1-ethoxy-2-fluorobenzene

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

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

Procedure: Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-fluorophenetole. Synthesis

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

Procedure: Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-fluorophenetole. Synthesis

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1, found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). freshly crushed under N2) under ether The mixture was warmed to RT extracted with ethyl acetate (2×30 mL) washed with 10 mL brine dried over MgSO4

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1, found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). freshly crushed under N2) under ether The mixture was warmed to RT extracted with ethyl acetate (2×30 mL) washed with 10 mL brine dried over MgSO4

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

Procedure: A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 mL, 120 mmol) and potassium carbonate (21 g, 150 mmol) (finely powdered) was stirred in acetone (100 mL) at 50° C. overnight, then at room temperature for 24 h. The mixture was filtered over a pad of silica gel, and was rinsing with ether. The solution was carefully concentrated (due to volatility of product), then microfiltered to give 1-ethoxy-2-fluoro-benzene (92%) as a yellow oil. 1H NMR (CDCl3, 500 MHz), δ 7.12-6.94 (m, 2H), 6.91-6.86 (m, 1H), 6.83-6.77 (m, 1H), 4.01 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). The mixture was filtered over a pad of silica gel was rinsing with ether The solution was carefully concentrated (due to volatility of product)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1, found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). freshly crushed under N2) under ether The mixture was warmed to RT extracted with ethyl acetate (2×30 mL) washed with 10 mL brine dried over MgSO4

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

Procedure: A mixture of 2-fluorophenol (8.6 g, 77 mmol), iodoethane (9.2 mL, 120 mmol) and potassium carbonate (21 g, 150 mmol) (finely powdered) was stirred in acetone (100 mL) at 50° C. overnight, then at room temperature for 24 h. The mixture was filtered over a pad of silica gel, and was rinsing with ether. The solution was carefully concentrated (due to volatility of product), then microfiltered to give 1-ethoxy-2-fluoro-benzene (92%) as a yellow oil. 1H NMR (CDCl3, 500 MHz), δ 7.12-6.94 (m, 2H), 6.91-6.86 (m, 1H), 6.83-6.77 (m, 1H), 4.01 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). The mixture was filtered over a pad of silica gel was rinsing with ether The solution was carefully concentrated (due to volatility of product)

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

Procedure: 5-bromo-2-chloro-benzoyl chloride 2a (12.4 g, 48.8 mmol) and 1-ethoxy-2-fluoro-benzene 4b (6.84 g, 48.8 mmol) were dissolved in 100 mL dichloromethane and cooled to 0° C., followed by addition of aluminum trichloride (5.86 g, 44 mmol) in batch. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was partitioned after 20 mL 2 M hydrochloric acid was dropwise added in an ice bath. The aqueous phase was extracted with 30 mL dichloromethane and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (12.7 g, yellow solid), yield: 72.6%. Thereafter, the reaction mixture was partitioned after 20 mL 2 M hydrochloric acid was dropwise added in an ice bath The aqueous phase was extracted with 30 mL dichloromethane the organic extract dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure

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

Procedure: 2-fluorophenol 4a (6.7 g, 60 mmol) was dissolved in 66 mL acetone, followed by addition of ethyl iodide (6.3 mL, 78 mmol) and potassium carbonate (12.4 g, 90 mmol). The reaction mixture was refluxed in an oil bath for 5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 100 mL ethyl acetate and 60 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-ethoxy-2-fluoro-benzene 4b (6.9 g, red grease), yield: 82.1%. MS m/z (ESI): 280.2 [2M+1]. The reaction mixture was refluxed in an oil bath for 5 hours Thereafter, the reaction mixture was concentrated under reduced pressure partitioned after 100 mL ethyl acetate and 60 mL water were added The aqueous phase was extracted with ethyl acetate (30 mL×2) the organic extract dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1. found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). freshly crushed under N2) under ether The mixture was warmed to RT extracted with ethyl acetate (2×30 mL) washed with 10 mL brine dried over MgSO4