3-piperazin-1-ylpropan-1-ol

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

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

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

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

Procedure: 1-(3-Hydroxypropyl)-4-piperazine (0.63 g, 4.0 mmol) was dissolved in DCM (30 mL) and cooled to 0° C. DIPEA (1.39 mL, 8.0 mmol) and p-nitrophenyl chloroformate (0.80 g, 4.0 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then phenylpiperazine (0.61 mL, 4.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed sequentially with 1M aq Na2CO3 solution (4×100 mL), and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (30 mL) and stirred with solid Na2CO3 for 20 minutes, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (gradient eluting with acetonitrile in water, 5-45%) to give 3-(4-methyl-piperazin-1-yl)propyl 4-phenylpiperazine-1-carboxylate (148 mg, 11%) as a colourless oil. The reaction mixture was stirred at room temperature for 16 hours concentrated in vacuo The residue was dissolved in EtOAc (100 mL) washed sequentially with 1M aq Na2CO3 solution (4×100 mL) concentrated in vacuo The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%) The resulting residue was dissolved in DCM (30 mL) stirred with solid Na2CO3 for 20 minutes filtered concentrated in vacuo The resulting residue was purified by reverse phase HPLC (gradient eluting with acetonitrile in water, 5-45%)

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

Procedure: 1-Piperazinepropanol was reacted with benzhydryl bromide in the same manner as Reference Example 1-(1) to give crystals of 4-benzhydryl-1-piperazinepropanol, m.p. 126°-128° C. Yield 76.3%.

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

Procedure: A mixture of 5.39 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c., and 17 g of 1-piperazinepropanol in a pressurized bottle was heated to 220° C. overnight. The reaction mixture was dissolved in CH2Cl2 and then was washed with water. Removal of solvent in vacuo followed by recrystallization from EtOH gave the title compound, a colorless solid, mp 174°-175° C. was washed with water Removal of solvent in vacuo followed by recrystallization from EtOH

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

Procedure: A mixture of 5.39 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c., and 17 g of 1-piperazinepropanol in a pressurized bottle was heated to 220° C. overnight. The reaction mixture was dissolved in CH2Cl2 and then was washed with water. Removal of solvent in vacuo followed by recrystallization from EtOH gave the title compound, a colorless solid, mp 174°-175° C. was washed with water Removal of solvent in vacuo followed by recrystallization from EtOH

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

Procedure: Grams 8.65 of 1-(3-hydroxypropyl)piperazine and 4.7 g of 2-chloronicotinic acid in 100 ml dioxane were refluxed for 6 hours. The reaction mixture was cooled and settled. The residual oil, crystallized from 95° ethanol, gave 2.3 g of 2-[4-(3-hydroxypropyl)piperazin-1-yl]nicotinic acid, melting at 222°-225° C. (with decomposition). The reaction mixture was cooled The residual oil, crystallized from 95° ethanol

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

Procedure: To a solution of 1-(3-hydroxypropyl)piperazine (700 mg, 4.88 mmol) in acetonitrile (15 ml) were added potassium carbonate (805 mg, 5.82 mmol) and 2-bromo-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (1.53 g, 4.88 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a saturated ammonium chloride solution and the mixture was extracted with chloroform-methanol mixture solvent. The organic layer was washed with water and a saturated sodium chloride successively and dried over anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was recrystallized from chloroform-methanol-hexane to provide 1.13 g (yield 62%) of 2-[4-(3-hydroxypropyl)piperazin-1-yl]-N-[2,6-diisopropyl-4-hydroxyphenyl]acetamide as colorless powdery crystals. the mixture was extracted with chloroform-methanol mixture solvent The organic layer was washed with water a saturated sodium chloride successively and dried over anhydrous sodium sulfate the solvent was evaporated The resulting residue was recrystallized from chloroform-methanol-hexane

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

Procedure: Potassium carbonate (2.49 g, 18 mmol) was added to a solution of 2-bromo-N-heptylacetamide (3.30 g, 15 mmol) obtained in Example 16 and 1-(3-hydroxypropyl)piperazine (2.16 g, 15 mmol) in acetonitrile (60 ml) and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution successively and dried over anhydrous sodium carbonate and the residue obtained after evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 4.38 g (yield 97%) of N-heptyl-2-[4-[3-hydroxypropyl]piperazin-1-yl]acetamide as colorless oil. The reaction solution was concentrated the residue was extracted with ethyl acetate The organic layer was washed with water and saturated sodium chloride solution successively dried over anhydrous sodium carbonate the residue obtained after evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20)

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

Procedure: Potassium carbonate (2.49 g, 18 mmol) was added to a solution of 2-bromo-N-heptylacetamide (3.30 g, 15 mmol) obtained in Example 16 and 1-(3-hydroxypropyl)piperazine (2.16 g, 15 mmol) in acetonitrile (60 ml) and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution successively and dried over anhydrous sodium carbonate and the residue obtained after evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 4.38 g (yield 97%) of N-heptyl-2-[4-[3-hydroxypropyl]piperazin-1-yl]acetamide as colorless oil. The reaction solution was concentrated the residue was extracted with ethyl acetate The organic layer was washed with water and saturated sodium chloride solution successively dried over anhydrous sodium carbonate the residue obtained after evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20)

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

Procedure: In analogy to the procedure described in Example 181, 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) and 1-piperazinepropanol gave after suspending in a small amount of EtOAc and filtration the title compound in 59% yield as light yellow powder. MS: 459.3 (MH+). gave after suspending in a small amount of EtOAc and filtration the title compound in 59% yield as light yellow powder