ethyl piperidine-2-carboxylate;hydrochloride

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

Procedure: To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+. The reaction was heated up to 80° C. for 3 h After reaction completion (by TLC) extracted with EtOAc (3×100 mL) The combined organic layer was washed with brine dried over anhydrous Na2SO4 evaporated under reduced pressure The crude residue was purified over 100-200 M silica-gel

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

Procedure: To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+. The reaction was heated up to 80° C. for 3 h After reaction completion (by TLC) extracted with EtOAc (3×100 mL) The combined organic layer was washed with brine dried over anhydrous Na2SO4 evaporated under reduced pressure The crude residue was purified over 100-200 M silica-gel

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

Procedure: A mixture of 3thlorobenzyl chloride (11 mmol, 1.4 mL), ethyl pipecolinate hydrochloride (10 mmol, 1.94 g) and K2CO3 (12 mmol, 1.69 g) in DMF (10 mL) was stirred at 60° C. for 3 days. It was then diluted with ether (50 mL) and filtered. The filtrate was concentrated in vacuo to give ethyl N-(3chlorophenylmethyl)pipecolinate as a yellow oil (2.79g): 1H NMR (300 MHz) δ 7.21-7.35 (m, 4 H), 4.20 (q, J=7.1 Hz, 2 H), 3.77 (d, J=13.6 Hz, 1 H), 3.37 (d, J=13.6 Hz, 1 H), 3.14 (dd, J=7.5 Hz, 4.6 Hz, 1 H), 2.92 (dt, J=11.9, 5.4 Hz, 1 H), 2.15 (m, 1 H), 1.34-1590 (m, 6 H), 1.29 (t, J=7.1 Hz, 3 H); 13C NMR δ 173.74 (s), 140.73 (s), 134.06 (s), 129.35 (d), 128.99 (d), 127.14 (d), 64.33 (d), 60.34 (t), 59.98 (t), 50.11 (t), 29.52 (t), 25.25 (t), 22.39 (t), 14.30 (q); MS (FAB) 282 (98, M+H), 208 (100); HRMS (FAB) m/e calcd for (C15H20ClNO2+H) 282.1261, found 282.1248. filtered The filtrate was concentrated in vacuo

Conditions: temp:62.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methoxy benzyl chloride (55 mmol, 8.61 g) was add ed t o a mixture of K2C3 (56 mmol, 7.7 4 g) and ethyl pipecolinate hydrochloride (50 mmol, 9.68 g) in DMF (55 mL). The mixture was stirred for 3 days at 62° C., and was filtered. Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL). The aqueous phase was basified with NaOH solution (40%) and extracted with ether (5×100 mL). The combined extracts were washed with brine, dried with Na2SO4 and MgSO4 and concentrated in vacuo to give ethyl N-(4-methoxyphenylmethyl)-pipecolinate as a yellow oil (7.12 g): 1H NMR (300 MHz) δ 7.23 (d, J=8.6 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 4.22 (q, J=7.1 Hz, 2 H), 3.70 (s, Me), 3.73 (d, J=13.1 Hz, 1 H), 3.34 (d, J=13.6 Hz, 1 H), 3.08 (dd, J=8.2, 4.3 Hz, 1 H), 2.93 (m, 1 H), 2.10 (m, 2 H), 1.80 (m, 2 H), 1.56 (m, 3 H), 1.30 (t, J=7.1 Hz, 3 H); 13C NMR δ 174.00, 158.68, 130.43, 130.01, 113.46, 64.55, 60.30, 59.87, 55.20, 50.15, 29.64, 25.24, 22.67, 14.33; MS (E) 277 (2, M), 204 (90), 121 (100); HRMS (EI) m/e calcd for C16H23NO3 277.1678, found 277.1682. was filtered Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL) extracted with ether (5×100 mL) The combined extracts were washed with brine dried with Na2SO4 and MgSO4 concentrated in vacuo

Conditions: temp:62.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methoxy benzyl chloride (55 mmol, 8.61 g) was add ed t o a mixture of K2C3 (56 mmol, 7.7 4 g) and ethyl pipecolinate hydrochloride (50 mmol, 9.68 g) in DMF (55 mL). The mixture was stirred for 3 days at 62° C., and was filtered. Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL). The aqueous phase was basified with NaOH solution (40%) and extracted with ether (5×100 mL). The combined extracts were washed with brine, dried with Na2SO4 and MgSO4 and concentrated in vacuo to give ethyl N-(4-methoxyphenylmethyl)-pipecolinate as a yellow oil (7.12 g): 1H NMR (300 MHz) δ 7.23 (d, J=8.6 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 4.22 (q, J=7.1 Hz, 2 H), 3.70 (s, Me), 3.73 (d, J=13.1 Hz, 1 H), 3.34 (d, J=13.6 Hz, 1 H), 3.08 (dd, J=8.2, 4.3 Hz, 1 H), 2.93 (m, 1 H), 2.10 (m, 2 H), 1.80 (m, 2 H), 1.56 (m, 3 H), 1.30 (t, J=7.1 Hz, 3 H); 13C NMR δ 174.00, 158.68, 130.43, 130.01, 113.46, 64.55, 60.30, 59.87, 55.20, 50.15, 29.64, 25.24, 22.67, 14.33; MS (E) 277 (2, M), 204 (90), 121 (100); HRMS (EI) m/e calcd for C16H23NO3 277.1678, found 277.1682. was filtered Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL) extracted with ether (5×100 mL) The combined extracts were washed with brine dried with Na2SO4 and MgSO4 concentrated in vacuo

Conditions: temp:62.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methoxy benzyl chloride (55 mmol, 8.61 g) was add ed t o a mixture of K2C3 (56 mmol, 7.7 4 g) and ethyl pipecolinate hydrochloride (50 mmol, 9.68 g) in DMF (55 mL). The mixture was stirred for 3 days at 62° C., and was filtered. Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL). The aqueous phase was basified with NaOH solution (40%) and extracted with ether (5×100 mL). The combined extracts were washed with brine, dried with Na2SO4 and MgSO4 and concentrated in vacuo to give ethyl N-(4-methoxyphenylmethyl)-pipecolinate as a yellow oil (7.12 g): 1H NMR (300 MHz) δ 7.23 (d, J=8.6 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 4.22 (q, J=7.1 Hz, 2 H), 3.70 (s, Me), 3.73 (d, J=13.1 Hz, 1 H), 3.34 (d, J=13.6 Hz, 1 H), 3.08 (dd, J=8.2, 4.3 Hz, 1 H), 2.93 (m, 1 H), 2.10 (m, 2 H), 1.80 (m, 2 H), 1.56 (m, 3 H), 1.30 (t, J=7.1 Hz, 3 H); 13C NMR δ 174.00, 158.68, 130.43, 130.01, 113.46, 64.55, 60.30, 59.87, 55.20, 50.15, 29.64, 25.24, 22.67, 14.33; MS (E) 277 (2, M), 204 (90), 121 (100); HRMS (EI) m/e calcd for C16H23NO3 277.1678, found 277.1682. was filtered Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL) extracted with ether (5×100 mL) The combined extracts were washed with brine dried with Na2SO4 and MgSO4 concentrated in vacuo

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

Procedure: A mixture of 2-piperidinecarboxylic acid ethyl ester hydrochloride (0.60 g, 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.60 g, 0.002 mol, prepared similarly as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1.03 g, 0.008 mol) and N,N-dimethylformamide (5 ml) was heated at reflux temperature for 85 h. Water (50 ml) was added, and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (15 g) using a gradient of heptane and ethyl acetate (100:0→100:25), affording 0.83 g (97%) of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil. prepared similarly was heated at reflux temperature for 85 h the aqueous solution was extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with brine (2×50 ml) dried (MgSO4) concentrated in vacuo The product was purified by column chromatography on silica gel (15 g)

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

Procedure: A mixture of ethyl pipecolinate hydrochloride (10 g, 52 mmol), benzylbromide (7 mL, 57 mmol) and potassium carbonate (15 g, 114 mmol) in DMF (80 mL) was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane (100 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), dried over Na2SO4, then evaporated to give a yellow oil. The crude product was chromatographed (500 g silica gel) eluting with a stepgradient of 8%-15% ethyl acetate in hexane. Pure fractions were combined to give title compound (12.3 g, 96%) as a colorless oil. The solvent was removed in vacuo The residue was partitioned between dichloromethane (100 mL) and water (50 mL) The aqueous layer was extracted with dichloromethane (2×100 mL) dried over Na2SO4 evaporated to give a yellow oil The crude product was chromatographed (500 g silica gel) eluting with a stepgradient of 8%-15% ethyl acetate in hexane

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

Procedure: A mixture of 2-piperidinecarboxylic acid ethyl ester hydrochloride (0.60 g, 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.60 g, 0.002 mol, prepared similarly as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1.03 g, 0.008 mol) and N,N-dimethylformamide (5 ml) was heated at reflux temperature for 85 h. Water (50 ml) was added, and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (15 g) using a gradient of heptane and ethyl acetate (100:0→100:25), affording 0.83 g (97%) of 1-(3-(10,11-dihydro-5 H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil. prepared similarly was heated at reflux temperature for 85 h the aqueous solution was extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with brine (2×50 ml) dried (MgSO4) concentrated in vacuo The product was purified by column chromatography on silica gel (15 g)

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

Procedure: A mixture of 2-piperidinecarboxylic acid ethyl ester hydrochloride (0.60 g, 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.60 g, 0.002 mol, prepared similarly as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1.03 g, 0.008 mol) and N,N-dimethylformamide (5 ml) was heated at reflux temperature for 85 h. Water (50 ml) was added, and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (15 g) using a gradient of heptane and ethyl acetate (100:0→100:25), affording 0.83 g (97%) of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil. prepared similarly was heated at reflux temperature for 85 h the aqueous solution was extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with brine (2×50 ml) dried (MgSO4) concentrated in vacuo The product was purified by column chromatography on silica gel (15 g)

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

Procedure: A mixture of 2-piperidinecarboxylic acid ethyl ester hydrochloride (0.60 g, 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.60 g, 0.002 mol, prepared similarly as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1.03 g, 0.008 mol) and N,N-dimethylformamide (5 ml) was heated at reflux temperature for 85 h. Water (50 ml) was added, and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (15 g) using a gradient of heptane and ethyl acetate (100:0→100:25), affording 0.83 g (97%) of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid ethyl ester as an oil. prepared similarly was heated at reflux temperature for 85 h the aqueous solution was extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with brine (2×50 ml) dried (MgSO4) concentrated in vacuo The product was purified by column chromatography on silica gel (15 g)

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

Procedure: To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+. The reaction was heated up to 80° C. for 3 h After reaction completion (by TLC) extracted with EtOAc (3×100 mL) The combined organic layer was washed with brine dried over anhydrous Na2SO4 evaporated under reduced pressure The crude residue was purified over 100-200 M silica-gel