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Preparation method of bazedoxifene acetate crystal form A

A technology of bazedoxifene acetate and crystal form, applied in the field of chemical pharmacy, can solve problems such as difficulty, and achieve the effects of good reproducibility, obvious advantages in preparation process, and high purity and yield

Inactive Publication Date: 2014-09-10
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, crystal form A is a metastable crystal form, while crystal form B is a thermodynamically stable crystal form. When crystal form A is in an organic solvent (such as ethanol or a mixture of ethanol and other solvents), it is very easy to transform into crystal form B or crystal Form D, so it is more difficult to prepare crystal form A with a purity of more than 99%

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
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Preparation of bazedoxifene free base III

[0061]Add distilled water to 10% Pd / C and wash twice, filter off part of distilled water to control its water content at 50~56%; 20g (0.031mol) 5-benzyloxy-2-(4-benzyloxyphenyl )-3-methyl-1-[4-(2-azepan-1-ylethoxy) benzyl]-1H-indole II was dissolved in 120ml ethyl acetate and 40ml ethanol, added 13.5 g The above Pd / C is heated to 50~55°C, stirred and reacted at 0.1MPa for 4~5h, and the reaction is completed by TLC monitoring. Filter out Pd / C under the protection of argon, add trace vitamin C and acetic acid to the solution directly at 50~55°C to form acetate, the yield is 100%

Embodiment 2

[0062] Embodiment 2: Preparation of bazedoxifene acetate I

[0063] Put the filtrate in Example 1 in a 250ml reaction bottle, add a small amount of vitamin C, vacuumize, replace with argon 1~2 times, heat up to 50°C~55°C, add 2.06g (0.034mol) of glacial acetic acid dropwise to the reaction solution, stirred at 50°C~55°C for 1~1.5h, stirred at room temperature for 2h, filtered to obtain an off-white solid, washed the solid with ethanol for 1~2 times, and dried to obtain 12.11g of off-white solid, yield 83.7%, HPLC: 99.67 %, mp177-180°C.

Embodiment 3

[0064] Embodiment 3: Refining of bazedoxifene acetate I

[0065] Add 83.8ml of ethanol, 51.2ml of acetone, 10.48ml of water and a small amount of vitamin C to the dried 12.11g of solid, heat to reflux until all the solid is dissolved, then slowly cool down to room temperature, and put it in the refrigerator (-5~-0°C) After overnight, it was filtered and dried to obtain 9.81 g of off-white solid, yield 81.2%, HPLC: 99.86%, mp 178-180°C.

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Abstract

Bazedoxifene is one of novel SERMs (Selective Estrogen Receptor Modulators) which are strictly screened, are specially used for preventing or treating osteoporosis of postmenopausal women and almost have no stimulation for breasts and uterus; just like other SERMs (tamoxifen and raloxifene), bazedoxifene takes double effects of excitement and antagonism for ER (Estrogen Receptor) in a target tissue. Preclinical and clinical experiments both prove that bazedoxifene has the characteristics of good curative effect, small side effect and strong specifity so as to be the first choice drug for treating and preventing woman postmenopausal osteoporosis in future. Compared with other crystal forms (B, C and D), a bazedoxifene acetate crystal form A has better solubleness and bioavailability and is the first choice crystal form on the market. The invention discloses a preparation method of the bazedoxifene acetate crystal form A, and the bazedoxifene acetate crystal form A is prepared by using the method.

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 (trade name: Conbriza), chemical name: 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-( 4-hydroxyphenyl)-3-methyl-1H-indole-5-phenolacetic acid, the structural formula is as follows: [0003] [0004] Bazedoxifene is the third generation of selective estrogen receptor modulators (SERMs) developed by Wyeth in 1997. In addition to having the therapeutic effect of the previous two generations of SERMs on osteoporosis, it has no such effects as Raloxifene responds to an increase in the incidence of hot flashes, and has less stimulation to cardiovascular and mammary glands than the previous two generations of SERMs, and basically has no side effects of endometrial hyperplasia. It has definite efficacy, high tolerance, and no toxic side effects Small, with broad market pr...

Claims

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Application Information

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IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 吴勇海俐胥涛裴叔宸屈博毅
Owner SICHUAN UNIV
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