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Preparation method and application of canagliflozin alpha isomer

A technology for alpha isomer and canagliflozin, which is applied in the field of preparation of canagliflozin alpha isomer, can solve the problems of harsh reaction conditions, unfavorable production operations, and difficulty in obtaining reaction raw materials, and achieves a simple preparation method. , Improve the level of quality control and ensure the effect of clinical medicinal safety

Pending Publication Date: 2021-01-01
HINYE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] However, this method has difficulties in obtaining reaction raw materials, harsh reaction conditions, ZnBr 2 Easy to absorb water and other shortcomings, which is not conducive to actual production operations

Method used

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  • Preparation method and application of canagliflozin alpha isomer
  • Preparation method and application of canagliflozin alpha isomer
  • Preparation method and application of canagliflozin alpha isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation method of formula IV compound is as follows:

[0030] Add 52.7g of the compound of formula II to reaction bottle A, replace with nitrogen for 3 times, add 105mL of toluene under nitrogen atmosphere, cool down to -5~-10°C, slowly add isopropylmagnesium chloride lithium chloride complex dropwise under nitrogen atmosphere 129 mL (1.3 mol / L) of tetrahydrofuran solution, temperature controlled at -5 to -10°C, stirred for 2 hours to obtain the magnesium chloride lithium Grignard reagent of the compound of formula II;

[0031] Take another reaction bottle B, replace it with nitrogen for 3 times, add 119g of 50% toluene solution of the compound of formula Ⅲ, add 105mL of tetrahydrofuran, cool down to -45~-40°C, and add dropwise the prepared magnesium chloride lithium format of the compound of formula Ⅲ under nitrogen atmosphere Reagent, temperature control -45~-40°C, react for 2 hours, then add 70mL dilute hydrochloric acid (volume ratio of concentrated hydrochl...

Embodiment 2

[0033] The preparation method of canagliflozin α isomer is as follows:

[0034] Put 300mg of formula IV compound, 3mL of dichloromethane and 3mL of acetonitrile into the reaction flask, cool down to -20~-10°C, and add a mixture of 72mg of trifluoroacetic acid and 140mg of trimethylsilyl trifluoromethanesulfonate to the system ( Molar ratio 1:1), nitrogen replacement 3 times, then add 228mg 1,1,3,3-tetramethyldisiloxane, react at -15~-10℃ for 5h, add 2mL saturated sodium bicarbonate solution, The system was distilled under reduced pressure at 40°C to remove the organic solvent, then added 10mL of ethyl acetate and 5mL of water, separated, and the organic phase was shrunk to dryness to obtain 260mg of the crude product of canagliflozin α-isomer of the compound of formula I (HPLC of the crude product of the compound of formula I Purity: 52%), the crude product was purified by preparative chromatography to obtain the compound canagliflozin α-isomer of formula I (HPLC purity: 97.61...

Embodiment 3

[0039] The preparation method of canagliflozin α isomer is as follows:

[0040]Put 300mg of the compound of formula IV, 3mL of dichloromethane and 3mL of acetonitrile into the reaction flask, cool down to -20~-10°C, add a mixture of 129mg of trifluoroacetic acid and 28mg of trimethylsilyl trifluoromethanesulfonate ( Molar ratio 9:1), nitrogen replacement 3 times, then add 228mg 1,1,3,3-tetramethyldisiloxane, react at -15~-10℃ for 5h, add 2mL saturated sodium bicarbonate solution, The system was distilled under reduced pressure at 40°C to remove the organic solvent, then added 10 mL of ethyl acetate and 5 mL of water, separated, and the organic phase was shrunk to dryness to obtain 250 mg of the crude product of canagliflozin α-isomer of the compound of formula Ⅰ (HPLC of the crude product of the compound of formula Ⅰ Purity: 45%), the crude product was purified by preparative chromatography to obtain canagliflozin α-isomer of the compound of formula I (HPLC purity: 95.78%, yie...

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Abstract

The invention discloses a preparation method and application of a canagliflozin alpha isomer, the preparation method comprises the following steps: in the presence of Lewis acid, a compound of formulaIV and a reducing agent are subjected to a reduction reaction in an organic solvent to obtain the canagliflozin alpha isomer, wherein the lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate; the reducing agent is 1, 1, 3, 3-tetramethyldisiloxane. The preparation method is simple, the high-purity canagliflozin related substance reference substance can be rapidly obtained, the yield of the product canagliflozin alpha isomer is 37.5%, the purity is as high as 97.61%, the purity requirement of a standard substance is completely met, and the canagliflozin alpha isomer can be used as the standard substance and can be applied to quality control and research of canagliflozin bulk drugs. Therefore, the quality control level of canagliflozin is improved, andthe clinical medicinal safety is ensured.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more specifically, to a preparation method and application of canagliflozin alpha isomer. Background technique [0002] Canagliflozin, English name: Canagliflozin, chemical name: (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl ]-4-methylphenyl]-D-glucitol. Canagliflozin is the first SGLT2 inhibitor drug approved by the US FDA jointly developed by Mitsubishi Tanabe Pharmaceutical Co., Ltd. and Johnson & Johnson. blood sugar concentration. [0003] Canagliflozin isomers are divided into β-configuration and α-configuration, the two are chiral isomers, and the chemical names are (1S)-1,5-dehydro-1-C-[3-[ [5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and (1R)-1,5-dehydro-1-C-[3- [[5-(4-Fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, the specific structural formulas are respectively I and II in the figure below. Among the two isomers of canagl...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 黄治超蒋迎香习培华
Owner HINYE PHARM CO LTD
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