Preparation method of novel azacycloheptane derivative

A technology of cycloheptane base body and compound is applied in the field of pharmaceutical synthesis, which can solve the problems of high cost, many impurities and high yield, and achieves the effects of high toxicity, good product quality 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

[0011] The invention provides a method for preparing 1-(2-chloroethyl)azepane hydrochloride by using 1,6-hexanediol as a raw material, which not only solves the problem of high toxicity and high cost of raw materials in the existing process , the problem of many impurities, and the product quality is good and the yield is high

Method used

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  • Preparation method of novel azacycloheptane derivative
  • Preparation method of novel azacycloheptane derivative
  • Preparation method of novel azacycloheptane derivative

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0017] Example 1: Preparation of 1,6-di-hexanediol-toluenesulfonate

[0018] Weigh 1.77 g of 1,6-hexanediol (15.0 mmol) and mix with 30 ml of anhydrous pyridine, stir and cool down to 0°C, and add 8.58 g of p-toluenesulfonyl chloride (45.0 mmol). After the addition, react at room temperature for 3 hours, add 3ml of 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 methyl chloride layer was washed with water and saturated brine successively, then dried (anhydrous sodium sulfate), filtered, dichloromethane was distilled off under reduced pressure, and the residue was first purified by column chromatography (dichloromethane / n-hexane / acetone=48:50 : 2), and then recrystallized (dichloromethane / n-hexane) to obtain 5.12 g of 1,6-dihexanediol di-p-toluenesulfonate (80%). Mp:77-79℃, 1 H NMR (500MHz, CDCl 3 )δ1.25-...

Embodiment 2

[0019] Example 2: Preparation of 2-(azepane)-1-ethanol

[0020] A certain amount of 1,6-dihexanediol di-p-toluenesulfonate is mixed with excess ethanolamine and toluene, stirred and heated to 120°C, and reacted for 2 hours. After the reaction is completed, excess ethanolamine is evaporated under reduced pressure, and di Chloromethane, then washed with water and saturated brine successively, dried (anhydrous magnesium sulfate), filtered, distilled to remove dichloromethane, the residue was purified by column chromatography (n-hexane / ethyl acetate=98:2) to obtain oil 2 -(azepane)-1-ethanol, yield 90%.

[0021] Bp: 97°C (14mmHg)

Embodiment 3

[0022] Example 3: Preparation of 1-(2-chloroethyl)azepane hydrochloride

[0023] Mix a certain amount of 2-(azepane)-1-ethanol with dichloromethane, add 5 molar equivalents of thionyl chloride and a catalytic amount of DMF, stir and heat to reflux, react for 2 hours, cool down and filter, filter The cake was washed with dichloromethane, recrystallized from isopropanol, and dried in vacuo to give 1-(2-chloroethyl)azepane hydrochloride in a yield of 85%. Mp: 208-209°C.

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Abstract

The invention provides a preparation method of 1-(2-haloethyl)azacycloheptane base ligand and its acid salt. The preparation method is suitable for industrial production. The preparation method is characterized in that 1,6-hexanediol as an initial raw material undergoes three-step reactions to produce the 1-(2-haloethyl)azacycloheptane base ligand and its acid salt. The 1-(2-haloethyl)azacycloheptane base ligand and its acid salt are key intermediates for bazedoxifene synthesis. The preparation method has the advantages of cheap raw material, operation simpleness, mild conditions, simple after-treatment and high yield and is a preparation route 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): C07D295/067C07D209/12
CPCC07D295/067
Inventor 温光辉宛六一付冀峰
Owner BEIJING LABWORLD BIO MEDICINE TECH
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