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Preparation method of high-purity canagliflozin intermediate

An intermediate and high-purity technology, applied in the field of medicinal chemistry, can solve the problems of low purity and achieve high purity, easy operation and good yield

Inactive Publication Date: 2020-08-21
JIANGSU DEYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This method uses Grignard reagent instead of butyllithium to prepare intermediate (II), the reaction can be carried out at 0-5°C, the temperature requirement is low, and the operation is simple. Although the obtained intermediate (II) has been crystallized and purified, its purity is still low

Method used

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  • Preparation method of high-purity canagliflozin intermediate
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Embodiment 1

[0045] Embodiment 1, a kind of preparation method of high-purity canagliflozin intermediate, described preparation method comprises the following steps:

[0046] (1) Under an inert environment, dissolve the thiophene compound in the organic solvent A, add an alkaline reagent under low temperature conditions, and add 2,3,4,6-tetra-O-(trimethylsilyl)-D after the reaction is complete -Condensation reaction of the mixed solution of gluconolactone and organic solvent B; then drop strong acid and water, add alkaline solution after the reaction to quench, separate the organic phase, concentrate, add organic solvent C to crystallize, and dry to obtain the compound of formula I That is, intermediate I;

[0047] (2) After intermediate I reacts with strong acid in methanol, add alkaline solution to quench, then add organic solvent D for extraction, after liquid separation, the organic phase is concentrated, add organic solvent E to crystallize to obtain formula II canagliflozin intermedi...

Embodiment 2

[0060] Embodiment 2, a kind of preparation method of high-purity canagliflozin intermediate, described preparation method comprises the following steps:

[0061] (1) Under an inert environment, dissolve the thiophene compound in the organic solvent A, add an alkaline reagent under low temperature conditions, and add 2,3,4,6-tetra-O-(trimethylsilyl)-D after the reaction is complete -Condensation reaction of the mixed solution of gluconolactone and organic solvent B; then drop strong acid and water, add alkaline solution after the reaction to quench, separate the organic phase, concentrate, add organic solvent C to crystallize, and dry to obtain the compound of formula I That is, intermediate I;

[0062] (2) After intermediate I reacts with strong acid in methanol, add alkaline solution to quench, then add organic solvent D for extraction, after liquid separation, the organic phase is concentrated, add organic solvent E to crystallize to obtain formula II canagliflozin intermedi...

Embodiment 3

[0073] Embodiment 3, the preparation method experiment 1 of the high-purity canagliflozin intermediate:

[0074] 1. (2R,3S,4R,5R)-1-{3-[(5-(4-fluorophenyl)thiophen-2-yl)methyl]-4-methylphenyl}-2,3, The preparation of 4,5,6-pentahydroxyhexan-1-one (formula I):

[0075] 20.0g 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, 200mL tetrahydrofuran and 60mL toluene were added to the reaction flask, stirred to dissolve, nitrogen protection, in At -80~-70°C, add 22mL of n-butyllithium (2.5M n-hexane solution) dropwise, and react for 1h; maintain the temperature, add 28.5g of 2,3,4,6-tetra-O-(trimethyl Silylyl)-D-gluconolactone / 50mL toluene mixture, react for 1h after dropping; add 9.5g trifluoroacetic acid / 20mL water mixture, add and rise to room temperature for reaction. After the reaction is completed, add saturated aqueous sodium bicarbonate solution to adjust the pH to 6-8, separate the two phases after standing for stratification, and add water to the organic ph...

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Abstract

The invention discloses a preparation method of a high-purity canagliflozin intermediate, which comprises the following steps: reacting a thiophene compound with an alkaline reagent in an inert environment at low temperature, and condensing the reaction product with 2, 3, 4, 6-tetra-O-(trimethylsilyl)-D-glucolactone; dropwise adding a strong acid aqueous solution into the obtained reaction solution, quenching after reaction, separating out an organic phase for concentrating, and performing crystallizing and drying to obtain an intermediate I; reacting the intermediate I with strong acid in methanol to obtain a high-purity canagliflozin intermediate II. By preparing the intermediate I with excellent crystallization performance, the purity of the canagliflozin intermediate II is improved. The operation is simple and convenient, the production process is stable, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a high-purity canagliflozin intermediate. Background technique [0002] Canagliflozin is a new sodium-glucose co-transporter 2 (SGLT2) inhibitor drug, which can specifically inhibit the reabsorption of glucose by the kidney, allowing more sugar to be excreted through the patient's urine, thereby lowering the patient's blood sugar. More importantly, the therapeutic target of SGLT-2 inhibitors is limited to the kidney, and the potential adverse reactions outside the target are very small. The current clinical research data show that SGLT2 inhibitors have good efficacy, safety and tolerability. Canagliflozin was jointly developed by Mitsubishi Tanabe of Japan and Johnson & Johnson of the United States, and was approved by the FDA for marketing in March 2013. The chemical name of canagliflozin: (1S)-1,5-dehydro-1-[3-[[5-(4-fluorophen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22C07H15/04C07H1/00
CPCC07B2200/07C07B2200/13C07D333/22C07H1/00C07H15/04
Inventor 王建涛杨汉跃董淑波李喆陈学民朱思梅
Owner JIANGSU DEYUAN PHARMA
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