* 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.
52.1 Step 1
To a 100 mL round-bottom flask was added dioxane 60 mL, l-fluoro-2- nitrobenzene (5.92 g, 42 mmol, 1.0 eq), potassium carbonate (14.5 g, 105 mmol, 2.5 eq) and 4- methylpiperidine (5 g, 50 mmol, 1.2 eq) was dropped into the stirred mixture and refluxed overnight. LC-MS showed the reaction was completed. This reaction was added water 100mL and extracted with EA (40 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the compound 52A (8 g). Yield: 86.6 %.
86.6%
With potassium carbonate In 1,4-dioxane Reflux;
52.1 Step 1
To a 100 mL round-bottom flask was added dioxane 60 mL, l-fluoro-2- nitrobenzene (5.92 g, 42 mmol, 1.0 eq), potassium carbonate (14.5 g, 105 mmol, 2.5 eq) and 4- methylpiperidine (5 g, 50 mmol, 1.2 eq) was dropped into the stirred mixture and refluxed overnight. LC-MS showed the reaction was completed. This reaction was added water 100mL and extracted with EA (40 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the compound 52A (8 g). Yield: 86.6 %.
In dimethyl sulfoxide
With PS-morpholine In chloroform at 50℃; for 2h;
In N,N-dimethyl-formamide at 60℃; for 0.25h;
41.a
Example 41; 4-Cyano-lH-imidazole-2-carboxylic acid [2-(4-methyl-piperidin-l-yl)-phenyl]-amide trifluoroacetic acid salt ; a) 4-Cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid [2-(4- methyl-piperidin- 1 -yl)-phenyl] -amide; A solution of 1.00 g (7.09 mmol) of l-fluoro-2-nitro-benzene in DMF (5 niL) was treated with 2.52 mL (21.3 mmol) of 4-methyl-piperidine and heated to 600C for 15 min. The mixture was diluted with EtOAc (50 mL) and washed with water (6 x 30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. A 250 mg (1.14 mmol) portion of the residue was taken up in THF (5 mL) and treated with 15 mg of 10 % Pd/C (Degussa type E101-NE/W, Aldrich, 50 % by weight water) under H2 (1 atm). When this reaction was complete, the mixture was filtered through Celite directly into a suspension of 24.5 mg (0.147 mmol) of PyBroP, 30.0 mg (0.0980 mmol) of 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 51.0 μL (0.295 mmol) of DIEA in THF (5 mL). The mixture was flushed with Ar and stirred at RT for 16 h. An additional 24.5 mg (0.147 mmol) of PyBroP, 30.0 mg (0.0980 mmol) of 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 51.0 μL (0.295 mmol) of DEEA were added, and the mixture stirred for 2 h. The mixture was diluted with EtOAc (10 mL), washed with water (1 x 10 mL) and saturated aqueousS3 NaHCO3 (1 x 10 mL), dried (MgSO4), and concentrated in vacuo to afford 153 mg (30 %) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C23H33N5Si, 440.2 (M+H), found 440.0.
With 5%-palladium/activated carbon; hydrazine hydrate; In ethanol; for 8.5h;Reflux;
General procedure: In an 100 mL three-necked flask equipped with a dropping funnel, 1-(2-nitrophenyl)piperidine (4.0 g)and ethanol (50 mL) were mixed and heated to reflux. Palladized charcoal (0.1 g, 5%, previously moistened with alcohol) was added. Next 80% hydrazine hydrate (15 mL) was added from a dropping funnel during 30 min. The reaction was continued for 8 h and then cooled [18,19]. The solid was filtered off and the filtrate was concentrated to give a crude product that was recrystallized from ethyl acetate and petroleum ether solution (15:1) to afford the title compound as a white powder, yield 95 %
With palladium on activated charcoal; hydrazine hydrate; In ethanol; for 8h;Reflux; Heating;
General procedure: In a 100 mL three-necked flask equipped with a dropping funnel, 2-(2-nitrophenyl)benzo[d]- thiazole (1, 3.0 g, 12.5 mmol) and ethanol (50 mL) were mixed and heated to reflux. Palladized charcoal (0.1 g, 5%) was added, then 80% hydrazine hydrate solution (10 mL) was added from a dropping funnel during 30 min [10,11]. The heating was continued for 8 h and then the mixture cooled. The solid was filtered off and the filtrate was concentrated to give a crude product that was recrystallized from ethyl acetate and petroleum ether solution (1:5) to afford compound 2 as a yellow powder (yield: 3.76 g, 85%).
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; under 760.051 Torr;
Example 41; 4-Cyano-lH-imidazole-2-carboxylic acid [2-(4-methyl-piperidin-l-yl)-phenyl]-amide trifluoroacetic acid salt <n="85"/>; a) 4-Cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid [2-(4- methyl-piperidin- 1 -yl)-phenyl] -amide; A solution of 1.00 g (7.09 mmol) of l-fluoro-2-nitro-benzene in DMF (5 niL) was treated with 2.52 mL (21.3 mmol) of 4-methyl-piperidine and heated to 600C for 15 min. The mixture was diluted with EtOAc (50 mL) and washed with water (6 x 30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. A 250 mg (1.14 mmol) portion of the residue was taken up in THF (5 mL) and treated with 15 mg of 10 % Pd/C (Degussa type E101-NE/W, Aldrich, 50 % by weight water) under H2 (1 atm). When this reaction was complete, the mixture was filtered through Celite directly into a suspension of 24.5 mg (0.147 mmol) of PyBroP, 30.0 mg (0.0980 mmol) of 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 51.0 muL (0.295 mmol) of DIEA in THF (5 mL). The mixture was flushed with Ar and stirred at RT for 16 h. An additional 24.5 mg (0.147 mmol) of PyBroP, 30.0 mg (0.0980 mmol) of 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 51.0 muL (0.295 mmol) of DEEA were added, and the mixture stirred for 2 h. The mixture was diluted with EtOAc (10 mL), washed with water (1 x 10 mL) and saturated aqueousS3 <n="86"/>NaHCO3 (1 x 10 mL), dried (MgSO4), and concentrated in vacuo to afford 153 mg (30 %) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C23H33N5Si, 440.2 (M+H), found 440.0.