Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine

A technology of ticagrelor and aminopyrimidine is applied in the field of preparation of ticagrelor intermediate 4,6-dichloro-2--5-aminopyrimidine, and can solve the problem of difficult filtration, large amount of solvent for extraction, and amount of solid waste. major problems, to achieve the effect of promoting economic technology, simplifying nitro reduction, and promoting development

Inactive Publication Date: 2013-06-05
许学农
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in actual operation, there are problems such as difficult filtration, large amount of solid waste, large amount of solvent extracted and low yield.
[0015] In summary, in the preparation methods of intermediate A reported so far, most of the methods involving the formation of amino groups use reduction of azo compounds or high-pressure hydrogenation under platinum-carbon catalysis, which have high cost, low yield and difficult operation. Weakness, not conducive to industrial production

Method used

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  • Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine
  • Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine
  • Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine

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Embodiment 1

[0031] Into a 1L reaction flask was added 4,6-dichloro-5-nitro-2-(propylmercapto)pyrimidine (V) (26.6g, 0.1mol), sodium hydrosulfite (43.5g, 0.25mol), methanol 250mL and Water 250mL, start stirring, keep stirring and reacting at 55 DEG C for 5 hours, TLC detects that the reaction is complete. Concentrate to half the volume under reduced pressure and extract three times with dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate and water successively, dried, and the solvent was recovered by distillation under reduced pressure.

Embodiment 2

[0033] Into a 1L reaction flask, add 4,6-dichloro-5-nitro-2-(propylmercapto)pyrimidine (V) (26.6g, 0.1mol), sodium hydrosulfite (69.6g, 0.40mol), 250mL of acetonitrile and Water 250mL, start stirring, keep stirring and reacting at 55 DEG C for 4 hours, TLC detects that the reaction is complete. Concentrate to half the volume under reduced pressure and extract three times with toluene. The organic phases were combined, washed successively with 5% sodium bicarbonate and water, dried, and the solvent was recovered by distillation under reduced pressure. The residual oil was frozen and crystallized with isopropyl ether to obtain a pale yellow solid Intermediate A21.7g with a yield of 91.6%.

Embodiment 3

[0035] Into a 1L reaction flask, add 4,6-dichloro-5-nitro-2-(propylmercapto)pyrimidine (V) (26.6g, 0.1mol), sodium hydrosulfite (69.6g, 0.40mol), 250mL of toluene and 250 mL of water was added simultaneously with 2.5 g of tetrabutylammonium bromide. Start stirring, keep stirring and react at 65 DEG C for 4 hours, and TLC detects that the reaction is complete. Cooled to room temperature, the organic layer was separated, the aqueous layer was washed twice with toluene, the organic phases were combined, washed with 5% sodium bicarbonate and water in turn, dried, and distilled under reduced pressure to recover the solvent, and the residual oil was washed with methyl tert-butyl The ether was frozen and crystallized to obtain a light yellow solid intermediate A22.3g, the yield was 94.0%.

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Abstract

The invention discloses a preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine. The preparation method of the Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine includes the following steps: using 4,6- dichloro-2-nitro-2-(pyridinecarboxylic) pyrimidine(V), enabling the nitro of a molecular structure to be reduced to amino through the reduction reaction of reducing agent sodium hydrosulfite, and obtaining the Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine. The preparation method of the Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine is easy, convenient to implement, economical and environment-friendly, beneficial to industrial production and capable of facilitating the development of economic technology 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, in particular to a preparation method of ticagrelor intermediate 4,6-dichloro-2-(propylmercapto)-5-aminopyrimidine. Background technique [0002] Ticagrelor (also known as ticagrelor) is a novel and selective small molecule anticoagulant developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine bisulfite. Phosphoreceptor antagonists have obvious inhibitory effect on platelet aggregation caused by ADP, 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 U.S. Food and Drug Administration (FDA) in 2010 and 2011, respectively, to be marketed in the European Union and the United States, and its imported preparation, ticagrelor tablets, has been approved by the SFDA for listing in my countr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
Inventor 许学农
Owner 许学农
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