1,4-dimethylpiperazine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5000 mL four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer, thermometer and a dropping funnel was charged with 1198.5 (5.0 moles) of a 47.6 percent aqueous solution of 1,4-dimethylpiperazine. The solution was cooled by means of an ice-water bath and 985.5 g (10.0 moles) of 37 percent hydrochloric acid was added at such a rate as to keep the temperature below 45° C. To the well-agitated 1,4-dimethylpiperazine dihydrochloride solution so obtained, 925.2 g (10.0 moles) of epichlorohydrin was added slowly, again at such a rate as to keep the temperature below 45° C. After the addition was completed, the temperature of the reaction mixture was raised to between 60 and 70° C. for 30 minutes, followed by another hour at 100° C. A 59.8 percent solution of N,N'-dimethyl-N,N'-bis-(3-chloro-2-hydroxypropyl)piperazinium dichloride was obtained. A 5000 mL four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer The solution was cooled by means of an ice-water bath the temperature below 45° C

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5000 mL four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer, thermometer and a dropping funnel was charged with 1198.5 g (5.0 moles) of a 47.6 percent aqueous solution of 1,4-dimethylpiperazine. The solution was cooled by means of an ice-water bath and 985.5 g (10.0 moles) of 37 percent hydrochloric acid was added at such a rate as to keep the temperature below 45° C. To the well-agitated 1,4-dimethylpiperazine dihydrochloride solution so obtained, 925.2 g (10.0 moles) of epichlorohydrin was added slowly, again at such a rate as to keep the temperature below 45° C. After the addition was completed, the temperature of the reaction mixture was raised to between 60 and 70° C for 30 minutes, followed by another hour at 100° C. A 59.8 percent solution of N,N'-dimethyl-N,N'-bis-(3-chloro-2-hydroxypropyl) piperazinium dichloride was obtained. A 5000 mL four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer The solution was cooled by means of an ice-water bath the temperature below 45° C

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromoethyl thiolacetate *(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 mL, 0.014 mol) in acetone (4 mL) was stirred at 50° C. for 65 h. After cooling to 25° C., the liquid phase was decanted from the gum which was triturated twice in diethyl ether; a hygroscopic yellowish powder, 3.2 g (90%) was obtained; ir (Nujol) νmax : 1685 (C=O of thioester) cm-1 ; 1Hmr (D2O) δ: ##STR141## the liquid phase was decanted from the gum which was triturated twice in diethyl ether a hygroscopic yellowish powder, 3.2 g (90%) was obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5000 ml four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer, thermometer and a dropping funnel was charged with 1198.5 g (5.0 moles) of a 47.6 percent aqueous solution of 1,4-dimethylpiperazine. The solution was cooled by means of an ice-water bath and 985.5 g (10.0 moles) of 37 percent hydrochloric acid was added at such a rate as to keep the temperature below 45° C. To the well-agitated 1,4-dimethylpiperazine dihydrochloride solution so obtained, 925.2 g (10.0 moles) of epichlorohydrin was added slowly, again at such a rate as to keep the temperature below 45° C. After the addition was completed, the temperature of the reaction mixture was raised to between 60° and 70° C. for 30 minutes, followed by another hour at 100° C. A 59.8 percent solution of N,N'-dimethyl-N,N'-bis(3-chloro-2-hydroxypropyl) piperazinium dichloride was obtained. A 5000 ml four-neck round-bottom flask equipped with a reflux condenser, mechanical stirrer The solution was cooled by means of an ice-water bath the temperature below 45° C

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner, N,N'-di-methylpiperazine is reacted with α-chloroethyl chloroformate (ACE-Cl) to give the intermediate N-α-chloroethoxycarbonyl N'-methyl piperazine, which is then dehydrohalogenated as in Example 21b to give N-(vinyloxycarbonyl)N'-methylpiperazine.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner, N,N'-di-methylpiperazine is reacted with α-chloroethyl chloroformate (ACE-Cl) to give the intermediate N-α-chloroethoxycarbonyl N'-methyl piperazine, which is then dehydrohalogenated as in Example 21b to give N-(vinyloxycarbonyl)N'-methylpiperazine.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis(2-chloroethyl)amine hydrochloride (5 g, 0.028 mol) is put into a 100 mL two-necked flask, and N,N′-Dimethylpiperazine (7.1 eq) is added into the flask. After cooling the flask and the reactants therein to about 4° C., POCl3 (4.49 g, 1.04 eq) is slowly dropped into the flask, and the mixture in the flask is stirred at room temperature for 5 hours. After that, the mixture in the flask is cooled to about 4° C., and 3-aminopropanol (2.1 g, 1.0 eq) is slowly dropped into the flask for 3 hours. After adding 3-aminopropanol into the flask, the mixture in the flask is stirred at room temperature for 15 hours. (The conversion yield determined with HPLC is about 11.84%.) After cooling the flask After that, the mixture in the flask is cooled to about 4° C. the mixture in the flask is stirred at room temperature for 15 hours (The conversion yield

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis(2-chloroethyl)amine hydrochloride (5 g, 0.028 mol) is put into a 100 mL two-necked flask, and N,N′-Dimethylpiperazine (7.1 eq) is added into the flask. After cooling the flask and the reactants therein to about 4° C., POCl3 (4.49 g, 1.04 eq) is slowly dropped into the flask, and the mixture in the flask is stirred at room temperature for 5 hours. After that, the mixture in the flask is cooled to about 4° C., and 3-aminopropanol (2.1 g, 1.0 eq) is slowly dropped into the flask for 3 hours. After adding 3-aminopropanol into the flask, the mixture in the flask is stirred at room temperature for 15 hours. (The conversion yield determined with HPLC is about 11.84%.) After cooling the flask After that, the mixture in the flask is cooled to about 4° C. the mixture in the flask is stirred at room temperature for 15 hours (The conversion yield

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl indole-3-carboxylate and dichloromethane is cooled to 0° C. 1,4-dimethylpiperazine (0.55 eq.) and N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir for two hours to give a slurry containing the compound of formula (C) above. The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining the temperature below 0° C. The reaction mixture is left to stir for half an hour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water. The organic solution is dried over sodium sulphate, filtered and the solvent evaporated. Toluene is added and the mixture stirred at 0-5° C. for one hour. The product is then filtered, washed with toluene and dried to give the title product in 83% yield. the mixture left to give a slurry maintaining the temperature below 0° C The reaction mixture is left to stir for half an hour washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water The organic solution is dried over sodium sulphate filtered the solvent evaporated Toluene is added the mixture stirred at 0-5° C. for one hour The product is then filtered washed with toluene dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl indole-3-carboxylate and dichloromethane is cooled to 0° C. 1,4-dimethylpiperazine (0.55 eq.) and N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir for two hours to give a slurry containing the compound of formula (C) above. The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining the temperature below 0° C. The reaction mixture is left to stir for half an hour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water. The organic solution is dried over sodium sulphate, filtered and the solvent evaporated. Toluene is added and the mixture stirred at 0-5° C. for one hour. The product is then filtered, washed with toluene and dried to give the title product in 83% yield. the mixture left to give a slurry maintaining the temperature below 0° C The reaction mixture is left to stir for half an hour washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water The organic solution is dried over sodium sulphate filtered the solvent evaporated Toluene is added the mixture stirred at 0-5° C. for one hour The product is then filtered washed with toluene dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromoethyl thiolacetate *(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 mL, 0.014 mol) in acetone (4 mL) was stirred at 50° C. for 65 h. After cooling to 25° C., the liquid phase was decanted from the gum which was triturated twice in diethyl ether; a hygroscopic yellowish powder, 3.2 g (90%) was obtained; ir (Nujol) νmax : 1685 (C=O of thioester) cm-1 ; 1Hmr (D2O) δ: 2.37, 2.39 ##STR122## the liquid phase was decanted from the gum which was triturated twice in diethyl ether a hygroscopic yellowish powder, 3.2 g (90%) was obtained