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Synthesis method of chiral tert-leucine and final product obtained in method

A technology for the synthesis of tertiary leucine and its synthesis method, which is applied in the field of chiral tertiary leucine synthesis and its final products, can solve the problems of poor operation stability and expensive chiral catalyst, and achieve mild chemical reaction conditions and environmental protection. Friendly, Inexpensive Effects

Inactive Publication Date: 2011-11-23
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] (3) Chemical catalysis, including chemical catalysis asymmetric synthesis, chemical catalysis kinetic resolution and chemical catalysis dynamic kinetic resolution; theoretically speaking, the use of chemical catalysis is to make latent chiral compounds or mixed rotations However, there are still many problems such as the need to prepare special substrates, the cost of chiral catalysts, and sometimes poor operational stability during amplification;

Method used

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  • Synthesis method of chiral tert-leucine and final product obtained in method
  • Synthesis method of chiral tert-leucine and final product obtained in method

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Preparation of deuterated L-tert-leucine,

[0031] Add 20kg raw material deuterated trimethylpyruvate in 200L reactor 60L of pure water, add 36kg of ammonium formate solid, after all dissolved, adjust the pH to 6.5-8.5 with saturated ammonia water. After the adjustment, 200g of ammonium formate buffer solution of oxidized coenzyme, 40g of formate dehydrogenase buffer solution and 18g of L-leucine dehydrogenase buffer solution were added successively, stirred for 0.5h, and the temperature of the system was raised to 20±2°C. Control the temperature to start the reaction, 2D-NMR tracking to the end of the reaction, lower the temperature, concentrate the system, and dry it by centrifugation to obtain the product deuterated L-tert-leucine. 17.6kg, yield 87%, HPLC:>99%, ee 1 H-NMR: 3.4ppm, s, 1H; 2 D-NMR: 1.0ppm, s, 9D;

Embodiment 2

[0033] To prepare L-tert-leucine,

[0034] Add 15kg raw material trimethylpyruvate in 200L reactor Add 37.5kg of solid ammonium formate to 75L of purified water, and after all of it is dissolved, adjust the pH to 6.5-8.5 with 0.1M disodium hydrogen phosphate / sodium dihydrogen phosphate. After the adjustment, add the ammonium formate buffer solution of 120g of oxidized coenzyme, the buffer solution of 25.5g of formate dehydrogenase and the buffer solution of 10.5g of L-leucine dehydrogenase successively, stir for 0.5h, and the temperature of the system is raised to 38±2 ℃, temperature control to start the reaction, 2D-NMR tracking to the end of the reaction, cooling down, concentrating the system, centrifuging and drying to obtain the product preparation L-tert-leucine, 13.6kg, yield 90%, HPLC:>99%, ee

[0035] ( 1 H-NMR: 3.4ppm, s, 1H, 1.0ppm, s, 9H ;)

Embodiment 3

[0037] Preparation of deuterated D-tert-leucine,

[0038] Add 15kg raw material deuterated trimethylpyruvate in 200L reactor 60L of pure water, add 30kg of ammonium formate solid, after all dissolved, adjust the pH to 6.5-8.5 with 0.2M dipotassium hydrogen phosphate / potassium dihydrogen phosphate. After the adjustment, add the ammonium formate buffer solution of 180g of oxidized coenzyme, the buffer solution of 34.5g of formate dehydrogenase and the buffer solution of 16.5g of D-leucine dehydrogenase successively, stir for 0.5h, and the temperature of the system is raised to 20±2 ℃, temperature control to start the reaction, 2D-NMR tracking to the end of the reaction, cooling down, concentrating the system, centrifuging and drying to obtain the product deuterated D-tert-leucine, 13.4kg, yield 89%, HPLC:>99%, ee 1 H-NMR: 3.4ppm, s, 1H; 2 D-NMR: 1.0ppm, s, 9D;

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Abstract

The invention provides a synthesis method of chiral tert-leucine, and the synthesis method is characterized by comprising the following steps: adding raw materials and water to a reaction kettle; adding ammonium formate solid and adding a pH regulator to regulate the pH value after completely dissolving; then sequentially adding an ammonium formate buffer of catalyst oxidized coenzyme, a buffer solution of formic dehydrogenase and a buffer solution of chiral leucine dehydrogenase; stirring to start reaction while controlling the reaction temperature at 10-40 DEG C and the pH value of the reaction system at 6.0-10.0; and after the reaction is finished, acquiring a final product, namely deuterated chiral tertleucine. The synthesis method provided by the invention has the advantages that: the used raw materials are easily available and inexpensive; the used raw materials are commercial raw materials or easily prepared raw materials, and can meet the needs of large-scale production; and the product is obtained by one-step reaction, water is used as the solvent, enzyme protein is used as the catalyst, and the product has a yield more than 80% and both chemical purity and chiral purity greater than 99%.

Description

(1) Technical field: [0001] The invention relates to a compound synthesis method and its product, especially a chiral tertiary leucine synthesis method and its final product. (two) background technology: [0002] Amino acids and their important compounds and organic drug intermediates are widely used in medicine, food, feed, cosmetics, agriculture and chemical industry. During the generation and evolution of life, proteins, nucleic acids, enzymes and cell surface receptors in organisms have specific chiral structures, so organisms have different physiological and chemical reactions to different stereochiral molecules, resulting in Chiral molecules with different optical activities have different pharmacological and toxicological effects. [0003] Tert-leucine is a non-protein source chiral amino acid. Due to the special structure and properties of tert-butyl, it is an important pharmaceutical intermediate and a chiral induction template and catalyst for asymmetric synthesis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04C07C229/08
Inventor 洪浩韦建杨建波
Owner ASYMCHEM LAB TIANJIN
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