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A method for synthesizing pseudoproline heterocyclic peptides by resin catalysis

A pseudo-proline and heterocyclic technology, which is applied in the field of synthetic pseudo-proline heterocyclic peptides by resin catalysis, can solve the problems of low total yield, complex operation, and many impurities in the product, and achieve low impurity content and post-processing The effect of simplicity and process cost reduction

Inactive Publication Date: 2019-11-19
SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of polypeptide drugs in the above-mentioned documents has been applied to pseudoproline dipeptide (a heterocyclic peptide), but the synthetic method of pseudoproline dipeptide has not been reported
[0007] Regarding the synthesis of pseudo-proline heterocyclic peptides: there is a document (CN 101472939 A) that undergoes repeated salt formation and condensation, the operation is complicated, and the total yield is low; another document records that p-toluenesulfonic acid or pyridine p-toluenesulfonate can be used for Catalysis, but the disadvantage caused by the use of conventional acid-catalyzed condensation is that the acid must be removed to obtain high-purity products
To remove the acid, water must be involved, and the heterocyclic dipeptide product has extremely poor stability in the acid water system, and is easily decomposed into raw materials, resulting in low product yield, and it is difficult to obtain the target product with ideal yield and purity.
After 20 hours of reflux reaction in the literature method, the reaction is still incomplete, and the product has many impurities and complex components, which requires column chromatography purification, and the product yield is less than 40%.

Method used

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  • A method for synthesizing pseudoproline heterocyclic peptides by resin catalysis
  • A method for synthesizing pseudoproline heterocyclic peptides by resin catalysis
  • A method for synthesizing pseudoproline heterocyclic peptides by resin catalysis

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Embodiment 1

[0028] The pseudoproline heterocyclic peptide (I) was synthesized according to the following method:

[0029] (1) The isoleucine (N-fluorenylmethoxycarbonyl-L-isoleucine) protected by Fmoc is reacted with serine to generate dipeptide, wherein the carboxyl group of serine is protected by benzyl, and the synthesis method of dipeptide is according to Existing routine method, obtains the structural formula of dipeptide as follows:

[0030]

[0031] Wherein, Bn is benzyl;

[0032] (2) Dissolve the dipeptide obtained in step (1) with 2,2-dimethoxypropane first, then add catalyst Dowex 50 resin therein, the amount of catalyst used is 5% of the mass fraction of the dipeptide, then heat and reflux and stir for 2h, Use TLC to monitor whether the condensation reaction is complete;

[0033] (3) The condensation reaction product is dissolved in methanol solution, 5% Pd-C catalyst of catalytic amount and 2 equivalents of formic acid are added therein, stirred at room temperature for ab...

Embodiment 2

[0040] The pseudoproline heterocyclic peptide (II) was synthesized according to the following method:

[0041] (1) React Fmoc-protected isoleucine (N-fluorenylmethoxycarbonyl-L-isoleucine) with threonine to generate a dipeptide, wherein the carboxyl group of threonine is protected by benzyl, and the dipeptide The synthetic method according to existing routine method, obtains the structural formula of dipeptide as follows:

[0042]

[0043] Wherein, Bn is benzyl;

[0044] (2) Dissolve the dipeptide obtained in step (1) with 2,2-dimethoxypropane first, then add catalyst Dowex 50 resin therein, the amount of catalyst used is 10% of the mass fraction of the dipeptide, then heat and reflux and stir for 2h, Use TLC to monitor whether the condensation reaction is complete;

[0045] (3) The condensation reaction product is dissolved in the methanol solution, wherein the Pd-C catalyst of 5% catalytic amount and 3 equivalents of formic acid are added, stirred at room temperature fo...

Embodiment 3

[0050] The pseudoproline heterocyclic peptide (Ⅲ) was synthesized according to the following method:

[0051] (1) The leucine (Fmoc-L-leucine) protected by Fmoc is reacted with cysteine ​​to generate dipeptide, wherein the carboxyl group of cysteine ​​is protected by benzyl, and the synthesis method of dipeptide is according to the present The conventional method that has, obtains the structural formula of dipeptide as follows:

[0052]

[0053] Wherein, Bn is benzyl;

[0054] (2) After dissolving the dipeptide obtained in step (1) with 2,2-dimethoxypropane, add the catalyst Dowex50 resin therein, the amount of the catalyst is 5% of the mass fraction of the dipeptide, then heat and reflux and stir for 2h, using TLC monitors whether the condensation reaction is complete;

[0055] (3) The condensation reaction product is dissolved in the methanol solution, and the formic acid of the Pd-C catalyst of 5% catalytic amount and 2 equivalents is added wherein, stirs at room tempe...

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Abstract

The invention provides a method for synthesizing pseudoproline heterocyclic peptide by resin catalysis, and belongs to the technical field of peptide synthesis. The method comprises the steps as follows: (1) amino acid protected by Fmoc reacts with one of serine, threonine or cysteine to generate a dipeptide; (2) dipeptide obtained in the step (1) is subjected to a condensation reaction with 2, 2-dimethoxypropane under the catalysis of acidic resin, an obtained product is filtered for removal of the acidic resin and then concentrated and separated, and the target product pseudoproline heterocyclic peptide is obtained. According to the method for synthesizing pseudoproline heterocyclic peptide, repeated salt formation and decomposition are not needed, repeated column chromatography is not required for purification of the product, the yield of the final product can be up to 90%, and the purity can be up to 97%; the method has the characteristics of simple reaction operation, high reaction yield, small product impurity content, low preparation cost and the like, and can adapt to industrial production. The structure of pseudoproline heterocyclic peptide is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of peptide synthesis, and in particular relates to a method for synthesizing pseudo-proline heterocyclic peptides by resin catalysis. Background technique [0002] All amino acid sequences in biosynthetic polypeptides and proteins exist in the state of Trans configuration; the formation of secondary structures in protein biosynthesis in ribosomes has begun and is a rapid process, while Cis / Trans isomerization is the bottleneck for the overall folding rate of the protein. In the polypeptide sequence, the amide-peptide bond formed by proline and its preceding amino acid residue is called peptide-proamide bond (Xaa-Pro bond). Cis peptide bond is rare in proteins, but proline-containing Xaa-Pro bond contains 10-30% Cis-like ratio, and in the short-chain polypeptide solution, the ratio of Cis / Trans conformation is even equal. [0003] This unusual assignment of the Cis / Trans ratio of the Xaa-Pro bond can be exp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/065C07K1/04C07K1/06
CPCC07K5/06078Y02P20/55
Inventor 贾爱琼赵经伟汪令李波李直宋艳霞马晓黎杨明波梁悦
Owner SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP