7-chloro-3H-2-benzofuran-1-one

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.48 g of 7-chlorophthalide are dissolved in 80 ml of THF. The solution is cooled to -70° C. and 1.5M IDA in THF (6 ml) is syringed in at -70° C. over 3 min. Stirring is continued for 15 min at -70°, 1.54 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine in 50 ml of THF added dropwise and the mixture is then allowed to warm to -20°. The mixture is again cooled to -70°, and 1 ml of conc. HCl in 10 ml of water is added. The mixture is stirred for 25 min and allowed to warm to RT and the THF is removed by evaporation. The residue is partitioned between CH2Cl2 and water (50 ml each) and the aqueous phase extracted with an additional 30 ml of CH2Cl2. The combined organic phases are washed with 30 ml of water and concentrated to give a yellow gum. This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml). Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane yielded title product m.p. 126°-127° as a yellow solid. to warm to -20° The mixture is again cooled to -70° The mixture is stirred for 25 min to warm to RT the THF is removed by evaporation The residue is partitioned between CH2Cl2 and water (50 ml each) the aqueous phase extracted with an additional 30 ml of CH2Cl2 The combined organic phases are washed with 30 ml of water concentrated to give a yellow gum This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml) Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.68 g (0.0 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C. the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C warmed concentrated on a rotovaporator The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) the aqueous phase separated treated with further 30 ml of CH2Cl2 The combined CH2Cl2 phases are washed with 30 ml of water separated concentrated chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.68 g (0.0 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C. the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C warmed concentrated on a rotovaporator The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) the aqueous phase separated treated with further 30 ml of CH2Cl2 The combined CH2Cl2 phases are washed with 30 ml of water separated concentrated chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml)

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

Procedure: 2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (4.82 g, 10.59 mmol) suspended in PhMe (72 mL) and AlMe3 in heptane (31 mL of 1.0 M, 31 mmol) added at RT under N2. After 30 minutes, a solution of 7-chloro-3H-isobenzofuran-1-one (3.570 g, 21.18 mmol) in DCM (72 mL) added with cooling on an ice bath. Reaction mixture stirred overnight, temperature rising to ambient. Reaction mixture re-cooled on an ice bath and water (˜30 mL) added slowly. After 5 minutes mixture diluted with DCM. Resulting mixture stirred vigorously for 30 mins then filtered through celite to remove bulk of Al salts. Layers separated. Aqueous extracted with DCM (×2). Combined organics dried and concentrated to a brown solid. This material dissolved in THF (200 mL) under N2 and Ph3P (4.165 g, 15.88 mmol) then DEAD (2.00 mL, 12.71 mmol) added. Reaction mixture stirred overnight at RT then concentrated. Residue partitioned between DCM and brine. Aqueous phase extracted with DCM and combined organics dried and concentrated. Resulting black residue taken up in DCM. Some product precipitates and is collected by filtration. Filtrate purified by chromatography (silica, 0-5% MeOH-DCM gradient elution). Product fractions concentrated to a brown solid and further purified by trituration with DCM/MeOH (˜1:1) to give a yellow solid. Combined product dried under vacuum at 60° C. to give the title compound as a yellow solid (2.39 g, 37% over two steps); 1H NMR (400 MHz, DMSO) δ 5.85 (2H, s), 7.76-7.84 (15H, m), 7.97 (1H, d), 8.12 (1H, t), 8.21 (1H, d), 8.54 (1H, s), 9.22 (1H, s) ppm; MS (ES+) 606.0. with cooling on an ice bath Reaction mixture Reaction mixture re-cooled on an ice bath Resulting mixture stirred vigorously for 30 mins then filtered through celite to remove bulk of Al salts Layers separated Aqueous extracted with DCM (×2) Combined organics dried concentrated to a brown solid This material dissolved in THF (200 mL) under N2 Reaction mixture stirred overnight at RT then concentrated Residue partitioned between DCM and brine Aqueous phase extracted with DCM combined organics dried concentrated Resulting black residue Some product precipitates is collected by filtration Filtrate purified by chromatography (silica, 0-5% MeOH-DCM gradient elution) Product fractions concentrated to a brown solid further purified by trituration with DCM/MeOH (˜1:1) to give a yellow solid Combined product dried under vacuum at 60° C.

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.68 g (0.01 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C. the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C warmed concentrated on a rotovaporator The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) the aqueous phase separated treated with further 30 ml of CH2Cl2 The combined CH2Cl2 phases are washed with 30 ml of water separated concentrated chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.48 g of 7-chlorophthalide are dissolved in 80 ml of THF. The solution is cooled to -70° C. and 1.5M IDA in THF (6 ml) is syringed in at -70° C. over 3 min. Stirring is continued for 15 min at -70°, 1.54 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine in 50 ml of THF added dropwise and the mixture is then allowed to warm to -20°. The mixture is again cooled to -70°, and 1 ml of conc. HCl in 10 ml of water is added. The mixture is stirred for 25 min and allowed to warm to RT and the THF is removed by evaporation. The residue is partitioned between CH2Cl2 and water (50 ml each) and the aqueous phase extracted with an additional 30 ml of CH2Cl2. The combined organic phases are washed with 30 ml of water and concentrated to give a yellow gum. This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml). Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane yielded title product m.p. 126°-127° as a yellow solid. to warm to -20° The mixture is again cooled to -70° The mixture is stirred for 25 min to warm to RT the THF is removed by evaporation The residue is partitioned between CH2Cl2 and water (50 ml each) the aqueous phase extracted with an additional 30 ml of CH2Cl2 The combined organic phases are washed with 30 ml of water concentrated to give a yellow gum This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml) Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.68 g (0.0 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C. the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C warmed concentrated on a rotovaporator The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) the aqueous phase separated treated with further 30 ml of CH2Cl2 The combined CH2Cl2 phases are washed with 30 ml of water separated concentrated chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml)

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

Procedure: 2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (4.82 g, 10.59 mmol) suspended in PhMe (72 mL) and AlMe3 in heptane (31 mL of 1.0 M, 31 mmol) added at RT under N2. After 30 minutes, a solution of 7-chloro-3H-isobenzofuran-1-one (3.570 g, 21.18 mmol) in DCM (72 mL) added with cooling on an ice bath. Reaction mixture stirred overnight, temperature rising to ambient. Reaction mixture re-cooled on an ice bath and water (˜30 mL) added slowly. After 5 minutes mixture diluted with DCM. Resulting mixture stirred vigorously for 30 mins then filtered through celite to remove bulk of Al salts. Layers separated. Aqueous extracted with DCM (×2). Combined organics dried and concentrated to a brown solid. This material dissolved in THF (200 mL) under N2 and Ph3P (4.165 g, 15.88 mmol) then DEAD (2.00 mL, 12.71 mmol) added. Reaction mixture stirred overnight at RT then concentrated. Residue partitioned between DCM and brine. Aqueous phase extracted with DCM and combined organics dried and concentrated. Resulting black residue taken up in DCM. Some product precipitates and is collected by filtration. Filtrate purified by chromatography (silica, 0-5% MeOH-DCM gradient elution). Product fractions concentrated to a brown solid and further purified by trituration with DCM/MeOH (˜1:1) to give a yellow solid. Combined product dried under vacuum at 60° C. to give the title compound as a yellow solid (2.39 g, 37% over two steps); 1H NMR (400 MHz, DMSO) δ 5.85 (2H, s), 7.76-7.84 (15H, m), 7.97 (1H, d), 8.12 (1H, t), 8.21 (1H, d), 8.54 (1H, s), 9.22 (1H, s) ppm; MS (ES+) 606.0. with cooling on an ice bath Reaction mixture Reaction mixture re-cooled on an ice bath Resulting mixture stirred vigorously for 30 mins then filtered through celite to remove bulk of Al salts Layers separated Aqueous extracted with DCM (×2) Combined organics dried concentrated to a brown solid This material dissolved in THF (200 mL) under N2 Reaction mixture stirred overnight at RT then concentrated Residue partitioned between DCM and brine Aqueous phase extracted with DCM combined organics dried concentrated Resulting black residue Some product precipitates is collected by filtration Filtrate purified by chromatography (silica, 0-5% MeOH-DCM gradient elution) Product fractions concentrated to a brown solid further purified by trituration with DCM/MeOH (˜1:1) to give a yellow solid Combined product dried under vacuum at 60° C.