The specific synthesis method of intermediate 1 is as follows: In a 2500 mL round-bottom flask, add 180 g (3.0 mol) of urea, 370 g (2.5 mol) of triethyl orthoformate, and 226 g (2.0 mol) of ethyl cyanoacetate. Stir and reflux for 4 hours, constantly observing the reflux phenomenon to ensure uniform and stable reflux. After the reaction is stopped, cool and filter, collect the yellowish-white solid, wash with acetone, dry, and obtain intermediate 1, a yellowish-white powdery solid of 294.5 g, with a yield of 81%.
The specific synthesis method of intermediate 2 is as follows: Add 1000 mL of anhydrous methanol to a 2500 mL round-bottom flask, then add 23 g (1 mol) of metallic sodium in portions. After the metallic sodium is completely dissolved, add 183 g (1 mol) of intermediate 1, followed by 5.6 g (0.1 mol) of nano-calcium oxide powder. Heat to 60 °C and reflux for 3 hours. Stop the reaction, cool, and collect the yellow solid by suction filtration. Dissolve the obtained solid in 500 mL of water, adding water while stirring until the yellow solid is completely dissolved. Acidify with dilute hydrochloric acid (prepared from concentrated hydrochloric acid and water in a volume ratio of 1:3) to a pH between 6 and 7. A precipitate forms; collect the white solid by suction filtration and wash with a small amount of acetone. Dry to obtain intermediate 2, a white powdery solid, 53 g, yield 29%. The specific synthesis method of intermediate 3 is as follows: 800 mL of 10% NaOH solution was prepared and added to a 2500 mL round-bottom flask. The solution was heated to 90°C, and 91.5 g (0.5 mol) of intermediate was added and stirred for 15 minutes. The solution was rapidly cooled to room temperature, and then acidified with hydrochloric acid to pH 5. A white precipitate was formed. The precipitate was filtered, washed with water, and dried to obtain 73.6 g of 5-carboxycytosine, a white powdery solid, with a yield of 95%. The decarboxylation synthesis of cytosine was performed as follows: 77.5 g (0.5 mol) of intermediate 3, 26.8 g (0.5 mol) of ammonium chloride, and 500 mL of N-methylpyrrolidone were added to a 1000 mL round-bottom flask. Nitrogen gas was introduced for protection, and the mixture was stirred until homogeneous. The mixture was then heated to 180 °C and maintained at this temperature for 8 hours. The mixture was then refluxed until few bubbles were removed. The reaction was stopped, and the mixture was cooled to room temperature. 150 mL of diethyl ether was added, and the precipitated solid was filtered. The white solid collected was the final product, cytosine. After drying, 49 g of a white crystalline solid was obtained, with a yield of 87.0%.
