ethyl 3-bromo-2-fluorobenzoate

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

Procedure: A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was dissolved in 50 ml of Tol solution, 15.8 ml of tributyl(vinyl)tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 10 wt % hexane solution were added thereto in order, and stirred at room temperature for 13 hours in an atmosphere of argon. This was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride and 5 ml of purified water and stirred for 30 minutes, the insoluble matter was filtered using a Kiriyama funnel, and then the mother liquid was concentrated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1) to obtain 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference Example 17-1). were added stirred for 30 minutes the insoluble matter was filtered the mother liquid was concentrated The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min). 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min after completion of the reaction stirred at RT for 15 min The resultant solution was filtered through celite washed with hexane (100 mL) The filtrate was washed water (250 mL) dried over Na2SO4 filtered concentrated under reduced pressure to obtain the crude The crude was purified through silica gel column chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min). 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min after completion of the reaction stirred at RT for 15 min The resultant solution was filtered through celite washed with hexane (100 mL) The filtrate was washed water (250 mL) dried over Na2SO4 filtered concentrated under reduced pressure to obtain the crude The crude was purified through silica gel column chromatography

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

Procedure: To a stirred solution of 3-bromo-2-fluorobenzoic acid A1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound A2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). at reflux temperature for 24 h after completion of the reaction the reaction mixture was concentrated to obtain the residue washed with water (300 mL), brine (300 mL) dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound 2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound 3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min). 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min after completion of the reaction stirred at RT for 15 min The resultant solution was filtered through celite washed with hexane (100 mL) The filtrate was washed water (250 mL) dried over Na2SO4 filtered concentrated under reduced pressure to obtain the crude This was purified by silica gel column chromatography

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

Procedure: To a stirred solution of 3-bromo-2-fluorobenzoic acid 1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). at reflux temperature for 24 h after completion of the reaction the reaction mixture was concentrated to obtain the residue washed with water (300 mL), brine (300 mL) dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a stirred solution of 3-bromo-2-fluorobenzoic acid 1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). at reflux temperature for 24 h after completion of the reaction the reaction mixture was concentrated to obtain the residue washed with water (300 mL), brine (300 mL) dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was dissolved in 50 ml of Tol solution, 15.8 ml of tributyl(vinyl)tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 10 wt % hexane solution were added thereto in order, and stirred at room temperature for 13 hours in an atmosphere of argon. This was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride and 5 ml of purified water and stirred for 30 minutes, the insoluble matter was filtered using a Kiriyama funnel, and then the mother liquid was concentrated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1) to obtain 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference Example 17-1). were added stirred for 30 minutes the insoluble matter was filtered the mother liquid was concentrated The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1)

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

Procedure: A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was dissolved in 50 ml of Tol solution, 15.8 ml of tributyl(vinyl)tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 10 wt % hexane solution were added thereto in order, and stirred at room temperature for 13 hours in an atmosphere of argon. This was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride and 5 ml of purified water and stirred for 30 minutes, the insoluble matter was filtered using a Kiriyama funnel, and then the mother liquid was concentrated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1) to obtain 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference Example 17-1). were added stirred for 30 minutes the insoluble matter was filtered the mother liquid was concentrated The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1)

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

Procedure: A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was dissolved in 50 ml of Tol solution, 15.8 ml of tributyl(vinyl)tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 10 wt % hexane solution were added thereto in order, and stirred at room temperature for 13 hours in an atmosphere of argon. This was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride and 5 ml of purified water and stirred for 30 minutes, the insoluble matter was filtered using a Kiriyama funnel, and then the mother liquid was concentrated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1) to obtain 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference Example 17-1). were added stirred for 30 minutes the insoluble matter was filtered the mother liquid was concentrated The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min). 1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min after completion of the reaction stirred at RT for 15 min The resultant solution was filtered through celite washed with hexane (100 mL) The filtrate was washed water (250 mL) dried over Na2SO4 filtered concentrated under reduced pressure to obtain the crude The crude was purified through silica gel column chromatography

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

Procedure: To a stirred solution of 3-bromo-2-fluorobenzoic acid A1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound A2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). at reflux temperature for 24 h after completion of the reaction the reaction mixture was concentrated to obtain the residue washed with water (300 mL), brine (300 mL) dried over Na2SO4 filtered concentrated under reduced pressure