2-bromo-5-fluorobenzaldehyde

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

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

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

Procedure: Alternate Preparation. This procedure uses DABCO as a more economical substitute for (4s)-quinuclidin-3-ol. A 1 L flask was charged with 2-bromo-5-fluorobenzaldehyde (13.4 g, 66.0 mmol), DABCO (14.81 g, 132 mmol), DMF (53.6 mL) and water (13.4 mL). To this reaction mixture was added tert-butyl acrylate (12.68 g, 99.0 mmol). The mixture was then stirred at rt for 12 h. At this time TLC indicated consumption of starting material. The reaction mixture was diluted with 25 mL of water and then extracted with two 100 mL portions of MTBE. The combined organic phases were washed with 0.1N HCl, water and brine. It was then dried over MgSO4, filtered and concentrated to yield 25 g (>100%) of the product as a colorless oil which was used without further purification. Alternate Preparation consumption of starting material The reaction mixture was diluted with 25 mL of water extracted with two 100 mL portions of MTBE The combined organic phases were washed with 0.1N HCl, water and brine It was then dried over MgSO4 filtered concentrated

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

Procedure: To a solution of 2-bromo-5-fluoro-benzaldehyde (21.34 g, 105 mmole) in methanol (170 mL) was added at 0-5° C. portionwise NaBH4 (3.99 g, 105 mmole). At the end of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. On concentration, the solution generated a white solid that was added with water, filtered and dried under vacuum to yield compound PRE7 (19.23 g; white powder) (Yield=91 Rt: 10.64 min. At the end of the addition the cooling bath was removed On concentration that was added with water filtered dried under vacuum to yield compound PRE7 (19.23 g; white powder) ( Yield=91 Rt: 10.64 min.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyltriphenylphosphonium iodide (1.195 g, 2.96 mmol) in tetrahydrofuran (25 mL) was added BuLi (1.182 mL, 2.96 mmol) at 0° C. and stirred at 0° C. for 0.5 h. It was then added 2-bromo-5-fluorobenzaldehyde (0.5 g, 2.463 mmol) and stirred at rt for 16 h. The reaction was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 5% EtOAc/hexane to obtain 1-bromo-4-fluoro-2-vinylbenzene (320 mg, 1.592 mmol, 64.6% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 1H), 7.33-7.23 (m, 1H), 7.09-6.96 (m, 1H), 6.89 (td, J=8.3, 3.1 Hz, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H). extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil, which was then purified by biotage eluting with 5% EtOAc/hexane

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

Procedure: To a mixture of zinc powder (704 mg, 10.8 mmol) in dry THF (50 mL) under nitrogen atmosphere, 1,2 dibromoethane (0.016 mL, 0.181 mmol) followed by trimethylchlorosilane (114 mg, 1.05 mmol) were added. A solution of 2-bromo-5-fluoro-benzaldehyde (2.13 g 10.50 mmol) and ethylbromodifluoroacetate (2.13 g, 10.50 mmol) in THF (25 mL) were added and the reaction mixture was refluxed overnight. The mixture was cooled and poured in ice/water (250 mL). HCl 1M (100 mL) was added while stirring. The mixture was stirred 1 hour and extracted with t-Butylmethylether (200 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated. The obtained residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated in vacuo yielding ethyl 3-(2-bromo-5-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (1096 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.0 Hz, 3H), 4.37 (q, J=7.0 Hz, 2H), 5.72 (ddd, J=15.7, 6.1, 1.0 Hz, 1H), 6.99 (ddd, J=8.8, 7.7, 3.1 Hz, 1H), 7.39 (ddd, J=9.5, 3.1, 1.0 Hz, 1H), 7.54 (dd, J=8.8, 5.3 Hz, 1H) The procedure was repeated on a larger scale of 2-bromo-5-fluoro-benzaldehyde (71.2 g, 351 mmol) yielding ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2-difluoro-3-hydroxy-propanoate (86 g). DAST (48.3 mL, 394.4 mmol) was added dropwise to a solution of ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2-difluoro-3-hydroxy-propanoate (86 g) in dichloromethane (500 mL) during 15 minutes in an icebath. The reaction mixture was stirred and allowed to reach room temperature overnight. The mixture was slowly added to a vigorously stirred saturated NaHCO3 solution (1.5 L) over 15 minutes. The mixture was stirred for 30 minutes more. The organic layer was dried over magnesium sulphate, filtered and concentrated yielding ethyl 3-(2-bromo-5-fluorophenyl)-2,2,3-trifluoropropanoate (78.0 g) as a light brown oil which was used as such. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (t, J=7.2 Hz, 3H), 4.37-4.44 (m, 2H), 6.19-6.41 (m, 1H), 7.01-7.10 (m, 1H), 7.29-7.37 (m, 1H), 7.58 (ddd, J=8.9, 5.1, 1.2 Hz, 1H). Ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2,3-trifluoro-propanoate (55.4 g 163.5 mmol), lithium hydroxide (3.92 g, 163.5 mmol), THF (100 mL) and distilled water (200 mL) were stirred 5 minutes at room temperature resulting in a clear solution (1 layer). The reaction mixture was acidified with HCl 1M (164 mL). The resulting emulsion was extracted with CH2Cl2 (500 mL). The organic layer was dried over sodium sulphate, filtered and concentrated yielding a light brown oil (58.7 g). To part of this oil (52.5 g) in dichloromethane (2.6 L) and DMF (7 mmol), oxalylchloride (89.3 g) was added during 15 minutes and the mixture was stirred overnight. The reaction mixture was concentrated, yielding a light brown oil which was used as such. To this oil in dichloromethane (1000 mL), N,O-dimethylhydroxylamine hydrochloride (16.07 g, 149.8 mmol) and sodium carbonate (17.46 g, 164.8 mmol) were added and the mixture was stirred for 90 minutes. Water (500 mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using a gradient from 0 till 10% CH3OH in CH2Cl2. The product fractions were combined and concentrated resulting in 3-(2-bromo-5-fluorophenyl)-2,2,3-trifluoro-N-methoxy-N-methylpropanamide (37.1 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.32 (s, 3H), 3.82 (s, 3H), 6.41-6.64 (m, 1H), 7.01-7.07 (m, 1H), 7.34-7.41 (m, 1H), 7.56 (ddd, J=8.9, 5.2, 1.1 Hz, 1H). Buthyllithium (49.5 mL, 1.6M in hexanes) was added during 30 minutes at −70° C. to a solution of 3-(2-bromo-5-fluoro-phenyl)-2,2,3-trifluoro-N-methoxy-N-methylpropanamide (25.9 g, 75.4 mmol) in dry THF (225 mL). The mixture was stirred 30 minutes and then allowed to reach room temperature during 90 minutes. The reaction mixture was quenched with HCl (1M, 100 mL) and diluted with diisopropylether (250 mL). The water layer was extracted twice with CH2Cl2 (250 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were concentrated yielding compound 164 (12.6 g) as an oil. Method L; Rt: 1.69 m/z; 202.8 (M−H)− Exact mass: 204.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.80-6.01 (m, 1H), 7.42 (tt, J=8.6, 1.8 Hz, 1H), 7.47-7.54 (m, 1H), 8.00 (ddd, J=8.6, 5.1, 1.3 Hz, 1H). were added the reaction mixture was refluxed overnight The mixture was cooled The mixture was stirred 1 hour extracted with t-Butylmethylether (200 mL) The organic layer was separated dried over sodium sulphate filtered concentrated The obtained residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane concentrated in vacuo

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

Procedure: To a mixture of zinc powder (704 mg, 10.8 mmol) in dry THF (50 mL) under nitrogen atmosphere, 1,2 dibromoethane (0.016 mL, 0.181 mmol) followed by trimethylchlorosilane (114 mg, 1.05 mmol) were added. A solution of 2-bromo-5-fluoro-benzaldehyde (2.13 g 10.50 mmol) and ethylbromodifluoroacetate (2.13 g, 10.50 mmol) in THF (25 mL) were added and the reaction mixture was refluxed overnight. The mixture was cooled and poured in ice/water (250 mL). HCl 1M (100 mL) was added while stirring. The mixture was stirred 1 hour and extracted with t-Butylmethylether (200 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated. The obtained residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated in vacuo yielding ethyl 3-(2-bromo-5-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (1096 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.0 Hz, 3H), 4.37 (q, J=7.0 Hz, 2H), 5.72 (ddd, J=15.7, 6.1, 1.0 Hz, 1H), 6.99 (ddd, J=8.8, 7.7, 3.1 Hz, 1H), 7.39 (ddd, J=9.5, 3.1, 1.0 Hz, 1H), 7.54 (dd, J=8.8, 5.3 Hz, 1H) The procedure was repeated on a larger scale of 2-bromo-5-fluoro-benzaldehyde (71.2 g, 351 mmol) yielding ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2-difluoro-3-hydroxy-propanoate (86 g). DAST (48.3 mL, 394.4 mmol) was added dropwise to a solution of ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2-difluoro-3-hydroxy-propanoate (86 g) in dichloromethane (500 mL) during 15 minutes in an icebath. The reaction mixture was stirred and allowed to reach room temperature overnight. The mixture was slowly added to a vigorously stirred saturated NaHCO3 solution (1.5 L) over 15 minutes. The mixture was stirred for 30 minutes more. The organic layer was dried over magnesium sulphate, filtered and concentrated yielding ethyl 3-(2-bromo-5-fluorophenyl)-2,2,3-trifluoropropanoate (78.0 g) as a light brown oil which was used as such. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (t, J=7.2 Hz, 3H), 4.37-4.44 (m, 2H), 6.19-6.41 (m, 1H), 7.01-7.10 (m, 1H), 7.29-7.37 (m, 1H), 7.58 (ddd, J=8.9, 5.1, 1.2 Hz, 1H). Ethyl 3-(2-bromo-5-fluoro-phenyl)-2,2,3-trifluoro-propanoate (55.4 g 163.5 mmol), lithium hydroxide (3.92 g, 163.5 mmol), THF (100 mL) and distilled water (200 mL) were stirred 5 minutes at room temperature resulting in a clear solution (1 layer). The reaction mixture was acidified with HCl 1M (164 mL). The resulting emulsion was extracted with CH2Cl2 (500 mL). The organic layer was dried over sodium sulphate, filtered and concentrated yielding a light brown oil (58.7 g). To part of this oil (52.5 g) in dichloromethane (2.6 L) and DMF (7 mmol), oxalylchloride (89.3 g) was added during 15 minutes and the mixture was stirred overnight. The reaction mixture was concentrated, yielding a light brown oil which was used as such. To this oil in dichloromethane (1000 mL), N,O-dimethylhydroxylamine hydrochloride (16.07 g, 149.8 mmol) and sodium carbonate (17.46 g, 164.8 mmol) were added and the mixture was stirred for 90 minutes. Water (500 mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using a gradient from 0 till 10% CH3OH in CH2Cl2. The product fractions were combined and concentrated resulting in 3-(2-bromo-5-fluorophenyl)-2,2,3-trifluoro-N-methoxy-N-methylpropanamide (37.1 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.32 (s, 3H), 3.82 (s, 3H), 6.41-6.64 (m, 1H), 7.01-7.07 (m, 1H), 7.34-7.41 (m, 1H), 7.56 (ddd, J=8.9, 5.2, 1.1 Hz, 1H). Buthyllithium (49.5 mL, 1.6M in hexanes) was added during 30 minutes at −70° C. to a solution of 3-(2-bromo-5-fluoro-phenyl)-2,2,3-trifluoro-N-methoxy-N-methylpropanamide (25.9 g, 75.4 mmol) in dry THF (225 mL). The mixture was stirred 30 minutes and then allowed to reach room temperature during 90 minutes. The reaction mixture was quenched with HCl (1M, 100 mL) and diluted with diisopropylether (250 mL). The water layer was extracted twice with CH2Cl2 (250 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were concentrated yielding compound 164 (12.6 g) as an oil. Method L; Rt: 1.69 m/z; 202.8 (M−H)− Exact mass: 204.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.80-6.01 (m, 1H), 7.42 (tt, J=8.6, 1.8 Hz, 1H), 7.47-7.54 (m, 1H), 8.00 (ddd, J=8.6, 5.1, 1.3 Hz, 1H). were added the reaction mixture was refluxed overnight The mixture was cooled The mixture was stirred 1 hour extracted with t-Butylmethylether (200 mL) The organic layer was separated dried over sodium sulphate filtered concentrated The obtained residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane concentrated in vacuo

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

Procedure: Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-fluorobenzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester. Prepared

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

Procedure: Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-fluorobenzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester. Prepared

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.0 g (9.9 mmol) 2-bromo-5-fluorobenzaldehyde in 20 ml toluene were added 0.722 ml (13.0 mmol) ethane-1,2-diol and 5 mg (0.03 mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture was heated in a rotary evaporator at 60° C. and 200 mbar during 4 h. After evaporation of the solvent and flash chromatography 2.32 g (95%) of the title compound were obtained as a colorless liquid. After evaporation of the solvent

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

Procedure: To a solution of 2-bromo-5-fluorobenzaldehyde (2.44 g, 12.0 mmol) and (S)-(−)-2-methyl-2-propane-sulfinamide (1.45 g, 12.0 mmol) in THF (30 mL, anhyd.) was added titanium tetraethoxide (2.8 mL, 13.2 mmol, tech) at room temperature. After stirring 16 hours the reaction mixture was charged with brine (25 mL) and EtOAc (40 mL). After stirring 10 minutes the mixture was filtered through a pad of Celite™. Combined filtrates were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica chromatography with EtOAc/Hex (0-25%) as eluent to give (S,E)-N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (I-44) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.2 Hz, 1 H), 7.77 (dd, J=3.1, 9.1 Hz, 1 H), 7.64 (dd, J=5.0, 8.8 Hz, 1 H), 7.12 (ddd, J=3.1, 7.5, 8.8 Hz, 1 H), 1.30 (s, 9 H). After stirring 10 minutes the mixture was filtered through a pad of Celite™ Combined filtrates were washed with water and brine dried over sodium sulfate concentrated The residue was purified by silica chromatography with EtOAc/Hex (0-25%) as eluent

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

Procedure: To a solution of 2-bromo-5-fluorobenzaldehyde (2.44 g, 12.0 mmol) and (S)-(−)-2-methyl-2-propane-sulfinamide (1.45 g, 12.0 mmol) in THF (30 mL, anhyd.) was added titanium tetraethoxide (2.8 mL, 13.2 mmol, tech) at room temperature. After stirring 16 hours the reaction mixture was charged with brine (25 mL) and EtOAc (40 mL). After stirring 10 minutes the mixture was filtered through a pad of Celite™. Combined filtrates were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica chromatography with EtOAc/Hex (0-25%) as eluent to give (S,E)-N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (I-44) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.2 Hz, 1 H), 7.77 (dd, J=3.1, 9.1 Hz, 1 H), 7.64 (dd, J=5.0, 8.8 Hz, 1 H), 7.12 (ddd, J=3.1, 7.5, 8.8 Hz, 1 H), 1.30 (s, 9 H). After stirring 10 minutes the mixture was filtered through a pad of Celite™ Combined filtrates were washed with water and brine dried over sodium sulfate concentrated The residue was purified by silica chromatography with EtOAc/Hex (0-25%) as eluent