A process for the preparation of acipimox

Abstract

The application provides a process for preparing acipimox. The process uses 2-methyl-5-cyanopyrazine as a starting material, greatly shortens the related process route, uses a mixed solution of acetonitrile / water as a solvent in the synthesis step of compound 2, avoids the problem that the generated compound 2 wraps the starting material 1, effectively improves the oxidation efficiency, and makes the reaction complete, and the route also avoids the generation of impurity 3a. Therefore, the problems of previous process operation complexity, low yield and low product quality are overcome.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a process for preparing acipimox. BACKGROUND

[0002] Acipimox is a nicotinic acid derivative, which can reduce the release of free fatty acids and the synthesis of triacylglycerol by inhibiting the decomposition of adipose tissue, thereby reducing the contents of total cholesterol, triglyceride, low-density lipoprotein and very low-density lipoprotein in blood plasma and increasing the content of high-density lipoprotein. Acipimox is mainly used for treating hypertriglyceridemia (type IV), hypercholesterolemia (type IIa and type IIb), type III and type V hyperlipoproteinemia. Acipimox has better curative effect on hyperlipidemia patients with gout and diabetes.

[0003] There are many literatures about the synthesis of acipimox at home and abroad. The early literatures all take the synthesis of key intermediate 5-methylpyrazine-2-carboxylic acid as the common point. For example, J. Org. Chem, 1961, 26(1): 126-131 takes 2,5-dimethylpyrazine as the raw material, and obtains the intermediate 5-methylpyrazine-2-carboxylic acid through oxidation, esterification and hydrolysis, and then obtains acipimox through oxidation under the condition of hydrogen peroxide. The total yield of the route is about 10%, which is not suitable for industrial production, and the product quality is not high.

[0004] Org. Prep. Proced. Int. 1991, 23(2) also takes 2,5-dimethylpyrazine as the raw material, and obtains 5-methylpyrazine-2-carboxylic acid through acetylation, hydrolysis, oxidation with potassium permanganate and acidification, and then obtains acipimox through oxidation. The route is complex in operation, and needs to use more catalysts, which does not meet the requirements of industrial production.

[0005] Patent CN1651417A discloses a method for preparing acipimox, which also takes 2,5-dimethylpyrazine as the raw material. Although the process for synthesizing 5-methylpyrazine-2-carboxylic acid is optimized, the operation is still complex.

[0006] Patent CN101899012A discloses another method for preparing acipimox in order to overcome the above problems. The method takes methylglyoxal and o-phenylenediamine as the starting raw materials, and then performs cyclization, oxidation, acidification, decarboxylation and oxidation in one pot to directly prepare acipimox. The method simplifies some steps, but involves rectification operation in the cyclization reaction, which increases the investment and maintenance of related equipment in workshop scale-up production, and thus is not suitable for industrial production.

[0007] Patent CN103664805 discloses a preparation method of acipimox, which is prepared by synthesis reaction from 5-methyl pyrazine-2,3-dicarboxylic acid, water, acid, sodium tungstate and hydrogen peroxide. The method simplifies the operation steps, but a large amount of acid is used in the reaction, the wastewater discharge does not meet the requirements of green chemistry, and the product quality is not high due to the absence of refining and impurity removal process.

[0008] The above processes inevitably encounter two problems in the preparation of acipimox, one is low oxidation efficiency, and the other is the generation of impurities. In the last step of oxidation operation to obtain acipimox, the generated acipimox will wrap the unreacted raw materials, resulting in the presence of residual raw materials. At the same time, we found an impurity 3a in the reaction process, which affects the quality of the product.

[0009] SUMMARY

[0010] The present application aims to provide an improved synthesis process of acipimox. We use 2-methyl-5-cyanopyrazine as the starting material, which can greatly shorten the related process route. The inventors unexpectedly found that using acetonitrile / water mixture as the solvent in the synthesis step of compound 2 can not only avoid the problem of compound 2 wrapping the raw material 1, but also effectively improve the oxidation efficiency, making the reaction complete. This route can also avoid the generation of impurity 3a. At the same time, in the step of hydrolyzing compound 2 to generate compound 3, we can effectively remove impurities by improving the product precipitation method, and the product purity is higher than 99.9%. Thus, the problems of complex process operation, low yield and low product quality are overcome.

[0011] The specific technical solutions of the process method of the present application are as follows:

[0012]

[0013] Step one: 2-methyl-5-cyanopyrazine is added to a mixture of acetonitrile / water, hydrogen peroxide and sodium tungstate are added, and the reaction is completed after stirring and keeping warm. Then, pure water is added dropwise, and the stirring and keeping warm are continued after the dropwise addition is completed. Filtration is performed, the filter cake is washed with pure water, and then dried to obtain compound 2;

[0014] Step two: compound 2 is added to purified water, hydrolysis acid is added dropwise, then heated to reflux, after reflux, temperature is lowered to T1, then pH is adjusted to 8-10 with base, after adjustment, temperature is lowered to T2, and the mixture is stirred for a while, filtered, the filter cake is added to water solution, pH is adjusted to 1-3 with acid, temperature is lowered to 0-10℃, and the mixture is stirred for a while; filtered, the filter cake is washed with purified water, dried, and white solid acipimox is obtained.

[0015] Preferably, the acetonitrile / water mixed solution in step one has a volume ratio of acetonitrile of 5%-50%, more preferably 15%-25%.

[0016] Preferably, the mass / volume ratio of compound 1 to the mixed solution in step one is 1:0.5-5, wherein the mass is measured in grams and the volume is measured in milliliters; preferably 1:1-2.

[0017] Preferably, the mass fraction of hydrogen peroxide in step one is preferably 15%-70%, more preferably 30%.

[0018] Preferably, the molar ratio of compound 1 to hydrogen peroxide in step one is 1:1-4; preferably 1:1-2.

[0019] Preferably, the mass ratio of compound 1 to sodium tungstate in step one is 1:0.01-0.1.

[0020] Preferably, the temperature of the stirring and heating in step one is 30-90℃; preferably 50-60℃.

[0021] Preferably, the time of the stirring and heating in step one is 1-8h; preferably 3-5h.

[0022] Preferably, the temperature of the lowering in step one is 0-10℃.

[0023] Preferably, the mass / volume ratio of compound 1 to the added purified water in step one is 1:2-4, wherein the mass is measured in grams and the volume is measured in milliliters.

[0024] Preferably, the time of the continued stirring and heating in step one is 0.5-3h; preferably 1-2h.

[0025] Preferably, the hydrolysis acid in step two is one or more of hydrochloric acid, sulfuric acid, and acetic acid; preferably hydrochloric acid. Further preferably, the molar ratio of compound 2 to the hydrolysis acid in step two is 1:1-2.

[0026] Preferably, the time of the hydrolysis reaction in step two is 6-20h; preferably 10-12h.

[0027] Preferably, T1 in step two is 30-40℃.

[0028] Preferably, T2 in step two is 0-10℃.

[0029] Preferably, the time for the incubation stirring in step two is 0.5-2h; preferably 1h.

[0030] Preferably, the time for the continued incubation stirring in step two is 1-5h; preferably 2h.

[0031] Preferably, the method for the post-treatment purification in step two is: first adjusting the pH to 8-10, the product is precipitated in the form of salt, and then adjusting the pH to 1-3 again, the product is precipitated in the form of acid.

[0032] Preferably, the acid for the pH adjustment in step two is one or more of hydrochloric acid, sulfuric acid, and acetic acid.

[0033] Preferably, the base in step two is one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0034] Compared with the prior art, the present application has the following technical effects:

[0035] (1) Using 2-methyl-5-cyanopyrazine as the starting material, the related process route can be greatly shortened, and the problems of complicated operation and low yield in the prior art are overcome.

[0036] (2) In the synthesis step of compound 2, using a mixed solution of acetonitrile / water as the solvent can not only avoid the problem of the generated compound 2 wrapping the starting material 1, but also effectively improve the oxidation efficiency, so that the reaction is complete and the utilization efficiency is improved.

[0037] (3) This route can avoid the generation of impurity 3a, and through the improvement of the product precipitation method, the impurities can be effectively removed, and the product purity is higher than 99.9%, and the problem of low product quality is overcome. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 HPLC spectrum of acipimox obtained in Comparative Example 1

[0039] Figure 2 HPLC spectrum of acipimox obtained in Example 1 DETAILED DESCRIPTION

[0040] The present application will be further described by the following examples, it should be understood that: the examples of the present application are only used to illustrate the present application, but not limit the present application, so, the simple improvement of the present application under the method of the present application is within the scope of the present application.

[0041] Example 1

[0042] Take 120g of 2-methyl-5-cyanopyrazine, add to 180ml of acetonitrile / water (acetonitrile 27ml) mixed solution, then add 171.0g of 30% hydrogen peroxide and 4.8g of sodium tungstate, 60°C for 3h, after the reaction is completed, cooling to 0-10°C, drop 180ml of pure water, after the drop is completed, stirring for 1.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 94.86%.

[0043] Compound 2 is added to 250ml of purified water, 100ml of concentrated hydrochloric acid is added, heated to reflux for 12h, after the reaction is completed, cooling to 40°C, adjusting pH to 8-10 with sodium hydroxide, then cooling to 5°C, stirring for 1.0h; suction filtration, the filter cake is added to 130ml of purified water, adjusting pH to 1-3 with concentrated hydrochloric acid, cooling to 0-10°C, stirring for 2.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 94.98%, HPLC: 99.96%.

[0044] Example 2

[0045] Take 120g of 2-methyl-5-cyanopyrazine, add to 240ml of acetonitrile / water (acetonitrile 36ml) mixed solution, then add 228g of 30% hydrogen peroxide and 12g of sodium tungstate, 50°C for 5h, after the reaction is completed, cooling to 0-10°C, drop 180ml of purified water, after the drop is completed, stirring for 1.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 92.95%.

[0046] Compound 2 is added to 250ml of purified water, 78ml of concentrated hydrochloric acid is added, heated to reflux for 12h, after the reaction is completed, cooling to 40°C, adjusting pH to 8-10 with sodium hydroxide, then cooling to 10°C, stirring for 2h; suction filtration, the filter cake is added to 130ml of purified water, adjusting pH to 1-3 with concentrated hydrochloric acid, cooling to 0-10°C, stirring for 3h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 93.12%, HPLC: 99.93%.

[0047] Example 3

[0048] Take 120g of 2-methyl-5-cyanopyrazine, add to 120ml of acetonitrile / water (acetonitrile 30ml) mixed solution, then add 114g of 30% hydrogen peroxide and 2.4g of sodium tungstate, 65°C for 5h, after the reaction is completed, cooling to 0-10°C, drop 180ml of purified water, after the drop is completed, stirring for 1.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 90.37%.

[0049] Compound 2 is added to 250ml of purified water, 115ml of concentrated hydrochloric acid is added, heated to reflux for 10h, after the reaction is completed, cooling to 30°C, adjusting pH to 8-10 with sodium hydroxide, then cooling to 0°C, stirring for 2h; suction filtration, the filter cake is added to 130ml of purified water, adjusting pH to 1-3 with concentrated hydrochloric acid, cooling to 0-10°C, stirring for 2.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 91.26%, HPLC: 99.95%.

[0050] Example 4

[0051] Take 120g of 2-methyl-5-cyanopyrazine, add to 60ml of acetonitrile / water (acetonitrile 30ml) mixed solution, then add 171.0g of 30% hydrogen peroxide and 4.8g of sodium tungstate, 30°C for 8h, after the reaction is completed, cooling to 0-10°C, drop 120ml of purified water, after the drop is completed, stirring for 1.0h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 88.56%.

[0052] Compound 2 is added to 250ml of purified water, 148ml of concentrated hydrochloric acid is added, heated to reflux for 6h, after the reaction is completed, cooling to 40°C, adjusting pH to 8-10 with sodium hydroxide, then cooling to 10°C, stirring for 0.5h; suction filtration, the filter cake is added to 130ml of purified water, adjusting pH to 1-3 with concentrated hydrochloric acid, cooling to 0-10°C, stirring for 1h, suction filtration, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 89.23%, HPLC: 99.91%.

[0053] Example 5

[0054] Take 120g of 2-methyl-5-cyanopyrazine, add to 400ml of acetonitrile / water (acetonitrile 200ml) mixed solution, then add 91g of 30% hydrogen peroxide and 4.8g of sodium tungstate, 80°C for 6h, after the reaction is completed, cooling to 15°C, drop 180ml of purified water, drop after completion of 1.0h, filter, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 81.28%.

[0055] Compound 2 is added to 250ml of purified water, 60ml of concentrated hydrochloric acid is added, heated to reflux for 20h, after the reaction is completed, the pH is adjusted to 8-10 with potassium hydroxide, then cooled to 0-10°C, 3h of stirring; filter, the filter cake is added to 130ml of purified water, the pH is adjusted to 1-3 with concentrated hydrochloric acid, cooled to 0-10°C, 5h of stirring, filter, the filter cake is washed with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 83.56%, HPLC: 98.15%.

[0056] Example 6

[0057] Take 120g of 2-methyl-5-cyanopyrazine, add to 180ml of water, then add 171.0g of 30% hydrogen peroxide and 4.8g of sodium tungstate, 60°C for 8h, after the reaction is completed, cooling to 0-10°C, drop 180ml of purified water, drop after completion of 1.0h, filter, filter cake with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get solid compound 2, yield 82.56%.

[0058] Compound 2 is added to 250ml of purified water, 90ml of concentrated hydrochloric acid is added, heated to reflux for 12h, after the reaction is completed, cooling to 40°C, the pH is adjusted to 8-10 with sodium hydroxide, then cooled to 5°C, 1.0h of stirring; filter, the filter cake is added to 130ml of purified water, the pH is adjusted to 1-3 with concentrated hydrochloric acid, cooled to 0-10°C, 2.0h of stirring, filter, the filter cake is washed with 13ml of cooled purified water, then vacuum drying at 80-90°C for 10h, to get white solid, yield 87.32%, HPLC: 96.62%.

[0059] Comparative Example 1

[0060] Sodium tungstate dihydrate 4.8g was weighed into 200ml purified water, 2.0g of concentrated sulfuric acid was added with stirring, 170g of 30% hydrogen peroxide was continuously added, and stirred until uniform. 5-methylpyrazine-2-carboxylic acid 120.0g was added, heated to 60°C in a water bath, and stirred for 8h. After cooling, the product was filtered and dried in vacuum to obtain a white solid with a yield of 89.84%, HPLC: 94.88%; impurity 3a: 0.4616%, relative retention time: 0.918.

[0061] Detection:

[0062] [HPLC normalization method: Shim-pack VP ODS C 18 column (4.6mm x 150mm, 5μm); mobile phase: methanol: 0.01mol / L tetrabutylammonium hydroxide solution (15:85) (pH 6.0 adjusted with phosphoric acid); detection wavelength 264nm; column temperature 25°C; flow rate 1ml / min].

Claims

1. A process for the preparation of acipimox, characterized in that, The method comprises the following steps: ； Step one: 2-methyl-5-cyanopyrazine is added to a mixed solution of acetonitrile / water, hydrogen peroxide and sodium tungstate are added, and the mixture is stirred and incubated; after the reaction is completed, the temperature is lowered, then purified water is added dropwise, and after the dropwise addition is completed, the mixture is continuously stirred and incubated; the mixture is filtered, the filter cake is washed with purified water, and then dried to obtain compound 2; Step two: compound 2 is added to purified water, a hydrolysis acid is added dropwise, and then heated to reflux; after the reflux is completed, the temperature is lowered to T1, then the pH is adjusted to 8-10 with a base, and after the adjustment is completed, the temperature is continuously lowered to T2; the mixture is stirred and incubated, filtered, the filter cake is added to an aqueous solution, the pH is adjusted to 1-3 with an acid, the temperature is lowered to 0-10℃, and the mixture is continuously stirred and incubated; the mixture is filtered, the filter cake is washed with purified water, dried, and then a white solid of acipimox is obtained; In step one, the mixed solution of acetonitrile / water has a volume ratio of acetonitrile of 5%-50%; in step one, the molar ratio of compound 1 to hydrogen peroxide is 1:1-4; in step one, the mass ratio of compound 1 to sodium tungstate is 1:0.01-0.1; in step two, the molar ratio of compound 2 to the hydrolysis acid is 1:1-2; in step two, T1 is 30-40℃; and in step two, T2 is 0-10℃.

2. The process for the preparation of acipimox as claimed in claim 1, wherein, In step one, the temperature for stirring and incubation is 30-90℃, and the time for stirring and incubation is 1-8h.

3. The process for the preparation of Acipimox as claimed in claim 1, wherein, In step two, the hydrolysis acid is one or more of hydrochloric acid, sulfuric acid and acetic acid.

4. The process for the preparation of acipimox as claimed in claim 1, wherein, In step two, the time for stirring and incubation is 0.5-2h, and the time for continuously stirring and incubation is 1-5h.

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