WO2021223425A1 - Procédé de raffinage de produit brut de dabigatran - Google Patents

Procédé de raffinage de produit brut de dabigatran Download PDF

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Publication number
WO2021223425A1
WO2021223425A1 PCT/CN2020/133012 CN2020133012W WO2021223425A1 WO 2021223425 A1 WO2021223425 A1 WO 2021223425A1 CN 2020133012 W CN2020133012 W CN 2020133012W WO 2021223425 A1 WO2021223425 A1 WO 2021223425A1
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WO
WIPO (PCT)
Prior art keywords
dabigatran etexilate
refining
dabigatran
crude
acetone
Prior art date
Application number
PCT/CN2020/133012
Other languages
English (en)
Chinese (zh)
Inventor
李恒农
赵鹏
万义斌
左飞鸿
葛友群
杨明
余承祥
孟周钧
姚文涛
柒伟超
Original Assignee
江西国药有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江西国药有限责任公司 filed Critical 江西国药有限责任公司
Publication of WO2021223425A1 publication Critical patent/WO2021223425A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine refining, and relates to a refining process of medicines, in particular to a refining process of crude dabigatran etexilate.
  • Dabigatran etexilate mesylate is a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany. Dabigatran etexilate mesylate was first marketed in Germany and the UK in April 2008 under the trade name Pradaxa. In October 2010, it was approved by the FDA to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate mesylate is the first new oral direct anticoagulant drug to be marketed in 50 years after warfarin. The launch of dabigatran etexilate mesylate is a major breakthrough in the field of anticoagulation therapy and the field of potentially fatal thrombosis prevention and is of milestone significance.
  • the total impurities of the existing dabigatran mesylate compounds generally require ⁇ 3.6%, which has higher requirements for product purity.
  • the current purification method of dabigatran etexilate mesylate is mainly to first refine the crude dabigatran etexilate, and then use the refined dabigatran etexilate to react with methanesulfonic acid to synthesize dabigatran etexilate mesylate.
  • the difficulty in refining crude dabigatran etexilate lies in the following points: 1. There are too many refining times, which is not conducive to industrial production; 2. The yield after multiple refining is too low 3. There are multiple stubborn impurities and the content of impurities in the refining process The reduction is very slow, and the purity of the product is not up to standard;
  • Patent No. WO2014/020546A2 uses hexanol, tert-butanol, and toluene as solvents to refine dabigatran etexilate and prepare the corresponding crystal form. Except for toluene, the refining rate is only 60% to 70%. After being qualified, there is almost no yield, and the impurity content in the refining process continues to increase; although the refining rate of toluene as a solvent can reach 85%, there is almost no refining effect, and the impurity content hardly decreases.
  • the purpose of the present invention is to provide a method for refining crude dabigatran etexilate, which improves product purity, improves refining rate, reduces refining times, reduces solvent usage, improves work efficiency, and is simple to operate and easy to realize industrialization .
  • the method for refining crude dabigatran etexilate provided by the present invention includes the following steps:
  • the volume of acetone added in step (1) is 10-15 times of the crude quality of dabigatran etexilate, and the volume of purified water added is 5-10 times of the crude quality of dabigatran etexilate.
  • the temperature for heating and dissolving in step (1) is 30-50°C
  • the temperature for stirring and crystallization is 15-30°C
  • step (2) the volume of ethyl acetate added in step (2) is 10-15 times the mass of the solid
  • the temperature for heating and dissolving in step (2) is 70-80°C
  • the temperature for stirring and crystallization is 15-25°C
  • the crude dabigatran etexilate was synthesized using the compounds 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionate ethyl and N-(4-cyanophenyl)amino Acetic acid is the starting material, CDI is used as a condensing agent, cyclized in acetic acid, and then the intermediate product is amidinated with hydrochloric acid ethanol and ammonia gas, and finally potassium carbonate is used as an acid binding agent to react with n-hexyl chloroformate to obtain the product.
  • Crude dabigatran etexilate HPLC purity 95%.
  • Acetone crystal 1 time 82.1% 97.216% 1.410% Acetone/water (1/1) crystallize once 90.4% 98.912% 0.215% Acetone/water (2/1) crystallize once 94.1% 98.938% 0.208% Acetone/water (3/1) crystallize once 91.7% 98.915% 0.245% Acetone/water (4/1) crystallize once 85.0% 98.907% 0.221%
  • Acetone/water recrystallization can effectively remove large-polar impurities, while ethyl acetate recrystallization can effectively remove small-polar impurities.
  • ethyl acetate recrystallization can effectively remove small-polar impurities.
  • due to the poor stability of the final product dabigatran etexilate mesylate in aqueous solvents it is required to control the water content of the subsequent salt-forming reaction system. Therefore, it is finally formulated to recrystallize with acetone/water (volume ratio greater than 1) and then use it.
  • the purification scheme of ethyl acetate recrystallization, this acetone/water dosage ratio and crystallization sequence facilitates the control of the moisture in the refined dabigatran etexilate.
  • the present invention uses acetone/water and ethyl acetate as solvents to refine the crude dabigatran etexilate, analyzes the different impurities in the crude dabigatran etexilate, and selects a suitable variety of solvents and a suitable amount of solvent to ensure The yield of the product is improved, and the purity of the product is guaranteed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte à un procédé de raffinage d'un produit brut de dabigatran. Le procédé consiste à raffiner un produit brut de dabigatran au moyen d'acétone/eau, puis à raffiner ce dernier à l'aide d'acétate d'éthyle pour obtenir du dabigatran raffiné. Le procédé présente un rendement élevé de raffinage de produit brut de dabigatran, une pureté de produit élevée et un petit nombre de raffinages, peut réduire la quantité de solvant utilisée et améliorer l'efficacité de travail, et est susceptible d'être industrialisé.
PCT/CN2020/133012 2020-05-08 2020-12-01 Procédé de raffinage de produit brut de dabigatran WO2021223425A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010379748.2A CN111393412A (zh) 2020-05-08 2020-05-08 一种达比加群酯粗品的精制方法
CN202010379748.2 2020-05-08

Publications (1)

Publication Number Publication Date
WO2021223425A1 true WO2021223425A1 (fr) 2021-11-11

Family

ID=71426210

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/133012 WO2021223425A1 (fr) 2020-05-08 2020-12-01 Procédé de raffinage de produit brut de dabigatran

Country Status (2)

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CN (1) CN111393412A (fr)
WO (1) WO2021223425A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111393412A (zh) * 2020-05-08 2020-07-10 江西国药有限责任公司 一种达比加群酯粗品的精制方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859686A (zh) * 2016-05-24 2016-08-17 浙江华海药业股份有限公司 一种高纯度达比加群酯的制备工艺
CN106349221A (zh) * 2016-08-29 2017-01-25 常州市阳光药业有限公司 高纯度达比加群酯的制备方法
CN108727334A (zh) * 2018-07-12 2018-11-02 江西国药有限责任公司 一种甲磺酸达比加群酯的生产工艺
CN111393412A (zh) * 2020-05-08 2020-07-10 江西国药有限责任公司 一种达比加群酯粗品的精制方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859686A (zh) * 2016-05-24 2016-08-17 浙江华海药业股份有限公司 一种高纯度达比加群酯的制备工艺
CN106349221A (zh) * 2016-08-29 2017-01-25 常州市阳光药业有限公司 高纯度达比加群酯的制备方法
CN108727334A (zh) * 2018-07-12 2018-11-02 江西国药有限责任公司 一种甲磺酸达比加群酯的生产工艺
CN111393412A (zh) * 2020-05-08 2020-07-10 江西国药有限责任公司 一种达比加群酯粗品的精制方法

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