Preparation method of bazedoxifene

A technology of bazedoxifene and oxygen, which is applied in the field of preparation of a new generation of selective estrogen receptor modulator bazedoxifene, can solve the problems of difficult acquisition of raw materials, many reaction steps, and high pressure on environmental protection, and achieve product The yield and product purity are high, and the preparation process is fast and convenient.

Active Publication Date: 2014-05-07
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Analyzing the disclosed preparation methods of bazedoxifene and its intermediates, there are generally disadvantages such as difficult to obtain raw materials, many reaction steps, high pressure on environment

Method used

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  • Preparation method of bazedoxifene
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  • Preparation method of bazedoxifene

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Experimental program
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Embodiment 1

[0031] Under nitrogen protection, add 1-(4-methoxy-phenyl) propyne (II) (1.46g, 10mmol), N-[4-(2-azepan-1-yl) in the reaction flask -ethoxy-benzyl)]-N-[4-(methoxyphenyl)]hydrazine (III) (6.64g, 18mmol), bis(dimethylamino)bis(pentafluorobenzenethiol) ( Dimethylamino)titanium (76.5 mg, 0.2 mmol) and 50 mL of toluene were heated up to 100° C. and stirred for 36 hours. Anhydrous zinc chloride (4.1 g, 30 mmol) was added, the temperature was raised to reflux, and the reaction was continued for 24 hours, and TLC detected that the reaction was complete. 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)- 3-Methyl-5-methoxy-1H-indole (IV) 3.8g, yield 76.3%.

Embodiment 2

[0033] Under nitrogen protection, 1-(4-benzyloxy-phenyl) propyne (II) (2.22g, 10mmol), N-[4-(2-azepan-1-yl) -Ethoxy-benzyl)]-N-[4-(benzyloxyphenyl)]hydrazine (III) (9.0g, 20mmol), bis(dimethylamino)bis(pentafluorobenzenethiol) ( Dimethylamino)titanium (76.5 mg, 0.2 mmol) and 50 mL of toluene were heated up to 100° C. and stirred for 40 hours. Anhydrous zinc chloride (4.1g, 30mmol) was added, the temperature was raised to reflux, and the reaction was continued for 20 hours, and TLC detected that the reaction was complete. 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-benzyloxy-phenyl)- 5.1 g of 3-methyl-5-benzyloxy-1H-indole (IV), yield 78.5%.

Embodiment 3

[0035] Under nitrogen protection and at -78°C, add 1-[4-(2-azepan-1-yl-ethoxy-benzyl)]-2-(4-methoxy-benzene base)-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 reaction was carried out 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 recrystallized from ethyl acetate and n-hexane (1 / 1) to obtain 2.0 g of off-white solid bazedoxifene (I), with a yield of 85.1%.

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Abstract

The invention discloses a preparation method of bazedoxifene. The preparation method of the bazedoxifene comprises the following steps: taking 1-(4-Pg1oxy-phenyl)-allylene (II) and N-[4-(2-azacycloheptane-1-yl- ethyoxyl-benzyl)]-N-[4-(Pg2 oxyphenyl)] hydrazine (III) to perform addition cyclization reaction and acquire 1-[4-(2-azacycloheptane-1-yl- ethyoxyl-benzyl)]-2-(4-Pg1oxy-phenyl)-3-methyl-5-(Pg2oxy)-1H-benzpyrole (IV); performing deprotection on an intermediate (IV) to prepare bazedoxifene (I). The preparation method is simple in process, high in yield, economical and environmental-friendly, so that a novel preparation method for industrial production of the bazedoxifene.

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 bazedoxifene, a new generation of selective estrogen receptor modulator. Background technique [0002] Bazedoxifene is a small molecule drug originally developed by Wyeth and later acquired by Pfizer. Bazedoxifene was first listed in Italy and Spain through the approval of the European Medicines and Drug Administration (EMEA) in April 2009, with the trade name Conbriza; in July 2010, it was launched in Japan with the trade name Viviant; in October 2013, it was approved by the US Food and Drug Administration. Approved by the Food and Drug Administration (FDA), it is marketed in the United States under the trade name Duavee for the treatment of moderate to severe menopause-related vasomotor symptoms (hot flashes) and the prevention of postmenopausal osteoporosis in postmeno...

Claims

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Application Information

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IPC IPC(8): C07D209/12
CPCY02P20/55C07D209/12
Inventor 许学农张青舒亮谢玲玲任新年苏爱蓉
Owner SUZHOU LIXIN PHARMA
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