Synthetic method of a class of cyclic dipeptides containing glutamine or asparagine

A technology of glutamine and asparagine, which is applied in the field of cyclic dipeptide synthesis, can solve problems such as surplus raw materials, inability to cyclize sequences, and affect cyclization efficiency, so as to increase the concentration of reactants, avoid raw material residues, and avoid organic The effect of solvent use

Active Publication Date: 2022-05-27
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Usually, raw materials are left due to incomplete activation of carboxyl groups, and purification operations such as column chromatography are required; and glutamine and asparagine often choose trityl for side chain protection groups, and excessive steric hindrance seriously affects Cycling efficiency, some sequences cannot even be cyclized

Method used

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  • Synthetic method of a class of cyclic dipeptides containing glutamine or asparagine
  • Synthetic method of a class of cyclic dipeptides containing glutamine or asparagine
  • Synthetic method of a class of cyclic dipeptides containing glutamine or asparagine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of glutamine-phenylalanine cyclic dipeptide

[0045] 1. Synthesis of trifluoroacetate of H-Glu-Phe-OH

[0046] Weigh 10g 2-Chlorotrityl Chloride Resin (degree of substitution 1.6mmol / g) and swell in dichloromethane for 10 minutes, then add 6.82g (17.6mmol) Fmoc-Phe-OH, 10.6mL (64mmol) N,N'-dichloromethane Isopropylethylamine was reacted at room temperature for 2 hours, then anhydrous methanol was added to seal for 30 minutes, suction filtration, and the filter cake was washed with 50 mL of isopropanol and 50 mL of N,N-dimethylformamide in turn, and then washed with 60 mL of 20 mL of isopropanol. % piperidine in N,N-dimethylformamide solution to remove the Fmoc protecting group for 30 minutes, then suction filtration, the filter cake was washed twice with isopropanol and N,N-dimethylformamide in turn, each 50mL, the resin was positive black. The washed filter cake was added to 60 mL of N,N-dimethylformamide, and 13.6 g (32 mmol) of Fmoc-Glu(OtBu)-OH, 6.5 g (4...

Embodiment 2

[0055] Synthesis of glutamine-tyrosine cyclic dipeptide

[0056] In step 1 of this example, 8.1 g (17.6 mmol) of Fmoc-Tyr(tBu)-OH was added, and other steps were the same as in step 1 of Example 1, and 6.5 g of H-Glu-Tyr-OH trifluoride was obtained by solid-phase synthesis acetate.

[0057] In step 2 of this example, 6.5 g (15.3 mmol) of the trifluoroacetate salt of H-Glu-Tyr-OH was added to 100 mL of methanol, and 3.2 mL (45.9 mmol) of difluoroacetate was added dropwise at -10 to 0 °C. Thionyl chloride, other steps are the same as step 2 of Example 1, through methyl esterification reaction, an aqueous solution of H-Glu(OMe)-Tyr-OMe hydrochloride is obtained.

[0058] In step 3 of the present embodiment, sodium bicarbonate is added to the collected water phase, pH=8 is adjusted, and the reaction is carried out at room temperature for 6 hours, the product is precipitated from the water, filtered to obtain a white solid Cyclo[Glu(OMe)-Tyr], dried Got 3.9g.

[0059] In step 4 ...

Embodiment 3

[0061] Synthesis of glutamine-tryptophan cyclic dipeptide

[0062] In step 1 of this example, 7.5 g (17.6 mmol) of Fmoc-Trp-OH was added, and other steps were the same as in step 1 of Example 1, and 6.9 g of H-Glu-Trp-OH trifluoroacetate was obtained by solid-phase synthesis .

[0063] In step 2 of this example, 6.9 g (15.8 mmol) of the trifluoroacetate salt of H-Glu-Tyr-OH was added to 100 mL of methanol, and 2.3 mL (31.7 mmol) of difluoroacetate was added dropwise at -10 to 0 °C. Thionyl chloride, other steps are the same as step 2 of Example 1, through methyl esterification reaction, an aqueous solution of H-Glu(OMe)-Trp-OMe hydrochloride is obtained.

[0064] In step 3 of this example, sodium bicarbonate was added to the collected aqueous phase, pH was adjusted to 8, the reaction was carried out at room temperature for 8 hours, the water was removed under reduced pressure, methanol was added to filter out the inorganic salts, and the filtrate was concentrated to obtain 4....

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Abstract

The invention discloses a method for synthesizing a class of cyclic dipeptides. The sequence of the cyclic dipeptides contains L-asparagine or L-glutamine. The method uses 2‑Chlorotrityl Chloride Resin as a carrier to synthesize linear dipeptide fragments in solid phase; then undergoes methyl esterification to obtain linear dimethyl ester protected dipeptide; and then obtains side chain carboxymethyl ester by aqueous alkaline cyclization Protected cyclic dipeptide Cyclo[Glu(OMe)‑AA] or Cyclo[Asp(OMe)‑AA]; Finally, the cyclic dipeptide containing glutamine or asparagine is obtained by aminolysis. The method of the invention has simple synthesis process and safe operation, effectively avoids incomplete cyclization caused by steric hindrance of amino acid side chain protecting groups in the cyclization process, has few by-products, is easy to purify, and can synthesize rings containing Gln and Asn in batches dipeptide.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, in particular to a method for synthesizing a class of cyclic dipeptides. Background technique [0002] Cyclic dipeptides, also known as 2,5-diketopiperazines, are the smallest cyclic peptides in nature that do not exist in the form of zwitterions, consisting of two amino acids through a peptide bond cyclization is formed. Cyclic dipeptide has a simple structure and stable conformation, and is more stable in vivo than the corresponding linear dipeptide, and some cyclic dipeptides have antiviral, antibacterial, antitumor and other activities, so cyclic dipeptide and its derivatives are often used. As a candidate, it has been sought after by synthetic chemists and biologists. [0003] L-asparagine is a non-essential amino acid for various biomedical purposes, and is involved in the metabolic control of cell functions in nerve and brain tissue. L-glutamine has many effects on the bod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/12C07K1/04C07K1/06C07K1/02
CPCC07K5/12Y02P20/55
Inventor 李晨王惠嘉王万科张忠旗杨小琳赵金礼
Owner SHAANXI HUIKANG BIO TECH CO LTD
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