Methyl 4-chloro-2-methoxybenzoate

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

Procedure: A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%). was refluxed overnight MeOH was evaporated the residue was extracted to EtOAc successively washed with water and brine dried over MgSO4 filtered evaporated

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

Procedure: A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%). was refluxed overnight MeOH was evaporated the residue was extracted to EtOAc successively washed with water and brine dried over MgSO4 filtered evaporated

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

Procedure: To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron (III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22(t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H). giving a red color quenched upon the addition of aq. HCl (1M, 50 mL) The crude product was extracted with ether the combined organic layers were successively washed with water and brine dried over MgSO4 filtered evaporated The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil. After the reaction mixture was cooled to room temperature The ethyl acetate layer was washed successively with water and brine dried over anhydrous sodium sulfate The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1)

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

Procedure: A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%). was refluxed overnight MeOH was evaporated the residue was extracted to EtOAc successively washed with water and brine dried over MgSO4 filtered evaporated

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

Procedure: To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron(III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22 (t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H). giving a red color quenched upon the addition of aq. HCl (1M, 50 mL) The crude product was extracted with ether the combined organic layers were successively washed with water and brine dried over MgSO4 filtered evaporated The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes)

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

Procedure: To a suspension of 60% sodium hydride oil (3.4 g) in dimethylformamide (25 ml) was added 4-chlorosalicylic acid (7.33 g) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. After the stirring, iodomethane (25 g) was dropwise added to the mixture and the mixture was reacted for 1 hour at 50° C., which was followed by extraction with ether. The extract was washed with water and dried over magnesium sulfate. After the concentration, the residue was chromatographed on silica gel (hexane-ethyl acetate) to give 6.60 g of a colorless transparent liquid (yield 77.4%). cooling the mixture was reacted for 1 hour at 50° C. which was followed by extraction with ether The extract was washed with water dried over magnesium sulfate After the concentration the residue was chromatographed on silica gel (hexane-ethyl acetate)

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

Procedure: A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%). was refluxed overnight MeOH was evaporated the residue was extracted to EtOAc successively washed with water and brine dried over MgSO4 filtered evaporated

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

Procedure: To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron (III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22(t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H). giving a red color quenched upon the addition of aq. HCl (1M, 50 mL) The crude product was extracted with ether the combined organic layers were successively washed with water and brine dried over MgSO4 filtered evaporated The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil. After the reaction mixture was cooled to room temperature The ethyl acetate layer was washed successively with water and brine dried over anhydrous sodium sulfate The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1)