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Empagliflozin preparation method

A technology for raw materials and compounds, applied in the field of preparation of empagliflozin, can solve problems such as unfavorable environmental protection, complicated operation, etc., and achieve the effects of being beneficial to environmental protection, good in purity and yield, and reducing the generation of waste water

Inactive Publication Date: 2019-03-12
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method will generate a large amount of acidic wastewater during the quenching and separating process, which is not conducive to environmental protection, and the subsequent steps must be separated, and the operation is relatively cumbersome.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: Preparation of Compound II

[0027] Compound IV obtained in Test Example 1 was lowered to -25°C, and compound III (prepared according to Test Example 2) was slowly added dropwise. After the drop was complete, the temperature was raised to -5°C, and stirring was continued at this temperature for 1 hour. After the reaction was completed, 22 Kg of methanol was added dropwise, stirred for 0.5 hours, 17 Kg of cation exchange resin (Dowex50WX8-400-H+) was added, the temperature was raised to 25°C, the reaction was stirred for 12 hours and filtered, and the filtrate was concentrated under reduced pressure to obtain light yellow viscous The thick oil was directly used in the next reaction without purification.

Embodiment 2

[0028] Embodiment 2: the preparation of compound I

[0029] Add 205 Kg of anhydrous acetonitrile, 36 Kg of anhydrous AlCl3, and 45 Kg of triethylsilane into the reaction kettle and cool down to -10°C with stirring. The oil obtained in Example 1 was dissolved in 140 Kg of dichloromethane, and was dropped into the above mixture. After the drop was completed, the temperature was raised to 20° C., and the reaction was kept for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, 230 Kg of water (temperature control ≤ 10°C) was slowly added to the reaction liquid, concentrated under reduced pressure, 275 Kg of isopropyl acetate was added, and concentrated under reduced pressure. Add 275 Kg of isopropyl acetate to the above concentrate, raise the temperature to 45°C, and keep stirring for 0.5 hours. The temperature was slowly lowered to 10° C. within 3 hours, and stirring was continued for 4 hours. After filtering, the filter cake was rinsed with a small a...

Embodiment 3

[0030] Embodiment 3: Preparation of Compound II

[0031] Compound IV obtained in Test Example 1 was lowered to -20°C, and compound III (prepared according to Test Example 2) was slowly added dropwise. After the drop was complete, the temperature was raised to -5°C, and stirring was continued at this temperature for 1 hour. After the completion of the reaction, add methanol 218Kg dropwise, stir for 0.5 hour, add cation exchange resin (Dowex50WX8-400-H + ) 6.5 Kg, heated up to 60°C, and reacted for 0.5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a light yellow viscous oil, which was directly used in the next reaction without purification.

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PUM

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Abstract

The invention relates to an empagliflozin preparation method, and belongs to the technical field of bulk pharmaceutical chemical preparation. The method includes the steps: firstly, performing reaction on Grignard reagents prepared from 2, 3, 4, 6-tetra-O-(trimethylsilyl)-D-grape pyranone and (S)-3-[4-(5-iodine-2-chloro-benzyl)-phenoxy]-tetrahydrofuran; secondly, adding methyl alcohol and acidiccation exchange resin to transform into a formula II; reducing the formula II to obtain a compound I. According to the preparation method, wastewater in process is decreased, environmental protectionis facilitated, operations are simple and convenient, operations are easy in industrial production, and the yield and the purity of a product are greatly improved.

Description

technical field [0001] The invention relates to a preparation method of empagliflozin, which belongs to the technical field of raw material medicine preparation. Background technique [0002] Empagliflozin, also known as Epagliflozin, Epagliflozin, and Empagliflozin, was first launched in Europe in May 2014, and later in the United States and Japan in August and December 2014, respectively. And it went public in China in September 2017. 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. It is a new type of oral hypoglycemic drug. [0003] Patent WO 2006 / 120208 (CN103524468A) discloses a preparation method of Empagliflozin, referring to Example XVIII scheme E, the specific process is as follows: (S)-3-[4-(5-iodo-2 -chloro-benzyl)-phenoxy]-tetrahydrofuran and i -PrMgCl / LiCl conducts halogen-metal exchange in THF, then adds 2,3,4,6-tetra-O-(trimethylsilyl)-D-glup...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12
CPCC07D407/12
Inventor 潘昭喜苗华明蔡亚辉郝宪宵张明明寇磊
Owner 迪嘉药业集团股份有限公司
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