Method for preparing high purity Empagliflozin

An empagliflozin and high-purity technology, which is applied in the field of high-purity empagliflozin preparation, can solve the problems that stubborn impurities cannot be effectively removed, qualified raw materials cannot be achieved, and product purity is low, so as to avoid damage to anhydrous anhydrous Oxygen environment, reduce the number of feeding and detection times, overcome the effect of cumbersome operation

Inactive Publication Date: 2017-09-15
YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] But in actual repeated experiment, the inventor finds that this method is loaded down with trivial details, and the resulting product purity is low (HPLC purity is about 80%), and with conventional purification method (recrystallization, beating etc.), repeated purification still can not reach qualified raw material drug standards, and there are unknown stubborn impurities that cannot be effectively removed

Method used

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  • Method for preparing high purity Empagliflozin
  • Method for preparing high purity Empagliflozin
  • Method for preparing high purity Empagliflozin

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1 (2S,3R,4S,5R,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-3, Synthesis of 4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-ol(3)

[0030] Under nitrogen protection, anhydrous tetrahydrofuran (2.0L), compound 1 (1.0kg, 2.4116mol) and compound 2 (1.46kg, 3.1350mol) were added to a 10L glass reaction kettle, stirred and cooled to -30 ℃~-20 ℃, add iPrMgCl / LiCl (2.4L) dropwise to the reaction kettle, control the temperature -30 ℃~-20 ℃, after the reaction HPLC monitoring is completed, the configured 5% citric acid aqueous solution is added dropwise into the reaction kettle, and the addition is finished. After stirring for 30 min, let stand for 30 min, separate the liquid, and collect the organic phase. The organic phase was concentrated under reduced pressure until no condensation dripped out, and the concentrate was collected. After concentration, 2.2 L of n-heptane was added to make a slurry at room tempera...

Embodiment 2

[0031] Example 2 (2S,3R,4S,5R,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-3, Synthesis of 4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-ol(3)

[0032] Under nitrogen protection, anhydrous tetrahydrofuran (2.0L), compound 1 (1.0kg, 2.4116mol) and compound 2 (1.46kg, 3.1350mol) were added to a 10L glass reaction kettle, stirred and cooled to -30 ℃~-20 ℃, add iPrMgCl / LiCl (2.4L) dropwise to the reactor, control the temperature -30 ℃~-20 ℃, after the reaction HPLC monitoring is completed, the configured 10% citric acid aqueous solution is added dropwise to the reactor, and the addition is completed. After stirring for 30 min, let stand for 30 min, separate the liquid, and collect the organic phase. The organic phase was concentrated under reduced pressure, concentrated until no condensation dripped out, and the concentrate was collected. After concentration, 5L of a mixed solvent of n-heptane and methanol (volume ratio 2...

Embodiment 3

[0033] Example 3 1-C-[4-Chloro-3-[[4-[[(3S)-tetrahydro-3-furyl]oxy]phenyl]methyl]phenyl]-D-glucopyranose glycosides (4)

[0034]Add 1.0 kg of (3) prepared in Example 1 or 2 into the reaction kettle, add 2.1 L of methanol, dropwise add concentrated hydrochloric acid, stir to dissolve, and react at room temperature for 4 hours; after the reaction is completed, adjust the pH to Neutral, extract twice with ethyl acetate, combine the organic phases; remove the organic phase by rotary evaporation (40°C ± 5°C), rotate until there is no condensation droplets drop, and obtain a yellow oily liquid with HPLC purity 92.0%. (Agilent liquid phase Chromatography, column with octadecylsilane-bonded silica gel as filler, gradient elution with trifluoroacetic acid aqueous solution / acetonitrile as mobile phase)

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Abstract

The present invention provides an improved method for preparing high purity Empagliflozin, the method includes the following steps: step a. under the protection of nitrogen, performing reaction of compounds 1 and 2 to obtain a compound 3; step b. adding the compound 3 into a reactor, adding methanol, dropwise adding concentrated hydrochloric acid, stirring, dissolving, clarifying, and performing reaction at room temperatur to obtain a compound 4; step c. adding dropwise an acetonitrile and dichloromethane solution of the compound 4 to an aluminium chloride, triethyl silicane, acetonitrile and dichloromethane solution for reaction, after completion of the reaction, adding water for quenching the reaction, stirring until a solid is precipitated, filtering by suction, and collecting a filter cake to obtain a crude product of compound 5, namely Empagliflozin; and d. refining the crude product. The method is suitable for industrial production,and can be used for the preparation of the high purity Empagliflozin.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparation, and in particular relates to a method for preparing high-purity empagliflozin. By using the method to prepare empagliflozin, the obtained product has high purity and easy control of impurities. Background technique [0002] On August 1, 2014, the Boehringer Ingelheim-Lilly Diabetes Alliance jointly announced that the new diabetes drug Jardiance (Empagliflozin, Chinese name empagliflozin) was approved by the FDA for the treatment of adult patients with type 2 diabetes in combination with diet and exercise. Improve blood sugar control. [0003] Epagliflozin purification chemical structural formula: [0004] [0005] In Chinese patent CN102574829A, a preparation method of empagliflozin is described. The method is to add isopropylmagnesium chloride / lithium chloride solution to the iodide (compound 1) at -21 to -15°C within a certain period of time. In the tetrahydrofuran solut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12
CPCC07D407/12
Inventor 王晓波陈东韩硕王建耀袁峰泉刘文东
Owner YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA
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