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A method for preparing empagliflozin

A technology of empagliflozin and Grignard reagents, which is applied in the field of preparing empagliflozin compounds, can solve the problems of easy isomerization of products, many operation steps, and low reaction temperature, and achieve the reduction of product impurity content and high product purity , the effect of high yield

Active Publication Date: 2018-01-09
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the temperature at which key intermediates react with sugar is still very low, resulting in low yields and difficult industrial control
[0007] At present, the process of synthesizing empagliflozin has many steps, the reaction temperature is low, it is difficult to control, and the yield is relatively low. It adopts Grignard reagent for coupling reaction, and the product is easy to isomerize

Method used

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  • A method for preparing empagliflozin
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Experimental program
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Effect test

Embodiment 1

[0034] Under nitrogen protection, dry THF (120 mL) was added to a 500 mL three-necked flask, cooled to -10 ° C, and a THF solution of i-PrMgCl LiCl (27.2 mL, 27.2 mmol) and n-BuLi in n-hexane ( 21.8mL, 54.4mmol), stirred for 30min. (S)-4-Bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (10.0 g, 27.2 mmol) was dissolved in dry THF (10 mL) and slowly added dropwise to In a three-necked flask, the reaction was stirred at -10°C for 2.0 h. Keeping at -10°C, a THF (10 mL) solution of 2,3,4,6-tetraacetoxy-α-D-glucopyranose bromide (11.2 g, 27.2 mmol) was slowly added dropwise, and reacted for 3.0 h. After the reaction was completed, a solution of 6N HCl (20 mL) in methanol (100 mL) was added, the temperature was raised to 25 ° C, stirred for 20.0 h, and saturated NaHCO 3 The pH of the solution was adjusted to 7, extracted twice with EA (100mL), the organic phase was washed with water (100mL) and saturated NaCl solution (100mL) successively, and anhydrous NaCl was added 2...

Embodiment 2

[0037] Under nitrogen protection, add dry THF (40 mL) and 40 mL of toluene to a 500 mL three-necked flask, cool to -10 °C, add n-BuMgCl in THF (12.1 mL, 12.1 mmol) and n-BuLi in n-hexane (9.7mL, 24.2mL), stirred for 20min. Dissolve (S)-4-iodo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (5.0 g, 12.1 mmol) in dry toluene (20 mL) and slowly add dropwise to In the reaction liquid, react at -10°C for 1.0 h. Keeping at -10°C, a solution of 2,3,4,6-tetraacetoxy-α-D-glucopyranose bromide (5.0 g, 12.1 mmol) in toluene (20 mL) was slowly added dropwise and reacted for 2.0 h. After the reaction was complete, a solution of methanesulfonic acid (5.6 mL) in methanol (50 mL) was added, and the temperature was slowly raised to 25° C., stirred for 16.0 h, and saturated NaHCO 3 The pH of the solution was adjusted to 7, extracted twice with EA (100mL), the organic phase was washed with water (100mL) and saturated NaCl solution (100mL) successively, washed with anhydrous NaCl 2 SO 4 ...

Embodiment 3

[0040] Under nitrogen protection, add dry THF (40mL) and toluene (40mL) into a 500mL three-necked flask, cool to -10°C, add a THF solution of n-BuMgCl LiCl (27.2mL, 27.2mmol) and n-BuLi n-hexane solution (21.8mL, 54.4mL), stirred for 10min. Dissolve (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (10.0 g, 27.2 mmol) in dry toluene (20 mL) and add dropwise to the reaction solution, reacted at -10°C for 1.0h. Then a solution of 2,3,4,6-tetraacetoxy-α-D-glucopyranose bromide (11.2 g, 27.2 mmol) in toluene (20 mL) was slowly added dropwise, and the reaction was maintained at -10°C for 3.0 h. After the reaction was completed, a solution of methanesulfonic acid (5.2 mL) in methanol (80 mL) was added, and the temperature was slowly raised to 30° C., stirred for 20 h, washed with saturated NaHCO 3 The pH of the solution was adjusted to neutral, extracted twice with EA (100mL), the organic phase was washed with water (100mL) and saturated NaCl solution (100mL) succes...

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Abstract

A method for preparing empagliflozin is provided. The method includes steps of preparing a composite organometallic reagent to promote condensation of (S)-4-halogen-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl) benzene and halogenated glucose, and then removing a protecting group to obtain a product, wherein the organometallic reagent is a product by mixing a Grignard reagent or a lithium chloridepromoted Grignard reagent with a lithium reagent. The organometallic reagent can allow the temperature of a coupling reaction to be increased from -78 DEG C to -10 DEG C, thus improving process reaction conditions, making operation simple and convenient, reducing byproducts and reducing the production cost. The method reduces process steps, avoids reactions at excessively low temperatures, increases the total yield and has an industrial application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new method for preparing empagliflozin compounds. Background technique [0002] Empagliflozin, English name: Empagliflozin, is a type 2 sodium glucose cotransporter (SGLT2, sodium-dependent glucose cotransporter2) inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly for the treatment of type II Diabetes, indicated for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The product is also the first hypoglycemic drug to reduce the risk of cardiovascular disease, heart attack and stroke. [0003] Documents US20050209166 and US20100099641 etc. take 5-bromo-2-chlorobenzoic acid as raw material, through acid chlorination, Friedel-Crafts (Friedel-Crafts) acylation reaction, reduction, hydrolysis with anisole, the phenolic hydroxyl product obtained, and then use tert-butyldimethylsilyl chloride protection, und...

Claims

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Application Information

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IPC IPC(8): C07D407/12
CPCY02P20/55
Inventor 石克金陈林李江红苟小军任凤英杨晨
Owner CHENGDU UNIV
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