2-amino-6-methoxybenzonitrile

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

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

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 113 using Compound 83 (100 mg, 0.43 mmol) and 2-amino-6-methoxy-benzonitrile (77 mg, 0.52 mmol) to provide 157 (128 mg, 86% yield) as a yellow solid. LC-MS (M+H=343, obsd.=343). The title compound was synthesized

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Methoxyanthranilonitrile (14.0 g) was dissolved in nitrobenzene (150 ml) and cyclohexanone (18.45 g), and freshly fused zinc chloride (25.6 g) was added. The reaction mixture was warmed at 125° C. for 1.5 hr, cooled to room temperature, and poured into ether (1 l). The solid was collected, washed with ether, and distributed between 2-butanone and ammonium hydroxide. The organic phase was washed with brine, dried, filtered, and evaporated. The residue was recrystallized two times from ethyl acetate to give 13.7 g (63.8%), mp 187°-188° C. cooled to room temperature The solid was collected washed with ether The organic phase was washed with brine dried filtered evaporated The residue was recrystallized two times from ethyl acetate to give 13.7 g (63.8%), mp 187°-188° C.

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

Procedure: A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H). filtered evaporated

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

Procedure: A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H). filtered evaporated

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

Procedure: Prepared as in Example 53a from 2-amino-6-methoxybenzonitrile and benzoyl isocyanate as light orange solid (118 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.54 (t, J=8 hz, 2H), 7.64 (t, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.6 Hz, 2H), 11.35 (s, 1H), 11.51 (s, 1H). MS 295 (MH+).

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

Procedure: A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H). filtered evaporated

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

Procedure: A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H). filtered evaporated

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

Procedure: Prepared as in Example 53a from 2-amino-6-methoxybenzonitrile and benzoyl isocyanate as light orange solid (118 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.54 (t, J=8 hz, 2H), 7.64 (t, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.6 Hz, 2H), 11.35 (s, 1H), 11.51 (s, 1H). MS 295 (MH+).

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

Procedure: Fifty-four grams (0.364 mol) of the product prepared in (a) are refluxed with 800 ml of a 25% aqueous solution of potassium hydroxide for 16 hours. After cooling, the reaction solution is adjusted to a pH of 6 by the addition of acetic acid and then extracted several times, each time with one-half liter of ethyl acetate. The combined extracts are dried with sodium sulfate, and the ethyl acetate is distilled off. The residue is purified by column chromatography [silica gel; ethylene chloride/acetone (19:1)]. The uniform fractions are concentrated to dryness. After cooling extracted several times The combined extracts are dried with sodium sulfate the ethyl acetate is distilled off The residue is purified by column chromatography [silica gel; ethylene chloride/acetone (19:1)] The uniform fractions are concentrated to dryness

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

Procedure: One hundred ten grams (0.617 mol) of 2-methoxy-6-nitro-benzonitrile are dissolved in 1 liter of methanol and hydrogenated in the presence of 10% palladium on charcoal at ambient temperature and under a hydrogen pressure of 5 bar over a period of one hour. The catalyst is removed by filtration, the solvent is distilled off, and the residue is recrystallized from ethanol/diisopropyl ether. The catalyst is removed by filtration the solvent is distilled off the residue is recrystallized from ethanol/diisopropyl ether

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

Procedure: A solution of 70 g (0.5 mol) of 2-amino-6-fluorobenzonitrile (prepared, e.g. according to U.S. Pat. No. 4,504,660) in 250 ml of N,N-dimethylformamide was prepared, and a solution of 30.6 g (0.55 mol) of sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours with stirring. The completion of the reaction was monitored by TLC. An additional 25 g of sodium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for an additional 4 hours while stirring. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with water, filtered off with suction and the solids obtained were dissolved in ethyl acetate. The resulting solution was concentrated in vacuo. The obtained residue was triturated with petroleum ether and filtered off with suction. Yield: 48 g (63% of theory) of a brownish solid having a melting point of 143-146° C. The mixture was then refluxed for 5 hours with stirring the reaction mixture was refluxed for an additional 4 hours while stirring The reaction mixture was concentrated under reduced pressure The resulting residue was triturated with water filtered off with suction the solids obtained The resulting solution was concentrated in vacuo The obtained residue was triturated with petroleum ether filtered off with suction