Preparation method of bazedoxifene acetate and a crystal form thereof

A technology of bazedoxifene acetate and crystal form, applied in the field of medicinal chemistry, can solve the problems of difficulty in controlling crystal form purity, poor reproducibility, unfavorable solvent recovery, etc., and achieves high crystal form purity, simple operation, and easy recovery and reuse. Effect

Active Publication Date: 2019-06-04
上海医药集团(本溪)北方药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the preparation process of all the compounds that have been disclosed so far must use hydrogenation kettles for low-pressure hydrogenation. Hydrogenation kettles are special equipment that have high safety requirements for operation and use, and the site must be approved and inspected by relevant state departments before use.
In addition, the preparation process of Bazedoxifene Acetate A crystal form obtained in the prior art still has poor reproducibility, the types of solvents used are not conducive to recovery, and seed crystals need to be added in the process, making it difficult to control the purity of the crystal form, etc. technical problem

Method used

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  • Preparation method of bazedoxifene acetate and a crystal form thereof
  • Preparation method of bazedoxifene acetate and a crystal form thereof
  • Preparation method of bazedoxifene acetate and a crystal form thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The preparation of embodiment 1 bazedoxifene acetate

[0027] The reaction formula is as follows:

[0028]

[0029] Add 540g of tetrahydrofuran, 180g of the compound of formula A, 360g of ethanol, 45g of ammonium formate and 9g of 5% palladium carbon catalyst into a 2000ml three-necked flask in turn under stirring; heat up to 65°C and react for 16-28 hours until TLC shows that the raw materials and monobenzyl The point disappears, (or the residual monobenzyl compound detected by HPLC≤0.1%). Filtrate under reduced pressure, rinse the filter cake with 900g of ethyl acetate, put the filtrate into a 5L separatory funnel, wash with 600g×3 water, add 25.0g of acetic acid to the organic layer while stirring in a 2L single-necked bottle, and a solid precipitates out in about 10 minutes, then After stirring for 20 minutes, cool in an ice-water bath at 0-5°C for 2 hours, filter under reduced pressure, rinse the filter cake with 200 g of ethyl acetate, and dry the solid under ...

Embodiment 2

[0031] The preparation of embodiment 2 bazedoxifene acetate

[0032] The reaction formula is as follows:

[0033]

[0034] Add 600g of ethyl acetate, 180g of the compound shown in Formula A, 360g of ethanol, 45g of ammonium formate and 9g of 5% palladium-carbon catalyst in a 2000ml three-necked flask successively under stirring; heat up to 65°C and react for 16-28 hours until TLC shows that the raw materials and single The benzyl point disappears, (or the remaining single benzyle detected by HPLC≤0.1%). Filtrate under reduced pressure, rinse the filter cake with 900g of ethyl acetate, put the filtrate into a 5L separatory funnel, wash with 600g×3 water, add 25.0g of acetic acid to the organic layer while stirring in a 2L single-necked bottle, and a solid precipitates out in about 10 minutes, then After stirring for 20 minutes, cool in an ice-water bath at 0-5°C for 2 hours, filter under reduced pressure, rinse the filter cake with 200 g of ethyl acetate, and dry the solid ...

Embodiment 3

[0035] The preparation of embodiment 3 bazedoxifene acetate

[0036] The reaction formula is as follows:

[0037]

[0038]Add 590g of ethyl acetate, 180g of the compound represented by formula A, 360g of ethanol, 58g of 1,3-cyclohexadiene and 9g of 5% palladium carbon catalyst in a 2000ml three-necked flask in sequence; heat up to 65°C and react for 16-28 hours. Until TLC shows that the raw material and the monobenzyl point disappear, (or the monobenzyl residue detected by HPLC≤0.1%). Filtrate under reduced pressure, rinse the filter cake with 500g of ethyl acetate, add 25.0g of acetic acid to the filtrate under stirring in a 2L single-necked bottle, and solids will precipitate out in about 10 minutes, then stir for 20 minutes, then cool in an ice-water bath at 0-5°C for 2 hours, reduce Filter under pressure, rinse the filter cake with 200 g of ethyl acetate, and dry the solid under vacuum at 45° C. for 2 hours. 130.8 g of off-white solid, namely the compound represented ...

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Abstract

A preparation method of bazedoxifene acetate is characterized by including the following steps: (1) performing a reaction by mixing and suspending a compound represented in the formula (A), ammonium formate or cyclohexadiene, and a palladium-carbon catalyst in an organic solvent, reaction terminal being detected with TLC or HPLC; (2), filtering and washing a reaction product, adding acetic acid with stirring, and filtering and drying the mixture to prepare the bazedoxifene acetate. The invention also provides a preparation method of a bazedoxifene acetate crystal form A. The preparation method is free of hydrogen and avoids usage of special devices, such as a hydrogenation kettle, while a safe hydrogen donor is employed, so that the method can be carried out even with a common reaction kettle and a reaction workshop, thereby reducing dangerousness of the synthesis and building and operation cost of a special device workshop. The preparation method of the crystal form A, compared with the prior art, is simple in operation, is free of a crystal seed for inducing crystallization, is high in crystal form purity and is simple in solvent system which can be recycled and reused.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of bazedoxifene acetate and its A crystal form. Background technique [0002] The original research Wyeth company discloses bazedoxifene acetate compound (i.e. bazedoxifene acetate) in publication number CN1170719, CN1281429 patent application, discloses the compound of this compound in publication number CN1938271, CN1938272 patent application respectively Form B and Form A. Afterwards, many companies applied for patents related to the synthesis and crystal forms. The chemical structural formula of bazedoxifene acetate is: [0003] [0004] Publication No. CN1938272 discloses the crystalline polymorph (type A) of bazedoxifene acetate, its powder X-ray diffraction pattern includes at least 5 characteristic peaks, and its 2θ is selected from about 9.8 °, 12.7 °, 15.2°, 16.0°, 17.1°, 17.4°, 18.5°, 18.8°, 19.6°, 20.4°, 20.7°, 22.3°,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12
CPCC07B2200/13C07D209/12
Inventor 李柏俊贾国慧徐丹庆谢建树
Owner 上海医药集团(本溪)北方药业有限公司
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