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Canagliflozin impurity compound and preparation method thereof

A compound and oxidant technology, applied in organic chemistry, measuring devices, instruments, etc., can solve problems such as low product purity and lack of single impurity control

Pending Publication Date: 2018-09-14
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Therefore, in the existing canagliflozin preparation technology, there are deficiencies such as low product purity and lack of control of individual impurities.

Method used

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  • Canagliflozin impurity compound and preparation method thereof
  • Canagliflozin impurity compound and preparation method thereof
  • Canagliflozin impurity compound and preparation method thereof

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Effect test

preparation example Construction

[0038] Canagliflozin (Formula I) can be prepared, for example, according to the method reported in patent WO2005012326 (same family patent CN1829729), the entirety of which is incorporated into the present invention for reference. In addition, it can also be purchased through commercial channels.

[0039] The instruments used for mass spectrometry were Agilent 1200 high performance liquid chromatography system and Agilent G6410A tandem triple quadrupole mass spectrometer. The ion source was electrospray ion source in positive ion mode. Split the HPLC eluate, allowing approximately 1 μg / ml into the ion source of the mass spectrometer.

[0040] The instrument used for nuclear magnetic resonance analysis is Bruker Avance 600 nuclear magnetic resonance spectrometer, and the deuterated solvent is DMSO-d6. TMS was used as a proton resonance (δ1H 0.00) and solvent internal reference, and DMSO-d6 as carbon resonance internal standard (δ13C 39.10-40.10).

[0041] The following abbrevi...

Embodiment 1

[0043] Embodiment 1: the HPLC purity analysis method of canagliflozin impurity IV

[0044] Take about 12.5mg of this product, weigh it accurately, put it in a 25ml measuring bottle, add acetonitrile to dissolve and dilute to the mark, shake well, and use it as the test solution; test according to the high performance liquid chromatography (General Rule 0512 of the Chinese Pharmacopoeia 2015 Edition). Butylsilane bonded silica gel is used as filler (C4, 4.6mm×250mm, 5μm); water is used as mobile phase A, acetonitrile is used as mobile phase B, and elution is carried out according to the gradient elution table; the flow rate is 1.0 per minute ml; the detection wavelength is 210nm; the column temperature is 25°C; precisely measure 20μl of the test solution and inject it into the liquid chromatograph, and the collection time is 60min. Should meet the requirements. In the chromatogram of the test solution, except for the solvent peak, calculated by the area normalization method, t...

Embodiment 2

[0046] Embodiment 2: the preparation of formula II compound

[0047] Dissolve canagliflozin (30g, 67.5mmol) in 300ml absolute ethanol, slowly add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (30.6 g, 134.8mmol) in absolute ethanol solution (240ml), react at room temperature for about 24 hours, TLC detects that the reaction is complete, stop the reaction. Under cooling in an ice bath, slowly pour the reaction solution into a mixture of dichloromethane and water, separate the liquids, extract the water phase twice with dichloromethane, combine the dichloromethane layers, dry over anhydrous magnesium sulfate, filter, and reduce Concentrate under pressure to dryness to obtain crude product.

[0048] The crude product was purified by column chromatography using a mixed system of methanol and dichloromethane as the eluent to obtain [2-methyl-5-(β-D-glucopyranosyl)phenyl][5-(4-fluoro Phenyl)-2-thienyl]methanone (compound of formula II), HPLC: 99.3%.

[0049] The M+H+ peak in th...

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Abstract

The invention relates to a novel type 2 diabetes resistant drug canagliflozin impurity compound [2-methyl-5-(beta-D-glucopyranose)phenyl][5-(4-fluorophenyl)-2-thienyl]methyl hydroperoxide (a compoundof a formula IV) and a preparation method thereof, and application of the impurity compound serving as a canagliflozin quality control reference standard substance.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and drug analysis, and specifically relates to impurity compounds of canagliflozin and preparation methods thereof, and the use of these impurities as canagliflozin quality control reference standards and testing methods of canagliflozin and its impurities . Background technique [0002] Canagliflozin, the chemical name is 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene , CAS: 842133-18-0, the structural formula is shown in formula I. [0003] [0004] Canagliflozin, trade name Invokana, is a selective type 2 sodium-glucose co-transporter (SGLT2) inhibitor developed by Johnson & Johnson's Janssen pharmaceutical company (Janssen), mainly used for exercise or control. Treatment of type 2 diabetics who are diet ineffective, with good glycemic control. The drug was approved by the US Food and Drug Administration (FDA) and the European Commission in 2013 for the tr...

Claims

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Application Information

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IPC IPC(8): C07D409/10G01N30/02
CPCG01N30/02C07D409/10
Inventor 邹益品罗云雷院兴姜芳陈皓黄桂琴邹春兰袁泉尹佳
Owner CHONGQING PHARMA RES INST
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