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CAS No. : | 1556-34-9 | MDL No. : | MFCD01321146 |
Formula : | C14H10BrN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MZFYKBHQWLWIBI-UHFFFAOYSA-N |
M.W : | 272.14 | Pubchem ID : | 150930 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 14 |
Fraction Csp3 : | 0.07 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 72.09 |
TPSA : | 12.89 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.06 cm/s |
Log Po/w (iLOGP) : | 2.6 |
Log Po/w (XLOGP3) : | 4.09 |
Log Po/w (WLOGP) : | 4.13 |
Log Po/w (MLOGP) : | 3.71 |
Log Po/w (SILICOS-IT) : | 4.5 |
Consensus Log Po/w : | 3.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.69 |
Solubility : | 0.00561 mg/ml ; 0.0000206 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.07 |
Solubility : | 0.0234 mg/ml ; 0.0000859 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.63 |
Solubility : | 0.0000634 mg/ml ; 0.000000233 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 | UN#: | 3261 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 5h; Heating; | |
95% | With N-Bromosuccinimide; dibenzoyl peroxide In 1,1,2,2-tetrachloroethylene at 20 - 60℃; for 5h; Large scale; Further stages; | 1-6 Example 6 The preparation method of 9-bromomethyl acridine After mixing (60kg) 9-methylacridine and (300kg) tetrachloroethylene at room temperature, add (38kg) N bromosuccinimide and (3kg) BPO under stirring, and stir for 60min For dispersion, the temperature is raised to 40°C, and the reaction is kept for 1 hour. (2) Then the temperature was increased to 55C and the reaction was incubated for 1h.(3) After that, the temperature was lowered to 25° C., N-bromosuccinimide was added (18.8 kg), and the temperature was raised to 60° C. and the reaction was incubated, TLCCentral control, the reaction is complete in 2h.[0060] (4) Cool down to 25° C. and keep the temperature for 1 h. The solid obtained by filtration is the crude 9-bromomethyl acridine, which is then added to the crude product.Add (240kg) 50% methanol aqueous solution, heat up to 20°C, after keeping it for 3h, decrease the temperature to 25°C, keep it warm and stir for 2h, filter and dryObtained a yellow solid powder of 9-bromomethylacridine (81.2kg, purity 98.9%, yield 95.0%) |
87% | Stage #1: 9-methyl-acridine With 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 60℃; for 0.5h; Stage #2: With N-Bromosuccinimide In tetrachloromethane at 60 - 80℃; for 4h; | 5.2.10 9-(Bromomethyl)acridine (12) To a solution of 11 (2.0g, 10.4mmol) in CCl4 (100mL) was added AIBN (0.17g, 1.0mmol) and heated to 60°C under stirring for 30min. Then NBS (0.17g, 11.4mmol) was added and the reaction mixture was heated under refluxing conditions for 4h. After completion of the reaction, the reaction solution was diluted with CH2Cl2. The organic layer was separated, dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel using petroleum ether/EtOAc (5/1) as eluent to afford intermediate 12 (2.45g) in 87% yield. 1H NMR (400MHz, DMSO-d6) δ 8.85 (d, J=8.8Hz, 1H), 8.29 (d, J=8.6Hz, 4H), 7.98-7.94 (m, 2H), 7.80 (d, J=7.7Hz, 1H), 5.89 (s, 2H). MS (ESI) m/z calcd for C14H10BrN [M+ H]+, 272.0, found: 274.3. |
87% | Stage #1: 9-methyl-acridine With 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 60℃; for 0.5h; Stage #2: With N-Bromosuccinimide In tetrachloromethane for 4h; Reflux; | 7 Example 7: Preparation of 9-(bromomethyl)acridine (9) The intermediate 9-methylacridine (2.0 g, 10.4 mmol) prepared in Example 6 was weighed, 100 mL of carbon tetrachloride was added as a solvent, and the temperature was raised to 60°C. Then, azobisisobutyronitrile (0.17 g, 1.0 mmol) was added as an initiator to the solution, and the mixture was stirred at this temperature for 30 min. Then N-bromosuccinimide (0.17g, 11.4mmol) was added, and the temperature was raised to a reflux state, and heating was continued for 4h. After the completion of the reaction was monitored by TLC, dichloromethane was added to dilute. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Then, it was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain 2.45 g of intermediate 9 with a yield of 87%. |
80% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 6h; Irradiation; | |
77% | With N-Bromosuccinimide In dichloromethane | 9-(bromomethyl)acridine (10) 9-(bromomethyl)acridine (10) To a solution of 9-methylacridine (1.93 g, 10 mmol) in dichloromethane (100 mL) was added NBS (1.78 g, 10 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 10 (2.08 g) in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.8 Hz, 4H), 7.81 (t, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 2H), 5.42 (s, 2H). 13C NMR (400 MHz, CDCl3) δ 148.9, 138.7, 130.5, 130.1, 126.8, 123.8, 123.4, 23.1. MS (FAB) m/z Calcd for C14H10BrN 272.1. Found 2722. [M]+. |
77% | With N-Bromosuccinimide In dichloromethane at 20℃; Cooling with ice; | [0115] To a solution of 9-methylacridine (1.93 g, 10 mmol) in dichloromethane (100 mE) was added N135 (1.78 g, 10 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1 :5) as eluent to afford 10(2.08 g) in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.8 Hz, 4H), 7.81 (t, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 2H), 5.42 (s, 2H). 13C NMR (400 MHz, CDCl3)δ148.9,138.7, 130.5, 130.1,126.8,123.8,123.4,23.1. MS (FAI3)mlz Calcd for C,4H,0BrN 272.1. Found 2722. [M]+. |
77% | With N-Bromosuccinimide In dichloromethane at 20℃; Cooling with ice; | 9-Bromomethylacridine (2) To a solution of 9-methylacridine (0.193 g, 1 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (0.178 g, 1 mmol) portionwise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulphate, and the solvent was removed. The residue was purified by column chromatography (eluent ethyl acetate/petroleum ether = 1/5 v/v). Yield 77%; the % of elementsfound/calculated, C 61.26/61.79, H 3.64/3.70, N 5.03/5.15; 1H NMR (CDCl3), δ, ppm (J, Hz): 5.38 (2H, s); 7.62 (2H, t, J = 7.7); 7.78 (2H, t, J = 7.7); 8.31 (4H, d, J = 8.8). |
With tetrachloromethane; N-Bromosuccinimide; dibenzoyl peroxide | ||
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane Reflux; | ||
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2h; Reflux; | ||
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 6h; | ||
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In acetone at 0℃; for 0.5h; | |
With benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile for 12h; Ambient temperature; | ||
In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | for 4h; Reflux; | [0116] The mixture of 10 (1.5 g, 5.5 mmol) and triethyl phosphite (2 mE) was heated to reflux for 4 h. After cooling down to room temperature, the excess triethyl phosphite was removed under vacuum to afford 11(1.7 g) in 94% yield. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.8 Hz, 2H), 8.17 (d, J=8.8 Hz, 2H), 7.72 (t, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 4.13 (d, J=24 Hz, 2H), 3.92-3.77 (m, 4H), 1.04 (t, J=7.2 Hz,6H). 13C NMR (400 MHz, CDCl3) δ 148.4, 148.3, 135.8,135.7, 129.9, 129.8, 125.8, 125.3, 125.2, 124.9, 124.8, 62.4,27.5, 26.1, 16.1. |
92% | for 4h; Reflux; | 5.2.11 Diethyl (acridin-9-ylmethyl)phosphonate (13) The mixture of 12 (1.0g, 3.7mmol) and triethyl phosphite (4mL) was heated to reflux for 4h. After cooling down to room temperature, the excess triethyl phosphite was removed under reduced pressure to afford intermediate 13 (1.1g) in a 92% yield. |
92% | for 4h; Reflux; | 8 Example 8: Preparation of diethyl (acridine-9-methyl)phosphonate (10) Weigh out the intermediate 9-(bromomethyl)acridine (1.0 g, 3.7 mmol) prepared in Example 7 above, and dissolve it in 4 mL of triethyl phosphite, heat the reaction solution to reflux, and react for 4 hours. After the completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove excess triethyl phosphite to obtain 1.1 g of an oily substance, namely Intermediate 10, with a yield of 92%. |
for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sodium hydroxide; tetrabutyl-ammonium chloride In dichloromethane; water at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In acetonitrile at 30℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In acetonitrile at 30℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | at 120℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min | ||
Multi-step reaction with 2 steps 1.1: sodium; 2-nitropropane / methanol; dimethyl sulfoxide / 20 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / -10 °C 2.2: 13 h / -10 - 20 °C | ||
Multi-step reaction with 2 steps 1: 4 h / Reflux 2: sodium hydride / mineral oil; tetrahydrofuran / 20 °C / Cooling with ice |
Multi-step reaction with 2 steps 1: 4 h / Reflux 2: sodium hydride / tetrahydrofuran; mineral oil / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 4 h / Heating 2: 1.) NaH, 15-crown-5, 2.) EtOH / 1.) THF, 2 h, r. t., 2.) reflux, 30 min 3: 89 percent / SnCl2 / 96 h / Heating 4: acetone / 12 °C / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ethanol 2: water; ethanol; NaOH-solution | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 6 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 6 h / 20 °C 2: acetonitrile; water / Photolysis |
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 6 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 6 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 6 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 7 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 7 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 8 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 8 h / 20 °C 2: acetonitrile; water / Photolysis | ||
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 9 h / 20 °C 2: acetonitrile; water / Photolysis |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethanol | 13 EXAMPLE 13, 2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol dihydochoride EXAMPLE 13 2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol dihydochoride Bromination of 9-methylacridine (Lancaster Synthesis Ltd., P.O. Box 1000, Industrial Drive, Wyndham, NH 03087) by the procedure of A. Campbell et al , J . Chem . Soc . 1145 (1958) gave 9-bromomethylacridine. To a round bottomed flask equipped with magnetic stirring bar, condenser, and nitrogen inlet tube and bubbler was added 9-bromomethylacridine (10.5g, 38.58 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich Chemical Co., Milwaukee, WI, 53201, 4.06g, 38.58 mmol), anhydrons potassium carbonate (Mallinckrodt Co., St. Louis, MO, 53147, 10.50g, 76.0 mmol) and abs. ethanol (150 ML). The mixture was refluxed for 4 hours, cooled and filtered. The solvent was then removed by rotary evaporation. The crude product was dissolved in methanol (200 ML) filtered again and diluted to 2L with diethyl ether. The dark coloured crude product wasthen recrystallized one additional time from methanol+/diethyl ether and then twice from methanol to give 2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol 0.6H2 mp 210-211°(d), which analyzed correctly for the assigned strucure (C,H,N,Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 60℃; for 24h; | 1 In a 40 mL vial, 9-(bromomethyl)acridine (272 mg, 1 mmol) in 10 mL CH3CN (suspension) was added to a solution of 2-(pyridin-2-yl)hydrazine (327 mg, 3 mmol). The reaction mixture was heated and magnetically stirred (60 °C oil bath) for 24 hours. The reaction initially turned clear but soon became cloudy, and remained so throughout the reaction. At the end of the reaction, the mixture was cooled to room EPO temperature and filtered to collect crude product. The crude product was washed with CH2Cl2 and dried, leaving the pure desired product (Calc'd for C19H16N4: 300.1, [M- H]+ found: 299.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine at 40℃; for 8h; | 1 To a solution of 9-bromomethylacridine (0.2 g, 0.7 mmo) in 4 mL of DMF was added diisopropylethylamine (0.14 g, 1.1 mmol, 0.2 mL) and 3-isopropyl-1-pheynyl-1H- pyrazol-5-amine (0.18 g, 0.9 mmol). The reaction was stirred at 40 °C for 8 h. Upon cooling, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was washed with EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. The crude material was purified by silica chromatography (0-40% Hexanes/EtOAc) to afford the desired product. (Calc'd for C26H24N4: 392.5, [M+H]+ found: 393) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.3% | In methanol; ethanol | 13 2-[(9-Acridinylmethyl)amino]-2methyl-1,3-propanediol dihydrochloride To a RB flask equipped with magnetic stirring bar, condenser, and N2 inlet line with bubbler was added 9-bromomethylacridine (10.5 g, 39.58 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 4.06 g, 38.58 mmol), anhydrous K2 CO3 (Mallinckrodt, 10.50 g, 76.0 mmol) and abs. EtOH (250 mL). The mixture was refluxed for 4 h, cooled and filtered. The solvent was then removed by rotary evaporation. The crude product was dissolved in CH3 OH (200 mL) filtered again and diluted to 2 L with Et2 O. The dark colored crude product was then recrystallized one additional time from CH3 OH/Et2 O and then twice from CH3 OH to give 3.46 g (24.3% yield) of 2-[(9-acridinylmethyl)amino]-2-methyl-1,3-propanediol dihydrochloride 0.6 H2 O, mp 210°-211° (dec), (C,H,N,Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 2-nitropropane; sodium In methanol; dimethyl sulfoxide at 20℃; | |
With methanol; 2-nitropropane; sodium In N,N-dimethyl-formamide at 20℃; | ||
With 2-nitropropane; sodium In dimethyl sulfoxide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethyl phosphite | Diethyl acridin-9-ylmethylphosphonate (11) Diethyl acridin-9-ylmethylphosphonate (11) The mixture of 10 (1.5 g, 5.5 mmol) and triethyl phosphite (2 mL) was heated to reflux for 4 h. After cooling down to room temperature, the excess triethyl phosphite was removed under vacuum to afford 11 (1.7 g) in 94% yield. NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.8 Hz, 2H), 8.17 (d, J=8.8 Hz, 2H), 7.72 (t, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 4.13 (d, J=24 Hz, 2H), 3.92-3.77 (m, 4H), 1.04 (t, J=7.2 Hz, 6H). 13C NMR (400 MHz, CDCl3) δ 148.4, 148.3, 135.8, 135.7, 129.9, 129.8, 125.8, 125.3, 125.2, 124.9, 124.8, 62.4, 27.5, 26.1, 16.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethyl phosphite 2: NaH / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: 4 h / Reflux 2: sodium hydride / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethyl phosphite 2: NaH / tetrahydrofuran 3: acetonitrile | ||
Multi-step reaction with 3 steps 1: 4 h / Reflux 2: sodium hydride / tetrahydrofuran / 20 °C 3: acetonitrile / 24 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethyl phosphite 2: NaH / tetrahydrofuran 3: acetonitrile | ||
Multi-step reaction with 3 steps 1: 4 h / Reflux 2: sodium hydride / tetrahydrofuran / 20 °C 3: acetonitrile / 24 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: thiazoline-2,4-dione With sodium hydroxide In ethanol at 25℃; for 0.166667h; Stage #2: 9-(bromomethyl)acridine In ethanol at 60℃; for 7h; | |
51% | Stage #1: thiazoline-2,4-dione With sodium hydroxide In ethanol at 25℃; for 0.166667h; Stage #2: 9-(bromomethyl)acridine In ethanol at 62℃; for 7h; | 2.1.1. Synthesis of 3-(acridin-9-ylmethyl)thiazolidine-2,4-dione (LPSF/AA-1A) (3) Thiazolidine-2,4-dione, compound 3, (1.5 eq) and sodiumhydroxide, previously solubilized in ethanol, were stirred for10 min at room temperature (25°C). 9-Bromomethylacridine,compound 4, (1.0 eq) was added, and the mixture was stirredat 62°C for 7 h. After completion of the reaction, the mixturewas filtered and washed with water. The product obtained wasa yellow solid. Formula: C17H12N2O2S. Melting point (m.p.):196-197°C. Yield: 51%. IR (KBr, cm-1): 2889 (-CH2-), 1750(C=O), 1694 (C=O), 750 (C-H). H1 NMR (300 MHz, DMSOd6)δ 8.42 (d, 2H, J = 8.7 Hz, Acr-H), 8.17 (d, 2H, J = 8.4 Hz,Acr-H), 7.83-7.88 (m, 2H, Acr-H), 7.65-7.70 (m, 2H, Acr-H), 5.75 (s, 2H, N-CH2), 4.23 (s, 2H, S-CH2). MS m/z (%):(M+H) + 309.1 (100), calculated 308; +MS2 309.1 (56), 235(100), 192 (98). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 0.17 h / 25 °C 1.2: 7 h / 60 °C 2.1: piperidine / ethanol / 4 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In dichloromethane at 20℃; for 6h; | |
69% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In dichloromethane at 20℃; for 6h; | |
49% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; | |
87% | With potassium carbonate In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In dichloromethane at 20℃; for 7h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: zinc(II) chloride / 5 h / 180 - 220 °C 2: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2 h / Reflux | ||
Multi-step reaction with 2 steps 1: zinc(II) chloride / 6 h / 220 °C 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 6 h / 80 °C / Irradiation | ||
Multi-step reaction with 2 steps 1: zinc(II) chloride / 17 h / 220 °C 2: N-Bromosuccinimide / dichloromethane / 20 °C / Cooling with ice |
Multi-step reaction with 2 steps 1.1: zinc(II) chloride / 180 - 200 °C 2.1: 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 0.5 h / 60 °C 2.2: 4 h / 60 - 80 °C | ||
Multi-step reaction with 2 steps 1.1: zinc(II) chloride / 5 h / 180 - 220 °C 2.1: 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 0.5 h / 60 °C 2.2: 4 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In dichloromethane at 20℃; for 9h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In dichloromethane at 20℃; for 7h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In 1,4-dioxane; ethanol at 0 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; for 30h; | 4.2.3 N-(2-Nitrobenzyloxycarbonyl)-l-alanine (acridin-9-yl)methyl ester, 6 To a solution of compound 2 (0.073g, 2.73×10-4mol) in dry DMF (3mL), potassium fluoride (0.047g, 8.16×10-4mol) and 9-(bromomethyl)acridine 3 (0.074g, 2.72×10-4mol) were added. The reaction mixture was stirred at room temperature for 30h. Potassium fluoride was removed by filtration, the solvent was removed by rotary evaporation under reduced pressure and the crude residue was purified by column chromatography using mixtures of ethyl acetate and light petroleum of increasing polarity as eluent. Compound 6 was obtained as light brown oil (0.040g, 32%). Rf=0.51 (ethyl acetate/light petroleum, 1:1). 1H NMR (CDCl3, 400MHz): δ=1.33 (d, J 7.2Hz, 3H, β-CH3), 4.30-4.40 (m, 1H, α-CH), 5.45 (s, 2H, CH2 NB), 5.58 (d, J 7.6Hz, 1H, NH), 6.08 (d, J 6.8Hz, 1H, CH2 OAcm), 6.20 (d, J 6.8Hz, 1H, CH2 OAcm), 7.35-7.45 (m, 1H, H-4′), 7.46-7.55 (m, 2H, H-5′and H-6′), 7.56-7.62 (m, 2H, H-2 and H-7), 7.73-7.79 (m, 2H, H-3 and H-6), 8.043 (dd, J 6.4 and 1.6Hz, 1H, H-3′), 8.20-8.30 (m, 4H, H-1, H-8, H-4 and H-5). 13C NMR (CDCl3, 100.6MHz): δ=18.14 (β-CH3), 49.77 (α-CH), 58.57 (CH2 OAcm), 63.37 (CH2 NB), 123.74 (C-1 and C-8), 124.83 (C-3′), 125.16 (C-8a and C-9a), 126.82 (C-2 and C-7), 128.34 (C-4′), 128.41 (C-5′), 129.85 (C-4 and C-5), 130.11 (C-3 and C-6), 132.78 (C-1′), 133.65 (C-6′), 136.49 (C-9), 147.06 (C-2′), 148.32 (C-4a and C-10a), 155.04 (C=O carbamate), 172.69 (C=O ester). IR (film, cm-1): ν=3420, 3331, 3056, 2985, 2941, 2878, 1727, 1630, 1611, 1579, 1526, 1452, 1421, 1344, 1305, 1266, 1209, 1170, 1115, 1068, 966, 910, 897, 859, 819, 790, 738, 704, 674, 642. HRMS (EI): calcd for C25H21N3O6 [M+]: 459.14313; found: 459.14292. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In diethyl ether at 20℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 40 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 27 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hexamethylenetetramine In chloroform at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 50 h / 20 °C 4.1: mesitylenecarbonitrile oxide / tetrahydrofuran / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 20 °C 4.1: mesitylenecarbonitrile oxide / tetrahydrofuran / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 6 h / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine / chloroform / 24 h / 20 °C 2.1: sodium carbonate / water 2.2: 20 °C 3.1: benzene / 50 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 30 h / 20 °C 2: chloroform / 20 °C 3: mesitylenecarbonitrile oxide / acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In diethyl ether at 20℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium fluoride In N,N-dimethyl-formamide at 20℃; for 15h; | Synthesis of (acridin-9-yl)methyl butyrate, 8 To a solution of 9-(bromomethyl) acridine 2 (0.038 g,1.39 x 10-4 mol) in dry DMF (3 mL) potassium fluoride (0.073 g,4.17 x 10-4 mol) and butyric acid (0.014 mL, 1.52 x 10-4 mol) were added. The reaction was followed by TLC (ethyl acetate/light petroleum, 1:1), and stirred at room temperature for 15 h. The solvent was removed by rotary evaporation under reduced pressure and the crude residue was purified by column chromatography using ethyl acetate/light petroleum, mixtures of increasing polarity as eluent. Compound 8 was obtained as a brown oily solid (0.027 g, 69%). Rf = 0.48 (ethyl acetate/light petroleum, 1:1). 1H NMR (400 MHz, CDCl3): δH = 0.89 (t, J = 7.2 Hz, 3H, CH3-CH2-CH2),1.63 (sext, J = 7.2 Hz, 2H, CH3-CH2-CH2), 2.32 (t, J = 7.2 Hz, 2H,CH3-CH2-CH2), 6.12 (s, 2H, CH2), 7.62 (dt, J = 7.6 and 1.2 Hz, 2H,H-2 and H-7), 7.79 (dt, J = 7.8 and 1.2 Hz, 2H, H-3 and H-6), 8.28 (d,J = 8.6 Hz, 2H, H-4 and H-5), 8.34 (d, J = 9.0 Hz, 2H, H-1 and H-8).13C NMR (100.6 MHz, CDCl3): δC = 13.54 (CH3-CH2-CH2), 18.34(CH3-CH2-CH2), 35.96 (CH3-CH2-CH2), 57.31 (CH2), 124.03(C-1 and C-8), 125.32 (C-8a and C-9a), 126.68 (C-2 and C-7),129.97 (C-4 and C-5), 130.08 (C-3 and C-6), 137.53 (C-9), 148.46(C-4a and C-4b), 173.42 (CO). IR (KBr 1%): ν = 3067, 2965, 2934,2875, 1737, 1692, 1629, 1603, 1557, 1519, 1498, 1461, 1441, 1416,1382, 1352, 1303, 1286, 1249, 1165, 1100, 1058, 1040, 1018, 976, 911,862, 753, 733, 643 cm-1. HRMS(ESI) for C18H18NO2 [M+ + H]: calculated 280.13384, found: 280.13403. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide In N,N-dimethyl-formamide at 4℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 22 h / 4 °C 2: 2,6-dimethylpyridine; copper(I) bromide / tetrahydrofuran / Inert atmosphere 3: copper(I) bromide; tris[(1-benzyl-1H-1,2,3-triazol-4yl)methyl]amine / tetrahydrofuran; dimethyl sulfoxide; water / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 22 h / 4 °C 2: 2,6-dimethylpyridine; copper(I) bromide / tetrahydrofuran / Inert atmosphere 3: copper(I) bromide; tris[(1-benzyl-1H-1,2,3-triazol-4yl)methyl]amine / tetrahydrofuran; dimethyl sulfoxide; water / 16 h / 20 °C |
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