A method for purifying a nicorandil intermediate

Abstract

A method for refining a nicorandil intermediate, the reaction system for preparing N-(2-hydroxyethyl)nicotinamide is slowly cooled to 50 DEG C to 60 DEG C, without filtration, aprotic solvent is directly added to the reaction liquid while stirring, the solid separated out in the reaction is stirred and dissolved; wherein, the volume ratio of the aprotic solvent to the reaction system is controlled to be 0.6 to 6:1; the reaction liquid system of the dissolved solution in step 1) is continuously stirred and cooled, when the temperature is cooled to below 40 DEG C, white solid begins to separate out in the solution; then continuous stirring and temperature adjustment is carried out, and the solution is incubated and stirred at 20 to 30 DEG C, and the intermediate N-(2-hydroxyethyl)nicotinamide is obtained after filtration. In the present application, the reaction liquid is crystallized once, the product purity can reach more than 98%, the reaction yield is more than 93%, the operation is simple, the high-temperature distillation process is avoided, the yield is high, the production cost is low, the process is stable, and it is suitable for industrial production.

Description

A method for purifying nicotinic acid intermediates Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation, specifically relating to a purification method for nicorandil intermediate. Background Technology

[0002] Nicorandil, as the first potassium channel opener, possesses a dual effect of nitrate-like properties and potassium channel opening, effectively alleviating symptoms and improving prognosis. It significantly reduces the incidence of cardiovascular events in angina patients, filling a market gap for dual-action angina treatment and making it an ideal drug for angina. In the current process for manufacturing nicorandil, the most critical intermediate is shown below:

[0003]

[0004] The key intermediate is called N-(2-hydroxyethyl)nicotinamide, with the molecular formula C8H10. 10 N2O2 has a molecular weight of 166.18.

[0005] The mainstream synthetic process for this key intermediate generally uses ethyl nicotinate as the starting material, adds ethanolamine, directly heats under reflux to react, and then proceeds with post-treatment to obtain the final product. The reaction equation is shown below:

[0006]

[0007] The above method, due to the absence of solvent and the high reaction temperature, results in numerous impurities in the reaction system. Conventional treatment methods are cumbersome, and removing these impurities is difficult. Based on relevant literature, the existing technologies for synthesizing this key intermediate analogue mainly include the following:

[0008] US Patent US20120277444 discloses a method for synthesizing hydroxyalkylamides from esters, involving the preparation process of this key intermediate. The ester is reacted with ethanolamine in the presence of a heterogeneous catalyst in an aqueous solution to form hydroxyalkylamides. However, the product is obtained by removing the solvent through filtration and distillation, and the purification process of this key intermediate is not mentioned.

[0009] Chinese invention patent CN107915653A discloses a method for preparing amides by using an alkoxy rare earth metal cluster containing sodium alkali metal as a catalyst to catalyze the reaction of esters and amines under anhydrous, oxygen-free, and argon-protected conditions. The separation and purification method after the reaction is column chromatography and / or thin-layer chromatography. This post-processing method is only suitable for laboratory research and cannot be applied to the industrial production of active pharmaceutical ingredients.

[0010] Chinese patent application CN102964195A discloses a method for preparing secondary and tertiary substituted amides, which involves reacting nitriles and amines with an alkaline catalyst under air or inert gas conditions at a reaction temperature of 100–200°C for 24–72 hours, and obtaining the products by column chromatography or column chromatography separation.

[0011] N-(2-hydroxyethyl)nicotinamide is an important intermediate in the production of nicorandil active pharmaceutical ingredient (API). Its product quality and purification process have a significant impact on the production of nicorandil API. If the content of this intermediate is too low, the quality of the subsequently prepared nicorandil API will be substandard. The treatment methods reported above are only applicable to small-scale laboratory studies and cannot be applied to the large-scale production process of API.

[0012] In existing processes, the prepared intermediate reaction liquid system is first distilled at high temperature and reduced pressure at temperatures above 100°C, and then the intermediate product is obtained through processes such as cooling and crystallization. However, high-temperature distillation has high requirements for equipment and safety in industrial production; or multiple recrystallization and rinsing processes are required to obtain qualified intermediates, which is still quite cumbersome and the product yield is low. Summary of the Invention

[0013] The purpose of this invention is to provide a purification method for nicorandil intermediates. The reaction solution is crystallized once to obtain the key intermediate of nicorandil with a purity of over 98% and a reaction yield of over 93%. The method is simple to operate, avoids the high-temperature distillation process, has a high yield, low production cost, stable process, and is suitable for industrial production.

[0014] To achieve the above objectives, the present invention provides the following technical solution:

[0015] A method for purifying nicorandil intermediates includes the following steps:

[0016] 1) Dissolve

[0017] N-(2-hydroxyethyl)nicotinamide was prepared by amination reaction using ethyl nicotinate and ethanolamine as starting materials, as shown in the following reaction formula:

[0018]

[0019] After the reaction is complete, the reaction system is slowly cooled to 50℃~60℃. Without filtration, an aprotic solvent is added directly to the reaction solution while stirring to dissolve the solid precipitated during the reaction. The volume ratio of the aprotic solvent to the reaction system is 0.6~6:1.

[0020] 2) Cooling and crystallization

[0021] Continue stirring and cooling the reaction solution system dissolved in step 1). When the temperature drops below 40°C, a white solid begins to precipitate in the solution. Then continue stirring and adjust the temperature, keeping it at 20-30°C with stirring. After filtration, the intermediate N-(2-hydroxyethyl)nicotinamide is obtained.

[0022] Preferably, the cooling rate in step 1) is 5-10°C / 30 min.

[0023] Furthermore, in step 1), during the amination reaction, the starting materials ethyl nicotinic acid and ethanolamine react under solvent-free conditions.

[0024] Preferably, the molar ratio of ethyl nicotinic acid to ethanolamine is 1:1.1 to 1.5.

[0025] Furthermore, in step 1), the aprotic solvent is selected from one or more of the following solvents: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, chloroform, or dichloromethane.

[0026] Preferably, in step 1), the aprotic solvent is a mixed solvent of acetonitrile and dimethyl sulfoxide, wherein the ratio of acetonitrile to dimethyl sulfoxide is 1:0.5 to 3 (v / v).

[0027] Furthermore, in step 1), the volume ratio of the aprotic solvent to ethyl nicotinate is 1 to 10:1, and in step 2), the cooling and crystallization temperature is -10 to 40°C.

[0028] Preferably, in step 1), the volume ratio of the aprotic solvent to ethyl nicotinate is 2 to 6:1.

[0029] Furthermore, in step 2), the cooling temperature for crystallization is 0–30°C.

[0030] Preferably, in step 1), the volume ratio of the aprotic solvent to ethyl nicotinate is 3-4:1, and in step 2), the cooling and crystallization temperature is 20-25°C, and the mixture is kept at 20-30°C and stirred for 2-5 hours to obtain N-(2-hydroxyethyl)nicotinamide with a purity of over 98% and a reaction yield of over 93%.

[0031] In this invention, the product in the reaction system for preparing N-(2-hydroxyethyl)nicotinamide is directly crystallized. If the crystallization solvent is not chosen properly, impurities in the reaction solution will remain in the crystallized product, resulting in substandard quality of the target product. This invention selects a specific type of aprotic solvent and controls its amount in the reaction system, which can prevent the inclusion of ethanolamine during the precipitation of N-(2-hydroxyethyl)nicotinamide, reducing the possibility of further reaction of ethanolamine to produce byproducts and impurities. It can also remove byproducts in the reaction solution, further reducing the content of impurities in the precipitated N-(2-hydroxyethyl)nicotinamide, such as nitrogen oxides and residual nicotinic acid. Furthermore, the crystallization solvent also has a significant impact on the crystallization yield; different solvents can lead to large differences in the yield of the target intermediate.

[0032] In this invention, after the reaction solution is slowly cooled, a crystallization solvent is added and its amount is strictly controlled. The precipitated solid is dissolved first, and a high-purity product can be obtained through one crystallization. This effectively removes impurities such as nitrogen oxides and residual nicotinic acid from N-(2-hydroxyethyl)nicotinamide, thereby achieving a weight percentage content of over 98% and a yield of over 93% for N-(2-hydroxyethyl)nicotinamide. This avoids yield losses caused by high-temperature distillation, multiple crystallizations, or multiple post-processing methods.

[0033] Experiments have shown that when using mixed solvents in this invention, the mixed system of two specific solvents is more conducive to the crystallization of the target intermediate, resulting in fewer impurities after crystallization. The main impurity, nicotinic acid, can be completely removed, leading to higher product purity, reaching over 99.9%, and a significantly improved yield, reaching over 96%.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] In this invention, the reaction solution for preparing the key intermediate of nicorandil is slowly cooled. Once the reaction solution has reached a suitable temperature, a specific solvent is added directly to dissolve the solid without filtration, and crystallization is then carried out. High-purity target compounds can be obtained through a single crystallization process, avoiding the high-temperature crystallization operation and reducing the stringent requirements on equipment, energy consumption, and safety in the production process caused by high-temperature distillation.

[0036] This invention allows for direct crystallization in a single step after the reaction system is cooled, avoiding multiple recrystallization operations. It simplifies the process by eliminating the need for repeated recrystallization and rinsing, thus saving steps and improving production efficiency while obtaining high-purity target compounds.

[0037] The present invention can be used to prepare key intermediates of nicotinic acid with a yield of over 93% and an N-(2-hydroxyethyl)nicotinamide weight percentage of over 98%. When a mixed solvent is used as the crystallization solvent, the N-(2-hydroxyethyl)nicotinamide weight percentage of the obtained product reaches over 99.9%. It has the advantages of simple process, convenient operation, low production cost, high product purity, stable process, and suitability for industrial production. Attached Figure Description

[0038] Figure 1 is an HPLC chromatogram of the purified material using dimethyl sulfoxide in Example 2 of this invention.

[0039] Figure 2 is an HPLC chromatogram of the purified product of N,N-dimethylformamide in Example 3 of the present invention.

[0040] Figure 3 is an HPLC chromatogram of the product purified by dimethyl sulfoxide / acetonitrile mixed solvent in Example 4 of the present invention.

[0041] Figure 4 is an HPLC chromatogram of the acetonitrile purified product in Example 5 of the present invention.

[0042] Figure 5 is an HPLC chromatogram of the product after purification of dichloromethane in Example 6 of the present invention.

[0043] Figure 6 is an HPLC chromatogram of the acetone purified product in the comparative example of this invention. Detailed Implementation

[0044] The present invention will be further described below with reference to specific embodiments.

[0045] The synthesis process of the nicotinamide intermediate N-(2-hydroxyethyl)nicotinamide in this invention can be carried out according to the synthesis methods disclosed in the prior art. In the examples, nicotinic acid and ethanol are used as starting materials, and the key intermediate is obtained through esterification and amination reactions, as shown in the following reaction formula:

[0046]

[0047] HPLC detection can be performed using known methods, such as under the following conditions:

[0048] Chromatographic column: A chromatographic column packed with hydrophilic octadecyl bonded silica gel (XBridge Shield RP184.6×50mm, 3.5μm);

[0049] Mobile phase: 0.05% sodium octane sulfonate aqueous solution (pH 2.5) was used as mobile phase A, and methanol was used as mobile phase B;

[0050] Detection wavelength: 254nm;

[0051] Flow rate: 0.5 ml per minute;

[0052] Column temperature: 30℃;

[0053] Injection volume: 20 μl;

[0054] Collection time: 50 minutes;

[0055] Gradient elution procedure:

[0056] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 98 25 98 22 57 0 30 28 70 30 28.19 82 50 98 2 surface

[0057] Example 1

[0058] Ethanol (400 mL) and nicotinic acid (200 g, 1.62 mol) were drawn into a 1 L glass reaction vessel. Concentrated sulfuric acid (200 mL) was added dropwise while stirring. After the addition of concentrated sulfuric acid was complete, the mixture was heated to reflux (100℃~110℃) and reacted for 3 hours. Then, the temperature was lowered to below 40℃, and pure water (1200 mL) was added and stirred to dissolve. The pH of the system was adjusted to 7.5~8.5 by adding a 30% sodium hydroxide aqueous solution. The mixture was filtered, and the filtrate was extracted with ethyl acetate (2 × 600 mL). The ethyl acetate phase was then concentrated to obtain an oily substance (198.01 g, 1.31 mol) of ethyl nicotinic acid with a purity of 99.92%.

[0059] The above-mentioned ethyl nicotinate oil (198.01 g, 1.31 mol) and ethanolamine (120 g, 1.96 mol) were added to a 500 mL reaction flask, heated to reflux at 100 °C–110 °C, and kept at this temperature for 3 hours. Then, the temperature was lowered to 50–60 °C, and acetonitrile-dimethyl sulfoxide mixed solvent (200 mL, V / V = 1:1) was slowly added. The temperature was then slowly lowered to 20–30 °C, and the mixture was stirred at this temperature for 3 hours to induce crystallization. After the temperature was maintained, the mixture was filtered, and the filter cake was vacuum dried at 50 ± 5 °C to constant weight to obtain N-(2-hydroxyethyl)nicotinamide (210.10 g, 1.26 mol), a key intermediate of nicotinamide, with a molar yield of 96.18% and an HPLC purity of over 99.95%.

[0060] Example 2

[0061] After the reaction system containing ethyl nicotinic acid (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, the temperature was slowly reduced to 50–60 °C at a rate of 5–10 °C / 30 min. Without filtration, dimethyl sulfoxide (1000 ml) was added and stirred until the solution was clear. The temperature was then further reduced to 20–25 °C and stirred to induce crystallization, yielding a solid. The solid was dried under vacuum at 50 °C to obtain N-(2-hydroxyethyl)nicotinamide, a white solid (210 g, 1.26 mol), with a yield of 95.5% and an HPLC purity of 98.40%. The chromatogram is shown in Figure 1.

[0062] As shown in Figure 1, the nicotinic acid content is 1.58%, and there is one other impurity with a content of 0.02%.

[0063] Example 3

[0064] After the reaction system containing ethyl nicotinic acid (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, the temperature was slowly reduced to 50–60 °C at a rate of 5–10 °C / 30 min. Without filtration, N,N-dimethylformamide (800 ml) was added and stirred until dissolved. The temperature was then further reduced to 20–25 °C and stirred to induce crystallization, yielding a solid. The solid was then dried under vacuum at 50 °C to obtain N-(2-hydroxyethyl)nicotinamide, a white solid (208 g, 1.25 mol), with a yield of 94.7% and an HPLC purity of 98.52%. The chromatogram is shown in Figure 2.

[0065] As shown in Figure 2, the nicotinic acid content is 1.25%, and there are 4 other impurities, with the highest content being 0.09%.

[0066] Example 4

[0067] After the reaction system containing ethyl nicotinate (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, the temperature was slowly reduced to 50–60 °C at a rate of 5–10 °C / 30 min. Without filtration, acetonitrile / dimethyl sulfoxide mixed solvent (1000 ml, V / V = 1:1) was directly added, and the mixture was stirred and heated until the solution was clear. The temperature was then further reduced to 25–30 °C and stirred to induce crystallization, yielding a solid. The obtained solid was dried under vacuum at 50 °C to obtain N-(2-hydroxyethyl)nicotinamide, a white solid (212 g, 1.28 mol), with a yield of 96.7% and an HPLC purity of 99.97%. The chromatogram is shown in Figure 3.

[0068] As shown in Figure 3, nicotinic acid was completely removed and no peak was observed. Only one impurity was present, with a content of 0.02%.

[0069] Example 5

[0070] After the reaction system containing ethyl nicotinic acid (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, the temperature was slowly reduced to 50–60 °C at a rate of 5–10 °C / 30 min. Without filtration, acetonitrile (1000 ml) was added, and the mixture was stirred and heated until the solution was clear. The temperature was then further reduced to 25–30 °C and stirred to induce crystallization, yielding a solid. The solid was then dried under vacuum at 50 °C to obtain a white solid of N-(2-hydroxyethyl)nicotinamide (206 g, 1.24 mol), with a yield of 93.9% and an HPLC purity of 99.01%. The chromatogram is shown in Figure 4.

[0071] As shown in Figure 4, the nicotinic acid content is 0.98%, and there is one other impurity with a content of 0.01%.

[0072] Example 6

[0073] After the reaction system containing ethyl nicotinic acid (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, it was slowly cooled to 50–60 °C at a rate of 5–10 °C / 30 min. Without filtration, dichloromethane (1000 ml) was added, and the mixture was stirred and heated until the solution was clear. The temperature was then further reduced to 25–30 °C and stirred to induce crystallization, yielding a solid. The solid was dried under vacuum at 50 °C to obtain N-(2-hydroxyethyl)nicotinamide, a white solid (204 g, 1.23 mol), with a yield of 93.2% and an HPLC purity of 99.28%. The chromatogram is shown in Figure 5.

[0074] As shown in Figure 5, the nicotinic acid content is 0.56% and the ethyl nicotinate content is 0.03%.

[0075] Comparative Example

[0076] After the reaction system of ethyl nicotinic acid (200 g, 1.32 mol) and ethanolamine (117.6 g, 1.93 mol) was refluxed, it was cooled to 50-60 °C, acetone (200 ml) was added, stirred and heated, and then cooled to 20-30 °C to crystallize. The obtained solid was dried under vacuum at 50 °C to obtain a white solid N-(2-hydroxyethyl)nicotinamide (197 g, 1.19 mol), with a yield of 89.91% and an HPLC purity of 96.30%. The chromatogram is shown in Figure 6.

[0077] As shown in Figure 6, the nicotinic acid content is 3.47%, which is difficult to remove with acetone. There are also several other impurities with contents ranging from 0.01% to 0.09%.

Claims

1. A method for purifying a nicorandil intermediate, comprising the following steps: 1) N-(2-hydroxyethyl)nicotinamide was prepared by dissolving ethyl nicotinate and ethanolamine as starting materials and then reacting them via an amination reaction, as shown in the following reaction formula: After the reaction is complete, the reaction system is slowly cooled to 50℃~60℃. Without filtration, an aprotic solvent is added directly to the reaction solution while stirring, and the solid precipitated during the reaction is stirred until dissolved. The volume ratio of the aprotic solvent to the reaction system is 0.6~6:1, and the aprotic solvent is one or a mixture of two or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, or dichloromethane. The cooling rate in step 1) is 5~10℃ / 30min; 2) Cooling To prevent crystallization, the reaction solution system dissolved in step 1) was stirred and cooled. When the temperature dropped below 40°C, a white solid began to precipitate from the solution. Then, stirring was continued and the temperature was adjusted to maintain the temperature at 20-30°C. After filtration, the intermediate N-(2-hydroxyethyl)nicotinamide was obtained. In step 2), the cooling and crystallization temperature was 20-30°C. The N-(2-hydroxyethyl)nicotinamide obtained had a purity of over 98% and a reaction yield of over 93%.

2. The method for purifying the nicorandil intermediate according to claim 1, characterized in that, In step 1), the amination reaction is carried out by reacting the starting materials ethyl nicotinate and ethanolamine under solvent-free conditions.

3. The method for purifying the nicorandil intermediate according to claim 1, characterized in that, In step 1), the molar ratio of ethyl nicotinic acid to ethanolamine in the amination reaction is 1:1.1 to 1.

5.

4. The method for purifying the nicorandil intermediate according to claim 1, characterized in that, In step 1), the aprotic solvent is a mixed solvent of acetonitrile and dimethyl sulfoxide, wherein the ratio of acetonitrile to dimethyl sulfoxide is 1:0.5 to 3 (v / v).

5. The method for purifying the nicorandil intermediate according to claim 1, characterized in that, In step 1), the volume ratio of the aprotic solvent to ethyl nicotinate is 3 to 5:

1.

6. The method for purifying the nicorandil intermediate according to claim 1, characterized in that, In step 2), the cooling temperature for crystallization is 20–25°C.

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