3-chloropropylcyclohexane

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

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

Procedure: Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-cyclohexylpropyl chloride (161 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (342 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate)

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

Procedure: Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-cyclohexylpropyl chloride (161 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (342 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate)

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

Procedure: 1-Chloro-3-cyclohexylpropane (11.1 g, 69.0 mmol), 2-aminoacetaldehyde (15.0 mL, 138.0 mmol, 2.0 equiv), and sodium iodide (2.1 g, 14.0 mmol, 0.2 equiv) were combined in anhydrous N,N-dimethylformamide (20 mL). The solution was stirred over solid potassium carbonate (9.66 g, 70 mmol) at 80° C. for 16 hours. The mixture was cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate (2×). The combined organic phase was washed with brine (3×), dried (MgSO4), and concentrated in vacuo to a crude oil. Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate) yielded the title compound as a yellow oil (12.0 g, 76%). 1H NMR (CDCl3, 300 MHz) δ 4.46 (t, 5.5 Hz, 1H), 3.38 (s, 6H), 2.71 (d, 5.5 Hz, 2H), 2.57 (t, 7.4 Hz, 2H), 1.75-1.60 (m, 3H), 1.47 (m, 2H), 1.17 (m, 8H), 0.86 (m, 2H); Rf=0.27 (50:50 hexane/ethyl acetate). The solution was extracted with ethyl acetate (2×) The combined organic phase was washed with brine (3×) dried (MgSO4) concentrated in vacuo to a crude oil Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate)

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

Procedure: 1-Chloro-3-cyclohexylpropane (11.1 g, 69.0 mmol), 2-aminoacetaldehyde (15.0 mL, 138.0 mmol, 2.0 equiv), and sodium iodide (2.1 g, 14.0 mmol, 0.2 equiv) were combined in anhydrous N,N-dimethylformamide (20 mL). The solution was stirred over solid potassium carbonate (9.66 g, 70 mmol) at 80° C. for 16 hours. The mixture was cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate (2×). The combined organic phase was washed with brine (3×), dried (MgSO4), and concentrated in vacuo to a crude oil. Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate) yielded the title compound as a yellow oil (12.0 g, 76%). 1H NMR (CDCl3, 300 MHz) δ 4.46 (t, 5.5 Hz, 1H), 3.38 (s, 6H), 2.71 (d, 5.5 Hz, 2H), 2.57 (t, 7.4 Hz, 2H), 1.75-1.60 (m, 3H), 1.47 (m, 2H), 1.17 (m, 8H), 0.86 (m, 2H); Rf=0.27 (50:50 hexane/ethyl acetate). The solution was extracted with ethyl acetate (2×) The combined organic phase was washed with brine (3×) dried (MgSO4) concentrated in vacuo to a crude oil Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate)

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

Procedure: 1-Chloro-3-cyclohexylpropane (11.1 g, 69.0 mmol), 2-aminoacetaldehyde (15.0 mL, 138.0 mmol, 2.0 equiv), and sodium iodide (2.1 g, 14.0 mmol, 0.2 equiv) were combined in anhydrous N,N-dimethylformamide (20 mL). The solution was stirred over solid potassium carbonate (9.66 g, 70 mmol) at 80° C. for 16 hours. The mixture was cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate (2×). The combined organic phase was washed with brine (3×), dried (MgSO4), and concentrated in vacuo to a crude oil. Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate) yielded the title compound as a yellow oil (12.0 g, 76%). 1H NMR (CDCl3, 300 MHz) δ 4.46 (t, 5.5 Hz, 1 H), 3.38 (s, 6 H), 2.71 (d, 5.5 Hz, 2 H), 2.57 (t, 7.4 Hz, 2 H), 1.75-1.60 (m, 3 H), 1.47 (m, 2 H), 1.17 (m, 8 H), 0.86 (m, 2 H); Rf =0.27 (50:50 hexane/ethyl acetate). The solution was extracted with ethyl acetate (2×) The combined organic phase was washed with brine (3×) dried (MgSO4) concentrated in vacuo to a crude oil Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 100% ethyl acetate)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/diethyl ether. The suspension is concentrated under vacuum the product obtained the solution is filtered the residue washed with petroleum ether (40°-60° C.) The filtrate obtained is concentrated maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution The ethanol is removed under a low vacuum the precipitate is filtered under vacuum extracted with dichloromethane the organic phase is concentrated

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/ diethyl ether. The suspension is concentrated under vacuum the product obtained the solution is filtered the residue washed with petroleum ether (40°-60° C.) The filtrate obtained is concentrated maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution The ethanol is removed under a low vacuum the precipitate is filtered under vacuum extracted with dichloromethane the organic phase is concentrated

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/ diethyl ether. The suspension is concentrated under vacuum the product obtained the solution is filtered the residue washed with petroleum ether (40°-60° C.) The filtrate obtained is concentrated maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution The ethanol is removed under a low vacuum the precipitate is filtered under vacuum extracted with dichloromethane the organic phase is concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 408.3 (M+H)+, HRMS calcd for C25H34N3O2 408.2651 (M+H)+, found 408.2652, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=13.3 min, 100% purity. increase the temperature to 80° C. for 3.5 hours Cool the reaction mixture to room temperature Wash with water (1× 30 mL), brine (1× 30 mL) dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 408.3 (M+H)+, HRMS calcd for C25H34N3O2 408.2651 (M+H)+, found 408.2652, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=13.3 min, 100% purity. increase the temperature to 80° C. for 3.5 hours Cool the reaction mixture to room temperature Wash with water (1× 30 mL), brine (1× 30 mL) dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-cyclohexylpropyl chloride (161 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (342 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate)