3-chloro-4-methylsulfonylaniline

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

Procedure: The title compound was prepared according to the procedure of step 1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)aniline from step3 instead of 3-chloro-4-(methylsulfonyl)aniline.

Conditions: temp:230.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at 230° C. for 1 hour using a microwave reaction system. Thereafter, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190° C. for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product. This product was heated with ethanol and washed to give a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and insoluble materials were separated by filtration and the filtrate was concentrated. After the filtrate was concentrated, the residue was heated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a light yellow solid. a microwave reaction system stirred at 190° C. for 30 minutes a microwave reaction system After cooling the reaction liquid was partitioned the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride After drying over anhydrous magnesium sulfate the solvent was distilled off the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product washed to give a light yellow solid heated insoluble materials were separated by filtration the filtrate was concentrated After the filtrate was concentrated the residue was heated washed with ethanol

Conditions: temp:230.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at 230° C. for 1 hour using a microwave reaction system. Thereafter, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190° C. for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product. This product was heated with ethanol and washed to give a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and insoluble materials were separated by filtration and the filtrate was concentrated. After the filtrate was concentrated, the residue was heated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a light yellow solid. a microwave reaction system stirred at 190° C. for 30 minutes a microwave reaction system After cooling the reaction liquid was partitioned the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride After drying over anhydrous magnesium sulfate the solvent was distilled off the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product washed to give a light yellow solid heated insoluble materials were separated by filtration the filtrate was concentrated After the filtrate was concentrated the residue was heated washed with ethanol

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

Procedure: To a stirred suspension of 3-chloro-4-(methylsulfonyl)aniline (3.0 g, 15.0 mmol, Ish. K. Khanna et al., J. Med. Chem. 40, 1619 (1997)) in 20% aqueous HCl (20 mL) was added dropwise a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (20 mL) below −5° C. After stirring for 1 hour at that temperature, tin(II) chloride dihydrate in 20% aqueous HCl (20 mL) was added dropwise below −5° C. The resulting suspension was stirred for 1 h at room temperature. The mixture was basified with aqueous NaOH (pH=14) and extracted with CHCl3 (200 mL×2), dried over MgSO4, and concentrated in vacuo. The solid (5 g) was dissolved in 10% methanolic HCl (30 mL), and volatiles were removed by evaporation. The residue was washed with ethanol to give the title compound (1.3 g, 34%). was added dropwise below −5° C extracted with CHCl3 (200 mL×2) dried over MgSO4 concentrated in vacuo The solid (5 g) was dissolved in 10% methanolic HCl (30 mL) volatiles were removed by evaporation The residue was washed with ethanol

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

Procedure: To a stirred suspension of 3-chloro-4-(methylsulfonyl)aniline (3.0 g, 15.0 mmol, Ish. K. Khanna et al., J. Med. Chem. 40, 1619 (1997)) in 20% aqueous HCl (20 mL) was added dropwise a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (20 mL) below −5° C. After stirring for 1 hour at that temperature, tin(II) chloride dihydrate in 20% aqueous HCl (20 mL) was added dropwise below −5° C. The resulting suspension was stirred for 1 h at room temperature. The mixture was basified with aqueous NaOH (pH=14) and extracted with CHCl3 (200 mL×2), dried over MgSO4, and concentrated in vacuo. The solid (5 g) was dissolved in 10% methanolic HCl (30 mL), and volatiles were removed by evaporation. The residue was washed with ethanol to give the title compound (1.3 g, 34%). was added dropwise below −5° C extracted with CHCl3 (200 mL×2) dried over MgSO4 concentrated in vacuo The solid (5 g) was dissolved in 10% methanolic HCl (30 mL) volatiles were removed by evaporation The residue was washed with ethanol

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

Procedure: The title compound was prepared according to the procedure of step 1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)aniline from step3 instead of 3-chloro-4-(methylsulfonyl)aniline.

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

Procedure: The title compound was prepared according to the procedure of step1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)aniline from step3 instead of 3-chloro-4-(methylsulfonyl)aniline.

Conditions: temp:230.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at 230° C. for 1 hour using a microwave reaction system. Thereafter, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190° C. for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product. This product was heated with ethanol and washed to give a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and insoluble materials were separated by filtration and the filtrate was concentrated. After the filtrate was concentrated, the residue was heated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a light yellow solid. a microwave reaction system stirred at 190° C. for 30 minutes a microwave reaction system After cooling the reaction liquid was partitioned the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride After drying over anhydrous magnesium sulfate the solvent was distilled off the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product washed to give a light yellow solid heated insoluble materials were separated by filtration the filtrate was concentrated After the filtrate was concentrated the residue was heated washed with ethanol

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

Procedure: To a stirred suspension of 3-chloro-4-(methylsulfonyl)aniline (3.0 g, 15.0 mmol, Ish. K. Khanna et al., J. Med. Chem. 40, 1619 (1997)) in 20% aqueous HCl (20 mL) was added dropwise a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (20 mL) below −5° C. After stirring for 1 hour at that temperature, tin(II) chloride dihydrate in 20% aqueous HCl (20 mL) was added dropwise below −5° C. The resulting suspension was stirred for 1 h at room temperature. The mixture was basified with aqueous NaOH (pH=14) and extracted with CHCl3 (200 mL×2), dried over MgSO4, and concentrated in vacuo. The solid (5 g) was dissolved in 10% methanolic HCl (30 mL), and volatiles were removed by evaporation. The residue was washed with ethanol to give the title compound (1.3 g, 34%). was added dropwise below −5° C extracted with CHCl3 (200 mL×2) dried over MgSO4 concentrated in vacuo The solid (5 g) was dissolved in 10% methanolic HCl (30 mL) volatiles were removed by evaporation The residue was washed with ethanol

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

Procedure: The title compound was prepared according to the procedure of step 1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)aniline from step3 instead of 3-chloro-4-(methylsulfonyl)aniline.