2-amino-6-methylbenzonitrile

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: This compound was prepared in a manner analogous to that of Step E of Example 1, using 1 0.0 grams (0.076 mole) of 2-amino-6-methylbenzonitrile (prepared as in Example 1, Step B), and 10.0 grams (0.087 mole) of chloroformamidine hydrochloride in 40 mL of 2-methoxyethyl ether, yielding 11.5 grams of 2,4-diamino-5-methylquinazoline. The NMR spectrum was consistent with the proposed structure. This compound was prepared in a manner analogous to that of Step E of Example 1

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

Procedure: A stirred solution of 8.3 grams (0.063 mole) of 2-amino-6-methylbenzonitrile in 125 mL of N,N-dimethylformamide was cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide was added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, the reaction mixture was poured into 1 liter of aqueous 3N sodium hydroxide. The mixture was then diluted to a volume of about 1700 mL with distilled water. A solid precipitate was collected by filtration and dried under reduced pressure, yielding 12.3 grams of 2-amino-5-bromo-6-methylbenzonitrile, mp 111°-113° C. The NMR spectrum was consistent with the proposed structure. while maintaining the reaction mixture temperature at about 15°-25° C Upon completion of addition A solid precipitate was collected by filtration dried under reduced pressure

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1. 66.2 g of 2-amino-6-methylbenzonitrile and 22 g of acetonitrile are dissolved in 750 ml of absolute dioxan and the solution is cooled to 5° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 7° C. The mixture is stirred at room temperature for a further 15 h. and then again cooled to 5° C. A further 11 g of acetonitrile are added thereto, hydrochloric acid gas is introduced for 8 h. and the mixture is stirred at room temperature for a further 15 h. The suspension is subsequently evaporated at 30° C. in a vacuum. The crystalline residue is triturated with 0.71 of water, cooled to 0° to 5° C. neutralized with saturated sodium hydrogen carbonate solution and filtered. The crystals are washed with water and dried in a vacuum. There are obtained 107 g of crude 4-amino-2,5-dimethylquinazoline which still contains inorganic salts. This compound melts at 198°-199° C. after recrystallization from ethanol. again cooled to 5° C the mixture is stirred at room temperature for a further 15 h The suspension is subsequently evaporated at 30° C. in a vacuum The crystalline residue is triturated with 0.71 of water cooled to 0° to 5° C. filtered The crystals are washed with water dried in a vacuum

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1. 66.2 g of 2-amino-6-methylbenzonitrile and 22 g of acetonitrile are dissolved in 750 ml of absolute dioxan and the solution is cooled to 5° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 7° C. The mixture is stirred at room temperature for a further 15 h. and then again cooled to 5° C. A further 11 g of acetonitrile are added thereto, hydrochloric acid gas is introduced for 8 h. and the mixture is stirred at room temperature for a further 15 h. The suspension is subsequently evaporated at 30° C. in a vacuum. The crystalline residue is triturated with 0.71 of water, cooled to 0° to 5° C. neutralized with saturated sodium hydrogen carbonate solution and filtered. The crystals are washed with water and dried in a vacuum. There are obtained 107 g of crude 4-amino-2,5-dimethylquinazoline which still contains inorganic salts. This compound melts at 198°-199° C. after recrystallization from ethanol. again cooled to 5° C the mixture is stirred at room temperature for a further 15 h The suspension is subsequently evaporated at 30° C. in a vacuum The crystalline residue is triturated with 0.71 of water cooled to 0° to 5° C. filtered The crystals are washed with water dried in a vacuum

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

Procedure: A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H). the precipitate was filtered washed with dioxane The filtrate was concentrated under reduced pressure the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7)

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

Procedure: Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.6 Hz, 1H), 7.52-7.68 (m, 5H), 8.02-8.08 (m, 2H), 11.32 (s, 1H), 11.46 (s, 1H). MS 280 (MH+).

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

Procedure: Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (m, 1H), 7.52-7.69 (m, 5H), 7.98-8.01 (m, 2H), 11.99 (s, 1H), 12.54 (s, 1H). MS 296 (MH+).

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

Procedure: A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H). the precipitate was filtered washed with dioxane The filtrate was concentrated under reduced pressure the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7)

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

Procedure: A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H). the precipitate was filtered washed with dioxane The filtrate was concentrated under reduced pressure the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7)

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

Procedure: Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.6 Hz, 1H), 7.52-7.68 (m, 5H), 8.02-8.08 (m, 2H), 11.32 (s, 1H), 11.46 (s, 1H). MS 280 (MH+).