7-azabicyclo[2.2.1]heptane;hydrochloride

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

Procedure: 4-fluoro-1-nitro-2-(trifluoromethyl)benzene was dissolved in 3 vol DCM. Tetrabutylammoniumbromide (0.05 eq) and KOH (50 wt %, 3.6 eq) were added. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) was then added at 0-5° C. The reaction was warmed up to ambient temperature and monitored by HPLC. Once substantially complete, the layers were separated and the organic layer was washed with 1M HCl. The layers were separated and the aqueous layer was discarded. The organic layer was washed once with water, once with brine, and then distilled. The resulting material was recrystallized from cyclohexane at reflux. The solid was filtered, washed with cyclohexane, and dried in a vacuum oven at 45° C. with a N2 gas bleed to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9). Once substantially complete, the layers were separated the organic layer was washed with 1M HCl The layers were separated The organic layer was washed once with water, once with brine distilled The resulting material was recrystallized from cyclohexane at reflux The solid was filtered washed with cyclohexane dried in a vacuum oven at 45° C. with a N2 gas

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel along with Na2CO3 (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere and stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (633.4 g, 4.740 mol) was then added to the vessel in portions. The temperature was gradually raised to 55° C. When the reaction was substantially complete, the mixture was diluted with 10 vol EtOAc and washed with water (5.5 vol) three times or until DMSO in the aqueous layer disappeared (HPLC). The organic layer was concentrated to 4 vol and then the solvent was swapped with cyclohexane until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. Then the solution was cooled to room temperature with stirring or rotation for 3 h. When all the solid crystallized, the solution was concentrated to dryness to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9). washed with water (5.5 vol) three times or until DMSO in the aqueous layer The organic layer was concentrated to 4 vol was removed containing cyclohexane The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min Then the solution was cooled to room temperature with stirring When all the solid crystallized the solution was concentrated to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (4.6 g, 34.43 mmol, obtained from under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 ml, 86.07 mmol) in acetonitrile (50 ml). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H). obtained from under a nitrogen atmosphere to cool was partitioned between water and dichloromethane The organic layer was washed with 1 M HCl dried over Na2SO4 filtered concentrated to dryness Purification by silica gel chromatography (0-10% ethyl acetate in hexanes)

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

Procedure: To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (8) dissolved in 3 vol DCM, tetrabutylammoniumbromide (0.05 eq) and 50 wt % KOH (3.6 eq) were added. 7-azabicyclo[2.2.1]heptane hydrochloride (9) was then added at 0-5° C. The reaction was warmed to ambient temperature. The reaction was monitored by HPLC, and when the substrate was <1% AUC, the reaction was considered complete, and the layers are separated. The organic layer was washed with 1M HCl, and the aqueous layer was discarded. The organic layer was then washed once with water, once with brine, and evaporated. The resulting material was recrystallized from cyclohexane at reflux. The solid was filtered, washed with cyclohexane, and dried in a vacuum oven at 45° C. under a nitrogen atmosphere to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane. were added the layers are separated The organic layer was washed with 1M HCl The organic layer was then washed once with water, once with brine evaporated The resulting material was recrystallized from cyclohexane at reflux The solid was filtered washed with cyclohexane dried in a vacuum oven at 45° C. under a nitrogen atmosphere

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (8) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel, along with sodium carbonate (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere, with stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (9) (633.4 g, 4.740 mol) was then added to the vessel in portions, and the temperature was gradually raised to 55° C. The reaction was monitored by HPLC, and when the substrate was <1% AUC, the reaction was considered complete. The mixture was then diluted with 10 vol EtOAc and washed with water (5.5 vol) three times. The organic layer was then concentrated to 4 vol and cyclohexane was added and concentrated to 4 vol. The process of adding cyclohexane and concentrating the resulting solution to 4 vol was repeated until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. The solution was then cooled to room temperature with stirring or rotation for 3 h. All the solid then crystallized, and was concentrated to dryness to provid 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (10A). washed with water (5.5 vol) three times The organic layer was then concentrated to 4 vol and cyclohexane was added concentrated to 4 The process of adding cyclohexane and concentrating the resulting solution to 4 vol was removed containing cyclohexane The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min The solution was then cooled to room temperature All the solid then crystallized was concentrated to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride (9) (4.6 g, 34.43 mmol, was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (8) (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 mL, 86.07 mmol) in acetonitrile (50 mL), under a nitrogen atmosphere. The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was then allowed to cool and partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H). to cool partitioned between water and dichloromethane The organic layer was washed with 1 M HCl dried over Na2SO4 filtered concentrated to dryness Purification by silica gel chromatography (0-10% ethyl acetate in hexanes)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-4-methyl-5-nitropyridine (150 mg, 0.96 mmol) in acetonitrile (5 mL) was added 7-azabicyclo[2.2.1]heptane hydrochloride (153 mg, 1.15 mmol) and triethylamine (335 μL, 2.40 mmol). The reaction was heated at 80° C. for 16 h. The reaction was quenched with water (2 mL) and solvent was evaporated. The residue was dissolved in ethyl acetate (15 mL), washed with 1N HCl (10 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methylpyridin-3-amine (160 mg, 71% yield) as yellow solid which was used in next step without purification. 1H NMR (400.0 MHz, CDCl3) δ 8.96 (s, 1H), 6.37 (s, 1H), 4.59 (s, 2H), 2.59 (d, J=0.4 Hz, 3H), 1.83-1.80 (m, 4H), 1.61-1.54 (m, 4H). The reaction was quenched with water (2 mL) and solvent was evaporated The residue was dissolved in ethyl acetate (15 mL) washed with 1N HCl (10 mL) dried over MgSO4 filtered concentrated in vacuo

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

Procedure: 4-fluoro-1-nitro-2-(trifluoromethyl)benzene was dissolved in 3 vol DCM. Tetrabutylammoniumbromide (0.05 eq) and KOH (50 wt %, 3.6 eq) were added. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) was then added at 0-5° C. The reaction was warmed up to ambient temperature and monitored by HPLC. Once substantially complete, the layers were separated and the organic layer was washed with 1M HCl. The layers were separated and the aqueous layer was discarded. The organic layer was washed once with water, once with brine, and then distilled. The resulting material was recrystallized from cyclohexane at reflux. The solid was filtered, washed with cyclohexane, and dried in a vacuum oven at 45° C. with a N2 gas bleed to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9). Once substantially complete, the layers were separated the organic layer was washed with 1M HCl The layers were separated The organic layer was washed once with water, once with brine distilled The resulting material was recrystallized from cyclohexane at reflux The solid was filtered washed with cyclohexane dried in a vacuum oven at 45° C. with a N2 gas

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel along with Na2CO3 (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere and stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (633.4 g, 4.740 mol) was then added to the vessel in portions. The temperature was gradually raised to 55° C. When the reaction was substantially complete, the mixture was diluted with 10 vol EtOAc and washed with water (5.5 vol) three times or until DMSO in the aqueous layer disappeared (HPLC). The organic layer was concentrated to 4 vol and then the solvent was swapped with cyclohexane until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. Then the solution was cooled to room temperature with stirring or rotation for 3 h. When all the solid crystallized, the solution was concentrated to dryness to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9). washed with water (5.5 vol) three times or until DMSO in the aqueous layer The organic layer was concentrated to 4 vol was removed containing cyclohexane The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min Then the solution was cooled to room temperature with stirring When all the solid crystallized the solution was concentrated to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (4.6 g, 34.43 mmol, obtained from under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 ml, 86.07 mmol) in acetonitrile (50 ml). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H). obtained from under a nitrogen atmosphere to cool was partitioned between water and dichloromethane The organic layer was washed with 1 M HCl dried over Na2SO4 filtered concentrated to dryness Purification by silica gel chromatography (0-10% ethyl acetate in hexanes)

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

Procedure: Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g, 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of 7-azabicyclo[2.2.1]heptane hydrochloride (4.75 g; 36.0 mmol) and triethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give a solid which was crystallised from ethyl acetate to give the desired compound (5.45 g). the DCM evaporated in vacuo the residue azeotroped with toluene (2×15 mL) The mixture was stirred at RT for 18 hours the DCM evaporated in vacuo the residue partitioned between water (75 mL) and ethyl acetate (150 mL) The organic layer was washed with brine dried (MgSO4) evaporated to give a solid which was crystallised from ethyl acetate

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

Procedure: Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g, 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of 7-azabicyclo[2.2.1]heptane hydrochloride (4.75 g; 36.0 mmol) and triethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give a solid which was crystallised from ethyl acetate to give the desired compound (5.45 g). the DCM evaporated in vacuo the residue azeotroped with toluene (2×15 mL) The mixture was stirred at RT for 18 hours the DCM evaporated in vacuo the residue partitioned between water (75 mL) and ethyl acetate (150 mL) The organic layer was washed with brine dried (MgSO4) evaporated to give a solid which was crystallised from ethyl acetate