1-fluoro-3-iodopropane

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:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (0.5000 g, 1.005 mmol; prepared as described in example 8) and tetra-N-butylammonium bromide (0.340 g, 1.05 mmol) in toluene (10 mL, 90 mmol) was added potassium hydroxide (84.6 mg, 1.51 mmol) (powdered). The reaction was stirred at 50° C. for 10 minutes. 1-Iodo-3-fluoropropane (0.525 g, 2.79 mmol) was added and the reaction mixture was stirred for 1 hour at 50° C. The temperature was raised to 80° C. and the reaction mixture was stirred for another for 2 hours. The reaction mixture was cooled to room temperature and washed with 50 ml of water, dried over MgSO4 and was concentrated in vacuo to give 0.76 g (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester as an oil. The Boc-protection group was removed analogously to the method described in example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound. the reaction mixture was stirred for 1 hour at 50° C The temperature was raised to 80° C. the reaction mixture was stirred for another for 2 hours The reaction mixture was cooled to room temperature washed with 50 ml of water dried over MgSO4 was concentrated in vacuo

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

Procedure: The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H), 6.76-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.39 (t, 1H), 3.91 (t, 2H), 2.72 (t, 2H), 2.58-2.45 (m, 4H), 2.03 (s, 3H), 1.80-1.71 (m, 1H), 1.71-1.65 (m, 1H), 0.93 (t, 3H). LCMS: 478.1 (M+H)+.

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

Procedure: The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H), 6.76-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.39 (t, 1H), 3.91 (t, 2H), 2.72 (t, 2H), 2.58-2.45 (m, 4H), 2.03 (s, 3H), 1.80-1.71 (m, 1H), 1.71-1.65 (m, 1H), 0.93 (t, 3H). LCMS: 478.1 (M+H)+.

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

Procedure: The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(methylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.79 (d, 2H), 6.75-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.38 (t, 1H), 3.95 (t, 2H), 2.65 (t, 2H), 2.44 (t, 2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.81-1.72 (m, 1H), 1.72-1.69 (m, 1H). LCMS: 464.2 (M+H)+.

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

Procedure: The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(methylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.79 (d, 2H), 6.75-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.38 (t, 1H), 3.95 (t, 2H), 2.65 (t, 2H), 2.44 (t, 2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.81-1.72 (m, 1H), 1.72-1.69 (m, 1H). LCMS: 464.2 (M+H)+.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 140 mg (0.30 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-D-glutamate in 5 mL N,N-dimethylformamide were added 42 mg (0.3 mmol) of powdered potassium carbonate and 56 mg (0.30 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated. The reaction mixture was then filtered the solvent evaporated The organic phase was separated off washed with water until neutral, dried over sodium sulfate filtered the filtrate was concentrated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 140 mg (0.30 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-D-glutamate in 5 mL N,N-dimethylformamide were added 42 mg (0.3 mmol) of powdered potassium carbonate and 56 mg (0.30 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated. The reaction mixture was then filtered the solvent evaporated The organic phase was separated off washed with water until neutral, dried over sodium sulfate filtered the filtrate was concentrated in vacuo

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

Procedure: To 93 mg (0.20 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate (Example 1b) in 9 mL N,N-dimethylformamide were added 60.7 mg (0.44 mmol) of powdered potassium carbonate and 45 mg (0.24 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was stirred for 5 h at 60° C. and overnight at room temperature. The reaction mixture was than filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated. than filtered the solvent evaporated The organic phase was separated off washed with water until neutral, dried over sodium sulfate filtered the filtrate was concentrated in vacuo