4-(2-chlorophenyl)sulfanylpiperidine;hydrochloride

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

Procedure: A mixture of 88.76 g (0.23 mole) of 4-[(2-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 47.0 g (0.50 mole) of phenol and 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The mixture was made alkaline with 50% sodium hydroxide and extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The acidic layer was made alkaline and extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate, filtered and evaporated to give an oil, the free base of the title compound. The free base was converted to 4.30 g (36.5%) of a white crystalline hydrochloride salt, m.p. 202°-210° C. was refluxed for 1.5 hr extracted with diethyl ether The ether phase was extracted with 1N sulfuric acid extracted with methylene chloride The methylene chloride layer was dried over sodium sulfate filtered evaporated to give an oil

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

Procedure: To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.04 g, 0.00014 mol) in DMF (1 mL) was added DIPEA (0.05517 g, 0.00043 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0326 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride (0.0449 g, 0.00017 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.054 g (84%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chlorophenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.12 (M+1)+, 83.96%, 1H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.38 (t, 2H), 7.24 (t, 2H), 7.15 (s, 1H), 4.2 (m, 3H), 3.85 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.56 (m, 1H), 1.4 (m, 1H). The resulting precipitate was isolated by filtration dried

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

Procedure: To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.04 g, 0.00014 mol) in DMF (1 mL) was added DIPEA (0.05517 g, 0.00043 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0326 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride (0.0449 g, 0.00017 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.054 g (84%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chlorophenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.12 (M+1)+, 83.96%, 1H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.38 (t, 2H), 7.24 (t, 2H), 7.15 (s, 1H), 4.2 (m, 3H), 3.85 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.56 (m, 1H), 1.4 (m, 1H). The resulting precipitate was isolated by filtration dried

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

Procedure: To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%. The reaction mixture was then concentrated under reduced pressure the resulting residue was washed with hexane twice

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

Procedure: A mixture of 88.76 g (0.23 mole) of 4-[(2-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 47.0 g (0.50 mole) of phenol and 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The mixture was made alkaline with 50% sodium hydroxide and extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The acidic layer was made alkaline and extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate, filtered and evaporated to give an oil, the free base of the title compound. The free base was converted to 4.30 g (36.5%) of a white crystalline hydrochloride salt, m.p. 202°-210° C. was refluxed for 1.5 hr extracted with diethyl ether The ether phase was extracted with 1N sulfuric acid extracted with methylene chloride The methylene chloride layer was dried over sodium sulfate filtered evaporated to give an oil

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

Procedure: A mixture of 88.76 g (0.23 mole) of 4-[(2-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 47.0 g (0.50 mole) of phenol and 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The mixture was made alkaline with 50% sodium hydroxide and extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The acidic layer was made alkaline and extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate, filtered and evaporated to give an oil, the free base of the title compound. The free base was converted to 4.30 g (36.5%) of a white crystalline hydrochloride salt, m.p. 202°-210° C. was refluxed for 1.5 hr extracted with diethyl ether The ether phase was extracted with 1N sulfuric acid extracted with methylene chloride The methylene chloride layer was dried over sodium sulfate filtered evaporated to give an oil

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

Procedure: To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.04 g, 0.00014 mol) in DMF (1 mL) was added DIPEA (0.05517 g, 0.00043 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0326 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride (0.0449 g, 0.00017 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.054 g (84%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chlorophenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.12 (M+1)+, 83.96%, 1H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.38 (t, 2H), 7.24 (t, 2H), 7.15 (s, 1H), 4.2 (m, 3H), 3.85 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.56 (m, 1H), 1.4 (m, 1H). The resulting precipitate was isolated by filtration dried

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

Procedure: To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%. The reaction mixture was then concentrated under reduced pressure the resulting residue was washed with hexane twice

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

Procedure: A mixture of 88.76 g (0.23 mole) of 4-[(2-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 47.0 g (0.50 mole) of phenol and 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The mixture was made alkaline with 50% sodium hydroxide and extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The acidic layer was made alkaline and extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate, filtered and evaporated to give an oil, the free base of the title compound. The free base was converted to 4.30 g (36.5%) of a white crystalline hydrochloride salt, m.p. 202°-210° C. was refluxed for 1.5 hr extracted with diethyl ether The ether phase was extracted with 1N sulfuric acid extracted with methylene chloride The methylene chloride layer was dried over sodium sulfate filtered evaporated to give an oil