2-fluoro-3-iodo-4-methylbenzonitrile

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol, 2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere. N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for one hour. The clear solution became turbid indicating the salt formation. The reaction mixture was cooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 ml) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was re-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03 mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperature below −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a saturated solution of Na2S2O3 (10 ml) and stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over sodium sulphate. The volatiles were evaporated under reduced pressure. The crude product was purified under silica gel (60-120) column chromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg (38%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92 Hz), 7.48-7.50 (t, 1H, J=4.80 Hz). maintaining the temperature below −70° C After addition The reaction mixture was cooled to −80° C. maintaining temperature below −70° C The mixture was then warmed to −50° C. stirred for 30 minutes The mixture was re-cooled to −78° C. maintaining the temperature below −70° C After addition the mixture was warmed to ambient temperature stirred for 30 minutes The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with brine dried over sodium sulphate The volatiles were evaporated under reduced pressure The crude product was purified under silica gel (60-120) column chromatography

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol, 2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere. N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for one hour. The clear solution became turbid indicating the salt formation. The reaction mixture was cooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 ml) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was re-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03 mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperature below −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a saturated solution of Na2S2O3 (10 ml) and stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over sodium sulphate. The volatiles were evaporated under reduced pressure. The crude product was purified under silica gel (60-120) column chromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg (38%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92 Hz), 7.48-7.50 (t, 1H, J=4.80 Hz). maintaining the temperature below −70° C After addition The reaction mixture was cooled to −80° C. maintaining temperature below −70° C The mixture was then warmed to −50° C. stirred for 30 minutes The mixture was re-cooled to −78° C. maintaining the temperature below −70° C After addition the mixture was warmed to ambient temperature stirred for 30 minutes The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with brine dried over sodium sulphate The volatiles were evaporated under reduced pressure The crude product was purified under silica gel (60-120) column chromatography

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol, 2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere. N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for one hour. The clear solution became turbid indicating the salt formation. The reaction mixture was cooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 ml) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was re-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03 mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperature below −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a saturated solution of Na2S2O3 (10 ml) and stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over sodium sulphate. The volatiles were evaporated under reduced pressure. The crude product was purified under silica gel (60-120) column chromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg (38%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92 Hz), 7.48-7.50 (t, 1H, J=4.80 Hz). maintaining the temperature below −70° C After addition The reaction mixture was cooled to −80° C. maintaining temperature below −70° C The mixture was then warmed to −50° C. stirred for 30 minutes The mixture was re-cooled to −78° C. maintaining the temperature below −70° C After addition the mixture was warmed to ambient temperature stirred for 30 minutes The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with brine dried over sodium sulphate The volatiles were evaporated under reduced pressure The crude product was purified under silica gel (60-120) column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-3-iodo-4-methylbenzonitrile (3.9385 g, 11.316 mmol; 76% mass % pure) in 1,4-dioxane (10.0 mL, 128 mmol) was added water (4.0 mL, 220 mmol) and sulfuric acid (6.0 mL, 110 mmol). The reaction mixture was heated at 110° C. for 20 hours. The reaction mixture was cooled to room temperature and then poured into ˜200 mL ice water. The resulting tan precipitate was collected by filtration, washed with water and ethyl acetate, and dried under vacuum to provide the title product. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo to yield additional desired product for a combined yield of 3.8743 g which was carried forward without purification. The reaction mixture was cooled to room temperature The resulting tan precipitate was collected by filtration washed with water and ethyl acetate dried under vacuum

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-3-iodo-4-methylbenzonitrile (3.9385 g, 11.316 mmol; 76% mass % pure) in 1,4-dioxane (10.0 mL, 128 mmol) was added water (4.0 mL, 220 mmol) and sulfuric acid (6.0 mL, 110 mmol). The reaction mixture was heated at 110° C. for 20 hours. The reaction mixture was cooled to room temperature and then poured into ˜200 mL ice water. The resulting tan precipitate was collected by filtration, washed with water and ethyl acetate, and dried under vacuum to provide the title product. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo to yield additional desired product for a combined yield of 3.8743 g which was carried forward without purification. The reaction mixture was cooled to room temperature The resulting tan precipitate was collected by filtration washed with water and ethyl acetate dried under vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2,2,6,6-tetramethyl-piperidine (4.50 mL, 26.6 mmol) and tetrahydrofuran (40 mL, 500 mmol) at −78° C. was slowly added n-butyllithium (2.5 mol/L in hexane, 11.5 mL, 28.8 mmol). The reaction vessel was transferred to a 0° C. ice bath for 60 minutes and then recooled at −78° C. 2-fluoro-4-methylbenzonitrile (3.1095 g, 23.010 mmol) as a solution in tetrahydrofuran (20 mL, 200 mmol) was then slowly added. The reaction mixture was stirred at −78° C. for 2 hours, and then a solution of iodine (7.33 g, 28.9 mmol) in tetrahydrofuran (10 mL, 100 mmol) was slowly added and then the reaction mixture was allowed to warm to room temperature. After 1.5 hours the reaction mixture was poured into a solution of sodium thiosulfate (20 g) in water (40 mL) and stirred at room temperature for 15 minutes. The layers were separated, and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient 0-10% ethyl acetate in heptanes) to yield a mixture of regioisomeric products, with the desired product as the major component (3.9385 g, 76% pure). LCMS (ESI): M+H=262.1; 1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 2.56 (s, 3H). was transferred to a 0° C. for 60 minutes recooled at −78° C to warm to room temperature stirred at room temperature for 15 minutes The layers were separated the aqueous layer extracted with ethyl acetate dried over MgSO4 filtered evaporated in vacuo The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient 0-10% ethyl acetate in heptanes) to yield a mixture of regioisomeric products

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

Procedure: To a 250 mL three necked round-bottomed flask equipped with a mechanical stirrer under nitrogen was added anhydrous DMF (100 mL) and acetohydroxamic acid (4.65 g, 62 mmol). After a clear solution was obtained, potassium tert-butoxide (6.94 g, 62 mmol) was added. The cloudy white mixture was allowed to stir for 30 min. 2-Fluoro-3-iodo-4-methylbenzonitrile (8.0 g, 31 mmol) was added and the reaction mixture was allowed to stir at RT for 6 h. Additional acetohydroxarnic acid (1.16 g, 15.5 mmol) and potassium tert-butoxide (1.74 g, 15.5 mmol) were added, and stirring continued for 12 h. The reaction mixture was distilled under reduced pressure to remove most of the DMF and the residue was partitioned between ethyl acetate (250 mL) and sat. aqueous ammonium chloride (50 mL). The aqueous layer was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and then evaporated under reduced pressure. The crude product was loaded on an ISCO column (330 g, eluted with 20-70% ethyl acetate in hexanes) to provide the title compound as an off white crystalline solid. MS (ESI, pos. ion) m/z: 275.0 (M+1). After a clear solution was obtained to stir at RT for 6 h stirring continued for 12 h The reaction mixture was distilled under reduced pressure to remove most of the DMF the residue was partitioned between ethyl acetate (250 mL) and sat. aqueous ammonium chloride (50 mL) The aqueous layer was washed with ethyl acetate (2×100 mL) The combined organic layers were washed with brine (50 mL) dried over MgSO4 evaporated under reduced pressure The crude product was loaded on an ISCO column (330 g, eluted with 20-70% ethyl acetate in hexanes)

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

Procedure: To a 250 mL three necked round-bottomed flask equipped with a mechanical stirrer under nitrogen was added anhydrous DMF (100 mL) and acetohydroxamic acid (4.65 g, 62 mmol). After a clear solution was obtained, potassium tert-butoxide (6.94 g, 62 mmol) was added. The cloudy white mixture was allowed to stir for 30 min. 2-Fluoro-3-iodo-4-methylbenzonitrile (8.0 g, 31 mmol) was added and the reaction mixture was allowed to stir at RT for 6 h. Additional acetohydroxarnic acid (1.16 g, 15.5 mmol) and potassium tert-butoxide (1.74 g, 15.5 mmol) were added, and stirring continued for 12 h. The reaction mixture was distilled under reduced pressure to remove most of the DMF and the residue was partitioned between ethyl acetate (250 mL) and sat. aqueous ammonium chloride (50 mL). The aqueous layer was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and then evaporated under reduced pressure. The crude product was loaded on an ISCO column (330 g, eluted with 20-70% ethyl acetate in hexanes) to provide the title compound as an off white crystalline solid. MS (ESI, pos. ion) m/z: 275.0 (M+1). After a clear solution was obtained to stir at RT for 6 h stirring continued for 12 h The reaction mixture was distilled under reduced pressure to remove most of the DMF the residue was partitioned between ethyl acetate (250 mL) and sat. aqueous ammonium chloride (50 mL) The aqueous layer was washed with ethyl acetate (2×100 mL) The combined organic layers were washed with brine (50 mL) dried over MgSO4 evaporated under reduced pressure The crude product was loaded on an ISCO column (330 g, eluted with 20-70% ethyl acetate in hexanes)

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (45 mL, 267 mmol) in THF (400 mL) was cooled to −78° C. under an atmosphere of nitrogen. n-Butyl lithium (2.5 M in hexane, 110 mL, 275 mmol) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for 30 minutes. The clear solution became turbid indicating the salt formation. The reaction mixture was recooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (32.4 g, 240 mmol) in THF (150 mL) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was recooled to −70° C. and a saturated solution of iodine (67 g, 264 mmol) in THF (150 mL) was added slowly maintaining the temperature at −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a solution of Na2S2O3 (160 g in 1.5 L of water) and stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The volatiles were evaporated under reduced pressure. The crude product was subjected to vacuum distillation, and at about 60° C., the excess TMP was removed, at about 100° C., the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C., pure 2-fluoro-3-iodo-4-methylbenzonitrile was obtained as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 261.9 (M+1). maintaining the temperature below −70° C After addition was recooled to −80° C. maintaining temperature below −70° C The mixture was then warmed to −50° C. stirred for 30 minutes was recooled to −70° C. maintaining the temperature at −70° C After addition the mixture was warmed to ambient temperature stirred for 1 h The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with brine dried over Na2SO4 filtered The volatiles were evaporated under reduced pressure The crude product was subjected to vacuum distillation at about 60° C., the excess TMP was removed, at about 100° C. the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C.

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer, was added 2-fluoro-3-iodo-4-methyl-benzonitrile (33 g, 126.4 mmol), 70 ml of methanol, and 70 ml of 60% aqueous sulfuric acid. The flask was sealed and temperature was raised to 115° C. The reaction mixture was stirred at this temperature overnight. The precipitate that formed was filtered onto fritted filter, washed with 1 L of water, and dried under vacuum for 2 h and then in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1. 1H NMR (DMSO-d6, 400 MHz) δ 13.2 (broad s, 1H), 7.74 (t, 1H), 7.26 (d, 1H), 2.47 (s, 3H), and MS [MH+]=280). To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer The flask was sealed The precipitate that formed was filtered onto fritted filter washed with 1 L of water dried under vacuum for 2 h in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer, was added 2-fluoro-3-iodo-4-methyl-benzonitrile (33 g, 126.4 mmol), 70 ml of methanol, and 70 ml of 60% aqueous sulfuric acid. The flask was sealed and temperature was raised to 115° C. The reaction mixture was stirred at this temperature overnight. The precipitate that formed was filtered onto fritted filter, washed with 1 L of water, and dried under vacuum for 2 h and then in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1. 1H NMR (DMSO-d6, 400 MHz) δ 13.2 (broad s, 1H), 7.74 (t, 1H), 7.26 (d, 1H), 2.47 (s, 3H), and MS [MH+]=280). To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer The flask was sealed The precipitate that formed was filtered onto fritted filter washed with 1 L of water dried under vacuum for 2 h in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer, was added 2-fluoro-3-iodo-4-methyl-benzonitrile (33 g, 126.4 mmol), 70 ml of methanol, and 70 ml of 60% aqueous sulfuric acid. The flask was sealed and temperature was raised to 115° C. The reaction mixture was stirred at this temperature overnight. The precipitate that formed was filtered onto fritted filter, washed with 1 L of water, and dried under vacuum for 2 h and then in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1. 1H NMR (DMSO-d6, 400 MHz) δ 13.2 (broad s, 1H), 7.74 (t, 1H), 7.26 (d, 1H), 2.47 (s, 3H), and MS [MH+]=280). To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer The flask was sealed The precipitate that formed was filtered onto fritted filter washed with 1 L of water dried under vacuum for 2 h in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1