1-(2-chlorophenyl)piperazine;hydrochloride

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

Procedure: 200.0 mg of the target compound (0.55 mmol, 67.2%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 60 mg of the target compound (0.17 mmol, 20.7%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), 1-(2-chlorophenyl)piperazine hydrochloride (1.4 g), and potassium carbonate (2.1 g) in N,N-dimethylformamide (15 mL) was stirred under nitrogen gas at 145° C. for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethylacetate=5:1 to 2:1). The 2-[[4-(2-chlorophenyl)-1-piperazinyl]methyl)]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine thus obtained was dissolved in methanol and a stoichiometric excess of 10% hydrogen chloride solution in methanol was added. The mixture was concentrated under reduced pressure and recrystallized from ethanol/diethyl ether to provide 1.0 g of the title compound. Yield 44%. extracted with ethyl acetate The pooled organic layer was washed with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate (Na2SO4) and silica gel (eluted with ethyl acetate) concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethylacetate=5:1 to 2:1)

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

Procedure: 200.0 mg of the target compound (0.55 mmol, 67.2%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 200.0 mg of the target compound (0.55 mmol, 67.2%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 60 mg of the target compound (0.17 mmol, 20.7%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 60 mg of the target compound (0.17 mmol, 20.7%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C. stirring was continued for 2 days extracted with diethyl ether and ethyl acetate The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water were then dried on anhydrous sodium sulfate After evaporation to dryness in vacuo the residue was dissolved in 160 ml of acetonitrile excess hydrogen chloride in diethyl ether was added The insoluble title compound was recrystallized from acetonitrile

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

Procedure: A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C. stirring was continued for 2 days extracted with diethyl ether and ethyl acetate The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water were then dried on anhydrous sodium sulfate After evaporation to dryness in vacuo the residue was dissolved in 160 ml of acetonitrile excess hydrogen chloride in diethyl ether was added The insoluble title compound was recrystallized from acetonitrile

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

Procedure: To a solution of N-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide (60 mg, 0.12 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol) and 1,1′-carbonyldiimidazole (20.6 mg, 0.13 mmol). The resulting mixture was stirred at it for 1 h under nitrogen, then 1-(2-chlorophenyl)piperazine monohydrochloride (29.6 mg, 0.13 mmol) was added. The mixture was stirred overnight. The mixture was concentrated and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give white solid (54 mg, 62%). 1H NMR (MeOD-d4): δ 7.57 (d, J=2.8 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.28 (m, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.15 (m, 1H), 7.06 (m, 4H), 6.92 (m, 1H), 6.88 (m, 1H), 4.45 (s, 2H), 4.41 (s, 2H), 4.21 (s, 2H), 3.50 (t, J=5.0 Hz, 4H), 2.93 (t, J=5.0 Hz, 4H); MS (ESI): (M+H)+=743.2. The mixture was stirred overnight The mixture was concentrated purified by preparative HPLC Fractions containing the desired product concentrated

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

Procedure: 3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (20.7 mg, 0.094 mmol), 1-(2-chlorophenyl)piperazine hydrochloride (20.0 mg, 0.086 mmol), molecular sieve (5 beads), NaBH(OAc)3 (54.5 mg, 0.257 mmol) and diisopropylethylamine (26.9 L, 0.085 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.8 mg (87.2%) of the target compound was obtained.

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

Procedure: from 1-(2-chlorophenyl)piperazine, hydrochloride and 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one. Mp 119–121° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.35–2.50 (m, 4H); 2.55 (s, 4H); 3.95 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H); 7.15 (t, 1H); 7.20 (d, 1H); 7.25 (t, 1H); 7.40 (d, 1H); 8.10 (d, 1H). MS m/z: 384 (MH+), 265, 188.