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A kind of method of applying continuous flow reaction technology to prepare advanced intermediate of ticagrelor

A technology for ticagrelor and intermediates, applied in the field of compound synthesis, can solve problems such as unsatisfactory synthesis efficiency and immature synthesis process, and achieve the effects of no amplification effect, convenient real-time monitoring, and convenient operation

Active Publication Date: 2022-04-12
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for now, the continuous flow microchannel reactor has been mainly used in the synthesis of small organic molecules, and it is not common in the synthesis of macromolecules like mesopropylidene ticagrelor, which is mainly It is limited by the immature synthesis process and the unsatisfactory synthesis efficiency

Method used

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  • A kind of method of applying continuous flow reaction technology to prepare advanced intermediate of ticagrelor
  • A kind of method of applying continuous flow reaction technology to prepare advanced intermediate of ticagrelor
  • A kind of method of applying continuous flow reaction technology to prepare advanced intermediate of ticagrelor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1) Preparation of TGM-2:

[0037] Weigh 20g of TGM-1 (0.048mol, 1.0eq), 5.1g of concentrated hydrochloric acid (0.05mol, 1.05eq), measure 120mL of tetrahydrofuran and put it in the first raw material storage tank, stir evenly, as the first material;

[0038] Weigh 3.5g of sodium nitrite (0.05mol, 1.05eq), measure 50mL of water, place in the second raw material storage tank, stir evenly, and use it as the second material.

[0039] The temperature of the first microchannel reactor is controlled at 25-30°C through the high and low temperature integrated machine, and the first material is pumped into the first microchannel reactor through the metering pump 1 at a flow rate of 3mL / min; the second material Pump into the first microchannel reactor through the metering pump 2, and the pumping flow rate is 2mL / min. The diazotization and cyclization reactions were carried out in the first microchannel reactor, the reaction time was 10 min, and the reaction temperature was 28°C. ...

Embodiment 2

[0045] 1) Preparation of TGM-2:

[0046] Weigh 30g of TGM-1 (0.071mol, 1.0eq), measure 8.7mL of 9N sulfuric acid (0.078mol, 1.1eq), place 120mL of ethanol in the storage tank of the first raw material, stir well, and use it as the first material;

[0047] Weigh 5.4g of sodium nitrite (0.078mol, 1.1eq), measure 160mL of water, place in the second raw material storage tank, stir evenly, and use it as the second material.

[0048] The temperature of the first microchannel reactor is controlled at 25-30°C through the high and low temperature integrated machine, and the first material is pumped into the first microchannel reactor through the metering pump 1, and the pumping flow rate is 5mL / min; the second material Pump into the first microchannel reactor through the metering pump 2, and the pumping flow rate is 4 mL / min. The diazotization and cyclization reactions were carried out in the first microchannel reactor, the reaction time was 6 min, and the reaction temperature was 30°C....

Embodiment 3

[0054] 1) Preparation of TGM-2:

[0055] Weigh 50g of TGM-1 (0.12mol, 1.0eq), 18g of glacial acetic acid (0.3mol, 2.5eq), measure 300mL of tetrahydrofuran into the first raw material storage tank, stir evenly, and use it as the first material;

[0056] Weigh 10.7g of sodium nitrite (0.16mol, 1.3eq), measure 200mL of water, place in the second raw material storage tank, stir evenly, and use it as the second material.

[0057] The temperature of the first microchannel reactor is controlled at 25-30°C through the high and low temperature integrated machine, and the first material is pumped into the first microchannel reactor through the metering pump 1, and the pumping flow rate is 8mL / min; the second material Pump into the first microchannel reactor through the metering pump 2, and the pumping flow rate is 6mL / min. The diazotization and cyclization reactions were carried out in the first microchannel reactor, the reaction time was 4 min, and the reaction temperature was 32°C. ...

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Abstract

The invention discloses a method for preparing advanced intermediates of ticagrelor by applying continuous flow reaction technology. In the first microchannel reactor, TGM‑1 is reacted with sodium nitrite, and then cyclized through diazotization reaction process Triazole, in the second microchannel reactor, TGM‑2 and the intermediate TGC are docked and coupled under the action of an alkaline reagent to obtain the target product isopropylidene ticagrelor TGI. The overall preparation process of this scheme is simple, and the operation is convenient. By rationally designing the reaction parameters, it is possible to prepare the macromolecular compound isopropylidene ticagrelor by continuous flow reaction technology. Compared with the formula chemical synthesis method, this method has the advantages of high-speed mixing, narrow residence time of reactants, good repeatability, almost no amplification effect, convenient real-time monitoring of reaction process, high safety performance, etc., which is conducive to the large-scale production and application of the substance.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and in particular relates to a method for preparing ticagrelor advanced intermediate-isopropylidene ticagrelor by adopting continuous flow reaction technology and using a microchannel reactor. Background technique [0002] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, which can reversibly act on the purine 2 receptor subtype on vascular smooth muscle cells P2Y12 does not require metabolic activation, has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP), and has a rapid effect after oral administration, and can effectively improve the symptoms of patients with acute coronary heart disease. Ticagrelor is a reversible inhibitor of P2Y12 receptors, so it is especially suitable for patients who need to undergo surgery after anticoagulant therapy. In July 2011, it was approved for marketing by ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04B01J19/00
CPCC07D487/04B01J19/0093
Inventor 李泽标杨洋许兆青吴红当丁海明林燕峰
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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