2-N-cyclopropyl-4-fluorobenzene-1,2-diamine

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

Procedure: A mixture of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.724 g, 4.4 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.91 g, 4.8 mmol), HOAt (0.65 g, 4.8 mmol), 4-methylmorpholine (1.1 mL, 9.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.8 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclopropylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a brown oil (1.07 g, 72%). LCMS (Method B): RT 3.40 min [M+H]+ 338.2. 110180243 The reaction mixture was partitioned between DCM The organic fraction was washed with brine dried (MgSO4) concentrated in vacuo the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane)

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

Procedure: A mixture of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.724 g, 4.4 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.91 g, 4.8 mmol), HOAt (0.65 g, 4.8 mmol), 4-methylmorpholine (1.1 mL, 9.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.8 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclopropylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a brown oil (1.07 g, 72%). LCMS (Method B): RT 3.40 min [M+H]+ 338.2. 110180243 The reaction mixture was partitioned between DCM The organic fraction was washed with brine dried (MgSO4) concentrated in vacuo the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane)

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

Procedure: To a solution of cyclopropyl-(5-fluoro-2-nitrophenyl)amine (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 5 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a brown oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.76 (1H, dd, J=10.85, 2.76 Hz), 6.60 (1H, dd, J=8.38, 5.56 Hz), 6.34 (1H, td, J=8.45, 2.82 Hz), 4.15 (1H, br s), 3.03 (2H, br s), 2.45-2.36 (1H, m), 0.80-0.72 (2H, m), 0.56-0.49 (2H, m). The suspension was filtered through a pad of Celite® the filtrate concentrated in vacuo

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

Procedure: To a solution of cyclopropyl-(5-fluoro-2-nitrophenyl)amine (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 5 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a brown oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.76 (1H, dd, J=10.85, 2.76 Hz), 6.60 (1H, dd, J=8.38, 5.56 Hz), 6.34 (1H, td, J=8.45, 2.82 Hz), 4.15 (1H, br s), 3.03 (2H, br s), 2.45-2.36 (1H, m), 0.80-0.72 (2H, m), 0.56-0.49 (2H, m). The suspension was filtered through a pad of Celite® the filtrate concentrated in vacuo

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

Procedure: To a solution of the title compound from N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.065 g, 0.39 mmol) in dichloromethane (1.96 mL) were added 5-fluoropyridine-3-carboxylic acid (0.061 g, 0.43 mmol), EDC (0.082 g, 0.43 mmol), HOBt (0.066 g, 0.43 mmol), and diisopropylethylamine (0.280 mL, 1.56 mmol). The reaction was stirred at room temperature overnight, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-50% ethyl acetate in hexanes) provided the title compound: LCMS m/z 290.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1 H), 8.66 (d, J=2.0 Hz, 1 H), 7.97 (d, J=8.3 Hz, 1 H), 7.48 (br s, 1 H), 7.19 (m, 1 H), 6.92 (d, J=10.9 Hz, 1 H), 6.52-6.49 (m, 1 H), 4.50 (br s, 1 H), 2.47-2.44 (m, 1 H), 0.81-0.77 (m, 2 H), 0.54-0.51 (m, 2 H).

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

Procedure: To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.082 g, 0.495 mmol) in dichloromethane were added the title compound from Step A (0.090 g, 0.545 mmol), HATU (0.207 g, 0.545 mmol), HOAt (0.074 g, 0.545 mmol), and diisopropylethylamine (0.35 mL, 1.98 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 314.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 8.02 (br s, 1 H), 7.19-7.16 (m, 1 H), 6.91 (d, J=10.5 Hz, 1 H), 6.50-6.47 (m, 1 H), 4.64 (br s, 1 H), 2.69 (s, 3 H), 2.45-2.44 (m, 1 H), 0.78-0.77 (m, 2 H), 0.52-0.51 (m, 2 H). washed with water and brine dried over magnesium sulfate filtered concentrated Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes)

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

Procedure: To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.479 g, 2.88 mmol) in DMF (6.97 mL) and water (0.23 mL) were added the title compound from Step C (0.302 g, 1.83 mmol) and OXONE® (0.729 g, 1.19 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (100% ethyl acetate) provided a product that was further purified by reverse phase HPLC(C18 OBD column, 20 to 90% acetonitrile/water, both 0.1% v/v trifluoroacetitic acid). Fractions containing the desired product were combined, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound: LCMS m/z 312.01 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.7 Hz, 1 H), 9.85 (d, J=1.9 Hz, 1 H), 8.40 (s, 1 H), 7.73 (dd, J=8.8, 4.8 Hz, 1 H), 7.29 (dd, J=8.7, 2.2 Hz, 1 H), 7.08-7.04 (m, 1 H), 3.57-3.55 (m, 1 H), 2.21 (br s, 1 H), 1.69 (s, 6 H), 1.20-1.16 (m, 2 H), 0.79-0.75 (m, 2 H). the organic layer was separated washed with water and brine dried over magnesium sulfate filtered concentrated Purification by flash chromatography on silica gel (100% ethyl acetate) provided a product that was further purified by reverse phase HPLC(C18 OBD column, 20 to 90% acetonitrile/water Fractions containing the desired product washed sequentially with aqueous 1 N sodium hydroxide solution and brine dried over magnesium sulfate filtered concentrated

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

Procedure: To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.080 g, 0.48 mmol) in DMF (1.17 mL) and water (0.04 mL) were added the title compound from Example 8 Step A (0.084 g, 0.53 mmol) and OXONE® (0.192 g, 0.313 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: LCMS m/z 304.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H). the organic layer was separated washed with water and brine dried over magnesium sulfate filtered concentrated Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes

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

Procedure: To a solution of the title compound from Step E (0.058 g, 0.35 mmol) in DMF (1.68 mL) and water (0.06 mL) were added the title compound from Step C (0.076 g, 0.35 mmol) and OXONE® (0.139 g, 0.226 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was then added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% acetone in dichloromethane, then 30% acetone in dichloromethane) provided the title compound as a racemic mixture. That racemic mixture was then separated into two enantiomers by HPLC (ChiralCel AS column, 25% MeOH (0.2% DEA)/CO2, 70 mL/min, 100 bar, 35° C.). Data for EXAMPLE 6 (Enantiomer A): LCMS m/z 365.99 [M+H]+; 1 H NMR (500 MHz, CDCl3) δ 9.14 (s, 1 H), 8.85 (s, 1 H), 8.59 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.1 Hz, 1 H), 7.11-7.07 (m, 1 H), 4.85 (br s, 1 H), 3.55-3.53 (m, 1 H), 1.79 (s, 3 H), 1.22-1.12 (m, 2 H), 0.80-0.72 (m, 2 H). Data for Example 7 (Enantiomer B): LCMS m/z 365.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1 H), 8.88 (s, 1 H), 8.57 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.0 Hz, 1 H), 7.10-7.05 (m, 1 H), 3.91 (br s, 1 H), 3.56-3.55 (m, 1 H), 1.84 (s, 3 H), 1.18-1.15 (m, 2 H), 0.80-0.71 (m, 2 H). the organic layer was separated washed with water and brine dried over magnesium sulfate filtered concentrated Purification by flash column chromatography on silica gel (10% acetone in dichloromethane

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

Procedure: To the title compound from Step D (1.23 g, 6.27 mmol) were added 10% palladium on carbon (0.123 g, 1.16 mmol) and methanol (31.3 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The reaction mixture was then filtered through CELITE° using dichloromethane and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 30% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.76 (dd, J=10.9, 2.8 Hz, 1 H), 6.60 (dd, J=8.4, 5.6 Hz, 1 H), 6.34 (ddd, J=11.2, 8.4, 2.8 Hz, 1 H), 4.17 (br s, 1 H), 3.01 (br s, 2 H), 2.42-2.38 (m, 1 H), 0.77-0.72 (m, 2 H), 0.54-0.51 (m, 2 H). The reaction mixture was then filtered through CELITE° concentrated under reduced pressure Purification by flash chromatography on silica gel (0 to 30% ethyl acetate in hexanes)

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

Procedure: A mixture of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.724 g, 4.4 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.91 g, 4.8 mmol), HOAt (0.65 g, 4.8 mmol), 4-methylmorpholine (1.1 mL, 9.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.8 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclopropylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a brown oil (1.07 g, 72%). LCMS (Method B): RT 3.40 min [M+H]+ 338.2. 110180243 The reaction mixture was partitioned between DCM The organic fraction was washed with brine dried (MgSO4) concentrated in vacuo the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane)

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

Procedure: To a solution of cyclopropyl-(5-fluoro-2-nitrophenyl)amine (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 5 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a brown oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.76 (1H, dd, J=10.85, 2.76 Hz), 6.60 (1H, dd, J=8.38, 5.56 Hz), 6.34 (1H, td, J=8.45, 2.82 Hz), 4.15 (1H, br s), 3.03 (2H, br s), 2.45-2.36 (1H, m), 0.80-0.72 (2H, m), 0.56-0.49 (2H, m). The suspension was filtered through a pad of Celite® the filtrate concentrated in vacuo