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Method for preparing intermediates of gliflozin hypoglycemic drugs

A technology for hypoglycemic drugs and intermediates, applied in the field of drug synthesis, can solve the problems of difficult separation and purification, strong irritation and corrosiveness, and high production costs, and achieve the effects of being suitable for large-scale production, reducing production costs, and being easy to transfer.

Pending Publication Date: 2020-04-21
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This invention relates to methods that make it easier or cheaper than traditional ways of producing certain chemicals like cilostazol. It involves creating specific intermediate products from these starting material with different reactions under controlled conditions at once. These intermediate products have better properties compared to previous ones due to their unique structure. By controllably reacting them together through various steps, they may produce more valuable compounds while also being able to achieve desired results without making any extra effort on its own.

Problems solved by technology

Technologies described in this patented text involve different processes used to create chemical structures called sulfones or analogues like fuzzy aldehydes. These techniques include reacting certain sugars together under specific circumstances such as heat or acid catalysis. However, these conventional ways suffer from various drawbacks including low yields due to side products produced during their formation, difficulty separating them, and potential safety concerns associated therewith.

Method used

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  • Method for preparing intermediates of gliflozin hypoglycemic drugs
  • Method for preparing intermediates of gliflozin hypoglycemic drugs
  • Method for preparing intermediates of gliflozin hypoglycemic drugs

Examples

Experimental program
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Effect test

example 1

[0043] Example 1: Preparation of C-1

[0044]2-(2-Methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene (5.0 g, 13.85 mmol), tetrahydrofuran (50 mL), PMDTA (7.0 mL, 1.5 equiv) were sequentially added to 500 mL of three In the neck flask, after the air in the reaction flask was replaced by nitrogen, the temperature of the cold trap was controlled at about -78°C, and 1.6M n-butyllithium (13.0mL, 1.5equiv) was slowly added dropwise, and stirred for about 1h. Add TMS-protected gluconolactone 4 (8.5 g, 1.3 equiv) and toluene (50 mL) into another 100 mL round bottom flask and mix well, and control the temperature in a cold trap at about -78°C. The toluene solution of 4 was slowly dropped into a three-necked flask, and the temperature was kept constant, and stirred for 2h.

[0045] Keeping the temperature constant, methanol (35 mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature was raised to about -20°C, and 15% citric acid aqueous solution...

example 2

[0047] Example 2: Preparation of C-1

[0048] 2-(2-Methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene (5.0 g, 13.85 mmol), tetrahydrofuran (50 mL), PMDTA (7.0 mL, 1.5 equiv) were sequentially added to 500 mL of three In the neck flask, after the air in the reaction flask was replaced by nitrogen, the temperature of the cold trap was controlled at about -78°C, and 2.5M n-butyllithium (8.3mL, 1.5equiv) was slowly added dropwise, and stirred for about 1h. Add TMS-protected gluconolactone 4 (8.5 g, 1.3 equiv) and toluene (50 mL) into another 100 mL round bottom flask and mix well, and control the temperature in a cold trap at about -78°C. The toluene solution of 4 was slowly dropped into a three-necked flask, and the temperature was kept constant, and stirred for 2h.

[0049] Keeping the temperature constant, methanol (35 mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature was raised to about -20°C, and 15% citric acid aqueous solution...

example 3

[0051] Example 3: Preparation of D-1

[0052] Add 5-bromo-2-chloro-4'-ethoxydiphenylmethane (1.0g, 3.07mmol), tetrahydrofuran (16mL), PMDTA (1.4mL, 1.5equiv) into a 250mL three-necked flask in turn, and nitrogen replacement reaction After the air in the bottle was filled, the temperature of the cold trap was controlled at about -78°C, and 2.5M n-butyllithium (1.8mL, 1.5equiv) was slowly added dropwise, and stirred for about 1h. Add TMS-protected gluconolactone 4 (1.7 g, 1.3 equiv) and toluene (16 mL) into another 50 mL round bottom flask and mix well, and control the temperature in a cold trap at about -78°C. The toluene solution of 4 was slowly dropped into a three-necked flask, and the temperature was kept constant, and stirred for 2h.

[0053] Keeping the temperature constant, methanol (10 mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature was raised to about -20°C, and 15% citric acid aqueous solution (50 mL) was slowly droppe...

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Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.

Description

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Claims

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Application Information

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Owner SHENYANG PHARMA UNIVERSITY