Canagliflozin drug impurity as well as preparation method and application thereof

A compound and residue technology, applied in the field of compound and its preparation, can solve the problems of canagliflozin product quality evaluation method that needs to be improved, and achieve the effect of low cost, less by-products, and simplified process operation

Active Publication Date: 2017-10-24
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 as well as preparation method and application thereof
  • Canagliflozin drug impurity as well as preparation method and application thereof
  • Canagliflozin drug impurity as well as preparation method and application thereof

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 invention discloses a canagliflozin drug impurity as well as a preparation method and application thereof. The invention provides a compound as well as a preparation method and application thereof. The method comprises the following steps: (1) enabling the compound as shown in formula 2 to be in contact with an alkaline lithium hydroxide aqueous solution to obtain a coarse product containing a compound as shown in formula 3, wherein the coarse product contains a compound as shown in formula 1; (2) crystallizing and filtering the coarse product to obtain mother liquor; (3) concentrating the mother liquor to obtain residues; and (4) crystallizing and filtering the residues in an L-proline-containing organic solvent, thus obtaining the compound as shown in formula 1. The method provided by the invention can realize directed preparation of the compound as shown in formula 1, and a reliable impurity contrast is provided for quality research on industrially produced canagliflozin-series diabetes treatment drug products and quantitative control over impurities.

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 application. 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 techn...

Claims

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Application Information

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Patent Type & Authority Applications(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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