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Fmoc-strategy solid-phase synthesis method of thymopentin

A solid-phase synthesis and thymus technology, which is applied in the preparation of polypeptide drugs and the field of solid-phase synthesis of thymopentin, can solve the problems of increased transportation and storage costs, reduced scientific research convenience, and inconvenience for pharmaceutical companies, and achieves easy transportation and storage. The effect of storage, chemical stability and low price

Inactive Publication Date: 2014-04-09
HAINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020]① According to "Regulations on the Safety Management of Hazardous Chemicals" and "Regulations on the Administration of Precursor Chemicals", piperidine is a precursor-2 chemical. It is strictly controlled by the public security department, so it is not easy to obtain in daily scientific research, which greatly reduces the convenience of scientific research
[0021]② Pharmaceutical companies need to have a qualification certificate for the purchase and use of piperidine before they can use it. During the use process, there must be strict records and files, and regular inspections by the police are required. And the inspection of relevant departments has also caused a certain amount of inconvenience to pharmaceutical companies
[0022]③ Piperidine is a colorless liquid with hygroscopicity, can volatilize with water vapor, and is sensitive to carbon dioxide. Its solution is easy to deteriorate and become a light yellow liquid. Re-distillation is required, and these properties contribute to increased shipping and storage costs

Method used

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  • Fmoc-strategy solid-phase synthesis method of thymopentin
  • Fmoc-strategy solid-phase synthesis method of thymopentin
  • Fmoc-strategy solid-phase synthesis method of thymopentin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (1) The connection between the first amino acid and the resin:

[0050] ①Weigh the resin: Take 4g of Wang resin (with a degree of substitution of 1.02mmol / g) in the 80ml reactor No. 1 (accurately weigh its weight before the reaction), the total substitution of Wang resin is the degree of substitution multiplied by the mass, that is 4.08 mmol;

[0051] ② Bonding reaction between resin and amino acid: accurately weigh 4.08mmol (1874.90 mg) of Fmoc-Tyr(tBu)-OH in a 50ml centrifuge tube, add 30ml of DCM (dichloromethane) to dissolve it and add it to No. 1 reactor , To make the resin swell uniformly, the swelling time is about 30min; at the same time, add 4.08mmol (841.826 mg) DCC (dicyclohexylcarbodiimide), 0.408mmol (49.845mg) DMAP (4-two) into another 50ml centrifuge tube. Methylaminopyridine) and 10 mL of DCM, dissolve by mediation, quickly pour it into the No. 1 reactor, mediate uniformly, and oscillate with the swollen resin for about 4 hours to obtain Fmoc-Tyr(tBu)-Wang; ...

Embodiment 2

[0079] (1) The connection between the first amino acid and the resin:

[0080] ①Weigh the resin: take 4g of Wang resin (with a degree of substitution of 1.02mmol / g) in the reactor (accurately weigh its weight before the reaction), the total substitution of Wang resin is the degree of substitution multiplied by the mass, which is 4.08 mmol;

[0081] ② Bonding reaction between resin and amino acid: accurately weigh 3.627~4.488mmol Fmoc-Tyr(tBu)-OH and place it in a centrifuge tube, add 30ml DCM mediation to dissolve and add it to the reactor to make the resin swell evenly, the swelling time is about 30min ; At the same time, add 3.627~4.488mmol DCC, 0.3627~0.4488mmol DMAP and 10mL DCM in another centrifuge tube. After mediation dissolve, quickly pour into the reactor, mediation uniformly, and swell the resin evenly, shake reaction for about 4h to obtain Fmoc- Tyr(tBu)-Wang.

[0082] (2) Head of excess resin

[0083] ①Head capping reaction: Wash all the resin in the reactor with DMF unt...

Embodiment 3

[0103] In the present invention, DMF solutions of piperazine concentrations of 0.1 mol / L, 0.25 mol / L, 0.75 mol / L, and 1 mol / L piperazine are selected as the deprotection agent, and the solvent of the piperazine solution is also selected as NMP (N- Methylpyrrolidone), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide) and other dipolar aprotic solvents, referring to the operating method of Example 2, the corresponding dipeptide, tripeptide, tetrapeptide intermediates can also be prepared , And thymopentin.

[0104]

[0105] In the following, the polypeptide intermediates and thymopentin prepared in the examples are tested and compared with the corresponding products prepared using the traditional deprotecting agent piperidine.

[0106] 1. Determination of Wang resin loading

[0107] (1) Make Fmoc standard curve

[0108] ① Using Fmoc-Ala as the standard substance, accurately weigh 39.5 mg of Fmoc-Ala-OH, treat with 1ml 20% pip / NMP for 20 minutes, and dilute 0.1ml of it with NMP to 10ml. ...

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Abstract

The invention discloses an Fmoc-strategy solid-phase synthesis method of thymopentin. The method comprises the following steps: taking Fmoc protected amino acids as the monomers and sequentially connecting the amino acids to a resin, wherein while synthesizing pentapeptide, the solvent of the added amido acid Fmoc-Arg(Pbf)-OH solution is the mixed solution of DMF (Dimethyl Formamide) and THF (Tetrahydrofuran); depriving all Fmoc protecting groups by using a piperazine solution, and finally, removing the resin and the side chain protecting groups to obtain the thymopentin. According to the invention, the piperazine is taken as the deprotection agent for depriving Fmoc in stead of the traditional pyridine, and the piperazine is a substance unregulated as the dangerous chemical and the poison-making chemical, and is cheap and easy to get, and also stable in chemical properties; the piperazine is in the form of white acicular crystals at the normal temperature, while piperidine is a liquid at the normal temperature, and therefore, the piperazine is more convenient to transport and store; under the same concentration, the Fmoc depriving efficiency of the piperazine is higher than that of piperidine; and obviously, the piperazine has many advantageous in the synthesis of the thymopentin, and also has great stimulative significance in production and study of polypeptides.

Description

technical field [0001] The invention relates to the preparation of polypeptide drugs, in particular to a method for solid-phase synthesis of thymopentin, which belongs to the technical field of polypeptide solid-phase synthesis. Background technique [0002] Thymopentin, its English name is thymopentin, referred to as TP-5, and its Chinese name "Thymopentin" is its free translation. Thymopentin is a chemically synthesized pentapeptide compound (arginine-lysine-aspartic acid-valine-tyrosine), which is the 32nd-36th part of the thymus polypeptide hormone thymopoietin. The amino acid residue fragment at the position, its basic sequence is H-Arg-Lys-Asp-Val-Tyr-OH, retains the effective biological activity of thymopoietin. Thymopentin is a cellular immunomodulatory drug, which has the function of inducing T cell differentiation, promoting the development and activation of T lymphocyte subsets, and can be used to treat malignant tumors, hepatitis, autoimmune diseases, etc. It ha...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06
CPCY02P20/55
Inventor 张响胡碧煌杨顶建
Owner HAINAN UNIVERSITY
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