A method for preparing 1-methylnicotinamide chloride

Abstract

This invention discloses a method for preparing 1-methylnicotinamide chloride. The method involves treating 1-methylnicotinamide sulfonate with hydrogen chloride to prepare 1-methylnicotinamide chloride. This method is simple to operate, uses inexpensive raw materials, and has low production costs. Alternatively, this invention involves reacting a methyl sulfonate compound with nicotinamide, followed by direct treatment with hydrogen chloride after the reaction to obtain 1-methylnicotinamide chloride. This method is simple to operate, uses inexpensive raw materials, has even lower production costs, and poses minimal harm to workers.

Description

Technical Field

[0001] This invention relates to the fields of life and health and synthetic chemicals, and in particular to a method for preparing 1-methylnicotinamide chloride. Background Technology

[0002] 1-Methylnicotinamide chloride, with the structural formula shown in I, is a product of nicotinamide (vitamin B3) metabolism in the body. It has the effects of enhancing immunity, protecting the liver, protecting brain nerves, and improving memory. 1-Methylnicotinamide chloride is naturally found in green tea leaves, celery, poultry gizzards, and wakame seaweed, but the content is low and purification is difficult. The chemical synthesis of 1-methylnicotinamide chloride is reported in the literature as follows: 1-methylnicotinamide iodide is first generated by reacting nicotinamide with iodomethane, and then the anion is exchanged with silver chloride to obtain 1-methylnicotinamide chloride (Marcinek, Andrzej et al. Ionic Liquids: Novel Media for Characterization of Radical Ions. Journal of Physical Chemistry A, 2001; 105(40):9305-9309).

[0003]

[0004] This method has the following disadvantages: 1. Iodomethane is highly volatile and toxic, posing a risk to production workers; 2. Silver chloride is expensive, resulting in high production costs; 3. The product contains a high level of heavy metals, which may have potential side effects on the human body. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing 1-methylnicotinamide chloride.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] The first aspect of the present invention is a method for preparing a compound of structural formula I, wherein the method comprises treating a compound of structural formula II with hydrogen chloride to obtain a compound of structural formula I.

[0008]

[0009] In the preparation method of the compound of structural formula I of the present invention, hydrogen chloride can be hydrogen chloride gas or compressed gas, or hydrogen chloride solution, preferably hydrogen chloride methanol solution or hydrogen chloride ethanol solution.

[0010] In the preparation method of the compound of structural formula I of the present invention, the compound of structural formula II preferably has R as a C1 to C6 alkyl, phenyl and substituted phenyl, and most preferably R is methyl or ethyl or n-propyl or phenyl or p-tolyl.

[0011] In the preparation method of the compound of structural formula I of the present invention, the molar ratio of hydrogen chloride to the compound of structural formula II is 1:1 to 10:1, preferably 1:1 to 3:1, and most preferably 1.2:1 to 2:1;

[0012] In the preparation method of the compound of structural formula I of the present invention, the reaction solvent is preferably a type II or type III organic solvent as defined by ICH, and most preferably methanol, ethanol and propanol.

[0013] In the preparation method of the compound of structural formula I of the present invention, the reaction temperature is -20℃ to 60℃, preferably 0℃ to 40℃, and most preferably 10℃ to 30℃.

[0014] In the method for preparing compound I of this invention, it is preferable to react nicotinamide with compound III to prepare compound II, and then treat compound II with hydrogen chloride to obtain compound I. Most preferably, in the same reaction vessel, nicotinamide is reacted with compound III without separating compound II, and compound I is directly treated with hydrogen chloride to obtain compound I.

[0015] In the preparation method of the compound of structural formula I provided by the present invention, preferably, after the reaction is completed, the mixture is cooled to -20°C to room temperature for crystallization, and the product is obtained by filtration or centrifugation. Most preferably, after the reaction is completed, the mixture is cooled to 10-30°C for crystallization, and the product is obtained by filtration or centrifugation.

[0016] In the method of the present invention, the product separation and purification method is very simple. After the reaction is completed, the product can be obtained by direct filtration or centrifugation.

[0017] The second aspect of the present invention is a method for preparing a compound of structural formula I, wherein nicotinamide is reacted with a compound of structural formula III, and the compound of structural formula II is not separated, and the compound of structural formula I is directly treated with hydrogen chloride to obtain the compound of structural formula I.

[0018]

[0019] In compounds of structural formulas II and III, R is preferably a C1-C6 alkyl, phenyl, or substituted phenyl group, and most preferably R is methyl, ethyl, n-propyl, or phenyl.

[0020] In the method of this invention, the molar ratio of structural formula III to nicotinamide is 0.5:1 to 5:1, preferably 1:1 to 2:1; most preferably 1:1 to 1.2:1.

[0021] In the method of this invention, the molar ratio of hydrogen chloride to nicotinamide is 1:1 to 10:1, preferably 1:1 to 3:1, and most preferably 1.2:1 to 2:1;

[0022] In the method of this invention, the reaction solvent is preferably a Class II or Class III organic solvent as defined by ICH, and most preferably methanol, ethanol and n-propanol.

[0023] In the method provided by the present invention, the reaction temperature of nicotinamide with structural formula III is preferably 0 to 140°C, most preferably 20 to 100°C, and most preferably the boiling point of the selected solvent, i.e., the reflux temperature.

[0024] In the method of this invention, the reaction temperature of hydrogen chloride with structural formula II is -20℃ to 60℃, preferably 0℃ to 40℃, and most preferably 10℃ to 30℃.

[0025] In the method of this invention, the product separation and purification method is very simple. After the reaction is completed, the product can be obtained by direct filtration or centrifugation.

[0026] A third aspect of the present invention is to provide a compound with the structure shown in structural formula IV.

[0027]

[0028] Wherein R is a C1 to C6 alkyl group, preferably methyl, ethyl or n-propyl.

[0029] The fourth aspect of this invention provides a method for preparing a compound of structural formula IV.

[0030]

[0031] In compounds of structural formulas IV and V, R is preferably a C1-C6 alkyl group, and most preferably R is methyl, ethyl, or n-propyl. In the method for preparing compound IV provided by this invention, nicotinamide is reacted with compound V to prepare compound IV.

[0032] In the preparation method of the compound of structural formula IV provided by the present invention, the compound of structural formula V, R, is an alkyl group of C1 to C6, preferably an alkyl group of C1 to C3, namely methyl methanesulfonate, methyl ethanesulfonate and methyl propanesulfonate.

[0033] In the preparation method of the compound of structural formula IV provided by the present invention, the reaction solvent is preferably a type II or type III organic solvent as defined by ICH, and most preferably methanol, ethanol, n-propanol and isopropanol.

[0034] In the preparation method of the compound of structural formula IV provided by the present invention, the reaction temperature is preferably 0 to 140°C, most preferably 20 to 100°C, and most preferably the boiling point of the selected solvent, i.e., the reflux temperature.

[0035] In the preparation method of the compound of structural formula IV provided by the present invention, the molar ratio of nicotinamide to compound of structural formula V is 0.5:1 to 1:5, preferably 0.8:1 to 1:2.

[0036] In the preparation method of the compound of structural formula IV provided by the present invention, preferably after the reaction is completed, the mixture is cooled to -20°C to room temperature for crystallization, and the product is obtained by filtration or centrifugation. Most preferably, after the reaction is completed, the mixture is cooled to 10-30°C for crystallization, and the product is obtained by filtration or centrifugation.

[0037] In a fifth aspect, the present invention provides an application of a compound of structural formula IV for the preparation of a compound of structural formula I.

[0038] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:

[0039] The present invention provides a method for preparing 1-methylnicotinamide chloride by directly treating 1-methylnicotinamide sulfonate with hydrogen chloride. The method is simple to operate, uses inexpensive raw materials, and has low production costs.

[0040] The 1-methylnicotinamide methanesulfonate, 1-methylnicotinamide ethanesulfonate, and 1-methylnicotinamide propanesulfonate provided by this invention are novel compounds. They can be directly treated with hydrogen chloride to prepare 1-methylnicotinamide chloride. The method is simple to operate, uses inexpensive raw materials, and has low production costs.

[0041] The present invention discloses a method for preparing 1-methylnicotinamide chloride, which involves reacting a methyl sulfonate compound with nicotinamide, followed by direct treatment with hydrogen chloride after the reaction to obtain 1-methylnicotinamide chloride. The method is simple to operate, has low toxicity, uses inexpensive raw materials and auxiliary materials, has lower production costs, and poses less harm to workers. Detailed Implementation

[0042] The present invention will be further described below with reference to specific embodiments, but these are not intended to limit the invention. It should be noted that, unless otherwise specified, the embodiments and features described in the embodiments of the present invention can be combined with each other.

[0043] Example 1 Synthesis of 1-methylnicotinamide methanesulfonate

[0044] Dissolve 1g of nicotinamide and 1g of methyl methanesulfonate in 8g of anhydrous ethanol and heat under reflux for 6 hours. After cooling to room temperature, a precipitate forms. Filter the precipitate, remove the solid, and dry it to obtain the product with a yield of 83.7%.

[0045] 1HMR(400MHz,CD3OD)δ9.38(s,1H),9.05(d,1H),8.95(d,1H),8.20(m,1H),4.50(s,3H),2.68(3,3H)

[0046] Example 2 Synthesis of 1-methylnicotinamide ethanesulfonate

[0047] Dissolve 1 g of nicotinamide and 1.12 g of methyl ethanesulfonate in 8 g of anhydrous ethanol and heat under reflux for 8 hours. Cool to 0-5°C and let stand overnight; crystals precipitate. Filter the solid, dry it, and obtain the product with a yield of 86.3%.

[0048] 1HMR(400MHz,CD3OD)δ9.40(s,1H),9.07(d,1H),8.96(d,1H),8.20(m,1H),4.51(s,3H),2.79,(q,2H),1.28(t,3H)

[0049] Example 3 Synthesis of 1-methylnicotinamide propanesulfonate

[0050] Dissolve 1 g of nicotinamide and 1.25 g of methyl propanesulfonate in 8 g of anhydrous ethanol and heat under reflux for 10 hours. Cool to 0-5°C and let stand overnight; crystals precipitate. Filter the solid, dry it, and obtain the product with a yield of 84.8%.

[0051] 1HMR(400MHz,CD3OD)δ9.39(s,1H),9.06(d,1H),8.97(d,1H),8.20(m,1H),4.51(s,3H),2.77,(t,2H),1.88(m,3H),0.96(t,3H)

[0052] Example 4 Synthesis of 1-methylnicotinamide benzenesulfonate

[0053] 1 g of nicotinamide and 1.55 g of methyl benzenesulfonate were dissolved in 8 g of methanol and the mixture was heated under reflux for 6 hours. Upon cooling to 0-5°C, a precipitate formed. The precipitate was filtered off, dried, and the product was obtained with a yield of 85.83%.

[0054] 1HMR(400MHz,CD3OD)δ9.34(s,1H),9.00(d,1H),8.90(d,1H),8.14(m,1H),7.78(m,2H),7.42(m,3H),4.45(s,3H)

[0055] Example 5 Synthesis of 1-methylnicotinamide p-toluenesulfonate

[0056] 1 g of nicotinamide and 1.68 g of methyl p-toluenesulfonate were dissolved in 12 ml of anhydrous isopropanol and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the mixture was filtered, the solid was filtered off, dried, and the product was obtained with a yield of 94.2%.

[0057] 1HMR(400MHz,CD3OD)δ9.35(s,1H),9.01(d,1H),8.91(d,1H),8.14(m,1H),7.67(d,2H),7.22(d,2H),4.46(s,3H),2.36(s,3H)

[0058] Example 6 Synthesis of 1-methylnicotinamide hydrochloride

[0059] Dissolve 2g of 1-methylnicotinamide methanesulfonate in 10ml of methanol, add 3ml of 20wt% hydrogen chloride ethanol solution dropwise and stir for 2 hours. A solid precipitates out. Filter the solid, dry it, and obtain the product with a yield of 68%.

[0060] 1HMR(400MHz,CD3OD)δ9.43(s,1H),9.08(d,1H),8.97(d,1H),8.20(m,1H),4.51(s,3H)

[0061] Example 7 Synthesis of 1-methylnicotinamide hydrochloride

[0062] Dissolve 2g of 1-methylnicotinamide propanesulfonate in 10ml of n-propanol, pass hydrogen chloride through to saturation, stir for 1 hour, and a solid precipitates out. Filter the solid, dry it, and obtain the product with a yield of 73%.

[0063] Example 8 Synthesis of 1-methylnicotinamide hydrochloride

[0064] Dissolve 2g of 1-methylnicotinamide p-toluenesulfonate in 12ml of isopropanol, pass hydrogen chloride through to saturation, stir for 1 hour, and a solid precipitates out. Filter the solid, dry it, and obtain the product with a yield of 81%.

[0065] Example 9 Synthesis of 1-methylnicotinamide hydrochloride

[0066] Dissolve 1 g of nicotinamide and 1.12 g of methyl ethanesulfonate in 8 g of anhydrous ethanol, heat under reflux for 8 hours, cool to room temperature, purge with hydrogen chloride until saturated, and stir for 4 hours. Filter under vacuum, remove the solid, dry, and obtain the product with a yield of 89%.

[0067] Example 10 Synthesis of 1-methylnicotinamide hydrochloride

[0068] Dissolve 1g of nicotinamide and 1.55g of methyl benzenesulfonate in 8g of ethanol and heat under reflux for 6 hours. Cool to room temperature, add 3ml of 20wt% hydrogen chloride, stir for 4 hours, filter out the solid, dry to obtain the product, yield 92%.

[0069] The above description is merely a preferred embodiment of the present invention and does not limit the implementation and protection scope of the present invention. Those skilled in the art should realize that any equivalent substitutions and obvious changes made based on the content of the present invention specification should be included within the protection scope of the present invention.

Claims

1. A method for preparing 1-methylnicotinamide chloride, characterized in that, The preparation method includes the following reaction: reacting nicotinamide with a compound of structural formula III to obtain a compound of structural formula II, and treating with hydrogen chloride to obtain a compound of structural formula I: ； Wherein, R is a C1~C6 alkyl, phenyl, or substituted phenyl group; the hydrogen chloride is hydrogen chloride gas or hydrogen chloride solution, and the hydrogen chloride solution is hydrogen chloride methanol solution or hydrogen chloride ethanol solution.

2. The method for preparing 1-methylnicotinamide chloride according to claim 1, characterized in that, R is methyl, ethyl, n-propyl, phenyl, or p-tolyl.

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