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With sodium carbonate; sodium hydroxide In water at 40℃; for 2 h; Cooling with ice
To the reaction flask was added 38.00 g of 2-chloroethyl ethyl ether (compound 4, 0.35 mol) and 90.4 g of 4- (1H-benzo [d]Imidazol-2-yl) piperidine-1-carboxylate (compound 3, 0.3 mol) (40percent) in water was added 7 mlPolyethylene glycol-400,(0.25 mol NaOH and 0.1 mol Na2CO3) were added slowly under ice-cooling, and the mixture was stirred rapidly at 40C for 2 hours. After completion of the reaction, the reaction solution was cooled, extracted with ether, washed with saturated brine, dried and filtered , The solvent was removed to give 103.1 g of compound 5 in 92percent yield.
93 g
With sodium iodide; sodium hydroxide In dimethyl sulfoxide at 95 - 100℃; for 3 h;
Example-17: Preparation of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidine-l-carboxylate (Formula-32) Tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate compound of formula-31 (100 gm), sodium iodide (10 gm) and l-chloro-2-ethoxyethane (54 gm) were slowly added to a pre-heated mixture of dimethylsulfoxide (200 ml) and sodium hydroxide (39.8 gm) at 40-45°C. Heated the reaction mixture to 95-100°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 10-15°C and water was slowly added. Neutralized the reaction mixture using aqueous hydrochloric acid. Ethyl acetate was added to the reaction mixture and stirred for 20 min. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (50 ml) was added to the obtained compound. Heated the reaction mixture to 60-65°C and stirred for 15 min at the same temperature. Reduced the temperature of the reaction mixture to 40-45°C and petroleum ether (650 ml) was slowly added. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Filtered the precipitated solid, washed with petroleum ether and dried to get the title compound. Yield: 93.0 gm.
Example 11 : Preparation of4-[1 -(2-ethoxyethyl)-1 H-benzoimidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester; In a reaction vessel, 4-(1 H-benzoimidazol-2-yl)-piperidine-1 -carboxylic acid tert-butyl ester(1.5g) prepared in the Example 10, toluene(10ml_) and potassium hydroxide(O.δg) were introduced, and temperature of the mixture was controlled to 500C or more. To the mixture, ethoxyethanol methane sulfonate^ .3g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water(IOmL) was added to separate layers, and then an organic layer was condensed to obtain4-[1 -(2-ethoxyethyl)-1 H-benzoimidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester(1.7g, 91 percent).1H-NMR, 400 MHz, CDCI3, ppm : 1.07(t, 3H)1 1.47(s, 9H), 1.92(m, 2H), 2.01 (S, 2H), 2.85(s, 2H), 3.14(m, 1 H), 3.36(m, 2H), 3.69(t, 2H), 4.28(t, 2H), 7.12-7.26(m, 3H), 7.75(t, 1 H)
91%
Stage #1: With potassium hydroxide In toluene at 50℃; Stage #2: at 50℃;
Example 11 Preparation of 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester In a reaction vessel, 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) prepared in the Example 10, toluene (10 mL) and potassium hydroxide (0.8 g) were introduced, and temperature of the mixture was controlled to 50° C. or more. To the mixture, ethoxyethanol methane sulfonate (1.3 g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water (10 mL) was added to separate layers, and then an organic layer was condensed to obtain 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 91percent). 1H-NMR, 400 MHz, CDCl3, ppm: 1.07 (t, 3H), 1.47 (s, 9H), 1.92 (m, 2H), 2.01 (s, 2H), 2.85 (s, 2H), 3.14 (m, 1H), 3.36 (m, 2H), 3.69 (t, 2H), 4.28 (t, 2H), 7.12-7.26 (m, 3H), 7.75 (t, 1H)
Example 11 : Preparation of4-[1 -(2-ethoxyethyl)-1 H-benzoimidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester; In a reaction vessel, 4-(1 H-benzoimidazol-2-yl)-piperidine-1 -carboxylic acid tert-butyl ester(1.5g) prepared in the Example 10, toluene(10ml_) and potassium hydroxide(O.deltag) were introduced, and temperature of the mixture was controlled to 500C or more. To the mixture, ethoxyethanol methane sulfonate^ .3g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water(IOmL) was added to separate layers, and then an organic layer was condensed to obtain4-[1 -(2-ethoxyethyl)-1 H-benzoimidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester(1.7g, 91 %).1H-NMR, 400 MHz, CDCI3, ppm : 1.07(t, 3H)1 1.47(s, 9H), 1.92(m, 2H), 2.01 (S, 2H), 2.85(s, 2H), 3.14(m, 1 H), 3.36(m, 2H), 3.69(t, 2H), 4.28(t, 2H), 7.12-7.26(m, 3H), 7.75(t, 1 H)
91%
Example 11 Preparation of 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester In a reaction vessel, 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) prepared in the Example 10, toluene (10 mL) and potassium hydroxide (0.8 g) were introduced, and temperature of the mixture was controlled to 50 C. or more. To the mixture, ethoxyethanol methane sulfonate (1.3 g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water (10 mL) was added to separate layers, and then an organic layer was condensed to obtain 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 91%). 1H-NMR, 400 MHz, CDCl3, ppm: 1.07 (t, 3H), 1.47 (s, 9H), 1.92 (m, 2H), 2.01 (s, 2H), 2.85 (s, 2H), 3.14 (m, 1H), 3.36 (m, 2H), 3.69 (t, 2H), 4.28 (t, 2H), 7.12-7.26 (m, 3H), 7.75 (t, 1H)
Example 12: Preparation of1 -(2-ethoxyethyl)-2-piperidin-4-yl-1 H-benzoimidazole; In a reaction vessel,4-[1-(2-ethoxyethyl)-1 H-benzoimidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester(1.6g) prepared in the Example 11 , distilled water(15ml_) and hydrochloric acid(1.5g) were introduced, and then the mixture was stirred to conduct deprotection. And then, sodium hydroxide solution(I OmL) and dichloromethane(20ml_) were added thereto. An organic layer was separated and condensed to obtain1 -(2-ethoxyethyl)-2-piperidin-4-yl-1 H-benzoimidazole(1.2g, 100%). 1H-NMR, 400 MHz, CDCI3, ppm : 1.05(t, 3H), 2.09~2.23(m, 4H), 3.17(q, <n="20"/>2H), 3.24(d, 1 H), 3.39(q, 2H), 3.51(q, 3H), 3.77(t, 2H), 4.51(t, 2H), 7.27(m, 2H), 7.52(d, 1H), 7.62(d, 1 H)
100%
Example 12 Preparation of 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole In a reaction vessel, <strong>[1181267-36-6]4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.6 g) prepared in the Example 11, distilled water (15 mL) and hydrochloric acid (1.5 g) were introduced, and then the mixture was stirred to conduct deprotection. And then, sodium hydroxide solution (10 mL) and dichloromethane (20 mL) were added thereto. An organic layer was separated and condensed to obtain 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (1.2 g, 100%). 1H-NMR, 400 MHz, CDCl3, ppm: 1.05 (t, 3H), 2.09-2.23 (m, 4H), 3.17 (q, 2H), 3.24 (d, 1H), 3.39 (q, 2H), 3.51 (q, 3H), 3.77 (t, 2H), 4.51 (t, 2H), 7.27 (m, 2H), 7.52 (d, 1H), 7.62 (d, 1H)
96%
With hydrogenchloride; In tetrahydrofuran; water; at 0 - 5℃;
1) In a three-necked bottle, 100 g of intermediate II was added in sequence, 250 ml of tetrahydrofuran was added, and the reaction was cooled to 0 to 5 C, and 105 ml of concentrated hydrochloric acid was slowly added dropwise, and the mixture was stirred overnight; 2) The liquid phase is controlled to the raw material II <0.5%, and the post-treatment is started; 2) The solvent tetrahydrofuran was evaporated under reduced pressure, and then the mixture was evaporated to dryness. Combine the organic layers. Concentrated under reduced pressure to give the intermediate interrupter III, having a weight of 70.2g, a yield of 96%. The obtained intermediate III was subjected to high performance liquid chromatography analysis, and the spectrum is shown in Fig. 3. There are 5 peaks in the map, and the data is shown in Table 3.
93%
With succinic acid; for 22h;Reflux;
74.70 g of compound 5 (0.2 mol) was added to the reaction flask,Adding 3N succinic acid solution 1.1L,Heated to reflux for 22 hours, adjusted to pH = 7 with 10% aqueous sodium hydroxide solution, extracted with dichloromethane, and the solvent was removed to give 50.8 g of 1- (2-ethoxy-ethyl) -2-piperidin- -1H-benzimidazole (Compound 6) in a yield of 93%
34 g
With hydrogenchloride; In water; at 25 - 30℃; for 6h;
Example-18: Preparation of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole (Formula-9) A mixture of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidine-l- carboxylate compound of formula-32 (50 gm), hydrochloric acid (70 ml) and water (700 ml) was stirred for 6 hrs at 25-30C. Neutralized the reaction mixture using ammonia solution. Sodium chloride was added to the reaction mixture and stirred for 10 min. Extracted the reaction mixture with n-butanol and distilled off n-butanol completely. Dichloromethane (500 ml) was added to the obtained compound at 25-30C and stirred for 10 min at the same j temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Petroleum ether (250 ml) was added to the obtained compound at 25-30C and stirred for 5 min at the same temperature. Filtered the solid, washed with petroleum ether and dried to get the title compound. Yield: 34.0 gm.
With potassium hydroxide; In N,N-dimethyl acetamide; at 80℃;
1) In a three-necked bottle, 150 g of the compound of the formula I, 70.25 g of 2-ethoxychloroethane, 500 ml of N,N-dimethylacetamide, and 139.5 g of potassium hydroxide; 2) heating to 80 C reaction, when the liquid phase is controlled to the raw material I <0.5%, start post-treatment; 3) Evaporate the solvent N,N-dimethylacetamide under reduced pressure, and slowly add 500 ml of ice water under ice-cooling, then extract 200 ml*4 times with ethyl acetate, combine the organic layers, and wash 200 ml*2 times with saturated brine. The combined aqueous layers were extracted with ethyl acetate (200 ml). Combine the organic layers. Concentration under reduced pressure to abr. to afford Intermediate II, weight 180 g, yield 97%. The obtained intermediate II was subjected to high performance liquid chromatography analysis, and the spectrum is shown in Fig. 1. There are 4 peaks in the map, and the data is shown in Table 1.
92%
With sodium carbonate; sodium hydroxide; In water; at 40℃; for 2h;Cooling with ice;
To the reaction flask was added 38.00 g of 2-chloroethyl ethyl ether (compound 4, 0.35 mol) and 90.4 g of 4- (1H-benzo [d]Imidazol-2-yl) piperidine-1-carboxylate (compound 3, 0.3 mol) (40%) in water was added 7 mlPolyethylene glycol-400,(0.25 mol NaOH and 0.1 mol Na2CO3) were added slowly under ice-cooling, and the mixture was stirred rapidly at 40C for 2 hours. After completion of the reaction, the reaction solution was cooled, extracted with ether, washed with saturated brine, dried and filtered , The solvent was removed to give 103.1 g of compound 5 in 92% yield.
93 g
With sodium iodide; sodium hydroxide; In dimethyl sulfoxide; at 95 - 100℃; for 3h;
Example-17: Preparation of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidine-l-carboxylate (Formula-32) Tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate compound of formula-31 (100 gm), sodium iodide (10 gm) and l-chloro-2-ethoxyethane (54 gm) were slowly added to a pre-heated mixture of dimethylsulfoxide (200 ml) and sodium hydroxide (39.8 gm) at 40-45C. Heated the reaction mixture to 95-100C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 10-15C and water was slowly added. Neutralized the reaction mixture using aqueous hydrochloric acid. Ethyl acetate was added to the reaction mixture and stirred for 20 min. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (50 ml) was added to the obtained compound. Heated the reaction mixture to 60-65C and stirred for 15 min at the same temperature. Reduced the temperature of the reaction mixture to 40-45C and petroleum ether (650 ml) was slowly added. Cooled the reaction mixture to 0-5C and stirred for 10 min at the same temperature. Filtered the precipitated solid, washed with petroleum ether and dried to get the title compound. Yield: 93.0 gm.
In a 250 mL reaction bottle, add 14.94 g of Compound II and 1.2 mol/L hydrochloric acid 100 mL and stir, warm to 60C. After 1 h,TLC detected that the reaction was complete (dichloromethane: methanol: ammonia=10:1:0.1Rf=0.85).Cool to room temperature, adjust the pH to 12 with 4.8mol/L sodium hydroxide solution, add 40mL of dichloromethane for extraction, and concentrate the organic phase.Add 80mL of acetonitrile, 15.51g of N,N-diisopropylethylamine, dissolve with stirring, add 12.89g of the compound IV obtained in Example 1, warm to 65C and react for 3h,TLC detected that the reaction of compound IV was complete (petroleum ether: ethyl acetate = 20:1, Rf = 0.65), acetonitrile was distilled off under reduced pressure at 50C, and 80 mL of 6 mol/L hydrochloric acid was added.Stir to dissolve, wash three times with 30 mL of n-hexane-ethyl acetate mixture (2:1), adjust the pH of the aqueous phase to 6.0 with sodium hydroxide, and then adjust the pH to 7.5 with potassium carbonate, stir for 1 h, and filter,The filter cake was washed with 20 mL of water and dried under vacuum at 50 C. for 4 h to obtain compound V17.43 g with a yield of 91.2%.
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