1-(4-METHYLBENZYL)PIPERAZINE

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-[4-(4-methyl-benzyl)-piperazine-1-sulfonylamino]-propionic acid ethyl ester. A mixture of oxazolidione from Step A (40 mg, 0.065 mmol), 1-(4-methylbenzyl)piperazine (24.7 mg, 0.13 mmol), and triethylamine (20 mg, 0.2 mmol) in acetonitrile (3 mL) was heated at 85° C. for 2.5 hrs. TLC showed the reaction was completed. The solution was concentrated. Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution. The layers were separated, and the aqueous portion was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (32 mg, 69% yield) as a yellow solid. The solution was concentrated Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution The layers were separated the aqueous portion was extracted with ethyl acetate (20 mL) The combined organic layer was washed with brine (2×20 mL) dried over anhydrous sodium sulfate filtered concentrated

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-[4-(4-methyl-benzyl)-piperazine-1-sulfonylamino]-propionic acid ethyl ester. A mixture of oxazolidione from Step A (40 mg, 0.065 mmol), 1-(4-methylbenzyl)piperazine (24.7 mg, 0.13 mmol), and triethylamine (20 mg, 0.2 mmol) in acetonitrile (3 mL) was heated at 85° C. for 2.5 hrs. TLC showed the reaction was completed. The solution was concentrated. Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution. The layers were separated, and the aqueous portion was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (32 mg, 69% yield) as a yellow solid. The solution was concentrated Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution The layers were separated the aqueous portion was extracted with ethyl acetate (20 mL) The combined organic layer was washed with brine (2×20 mL) dried over anhydrous sodium sulfate filtered concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. the mixture was stirred for an additional hour the product was extracted with ether the extract was dried (sodium sulfate) treated with ethereal hydrochloric acid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. the mixture was stirred for an additional hour the product was extracted with ether the extract was dried (sodium sulfate) treated with ethereal hydrochloric acid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of bis(2-chloroethyl)disulfide (2.9 g) in dimethylsulfoxide (5 ml) is added dropwise to a warmed mixture of (4-methylbenzyl)piperazine (5.7 g), potassium hydroxide (5.0 g), and dimethylsulfoxide (55 ml). The resulting mixture is stirred an additional 4 hours after which it is poured over ice/water and the product extracted with methylene chloride, dried and concentrated. The resulting oil (6.5 g) is purified on a silica gel column (methylene chloride:methanol, 95:5), and the salt precipitated with ethereal hydrochloric acid to provide, after recrystallization from ethanol/water, 1,1'-(dithiodi-2,1-ethanediyl)bis[4-(4-methylbenzyl)piperazine] tetrahydrochloride as a white crystalline solid, m.p. 280°-282° C. the product extracted with methylene chloride dried concentrated The resulting oil (6.5 g) is purified on a silica gel column (methylene chloride:methanol, 95:5) the salt precipitated with ethereal hydrochloric acid to provide after recrystallization from ethanol/water, 1,1'-(dithiodi-2,1-ethanediyl)bis[4-(4-methylbenzyl)piperazine] tetrahydrochloride as a white crystalline solid, m.p. 280°-282° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example 1(b) was followed, using 7.7 g of thiourea, 23.0 g of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride, 6.5 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 16.4 g (72% of theory) of 3-[4-(4-methylbenzyl)piperazin-1-yl] propanethiol dihydrochloride as a white crystalline solid, M.p. 273°-277° C. (dec.). the mixture was stirred for an additional hour the product was extracted with ether the extract was dried (sodium sulfate) treated with ethereal hydrochloric acid

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-phenyl-3-(2-pyrimidinyl)propenal (1.25 g) in tetrahydrofuran (125 cc) is added to 4-(4-methylbenzyl)piperazine (11.2 g). The solution is stirred and heated to a temperature in the region of 65° C. for 3 hours. After being coiled to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl acetate (10 cc) and the solution obtained is poured onto silica (25 g) contained in a column 1.5 cm in diameter. Elution is performed with a mixture (750 cc) of ethyl acetate and cyclohexane (50:50 by volume); the corresponding eluates are discarded. Elution is then performed with the same mixture (300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (20 cc). Oxalic acid (120 mg) dissolved in methyl ethyl ketone (20 cc) is added and the mixture is stirred for approximately 15 minutes at a temperature in the region of 20° C. The precipitate formed is separated by filtration and then recrystallized in boiling isopropyl alcohol (50 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylpyrrolo[1,2-a]pyrimidine oxalate (300 mg), m.p. 205° C., is thereby obtained. After being coiled to a temperature in the region of 20° C. the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The residue obtained the solution obtained is poured onto silica (25 g) Elution Elution the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The oil obtained is added the mixture is stirred for approximately 15 minutes at a temperature in the region of 20° C The precipitate formed is separated by filtration recrystallized

反应条件: temp:66.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-(4-methylbenzyl)piperazine (9.5 g) in tetrahydrofuran (50 cc) is added in the course of 10 minutes at a temperature in the region of 20° C. to a stirred solution of 3-phenyl-3-pyrazinylpropenal (1 g) in tetrahydrofuran (50 cc), and the mixture is left with stirring for 3 hours at a temperature in the region of 66° C. After the solution is cooled to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. A residue is obtained which is dissolved in methylene chloride (10 cc). The solution obtained is poured onto silica (200 g) contained in a column 3.5 cm in diameter. Elution is performed with a mixture (500 cc) of methylene chloride and methanol (99.5:0.5 by volume) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in boiling methyl ethyl ketone (20 cc). A solution of oxalic acid (0.25 g) in boiling methyl ethyl ketone (20 cc) is added. After the mixture is cooled to a temperature in the region of 20° C., the precipitate formed is separated by filtration and then recrystallized in boiling isopropyl alcohol (80 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylpyrrolo[1,2-a]pyrazine oxalate (0.4 g), m.p. 128° C., is thereby obtained. the mixture is left After the solution is cooled to a temperature in the region of 20° C. the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C A residue is obtained which The solution obtained is poured onto silica (200 g) Elution the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The oil obtained is dissolved is added After the mixture is cooled to a temperature in the region of 20° C. the precipitate formed is separated by filtration recrystallized

反应条件: temp:66.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-(4-methylbenzyl)piperazine (14 g) in tetrahydrofuran (30 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution of 3-phenyl-3-(2-pyridyl)propenal (5.4 g) in tetrahydrofuran (150 cc), and the mixture is left with stirring for 8 hours at a temperature in the region of 66° C. After the solution is cooled to a temperature in the region of 20° C., the reaction mixture is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl ether (50 cc) and the solution obtained poured onto silica (400 g) contained in a column 4.7 cm in diameter. Elution is performed with a mixture (300 cc) of ethyl ether and petroleum ether (40°-65° C.) (80:20 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in boiling ethyl ether (200 cc). A boiling 2.5N solution (3 cc) of hydrochloric acid in ethyl alcohol is added. After the mixture is cooled to a temperature in the region of 20° C, the precipitate formed is separated by filtration and then recrystallized in boiling ethyl alcohol (400 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylindolizine hydrochloride (3.1 g), m.p. 210° C. with decomposition, is thereby obtained. the mixture is left After the solution is cooled to a temperature in the region of 20° C. the reaction mixture is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The residue obtained the solution obtained poured onto silica (400 g) Elution is performed with a mixture (300 cc) of ethyl ether and petroleum ether (40°-65° C.) (80:20 by volume) the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The oil obtained is dissolved After the mixture is cooled to a temperature in the region of 20° C the precipitate formed is separated by filtration recrystallized

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-4-phenylpyridine (11.4 g) and 4-(4-methylbenzyl)piperazine (11.4 g) in 1,2,4-trichlorobenzene (40 cc) is heated for 5 hours at 170° C. After the mixture is cooled to a temperature in the region of 20° C., isopropyl ether (200 cc) is added. The precipitate formed is separated by filtration, washed with isopropyl ether (50 cc) and then dissolved in ethyl acetate (250 cc). 5N aqueous sodium hydroxide solution (16 cc) is added, followed by distilled water (100 cc). The organic solution is decanted and the aqueous phase washed with ethyl acetate (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 2-propanol (75 cc); decolorizing charcoal (0.5 g) is added and the mixture is heated to 100° C. for 30 minutes, filtered on diatomaceous earth and cooled to 10° C. for 1 hour. The precipitate formed is separated by filtration and washed with 2-propanol (2×10 cc). 2-[4-(4-Methylbenzyl)-1-piperazinyl]-4-phenylpyridine (8 g), m.p. 103° C., is thereby obtained. is added The precipitate formed is separated by filtration washed with isopropyl ether (50 cc) dissolved in ethyl acetate (250 cc) 5N aqueous sodium hydroxide solution (16 cc) is added by distilled water (100 cc) The organic solution is decanted the aqueous phase washed with ethyl acetate (2×50 cc) dried over anhydrous magnesium sulphate filtered evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C The residue is dissolved in 2-propanol (75 cc) decolorizing charcoal (0.5 g) is added filtered on diatomaceous earth cooled to 10° C. for 1 hour The precipitate formed is separated by filtration washed with 2-propanol (2×10 cc)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. the mixture was stirred for an additional hour the product was extracted with ether the extract was dried (sodium sulfate) treated with ethereal hydrochloric acid