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Canagliflozin drug impurity and its preparation method and application

A compound and residue technology, applied in the field of compound and its preparation, can solve the problems that the quality evaluation method of canagliflozin products needs to be improved, and achieve the effect of easy control of process operation, cheap and easy-to-obtain raw materials, and efficient preparation

Active Publication Date: 2022-03-15
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the current quality evaluation method of canagliflozin products needs to be improved

Method used

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  • Canagliflozin drug impurity and its preparation method and application
  • Canagliflozin drug impurity and its preparation method and application
  • Canagliflozin drug impurity and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The preparation of compound shown in embodiment 1 formula 2

[0053] Step 1: Synthesis of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone:

[0054] Add 8.0 kg of tetrahydrofuran, 1.0 kg of gluconolactone, and 4.54 kg of N-methylmorpholine to the reaction kettle at room temperature. Under the protection of nitrogen, start to add 3.66 kg of trimethylchlorosilane dropwise. After the reaction is complete, add ice water to quench reaction. 26 kg of purified water and 5.0 kg of n-heptane were added to the reaction liquid, stirred, and allowed to stand to separate layers. Wash the organic layer with 15 kg of 5% sodium dihydrogen phosphate aqueous solution, 15 kg of purified water and 15 kg of sodium chloride aqueous solution, add anhydrous magnesium sulfate, dry, filter and concentrate under reduced pressure until there is no distillate. 2.41 kg of colorless oil was obtained, which was 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, with a yield of 92% and a gas phase purit...

Embodiment 2

[0061] Compound shown in embodiment 2 synthetic formula 3

[0062] Take the above solid (2,3,4,6-tetra-O-acetyl-(1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl ]methyl]-4-methylphenyl]-D-glucitol) 1.2kg, dissolved in 8.4 liters of methanol and 6.0 liters of tetrahydrofuran at room temperature, cooled to 0 ~ 5 ℃, then dropwise added monohydrate lithium hydroxide solution (48g dissolved in 480 ml of water), then reacted at room temperature for 2 hours. Add 4.0 L of water to dilute the reaction, concentrate under reduced pressure to remove the solvent, and extract the reaction solution with ethyl acetate. Washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of white foamy solid canagliflozin anhydrous (compound shown in formula 3), with a yield of 95% and a liquid phase purity of 99.2 %.

Embodiment 3

[0063] Compound shown in embodiment 3 preparation formula 1

[0064] Dissolve 800 g of the above compound in ethyl acetate, add purified water, heat up to 40 degrees Celsius, add n-heptane dropwise, add canagliflozin seed crystals, grow crystals for 3 hours and filter to obtain 135 g of mother liquor containing the compound shown in formula 1 In the concentrate, the liquid phase content of compound 1 was detected to be about 5.1%.

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Abstract

The present invention provides a compound and its preparation method and use, wherein the method comprises: 1) contacting the compound shown in formula 2 with an alkaline lithium hydroxide aqueous solution, so as to obtain a crude product containing the compound shown in formula 3, the crude product contains the compound shown in Formula 1; (2) crystallize and filter the crude product to obtain a mother liquor; (3) concentrate the mother liquor to obtain a residue; ‑proline in an organic solvent to crystallize and filter to obtain the compound shown in the formula 1. The directional preparation of the compound of formula 1 can be realized by using the method provided by the invention, and a reliable impurity reference substance can be provided for the quality research and the quantitative control of impurities of Liejing series diabetes therapeutic drug products in industrial production.

Description

technical field [0001] The present invention relates to the field of chemical synthesis, specifically, the present invention relates to a compound and its preparation method and use. Background technique [0002] Canagliflozin is currently a class of drugs clinically used to treat diabetes, and it is the first SGLT-2 inhibitor approved by the FDA. SGLT-2 is a new target for diabetes treatment. It has a different mechanism of action from traditional diabetes treatment drugs. It can excrete excess glucose from the urine, thereby reducing glycosylated proteins and improving insulin sensitivity in the liver and peripheral tissues. , Improve β-cell function, and further improve liver insulin resistance, thereby promoting the return of higher glycogen output to normal. [0003] However, the current quality evaluation method of canagliflozin products needs to be improved. [0004] Contents of the invention [0005] The present invention aims to solve one of the technical pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/10
CPCC07D409/10C07B2200/07
Inventor 徐助雄李言刘静孙梦颖钱丽娜崔健
Owner WATERSTONE PHARMA WUHAN
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