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Canagliflozin impurities, and preparation and removal methods thereof

A technology for process impurities and intermediates, applied in chemical instruments and methods, preparation of sugar derivatives, organic chemistry methods, etc.

Active Publication Date: 2022-03-15
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 impurities, and preparation and removal methods thereof
  • Canagliflozin impurities, and preparation and removal methods thereof
  • Canagliflozin impurities, and preparation and removal methods thereof

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 particularly relates to a canagliflozin impurity and a preparation and removal method thereof, the canagliflozin impurity disclosed by the invention is generated in a canagliflozin production process, and the disclosed impurity can provide a qualified impurity reference substance for quality control of a canagliflozin intermediate. According to the impurity removal method, the purity of the canagliflozin intermediate can be effectively improved, the purity of the intermediate can reach 99.91%, then the purity of the canagliflozin product is improved, a canagliflozin impurity reference substance can provide an important reference basis for monitoring of the impurity in research and development of a canagliflozin process, and the canagliflozin quality monitoring level is improved.

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 Applications(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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