tert-butyl N-[(2-bromophenyl)methyl]carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 1H-pyrazol-3-ylboronic acid (156 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (242 mg, 0.21 mmol), and sodium carbonate (222 mg, 2.1 mmol) in dimethylformamide (2 ml), was added tert-butyl-2-bromobenzylcarbamate (200 mg, 0.699 mmol). The suspension was stirred at 100° C. for 2 h, cooled to room temperature, poured onto saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate and concentrated in vacuo. The crude material was passed through silica (ISCO, 0-30% ethyl acetate/hexane) to give tert-butyl 2-(1H-pyrazol-3-yl)benzylcarbamate; MS (ES+) M+1 274.1 for C15H19N3O2. cooled to room temperature extracted with ethyl acetate The combined organic layers were washed with saturated sodium chloride dried with magnesium sulfate concentrated in vacuo

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

Procedure: To a solution of 3.2 g (8.2 mmol) of 4-(t-butyldiphenylsilyoxymethyl)phenylboronic acid (Step C) in 64 mL of benzene was added 2.2 mL of water, 6.4 mL of 5N aqueous sodium hydroxide, and 8.3 mL of isopropanol. To this mixture was added 180 mg (0.16 mmol) of tetrakis(triphenylphosphine) palladium and 2.20 g (7.81 mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step D). The resulting mixture was heated under nitrogen at reflux for 2 hours then cooled to room temperature. The reaction mixture was diluted with 100 mL of water, transferred to a separators funnel and extracted with ether (3×150 mL). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexaneslethyl acetate (9:1) to afford 4.31 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): d 1.11 (s, 9 H), 1.41 (s, 9 H), 4.27 (d, 6 Hz, 2 H), 4.45 (m, 1 H), 4.81 (s, 2 H), 7.20-7.49 (m, 14 H), 8.72 (m, 4 H). FAB-MS: calculated for C35H41NO3Si 551; found 552 (M+H). The resulting mixture was heated under nitrogen at reflux for 2 hours transferred to a separators funnel extracted with ether (3×150 mL) The combined ether extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL) dried over magnesium sulfate filtered The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexaneslethyl acetate (9:1)

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

Procedure: 3,5-Trans-N-(2-fluorobenzyl)-5-(2-tert-butoxycarbonylaminomethylphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-2-bromobenzylamine (3.82 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (42 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off. The residual oily compound was purified by means of a silica gel column chromatography to give a yellow solid product, which was recrystallized from n-hexane-isopropyl ether. The crystals were collected by filtration to afford 2-amino-2′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (1.3 g) as a pale yellow crystalline product. The organic layer was washed with water dried over anhydrous MgSO4 The solvent was then distilled off The residual oily compound was purified by means of a silica gel column chromatography to give a yellow solid product, which was recrystallized from n-hexane-isopropyl ether The crystals were collected by filtration

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

Procedure: 3,5-Trans-N-(2-fluorobenzyl)-5-(2-tert-butoxycarbonylaminomethylphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-2-bromobenzylamine (3.82 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (42 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off. The residual oily compound was purified by means of a silica gel column chromatography to give a yellow solid product, which was recrystallized from n-hexane-isopropyl ether. The crystals were collected by filtration to afford 2-amino-2′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (1.3 g) as a pale yellow crystalline product. The organic layer was washed with water dried over anhydrous MgSO4 The solvent was then distilled off The residual oily compound was purified by means of a silica gel column chromatography to give a yellow solid product, which was recrystallized from n-hexane-isopropyl ether The crystals were collected by filtration

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

Procedure: To a solution of 1.0 g (3.8 mmol) of 4-(t-butyldimethaylsilyoxymethyl)phenylboronic acid (Step E) in 24 mL of 1,2-dimethyoxyethane was added 4 mL of water,m 1.02 g (5.37 mmol) of barium hydroxide hexahydrate, 1.02 g (3.58 mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step F) and 206 mg (0.18 mmol) of tetrakis(triphenylphosphine) palladium. The resulting mixture was heated under nitrogen at 80° C. for 2.5 hours then cooled to room temperature. The reaction mixture was diluted with 40 mL of saturated aqueous ammonium chloride. The solution was transferred to a separatory funnel and extracted with ether (3×75 mL). The combined ether extracts were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and then filtered. The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (85:15) to afford 1.15 g (75%) of the product as a clear oil. FAB-MS: calculated for C25H37NO3Si 427; found 314. 1H NMR (200 MHz, CDCl3): 0.10 (s, 6H), 0.92 (s, 9H), 1.40 (s, 9H), 4.27 (d, 5 Hz, 2H), 4.60 (s, 1H), 4.78 (s, 2H), 7.18-7.45 (m, 8H). then cooled to room temperature The solution was transferred to a separatory funnel extracted with ether (3×75 mL) The combined ether extracts were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride dried over magnesium sulfate filtered The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (85:15)

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

Procedure: To a solution of 3.2 g (8.2 mmol) of 4-(t-butyldiphenylsilyoxymethyl)phenylboronic acid (Step B) in 64 mL of benzene was added 2.2 mL of water, 6.4 mL of 5N aqueous sodium hydroxide, and 8.3 mL of isopropanol. To this mixture was added 180 mg (0.16 mmol) of tetrakis(triphenylphosphine) palladium and 2.20 g (7.81 mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step C). The resulting mixture was heated under nitrogen at reflux for 2 hours then cooled to room temperature. The reaction mixture was diluted with 100 mL of water, transferred to a separatory funnel and extracted with is ether (3×150 mL). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (9:1) to afford 4.31 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): δ1.11 (s, 9H), 1.41 (s, 9H), 4.27 (d, 6Hz, 2H), 4.45 (m, 1H), 4.81 (s, 2H), 7.20-7.49 (m, 14H), 8.72 (m, 4H). FAB-MS: calculated for C35H41NO3Si 551; found 552 (M+H). The resulting mixture was heated under nitrogen at reflux for 2 hours transferred to a separatory funnel extracted The combined ether extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL) dried over magnesium sulfate filtered The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (9:1)

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

Procedure: 500 mg (1.75 mmol) of tert-butyl 2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2(dppf), 518.4 mg (1.34 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A), 3.36 ml of 2 M sodium carbonate solution and a further 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 ml of DMF are reacted by general method D. The crude product which has been dried under high vacuum is stirred in 4 ml of a 1:1-mixture of methanol and 4 M hydrogen chloride in dioxane at room temperature for 2 h. The reaction solution is concentrated, and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 121.6 mg (22.4% of theory) of the title compound are obtained. The crude product which has been dried under high vacuum The reaction solution is concentrated the resulting crude product is purified by preparative HPLC The product fractions are concentrated after addition of a 3:1 mixture of methanol and 1N hydrochloric acid again concentrated dried under high vacuum

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

Procedure: 500 mg (1.75 mmol) of tert-butyl 2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2(dppf), 518.4 mg (1.34 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A), 3.36 ml of 2 M sodium carbonate solution and a further 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 ml of DMF are reacted by general method D. The crude product which has been dried under high vacuum is stirred in 4 ml of a 1:1-mixture of methanol and 4 M hydrogen chloride in dioxane at room temperature for 2 h. The reaction solution is concentrated, and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 121.6 mg (22.4% of theory) of the title compound are obtained. The crude product which has been dried under high vacuum The reaction solution is concentrated the resulting crude product is purified by preparative HPLC The product fractions are concentrated after addition of a 3:1 mixture of methanol and 1N hydrochloric acid again concentrated dried under high vacuum

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

Procedure: 500 mg (1.75 mmol) of tert-butyl 2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2(dppf), 518.4 mg (1.34 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 3.36 ml of 2 M sodium carbonate solution and a further 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 ml of DMF are reacted by general method D. The crude product which has been dried under high vacuum is stirred in 8 ml of a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane at room temperature for 2 h. The reaction solution is concentrated and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 245.5 mg (44.5% of theory) of the title compound are obtained. The crude product which has been dried under high vacuum The reaction solution is concentrated the resulting crude product is purified by preparative HPLC The product fractions are concentrated after addition of a 3:1 mixture of methanol and 1N hydrochloric acid again concentrated dried under high vacuum

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

Procedure: 534.2 mg (1.87 mmol) of tert-butyl 2-bromobenzylcarbamate, 474.1 mg (1.87 mmol) of bis(pinacolato)diboron, 397.0 mg (4.04 mmol) of potassium acetate, 45.5 mg (0.06 mmol) of PdCl2(dppf), 500 mg (1.24 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 3.11 ml of 2 M sodium carbonate solution and a further 45.5 mg (0.06 mmol) of PdCl2(dppf) in 6.0 ml of DMF are reacted by general method D. Purification by preparative HPLC is followed by concentration of the combined product fractions, taking up in methanol, addition of 1N hydrochloric acid, and stirring at room temperature for 30 min. Concentration and drying under high vacuum result in 121 mg (20% of theory) of the title compound. Purification by preparative HPLC addition of 1N hydrochloric acid Concentration drying under high vacuum