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Method for preparing dapagliflozin

A compound and synthetic route technology, applied in the field of preparation of bulk drug dapagliflozin, can solve the problems of unfavorable base toxic impurities, long reaction steps, increased processing steps, etc., and achieves simple process operation, short synthetic route, and concise method. Effect

Inactive Publication Date: 2018-09-14
SOUTHEAST UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the existing gluconolactone method has long reaction steps and uses a strong acid / methanol system to treat acid-sensitive hemiacetal compounds, which is prone to side reactions, which not only increases the processing steps, but also inevitably produces alkyl halides. Or sulfonate genotoxic impurities, this step is very close to the finished product separation step, which is very unfavorable for the control of base toxic impurities in raw materials, it is necessary to develop a shorter and more effective synthetic Dapagliflozin formula I The method of the present invention is based on solving these problems and produces

Method used

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  • Method for preparing dapagliflozin
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  • Method for preparing dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Preparation of 4-bromo-1-chloro-2[(4-ethoxy-phenyl)-diethoxy-methyl]benzene (formula III, R=Et)

[0025]

[0026] 500mL four-necked flask with magnetic stirring, thermometer and reflux condenser, successively added 5-bromo-2-chloro-4'-ethoxybenzophenone (formula II, 33.96g, 100mmol), triethyl orthoformate ( 22.2g, 150mmol), p-toluenesulfonic acid monohydrate (1.9g, 10mmol) and absolute ethanol (200mL), heated to 60+5°C under stirring for 6 hours, cooled to room temperature, added triethylamine (2.0g ) to adjust the pH to alkaline, and evaporate ethanol under reduced pressure. Add toluene (150mL) to dissolve the residue, wash the layers with water (2×60mL) twice, concentrate the organic layer under reduced pressure again, add heptane for beating, filter, and dry the obtained solid to give the white title compound (Formula III, R=Et , 32.5g, yield 78.6%).

Embodiment 2

[0027] Example 2: Preparation of 4-bromo-1-chloro-2[(4-ethoxy-phenyl)-dimethoxy-methyl]benzene (formula III, R=Me)

[0028]

[0029] 250mL four-necked flask with magnetic stirring, thermometer and reflux condenser, successively added 5-bromo-2-chloro-4'-ethoxybenzophenone (formula II, 16.98g, 50mmol), trimethyl orthoformate ( 15.92g, 150mmol), methanesulfonic acid (0.96g, 10mmol), anhydrous methanol (40mL) and toluene (120mL), heated to 60+5°C with stirring for 10 hours, cooled to room temperature, added triethylamine ( 1.5g) adjusted the pH to alkaline, washed the layers (2×100mL) twice, concentrated the organic layer under reduced pressure, added heptane for beating treatment, filtered, and dried the obtained solid to give the white title compound (Formula III, R=Me, 15.9 g, yield 82.4%).

Embodiment 3

[0030]Example three: (4-ethoxy-phenyl)-[3-(2,3,4,5-tetrahydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-phenyl] - Preparation of ketone (formula IV)

[0031]

[0032] 250mL four-neck bottle rack with magnetic stirring, thermometer, constant pressure dropping funnel and reflux condenser, under the protection of positive nitrogen pressure, add 4-bromo-1-chloro-2[(4-ethoxy-phenyl)-dimethyl Oxy-methyl]benzene (formula III, R=Me, 3.86g, 10mmol), anhydrous THF (20mL) and magnesium chips (25.2, 100mmol), heated to 50°C under stirring, and continued stirring until the reaction was stabilized , start dropwise adding 4-bromo-1-chloro-2[(4-ethoxy-phenyl)-dimethoxy-methyl]benzene (formula III, R=Me, 34.7 g, 90mmol) dissolved in anhydrous THF (160mL) solution, exotherm is obvious, control the internal temperature during the dropwise addition between 40-55°C, after the dropwise addition is completed, keep warm at 40-55°C for 1 hour to obtain a gray grid Reagent solution, under nitrogen ...

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Abstract

The invention aims at providing a method for more effectively synthesizing dapagliflozin with shorter steps. The method comprises the steps: catalyzing 5-bromo-2-chloro-4'-ethoxybenzophenone serving as a starting material by using a strong acid to finish ketal protection, treating the obtained diaryl ketal compound by using magnesium, then, reacting the treated diaryl ketal compound with trimethylsilyl-protected glucolactone, and reducing a hemiketal compound obtained after dilute acid quenching to finish the preparation of dapagliflozin.

Description

technical field [0001] The invention belongs to the field of preparation methods of crude drugs, and in particular relates to the preparation of the crude drug dapagliflozin. Background technique [0002] Dapagliflozin Propanediol Monohydrate (dapagliflozin Propanediol Monohydrate) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which is manufactured by Bristol-Myers-Squibb (BMS) and AstraZeneca (AstraZeneca, AZ) jointly developed, first approved by the European Medicines Agency (EMA) on November 12, 2012, is the world's first SGLT2 inhibitor to be marketed for the treatment of type 2 diabetes. The U.S. Food and Drug Administration (FDA) announced on January 8, 2014 that it was approved for the treatment of type 2 diabetes. Treatment with the drug improved glycated hemoglobin A1c, based on results from 16 clinical trials in more than 9,400 people with type 2 diabetes. The mechanism of action of its oral drug is to reduce the renal glucose reabsorption and increase t...

Claims

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Application Information

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IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 胡林邹平邱小龙储玲玲苟少华李小跃王平时光好张新刚沈伟王东辉曹雷陈俊
Owner SOUTHEAST UNIV
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