Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine

Abstract

The invention provides a method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine. The method comprises the following steps: 1, adding 4,6-dyhydroxy-2-mercaptopyrimidine into water, dripping a 10 percent sodium hydroxide solution, adding methanol and 1-bromopropane, reacting by keeping temperature, and acidifying to separate out crystals so as to obtain 4,6-dyhydroxy-2-(propylthio)pyrimidine; 2, adding fuming nitric acid into glacial acetic acid, adding the 4,6-dyhydroxy-2-(propylthio)pyrimidine, and adding water to separate out crystals so as to obtain 4,6-dyhydroxy-5-nitro-2-(propylthio)pyrimidine; 3, adding a chloro agent into dichloromethane, adding the 4,6-dyhydroxy-5-nitro-2-(propylthio)pyrimidine in batches, adding saturated brine, and postprocessing to obtain 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine; and 4, adding iron powder into an organic solvent, adding the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine in batches, adding dichloromethane and water to dissolve residue, demixing, evaporating an organic layer to dryness under reduced pressure obtain an oily product, and adding a crystallizing solvent to obtain the 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine. The method overcomes defects of the prior art, so that production cost is reduced.

Description

technical field [0001] The invention relates to medicines, and relates to a preparation method of 4,6-dichloro-5-amino-2-propylthiopyrimidine. Background technique [0002] Ticagrelor is a selective anticoagulant drug and the first reversible binding P2Y12 adenosine diphosphate receptor antagonist, which can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells, It has obvious inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. The most critical intermediate of ticagrelor is 4,6-dichloro-5-amino-2-propylthiopyrimidine. Currently, there are generally two methods for preparing this intermediate, route 1: [0003] [0004] The disadvantage of this method is: the 1-iodopropane used is expensive and the cost is high; a large amount of fuming nitric acid (the molar ratio of intermediate and fuming nitric acid is 1:21) is directly used for nitration, and ...

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Problems solved by technology

[0004] The disadvantage of this method is: the 1-iodopropane used is expensive and the cost is high; a large amount of fuming nitric acid (the molar ratio of intermediate and fuming nitric acid is 1:21) is directly used for nitration, and the concentration of fuming nitric acid is 98 %, direct nitration without adding any reagent, not only consumes a large amount, but also is extremely dangerous, and will destroy 4,6-dihydroxy-2-propylthiopyrimidine, and the side reactions will increase, resulting in a decrease in yield; Phosphorus is heated to reflux for chlorination, the reaction temperature is high, side reactions are many, chromatographic separation and purification are required, a large amount of solvent and long-term elution are required, resulting in long preparation cycle, heavy workload and low yield; Route 2:

[0006] The disadvantages of this method are: the 1-iodopropane, methylpyrrolidone and platinum carbon catalysts used are expensive and costly; the reaction conditions such as azotization and pressurized hydrogenation reduction are demanding, and the yield and purity are also difficult. Guaranteed, the post-processing of the product is complicated, which is not conducive to large-scale industrial production

Moreover, the above two methods are difficult to apply to industrial production, which leads to high production cost of ticagrelor and makes it difficult to reduce the selling price, which brings a heavy economic burden to patients

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