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Compound and preparation method and application thereof

A compound, the technology of boron trifluoride ether, is applied in the field of preparation of the impurities of Liejing drugs, and achieves the effects of single structure, few by-products, and avoiding post-processing difficulties.

Inactive Publication Date: 2017-01-04
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the method for listing net drug impurities shown in the compound of formula I still needs to be improved

Method used

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  • Compound and preparation method and application thereof
  • Compound and preparation method and application thereof
  • Compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Compound shown in embodiment 1 synthetic formula 2

[0057] The steps of the compound shown in the synthetic formula 2 are as follows:

[0058] 1. Add a few drops of concentrated sulfuric acid dropwise to a methanol solution in which the compound 3,5,6-tribenzyl-D-glucofuranose (50g, 110mmol) is dissolved, stir and heat to 50 to 55°C for 2 hours, and monitor the raw material by TLC The response is complete.

[0059] 2. Concentrate the solvent under reduced pressure to remove water, and dissolve the residue in 300ml ethyl acetate

[0060] 3. Add 100ml of water to the product in step 2, and adjust the pH value to close to 8 with solid sodium bicarbonate.

[0061] 4. The product in step 3 was separated, washed with water and brine respectively, dried over anhydrous sodium sulfate, and concentrated to obtain about 51 g (109.8 mmol) of a colorless oil, which could be directly used in the next reaction.

Embodiment 2

[0062] Compound shown in embodiment 2 synthetic formula 3

[0063] The steps of the compound shown in the synthetic formula 3 are as follows:

[0064] 1. Weigh 34 g (about 73 mmol) of the oil obtained in Example 1, and dissolve it in N,N-dimethylformamide (340 ml).

[0065] 2. Cool the solution obtained in step 1 to 0-5° C. with an ice-water bath, and add 60% sodium hydride (3.07 g, 77 mmol, 1.05 equivalents) in batches.

[0066] 3. Stir at 0-5°C for 30 minutes. A N,N-dimethylformamide solution containing benzyl bromide (12.5g, 74.5mmol) was slowly added dropwise, and the internal temperature was controlled at 0-5°C during the dropwise addition.

[0067] 4. React the solution obtained in step 3 at room temperature for 2 hours.

[0068] 5. The reaction solution obtained in step 4 was poured into water, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 35 g (63.1 mmol) of a light yello...

Embodiment 3

[0069] Compound shown in embodiment 3 synthetic formula 4

[0070] The steps of the compound shown in the synthetic formula 4 are as follows:

[0071] 1. Weigh 21 g (about 37.9 mmol) of the oil obtained in Example 2, dissolve it in dioxane, and add 2N hydrochloric acid aqueous solution under stirring.

[0072] 2. Stir the solution obtained in step 1, and raise the temperature to 70-80° C. to react for 16 hours, and monitor the reaction to the end by thin-layer chromatography.

[0073] 3. Pour the reaction solution into water, and adjust the pH value to close to 8 with solid sodium bicarbonate.

[0074] 4. Extract the solution obtained in step 3 with ethyl acetate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a light yellow oil, which is the crude product of the compound shown in formula 4.

[0075] 5. The crude product obtained by the above treatment was purified by column chromatography to obtain 14 g of a colorles...

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Abstract

The invention provides a compound shown in the formula I and a preparation method thereof and a method for detecting Gliflozin medicine through high performance liquid chromatography. According to the preparation method, 3,5,6-tribenzyl-D-glucofuranose serves as a raw material, a methylation reaction, a benzyl substitution reaction, demethylating and ketalation are carried out, 3,5,6-tribenzyl-D-glucofuranose and a halide intermediate are subjected to a nucleophilic addition, the material makes contact with triethyl silicane and boron trifluoride diethyl etherate, finally, the material makes contact with ethanethiol and boron trifluoride diethyl etherate, and the target impurity product can be obtained. By means of the method, directional preparation is achieved for synthesis of the target product; the target product provides a reliable impurity reference substance for quality research and impurity quantitative control of industrially-produced Gliflozin series diabetes treatment medicine products. The formula I is shown in the specification.

Description

technical field [0001] The present invention relates to the field of chemical synthesis, in particular, the present invention relates to a preparation method and application of a net drug impurity. Background technique [0002] Canagliflozin, Dapagliflozin, and Empagliflozin are currently a class of drugs clinically used for diabetes treatment and belong to SGLT-2 inhibitors. SGLT-2 is a new target for diabetes treatment. It has a different mechanism of action from traditional diabetes treatment drugs. It can excrete excess glucose from the urine, thereby reducing glycosylated proteins and improving insulin sensitivity in the liver and peripheral tissues. Improve β-cell function, and at the same time further improve hepatic insulin resistance, thereby promoting the return of higher glycogen output to normal. [0003] A major impurity of Canagliflozin, Dapagliflozin and Empagliflozin is a five-membered ring furanose impurity (compound shown in formula I). [0004] [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20C07D409/10
CPCC07D307/20C07D409/10
Inventor 徐助雄喻耀孙梦颖崔健钱丽娜
Owner WATERSTONE PHARMA WUHAN
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