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5-nitro-2-(propylthio)pyriMdine-4,6-diol, also known as 4,6-dihydroxy-5-nitro-2-(propylthio)pyrimidine, is an intermediate in the synthesis of Ticagrelor. Ticagrelor is the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist, which effectively inhibits platelet aggregation induced by ADP and improves symptoms in patients with acute coronary syndrome.
In a 500ml round-bottom flask, 200ml of a 30% acetic acid solution is added. Then, 41g (200mmol) of 2-nitro-1,3-propanediolethyl ester, 19.5g (240mmol) of sodium thiocyanate, and 24.8g (400mmol) of ammonium acetate are added to the flask. The reaction mixture is stirred at 25°C for 5 hours, and the completion of the reaction is monitored by TLC. The reaction mixture is poured into ice water, and the pH is adjusted to 8 with sodium bicarbonate. The resulting mixture is filtered, and the filter cake is washed with water three times. The compound shown as II in the scheme is obtained with a yield of 45.7g (97.1%) after vacuum drying.
In a 250ml round-bottom flask, 80ml of ethanol solution is added. Then, 23.5g (100mmol) of the compound II and 10.8g (200mmol) of sodium methoxide are added to the flask. The reaction mixture is refluxed for 2 hours, and the completion of the reaction is monitored by TLC. After cooling to room temperature, the reaction mixture is concentrated and poured into 100ml of water. The mixture is extracted with ethyl acetate three times, and the combined ethyl acetate layers are dried with anhydrous sodium sulfate. After concentration, the compound shown as III in the scheme, 2-thio-5-nitro-2,4,6(1H,3H,5H)-pyrimidinetrione, is obtained with a yield of 18.0g (95.0%) after vacuum drying. The purity of the compound is 99.17% (area normalization method) by HPLC.
In a 250ml round-bottom flask, 100ml of 1,4-dioxane solution is added. Then, 18.9g (100mmol) of the compound III and 0.68g (5mmol) of zinc chloride are added to the flask. The mixture is stirred at room temperature for 20 minutes, and then 21.2g (200mmol) of sodium carbonate and 14.8g (120mmol) of 1-bromopropane are added. The reaction is continued at room temperature for 9 hours, and the completion of the reaction is monitored by TLC. The reaction mixture is concentrated to one-third, poured into 100ml of water, and the pH is adjusted to 3 with 1M HCl. The resulting mixture is filtered, and the filter cake is washed with water. The compound 5-nitro-2-(propylthio)pyriMdine-4,6-diol is obtained with a yield of 21.1g (91.4%) after recrystallization from petroleum ether. The purity of the compound is 98.82% (area normalization method) by HPLC.
[1] CN201610908155.4, Preparation method of intermediate for Ticagrelor.
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