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Resolution method for 2,6-dimethyltyrosine ester and application thereof

A technology of dimethyl tyrosine ester and tyrosine ester, applied in the direction of organic chemical methods, chemical instruments and methods, separation of optically active compounds, etc., can solve problems such as harsh conditions, high production costs, and expensive prices, and achieve Improve the resolution yield, convenient operation, and facilitate the effect of industrial production

Active Publication Date: 2019-11-19
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Different documents such as Dygos et al. in Synthesis.1992,741 and Praquin et al. in Org.Process.Res.Dev.2011,1124 use different noble metals to catalyze the preparation of 2,6-dimethyl-L-tyrosine by asymmetric hydrogenation , these synthetic routes use expensive noble metal catalysts and related ligands, and the production cost is very high; in addition, some documents such as Balducci et al. in Tetrahedron:Asymmetry.2009,1398 use chiral complexes to induce the construction of chiral centers, and the conditions are harsh Difficult, so, it is necessary to develop an industrialized easy-to-implement, simple and effective method to obtain 2,6-dimethyl-L-tyrosine

Method used

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  • Resolution method for 2,6-dimethyltyrosine ester and application thereof
  • Resolution method for 2,6-dimethyltyrosine ester and application thereof
  • Resolution method for 2,6-dimethyltyrosine ester and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Dissolve 245g of racemic 2,6-dimethyl-tyrosine in 1L of ethanol, drop into 179g of thionyl chloride at low temperature, heat to reflux for 2 hours, and concentrate to dryness after the reaction. Add water and dichloromethane for extraction, adjust the pH to 9-10 with 10% aqueous sodium hydroxide solution, separate layers, extract the aqueous phase once more, combine the organic phases and wash with water, and concentrate the organic phases to dryness to obtain about 225 g of 2,6 -Dimethyl-tyrosine ethyl ester.

Embodiment 2

[0040] Dissolve 238g of L-dibenzoyltartaric acid in 800g of isopropanol, heat to 70 degrees, slowly drop into 300g of isopropanol solution of 100g of 2,6-dimethyl-tyrosine ethyl ester, add a small amount of seed crystals , more crystals were precipitated, continued to stir at 70°C for 2 hours, cooled to 30°C, kept warm for 1 hour, filtered with suction, and the solid was washed with isopropanol at room temperature. The mother liquor is subjected to the next racemization operation, and the filter cake is blown and dried at 50 degrees to obtain the L-dibenzoyl tartrate product of 2,6-dimethyl-L-tyrosine ethyl ester. The yield is 38%, and the ee value is 96%.

Embodiment 3

[0042] Add dichloromethane and water to the mother liquor obtained in the previous step, adjust the pH to 9-10 with 10% aqueous sodium hydroxide solution, separate layers, extract the water phase once more, combine the organic phases and wash with water, and concentrate the organic phases to dryness. Add 1g of concentrated sulfuric acid, 5g of salicylaldehyde, and 300g of isopropanol, and reflux for 4 hours. Concentration to dryness recovered racemic 2,6-dimethyl-tyrosine ethyl ester. The recovery yield was 70%. Simultaneously, the aqueous phase also recovers L-dibenzoyl tartaric acid.

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Abstract

The invention discloses a preparation method for 2,6-dimethyl-L-tyrosine. The preparation method comprises the following steps: preparing an ester from racemic 2,6-dimethyl-tyrosine; then performing kinetic resolution to obtain a double salt of 2,6-dimethyl-L-tyrosine ester; and then performing deprotection so as to obtain the target product of 2,6-dimethyl-L-tyrosine. The preparation method of the invention has the characteristics of easy availability of raw materials, convenient operation, high yield, and the like, and has good industrial application and economic value.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a preparation method for preparing 2,6-dimethyl-L-tyrosine ester through resolution and racemization. Background technique [0002] As an important unnatural amino acid, 2,6-dimethyl-L-tyrosine has been widely used in many new polypeptide compounds along with the further research on polypeptide drugs. [0003] There are different literatures reporting the synthesis of 2,6-dimethyl-L-tyrosine. Different documents such as Dygos et al. in Synthesis.1992,741 and Praquin et al. in Org.Process.Res.Dev.2011,1124 use different noble metals to catalyze the preparation of 2,6-dimethyl-L-tyrosine by asymmetric hydrogenation , these synthetic routes use expensive noble metal catalysts and related ligands, and the production cost is very high; in addition, some documents such as Balducci et al. in Tetrahedron:Asymmetry.2009,1398 use chiral complexes to induce ...

Claims

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Application Information

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IPC IPC(8): C07C227/34C07C227/36C07C229/36
CPCC07B57/00C07C227/34C07C227/36C07B2200/07C07C229/36
Inventor 王磊邵万成田鹏举庄程翰周雄飞唐小平
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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