4-ethoxy-3-fluoroaniline

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

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

Procedure: Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)

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

Procedure: Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)

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

Procedure: Reference Preparation Example [Preparation of Compound (Ie)]Carbon disulfide (2.0g, 26mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethyl-formamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)

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

Procedure: Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)

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

Procedure: Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)

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

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

Procedure: (4-Ethoxy-3-fluoro-phenyl)-methyl-amine hydrochloride: The free base of the title compound was synthesized as a clear, pale tan liquid by a procedure similar to that found in Example 221 from 4-ethoxy-3-fluoro-phenylamine (1.828 g, 11.78 mmol), 1H-benzotriazole (1.407 g, 11.8 mmol), 37 wt % aq formaldehyde (0.90 mL, 12.1 mmol) and sodium borohydride (447 mg, 11.8 mmol); with purification by MPLC (SiO2/0-33% EtOAc in hexanes). The title compound was obtained as an off-white solid after concentrating a soln of the free base in HCl-i-PrOH in vacuo. LC-MS (ESI+; 170 ([M+H]+)). with purification by MPLC (SiO2/0-33% EtOAc in hexanes)

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

Procedure: To a solution of 4-ethoxy-3-fluoroaniline SMA 44094 (464 mg, 2.99 mmol) in dry CH2Cl2 (15 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (2.0 mL, 12 mmol), DMAP (87 mg, 0.7 mmol) and acetic anhydride (1.7 mL, 18 mmol) and the mixture was stirred for 5 h at RT. The solution was then diluted with more CH2Cl2 (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(4-ethoxy-3-fluorophenyl)acetamide SMA 44098 as a beige solid (242 mg, 41% yield). washed with brine (10 mL) dried over Na2SO4 filtered concentrated at 40° C. under vacuum Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50)

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

Procedure: To a solution of 4-amino-2-fluorophenol (2.15 g, 16.9 mmol) in dry DMF (60 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added Cs2CO3 (10.6 g, 25.4 mmol) and the mixture was stirred for 10 min at RT before addition of bromoethane (1.5 mL, 20.3 mmol). The reaction mixture was then stirred for 7 h at RT, concentrated to dryness, and the residue was partitioned between CH2Cl2 (100 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 88:12) gave 4-ethoxy-3-fluoroaniline SMA 44094 as a brown oil (480 mg, 18% yield). concentrated to dryness the residue was partitioned between CH2Cl2 (100 mL) and water (20 mL) The organic layer was washed with brine (20 mL) dried over Na2SO4 filtered concentrated at 40° C. under vacuum Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 88:12)

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

Procedure: To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (5.9 g, 22.7 mmol) in 400 mL of isopropanol was added 4-ethoxy-3-fluoroaniline (3.7 g, 23.8 mmol). This mixture was heated to reflux to give a clear solution. To this solution, triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 18 hours. Additional triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 42 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40° C. to give 6.4 g (67%) of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a grey solid, mp 245-247° C.; MS 424.1, 426.1 (M+H)+ This mixture was heated to reflux to give a clear solution the reaction mixture was heated at reflux for 18 hours the reaction mixture was heated at reflux for 42 hours the solid was collected by filtration washed with ethyl acetate dried in vacuo at 40° C.

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

Procedure: Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C. The mixture was stirred at room temperature for 10 hours The mixture was stirred at room temperature for 30 minutes followed by extraction with diethyl ether The organic layer was washed with a saturated sodium chloride solution dried with anhydrous sodium sulfate concentrated under reduced pressure The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1)