Preparation method of mannityl nicotinate impurity

Abstract

The invention discloses a preparation method of mannityl nicotinate impurities, which comprises the following steps: by taking nicotinic acid as an initial raw material, reacting the nicotinic acid with carbonyl diimidazole to generate pyridine-3-carbonyl-imidazole, esterifying with mannitol, and refining and purifying with a mixed solvent to prepare the mannityl nicotinate impurities. The purity of the mannitol nicotinate prepared by the method is not lower than 99%, and the preparation method is simple to operate, simple in post-treatment and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical impurity preparation, in particular to a preparation method of mannitol nicotinate impurity. BACKGROUND

[0002] Mannitol nicotinate, also known as mannitol nicotinate, has the chemical name of hexapyridine-3-carboxylic acid hexitol ester, the molecular formula of C 42 H 32 N6O 12 , the molecular weight of 812.75, and the structural formula as follows: .

[0003] Mannitol nicotinate is a cardiovascular drug with the effects of dilating blood vessels and lowering blood lipids, and is clinically used for treating coronary heart disease, cerebral thrombosis, atherosclerosis, hypertension and hyperlipidemia. The production process of mannitol nicotinate is to react nicotinic acid with phosphorus oxychloride or thionyl chloride in pyridine, and then react with mannitol to obtain crude mannitol nicotinate, and the crude product is refined by decolorization to obtain fine mannitol nicotinate. In the preparation process of mannitol nicotinate, the esterification reaction of mannitol and nicotinyl chloride is not completely carried out, and the maximum single impurity in the mannitol nicotinate product is mannitol pentanicotinate, which is also the main degradation impurity. The quality standard currently implemented for mannitol nicotinate is WS-10001-(HD-0601)-2002-2017. Compared with the original standard WS-10001-(HD-0601)-2002, the standard adds the detection item of related substances, and changes the content calculation from titration to liquid phase external standard method for control. The detection item of related substances in the current standard specifies that the limit of the only known single impurity mannitol pentanicotinate should not be more than 1.0%, and the structural formula of mannitol pentanicotinate includes three structural isomers as follows: .

[0004] The three structural isomers of mannitol pentanicotinate are overlapped together to form a mixed peak in the range of liquid phase detection.

[0005] Chinese patent document CN103570611A discloses a preparation method of mannitol pentanicotinate, the main impurity of mannitol nicotinate. Whether using esterification method or hydrolysis method, the reaction selectivity is relatively low, and liquid phase preparation column technology is needed for separation and purification. The prepared mannitol pentanicotinate is in small quantity, the preparation period is long, the preparation cost is high, and it cannot meet the needs of mannitol nicotinate related substance and content detection analysis.

[0006] The Chinese patent document CN119569649A discloses a preparation method of mannitol pentanitrate. Mannitol pentanitrate is obtained by hydrolysis of mannitol hexanitrate with an organic base in a mixed solvent of methanol and dichloromethane, and then refined by beating in a mixed solvent of acetone and n-hexane for more than twice. The purity of mannitol pentanitrate is more than 95%, and the preparation yield is more than 60%. The preparation method uses mannitol hexanitrate as a raw material, and the refining process needs more than two beating steps, which not only affects the yield of mannitol pentanitrate, but also cannot further improve the purity of mannitol pentanitrate after multiple beating refinements.

[0007] Therefore, it is necessary to provide a preparation method of mannitol hexanitrate impurities to solve the above problems. SUMMARY

[0008] The present application provides a preparation method of mannitol hexanitrate impurities to at least solve one of the many problems in the prior art.

[0009] In view of this, the scheme of the present application is: The present application provides a preparation method of mannitol hexanitrate impurities, the impurities being mannitol pentanitrate, and the preparation method comprising the following steps: S1. Adding nicotinic acid to a solution system containing carbonyl diimidazole and a first solvent in batches, and after sufficient reaction, the reaction product is treated by dehydration to obtain a pyridine-3-carbonyl-imidazole reaction liquid; S2. Adding mannitol and the pyridine-3-carbonyl-imidazole reaction liquid to a second solvent to perform esterification reaction, and then separating to obtain mannitol pentanitrate crude product; S3. Dissolving and decolorizing the mannitol pentanitrate crude product in a mixed solvent, filtering, concentrating, and drying to obtain mannitol pentanitrate.

[0010] In a preferred embodiment, in step S1, the first solvent is toluene or xylene.

[0011] In a preferred embodiment, the amount ratio of the nicotinic acid to the carbonyl diimidazole and the first solvent is 1g:(1.844-2.108)g:(6-8)ml.

[0012] In a preferred embodiment, in step S1, the process of adding the nicotinic acid in batches is controlled at a temperature of-10-0℃, and the reaction temperature is-10-0℃. Preferably, the reaction time after adding the nicotinic acid is 1h.

[0013] In a preferred embodiment, in step S1, the dehydration treatment process is adding an excess of a dehydrating agent to the reaction product, and then filtering to obtain the pyridine-3-carbonyl-imidazole reaction liquid. More preferably, the dehydrating agent is at least one selected from common inorganic salt dehydrating agents such as anhydrous sodium sulfate and anhydrous magnesium sulfate.

[0014] In the above process, step S1 generates pyridine-3-carbonyl-imidazolium, and the reaction process is as follows: .

[0015] During the preparation of Ganlu Wuxin ester, the applicant discovered that the intermediate product—pyridine-3-carbonyl-imidazole—obtained from the reaction of nicotinic acid with carbonyl diimidazole contained a significant impurity, identified as di-pyridine-3-yl-methyl ketone. This impurity had limited removal capacity in subsequent esterification and purification processes, ultimately affecting the purity of the target product, Ganlu Wuxin ester. Through further optimization, the carbonyl diimidazole was added first during the reaction of nicotinic acid and carbonyl diimidazole, followed by the addition of nicotinic acid in portions. Adjusting the order of material addition significantly improved the purity of the intermediate product, ultimately yielding Ganlu Wuxin ester with an HPLC purity exceeding 99%. The reason for this is that, according to existing technology, adding nicotinic acid to the solvent first, followed by the addition of carbonyl diimidazole in portions, results in a prolonged excess of nicotinic acid in the reaction system. The target product, pyridine-3-carbonyl-imidazole, generated during the reaction further reacts with nicotinic acid, producing the impurity di-pyridine-3-yl-methyl ketone. Poor impurity removal in subsequent steps affects the purity of the final product.

[0016] The reaction process of nicotinic acid with carbonyl diimidazole to produce the impurity di-pyridin-3-yl-methyl ketone is as follows: .

[0017] In a preferred embodiment, in step S2, the second solvent is N,N-dimethylformamide.

[0018] In a preferred embodiment, the ratio of mannitol to the second solvent is 1 g : (2-3) ml.

[0019] In a preferred embodiment, in step S2, the pyridine-3-carbonyl-imidazolium reaction solution is added dropwise over a period of 30 to 45 minutes.

[0020] In a preferred embodiment, in step S2, the esterification reaction process is as follows: first, the temperature is raised to 70-75°C and kept at that temperature for 7-9 hours, and then the temperature is raised to 85-90°C and kept at that temperature for 1.5-2 hours.

[0021] In a preferred embodiment, in step S2, the separation process is as follows: after cooling the reaction solution, water is added, and the mixture is stirred at 20-25°C to allow crystal formation. After filtration, washing with water, and drying, crude mannitol ester is obtained.

[0022] In a preferred embodiment, in step S3, the mixed solvent includes dichloromethane, alcohol and N,N-dimethylformamide, wherein the alcohol is selected from methanol or ethanol; more preferably, the ratio of crude mannitol ester to dichloromethane, alcohol and N,N-dimethylformamide is 1g:(6-7)ml:(2-3)ml:(0.2-0.5)ml.

[0023] Compared with the prior art, the present invention has the following beneficial effects: The preparation method of the present invention uses nicotinic acid as the starting material. Nicotinic acid reacts with carbonyl diimidazole to generate pyridine-3-carbonyl-imidazole, which is then esterified with mannitol and purified by mixed solvent. The purity of the mannitol ester prepared by the method is not less than 99%. The preparation method is simple to operate and the post-processing is simple, making it suitable for industrial production.

[0024] In the preparation method described in this invention, the reaction process of nicotinic acid and carbonyl diimidazole is carried out by first adding carbonyl diimidazole and then adding nicotinic acid in stages, which helps to reduce the formation of impurity di-pyridin-3-yl-methyl ketone. In the esterification step, a mixed solvent system of toluene (xylene) / N,N-dimethylformamide is used for the reaction, which helps to shorten the esterification reaction time. In the purification step, a mixed solvent system of dichloromethane / alcohol / N,N-dimethylformamide is used for recrystallization, which is different from the acid dissolution (hydrochloric acid, sulfuric acid or nitric acid, etc.) and alkaline precipitation (ammonia water, sodium carbonate, etc.) purification of the existing technology. This avoids the situation of excessive inorganic salts due to chlorides, sulfates or nitrates being wrapped in the product, and at the same time, it significantly reduces the generation of wastewater in the purification process. Detailed Implementation

[0025] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0026] Example 1

[0027] 1) Add 92.2g of carbonyl diimidazole and 300ml of toluene to the reaction flask, cool to -10℃, and add 50g of nicotinic acid in four portions, maintaining the temperature between -10℃ and -5℃ during the addition of nicotinic acid. After the addition is complete, maintain the temperature at -10℃ to -5℃ for 1 hour. After the reaction is complete, add 20g of anhydrous sodium sulfate, stir for 1 hour, and filter to obtain a toluene solution of pyridine-3-carbonyl-imidazole.

[0028] 2) Add 14.8 g of mannitol and 30 ml of N,N-dimethylformamide to the reaction flask. Add the toluene solution of pyridine-3-carbonyl-imidazolium prepared above dropwise at 22±2℃, controlling the dropping temperature at 22±2℃ and the dropping time at 45 minutes. After the addition is complete, first raise the temperature to 70℃ and maintain the reaction for 9 hours, then continue to raise the temperature to 85℃ and maintain the reaction for 2 hours. After the reaction is complete, cool to 25℃, add 200 ml of water, stir at 25℃ for 2 hours, filter, wash with water, and dry to obtain 43.5 g of crude mannitol ester.

[0029] 3) Add 43.5g of crude mannopyridine, 265ml of dichloromethane, 130ml of ethanol, and 20ml of N,N-dimethylformamide to the reaction flask. Heat to 42℃ and keep warm for 1 hour. Add 5g of activated carbon for decolorization and continue to keep warm at 42℃ for 1 hour. Filter and concentrate the filtrate at normal pressure until the internal temperature reaches 70℃. Maintain the temperature at 70℃ for 0.5 hours. Cool down to 5℃, filter, and dry to obtain 36.9g of mannopyridine with an HPLC purity of 99.10%.

[0030] Example 2

[0031] 1) Add 105.4 g of carbonyl diimidazole and 400 ml of xylene to the reaction flask, cool to -5°C, and add 50 g of nicotinic acid in three portions, maintaining the temperature between -5°C and 0°C during the addition of nicotinic acid. After the addition is complete, maintain the temperature between -5°C and 0°C for 1 hour. After the reaction is complete, add 20 g of anhydrous sodium sulfate, stir for 1 hour, and filter to obtain a xylene solution of pyridine-3-carbonyl-imidazole.

[0032] 2) Add 14.8 g of mannitol and 44 ml of N,N-dimethylformamide to the reaction flask. Add the xylene solution of pyridine-3-carbonyl-imidazolium prepared above dropwise at 23±2℃, controlling the dropping temperature at 23±2℃ and the dropping time at 35 minutes. After the addition is complete, first raise the temperature to 75℃ and maintain the reaction for 7 hours, then continue to raise the temperature to 90℃ and maintain the reaction for 1.5 hours. After the reaction is complete, cool to 25℃, add 200 ml of water, stir at 20℃ for 2 hours, filter, wash with water, and dry to obtain 41.9 g of crude mannitol.

[0033] 3) Add 41.9g of crude mannopyridine, 290ml of dichloromethane, 85ml of methanol, and 9ml of N,N-dimethylformamide to the reaction flask. Heat to 40℃ and keep warm for 1 hour. Add 5g of activated carbon for decolorization and continue to keep warm at 40℃ for 1 hour. Filter and concentrate the filtrate at normal pressure until the internal temperature reaches 62℃. Keep warm at 65℃ for 0.5 hours. Cool down to 8℃, filter, and dry to obtain 32.7g of mannopyridine with an HPLC purity of 99.17%.

[0034] Example 3

[0035] 1) Add 98.8g of carbonyl diimidazole and 350ml of toluene to the reaction flask, cool to -8℃, and add 50g of nicotinic acid in three portions, maintaining the temperature between -8℃ and -3℃ during the addition of nicotinic acid. After the addition is complete, maintain the temperature at -8℃ to -3℃ for 1 hour. After the reaction is complete, add 20g of anhydrous sodium sulfate, stir for 1 hour, and filter to obtain a toluene solution of pyridine-3-carbonyl-imidazole.

[0036] 2) Add 14.8 g of mannitol and 40 ml of N,N-dimethylformamide to the reaction flask. Add the toluene solution of pyridine-3-carbonyl-imidazolium prepared above dropwise at 23±2℃, controlling the dropping temperature at 23±2℃ and the dropping time at 30 minutes. After the addition is complete, first raise the temperature to 72℃ and maintain the reaction for 8 hours, then continue to raise the temperature to 88℃ and maintain the reaction for 2 hours. After the reaction is complete, cool to 25℃, add 200 ml of water, stir at 22℃ for 2 hours, filter, wash with water, and dry to obtain 44.5 g of crude mannitol ester.

[0037] 3) Add 44.5g of crude mannopyridine, 310ml of dichloromethane, 120ml of methanol, and 16ml of N,N-dimethylformamide to the reaction flask. Heat to 38-42℃ and keep warm for 1 hour. Add 5g of activated carbon for decolorization and continue to keep warm at 38℃ for 1 hour. Filter and concentrate the filtrate at normal pressure until the internal temperature reaches 62℃. Maintain the temperature at 62℃ for 0.5 hours. Cool down to 10℃, filter, and dry to obtain 36.9g of mannopyridine with an HPLC purity of 99.22%.

[0038] Comparative Example 1

[0039] The preparation method is the same as in Example 1, except that in step 1), nicotinic acid is added to the reaction flask all at once, and the reaction conditions and other steps are the same. The final product has an HPLC purity of 93.08%.

[0040] Comparative Example 2

[0041] The preparation method is the same as in Example 1, except that in step 1), nicotinic acid and toluene are added to the reaction flask first, followed by carbonyl diimidazole. The reaction conditions and other steps are the same. The final product has an HPLC purity of 91.53%.

[0042] Comparative Example 3

[0043] The preparation method is the same as in Example 1, except that in step 3), the crude benzoyl peroxide was purified and recrystallized using a mixed solvent that did not contain N,N-dimethylformamide. All other steps were the same. Before adding activated carbon for decolorization, the product was not completely dissolved. After drying, 27.6 g of the final product was obtained, with an HPLC purity of 98.92%.

[0044] It is evident from the above examples that the preparation method proposed in this invention can obtain manno-5-nicotine ester with a purity of over 99%, meeting the purity requirements for quality control of manno-6-nicotine ester. In Comparative Example 1, the simultaneous addition of nicotinic acid, and in Comparative Example 2, the initial addition, both resulted in a decrease in product purity. The main reason for this is likely the formation of di-pyridin-3-yl-methyl ketone impurities. In Comparative Example 3, the absence of the co-solvent N,N-dimethylformamide hindered product dissolution, leading to a decrease in the yield of the purified product.

[0045] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a mannohexanediol impurity, wherein the impurity is mannopentanediol, characterized in that, The preparation method includes the following steps: S1. Nicotinic acid is added in batches to a solution system containing carbonyl diimidazole and the first solvent. After the reaction is complete, the reaction product is dehydrated to obtain pyridine-3-carbonyl-imidazole reaction solution. S2. Add mannitol and pyridine-3-carbonyl-imidazolium reaction solution to the second solvent to carry out esterification reaction, and obtain crude mannitol ester by separation; S3 involves dissolving and decolorizing crude mannitol ester in a mixed solvent, filtering, concentrating, and drying to obtain mannitol ester.

2. The preparation method according to claim 1, characterized in that, In step S1, the first solvent is toluene or xylene; And / or, the ratio of the amount of nicotinic acid to carbonyl diimidazole and the first solvent is: 1g: (1.844~2.108)g: (6~8)ml.

3. The preparation method according to claim 1, characterized in that, In step S1, nicotinic acid is added in batches during the reaction process, and the reaction temperature is -10 to 0°C.

4. The preparation method according to claim 1, characterized in that, In step S1, the dehydration process involves adding an excess of dehydrating agent to the reaction product and then filtering to obtain a pyridine-3-carbonyl-imidazolium reaction solution.

5. The preparation method according to claim 1, characterized in that, In step S2, the second solvent is N,N-dimethylformamide; And / or, the ratio of mannitol to the second solvent is 1 g : (2-3) ml.

6. The preparation method according to claim 1, characterized in that, In step S2, the pyridine-3-carbonyl-imidazolium reaction solution is added dropwise over a period of 30 to 45 minutes.

7. The preparation method according to claim 1, characterized in that, In step S2, the esterification reaction process is as follows: first, the temperature is raised to 70-75°C and kept at that temperature for 7-9 hours, and then the temperature is raised to 85-90°C and kept at that temperature for 1.5-2 hours.

8. The preparation method according to claim 1, characterized in that, In step S2, the separation process is as follows: after cooling the reaction solution, water is added, and the mixture is stirred at 20-25°C to allow crystal formation. After filtration, washing with water, and drying, crude mannitol ester is obtained.

9. The preparation method according to claim 1, characterized in that, In step S3, the mixed solvent includes dichloromethane, alcohol and N,N-dimethylformamide, wherein the alcohol is selected from methanol or ethanol.

10. The preparation method according to claim 9, characterized in that, The ratio of crude ganlufenoxate to dichloromethane, alcohol, and N,N-dimethylformamide is 1g:(6-7)ml:(2-3)ml:(0.2-0.5)ml.