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A kind of synthetic method of r-salmeterol

A synthesis method and compound technology, applied in the field of synthesis of drug R-salmeterol, can solve the problems of unstable product quality, poor stereoselectivity, harsh reaction conditions, etc., and achieve low production cost, simple route, and mild reaction conditions Effect

Active Publication Date: 2018-11-13
JOINCARE HAIBIN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The purpose of the present invention is to provide a new synthetic method of R-salmeterol to overcome the problems of harsh reaction conditions, cumbersome steps, poor stereoselectivity, low yield and unstable quality of finished products in the prior art

Method used

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  • A kind of synthetic method of r-salmeterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: the preparation of compound (II)

[0057] Weigh bromide 10g (30.5mmol), dissolve in 80mL dichloromethane, add K 2 CO 3 5.0 g (36.6 mmol), and 12.4 g (36.6 mmol) of N-benzyl-6-(4-phenylbutoxy)-1-hexylamine were slowly added dropwise under stirring, and the reaction system gradually became cloudy. React at room temperature (25°C) for 5 hours, stop stirring, remove the solid in the reaction liquid by suction filtration, add ethyl acetate (100 mL) to the filtrate to dilute, then wash with water and saturated brine in sequence, after the pH detection of the organic phase is neutral, anhydrous Dry over sodium sulfate, filter, and remove the solvent by rotary evaporation to obtain 17 g of oily product (II), with a yield of 95%.

[0058] 1 H NMR (CDCl 3 ):δ1.25-1.28(m,3H),1.50-1.67(m,9H),2.07(s,3H),2.34(s,3H),2.58-2.65(m,4H),3.32-3.41(m ,6H),3.72(s,1H),3.80(s,1H),5.07(s,2H),7.14-7.19(m,6H),7.24-7.34(m,7H).

Embodiment 2

[0059] Embodiment 2: the preparation of compound (II)

[0060] Weigh 10g (30.5mmol) of the bromide, dissolve it in 80mL of dichloromethane, add 3.7g (36.6mmol) of triethylamine, slowly add N-benzyl-6-(4-phenylbutoxy)- 12.4 g (36.6 mmol) of 1-hexylamine, the reaction system gradually became cloudy. React at room temperature (25°C) for 5 hours, stop stirring, remove the solid in the reaction liquid by suction filtration, add ethyl acetate (100 mL) to the filtrate to dilute, then wash with water and saturated brine in sequence, after the pH detection of the organic phase is neutral, anhydrous After drying over sodium sulfate, the solvent was removed by rotary evaporation to obtain 16 g of yellow oily product (II), with a yield of 90%.

[0061] 1 H NMR (CDCl 3 ):δ1.25-1.28(m,3H),1.50-1.67(m,9H),2.07(s,3H),2.34(s,3H),2.58-2.65(m,4H),3.32-3.41(m ,6H),3.72(s,1H),3.80(s,1H),5.07(s,2H),7.14-7.19(m,6H),7.24-7.34(m,7H).

Embodiment 3

[0062] Embodiment 3: the preparation of compound (II)

[0063] Weigh 10g (30.5mmol) of bromide, dissolve it in 60mL of methyl isobutyl ketone, add 3.7g (36.6mmol) of triethylamine, slowly add N-benzyl-6-(4-phenylbutoxy Base)-1-hexylamine 12.4g (36.6mmol), the reaction system gradually became cloudy. React at room temperature (25°C) for 5 hours, stop stirring, remove the solid in the reaction liquid by suction filtration, add ethyl acetate (100 mL) to the filtrate to dilute, then wash with water and saturated brine in sequence, after the pH detection of the organic phase is neutral, anhydrous Dry over sodium sulfate, filter, and remove the solvent by rotary evaporation to obtain 16.5 g of yellow oily product (II), with a yield of 92%.

[0064] 1 H NMR (CDCl 3 ):δ1.25-1.28(m,3H),1.50-1.67(m,9H),2.07(s,3H),2.34(s,3H),2.58-2.65(m,4H),3.32-3.41(m ,6H),3.72(s,1H),3.80(s,1H),5.07(s,2H),7.14-7.19(m,6H),7.24-7.34(m,7H).

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Abstract

The invention provides a synthesis method of R-salmeterol (V). The synthesis method comprises the following steps that a compound (I) and N-benzyl-6-(4-phenyl butoxy)-1-hexylamine take a reaction to obtain a compound (II); the compound (II) is hydrolyzed under the acidic condition to obtain a compound (III); the compound (III) is subjected to asymmetric reduction to obtain a compound (IV); the compound (IV) is subjected to deprotection to obtain the R-salmeterol (V). The route is simple; the target product of R-salmeterol (V) is obtained by using 2-acetoxyl group-5-(2-bromoacetyl) phenmethyl acetic ester and the N-benzyl-6-(4-phenyl butoxy)-1-hexylamine as raw materials through total four steps of reaction. The synthesis method has the advantages that the reaction conditions are mild; the operation is simple and convenient; the yield is high; the stereoselectivity is good; the production cost is low; the synthesis method is suitable for industrial production; great practical application values and social economical benefits are realized. The structural formula is shown as the accompanying drawing.

Description

technical field [0001] The present invention belongs to long-acting beta 2 -Receptor agonist synthesis technical field, specifically relates to a synthesis method of drug R-salmeterol. Background technique [0002] The present invention particularly relates to the synthesis of the long-acting anti-asthma drug R-salmeterol optically pure compound with significant curative effect. The structural formula of R-salmeterol is as follows: [0003] [0004] Asthma is the most common chronic respiratory disease in the world today. According to literature reports, nearly 300 million people in the world suffer from bronchial asthma, and the number is still increasing. For example, in the United States, the number of people suffering from asthma has almost doubled from the 1980s to the present, while the situation in Western Europe is even more serious, doubling in just ten years. Nearly 200,000 people die from asthma every year in the world. 1% of people in our country suffer fr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/02C07C217/10
CPCC07B2200/07C07C213/02C07C213/08C07C221/00C07C217/10C07C225/16
Inventor 张兴贤孙鑫哲宓森阳
Owner JOINCARE HAIBIN PHARM CO LTD
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