tert-Butyl (2-amino-4,5-difluorophenyl)carbamate

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

Procedure: 10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) 2,6-dimethoxynicotinic acid commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a 1M hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant. Off-white foam (72%). MS (Turbo Spray) m/z=521.5 [M+H]. 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added From the clear, light brown and slightly warm solution a suspension formed within a few minutes After stirring for 20 h The resulting solution was stirred at room temperature for 29 h the layers were separated The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with water and brine dried over magnesium sulfate filtered treated with silica gel evaporated to dryness The resulting solid was purified by silica gel chromatography eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant

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

Procedure: The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+. for the chromatographic purification

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

Procedure: 10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) 2,6-dimethoxynicotinic acid commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a 1M hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant. Off-white foam (72%). MS (Turbo Spray) m/z=521.5 [M+H]. 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added From the clear, light brown and slightly warm solution a suspension formed within a few minutes After stirring for 20 h The resulting solution was stirred at room temperature for 29 h the layers were separated The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with water and brine dried over magnesium sulfate filtered treated with silica gel evaporated to dryness The resulting solid was purified by silica gel chromatography eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant

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

Procedure: The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+. for the chromatographic purification

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

Procedure: To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (24.42 mg, 0.10 mmol, 1.0 equiv; Intermediate C) in MeOH (1.0 mL) was added cyclohexanecarbaldehyde (16.83 mg, 18.05 μl, 0.15 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (2-chloro-phenoxy)-acetic acid (18.66 mg, 0.10 mmol, 1.0 equiv; [CAS RN 614-61-9]) and cyclohexyl isocyanide (10.92 mg, 12.27 pi, 0.10 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile I water provided 17.5 mg (34%) of the title compound. MS (ISP): 516.2 [M+H]+. stirring continued at rt for 2 h the reaction mixture stirred at rt overnight Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile I water

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

Procedure: To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (36.64 mg, 0.15 mmol, 1.0 equiv) in methanol (2.0 mL) was added cyclohexanecarbaldehyde (25.80 mg, 27.08 μL, 0.23 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (3-chloro-phenyl)-acetic acid (34.12 mg, 0.20 mmol, 1.33 equiv; [CAS RN 1878-65-5]) and cyclohexyl isocyanide (16.38 mg, 18.41 μL, 0.15 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.7 mg (21%) of the title compound. MS (ISP): 500.2 [M+H]+. stirring continued at rt for 2 h the reaction mixture stirred at rt overnight Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water

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

Procedure: To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (36.64 mg, 0.15 mmol, 1.0 equiv) in methanol (2.0 mL) was added cyclohexanecarbaldehyde (25.80 mg, 27.08 μL, 0.23 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (3-chloro-phenyl)-acetic acid (34.12 mg, 0.20 mmol, 1.33 equiv; [CAS RN 1878-65-5]) and cyclohexyl isocyanide (16.38 mg, 18.41 μL, 0.15 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.7 mg (21%) of the title compound. MS (ISP): 500.2 [M+H]+. stirring continued at rt for 2 h the reaction mixture stirred at rt overnight Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water

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

Procedure: To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (0.2 g, 0.82 mmol) in methanol (4 mL) were added cyclohexanecarbaldehyde (0.16 mL, 1.22 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.13 g, 0.82 mmol, 1.0 equiv.) and trans-4-Isocyano-cyclohexanecarboxylic acid methyl ester (0.137 mg, 0.82 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (4 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in methanol (15 ml) and NaOH (5 ml) and DMF (1 ml) were added and the mixture heated to 50° C. overnight. The pH was adjusted to 4. A light brown solid appeared which was further purified by preparative HPLC. MS (ES+): 532 (M+H). the reaction mixture stirred at rt for 3 h The solution was concentrated by evaporation under reduced pressure the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 the aqueous layer extracted with ethyl acetate The combined organic phases were dried over MgSO4 concentrated by evaporation under reduced pressure The crude material was dissolved in methanol (15 ml) NaOH (5 ml) and DMF (1 ml) were added the mixture heated to 50° C. overnight was further purified by preparative HPLC

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

Procedure: To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (1.0 g, 4.1 mmol) in methanol (15 mL) were added cyclohexanecarbaldehyde (0.82 mL, 6.14 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.665 g, 4.1 mmol, 1.0 equiv.) and isocyanomethyl-benzene (0.48 mL, 10.24 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (10 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) and cooled to 0° C. Sodium nitrite (7.4 g, 107 mmol) were added in portions. After the addition the reaction was warmed to rt and stirred for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) and a pre-prepared solution of LiOH (2.1 g, 48.7 mmol) in hydrogen peroxide (10 mL, 30% solution in water) was added drop wise. The mixture was stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with ethyl acetate. The intermediate was not further purified but used as crude material for further modification. MS (ES−): 404 (M−H). the reaction mixture stirred at rt for 3 h The solution was concentrated by evaporation under reduced pressure the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 the aqueous layer extracted with ethyl acetate The combined organic phases were dried over MgSO4 concentrated by evaporation under reduced pressure The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) cooled to 0° C After the addition the reaction was warmed to rt stirred for 3 h The solution was concentrated by evaporation under reduced pressure the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 the aqueous layer extracted with ethyl acetate The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) The mixture was stirred at rt for 30 min The solution was concentrated by evaporation under reduced pressure the pH adjusted to 4 by addition of acetic acid the aqueous layer extracted with ethyl acetate The intermediate was not further purified

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

Procedure: The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+. for the chromatographic purification

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

Procedure: 10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) 2,6-dimethoxynicotinic acid commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a 1M hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant. Off-white foam (72%). MS (Turbo Spray) m/z=521.5 [M+H]. 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added From the clear, light brown and slightly warm solution a suspension formed within a few minutes After stirring for 20 h The resulting solution was stirred at room temperature for 29 h the layers were separated The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with water and brine dried over magnesium sulfate filtered treated with silica gel evaporated to dryness The resulting solid was purified by silica gel chromatography eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant