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Method for preparing phenylethanolamine compound intermediate

A technology of phenylethanolamine and compound, applied in the field of chemical synthesis, can solve problems such as many steps, harsh reaction conditions, increasing target product steps and time, etc.

Inactive Publication Date: 2018-04-27
CHINA ANIMAL DISEASE CONTROL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Wherein, steps (1) and (2) can be in the presence of sodium hydride or potassium carbonate, p-nitrobenzyl bromide and ethyl acetoacetate react to generate α-position alkylated ethyl acetoacetate, and then hydrolyze under acidic conditions and decarboxylation are realized, but the reaction of step (3) has not been reported in the prior art, and the patent US4,690,951 discloses the use of Raney nickel as a catalyst, methyl-2-(4-benzyloxyphenyl) ethyl The reaction of ketone and anhydrous ammonia to synthesize 1-methyl-3-(4-benzyloxyphenyl)propylamine under high pressure conditions, wherein the air pressure used is as high as 300psi, which is approximately equivalent to 20 atmospheric pressure, the reaction conditions are harsh, and the above-mentioned route There are many steps, which is not conducive to the scale-up production of products
[0008] 4-(4-nitrophenyl)butan-2-amine can also be obtained by nitration reaction using 1-methyl-3-phenylpropylamine, the selectivity of the nitro upper position is not easy to control, and the reaction may produce ortho-position nitration products and Impurities such as double-substituted products, and the target product and impurities are often isomers, separation and purification are difficult, the yield of the purified target product is low, and the purification steps will also increase the steps and time of the target product synthesis, affecting the overall yield of the reaction

Method used

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  • Method for preparing phenylethanolamine compound intermediate
  • Method for preparing phenylethanolamine compound intermediate
  • Method for preparing phenylethanolamine compound intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the preparation of 4-methoxymandelic acid

[0071]

[0072] Add 4-methoxybenzaldehyde (109g, 800mmol), chloroform (140mL) and benzyltriethylammonium chloride (9.12g, 40mmol) into a 1L three-necked flask, and heat the resulting solution to 58°C for 10 minutes Until all the solids were dissolved, then 50% aqueous sodium hydroxide solution (200 mL) was added dropwise into the reaction flask, and the reaction was continued at 58° C. for 30 minutes after the addition was completed. The reactant was cooled to about 5°C, acidified with 50% sulfuric acid, and the resulting aqueous solution was extracted with ether (3×1 L). The organic phase was dried with anhydrous magnesium sulfate, and the solvent was evaporated to obtain 164.1 g of milky white solid (yield: 90%). 1 The H NMR spectrum shows that it is completely consistent with the standard spectrum reported in the literature. Example 2: Preparation of 4-(4-nitrophenyl)-butan-2-amine and 4-(2-nitrophenyl)-b...

Embodiment 2

[0072] Add 4-methoxybenzaldehyde (109g, 800mmol), chloroform (140mL) and benzyltriethylammonium chloride (9.12g, 40mmol) into a 1L three-necked flask, and heat the resulting solution to 58°C for 10 minutes Until all the solids were dissolved, then 50% aqueous sodium hydroxide solution (200 mL) was added dropwise into the reaction flask, and the reaction was continued at 58° C. for 30 minutes after the addition was completed. The reactant was cooled to about 5°C, acidified with 50% sulfuric acid, and the resulting aqueous solution was extracted with ether (3×1 L). The organic phase was dried with anhydrous magnesium sulfate, and the solvent was evaporated to obtain 164.1 g of milky white solid (yield: 90%). 1 The H NMR spectrum shows that it is completely consistent with the standard spectrum reported in the literature. Example 2: Preparation of 4-(4-nitrophenyl)-butan-2-amine and 4-(2-nitrophenyl)-butan-2-amine

[0073]

[0074] Add fuming nitric acid (500mL) in a 1L thre...

Embodiment 3

[0076] Embodiment 3: the preparation of PEA intermediate

[0077]

[0078] The mixture (34.2g, 176mmol) of 4-(4-nitrophenyl)-butan-2-amine and 4-(2-nitrophenyl)-butan-2-amine prepared in Example 2, Example 1 The prepared 4-methoxymandelic acid (32g, 176mmol), EDC·HCl (52g, 270mmol), HOBt (36.5g, 270mmol) were dissolved in dichloromethane (300mL), stirred at room temperature for 48 hours until TLC showed The reaction is complete. The reacted mixture was washed with water (2×300 mL), part of the product was crystallized and filtered to obtain 13.3 g of the first batch of product. The filtrate was dried with anhydrous magnesium sulfate, and the solvent was spin-dried, and the obtained oil was washed with acetonitrile (50 mL) to obtain a second batch of product 29.9 g. The two batches of products were combined and recrystallized three times with DMF to remove a small amount of ortho-nitro impurity to obtain 27.6g (yield: 44%) of pure product without ortho-nitro impurity.

[...

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Abstract

The invention discloses a method for preparing a phenylethanolamine compound intermediate. The method comprises the following steps: (1) carrying out a nitrifying reaction on 1-methyl-3-phenylpropylamine and a nitrifying reagent to obtain a 4-(4-nitrophenyl)-butan-2-amine and 4-(2-nitrophenyl)-butan-2-amine mixture; and (2) reacting the mixture obtained in step (1) with a compound of formula III,and separating the obtained reaction product to obtain the phenylethanolamine compound intermediate of formula I. The method for preparing the phenylethanolamine compound intermediate has the advantages of simplicity in operation, short route and few steps; and an o-nitro impurities generated in the nitrifying reaction can be easily removed after being reacted without separation and becoming corresponding amides, so the reaction yield and the product purity are high, and the industrial production of the product is facilitated.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing a phenylethanolamine compound intermediate, in particular to a method for preparing a phenylethanolamine A intermediate. Background technique [0002] β-Phenylethanolamines are a well-known class of adrenaline stimulants, and there have been many reports on their biological activities. Many of these drugs have been used to treat tracheitis bronchitis and asthma. In addition to their use as therapeutic drugs, beta-adrenoreceptor stimulants are also illegally used as growth promoters, either to enhance performance in athletes or to improve nutrient distribution in livestock. These compounds can reduce fat formation and increase protein synthesis in livestock, thereby increasing the proportion of lean meat and improving the quality of meat products. However, the residues of such drugs or their metabolites in livestock have caused great harm to hum...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C235/34C07C213/02C07C217/70G01N30/02
CPCC07C209/76C07C213/02C07C231/02G01N30/02C07C235/34C07C217/70C07C211/29
Inventor 蔡英华于雷刘洪斌王传彬李颖姜艳彬
Owner CHINA ANIMAL DISEASE CONTROL CENT
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