Canagliflozin impurity, preparation and removal method

A technology of impurities and process impurities, applied in the field of canagliflozin process impurities, preparation and removal

Active Publication Date: 2022-05-20
南京安杰新生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The inventor discovered 2 kinds of canagliflozin process impurities during the verification process of the production process of canagliflozin, and there are no reports on the discovery, separation and removal of these 2 kinds of impurities in the prior art

Method used

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  • Canagliflozin impurity, preparation and removal method
  • Canagliflozin impurity, preparation and removal method
  • Canagliflozin impurity, preparation and removal method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of formula I compound

[0043] Take canagliflozin intermediate (Ia) and refine 900mL of mother liquor with isopropyl acetate, concentrate at 45°C under reduced pressure (-0.08~-0.1MPa), add 9.5g of silica gel when it is concentrated to about 70mL, and continue to concentrate to obtain Silicone adsorbent.

[0044] The above silica gel adsorbate was separated by column chromatography, eluent: V dichloromethane / methanol=30 / 1 (1L); V dichloromethane / methanol=25 / 1 (2L); V dichloromethane / methanol =20 / 1 (1L); V dichloromethane / methanol=10 / 1 (1L); V dichloromethane / methanol=1 / 1 (1L). Collect the eluent containing the target compound (TLC developer: V dichloromethane / methanol = 10 / 1, Rf target compound = 0.3, Rf canagliflozin = 0.5). Concentrate the eluent to obtain 0.21 g of off-white solid, which is the compound of formula I.

[0045] [1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 7.5, 2.5 Hz, 1H), 7.55(ddd, J = 8.7, 5.6, 2.8 Hz, 2H), 7.44 – 7.37 (m, 2H) , 7.3...

Embodiment 2

[0047] The preparation of formula II compound

[0048] Get canagliflozin impurity formula I (500mg, 0.55mmol), add 20mL dichloromethane to dissolve therein, then add 4-dimethylaminopyridine (29mg, 0.24mmol), add dropwise acetic anhydride (560mg, 5.50mmol), React at room temperature (20~30°C) for 2h, add 20mL of water, separate the liquid, collect the organic phase, wash with water twice, concentrate under reduced pressure (-0.08~-0.1MPa) at 45°C to obtain an oily concentrate, and pass column chromatography Purified by the method, eluent (V petroleum ether / ethyl acetate=2 / 1), collected the eluent containing the target compound, concentrated to dryness under reduced pressure (-0.08~-0.1MPa) at 45°C, and obtained 0.42 g Yellow solid (Formula II).

[0049] [1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 7.4, 2.4 Hz, 1H),7.52 (d, J = 2.0 Hz, 1H), 7.44 (ddt, J = 7.0, 5.2, 2.5 Hz , 3H), 7.23 – 7.15(m, 4H), 7.07 – 7.03 (m, 1H), 7.03 – 7.01 (m, 1H), 6.98 (d, J = 3.6 Hz, 1H), 6.92 (dd...

Embodiment 3

[0051] Removal of compounds of formula II

[0052] Add 5.0g of canagliflozin intermediate I-Ac, 10mL of ethyl acetate into a 50mL reaction bottle, heat up to 65~75°C, dissolve, then cool down to 20~30°C, add 10mL of tertiary methyl ether, 0.3 mL of water , after stirring for 2h, further lower the temperature to 0~5°C, stir and crystallize at 0~5°C for 1h, filter, rinse with an appropriate amount of tertiary methyl ether, and blow dry at 45°C to obtain 4.11g of refined canagliflozin intermediate I-Ac , yield 82.2%, HPLC detection purity 99.91%, formula II impurity content 0.09% (HPLC detection purity before refining 99.17%, impurity content 0.62%), formula II impurity removal rate 85.5%.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and specifically relates to canagliflozin impurities, preparation and removal methods. The canagliflozin impurities disclosed in the present invention are produced during the production process of canagliflozin, and the disclosed impurities can be canagliflozin The quality control of net intermediates provides qualified impurity reference substances. The impurity removal method provided by the present invention can effectively improve the purity of the canagliflozin intermediate, and the purity of the intermediate can reach 99.91%, thereby improving the purity of the canagliflozin product. The canagliflozin impurity reference substance can be developed for the canagliflozin process The monitoring of this impurity in the drug provides an important reference basis and improves the quality monitoring level of canagliflozin.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to canagliflozin process impurities, preparation and removal methods. Background technique [0002] Canagliflozin (canagliflozin), trade name Invokana, is a new type of SGLT2 inhibitor developed by Johnson & Johnson for the treatment of type 2 diabetes. . The glucose filtered by the renal tubular lumen is mainly expressed and reabsorbed by the sodium-glucose co-transporter in the renal tubule. Canagliflozin reduces the renal reabsorption of filtered glucose by inhibiting the sodium-glucose co-transporter. It can lower the renal sugar threshold and increase the excretion of renal sugar, thereby lowering blood sugar. [0003] The chemical name of canagliflozin is (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methanol phenyl]-D-glucitol, the CAS number is 842133-18-0, and the structural formula is shown in formula 1: [0004] . [0005]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/26C07H15/04C07H1/00C07D409/14C07D409/10
CPCC07H15/04C07H15/26C07H1/00C07D409/14C07D409/10C07B2200/07
Inventor 徐进王子月李龙霞姚书扬汤怀松
Owner 南京安杰新生物医药有限公司
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