Synthesis method of nicotinamide ribose chloride and intermediate thereof

Abstract

The invention discloses a synthesis method of nicotinamide ribose chloride and an intermediate thereof. The preparation method comprises the following steps: mixing chlorinated triacetyl ribose, nicotinamide, zinc chloride, tin tetrachloride and an organic solvent, and reacting to obtain triacetyl nicotinamide ribose chloride; or mixing tetraacetyl ribose, nicotinamide, zinc chloride, tin tetrachloride and an organic solvent, and reacting to obtain triacetyl nicotinamide ribose acetate; and adding the triacetyl nicotinamide ribose into an organic solvent solution of hydrogen chloride for deacetylation to obtain the nicotinamide ribose chloride. According to the method, the triacetyl nicotinamide ribose chloride is prepared by catalyzing the glycosylation of the chlorinated triacetyl ribose through the composite catalyst of zinc chloride and tin tetrachloride, so that the total yield, the product content and the purity are obviously improved; or a composite catalyst of zinc chloride and stannic chloride is used for catalyzing glycosylation of tetraacetyl ribose to prepare triacetyl nicotinamide ribose acetate, the purity is obviously improved, and further the preparation of nicotinamide ribose chloride also has obvious advantages.

Description

Technical Field

[0001] This invention belongs to the field of nicotinamide ribose technology, specifically relating to a method for synthesizing nicotinamide ribose chloride and its intermediates. Background Technology

[0002] Nicotinamide ribosyl (NR), with the chemical structure 3-(carbamoyl)-1β-D-rifuranosylpyridine, is a naturally occurring nucleotide and a form of vitamin B3 (niacin). As a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), NR plays a crucial coenzyme role in cellular energy metabolism, DNA repair, and various signal transduction pathways. Studies have shown that NAD+ levels decline significantly with cellular aging, which is closely related to the occurrence and development of various age-related diseases such as neurodegenerative diseases, cardiovascular diseases, and metabolic syndrome. Supplementing with NR can effectively increase NAD+ levels, thereby activating the Sirtuins (longevity proteins) family and exhibiting broad physiological activities such as delaying aging, neuroprotection, and improving metabolism. Therefore, it has enormous application potential in the biomedical and health care fields.

[0003] However, naturally occurring nicotinamide ribose is present in extremely low concentrations and is difficult to obtain through large-scale purification, which severely limits its large-scale application in the biopharmaceutical field. To meet market demand, current methods primarily rely on chemical or enzymatic synthesis to prepare nicotinamide ribose.

[0004] Existing methods for synthesizing nicotinamide ribose have the following main limitations: Traditional enzymatic synthesis method: This method is difficult to achieve large-scale production at the gram level or above during the preparation process, and cannot meet the needs of industrialization.

[0005] Chemical synthesis method: Poor stereoselectivity: The reported chemical synthesis methods usually suffer from insufficient stereoselectivity, which inevitably leads to the presence of about 13% α-isomers (i.e., inactive α-nicotinamide ribose) in the product.

[0006] Separation and purification are difficult: In order to obtain high-purity active products (β-isomers), complex post-processing operations such as activated carbon chromatography and multiple crystallizations are required, which makes the separation process complex, time-consuming, and ultimately results in a low yield of β-isomers.

[0007] High operational difficulty: Some chemical synthesis methods have not been widely adopted by laboratories and industries due to their demanding operating conditions and complicated steps.

[0008] In summary, existing technologies for the synthesis of nicotinamide ribose face challenges such as limitations in scalability, poor stereoselectivity, high purification costs, and low yields. Therefore, developing a synthetic method for nicotinamide ribose that exhibits high stereoselectivity, excellent yield, ease of operation, and suitability for large-scale industrial production is a critical technical issue that urgently needs to be addressed. Summary of the Invention

[0009] To overcome the shortcomings of the prior art, the present invention provides a method for synthesizing nicotinamide ribochloride and its intermediates; the method has the advantages of high total yield, high product content, high stereoselectivity, simple operation process and scalability, and can realize the low-cost preparation of high-purity nicotinamide ribochloride and its intermediates.

[0010] The technical solution adopted by this invention to solve its technical problem is: This invention provides a method for synthesizing triacetylnicotinamide ribose, comprising the following steps: Method 1: Mix chlorotriacetylribose, nicotinamide, zinc chloride, tin tetrachloride and organic solvent, and react to obtain triacetylnicotinamide ribose chloride; Alternatively, method two: mix tetraacetylribose, nicotinamide, zinc chloride, tin tetrachloride and organic solvent, and react to obtain triacetylnicotinamide riboacetate.

[0011] Preferably, in Method 1, the preparation method of chlorotriacetylribose is as follows: hydrogen chloride gas is passed into an organic solvent solution of tetraacetylribose until saturation, and the reaction is stirred to obtain chlorotriacetylribose.

[0012] More preferably, the mass ratio of tetraacetylribose to organic solvent in the organic solvent solution of tetraacetylribose is 5:(4-8).

[0013] More preferably, the organic solvent in the organic solvent solution of tetraacetylribose is one or more of toluene, dichloromethane, and chloroform.

[0014] Further preferably, the temperature of the organic solvent solution of tetraacetylribose is (-5)-0℃.

[0015] More preferably, the mass of hydrogen chloride gas introduced is 0.15-0.2 times the mass of tetraacetylribose, and the introduction time is 10-15 hours.

[0016] Further preferably, the stirring reaction time is 1-2 hours.

[0017] Further preferred, the stirring reaction was completely confirmed by TLC; the developing solvent for TLC was dichloromethane:methanol = 2:(0.1-0.2) (volume ratio), and 1-2 drops of acetic acid were added for every 2.15 mL, and the reaction was detected by iodine colorimetric method.

[0018] Further preferred, the reaction is followed by purification; the purification process is as follows: concentration under reduced pressure at 40-45℃, evaporation at 40-45℃, and evaporation with the addition of toluene at 40-45℃.

[0019] Preferably, in Method 1, the molar ratio of chlorotriacetylribose to nicotinamide is 1:(1-1.1).

[0020] Preferably, in Method 1, the mass ratio of nicotinamide to organic solvent is 10:(25-30).

[0021] Preferably, in method one, the organic solvent is one or more of acetonitrile, propionitrile, and dimethylformamide.

[0022] Preferably, in method one, the mixing process temperature is controlled to not exceed 15°C.

[0023] Preferably, in method one, the reaction temperature is 25-35℃ and the reaction time is 8-10 hours.

[0024] Preferably, in Method 1, the molar ratio of zinc chloride to tin tetrachloride is 1:(0.8-1.2).

[0025] Preferably, in Method 1, the total amount of zinc chloride and tin tetrachloride is 2.8%-4.5% of the molar amount of chlorotriacetylribose.

[0026] Preferably, in Method 1, the reaction is completely confirmed by TLC and liquid chromatography. The developing solvent for TLC is dichloromethane:methanol = 2:(0.1-0.2) (volume ratio), and 1-2 drops of acetic acid are added for every 2.15 mL. The reaction is detected by iodine colorimetric method.

[0027] Preferably, in method one, after the reaction, acetonitrile is recovered, acetone and triethylamine are added to form a slurry, the filter cake is washed with acetone after centrifugation, and then dried.

[0028] Preferably, in Method 2, the molar ratio of tetraacetylribose to nicotinamide is 1:(1-1.1).

[0029] Preferably, in method two, the mass ratio of nicotinamide to organic solvent is 10:(25-30).

[0030] Preferably, in method two, the organic solvent is one or more of acetonitrile, propionitrile, and dimethylformamide.

[0031] Preferably, in method two, the mixing process temperature is controlled to not exceed 15°C.

[0032] Preferably, in method two, the reaction temperature is 30-40℃ and the reaction time is 10-15 hours.

[0033] Preferably, in method two, the molar ratio of zinc chloride to tin tetrachloride is 1:(0.8-1.2).

[0034] Preferably, in Method 2, the total amount of zinc chloride and tin tetrachloride is 2.8%-4.5% of the molar amount of tetraacetylribose.

[0035] Preferably, in Method 2, the reaction is completely confirmed by TLC and liquid chromatography. The developing solvent for TLC is dichloromethane:methanol = 2:(0.1-0.2) (volume ratio), and 1-2 drops of acetic acid are added for every 2.15 mL. The reaction is detected by iodine colorimetric method.

[0036] Preferably, in method two, after the reaction, acetonitrile is recovered, acetone and triethylamine are added to form a slurry, the filter cake is washed with acetone after centrifugation, and then dried.

[0037] This invention provides a method for synthesizing nicotinamide ribochloride, comprising the following steps: Triacetylnicotinamide ribose was synthesized using the method described above. Triacetylnicotinamide ribose was then added to an organic solvent solution of hydrogen chloride to undergo a deacetylation reaction, yielding nicotinamide ribose chloride.

[0038] More preferably, the temperature of the organic solvent solution of hydrogen chloride is below 5°C.

[0039] More preferably, the mass-volume concentration of hydrogen chloride in the organic solvent solution of hydrogen chloride is 10%-12%, g / mL.

[0040] More preferably, the organic solvent in the organic solvent solution of hydrogen chloride is one or more of methanol, ethanol and isopropanol.

[0041] More preferably, the volume of the organic solvent solution of hydrogen chloride is 2-3 times the mass of triacetylnicotinamide ribose, in mL / g.

[0042] More preferably, the deacetylation reaction is carried out at a temperature of 5°C-10°C for 10-15 hours.

[0043] In a further preferred embodiment, after the deacetylation reaction, the temperature is lowered to below -4°C, and the mixture is kept at this temperature to crystallize. After centrifugation, the filter cake is washed with methanol, collected, and vacuum dried at 25°C-30°C to obtain nicotinamide ribochloride.

[0044] Compared with the prior art: (1) The present invention adopts a composite Lewis acid catalytic system of zinc chloride and tin tetrachloride. Tin tetrachloride can form a coordination bond with acetoxy groups, which can efficiently induce the formation of acyloxylon intermediates. Zinc chloride not only has moderate Lewis acidity, which can help activate the glycosidic bond of the reaction substrate, but also can regulate the catalytic active center of tin tetrachloride through electronic effects, thereby optimizing the formation rate and stability of acyloxylon intermediates. The two form a synergistic catalytic mode of "activating substrate + directional induction". The synergistic effect significantly improves the selectivity and efficiency of the glycosylation reaction, shortening the reaction time of intermediate 2 from 12 hours in the traditional process to 8-10 hours; (2) Zinc chloride in the composite catalyst of the present invention is inexpensive and environmentally friendly, while tin tetrachloride has high catalytic activity. The combination of the two not only reduces the cost of the catalyst, but also reduces the amount of a single catalyst, reducing the environmental burden and conforming to the trend of green chemical development; (3) The process route of the present invention is reasonably designed, the reaction conditions of each step are mild, no extreme temperature or pressure conditions are required, the operation is easy and safe, and the solvent (toluene, acetonitrile, methanol, etc.) can be recycled, further reducing the production cost; (4) The present invention effectively reduces the occurrence of side reactions by precisely controlling the reaction temperature, catalyst ratio and post-processing process. The final product yield is more than 46%, the purity can reach more than 97%, the content is more than 94%, the product quality is stable, and it can meet the application needs of high-end fields such as biomedicine and food health care; (5) The raw materials of the present invention are readily available, the operation is controllable, environmentally friendly and efficient, solving the problems of long reaction time, high cost and environmental unfriendliness in the traditional process, and is suitable for large-scale industrial production.

[0045] The beneficial effects of this invention are: (1) The present invention uses a composite catalyst of zinc chloride and tin tetrachloride to catalyze the glycosylation of chlorotriacetylribose to prepare triacetylnicotinamide ribochloride, which significantly improves the total yield, product content and purity, and thus has significant advantages in the preparation of nicotinamide ribochloride.

[0046] (2) The present invention uses a composite catalyst of zinc chloride and tin tetrachloride to catalyze the glycosylation of tetraacetyl ribose to prepare triacetyl nicotinamide riboacetate, which significantly improves the purity and also has a high total yield and product content, thus having significant advantages in the preparation of nicotinamide ribochloride. Detailed Implementation

[0047] The present invention will be further described below with reference to embodiments.

[0048] The following will clearly and completely describe the concept, specific solutions, and technical effects of the present invention with reference to embodiments, so as to fully understand the purpose, features, and effects of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention. The various technical features in the present invention can be combined interactively without contradicting each other.

[0049] This invention provides a method for the efficient synthesis of nicotinamide ribochloride, the synthetic route of which is as follows:

[0050] Includes the following steps: (1) Preparation of intermediate 1: Tetraacetylribose and toluene were added to a dry reaction vessel, stirred and cooled to (-5)-0℃, hydrogen chloride was introduced until saturation, and stirring was continued for 1-2 hours. After the reaction was confirmed by sampling and plate testing, the mixture was concentrated under reduced pressure at 40℃, acetic acid was removed by evaporation at 40℃, and toluene was added and evaporated again at 40℃ to remove acetic acid, thus obtaining intermediate 1. (2) Preparation of intermediate 2 by glycosylation reaction: Anhydrous acetonitrile, nicotinamide and Lewis acid composite catalyst are added to a dry reaction vessel. The Lewis acid composite catalyst is a mixture of zinc chloride and tin tetrachloride. The mixture is stirred and cooled to below 10°C. Intermediate 1 prepared in step (1) is added. The feeding temperature is controlled to not exceed 15°C. The reaction vessel of step (1) is rinsed with anhydrous acetonitrile and the rinsing liquid is combined. The temperature is raised to 30°C and kept for 8-10 hours. After confirming that the reaction is complete by plate spot detection and liquid phase detection, acetonitrile is recovered at 30-40°C. Acetone and triethylamine are added and slurry is made. After centrifugation, the filter cake is washed with acetone and dried to obtain intermediate 2. (3) Preparation of nicotinamide ribochloride by deprotection reaction: Add anhydrous methanol to the dry reaction vessel, cool down to below 5°C, introduce hydrogen chloride to adjust the mass volume concentration of hydrogen chloride in methanol to 10%-12% (g / mL), add intermediate 2 prepared in step (2), heat to 5°C-10°C and keep the reaction for 12 hours, detect by HPLC, after confirming that the reaction is complete, cool down to below -5°C, keep the temperature to crystallize, centrifuge, wash the filter cake with methanol, collect the filter cake and vacuum dry at 25°C-30°C to obtain nicotinamide ribochloride.

[0051] In one specific embodiment, in step (1), the mass ratio of tetraacetylribose to toluene is 5:6.

[0052] In one specific embodiment, in step (1), in addition to toluene, inert organic solvents such as dichloromethane or chloroform can also be used as reaction media. These solvents can also provide a dry reaction environment, which is conducive to the chlorination reaction. However, it may be necessary to adjust the concentration and solvent removal temperature according to the boiling point of the solvent.

[0053] In one specific embodiment, in step (1), the mass of hydrogen chloride introduced is 0.17 times the mass of tetraacetylribose, and the introduction time is approximately 12 hours.

[0054] In one specific embodiment, in step (1), the method of introducing hydrogen chloride can be replaced by adding a toluene or dichloromethane solution containing hydrogen chloride to improve operational safety, but the amount added needs to be precisely controlled to achieve a saturated concentration.

[0055] In one specific embodiment, in step (1), the developing solvent of the spotting plate is dichloromethane:methanol = 2:0.15 (volume ratio), and 1 drop of acetic acid is added for every 2.15 mL, and the detection is performed using iodine colorimetric method.

[0056] In one specific embodiment, in step (2), the mass ratio of nicotinamide to anhydrous acetonitrile is 10:28.5.

[0057] In one specific embodiment, in step (2), anhydrous acetonitrile can be replaced with anhydrous propionitrile or anhydrous dimethylformamide as an aprotic polar solvent, but the reaction temperature and time need to be adjusted accordingly.

[0058] In one specific embodiment, in step (2), the molar ratio of zinc chloride to tin tetrachloride in the Lewis acid composite catalyst is 1:(0.8-1.2), and the total amount of composite catalyst is 2.8%-4.5% of the molar amount of tetraacetylribose.

[0059] In one specific embodiment, in step (2), the amount of acetone added during pulping is 4.5 times the mass of nicotinamide, and the amount of triethylamine added is 0.05-0.075 times the mass of nicotinamide.

[0060] In one specific embodiment, in step (2), acetone in the pulping process can be replaced with a mixed solvent of acetonitrile / isopropanol, and triethylamine can be replaced with organic bases such as pyridine or N,N-diisopropylethylamine to neutralize the acidity and promote crystallization.

[0061] In one specific embodiment, in step (2), the mass of acetone used for rinsing the filter cake is 0.5 times the mass of nicotinamide.

[0062] In one specific embodiment, in step (3), the volume of methanol added is 2-3 times the mass of intermediate 2, mL / g.

[0063] In one specific embodiment, in step (3), methanol can be replaced with ethanol or isopropanol, but the concentration of hydrogen chloride and the reaction temperature need to be adjusted according to the properties of the alcohol solvent.

[0064] In one specific embodiment, in step (3), the amount of hydrogen chloride introduced is 10%-12% (g / mL) by mass volume concentration.

[0065] In one specific embodiment, in step (3), the source of hydrogen chloride can be replaced by the in-situ reaction of acetyl chloride or trimethylchlorosilane with methanol to generate hydrogen chloride, in order to replace the direct introduction of hydrogen chloride gas and improve the ease of operation.

[0066] In one specific embodiment, in step (3), the mass of methanol used for rinsing the filter cake is 0.5 times the mass of intermediate 2.

[0067] In one specific embodiment, in step (3), in addition to vacuum drying, freeze drying technology can also be used for drying nicotinamide ribochloride, especially for heat-sensitive products, which can effectively maintain their activity and purity.

[0068] Based on the above technical solution, the present invention provides a method for the efficient synthesis of nicotinamide ribochloride. By precisely controlling the reaction conditions and reagent ratios stepwise, the method achieves highly efficient synthesis of nicotinamide ribochloride, solving the problems of low yield, poor purity, and complex processes in traditional methods. The method of the present invention can be applied to the preparation of other ribose derivatives. For example, by replacing nicotinamide with other bases (such as adenine, guanine, etc.) and adjusting the catalyst system, the method can achieve efficient synthesis of other nucleotides, demonstrating good scalability and adaptability.

[0069] The specific working principle and derivation process of the above-mentioned synthesis method of the present invention are as follows: This invention first prepares intermediate 1 (tetraacetylribose chloride) through step (1). The key to this step is to saturate a toluene solution of tetraacetylribose with hydrogen chloride at a low temperature (-5°C). The low temperature and saturated hydrogen chloride environment are conducive to the substitution of the acetoxy group of tetraacetylribose with a chlorine atom, forming a stable chloroglycoside intermediate. At the same time, toluene as a solvent helps to ensure the homogeneity of the reaction system and the subsequent concentration and acid removal. After the reaction is completed, the reaction byproduct acetic acid is removed by vacuum concentration and evaporation, and then removed again with toluene to ensure the purity of intermediate 1, laying the foundation for the subsequent glycosylation reaction.

[0070] Next, a crucial glycosylation reaction is carried out in step (2) to prepare intermediate 2 (tetraacetylnicotinamide ribose). The core of this step is to activate intermediate 1 using a specific Lewis acid composite catalyst (a mixture of zinc chloride and tin tetrachloride) to promote its nucleophilic substitution reaction with nicotinamide. The combined use of zinc chloride and tin tetrachloride provides stronger Lewis acidity, synergistically activating the chlorosaccharide intermediate and making it easier for it to form a glycosidic bond with nicotinamide. The reaction is carried out in anhydrous acetonitrile solvent and controlled at a low temperature (feeding below 10°C, heating to 30°C and holding) to suppress side reactions and improve the stereoselectivity and yield of the target product intermediate 2. After the reaction is completed, acetonitrile is recovered, and acetone and triethylamine are added for pulping. Triethylamine, as a basic substance, is used to neutralize the acidic substances remaining in the reaction system, while acetone, as a poor solvent, promotes the crystallization of the target product intermediate 2, facilitating subsequent centrifugation and purification.

[0071] Finally, a deprotection reaction is carried out in step (3) to prepare the final product, nicotinamide ribochloride. This step involves introducing hydrogen chloride into methanol to adjust the mass-volume concentration of hydrogen chloride in the methanol to 10%-12% (g / mL), and then adding intermediate 2 and heating the reaction. The high concentration of hydrogen chloride in methanol forms a strongly acidic environment, which can efficiently catalyze the removal of the acetyl group on intermediate 2 (deprotection), while chloride ions act as counterions, ultimately forming nicotinamide ribochloride.

[0072] This invention also provides another efficient method for synthesizing nicotinamide ribochloride, the synthetic route of which is as follows:

[0073] Includes the following steps: (1) Preparation of triacetylnicotinamide riboacetate by glycosylation reaction: Anhydrous acetonitrile, nicotinamide and Lewis acid composite catalyst were added to a dry reaction vessel. The Lewis acid composite catalyst was a mixture of zinc chloride and tin tetrachloride. The mixture was stirred and cooled to below 10°C. Tetraacetyl ribose was added. The feeding temperature was controlled to not exceed 15°C. The temperature was raised to 35°C and kept for 10-15 hours. After confirming that the reaction was complete by plate spot detection and liquid phase detection, acetonitrile was recovered at 30-40°C. Acetone and triethylamine were added and the mixture was slurried. After centrifugation, the filter cake was washed with acetone and dried to obtain triacetylnicotinamide riboacetate. (2) Preparation of nicotinamide ribochloride by deprotection reaction: Add anhydrous methanol to the dry reaction vessel, cool down to below 5°C, introduce hydrogen chloride to adjust the mass volume concentration of hydrogen chloride in methanol to 10%-12% (g / mL), add triacetylnicotinamide riboacetate prepared in step (1), heat to 5°C-10°C and keep the reaction for 12 hours, detect by HPLC, after confirming that the reaction is complete, cool down to below -5°C, keep the temperature to crystallize, centrifuge, wash the filter cake with methanol, collect the filter cake and vacuum dry at 25°C-30°C to obtain nicotinamide ribochloride.

[0074] In one specific embodiment, in step (1), the molar ratio of zinc chloride to tin tetrachloride in the Lewis acid composite catalyst is 1:(0.8-1.2), and the total amount of composite catalyst is 2.8%-4.5% of the molar amount of tetraacetylribose. Other parameters are as described in steps (2) and (3) of the aforementioned method for efficient synthesis of nicotinamide ribochloride.

[0075] In the following examples and comparative examples, the total yield is the ratio of product mass to theoretical yield, i.e., total yield = product mass / 457g (theoretical yield); product content is the percentage of the total content of α-nicotinamide ribose and β-nicotinamide ribose in the product, i.e., product content = (α-nicotinamide ribose + β-nicotinamide ribose) / product mass; purity is the percentage of β-nicotinamide ribose in α-nicotinamide ribose and β-nicotinamide ribose in the product, i.e., purity = β-nicotinamide ribose / (α-nicotinamide ribose + β-nicotinamide ribose).

[0076] Example 1 A method for the efficient synthesis of nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: Add 500g of tetraacetylribose and 600g of toluene to a dry reaction vessel, stir and cool to -5℃, and introduce hydrogen chloride gas until saturation (introduction time 12 hours, introduction amount 85g), continue stirring for 1.5 hours, take a sample for plate detection (developing solvent is dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator), after confirming that the reaction is complete, concentrate under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporate at 40℃ to remove acetic acid, and then add 50g of toluene and evaporate at 40℃ to remove acetic acid, to obtain 498g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile, 200g of nicotinamide and Lewis acid composite catalyst (0.03mol of zinc chloride and 0.03mol of tin tetrachloride) were added to the dry reaction vessel, stirred and cooled to 8℃, and intermediate 1 (498g) obtained in step (1) was added. The temperature was controlled not to exceed 15℃. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30℃ and kept at that temperature for 9 hours. Samples were taken for plate detection and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 35℃ (vacuum degree ≤ -0.090MPa). 900mL of acetone and 12g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and separated. The filter cake was rinsed twice with 100g of acetone and dried under vacuum at 60℃ for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 406g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 1200 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 3 °C, 130 g of hydrogen chloride (11% mass-volume concentration, g / mL) was introduced, intermediate 2 (406 g) obtained in step (2) was added, the temperature was raised to 8 °C, and the reaction was kept at this temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -5 °C, and the crystals were kept at this temperature. The mixture was then centrifuged, and the filter cake was washed twice with 200 g of cold methanol (0~5 °C). The mixture was then vacuum dried at 28 °C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 265.5 g of nicotinamide ribochloride.

[0077] The test results showed a total yield of 58.1%, a product content of 95.0%, and a purity of 98.1%.

[0078] Example 2 A method for the efficient synthesis of nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: Add 500g of tetraacetylribose and 600g of toluene to a dry reaction vessel, stir and cool to -5℃, and introduce hydrogen chloride gas until saturation (introduction time 12 hours, amount 83g), continue stirring for 1 hour, take a sample for plate testing (developing solvent is dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator), after confirming that the reaction is complete, concentrate under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporate at 40℃ to remove acetic acid, and then add 50g of toluene and evaporate at 40℃ to remove acetic acid, to obtain 492g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile, 200g of nicotinamide and Lewis acid composite catalyst (0.025mol of zinc chloride and 0.02mol of tin tetrachloride) were added to the dry reaction vessel, stirred and cooled to 5℃, and intermediate 1 (492g) obtained in step (1) was added. The temperature was controlled not to exceed 15℃. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30℃ and kept at the temperature for 10 hours. Samples were taken for plate detection and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 32℃ (vacuum degree ≤ -0.090MPa). 900mL of acetone and 10g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and separated. The filter cake was rinsed twice with 100g of acetone and dried under vacuum at 60℃ for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 402g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 1200 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 4 °C, 125 g of hydrogen chloride (mass volume concentration 10.5%, g / mL) was introduced, intermediate 2 (402 g) obtained in step (2) was added, the temperature was raised to 5 °C, and the reaction was kept at this temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -6 °C, and the crystals were kept at this temperature. The mixture was separated by centrifugation, and the filter cake was washed twice with 200 g of cold methanol (0~5 °C). The mixture was then dried under vacuum at 25 °C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 261.9 g of nicotinamide ribochloride.

[0079] The test results showed a total yield of 57.3%, a product content of 95.2%, and a purity of 98.1%.

[0080] Example 3 A method for the efficient synthesis of nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: Add 500g of tetraacetylribose and 600g of toluene to a dry reaction vessel, stir and cool to -5℃, and introduce hydrogen chloride gas until saturation (introduction time 12 hours, introduction amount 86g), continue stirring for 2 hours, take a sample for plate detection (developing solvent is dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator), after confirming that the reaction is complete, concentrate under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporate at 40℃ to remove acetic acid, and then add 50g of toluene and evaporate at 40℃ to remove acetic acid, to obtain 502g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile, 200g of nicotinamide and Lewis acid composite catalyst (0.03mol of zinc chloride and 0.036mol of tin tetrachloride) were added to the dry reaction vessel, stirred and cooled to 9°C, and intermediate 1 (502g) obtained in step (1) was added. The temperature was controlled not to exceed 15°C. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30°C and kept at that temperature for 8 hours. Samples were taken for plate testing and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 38°C (vacuum degree ≤ -0.090MPa). 900mL of acetone and 15g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and separated. The filter cake was rinsed twice with 100g of acetone and dried under vacuum at 60°C for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 408g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 1200 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 2°C, 138 g of hydrogen chloride (mass volume concentration 11.5%, g / mL) was introduced, and intermediate 2 (408 g) obtained in step (2) was added. The temperature was raised to 10°C and kept at the temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -4°C and kept at the temperature for crystallization. After centrifugation, the filter cake was washed twice with 200 g of cold methanol (0~5°C) and dried under vacuum at 30°C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 267.3 g of nicotinamide ribochloride.

[0081] The test results showed a total yield of 58.5%, a product content of 95.8%, and a purity of 98.3%.

[0082] Comparative Example 1 A method for synthesizing nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: Add 500g of tetraacetylribose and 600g of toluene to a dry reaction vessel, stir and cool to -5℃, and introduce hydrogen chloride gas until saturation (introduction time 12 hours, introduction amount 85g), continue stirring for 1.5 hours, take a sample for plate detection (developing solvent is dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator), after confirming that the reaction is complete, concentrate under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporate at 40℃ to remove acetic acid, and then add 50g of toluene and evaporate at 40℃ to remove acetic acid, to obtain 498g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile and 200g of nicotinamide were added to a dry reaction vessel, stirred and cooled to 8°C, and intermediate 1 (498g) obtained in step (1) was added. The temperature was controlled not to exceed 15°C. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30°C and kept at that temperature for 20 hours. Samples were taken for plate testing and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 35°C (vacuum degree ≤ -0.090MPa). 900mL of acetone and 12g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and the filter cake was washed twice with 100g of acetone. The mixture was dried under vacuum at 60°C for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 258g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 770 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 3°C, 84.7 g of hydrogen chloride (11% mass-volume concentration, g / mL) was introduced, intermediate 2 (258 g) obtained in step (2) was added, the temperature was raised to 8°C, and the reaction was kept at this temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -5°C, and the mixture was kept at this temperature to crystallize. After centrifugation, the filter cake was washed twice with 200 g of cold methanol (0~5°C), and then dried under vacuum at 28°C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 148.1 g of nicotinamide ribochloride.

[0083] The test results showed a total yield of 32.4%, a product content of 89.2%, and a purity of 92.5%.

[0084] Comparative Example 2 A method for synthesizing nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: Add 500g of tetraacetylribose and 600g of toluene to a dry reaction vessel, stir and cool to -5℃, and introduce hydrogen chloride gas until saturation (introduction time 12 hours, introduction amount 85g), continue stirring for 1.5 hours, take a sample for plate detection (developing solvent is dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator), after confirming that the reaction is complete, concentrate under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporate at 40℃ to remove acetic acid, and then add 50g of toluene and evaporate at 40℃ to remove acetic acid, to obtain 498g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile, 200g of nicotinamide and 0.06mol of tin tetrachloride were added to a dry reaction vessel, stirred and cooled to 8℃, and intermediate 1 (498g) obtained in step (1) was added. The temperature was controlled not to exceed 15℃. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30℃ and kept at that temperature for 9 hours. Samples were taken for plate testing and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 35℃ (vacuum degree ≤ -0.090MPa). 900mL of acetone and 12g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and separated. The filter cake was rinsed twice with 100g of acetone. The mixture was dried under vacuum at 60℃ for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 372g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 1100 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 3 °C, 122 g of hydrogen chloride (11% by mass / volume concentration, g / mL) was introduced, and intermediate 2 (372 g) obtained in step (2) was added. The temperature was raised to 8 °C and the reaction was maintained for 12 hours. After confirming the completeness of the reaction by HPLC, the temperature was lowered to -5 °C and crystallized. The mixture was centrifuged, and the filter cake was washed twice with 200 g of cold methanol (0~5 °C). The mixture was then vacuum dried at 28 °C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 232.2 g of nicotinamide ribochloride.

[0085] The test results showed a total yield of 50.8%, a product content of 94.0%, and a purity of 96.8%.

[0086] Comparative Example 3 A method for synthesizing nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of intermediate 1: 500g of tetraacetylribose and 600g of toluene were added to a dry reaction vessel, stirred and cooled to -5℃, and hydrogen chloride gas was introduced until saturation (introduction time 12 hours, amount 85g). Stirring was continued for 1.5 hours, and samples were taken for plate testing (developing solvent was dichloromethane:methanol = 2:0.15 (2.15 mL) + 1 drop of acetic acid, iodine indicator). After confirming that the reaction was complete, the mixture was concentrated under reduced pressure at 40℃ to remove hydrogen chloride and toluene, evaporated at 40℃ to remove acetic acid, and then 50g of toluene was added and evaporated at 40℃ to remove acetic acid, yielding 498g of intermediate 1; (2) Preparation of intermediate 2: 540g of anhydrous acetonitrile, 200g of nicotinamide and 0.06mol of zinc chloride were added to a dry reaction vessel, stirred and cooled to 8℃, and intermediate 1 (498g) obtained in step (1) was added. The temperature was controlled not to exceed 15℃. The reaction vessel of the first step was rinsed with 30g of anhydrous acetonitrile and the rinsing liquid was combined. The temperature was raised to 30℃ and kept at that temperature for 15 hours. Samples were taken for plate testing and HPLC detection. After confirming that the reaction was complete, acetonitrile was recovered under reduced pressure at 35℃ (vacuum degree ≤ -0.090MPa). 900mL of acetone and 12g of triethylamine were added and stirred at room temperature for 1 hour. The mixture was centrifuged and the filter cake was washed twice with 100g of acetone. The mixture was dried under vacuum at 60℃ for 4 hours (vacuum degree ≤ -0.095MPa) to obtain 338g of intermediate 2. (3) Preparation of nicotinamide ribochloride: 1010 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 3°C, 111 g of hydrogen chloride (11% mass-volume concentration, g / mL) was introduced, intermediate 2 (338 g) obtained in step (2) was added, the temperature was raised to 8°C, and the reaction was kept at this temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -5°C, and the mixture was kept at this temperature to crystallize. The mixture was then centrifuged, and the filter cake was washed twice with 200 g of cold methanol (0~5°C). The mixture was then vacuum dried at 28°C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 193.8 g of nicotinamide ribochloride.

[0087] The test results showed a total yield of 42.4%, a product content of 92.5%, and a purity of 95.0%.

[0088] Example 4 A method for the efficient synthesis of nicotinamide ribochloride, the specific steps of which are as follows: (1) Preparation of triacetylnicotinamide riboacetate: 540 g of anhydrous acetonitrile, 200 g of nicotinamide and Lewis acid composite catalyst (0.03 mol of zinc chloride and 0.03 mol of tin tetrachloride) were added to a dry reaction vessel, stirred and cooled to 8 °C, 500 g of tetraacetyl ribose were added, the temperature was controlled not to exceed 15 °C, and the temperature was raised to 35 °C (5 °C higher than the glycosylation temperature in Example 1 to compensate for insufficient reaction activity without chlorination activation), and the reaction was kept at this temperature for 12 hours; after sampling and HPLC detection to confirm that the reaction was complete, acetonitrile was recovered under reduced pressure at 35 °C (vacuum degree ≤ -0.090 MPa), 900 mL of acetone and 12 g of triethylamine were added and stirred at room temperature for 1 hour, centrifuged, and the filter cake was washed twice with 100 g of acetone. The filter cake was dried under vacuum at 60 °C for 4 hours (vacuum degree ≤ -0.095 MPa) to obtain 340 g of triacetylnicotinamide riboacetate; (2) Preparation of nicotinamide ribochloride: 920 mL of anhydrous methanol was added to a dry reaction vessel, the temperature was lowered to 3°C, 101 g of hydrogen chloride (11% by mass / volume concentration, g / mL) was introduced, and 340 g of triacetylnicotinamide riboacetate obtained in step (1) was added. The temperature was raised to 8°C and kept at that temperature for 12 hours. After confirming the complete reaction by HPLC detection, the temperature was lowered to -5°C and kept at that temperature for crystallization. After centrifugation, the filter cake was washed twice with 200 g of cold methanol (0~5°C) and dried under vacuum at 28°C for 6 hours (vacuum degree ≤ -0.095 MPa) to obtain 213.8 g of nicotinamide ribochloride.

[0089] The test results showed a total yield of 46.8%, a product content of 94.8%, and a purity of 97.9%.

[0090] Conclusions: Comparative Example 1, without catalyst, showed relatively low overall yield, product content, and purity. While the addition of zinc chloride or tin tetrachloride improved the overall yield, product content, and purity of Comparative Examples 1 and 2 to some extent, they remained low. Examples 1-3, using a composite catalyst of zinc chloride and tin tetrachloride, significantly improved the overall yield, product content, and purity, indicating that the composite catalyst of zinc chloride and tin tetrachloride has a significant advantage in catalyzing the glycosylation of chlorotriacetylribose to prepare nicotinamide ribochloride. Example 4 showed high purity, demonstrating that the composite catalyst of zinc chloride and tin tetrachloride also has a significant advantage in catalyzing the glycosylation of tetraacetylribose to prepare nicotinamide ribochloride.

[0091] The above is a detailed description of the preferred embodiments of the present invention. However, the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention. All such equivalent modifications or substitutions are included within the scope defined by the claims of the present invention.

Claims

1. A method for synthesizing triacetylnicotinamide ribose, characterized in that, Includes the following steps: Method 1: Mix chlorotriacetylribose, nicotinamide, zinc chloride, tin tetrachloride and organic solvent, and react to obtain triacetylnicotinamide ribose chloride; Alternatively, method two: mix tetraacetylribose, nicotinamide, zinc chloride, tin tetrachloride and organic solvent, and react to obtain triacetylnicotinamide riboacetate.

2. The method for synthesizing triacetylnicotinamide ribose according to claim 1, characterized in that, In Method 1, the preparation method of chlorotriacetylribose is as follows: hydrogen chloride gas is passed into an organic solvent solution of tetraacetylribose until saturation, and the reaction is stirred to obtain chlorotriacetylribose.

3. The method for synthesizing triacetylnicotinamide ribose according to claim 2, characterized in that, In the organic solvent solution of tetraacetyl ribose, the mass ratio of tetraacetyl ribose to organic solvent is 5:(4-8). The organic solvent in the organic solvent solution of tetraacetyl ribose is one or more of toluene, dichloromethane and chloroform; The temperature of the organic solvent solution of tetraacetylribose is (-5) -0℃; The mass of hydrogen chloride gas introduced is 0.15-0.2 times the mass of tetraacetylribose, and the introduction time is 10-15 hours; The stirring reaction time is 1-2 hours.

4. The method for synthesizing triacetylnicotinamide ribose according to claim 1, characterized in that, In Method 1, the molar ratio of chlorotriacetylribose to nicotinamide is 1:(1-1.1). In Method 1, the mass ratio of nicotinamide to organic solvent is 10:(25-30); In Method 1, the organic solvent is one or more of acetonitrile, propionitrile, and dimethylformamide; In Method 1, the mixing process temperature is controlled to not exceed 15℃; In Method 1, the reaction temperature is 25-35℃ and the reaction time is 8-10 hours.

5. The method for synthesizing triacetylnicotinamide ribose according to claim 1, characterized in that, In Method 1, the molar ratio of zinc chloride to tin tetrachloride is 1:(0.8-1.2). In Method 1, the total amount of zinc chloride and tin tetrachloride used is 2.8%-4.5% of the molar amount of chlorotriacetylribose.

6. The method for synthesizing triacetylnicotinamide ribose according to claim 1, characterized in that, In Method 2, the molar ratio of tetraacetylribose to nicotinamide is 1:(1-1.1). In Method 2, the mass ratio of nicotinamide to organic solvent is 10:(25-30). In Method 2, the organic solvent is one or more of acetonitrile, propionitrile, and dimethylformamide; In Method 2, the mixing process temperature is controlled to not exceed 15℃; In Method 2, the reaction temperature is 30-40℃ and the reaction time is 10-15 hours.

7. The method for synthesizing triacetylnicotinamide ribose according to claim 1, characterized in that, In Method 2, the molar ratio of zinc chloride to tin tetrachloride is 1:(0.8-1.2). In Method 2, the total amount of zinc chloride and tin tetrachloride used is 2.8%-4.5% of the molar amount of tetraacetylribose.

8. A method for synthesizing nicotinamide ribochloride, characterized in that, Includes the following steps: Triacetylnicotinamide ribose is synthesized according to the method for synthesizing triacetylnicotinamide ribose according to any one of claims 1-7, wherein triacetylnicotinamide ribose is added to an organic solvent solution of hydrogen chloride and deacetylated to obtain nicotinamide ribose chloride.

9. The method for synthesizing nicotinamide ribochloride according to claim 8, characterized in that, The temperature of the organic solvent solution of hydrogen chloride is below 5°C; The mass-volume concentration of hydrogen chloride in the organic solvent solution of hydrogen chloride is 10%-12%, g / mL.

10. The method for synthesizing nicotinamide ribochloride according to claim 9, characterized in that, The organic solvent in the hydrogen chloride organic solvent solution is one or more of methanol, ethanol, and isopropanol; The volume of the organic solvent solution containing hydrogen chloride is 2-3 times the mass of triacetylnicotinamide ribose, in mL / g; The deacetylation reaction takes place at a temperature of 5℃-10℃ for 10-15 hours.

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