Process for preparing enantiomerically enriched 2-alkoxy-3-phenylpropionic acids

An enantiomer-enriched, enantiomer-selective technology applied in the field of 2-alkoxy-3-phenylpropionic acid

Inactive Publication Date: 2007-06-27
SALTIGO GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, these methods have the following disadvantages: firstly, due to the protection group technology used, a series of method steps for the selective introduction and removal of suitable protecting groups must be carried out, and secondly, all these methods have to be converted into the corresponding propanes in an additional step. The corresponding propionate of the acid

Method used

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  • Process for preparing enantiomerically enriched 2-alkoxy-3-phenylpropionic acids
  • Process for preparing enantiomerically enriched 2-alkoxy-3-phenylpropionic acids
  • Process for preparing enantiomerically enriched 2-alkoxy-3-phenylpropionic acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Preparation of Z-4'-hydroxy-2-methoxycinnamic acid:

[0077]

[0078] A solution of 150 g (1.20 mol) of 4-hydroxybenzaldehyde and 316 g (3.00 mol) of methyl methoxyacetate in 1.018 l (5.39 mol) of 30% sodium methoxide in methanol was heated under reflux for 6 hours. Subsequently, the mixture was cooled to 40° C. and mixed with 1 1 of water. 760 ml of methanol were distilled off from the reaction mixture, and the mixture was cooled to room temperature again. The reaction solution was adjusted to pH 2 with 410 ml of 37% aqueous hydrochloric acid, and the product was precipitated from the solution. The product suspension was stirred at room temperature for another 2 hours, filtered, and the filtered residue was dried under reduced pressure at 40°C overnight. 212.2 g of pure Z product (content: 92.4%, 83.8% of theory) were obtained as a yellowish solid.

[0079] 1 H NMR (400MHz, d 6 -DMSO): δ = 3.67 (s, 3H, O-CH 3 ); 6.79(d, 2H, Ar-H); 6.85(s, 1H, Ar-CH=); 7.61(d...

Embodiment 2

[0082] Preparation of Sodium (S)-3-(4-Hydroxyphenyl)-2-methoxypropionate by Hydrogenation Using Ruthenium Catalyst Salt

[0083]

[0084] 62.5mg (1.0mmol) [RuCl 2 (p-cymene)] 2 and 139.6mg (2.1mmol) of 2,2'-dichloro-3,3'-dimethoxy-6,6'-bis(diphenylphosphino)biphenyl were suspended in 150ml of degassed methanol and refluxing Lower heat for 1 hour. The resulting solution was then cooled to room temperature and added to a solution of 40.46 g (200 mmol) of Z-4'-hydroxy-2-methoxycinnamic acid in 150 ml of degassed methanol. Subsequently, the mixture was transferred to an autoclave and hydrogenated at 70° C. and a hydrogen pressure of 85 bar for 16 hours. The mixture was then cooled, depressurized and the solvent was removed under reduced pressure. The residue was taken up with 650 ml of isopropyl acetate, washed with 200 ml of 1N HCl and 100 ml of saturated NaCl solution, concentrated to a volume of 500 ml and mixed with a solution of 19.7 g of sodium acetate in 163 ml o...

Embodiment 3

[0088] Preparation of (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid sodium salt by hydrogenation with rhodium catalyst:

[0089]

[0090] 6.3mg (0.0154mmol) Rh(COD) 2 BF 4 and 6.8 mg (0.0154 mmol) of (S,S)-2,4-bis(diphenylphosphino)pentane were dissolved in 1 ml of degassed methanol and added to 100 mg (0.51 mmol) of Z-4'-hydroxy - a solution of 2-methoxycinnamic acid in 3 ml of degassed methanol. Then, the mixture was transferred to an autoclave and hydrogenated at 50° C. and 3 bar hydrogen pressure for 16 hours. The mixture was then cooled to room temperature, and the solvent was removed under reduced pressure and under reduced pressure. (S)-3-(4-Hydroxyphenyl)-2-methoxypropanoic acid was obtained as an oil in 80% enantiomeric excess (100% conversion of substrate).

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Abstract

The present invention relates to a process for preparing enantiomerically enriched, optionally substituted 2-alkoxy-3-phenylpropionic acids by asymmetrically hydrogenating alkoxycinnamic acids.

Description

technical field [0001] The present invention relates to a process for the preparation of enantiomerically enriched optionally substituted 2-alkoxy-3-phenylpropionic acids by asymmetric hydrogenation of 2-alkoxycinnamic acids. Background technique [0002] Substituted 2-alkoxy-3-phenylpropanoic acids constitute an interesting class of active ingredients that have, over the past few years, been used as structural membrane bodies, especially as proliferator-activated receptors in peroxisomes. Structural membrane bodies in agonists of (PPARs) are becoming increasingly important. Agonists of these receptors are mainly used as substances for the treatment of diabetes and disorders of lipid metabolism (eg ragaglitazar, tesaglitazar, NNC 61-4655, among others). The provision of highly enantiomerically pure 2-alkoxy-3-phenylpropionic acid units is therefore of particular interest for the preparation of these active substances. [0003] For the preparation of substituted 2-alkoxy-3-...

Claims

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Application Information

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IPC IPC(8): C07C59/13C07C51/36C07B53/00
CPCC07B2200/07C07C51/353C07C51/36C07C65/28C07C65/21
Inventor M·沃尔特林T·邦拉克萨纳努索恩A·格拉克
Owner SALTIGO GMBH
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