Preparation method of nicotinamide ribose and intermediate thereof

Abstract

The invention discloses a preparation method of nicotinamide ribose (I). The method comprises the following steps: by taking tetraacetyl ribose (V) as a raw material, carrying out chlorination reaction to obtain chlorinated triacetyl ribose (IV), reacting the intermediate (IV) with nicotinamide (III) in a proper solvent under the catalysis of Liewis acid sulfur dioxide to obtain triacetyl nicotinamide ribose chloride (II), and finally, removing acetyl from the intermediate (II) by using hydrogen chloride to obtain the product nicotinamide ribose (I). According to the method, under the catalysis of sulfur dioxide, the yield of the obtained intermediate triacetyl nicotinamide ribose chloride (IV) is high, and the proportion of a required beta isomer is high; the whole process is simple to operate, easy to remove sulfur dioxide, convenient to separate and purify the product, low in three wastes, high in productivity and suitable for large-scale industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of nicotinamide riboside preparation, and in particular to a method for preparing triacetyl nicotinamide riboside chloride, an intermediate of nicotinamide riboside. Background Art

[0002] Nicotinamide riboside, also known as nicotinamide riboside or nicotinamide ribonucleoside, is a derivative of vitamin B3 and a product of nicotinamide phosphoribosyltransferase reaction. It participates in the synthesis of nicotinamide purine dinucleotide (NAD) in cells. NR has anti-aging and life-extending effects, and is expected to become an effective drug or nutritional supplement for the treatment of neurodegenerative diseases and gray hair, making nicotinamide riboside a star molecule in regenerative medicine.

[0003] In the human body, NR is converted into β-nicotinamide mononucleotide (NMN), and then further converted into NAD to exert its physiological functions, such as activating the NAD substrate-dependent enzyme Sirt1, regulating cell survival and death, maintaining redox status, etc., but it will gradually decrease with age. Since NAD is difficult to be absorbed by the human body, NR can be converted into NAD after entering the body, increasing the concentration of NAD in cells, thereby preventing and improving various unhealthy conditions caused by NAD deficiency.

[0004] There are many methods for preparing nicotinamide ribose. Generally, tetraacetyl ribose (V) is used as a raw material, which reacts with nicotinamide (III) to obtain the intermediate triacetyl nicotinamide ribose chloride (II). The intermediate (II) is finally deprotected to obtain nicotinamide ribose (I). Since nicotinamide (III) has low activity, it is difficult to directly react with tetraacetyl ribose (V) to generate triacetyl nicotinamide ribose chloride (II). Therefore, current reports generally activate one raw material first and then react with another raw material. The glycosidic bond of nicotinamide ribose is a β configuration. Therefore, when preparing triacetyl nicotinamide ribose chloride (II) by reaction, the generation of α configuration isomers should be minimized.

[0005]

[0006] One solution is to add trimethylsilyl trifluoromethanesulfonate (TMSOTf) to activate nicotinamide, and then react with tetraacetyl ribose, such as patents CN113518782A, WO2023012182A1, WO2021214299A1, etc. Since TMSOTf is relatively expensive and will produce a large amount of three wastes during post-treatment, it is not suitable for industrial production.

[0007] Another scheme is to chlorinate or brominate tetraacetyl ribose (V) to generate an active intermediate of halogenated triacetyl ribose (IV), which is then reacted with nicotinamide (III) to obtain the intermediate triacetyl nicotinamide ribose chloride (II). In patent CN110642897B, acetonitrile is used as a solvent to directly react chlorotriacetyl ribose with nicotinamide; the proportion of α-configuration isomers in the direct reaction product is high, so the separation yield is low. WO2022233923A1 adds a tertiary amine to the reaction to promote the reaction, such as diisopropylethylamine (DIPEA); WO2018089830A1 also uses TMSOTf to activate nicotinamide, and then reacts with chlorotriacetyl ribose. Due to the use of DIPEA or TMSOTF, acid-base neutralization, water washing and other operations are required during post-treatment, which will cause problems such as decomposition of the product triacetyl nicotinamide ribose. Summary of the invention

[0008] The inventors have found through a large number of experiments that adding sulfur dioxide to the reaction system of chlorotriacetyl ribose (IV) and nicotinamide (III) can not only promote the reaction, but also increase the β isomer ratio in the product triacetyl nicotinamide ribose chloride (II). Therefore, the present invention proposes a method for preparing nicotinamide ribose (I). The method uses tetraacetyl ribose (V) as a raw material, obtains chlorotriacetyl ribose (IV) through a chlorination reaction, and the intermediate (IV) reacts with nicotinamide (III) in a suitable solvent under the catalysis of Liewis acid sulfur dioxide to obtain triacetyl nicotinamide ribose chloride (II), and finally the intermediate (II) is deacetylated with hydrogen chloride to obtain the product nicotinamide ribose (I).

[0009] A method for preparing triacetyl nicotinamide ribose chloride (II) comprises taking chlorotriacetyl ribose (IV) and nicotinamide (III) as raw materials, reacting them under the catalysis of sulfur dioxide and in a suitable solvent to obtain triacetyl nicotinamide ribose chloride (II).

[0010]

[0011] In one embodiment, the solvent used is acetonitrile, dichloromethane, acetone, sulfolane.

[0012] In a preferred embodiment, the solvent used is acetonitrile.

[0013] In one embodiment, the molar ratio of sulfur dioxide to chlorotriacetyl ribose (IV) is 0.1-10:1, and the molar ratio of nicotinamide (III) to chlorotriacetyl ribose (IV) is 1.0-1.5:1.

[0014] In a preferred embodiment, the molar ratio of sulfur dioxide to chlorotriacetyl ribose (IV) is 1:1, and the molar ratio of nicotinamide (III) to chlorotriacetyl ribose (IV) is 1.1:1.

[0015] In one embodiment, the weight ratio of solvent to triacetyl ribose (IV) is 0.5-5.0:1.

[0016] In a preferred embodiment, the weight ratio of the solvent to triacetyl ribose (IV) is 1.0 to 2.0:1.

[0017] In one embodiment, the reaction temperature is -10 to 30°C.

[0018] In a preferred embodiment, the reaction temperature is 15-25°C.

[0019] A method for preparing nicotinamide riboside (I), comprising the following steps: A, tetraacetyl ribose (V) is reacted in the presence of thionyl chloride and hydrogen chloride to generate chlorotriacetyl ribose (IV); B, converting chlorotriacetyl ribose (IV) into triacetyl nicotinamide ribose chloride (II) according to the method for preparing triacetyl nicotinamide ribose chloride (II) described herein; C, triacetyl nicotinamide ribose chloride (II) is deacetylated in the presence of hydrogen chloride to obtain nicotinamide ribose (I).

[0020]

[0021] In one embodiment of step A, the reaction solvent is dichloromethane and the suitable reaction temperature is -10 to 0°C.

[0022] In one embodiment of step C, the reaction solvent is methanol and the suitable reaction temperature is 0-10°C.

[0023] The present invention is beneficial in that: The product triacetyl nicotinamide ribose chloride obtained by the method has a high yield, greatly reduces the proportion of α-configuration isomers, and is easy to perform during crystallization and purification because the proportion of the required β-isomer is high; In addition, sulfur dioxide has a low boiling point and is easy to remove, which facilitates the separation and purification of products and is simple to operate; The process uses less solvent and sulfur dioxide, has low overall three wastes, has large production capacity, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0024] All the raw materials used in the examples of the present invention are chemically pure. The reagents were purchased from China National Pharmaceutical (Group) Shanghai Chemical Reagent Company and Shanghai Aladdin Biochemical Technology Co., Ltd.

[0025] Detection instrument: Liquid chromatograph (HPLC), manufacturer: Shimadzu, detector: UV 210nm.

[0026] Example 1: Preparation of chlorotriacetyl ribose (IV)

[0027] In a reaction flask, add 330g of dichloromethane and 500g of tetraacetyl ribose (1.57mol, 1.0eq), stir and dissolve, start cooling by about 10°C, add 187g of thionyl chloride (1.57mol, 1.0eq), continue cooling to -10°C, slowly pass 29g of hydrogen chloride gas (0.79mol, 0.5eq), raise the temperature to 5°C after passing, react for about 5 hours, and complete the reaction by TLC detection. Concentrate to remove dichloromethane to obtain 458g of crude product triacetyl ribose, with a molar yield of 99%.

[0028] Example 2: Preparation of triacetyl nicotinamide ribose chloride (II)

[0029] Dissolve 25.0g (84.8mmol, 1.0eq) of chlorotriacetyl ribose in 25.0g (1.0 w / w) of acetonitrile, cool to about 10 degrees, add 1.4g (42.4mmol, 0.5eq) of sulfur dioxide, add 11.3g (93.3mmol, 1.1eq) of nicotinamide in batches, keep warm at 20-25℃ for 20 hours after addition, and HPLC confirms that the chlorotriacetyl ribose has reacted completely.

[0030] The acetonitrile and sulfur dioxide were directly concentrated to obtain 39.8 g of crude triacetyl nicotinamide ribose chloride. HPLC showed that the isomer ratio was α:β=27:73. 100.0 g of dichloromethane was added, and the mixture was stirred at about 25°C for 5 hours to allow slow crystallization. The obtained solid was washed with dichloromethane, filtered and dried to obtain 24.1 g of triacetyl nicotinamide ribose chloride. The molar yield was 68.3%, and the α configuration was less than 0.5%.

[0031] By changing the molar ratio of different sulfur dioxide, the ratios of different isomers in the crude triacetyl nicotinamide riboside chloride and the product yield after crystallization are obtained, as shown in the following table.

[0032] Serial number Sulfur dioxide equivalent The crude isomer ratio is α: β Molar yield 1 No 40 : 60 54.2% 2 0.2 38 : 62 57.7% 3 0.5 27 : 73 68.3% 4 0.8 18 : 82 76.0% 5 1.0 12 : 88 84.4% 6 1.5 9 : 91 86.3% 7 2.0 6 : 94 87.7% 8 5.0 2 : 98 87.5% The above results show that as the equivalent number of sulfur dioxide increases, the proportion of β-isomer in the crude product becomes higher and higher, and the yield of the pure product also tends to increase.

[0033] Example 3: Preparation of triacetyl nicotinamide ribose chloride (II)

[0034] Dissolve 50.0g (169.6mmol, 1.0eq) of chlorotriacetyl ribose in 25.0g (1.0 w / w) of acetonitrile, cool to about 10 degrees, add 10.8g (169.6mmol, 1.0eq) of sulfur dioxide, add 22.6g (186.6mmol, 1.1eq) of nicotinamide in batches, keep warm at 20-25℃ for 20 hours after addition, and HPLC confirms that the chlorotriacetyl ribose is completely reacted.

[0035] The acetonitrile and sulfur dioxide were directly concentrated to obtain 70.8 g of crude triacetyl nicotinamide ribose chloride. HPLC showed that the isomer ratio α:β = 12:88. 100.0 g of dichloromethane was added, and the mixture was stirred at about 25°C for 5 hours to allow slow crystallization. The obtained solid was washed with dichloromethane, filtered and dried to obtain 59.0 g of triacetyl nicotinamide ribose chloride. The molar yield was 84.4%, and the α configuration was less than 0.5%.

[0036] By using 1.0 equivalent of sulfur dioxide, changing different solvents and reaction temperatures, the ratios of different isomers in the crude triacetyl nicotinamide riboside chloride and the product yield after crystallization are shown in the following table.

[0037] Serial number Solvents Reaction temperature (℃) Response time (hours) The crude isomer ratio is α: β Molar yield 1 Acetonitrile -10 60 11 : 89 78.3% 2 Acetonitrile 0 48 13 : 87 80.9% 3 Acetonitrile 10 36 13 : 87 82.8% 4 Acetonitrile 20 20 12 : 88 84.4% 5 Acetonitrile 30 20 14 : 86 83.7% 6 Dichloromethane 20 24 17 : 83 77.5% 7 Dichloromethane 10 35 16 : 84 76.3% 8 acetone 20 24 23 :77 72.7% 9 Sulfolane 20 24 10 : 90 70.1% 10 Chloroform 20 24 25 : 75 62.6% The above results show that, except for the different reaction times, the ratio of β isomer in the crude product and the yield of the pure product are similar when reacting at different temperatures in acetonitrile. Acetonitrile is the best solvent, while dichloromethane, acetone and cyclopentane are acceptable, and chloroform is poor.

[0038] Example 4: Preparation of triacetyl nicotinamide ribose chloride (II)

[0039] Dissolve 12.5g (42.4mmol, 1.0eq) of chlorotriacetyl ribose in 12.5g (1.0 w / w) of acetonitrile, cool to about 10 degrees, add 2.7g (42.4mmol, 1.0eq) of sulfur dioxide, add 5.7g (46.7mmol, 1.1eq) of nicotinamide in batches, keep warm at 20-25℃ for 20 hours after addition, and HPLC confirms that the chlorotriacetyl ribose has reacted completely.

[0040] Acetonitrile and sulfur dioxide were directly concentrated to obtain 18.0 g of crude triacetyl nicotinamide ribose chloride. HPLC showed that the isomer ratio α:β = 13:87; 50.0 g of dichloromethane was added, and the mixture was stirred at about 25°C for 5 hours to allow slow crystallization. The obtained solid was washed with dichloromethane, filtered and dried to obtain 14.7 g of triacetyl nicotinamide ribose chloride, with a molar yield of 84.1% and an α isomer content of less than 0.5%.

[0041] Using acetonitrile as solvent, changing different nicotinamide equivalents, different solvent amounts (weight ratio to raw material triacetyl ribose chloride), and the ratios of different isomers in the crude triacetyl nicotinamide ribose chloride, as well as the product yield after crystallization, are shown in the following table.

[0042] Serial number Solvent volume w / w Nicotinamide equivalent The crude isomer ratio is α: β Molar yield 1 1.0 0.8 13 : 87 69.8% 2 1.0 1.0 12 : 88 78.5% 3 1.0 1.1 13 : 87 84.1% 4 1.0 1.3 12 : 88 84.3% 5 1.0 1.5 11 : 89 83.9% 6 0.5 1.1 21 : 79 74.3% 7 2.0 1.1 13 : 87 85.1% 8 3.0 1.1 12 :88 84.7% 9 5.0 1.1 11 : 89 84.5% The above results show that when the equivalent number of nicotinamide does not exceed 1.0, the yield is low, and when it exceeds 1.1, the yield does not change much. When the amount of solvent is less than 1.0 times (w / w), it affects the yield and the ratio of β isomers in the crude product. When it exceeds 1.0 times (w / w), it is relatively stable and has little effect.

[0043] Example 5: Preparation of β-nicotinamide riboside chloride (I)

[0044] 150g of methanol and 54.5g (131mmol, 1.0eq) of triacetyl nicotinamide ribose chloride were added to the reaction bottle, cooled to about 0°C, and 68.8g (471mmol, 3.6eq) of 25% hydrochloric acid methanol solution was added dropwise. After about 1 hour of complete addition, the temperature was adjusted to 5-10°C for 15 hours. HPLC showed that the reaction was complete. The temperature was further lowered to -5°C and kept warm for 2 hours. The solid was crystallized and precipitated. The solid was filtered, washed with cold methanol, and dried to obtain 27.0g of β-nicotinamide ribose chloride with a molar yield of 71%, HPLC purity of 99.2%, and α isomer content of 0.4%.

[0045] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention and should be included in the scope of the present invention.

Claims

1. A method for preparing triacetyl nicotinamide ribose chloride (II), It is characterized in that Using chlorotriacetyl ribose (IV) and nicotinamide (III) as raw materials, reacting under the catalysis of sulfur dioxide and in a suitable solvent to obtain triacetyl nicotinamide ribose chloride (II); 2. The method according to claim 1, It is characterized in that Suitable solvents include acetonitrile, dichloromethane, acetone, sulfolane.

3. The method according to claim 1, It is characterized in that The molar ratio of sulfur dioxide to chlorotriacetyl ribose (IV) is 0.1-10:1, and the molar ratio of nicotinamide (III) to chlorotriacetyl ribose (IV) is 1.0-1.5:

1.

4. The method according to claim 1, It is characterized in that The weight ratio of the solvent to triacetyl ribose (IV) is 0.5-5.0:

1.

5. The method according to claim 1, It is characterized in that The suitable reaction temperature is -10~30℃.

6. A method for preparing nicotinamide riboside (I), comprising the following steps: A, tetraacetyl ribose (V) is reacted in the presence of thionyl chloride and hydrogen chloride to generate chlorotriacetyl ribose (IV); B, according to the method of claims 1 to 5, converting triacetyl ribose chloride (IV) into triacetyl nicotinamide ribose chloride (II); C, triacetyl nicotinamide ribose chloride (II) is deacetylated in the presence of hydrogen chloride to obtain nicotinamide ribose (I); 7. The method according to claim 6, wherein in step A, the reaction solvent is dichloromethane and the suitable reaction temperature is -10 to 0°C.

8. The method according to claim 6, wherein in step C, the reaction solvent is methanol and the suitable reaction temperature is 0-10°C.

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