Preparation method of bazedoxifene acetate

A technology of bazedoxifene acetate and acetic acid, which is applied in the design of organic synthesis routes and the field of preparation of raw materials and intermediates, can solve the problems of difficulty in obtaining raw materials, many reaction steps, and high pressure on environmental protection, and achieves product yield and product yield. High purity, quick and convenient preparation process

Active Publication Date: 2014-06-18
苏州特瑞药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] Analyzing the published preparation methods of bazedoxifene acetate and its intermediates, there are generally disadvantages such as difficult to obtain raw materials, many reaction steps, low yield and high pressure on environmental protection. The process route is very important for the economic and technological development of the API

Method used

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  • Preparation method of bazedoxifene acetate
  • Preparation method of bazedoxifene acetate
  • Preparation method of bazedoxifene acetate

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Under argon protection, 1-(4-methoxy-phenyl)propanol (II) (1.66g, 10mmol), N-[4-(2-azepane-1 -yl-ethoxy-benzyl)]-N-[4-(methoxyphenyl)]hydrazine (III) (3.69g, 10mmol), triruthenium dodecacarbonyl (0.13g, 0.2mmol), 2 , 2'-bis(diphenylphosphine)biphenyl (0.16 g, 0.3 mmol), crotononitrile (0.67 g, 10 mmol) and 2-methyl-2-butanol 50 mL. Anhydrous zinc chloride (1.36g, 10mmol) was added at room temperature, and after shaking for 5 minutes, the reaction tube was replaced with argon, sealed and placed in a 250W microwave oven, heated to 130°C, irradiated for 3 hours, and the reaction was detected by TLC. The reaction solution was concentrated, dissolved in dichloromethane, washed twice with water, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was recrystallized from ethanol to obtain off-white solid 1-[4-(2-azepan-1-yl-ethoxy-benzyl)]-2-(4-methoxy-phenyl)- 4.2 g of 3-methyl-5-methoxy-1H-indole ...

Embodiment 2

[0035] Under argon protection, 1-(4-benzyloxy-phenyl)propanol (II) (2.42g, 10mmol), N-[4-(2-azepane-1 -yl-ethoxy-benzyl)]-N-[4-(benzyloxyphenyl)]hydrazine (III) (4.45g, 10mmol), triruthenium dodecacarbonyl (0.13g, 0.2mmol), 2 , 2'-bis(diphenylphosphine)biphenyl (0.16 g, 0.3 mmol), crotononitrile (0.67 g, 10 mmol) and cyclopentyl methyl ether 50 mL. Anhydrous zinc chloride (1.36g, 10mmol) was added at room temperature, and after shaking for 5 minutes, the reaction tube was replaced with argon, sealed and placed in a 250W microwave oven, heated to 140°C, irradiated for 3 hours, and the reaction was detected by TLC. The reaction solution was concentrated, dissolved in dichloromethane, washed twice with water, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was recrystallized from ethanol to obtain off-white solid 1-[4-(2-azepan-1-yl-ethoxy-benzyl)]-2-(4-methoxy-phenyl)- 5.5 g of 3-methyl-5-methoxy-...

Embodiment 3

[0037]Under nitrogen protection and at -78°C, add 1-[4-(2-azepan-1-yl-ethoxy-benzyl)]-2-(4-methoxy-benzene yl)-3-methyl-5-methoxy-1H-indole (IV) (2.5g, 5mmol) and dichloromethane 25mL. Under stirring, a solution of boron tribromide (2.5 g, 10 mmol) in 25 mL of dichloromethane was added dropwise, and the mixture was reacted at room temperature for 10 hours. The reaction was quenched by adding saturated ammonium chloride solution, and the organic layer was separated, dried and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethanol, added with glacial acetic acid (0.3 g, 5 mmol), stirred at room temperature and crystallized at 5° C. for 3 hours to obtain 2.25 g of bazedoxifene acetate (I), with a yield of 84.9%.

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Abstract

The invention discloses a preparation method of bazedoxifene acetate. The method comprises the following steps: carrying out a condensation cyclization reaction on 1-(4-Pg1 oxygroup phenyl) propyl alcohol (II) and N-{4-(2-azacycloheptane-1-yl-ethyoxyl-benzyl)}N-{4-(Pg2 oxygroup phenyl)} hydrazine (III) so as to obtain 1-{4-(2-azacycloheptane-1-yl-ethyoxyl-benzyl)}-2-(4-Pg1 oxygroup-phenyl)-3-methyl-5-(Pg2 oxygroup)-1H-benzpyrole (IV); and carrying out deprotection on the intermediate (IV) and salifying the intermediate (IV) with acetic acid so as to obtain the bazedoxifene acetate (I). The preparation method is concise in process, high in yield, economical and environment-friendly, thereby providing a novel preparation way for the industrial production of the bazedoxifene acetate.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a new generation of selective estrogen receptor modulator bazedoxifene acetate. Background technique [0002] Bazedoxifene is a small molecule drug originally developed by Wyeth and later acquired by Pfizer. Its medicinal compound bazedoxifene acetate was first launched in Italy and Spain in April 2009 with the approval of the European Food and Drug Administration (EMEA) under the trade name Conbriza; in July 2010 it was launched in Japan under the trade name Viviant; in 2013 Approved by the U.S. Food and Drug Administration (FDA) in October 2019, it is marketed in the U.S. under the trade name Duavee, which is used for the treatment of moderate to severe menopause-related vasomotor symptoms (hot flashes) and the prevention of menopause in postmenopausal women without hys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 许学农王浩徐金峰
Owner 苏州特瑞药业股份有限公司
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