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Preparation method of bazedoxifene oxide

A bazedoxifene oxide technology, applied in the field of preparation of bazedoxifene oxide, can solve the problems affecting the purity of bazedoxifene acetate, toxic and side effects, etc.

Inactive Publication Date: 2020-04-17
北京鑫开元医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And the existence of bazedoxifene acetate impurity, not only can affect the purity of bazedoxifene acetate, also may bring toxic and side effects

Method used

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  • Preparation method of bazedoxifene oxide
  • Preparation method of bazedoxifene oxide
  • Preparation method of bazedoxifene oxide

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[0034] The embodiment of the present invention provides a preparation method of bazedoxifene oxide, comprising:

[0035] Step S11, using bazedoxifene free base as a raw material, dissolving it in the first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain intermediate 1;

[0036] Step S12, dissolving the intermediate 1 in a second benign solvent, adding an oxidizing agent to obtain intermediate 2 after oxidation;

[0037] Step S13, dissolving the intermediate 2 in a third benign solvent, adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide.

[0038] Further, in step S11, the first benign solvent includes at least one of dichloromethane, chloroform, tetrahydrofuran, dioxane and ethyl acetate; the silane protecting group includes trimethylchlorosilane , triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosil...

Embodiment 1

[0049] Step S201: Add bazedoxifene free base (3.1g, 6.6mmol) and dichloromethane (15mL) to the reaction flask, then add triethylamine (6.7g, 65.9mmol), and cool to 0°C, slowly add tert-butyldimethylsilyl chloride (5.0g, 32.9mmol) dissolved in dichloromethane (15mL) dropwise, after the dropwise addition, rise to room temperature and stir for 4 hours; after the reaction is complete, the reaction The solution was poured into 50 mL of purified water, extracted with dichloromethane (30 mL×3), the organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate After purification by column chromatography (eluent: dichloromethane:methanol=5:95), 4.3 g of intermediate 1 was obtained as a yellow oil with a yield of 93.48%.

[0050] Step S202: Dissolve the intermediate 1 (4.1g, 5.86mmol) obtained in S201 in dichloromethane (60mL), and slowly add hydrogen peroxide (30%, 60mL) dropw...

Embodiment 2

[0055] Step S301: Add bazedoxifene free base (5.0g, 10.6mmol) and dichloromethane (30mL) to the reaction flask, then add triethylamine (6.5g, 63.7mmol), and cool to 0°C, slowly add a solution of trimethylchlorosilane (5.8g, 53.1mmol) in dichloromethane (30mL) dropwise, after the dropwise addition, rise to room temperature and stir for 4 hours; after the reaction is complete, pour the reaction solution into 100mL for purification In water, extracted with dichloromethane (50mL×3), combined the organic phases, washed the organic phase with saturated brine (100mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (The eluent is dichloromethane:methanol=5:95), 5.9 g of yellow oily intermediate 1 was obtained, and the yield was 90.30%.

[0056] Step S302: Dissolve the intermediate 1 (5.0g, 8.1mmol) obtained in S301 in dichloromethane (60mL), slowly add hydrogen peroxide (30%, 60mL) dropwis...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of bazedoxifene oxide, wherein the preparation method comprises the steps: by using bazedoxifene free alkali as a raw material, dissolving in a first benign solvent, adding an organic alkali, and adding a silane protecting group to protect two phenolic hydroxyl groups, and thus obtaining anintermediate 1; dissolving the intermediate 1 in a second benign solvent, and adding an oxidant for oxidation to obtain an intermediate 2; and dissolving the intermediate 2 in a third benign solvent,and adding a protecting group removing reagent to remove two molecular silane protecting groups, and thus obtaining the bazedoxifene oxide. According to the preparation method of the bazedoxifene oxide provided by the invention, a preparation method of 1-[4-[2-(azacycloheptan-1-yl)ethoxy]benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indole-5-phenol-N-oxide is provided, and the preparation method has important significance in effectively controlling the quality of bazedoxifene.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of bazedoxifene oxide. Background technique [0002] Bazedoxifene Acetate, a small-molecule drug originally developed by Wyeth and later acquired by Pfizer, was approved by the European Food and Drug Administration in April 2009 for marketing in Italy and Spain. The trade name is Conbriza, and it is mainly used to treat postmenopausal women osteoporosis. And the existence of bazedoxifene acetate impurity, not only can influence the purity of bazedoxifene acetate, also may bring toxic and side effects. Therefore, in the actual drug production process, using clear and definite impurities for comparison is an indispensable link in drug production and a necessary means to effectively control drug ingredients and ensure drug safety. Contents of the invention [0003] The object of the present invention is to overcome the above-mentioned deficienc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12Y02P20/55
Inventor 武艳朋李静庞亚龙戴信敏葛志敏
Owner 北京鑫开元医药科技有限公司
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