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Preparation method of canagliflozin

An intermediate and molar ratio technology, applied in the field of medicine, can solve the problems of unfavorable industrialization reaction, unfavorable refining and impurity removal, poor product quality, etc., and achieve the effect of simple post-treatment process, reduced complexity, and simple and easy-to-obtain raw materials

Active Publication Date: 2014-10-29
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Boron trifluoride ether is light brown colorless fuming liquid, flammable and toxic
It is strongly irritating and corrosive, which is not conducive to the progress of industrial reactions, and the compound will decompose when it encounters water. If the reaction time is too long, it will gradually remove the protecting group (methoxyl group) of the reactant, which is not conducive to the later refining and impurity removal. , the final product quality will also be poor, and the yield on the process in route 3 is 65.6%

Method used

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  • Preparation method of canagliflozin
  • Preparation method of canagliflozin
  • Preparation method of canagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Add 20g of the main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl to a reaction flask containing 150ml of DMF )-D-glucopyranoside, stirred until the feed liquid was clarified, slowly added 29.6g (5 times the amount) of benzoyl chloride after the feed liquid was clarified, and reacted at room temperature for 3h; TLC monitored the completion of the reaction and added 100ml of dichloromethane and 100ml of water , stirred and extracted, and the upper aqueous phase was stirred and extracted twice with 80ml and 60ml of dichloromethane respectively, and the organic phase was combined and washed once with 100ml saturated saline water, and the organic phase was dried with anhydrous sodium sulfate for 30min, and then the feed liquid was evaporated to Drying yielded 37.6 g of intermediate I (molecular weight 890).

[0049] After the intermediate I obtained in the previous step was dissolved in 120ml of acetonitrile, 10.5g of trimethyl phosphi...

Embodiment 2

[0052] Add 20g of the main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl to a reaction flask containing 150ml of DMF )-D-glucopyranoside, stirred until the feed liquid was clear, and slowly added 29.6g (5 times the amount) of benzoyl chloride after the feed liquid was dissolved, and reacted at room temperature for 3h; TLC monitored the completion of the reaction and added 100ml dichloromethane and 100ml water, stirred and extracted, and the upper aqueous phase was stirred and extracted twice with 80ml and 60ml of dichloromethane respectively, and the organic phase was combined and washed once with 100ml saturated saline water, and the organic phase was dried with anhydrous sodium sulfate for 30min, and then the feed liquid was evaporated To dryness, 37.6 g of intermediate I were obtained.

[0053] After the intermediate I obtained in the previous step was dissolved in 120ml of acetonitrile, 11.6g of trimethyl phosphite (2.2 times the amou...

Embodiment 3

[0056] Add 20g of the main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl to a reaction flask containing 150ml of DMF )-D-glucopyranoside, stir until the feed solution is clear, and slowly add 23.7g (4 times the amount) of benzoyl chloride after the feed solution is clarified, and react at room temperature for 3h; TLC monitors the completion of the reaction and then adds 100ml dichloromethane and 100ml water, stirred and extracted, and the upper aqueous phase was stirred and extracted twice with 80ml and 60ml of dichloromethane respectively, and the organic phase was combined and washed once with 100ml saturated saline water, and the organic phase was dried with anhydrous sodium sulfate for 30min, and then the feed liquid was evaporated To dryness, 37.6 g of intermediate I were obtained.

[0057] After the intermediate I obtained in the previous step was dissolved in 120ml of acetonitrile, 11.6g of trimethyl phosphite (2.2 times the amount...

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Abstract

The invention discloses a preparation method of canagliflozin. The method comprises the following steps: (1) by using DMF (N,N-dimethylformamide) as a solvent, carrying out protective reaction on the main raw material SM1 by using benzoyl chloride to obtain an intermediate I; (2) by using acetonitrile as a solvent, removing methoxy group from the intermediate I under the action of trimethyl phosphite to obtain an intermediate II; and (3) by using tetrahydrofuran and anhydrous ethanol or methanol as solvents, removing benzoyl protection from the intermediate II under the action of sodium methoxide to obtain the canagliflozin. The purity of the product is at least 99.9%, and the yield is at least 81.6%. The method has the advantages of mild reaction conditions, high yield and high product quality, is economical and environment-friendly, and can easily implement industrial production.

Description

technical field [0001] The invention relates to a preparation method of canagliflozin, which belongs to the technical field of medicine. Background technique [0002] Canagliflozin, Chinese chemical name: (1S)-1,5-dehydro-1-{3-[(5-(4-fluorophenyl)-2-thienyl)methyl]-4-methyl Phenyl}-D-glucitol, structural formula: [0003] [0004] Canagliflozin is a novel SGLT-2 inhibitor for the treatment of type 2 diabetes in adult patients. Jointly developed by Mitsubishi Tanabe Pharmaceuticals and Johnson & Johnson Pharmaceuticals. On March 29, 2013, the US Food and Drug Administration (FDA) approved canagliflozin for improving blood sugar control in adults with type 2 diabetes. This product is the first SGLT-2 inhibitor approved by the FDA. In November 2013 On the 25th, it was approved by the European Commission (EC) for the treatment of adults with type 2 diabetes to improve blood sugar control. [0005] SGLT is a glucose transporter with two subtypes, SGLT-1 and SGLT-2, which a...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 常宝磊王树鹏秦春霞李保勇吴柯张兆珍董廷华柏明士李德才
Owner QILU PHARMA HAINAN
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