1-propylpiperazine;dihydrobromide

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

Procedure: A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 4.2 g (0.03 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min, then treated with 2.9 g (0.01 mole) of 1-propylpiperazine dihydrobromide in small portions. After 30 min, a few pieces of ice were added. After stirring for 17 hr, the reaction was diluted with 200 ml of water then extracted with methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo, yielding 4.84 g of crude residue. The residue was converted to the fumarate salt in 2-propanol, concentrated to a solid in vacuo and recrystallized from acetone with a trace of ethanol to yield 2.9 g (59.5%) of fine white crystals; m.p. 117°-123° C. After 30 min a few pieces of ice were added After stirring for 17 hr then extracted with methylene chloride (2×50 ml) The combined extracts were dried over magnesium sulfate concentrated in vacuo yielding 4.84 g of crude residue concentrated to a solid in vacuo recrystallized from acetone with a trace of ethanol

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

Procedure: A mixture of 2.8 g (0.01 mole of 3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarbonyl chloride and 4.2 g (0.03 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min, then treated with 2.9 g (0.01 mole) of 1-propylpiperazine dihydrobromide in small portions. After 30 min, a few pieces of ice were added. After stirring for 17 hr, the reaction was diluted with 200 ml of water then extracted with methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo, yielding 4.84 g of crude residue. The residue was converted to the fumarate salt in 2-propanol, concentrated to a solid in vacuo and recrystallized from acetone with a trace of ethanol to yield 2.9 g (59.5%) of fine white crystals; m.p 117°-123° C. After 30 min a few pieces of ice were added After stirring for 17 hr then extracted with methylene chloride (2×50 ml) The combined extracts were dried over magnesium sulfate concentrated in vacuo yielding 4.84 g of crude residue concentrated to a solid in vacuo recrystallized from acetone with a trace of ethanol

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

Procedure: A mixture of 2.8 g (0.01 mole of 3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarbonyl chloride and 4.2 g (0.03 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min, then treated with 2.9 g (0.01 mole) of 1-propylpiperazine dihydrobromide in small portions. After 30 min, a few pieces of ice were added. After stirring for 17 hr, the reaction was diluted with 200 ml of water then extracted with methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo, yielding 4.84 g of crude residue. The residue was converted to the fumarate salt in 2-propanol, concentrated to a solid in vacuo and recrystallized from acetone with a trace of ethanol to yield 2.9 g (59.5%) of fine white crystals; m.p 117°-123° C. After 30 min a few pieces of ice were added After stirring for 17 hr then extracted with methylene chloride (2×50 ml) The combined extracts were dried over magnesium sulfate concentrated in vacuo yielding 4.84 g of crude residue concentrated to a solid in vacuo recrystallized from acetone with a trace of ethanol

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

Procedure: 21 g (0.15 mol) of potassium carbonate were added in portions to a suspension of 14.5 g (0.05 mol) of 1-n-propyl-piperazine dihydrobromide in 200 ml of acetonitrile. 7.4 g (0.05 mol) of dichloroacetyl chloride were added dropwise to this mixture at room temperature, while stirring. The mixture was subsequently stirred at 20° C. for 5 hours and working up was then effected by a procedure in which the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from a mixture of toluene and petroleum ether. 11.5 g (96% of theory) of 1-dichloroacetyl-4-n-propyl-piperazine were obtained in the form of beige-colored crystals of melting point 88° C. The mixture was subsequently stirred at 20° C. for 5 hours was filtered the filtrate was evaporated under reduced pressure The residue was recrystallized from a mixture of toluene and petroleum ether

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was heated to 60° C. for 3 hours, then was diluted with water (5 mL) and acidified with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was collected by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40° C. Ethyl ether was then added until the mixture became slightly cloudy (˜8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for 30 minutes. The solid was collected by filtration and dried in vacuum at 80° C. for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3 H) 1.64-1.79 (m, 2 H) 2.43 (s, 3 H) 2.81-3.20 (m, 4 H) 3.21-4.90 (m, 6 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71-7.91 (m, 2 H) 7.93-8.74 (m, 4 H) 10.75 (br. s., 1 H) 13.23 (br. s., 1 H); [M+H]+ 431. to give an orange solution stirred at ambient temperature for 30 minutes to give a solid The solid was collected by filtration washed with water (3 mL) The suspension was treated with 1N aqueous hydrochloric acid (2 mL) heated to 40° C Ethyl ether was then added until the mixture to cool to ambient temperature to give a solid cooled in an ice bath for 30 minutes The solid was collected by filtration dried in vacuum at 80° C. for 1.5 hour

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was heated to 60° C. for 3 hours, then was diluted with water (5 mL) and acidified with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was collected by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40° C. Ethyl ether was then added until the mixture became slightly cloudy (˜8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for 30 minutes. The solid was collected by filtration and dried in vacuum at 80° C. for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3 H) 1.64-1.79 (m, 2 H) 2.43 (s, 3 H) 2.81-3.20 (m, 4 H) 3.21-4.90 (m, 6 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71-7.91 (m, 2 H) 7.93-8.74 (m, 4 H) 10.75 (br. s., 1 H) 13.23 (br. s., 1 H); [M+H]+ 431. to give an orange solution stirred at ambient temperature for 30 minutes to give a solid The solid was collected by filtration washed with water (3 mL) The suspension was treated with 1N aqueous hydrochloric acid (2 mL) heated to 40° C Ethyl ether was then added until the mixture to cool to ambient temperature to give a solid cooled in an ice bath for 30 minutes The solid was collected by filtration dried in vacuum at 80° C. for 1.5 hour

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

Procedure: This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-propylpiperazine dihydrobromide, which is commercially available from, for example, Sigma-Aldrich Corporation. m/z (ES+) M+1=273.2; HPLC tR=1.49 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.70-3.55 (m, 4H), 2.49-2.35 (m, 5H), 2.33-2.27 (m, 2H), 1.99-1.91 (m, 1H), 1.65 (dt, J=9.2, 4.7 Hz, 1H), 1.50 (sextet, J=7.5 Hz, 2H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

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

Procedure: This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-propylpiperazine dihydrobromide, which is commercially available from, for example, Sigma-Aldrich Corporation. m/z (ES+) M+1=273.2; HPLC tR=1.49 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.70-3.55 (m, 4H), 2.49-2.35 (m, 5H), 2.33-2.27 (m, 2H), 1.99-1.91 (m, 1H), 1.65 (dt, J=9.2, 4.7 Hz, 1H), 1.50 (sextet, J=7.5 Hz, 2H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

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

Procedure: 42 g (0.50 mol) sodium acetate were added in portions to 73 g (0.25 mol) N-propylpiperazine dihydrobromide in 1 l methanol at 40° C. Subsequently, this was cooled to 0° C. and 50 g (0.25 mol) Boc-4-piperidon and 16 g (0.25 mol) sodium cyanoborohydride, in portions, were added, one after the other. Everything was then stirred at room temperature for 16 h. The reaction mixture was concentrated in a vacuum and then distributed between ethyl acetate and 1M NaOH. The organic phase was separated, washed with 1M NaOH, H2O and conc. NaCl solution, dried and concentrated in a vacuum. The residue was chromatographically purified over silica gel (mobile phase: MeOH/CH2Cl2=1/15). 43.6 g of the product were obtained. The reaction mixture was concentrated in a vacuum The organic phase was separated washed with 1M NaOH, H2O and conc. NaCl solution dried concentrated in a vacuum The residue was chromatographically purified over silica gel (mobile phase: MeOH/CH2Cl2=1/15)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was heated to 60° C. for 3 hours, then was diluted with water (5 mL) and acidified with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was collected by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40° C. Ethyl ether was then added until the mixture became slightly cloudy (˜8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for 30 minutes. The solid was collected by filtration and dried in vacuum at 80° C. for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3H) 1.64-1.79 (m, 2H) 2.43 (s, 3H) 2.81-3.20 (m, 4H) 3.21-4.90 (m, 6H) 7.67 (d, J=7.58 Hz, 1H) 7.71-7.91 (m, 2H) 7.93-8.74 (m, 4H) 10.75 (br. s., 1H) 13.23 (br. s., 1H); [M+H]+ 431. to give an orange solution stirred at ambient temperature for 30 minutes to give a solid The solid was collected by filtration washed with water (3 mL) The suspension was treated with 1N aqueous hydrochloric acid (2 mL) heated to 40° C Ethyl ether was then added until the mixture to cool to ambient temperature to give a solid cooled in an ice bath for 30 minutes The solid was collected by filtration dried in vacuum at 80° C. for 1.5 hour

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was heated to 60° C. for 3 hours, then was diluted with water (5 mL) and acidified with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was collected by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40° C. Ethyl ether was then added until the mixture became slightly cloudy (˜8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for 30 minutes. The solid was collected by filtration and dried in vacuum at 80° C. for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3H) 1.64-1.79 (m, 2H) 2.43 (s, 3H) 2.81-3.20 (m, 4H) 3.21-4.90 (m, 6H) 7.67 (d, J=7.58 Hz, 1H) 7.71-7.91 (m, 2H) 7.93-8.74 (m, 4H) 10.75 (br. s., 1H) 13.23 (br. s., 1H); [M+H]+ 431. to give an orange solution stirred at ambient temperature for 30 minutes to give a solid The solid was collected by filtration washed with water (3 mL) The suspension was treated with 1N aqueous hydrochloric acid (2 mL) heated to 40° C Ethyl ether was then added until the mixture to cool to ambient temperature to give a solid cooled in an ice bath for 30 minutes The solid was collected by filtration dried in vacuum at 80° C. for 1.5 hour

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

Procedure: 42 g (0.50 mol) sodium acetate were added in portions to 73 g (0.25 mol) N-propylpiperazine dihydrobromide in 1 l methanol at 40° C. Subsequently, this was cooled to 0° C. and 50 g (0.25 mol) Boc-4-piperidon and 16 g (0.25 mol) sodium cyanoborohydride, in portions, were added, one after the other. Everything was then stirred at room temperature for 16 h. The reaction mixture was concentrated in a vacuum and then distributed between ethyl acetate and 1M NaOH. The organic phase was separated, washed with 1M NaOH, H2O and conc. NaCl solution, dried and concentrated in a vacuum. The residue was chromatographically purified over silica gel (mobile phase: MeOH/CH2Cl2=1/15). 43.6 g of the product were obtained. The reaction mixture was concentrated in a vacuum The organic phase was separated washed with 1M NaOH, H2O and conc. NaCl solution dried concentrated in a vacuum The residue was chromatographically purified over silica gel (mobile phase: MeOH/CH2Cl2=1/15)