Preparation method of ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine
A technology for ticagrelor and intermediates, applied in the field of preparation of ticagrelor intermediate 4,6-dichloro-5-nitro-2-pyrimidine, which can solve unfavorable industrial scale-up, equipment, environmental protection and safety Unfavorable and other problems, to achieve the effect of simple preparation process and promote the development of economy and technology
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Embodiment 1
[0026] Add 2-nitro-1,3-diethyl-1,3-malonate (I) (10.3g, 50mmol), thiourea (4.76g, 62.5mmol, 1.25eq) and 100mL of methanol into a dry reaction flask, start stirring and Warm to reflux. 12 g of 30% methanol solution of sodium methoxide was added dropwise, and the reaction was kept under reflux for about 5 hours. TLC detected that the reaction was complete. Cool to room temperature, filter, wash the filter cake with cold methanol, and dry under vacuum at 50-55°C to obtain 9.5 g of light yellow solid 5-nitro-2-thio-barbiturate sodium (III), yield 90.0% .
Embodiment 2
[0028] Add 5-nitro-2-thio-barbiturate sodium (III) (8.5g, 40mmol) to 50mL water and 50mL methanol solution in a reaction flask, add bromo-n-propane (IV) dropwise at room temperature (5.37g, 44mmol, 1.1eq), after stirring for 15 minutes, slowly add 20mL of 10% sodium hydroxide solution dropwise and keep at room temperature, continue to stir and react for about 20 hours, and TLC detects that the reaction is complete. Add 100 mL of water, adjust the pH to 1.8-2.2 with dilute hydrochloric acid, extract three times with toluene, combine the organic phases, wash with saline and water, dry over anhydrous sodium sulfate, and recover toluene under reduced pressure to obtain light brown oil 4,6-dihydroxy -5-nitro-2-(propylmercapto)pyrimidine (V) 7.5g, yield 81.2%.
Embodiment 3
[0030] Add 4,6-dihydroxy-5-nitro-2-(propylmercapto)pyrimidine (V) (6.9g, 30mmol) and phosphorus oxychloride (15g) into the reaction flask, add N, N - Diisopropylethylamine (7.2 g), keeping the temperature not exceeding 25°C. After the addition, the temperature was raised to 110-115° C., and the reaction was carried out for 4 hours. TLC detected that the reaction was complete. Cool to room temperature, slowly pour into 100 mL of water, stir for 15 minutes, extract twice with toluene, combine organic phases, wash with saturated sodium bicarbonate, saturated brine and water successively, and dry over anhydrous sodium sulfate. After distillation under reduced pressure, 7.0 g of ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (intermediate A) was obtained as a pale yellow oil, with a yield of 87.5%.
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