Process preparation method of beta-nicotinamide mononucleotide

Abstract

The invention provides a process preparation method of beta-nicotinamide mononucleotide. With tetraacetylribose and niacinamide or ethyl nicotinate as starting materials, through main process steps ofcondensation, ammonolysis, chemical resolution, phosphorylation and the like, and through optimization of the process method, the beta-nicotinamide mononucleotide is prepared; the method is based onthe purposes of quality control and safety of the beta-nicotinamide mononucleotide, industrial batch production feasibility of a preparation process and the like; the preparation method is improved onthe basis of an original process route, optimizes the selected materials and reagents, controls the material amount and the like, and has the advantages of simplicity in operation, easiness in process amplification, higher yield, controllable final product quality, controllable safety and the like compared with the original preparation process.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a process preparation method of β-nicotinamide mononucleotide. [0002] technical background [0003] β-nicotinamide mononucleotide (NMN) is one of the inherent substances in the human body and plays an important role in the energy generation of human cells. It participates in intracellular NAD (nicotinamide adenine dinucleotide, an important coenzyme for cell energy transformation The synthesis of β-nicotinamide mononucleotide (NMN) plays a key role in the energy metabolism of cells, and is used in anti-aging research. At present, human clinical trials are being conducted on the anti-aging effect and safety of β-nicotinamide mononucleotide (NMN) abroad . At the same time, studies have shown that β-nicotinamide mononucleotide (NMN) can also regulate the secretion of insulin and have an impact on the expression level of mRNA. Therefore, β-nicotinamide mononucleotide (NMN) is wide...

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Problems solved by technology

[0011] The first two routes have problems such as low yield, difficult reaction purification, and difficult process scale-up. The resolution and purification of the intermediate racemate are separated by activated carbon chromatography, and the quality of the obtained β-nicotinamide mononucleotide is uncontrollable. It can only be used for very small-scale synthesis in the laboratory. The third route, the invention patent application with the publication number CN109053838A, does not involve the process of chiral resolution of intermediates. The obtained intermediates and products are all racemates. The obtained final product β-nicotinamide mononucleotide contains chiral isomeric impurities, which has great safety problems in the field of medical treatment and cannot be used in the field of medical treatment

[0012] In addition, the patent reports that the biosynthesis method of this compound mainly contains a kind of method, using ribose, nicotinamide, triphosphate disodium salt as raw materials, in a buffer solution (phosphate buffered saline solution) by catalyzing enzymes (glucokinase and nicotinamide ribose phosphate) Transferase) action (promoting the biocatalytic activity of the catalytic enzyme through metal magnesium ions), and finally obtaining β-nicotinamide mononucleotide (NMN) through filtration, macroporous resin adsorption and recrystallization, this method provides an industrial batch The method for producing β-nicotinamide mononucleotide (NMN), but currently there are too few biocatalysts available for industrial applications; the development cycle of biocatalysts is long; biocatalysts are often unstable in the reaction medium, susceptible to heat, Some chemical substances and bacteria are destroyed and inactivated; the stability is poor, the temperature and pH range of the reaction are high, and the service life is short.

[0013] At present, the acquisition of β-nicotinamide mononucleotide (NMN) can only be synthesized in the laboratory, and there are limitations in the method of industrial batch production. On the one hand, the separation and purification of the racemate is separated by activated carbon column chromatography. method, the cost is extremely high and the scale of separation and purification is small, which limits the feasibility of its industrial production; on the other hand, in terms of material and reagent selection, such as the large amount of catalyst used in the condensation reaction, it is easy to remain in subsequent products Among them, methanesulfonic acid substances are genotoxic substances, which cause great safety problems for product applications. Many solvents used in them, such as 1,2-dichloroethane, belong to the first category of solvents, which are strictly controlled in pharmaceuticals. Solvents, 1,4-dioxane are genotoxic substances, etc., which limit the promotion of β-nicotinamide mononucleotide (NMN) in many aspects

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