New synthesis method by new thymus method

A synthetic method, a new technology of the thymus method, applied in the field of medicine, can solve the problems of difficulty in removing the amino protecting group Fmoc, difficulty in completing the amino acid condensation reaction, and low yield of the target product peptide, so as to facilitate industrial production and reduce Production cost, effect of improving purity

Active Publication Date: 2018-06-29
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The following problems exist in the current synthesis process: first, at some amino acid residues in the polypeptide sequence, side chain reactions will be caused by multiple condensation reactions; second, with the extension of the peptide segment, its solubility decreases, and molecular The internal folding structure, that is, the existence of the so-called "difficult sequence", makes it difficult to carry out the amino acid condensation reaction completely, and it is also very difficult to remove the amino protecting group Fmoc
These problems will lead to the continuous accumulation of by-products, so that there are a large number of missing peptides and hollow peptides in the final crude product, the yield of the target product peptide is low, and these impurities are very similar in structure to the target peptide, making it difficult to purify

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1) Synthesis of Fmoc-Asn(Trt)-CTC resin

[0030] Weigh 10 g of CTC resin with a replacement value of 0.3 mmol / g to 0.8 mmol / g, swell with 100 ml of DCM for 2 to 4 hours, drain it, add 3.0 equivalents of Fmoc-Asn(Trt)-OH 9.0 g, 3.6 equivalents of DIEA 3.0 ml, 100ml DMF solution, react at room temperature for 2-4 hours, drain the reaction solution, wash the resin with DMF and methanol, take about 0.2g resin to measure the substitution value, the substitution value is: 0.41mmol / g. Add 21ml of methanol and 100ml of DMF to the remaining resin to block for 1 hour, drain the reaction solution, and wash the resin with DMF.

[0031] 2) Coupling fragment 1-8 resin

[0032] Add Fmoc-Asn(Trt)-CTC resin to 20% piperidine / DMF solution to remove the Fmoc protecting group for 10min and 20min respectively, drain the deprotection solution, wash the resin with DMF, and weigh 3.0 equivalents of Fmoc-Glu(OtBu)- 5.2g of OH, 4.7g of 3.0 equivalent of HBTU, 1.7g of 3.0 equivalent of HOBT, di...

Embodiment 2

[0050] 1) Synthesis of Fmoc-Asn(Trt)-CTC resin

[0051] With embodiment 1.

[0052] 2) Coupling fragment 1-8 resin

[0053]Add Fmoc-Asn(Trt)-CTC resin to 10% piperidine / DMF solution to remove the Fmoc protecting group for 10min and 20min respectively, drain the deprotection solution, wash the resin with DMF, and weigh 3.0 equivalents of Fmoc-Glu(OtBu)- 5.2g of OH, 4.7g of 3.0 equivalent of HBTU, 1.7g of 3.0 equivalent of HOBT, dissolved in 100ml of DMF, and activated by adding 4.1ml of 6.0 equivalent of DIEA under ice bath, after activation, add it to the tube of peptide solid-phase synthesis, 20℃~30℃ React for 1.5h to 4.5h, use ninhydrin color reaction as the basis for judging the end point of the reaction, drain the reaction solution, wash the resin with DMF, repeat the above operations, and couple Fmoc-Ala-OH, Fmoc-Glu(OtBu)- OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Val-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu (OtBu)-Ala-Glu(OtBu)-Asn(Trt)-CTC (fragmen...

Embodiment 3

[0071] 1) Synthesis of Fmoc-Asn(Trt)-CTC resin

[0072] With embodiment 1.

[0073] 2) Coupling fragment 1-8 resin

[0074] Add Fmoc-Asn(Trt)-CTC resin to 50% piperidine / DMF solution to remove the Fmoc protecting group for 10min and 20min respectively, drain the deprotection solution, wash the resin with DMF, and weigh 3.0 equivalents of Fmoc-Glu(OtBu)- 5.2g of OH, 4.7g of 3.0 equivalent of HBTU, 1.7g of 3.0 equivalent of HOBT, dissolved in 100ml of DMF, and activated by adding 4.1ml of 6.0 equivalent of DIEA under ice bath, after activation, add it to the tube of peptide solid-phase synthesis, 20℃~30℃ React for 1.5h to 4.5h, use ninhydrin color reaction as the basis for judging the end point of the reaction, drain the reaction solution, wash the resin with DMF, repeat the above operations, and couple Fmoc-Ala-OH, Fmoc-Glu(OtBu)- OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Val-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu (OtBu)-Ala-Glu(OtBu)-Asn(Trt)-CTC (fragme...

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Abstract

The invention relates to a new synthesis method by a new thymus method. The synthesis method comprises the following steps: synthesizing three sections (fragments 1 to 8, fragments 9 to 18 and fragments 19 to 28) separately, and then performing condensation among the fragments. By the synthesis method provided by the invention, the purity of crude products can be effectively improved, the contentof impurities is reduced and purification is facilitated, so that the cost is reduced and the method is more suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a new synthetic method of thymus method. Background technique [0002] Thymus Faxin, formerly known as Thymosin α1 and Thymosin α1, is a new type of immunoregulatory factor. It was developed and marketed by Italian Sciclone Company in 1997, and its trade name is "Zadaxin". Faxin improves the immune function of T cells, treats viral hepatitis and delays the occurrence and development of certain senile diseases. In addition, Thymofasin also has anti-infection, anti-virus and anti-tumor effects, especially for immunotherapy of cancer. [0003] At present, there are mainly two new synthesis methods of the thymus method, one is the Boc strategy and the other is the Fmoc strategy. The Boc strategy is less used now because it uses highly toxic HF. There are many reports on the Fmoc strategy, such as "Fmoc Novel Solid-phase Synthesis of Thymosin α1 and Its Reaction Pathway" in "Tianjin P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCC07K14/57581Y02P20/55
Inventor 张贵民王孝花李彦磊赵亮亮
Owner LUNAN PHARMA GROUP CORPORATION
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