1-(3-CHLOROPROPYL)-PYRROLIDINE HYDROCHLORIDE

165 ml (2 mol) of tetrahydropyrrole, 67 ml (1 mol) of 3-chloropropanol and 200 ml toluene were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 3 h. After cooling to room temperature, a solid was separated out. The solid was filtered by sucking, and the filter cake was washed with 20 ml toluene. The temperature of the filtrate was controlled at about 75° C., and 200 ml thionyl chloride was added dropwise. After refluxing for 2 h, the mixture was cooled to room temperature and then concentrated to dry in a reduce pressure. The residue was recrystallized with absolute ethyl alcohol to obtain 105 g white solid with the yield of 62.3percent. m.p. 169-173° C.A mixture of l-(3-chloropropyl)pyrrolidine hydrochloride (0.25 g, 1.36 mmol), tert- butyl 4- hydroxyphenethylcarbamate (0.32 g, 1.36 mmol), cesium carbonate (1.33 g, 4.08 mmol) and Nal (21 mg, 0.14 mmol ) in acetone (10 mL) was stirred at 50 C for 48 h. The reaction mixture was filtered. The filtrate was concentrated and purified by column chromatography to afford the title compound as yellow oil (200 mg, 42.19% yield).To a mixture of 9-chloro-2-methoxy-6H, 7H, 8H-cyclopenta[b] 1, 5-naphthyridin-3-ol (350 mg, 1.40 mmol, 1.00 eq.) in MeCN (10 mL) was added 1-(3-chloropropyl)pynolidine hydrochloride (258mg, 1.40 mmol, 1.00 eq.), KI (465 mg, 2.80 mmol, 2.00 eq.) and Cs2CO3 (913 mg, 2.80 mmol, 2.00 eq.). The resulting mixture was allowed to stir at 80 C for 2h. The solids were filtered out and the filter cake was washed with MeCN (2 x 10 mL). The filtrate was concentrated under vacuum. The residue was as purified by chromatography on silica gel with MeOH/CH2C12 (1/9) to provide the title compound as a light yellow solid (300 mg, 59%). LCMS (ES) [M+1] mlz 362.0.General procedure: To a suspension of (3-hydroxyindazol-1-yl)ketone in 2-butanone or acetonitrile, potassium carbonate or triethylamineand a catalytic amount of potassium iodide, the correspondinghalide was added and stirred at reflux until the complete eliminationof starting material. The remaining solvent was eliminatedunder vacuum. To the residue aqueous was added, extracted withchloroform and the organic layer was evaporated. The final productwas purified by chromatography on silica or flash chromatography.Amounts of reagents, time reaction, conditions and specific proceduresare particularly specified in each case.Into a 50-mL round-bottom flask, was placed 2-ethoxy-5-nitrophenol (1 g, 5.46 mmol, 1 equiv), N, N-dimethylformamide (5 mL), Cs2CO3 (5.3 g, 16.22 mmol, 3.00 equiv), iodosodium (819.7 mg, 5.47 mmol, 1 equiv), Into a 100-mL round-bottom flask, was placed 5-bromo-2-chloropyridin-3-ol (1.1 g, 5.28 mmol, 1 equiv), Cs2C03 (5.3 g, 16.27 mmol, 3.08 equiv), N, N-dimethylformamide (10 mL), l-(3-chloropropyl)pyrrolidine hydrochloride (1 g, 5.43 mmol, 1.03 equiv). The resulting solution was stirred for 2 h at 80 C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.05 g (62%) of as a light yellow solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.827min, LCMS 45: m/z= 319.00 [M+l]. i-NMR: (300 MHz, Chloroform-d) delta 8.05 (d, J= 2.0 Hz, 1H), 7.41 (d, J= 2.0 Hz, 1H), 4.15 (t, J= 6.3 Hz, 2H), 2.73 - 2.46 (m, 6H), 2.17 - 1.93 (m, 2H), 1.92 - 1.73 (m, 4H).Into a 100-mL round-bottom flask, was placed 2-bromo-5-nitrophenol (2 g, 9.17 mmol, 1 equiv), l-(3-chloropropyl)pyrrolidine hydrochloride (1.69 g, 9.18 mmol, 1 equiv), Nal (1.65 g, 1.20 equiv), Cs2CO3 (5.96 g, 18.29 mmol, 2.00 equiv), CH3CN (30 mL). The resulting solution was stirred for 5 h at 80 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with ACN/H20(28percent). This resulted in 2.4 g (79percent) of as a yellow solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.964 min, LCMS33: m/z = 329 [M+l].Into a 100-mL round-bottom flask, was placed 5-bromo-2-(trifluoromethoxy)phenol (1000 mg, 3.89 mmol, 1 equiv), l-(3-chloropropyl)pyrrolidine hydrochloride (720 mg, 3.91 mmol, 1 equiv), Cs2C03 (2550 mg, 7.83 mmol, 2.00 equiv), Nal (589 mg, 1 equiv), N, N- dimethylformamide (10 mL). The resulting solution was stirred for 2 h at 90 C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.4 g (98%) of the title compound as red oil. Analytical Data: LC-MS: (ES, m/z): RT =1.346min, LCMS 53: m/z =368 [M+l].Into a 250-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (10 g, 59.12 mmol, 1.00 equiv.), l -(3-chloropropyl)pyrrolidine hydrochloride (10.8 g, 58.66 mmol, 1.00 equiv.), Cs2C03 (58 g, 178.01 mmol, 3.00 equiv.), Nal (8.9 g, 1.00 equiv.), N, N- dimethylformamide (100 mL). The resulting solution was stirred for 2 h at 110 C. The resulting solution was diluted with 300 mL of H20. The resulting solution was extracted with 3x400 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x400 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 14 g (84%) of l -[3-(2-methoxy-5-nitrophenoxy)propyl] pyrrolidine as a yellow solid.

Molecular Weight:184.10
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:3
Exact Mass:183.0581549
Monoisotopic Mass:183.0581549
Topological Polar Surface Area:3.2
Heavy Atom Count:10
Complexity:69.3
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes