Industrial production method for bazedoxifene acetate

A technology of bazedoxifene acetate and a production method, applied in the directions of organic chemistry, carboxylate preparation, etc., can solve problems such as difficult post-processing purification, achieve high economic value and social benefits, easy availability of cost, reduced complexity and low cost. The effect of manufacturing cost

Active Publication Date: 2018-03-13
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route has been improved on the previous basis, but in the preparation process of cyclohexyl imide brominated product, because 1,2-dibromoethane needs excessive, very easily produces the by-product that dicyclohexyl imine replaces, aftertreatment Purification is not easy, and this problem will become more prominent as the batch scales up

Method used

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  • Industrial production method for bazedoxifene acetate
  • Industrial production method for bazedoxifene acetate
  • Industrial production method for bazedoxifene acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]The specific synthetic operation of compound 3 is as follows:

[0042] In a 1000L reactor, add 200kg of DMF, add 17kg of compound 1 and 30kg of compound 2 at room temperature, raise the temperature to 40°C, add 600kg of purified water after the reaction is complete, separate the organic phase, concentrate and spin dry, and obtain 31.2kg of light brown Solid, yield: 93.5%, HPLC purity: 95.1%.

[0043] Table 1 Compound 3 yield quality compared with literature method

[0044]

[0045] [1] The literature method is CN 102690225B Example 1

Embodiment 2

[0047] The specific synthetic operation of compound 4 is as follows:

[0048] In a 500L reactor, add 130kg of boron trifluoride ether solution, 30kg of compound 3 prepared in Example 1, and 6.4kg of sodium borohydride, and react at 15°C for 2 hours. After the reaction, quench with 25kg of saturated ammonium chloride solution, and then Add 80kg of 5% sodium hydroxide solution, filter and dry to obtain off-white solid. The reaction kettle was cooled to 5°C, and 75kg of thionyl chloride was added dropwise. After the reaction, 100kg of acetone was added to stir, filtered, and dried to obtain 27.8kg of light brown solid, yield: 85.1%, HPLC purity: 96.3%.

[0049] Table 2 Compound 4 yield quality compared with literature method

[0050] Example

[0051] [1] The literature method is CN 104151265 B embodiment 1~4 method.

Embodiment 3

[0053] The specific synthetic operation of compound 5 is as follows:

[0054] Add 90kg of DMF to a 1000L reactor, add 30kg of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole at room temperature and stir until dissolved, add 60kg of sodium hydroxide and 12kg of water were activated for 1h, then the DMF solution of compound 4 prepared in Example 2 was added (24kg of compound 4 was dissolved in 210kg of DMF), and the reaction was carried out at room temperature for 3h. After the reaction was completed, 600kg of purified water was added, stirred and crystallized at room temperature for 8h , filtered and dried to obtain 38.5kg off-white solid, yield: 82.7%, HPLC purity 95.3%.

[0055] Add 90kg of DMSO to a 1000L reactor, add 30kg of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole at room temperature and stir until dissolved, add 50kg of solid sodium hydroxide and 12kg of water were activated for 1h, then the DMSO solution of compound 4 was added (24kg of compound...

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Abstract

The invention discloses an industrial production method for bazedoxifene acetate. The production method comprises the following steps: taking p-hydroxy benzaldehyde as a starting material, substituting with chloracetyl-hexamethyleneimine, reducing with borohydride and chlorinating with a chlorinating agent to obtain a compound 4; reacting the compound 4 with 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole to obtain a compound 5; and carrying out debenzylation to obtain a compound 6, and salifying with acetic acid to obtain a target compound which is the bazedoxifene acetate. The defective workmanship of preparation in the prior art is solved, the used reagent is low in cost and easy to obtain, environmental pollution is small, safety is high, an operation process is simple, and thus, the bazedoxifene acetate is suitable for being produced industrially.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to an industrial production method of bazedoxifene acetate. 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-phenol acetate is the third generation of selective estrogen receptor modulators (SERMs) developed by Wyeth in 1997; it passed the European Drug Administration in April 2009 The European Union (EMEA) approved the listing in Italy and Spain, with the product name Conbriza; it was launched in Japan and the United States in July 2010 and October 2013, respectively, for the treatment of moderate to severe menopause-related vasomotor symptoms (hot flashes) ) and prevention of postmenopausal osteoporosis. [0003] At present, the synthesis of bazedoxifene acetate reported in the literature has the following three methods: [0004] Rout...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12C07C51/41C07C53/10
CPCC07D209/12
Inventor 吴剑华徐镜人蔡伟朱晓鹤张海波吕慧敏胡涛肖灿顾诚徐辰俊
Owner YANGTZE RIVER PHARM GRP CO LTD
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