| 94% |
With triethylamine at 150℃; for 1h; Microwave irradiation; |
|
| 94% |
With triethylamine at 150℃; for 1h; Microwave irradiation; |
8 Compound Synthesis
To synthesize JMN3-003, N-(4-methoxyphenyl)-2-nitroaniline (FIG. 9A), P-anisidine (4.36 g, 35.4 mmol), 1-fluoro-2-nitrobenzene (3.8 ml, 36.0 mmol) and Et3N (4.93 ml, 35.4 mmol) were mixed in a microwave tube and heated at 150° C. for one hour. The mixture was stirred in water, ether added and the precipitate filtered. The reddish brown solid was washed with hexanes and dried under vacuum to give 8.0 g of substance (3) in 94% yield. 1H NMR (400 MHz, CDCl3, δ=7.24 ppm); (s, 1H), 10.01 (s, 1H), 8.18 (dd, J=8.0, 1.6 Hz, 1H), 7.33-6.68 (m, 7H), 3.83 (s, 3H). |
| 93% |
With potassium fluoride; potassium carbonate at 90℃; for 0.133333h; microwave irradiation; |
|
| 84% |
With potassium phosphate at 80℃; for 12h; Ionic liquid; |
|
| 80% |
With triethylamine In neat (no solvent) at 140℃; for 9h; |
General procedure for the synthesis of 3 in Table 3
General procedure: A mixture of 1-fluoro-2-nitrobenzene 1 (1.5 g, 11 mmol), 2 (16 mmol), and triethylamine (0.6 g, 5.5 mol) was stirred at 140 °C for 9 h. After completion of the reaction as indicated by TLC, the mixture was cooled to 20 °C and filtered. The filter cake was washed with water and anhydrous ethanol until the pH of filtrate reached 7, then dried in vacuum to obtain compound 3. |
| 79.7% |
Stage #1: 4-methoxy-aniline With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: ortho-nitrofluorobenzene In N,N-dimethyl-formamide at 25℃; for 16h; |
2 General procedure for preparation intermediates of N-substituted-2-nitroanilines (15a-15n)
General procedure: To the suspension of NaH (75 mol) in DMF (60 mL), substitutedamines (50 mmol) was added at 0 C. The mixture was stirred for30 min at the same temperature, and then 2-fluoronitrobenzene(60 mmol) diluted in DMF (30 mL) was added slowly. The mixturewas warmed to room temperature and stirred for 16 h. The reactionmixture was carefully poured into stirring saturated NH4Cl(500 mL), then filtered. The filter cake was washed with water,and recrystallized from methanol to afford corresponding N-aryl-2-nitroanilines 15a-15n.6.2.2 N-(4-methoxyphenyl)-2-nitroaniline (15b) Red solid; Yield: 79.7%; M.p.: 88.1-89.7 °C; MS (ESI) m/z (%): 243.3 [M-H]-. |
|
With 4-methyl-morpholine In N,N-dimethyl-formamide at 125℃; for 16h; |
|
|
With potassium carbonate In methanol; water; ethyl acetate |
1.A (4-Methoxy-phenyl)-(2-nitro-phenyl)-amine
Step A (4-Methoxy-phenyl)-(2-nitro-phenyl)-amine 1-Fluoro-2-nitrobenzene (37.6 g, 28.0 ml, 0.266 mmol), p-anisidine (32.8 g, 0.266) and K2CO3 (55.0 g, 0.399 mol) were combined in flask and heated at 160° C. overnight under an atmosphere of N2. The mixture was cooled to ca. 90° C. and water (200 ml) was added slowly to the reaction. The mixture was partitioned with EtOAc (1L). The remaining solid was stirred for 45 minutes in EtOAc (200 ml), MeOH (200 ml) and water (200 ml) until complete dissolution occurred. The mixture was extracted with EtOAc (3*400 ml), the aqueous washings were combined and further extracted with EtOAc (2*200 ml). All of the organic extracts were combined and washed with brine (600 ml), dried (MgSO4), filtered and concentrated by vacuum. The solid residue was recrystallized from hot hexanes (1L) to give (4-methoxy-phenyl)-(2-nitro-phenyl)-amine (46.07 g, 0.253 mol, 95%). MS (M+1) 245. 1H NMR (CDCl3) δH 9.40 (1H, br. s), 8.18 (1H, m), 7.23 (3H, overlapping m), 6.97 (3H, overlapping m), 6.70 (1H, m) and 3.84 (3H, s). |
|
Stage #1: 4-methoxy-aniline With sodium hydride In N,N-dimethyl-formamide for 0.5h;
Stage #2: ortho-nitrofluorobenzene In N,N-dimethyl-formamide for 16h; |
7.1
Step 1 : p-Anisidine (1.0 g, 8.1 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.31 g, 8.1 mmol) was added and the mixture was stirred for 30 minutes. 2- Fluoronitrobenzene (0.86 mL, 8.1 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH4CI and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via lsco chromatography (Redisep, silica, gradient 5-25% ethyl acetate in hexane) to afford 0.4 g of λ/-(4-methoxyphenyl)-2-nitroaniline that was carried on directly to the next step. HRMS: calculated for C13H12N2O3 + H+, 245.09207; found (ESI+, [M+H]+), 245.09144. |
|
In N,N-dimethyl-formamide at 20℃; |
|
|
With triethylamine In N,N-dimethyl-formamide at 60℃; |
|
|
With potassium carbonate at 160℃; for 14h; neat (no solvent); |
|
|
In N,N-dimethyl-formamide at 80℃; for 2h; |
II Intermediate N-(4-methoxyphenyl)-2-nitroaniline
Nitrofluorobenzene (1.5 g, 1 eq.) and p- anisidine (1.30 gr, 1 eq.) were mixed in DMF (20 mL) and heated at 80 °C for 2 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCC (2 x 20 mL), H20 (2 x 20 mL) and brine (20 mL). The organic layers were collected, dried (MgSC^) and concentrated under reduced pressure. The crude product was used in the following reaction without further purification (2 gr); LC MS [M + 1]+ m/z 245.00. |
|
With triethylamine In N,N-dimethyl-formamide at 80℃; for 12h; |
|
|
In water for 6h; Reflux; |
4.1.1. General procedure for synthesis of a1-a5
General procedure: o-Fluoronitrobenzene (14.10g, 100mmol) and 3,4,5-trimethoxyaniline (21.98g, 120mmol) were added into water (150mL). The mixture was reflux for 6 h under stirring. Then the reaction complex was cooled to room temperature, neutralized with NaHCO3, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and vacuum evaporated to obtain the crude product of compound a1. Compound a1 was purified by silica gel column chromatography. Compounds a2-a5 were prepared by performing the method above. |
|
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h; |
|
|
Alkaline conditions; Heating; |
General procedure for the synthesis of 2-nitroaniline1:
General procedure: A solution of the 1-fluoro-2-nitroarene (1~1.5 equiv) in a suitable solvent, such as DMF or DMSO (0.2~0.8 M), or neat was treated with the requisite amine (1 equiv) and a base such as DIPEA, TEA or K2CO3 (1.5~4 equiv), and the reaction mixture was warmed to 80~140 °C for 6~24 h. The reaction mixture was then cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted twice more with EtOAc, and the pooled extracts were washed consecutively with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified with flash chromatography if necessary. |
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