pyrrolidin-2-ylmethanamine

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of pyrrolidin-2-ylmethanamine (250 mg, 2.5 mmol) in toluene (8.5 mL) was added 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (635 mg, 2.5 mmol) under nitrogen. The solution was cooled with an ice-water bath and trimethylaluminum (2M in toluene, 2.2 mL, 4.4 mmol) was added. The resulting solution was transferred to a pressure tube and heated to 110° C. for 18 h. The reaction mixture was cooled to room temperature and water was added (10 mL). The mixture was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as a colorless oil (317 mg, 43.8%). MS (ES+) (M+H) 294.2; LCMS retention time: 1.03 minutes (Method M). The solution was cooled with an ice-water bath The resulting solution was transferred to a pressure tube The reaction mixture was cooled to room temperature The mixture was extracted with dichloromethane (40 mL×2) The combined organics were dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified via flash chromatography (0-12% methanol in dichloromethane)

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

Procedure: The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.94 (m, 2 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.47-7.45 (m, 2 H), 6.01 (s, 1 H), 5.33-5.25 (m, 2 H), 4.55-4.41 (m, 2 H), 3.96-3.73 (m, 3 H), 3.64 (s, 2 H), 3.38-3.31 (m, 1 H), 3.29-3.27 (m, 1 H), 2.37 (s, 3 H), 2.28-2.21 (m, 1 H), 2.13-1.96 (m, 2 H), 1.89-1.81 (m, 1 H).

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

Procedure: The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.94 (m, 2 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.47-7.45 (m, 2 H), 6.01 (s, 1 H), 5.33-5.25 (m, 2 H), 4.55-4.41 (m, 2 H), 3.96-3.73 (m, 3 H), 3.64 (s, 2 H), 3.38-3.31 (m, 1 H), 3.29-3.27 (m, 1 H), 2.37 (s, 3 H), 2.28-2.21 (m, 1 H), 2.13-1.96 (m, 2 H), 1.89-1.81 (m, 1 H).

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

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

Procedure: Pyrrolidin-2-ylmethylamine (527 mg) in dichloromethane (10 mL) was treated with triphenylmethyl chloride (1.47 g) and triethylamine (1.5 mL), stirred for 3 hours, treated with dichloromethane, washed with water, saturated NaHCO3, and water, and concentrated. The concentrate was flash chromatographed on silica gel with a gradient of 3%-10% methanol in 99:1 dichloromethane/triethylamine. 1H NMR (DMSO-d6) δ 7.4 (m, 6H), 7.3 (m, 6H), 7.2 (m, 3H), 3.2 (m, 1H), 2.8-2.5 (m, 2H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.5 (m, 2H), 1.2 (m, 1H). washed with water, saturated NaHCO3, and water concentrated chromatographed on silica gel with a gradient of 3%-10% methanol in 99:1 dichloromethane/triethylamine

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of pyrrolidin-2-ylmethanamine (250 mg, 2.5 mmol) in toluene (8.5 mL) was added 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (635 mg, 2.5 mmol) under nitrogen. The solution was cooled with an ice-water bath and trimethylaluminum (2M in toluene, 2.2 mL, 4.4 mmol) was added. The resulting solution was transferred to a pressure tube and heated to 110° C. for 18 h. The reaction mixture was cooled to room temperature and water was added (10 mL). The mixture was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as a colorless oil (317 mg, 43.8%). MS (ES+) (M+H) 294.2; LCMS retention time: 1.03 minutes (Method M). The solution was cooled with an ice-water bath The resulting solution was transferred to a pressure tube The reaction mixture was cooled to room temperature The mixture was extracted with dichloromethane (40 mL×2) The combined organics were dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified via flash chromatography (0-12% methanol in dichloromethane)

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

Procedure: The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.94 (m, 2 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.47-7.45 (m, 2 H), 6.01 (s, 1 H), 5.33-5.25 (m, 2 H), 4.55-4.41 (m, 2 H), 3.96-3.73 (m, 3 H), 3.64 (s, 2 H), 3.38-3.31 (m, 1 H), 3.29-3.27 (m, 1 H), 2.37 (s, 3 H), 2.28-2.21 (m, 1 H), 2.13-1.96 (m, 2 H), 1.89-1.81 (m, 1 H).