Preparation method of Nicodil

Abstract

The invention relates to a preparation method of Nicodil, which comprises the following steps: carrying out nitration reaction on ethanolamine serving as a first initial raw material to obtain an intermediate, reacting nicotinic acid serving as a second initial raw material with the intermediate to obtain a Nicodil crude product, mixing the Nicodil crude product with isopropanol, filtering, crystallizing and drying to obtain a Nicodil finished product, the preparation method of the intermediate comprises the following steps: putting fuming nitric acid and dichloromethane into a reaction kettle, continuing to add a dichloromethane solution of ethanolamine for nitration reaction, continuing to add acetic anhydride, crystallizing, filtering, washing, and drying under reduced pressure to obtain the intermediate. The high-temperature stability is better, and the impurity content is controlled, so that the medicine quality is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for preparing Nicorandil. Background Art

[0002] Nicorandil, chemically named N-(2-hydroxyethyl) nicotinamide nitrate, with a molecular formula of C8H9N3O4, is the first ATP-sensitive potassium channel opener used clinically. It is also known as nicotinamide nitrate in clinical practice. Its essence is a nicotinamide nitrate derivative. Clinical studies have shown that it has the effects of improving cardiac blood supply, inhibiting myocardial cell apoptosis, and alleviating microcirculatory disorders. It is a commonly used drug for the clinical treatment of coronary heart disease and angina pectoris.

[0003] The safety of drugs during use is not only directly related to the pharmacological activity of the drugs themselves, but also related to the impurities contained in the drugs. Some impurities can cause many adverse reactions. Therefore, to ensure the safety of drugs, it is necessary to study the impurities in the drugs, especially to explore how to control the limit of impurities in drugs under high temperature environments, so as to ensure the content of Nicorandil while controlling the stability of related substances, and improve the quality of drugs by controlling the impurity content. Summary of the invention

[0004] The present invention provides a method for preparing Nicorandil, comprising:

[0005] Intermediate preparation step: using ethanolamine as the first starting material and subjecting it to a nitration reaction to obtain an intermediate;

[0006] The preparation steps of the crude product are as follows: nicotinic acid as a second starting material reacts with an intermediate to obtain a crude nicorandil;

[0007] Purification step: the crude Nicorandil product is mixed with isopropyl alcohol, filtered, crystallized and dried to obtain the finished Nicorandil product;

[0008] The intermediate preparation step comprises:

[0009] S1: placing fuming nitric acid and dichloromethane in a reaction kettle;

[0010] S2: Continue to add the dichloromethane solution of ethanolamine to carry out nitration reaction, the reaction temperature is 10-30°C, and the time is 0.5-2h;

[0011] S3: Continue to add acetic anhydride, crystallize at a temperature of 10-30°C for 1-3 hours, filter, wash, and dry under reduced pressure at a drying temperature of 50-70°C for 5 hours to 10 hours to obtain an intermediate.

[0012] Preferably, the molar ratio of acetamide, fuming nitric acid and acetic anhydride is: 1:2-8:0.5-5.

[0013] Preferably, the molar ratio of acetamide, fuming nitric acid and acetic anhydride is 1:2-4:1-3.

[0014] Preferably, the nitration reaction temperature is 10-20°C, the time is 0.5-1h, the crystallization temperature is 10-15°C, the time is 1-2h, and the reduced pressure drying temperature is 55-60°C, the time is 6h-8h.

[0015] Preferably, the dichloromethane solution of ethanolamine is prepared by dissolving ethanolamine in dichloromethane, and the feed ratio of ethanolamine to dichloromethane is 1:6-12.

[0016] Preferably, in the step of preparing the crude product, nicotinic acid is used as the second starting material to react to obtain a nicotinic acid intermediate solution, and the nicotinic acid intermediate solution and the intermediate are subjected to an addition reaction to obtain a nicorandil crude product. The preparation of the nicotinic acid intermediate solution comprises the following steps:

[0017] S4: adding nicotinic acid, N,N-dimethylformamide and dichloromethane into a reaction kettle;

[0018] S5: Continue to add thionyl chloride to carry out acylation reaction at a temperature of 30-40°C for 2-5 hours, and concentrate to dryness under reduced pressure to obtain nicotinic acid intermediate;

[0019] S6: Add dichloromethane to the nicotinic acid intermediate state and stir to disperse the mixture to obtain a nicotinic acid intermediate state solution.

[0020] Preferably, the molar ratio of the intermediate, nicotinic acid and thionyl chloride is 1:1-3:1-3, and the feed ratio of nicotinic acid and N,N-dimethylformamide is 1:0.03-0.1.

[0021] Preferably, the molar ratio of the intermediate, nicotinic acid and thionyl chloride is 1:1-2:1.5-2, and the feed ratio of nicotinic acid and N,N-dimethylformamide is 1:0.04-0.08.

[0022] Preferably, the acylation reaction temperature is 35-40° C. and the time is 4-5 h.

[0023] The present application provides the use of the above intermediate and the niacin intermediate solution in the preparation of the nicorandil finished product.

[0024] The above technical scheme of the present invention has the following beneficial effects: the present invention achieves the purpose of ensuring the content of nicorandil while having good high temperature stability and controlling the impurity content to improve the quality of the drug by adjusting the preparation process of the intermediate and the preparation process of the nicotinic acid intermediate solution in the preparation of the nicorandil crude product. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The process flow chart of the preparation method of Nicorandil of the present invention is shown in FIG. DETAILED DESCRIPTION

[0026] The following examples further illustrate the content of the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention all fall within the scope of the present invention.

[0027] Although the present invention has been described in detail above by general description, specific implementation methods and experiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

[0028] In some embodiments of the present application, the chemical reaction formula of the preparation method of Nicorandil can be as follows Figure 1 As shown, wherein each substance is shown in Table 1:

[0029] Table 1: List of abbreviations or acronyms

[0030]

[0031] In some embodiments, the impurity structures to be detected in the nicorandil finished product prepared by the preparation method of the present application are shown in Table 2:

[0032] Table 2: Analysis of organic impurities in crude products

[0033]

[0034]

[0035] Embodiment 1:

[0036] Intermediate preparation steps:

[0037] Table 3: List of materials used in the synthesis of intermediates

[0038]

[0039]

[0040] Add 6.2 kg of fuming nitric acid and 12 L of dichloromethane to a 100 L double-layer glass reactor, stir evenly, control the temperature to 10 ° C, slowly add 3.0 kg of ethanolamine dichloromethane solution (ethanolamine is dissolved in 6 L of dichloromethane), control the temperature to 12 ° C, stir and react for 0.5;

[0041] After the reaction is completed, 2.5 kg of acetic anhydride is slowly added. After the addition is completed, the temperature is controlled to 10° C. and stirred for crystallization for 1 hour. The mixture is filtered and the filter cake is washed with an appropriate amount of dichloromethane. The filter cake is collected and dried under reduced pressure at 50° C. for 6 hours to obtain an intermediate.

[0042] Preparation steps of crude product:

[0043] Table 4: List of materials used in the synthesis of crude products

[0044]

[0045] Add 4.8 kg of nicotinic acid, 0.15 kg of DMF and 20 L of dichloromethane to a 50 L double-layer glass reactor, stir evenly, slowly add 4.6 kg of thionyl chloride, and after the addition, control the temperature to 30 ° C (reflux) and stir for 4 hours, and monitor the reaction progress by TLC (TLC monitoring method 1).

[0046] After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure at 30° C. to obtain an intermediate state of nicotinic acid. 33 L of dichloromethane was added and stirred to disperse to obtain a dichloromethane solution of the intermediate state of nicotinic acid, which was sealed for later use.

[0047] Add 6.5 kg of the intermediate, 10.4 kg of sodium carbonate, 33 L of dichloromethane and 65 L of purified water into a 150 L double-layer glass reactor, stir evenly, add the dichloromethane solution of the above nicotinic acid intermediate, and after the addition is complete, control the temperature to 10 ° C and stir the reaction for 1 hour, and monitor the reaction progress by TLC (TLC monitoring method 2).

[0048] After the reaction is completed, stand and separate, collect the organic phase, extract the aqueous phase with dichloromethane (13L×3), and combine the organic phases. Add 39L 1N hydrochloric acid solution to the organic phase, extract and separate, and collect the aqueous phase. Add an appropriate amount of saturated sodium carbonate solution to the aqueous phase, adjust the pH to neutral (7.0±0.5), control the temperature to 10°C, stir and crystallize for 1h, filter, wash the filter cake with an appropriate amount of purified water, collect the filter cake, and dry it under reduced pressure at 40°C for 8h to obtain a crude product.

[0049] Refining steps:

[0050] Table 5: List of materials used for crude product refining

[0051]

[0052] Add 5.9 kg of crude product and 35 L of isopropanol to a 100 L double-layer glass reactor, heat to 40 ° C, stir to dissolve, filter, collect the filtrate, cool to -10 ° C, stir and crystallize for 4 h, filter, collect the filter cake, and dry under reduced pressure at 40 ° C for 6 h to obtain the finished Nicorandil product.

[0053] Example 2

[0054] The same preparation method as in Example 1 was used, except that the materials and specific steps used were as shown in Tables 6 and 7:

[0055] Table 6: List of materials used in the synthesis of intermediate I

[0056]

[0057] Add fuming nitric acid and dichloromethane to the reaction kettle, stir evenly, control the temperature to 20°C, add dichloromethane solution (dissolve ethanolamine in 9L dichloromethane), control the temperature to 30°C and stir to react for 1h; add acetic anhydride, control the temperature to 25°C and stir to crystallize for 1h, and dry under reduced pressure at 65°C for 7h to obtain an intermediate.

[0058] Table 7: List of materials used in the synthesis of crude products

[0059]

[0060] After adding thionyl chloride to the reactor, the temperature was controlled to 35°C (reflux) and the reaction was stirred for 4.5 hours. The reaction solution was concentrated to dryness under reduced pressure at 25°C to obtain a nicotinic acid intermediate. Dichloromethane was added and stirred to disperse to obtain a nicotinic acid intermediate dichloromethane solution.

[0061] Example 3

[0062] The same preparation method as in Example 1 was used, except that the materials and specific steps used are shown in Table 8:

[0063] Table 8: List of materials used in the synthesis of intermediate I

[0064]

[0065]

[0066] Add fuming nitric acid and dichloromethane to the reaction kettle, stir evenly, control the temperature to 30°C, add dichloromethane solution (dissolve ethanolamine in 12L dichloromethane), control the temperature to 30°C and stir to react for 1h; add acetic anhydride, control the temperature to 20°C and stir to crystallize for 1h, and dry under reduced pressure at 55°C for 8h to obtain the intermediate.

[0067] Table 9: List of materials used in the synthesis of crude products

[0068]

[0069] After adding thionyl chloride to the reaction kettle, the temperature was controlled to 40°C (reflux) and stirred for reaction for 5 hours. The reaction solution was concentrated to dryness under reduced pressure at 30°C to obtain a nicotinic acid intermediate. Dichloromethane was added and stirred to disperse to obtain a nicotinic acid intermediate dichloromethane solution.

[0070] Comparative Example 1

[0071] The preparation method is the same as that in Example 2, except that the preparation steps of the intermediate are as follows: add fuming nitric acid and dichloromethane to a reaction kettle, stir evenly, control the temperature to -5°C, add ethanolamine dichloromethane solution, control the temperature to 10°C, stir and react for 2h; add acetic anhydride, control the temperature to 0°C, stir and crystallize for 2h, and dry under reduced pressure at 75°C for 5h to obtain an intermediate.

[0072] Comparative Example 2

[0073] The preparation method is the same as that in Example 2, except that the preparation steps of the intermediate are as follows: add fuming nitric acid and dichloromethane to a reaction kettle, stir evenly, control the temperature to 40°C, add ethanolamine dichloromethane solution, control the temperature to 55°C, and stir to react for 4 hours; add acetic anhydride, control the temperature to 35°C, stir and crystallize for 3 hours, and dry under reduced pressure at 45°C for 12 hours to obtain an intermediate.

[0074] Comparative Example 3

[0075] The preparation method is the same as that in Example 2, except that the preparation steps of the intermediate are as follows: add fuming nitric acid and dichloromethane to a reaction kettle, stir evenly, control the temperature to -5°C, add ethanolamine dichloromethane solution, control the temperature to 10°C, stir and react for 2h; add acetic anhydride, control the temperature to 0°C, stir and crystallize for 2h, and dry under reduced pressure at 75°C for 5h to obtain the intermediate;

[0076] Preparation steps of nicotinic acid intermediate dichloromethane solution: After adding thionyl chloride to the reaction kettle, control the temperature to 20°C (reflux) and stir to react for 1 hour, concentrate the reaction solution to dryness under reduced pressure at 45°C to obtain nicotinic acid intermediate, add dichloromethane and stir to disperse to obtain nicotinic acid intermediate dichloromethane solution.

[0077] Comparative Example 4

[0078] The preparation method is the same as that of Example 2, except that the preparation steps of the intermediates use the materials in Table 10:

[0079] Table 10: List of materials used in the synthesis of intermediates

[0080]

[0081]

[0082] Comparative Example 5

[0083] The preparation method is the same as that of Example 2, except that the preparation step of the dichloromethane solution of ethanolamine uses the materials in Table 11:

[0084] Table 11: List of materials used in the synthesis of crude products

[0085]

[0086] The test examples of this application are based on the "Guidelines for Stability Testing of APIs and Pharmaceutical Preparations" (9001, General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia), "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations) (Revised)" and other relevant guidelines, and refer to the relevant provisions of the Nicorandil quality standard to conduct stability inspections on the product's properties, pH value, clarity and color of the solution, related substances, water content, bacterial endotoxins, microbial limits, content determination and other items.

[0087] Test Example 1 Influencing Factor Test (High Temperature)

[0088] Nicorandil products were prepared by the preparation methods of Examples 1-3 and Comparative Examples 1-5, respectively. The products were placed at high temperature (40°C ± 2°C) for 30 days to investigate the contents of related substances. The results are shown in Table 12. Other undetectable impurities are not shown in Table 12.

[0089] Table 12: Test results of related substances in influencing factor test (high temperature)

[0090]

[0091] Analysis of test results:

[0092] Nicorandil products were prepared by the preparation methods of Examples 1-3 and Comparative Examples 1-5, respectively. When the products were placed at high temperature for 30 days, the indicators of various related substances were within the limit requirements, indicating that they had good high temperature stability. Among them, the high temperature stability of Example 2 was better than that of Comparative Examples 1-5 and other Examples 1 and 3.

[0093] Comparative Examples 1 and 2 are both based on Example 2, in which the process of the preparation step of the intermediate is adjusted. Although the relevant substances of the prepared finished products meet the requirements at 0 days, the related substances C and G increase significantly after the high temperature test, causing the total impurities to exceed the limit requirements, proving that the adjustment of the relevant parameters of the preparation process of the intermediate can affect the content of related substances in the nicorandil finished product in the high temperature stability test.

[0094] After studying Comparative Examples 1 and 2, in Comparative Example 3, the process for preparing the intermediate and the process for preparing the intermediate solution of nicotinic acid in the preparation of the crude product were adjusted at the same time. As a result, it was found that the relevant substances of the prepared finished product still met the requirements at 0 days, but for example, the impurity C was close to the critical value of the limit requirement, which indicated that the nicorandil finished product prepared by this method had poor high temperature stability in this experiment. After this test, it was found that not only the obvious increase of the related substances C and G exceeded the limit requirement, but the impurity D was also at the edge of the critical value, which proved that the coordinated adjustment of the relevant parameters of the preparation process of the intermediate and the preparation process of the intermediate solution of nicotinic acid could affect the content of related substances in the high temperature stability test of the nicorandil finished product.

[0095] Comparative Document 4 and Comparative Example 5 are respectively based on Example 2, and the materials for the preparation of the intermediate and the preparation of the nicotinic acid intermediate solution are adjusted. After the high temperature stability test, the impurity C slightly exceeds the limit requirement. Although other impurities do not exceed the limit requirement, the total impurities still do not meet the prescribed standards, which proves that Example 2 can affect the content of related substances in the nicorandil finished product to a certain extent by appropriately adjusting the material ratios required in the preparation of the intermediate or the preparation of the nicotinic acid intermediate solution.

[0096] Test Example 2 Batch Production Test of Nicorandil Finished Product

[0097] Three batches of finished nicorandil were prepared by the preparation methods of Examples 1-3, respectively. The results are shown in Table 13:

[0098] Table 13: Batch production test results of Nicorandil finished product

[0099]

[0100] Analysis of the test results: It is proved that the preparation method of Examples 1-3 has good repeatability when used for batch production, and the prepared Nicorandil has high stability.

[0101] The above-described embodiments are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for preparing Nicorandil, comprising: Intermediate preparation step: using ethanolamine as the first starting material and subjecting it to a nitration reaction to obtain an intermediate; The preparation steps of the crude product are as follows: nicotinic acid as a second starting material reacts with an intermediate to obtain a crude nicorandil; Purification step: the crude Nicorandil product is mixed with isopropyl alcohol, filtered, crystallized and dried to obtain the finished Nicorandil product; It is characterized in that The intermediate preparation step comprises: S1: placing fuming nitric acid and dichloromethane in a reaction kettle; S2: Continue to add the dichloromethane solution of ethanolamine to carry out nitration reaction, the reaction temperature is 10-30°C, and the time is 0.5-2h; S3: Continue to add acetic anhydride, crystallize at a temperature of 10-30°C for 1-3 hours, filter, wash, and dry under reduced pressure at a drying temperature of 50-70°C for 5 hours to 10 hours to obtain an intermediate.

2. The method for preparing Nicorandil according to claim 1, characterized in that: The molar ratio of the acetamide, fuming nitric acid and acetic anhydride is 1:2-8:0.5-5.

3. The method for preparing Nicorandil according to claim 1, characterized in that: The molar ratio of the acetamide, fuming nitric acid and acetic anhydride is 1:2-4:1-3.

4. The method for preparing Nicorandil according to claim 1, characterized in that: The nitration reaction temperature is 10-20°C, the time is 0.5-1h, the crystallization temperature is 10-15°C, the time is 1-2h, and the reduced pressure drying temperature is 55-60°C, the time is 6h-8h.

5. The method for preparing Nicorandil according to claim 1, characterized in that: The dichloromethane solution of ethanolamine is prepared by dissolving ethanolamine in dichloromethane, and the feed ratio of ethanolamine to dichloromethane is 1:6-12.

6. The method for preparing Nicorandil according to claim 1, characterized in that: In the step of preparing the crude product, nicotinic acid is used as the second starting material to react to obtain a nicotinic acid intermediate solution, and the nicotinic acid intermediate solution and the intermediate are subjected to an addition reaction to obtain a nicorandil crude product. The preparation of the nicotinic acid intermediate solution comprises the following steps: S4: adding nicotinic acid, N,N-dimethylformamide and dichloromethane into a reaction kettle; S5: Continue to add thionyl chloride to carry out acylation reaction at a temperature of 30-40°C for 2-5 hours, and concentrate to dryness under reduced pressure to obtain nicotinic acid intermediate; S6: Add dichloromethane to the nicotinic acid intermediate state and stir to disperse the mixture to obtain a nicotinic acid intermediate state solution.

7. The method for preparing Nicorandil according to claim 6, characterized in that: The molar ratio of the intermediate, nicotinic acid and thionyl chloride is 1:1-3:1-3, and the feeding ratio of nicotinic acid and N,N-dimethylformamide is 1:0.03-0.

1.

8. The method for preparing Nicorandil according to claim 6, characterized in that: The molar ratio of the intermediate, nicotinic acid and thionyl chloride is 1:1-2:1.5-2, and the feeding ratio of nicotinic acid and N,N-dimethylformamide is 1:0.04-0.

08.

9. The method for preparing Nicorandil according to claim 6, characterized in that: The acylation reaction temperature is 35-40° C. and the reaction time is 4-5 hours.

10. Use of the intermediate according to any one of claims 1 to 9 and a nicotinic acid intermediate solution in the preparation of a nicorandil finished product.

Images