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New synthetic method of bazedoxifene

A new synthesis, benzyloxy technology, applied in the direction of organic chemistry, can solve the problems of increasing the difficulty of purification of the final product, increasing the cost of synthesis, and increasing the amount of starting material, so as to improve the overall conversion rate, shorten the reaction steps, The effect of mild reaction conditions

Active Publication Date: 2012-09-26
南京正济医药销售有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (1) The yield of the substitution reaction on indole N is low, and the reagent sodium hydride used is not easy to preserve
[0010] (2) The LAH active reagent used for reduction also has hidden dangers such as storage safety
[0011] (3) The yield is low during indole synthesis, only 50%-60%, and there are four steps of reaction after the indole cyclization, which makes the initial charge increase and improves the synthesis cost
[0012] (4) The impurities generated by the azepine ring modification reaction are not easy to control, and the modification in the last few steps will directly increase the difficulty of purification of the final product
[0016] (1) In the sodium borohydride reduction reaction of benzaldehyde, the sodium borohydride equivalent number used is high, quenching takes a lot of time and produces a large amount of flammable and explosive hydrogen, which has potential safety hazards
[0017] (2) The yield of the substitution reaction on the indole N is low, and the reagent sodium hydride used is not easy to preserve
[0020] The yield of this reaction is only 50%-60%, so it should not be placed in the first half of the route

Method used

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  • New synthetic method of bazedoxifene
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the synthesis of intermediate 4-(2-(azepan-1-yl)ethoxy)benzaldehyde (4)

[0032] The first step: the synthesis of intermediate 1-(2-bromoethyl)azepine (2)

[0033]

[0034] Add 100g of azepane (1), 246.2g of 1,2-dibromoethane (2), and 208.9g of potassium carbonate into a 2L three-necked flask, and finally add 1.25L of acetonitrile, and heat at 100 degrees to react after everything is mixed evenly. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, potassium carbonate was removed by filtration, the organic solvent was removed from the filtrate under reduced pressure, the residue was evaporated and dissolved in 800 mL of dichloromethane, washed 2-3 times with water, dried over anhydrous sodium sulfate, and then decompressed. Removal of the dichloromethane gave an oil 185.5 g, 89.1% yield.

[0035] The second step: the synthesis of intermediate 4-(2-(azepan-1-yl)ethoxy)benzaldehyde (4)

[0036]

[0037] Add 1...

Embodiment 2

[0038] Embodiment 2: Synthesis of intermediate N-(4-(2-(azepan-1-yl)ethoxy)benzyl)-4-(benzyloxy)aniline (6)

[0039]

[0040] Add 50.0g of 4-(benzyloxy)aniline (5) and 74.4g of 4-(2-(azepan-1-yl)ethoxy)benzaldehyde (4) into a 1L three-necked flask, and dissolve them in 500mL of ethanol , the reaction system was cooled to 0-5 degrees in an ice-water bath, and 106.3 g of sodium triacetoxyborohydride was slowly added in batches. After the addition, the temperature of the reaction solution was raised to 35 degrees, and the reaction was stirred. After the reaction was detected by TLC, the reaction solution was cooled to 0-5 degrees, and 200 mL of water was slowly added to it. After the addition, it was stirred for two small tests, separated, the water phase was discarded, the organic phase was concentrated to dryness, and the product was purified by silica gel column chromatography. 85.5 g, yield 79.2%.

Embodiment 3

[0041] Example 3: 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl Synthesis of )-3-methyl-1H-indole (8)

[0042]

[0043] Add N-(4-(2-(azepan-1-yl)ethoxy)benzyl)-4-(benzyloxy)aniline (6) 5.0g in a 25mL single-necked bottle, 1-(4 -(Benzyloxy)phenyl)-2-bromoethane-1-one (7) 9.2g, and triethylamine 2.9g, dissolved in 4mL N,N-dimethylformamide, heated to 120 degrees under stirring to react After the reaction was detected by TLC, the reaction liquid was cooled to 0-5 degrees, poured into 20 mL of water, extracted with ethyl acetate and recrystallized in methanol to obtain 10.3 g of solids, with a yield of 55.0%.

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Abstract

The invention discloses a new synthetic method of bazedoxifene. Bazedoxifene is prepared by the steps of bromination, substitution, reductive amination, substitution, cyclization, deprotection, and the like of azepane which is selected as a raw material. The synthetic method of the invention has the advantages of mild reaction conditions, simple and convenient operating process, easily obtained reagent, and low cost.

Description

(1) Technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular, the invention relates to a new synthesis method of bazedoxifene, a medicine for treating postmenopausal women's osteoporosis. (2) Technical background [0002] Bazedoxifene, English name Bazedoxifene, is an indole derivative, its chemical name is 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4 -hydroxyphenyl)-3-methyl-1H-indole-5-ol. Its chemical structural formula is as follows: [0003] [0004] Bazedoxifene, originally developed by Wyeth, is a third-generation selective estrogen receptor modulator. Launched in Italy and Spain in April 2009, the trade name is Conbriza, which is used to treat osteoporosis in postmenopausal women. [0005] There are mainly two synthetic methods of bazedoxifene reported in the literature at present. [0006] 1. EP 0802183, JP 1998036346, and US 5998402 use p-hydroxybenzyl alcohol as the starting material and replace it with ethyl brom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
Inventor 葛敏叶援赞付明伟胡春晨
Owner 南京正济医药销售有限公司
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