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Preparation and refining method of high-purity empagliflozin

A purification method and technology for empagliflozin, which are applied in the field of preparation and purification of high-purity empagliflozin, can solve the problems of increasing production costs, harsh use conditions, and many times of purification and purification, saving production costs and being beneficial to The effect of industrial production

Active Publication Date: 2020-01-07
BEIJING LUNARSUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] It has been reported in the literature that there are mainly four reaction routes to prepare Empagliflozin in the prior art. However, we have found in actual research that these methods have their own defects. Some crude products have low purity and high total impurity content, resulting in many times of purification Thereby yield is low; Some have used tert-butyllithium (t-BuLi) or n-butyllithium (n-BuLi) in the middle of reaction, and this material use condition is harsh, has danger extremely again, and product yield is also relatively high. Low; some methods have lengthy reaction steps and low yields, resulting in high production costs and no market advantage
The following method (hereinafter referred to as method 4) has few reaction steps, does not use special chemicals, and has mild conditions, which is beneficial to industrial production, but the purity of the crude product obtained by this method is low, and the high total impurity content leads to many refining and purification times, resulting in a large yield. reduce, thereby greatly increasing production costs

Method used

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  • Preparation and refining method of high-purity empagliflozin
  • Preparation and refining method of high-purity empagliflozin
  • Preparation and refining method of high-purity empagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the preparation of crude product

[0069] Add SM1 (2000g) and THF (3575ml) to a dry 20L four-necked bottle under nitrogen protection, install a tail gas absorption device, stir and dissolve completely at 20-25°C, cool the inner temperature to -16°C, and add (1.3N) dropwise Isopropylmagnesium chloride-lithium chloride THF solution 4410ml, control the internal temperature at -14±2°C during the dropwise addition, drop it in 1.5 hours, continue to stir and react for 0.5 hours, add 2251.5g SM2 dropwise between the temperature control -14±2°C, After 50 minutes of dropwise addition, continue to keep warm for 1 hour, and TLC detects that the reaction is basically complete (developing solvent: petroleum ether / ethyl acetate=3 / 1).

[0070] Control the internal temperature below 5°C and add 6,000ml of 10% citric acid aqueous solution dropwise. After 20 minutes, the dropwise addition is completed, and continue to stir for 5 minutes. Separate the upper organic phase, ex...

Embodiment 2

[0076] Embodiment 2: the refinement of embodiment 1 crude product

[0077] Refining: Add 200 g of the crude product into a 2 L single-necked bottle, add 400 mL of ethanol, and 800 mL of (1N) NaOH aqueous solution. Heat to reflux to dissolve the clear. Add 10 g of activated carbon, stir for 1 hour, and filter with suction. Heat (ethanol: water = 1:2) to wash the filter cake. The filtrate was heated to reflux and added to 6.4 L of (1N) NaOH aqueous solution at 80°C. After the dropwise addition was completed, the mixture was stirred at 15-20° C. for 16 hours. Suction filtration, the solid was washed with purified water and suction filtration until neutral. The wet product was air-dried at 50° C. for 15 hours to obtain 192.5 g of dry product. Yield: 96.25%. HPLC: 99.97%. (See Figure 4 )

Embodiment 3

[0078] Example 3: Comparison of the solvent effects of the crystallization of the crude product of Empagliflozin

[0079] Using the oil of Example 1 as a raw material to study the solvent effect of crystallization of the crude product, the oil: impurity 1: 5.038%, impurity 2: 2.375%, and total other impurities: 16.242%.

[0080] In this example, the system numbered 6 is Example 1.

[0081] Solvent system No. 1-5: Add the mixed solvent or solvent in the stated proportion to the oil at room temperature at one time, then stir at 10-15°C for 15 hours, and filter with suction to obtain the crude product.

[0082] Table 1: Comparison of impurities and purity after crystallization of crude products in different solvents:

[0083]

[0084] As can be seen from Table 1, the present invention selects different crude product crystallization solvents, oily matter: dichloromethane: 1N NaOH aqueous solution is 1:3:3 in dosage ratio, and temperature crystallizes under the condition of 10 ...

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Abstract

The invention relates to a crystallization method of a high-purity empagliflozin crude product and a further refining method of the crude product. The refining method is capable of increasing the purity of the crude product with ensured crude product yield, so that the refining and purifying times are obviously reduced; the refining method is further optimized, the refining purity and yield are improved, and high-purity empagliflozin is obtained. The method provided by the invention can reduce the production cost and is more suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing and refining high-purity empagliflozin. Background technique [0002] Empagliflozin (1), the chemical name is (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furan Base] oxy] phenyl] methyl] phenyl] -D-glucitol, molecular formula: C 23 h 27 ClO 7 , molecular weight: 450.91, CAS registration number: 864070-44-0. The drug is a sodium glucose cotransporter 2 (SGLT-2) inhibitor jointly developed by Boehringer Ingelheim of Germany and Eli Lilly and Company of the United States. Empagliflozin is a new type of oral hypoglycemic agent, which effectively lowers blood sugar and improves insulin sensitivity (IS) and islet β-cell function through a mechanism independent of insulin secretion and insulin action. [0003] It has been reported in the literature that there are mainly four reaction routes to prepare Empagliflozin in the prior...

Claims

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Application Information

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IPC IPC(8): C07D407/12
CPCC07D407/12
Inventor 崔东冬刘保全张玉良
Owner BEIJING LUNARSUN PHARMA
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