| 99% |
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone for 0.5h; Inert atmosphere;
Stage #2: methyl iodide In acetone at 60℃; Inert atmosphere; |
|
| 99% |
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; |
4-Fluoro-2-methoxy-1-nitro-benzene(36b):
To a stirred suspension of 4-fluoro-2-hydroxy- 1-nitrobenzene(35) (100 mg, 0.64 mmol) and K2CO3(132 mg, 0.96 mmol) in DMF (3.2 mL) was added methyl iodide (108 mg, 0.76 mmol)at 0 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo to give thetitle compound (118 mg, 99%) as a yellow oil; |
| 99.1% |
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone at 20℃; for 0.5h; Inert atmosphere;
Stage #2: methyl iodide In acetone at 60℃; |
3.1 Step 1: Preparation of 4-fluoro-2-methoxynitrobenzene (the compound of Formula I-21)
5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g, 63.65 mmol) and acetone (100mL) wereadded in a 250 mL three-necked flask and stirred at room temperature for 30 minutes under the protection of nitrogengas. Iodomethane (9.03 g, 63.65 mmol) was then slowly added dropwise thereto, and the mixture was warmed up to60°C and reacted overnight. After the reaction was completed, the reaction solution was added with water (200 mL),extracted with ethyl acetate (100 mL 3 4), washed with 1M sodium hydroxide (100mL 3 3) and saturated brine (100mL 3 2) successively, dried over anhydrous sodium sulfate, filtered by suction and evaporated under reduced pressureto remove the solvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1% yield). |
| 98% |
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone at 20℃; for 0.5h;
Stage #2: methyl iodide In acetone at 20 - 60℃; for 30h; |
1.a
4-fluoro-2-methoxy-1-nitro-benzene 20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo. Yield: 21.1 g (123 mmol; 98%) UV max: 230/266/322 nm. |
| 98% |
With potassium carbonate In acetonitrile at 50℃; for 3h; |
8.3 (3) Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
(0540) 5-Fluoro-2-nitrophenol (7.85 g, 0.05 mol), iodomethane (8.52 g, 0.06 mol) and potassium carbonate (10.35 g, 0.075 mol) were added to acetonitrile (150 mL). The mixture was heated at 50° C. for 3 h, and the solvent was removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried and concentrated to get the product (8.4 g, yield: 98%). |
| 98% |
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; |
|
| 97% |
With potassium carbonate In acetone for 4h; Heating / reflux; |
5.60.1
5.60.1 4-Fluoro-2-methoxy-1-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3×250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97% yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H). |
| 96% |
With potassium carbonate In acetone for 3h; Reflux; |
4.1.17 4-Fluoro-2-methoxy-1-nitro-benzene (24)
To a stirred solution of 23 (0.60 g, 3.82 mmol) in acetone (20 mL) was added K2CO3 (1.1 g, 7.6 mmol) and iodomethane (0.5 mL, 7.6 mmol). The reaction mixture was refluxed for 3 h and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 24 as a white solid (0.63 g, 96%). |
| 94% |
With potassium carbonate In acetonitrile at 16 - 85℃; for 5h; |
26.1
Step 1 : K2C03 (131 g, 955 mmol) and CH3I (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in MeCN (750 mL) at rt and the resulting mixture was heated to 85°C for 5 h. The RM was chilled, filtered and washed with MeCN. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to give the desired compound (75 g, 94%). |
| 94% |
With potassium carbonate In acetonitrile at 85℃; for 5h; |
5.1
Step 1: K2C03 (131 g, 955 mmol) and Mel (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in acetonitrile (750 mL) at rt and the resulting mixture was heated to 85 C for 5 h. The reaction mixture was chilled, filtered and washed with acetonitrile. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reducedpressure to give the desired compound (75 g, 94%). |
| 94% |
With potassium carbonate In acetone at 20℃; for 50h; Cooling with ice; |
1 Compound (1): Synthesis of 4-Fluoro-2-methoxy-1-nitrobenzene (1)
A solution of 5-fluoro-2-nitrophenol (3.00 g, 19.1 mmol) in acetone (42.0 mL) is dissolved in methyl iodide (2.37 mL, 38.2 mL) with stirring under ice-cooling. Add mmol) dropwise,Potassium carbonate (5.30 g, 38.2 mmol) was added.room temperatureAfter stirring for 50 hours, the solvent was evaporated under reduced pressure, dissolved in ethyl acetate, and washed with distilled water. The organic layer was washed with saturated brine and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.00 g of a compound (1) (yield 94%). |
| 92% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
22.A
To 2-nitro-5-fluoro-phenol (56.0 g, 357 mmol) and iodomethane (24.5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54.2 g, 393 mmol). Significant bubbling occurred. The mixture was stirred at rt overnight. The mixture was poured into H2O (800 mL) and the H2O washed with diethyl ether (3×200 mL). The ether washes were combined and washed with H2O (2×400 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (56.0 g, 327 mmol, 92%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 1H), 6.79-6.67 (m, 2H), 3.93 (s, 3H). |
| 92% |
With potassium carbonate In N,N-dimethyl-formamide |
|
| 92% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
20.A
To 2-nιtro-5-fluoro-phenol (56 0 g, 357 mmol) and iodomethane (24 5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54 2 g, 393 mmol) Significant bubbling occurred The mixture was stirred at rt overnight The mixture was poured into H2O (800 mL) and the H2O washed with ether (3 x 200 mL) The ether washes were combined and washed with H2O (2 x 400 mL) The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (56 0 g, 327 mmol, 92 %) as a yellow solid 1H-NMR (400 MHz, CDCI3) δ 7 96 - 7 90 (m, 1 H), 6 79 - 6 67 (m, 2 H) and, 3 93 (s, 3 H) |
| 91% |
With potassium carbonate In acetone at 0 - 20℃; for 144h; |
|
| 90% |
With potassium carbonate In N,N-dimethyl-formamide for 1h; |
4-fluoro-2-methoxy-1-nitrobenzene (6).
To a solution of 5 (2 g, 12.8 mmol) and K2CO3 (2.64 g, 19.2 mmol) in DMF (20 ml) was added MeI (2.16g, 15.2 mmol) dropwise at 0 °C. The reaction mixture was heated for 1 h at 60 °C followed by cooling to room temperature. Water (20 ml) was added and the mixture was extracted with EtOAc (20 mL) for three times. The combined organic layer was washed with water and dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6 as a light yellow solid in an 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.23 (dd, J = 11.0, 2.6 Hz, 1H), 6.92 (ddd, J = 9.0, 7.8, 2.6 Hz, 1H), 3.90 (s, 3H). |
| 88% |
With potassium carbonate In acetone at 20℃; for 96h; |
11.a
Methyl iodide (11.94 mL, 191 mmol) was added dropwise to a stirred suspension of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) and potassium carbonate (17.59 g, 127 mmol) in acetone (318 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 days, whereupon the acetone was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralised with concentrated hydrochloric acid. The organic layer was separated, washed with water and brine, dried (MgSO.)), filtered and evaporated to give an off-white solid that was recrystallised from isopropanol/dichloromethane to give 4-fiuoro-2-methoxy-l- nitrobenzene as an off-white solid (9.6 g, 88%). |
| 81% |
With potassium carbonate at 67 - 69℃; for 6h; |
|
| 79% |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Sealed tube; |
|
| 38% |
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 23h; |
A mixture of commercially available 5-fluoro-2-nitrophenol (1.00 g, 6.37 mmol), MeI (1.36 g, 9.58 mmol), and potassium carbonate (1.32 g, 9.55 mmol) in DMF (10 mL) was heated at 140° C. for 23 hours. The reaction was diluted with aq. 0.5 N NaOH (50 mL) and extracted with EtOAc (2×50 mL). The EtOAc-extracts were washed once more with aq. 0.5 N NaOH (50 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane: 1/1) to obtain 4-fluoro-2-methoxy-nitrobenzene (416 mg, 38%, purity (GC)>95%).MS: [M]+=171. |
| 26% |
With potassium carbonate In N,N-dimethyl-formamide at 140℃; Sealed pressure flask; |
73
4-Fluoro-2-methoxy-l-nitro-benzene was synthesized by suspending 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol, 1.0 equiv.), potassium carbonate (6.59 g, 47.7 mmol, 1.5 equiv.), and Iodomethane (2.98 mL, 47.7 mmol, 1.5 equiv.) in DMF (50 mL) and allowing the resulting reaction mixture to stir overnight at 14O0C inside a sealed pressure flask. The reaction mixture was partitioned between ethyl acetate and distilled water three times. The organic layer was washed once with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The product was isolated by column chromatography in 30% ethyl acetate and hexanes as a yellow solid (1.44 g, 26%). 1H NMR (300 MHz, CDCl3): δ(pρm) 7.98(dd, IH), 6.77(m, 2H), 3.99(s, 3H). |
| 9.7% |
With potassium carbonate In ethanol for 12h; Heating / reflux; |
49.1 4-fluoro-2-methoxynitrobenzene
Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7%). NMR (CDCl3): 4.0 (s, 3H), 6.8 (m, 2H), 8.0 (m, 1H). |
|
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 15h; |
|
|
With potassium hydroxide; sodium hydroxide In water; dimethyl sulfoxide |
2 Synthesis of 4-fluoro-2-methoxy-1-nitrobenzene (1):
Synthesis of 4-fluoro-2-methoxy-1-nitrobenzene (1): 25 g (0.159 mol) of 5-fluoro-2-nitrophenol are added to 125 ml of DMSO. 22.5 g (0.159 mol) of methyl iodide are then added, followed by dropwise addition, while keeping the temperature below 25° C., of 17.8 g of aqueous 50% potassium hydroxide solution. The mixture is stirred for one hour at ambient temperature and a further 22.5 g (0.159 mol) of methyl iodide are then added. After stirring for 24 hours, the reaction medium is poured into 125 ml of water and then extracted with 60 ml of dichloromethane. The organic phase is washed with 90 ml of aqueous sodium hydroxide solution (1N) and then with 60 ml of water. After drying over MgSO4, the organic phase is concentrated under reduced pressure. 20.59 g (76%) of 4-fluoro-2-methoxy-1-nitrobenzene (1) are thus recovered. |
|
In <i>N</i>-methyl-acetamide |
40.1 (1)
(1) Synthesis of 4-Fluoro-2-methoxynitrobenzene To a suspension of sodium hydride (1.3 g) in dimethylformamide (10 ml) was added a solution of 5-fluoro-2-nitrophenol (5.0 g) in dimethylformamide (20 ml)under ice-cooling. This reaction mixture was stirred at room temperature for 1 hr. To this solution was added methyl iodide (2.0 ml) and the mixture was left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a red solid. This solid was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (4.3 g) as a yellow solid. 1H-NMR(CDCl3)δ: 3.97(3H, s), 6.69-6.82(2H, m), 7.96(1H, dt, J=3.3, 2.6 Hz). IR(KBr): 3124, 3086, 2994, 1624, 1587 cm-1; MS(EI): 171(M+). |
|
With potassium carbonate In acetone |
32.a 3,5-Diisopropyl-4-(7-2H-1,4-benzoxazinoxy-3(4H)-one)phenylpropionic Acid
(a) 5-Fluoro-2-nitrophenol (10.3 g), potassium carbonate (27.1 g), methyl iodide (11.1 g) and acetone (100 mL) was heated at reflux until the starting materials were consumed. After cooling down to room temperature, the reaction mixture was diluted with ethylacetate, washed with hydrogen chloride (1 N) and brine. After puridication on column (silica gel, ethyl acetate/petrolium ether, 1:9), 10.8 g (96%) of of 5-fluoro-2-nitroanisole was obtained. |
|
With potassium carbonate In acetone for 3h; Heating / reflux; |
14
;A mixture of 5-fluoro-2-nitro-phenol (4.90 g, 31.8 mmol), MeI (4 mL, 63.6 mmol), and K2CO3 (8.82 g, 63.6 mmol) in acetone (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was concentrated to yield a light yellow solid. The crude intermediate was dissolved in methanol (50 mL). Pd/C (10%, 0.42 g) was added the solution. The reaction was stirred at room temperature under H2 at atmosphere pressure for 6 hours. TLC showed the reaction was complete. The reaction was filtered through the celites and concentrated under reduced pressure to give the desired product as brown oil (3.43 g). |
|
Stage #1: 5-fluoro-2-nitrophenol; methyl iodide With sodium hydride In tetrahydrofuran at 20℃; for 10h;
Stage #2: With caesium carbonate In tetrahydrofuran at 20℃; for 4h; |
75
To a solution of 5-fluoro-2-nitro-phenol (369 mg, 2.35 mmol) in 5 mL THF, sodium hydride (96 mg, 2.46 mmol) was added at room temperature, followed by methyl iodide (0.88 ml, 14 mmol). The mixture was stirred at room temperature for 10 hours, and then cesium carbonate (744mg, 2. 35 mmol) was added. The mixture was stirred at room temperature for additional 4 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give pure 4-fluoro- 2-methoxy-1-nitro-benzene. |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; |
157.1
5-Fluoro-2-nitrophenol (6 g, 38.2 mmol) was dissolved in anhydrous DMF (20 ml). Potassium carbonate (5.3g, 38.2 mmol) was added, followed by iodomethane (2.28 ml, 38.2 mmol) . The reaction was stirred at room temperature for 16h, then partitioned between dichloromethane and water. The organic layer was washed three times with IM sodium hydroxide and once with brine, then dried over sodium sulfate. Removal of the solvent in vacuo afforded the title compound as a yellow oil, which solidified upon standing. |
|
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h; |
|
| 4.5 g |
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 2h; |
32.1 Preparation of 4-fluoro-2-methoxy- 1 -nitrobenzene
To a solution of 4-fluoro-2-hydroxy-l -nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added K2CO3 (13.1 g, 95.4 mmol). The reaction mixture was stirred at RT for 1 h followed by addition of methyl iodide (9.93 g, 69.9 mmol) and the reaction mixture was stirred at 60 C for 2 h. The reaction mass was concentrated and quenched in water. The reaction mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.93 (s, 3H), 6.97 (t, J= 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H). |
|
With potassium carbonate In acetone for 4h; Reflux; |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 50℃; |
1.1 Step 1: Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
5-fluoro-2-nitrophenol (300 mg), methyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification. |
|
With potassium carbonate In N,N-dimethyl-formamide at 50℃; |
1.1 Step 1:
Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
Step 1: Preparation of 4-fluoro-2-methoxy-1-nitrobenzene 5-fluoro-2-nitrophenol (300 mg), methyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50°C overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification. |
|
With potassium carbonate at 80℃; Sealed tube; |
2C Example 2C: Synthesis of orf/w-S bstit ted Phenoxyalkyl Linker Anti-Parasitic Compounds
General procedure: FIG, 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds lr-lt. Generally, reagents and conditions for synthesis of compounds according to FIG, 2C included: a) RI, K2C03, sealed tube, 80°C; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K2C03, CH3CN, reflux; d) imidazole, K2C03, CH3CN, reflux; e) 8ηΟ2'2Η20, EtOAc, refux; f) S~(2~ naphih}'lmethyl)thioimidaie hydrobromide, CH3CN/EtOH, rt.. |
|
With potassium carbonate In acetone at 0℃; for 5h; |
|
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