent: CN103755634, 2016, B,
[8] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 926 - 935
[9] Patent: CN107721925, 2018, A,
[10] RSC Advances, 2018, vol. 8, # 68, p. 38995 - 39004
Add <strong>[1207-69-8]9-chloroacridine</strong> (0.201 g, 0.94 mmol) and phenol to the test tube(1.30 g, 13.8 mmol), heated in a 80C oil bath for 1 hour.The reaction mixture was removed from the oil bath and cooled to room temperature.The reaction mixture was dissolved in dichloromethane (50 ml),And wash them in batches with 1mol/L sodium hydroxide solution (30 ml).Until phenol disappears.The organic phase is washed with saturated sodium chloride solution,Dry with sodium sulfate.After evaporation and pumping dry,That is, the target product was 9-phenoxyacridine 230 mg (light brown solid, yield 90%).
78%
In phenol (1.27 mol), 7.2 g (180 mmol) of sodium hydroxide was dissolved at 100 C, and <strong>[1207-69-8]9-chloroacridine</strong> (28 g, 131 mmol) added with stirring. The solution was kept at 100 C for 1.5 h, then poured into 2 M sodium hydroxide (500 mL), stirred and set aside overnight. The precipitated material was filtered off, washed with water, powdered and dried. The crude product was purified by gravitational column chromatography (eluent toluene/methanol = 10/1 v/v). Yield 78%; the % of elements found/calculated, C 84.19/84.11, H 4.81/4.83, N 5.20/5.16; 1H NMR (DMSO-d6), delta, ppm (J, Hz): 6.88 (2H, d, J = 8.6); 7.08 (1H, t, J = 7.5); 7.32 (2H, t, J = 7.5); 7.59 (2H, t, J = 7.5); 7.88 (2H, t, J = 7.5); 8.04 (2H, d,J = 8.9); 8.23 (2H, d, J = 8.6).
at 60℃;
Initially, compound 4 (1.0 mmol) and phenol (10 mmol) were added to a 100 mL driedround-bottom. The mixture was incubated at 60 C for 1 h under argon atmosphere to give the intermediate 5.
With sulfuric acid; trichlorophosphate; for 12h;Reflux; Inert atmosphere;
A magnetically stirred solution of N-phenylanthranilic acid (5.45 g,26 mmol) in phosphorus oxychloride (100 mL, 1.07 mol) was treated with concentrated sulfuric acid (0.5mL), then 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 ammonium hydroxide. 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 4.67 g (84% yield) of 10 as fine yellow needles having one medium Rf spot by TLC; mp 117-119 C (lit.15 mp 119-120 C); 1H NMR (CDCl3): 8.50-8.10 (m, 4H),7.95-7.50 (m, 4H); IR (THF): 3075, 1622, 1562, 1438, 1404, 1324, 1287, 1014, 831, 767, 647, 608cm-1; Vis (CHCl3): lambdamax (") 360.5 nm (10,000); MS EI: m/e (relative intensity) 215 (33, M++2), 213(100, M+), 178 (21), 177 (16). Anal. Calcd for C13H8ClN: C, 73.07; H, 3.77; N, 6.55; Cl, 16.59. Found: C, 72.99; H, 3.80; N, 6.55; Cl, 16.58.
75%
With trichlorophosphate; at 100℃;
Add 2- (phenylamino) benzoic acid (1.19 mmol) obtained in step 1 to phosphorus oxychloride (10 ml),And refluxed for 3-5 hours at 100 C,The resulting reaction solution is then cooled and slowly added to an ice-water mixture of about 150-200 ml.Then the pH value of the system was adjusted to about 8 with sodium hydroxide solution.After the mixture was stirred at room temperature for 30 minutes,There is a large amount of precipitation,TLC detection (developing solvent is ethyl acetate: petroleum ether = 1: 1).Suction filtration and drying the resulting precipitate,A gray solid powder was obtained, which was 9-chloroacridine.75% yield,
69%
With trichlorophosphate;Reflux;
General procedure: The phenyl amino benzoic acid derivatives (47 mmol) (2a-c) were cyclized intra molecularly to 9-chloroacridine derivatives(3a-c) by refluxing them in 60 mL of POCl3 for 4 h and the reaction was monitored by TLC. After completion, the excess POCl3 was removed by rota evaporator under reduced pressure to the crude reaction mass crushed ice was added, pH was adjusted 7 by adding saturated bicarbonate solution. The solid separated was filtered,dried and purified by flash column chromatography using 5-10% ethyl acetate: hexane as eluent in 60-120 mesh silica gelto get the corresponding 9-chloroacridine derivatives in good yield. These intermediates were confirmed by mass analysis (ESI mode) and proceed to next step.
67%
With trichlorophosphate; at 80℃; for 3.75h;
10 g of <strong>[91-40-7]2-(phenylamino)benzoic acid</strong> (2) was dissolved in 16 ml offreshly distilled phosphorous oxychloride and warmed on a water bathup to 80 C for 15 min. and then refluxed for 3.5 hrs on oil bath. The progress of reaction was monitored constantly using TLC until room temperature. Excess of Phosphorous oxychloride was removed by distillation under reduced pressure. To this, a mixture of ice, ammoniaand chloroform was added with vigorous stirring. The chloroform layerwas separated and the aqueous layer was further extracted with chloroform. The chloroform extracts were combined and dried usingrotary evaporator to get 9-chloroacridine as greenish residue. It was obtained as pure crystals using hexane (Yield 67%) [25].
56%
With trichlorophosphate; at 110℃; for 3h;
In a 100ml eggplant type bottle,N-phenylanthranilic acid (5.0 g, 23.5 mmol) was added,Phosphorus oxychloride (50 ml, 537 mmol). Put it in a 110C oil bath and stir for 3 hours.TLC (developer: dichloromethane/methanol=20/1) detects complete disappearance of compound III-14.Withdraw from the oil bath and naturally cool to room temperature.The reaction mixture was slowly added to 150 g of ice and stirred vigorously. After the heat is released,The pH was adjusted with saturated sodium bicarbonate solution until bubbles ceased to form.After filtration, the filter cake is washed with water 2 or 3 times and drained.This gave the solid, 9-chlorohydrazine, 2.8 g (brown solid, yield 56%).
With trichlorophosphate; at 130℃; for 3h;
General procedure: The crude product of 3a (2.00 g) was dissolved in POCl3 (25 mL) and heated at 130 ºC for 3 h. The reaction mixture was cooled to room temperature and poured into a mixture of crushed ice (150 g), ammonia (150 mL) and chloroform (200 mL) under vigorous stirring. The mixture was separated and the organic phase was evaporated to afford yellow solid. The crude solid was filtered and puri?ed by ethyl acetate.
With trichlorophosphate; at 100℃; for 4h;
2-phenylamino benzoic acid (3) (1.0 mmol) and phosphorus oxychloride (5 mL) were added into a dried round-bottom flask. The mixture was refluxed in 100 oC for 4 h. Then the reaction was cooled to room temperature and poured into a mixture of ammonia (100 mL) and dichloromethane(100 mL) under vigorous agitation. Then the mixture was extracted with dichloromethane (100 mL) for 3 times. The organic extracts were dried over anhydrous Na2SO4 and then the solvents were removed by evaporation to get the crude product 4. The crude product was purified by column chromatography ( petroleum ether : ethyl acetate = 300:1, v/v ) to yield yellow solids.
With trichlorophosphate; at 105℃;
General procedure: The crude products 3 (2.0 g) was dissolved in POCl3 (5 mL) and refluxed at 105 C for 2-4 h. The reaction mixture was cooled to room temperature and poured into a mixture of ammonia (100 mL) and chloroform (100 mL) under vigorous stirring. The mixture was separated and the organic phase was collected. The chloroform was removed by vacuum evaporation to afford yellow solid. The crude solid was purified by recrystallization using petroleum ether.
With trichlorophosphate; In N,N-dimethyl-formamide;Reflux;
General procedure: Different substituent of 2-chlorobenzoic acid 1a-b (6 mM), different substituent of aniline 2a-d (4 mM) in 20 mL DMF were stirred vigorously and then K2CO3 (6 mM) and Cu (1 mM) were added. The reaction was stirred overnight at 130C . Cu was removed by filtration. Water was added with slow stirring and then add HCl (6 mol/L) until pH=4. Precipitate (3a-3e) was formed, which was filtered and drying. Compound 3a-3e in 20 mL DMF were stirred and then add POCl3 (5 mL). The reaction was refluxed 3-5 h. After cooling to room temperature, reaction liquid was slowly added in ice-water with rapid stirring. 20% NaOH was add until pH=8, precipitate was formed. Solids (4a-e) were obtained after filtration and drying, which were used without further purification.
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;
Anhydrous 1,4-dioxidiane was added to mixture of imidazole (6.8 g, 100 mmol) and oil-free sodium hydride (2.4 g, 100 mmol) under nitrogen atmosphere and stired for 6 h at room temperature, then 9-(1-imidazolyl) acridine (4.26 g, 20 mmol) and copper (0.127 g, 2 mmol) were added to the suspension mixture. The mixture was continued to stir for 48 h at 130 C then cooled to room temperature. Solvent was removed under vacuum and water was added to the residue. The solution was extracted with CHCl3 (100 ml×3), and the extracting solution was dried with anhydrous MgSO4. Pure product was obtained through silica gel column Chromatography (ethyl acetate/petroleum ether, 1:1) as yellow solid. Yield: 4.10 g (83.5%), Mp: 220-222C. Anal. Calcd for C16H11N3: C, 78.35; H, 4.52; N, 17.13%; Found: C, 78.31, H, 4.58, N, 17.16%. 1H NMR (CDCl3, TMS): delta (ppm) 7.35-7.36 (t, 1H, J=1.26Hz), 7.47-7.48 (t, 1H, J=1.08Hz), 7.57-7.59 (m, 4H, Acr-H), 7.82-7.86 (m, 3H, Acr-H), 8.30 (t, 1H, J=0.90Hz), 8.32-8.33 (t, 1H, J=0.90Hz), 13C NMR (CDCl3, TMS): delta (ppm) 149.23, 138.98, 138.33, 130.65, 130.10, 129.76, 127.59, 122.89, 122.46, 122.33.
Stage #1: 9-Chloroacridine With phenol at 120℃; for 1h;
Stage #2: N-(3-aminopropyl)-1,4-diaminobutane for 2.5h;
20 Synthesis of Spermidine-Diacridine (Compound 1)
Example 20 Synthesis of Spermidine-Diacridine (Compound 1) Heat a mixture of phenol (3.51 g, 37.3 mmol) and 9-chloroacridine (1.6 g, 7.46 mmol) in an oil bath at 120° C. for 1 h. To this mixture add spermidine (0.54 g, 0.58 mL, 3.73 mmol) and continue heating for another 2.5 h. Pour into 75 mL of 2N NaOH solution and extract with chloroform (2*50 mL). Wash the organic layer with 1N NaOH (1*75 mL), water (2*100 mL), brine (2*100 mL) and dry with MgSO4. Recrystallize the yellow solid thus obtained with ethanol to obtain Compound 1 (30% yield).
27
General procedure: The suitable starting heterocycle (1 mmol), the corresponding amine [1 equiv, except ethylenediamine (4 equiv), imidazole and benzimidazole (2 equiv)] and 2 equiv of phenol were charged in a pressure-tight microwave tube containing a stirring bar. The reaction mixture was submitted to microwave irradiation for 30-45 min at 120 °C, with an irradiation power of 150 W, using a CEM Discover SP focused microwave reactor. The crude mixture was diluted with 5 ml of a 10% KOH aqueous solution and stirred until a precipitate was formed. Filtration afforded a solid was dried overnight in the presence of P2O5 to give the pure final products ;Orange solid; mp: 234 °C; 1H NMR (250 MHz, acetone) δ 8.36 (br s, 1H), 8.04 (s, 2H), 7.55-7.49 (m, 4H), 7.09-7.03 (m, 3H), 6.92 (dd, J=8.3, 2.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 3.70 (s, 3H), 3.01 (s, 3H) ppm; 13C NMR (63 MHz, acetone-d6) δ 150.3 (2C), 143.2 (broad signal, 2C), 134.0, 132.2 (4C), 128.2 (2C), 121.8, 121.8 (broad signal, 2C), 119.9, 115.8 (2C), 107.9 (2C), 56.4, 39.1 ppm; IR (NaCl): ν 3798, 3347, 1560, 1512, 1474, 1321, 1149, 730, 667 cm-1. Elemental analysis calcd (%) for C21H19N3S: C 64.10, H 4.87, N 10.68, S 8.15; found: C 64.39, H 4.98, N 10.85, S 8.29.
5 Production of Methanesulfon-m-anisidide, 4'-(9-acridinylamino)-, monohydrochloride (V)
EXAMPLE 5 Production of Methanesulfon-m-anisidide, 4'-(9-acridinylamino)-, monohydrochloride (V) To a 100-gallon Pfaudler, purged with nitrogen to a measured oxygen depletion of less than 2%, was added methanesulfon-m-anisidide, 4'-amino-(IV) (8709 g; 40.27 moles), methanol (114 l.), and concentrated hydrochloric acid (589 ml). The stirred mixture was heated to 60°, then a solution of 9-chloroacridine (8004 g; 37.46 moles) in chloroform (68.4 l.) was added in a thin stream during 2.25 hours. The mixture was refluxed for 3 hours, cooled to room temperature, then stored for 15 hours under a nitrogen atmosphere. The solid was collected, washed with methanol-chloroform (1:1) (76 l.), then dried to constant weight in vacuo (65°) to give 16100 g (100%) of product; m.p. 284°-288° (d).
With toluene-4-sulfonic acid; In methanol; at 130℃; for 1h;Microwave irradiation;
General procedure: The <strong>[1207-69-8]9-chloroacridine</strong> derivatives (3a-c) (10 mmol) (3a-b) were further reacted with p-phenylenediamine (1.8 g, 10.7 mmol) under microwave conditions in methanol using PTSA (para-toluene sulphonic acid) as a catalyst (5-10 mg) at 130 C for 1 h, reaction was monitored by TLC. After completion of reaction, methanol was evaporated under vacuum the crude was dissolved in ethyl acetate, washed with saturated bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure obtained crude was further purified by flash column chromatography in 60-120 silica gel using 10-35% ethyl acetate: hexane as eluent to get an orange to yellow solid in moderate yields.
With ammonium carbonate; In phenol; at 70 - 120℃; for 2h;
Intermediate compound 1 was dissolved in phenol in a round bottom flask at 70 C, 1 mmol of <strong>[1207-69-8]9-chloroacridine</strong> was added, 2 mmol of ammonium carbonate was added, and the temperature was rapidly raised to 120 C for 2 h, and the reaction was completed and poured into 10 wt. It was filtered, washed with 10 wt% NaHH and water to give a pale yellow solid with strong blue fluorescence. 9-Amino Acridine Intermediate Compound 2, yield 93%.
93%
With ammonium carbonate; In phenol; at 70 - 120℃; for 2h;
Intermediate compound I was dissolved in phenol in a round bottom flask at 70 C with 1 mmol of <strong>[1207-69-8]9-chloroacridine</strong> and 2 mmol of ammonium carbonate was added.Rapidly warm to 120 C for 2 h,Pour into 10% NaOH until the reaction is complete.Filtered and washed with 10% NaOH and water to give a pale yellow solid.Has strong blue fluorescence.9-aminoacridine intermediate compound II,The yield was 93%.
93%
With ammonium carbonate; In phenol; at 70 - 120℃; for 2h;
The intermediate compound I (<strong>[1207-69-8]9-chloroacridine</strong>) was dissolved in phenol in a round bottom flask at 70 C, 1 mmol of <strong>[1207-69-8]9-chloroacridine</strong> was added, 2 mmol of ammonium carbonate was added, and the temperature was rapidly raised to 120 C for 2 h. After the reaction was completed, it was poured into 10% NaOH, filtered, and washed with 10% NaOH and water to give a pale yellow solid, 9-amino acridine intermediate compound II with strong blue fluorescence, yield 93%.
9.5 g
With sodium tetrahydroborate; sodium azide; tetrabutylammomium bromide; In dichloromethane; at 20℃; for 3h;
Intermediate () 10. 68 g (0.05 mol) was dissolved in 500 ml of methylene chloride, and the mass ratio of 1:10A mixed solution of sodium azide and distilled water, and 17.5 g of tetrabutylammonium bromide were placed in a stoppered flat-bottomed flask at room temperatureUnder stirring lh,Then 3 g of sodium borohydride was added and the mixture was stirred for 2 h. The layers were separated and the aqueous phase was extracted twice with methylene chloride.Machine phase, drying, concentration, purification intermediates (f) 9. 5g;
With ammonium carbonate; phenol; at 70 - 120℃; for 2h;
Add 3 mmol of acridinone 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 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 <strong>[1207-69-8]9-chloroacridine</strong>. In a 100 mL round-bottom flask, dissolve 1 mmol of <strong>[1207-69-8]9-chloroacridine</strong> 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;
methyl α-(9-acridinyl)-α-(4-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.2 g (79.4%)
With NaH; In N,N-dimethyl-formamide;
EXAMPLE 7 Methyl alpha-(9-acridinyl)-alpha-(p-chlorophenyl)acetate After a mixture of DMF (250 ml), methyl p-chlorophenylacetate (25.9 g, 140 mmol) and NaH (211 mmol) was stirred at room temperature for 1 hour, 9-chloroacridine (15.0 g, 70.2 mmol) dissolved in 250 ml of DMF was added slowly. The resultant reaction mixture was stirred at room temperature for 18 hours. This reaction mixture was then poured onto 1.5 l. of an ice/H2 O mixture and extracted with CHCl3 (500 ml). The CHCl3 extract was washed with H2 O (3*500 ml) and dried over MgSO4. Evaporation of the CHCl3 extract gave a crude residual solid which was recrystallized from cyclohexane; yield, 20.2 g (79.4%), mp 192-193. Anal. Calcd. for C22 H16 ClNO2 C, H, N, Cl.
methyl α-(9-acridinyl)-3,4-dimethoxyphenylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH; In N,N-dimethyl-formamide;
EXAMPLE 5 Methyl alpha-(9-acridinyl)-3,4-dimethoxyphenylacetate To a mixture of <strong>[15964-79-1]methyl 3,4-dimethoxyphenylacetate</strong> (19.7 g,.094 mol) 0.14 mole of NaH and 250 ml of dry DMF stirred at RT for 1 hour, was added 10.0 g (46.3 mmol) of 9-chloroacridine in 250 ml of DMF. The resultant mixture was stirred at RT for 18 hours, poured onto 1 l. ice/H2 O and extracted with Et2 O (1*500 ml) and CHCl3 (1*500 ml). The combined organics were washed with H2 O (3*500 ml), dried over MgSO4 and evaporated to give a quantitative yield of the crude product. The crude oily residue was triturated with Et2 O-hexane and 16.4 g (90.5%) of solid product mp 148-154 was obtained. The analytical sample was obtained by recrystallization from MeOH/H2 O; yield 14.3 g, mp 157-158. Anal. Calcd. for C24 H21 NO4 C, H, N.
9-(2-aminoanilino)acridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In methanol; at 110℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of the <strong>[1207-69-8]9-chloroacridine</strong> 4a-n (1.0 mmol, 1equiv) and the phenylenediamine 5a-c (2.2mmol, 2.2 equiv) was suspended in MeOH (5 mL) and subjected to microwaveirradiation (generally 110 C, 10 min). The reaction mixture was allowed tocool slowly to room temperature giving a red liquid often with a red/orangeprecipitate forming. The mixture was then slowly transferred into rapidlystirred Et2O (200 mL) washing in any solid from the vial withfurther MeOH (2×2.5 mL). After stirring for 5 min, the solid was isolated byvacuum filtration, washed (3×20 mL Et2O) and dried giving theproducts 6a-n (as HCl salts) generallyin the form of orange/red solids.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 40℃; for 3h;
In a 250 mL three-necked flask, 21.4 g (0.1 mol) of 9-chloroacridine, 14.6 g (0.12 mol) of phenylboronic acid, 0.11 g of Pd (PPh3) 4 catalyst, 100 g of toluene, 2 g of sodium carbonate, and 18 g of deionized water were sequentially added. , Heated to 40 C., reacted for 3 hours, cooled to 25 C., removed the solvent by rotary evaporation, washed with 100 g of methanol and dispersed, and filtered to obtain a crude product. The crude product was purified with 80 g of toluene and dried to obtain 24.7 g of the product, a yield of 96.8%. HPLC The content is 99.65%.
3-(9-acridinylamino)-5-hydroxymethylphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.6%
With 4-methyl-morpholine; In ethanol; chloroform; at -5 - 0℃; for 3.5h;
3-(Acridin-9-ylamino)-5-hydroxymethylphenol (76) A solution of <strong>[1207-69-8]9-chloroacridine</strong> (8.56 g, 40.0 mmol) in CHCl3 (30 mL) was added dropwise to a solution of 3-amino-5-hydroxymethylphenol (7.03 g, 40 mmol) and 4-methylmorpholine (4.2 ml g, 40 mmol) in EtOH (150 mL) at -5 C. during 2.5 h. The reaction mixture was stirred for additional 1 h in an ice bath and then concentrated in vacuo to dryness and the residue was crystallized from ethanol to give 76; 4.73 g. Additional product, 4.97 g, was obtained from mother liquid after chromatography (SiO2, 6*30 cm, solvent: CHCl3: MeOH, 10:1 v/v); total 9.69 g (75.6%); mp 201-202 C.; 1H NMR (DMSO-d6) delta 4.43 (2H, s. CH2), 5.23 (1H, brs, exchangeable, OH), 6.69 (1H, s, ArH), 6.80 (1H, s, ArH), 6.83 (1H, s, ArH), 7.45 (2H, m, 2*ArH), 7.99 (2H, m, 2*ArH), 8.10 (2H, m, 2*ArH), 8.29 (2H, m, 2*ArH), 9.88 (1H, brs, exchangeable, NH or OH), 11.43 (1H, br, exchangeable, NH or OH). Anal. Calcd. for C20H15N2O2·HCl·0.6H2O: C, 65.84; H, 5.07; N, 7.68. Found. C, 65.86; H, 5.12; N, 7.51.
5-(9-acridinylamino)-m-toluidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With 4-methyl-morpholine; In methanol; chloroform; at -10 - 20℃; for 4h;
A solution of <strong>[1207-69-8]9-chloroacridine</strong> (4.27 g; 20 mmol) in CHCl3 (20 mL) was added dropwise to a mixture of 3,5-diaminotoluene hydrochloride (3.90 g; 20 mmol) and 4-methylmorpholine (4.4 mL; 40.mmol) in MeOH (50 mL) at -10-5 C. After being stirred for 1 hour, the temperature was raised to room temperature and was continuously stirred for additional 3 hours. The orange precipitated product was collected by filtration, washed with EtOH and recrystallized from MeOH/CHCl3 to give 3-(9-acridinylamino)-p)-toluidine hydrochloride, 4.85 g (85%): mp >280 C. (dec); 1H NMR (DMSO-d6) delta 2.26 (3H, s, ArMe), 6.90 (2H, s, ArH), 6.95 (1H, s, ArH), 7.48 (2H, m, 2×ArH), 8.02 (2H, m, 2×ArH), 8.16 (2H, m, 2xArH), 8.33 (2H, m, 2×ArH), 10.05 and 11.53 (each 1H, brs, exchangeable, NH). Calculated for C20H17N3.2HCl.1.75H2O: C, 59.48; H, 5.62; N, 10.41. Found: C, 59.58; H, 5.61; N, 10.02.
9-(10-naphthalen-2-yl-anthracen-9-yl)-acridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 6h;Heating / reflux;
One point three grams (6.1 mmol) of 9-chloro-acridine, 2.0 g (5.7 mmol) of 10-naphthalen-2-yl-anthrathene-9-boronic acid and 0.10 g of tetrakis (triphenylphosphine) palladium into 20 milliliter of 1,2-dimethoxyethane, and adding 8 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, the precipitated solids were dissolved into the dichloro-methane, washed with water and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the resultant substance was washed with methanol thereby obtaining 2.16 g of yellowish white solid (yield: 74 %). As a result of mass spectrum (MS) analysis, the yellowish white solids were identified as the aimed substance (Compound 13-4), and it was recognized that m/e= 481 for molecular weight of 481.18.
acridin-9-yl-[4-(piperidin-1-yl)phenyl]amine[ No CAS ]
[ 2359-60-6 ]
Yield
Reaction Conditions
Operation in experiment
6%
Following the procedure outlined in Step 2 of Example 1, but substituting 4-piperidin-1-yl-1-nitrobenzene for 1-methyl-4-(4-nitrophenyl)piperazine, afforded 4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine (according to Step 4 in the procedure of Example 1) to obtain the title compound with 6% overall yield. 1H NMR (CDCl3, 500 MHz): 8.05 (2H, m), 8.00 (2H, m), 7.48 (2H, m), 7.09 (4H, m), 6.86 (2H, m), 3.13 (4H, m), 1.71 (4H, m), 1.58 (2H, m); MS (ESI+TOF): 354 (M+)
Example 18 (R)-3-(Acridin-9-ylamino)propane-1,2-diol (Compound 5a) 9-chloro-acridine (1 g, 4.68 mmol) and (R)-3-amino-propane-1,2-diol (0.42 g, 4.68 mmol) in 2-ethoxyethanol (40 ml) was heated at 120 C. for 30 min. Removal of the solvent yielded the desired compound (0.9 g, 75%) as a yellow solid. HPLC (conditions in example 1) single peak of retention time 8.4 min. 1H-NMR [MeOD delta, ppm]: 8.01 (m, 2H), 7.84 (m, 2H), 7.60 (m, 2H), 4.37-4.28 (m, 2H, (CH2NH), 4.17 (m, 1H, CHOH), 3.82-3.75 (m, 2H, CH2OH). MS (Cl/NH3) found 269.1, expected for C16H16N2O2 268.3.
General procedure: Various amines (2.00 mmol) were dissolved in absolute alcohol (15 mL) and then potassium carbonate (2.00 mmol) was added.The mixture was stirred for 45 min at room temperature. The compound 4(a-f) (1.00 mmol) and potassium iodide (0.25 mmol) were added. The mixture was stirred and refluxed overnight. Then the mixture was poured into water (50 mL), extracted with ethyl acetate to give the crude product. The crude product was purified by column chromatography using petroleum ether and ethyl acetate (5:1 v/v).
To a suspension of NaH (60% in mineral oil, 80 mg) in 10 mL of DMF was added benzamide (2.00 mmol) and the mixture was stirred at room temperature for 15 min. To the resultant yellow solution was added 4b (1.00 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled and added to a mixture of 1 M HCl and ethyl acetate. The mixture was filtered and the crude product was purified by column chromatography using petroleum ether and ethyl acetate (10:1 v/v). Yield 75%; mp 166-169 C; 1H NMR (400 MHz, DMSO-d6) delta 8.18 (d, J = 20.0 Hz, 2H),8.05-7.78 (m, 5H), 7.68 (d, J = 42.1 Hz, 1H), 7.57-7.26 (m, 6H). 13C NMR (101 MHz, DMSO-d6) delta 167.87, 134.27, 133.37, 132.12,131.12, 128.60, 128.12, 127.40, 125.98, 120.94, 117.27, 106.57; HR-MS(ESI): calcd for C20H14N2O [M+H]+ 299.1184; found:299.1188.
N-((1H-benzo[d]imidazol-2-yl)methyl)acridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N,N'-trans,trans-methylenedi-4,1-cyclohexanediyl-bis(9-acridinamine)[ No CAS ]
N,N'-cis,cis-methylenedi-4,1-cyclohexanediyl-bis(9-acridinamine)[ No CAS ]
N,N'-cis,trans-methylenedi-(4,1-cyclohexanediyl)-bis(9-acridin-amine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In phenol; at 80℃; for 4h;Inert atmosphere;
A magnetically stirredsolution of 9-chloroacridine (10) (0.51 g, 2.39 mol) and <strong>[1761-71-3]4,4'-diaminodicyclohexylmethane</strong> (0.13 g, 0.62mmol) was warmed at 80 C in phenol (20 g, 0.21 mol) for 4 h. After being cooled to rt, the solidifiedyellow-orange reaction mixture was dissolved in chloroform (100 mL) and extracted with 0.1 N NaOH (2x 100 mL), water (3 x 100 mL), and brine (1 x 100 mL). The organic phase was separated, dried overanhydrous sodium sulfate, and then concentrated in vacuo to afford, after flash chromatography (silicagel/95% ethyl ether, 5% triethylamine), a bright yellow, hygroscopic solid. The solid was recrystallizedfrom THF/hexane and dried in vacuo at 40 C for 2 d to give 0.25 g (71%) of 14-16 as a yellow powdershowing a single, very low Rf spot by TLC; 1H NMR (60 MHz, CF3COOD): 8.45-7.20 (m, 16H),2.70-1.25 (m, 22H); IR (THF): 3578, 3508, 3352, 1631, 1565, 1526, 1428, 1356, 1077, 766 cm-1; Vis(CHCl3): max (") 398.5 nm (15,400); MS FAB: m/e 565 (MH+). Anal. Calcd for C39H40N4?1/2 H2O:C, 81.64; H, 7.20; N, 9.76. Found: C, 81.53; H, 7.39; N, 9.36. In vitro L1210: ID50 = 0.09 muM(Vermont).
With hydrogenchloride; In ethanol; chloroform; water; at 20℃; for 12h;Cooling with ice;
The compound 2-methoxy-4-nitroaniline 96 mg (0.57 mmol) was dissolved in 7 mL of absolute ethanol,2 drops of concentrated hydrochloric acid (about 0.05 mL) were added dropwise to the ice bath,A solution of <strong>[1207-69-8]9-chloroacridine</strong> 76 mg (0.35 mmol) was dissolved in 13 mL of chloroform,Dropping into the solution dropwise,Ice bath for 10 minutes,Place room temperature overnight (reaction time is 12h).Filter,The resulting precipitate was washed with saturated aqueous Na2C03,Extracted with dichloromethane,The solvent is distilled off,dry,The crude product was separated by column chromatography (eluent: ^ 2: = 3: 1) to give compound 2 in 68.2% yield.
With palladium diacetate; sodium carbonate; In water; toluene; at 40℃; for 3h;
In a 250 mL three-necked flask, 21.4 g (0.1 mol) of <strong>[1207-69-8]9-chloroacridine</strong>, 16.3 g (0.12 mol) of 3-methylphenylboronic acid, 0.11 g of Pd (OAc) 2 catalyst, 100 g of toluene, and 2 g of sodium carbonate were sequentially added. 18 g of deionized water, heated to 40 C., reacted for 3 hours, cooled to 25 C., removed the solvent by rotary evaporation, washed with 100 g of methanol and dispersed, and filtered to obtain a crude product. The crude product was refined with 80 g of toluene, and dried to obtain 26.1 g of the product, yield 96.9%, HPLC content 99.69%.
N-(acridin-9(10H)-ylidene)-4-propylbenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 20 - 80℃; for 3h; Inert atmosphere;
4.4 General synthesis of 3a-3o using palladium catalysis
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80°C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-2,4,6-trimethylbenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 20 - 80℃; for 15h; Inert atmosphere;
4.4 General synthesis of 3a-3o using palladium catalysis
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80°C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-4-methoxybenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 20 - 80℃; for 16h; Inert atmosphere;
4.4 General synthesis of 3a-3o using palladium catalysis
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80°C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-4-fluorobenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 20 - 80℃; for 12h;Inert atmosphere;
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-4-nitrobenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 20 - 80℃; for 12h; Inert atmosphere;
4.4 General synthesis of 3a-3o using palladium catalysis
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80°C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-3-nitrobenzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 20 - 80℃; for 16h;Inert atmosphere;
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)-4-(trifluoromethyl)benzenesulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 20 - 80℃; for 12h;Inert atmosphere;
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)naphthalene-1-sulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 20 - 80℃; for 14h;Inert atmosphere;
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)naphthalene-2-sulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 20 - 80℃; for 17h; Inert atmosphere;
4.4 General synthesis of 3a-3o using palladium catalysis
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80°C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
N-(acridin-9(10H)-ylidene)quinoline-8-sulfonimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 20 - 80℃; for 13h;Inert atmosphere;
General procedure: A dry round bottom flask was cooled to rt under nitrogen, and was charged with Pd2(dba)3 (3.38mg, 0.0037mmol), cesium carbonate (361mg, 1.11mmol), and arenesulfonamide (69mg, 0.44mmol). Tertiary-butanol (2mL) was added, followed by ligand, xantphos (6.4mg, 0.011mmol) and 9-chloroacridine (80mg, 0.37mmol). The resulting suspension was stirred at rt for 5min, then heated to 80C for 12-17h. The reaction mixture was then cooled to rt and filtered through suction filtration. The organic fraction was evaporated, and the resulting residue was purified by silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
O-(4-nitrobenzyl)-N-(9'-acridinyl)hydroxylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate; In phenol; at 80 - 100℃;
General procedure: The appropriate salt, 4a-l, (7.02x10-4 mol) was treated with commercially available 9-chloroacridine (5) (4.68x10-4 mol). The reaction was carried out in molten phenol using 3.0 grams of phenol per gram of 9-chloroacridine (5). The reaction was heated between 80-100 C for a period of 6-8 hours, then cooled to room temperature and dissolved in CH2Cl2. The resulting orange or red organic solution was washed repeatedly with 0.25 M NaOH until greater than a 1:1 molar ratio of hydroxide to phenol was used. The organic phase was then washed with water (once) and brine (once). The organic layer was dried over anhydrous sodium sulfate, gravity filtered, and concentrated to a final volume of approximately 1 mL. This sample was then transferred to the top of a 5-cm column of silica gel constructed from a 10-mL syringe barrel and eluted with ethyl acetate. The orange filtrate was collected, concentrated to a final volume of 0.5-1.0 mL, and subjected to radial chromatography (2mm plate, silica gel, CH2Cl2:Et2O 100:0 to 90:10 gradient elution). Compounds 6a-l were obtained in pure form by evaporation of the solvent from the bands that eluted.
General procedure: A mixture of 9-chloroacridine derivatives1a or 1b(1.0 equiv) and 3-(4-aminophenyl)propanoicacid 9(1.0 equiv) were heated in phenol under 120 oC for 2 h under nitrogen atmosphere. Then the mixture was poured into ether to get yellow precipitation. The yellow precipitation was washed with ethyl acetate twice and sodium bicarbonate solution onceto get pure 10a-10b.A few drops of sulfoxide chloride (2.0 equiv) were added dropwise to the methanol solution of 10aor10b(1.0 equiv).The reaction mixture was stirred at room temperature for 2 h. Concentration in vacuo gave crude product. The crude product was dissolved in DCM and concentrated three times repeatedly to get 11a-11b.
4-(3-(4-(acridin-9-yl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In phenol; at 60 - 120℃; for 2.5h;Inert atmosphere;
General procedure: Intermediates 8 (1 eq) and respective 9-chloroacridine derivatives 4a-4f (1.1 eq) were added to a round flask, and then excessphenol was added as solvent. The reaction system was warmed up to 60 C until phenol was melted and stirred for 0.5 h under argonprotection. Then the mixture was warmed up to 120 C and continued to reaction for more 2 h. After the reaction was completed, themixture was added to ethyl ether drop by drop [2]. The precipitate was filtered and washed twice with new ethyl ether to give pureproducts 9a-9f, which were then characterized by 1H NMR, 13C NMR, melting point and high resolution mass spectrum (HRMS, ESI).
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.
With sodium carbonate; palladium dichloride; In water; toluene; at 50℃; for 4h;
In a 250 mL three-necked flask, 21.4 g (0.1 mol) of 9-chloroacridine, 20.7 g (0.14 mol) of <strong>[15016-43-0]3-vinylphenylboronic acid</strong>, 0.12 g of PdCl2 catalyst, 100 g of toluene, 2 g of potassium carbonate, and 18 g of deionized water were sequentially added. , Heating to 50 C, reacting for 4 hours, cooling to 25 C, removing the solvent by rotary evaporation, adding 100g of methanol to wash and disperse, suction filtration to obtain a crude product, refining the crude product with 80g toluene, and drying to obtain 27.1g of the product, a yield of 96.5%, HPLC The content is 99.58%.
With bis(triphenylphosphine)palladium(II) dichloride; sodium carbonate; In water; toluene; at 50℃; for 4h;
In a 250 mL three-necked flask, 21.4 g (0.1 mol) of <strong>[1207-69-8]9-chloroacridine</strong>, 20.4 g (0.14 mol) of 3-ethynylphenylboronic acid, 0.12 g of PdCl2 (PPh3) 4 catalyst, 100 g of toluene, and 2 g of potassium carbonate were added in this order. 18g of deionized water, heated to 50 C, reacted for 4 hours, cooled to 25 C, removed the solvent by rotary evaporation, added 100g of methanol to wash and disperse, suction-filtered to obtain a crude product, the crude product was purified with 80g toluene, and dried to obtain 27.1g of the product, yield 97.1%, HPLC content 99.66%.
With [1,4-bis(diphenylphosphino)butane] palladium(ll) dichloride; sodium carbonate; In water; toluene; at 60℃; for 5h;
In a 250 mL three-necked flask, 21.4 g (0.1 mol) of 9-chloroacridine, 18.0 g (0.11 mol) of <strong>[216019-28-2]3-isopropylphenylboronic acid</strong>, 0.11 g of PdCl2 (dppb) catalyst, 100 g of toluene, and 2 g of sodium carbonate were sequentially added. 18 g of deionized water, heated to 60 C., reacted for 5 hours, cooled to 25 C., removed the solvent by rotary evaporation, washed with 100 g of methanol and dispersed, and filtered to obtain a crude product. The crude product was refined with 80 g of toluene and dried to obtain 28.9 g of the product in a yield 97.3%, HPLC content 99.57%.
N-hydroxy-3-(acridin-9-ylamino)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogenchloride; In 2-methoxy-ethanol; water; at 0 - 20℃;
General procedure: To a solution of compound 4a (72 mg, 0.47 mmol) and <strong>[1207-69-8]9-chloroacridine</strong> 5 (100 mg, 0.47 mmol) in CH3O(CH2)2OH (1 mL)was added two drops of 12N HCl(aq). The resulting solution wasstirred at RT and then concentrated in vacuo. The residue wasdiluted with distd H2O (10 mL), neutralized with 1 N HCl(aq) to pH 7,and extracted with EtOAc (30 mL 3). The organic layer was driedover Na2SO4 and filtered the solvent was then removed in vacuo.The residue was recrystallized from MeOH-THF (1: 9) to give 6a(64 mg, 41%) as a solid.
N-hydroxy-4-(acridin-9-ylamino)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With hydrogenchloride; In 2-methoxy-ethanol; water; at 0 - 20℃;
To a solution of compound 4a (72 mg, 0.47 mmol) and <strong>[1207-69-8]9-chloroacridine</strong> 5 (100 mg, 0.47 mmol) in CH3O(CH2)2OH (1 mL)was added two drops of 12N HCl(aq). The resulting solution wasstirred at RT and then concentrated in vacuo. The residue wasdiluted with distd H2O (10 mL), neutralized with 1 N HCl(aq) to pH 7,and extracted with EtOAc (30 mL 3). The organic layer was driedover Na2SO4 and filtered the solvent was then removed in vacuo.The residue was recrystallized from MeOH-THF (1: 9) to give 6a(64 mg, 41%) as a solid. Mp 202-205 C. IR (KBr) 3417, 3199, 1629,1518, 1338, 1152 cm1. 1H NMR (500 MHz, DMSO-d6) d 15.07(s, 1H),11.62(s, 1H), 11.32(s, 1H), 8.29(d, J 8.8 Hz, 2H), 8.16 (d, J 8.8 Hz,2H), 8.04 (t, J 7.4 Hz, 2H), 7.86 (d, J 8.8 Hz, 2H), 7.51 (d, J 7.4 Hz,2H), 7.48 (d, J 8.8 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) d 163.3,154.8, 140.2, 135.4, 133.4, 130.3, 128.4, 125.8, 124.1, 123.2, 119.4,114.6. HRMS-ESI: m/z [MH] caclcd for C20H16O2N3 330.1243,found 330.1237.
N-hydroxy-2-(4-(acridin-9-ylamino)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With hydrogenchloride; In 2-methoxy-ethanol; water; at 0 - 20℃;
General procedure: To a solution of compound 4a (72 mg, 0.47 mmol) and <strong>[1207-69-8]9-chloroacridine</strong> 5 (100 mg, 0.47 mmol) in CH3O(CH2)2OH (1 mL)was added two drops of 12N HCl(aq). The resulting solution wasstirred at RT and then concentrated in vacuo. The residue wasdiluted with distd H2O (10 mL), neutralized with 1 N HCl(aq) to pH 7,and extracted with EtOAc (30 mL 3). The organic layer was driedover Na2SO4 and filtered the solvent was then removed in vacuo.The residue was recrystallized from MeOH-THF (1: 9) to give 6a(64 mg, 41%) as a solid.
3-(4-(acridin-9-ylamino)phenyl)-N-hydroxypropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With hydrogenchloride; In 2-methoxy-ethanol; water; at 0 - 20℃;
General procedure: To a solution of compound 4a (72 mg, 0.47 mmol) and <strong>[1207-69-8]9-chloroacridine</strong> 5 (100 mg, 0.47 mmol) in CH3O(CH2)2OH (1 mL)was added two drops of 12N HCl(aq). The resulting solution wasstirred at RT and then concentrated in vacuo. The residue wasdiluted with distd H2O (10 mL), neutralized with 1 N HCl(aq) to pH 7,and extracted with EtOAc (30 mL 3). The organic layer was driedover Na2SO4 and filtered the solvent was then removed in vacuo.The residue was recrystallized from MeOH-THF (1: 9) to give 6a(64 mg, 41%) as a solid.