Preparation method of mannityl nicotinate

Abstract

The invention discloses a preparation method of mannityl nicotinate. The preparation method of the mannityl nicotinate comprises the following steps: mixing pyridine and a diluting solvent, adding nicotinic acid under stirring, continuously stirring uniformly, adding thionyl chloride under a cooling condition, heating to 60-65 DEG C after the thionyl chloride is added, and carrying out heat preservation for acylating chlorination reaction; cooling a sample after the acylating chlorination reaction, mixing with mannitol, heating to 85-90 DEG C, keeping the temperature, carrying out esterification reaction, cooling to below 50 DEG C after the reaction is finished, adding water, continuously cooling to below 10 DEG C, then adjusting the pH value of the system to 6.7-7.0, and centrifuging to obtain a filter cake; washing the filter cake with water to obtain a mannityl nicotinate crude product, and decolorizing and refining the mannityl nicotinate crude product to obtain a mannityl nicotinate refined product. The diluting solvent is added in the acylating chlorination reaction process, so that not only is the use amount of the expensive pyridine solvent greatly reduced, but also the condition of stirring locking caused by excessive viscosity of the reaction system in the crude product preparation process is avoided.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical compounds, and in particular relates to a method for preparing mannohexanic acid ester. Background Art

[0002] Mannitol hexanicotinate is also known as mannitol nicotinate, its chemical name is hexapyridine-3-carboxylic acid hexacol ester, its English name is Mannityl Nicotinate, its molecular formula is C 42 H 32 N6O 12 , whose structural formula is as follows: .

[0003] Mannohexanicotinate is a cardiovascular drug that has the effects of dilating blood vessels and lowering blood lipids. It is clinically used to treat coronary heart disease, cerebral thrombosis, atherosclerosis, hypertension and hyperlipidemia. Compared with similar drugs such as inositol nicotinate and sorbitol nicotinate, mannohexanicotinate is easier to hydrolyze in the body, exerts its efficacy faster, and can effectively alleviate the strong dilation of peripheral effects caused by niacin, reducing side effects such as facial flushing and gastrointestinal discomfort.

[0004] In the existing production process of ganlu six nicotinate, pyridine is used as a solvent in large quantities, and the specific amount is 1kg:2.71L (2.65kg) of nicotinic acid to pyridine. In the process of producing 1 ton of ganlu six nicotinate products, 3.5 to 4 tons of pyridine are consumed. The moisture content in pyridine must be strictly controlled below 0.3%, because too high a moisture content will seriously affect the yield and quality of ganlu six nicotinate products, and may even cause the entire batch of products to be scrapped. In the preparation process of crude products, due to the excessive viscosity of the system materials, the stirring is prone to lock. In order to prevent the stirring motor from burning out, a frequency converter is usually installed to improve the stirring effect. If the pyridine-containing wastewater generated by the crude product process is discharged directly, it will not only pollute the environment, but also cause a waste of resources. The price of pyridine is relatively high, with a market price of about 38,000 yuan / ton. Its physical properties are: it is easy to absorb moisture in the air, miscible with water, with an azeotropic point of 92-93°C, and the weight percentage of water in the azeotrope is 41.3%. The existing recovery process of pyridine includes adding caustic soda flakes to adjust the pH of the pyridine-containing wastewater solution, and then crudely distilling it in a distillation kettle. After adding caustic soda flakes to the distillate again and layering, it is transferred to a distillation tower for distillation to recover pyridine. After testing, when the moisture content of the recovered pyridine is lower than 0.3%, it can be used for the production of crude manlu hexanic acid ester; if the moisture content reaches or exceeds 0.3%, it is necessary to continue distillation until the moisture content is qualified. In summary, the existing preparation method of manlu hexanic acid ester has the problems of large pyridine consumption, high energy consumption for pyridine recovery, and high production cost. Summary of the invention

[0005] In view of the shortcomings of the prior art, the primary purpose of the present invention is to provide a method for preparing mannose hexanic acid ester. The method provided by the present invention is simple and easy to implement and is suitable for large-scale industrial production.

[0006] The purpose of the present invention is achieved through the following technical solutions: A method for preparing mannose hexanic acid ester comprises the following steps: (1) Pyridine and a diluent solvent are mixed, nicotinic acid is added under stirring, thionyl chloride is added under cooling after continued stirring, and after the addition is completed, the temperature is raised to 60-65°C and kept warm to carry out acyl chlorination reaction; (2) Cooling the sample after the acyl chloride reaction and mixing it with mannitol, heating it to 85-90°C and keeping it warm for esterification reaction, cooling it to below 50°C after the reaction, adding water and continuing to cool it to below 10°C, then adjusting the system pH to 6.7-7.0, and centrifuging to obtain the mother liquor and filter cake; (3) The filter cake is washed with water to obtain a crude product of ganlu hexanic acid ester, and the crude product is decolorized and refined to obtain a refined product of ganlu hexanic acid ester.

[0007] Preferably, in step (1), the mass ratio of pyridine to nicotinic acid is 1:1.

[0008] Preferably, in step (1), the mass ratio of the dilution solvent to nicotinic acid is 2-3:1.

[0009] Preferably, in step (1), the water content of pyridine does not exceed 0.3%.

[0010] Preferably, in step (1), the acyl chlorination reaction time is 6 hours.

[0011] Preferably, in step (1), the dilution solvent is at least one of toluene and xylene.

[0012] Preferably, in step (2), the sample after the acyl chlorination reaction is cooled to 55° C. and then mixed with mannitol.

[0013] Preferably, in step (2), the mass ratio of mannitol to niacin is 28:100.

[0014] Preferably, in step (2), the esterification reaction time is 3 hours.

[0015] Preferably, in step (2), the mass ratio of the added amount of water to the nicotinic acid is 1:1.

[0016] Preferably, in step (2), the specific method of adjusting the system pH to 6.7-7.0 is: adjusting the pH by adding a 10 wt % sodium hydroxide aqueous solution.

[0017] Preferably, in step (2), the mother liquor is treated as follows: the mother liquor is transferred into a layering kettle, caustic soda is added into the layering kettle, the mixture is stirred and allowed to stand, and the lower aqueous layer is separated to obtain a primary upper organic layer; a layering reagent is added into the primary upper organic layer, the mixture is stirred and allowed to stand, and the lower aqueous layer is separated to obtain a secondary upper organic layer; the secondary upper organic layer is transferred into a distillation kettle, refluxed and separated to obtain a mixed solvent with a moisture content of less than 0.3%, and the mixed solvent is reused in the acyl chlorination reaction of step (1).

[0018] Preferably, the layering agent is industrial salt.

[0019] Preferably, in step (3), the specific operation of decolorization is as follows: add the crude product of mannose hexanic acid ester to water and stir evenly, add hydrochloric acid with a concentration greater than 35% until it is completely dissolved, continue stirring and then add activated carbon for decolorization, and filter after decolorization to obtain a filtrate.

[0020] Preferably, in step (3), the specific refining operation is as follows: take the filtrate after decolorization, cool it down, adjust the pH value of the system to 6.7-7.0 with a 10% sodium carbonate aqueous solution, then centrifuge and spin dry to obtain a first solid phase, then wash it with hot water and spin dry, and finally dry it.

[0021] Compared with the prior art, the beneficial effects of the present invention include: (1) Adding a diluent solvent during the acyl chloride reaction not only greatly reduces the amount of expensive pyridine solvent, but also avoids the situation in which the reaction system is too viscous and causes the stirring to be stuck during the preparation of the crude product. The selected diluent solvent is at least one of toluene and xylene. Toluene and xylene are insoluble in water and can form an azeotropic mixture with water. In the process of recovering the solvent by treating the esterification mother liquor, the azeotropic characteristics of the diluent and water are utilized to remove the water in the system by a simple distillation method, and finally a mixed solvent with a water content of less than 0.3% is obtained, which can be directly used in the acyl chloride reaction.

[0022] (2) In the secondary stratification process of mother liquor treatment, industrial salt is added to form saturated brine for salting out extraction, and pyridine and water are separated into organic phase and aqueous phase, thereby further removing water from the system and reducing the amount of caustic soda flakes used, thereby alleviating the pressure on wastewater treatment.

[0023] (3) After two stratifications and one distillation, the esterification mother liquor can obtain a mixed solvent with a moisture content of less than 0.3%, which can be directly used in the acyl chlorination reaction. Compared with the traditional pyridine recovery method, this method omits the equipment investment of the distillation tower and reduces the distillation process of the distillation tower. After the introduction of the diluent solvent, the moisture content in the mixed solvent system can be more easily controlled within 0.3% by reflux water separation, without the need to first obtain a single solvent-pyridine with a moisture content of less than 0.3% before use, thereby significantly reducing the difficulty of recovering the solvent for acyl chlorination.

[0024] (4) The present invention significantly reduces the amount of pyridine used in the chlorination reaction of nicotinic acid hexanicotinate, and significantly reduces the ratio of nicotinic acid to pyridine from 100kg:265kg in the prior art to 100kg:100kg when using fresh pyridine solvent, and 100kg:20kg when the esterification mother liquor is treated and recycled. The process of recovering the solvent from the esterification mother liquor does not require the use of a distillation tower, thereby reducing the distillation process of the distillation tower. Through a simple reflux water separation method, the water content in the solvent system of the esterification mother liquor can be easily controlled within 0.3%, avoiding the need for repeated distillation due to the solvent water content ≥0.3%. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] Example 1 A method for preparing mannose hexanic acid ester comprises the following steps: (1) Acid chlorination reaction: add 100 kg of pyridine with a water content of no more than 0.3% and 200 kg of toluene into a pre-dried 1000 L glass-lined reactor, add 100 kg of nicotinic acid under stirring, stir evenly and then add 110 kg of thionyl chloride dropwise under cooling conditions. After the addition is complete, slowly raise the temperature to 60-65°C for more than 1 hour and keep the temperature for 6 hours to carry out the acid chlorination reaction; (2) Esterification reaction: After the acyl chloride heat preservation reaction is completed, the temperature is lowered to 55°C, 28 kg of mannitol is added in portions, and the temperature is raised to 85-90°C after the addition of mannitol. The temperature is kept for reaction for 3 hours. After the reaction is completed, the temperature is lowered to below 50°C, 100 kg of water is added, and the temperature is further lowered to below 10°C. A 10 wt% sodium hydroxide aqueous solution is added dropwise to adjust the pH of the system to 6.7-7.0, centrifuge, collect the mother liquor, and wash the filter cake with water to obtain the crude product of mannitol hexanic acid ester; (3) Decolorization and refining: Add the crude wet material of ganlu six nicotinate to 300 kg of purified water and stir evenly, add refined hydrochloric acid with a concentration of more than 35 wt% until it is completely dissolved, continue stirring for 30 minutes, add activated carbon for decolorization and filter, cool the filtrate and adjust the pH to 6.7-7.0 with a 10 wt% sodium carbonate aqueous solution. Centrifuge and dry, then wash with purified water at a temperature of 50-60 ° C, dry and dry to obtain 80.0 kg of ganlu six nicotinate fine product with a dry content of 100.01%.

[0027] The mother liquor treatment process of esterification is as follows: the mother liquor of esterification reaction centrifugation is transferred into a layering kettle, 60 kg of flake caustic soda is added into the layering kettle, stirred for 0.5 h, allowed to stand for 1 h, the lower water layer is separated to obtain a primary upper organic layer. 15 kg of industrial salt is added into the primary upper organic layer, stirred for 0.5 h, allowed to stand for 0.5 h, the lower water layer is separated to obtain a secondary upper organic layer. The secondary upper organic layer is transferred into a distillation kettle, refluxed and separated to obtain 285 kg of mixed solvent with a moisture content of 0.19%; The treated esterification mother liquor and 20 kg of pyridine were put into acylation reaction, and other process steps remained unchanged to obtain 80.5 kg of mannose hexanic acid ester with a dry content of 99.95%.

[0028] Example 2 A method for preparing mannose hexanic acid ester comprises the following steps: (1) Acid chlorination reaction: add 100 kg of pyridine with a water content of no more than 0.3% and 300 kg of xylene into a pre-dried 1000 L glass-lined reactor, add 100 kg of nicotinic acid under stirring, stir evenly and then add 110 kg of thionyl chloride dropwise under cooling conditions. After the addition is complete, slowly raise the temperature to 60-65°C for more than 1 hour, keep the temperature for 6 hours, and carry out the acid chlorination reaction; (2) Esterification reaction: After the acyl chloride heat preservation reaction is completed, the temperature is lowered to 55°C, 28 kg of mannitol is added in portions, and the temperature is raised to 85-90°C after the addition of mannitol. The temperature is kept for reaction for 3 hours. After the reaction is completed, the temperature is lowered to below 50°C, 100 kg of water is added, and the temperature is further lowered to below 10°C. A 10 wt% sodium hydroxide aqueous solution is added dropwise to adjust the pH of the system to 6.7-7.0, centrifuge, collect the mother liquor, and wash the filter cake with water to obtain the crude product of mannitol hexanic acid ester; (3) Decolorization and refining: Add the crude wet material of ganlu six nicotinate to 300 kg of purified water and stir evenly, add refined hydrochloric acid with a concentration of more than 35 wt% until it is completely dissolved, continue stirring for 30 minutes, add activated carbon for decolorization and filter, cool the filtrate and adjust the pH to 6.7-7.0 with a 10 wt% sodium carbonate aqueous solution. Centrifuge and dry, then wash with purified water at a temperature of 50-60 ° C, dry and dry to obtain 80.6 kg of ganlu six nicotinate fine product with a dry content of 99.98%.

[0029] The mother liquor treatment process of esterification is as follows: the mother liquor of esterification reaction centrifugation is transferred into a layering kettle, 60 kg of flake caustic soda is added into the layering kettle, stirred for 0.5 h, allowed to stand for 1 h, the lower water layer is separated to obtain a primary upper organic layer. 15 kg of industrial salt is added into the primary upper organic layer, stirred for 0.5 h, allowed to stand for 0.5 h, the lower water layer is separated to obtain a secondary upper organic layer. The secondary upper organic layer is transferred into a distillation kettle, refluxed and separated to obtain 379 kg of mixed solvent with a moisture content of 0.12%; The treated esterification mother liquor and 20 kg of pyridine were put into the acylation reaction, and the other process steps remained unchanged to obtain 81.0 kg of mannose hexanic acid ester with a dry content of 100.02%.

[0030] Comparative Example 1 A method for preparing mannose hexanic acid ester comprises the following steps: (1) Acylation reaction: Add 265 kg of pyridine with a water content of no more than 0.3% into a pre-dried 1000 L glass-lined reactor, add 100 kg of nicotinic acid while stirring, and then add 110 kg of thionyl chloride dropwise under cooling conditions after stirring. After the addition is complete, slowly raise the temperature to 60-65°C over 1 hour and keep the temperature for 6 hours; (2) Esterification reaction: After the acyl chloride heat preservation reaction is completed, the temperature is lowered to 55°C, and 28kg of mannitol is added in batches. When 20kg of mannitol is added, the reaction kettle system is too viscous and the stirring is blocked. After adding 100kg of pyridine, the stirring is basically normal. After adding mannitol, the temperature is raised to 85-90°C, and the heat preservation reaction is carried out for 3h. After the reaction is completed, the temperature is lowered to below 50°C, 100kg of water is added, and the temperature is further lowered to below 10°C. A 10wt% sodium hydroxide aqueous solution is added dropwise to adjust the pH to 6.7-7.0, centrifuge, collect the mother liquor, and wash the filter cake with water to obtain the crude product of mannitol hexanic acid ester.

[0031] By comparing Examples 1 to 3 with Comparative Example 1, we found that when only pyridine is used as a solvent in the prior art in the preparation of the crude product of mannose hexanic acid ester, the system material will be too viscous and prone to stirring lock. In order to ensure the stirring effect, the amount of pyridine used has to be increased, which not only increases the raw material cost, but also increases the production cost.

[0032] 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 mannohexanic acid ester, characterized in that: The steps include: (1) Pyridine and a diluent solvent are mixed, nicotinic acid is added under stirring, thionyl chloride is added under cooling after continued stirring, and after the addition is completed, the temperature is raised to 60-65°C and kept warm to carry out acyl chlorination reaction; (2) Cooling the sample after the acyl chloride reaction and mixing it with mannitol, heating it to 85-90°C and keeping it warm for esterification reaction, cooling it to below 50°C after the reaction, adding water and continuing to cool it to below 10°C, then adjusting the system pH to 6.7-7.0, and centrifuging to obtain the mother liquor and filter cake; (3) The filter cake is washed with water to obtain a crude product of ganlu hexanic acid ester, and the crude product is decolorized and refined to obtain a refined product of ganlu hexanic acid ester.

2. The method for preparing mannohexanic acid ester according to claim 1, characterized in that: The mass ratio of pyridine to nicotinic acid in step (1) is 1:1; The mass ratio of the dilution solvent to nicotinic acid in step (1) is 2-3:

1.

3. The method for preparing mannohexanic acid ester according to claim 2, characterized in that: The water content of the pyridine in step (1) is no more than 0.3%; The acyl chlorination reaction time in step (1) is 6 hours; The esterification reaction time in step (2) is 3 hours.

4. The method for preparing mannohexanic acid ester according to claim 1, characterized in that: The dilution solvent in step (1) is at least one of toluene and xylene; After the acyl chlorination reaction in step (2), the sample is cooled to 55° C. and then mixed with mannitol.

5. The method for preparing mannohexanic acid ester according to claim 1, characterized in that: The mass ratio of the mannitol in step (2) to the nicotinic acid in step (1) is 28:

100.

6. The method for preparing mannohexanic acid ester according to claim 3, characterized in that: In step (2), the mass ratio of the amount of water added to the amount of nicotinic acid in step (1) is 1:

1.

7. The method for preparing mannohexanic acid ester according to claim 1, characterized in that: The specific method of adjusting the pH value of the system to 6.7-7.0 in step (2) is to adjust the pH value by adding a 10 wt % sodium hydroxide aqueous solution.

8. The method for preparing mannohexanic acid ester according to claim 1, characterized in that: The mother liquor treatment steps of step (2) are as follows: the mother liquor is transferred into a layering kettle, caustic soda is added into the layering kettle, the mixture is stirred and allowed to stand, and the lower water layer is separated to obtain a primary upper organic layer; a layering reagent is added into the primary upper organic layer, the mixture is stirred and allowed to stand, and the lower water layer is separated to obtain a secondary upper organic layer; the secondary upper organic layer is transferred into a distillation kettle, refluxed and separated to obtain a mixed solvent with a water content of less than 0.3%, and the mixed solvent is reused in the acyl chlorination reaction of step (1).

9. The method for preparing mannohexanic acid ester according to claim 8, characterized in that: The specific operation of the decolorization in step (3) is as follows: add the crude product of mannose hexanic acid ester to water and stir evenly, add hydrochloric acid with a concentration greater than 35% until it is completely dissolved, continue stirring and then add activated carbon for decolorization, and filter after decolorization to obtain a filtrate; The layering agent is industrial salt.

10. The method for preparing mannohexanic acid ester according to claim 9, characterized in that: The specific operation of the purification in step (3) is as follows: take the filtrate after decolorization, cool it down, adjust the system pH to 6.7-7.0 with a 10% sodium carbonate aqueous solution, then centrifuge and spin dry to obtain a first solid phase, then wash it with hot water and spin dry, and finally dry it.