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Preparation method of bazedoxifene acetate

A technology of bazedoxifene acetate and acetic acid, applied in the field of medicine, can solve the problems of high equipment requirements, industrialized amplification, complicated operation, etc., and achieve the effects of high reaction efficiency, short reaction time, safe and controllable operation

Active Publication Date: 2017-05-10
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the above hydrogenation reduction deprotection method is simple and feasible, relatively expensive palladium carbon is used in the reaction and needs to be reacted under high temperature and high pressure (high pressure of 3-10Mpa). There are potential safety hazards such as leakage and explosion, and it is difficult to scale up industrialization

Method used

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  • Preparation method of bazedoxifene acetate
  • Preparation method of bazedoxifene acetate
  • Preparation method of bazedoxifene acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 1) Preparation of slurry: Dissolve 100 g of compound I completely in 500 ml of ethanol, add 3 g of Raney nickel at room temperature, stir evenly, and obtain a slurry for later use.

[0027] 2) Microreactor reaction: Use nitrogen to fully replace the air in the heating zone of the microreactor, then preheat the heating zone of the microreactor to an internal temperature of 30°C, then pass in hydrogen, and control the pressure at 0.2-0.3MPa to complete the step 1) The slurry is pumped into the heating zone of the microreactor through the slurry pump to control the temperature at 30°C and react for 3-8s; after the reaction is completed, pass through the cooling zone (the cooling zone is cooled by circulating water), and then collect the reaction solution;

[0028] 3) Generate bazedoxifene acetate: remove the insoluble matter by filtration, slowly add 10 g of acetic acid dropwise to the filtrate, and a white solid will slowly precipitate out. After the dropwise addition, coo...

Embodiment 2

[0030] 1) Preparation of slurry: Dissolve 500g of compound I completely in 4000ml of ethanol and ethyl acetate (3:1) mixture, add 20g of Raney nickel at room temperature, stir well, and set aside;

[0031] 2) Micro-reactor reaction: Use nitrogen to fully replace the air in the micro-reactor, preheat the micro-reactor to an internal temperature of 40°C, feed hydrogen, control the reaction pressure at 0.3-0.4MPa, and pump the slurry into the micro-reactor by the slurry pump In the reactor, control the temperature in the heating area at 40°C for 1-5s; after the reaction is completed, pass through the cooling area to cool (the cooling area is cooled by circulating water), and then collect the reaction liquid;

[0032] 3) Remove insoluble matter by filtration, slowly add 50g of acetic acid dropwise to the filtrate, and a white solid will slowly precipitate out. After the dropwise addition, cool down to 10°C-20°C, keep warm for crystallization for 1h, filter with suction, and air-dry...

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Abstract

The invention discloses a preparation method of bazedoxifene acetate. The method is characterized in that raney nickel is used as a catalyst, and a compound I and hydrogen react in a microreactor to obtain bazedoxifene under the conditions that the temperature is 20 to 40DEG C and the hydrogen pressure is controlled to be 0.1 to 0.5Mpa. According to the method, the raney nickel with lower price is used to replace expensive palladium carbon, so that the production cost is effectively reduced, the microreactor is used and the production is in streamline operation; an obtained product is high in yield and good in quality; the preparation method has the advantages of high reaction efficiency, mild reaction conditions, safe and controllable operation, short reaction time and low cost; the method is easier for industrial production (The formula is shown in the description).

Description

technical field [0001] The invention relates to a preparation method of bazedoxifene acetate, which belongs to the technical field of medicine. Background technique [0002] Bazedoxifene is a new generation of selective estrogen receptor modulator (SERM), which can competitively inhibit the binding of 1713-estradiol to estrogen receptors ERoc and ER13, and has estrogen agonists on bone Active, can improve the bone density of the spine and hip, so it can significantly reduce the risk of vertebral fractures in postmenopausal women with osteoporosis. Its structural formula is as follows: [0003] [0004] There are many synthetic methods of bazedoxifene, but at present most of the synthetic methods all prepare 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy Base-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole, and then debenzyl protection by hydrogenation reduction to obtain bazedoxifene. Most of the debenzylation methods in this route use palladium carbon catalytic hydrogenati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 江海平杨庆坤李保勇吴柯张兆珍董廷华杨波勇周学文高大龙吴兆申
Owner 山东安信制药有限公司
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