Preparation method of Dapagliflozin intermediate used for treating II-type diabetes

An intermediate, the technology of chlorobenzoyl chloride, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems of many by-products and difficulty in purification, and achieve the effects of short reaction time, mild conditions and high yield

Inactive Publication Date: 2017-09-26
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the defects that there are too many by-products and difficult to purify in the existing preparation process of dapagliflozin intermediate 5-bromo-2-chloro-4'-ethoxybenzophenone, and provide a Preparation method of dapagliflozin intermediate suitable for industrial production, good selectivity and high yield

Method used

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  • Preparation method of Dapagliflozin intermediate used for treating II-type diabetes
  • Preparation method of Dapagliflozin intermediate used for treating II-type diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A method for preparing a dapagliflozin intermediate for treating type Ⅱ diabetes, comprising the following steps:

[0028] 1) Under nitrogen protection, 235.5g (1mol) of 5-bromo-2-chlorobenzoic acid, 380.9g (3mol) of oxalyl chloride and a catalytic amount of DMF (2ml) were added to 1500ml of anhydrous dichloromethane at room temperature for contact reaction 1 ~2 hours, remove the solvent and unreacted oxalyl chloride under reduced pressure to obtain 5-bromo-2-chlorobenzoyl chloride;

[0029] 2) Under nitrogen protection, mix 25 g of tert-butyldimethylsilyl chloride and 5-bromo-2-chlorobenzoyl chloride obtained in step 1) in anhydrous dichloromethane for 30 minutes at 0 to 10°C, and then keep Add 134.4 g (1.1 mol) of phenetole and 194.6 g (1.2 mol) of ferric chloride to the reaction system in sequence, stir for 3 hours, and when the reaction is complete, pour into ice water to quench the reaction, extract with dichloromethane, wash with water , and concentrated to obtai...

Embodiment 2

[0033] A method for preparing a dapagliflozin intermediate for treating type Ⅱ diabetes, comprising the following steps:

[0034] 1) Under nitrogen protection, 23.6g (0.1mol) of 5-bromo-2-chlorobenzoic acid, 25.4g (0.2mol) of oxalyl chloride and a catalytic amount of DMF (0.2ml) were added to anhydrous dichloromethane and contacted at room temperature React for 1 to 2 hours, remove the solvent and unreacted oxalyl chloride under reduced pressure to obtain 5-bromo-2-chlorobenzoyl chloride;

[0035] 2) Under nitrogen protection, mix 2.1 g of tert-butyldimethylsilyl chloride and 5-bromo-2-chlorobenzoyl chloride obtained in step 1) in anhydrous dichloromethane for 30 minutes at 0 to 10°C, and then Keeping the temperature, 14.7g (1.2mol) of phenetole and 17.8g (1.1mol) of ferric chloride were successively added to the reaction system, and the reaction was stirred for 5 hours. After the reaction was completed, it was poured into ice water to quench the reaction, extracted with dichl...

Embodiment 3

[0037] A method for preparing a dapagliflozin intermediate for treating type Ⅱ diabetes, comprising the following steps:

[0038] 1) Under nitrogen protection, 23.6g (0.1mol) of 5-bromo-2-chlorobenzoic acid, 50.8g (0.4mol) of oxalyl chloride and a catalytic amount of DMF (0.3ml) were added to anhydrous dichloromethane and contacted at room temperature React for 1 to 2 hours, remove the solvent and unreacted oxalyl chloride under reduced pressure to obtain 5-bromo-2-chlorobenzoyl chloride;

[0039]2) Under nitrogen protection, mix 2.5 g of tert-butyldimethylsilyl chloride and 5-bromo-2-chlorobenzoyl chloride obtained in step 1) in anhydrous dichloromethane for 20 minutes at 0 to 10°C, and then Keeping the temperature, 14.7 g (1.2 mol) of phenetole and 19.5 g (1.2 mol) of ferric chloride were added to the reaction system in turn, and the reaction was stirred for 5 hours. After the reaction was completed, it was poured into ice water to quench the reaction, extracted with dichlor...

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Abstract

The invention discloses a preparation method of a Dapagliflozin intermediate used for treating II-type diabetes. The preparation method comprises the following steps: 1) performing a reaction on 5-bromine-2-chlorobenzoic acid and oxalyl chloride in anhydrous dichloromethane under the catalysis of DMF (dimethyl formamide), so as to obtain 5-bromine-2-chloro-benzoyl chloride; 2) under the condition that tert-Butyldimethylsilyl chloride exists, performing a reaction on 5-bromine-2-chloro-benzoyl chloride obtained in step 1) and phenetole under the catalysis of ferric trichloride, so as to obtain 5-bromine-2-chloro-4'-ethyoxyl benzophenone. According to the preparation method provided by the invention, no ortho-by-product is generated, and the yield of a target product is high, so that the good support of storage of raw materials is provided for Dapagliflozin. Additionally, the preparation method is mild in conditions and short in reaction time, therefore, the preparation method is suitable for industrial production and promotion.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical compounds, in particular to a preparation method of a dapagliflozin intermediate for treating type II diabetes. Background technique [0002] Diabetes is a metabolic disease characterized by high blood sugar. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both. The long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Therefore, diabetes treatment drugs have always been a hot spot in drug development. [0003] On November 14, 2012, the European Commission approved Forxiga (dapagliflozin) jointly developed by Bristol-Myers Squibb and AstraZeneca for the treatment of type 2 diabetes. Glucose co-transporters, referred to as SGLT-2) as the first drug targeting. The sugar group and the aryl side chain in the chemical structure of Daglie a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/46C07C49/84
CPCC07C45/46C07C51/60C07C49/84C07C63/70
Inventor 鲍文佳
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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