Peptide Knowledge Center

Synthesis of peptide drugs based on liquid phase technology

At present, chemists and special researchers actively participate in the research and development activities of peptide drugs, and put forward constructive opinions on the application of liquid phase technology based on the clinical medicinal value, which promotes the clinical role of peptide drugs to be fully highlighted. During this period, the liquid phase technology provides a reliable technical guarantee for the purification of polypeptide separation and protein synthesis. Peptide drugs synthesized by liquid phase technology occupy a leading position in the international competition of new drug technology. Nowadays, liquid phase technology has been transferred from laboratory to industrial production and has become an effective separation technology in the field of biotechnology. In order to study the synthetic content of peptide drugs, the synthetic route of peptide drugs was designed by liquid phase technology, and the raw materials were successfully obtained, which provided a reference for further research.

(1) overview of liquid phase method

The practice of liquid phase technology to synthesize polypeptide drugs is not accomplished overnight. If we want to continue to achieve remarkable results, we must formulate a reasonable and feasible liquid phase synthesis plan. When planning synthesis, the utilization strategy of synthesis method should be analyzed first, such as general chemical synthesis, especially linear or phase conversion synthesis, selection and assembly of fragments, and rational application of orthogonal strategy. When the method is relatively mature, we should pay attention to the particularity of the method, not only to solve the chemical technical problems, but also to meet the requirements of the regulatory authorities. The above factors need to be considered in the pharmaceutical industry.

(2) analysis of liquid phase peptide synthesis

2.1 amino protection

In liquid phase synthesis, tert butoxycarbonyl (BOC) and benzyloxycarbonyl (z) have certain utilization value. In contrast, the application rate of Fmoc group in liquid phase peptide synthesis is low. The reason is that the dissolution effect of by-products is poor and the reaction speed is slow. It should be noted that tert butoxycarbonyl (BOC) is used in combination with acid removal and ethyl acetate reagent. Generally, the hydrochloride substance is in solid form, which increases the separation probability. The reduction method is usually selected to remove the Z-Group. The catalyst is used to complete the catalytic hydrogenolysis, and the liquid ammonia can also be used for the reduction reaction.

2.2 carboxyl protection

At present, many peptides exist in the form of C-terminal amino compounds, which lose the necessity of protecting carboxyl groups. In order to obtain the orthogonal effect of protecting group, it is very necessary to apply benzyl or tert butyl group effectively in the process of protecting function.Fmoc-Pen(Trt)-OH If aliphatic ester is used, the protection method is to carry out saponification reaction with NaOH or KOH. Although there is a risk of racemization and the reaction efficiency is reduced, it can be converted into hydrazine salt through hydrazine treatment.Fmoc-OSu In the azide method, hydrazine salt can directly carry out condensation reaction.

Liquid phase synthesis design of 3 peptide drugs

According to data statistics, the incidence rate of breast cancer is increasing year by year, and the death rate of this type of cancer is high, resulting in the negative state of patients and their families. With the increase of the incidence rate of breast cancer, the demand of NORAD in the Chinese market has increased correspondingly, and NORAD is expensive. Therefore, the study on liquid phase synthesis of NORAD has certain practical significance

3.1 synthesis route design

On the one hand, a fragment condensation method (4 + 6 fragment condensation method) is preferable. That is, determine the position of the breaking segment, provide necessary methyl ester protection for it, and complete the methyl ester removal task through the azide method. On the other hand, short peptide fragments are subdivided to obtain the desired target polypeptide through peptide fragment synthesis, condensation and other operations. According to comprehensive analysis, the target compound should be divided into two segments. For the first four peptides, the condensation mode of 2 + 2 fragments was initially selected, and the peptide receiving method was the azide method. Since the minimum protection was selected, two dipeptide fragments pgiu his OME and Trp ser ome were synthesized. The amide is very stable, so there is no need to advance the amide protection. The hydrochloride (pyroglutamic acid and histidine methyl ester) synthesis is pgiu his OME. Tryptophan is not stable enough. If BOC Trp Oh peptide is selected, it is easy to be oxidized when BOC protection is removed, and finally z-trp-ome is synthesized by condensation.