| 89.09% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 2h; Inert atmosphere;
Stage #2: With hydrazine hydrate monohydrate; glacial acetic acid In ethanol at 0 - 30℃; for 4h; Inert atmosphere; |
4 Step 4 ;3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole I-1-5
To a solution of I-1-4 (21.00 g, 107.06 mmol) in DMF-DMA (100 mL, Bide) was stirred at 95° C. for 2 hrs. The reaction mixture was cooled to rt and concentrated. The resulting yellow oil was dissolved in 1,2-dichloroethane (40 mL) and concentrated twice to remove DMF-DMA. Then the crude oil was dissolved in ethanol (50 mL) to obtain a solution A. The solution of HOAc (70 mL) in EtOH (350 mL) was cooled to 0° C. and NH2NH2.H2O (7.29 g, 214.11 mmol, SCRC) was added dropwise. then the solution A was added to the mixture dropwise. After the addition, the reaction was warmed to rt and stirred for 4 h. The reaction mixture was concentrated, the residue was with water and filtered to collect the solid. The solid was washed with water, air dried under vacuum to afford the tittle compound I-1-5 (21 g, 95.37 mmol, 89.09% yield). |
| 69% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 0.5h;
Stage #2: With hydrazine monohydrate; glacial acetic acid In ethanol at 20 - 25℃; for 4h; Cooling with ice; |
18.3
[00225j 2-Methoxy-3-nitrobenzamide (7.1 g, 36.2 mmol) was slurried in N,Ndimethylformamide dimethyl acetal (DMF-DMA, 48.5 mL, 362 mmol) and the mixturewas heated to 95 °C giving a clear, pale yellow solution. After heating for 30 minutes at this temperature, the reaction was cooled to room temperature and concentrated. The resulting yellow oil was azeotroped twice with 1 ,2-dichloroethane (40 mL portions) to ensure complete removal of any residual DMF-DMA. The crude oil thus obtained was immediately dissolved in 35 mL of ethanol and was used in the following step.[00226j In a separate flask was prepared a mixture of ethanol (150 mL) and acetic acid (35 mL) and the resulting solution was cooled in an ice bath. Once cooled, hydrazine hydrate (17.59 mL, 362 mmol) was added dropwise. At this time, the solution containing the crude DMF-DMA adduct of the substrate prepared above was transferred dropwise over 15 minutes via cannula into the previously prepared well-stirred ice-cold mixture containing the hydrazine. During the addition, a pale yellow solid formed in the solution. After the addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stir for 4 h. The reaction mixture was concentrated to remove some of the ethanol, diluted with additional water and filtered to collect the solid.The solid was washed with additional portions of water, air dried in the funnel then under vacuum to afford 5.5 g (69%) of a pale yellow solid as the desired product. LC retention time 0.62 [J]. MS(Ej m/z: 221 (MHj. |
| 69% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 0.5h;
Stage #2: With hydrazine monohydrate; glacial acetic acid In ethanol for 0.25h; |
9.3
Step 3[00196j 2-Methoxy-3-nitrobenzamide (7.1 g, 36.2 mmol) was slurried in dimethyl formamide dimethyl acetal (48.5 mL, 362 mmol) and the mixture was heated to 95 °C giving a clear, pale yellow solution. After heating for 30 mm at this temp the reaction was cooled and was concentrated on the rotovap and the resulting yellow oil wasazeotroped twice with 1 ,2-dichloroethane (40 mL portions) to ensure complete removal of any residual dimethyl formamide dimethyl acetal. The crude oil thus obtained was immediately dissolved in 35 mL of ethanol and was immediately used in the following step.[00197j In a separate flask was prepared a mixture of ethanol (150 mL) and acetic acid(AcOH, 35 mL) and the resulting solution was cooled in an ice bath. Once cooled,hydrazine hydrate (17.59 mL, 362 mmol) was added dropwise. At this time, the solution containing the crude dimethyl formamide dimethyl acetal adduct as prepared above was transferred dropwise over 15 mm by cannula into the previously prepared well-stirred ice-cold mixture containing the hydrazine. During the addition, a pale yellow solidformed in the solution. After the addition was complete, the resulting cloudy yellow mixture was allowed to warm to room temperature and stir for 4 h. The reaction mixture at this time was concentrated on the rotovap to remove some of the ethanol, diluted with additional water and filtered to collect the solid. The solid was washed with additional portions of water, air dried in the funnel then under vacuum to afford 5.5 g (69%) of a pale yellow solid as the desired product. LC retention time 0.62 [J]. MS(E) m/z: 221(MHj. |
| 69% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 0.5h; Inert atmosphere;
Stage #2: With hydrazine hydrate monohydrate; glacial acetic acid In ethanol at 20℃; for 4.25h; Inert atmosphere; Cooling with ice; |
|
| 68% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 0.5h;
Stage #2: With hydrazine hydrate monohydrate; glacial acetic acid In ethanol at 20℃; Cooling with ice; |
69.3
Step 3: 2-Methoxy-3-nitrobenzamide (69-c, 3.0 g, 15.3 mmol) was suspended in DMF-DMA (20 mL), heated to 95°C, stirred for 30 minutes, until the reaction solution It was clarified, concentrated under reduced pressure to remove volatiles, and added 20 mL of ethanol to dissolve for later use. Under ice-water bath conditions, 63 mL of ethanol, 15 mL of acetic acid and hydrazine hydrate (7.4 mL, 152 mmol) were sequentially added to the reaction flask, and the mixture was stirred at room temperature overnight. The completion of the reaction was monitored by TLC, the organic solvent was removed, water (100 mL) was added, a solid was precipitated, and 3-(2-methoxy-3-nitrobenzene)-1-H-1,2,4-triazole was obtained by suction filtration ( 69-d, 2.31 g, 10.5 mmol, 68% yield). |
| 54.8% |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 0.5h;
Stage #2: With hydrazine monohydrate; glacial acetic acid In ethanol at 20℃; for 4.25h; Cooling with ice; |
3 Step 1: synthesis of compound Ab
To a solution of methyl 2-hydroxy-3-nitrobenzoate (10 g, 50.7 mmol) in DMF (100 mL) at room temperature was added potassium carbonate (14.02 g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 °C for 1 h. The reaction was cooled to room temperature and then crushed ice (~100 mL) was added, followed by water to a total volume of ~400 mL 10 causing a yellow solid to crystallize from solution. The slurry was stirred for a few minutes and then collected by vacuum filtration and the resulting initially yellow solid was rinsed with additional water (~100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a flask and further dried under vacuum over night to afford Ab (10.5 g, 98%) of a yellow solid as the desired product. LCMS [M+1]+ = 197.1. |
| 6 g |
Stage #1: 2-methoxy-3-nitrobenzamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 95℃; for 2h;
Stage #2: With hydrazine hydrate monohydrate; glacial acetic acid In ethanol at 0 - 20℃; for 12h; |
1.3 3- (2-Methoxy-3-nitrophenyl) -1H-1, 2, 4-triazole (1d) [0074] A solution of 2-methoxy-3-nitrobenzamide 1c
(10 g, 51 mmol) in N,N-dimethylformamide dimethyl acetal (50 mL) was heat to 95°C and stirred for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in ethanol (30 mL) to obtain solution A. Hydrazine hydrate (25 mL) was slowly added to a mixture of acetic acid (35 mL) and ethanol (150 mL) at 0°C, followed by addition of solution A. After gradually warming to room temperature and stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dispersed in water (400 mL) and filtered. The obtained solid was washed with water and dried to give the target compound 1d (6 g, solid) with a yield of 55%. [0075] MS m/z (ESI) : 221 [M+1] |
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