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Splitting method of 2-hydracrylic acid racemic mixture

A technology for hydroxypropionic acids and racemates, applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylate, etc., can solve the problems of large yield loss, inconvenient operation, high market price, etc., and achieve reduction Production energy consumption, improved operability, and low-cost effects

Active Publication Date: 2013-05-08
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield loss is very large, and the operation process is complicated
The market price of optically active base (S)-1-(4-nitrophenyl)ethylamine and 1-(4-chlorophenyl)ethylamine is relatively high, and a large amount of seed crystals need to be added in the preparation process, which is difficult to recover and disassemble. The division process is complicated, the operation is inconvenient, and the cost of industrial scale-up production is high
[0007] WO2011004402 also describes the use of (S)-1-(4-chlorophenyl)ethylamine analogs, (S)-2,4-dichlorophenethylamine, (R)-2,4-dichlorophenethylamine, respectively Amines and (S)-3-methoxyphenethylamine are used as optically active bases to prepare single isomers of 2-hydroxypropionic acid compounds. Such resolving agents are costly and have no market competitiveness

Method used

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  • Splitting method of 2-hydracrylic acid racemic mixture
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  • Splitting method of 2-hydracrylic acid racemic mixture

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Preparation of (S)-2,3-dihydroxy-3,3-diphenylpropionic acid by resolution of racemate

[0027] In reaction bottle, drop into 150g ethanol, 75g ethyl acetate, 20g (77.2mmol) 2,3-dihydroxyl-3,3-diphenylpropionic acid and 4.8g (42.5mmol) L-proline amide, under stirring The temperature of the reaction solution was raised to 56°C, and after 30 minutes of heat preservation and stirring, the temperature of the reaction solution was slowly cooled to 0-5°C and filtered to obtain (S)-2,3-dihydroxy-3,3-diphenylpropionic acid L-proline Aminoamide salt. .

[0028] Add 100 g of ethyl acetate and 100 g of water to the filter cake, stir, and adjust the pH of the solution to 2 to 3. After adjustment, separate the layers, and extract the water layer once with 50 g of ethyl acetate. The organic layers were combined, washed once with 50 g of water, and separated. The organic layer was concentrated under reduced pressure to obtain 140 g of ethyl acetate. After the concentration was compl...

Embodiment 2

[0032] Preparation of (S)-2-hydroxy-3-methyl-3,3-diphenylpropionic acid by resolution of racemate

[0033] Drop into 250g methanol and 120g methyl tert-butyl ether, 20g (75.7mmol) 2-hydroxyl-3-methyl-3,3-diphenyl propionic acid and 4.5g (39.4mmol) L-proline in the reaction flask Amide, the temperature of the reaction solution was raised to 80.5°C under stirring, and the temperature of the reaction solution was slowly cooled to 0-5°C after stirring for 30 minutes, and filtered to obtain (S)-2-hydroxy-3-methyl-3,3-di Phenylpropionate L-Prolinamide Salt.

[0034]Add 100 g of ethyl acetate and 50 g of water to the filter cake, stir, and adjust the pH of the solution to 2 to 3. After adjustment, separate the layers, and extract the water layer once with 50 g of ethyl acetate. The organic layers were combined, washed once with 50 g of water, and separated. The organic layer was concentrated under reduced pressure to obtain 140 g of ethyl acetate. After the concentration was comple...

Embodiment 3

[0038] Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid by resolution of racemate

[0039] 200g of isopropanol is pumped into the reactor, and then 10kg (36.5mmol) of 2-hydroxyl-3methoxy-3,3-diphenylpropionic acid and 2.3g (20mmol) of L-prolinamide are dropped into the kettle , the temperature of the reaction solution was raised to 75°C under stirring, and the reaction solution was slowly cooled to 25°C after 30 minutes of insulated stirring, and filtered to obtain (S)-2-hydroxy-3-methoxy-3,3-diphenyl Propionic acid L-prolinamide salt.

[0040] Add 50 g of ethyl acetate and 20 g of water to the filter cake, stir to adjust the pH of the solution to 2 to 3, after adjustment, separate the layers, and extract the water layer once with 25 g of ethyl acetate. The organic layers were combined, washed once with 10 g of water, and separated. The organic layer was concentrated under reduced pressure to obtain 70 g of ethyl acetate. After the concentration was complete...

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PUM

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Abstract

The invention relates to a splitting method of 2-hydracrylic acid racemic mixture. The method comprises the following steps of: carrying out optical active alkali reaction on 2-hydracrylic acid racemic mixture and L-prolinamide, separating a single isomer L-prolinamide salt of 2-hydroxyl acrylic acid compound; and taking the single isomer of the 2-hydroxyl acrylic acid compound as important intermediate for synthetizing endothelin receptor antagonist for treating cardiovascular disease. Therefore, the single isomer with high optical purity is separated by the splitting method which is simple to operate and is provided by the invention; and the method is cheap in required material and reagent, and suitable for industrial production, and has good economic benefit.

Description

technical field [0001] The invention relates to a method for resolving 2-hydroxypropionic acid racemates technical background [0002] The single isomer of 2-hydroxypropionic acid compounds is an important intermediate for the synthesis of plant protection agents and medicines. Therefore, a single isomer of 2-hydroxypropionic acid compounds with high optical purity is prepared by splitting and separating the racemic intermediates by a synthetic method. Isomers are of great significance. [0003] WO1996011914 describes propionic acids substituted at the 2-position by heterocycles as potent endothelin-receptor antagonists for the treatment of cardiovascular diseases, wherein the single isomer of 2-hydroxypropionic compounds serves as an important intermediate for the synthesis of these active substance. The invention discloses the preparation of (S)-2-hydroxyl-3-methanol on a laboratory scale using L-proline methyl ester and (S)-1-(4-nitrophenyl)ethylamine through the resolu...

Claims

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Application Information

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IPC IPC(8): C07C59/48C07C59/64C07C51/487
Inventor 钱刚张文灵颜峰峰
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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