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Method for preparing Canagliflozin intermediate

An intermediate and thiophene technology, which is applied in the field of industrial preparation of canagliflozin intermediates, can solve the problems of unpurified crude products, few supply sources, and high operation requirements, so as to achieve high safety in reaction operations, reduce equipment requirements, Operational Security Effects

Active Publication Date: 2019-04-02
NEW FOUNDER HLDG DEV LLC +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to the strict temperature control requirements, high operating requirements, stronger tert-butyllithium activity, more likely to produce impurities, and unpurified crude products, the method also mainly has the expensive starting material (formula IV) used for coupling, which is expensive and difficult to supply. Disadvantages of less sources

Method used

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  • Method for preparing Canagliflozin intermediate
  • Method for preparing Canagliflozin intermediate
  • Method for preparing Canagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] This embodiment is a preparation method of a canagliflozin intermediate, and the preparation method comprises the following steps:

[0064] 1) Under nitrogen protection, 100g (0.245mol) 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene was fully dissolved in 300mL tetrahydrofuran, in At a temperature of -25°C to -20°C, add 100g (0.245mol) of sec-butylmagnesium chloride and lithium chloride dropwise. After the dropwise addition, continue the reaction for 1 hour; maintain the temperature, then add 171.6g (0.368mol)2 ,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone, after the dropwise addition, continue to react for 2 hours; where 2,3,4,6-tetra-O-( Trimethylsilyl)-D-gluconolactone was pre-dissolved in 200mL THF;

[0065] 2) Add 51.8g (0.539mol) of methanol solution of methanesulfonic acid dropwise to the reaction liquid after the reaction in step 1), stir, and react with natural temperature rise for 18 hours. The reaction was quenched with aqueous sodium bic...

Embodiment 2

[0071] This embodiment is a preparation method of a canagliflozin intermediate, and the preparation method comprises the following steps:

[0072] 1) Under nitrogen protection, 100g (0.245mol) 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene was fully dissolved in 300mL tetrahydrofuran, in At a temperature of -25°C to -20°C, add 0.367mol of isopropylmagnesium chloride and lithium chloride dropwise. After the dropwise addition, continue the reaction for 1 hour; maintain the temperature, then add dropwise 171.6g (0.368mol) 2,3, 4,6-tetra-O-(trimethylsilyl)-D-gluconolactone, after the dropwise addition, continue to react for 2 hours; where 2,3,4,6-tetra-O-(trimethyl Silyl)-D-gluconolactone was pre-dissolved in 200mL THF;

[0073] 2) Add 20.57 g (0.563 mol) of hydrochloric acid methanol solution dropwise to the reaction solution after the reaction in step 1), stir, and react at natural temperature for 17 hours. The reaction was quenched with aqueous sodium solution...

Embodiment 3

[0076] The present embodiment is as comparative test, a kind of preparation method of canagliflozin intermediate, and described preparation method comprises the following steps:

[0077] 1) Under nitrogen protection, 50g (0.122mol) 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene was fully dissolved in 150mL tetrahydrofuran, in At a temperature of -40°C to -35°C, slowly drop in 0.367mol of isopropylmagnesium chloride and lithium chloride. After the dropwise addition, continue the reaction for 1 hour; maintain the temperature, then add dropwise 74.3g (0.159mol) 2, 3,4,6-Tetra-O-(trimethylsilyl)-D-gluconolactone, after the dropwise addition, continue to react for 2 hours; where 2,3,4,6-tetra-O-(three Methylsilyl)-D-gluconolactone was pre-dissolved in 100mL THF;

[0078] 2) Add 24.7g (0.257mol) of methanol solution of methanesulfonic acid dropwise to the reaction liquid after the reaction in step 1), stir, and react overnight at natural temperature. The reaction w...

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Abstract

The invention relates to a method for preparing a Canagliflozin intermediate. The preparation method comprises the following steps: 1) in an inert environment, at a temperature of -30 DEG C to -15 DEGC, a thiophene compound and an alkaline reagent and 2, 3, 4, 6-tetra-O-(trimethylsilane)-D-Gluconolactone are fully reacted; and 2) a methanol solution containing strong acid is added dropwise to thereaction liquid obtained in the step 1), and after full reacting, quenching and purifying are carried out to obtain the Canagliflozin intermediate. The product of the preparation method has good yield and high purity; the method has low temperature requirement for equipment, safer operation and small equipment volume requirement, and the method is more suitable for industrial scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to an industrial preparation method of a canagliflozin intermediate. Background technique [0002] In diabetes treatment drugs, SGLT2 inhibitors can effectively inhibit the reabsorption of glucose by the kidneys, excrete excess glucose from the urine, and directly lower blood sugar. For type 2 diabetes that is poorly controlled by diet and exercise, SGLT2 inhibitors Drugs can not only effectively improve blood sugar, but also lose weight and lower blood pressure. [0003] Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor jointly developed by Mitsubishi Tanabe Corporation of Japan and Johnson & Johnson of the United States. FDA-approved SGLT2 inhibitor for glycemic control in adults with type 2 diabetes. The chemical name of canagliflozin: (1S)-1,5-dehydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylbenzene Base]-D-glucose hem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00
CPCC07H1/00C07H15/04
Inventor 魏可贵易崇勤马亚峰刘金凤万蕾崔畅谭祖磊黄琪冀蕾
Owner NEW FOUNDER HLDG DEV LLC