Synthetic method of a class of cyclic dipeptides containing aspartic acid and glutamic acid

A technology of aspartic acid and synthesis method, applied in the directions of organic chemistry, bulk chemical production, etc., can solve the problems of increasing synthesis steps, low safety, air sensitivity, etc., and achieves easy removal, high safety, and simple process. Effect

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

AI Technical Summary

Problems solved by technology

Using the Fmoc / tBu / OAL orthogonal strategy, the highly toxic reagent 3-bromopropene must be used, which has low safety, and the transition metal catalyst palladium must be used for deprotection, which is sensitive to air and expensive, and the reagent residue in the deprotection reaction affects the cyclization The occurrence of the reaction; using the Fmoc / tBu / Dmab orthogonal strategy, the carboxyl protecting group needs to use 2-{1-[4-(hydroxymethyl)anilino]-3-methylbutylene}-5,5-dimethyl Dmab-1,3-cyclohexanedione (Dmab-OH), the price is about 2400 yuan / g, which is expensive, and hydrazine hydrate is required for deprotection, which increases the synthesis steps, so it is rarely used

Method used

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  • Synthetic method of a class of cyclic dipeptides containing aspartic acid and glutamic acid
  • Synthetic method of a class of cyclic dipeptides containing aspartic acid and glutamic acid
  • Synthetic method of a class of cyclic dipeptides containing aspartic acid and glutamic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of Aspartate-Aspartate Cyclic Dipeptides

[0045] 1. Weigh 40g (97.3mmol) of Fmoc-Asp(OtBu)-OH, 21g (107mmol) of 9-fluorene methanol and dissolve it in 500mL of dry dichloromethane, under stirring conditions, add 1.19g (9.73mmol) of 4- Dimethylaminopyridine, cooled to 0°C, added dropwise 50 mL of a dichloromethane solution containing 24.1g (116.8mmol) N,N'-dicyclohexylcarbodiimide, kept at 0°C for 30 minutes after the dropwise addition, and filtered. The precipitate was removed, the temperature was naturally raised to room temperature, and the reaction was performed for 7 hours. TLC monitored the reaction to complete. The reaction solution was concentrated under reduced pressure, the concentrate was dissolved in a little dichloromethane, and subjected to column chromatography with petroleum ether-ethyl acetate system (volume ratio PE:EA=5:1) to obtain 48 g of white solid Fmoc-Asp(OtBu)-OFm.

[0046] 400 mL of trifluoroacetic acid and 20 mL of water were added...

Embodiment 2

[0054] Synthesis of glutamine-aspartate cyclic dipeptide

[0055] Steps 1, 2, and 3 in this embodiment are the same as those in Embodiment 1.

[0056] In step 4 of this example, the H-Asp(2-CTC Resin)-OFm obtained in step 3 was added to 60 mL of N,N-dimethylformamide, and 19 g (32 mmol) of Fmoc-Asn(Trt)- OH, 6.5g (48mmol) 1-hydroxyphenyltriazole, 7.4mL (48mmol) N,N'-diisopropylcarbodiimide, other steps are the same as in Example 1, step 4, to obtain straight chain fully protected diisopropylamine Peptide Fmoc-Asn(Trt)-Asp(2-CTC Resin)-OFm.

[0057] Steps 5 and 6 in this embodiment are the same as steps 5 and 6 in Embodiment 1.

[0058]In step 7 of this example, 92 mL of trifluoroacetic acid, 5 mL of triisopropylsilane, and 3 mL of water were added to Cyclo(Asn(Trt)-Asp(2-CTC Resin)) obtained in step 6, and the reaction was stirred at room temperature for 2 hours. It was concentrated under pressure until no fraction overflowed, 30 mL of pure water was added, and after filtra...

Embodiment 3

[0060] Synthesis of arginine-aspartate cyclic dipeptide

[0061] Steps 1, 2, and 3 in this embodiment are the same as those in Embodiment 1.

[0062] In step 4 of this example, the H-Asp(2-CTC Resin)-OFm obtained in step 3 was added to 60 mL of N,N-dimethylformamide, and 20.8 g (32 mmol) of Fmoc-Arg(Pbf) was added -OH, 6.5g (48mmol) 1-hydroxyphenyltriazole, 7.4mL (48mmol) N,N'-diisopropylcarbodiimide, other steps are the same as in Example 1, step 4, to obtain straight chain full protection The dipeptide Fmoc-Arg(Pbf)-Asp(2-CTC Resin)-OFm.

[0063] Steps 5 and 6 in this embodiment are the same as steps 5 and 6 in Embodiment 1.

[0064] In step 7 of this example, 88 mL of trifluoroacetic acid, 5 mL of triisopropylsilane, 4 mL of anisole, and 3 mL of water were added to Cyclo(Arg(Pbf)-Asp(2-CTC Resin)) obtained in step 6, at room temperature. The reaction was stirred for 2 hours, concentrated under reduced pressure until no fraction overflowed, 50 mL of pure water was added, ...

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Abstract

The invention discloses a method for synthesizing a cyclic dipeptide containing aspartic acid and glutamic acid. The method uses Fmoc-Asp(OtBu)-OH or Fmoc-Glu(OtBu)-OH as raw materials, and 9- Fluorenemethanol reaction to obtain the fluorenylmethyl ester of fully protected amino acid, and then remove the side chain tert-butoxy group to obtain the protected amino acid Fmoc-Asp-OFm or Fmoc-Glu-OFm; then use 2-CTC Resin resin as the carrier and Fmoc-Asp -OFm or Fmoc-Glu-OFm side chain γ-carboxyl linkage, solid-phase cyclization to synthesize a fully protected cyclic dipeptide, cleavage and cleavage to obtain a cyclic dipeptide with aspartic acid or glutamic acid at the carbon end. The method protects the carboxyl group by introducing 9-fluorenemethanol, which can be successfully removed during the solid-phase synthesis of dipeptide. The whole process is simple to operate, high in solid-phase cyclization efficiency, and high in purity. It is suitable for batch synthesis of asparagus Cyclic dipeptides of amino acid or glutamic acid.

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 containing aspartic acid and glutamic acid. Background technique [0002] Cyclic dipeptides, also known as 2,5-diketopiperazines, are the smallest cyclic peptides in nature. These compounds are found in humans, vertebrates, invertebrates, plants, Found in fungi and bacteria. Since the cyclic dipeptide forms a stable six-membered ring structure, it has certain conformational constraints. There are two hydrogen bond donors and two hydrogen bond acceptors. Hydrogen bonding is one of the main ways of interaction between drugs and receptors, so cyclic dipeptide is an important pharmacophore in medicinal chemistry. Some cyclic dipeptides discovered so far have antiviral, antibacterial, antitumor and other biological activities, so cyclic dipeptides and their derivatives are often used as candidates and have been sou...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/08
CPCC07D241/08Y02P20/55
Inventor 高长波李晨王惠嘉张忠旗王慧赵金礼
Owner SHAANXI HUIKANG BIO TECH CO LTD
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