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Bicyclic derivative of heterocyclic glucoside as well as preparation method and application of bicyclic derivative

A technology of heterocyclic groups and compounds, applied in the field of bicyclic derivatives of heterocyclic glucosides and their preparation

Active Publication Date: 2021-07-20
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 derivative of heterocyclic glucoside as well as preparation method and application of bicyclic derivative
  • Bicyclic derivative of heterocyclic glucoside as well as preparation method and application of bicyclic derivative
  • Bicyclic derivative of heterocyclic glucoside as well as preparation method and application of bicyclic derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Embodiment 1, the preparation of benzo [b] thiophene (5-bromo-2-chlorophenyl) methanol (Ⅴ-1)

[0196]

[0197] Dissolve benzothiophene (6.1g, 45.57mmol) in anhydrous tetrahydrofuran (50ml), under nitrogen protection, cool to -70°C with dry ice-acetone, slowly add 2.5M n-BuLi n-hexane solution (20ml, 50mmol) dropwise , so that the temperature is not higher than -60 ° C, and the drop is completed for 30 minutes, which is recorded as bottle A; 5-bromo-2-chlorobenzaldehyde (10.0g, 45.57mmol) is dissolved in anhydrous tetrahydrofuran (125ml), nitrogen protection, Cool down to -70°C and record as bottle B; transfer the solution in bottle A to bottle B and react for 4 hours. TLC monitoring showed that the reaction was complete. The low temperature bath was removed, and 30ml of purified water was added to quench. The tetrahydrofuran was removed by rotary evaporation, extracted with 3×100ml ethyl acetate, the organic phase was washed with 100ml saturated sodium chloride so...

Embodiment 2

[0200] Preparation of Example 2, 2-(5-bromo-2-chlorobenzyl)benzo[b]thiophene (Ⅲ-1)

[0201]

[0202] 6.0g (16.97mmol) of benzo[b]thiophene (5-bromo-2-chlorophenyl)methanol (V-1 (13.5ml, 84.85mmol) was slowly added dropwise with boron trifluoride ether (5.0ml, 40.73 mmol), so that the internal temperature is not higher than 10 ° C. Add, remove the ice bath, react for 4h. TLC detection, the reaction is complete. Add 2M potassium hydroxide solution to quench the reaction, stir. Extract with 3 × 20ml dichloromethane, organic The phases were washed successively with 3×25ml 2M potassium hydroxide solution, 3×40ml saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off and evaporated, and the residue was separated by silica gel column chromatography to obtain a white solid 3.8 g, yield 66.3%.

[0203] 1 H-NMR(400MHz,DMSO-d6,ppm)δ:7.87(1H,d),7.73-7.77(2H,m),7.53(1H,d),7.44(1H,d),7.27-7.35(2H, m),7.18(1H,m),4.36(1H,s);

[020...

Embodiment 3

[0205] Example 3, (3R, 4S, 5S, 6R)-2-(3-(benzo[b]thiophene-2-yl-methyl)-4-chlorophenyl)-6-(hydroxymethyl Preparation of -2-methoxy-5,6,7,7a-tetrahydro-2H-pyran-3,4,5-triol (Ⅱ-1)

[0206]

[0207] Dissolve 3.8g (11mmol) of 2-(5-bromo-2-chlorobenzyl)benzo[b]thiophene (Ⅲ-1) in anhydrous toluene (60ml), under nitrogen protection, add anhydrous tetrahydrofuran (20ml), Cool down to -70°C, slowly add 2.5M n-BuLi n-hexane solution (5.6ml, 14mmol) dropwise, so that the internal temperature is not higher than -60°C, and react for 30min after dropping, record as bottle A; put 2,3, 4,6-Tetra-O-trimethylsilyl-β-D-gluconolactone (5.8g, 12mmol) was dissolved in toluene (55ml), cooled to -70°C, recorded as bottle B; The solution was transferred to bottle B and reacted for 2h. TLC detects that the reaction is complete. Add methanesulfonic acid (6ml) and anhydrous methanol (110ml), remove the ice bath and nitrogen protection, and stir overnight at room temperature. As detected by TLC, t...

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Abstract

The invention relates to a bicyclic derivative of heterocyclic glucoside as well as a preparation method and application of the bicyclic derivative, in particular to a compound shown in a formula I, a stereoisomer or pharmaceutically acceptable salt or ester of the compound, a pharmaceutical composition of the compound and application of the compound to preparation of drugs for treating diabetes or related diseases of the diabetes.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular, the invention relates to bicyclic derivatives of heterocyclic glucosides and their preparation methods and applications. 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. [0003] WO01 / 27128A1 discloses C-aryl glucoside SGLT2 inhibitor, which has the following molecular structure general formula: [0004] [0005] SGLT2 is the major Na in the epithelial cells of the S1 segment of the proximal tubule...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H9/06C07H1/00A61K31/7056A61P3/10A61P13/12A61P27/02A61P9/00A61P25/00
CPCC07H9/06C07H1/00A61P3/10A61P13/12A61P27/02A61P9/00A61P25/00
Inventor 何阳翟建国朱英杰周宜遂马红敏宋萌孟祥峰李传聪路廷伟李涛涛盛洪涛曹硕何茜
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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