A solution of 1-(3-pyridyl)-piperazine (0.35 g, 2.1 mmol), formic acid (1.0 g, 21.7 mmol), formaldehyde (0.64 g, 37%) and water (2 ml) was stirred at reflux for 15 hours. The mixture was evaporated and sodium hydroxide (30 ml, 1 M) was added and the product was extracted three times with ethyl acetate (15 ml). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Yield 0.21 g, 34% Mp. 144.5–145.9° C. 1-[5-(trans-Hex-2-en-1-yl-oxy-3-Pyridyl]-4-Methyl-Piperazine Fumaric Acid Salt (Compound 1A3) Was prepared according to method A. Mp. 113.0–114.9° C. Method B 1-(3-Pyridyl)-Piperazine Fumaric Acid Salt (Compound 1B1) A solution of 1-(3-pyridyl)-4-tert-butoxycarbonylpiperazine (1.3 g, 4.9 mmol), trifluoroacetic acid (11.3 g, 99 mmol) and dichloromethane (50 ml) was stirred for 15 hours. The mixture was evaporated. Sodium hydroxide (30 ml, 4 M) was added. The product was extracted three times with dichloromethane (50 ml) and isolated as an oil. Yield 0.72 g, 90%. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1), saturated with fumaric acid. Mp. 161.7–164.8° C. Method C 1-(3-Pyridyl)-4-Tert-Butoxycarbonyl-Piperazine (Compound 1C1) A mixture of 3-bromopyridine (7.8 g, 49.4 mmol), 1-tert-butoxycarbonylpiperazine (9.2 g, 49.4 mmol), tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.247 mmol), potassium tert-butoxide (11.1 g, 98.8 mmol) and anhydrous toluene (100 ml) was stirred at 80° C. for 0.5 hours. Water (100 ml) was added and the mixture was extracted three times with ethyl acetate (75 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 1.34 g, 10%. Method D 1-(5-Ethoxy-3-Pyridyl)Piperazine Fumaric Acid Salt (Compound 1D1) A mixture of 3-chloro-5-ethoxypyridine (6.5 g, 45.8 mmol), piperazine (19.7 g, 229 mmol), potassium tert-butoxide (11.2 g, 91.6 mmol) and 1,2-dimethoxyethane (150 ml) was stirred at reflux for 1 hours. Aqueous sodium hydroxide (1 M, 100 ml) was added and the mixture was extracted two times with ethyl acetate (150 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 4.6 g, 48%. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp. 160.0–161.2° C. 1-[5-(Butoxy)-3-Pyridyl]-1,5-Diazacyclooctane Fumaric Acid Salt (Compound 1D2). Was prepared according to methanol D, from 3-chloro-5-(butoxy)-pyridine, stirred at room temperature for 3 days. 1,5-Diazacyclooctane was prepared according to J. Hernandez-Mora “Derivatives of 1,5-diazacyclooctane” Ph.D. Dissertation, University of Michigan (1959). Mp. 146–148° C. 1-(5-Ethoxy-3-Pyridyl)-4-Ethyl-Piperazine Fumaric Acid Salt (Compound 1D3) A mixture of 1-(5-ethoxy-3-pyridyl)-piperazine (1.4 g, 6.8 mmol), triethylamine (0.69 g, 6.8 mmol), bromoethane (0.88 g, 8.1 mmol) and dimethylformamide (25 ml). Aqueous sodium hydroxide (1 M, 50 ml) was added and the mixture was extracted two times with ethy acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 0.75 g, 47%. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1), saturated with fumaric acid. Mp. 144.8–145.9° C. 1-(5-Methoxy-3-Pyridyl)-4-Ethyl-Piperazine Fumaric Acid Salt (Compound 1D4) Was prepared according to 1-(5-ethoxy-3-pyridyl)-4-ethyl-piperazine. Mp. 147.9–148.3° C. 4-Ethyl-1-(5-Propyloxy-3-Pyridyl)-Piperazine Fumaric Acid Salt (Compound 1D5) Was prepared according to 1-(5-ethoxy-3-pyridyl)-4-ethyl-piperazine. Mp. 128.7–130.5° C.
