Preparation method of high-purity mannityl pentanicotinate

Abstract

The invention discloses a preparation method of high-purity mannitin-5-nicotinate, which comprises the following steps: mixing mannitin-6-nicotinate with a first solvent, heating and stirring until the mixture is fully dispersed, then adding organic alkali, and carrying out heat preservation reflux reaction at 40-45 DEG C for 3-4 hours to obtain a primary mixed solution; adding an acid into the primary mixed solution to adjust the pH value to 5-6, then stopping adding the acid, raising the temperature to 65-70 DEG C, carrying out atmospheric distillation treatment, and after full distillation, cooling and washing to obtain a mannityl pentanicotinate crude product; and mixing the mannityl pentanicotinate crude product with a second solvent, and sequentially carrying out pulping refining, cooling crystallization and solid-liquid separation to obtain the high-purity mannityl pentanicotinate. According to the method, mannitol hexanicotinate is used as a raw material, the mannitol hexanicotinate and the organic base are hydrolyzed in the mixed solvent of methyl alcohol and methyl chloride to obtain the mannitol pentanicotinate crude product, the reaction selectivity is high, few by-products are produced, the purity is high, the yield is high, the method can be effectively used for mannitol hexanicotinate quality control, and the accuracy of the detection method is improved.

Description

Technical Field

[0001] The invention relates to the field of quality control of raw materials, and in particular to a method for preparing high-purity mannocin. Background Art

[0002] Mannitol nicotinate, also known as mannitol nicotinate, chemical name: hexapyridine-3-carboxylic acid hexadecene, molecular formula: C 42 H 32 N6O 12 , molecular weight: 812.75.

[0003] In the vast field of drug research and development and production, precise control of impurities has always been the core point to ensure drug quality and safety. Mannohexanic acid ester is a widely used drug ingredient, mainly used for the treatment of coronary heart disease, cerebral thrombosis, atherosclerosis, hyperlipidemia, hypertension, etc. Its quality is directly related to the treatment effect and health and safety of patients. As an important impurity of mannohexanic acid ester, it is of great significance to conduct in-depth research and effective preparation of it. Its structural formula is as follows (three isomers):

[0004] Formula I, Formula II, and Formula III are three isomers of mannose pentaerythritol, and the peaks overlap to form mixed peaks within the range of liquid phase detection. The following takes Formula I as an example, and the preparation and detection methods of Formula II and Formula III are the same as those of Formula I.

[0005] The impurity components of ganluhexanicotinate and ganlupentannicotinate significantly increase during storage and production, among which ganlupentannicotinate has the highest content, followed by ganludinicotinate and ganlumononicotinate. There are relatively few existing documents on the preparation methods of high-purity ganlupentannicotinate, and some existing methods often have many shortcomings. On the one hand, the preparation methods disclosed in some patents are cumbersome and complicated to operate, requiring the use of expensive equipment and special reaction conditions. This not only increases the production cost, but also puts higher requirements on the production environment and operators. For example, the esterification and hydrolysis methods involved in patent CN103570611B prepare mannopentinic acid ester, control the molar ratio of mannitol and chlorinated nicotinic acid, and make mannitol and chlorinated nicotinic acid undergo hydrolysis reaction through mannohexanic acid ester and inorganic base to generate mannopentinic acid ester; due to the low reaction selectivity, while actually generating the target product, there will also be a variety of derivatives such as mannotetranic acid ester and mannotrinic acid ester generated. In order to obtain the target product with higher purity, the patent adopts the method of collecting the corresponding components with a preparative liquid chromatography column and then concentrating and crystallizing to obtain mannopentinic acid ester with higher purity. The preparation of mannopentinic acid ester by this process is not only complicated and time-consuming, but also has high requirements on personnel, and the generated by-products affect the yield. Therefore, it is necessary to propose a new synthesis process of mannopentinic acid ester. Summary of the invention

[0006] The present invention aims to provide a method for preparing high-purity ganlufenic acid ester, which is used to solve the problem that there are many by-products in the existing ganlufenic acid ester preparation process.

[0007] In order to achieve the above technical purpose, the technical solution provided by the present invention is as follows: The present invention provides a method for preparing high-purity mannose pentaerythritol, comprising the following steps: (1) Mixing the mannolic acid ester with the first solvent, heating and stirring until fully dispersed, then adding an organic base, and refluxing at 40-45° C. for 3-4 hours to obtain a primary mixed solution; (2) Acid is added to the primary mixed solution to adjust the pH to 5-6, then the acid addition is stopped and the temperature is raised to 65-70°C for atmospheric distillation. After sufficient distillation, the temperature is lowered and washed with water to obtain a crude product of ganlu pentose ester; (3) mixing the crude ganlufenic acid ester with the second solvent, and sequentially performing pulping, crystallization by cooling, and solid-liquid separation to obtain high-purity ganlufenic acid ester; The first solvent is a mixed solvent of methanol and dichloromethane, and the second solvent is a mixed solvent of acetone and n-hexane.

[0008] The reaction principle of the preparation process of high-purity mannose pentachlorophenol ester in the present invention is as follows:

[0009] In the preparation method, mannose hexanic acid ester is used as a raw material, and under the action of an organic base in a quantitative molar ratio, mannose pentanic acid ester is hydrolyzed to obtain mannose pentanic acid ester, with high reaction selectivity and few by-products. The selective hydrolysis is carried out by utilizing the nucleophilicity generated by the lone pair electrons in the structure of the organic base, thereby avoiding the disadvantage that the inorganic base has a high alkalinity and strong reaction activity, resulting in hydrolysis at multiple sites and increasing side reactions, and effectively solving the problem that there are many by-products in the existing mannose pentanic acid ester preparation process, thereby affecting the yield.

[0010] In some embodiments, in step (1), the ratio of mannose hexanic acid ester, methanol, and dichloromethane is 3 g: (15-18) mL: (50-60) mL.

[0011] In some embodiments, in step (1), the organic base is at least one of pyridine, isoamyl alcohol, DMF, DMSO, aqueous ammonia, and triethylamine, and the molar ratio of mannohexanic acid ester to the organic base is 1:(1.9-2.2).

[0012] In some more specific embodiments, in step (1), the organic base is triethylamine, and the molar ratio of mannoxacorbyl ester to triethylamine is 1:(1.9-2.2).

[0013] In some embodiments, in step (2), the acid is at least one of phosphoric acid, acetic acid, citric acid, and p-toluenesulfonic acid.

[0014] In some embodiments, in step (2), after the acid addition is terminated, the temperature is raised to 65-70°C and atmospheric distillation is performed until no liquid drops fall, then the temperature is lowered to 5-10°C and stirred for 3 hours to crystallize, and the mixture is filtered and washed with water to obtain a crude product of ganlu pentose ester.

[0015] In some embodiments, in step (3), the ratio of crude mannose pentanoate, acetone, and n-hexane is 1 g: (8-10) mL: (2-2.5) mL.

[0016] In some embodiments, in step (3), the specific process conditions for pulping and refining are: pulping and refining at 55-60°C for 1 hour.

[0017] In some embodiments, in step (3), after the pulping and refining is completed, the temperature is lowered to 5-10°C and stirred for 2 hours to crystallize, and after suction filtration, high-purity mannoxacor is obtained.

[0018] In some embodiments, step (3) is further repeated 2 to 3 times to obtain high-purity mannose pentaerythritol. The number of repetitions of the pulping refining-cooling crystallization-solid-liquid separation process in step (3) can be selected according to actual needs, and the specific number is not limited here.

[0019] Compared with the prior art, the beneficial effects of the present invention include: (1) The present invention selects a specific proportion of organic base to hydrolyze mannose hexanic acid ester to obtain the target product mannose pentanic acid ester. The reaction has strong selectivity and few by-products. The organic base is selectively hydrolyzed by the nucleophilicity generated by the lone pair of electrons in its structure, thereby avoiding the disadvantage that the inorganic base has a high alkalinity and strong reaction activity, which leads to hydrolysis at multiple sites and increases the side reactions. The single-site hydrolysis reaction of mannose hexanic acid ester is achieved to synthesize the target product mannose pentanic acid ester.

[0020] (2) The present invention uses a mixed solvent of acetone and n-hexane in a specific ratio to purify the synthesized mannoxacin crude product. The solvents are all commonly used solvents, with low solvent loss, simple process, short cycle, good refining effect, and the prepared mannoxacin has high purity. The average purity can reach more than 95% after testing, and the yield can reach more than 60%.

[0021] In summary, the present invention proposes a method for preparing mannitol penta-nicotinamide, an important impurity of mannitol hexa-nicotinamide. Mannitol hexa-nicotinamide raw material is selected and hydrolyzed with an organic base in a mixed solvent of methanol and methyl chloride to obtain a crude mannitol penta-nicotinamide product. The reaction has high selectivity, few by-products and high yield. The crude product is pulped and refined twice with a mixed solvent of acetone and n-hexane in a specific ratio to obtain a fine mannitol penta-nicotinamide product. The refining method is simple and effective. The prepared mannitol penta-nicotinamide has high purity and high yield, and can be effectively used for mannitol hexa-nicotinamide quality control to improve the accuracy of the detection method. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the technical solution of the present application, the following is a brief introduction to the drawings used in the present application. Obviously, the drawings described below are only some embodiments of the present application, and for ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0023] Figure 1 This is a liquid phase diagram of the finished product of Manlu Penta-nicotinate prepared in Example 1 of the present invention; Figure 2 This is a liquid phase diagram of the reaction solution 1 obtained after hydrolysis using an inorganic base in Comparative Example 1 of the present invention; Figure 3 This is a liquid phase diagram of the reflux reaction product after reducing the organic base ratio in Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiment.It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.The present invention is further described in detail below through specific embodiments.

[0025] 1. Preparation method Example 1 The preparation steps of high-purity mannose pentachlorophenol in this embodiment 1 are as follows: (1) Take 30 g of mannose hexanic acid ester and dissolve it in a mixed solvent of 150 mL of methanol and 500 mL of dichloromethane, stir and heat until the solution becomes clear, add 9.5 mL of triethylamine, and keep the temperature at 42°C for 3.5 hours.

[0026] (2) After the reaction, acetic acid was added dropwise to adjust the pH to 5.5, and the temperature was gradually raised to 65° C. and distilled under normal pressure until almost no dripping occurred. The system was cooled to 8° C. and stirred for 3 h to crystallize. After suction filtration and washing with water, 24.75 g of crude ganlu pentanoate was obtained.

[0027] (3) The obtained crude ganlu pentanoic acid ester was added to a mixed solvent of 230 mL of acetone and 57.5 mL of n-hexane, and the mixture was slurried and refined at 58° C. for 1 h, cooled to 8° C., kept stirred for 2 h, and then filtered; this step was repeated twice to obtain 18.29 g of ganlu pentanoic acid ester.

[0028] Example 2 The preparation steps of high-purity mannose pentachlorophenol in this embodiment 2 are as follows: (1) Take 30 g of mannose hexanic acid ester and dissolve it in a mixed solvent of 150 mL of methanol and 500 mL of dichloromethane, stir and heat until the solution becomes clear, add 10.5 mL of triethylamine, and keep the temperature at 42°C for 4 hours.

[0029] (2) After the reaction, acetic acid was added dropwise to adjust the pH to 5.5, and the temperature was gradually raised to 68°C for atmospheric distillation until almost no dripping occurred. The system was cooled to 8°C and stirred for 3 h to wait for crystallization. After suction filtration and washing with water, 25.22 g of crude ganlu pentanoate was obtained.

[0030] (3) The obtained crude ganlu pentanoic acid ester was added to a mixed solvent of 230 mL of acetone and 60 mL of n-hexane, and the mixture was slurried and refined at 55° C. for 1 h, cooled to 8° C., kept stirred for 2 h, and then filtered; this step was repeated twice to obtain 19.02 g of ganlu pentanoic acid ester.

[0031] Example 3 The preparation steps of high-purity mannose pentachlorophenol in this embodiment 3 are as follows: (1) Take 30 g of mannose hexanic acid ester and dissolve it in a mixed solvent of 150 mL of methanol and 500 mL of dichloromethane, stir and heat until the solution becomes clear, add 6 ml of pyridine, and reflux at 45°C for 5 h.

[0032] (2) After the reaction, acetic acid was added dropwise to adjust the pH to 5.5, and the temperature was gradually raised to 70°C for atmospheric distillation until almost no dripping occurred. The system was cooled to 8°C and stirred for 3 h to wait for crystallization. After suction filtration and washing with water, 25.22 g of crude mannose pentaerythritol was obtained.

[0033] (3) The obtained crude ganlu pentanoic acid ester was added to a mixed solvent of 240 mL of acetone and 60 mL of n-hexane, and the mixture was beaten and refined at 55° C. for 1 h, cooled to 8° C., kept stirred for 2 h, and then filtered; this step was repeated twice to obtain 18.32 g of ganlu pentanoic acid ester.

[0034] Comparative Example 1 The preparation steps of this comparative example 1 are as follows: (1) Take 10 g of mannohexanic acid ester and dissolve it in 50 mL of 1.0 mol / L sodium hydroxide solution. Keep the temperature at 25-35°C for 1.5 h.

[0035] (2) After reacting for 1.5 h, 1.0 mol / L hydrochloric acid was added dropwise to adjust the mixture to neutrality to obtain reaction solution 1.

[0036] Comparative Example 2 The preparation steps of this comparative example 2 are as follows: Take 10 g of mannolic acid hexanic acid ester, add excess 0.3 mol / L hydrochloric acid to dissolve, adjust the pH to 2.0 with 5% sodium hydroxide, heat to 50°C and stir to react for 48 hours to obtain reaction solution 2.

[0037] Comparative Example 3 The preparation steps of this comparative example 3 are as follows: (1) Take 30 g of mannose hexanic acid ester and dissolve it in a mixed solvent of 150 mL of methanol and 500 mL of dichloromethane. Stir and heat until the solution becomes clear. Add triethylamine and mannose hexanic acid ester 8 ml (the molar ratio of triethylamine to mannose hexanic acid ester is about 1.35:1). Keep the temperature at 45°C and reflux for 5 hours.

[0038] (2) After the reaction, acetic acid was added dropwise to adjust the pH to 5.5, and the temperature was gradually raised to 65°C for atmospheric distillation until almost no dripping occurred. The system was cooled to 8°C and stirred for 3 h to wait for crystallization. After suction filtration and washing with water, 26.35 g of a crude solid product was obtained.

[0039] (3) The obtained crude mannocin ester was added to a mixed solvent of 240 mL of acetone and 60 mL of n-hexane, and the mixture was slurried and refined at 55°C for 1 hour, cooled to 8°C, kept stirred for 2 hours, and then filtered; this step was repeated twice to obtain a solid product 3:19.64 g.

[0040] Comparative Example 4 The preparation steps of this comparative example 4 are as follows: (1) Take 30g of mannose hexanic acid ester and dissolve it in a mixed solvent of 150mL methanol and 500mL dichloromethane, stir and heat until the solution is clear, add triethylamine and mannose hexanic acid ester 13ml (the molar ratio of triethylamine to mannose hexanic acid ester is about 2.5:1), and keep the temperature at 45℃ for 5h.

[0041] (2) After the reaction, acetic acid was added dropwise to adjust the pH to 5.5, and the temperature was gradually raised to 65°C for atmospheric distillation until almost no dripping occurred. The system was cooled to 8°C and stirred for 3 h to wait for crystallization. After suction filtration and washing with water, 26.35 g of a crude solid product was obtained.

[0042] (3) The obtained crude product of mannose pentaerythritol was added to a mixed solvent of 240 mL of acetone and 60 mL of n-hexane, and the mixture was slurried and refined at 55°C for 1 h, cooled to 8°C, kept stirred for 2 h, and then filtered; this step was repeated twice to obtain a solid product 4:17.62 g.

[0043] 2. Test Method High performance liquid chromatography (HPLC) was used to test the chemical components and purity of the ganlu pentanoic acid ester prepared in Examples 1 to 3 and the reaction products 1 to 3 prepared in Comparative Examples 1 to 3, and the corresponding yields were calculated.

[0044] 3. Test Analysis Table 1

[0045] A) As shown in Table 1, the purity of the ganlufenacic acid ester prepared in Examples 1 to 3 can reach more than 95%, and the mass yield can reach more than 60%, which proves that the above-mentioned preparation method of the present invention can obtain a high-purity and high-yield ganlufenacic acid ester product.

[0046] B) The reaction solution 1 prepared in Comparative Example 1 was subjected to liquid phase detection, and a variety of substances were generated in the reaction solution 1, including mannohexanicotinate, mannopentanicotinate, mannotetranicotinate, mannotrinicotinate, mannodinicotinate, mannohexanicotinate, nicotinic acid, and mannitol that cannot be detected under ultraviolet light. Since sodium hydroxide has a strong alkalinity, mannohexanicotinate is easily hydrolyzed in its aqueous solution, and it will be completely hydrolyzed into mannitol and nicotinic acid after controlling the reaction temperature to be higher or prolonging the reaction time, which proves that the use of inorganic bases to prepare mannopentanicotinate will obtain a large amount of by-products, which is not conducive to improving the purity and yield of the product.

[0047] C) Liquid phase detection was performed on the reaction solution 2 prepared in Comparative Example 2. A variety of substances were generated in the reaction solution 2, including mannose hexanicotinate, mannose pentanicotinate, mannose tetranicotinate, mannose trinicotinate, mannose dinicotinate, mannose ethylnicotinate, nicotinic acid, and mannitol that could not be detected under ultraviolet light. The maximum peak area in the HPLC spectrum was about 19%, which was mannose pentanicotinate. This proved that the simple extraction method could not purify it, and the separation and purification by the preparation column required high equipment and personnel, and took a long time.

[0048] D) The solid product 3 prepared in Comparative Example 3 was subjected to liquid phase detection, and the purity of the prepared product, mannose penta-nicotinic acid ester, was only 76.38%, and the impurities mainly contained more than 20% of the converted mannose hexa-nicotinic acid ester. This proves that a low ratio of organic base can easily lead to the inability to completely convert mannose hexa-nicotinic acid ester.

[0049] E) The solid product 4 prepared in Comparative Example 4 was subjected to liquid phase detection, and the purity of the prepared product, ganlufenic acid ester, was only 82.61%, and the impurities mainly contained ganlufenic acid ester, ganlufenic acid ester, ganlufenic acid ester and other substances such as ganlufenic acid ester hydrolysis byproducts. This proves that a high ratio of organic base can easily lead to excessive hydrolysis of part of ganlufenic acid ester to produce a small amount of other hydrolysis products.

[0050] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing high-purity mannose pentaerythritol ester, characterized in that: The following steps are involved: (1) Mixing the mannolic acid ester with the first solvent, heating and stirring until fully dispersed, then adding an organic base, and refluxing at 40-45° C. for 3-4 hours to obtain a primary mixed solution; (2) adding acid to the primary mixed solution to adjust the pH to 5-6, then stopping the addition of acid and heating the solution to 65-70° C., performing atmospheric distillation, and after sufficient distillation, cooling the solution and washing with water to obtain a crude product of ganlu pentylene glycol ester; (3) mixing the crude ganlufenic acid ester with a second solvent, and sequentially performing pulping, crystallization by cooling, and solid-liquid separation to obtain high-purity ganlufenic acid ester; The first solvent is a mixed solvent of methanol and dichloromethane, and the second solvent is a mixed solvent of acetone and n-hexane.

2. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: In the step (1), the ratio of mannose hexanic acid ester, methanol and dichloromethane is 3 g: (15-18) mL: (50-60) mL.

3. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: In the step (1), the organic base is at least one of pyridine, isoamyl alcohol, DMF, DMSO, aqueous ammonia, and triethylamine, and the molar ratio of the mannohexanic acid ester to the organic base is 1:(1.9-2.2).

4. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 3, characterized in that: In the step (1), the organic base is triethylamine, and the molar ratio of the mannoxacorbyl ester to triethylamine is 1:(1.9-2.2).

5. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: In the step (2), the acid is at least one of phosphoric acid, acetic acid, citric acid, and p-toluenesulfonic acid.

6. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: In the step (2), after the acid addition is terminated, the temperature is raised to 65-70°C, and atmospheric distillation is performed until no liquid drops fall. The temperature is then lowered to 5-10°C and stirred for 3 hours to crystallize. The mixture is filtered and washed with water to obtain a crude product of ganlu pentose ester.

7. The method for preparing high-purity mannose pentaerythritol ester according to claim 1, characterized in that: In the step (3), the ratio of the crude mannoxacorbyl ester, acetone and n-hexane is 1 g: (8-10) mL: (2-2.5) mL.

8. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: In the step (3), the specific process conditions of the pulping and refining are: pulping and refining at 55-60°C for 1 hour.

9. The method for preparing high-purity mannose pentachlorophenol according to claim 1, characterized in that: In the step (3), after the beating and refining is completed, the temperature is lowered to 5-10°C and stirred for 2 hours to crystallize, and high-purity mannoxacor is obtained after suction filtration.

10. The method for preparing high-purity mannose pentafluoroacetic acid ester according to claim 1, characterized in that: The method further comprises repeating step (3) 2 to 3 times to obtain high-purity mannose pentaerythritol ester.

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