piperidin-4-amine

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

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

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

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 mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (200 mg, 0.4 mmole) and 4-amino-piperidine (1.2 g, 30 equiv.) in a vial was placed in microwave reactor (Personal Chemistry's Smith Creator) and irradiated at 150° C. for 20 min. Ethyl formate (3 ml) was added to above mixture and irradiation was continued at 135° C. for 30 min. Concentration of the reaction mixture followed by preparative HPLC purification afforded N-(1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-yl)-formamide (71 mg, 36%). This was dissolved in dry THF (0.3 ml) and added dropwise to a stirred solution of LiAlH4 (1M in ether, 0.57 ml, 4 equiv.). Water (0.5 mL) was slowly added after 20 hr and the title compound (16 mg, 23%) was isolated by preparative HPLC. MS: 485 (M+H)+; HPLC Ret Time: 1.02 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min). was placed in microwave reactor (Personal Chemistry's Smith Creator) and irradiated at 150° C. for 20 min Concentration of the reaction mixture followed by preparative HPLC purification

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

Procedure: 4-Aminopiperidine (4.01 g, 40 mmol) and benzaldehyde (4.251 g, 40 mmol) were dissolved in toluene (70 mL) and refluxed on a Dean-Stark trap until water ceased to evolve. The solvent was evaporated and the residue was reconstituted in dry THF (75 mL). Triethylamine (4.04 g, 40 mmol) was added and the reaction was cooled in an ice bath. With vigorous stirring, propionyl chloride (3.70 g, 40 mmol) was added and the reaction continued for 1.5 hours at rt. The reaction was filtered, and the filtrate was evaporated and treated with 1N HCl (50 mL) for 1 hour. The aqueous phase was washed with Et2O (3×50 mL), basified to pH>10 with NaOH, saturated with sodium chloride and extracted with DCM (5×75 mL). The combined DCM extract was evaporated and azeotropically dried with toluene to give intermediate 1 (4.74 g, 64%) as a light brown oil: 1H NMR (500 MHz, DMSO-d6) δ 4.18 (d, J=11.8 Hz, 1H), 3.74 (d, J=11.8 Hz, 1H), 3.00 (dd, J=11.8, 11.8 Hz, 1H), 2.89 (brs, 2H), 2.82-2.15 (m, 1H), 2.67 (dd, J=11.8 Hz, 11.8 Hz, 1H), 2.28 (q, J=7.1 Hz, 2H), 1.72 (d, J=11.8 Hz, 1H), 1.67 (d, J=11.8 Hz, 1H), 1.14 (q, J=10.2 Hz, 1H), 1.04 (q, J=10.2 Hz, 1H), 0.98 (t, J=7.1 Hz, 3H). The solvent was evaporated the reaction was cooled in an ice bath The reaction was filtered the filtrate was evaporated treated with 1N HCl (50 mL) for 1 hour The aqueous phase was washed with Et2O (3×50 mL) extracted with DCM (5×75 mL) The combined DCM extract was evaporated azeotropically dried with toluene

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

Procedure: 4-Aminopiperidine (4.01 g, 40 mmol) and benzaldehyde (4.251 g, 40 mmol) were dissolved in toluene (70 mL) and refluxed on a Dean-Stark trap until water ceased to evolve. The solvent was evaporated and the residue was reconstituted in dry THF (75 mL). Triethylamine (4.04 g, 40 mmol) was added and the reaction was cooled in an ice bath. With vigorous stirring, propionyl chloride (3.70 g, 40 mmol) was added and the reaction continued for 1.5 hours at rt. The reaction was filtered, and the filtrate was evaporated and treated with 1N HCl (50 mL) for 1 hour. The aqueous phase was washed with Et2O (3×50 mL), basified to pH>10 with NaOH, saturated with sodium chloride and extracted with DCM (5×75 mL). The combined DCM extract was evaporated and azeotropically dried with toluene to give intermediate 1 (4.74 g, 64%) as a light brown oil: 1H NMR (500 MHz, DMSO-d6) δ 4.18 (d, J=11.8 Hz, 1H), 3.74 (d, J=11.8 Hz, 1H), 3.00 (dd, J=11.8, 11.8 Hz, 1H), 2.89 (brs, 2H), 2.82-2.15 (m, 1H), 2.67 (dd, J=11.8 Hz, 11.8 Hz, 1H), 2.28 (q, J=7.1 Hz, 2H), 1.72 (d, J=11.8 Hz, 1H), 1.67 (d, J=11.8 Hz, 1H), 1.14 (q, J=10.2 Hz, 1H), 1.04 (q, J=10.2 Hz, 1H), 0.98 (t, J=7.1 Hz, 3H). The solvent was evaporated the reaction was cooled in an ice bath The reaction was filtered the filtrate was evaporated treated with 1N HCl (50 mL) for 1 hour The aqueous phase was washed with Et2O (3×50 mL) extracted with DCM (5×75 mL) The combined DCM extract was evaporated azeotropically dried with toluene

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzoic acid ethyl ester (25.0 g, 149 mmol) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) (100 mL), and potassium carbonate (31.0 g, 224 mmol) and 4-aminopiperidine (18.8 mL, 177 mmol) were added thereto, followed by stirring at 130° C. for 20 hours. After the reaction mixture was cooled to room temperature, water was added to the mixture and the precipitate was collected by filtration, thereby giving ethyl 4-(4-aminopiperidin-1-yl)benzoate (36.0 g, 98%) as a yellow solid. This amino compound (15.7 g, 63.2 mmol) was dissolved in THF (200 mL), and a 2N sodium carbonate aqueous solution (63 mL) was added thereto. Subsequently, benzyloxycarbonyl chloride (11.7 mL, 82.2 mmol) was added to the mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to precipitate a solid, which was collected by filtration and dried under reduced pressure, thereby giving the title compound (18.0 g, 74%) as a white solid. were added After the reaction mixture was cooled to room temperature the precipitate was collected by filtration by stirring at room temperature for 2 hours followed by extraction with ethyl acetate The organic layer was washed with water a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate After the desiccant was filtered off the solvent was evaporated under reduced pressure to precipitate a solid, which was collected by filtration dried under reduced pressure

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

Procedure: The title compound was prepared in analogy to Example 9-1 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 piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (m, 1 H), 7.84-7.71 (m, 3 H), 7.62-7.59 (m, 3 H), 6.50 (s, 1 H), 5.34 (s, 2 H), 4.57-4.55 (m, 2 H), 3.96-3.86 (m, 2 H), 3.78-3.76 (m, 2 H), 3.48-3.45 (m, 1 H), 3.13-3.08 (m, 2 H), 2.48 (s, 3 H), 2.27-2.23 (m, 2 H), 2.02-1.92 (m, 2 H).

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

Procedure: The title compound was prepared in analogy to Example 9-1 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 piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (m, 1 H), 7.84-7.71 (m, 3 H), 7.62-7.59 (m, 3 H), 6.50 (s, 1 H), 5.34 (s, 2 H), 4.57-4.55 (m, 2 H), 3.96-3.86 (m, 2 H), 3.78-3.76 (m, 2 H), 3.48-3.45 (m, 1 H), 3.13-3.08 (m, 2 H), 2.48 (s, 3 H), 2.27-2.23 (m, 2 H), 2.02-1.92 (m, 2 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 piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (t, J=8 Hz, 2 H), 7.88 (d, J=8 Hz, 1 H), 7.73-7.69 (m, 2 H), 7.59-7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H), 4.18-4.11 (m, 1 H), 3.74 (s, 2 H), 3.61-3.57 (m, 2 H), 3.33-3.26 (m, 2 H), 2.46 (s, 3 H), 2.24-2.19 (m, 2 H), 2.01-1.91 (m, 2 H).