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Method and device for continuously preparing prasugrel intermediate by countercurrent extraction

An intermediate and extraction technology, applied in the field of medicine, can solve the problems of inability to stir, difficulty, viscosity of the reaction liquid, etc., and achieve the effect of realizing continuous industrial production, simplifying the purification method and reducing the viscosity

Active Publication Date: 2020-04-03
南京恒道医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, because the hydrogen bromide that produces in this reaction can generate triethylamine hydrobromide with acid-binding agent triethylamine, its solubility in methylene chloride system is extremely low, separates out with solid form, thereby makes reaction solution relatively Viscous, often unable to stir after a large amount of precipitation, which has caused great difficulties for industrial scale-up production

Method used

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  • Method and device for continuously preparing prasugrel intermediate by countercurrent extraction
  • Method and device for continuously preparing prasugrel intermediate by countercurrent extraction
  • Method and device for continuously preparing prasugrel intermediate by countercurrent extraction

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Effect test

Embodiment 1

[0043] Embodiment 1: A kind of method and device thereof for the continuous preparation of prasugrel intermediate by countercurrent extraction, as attached figure 1 Shown:

[0044] S1. Pump compound I and compound II molar ratio of 1:1, compound I and triethylamine dichloromethane mixed solution of 1:8 molar ratio into reaction kettle 1 at a flow rate of 10L / h, and heat to 30°C , reaction 6h;

[0045] S2. Pump the feed liquid in the reaction kettle 1 into the top of the turntable tower 2 at a flow rate of 4L / h, and pump purified water from the bottom of the turntable tower 2 at a flow rate of 8L / h at the same time, and adjust the rotating speed of the turntable in the turntable tower 2 to 240rpm for countercurrent extraction;

[0046] S3. The raffinate water phase is discharged from the top of the rotary table tower 2, and the raffinate dichloromethane phase is discharged from the bottom of the rotary table tower 2, and sent to the evaporator 3 for concentration under reduce...

Embodiment 2

[0047] Embodiment 2: A kind of method and device thereof for continuously preparing prasugrel intermediate by countercurrent extraction, as attached figure 1 Shown:

[0048] S1. Compound and compound The molar ratio is 1:1.5, the compound The dichloromethane mixed solution with triethylamine molar ratio of 1:1 was pumped into Reactor 1 at a flow rate of 10L / h, heated to 40°C, and reacted for 8h;

[0049] S2. Pump the feed liquid in the reactor 1 into the top of the turntable tower 2 at a flow rate of 6L / h, and pump purified water from the bottom of the turntable tower 2 at a flow rate of 6L / h at the same time, and adjust the rotating speed of the turntable in the turntable tower 2 to 180rpm. countercurrent extraction

[0050] S3. The raffinate water phase is discharged from the top of the rotary table tower 2, and the raffinate dichloromethane phase is discharged from the bottom of the rotary table tower 2; The dichloromethane distillate obtained is discharged from the...

Embodiment 3

[0051] Embodiment 3: A kind of method and device thereof for the continuous preparation of prasugrel intermediate by countercurrent extraction, as attached figure 1 Shown:

[0052] S1. Compound and compounds The molar ratio is 1:2, the compound The mixed solution of dichloromethane and triethylamine with a molar ratio of 1:2.5 is pumped into the reaction kettle 1 at a flow rate of 10L / h, heated to 10°C, and reacted for 10h;

[0053] S2. Pump the feed liquid in the reactor 1 into the top of the turntable tower 2 at a flow rate of 8L / h, and pump purified water from the bottom of the turntable tower 2 at a flow rate of 2.67L / h at the same time, and adjust the rotation speed of the turntable in the turntable tower 2 to 120rpm Perform countercurrent extraction;

[0054] S3. The raffinate water phase is discharged from the top of the rotary table tower 2, and the raffinate dichloromethane phase is discharged from the bottom of the rotary table tower 2, and sent to the evapora...

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Abstract

The invention relates to the field of medicines, and particularly discloses a method for continuously and efficiently preparing prasugrel. The method comprises the steps: pumping a dichloromethane solution of a compound I, a compound II and triethylamine which are mixed according to a molar ratio into a reaction kettle, heating to a reaction temperature, and carrying out a reaction for a certain time; pumping a feed liquid in the reaction kettle into the top of a turntable tower at a certain flow rate, pumping purified water from the bottom of the turntable tower for countercurrent extraction,and adjusting the rotating speed of a turntable in the turntable tower to fully mix two phases; discharging the raffinate water phase from the tower top, and discharging the raffinate dichloromethanephase from the tower bottom; and concentrating the dichloromethane phase under reduced pressure, cooling, crystallizing and filtering to obtain the prasugrel intermediate. The triethylamine hydrobromide generated in the reaction process can be synchronously and effectively removed through the countercurrent extraction method, the problems of difficult stirring and the like caused by precipitationof triethylamine hydrobromide in a dichloromethane system are avoided, and the reaction conversion rate and the yield of the prasugrel intermediate are effectively improved through application of themethod.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a continuous production of prasugrel intermediate 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6 by countercurrent extraction, 7,7 a -Tetrahydrothieno[3,2- c ]-2(4 H )-pyridone method and device thereof. Background technique [0002] Prasugrel is an oral anti-platelet drug jointly developed by Eli Lilly and Japan's Daiichi Pharmaceutical Sankyo Co., Ltd. Its hydrochloride is clinically used. It was approved by the FDA in July 2009 and listed in the United States under the trade name Efient. Prasugrel is a prodrug whose pharmacological action is to inhibit platelet activation and aggregation through the irreversible binding of active metabolites to platelet adenosine diphosphate receptors. Clinically, it is mainly used to prevent atherosclerotic thrombosis events in patients with acute coronary syndrome who have received emergency treatment and who will undergo delayed percutaneou...

Claims

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Application Information

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IPC IPC(8): C07D495/04B01D3/00
CPCC07D495/04B01D3/009
Inventor 凌岫泉陶义华穆加兵
Owner 南京恒道医药科技股份有限公司
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