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Method for preparing bazedoxifene acetate intermediate

A technology of bazedoxifene acetate and an intermediate is applied in the field of intermediate synthesis of a drug bazedoxifene acetate for treating or preventing osteoporosis in postmenopausal women, and can solve the problems of many steps, many steps in the synthesis route and reaction yield. lower problem

Active Publication Date: 2014-04-23
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this patent are: there are many steps in the synthetic route; the yield of the substitution reaction on the indole N in the third step is low; LAH and NaH have potential safety hazards; Product purification difficulty
The disadvantages of this patent are: sodium borohydride and sodium hydrogen have potential safety hazards; azepine is brought in from the starting material, and inert gas or antioxidant protection is required for subsequent reactions and drying if there is a free base.
The disadvantage of this patent is that: the azepine ring is brought in from the first step reaction, because the N on the azepine ring is easy to introduce new impurities; the yield of the last two-step reaction is low
The weak point of this patent is: the price of starting materials is expensive and difficult to purchase
The weak point of this patent is: the 4th and the 5th step reaction yield are low
The weak point of this patent is: more steps

Method used

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  • Method for preparing bazedoxifene acetate intermediate
  • Method for preparing bazedoxifene acetate intermediate
  • Method for preparing bazedoxifene acetate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Preparation of 4-(formylphenoxy)-ethyl acetate

[0071]

[0072] Add p-hydroxybenzaldehyde (24.4g, 0.2mol), ethyl 2-bromoacetate (33.4g, 0.2mol) and potassium carbonate (55.2g, 0.4mol) into a 500ml three-necked flask, then add 300ml of acetonitrile, at 50°C The reaction was stirred for 5h. After cooling to room temperature, filter out the insoluble matter, spin the filtrate potassium salt, dissolve the residual soluble matter in 200ml of dichloromethane, wash 3 times with water, dry over anhydrous magnesium sulfate, filter, spin the filtrate, and dry the crude product to obtain 37.98g of the product , yield 91.3%.

[0073] Preparation of N-(4-(ethyl acetate ethyl ether) benzyl)-4-benzyloxyaniline

[0074]

[0075] Add 300ml of ethanol, 4-benzyloxyaniline (29.8g, 0.15mol) and 4-(formylphenoxy)-ethyl acetate (31.2g, 0.15mol) into a 500ml three-necked flask, stir well, and cool the solution At 0-5°C, sodium borohydride (14.0 g, 0.37 mol) was added in batches. Afte...

Embodiment 2

[0080] Preparation of 2-(4-formylphenoxy)-acetonitrile

[0081]

[0082] Add p-hydroxybenzaldehyde (24.4g, 0.2mol), 2-bromoacetonitrile (24g, 0.2mol) and potassium carbonate (55.2g, 0.4mol) into a 500ml three-necked flask, then add 300ml of acetonitrile, and stir at 50°C for 5h . After cooling to room temperature, filter out the insoluble matter, spin-evaporate the potassium salt of the filtrate, dissolve the residual soluble matter in 200ml of dichloromethane, wash 3 times with water, dry over anhydrous magnesium sulfate, filter, spin-evaporate the filtrate, and dry the crude product to obtain 28.72g of the product , yield 89.1%.

[0083] Preparation of N-(4-(acetonitrile ether)benzyl)-4-benzyloxyaniline

[0084]

[0085] Add 300ml of ethanol, 4-benzyloxyaniline (29.8g, 0.15mol) and 2-(4-formylphenoxy)-acetonitrile (24.15g, 0.15mol) into a 500ml three-necked flask, stir well, and cool the solution At 0-5°C, sodium borohydride (14.0 g, 0.37 mol) was added in batches. ...

Embodiment 3

[0090] Amide group

[0091] Preparation of 4-(formylphenoxy)-acetamide

[0092]

[0093] Add p-hydroxybenzaldehyde (24.4g, 0.2mol), 2-bromoacetamide (27.6g, 0.2mol) and potassium carbonate (55.2g, 0.4mol) into a 500ml three-necked flask, then add 300ml of acetonitrile and stir at 50°C Reaction 5h. After cooling to room temperature, filter out the insoluble matter, spin the filtrate potassium salt, dissolve the residual soluble matter in 200ml of dichloromethane, wash with water 3 times, dry over anhydrous magnesium sulfate, filter, spin the filtrate, and dry the crude product to obtain 27.31g of the product , yield 76.3%.

[0094] Preparation of N-(4-(acetamide)benzyl)-4-benzyloxyaniline

[0095]

[0096] Add 200ml of ethanol, 4-benzyloxyaniline (19.9g, 0.10mol) and 4-(formylphenoxy)-acetamide (14.3g, 0.08mol) into a 500ml three-necked flask, stir well, and cool the solution to At 0-5°C, sodium borohydride (7.57g, 0.20mol) was added in batches. After the addition, th...

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Abstract

The invention discloses a method for preparing a bazedoxifene acetate intermediate. The preparation method comprises the following steps: 1, condensing 4-hydroxybenzaldehyde S01 and alkylate S02 to prepare a 4-formyl phenoxy derivative M01; 2, performing reduction and ammoniation on the 4-formyl phenoxy derivative M01 and 4-benzyloxyaniline S03 to prepare an N-(4-benzyl)-4-benzyloxyaniline derivative M02; and 3, performing ring formation on the N-(4-benzyl)-4-benzyloxyaniline derivative M02 and 4'-benzyloxy-2-bromopropiophenone S04 to prepare a 5-benzyloxy-2-(4-(benzyloxyphenyl)-3-methyl-1H-indol derivative M03.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular, the invention relates to a method for synthesizing an intermediate of bazedoxifene acetate, a medicine for treating or preventing osteoporosis in postmenopausal women. Background technique [0002] Bazedoxifene Acetate, chemical name: 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl )-3-methyl-1H-indole-5-phenol acetate, its structure is as follows: [0003] [0004] Bazedoxifene Acetate, a selective estrogen receptor modulator drug jointly developed by Ligand Company, Wyeth and Almirall Company, was first approved in Europe in April 2009, with the trade name "Conbriza". [0005] Preclinical test data show that bazedoxifene has more targeted activity than other selective estrogen receptor modulators (SERMs) known so far, and is the "best-in-class product" so far. Clinical studies have shown that it is significantly better than placebo in terms of increasing b...

Claims

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Application Information

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IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 宋波高波李日东杨琰
Owner CHINA RESOURCES SAIKE PHARMA