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Stage #1: 8-iodoquinazolin-4(1H)-one With trichlorophosphate for 8h; Reflux;
Stage #2: With dihydrogen peroxide In lithium hydroxide monohydrate
2 Comparative Example 2
Tosylic acid dihydrate (0.038 g) was added to a suspension of 2-amino-3-iodobenzamide (0.513 g) supplemented with methyl orthoformate (5 ml) and NMP (1 ml), and the mixture was heated to reflux for 3 hours. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-iodoquinazolin-4(1H)-one (0.481 g). Phosphorus oxychloride (10 ml) was added to the obtained 8-iodoquinazolin-4(1H)-one (1.17 g), and the mixture was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate) to obtain 4-chloro-8-iodoquinazoline (0.946 g). 4-(4-Chloroquinazolin-8-yl)-2-(4-hydroxycyclohexylamino)benzonitrile was obtained according to Example 2(1) using the obtained 4-chloro-8-iodoquinazoline instead of compound (1b) and PdCl2dppf instead of Pd(PPh3)4. A compound of Comparative Example 2 was obtained as a pale yellow solid (yield based on 5 steps: 10%) according to Example 79 using the obtained 4-(4-chloroquinazolin-8-yl)-2-(4-hydroxycyclohexylamino)benzonitrile instead of compound (4b) and 3-quinolineboronic acid instead of 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester.
With dichlorosulfoxide In N,N-dimethyl-formamide at 90℃; for 14h;
6.3 third step
Compound 6-3 (370 mg, 1.36 mmol) was added to N,N-dimethylformamide (0.1 mL), then thionyl chloride (4 mL) was added, and the reaction solution was stirred at 90 degrees Celsius for 14 hours.The reaction solution was cooled to room temperature and concentrated under reduced pressure.Toluene (20 mL) was added to the residue obtained by concentration under reduced pressure, and the mixture was washed once with saturated sodium bicarbonate (20 mL).The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 6-4.
With anhydrous sodium carbonate In isopropanol at 60℃; for 15h;
6.4 the fourth step
Compound 6-4 (220 mg, 757 μmol) and Intermediate B (205 mg, 757 μmol) were dissolved in isopropanol (5 mL) and sodium carbonate (161 mg, 1.51 mmol) was added.The reaction solution was stirred at 60 degrees Celsius for 15 hours.The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate, 10/14/1, V/V) to obtain compound 6-5.
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