Resolution method of 2-hydroxy-3-methoxy-3,3-dibenzylpropionic acid racemate

A technology of diphenylpropionic acid and methoxy, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds. problem, to achieve the effect of strong reproducibility and easy industrial implementation

Active Publication Date: 2014-10-15
CHANGZHOU HANSOH PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] CN1129571C patent describes the resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid racemate with (S)-1-(4-chlorophenyl)ethylamine as the optically active base, The patent describes that the chemical purity of the resolved compound reaches 99.8%, and the optical purity is greater than 99.95%. In the WO9611914 patent, the resolution of the above-mentioned racemate with S-4-nitrophenylethylamine (Example 11) is described. Preparation of (S)-2-hydroxyl-3-methoxy-3,3-diphenylpropionic acid, the optical purity of its monomer after resolution is 100%; But above-mentioned two kinds of resolution reagents are all expensive, and Not suitable for industrial production
[0004] In the WO2011004402 patent, it is also mentioned that S-2,4-dichlorophenethylamine is used to resolve 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid racemate, although the chemical purity after resolution is up to 99.9%, and the optical purity reaches 99.4%, but the resolution reagent is expensive, and the resolution results are limited to laboratory scale, and have not been confirmed by industrial amplification; in this patent, it is also mentioned that S-3-methoxy Phenylethylamine resolves the above racemates, but the resolution is poor, the optical purity is only 98.3%, and it is limited to the laboratory scale

Method used

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  • Resolution method of 2-hydroxy-3-methoxy-3,3-dibenzylpropionic acid racemate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add L-proline methyl ester hydrochloride (6.5kg, 39.25mol) and anhydrous methanol (3.5L) into a 10L reaction flask, stir well, then add sodium methoxide (2.12kg, 39.25mol) in batches Anhydrous methanol (5.0L) mixture, after the addition, stirred and reacted at (15-30°C) for 20-30min, filled the mixed solution into a 300L reactor, and then filled the raw material A (10.68kg, 39.25mol) The methyl tert-butyl ether (90L) solution is also filled into the above reaction kettle, the temperature is controlled at (15-30°C) and the reaction is stirred for 20 hours, and the methyl tert-butyl ether (180L) is added to the reaction kettle, and the temperature is reduced by circulation. Control the internal temperature at -5~0°C and stir for 30 minutes, filter, transfer the filtrate to a 500L reaction kettle, add 3.5L of hydrochloric acid and 130L of purified water while stirring, stir for 3~5min, let stand for 10~15min, discard the water layer, organic The layer was dried with anhydr...

Embodiment 2

[0031] Add L-proline methyl ester hydrochloride (6.5kg, 39.25mol) and anhydrous methanol (3.5L) into a 10L reaction flask, stir well, then add sodium methoxide (2.12kg, 39.25mol) in batches Anhydrous methanol (5.0L) mixture, after the addition, stirred and reacted at (15-30°C) for 20-30min, filled the mixture into a 300L reactor, and then filled the raw material A (9.72kg, 35.68mol) The methyl tert-butyl ether (90L) solution is also filled into the above reaction kettle, the temperature is controlled at (15-30°C) and the reaction is stirred for 20 hours, and the methyl tert-butyl ether (180L) is added to the reaction kettle, and the temperature is reduced by circulation. Control the internal temperature at -5~0°C and stir for 30 minutes, filter, transfer the filtrate to a 500L reactor, add 3.5L of hydrochloric acid and 130L of purified water while stirring, stir for 3~5min, let stand for 10~15min, discard the water layer, organic The layer was dried with anhydrous magnesium su...

Embodiment 3

[0033] Add raw material A (11kg, 40.4mol), anhydrous methanol (51L), methyl tert-butyl ether (51L) into a 200L reactor, drop (R)-(+)-α- Phenylethylamine (4.4kg, 36.3mol), after dropping, stirred at 10-30°C for 3-4h, filtered, washed the filter cake with methyl tert-butyl ether (12L×2), dried to obtain 3.55kg, yield 64.5 %. HPLC purity: 99.5%, chiral purity: 68.3%.

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Abstract

The invention relates to a resolution method of 2-hydroxy-3-methoxy-3,3-dibenzylpropionic acid racemate. The method comprises the following steps: reacting racemic acid with an optical alkali, and separating non-enantiomeric salts of acid and alkali. L-proline methyl ester hydrochloride and R-(+)-alpha-phenylethylamine are used as optically active alkalis. Highly pure target compounds can be obtained in a high yield mode by using an efficient and cheap resolution reagent, and the method has good reappearance in industrial production and has a wide industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of resolution of pharmaceutical intermediates, and in particular relates to a resolution method of ambrisentan intermediate 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid racemate. Background technique [0002] Ambrisentan is a selective endothelin receptor A (ETAR) antagonist with the chemical name (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]- 3-methoxy 3,3-diphenylpropionic acid, this drug is another drug for the treatment of pulmonary arteries following bosentan and sitaxsentan. 3,3-diphenylpropionic acid racemate intermediate, which is resolved to obtain (S)-2-hydroxyl-3-methoxyl-3,3-diphenylpropionic acid monomer, and then The monomer is reacted with 4,6-dimethyl-2-methylsulfonylpyrimidine to obtain ambrisentan. [0003] CN1129571C patent describes the resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid racemate with (S)-1-(4-chlorophenyl)ethylamine as the optically active base, The patent d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/64C07C51/487
CPCC07B2200/07C07C51/487C07C59/64
Inventor 潘必高戚郜飞赵军军
Owner CHANGZHOU HANSOH PHARM CO LTD
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