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Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane

A technology of nitrobenzoyloxy and ethoxyphenoxy, applied in the field of medicinal chemistry, can solve the problems of reducing production capacity, wasting raw materials, expensive pyridine and the like

Inactive Publication Date: 2011-06-22
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the literature Tetrahedron Vol 41, No.7, PP1393~1399 (1985) Reboxetine mesylate intermediate (2RS, 3SR)-3-(2-ethoxyphenoxy)-2-hydroxyl-1 The preparation method of -(4-nitrobenzoyloxy group)-3-phenylpropane has been described, and it adopts pyridine as both an acid-binding agent and a solvent, and the post-reaction treatment will neutralize with a large amount of acid, so that the operation It is cumbersome, wastes raw materials and reduces production capacity, especially pyridine is more expensive
In patent CN1887852, although halogenated hydrocarbon is used as solvent, pyridine is still used as acid binding agent, so there are still many problems such as high production cost

Method used

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  • Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane
  • Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane
  • Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane

Examples

Experimental program
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example 1

[0013] Dissolve 25g (0.0865mol) of II in 250ml of ethyl acetate, add 32ml of triethylamine (0.22mol), blow in nitrogen, cool to -20°C, and slowly add 16.1g (0.085mol) of 4-nitrate A solution composed of benzoyl chloride and 200ml ethyl acetate was dropped within 1.5h. After reacting for 0.5h, the solution was transferred to a solution composed of 160ml 2mol / L hydrochloric acid and 665g ice, an oily precipitate was produced, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water, and then washed with anhydrous Sodium sulfate was dried and dehydrated, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of isopropyl ether: ethyl acetate = 12:1, and the product gradually solidified to obtain 25.4 g of the product, with a yield of 67.2%. m.p.92-95℃, IR(KBr)cm -1 3540(OH), 1730(CO) 1590, 1500(arom.C=C), 1525, 1350(NO 2 ).

example 2

[0015] Dissolve 25g (0.0865mol) of II in 250ml of ethyl acetate, add 12.5ml of triethylamine (0.0865mol), pass through nitrogen, cool to -20°C, and slowly dropwise add 16.1g (0.085mol) of 4- The solution composed of nitrobenzoyl chloride and 200ml ethyl acetate was dropped within 1.5h. After reacting for 0.5h, the solution was transferred to a solution composed of 160ml 2mol / L hydrochloric acid and 665g ice, an oily precipitate was produced, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water, and then washed with anhydrous Sodium sulfate was dried and dehydrated, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of isopropyl ether: ethyl acetate = 12:1, and the product gradually solidified to obtain 12.1 g of the product, with a yield of 32%. m.p.93-95℃, IR(KBr)cm -1 3540(OH), 1730(CO) 1590, 1500(arom.C=C), 1525, 1350(NO 2 ).

example 3

[0017] Dissolve 25g (0.0865mol) of II in 250ml of toluene, add 32ml of triethylamine (0.22mol), blow in nitrogen, cool to -20°C, and slowly add 16.1g (0.085mol) of 4-nitrobenzene The solution composed of acid chloride and 200ml toluene was dropped within 1.5h. After reacting for 0.5h, the solution was transferred to a solution composed of 160ml 2mol / L hydrochloric acid and 665g ice, an oily precipitate was produced, the organic phase was separated, the aqueous phase was extracted with toluene, the combined organic phases were washed with water, and then washed with anhydrous sodium sulfate After drying and dehydration, the solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of isopropyl ether: ethyl acetate = 12:1, and the product gradually solidified to obtain 24.8 g of the product, with a yield of 65.6%. m.p.92-95℃, IR(KBr)cm -1 3540(OH), 1730(CO) 1590, 1500(arom.C=C), 1525, 1350(NO 2 ).

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Abstract

The invention relates to a preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane as expressed in the formula (I), which is an intermediate of reboxetine. In the method the compound as expressed in the formula (II) and 4-nitrobenzoyl chloride are employed as raw materials; aliphatic caboxylic ester, lower halogenated hydrocarbon, benzene, or toluene is employed as solvent; triethylamine is employed as an acid-binding agent; and the target product (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane is obtained by reaction of the above-mentioned compounds. Compared with the prior methods, the method in the present invention requires inexpensive raw materials, can be simply operated, needs no special apparatus and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, specifically for the preparation of (2RS, 3SR)-3-(2-ethoxyphenoxy)-2-hydroxyl-1-(4-nitrobenzoyloxy)-3-benzene propane method Background technique [0002] Reboxetine mesylate was developed by Pharmacia & Upjohn Company and first launched in the UK in 1997. It has been listed in more than 40 countries including the European Union and the United States for the treatment of depression. Our country also already has this drug on the market. Reboxetine mesylate is a new generation of norepinephrine reuptake inhibitor, which shows good efficacy and high tolerance in the treatment of depression. (2RS, 3SR)-3-(2-ethoxyphenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenylpropane is a synthetic reboxetine mesylate One of the intermediates. [0003] In the literature Tetrahedron Vol 41, No.7, PP1393~1399 (1985) Reboxetine mesylate intermediate (2RS, 3SR)-3-(2-ethoxyphenoxy)-2-hydroxyl-1 The preparation me...

Claims

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Application Information

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IPC IPC(8): C07C205/57C07C201/12
Inventor 赵世明尚嘉鹏罗振福
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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