The preparation method of bazedoxifene acetate polymorph a

A technology of bazedoxifene acetate and bazedoxifene, applied in the direction of organic chemistry, to achieve the effects of high product yield, high crystal purity and convenient operation

Active Publication Date: 2021-03-23
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, in the method that disclosed first kind of direct salification prepares bazedoxifene acetate polymorph A, all adopt mixed solvent (or claim modified solvent), the preparation of this mixed solvent and reclaim will inevitably bring industrialized production. To a certain degree of environmental protection and cost pressure

Method used

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  • The preparation method of bazedoxifene acetate polymorph a
  • The preparation method of bazedoxifene acetate polymorph a
  • The preparation method of bazedoxifene acetate polymorph a

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In a nitrogen atmosphere, add the raw materials bazedoxifene free base (4.7g, 10mmol) and 35mL of methanol into the reaction flask, heat up to 40-45 degrees, stir until dissolved; cool down to 10-20 degrees, dropwise add acetic acid (0.72g , 12mmol) in methanol 10mL solution, keep the temperature and continue to stir for 2-4 hours after dropping; white crystals are precipitated, filtered, washed with cold methanol, and vacuum-dried at 50-60 degrees to obtain white solid bazedoxifene acetate polymorph A 3.9 g, yield 73.6%. For the XRD spectrum of the product bazedoxifene acetate polymorph A, please refer to figure 1 shown.

[0029] Wherein the XRD diffraction spectrum figure 2 The main peaks at θ are: 9.8, 12.7, 15.2, 16.0, 17.1, 17.4, 18.5, 18.8, 19.6, 20.3, 20.7, 22.3, 23.5, 24.9, 25.6, 26.1, 27.4, 28.0, 28.7, 29.9, 30.7; The peaks include: 12.7, 16.0, 18.5, 20.7, 22.3, consistent with the characteristic peaks of polymorphic form A of bazedoxifene acetate. Please ...

Embodiment 2

[0034] In a nitrogen atmosphere, add bazedoxifene free base (4.7 g, 10 mmol) and 45 mL of ethanol into the reaction flask, heat up to 35-45 degrees, and stir until dissolved. Cool down to 15-25 degrees, add dropwise acetic acid (0.72g, 12mmol) ethanol 10mL solution, after dropping, keep stirring at this temperature for 2-4 hours, white crystals precipitate, filter, wash with cold ethanol, vacuum at 50-60 degrees After drying, 4.3 g of polymorphic form A of bazedoxifene acetate was obtained as a white solid, with a yield of 81.1%. For the XRD spectrum of the product bazedoxifene acetate polymorph A, please refer to figure 2 shown.

[0035] Wherein the XRD diffraction spectrum figure 2 The main peaks at θ are: 9.8, 12.7, 15.2, 16.0, 17.1, 17.4, 18.5, 18.8, 19.6, 20.3, 20.7, 22.3, 23.5, 24.9, 25.6, 26.1, 27.4, 28.0, 28.7, 29.8, 30.7; The peaks include: 12.7, 16.0, 18.5, 20.7, 22.3, consistent with the characteristic peaks of polymorphic form A of bazedoxifene acetate. Pleas...

Embodiment 3

[0040] In a nitrogen atmosphere, the raw materials bazedoxifene free base (4.7 g, 10 mmol) and 50 mL of ethyl acetate were added to the reaction flask, the temperature was raised to 40-45 degrees, and stirred until dissolved. Cool down to 15-25 degrees, add acetic acid (0.72g, 12mmol) in ethyl acetate 10mL solution dropwise, keep stirring at this temperature for 2-4 hours, white crystals precipitate, filter, wash with cold ethyl acetate, 50 Vacuum drying at ~60°C gave 4.5 g of polymorphic form A of bazedoxifene acetate as a white solid, with a yield of 84.9%. For the XRD spectrum of the product bazedoxifene acetate polymorph A, please refer to image 3 shown.

[0041] Wherein the XRD diffraction spectrum figure 2 The main peaks at θ are: 9.8, 12.7, 15.2, 16.0, 17.1, 17.4, 18.5, 18.8, 19.6, 20.3, 20.7, 22.3, 23.5, 24.9, 25.6, 26.1, 27.4, 28.0, 28.7, 29.8, 30.7; The peaks include: 12.7, 16.0, 18.5, 20.7, 22.3, consistent with the characteristic peaks of polymorphic form A of...

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Abstract

The present invention discloses a Bazedoxifene Acetate polymorphism A preparation method, wherein a raw material Bazedoxifene free alkali is dissolved in a single solvent methanol, and salt forming and crystallization are performed to directly obtain the high-purity Bazedoxifene Acetate polymorphism A. According to the present invention, the preparation method has characteristics of simple process, economy and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of raw materials and intermediates, and in particular relates to a preparation method of polymorphic form A of bazedoxifene acetate, a new generation of selective estrogen receptor modulator. Background technique [0002] Bazedoxifene Acetate is a small molecule drug originally developed by Wyeth and later acquired by Pfizer. Bazedoxifene acetate was first launched in Italy and Spain with the approval of the European Medicines and Drug Administration (EMEA) in April 2009, with the product name Conbriza; in July 2010, it was launched in Japan with the product name Viviant; in October 2013, it was launched in the United States. 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 postmenopaus...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12
Inventor 许学农包志坚薛佳舒亮顾新禹张文件曾得利
Owner SUZHOU LIXIN PHARMA
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