2-aMino-4,6-diMethoxybenzaMide

EDC (0.15 g, 0.76 mmol), HOBt (0.10 g, 0.76 mmol), and NMM (84 μL, 0.76 mmol) wereadded to a solution of2-amino-4, 6-dimethoxybenzoic acid (0.10 g, 0.51 mmol) in THF (5 mL). Themixture was stirred for 4 h beforeNHThe starting materials H30-2 (19.7 g, 0.1 mol), HOBt (20.3 g, 0.15 mol), carbodiimide EDCI (28.8 g, 0.15 mol), DIPEA (32.3 g, 0.25 mol), and THF (1 L) were added into a three-necked round bottom flask, and stirred for 3h. Then40 mL of aqueous ammonia was added, stirring overnight at room temperature. After the completion of reaction detectedby TLC, the mixture was extracted with DCM (2 3 200 mL). The organic layer was separated, then washed twice withwater, and distilled under reduced pressure. Ether (50 mL) was added into the residue. After stirring and mixing homogeneously, the mixture was filtrated. The filtrate was discarded to give the intermediate H30-3 (13.4 g, yield 68percent).3, 5-dimethoxy aniline (199g, 1.30mol) in diethyl ether (5.0 L) was added inthe flask 5L3 Cooled to 0° C. After 45 minutes the HCl gas (227g)introduced into the solution.at 10°C 45 Minutes the mixture was filtered, (4L) and washed withisopropyl acetate, under high vacuum, dried at 45 ° C Night to give the hydrochloride as a white solid (242.3g, 98percent). Under stirring the above hydrochloride (20g, 0The mixture.105mol) and oxalyl chloride (33 mL of) isequipped with a reflux condenser, 3-neck flask was heated 2 Hour (170 ° C externaltemperature), oxalyl chloride was distilled off from the reactionmixture. The flask was cooled to 0° C, was added methanol (40mL). The reactionmixture was heated at reflux for 45 minutes, filtered while hot, with A Alcohol(80mL) and washed to give a yellow-green solid4, 6-dimethoxy isatin (17.2g, 79percent). After 2 Hour to isatin (162g, 0.78mol) was heated in aqueous NaOH solution(40percent, 1.5L) in (externalTemperature 70 ° C) was slowly added to H 2 O 2(35percent, 405mL). H 2 O 2 was added after each batch, the internal temperature of the reaction Degree(initially 64 ° C) increase (to a maximum temperature of 80 ° C). Afterthe addition was complete, then at 70 ° C will blister The reaction mixture wasstirred for an additional 2hours, the mixture was stirred overnight while cooling to roomtemperature. The mixtureIt was heated to 70 ° C. An additional H 2 O 2 (75mL), at 70 ° C and themixture was stirred for an additional 2 Hours until the reaction was complete.Cooled to 10 ° C (bath temperature), a solution of Na 2 S 2 O 3 solution (150mL, saturation). The mixture was washed with HCl (37percent, 1.6L) was adjusted to pH8, with acetic acid(glacial acetic acid, 75mL) transfer To pH6, while not allowing thereaction mixture was warmed exceed 40 ° C. The reaction mixture was filtered, washed with water (4L) and washed to give the desired brownsolid amino acid (83.7g, 55percent). The amino acid (82.7g, 0.42mol) (4.2L) was added in dry THF EDCl (89.2g, 0.48mol), HOBT(65g, 0.48mol) and NMM (51.3mL), and the mixturewas stirred at roomtemperature for 3 hours. Adding NH3 Aqueoussolution (83mL, 50percent), and the mixture was stirred at room temperature for 16 hours.Was added water (1.25L), the The mixture (2 × 250mL) and extracted with DCM.Then the combined extracts were washed with water (2 × 500mL) washed Fandi.Concentrated, slurried with ethyl ether (550mL), filtered, and dried under highvacuum to afford a brown The solid4, 6-dimethoxy-2-amino-benzamide (46.7g, 57percent).2-Amino-4, 6-dimethoxy - benzamide (1.06g, 5.4mmol), 3, 5- dimethyl-4-hydroxy Benzaldehyde (0.810g, 5.4mmol), K 2 CO 3 (0.747g, 5.4mmol) and I 2(1.645g, 6.5mmol) DMF (20mL) in mixing, at 80 ° C and the reaction mixture was heated for 12 hours. It was cooledto Room temperature, poured onto crushed ice. The solid was collected, whichwas purified by column chromatography to give a white solid State of 2- (4-hydroxy-3, 5-dimethylphenyl)-5, 7-dimethoxy-quinazolin -4 (3H) - one (0.9g, 51percent). Selected data:MP291-293 ° C.A solution of 3, 5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0°C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10°C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45°C to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170°C external EXAMPLE 5 2-amino-4, 6-dimethoxybenzamide [00160] 2-amino-4, 6-dimethoxybenzonitrile (10.0 g, 0.056 mol, 1 eq.) was charged to a 1-L glass vessel under NCompound 7 (1.78 g, 10 mmol) was added to a 100 mL single-mouth bottle.Methanesulfonic acid (31.72 g, 330 mmol) was added to dissolve it.The reaction system is protected by N2, The temperature was raised to 110 ° C for 2 hours.After the reaction is over, A mixture of water and methylene chloride (1:2 by volume) is added to the system.Adjust the pH to neutral with a mass fraction of 30percent sodium hydroxide solution.The mixture was extracted three times with dichloromethane (3*20 mL).Combine the organic phase, Dry with anhydrous sodium sulfate, filter, Distilling under reduced pressure to obtain a mixture, Purified by column chromatography (eluent is petroleum ether / ethyl acetate, volume ratio 1:1).The brown solid was obtained as Compound 8 (1.47 g, yield: 75percent).A solution of 3, 5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4, 6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H