tert-butyl 3-iodobenzoate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L glass pressure vessel was charged with 5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (5.38 g, 0.028 mol) and 3-iodobenzoic acid tert-butyl ester (12.8 g, 0.042) in toluene (300 mL). The solution was stirred and sparged with argon for 10 min. Palladium(II)acetate (0.38 g, 0.00168 mol, 6 mole %) and cesium carbonate (18.3 g, 0.056 mol) were added and sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added and the vessel was sealed and heated at 100° C. overnight. HPLC analysis and TLC (ethyl acetate:hexane; 1:1) showed the reaction was complete. The reaction mixture was filtered and filter paper was washed with ethyl acetate (250 mL). The filtrate was washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×100 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top packed with hexane. The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32. All fractions checked by TLC. The product was eluted in fractions 19-28 to give the title compound (6.9 g, 67%) as a viscous oil. 1H NMR 60 MHz, (CDCl3), δ 9.0 (s, 1H), 8.6 (s, 1H), 7.4 (m. 5H), 4.5 (s, 2H), 4.0 (s, 3H), 3.6 (m, 4H), 1.7 (s, 9H). sparged with argon for 10 min sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added the vessel was sealed The reaction mixture was filtered filter paper was washed with ethyl acetate (250 mL) The filtrate was washed with water (250 mL) The aqueous layer was separated extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with brine (3×100 mL) filtered through 1 PS filter paper concentrated under reduced pressure to give an oil The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32 The product was eluted in fractions 19-28

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1′-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40° C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40° C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2×500 mL). The combined organic layers were washed with water (2×400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), δ 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H). heated at 40° C. overnight The reaction was cooled to room temperature extracted with hexane (2×500 mL) The combined organic layers were washed with water (2×400 mL), brine (250 mL) dried over anhydrous magnesium sulfate (15 g) filtered concentrated under reduced pressure

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid tert-butyl ester (4.6g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min., when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL) was added and the mixuture was heated at 40 to 45° C. overnight. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc: MeOH=6:1) gave the desired product (0.46 g). the reaction was kept at rt for 1 h extracted with EtOAc (2×100 mL) the combined organics dried over Na2SO4 concentrated Purification of the crude product by column chromatography (EtOAc: MeOH=6:1)

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid tert-butyl ester (4.6g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min., when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL) was added and the mixuture was heated at 40 to 45° C. overnight. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc: MeOH=6:1) gave the desired product (0.46 g). the reaction was kept at rt for 1 h extracted with EtOAc (2×100 mL) the combined organics dried over Na2SO4 concentrated Purification of the crude product by column chromatography (EtOAc: MeOH=6:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L glass pressure vessel was charged with 5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (5.38 g, 0.028 mol) and 3-iodobenzoic acid tert-butyl ester (12.8 g, 0.042 mmol) in toluene (300 mL). The solution was stirred and sparged with argon for 10 min. Palladium(II)acetate (0.38 g, 0.00168 mol, 6 mole %) and cesium carbonate (18.3 g, 0.056 mol) were added and sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added and the vessel was sealed and heated at 100° C. overnight. HPLC analysis and TLC (ethyl acetate:hexane; 1:1) showed the reaction was complete. The reaction mixture was filtered and filter paper was washed with ethyl acetate (250 mL). The filtrate was washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×100 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top packed with hexane. The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32. All fractions checked by TLC. The product was eluted in fractions 19-28 to give the title compound (6.9 g, 67%) as a viscous oil. 1H NMR 60 MHz, (CDCl3), δ 9.0 (s, 1H), 8.6 (s, 1H), 7.4 (m. 5H), 4.5 (s, 2H), 4.0 (s, 3H), 3.6 (m, 4H), 1.7 (s, 9H). sparged with argon for 10 min sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added the vessel was sealed The reaction mixture was filtered filter paper was washed with ethyl acetate (250 mL) The filtrate was washed with water (250 mL) The aqueous layer was separated extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with brine (3×100 mL) filtered through 1PS filter paper concentrated under reduced pressure to give an oil The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32 The product was eluted in fractions 19-28

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1′-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40° C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40° C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2×500 mL). The combined organic layers were washed with water (2×400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), δ 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H). heated at 40° C. overnight The reaction was cooled to room temperature extracted with hexane (2×500 mL) The combined organic layers were washed with water (2×400 mL), brine (250 mL) dried over anhydrous magnesium sulfate (15 g) filtered concentrated under reduced pressure

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

Procedure: A mixture of 4-methylphenylboronic acid (0.65 g, 4.3 mmol), t-butyl-3-iodobenzoate (0.87 g, 2.86 mmol), K2CO3 (0.59 g, 4.3 mmol), and (Ph3P)4 Pd (0.17 g, 0.14 mmol) in DME (15 mL) was degassed and flushed with N2 before being brought to reflux for 2 h. Following a standard aqueous/EtOAc work-up, the residue was triturated with 1:10 EtOAc/hexane. The excess boronic acid was removed by filtration, and the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane) to give an oil (0.6 g). This material (≈60% pure) was used as such for the next step. was degassed flushed with N2 to reflux for 2 h the residue was triturated with 1:10 EtOAc/hexane The excess boronic acid was removed by filtration the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane)

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

Procedure: A mixture of 4-methylphenylboronic acid (0.65 g, 4.3 mmol), t-butyl-3-iodobenzoate (0.87 g, 2.86 mmol), K2CO3 (0.59 g, 4.3 mmol), and (Ph3P)4 Pd (0.17 g, 0.14 mmol) in DME (15 mL) was degassed and flushed with N2 before being brought to reflux for 2 h. Following a standard aqueous/EtOAc work-up, the residue was triturated with 1:10 EtOAc/hexane. The excess boronic acid was removed by filtration, and the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane) to give an oil (0.6 g). This material (≈60% pure) was used as such for the next step. was degassed flushed with N2 to reflux for 2 h the residue was triturated with 1:10 EtOAc/hexane The excess boronic acid was removed by filtration the filtrate was concentrated to give an oil which was purified by flash chromatography (hexane)

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid tert-butyl ester (4.6 g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min., when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL) was added and the mixture was heated at 40 to 45° C. overnight. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc: MeOH=6:1) gave the desired product (0.46 g). the reaction was kept at rt for 1 h extracted with EtOAc (2×100 mL) the combined organics dried over Na2SO4 concentrated Purification of the crude product by column chromatography (EtOAc: MeOH=6:1)

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-iodobenzoic acid tert-butyl ester (4.6 g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min., when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL) was added and the mixture was heated at 40 to 45° C. overnight. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc: MeOH=6:1) gave the desired product (0.46 g). the reaction was kept at rt for 1 h extracted with EtOAc (2×100 mL) the combined organics dried over Na2SO4 concentrated Purification of the crude product by column chromatography (EtOAc: MeOH=6:1)

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

Procedure: To a mixture of 244 mg of 3-(2-aminoethyl)pyridine (2.0 mmol) and 604 mg of t-butyl 3-iodobenzoate (2.0 mmol) in 10 mL of toluene was added 250 mg of sodium t-butoxide (2.5 mmol), 30 mg of tri-t-butylphosphonium tetrafluoroborate (0.1 mmol) and 50 mg of tris(dibenzylidineacetone)dipalladium(0) (0.055 mmol). The mixture was stirred for 16 h and filtered through celite. The celite was washed with 3×5 mL of toluene and the filtrate was concentrated in vacuo. The residue was purified by column chromatography using 35%-45% EtOAc in hexanes as eluant to give 103 mg of t-butyl N-(2-(3-pyridyl)ethyl)-3-aminobenzoate as a bright yellow oil (17% yield). filtered through celite The celite was washed with 3×5 mL of toluene the filtrate was concentrated in vacuo The residue was purified by column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L glass pressure vessel was charged with 5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (5.38 g, 0.028 mol) and 3-iodobenzoic acid tert-butyl ester (12.8 g, 0.042) in toluene (300 mL). The solution was stirred and sparged with argon for 10 min. Palladium(II)acetate (0.38 g, 0.00168 mol, 6 mole %) and cesium carbonate (18.3 g, 0.056 mol) were added and sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added and the vessel was sealed and heated at 100° C. overnight. HPLC analysis and TLC (ethyl acetate:hexane; 1:1) showed the reaction was complete. The reaction mixture was filtered and filter paper was washed with ethyl acetate (250 mL). The filtrate was washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×100 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top packed with hexane. The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32. All fractions checked by TLC. The product was eluted in fractions 19-28 to give the title compound (6.9 g, 67%) as a viscous oil. 1H NMR 60 MHz, (CDCl3), δ 9.0 (s, 1H), 8.6 (s, 1H), 7.4 (m. 5H), 4.5 (s, 2H), 4.0 (s, 3H), 3.6 (m, 4H), 1.7 (s, 9H). sparged with argon for 10 min sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added the vessel was sealed The reaction mixture was filtered filter paper was washed with ethyl acetate (250 mL) The filtrate was washed with water (250 mL) The aqueous layer was separated extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with brine (3×100 mL) filtered through 1 PS filter paper concentrated under reduced pressure to give an oil The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32 The product was eluted in fractions 19-28