4-(2-chloroethyl)piperidine;hydrochloride

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

Procedure: 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (885 mg) was dissolved in acetone (50 ml), Sodium iodide (45 mg) and potassium carbonate (4.14 g) were added followed by 4-(2-chloroethyl)piperidine hydrochloride (1.67 g). The resultant mixture was stirred at 60° C. for 18 hours. 2N NaOH (9.4 ml) was added and stirred for 20 minutes, cooled and the insoluble material removed by filtration. The filtrate was concentrated, acidified to pH 1 with concentrated hydrochloric acid and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[7-(2-piperidin-1-ylethoxy)-1-oxoisoquinolin-2(1H)-yl]benzoic acid as an oil (205 mg); NMR Spectrum: (DMSOd6) 2.13 (s, 1H), 3.00 (m, 4H), 3.35 (m, 2H), 3.95 (m, 4H), 4.58 (m, 2H), 6.46 (d, 1H), 6.90 (d, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.50 (d, 1H), 7.80 (d, 1H), 7.87 (d, 1H), 7.98 (m, 1H); Mass Spectrum: M+H+ 407. cooled the insoluble material removed by filtration The filtrate was concentrated purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) a 99:1 mixture of methanol and aqueous ammonia solution

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

Procedure: 4--Hydroxybenzaldehyde (25.0 g) and 4-(2-chloroethyl)piperadine hydrochloride (60.38 g) are dissolved in DMF (650 ml) and solid potassium carbonate (45 g) is added. The reaction is refluxed for 24 hr, cooled to 20°-25° and the DMF is removed under reduced pressure. The remainder of the reaction is dissolved in chloroform and washed with 1N aqueous sodium hydroxide, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling and concentrating the appropriate fractions gives the title compound, NMR (300 MHz, CDCl3) 9.75, 7.69, 6.87, 4.10, 2.73, 2.45, 1.52, 1.36 δ. The reaction is refluxed for 24 hr cooled to 20°-25° the DMF is removed under reduced pressure The remainder of the reaction is dissolved in chloroform washed with 1N aqueous sodium hydroxide, saline dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling concentrating the appropriate fractions

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

Procedure: 4--Hydroxybenzaldehyde (25.0 g) and 4-(2-chloroethyl)piperadine hydrochloride (60.38 g) are dissolved in DMF (650 ml) and solid potassium carbonate (45 g) is added. The reaction is refluxed for 24 hr, cooled to 20°-25° and the DMF is removed under reduced pressure. The remainder of the reaction is dissolved in chloroform and washed with 1N aqueous sodium hydroxide, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling and concentrating the appropriate fractions gives the title compound, NMR (300 MHz, CDCl3) 9.75, 7.69, 6.87, 4.10, 2.73, 2.45, 1.52, 1.36 δ. The reaction is refluxed for 24 hr cooled to 20°-25° the DMF is removed under reduced pressure The remainder of the reaction is dissolved in chloroform washed with 1N aqueous sodium hydroxide, saline dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling concentrating the appropriate fractions

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Nitroindazole (mmol) and potassium carbonate (mmol) in 60 mL of DMF was added was stirred for 30 minutes, after which 4-(2-chloro-ethyl)-piperidine hydrochloride (mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and the mixture filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure, and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (m, 6 H), 2.36 (m, 4 H), 2.73 (t, J=6.44 Hz, 2 H), 4.63 (t, J=6.44 Hz, 2 H), 7.64 (m, 1 H), 8.16 (m, 1 H), 8.28 (m; 1 H), 8.51 (s, 1 H); MS (DCI/NH3) m/z 275 [M+H]+. cooled to room temperature the mixture filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4) The filtrate was concentrated under reduced pressure the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30)

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

Procedure: 4-Hydroxybenzaldehyde (25.0 g) and 4-(2-chloroethyl)piperadine hydrochloride (60.38 g) are dissolved in DMF (650 ml) and solid potassium carbonate (45 g) is added. The reaction is refluxed for 24 hr, cooled to 20°-25° and the DMF is removed under reduced pressure. The remainder of the reaction is dissolved in chloroform and washed with 1N aqueous sodium hydroxide, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling and concentrating the appropriate fractions gives the title compound, NMR (300 MHz, CDCl3) 9.75, 7.69, 6.87, 4.10, 2.73, 2.45, 1.52, 1.36 δ. The reaction is refluxed for 24 hr cooled to 20°-25° the DMF is removed under reduced pressure The remainder of the reaction is dissolved in chloroform washed with 1N aqueous sodium hydroxide, saline dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by flash column chromatography eluting with a gradient of 50% ethyl acetate/hexane to 5% methanol/ethyl acetate, pooling concentrating the appropriate fractions

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

Procedure: 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (885 mg) was dissolved in acetone (50 ml), Sodium iodide (45 mg) and potassium carbonate (4.14 g) were added followed by 4-(2-chloroethyl)piperidine hydrochloride (1.67 g). The resultant mixture was stirred at 60° C. for 18 hours. 2N NaOH (9.4 ml) was added and stirred for 20 minutes, cooled and the insoluble material removed by filtration. The filtrate was concentrated, acidified to pH 1 with concentrated hydrochloric acid and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[7-(2-piperidin-1-ylethoxy)-1-oxoisoquinolin-2(1H)-yl]benzoic acid as an oil (205 mg); NMR Spectrum: (DMSOd6) 2.13 (s, 1H), 3.00 (m, 4H), 3.35 (m, 2H), 3.95 (m, 4H), 4.58 (m, 2H), 6.46 (d, 1H), 6.90 (d, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.50 (d, 1H), 7.80 (d, 1H), 7.87 (d, 1H), 7.98 (m, 1H); Mass Spectrum: M+H+ 407. cooled the insoluble material removed by filtration The filtrate was concentrated purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) a 99:1 mixture of methanol and aqueous ammonia solution