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Preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine

A technology of ticagrelor and aminopyrimidine, which is applied in the field of preparation of ticagrelor intermediate 4,6-dichloro-2--5-aminopyrimidine, can solve the problem of unfavorable industrialized production, great environmental protection and safety pressure and other problems, to achieve the effect of promoting development, promoting economy and technology, and simplifying the preparation process

Active Publication Date: 2015-12-02
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Considering the above methods, no matter which route is selected, diazotization or nitrification reactions must be carried out, so there is a greater pressure on environmental protection and safety
In addition, at the same time as the hydrogenation reduction of the nitro group, reducing agents such as hydrogen are also easy to reduce the halogen chlorine on the 4.6-position of the pyrimidine ring, resulting in new side reactions, which is not conducive to industrial production

Method used

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  • Preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine
  • Preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine
  • Preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine

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Experimental program
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Embodiment 1

[0031] Add 2-acetylamino-1,3-diethyl malonate (I) (10.9g, 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 3 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 10.5 g of off-white solid 5-acetylamino-2-thio-barbiturate sodium (III), yield 94.2%.

Embodiment 2

[0033] Add 2-benzyloxycarboxamido-1,3-diethyl-1,3-malonate (I) (15.5g, 50mmol), thiourea (4.76g, 62.5mmol, 1.25eq) and 150mL of methanol into a dry reaction flask, Stirring was started and the temperature was raised to reflux. 12 g of 30% methanol solution of sodium methoxide was added dropwise, and the reaction was kept under reflux for about 4 hours, and the reaction was detected by TLC. Cool to room temperature, filter, wash the filter cake with cold methanol, and dry under vacuum at 50-55°C to obtain 14.6 g of white solid 5-benzyloxycarboxamido-2-thio-barbiturate sodium (III), yield 92.7 %.

Embodiment 3

[0035] 5-Acetamido-2-thio-barbiturate sodium (III) (8.92g, 40mmol) was added to 50mL water and 50mL methanol solution in a reaction flask, and bromo-n-propane (IV) was added 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 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, and slowly stir for crystallization. After filtering, the filter cake was washed three times with water, and dried under vacuum at 55-60° C. to obtain 7.29 g of off-white solid 4,6-dihydroxy-5-acetylamino-2-(propylthio)pyrimidine (V), with a yield of 75.0%.

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Abstract

The invention discloses a preparation method of a Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine, which comprises the following steps that: 2-protected amino-l,3-alkyl ester malonate (I) and thiourea (II) have a cyclization reaction so as to generate 5-protected amino-2-thio-sodium barbiturate (III); the compound (III) and halogenated propane (IV) have a thio-alkylation reaction so as to obtain 4,6-dyhydroxyl-5-protected amino-2-(mercaptopropionic) pyrimidine (V); the compound (V) is subjected to a chlorinated reaction so as to obtain 4,6-dichloro-5-protected amino-2-(mercaptopropionic) pyrimidine (VI); and the compound (VI) is subjected to de-protection so as to obtain the Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine. The preparation method is simple, economic, and environment-friendly, facilitates the industrialized production of the drug, and can promote the economic and technological development of the bulk drug.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine. 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 a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCY02P20/55
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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