3-fluoropropan-1-amine;hydrochloride

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

Procedure: 3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.

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

Procedure: A solution of 4-bromobenzylbromide 119 (0.30 g, 1.20 mmol) and amine 113 (0.272 g, 2.40 mmol, 2.0 equiv) in anhydrous DMF (8.0 mL) was treated with diisopropylethylamine (Hunig's base, 2.0 mL) at room temperature. The resulting reaction mixture was warmed to 60° C. for 24 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to 25° C. before being treated with water (8.0 mL). The resulting aqueous solution was then treated with solid sodium bicarbonate (NaHCO3, 0.30 g, 3.60 mmol, 3.0 equiv) and BOC2O (0.524 g, 2.40 mmol, 2.0 equiv) at 25° C. and stirred for 24 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (20 mL) and EtOAc, 20 mL. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (3% EtOAc/hexanes) to afford the desired (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115 (0.24 g, 57.8% yield) as a colorless oil. The resulting reaction mixture the reaction mixture was cooled to 25° C. The two layers were separated the aqueous layer was extracted with EtOAc (2×30 mL) The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL) dried over MgSO4 concentrated in vacuo The residue was purified by column chromatography (3% EtOAc/hexanes)

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

Procedure: 3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.

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

Procedure: Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and 3-fluoropropylamine hydrochloride [64068-31-1] (43 mg, 0.4 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 6H) 2.12-2.25 (m, 1H) 2.54 (s, 1H) 3.66-3.72 (m, 1H) 4.72 (t, J=5.51 Hz, 1H) 7.21 (s, 2H) 7.63-7.67 (m, 1H). LRMS (ESI) m/z 319.1 [(M+H)]+, calc'd for C15H15FN4OS: 318.38.

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

Procedure: Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and 3-fluoropropylamine hydrochloride [64068-31-1] (43 mg, 0.4 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 6H) 2.12-2.25 (m, 1H) 2.54 (s, 1H) 3.66-3.72 (m, 1H) 4.72 (t, J=5.51 Hz, 1H) 7.21 (s, 2H) 7.63-7.67 (m, 1H). LRMS (ESI) m/z 319.1 [(M+H)]+, calc'd for C15H15FN4OS: 318.38.

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

Procedure: 3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.

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

Procedure: 3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.

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

Procedure: To a solution of 3-Fluoro-propylamine hydrochloride (0.072 g, 0.636 mmol) in acetonitrile (5 mL) is added diisopropylethylamine (0.082 mL, 0.636 mmol) at room temperature. After stirring for 30 minutes methane sulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.211 mmol) is added then the resulting mixture is stirred at room temperature for overnight. Solvent is evaporated under reduced pressure and the crude material is purified by combi-flash chromatography using 12% methanol in CH2Cl2 as an eluent to afford the title compound (0.093 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (s, 3H), 1.60 (S, 3H), 2.06-2.14 (m, 2H), 3.57-3.60 (m, 2H), 4.35 (s, 2H), 4.49-4.51 (m, 1H), 4.52-4.56 (m, 0.5H), 4.57-4.63 (m, 1H), 4.64-4.70 (m, 1H), 4.83-4.86 (m, 0.5H), 4.93-4.97 (m, 1H), 5.28 (d, J=3.48 Hz, 1H), 6.66 (t, J=52.3 Hz, 1H), 7.61-7.65 (m, 3H), 7.84 (d, J=8.2 Hz, 2H), 8.21-8.23 (dd, J1=3.04 Hz, J2=8.16 Hz, 1H), 8.97 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=454.1. is added Solvent is evaporated under reduced pressure the crude material is purified by combi-flash chromatography

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

Procedure: 3-Fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on a SCX-3 ion exchange column (TEA/MeOH). 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol) and 3-fluoropropan-1-amine (0.15 M in MeOH/TEA:4/1, 5 ml) was heated under microwave radiation at 120° C. for 1 h 20 min. ESIMS: m/z 322 (M+H)+.

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

Procedure: 3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (0.470 g, 2.3832 mmol, 29.42%) as pink crystals.

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

Procedure: A solution of 4-bromobenzylbromide 119 (0.30 g, 1.20 mmol) and amine 113 (0.272 g, 2.40 mmol, 2.0 equiv) in anhydrous DMF (8.0 mL) was treated with diisopropylethylamine (Hunig's base, 2.0 mL) at room temperature. The resulting reaction mixture was warmed to 60° C. for 24 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to 25° C. before being treated with water (8.0 mL). The resulting aqueous solution was then treated with solid sodium bicarbonate (NaHCO3, 0.30 g, 3.60 mmol, 3.0 equiv) and BOC2O (0.524 g, 2.40 mmol, 2.0 equiv) at 25° C. and stirred for 24 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (20 mL) and EtOAc, 20 mL. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (3% EtOAc/hexanes) to afford the desired (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115 (0.24 g, 57.8% yield) as a colorless oil. The resulting reaction mixture the reaction mixture was cooled to 25° C. The two layers were separated the aqueous layer was extracted with EtOAc (2×30 mL) The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL) dried over MgSO4 concentrated in vacuo The residue was purified by column chromatography (3% EtOAc/hexanes)

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

Procedure: A solution of 4-bromobenzylbromide 119 (0.30 g, 1.20 mmol) and amine 113 (0.272 g, 2.40 mmol, 2.0 equiv) in anhydrous DMF (8.0 mL) was treated with diisopropylethylamine (Hunig's base, 2.0 mL) at room temperature. The resulting reaction mixture was warmed to 60° C. for 24 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to 25° C. before being treated with water (8.0 mL). The resulting aqueous solution was then treated with solid sodium bicarbonate (NaHCO3, 0.30 g, 3.60 mmol, 3.0 equiv) and BOC2O (0.524 g, 2.40 mmol, 2.0 equiv) at 25° C. and stirred for 24 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (20 mL) and EtOAc, 20 mL. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (3% EtOAc/hexanes) to afford the desired (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115 (0.24 g, 57.8% yield) as a colorless oil. The resulting reaction mixture the reaction mixture was cooled to 25° C. The two layers were separated the aqueous layer was extracted with EtOAc (2×30 mL) The combined organic extracts were washed with H2O (4×10 mL) and saturated aqueous NaCl (10 mL) dried over MgSO4 concentrated in vacuo The residue was purified by column chromatography (3% EtOAc/hexanes)