Synthesis method of cyclic dipeptide containing glutamine and asparagine

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

Active Publication Date: 2020-11-03
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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  • Synthesis method of cyclic dipeptide containing glutamine and asparagine
  • Synthesis method of cyclic dipeptide containing glutamine and asparagine
  • Synthesis method of cyclic dipeptide containing glutamine and 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 of 2-Chlorotrityl Chloride Resin (degree of substitution 1.6mmol / g) and swell in dichloromethane for 10 minutes, then add 6.82g (17.6mmol) of Fmoc-Phe-OH, 10.6mL (64mmol) of N,N′-di Isopropylethylamine, react at room temperature for 2 hours, then add anhydrous methanol to seal for 30 minutes, filter with suction, wash the filter cake with 50mL isopropanol, 50mL N,N-dimethylformamide in turn, and wash with 60mL volume concentration of 20 % piperidine in N,N-dimethylformamide solution to remove the Fmoc protecting group for 30 minutes, and then suction-filtered, the filter cake was washed twice with isopropanol and N,N-dimethylformamide successively, each 50mL each time, the resin is positive and black. Add the washed filter cake to 60mL N,N-dimethylformamide, and add 13.6g (32mmol) Fmoc-Glu(OtBu)-OH, 6.5g (48mmol) 1-hydroxybenzotriazole, 7....

Embodiment 2

[0055] Synthesis of glutamine-tyrosine cyclic dipeptide

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

[0057] In step 2 of this example, 6.5 g (15.3 mmol) of trifluoroacetic acid salt of H-Glu-Tyr-OH was added to 100 mL of methanol, and 3.2 mL (45.9 mmol) of di Thionyl chloride, other steps are the same as step 2 of Example 1, through methyl esterification, to obtain the aqueous solution of H-Glu(OMe)-Tyr-OMe hydrochloride.

[0058] In step 3 of this example, add sodium bicarbonate to the collected water phase, adjust pH=8, react at room temperature for 6 hours, the product is precipitated from water, filtered to obtain Cyclo[Glu(OMe)-Tyr] as a white solid, and dried 3.9g was obtained.

[0059] In step 4 of this example, 3.9 g (12.7 mmol) of Cyclo[Glu(OMe)-Tyr] was dissolved in 100 mL of 0.4 mol / L ammonia ...

Embodiment 3

[0061] Synthesis of glutamine-tryptophan cyclic dipeptide

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

[0063] In step 2 of this example, 6.9 g (15.8 mmol) of trifluoroacetic acid salt of H-Glu-Tyr-OH was added to 100 mL of methanol, and 2.3 mL (31.7 mmol) of di Thionyl chloride, other steps are the same as step 2 of Example 1, through methyl esterification, to obtain the aqueous solution of H-Glu(OMe)-Trp-OMe hydrochloride.

[0064] In step 3 of this embodiment, sodium bicarbonate was added to the collected water phase, adjusted to pH=8, reacted at room temperature for 8 hours, water was removed under reduced pressure, methanol was added to filter to remove inorganic salts, and the filtrate was concentrated to obtain 4.2 g of Cyclo[ Glu(OMe)-Trp].

[0065] In step 4 of this example, 4.2 g (12.8 mmol) ...

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Abstract

The invention discloses a synthesis method of a cyclic dipeptide. A cyclic dipeptide sequence contains L-asparagine or L-glutamine. The method comprises the following steps: by taking 2-Chlorotrityl Chloride Resin as a carrier, carrying out solid-phase synthesis to obtain a straight-chain dipeptide fragment H-Glu-AA-OH or H-Asp-AAOH, wherein AA is other alpha-amino acids except asparagine, glutamine, glutamic acid, aspartic acid and cysteine; then carrying out a methyl esterification reaction to obtain straight-chain dimethyl ester protected dipeptide H-Glu (OMe) -AA-OMe or H-Asp (OMe)- AA-OMe; then carrying out water-phase alkaline cyclization to obtain cyclic dipeptide Cyclo[ Glu (OMe)- AA] or Cyclo[ Asp (OMe)- AA] protected by side chain carboxyl methyl ester; and finally, carrying outammonolysis to obtain the cyclic dipeptide containing glutamine or asparagine. The method is simple in synthesis process and safe to operate, incomplete cyclization caused by steric hindrance of aminoacid side chain protecting groups in the cyclization process is effectively avoided, few byproducts are produced, purification is easy, and cyclic dipeptide containing Gln and Asn can be synthesizedin batches.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a synthesis method of 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. Cyclization is formed. Cyclic dipeptides have a simple structure and a stable conformation, and are more stable in vivo than corresponding linear dipeptides, and some cyclic dipeptides have antiviral, antibacterial, and antitumor activities, so cyclic dipeptides and their 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 a variety of biomedical purposes, and is involved in the metabolic control of nerve and brain tissue cell functions. L-glutamine has many effects on the body: for example, it can promote the synthesis ...

Claims

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Application Information

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Patent Type & Authority Applications(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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