2-bromo-1-cyclohexylethanone

Conditions: temp:48.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to M6, 2.7 g (13.2 mmol) of 2-bromo-1-cyclohexylethanone (Tetrahedron, 48, 1, 67-78, 1992) are mixed with 1.92 g (13.7 mmol) of hexamethylenetetramine in 20 ml of chloroform. The mixture is heated at 48° C. for 4 hours and then evaporated to dryness. The residue is taken up in 20 ml of ethanol and 9 ml of 36% hydrochloric acid. After leaving overnight at room temperature, the reaction medium is filtered. The filtrate is evaporated to dryness to give an oil which is crystallized from diethyl ether. After filtration and drying, 2.08 g (80%) of 2-amino-1-cyclohexylethanone hydrochloride are obtained in the form of a paste. evaporated to dryness After leaving overnight at room temperature the reaction medium is filtered The filtrate is evaporated to dryness to give an oil which is crystallized from diethyl ether After filtration drying

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

Procedure: The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromoacetylcyclohexane (Lotfield, Schaad, J. Am. Chem. Soc., 1954, 76, 35).

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

Procedure: The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromoacetylcyclohexane (Lotfield, Schaad, J. Am. Chem. Soc., 1954, 76, 35).

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

Procedure: Cyclohexyl methyl ketone (0.30 mL, 2.4 mmol) [Alfa Aesar cat#L05501] was dissolved in methanol (3.0 mL, 74 mmol) cooled in an ice bath and bromine (0.38 g, 2.4 mmol) was added drop wise. The mixture was stirred for 2 h and then water (3.0 mL) was added and the reaction mixture was allowed to stir for 4 h. The reaction mixture was extracted with EtOAc:hexane (3:1). The combined organic layer was washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give as 2-bromo-1-cyclohexylethanone as a clear oil (0.49 g, 100%). 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 2H), 2.86-2.55 (m, 1H), 2.24-1.08 (m, 10H). cooled in an ice bath to stir for 4 h The reaction mixture was extracted with EtOAc:hexane (3:1) The combined organic layer was washed with water saturated potassium carbonate, brine dried over magnesium sulfate concentrated

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

Procedure: Cyclohexyl methyl ketone (0.30 mL, 2.4 mmol) [Alfa Aesar cat#L05501] was dissolved in methanol (3.0 mL, 74 mmol) cooled in an ice bath and bromine (0.38 g, 2.4 mmol) was added drop wise. The mixture was stirred for 2 h and then water (3.0 mL) was added and the reaction mixture was allowed to stir for 4 h. The reaction mixture was extracted with EtOAc:hexane (3:1). The combined organic layer was washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give as 2-bromo-1-cyclohexylethanone as a clear oil (0.49 g, 100%). 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 2H), 2.86-2.55 (m, 1H), 2.24-1.08 (m, 10H). cooled in an ice bath to stir for 4 h The reaction mixture was extracted with EtOAc:hexane (3:1) The combined organic layer was washed with water saturated potassium carbonate, brine dried over magnesium sulfate concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (60% in mineral oil, 0.020 g, 0.49 mmol) was added to dry DMF (3 mL). The suspension was cooled to about 0° C. and a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.19 g, 0.489 mmol, Example #8, Step A) in dry DMF (2 mL) was added drop-wise. The reaction mixture was allowed to warm to ambient temperature and 2-bromo-1-cyclohexylethanone (0.10 g, 0.49 mmol, 3B PharmaChem) was added. The reaction mixture was stirred for about 2 h and then concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with 100% heptane for 10 min and a gradient of 10-20% EtOAc in heptane over 20 min yielded tert-butyl 2-cyclohexyl-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate as a yellow amorphous solid (0.080 g, 32%): LC/MS (Table 2, Method a) Rt=3.13 min; MS m/z: 513 (M+H)+. to warm to ambient temperature concentrated under reduced pressure Purification by silica gel flash chromatography eluting with 100% heptane for 10 min

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (60% in mineral oil, 0.020 g, 0.49 mmol) was added to dry DMF (3 mL). The suspension was cooled to about 0° C. and a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.19 g, 0.489 mmol, Example #8, Step A) in dry DMF (2 mL) was added drop-wise. The reaction mixture was allowed to warm to ambient temperature and 2-bromo-1-cyclohexylethanone (0.10 g, 0.49 mmol, 3B PharmaChem) was added. The reaction mixture was stirred for about 2 h and then concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with 100% heptane for 10 min and a gradient of 10-20% EtOAc in heptane over 20 min yielded tert-butyl 2-cyclohexyl-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate as a yellow amorphous solid (0.080 g, 32%): LC/MS (Table 2, Method a) Rt=3.13 min; MS m/z: 513 (M+H)+. to warm to ambient temperature concentrated under reduced pressure Purification by silica gel flash chromatography eluting with 100% heptane for 10 min

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+. The solvent was removed under reduced pressure

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+. The solvent was removed under reduced pressure

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

Procedure: 1-(5-Fluoro-2-hydroxyphenyl)ethanone (4.0 g) was dissolved in acetonitrile (80 mL). To the reaction mixture were added potassium carbonate (4.8 g) and 2-bromo-1-cyclohexylethanone (7.3 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was filtered through celite, rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL) was added to the solution, and the mixture was stirred with heating at 110° C. for 1 hr. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-ethanol to give the title object compound (4.7 g, 76%) as a colorless solid. synthesized in Example A51(1) at room temperature The reaction mixture was filtered through celite rinsed with ethyl acetate the filtrate was concentrated under reduced pressure The residue was dissolved in N,N-dimethylformamide (50 mL) 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL) was added to the solution the mixture was stirred with heating at 110° C. for 1 hr After cooling to room temperature the reaction mixture was quenched with 1N hydrochloric acid the mixture was extracted with diethyl ether The extract was concentrated under reduced pressure the precipitated compound was recrystallized from diisopropyl ether-ethanol

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

Procedure: 1-[5-Bromo-2-hydroxyphenyl]ethanone (13.4 g) was dissolved in N,N-dimethylformamide (300 mL). To the reaction mixture were added potassium carbonate (25.8 g) and 2-bromo-1-cyclohexylethanone (19.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was filtered through celite, water (200 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (150 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.3 mL) was added to the solution at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (70 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title object compound (15.4 g, 77%) as a pale-yellow solid. synthesized in Example A51(1) at room temperature The reaction mixture was filtered through celite, water (200 mL) was added the mixture was extracted with diethyl ether (100 mL×2) The extract was washed with saturated brine dried over magnesium sulfate concentrated under reduced pressure The residue was dissolved in N,N-dimethylformamide (150 mL) 1,8-diazabicyclo[5.4.0]undec-7-ene (9.3 mL) was added to the solution at room temperature the mixture was stirred at 100° C. for 1 hr 1N hydrochloric acid (70 mL) was added the mixture was extracted with diethyl ether (100 mL×2) The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate concentrated under reduced pressure The precipitate was washed with diisopropyl ether

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

Procedure: To a solution (50 mL) of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (2.8 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (3.1 g, 70%) as a colorless solid. synthesized in Example A51(1) at room temperature to cool to room temperature filtered through celite Water was added to the filtrate the mixture was extracted with diethyl ether The extract was washed with saturated brine dried over magnesium sulfate concentrated under reduced pressure The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution the mixture was stirred at 110° C 1 hr with heating After cooling to room temperature the reaction mixture was quenched with 1N hydrochloric acid the reaction mixture was extracted with diethyl ether The extract was concentrated under reduced pressure the precipitated compound was recrystallized from diisopropyl ether-hexane