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Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid

A technology of phenylpropionic acid and hydroxymethyl, which is applied in the field of splitting racemic 2-hydroxymethyl-3-phenylpropionic acid to obtain its optical isomers, which can solve the problems of high price, troublesome recycling, and separation Low efficiency and other problems, to achieve the effect of low price, easy recycling, and high disassembly efficiency

Active Publication Date: 2009-10-07
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] It can be seen that in the existing reported methods, the best resolution reagent is cis-1-amino-2-indanol, but this resolution agent raw material itself is not easy to obtain and is expensive; 3-methyl-2 -Phenyl-1-butylamine is also very expensive, and the cost of industrialization is high; splitting with α-phenylethylamine has the disadvantages of low split efficiency and troublesome recycling

Method used

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  • Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid
  • Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid
  • Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid

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Effect test

Embodiment 1

[0028] 10.0g (55.6mmol) of 2-hydroxymethyl-3-phenylpropionic acid and 16.3g of octylglucamine were added to a 250ml single-necked bottle, and 120ml of ethanol was added, and after reflux for 10 minutes, it was naturally cooled to room temperature, left to stand for 2 days, and filtered to obtain Solid 10.0 g. Then recrystallized once with 100ml of ethanol to obtain 9.4g of solid.

[0029] Add the solid to 50ml of water, adjust the pH to 9 with 10% NaOH aqueous solution under stirring, filter, and then adjust the pH to 2 with 10% dilute hydrochloric acid in the filtrate, extract with 80ml of ethyl acetate, dry and concentrate the organic phase. Add 100ml of petroleum ether and stir to crystallize to obtain 3.6g of white solid (yield 36%, mp 68-69°C).

[0030] 1 HNMR (CDCl 3 ): 7.19-7.31 (5H, m), 5.91 (1H, br), 3.71-3.81 (2H, m), 2.92-3.12 (1H, m), 2.84-2.92 (2H, m)

[0031] [α] D 20 =+13.1° (c=1, CHCl 3 )

Embodiment 2

[0033] Add 18g (100mmol) of 2-hydroxymethyl-3-phenylpropionic acid and 29.3g (100mmol) of octylglucosamine into a 100ml single-necked bottle, add 150ml of isopropanol and 10nl of water, stir at 80°C for 10 minutes and naturally cool to Stand at room temperature for 24 hours, and filter to obtain 21.7 g of solid. Then recrystallized twice with 30ml of ethanol to obtain 19.8g of solid.

[0034] Add 50ml of water to the solid, adjust the pH to 2 with 10% dilute hydrochloric acid under stirring, filter and dry to obtain 7.2g of white solid (yield 40.3%)

Embodiment 3

[0036] Add 13.6g (75.6mmol) of 2-hydroxymethyl-3-phenylpropionic acid and 13.3g (45.4mmol) of octylglucamine into a 100ml single-necked bottle, add 50ml of methanol, reflux for 10 minutes, then cool to room temperature naturally, and let stand After 2 days, 15.6 g of solid was obtained by filtration. Then recrystallized twice with 30ml of ethanol to obtain 14.2g of solid. Add 50ml of water to the solid, adjust the pH to 2 with 10% dilute hydrochloric acid while stirring, extract with 80ml of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Stir and crystallize with 100ml of petroleum ether to obtain 5.4g of white solid (yield 39.8%)

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Abstract

The invention provides a method for resolving 2-hydroxymethyl-3-phenylpropionic acid optical isomers, by using octylglucamine as a resolving agent and racemic 2-hydroxymethyl-3-phenylpropionic The acid forms two diastereomers in a certain solvent, and the diastereomers with smaller solubility are separated, and then obtained by recrystallization, acid or alkali free; the resolution solvents used are methanol, ethanol, isopropanol, acetone, Butanone, etc. or its mixed solution with water. The method of the invention has high resolution efficiency, and the adopted resolution agent is easy to obtain, low in price and easy to recycle, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for resolving optical isomers in the field of chemistry, in particular to a method for resolving racemic 2-hydroxymethyl-3-phenylpropionic acid to obtain its optical isomers. Background technique [0002] (R)-2-hydroxymethyl-3-phenylpropionic acid shown in the following formula (1) is a renin inhibitor (Chem.Lett, 505-508, 1990) and an antiviral drug (J.O.C, 66, 3474 -52, 2001) is an important intermediate and an important raw material for the synthesis of the antihypertensive drug ecadotril (ecadotril) with dual inhibitory effects on ACE / NEP. [0003] [0004] For the synthesis of compound (1), document EP906900 reports that it is prepared by resolving 2-hydroxymethyl-3-phenylpropionic acid 2 with chiral amines. The resolving agent used and its resolution results are shown in Table 1: [0005] [0006] Resolution results of racemic 2-hydroxymethyl-3-phenylpropionic acid reported in the literature in Table 1 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C59/48C07C51/42
Inventor 侯建赵惠清王国平何康永陈旭东
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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