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Synthetic method of cyclic dipeptide containing aspartic acid and glutamic acid

A technology of aspartic acid and synthesis method, applied in the field of cyclic dipeptide synthesis, can solve problems such as low safety, air sensitivity, and increased synthesis steps

Active Publication Date: 2021-07-06
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • 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 cyclic dipeptide containing aspartic acid and glutamic acid
  • Synthetic method of cyclic dipeptide containing aspartic acid and glutamic acid
  • Synthetic method of cyclic dipeptide containing aspartic acid and glutamic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of aspartate-aspartate cyclic dipeptide

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

[0046] Add 400mL trifluoroacetic acid and 20mL water to 48g (81.4mmol) Fmoc-As...

Embodiment 2

[0054] Synthesis of glutamine-aspartic acid cyclic dipeptide

[0055] Steps 1, 2, and 3 of this embodiment are the same as those of 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-hydroxybenzotriazole, 7.4mL (48mmol) N,N'-diisopropylcarbodiimide, and other steps are the same as step 4 of Example 1 to obtain a linear fully protected di Peptide Fmoc-Asn(Trt)-Asp(2-CTC Resin)-OFm.

[0057] Steps 5 and 6 of this embodiment are the same as steps 5 and 6 of 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, stirred at room temperature for 2 hours, and then Concentrate under pressure until no fraction overflows, add 30mL of pure water, filter and prepare and purify by hydrophilic chromatograph...

Embodiment 3

[0060] Synthesis of Arginine-Aspartic Acid Cyclic Dipeptide

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

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

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

[0064] In Step 7 of this example, add 88 mL of trifluoroacetic acid, 5 mL of triisopropylsilane, 4 mL of sulfide anisole, and 3 mL of water to Cyclo (Arg(Pbf)-Asp(2-CTC Resin)) obtained in Step 6, and Stir the reaction for 2 hours, concentrate under reduced pressure until no fraction overflows, add 50mL of pure water, filter and prepare and purify by reve...

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Abstract

The invention discloses a synthetic method of cyclic dipeptide containing aspartic acid and glutamic acid, which comprises the following steps: by taking Fmoc-Asp (OtBu)-OH or Fmoc-Glu (OtBu)-OH as a raw material, reacting with 9-fluorene methanol to obtain fluorene methyl ester of fully protected amino acid, and then removing side chain tert-butoxy to obtain protected amino acid Fmoc-Asp-OFm or Fmoc-Glu-OFm; 2-CTC Resin resin is used as a carrier to be bonded with Fmoc-Asp-OFm or Fmoc-Glu-OFm side chain gamma-carboxyl, solid-phase cyclization is carried out to synthesize full-protection cyclic dipeptide, and the cyclic dipeptide with aspartic acid or glutamic acid at the carbon end is obtained through cutting and cracking. According to the method, 9-fluorene methanol is introduced to protect carboxyl, the carboxyl can be smoothly removed in the solid-phase synthesis process of the dipeptide, the whole process is easy to operate, the solid-phase cyclization efficiency is high, the purity is high, and the method can be suitable for batch synthesis of cyclic dipeptide with aspartic acid or glutamic acid at the carbon end.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates 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 (2,5-diketopiperazines), are the smallest cyclic peptides in nature. Found in both 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, and hydrogen bonding is one of the main ways for drugs to interact with receptors, so cyclic dipeptides are an important pharmacophore in medicinal chemistry. Some cyclic dipeptides discovered so far have biological activities such as antiviral, antibacterial, and antitumor, so cyclic dipeptides and their derivatives are often used as candidates, and have been sought after by synthetic chemis...

Claims

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Application Information

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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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