# Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide
## 2 Chemical Catalytic Synthesis of NMN  
The synthesis of NMN involves the chemical catalytic conversion of tetraacetyl ribose, benzyl-\(\beta\)-D-ribose, and nicotinamide (NAM) as the main raw materials through ammonolysis, phosphorylation, glycosylation, and other chemical reactions. The three main synthetic routes are the bromoacetyl ribose method, trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalytic condensation, and acid hydrolysis of AMP.  
Ribose protected by acetyl or benzoyl groups can be brominated or chlorinated, and the protective group can then be removed through hydrolysis to yield NMN. [PERSON] et al. [20] utilized tribenzoyl-\(\beta\)-D-ribose as the starting material, which was first brominated with hydrobromide, and the bromine was subsequently replaced with nicotinamide. The benzoyl group was then eliminated under alkaline conditions, followed by phosphorylation using phosphorus trichloride/trimethyl phosphate to produce \(\beta\)-NMN. This method involves four steps and affords a total yield of approximately 31%. Based on the afore  
Figure 2: The common metabolic pathways of NAD\({}^{+}\) and NMN. There are three major biosynthetic pathways of NAD+: the Preiss–Handler path-way (blue); the de novo synthesis pathway (green); and the salvage pathway (pink).  
mentioned route, [PERSON] et al. [21] utilized tetraacetyl ribose and subjected it to bromination with hydrobromic acid, followed by nicotinamide substitution to generate nicotinamide triacetate. Subsequently, the acetyl group was eliminated using ammonia, and ultimately, \(\beta\)-NMN was obtained through phosphorylation with phosphorus oxychloride/trimethyl phosphate, followed by purification via resin chromatography. The overall yield amounted to approximately 57%, with purity exceeding 97% (Figure 3).  
In the TMSOTf approach, nicotinamide is silanized and condensed with hydroxyl-protected ribose in the presence of TMSOTf, which generates the \(\beta\)-nucleoside with high stereoselectivity. Then, the nicotinamide is deprotected by NH\({}_{3}\) or MeOH and hydrolyzed to NMN [22; 23]. Compared with the previous approaches, this method shortened the reaction time and increased the stereoselectivity, while solvent utilization and product extraction were relatively simple, with a high yield of NMN (Figure 4). In the hydrolysis of adenosine monophosphate (AMP) under acidic conditions, ribose-5-phosphate is first formed, which is subsequently treated with anhydrous ammonia in dry ethylene glycol to yield ribose-5-phosphate amine. This intermediate compound is then reacted with l-(2,4-dinitrophenyl)-3-carbamoylpyridinium chloride (NDC) to produce NMN (\(\alpha\):\(\beta\) = 2:3) [24; 25; 26]. However, this method involves harsh reaction conditions and requires anhydrous intermediate steps, resulting in a higher proportion of the inactive \(\alpha\) isomer (Figure 5).  
Figure 4: TMSOTf catalytic condensation.  
Figure 3: Bromoacetyl ribose method.  
Chemical catalysis methods offer advantages such as cost effectiveness, easy availability of raw materials, scalability, and high yields. Currently, industrial-scale production of NMN is predominantly achieved through chemical methods. However, chemical approaches come with drawbacks such as stringent reaction conditions, the use of organic solvents, and limited stereoselectivity. By contrast, biological synthesis pathways are characterized by high stereoselectivity, mild reaction conditions, and minimal by-products. These qualities make biological synthesis a primary area of research in the current exploration of NMN synthesis methods, offering a promising alternative to address the limitations of chemical approaches.