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Production process of ticagrelor fine product

A technology of ticagrelor and production process, which is applied in the field of production technology of ticagrelor fine products, can solve the problems of complex intermediates, low atomic economic benefits and high production costs, and achieves simple reaction conditions, low production costs, and low production costs. Handling convenient effects

Pending Publication Date: 2020-11-24
南京一心和医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the intermediates obtained by the fourth scheme are relatively complicated, and need two deprotection operations, the atomic economic benefit is low, and the production cost is high.

Method used

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  • Production process of ticagrelor fine product
  • Production process of ticagrelor fine product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A kind of production technology of ticagrelor, concrete process is as follows:

[0022] At a temperature of 15°C, mix 17.2kg of 4,6-dichloro-5-amino-2-propylthiopyrimidine (IIa), 18.2kg of sodium bicarbonate and 25kg of water, raise the temperature until the internal temperature of the mixture reaches 90°C 26.6kg of compound (IIb) (dissolved in 34kg of water) was added in batches, the reaction temperature was controlled at 90°C, and the reaction was stirred until the HPLC monitoring reaction was complete. Stop heating, lower the temperature to 50°C, add 30kg of ethyl acetate to dissolve, separate the liquid while it is hot, discard the water phase, wash the organic phase with 44kg of water, slowly add 135kg of n-hexane, stir, there is solid precipitation, stir for 2 hours, filter, filter The cake was rinsed with 2*35 kg of n-hexane, filtered, and the filter cake was dried under reduced pressure to obtain 27.1 kg of intermediate (III) with a moisture content of ≤5% and a...

Embodiment 2

[0028] A kind of production technology of ticagrelor, concrete process is as follows:

[0029] At a temperature of 25°C, mix 19.8kg of 4,6-dichloro-5-amino-2-propylthiopyrimidine (IIa), 24.3kg of sodium bicarbonate and 26.6kg of water, raise the temperature until the internal temperature of the mixture reaches 85 At ℃, 26.6kg of compound (IIb) (dissolved in 34kg of water) was added in batches, the reaction temperature was controlled at 85℃, and the reaction was stirred until the reaction was complete as monitored by HPLC. Stop heating, lower the temperature to 55°C, add 40kg of ethyl acetate to dissolve, separate liquids while hot, discard the water phase, wash the organic phase with 54kg of water, slowly add 147kg of n-hexane, stir, and solids are precipitated, stir for 2 hours, filter, filter The cake was rinsed with 2*35 kg of n-hexane, filtered, and the filter cake was dried under reduced pressure to obtain 27.1 kg of intermediate (III) with a moisture content of ≤5% and a...

Embodiment 3

[0035] A kind of production technology of ticagrelor, concrete process is as follows:

[0036] At a temperature of 20°C, mix 20.7kg of 4,6-dichloro-5-amino-2-propylthiopyrimidine (IIa), 30.4kg of sodium bicarbonate and 26.6kg of water, and heat up until the internal temperature of the mixture reaches 87 At ℃, 26.6kg of compound (IIb) (dissolved in 34kg of water) was added in batches, the reaction temperature was controlled at 87℃, and the reaction was stirred until the reaction was complete as monitored by HPLC. Stop heating, lower the temperature to 52°C, add 40kg of ethyl acetate to dissolve, separate the liquid while it is hot, discard the water phase, wash the organic phase with 54kg of water, slowly add 147kg of n-hexane, stir, there is solid precipitation, stir for 2 hours, filter, filter The cake was rinsed with 2*35kg of n-hexane, filtered, and the filter cake was dried under reduced pressure to obtain 27.3kg of intermediate (III) with a moisture content of ≤5% and a y...

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Abstract

The present invention discloses a production process of a ticagrelor fine product. The process comprises the steps of adopting 4,6-dichloro-5-amino-2-propylthiopyrimidine (IIa) and a compound (IIb) asstarting raw materials, and carrying out five processes including a substitution process I, a cyclization process, a substitution process II, a hydrolysis process and a refining process to finally obtain the ticagrelor fine product. The method provides a ticagrelor production process, uses cheap and easily available raw materials, has the advantages of low production cost, simple reaction conditions, convenient post-treatment, high yield and high product purity, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a production process of ticagrelor high-quality goods. Background technique [0002] Ticagrelor, which belongs to the cyclopentyltriazole pyrimidine family of non-thienopyridine drugs, is the first oral reversible P2Y12 receptor inhibitor developed by Astrazeneca. The drug was approved for marketing by the European Medicines Agency at the end of 2010, and was approved for marketing by the US FDA in July 2011. It is used to reduce the incidence of thrombotic cardiovascular events in patients with acute coronary syndrome. In November 2012, the drug obtained the import drug license issued by the State Food and Drug Administration and was officially launched in China. [0003] In the prior art, the synthesis methods of ticagrelor mainly include the following schemes disclosed in relevant documents: 1. The preparation scheme disclosed in the CN1128801C patent is: 4...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 袁方吕伏生周步高李守忠张盼
Owner 南京一心和医药科技有限公司