A kind of preparation method of folic acid thiolated derivative

Abstract

The invention discloses a preparation method of a folic acid sulfhydrylation derivative. The preparation method comprises the following steps that -SH in thiol is protected to obtain a derivative of thiol, so that sulfydryl having high reaction activity is protected; then, in the presence of a catalyst and a dehydrating agent, esterification reaction is carried out between hydroxyl on the protected thiol derivative and folic acid, so that a modified folic acid derivative is obtained; a carbon sulphur bond in the folic acid derivative is broken through reduction reaction; sulfydryl is formed again in a product, and therefore, the target product, namely sulfhydrylation folic acid, is obtained. According to the preparation method disclosed by the invention, trityl chloride is replaced by triphenylcarbinol; the disadvantages of difficulty in separation of products and lower product yield are overcome; the product yield is increased; in the esterification reaction, a solid catalyst (macroporous cation exchange resin) is adopted, so that the separation efficiency of products is greatly improved; micromolecules, such as 4-dimethylamino-pyridine (DMAP), are adopted in normal biological preparation; the micromolecules are easily dissolved in a solvent and difficult to separate.

Description

technical field [0001] The invention relates to a preparation method of folic acid mercapto derivatives, belonging to the technical field of organic synthesis. Background technique [0002] Improving the drug efficiency of disease treatment is the ultimate goal of the medical field. After oral administration or injection of ordinary drugs, the part that actually reaches the target lesion tissue is extremely low, and most of the drugs accumulate in the healthy tissues of the human body, failing to achieve the therapeutic effect. At the same time, all drugs have certain toxic and side effects, which have a negative impact on healthy cells. In recent years, the nano-loading and targeted delivery of drugs has been extensively studied, which has greatly improved the utilization rate of drugs and the therapeutic effect of diseases. The targeting of drugs is provided by targeting reagents such as biological antigens, antibodies, DNA, RNA and biological ligands, which have specifi...

AI Technical Summary

Problems solved by technology

All the preparation steps of the folic acid-modified nano-gold complex obtained by this method are carried out in aqueous solution. First, the concentration of gold nanoparticles in the initial stage of the entire preparation process is very low, and the coupling agent and folic acid are usually organic substances. The solubility in aqueous solution is low, and various intermediate products and final products cannot be prepared at high concentrations; moreover, the preparation conditions and storage conditions of nano gold itself are strict, and all solvents and drugs mixed with it need to be highly purified, otherwise It is very easy to cause the agglomeration of nano-metal particles, which increases the difficulty of operation. Therefore, the product preparation efficiency is low, separation and purification are difficult, and the target product cannot be produced in large quantities

In addition, there is another method that first uses polyethylene glycol to coat nano-gold, and then adsorbs folic acid on the outer layer of nanoparticles by physical adsorption. This method is difficult to achieve folic acid on the monolayer modification of nano-gold, and the modification fastness is also difficult. Guaranteed to last

The concentration of the above-mentioned products is very low, it is difficult to realize large-scale production, and the large-scale storage and transportation of products will also be difficult problems to overcome

[0004] The project team published a paper on the preparation and characterization of thiolated folic acid in "Guangzhou Chemical Industry". Yu Yanan et al. used triphenylmethyl chloride as a protective agent to react with mercaptoethanol to achieve the protection of mercapto groups. However, they used mercaptoethanol and Triphenylmethylene chloride is used as a reactant. On the one hand, triphenylmethyl chloride is toxic and inconvenient to use. On the other hand, the by-product sodium chloride is produced in the reaction process, which causes difficulties in the separation of products and lower product yields.

[0005] The project team’s previous patent 2013100094201 invented a method for preparing thiolated folic acid, which can be directly used for the modification of nano-metal particles, but the problem is that the yield is low (the highest yield is 50%), and the post-treatment of the product is relatively difficult. complex

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