2-chloro-1-pyrrolidin-1-ylethanone

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 solution of mL 2-chloroacetyl chloride (1.409 mL, 17.71 mmol) and THF (50 mL) was cooled to 0° C. and pyrrolidine (1.259 g, 17.71 mmol) was slowly added and stirred at ambient temperature for 3 hours. Partitioned between CH2Cl2 and water, and the organic layer was separated, dried, filtered, and concentrated to give the title compound (1.73 g, 66.19% yield) as a clear oil. Partitioned between CH2Cl2 and water the organic layer was separated dried filtered concentrated

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

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

Procedure: This compound was obtained as a brown solid in 74% yield following the same procedure described in Scheme 21 for the synthesis of 2-[[2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide, using 2-chloro-1-pyrrolidin-1-yl-ethanone as the reagent instead of 2-chloro-N,N-dimethyl-acetamide. This compound was obtained as a brown solid in 74% yield

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 4-hydroxypiperidine-1-carboxylate (4 g, 19.87 mmol), tetrabutylammonium hydrogensulfate (0.337 g, 0.99 mmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (3.87 g, 25.84 mmol) were added to toluene (50 mL) to this was added NaOH (19.87 g, 198.75 mmol) in water (20 ml) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as an orange liquid (7.20 g, >100% yield); 1H NMR (400.13 MHz, DMSO-d6) δ 1.40 (9H, s), 1.86 (8H, m), 3.02 (4H, s), 3.38 (2H, t), 3.54 (1H, m), 3.60 (2H, m), 4.07 (2H, s). The reaction mixture was quenched with water (100 mL) extracted with Et2O (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 4-hydroxypiperidine-1-carboxylate (4 g, 19.87 mmol), tetrabutylammonium hydrogensulfate (0.337 g, 0.99 mmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (3.87 g, 25.84 mmol) were added to toluene (50 mL) to this was added NaOH (19.87 g, 198.75 mmol) in water (20 ml) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as an orange liquid (7.20 g, >100% yield); 1H NMR (400.13 MHz, DMSO-d6) δ 1.40 (9H, s), 1.86 (8H, m), 3.02 (4H, s), 3.38 (2H, t), 3.54 (1H, m), 3.60 (2H, m), 4.07 (2H, s). The reaction mixture was quenched with water (100 mL) extracted with Et2O (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated

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

Procedure: The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-chloro-1-(pyrrolidin-1-yl)ethanone (75 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 15 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). The title compound was prepared The reaction mixture was heated at 90° C. for 12 h After completion of reaction the reaction mixture was filtered through Celite DMF was evaporated under reduced pressure extracted with ethyl acetate The organic layer was dried over Na2SO4 concentrated under reduced pressure

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

Procedure: The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-chloro-1-(pyrrolidin-1-yl)ethanone (75 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 15 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). The title compound was prepared The reaction mixture was heated at 90° C. for 12 h After completion of reaction the reaction mixture was filtered through Celite DMF was evaporated under reduced pressure extracted with ethyl acetate The organic layer was dried over Na2SO4 concentrated under reduced pressure

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

Procedure: The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-(pyrrolidin-1-yl)ethanone (82 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 4 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). The title compound was prepared The reaction mixture was heated at 90° C. for 12 h After completion of reaction the reaction mixture was filtered through Celite DMF was evaporated under reduced pressure extracted with ethyl acetate The organic layer was dried over Na2SO4 concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and K2CO3 (72 mg, 0.52 mmol). The reaction mixture was heated to 70° C. and stirred at 70° C. until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one (35 mg, 27%) as a yellow foam. The free base was converted to the HCl salt to the give title compound (30 mg, 80%) as a yellow solid: mp 162-166° C.; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J=14.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 97.9% (AUC), tR=13.4 min. After it was cooled the reaction was quenched with water extracted with CH2Cl2 The organic layer was washed with H2O and 5% LiCl dried with Na2SO4 filtered concentrated Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and K2CO3 (72 mg, 0.52 mmol). The reaction mixture was heated to 70° C. and stirred at 70° C. until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one (35 mg, 27%) as a yellow foam. The free base was converted to the HCl salt to the give title compound (30 mg, 80%) as a yellow solid: mp 162-166° C.; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J=14.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 97.9% (AUC), tR=13.4 min. After it was cooled the reaction was quenched with water extracted with CH2Cl2 The organic layer was washed with H2O and 5% LiCl dried with Na2SO4 filtered concentrated Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2)