6-halogenated glucose C-glycoside as well as preparation method and application thereof

A technology of glucose and carbon glycosides, applied in 6-halogenated glucose carbon glycosides and its preparation, preparation of SGLT inhibitor-type diabetes drug intermediates and preparation fields, can solve the problem of poor stability, poor selectivity, and increase of epoxide intermediates. problems such as the quality risk of large raw materials, to achieve the effect of low cost, low price and environmental friendliness

Active Publication Date: 2018-10-19
ZHEJIANG HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The stability of the key intermediate epoxy sugar in this synthetic route is poor; secondly, when forming carbon glycosides, the selectivity of 1 and 2 positions is poor; in addition, the selectivity of α / β in C-1 position carbon glycoside products is also poor. Poor; and the use of toxic copper reagents in the process increases the quality risk of raw materials

Method used

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  • 6-halogenated glucose C-glycoside as well as preparation method and application thereof
  • 6-halogenated glucose C-glycoside as well as preparation method and application thereof
  • 6-halogenated glucose C-glycoside as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolane-5-carboxylic acid (compound A) Synthesis

[0063]

[0064] Synthesis of (3aS,5R,6S,6aS)-5-hydroxymethyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolane-6-ol

[0065] To a 3 L three-necked flask was added L-(-)-xylose (100.00 g, 0.67 mol), acetone (1 L) and anhydrous magnesium sulfate (160.00 g, 1.32 mol). The obtained suspension was stirred at room temperature for 10 to 15 minutes, and then 10 mL of concentrated sulfuric acid (0.19 mol) was slowly added dropwise. The reaction was continued to stir overnight at room temperature. After TLC detected the reaction, the reaction mixture was filtered, and the filter cake was washed twice with 100 mL×2 acetone. The obtained filtrate was adjusted to pH 8-9 with ammonia water, and after stirring for 30 minutes, the suspension was filtered. The filtrate was concentrated to dryness under reduced pressure at 35-45°C to obtain 143.89 g of a yel...

Embodiment 2

[0069] Example 2: ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolane-5-)( Synthesis of morpholino)methanone (compound B)

[0070]

[0071] The above-obtained acid A (99.9g, 0.49mol) was added to a 3L three-necked flask, 1L of tetrahydrofuran was added, stirred to dissolve, and TBTU (235.76g, 0.74mol) and N-methylmorpholine (NMM, 82mL) were added successively. 0.74mol). The resulting reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filter cake was washed with 200 mL×2 tetrahydrofuran. The filtrate was concentrated to dryness under reduced pressure at 35-45 °C, 400 mL of hexane was added to the obtained slurry, heated to 60-70 °C, stirred for 1 hour, cooled to room temperature for 2 hours, and then cooled to 0-10 °C for 2 hours. After 1 hour, 111.02 g of white solid was obtained by filtration, and the yield was 82.6%. ESI-MS: m / z 274[M+H] + .

Embodiment 3

[0072] Example 3: Synthesis of 1-chloro-2-(4-ethoxybenzyl)-4-bromobenzene

[0073]

[0074] Into a 500 mL three-necked round bottom flask, were added 5-bromo-2-chlorobenzoic acid (20 g, 84.9 mmol), dichloromethane (100 mL), and N,N-dimethylformamide (0.1 mL). After stirring for 10 minutes, oxalyl chloride (13.0 g, 102.7 mmol, 1.2 eq) was added dropwise to the mixture at room temperature. After the dropwise addition, the reaction was stirred at room temperature for 3-4 hours. The reaction solution was concentrated to dryness under reduced pressure at 30-40° C. to obtain an off-white solid, that is, crude 5-bromo-2-chlorobenzoyl chloride. The obtained crude 5-bromo-2-chlorobenzoyl chloride was dissolved in 50 mL of dichloromethane and used for later use.

[0075] Take another 500mL three-necked round bottom flask, add phenethyl ether (13.5g, 110.4mmol, 1.3eq), dichloromethane (100mL), aluminum trichloride (17.0g, 127.4mmol, 1.5eq). The obtained mixed solution is fully stir...

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Abstract

The invention discloses a 6-halogenated glucose C-glycoside as well as a preparation method and application thereof. A structure of 6-halogenated glucose C-glycoside is shown in formula I; an intermediate can be synthesized efficiently with cheap and easily available raw materials; meanwhile, when the raw material is used for synthesizing Jardiance, dapagliflozin and the like, a reaction yield ishigh, and an obtained product has high purity and relatively high industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, and relates to a 6-halogenated glucoside and a preparation method and application thereof. More specifically, the present invention discloses an intermediate for preparing SGLT inhibitor-type diabetes medicine, and its preparation method and application. Background technique [0002] Diabetes is a group of metabolic diseases characterized by hyperglycemia, and the International Diabetes Federation (IDF) expects the number of people with diabetes worldwide to reach nearly 6 billion by 2035. Currently, diabetes is clinically divided into two types, namely insulin-dependent diabetes mellitus (type I diabetes) and non-insulin-dependent diabetes mellitus (type II diabetes mellitus), of which about 90% of patients with type II diabetes mellitus. Most of the traditional hypoglycemic drugs that can be used for the treatment of type 2 diabetes include insulin sensitizers...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10C07D407/12
CPCC07D309/10C07D407/12Y02P20/55
Inventor 汪海波梅光耀金辉张伟刘学晟林文静王凯明
Owner ZHEJIANG HONGYUAN PHARMA
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