Preparation method of high-purity pentamannosyl nicotine

Abstract

The application discloses a preparation method of high-purity mannitol pentanitrate, which comprises the following steps: mixing mannitol hexanitrate with a first solvent, stirring and heating until fully dispersed, adding an organic base, and performing heat preservation and reflux reaction at 40-45 DEG C for 3-4 h to obtain a primary mixed solution; adding acid in the primary mixed solution to adjust the pH to 5-6, then stopping adding the acid, heating to 65-70 DEG C, and performing normal-pressure distillation treatment; after sufficient distillation, cooling and water washing, a mannitol pentanitrate crude product is obtained; the mannitol pentanitrate crude product is mixed with a second solvent, and is sequentially subjected to beating refining, cooling and crystallization, and solid-liquid separation to obtain the high-purity mannitol pentanitrate. The mannitol hexanitrate raw material is hydrolyzed with an organic base in a mixed solvent of methanol and chloromethane to obtain the mannitol pentanitrate crude product, the reaction selectivity is high, the by-products are few, the purity is high, and the yield is high, so that the mannitol hexanitrate quality control can be effectively realized, and the accuracy of a detection method is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of quality control of raw drugs, in particular to a preparation method of high-purity mannitol pentanicotinate. 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 , and the molecular weight of 812.75.

[0003] In the vast field of drug research and production, accurate control of impurities is always the core point to ensure the quality and safety of drugs. Mannitol nicotinate, as a widely used drug ingredient, is mainly used for the treatment of coronary heart disease, cerebral thrombosis, atherosclerosis, hyperlipidemia, hypertension, etc. The quality of mannitol nicotinate is directly related to the treatment effect and health safety of patients. Mannitol pentanicotinate, as an important impurity of mannitol nicotinate, has important significance for its in-depth research and effective preparation. Its structural formula is as follows (three isomers):

[0004]

[0005] Formula I, formula II and formula III are three isomers of mannitol pentanicotinate. The peaks overlap together to form a mixed peak in the range of liquid phase detection. The following is an example of formula I. The preparation method and detection method of formula II and formula III are the same as those of formula I.

[0006] The content of mannopenta nicotine increases obviously during storage and production of mannose hexanicotinate, and the content of mannopenta nicotine is the highest, followed by mannodi nicotine and mannomononicotinate. There are relatively few methods for preparing high-purity mannopenta nicotine in the existing literature, and some of the existing methods have many shortcomings. On the one hand, the preparation methods disclosed in some patents are complicated and need to use expensive equipment and special reaction conditions. This not only increases the production cost, but also puts forward higher requirements for the production environment and the operating personnel. For example, the esterification method and hydrolysis method for preparing mannopenta nicotine in patent CN103570611B control the molar ratio of mannitol and chloroesterified nicotinic acid, so that mannitol and chloroesterified nicotinic acid are subjected to hydrolysis reaction with inorganic alkali through mannose hexanicotinate to generate mannopenta nicotine. Since the selectivity of the reaction is low, various derivatives such as mannopenta nicotine, mannodi nicotine and mannomononicotinate are generated at the same time. In order to obtain high-purity target product, the patent adopts the method of collecting corresponding components by preparing liquid chromatography column and then concentrating and crystallizing to obtain high-purity mannopenta nicotine. The preparation of mannopenta nicotine by using this process is not only time-consuming and complicated, but also requires high personnel requirements, and the generated by-products affect the yield. Therefore, it is necessary to propose a new synthesis process of mannopenta nicotine. SUMMARY

[0007] The present application aims to provide a preparation method of high-purity mannopenta nicotine, which is used to solve the problem of too many by-products in the existing preparation process of mannopenta nicotine.

[0008] In order to achieve the above technical purposes, the technical solutions provided by the present application are as follows:

[0009] The present application provides a preparation method of high-purity mannopenta nicotine, comprising the following steps:

[0010] (1) mixing mannose hexanicotinate with a first solvent, heating and stirring to fully disperse, then adding an organic base, and reacting at 40-45 DEG C under heat preservation reflux for 3-4 h to obtain a primary mixed solution;

[0011] (2) adding acid to the primary mixed solution to adjust the pH to 5-6, then stopping adding acid and heating to 65-70 DEG C, and performing normal pressure distillation treatment, and then obtaining mannopenta nicotine crude product through cooling and water washing after sufficient distillation;

[0012] (3) mixing the mannopenta nicotine crude product with a second solvent, and then performing beating refining, cooling and crystallization, and solid-liquid separation in sequence to obtain high-purity mannopenta nicotine;

[0013] The first solvent is a mixed solvent of methanol and dichloromethane, and the second solvent is a mixed solvent of acetone and n-hexane.

[0014] The reaction principle of the preparation process of high-purity mannopenta nicotine in the present application is as follows:

[0015]

[0016] In the preparation method, mannitol hexanitrate is used as a raw material, and mannitol pentanitrate is obtained by hydrolysis under the action of an organic base in a quantitative molar ratio. The reaction selectivity is high, and the by-products are few. The nucleophilicity of the lone pair of electrons in the structure of the organic base is used for selective hydrolysis, which avoids the disadvantages of inorganic bases, such as strong alkalinity and strong reactivity, which leads to the hydrolysis of multiple sites and the increase of side reactions. The problem of the existing preparation process of mannitol pentanitrate, that is, the high yield is affected by many by-products, is effectively solved.

[0017] In some embodiments, in step (1), the ratio of mannitol hexanitrate, methanol, and dichloromethane is 3 g: (15-18) mL: (50-60) mL.

[0018] In some embodiments, in step (1), the organic base is at least one of pyridine, isoamyl alcohol, DMF, DMSO, ammonia water, and triethylamine, and the molar ratio of mannitol hexanitrate to the organic base is 1: (1.9-2.2).

[0019] In some more specific embodiments, in step (1), the organic base is triethylamine, and the molar ratio of mannitol hexanitrate to triethylamine is 1: (1.9-2.2).

[0020] In some embodiments, in step (2), the acid is at least one of phosphoric acid, acetic acid, citric acid, and p-toluenesulfonic acid.

[0021] In some embodiments, in step (2), after the acid is added, the temperature is raised to 65-70℃, and normal pressure distillation treatment is performed until no liquid drops are dropped, then the temperature is lowered to 5-10℃ and stirred for 3h to crystallize, and after suction filtration, water washing is performed to obtain the crude mannitol pentanitrate.

[0022] In some embodiments, in step (3), the ratio of the crude mannitol pentanitrate, acetone, and n-hexane is 1 g: (8-10) mL: (2-2.5) mL.

[0023] In some embodiments, in step (3), the specific process conditions for beating and refining are as follows: beating and refining at 55-60℃ for 1h.

[0024] In some embodiments, in step (3), after beating and refining is completed, the temperature is lowered to 5-10℃ and stirred for 2h to crystallize, and after suction filtration, high-purity mannitol pentanitrate is obtained.

[0025] In some embodiments, step (3) is repeated 2-3 times to obtain high-purity mannitol pentanitrate. The number of times of repeating the beating and refining-temperature lowering-crystallization-solid-liquid separation process in step (3) can be selected according to actual needs, and the specific number is not limited herein.

[0026] Compared with the prior art, the beneficial effects of the present application include:

[0027] (1) The present application selects a specific proportion of organic base to hydrolyze mannitol hexanitrate to obtain the target product mannitol pentanitrate. The reaction has high selectivity and less by-products. The nucleophilicity of the lone pair of electrons in the structure of the organic base is used for selective hydrolysis, which avoids the disadvantages of inorganic bases, such as strong alkalinity and strong reactivity, which leads to the increase of side reactions caused by hydrolysis at multiple sites. The present application realizes the single-point hydrolysis reaction of mannitol hexanitrate and synthesizes the target product mannitol pentanitrate.

[0028] (2) The present application uses a mixture of acetone and n-hexane in a specific ratio as a solvent to refine the synthesized mannitol pentanitrate crude product. The solvents are commonly used solvents, the solvent loss is small, the process is simple, the cycle is short, the refining effect is good, the prepared mannitol pentanitrate has high purity, and the average purity can reach more than 95%, and the yield can reach more than 60%.

[0029] In summary, the present application provides a preparation method of mannitol pentanitrate, an important impurity of mannitol hexanitrate. The method uses mannitol hexanitrate as raw material, hydrolyzes it with an organic base in a mixed solvent of methanol and chloromethane to obtain mannitol pentanitrate crude product. The reaction has high selectivity, less by-products, and high yield. The crude product is refined twice by beating with a mixture of acetone and n-hexane in a specific ratio to obtain mannitol pentanitrate. The refining method is simple and effective, the prepared mannitol pentanitrate has high purity and high yield, and can be effectively used for quality control of mannitol hexanitrate, and improve the accuracy of the detection method. BRIEF DESCRIPTION OF DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the present application, the following will briefly introduce the drawings used in the present application. Obviously, the drawings described below are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creating laborious work.

[0031] Figure 1 The liquid chromatogram of the mannitol pentanitrate product prepared in Example 1 of the present application;

[0032] Figure 2 The liquid chromatogram of the reaction liquid 1 obtained by hydrolysis with inorganic base in Comparative Example 1 of the present application;

[0033] Figure 3 The liquid chromatogram of the reaction product obtained by refluxing after reducing the proportion of organic base in Comparative Example 3 of the present application. DETAILED DESCRIPTION

[0034] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not to limit the present application. The present application will be further described in detail below through specific embodiments.

[0035] I. Preparation method

[0036] Example 1

[0037] The preparation steps of high-purity mannopentaenamide in this example 1 are as follows:

[0038] (1) Take mannohexaenamide 30 g, dissolve in 150 mL of a mixed solvent of methanol and 500 mL of dichloromethane, stir and heat to dissolve, add triethylamine 9.5 mL. Keep the system at 42°C and reflux for 3.5 h.

[0039] (2) After the reaction is completed, add acetic acid dropwise to adjust the pH to 5.5, gradually heat to 65°C and distill under normal pressure until there is basically no drop, cool the system to 8°C, keep stirring for 3 h, and then filter and wash with water to obtain 24.75 g of crude mannopentaenamide.

[0040] (3) Add the obtained crude mannopentaenamide to a mixed solvent of acetone 230 mL and n-hexane 57.5 mL, refine at 58°C for 1 h, cool to 8°C, keep stirring for 2 h, and then filter and wash with water; this step is repeated twice to obtain 18.29 g of high-purity mannopentaenamide.

[0041] Example 2

[0042] The preparation steps of high-purity mannopentaenamide in this example 2 are as follows:

[0043] (1) Take mannohexaenamide 30 g, dissolve in 150 mL of a mixed solvent of methanol and 500 mL of dichloromethane, stir and heat to dissolve, add triethylamine 10.5 mL. Keep the system at 42°C and reflux for 4 h.

[0044] (2) After the reaction is completed, add acetic acid dropwise to adjust the pH to 5.5, gradually heat to 68°C and distill under normal pressure, until there is basically no drop, cool the system to 8°C, keep stirring for 3 h, and then filter and wash with water to obtain 25.22 g of crude mannopentaenamide.

[0045] (3) Add the obtained crude mannopentaenamide to a mixed solvent of acetone 230 mL and n-hexane 60 mL, refine at 55°C for 1 h, cool to 8°C, keep stirring for 2 h, and then filter and wash with water; this step is repeated twice to obtain 19.02 g of high-purity mannopentaenamide.

[0046] Example 3

[0047] The preparation steps of high purity mannopentaenamine in Example 3 are as follows:

[0048] (1) Take mannopentaenamine 30 g, dissolve in 150 mL of methanol and 500 mL of dichloromethane mixed solvent, stir and heat to dissolve, add pyridine 6 ml. Keep at 45℃ for 5h.

[0049] (2) After the reaction is completed, add acetic acid dropwise to adjust the pH to 5.5, gradually heat to 70℃ and distill under normal pressure until basically no drop, and the system is cooled to 8℃ and stirred for 3h to wait for crystallization. After filtration and water washing, mannopentaenamine crude product 25.22g is obtained.

[0050] (3) The obtained mannopentaenamine crude product is added into a mixed solvent of acetone 240 mL and n-hexane 60 mL, and refined at 55℃ for 1h. After cooling to 8℃ and stirring for 2h, the crystallization is filtered; this step is repeated twice to obtain mannopentaenamine fine product 18.32g.

[0051] Comparative Example 1

[0052] The preparation steps of Comparative Example 1 are as follows:

[0053] (1) Take mannopentaenamine 30 g, dissolve in 150 mL of methanol and 500 mL of dichloromethane mixed solvent, stir and heat to dissolve, add pyridine 6 ml. Keep at 45℃ for 5h.

[0054] (2) After 1.5h of reaction, add 1.0 mol / L hydrochloric acid dropwise to adjust to neutral, to obtain reaction liquid 1.

[0055] Comparative Example 2

[0056] The preparation steps of Comparative Example 2 are as follows:

[0057] Take mannopentaenamine 10 g, add excess 0.3 mol / L hydrochloric acid to dissolve, adjust the pH to 2.0 with 5% sodium hydroxide, heat to 50℃ and stir for 48h to obtain reaction liquid 2.

[0058] Comparative Example 3

[0059] The preparation steps of Comparative Example 3 are as follows:

[0060] (1) Take mannopentaenamine 30 g, dissolve in 150 mL of methanol and 500 mL of dichloromethane mixed solvent, stir and heat to dissolve, add pyridine 6 ml. Keep at 45℃ for 5h.

[0061] (2) After the reaction is completed, add acetic acid dropwise to adjust the pH to 5.5, gradually heat to 70℃ and distill under normal pressure until basically no drop, and the system is cooled to 8℃ and stirred for 3h to wait for crystallization. After filtration and water washing, mannopentaenamine crude product 25.22g is obtained.

[0062] (3) The obtained crude mannopentaenamide was added into a mixed solvent of acetone 240 mL and n-hexane 60 mL, and refined by beating at 55°C for 1 h. After cooling to 8°C, the mixture was stirred for 2 h, and then filtered. The above step was repeated twice to obtain solid product 3: 19.64 g.

[0063] Comparative Example 4

[0064] The preparation steps of the present comparative example 4 are as follows:

[0065] (1) Mannohexaenamide 30 g was dissolved in a mixed solvent of 150 mL of methanol and 500 mL of dichloromethane, and stirred to dissolve. Then triethylamine and mannohexaenamide 13 mL (the molar ratio of triethylamine to mannohexaenamide was about 2.5:1) were added. The mixture was refluxed at 45°C for 5 h.

[0066] (2) After the reaction was completed, acetic acid was added dropwise to adjust the pH to 5.5. The mixture was distilled at atmospheric pressure while gradually increasing the temperature to 65°C until no drops were observed. The system was cooled to 8°C, and then stirred for 3 h to allow crystallization. After filtration and water washing, a solid crude product 26.35 g was obtained.

[0067] (3) The obtained crude mannopentaenamide was added into a mixed solvent of acetone 240 mL and n-hexane 60 mL, and refined by beating at 55°C for 1 h. After cooling to 8°C, the mixture was stirred for 2 h, and then filtered. The above step was repeated twice to obtain solid product 3: 19.64 g.

[0068] II. Test method

[0069] The chemical components and the purity of mannopentaenamide prepared in Examples 1-3 and the reaction products 1-3 prepared in Comparative Examples 1-3 were tested by high performance liquid chromatography (HPLC), and the corresponding yield was calculated.

[0070] III. Test analysis

[0071] Table 1

[0072]

[0073] A) As shown in Table 1, the purity of mannopentaenamide prepared in Examples 1-3 can reach more than 95%, and the mass yield can reach more than 60%, which proves that the above preparation method can obtain high-purity and high-yield mannopentaenamide product.

[0074] B) The reaction solution 1 prepared in Comparative Example 1 was subjected to liquid phase detection, and a plurality of substances were generated therein, including mannopenta nicotine, mannose hexa nicotine, mannose tetra nicotine, mannose tri nicotine, mannose di nicotine, mannose hexyl nicotine, nicotinic acid, and mannitol which cannot be detected under ultraviolet light. Since the sodium hydroxide is highly alkaline, mannose hexa nicotine is easily hydrolyzed in its aqueous solution, and after controlling the reaction temperature to be high or prolonging the reaction time, it is completely hydrolyzed into mannitol and nicotinic acid, thereby proving that the preparation of mannose penta nicotine using inorganic base will generate a large amount of by-products, which is not conducive to improving the purity and yield of the product.

[0075] C) The reaction solution 2 prepared in Comparative Example 2 was subjected to liquid phase detection, and a plurality of substances were generated therein, including mannose hexa nicotine, mannose penta nicotine, mannose tetra nicotine, mannose tri nicotine, mannose di nicotine, mannose hexyl nicotine, nicotinic acid, and mannitol which cannot be detected under ultraviolet light. Among them, the largest peak area in the HPLC spectrum is about 19%, which is mannose penta nicotine. It is proved that simple extraction method cannot be purified, and separation and purification by preparation column requires high equipment and personnel, and takes a long time.

[0076] 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 nicotine was only 76.38%, and the impurities mainly included more than 20% of the converted mannose hexa nicotine. It is proved that the low proportion of organic base will lead to incomplete conversion of mannose hexa nicotine.

[0077] E) The solid product 4 prepared in Comparative Example 4 was subjected to liquid phase detection, and the purity of the prepared product mannose penta nicotine was only 82.61%, and the impurities mainly included mannose tetra nicotine, mannose tri nicotine and other substances which were hydrolysis by-products of mannose hexa nicotine. It is proved that the high proportion of organic base will lead to excessive hydrolysis of part of mannose hexa nicotine to produce a small amount of other hydrolysis products.

[0078] The specific embodiments of the application described above do not constitute a limitation on the scope of protection of the application. Any other corresponding changes and modifications made in accordance with the technical concept of the application shall be included in the scope of protection of the claims of the application.

Claims

1. A process for the preparation of high purity mannosylpentasaccharide, characterized by, The method comprises the following steps: (1) mixing mannitol hexanitrate with a first solvent, stirring to fully disperse under heating, then adding an organic base, and reacting at 40-45°C for 3-4h to obtain a primary mixture; (2) adding an acid to the primary mixture to adjust the pH to 5-6, then stopping adding the acid and heating to 65-70°C, and performing normal pressure distillation treatment, and then cooling and washing with water to obtain a crude mannitol pentanitrate; (3) mixing the crude mannitol pentanitrate with a second solvent, and then performing beating refining, cooling and crystallization, and solid-liquid separation to obtain high-purity mannitol pentanitrate. The first solvent is a mixed solvent of methanol and dichloromethane, the second solvent is a mixed solvent of acetone and n-hexane, the organic base is at least one of pyridine and triethylamine, and the molar ratio of mannitol hexanitrate to the organic base is 1:(1.9-2.2).

2. The process for the preparation of high purity mannosylpentasaccharide according to claim 1, characterized in that, In step (1), the mannitol hexanitrate, methanol and dichloromethane are mixed in a ratio of 3g:(15-18)mL:(50-60)mL.

3. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (1), the organic base is triethylamine, and the molar ratio of mannitol hexanitrate to triethylamine is 1:(1.9-2.2).

4. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (2), the acid is at least one of phosphoric acid, acetic acid, citric acid and p-toluenesulfonic acid.

5. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (2), after stopping adding the acid, heating to 65-70°C, performing normal pressure distillation treatment until no liquid drops, then cooling to 5-10°C and stirring for 3h to crystallize, and then washing with water after suction filtration to obtain the crude mannitol pentanitrate.

6. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (3), the crude mannitol pentanitrate, acetone and n-hexane are mixed in a ratio of 1g:(8-10)mL:(2-2.5)mL.

7. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (3), the beating refining is performed at 55-60°C for 1h.

8. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, In step (3), after the beating refining is completed, cooling to 5-10°C and stirring for 2h to crystallize, and then suction filtration to obtain the high-purity mannitol pentanitrate.

9. The process for the preparation of high purity mannosylpentasaccharide as claimed in claim 1, wherein, The step (3) is repeated for 2-3 times to obtain the high-purity mannitol pentanitrate.

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