Preparation method of (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol

A technology of azepane and ethoxy, which is applied in the field of drug synthesis, can solve the problems of good product quality, high toxicity of raw materials, and high yield, and achieve the effect of good product quality, high toxicity of raw materials, and high yield

Inactive Publication Date: 2015-06-24
BEIJING LABWORLD BIO MEDICINE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The invention provides the preparation of (4-(2-(azepan-1-yl)ethoxy)phenyl) with low toxicity 2-(azepane)-1-ethanol as the starting material The

Method used

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  • Preparation method of (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol
  • Preparation method of (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol
  • Preparation method of (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: Preparation of 2-(azepan-1-yl)ethyl-4-methylbenzenesulfonate

[0022] Weigh 2.15 g of 2-(azepane)-1-ethanol (15.0 mmol) and mix with 20 ml of anhydrous pyridine, stir to cool to 0°C, and add 2.86 g of p-toluenesulfonyl chloride (15.0 mmol). After the addition, react at room temperature for 3 hours, add water to quench the reaction, continue to stir for 30 minutes, add dichloromethane, add 1M hydrochloric acid dropwise under stirring to adjust the pH=6-7, stir for 30 minutes and then let it stand for stratification. The methane layer was washed with water and saturated brine successively, then dried (anhydrous sodium sulfate), filtered, and dichloromethane was distilled off under reduced pressure to obtain a purple oil, which was directly used in the next reaction without further purification.

Embodiment 2

[0023] Embodiment two: the preparation of 4-(2-(azepan-1-yl)ethoxy)benzaldehyde

[0024] A certain amount of 2-(azepan-1-yl)ethyl-4-methylbenzenesulfonate and an equimolar amount of 4-formylphenol sodium were mixed in DMF, stirred and heated to 80°C, and monitored The response is complete. After the reaction is completed, cool to room temperature, pour the reaction solution into water, add dichloromethane to extract, combine the dichloromethane phases, wash with water and saturated brine successively, dry (anhydrous magnesium sulfate), filter, and distill off the dichloromethane, leaving The product was purified by column chromatography (n-hexane / ethyl acetate=98:2) to obtain 4-(2-(azepan-1-yl)ethoxy)benzaldehyde as a colorless oil with a yield of 80% . IR (nujol): 2926, 2853, 1695, 1603, 1507, 1312, 1259, 1160, 1021 and 834cm -1 . 1 H NMR (300MHz, CDCl 3 ): δ1.65-1.70(8H,m,4×CH2),2.87(4H,brs,2×NCH 2 ),3.06(2H,t,NCH2),4.22(2H,t,OCH 2 ), 7.05 (2H, d, 2×Ar-H), 7.86 (2H, d...

Embodiment 3

[0025] Example 3: Preparation of (4-(2-(azepan-1-yl)ethoxy)phenyl)methanol

[0026] Mix 4.5mmol of the reaction product of the previous step with 25ml of methanol, add 3.1mmol of sodium borohydride in batches at room temperature, and react for 3-5 hours at room temperature after addition, monitor the reaction by TLC (developer: methanol / dichloromethane=1: 9). After the reaction was completed, methanol was distilled off under reduced pressure, and 15ml of water was added to the residue, extracted 3 times with ethyl acetate (50ml x 3 times), the combined ethyl acetate phase was washed with water 3 times (50ml x 3 times), dried (anhydrous sodium sulfate), filtered, and distilled off ethyl acetate under reduced pressure to obtain an oily product with a yield of 80-90%. IR (nujol): 3360, 2934, 2867, 1610, 1513, 1456, 1325, 1300, 1247, 1176, 1055, 1010, 823cm -1 . 1 HNMR (CDCl 3 / TMS):7.28(d,2H),6.86(d,2H),4.61(s,2H),4.06(t,2H),2.94(t,2H),2.76(m,4H),1.7-1.5( m, 8H).

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Abstract

The invention provides a preparation method suitable for industrial production of (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol. The method is characterized in that a bazedoxifene synthesis key intermediate (4-(2-azacycloheptane-1-yl)ethoxy)phenyl)methanol is obtained through a three step reaction of low-toxicity 2-(azacycloheptane)-1-ethanol as an initial raw material. The method has the advantages of low-toxicity cheap raw material, simple operation, mild condition, simple post-treatment and high yield, and is a preparation route very suitable for industrialization.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular, the invention relates to the synthesis of a key intermediate of bazedoxifene acetate, a medicine for treating osteoporosis in postmenopausal women. Background technique [0002] Bazedoxifene acetate, the English name is Bazedoxifene Acetate, its structural formula is: [0003] [0004] Bazedoxifene acetate was originally developed by Wyeth and later transferred to Pfizer. It is a third-generation selective estrogen receptor modulator and is mainly used for the treatment of osteoporosis in postmenopausal women. It was launched in Italy and Spain in April 2009 under the product name Conbriza, in 2010 it was launched in Japan under the product name Viviant, and in October 2013 it was approved for listing in the United States under the product name Duavee. [0005] At present, the method for the preparation of bazedoxifene reported is relatively simple and feasible to ha...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D209/12
CPCC07D295/088C07D209/12
Inventor 温光辉宛六一付冀峰
Owner BEIJING LABWORLD BIO MEDICINE TECH
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