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Synthesis of 2-Chloro-6-fluoro-4-methyl-quinazoline To a solution of compound 3 (5 g,0.037 mol) in 50 ml_ of THF was added asolution of MeMgBr (50 ml_, 0.147 mol) dropwise at 0°C. After addition, themixture was heated to reflux for 4 hours. The mixture was quenched by additionof 10percent HCI, heated to reflux for another 1hour. The resulting mixture was extracted with EtOAc, washed with brine. Thesolvent was evaporated and the residue was purified with chromatography onsilica gel to afford compound 3a (2.8 g, yield: 50percent).To a solution of compound 3a (1 g,6.54 mmol) in 10 mL of AcOH was added KNCO(2.65 g, 0.033 mol), then the mixture was kept at room temperature for 30 minthen heated to 60°C overnight. H2O was added, theformed precipitate was collected by filtration and dried under vacuum to afford6-fluoro-4-methyl-1 H-quinazolin-2-one (0.4 g, yield: 34percent), which was used fornext step without further purification. 1H NMR (DMSO+HCI 400 MHz TMS): 58.12 (d, J = 6.8 Hz, 1 H), 7.97 (s, 1 H),7.68 (d, J = 6.8 Hz, 1 H). m/z = 179 [M + H]+ .The solution of 6-fluoro-4-methyl-1 H-quinazolin-2-one (0.1 g, 0.56mmol) in 5 mL of toluene and 0.4 mL of DIPEA was added 0.2 mL of POCI3, then the mixture was heated to 80°C for 3hours. The toluene layer was collected, and the residue was extracted withether. The combined organic layer wasconcentrated to afford crude 2-chloro-6-fluoro-4-methyl-quinazoline (80mg, yield: 73percent) which was used for next step without further purification.
1-(2-methylcarbonyl-4-fluorophenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; triethylamine; In dichloromethane;
EXAMPLE II Preparation of: 1-(2-methylcarbonyl-4-fluorophenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 2 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.53 grams of 5-fluoro-2-amino-acetophenone was added dropwise. The stirred reaction mixture was permitted to warm to room temperature and was then shaken once with 2 percent aqueous hydrochloric acid then twice with water. Removal of solvent afforded a crystalline solid which was washed with a small amount of diethyl ether. Suction drying afforded light tan crystals identified by NMR analysis as the desired product.
With hydrogenchloride; triethylamine; In dichloromethane;
Example II Preparation of: 1-(2-methylcarbonyl-4-fluorophenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0-5°C via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 2 hours at ice bath temperature a methylene chloride solution containi ng 1.0 gram of triethylamine and 1.53 grams of 5-fluoro-2-amino-acetophenone was added dropwise. The stirred reaction mixture was permitted to warm to room temperature and was then shaken once with 2 percent aqueous hydrochloric acid then twice with water. Removal of solvent afforded a crystalline solid which was washed with a small amount of diethyl ether. Suction drying afforded light tan crystals identified by NMR analysis as the desired product.
In acetonitrile at 20℃; for 20h; Inert atmosphere; UV-irradiation;
With nitriding Carbon In 1,4-dioxane at 40℃; for 44h; Inert atmosphere; Irradiation;
1.1; 2.1 Preparation of 2-amino-5-fluoroacetophenone:
Under the protection of argon atmosphere, add 15.3g (100mmol) of 4-fluoroacetanilide (Compound 4) and 200mL of dioxane solvent to a 500mL single-necked flask with magnetic stir bar, then add 306mg of visible light catalyst for nitriding Carbon (g-C3N4) (w / w = 2.35%), heated to 40 under stirring, while a 36-watt LED lamp was used to photocatalyze the Fries rearrangement reaction to the light of the reaction system, and the reaction system was kept at The reaction was carried out under light for 44h. After the raw material reaction was completed, the temperature was lowered to room temperature. The reaction solution was filtered through celite to remove the visible light catalyst and filtered with suction. The filter residue was washed with 50mL of dioxane. The filtrate was collected. The filtrate was concentrated under reduced pressure to remove solvent 2. Oxygen hexacyclo to give 15.3g of brownish yellow solid. This crude product is 2-amino-5-fluoroacetophenone (compound 5). This product is used as raw material for the next reaction without purification. The yield is calculated as 100% ;
Synthesis of 2-Chloro-6-fluoro-4-methyl-quinazoline To a solution of compound 3 (5 g,0.037 mol) in 50 ml_ of THF was added asolution of MeMgBr (50 ml_, 0.147 mol) dropwise at 0C. After addition, themixture was heated to reflux for 4 hours. The mixture was quenched by additionof 10% HCI, heated to reflux for another 1hour. The resulting mixture was extracted with EtOAc, washed with brine. Thesolvent was evaporated and the residue was purified with chromatography onsilica gel to afford compound 3a (2.8 g, yield: 50%).To a solution of compound 3a (1 g,6.54 mmol) in 10 mL of AcOH was added KNCO(2.65 g, 0.033 mol), then the mixture was kept at room temperature for 30 minthen heated to 60C overnight. H2O was added, theformed precipitate was collected by filtration and dried under vacuum to afford6-fluoro-4-methyl-1 H-quinazolin-2-one (0.4 g, yield: 34%), which was used fornext step without further purification. 1H NMR (DMSO+HCI 400 MHz TMS): 58.12 (d, J = 6.8 Hz, 1 H), 7.97 (s, 1 H),7.68 (d, J = 6.8 Hz, 1 H). m/z = 179 [M + H]+ .The solution of 6-fluoro-4-methyl-1 H-quinazolin-2-one (0.1 g, 0.56mmol) in 5 mL of toluene and 0.4 mL of DIPEA was added 0.2 mL of POCI3, then the mixture was heated to 80C for 3hours. The toluene layer was collected, and the residue was extracted withether. The combined organic layer wasconcentrated to afford crude 2-chloro-6-fluoro-4-methyl-quinazoline (80mg, yield: 73%) which was used for next step without further purification.
Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 5-fluoro-2-amino-acetophenone In tetrahydrofuran at 20℃; Inert atmosphere;
Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.666667h;
Stage #2: 5-fluoro-2-amino-acetophenone In tetrahydrofuran at 0 - 20℃;
Stage #1: methyl-triphenylphosphonium iodide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 5-fluoro-2-amino-acetophenone In tetrahydrofuran at 20℃; Inert atmosphere;
In a 500 mL open three-necked flask with magnetic stirring, add 15.3 g of the crude product of the previous step, 2-amino-5-fluoroacetophenone (Compound 5), then add 200 mL of hydrochloric acid (3 mol / L), use The bath lowered the temperature of the reaction system to 5 ,With stirring, 10mL (10mol / L) of an aqueous solution of potassium nitrite was added dropwise to carry out the diazotization reaction.Keep the reaction temperature not more than 10 for 30min. After tracking the reaction until the diazotization is complete, keep adding 20mL (10mol / L) of potassium iodide aqueous solution dropwise at 5 .Then the temperature was raised to 60 for iodine reaction, and the reaction was continued to stir for 12h,After the reaction was completed, the aqueous phase was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined,The organic phase was washed once with saturated aqueous sodium bicarbonate solution (5 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to remove the ethyl acetate solvent to obtain the crude product of the target product (Compound 1). The crude product was reduced by an oil pump Pressure distillation yielded 22.2g of colorless liquid, which was pure 3-fluoro-6-iodoacetophenone with a two-step yield of 84% and a product purity greater than 95% by weight.
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