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Preparation method of bazedoxifene acetate crystal form A

A technology of xifene crystal form and acetic acid, applied in the field of preparation of bazedoxifene acetate crystal form A, can solve the problems of easy conversion to crystal form B, no industrialized production scale, etc., and achieves low cost, convenient operation, heavy weight and the like. Strong effect

Active Publication Date: 2015-04-22
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Denatured ethanol is used in the above methods, and it is reported in US2005 / 0227965 and WO2009 / 102773 A1 that crystal form A can be easily converted into crystal form B in contact with ethanol or its vapor, and it is reported in WO2010151541A and WO2012037187A that crystal form A Certain solvents (such as ethyl acetate: ethanol = 2.5:1), long-term and low temperature (such as 0.5 ° C) conditions will transform crystals to obtain crystal form D, which makes it difficult for people to prepare high-purity crystal form A in denatured ethanol challenge
[0009] WO2012 / 089593 A1 reported that bazedoxifene acetate was dissolved in a single or mixed cyclic ether solvent (such as tetrahydrofuran, 1,4-dioxane, methyl tetrahydrofuran), filtered, and the filtrate was stirred and crystallized to obtain the crystal form A, disclosed in its Example 1 the example of preparing crystal form A by dissolving amorphous bazedoxifene acetate in tetrahydrofuran, and there is no report on industrial production scale in this patent

Method used

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  • Preparation method of bazedoxifene acetate crystal form A
  • Preparation method of bazedoxifene acetate crystal form A
  • Preparation method of bazedoxifene acetate crystal form A

Examples

Experimental program
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Effect test

Embodiment 1

[0083] The preparation of embodiment 1 bazedoxifene acetate crystal form A

[0084]

[0085] Weigh hexamethyleneimine benzyloxyindole (2kg), ammonium formate (0.58kg), 10% palladium carbon (0.2kg, moisture content 50%) and add in the reactor containing tetrahydrofuran (12L) , heated to 45-50°C and reacted for about 2-3 hours. After the reaction was complete, the palladium carbon was filtered off, the solution was cooled to 10-15°C, and then acetic acid (0.37kg) and methyl tert-butyl ether (10L ), the solution continued to stir for 12 hours at 10‐15 °C. Suction filtration and vacuum drying of the solid at 50° C. for 10 hours gave 1.12 kg of white powdery solid with a yield of 68.7%.

[0086] Weigh the crude form A (1kg) obtained above into a reactor containing tetrahydrofuran (8L), raise the temperature to 45-50°C under the protection of an inert gas, filter the solution after the solid is completely dissolved, and continue cooling the filtrate to 10-15°C , and then add me...

Embodiment 2

[0087] The preparation of embodiment 2 bazedoxifene acetate crystal form A

[0088] Weigh hexamethyleneimine benzyloxyindole (2kg), ammonium formate (0.58kg), 10% palladium carbon (0.1kg, water content 50%) and add in the reactor containing tetrahydrofuran (12L) , heated to 45-50°C and reacted for about 2-3 hours. After the reaction was complete, the palladium carbon was filtered off, the solution was cooled to 10-15°C, and then acetic acid (0.185kg) and methyl tert-butyl ether (5L ), the solution continued to stir for 12 hours at 10‐15 °C. Suction filtration, the solid was vacuum dried at 50°C for 10 hours to obtain the crude crystal form A.

[0089] Weigh the crude form A (1kg) obtained above into a reactor containing tetrahydrofuran (8L), raise the temperature to 45-50°C under the protection of an inert gas, filter the solution after the solid is completely dissolved, and continue cooling the filtrate to 10-15°C , and then add methyl tert-butyl ether (5L) in batches, and ...

Embodiment 3

[0090] The preparation of embodiment 3 bazedoxifene acetate crystal form A

[0091] Weigh hexamethyleneimine benzyloxyindole (2kg), ammonium formate (0.58kg), 10% palladium carbon (0.4kg, water content 50%) and add in the reactor containing tetrahydrofuran (12L) , heated to 45-50°C and reacted for about 2-3 hours. After the reaction was complete, the palladium carbon was filtered off, the solution was cooled to 10-15°C, and then acetic acid (0.185kg) and methyl tert-butyl ether (5L ), the solution continued to stir for 12 hours at 10‐15 °C. Suction filtration, the solid was vacuum dried at 50°C for 10 hours to obtain the crude crystal form A.

[0092] Weigh the crude form A (1kg) obtained above into a reactor containing tetrahydrofuran (8L), raise the temperature to 45-50°C under the protection of an inert gas, filter the solution after the solid is completely dissolved, and continue cooling the filtrate to 10-15°C , and then add methyl tert-butyl ether (5L) in batches, and ...

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Abstract

The invention belongs to the technical field of chemical pharmacy and relates to a preparation method of a bazedoxifene acetate crystal form A. The preparation method of the bazedoxifene acetate crystal form A comprises the following steps: step 1, in the presence of palladium / carbon serving as a catalyst, dissolving hexamethyleneimine benzyloxy benzpyrole and ammonium formate in a benign organic solvent to have reaction; step 2, after the reaction is finished completely, filtering the palladium on activated carbon, cooling the filtrate, adding acetic acid and a toxic inorganic solvent, stirring, crystallizing, filtering and drying to obtain a crude crystal form A product; step 3, under the protection and presence of inert gas, dissolving the crude crystal form A product in the benign organic solvent, heating and dissolving; step 4, thermally filtering the solution, cooling the filtrate, dropwise adding the toxic inorganic solvent and crystallizing; step 5, after the crystallization is ended, filtering the solution and drying the solid to obtain the bazedoxifene acetate crystal form A.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of bazedoxifene acetate crystal form A. Background technique [0002] Bazedoxifene Acetate, chemical name: 1‐[4‐(2‐azepane‐1‐yl‐ethoxy)‐benzyl]‐2‐(4‐hydroxy‐phenyl )-3-methyl-1H-indole-5-phenol acetate, the structural formula is as follows: [0003] [0004] Bazedoxifene Acetate, a selective estrogen receptor modulator drug developed for Ligand, Wyeth, and Almirall, was first approved in Europe in April 2009, with the trade name "Conbriza" in 2010 It was launched in Japan for the first time in June under the product name "Viviant", and has since been launched in Spain. At present, the drug has been approved for marketing in South Korea, but it has not yet been marketed and is under review by the FDA in the United States. [0005] Preclinical test data show that bazedoxifene acetate has more targeted activity than other selective estrogen recepto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 宋波白雪松贾贵鹏刘沫毅刘蕴秀
Owner CHINA RESOURCES SAIKE PHARMA
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