Preparation method of bazedoxifene acetate polycrystalline type B

A technology of bazedoxifene acetate and its polymorphic forms, which is applied in the field of pharmacy, can solve the problems of no public preparation of polymorphic form B, no detailed description of the salt-forming process, and unsuitability for large-scale production, so as to shorten the production cycle and cost Salt crystallization time is short, suitable for industrial production

Active Publication Date: 2015-02-25
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN101977897A and US8618284 disclose a method for preparing bazedoxifene acetate crystal form A, which mainly studies the process of debenzylation to prepare bazedoxifene, but does not describe the salt-forming process in detail
In 2010, Wyeth reported the crystal form D in WO2010151541, and its melting point was determined to be 166.7°C by DSC; and a detailed comparative study was made on the three crystal forms A, B, and D. Experiments showed that crystal A was in some solvent systems Type can be transformed into D crystal form, and B and D two kinds of crystal forms are also not easy to produce mutual crystallization phenomenon even under the situation of adding crystal seed; When directly preparing bazedoxifene acetate by bazedoxifene free base The catalyst in the previous step needs to be filtered out with diatomaceous earth, and acetic acid is added in two times, and the operation is relatively cumbersome; while the preparation process of crystal form D obtained from bazedoxifene acetate crystal form A is more cumbersome and is not suitable for large-scale production
CN103864664A discloses a bazedoxifene acetate polymorph E, which needs to use petroleum ether in the preparation process, which belongs to flammable and explosive raw materials, is not easy to operate in workshop production, and has great potential safety hazards
[0008] In the preparation method of bazedoxifene acetate polymorph B disclosed in US20050250762, the preparation process needs to be prepared under the protection of an inert gas, react overnight, the reaction cycle is too long, and the reaction system is a mixed solvent system that requires denaturation of the solvent. Too cumbersome, not conducive to workshop operations
The preparation of polymorph B of bazedoxifene acetate disclosed by CN1938271A is obtained by transcrystallization of polymorph A, and there is no disclosed method for directly preparing polymorph B from free base

Method used

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  • Preparation method of bazedoxifene acetate polycrystalline type B
  • Preparation method of bazedoxifene acetate polycrystalline type B
  • Preparation method of bazedoxifene acetate polycrystalline type B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Weigh 4.0g of bazedoxifene free base and 12.0g of methyl tert-butyl ether into a 250mL three-neck flask, control the temperature and stir to dissolve at 18°C, add 1.1g (3eq) of glacial acetic acid and continue to insulate and stir for 1 hour, then cool down to Suction filtration at 10°C, and the filter cake was washed with an appropriate amount of methyl tert-butyl ether to obtain bazedoxifene acetate polymorph B solid. The solid was vacuum-dried at 35°C to obtain 3.19 g of bazedoxifene acetate, with a yield of 98.0%.

Embodiment 2

[0036] Weigh 4.0g of bazedoxifene free base and 40.0g of methyl tert-butyl ether in a 250mL three-neck flask, stir and dissolve under temperature control at 27°C, add 0.37g (1eq) of glacial acetic acid and continue to insulate and stir for 2 hours before cooling down to Suction filtration at 20°C, and the filter cake was washed with an appropriate amount of methyl tert-butyl ether to obtain bazedoxifene acetate polymorph B solid. The solid was vacuum-dried at 40°C to obtain 3.16 g of bazedoxifene acetate, with a yield of 97.0%.

Embodiment 3

[0038] Weigh 4.0g of bazedoxifene free base and 160.0g of methyl tert-butyl ether in a 250mL three-necked flask, control the temperature and stir to dissolve at 35°C, add 0.73g (2eq) of glacial acetic acid and continue to insulate and stir for 3 hours before cooling down to Suction filtration at 10°C, and the filter cake was washed with an appropriate amount of 4-methyl-2-pentanone to obtain bazedoxifene acetate polymorph B solid. The solid was vacuum-dried at 40°C to obtain 3.18 g of bazedoxifene acetate, with a yield of 97.5%.

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Abstract

The invention discloses a preparation method of bazedoxifene acetate polycrystalline type B. Bazedoxifene free alkali and glacial acetic acid are taken as raw materials and salified to obtain the bazedoxifene acetate polycrystalline type B. The operation conditions of the preparation process are simple and do not need to be carried out under the protection of inert gas; no antioxidant is used in the preparation process; the yield and purity of the prepared product are high, and therefore the product is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of bazedoxifene acetate polymorph B. Background technique [0002] The chemical name of bazedoxifene acetate is 1-(4-(2-azepan-1-yl-ethoxy-benzyl)-2-(4-hydroxy-phenyl)-3-methyl -1H-indole-5-phenolacetic acid, having the structural formula shown below: [0003] [0004] Bazedoxifene acetate belongs to the class of selective estrogen receptor modulators (SERMs), which have affinity for the estrogen receptor (ER) and exhibit tissue-selective estrogenic effects. Bazedoxifene acetate exhibits estrogen agonist-like effects in preventing bone loss and reducing cholesterol in an ovariectomized mouse model of osteopenia. In the MCF-7 cell line (a human breast cancer cell line), bazedoxifene acetate acts as an estrogen antagonist. Bazedoxifene acetate not only has obvious curative effect on osteoporosis, but also has less stimulation to cardiovascular and mamm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07B2200/13C07D209/12
Inventor 宣景安孟志罗宏军骆宏鹏袁峰泉尹必喜李国贤朱晶
Owner YANGTZE RIVER PHARM GRP CO LTD
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