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Bicyclic derivatives of glucoside and its preparation method and use

A technology of diols and compounds, applied in the field of medicine and chemical industry

Active Publication Date: 2020-06-30
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are mainly sulfonylureas, thiazolidinediones, metformin and insulin for the treatment of diabetes, but these drugs have their potential side effects

Method used

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  • Bicyclic derivatives of glucoside and its preparation method and use
  • Bicyclic derivatives of glucoside and its preparation method and use
  • Bicyclic derivatives of glucoside and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] The preparation of embodiment 1,5-bromo-2-chloro-4'-ethoxybenzophenone (Ⅴ-1)

[0177]

[0178] Add 5-bromo-2-chlorobenzoic acid (20.0g, 0.085mol) to 2.0M oxalyl chloride in dichloromethane solution (50ml, 0.1mol), stir to form a suspension, then add 8 drops of DMF solution dropwise, there are bubbles After 3 hours of reaction, the reaction is basically complete, and the solvent is spin-dried on a rotary evaporator, then 15ml of dichloromethane is added, and the solvent is spin-dried. After spin-drying, add 30ml of dichloromethane, stir, cool down to 0-5°C, add phenetole (10.9g, 0.089mol), add anhydrous aluminum chloride (12.5g, 0.093mol) in batches, control the temperature If the temperature is higher than 5°C, continue to stir at 4°C for 1 hour after the addition is complete. TLC monitors that the reaction is almost complete. Place the reactant on an ice-water mixture to quench the reaction, separate the organic phase, extract the aqueous phase with dichloromethane...

Embodiment 2

[0181] Preparation of embodiment 2, 5-bromo-2-chloro-4'-ethoxydiphenylmethane (Ⅲ-1)

[0182]

[0183] Add 5-bromo-2-chloro-4'-ethoxybenzophenone (V-1) (18.0 g, 0.053 mol) in 135 ml of acetonitrile / dichloromethane mixed solvent (volume ratio 2:1), Cool down to 5-10°C, add triethylsilane (18.6ml, 0.117mol), then add boron trifluoride diethyl ether (9.4ml, 0.074mol) dropwise, remove the ice bath after the dropwise addition, and let it rise to room temperature to react overnight . TLC monitors that the reaction is almost complete, adding saturated sodium bicarbonate solution to adjust the pH to neutral, extracting with ethyl acetate, washing the organic phase twice with saturated sodium chloride, and drying over anhydrous sodium sulfate. Filter with suction and spin dry the solvent to obtain an oily substance. 13.2 g (76.5%) of oil were obtained after column chromatography.

[0184] 1 H-NMR (400MHz, CDCl 3 , ppm- 1 )δ: 7.23(m,3H), 7.08(m,2H), 6.83(m,2H), 4.01(q,2H), 3.9...

Embodiment 3

[0185] Example 3, methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-α-D-glucopyranoside (Ⅱ-1) Preparation

[0186]

[0187] Under nitrogen protection, add 5-bromo-2-chloro-4'-ethoxydiphenylmethane (Ⅲ-1) (12.5, 0.038mol), 40ml dry tetrahydrofuran and 80ml toluene into a 250ml three-necked flask (numbered bottle A) (dry with calcium chloride), cool down to -72°C with dry ice acetone under stirring, add 2.5M n-BuLi n-hexane solution (18.4ml, 0.046mol) dropwise, make sure the temperature is not higher than -60°C, and stir for 30min. Prepare another 500ml three-necked bottle (number B), nitrogen protection, add 2,3,4,6-tetra-O-trimethylsilyl-β-D-gluconolactone (19.7g, 0.042mol) and 110ml of toluene (dried over calcium chloride), cooled to -72°C with dry ice acetone. When the reaction time in bottle A is up, introduce the solution in bottle A into bottle B, continue the reaction at low temperature for 2 hours, add methanesulfonic acid (14.8g, 0.154mol) and 110ml methano...

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PUM

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Abstract

The invention relates to a dicyclic derivative of glucoside as well as a preparation method and the application of the dicyclic derivative. Specifically, the invention relates to a compound as shown in Formula I, a stereisomer or pharmaceutically acceptable salt or ester of the compound, a pharmaceutical composition of the compound, and application of the compound in preparation of drugs for treating diabetes or relevant diseases.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular, the invention relates to a bicyclic derivative of glucoside, a preparation method and application thereof. Background technique [0002] Diabetes mellitus is a metabolic disease characterized by hyperglycemia. Hyperglycemia is caused by defects in insulin secretion, or impairment of its biological effects, or both. Most of them are type Ⅱ diabetes patients. Long-term hyperglycemia is very harmful to the patient's body and can cause various complications. At present, there are mainly sulfonylureas, thiazolidinediones, metformin and insulin for the treatment of diabetes, but these drugs all have their potential side effects. The clinical application of SGLT2 inhibitors has opened up another treatment mode and provided a new option for diabetic patients to overcome hyperglycemia. [0003] SGLT2 is the major Na in the epithelial cells of the S1 segment of the proximal tu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H9/06A61K31/7056A61P3/10A61P13/12A61P9/10A61P9/00A61P25/00
CPCC07H9/06
Inventor 翟建国何阳朱英杰周宜遂马红敏宋萌
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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