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Preparation method and application of empagliflozin impurity

A technology for empagliflozin and impurities, applied in the field of preparation of empagliflozin impurities, can solve the problems such as no preparation method reported in the literature

Pending Publication Date: 2022-03-11
江西天戌药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the synthetic route of empagliflozin, the operation of acetyl group protection is required, and it is easy to introduce the empagliflozin impurity shown in formula I, but there is no literature reporting its preparation method at present

Method used

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  • Preparation method and application of empagliflozin impurity
  • Preparation method and application of empagliflozin impurity
  • Preparation method and application of empagliflozin impurity

Examples

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preparation example Construction

[0029] The present invention provides a kind of preparation method of empagliflozin impurity as shown in formula I, comprises the following steps:

[0030] S1. Dissolve empagliflozin in an organic solvent (including acetonitrile, pyridine) to obtain a mixed solution, cool to -25°C-25°C, wherein the molar ratio of empagliflozin to pyridine is 1:(0.5-2) ;

[0031] S2. Add acetic anhydride dropwise to the mixed solution, wherein the molar ratio of empagliflozin and acetic anhydride is 1:(0.5-2), and the heat preservation reaction is 0.5h-48. After post-treatment, first concentrate under reduced pressure, and then Dissolved with ethyl acetate, washed with water at least twice, and then purified by silica gel column chromatography after vacuum distillation of the obtained organic phase, wherein the silica gel was selected from 200 to 300 mesh, and the eluent was V (dichloromethane / methanol) = 20 / 1 mixed solvent; thereby obtaining Empagliflozin impurities.

[0032] The reaction f...

Embodiment 1

[0037] The present embodiment provides a kind of preparation method of empagliflozin impurity, concrete steps are as follows:

[0038] S1. Dissolve 2.7g of Empagliflozin (6.0mmol) in 50mL of acetonitrile and 0.50g of pyridine (6.3mmol) to obtain a mixed solution, and cool to 0°C in an ice-water bath;

[0039] S2. Add 0.65 g of acetic anhydride (6.4 mmol) dropwise to the above mixed solution, keep the temperature for 3 hours, and after distillation under reduced pressure, dissolve the residue with 50 mL of ethyl acetate, wash twice with water, and obtain the organic phase after distillation under reduced pressure , and then purified by silica gel column chromatography, the silica gel is selected from 200 to 300 meshes, the eluent: DCM / MeOH=20 / 1, and then through rotary evaporation, to obtain the empagliflozin impurity shown in formula I, white solid 1.82g , yield 61.6%, HPLC purity 97.18%. 1 H NMR(400MHz,Chloroform-d)δ7.36(d,J=8.0Hz,1H), 7.23-7.14(m,2H),7.13-7.05(m,2H),6.80-6....

Embodiment 2

[0043] This embodiment provides a preparation method of empagliflozin impurities, the specific steps are basically the same as in Example 1, the difference is that the pyridine added in the S1 step is 0.237g (3mmol), and the finally obtained white solid is 0.65 g, the yield is 22%; wherein, the molar ratio of empagliflozin to pyridine is 1:0.5.

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Abstract

The invention provides a preparation method of an empagliflozin impurity as shown in a formula I. The preparation method comprises the following steps: S1, dissolving empagliflozin in an organic solvent to obtain a mixed solution, and cooling to-25 DEG C to 25 DEG C; and S2, dropwise adding acetic anhydride into the mixed solution, carrying out heat preservation reaction, and carrying out post-treatment to obtain the empagliflozin impurity, the empagliflozin impurity as shown in the formula I is prepared through a simple method and serves as a standard substance, the impurity existing in an empagliflozin medicine can be effectively analyzed, and then a guarantee is provided for quality control of empagliflozin.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing an impurity of empagliflozin and the use of the impurity as a reference standard for quality control of empagliflozin. Background technique [0002] Empagliflozin, Chinese chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[(3S)-tetrahydro-3-furyl]oxy]phenyl] Methyl]phenyl]-D-glucitol (as shown in formula A), jointly developed by Eli Lilly and Company of the United States and Boehringer Ingelheim Pharmaceutical Company of Germany, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are a new type of hypoglycemic drugs, mainly by inhibiting the expression of SGLT-2 in the kidney, reducing the reabsorption of glucose in the kidney, increasing the excretion of glucose in the urine, thereby reducing the plasma glucose level. And the hypoglycemic effect is independent of β-cell function and insulin resistance. The European Commission approv...

Claims

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Application Information

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IPC IPC(8): C07D407/10G01N30/02
CPCC07D407/10G01N30/02
Inventor 倪润炎李俊永师梦凡曹标俞蒋辉柏加康郑雷鸣林振铭
Owner 江西天戌药业有限公司
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