5-fluoro-3-piperidin-4-yl-1H-indole

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:0.00; pressure:0.00; stir:

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

Procedure: A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (2.7 g) in dimethyl formamide (75 mL), 2-(2-bromoethyl)-1-methyl-4-nitrobenzene (3.7 g) in butanone (200 mL) and triethylamine (9.3 mL) was boiled under reflux for 20 h, and the resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/triethylamine 100:4) to give 5-fluoro-3-{1-[2-(2-methyl-5-nitrophenyl)ethyl]piperidin-4-yl}-1H-indole (3.6 g), which subsequently was dissolved in acetic acid (25 ml) followed by the addition of ethanol (75 mL) and platinum oxide (50 mg). The resulting mixture was shaken under 3 atmosphere hydrogen pressure for 3 h at room temperature. The mixture was reduced in vacuo (50 mL), poured onto an ice/water mixture followed by the addition of aqueous ammonia to basic pH. The aqueous phase was extracted with an ethyl acetate/tetrahydrofuran mixture, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give 3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-5-fluoro-1H-indole (1.0 g), which subsequently was dissolved in tetrahydrofuran (45 mL) and triethylamine (1.3 mL) at 5° C. followed by the addition of cyclobutancarbonyl chloride (0.3 g) in tetrahydrofuran (15 mL). The resulting mixture was stirred at 5° C. for 1 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product that was isolated as the oxalate salt from ethyl acetate as a white crystalline compound (0.7 g). Mp 116-125° C. 1H NMR (DMSO-d6): 1.75-1.85 (m, 1H); 1.85-2.05 (m, 3H); 2.05-2.25 (m, 6H); 2.30 (s, 3H); 2.90-3.25 (m, 8H); 3.65 (d, 2H); 6.85-6.95 (m, 1H); 7.10 (d, 1H); 7.25 (s, 1H); 7.30-7.40 (m, 2H); 7.40 (d, 1H); 7.55 (s, 1H); 9.65 (s, 1H); 11.00 (s, 1H). MS m/z: 434 (MH+). under reflux for 20 h the resulting mixture was concentrated in vacuo The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/triethylamine 100:4)

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

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

Procedure: Pulverized potassium carbonate (0.35 g, 2.5 mmole) and potassium iodide (0.44 g, 2.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-yl)piperidine (0.5 g, 2.3 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.58 g, 2.3 mmole) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 3 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.83 g, 83 %). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol. The resulting mixture was heated to reflux under nitrogen for 3 hours After cooling the product extracted into ethyl acetate (50 ml) The organic layer was washed with water (50 ml), brine (50 ml) after drying over sodium sulfate, filtration and concentration in vacuo

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

Procedure: Pulverized potassium carbonate (0.35 g, 2.5 mmole) and potassium iodide (0.44 g, 2.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-yl)piperidine (0.5 g, 2.3 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.58 g, 2.3 mmole) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 3 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.83 g, 83 %). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol. The resulting mixture was heated to reflux under nitrogen for 3 hours After cooling the product extracted into ethyl acetate (50 ml) The organic layer was washed with water (50 ml), brine (50 ml) after drying over sodium sulfate, filtration and concentration in vacuo

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

Procedure: The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(piperidin-4-yl)-1H-indole (0.87 g, 4.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.76 g, 4.0 mmol). The product was isolated as a white foam. Yield 1.14 g (70%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+8.36 (c=1.00, methanol/dimethylsulfoxide). The product was isolated as a white foam