Preparation method of ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine

Abstract

The invention discloses a preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine (intermediate A). The preparation method comprises the steps of carrying out ring-closure reaction on 2-nitro-1, 3 malonic acid alkyl ester (I) and thiourea (II) to generate 5-nitro-2-sulfo-barbituric acid (III); carrying out sulfur alkylation reaction on the obtained 5-nitro-2-sulfo-barbituric acid (III) and halogenated propane (IV) to obtain 4, 6-dyhydroxyl-5-nitro-2-(propylthio) pyrimidine (V); carrying out chlorination on the 4, 6-dyhydroxyl-5-nitro-2-(propylthio) pyrimidine (V) to obtain the Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine (intermediate A). The preparation method is simple and convenient as well as economical and environmentally friendly, is beneficial to the industrial production of the medicine, and is capable of promoting the development of the economic technology of the raw material medicine, and raw materials are easily available.

Description

technical field

[0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to the preparation of a ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine method. Background technique

[0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine di The phosphate receptor antagonist has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011, respectively, and was launched in the EU and the US under the trade name Brilinta. Its imported preparation, ticagrelor tablets, has been approved by the China Food and Drug Ad...

Examples

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%.

technical field

[0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to the preparation of a ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine method. Background technique

[0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine di The phosphate receptor antagonist has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011, respectively, and was launched in the EU and the US under the trade name Brilinta. Its imported preparation, ticagrelor tablets, has been approved by the China Food and Drug Ad...

Examples

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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