Synthesis method and synthesis device of metformin hydrochloride

Abstract

The invention belongs to the technical field of medical chemical synthesis, and particularly relates to a synthetic method and a synthetic device of metformin hydrochloride. A dimethylamine aqueous solution and dicyandiamide are used as reaction raw materials, a small amount of water is used as a solvent, the dimethylamine aqueous solution, dicyandiamide and water are fully mixed firstly, then excessive hydrogen chloride solution or hydrogen chloride gas is introduced, and a reaction is performed at 150-250 DEG C, so that the reaction is more sufficient, the reaction efficiency is higher, the reaction time is shortened, and the yield is increased. And the ideal yield of metformin hydrochloride is obtained. Experiments show that the yield of metformin hydrochloride can be increased to 90% or above, and the reaction time can be shortened to be within 60 min.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of synthetic medicine chemistry, and particularly relates to a synthesis method and a synthesis device of metformin hydrochloride. BACKGROUND

[0002] Metformin hydrochloride is a commonly used drug for reducing blood sugar, and is used for non-insulin-dependent diabetes. It can improve the blood sugar tolerance of type II diabetes patients, and reduce the basal blood sugar and postprandial blood sugar. The mechanism of action of metformin hydrochloride is different from other types of oral hypoglycemic drugs. It can reduce the production of liver sugar, reduce the absorption of glucose by the small intestine, and increase the uptake and utilization of glucose by peripheral tissues to improve insulin sensitivity. Unlike sulfonylurea drugs, metformin hydrochloride does not cause hypoglycemia in type II diabetes patients or normal blood sugar patients. After metformin hydrochloride treatment, the secretion of insulin remains unchanged, and the fasting insulin level and daily plasma insulin level are reduced, so it is widely used by most doctors for the treatment of type II diabetes.

[0003] At present, the synthesis methods of metformin hydrochloride mainly include dry method and wet method. The dry method, i.e. the melting method, is widely used. However, the initial and later stages of the reaction are solid materials, which have high requirements for the performance of the equipment. In addition, the reaction process is exothermic, which has safety hazards. The wet method mainly uses cyclohexanol, n-hexanol, n-pentanol, and isopentanol, etc. as solvents, which have boiling points of 120-180℃. However, such solvents have strong viscosity at low temperatures, the separation of the product and the solvent is difficult, and the price is relatively high.

[0004] In the prior art, the Chinese invention patent with the application number 202311606318.X discloses a preparation method of metformin, which comprises the following steps: (a) heating a mixture of dimethylammonium chloride, dicyandiamide, 0 to 20% by weight of water based on the total weight of dimethylammonium chloride and dicyandiamide present in the mixture, and 0 to 50% by weight of metformin hydrochloride to a temperature in the range of 70-250℃ and maintaining the temperature in the range for 0.1 minutes to 20 hours; (b) cooling the reaction mixture, and collecting the obtained crystalline metformin hydrochloride. However, in the specific experiment, although the reaction time of the synthesis of metformin hydrochloride can be shortened to about 1 hour, the yield of metformin hydrochloride is too low, only 63.97%. SUMMARY

[0005] Therefore, the present application provides a synthesis method and a synthesis device of metformin hydrochloride to solve the technical problem that the yield is low in the prior art although the reaction time is shortened.

[0006] The technical solution of the present application to solve the above technical problem is as follows:

[0007] A synthesis method of metformin hydrochloride, comprising the following steps:

[0008] S10. An aqueous dimethylamine solution, dicyandiamide and water are respectively added to a reactor, heated to a first temperature for mixing to obtain a first mixture;

[0009] S20. Hydrogen chloride is introduced into the first mixture, heated to a second temperature for reaction, and after reaction, the temperature is lowered to a third temperature to obtain crude metformin hydrochloride; wherein, in step S20, the reaction time is 20 min to 60 min;

[0010] S30. The crude metformin hydrochloride is subjected to crystallization separation and drying to obtain crystalline metformin hydrochloride.

[0011] Preferably, in the above synthesis method of metformin hydrochloride, the molar ratio of dimethylamine, dicyandiamide and hydrogen chloride is 1:(0.95 to 1.05):(1 to 1.5).

[0012] Preferably, in the above synthesis method of metformin hydrochloride, the amount of water added is such that the water content in the mixing system is 30% to 50%.

[0013] Preferably, in the above synthesis method of metformin hydrochloride, in step S10, the first temperature is 80℃ to 100℃.

[0014] Preferably, in the above synthesis method of metformin hydrochloride, in step S20, the second temperature is 150℃ to 250℃.

[0015] Preferably, in the above synthesis method of metformin hydrochloride, in step S20, the third temperature is 30℃ to 50℃.

[0016] Preferably, in the above synthesis method of metformin hydrochloride, in step S20, the hydrogen chloride includes any one of hydrogen chloride solution and hydrogen chloride gas.

[0017] Preferably, in the above synthesis method of metformin hydrochloride, in step S20, the pH of the reaction system is 6 to 8.

[0018] A synthesis device of metformin hydrochloride, applied to the above synthesis method of metformin hydrochloride, the synthesis device comprising:

[0019] The body is sequentially provided with a contact section, a reaction section and a cooling section in the flow direction of the material; the contact section is provided with a dimethylamine aqueous solution feeding port, a dicyandiamide feeding port and a water feeding port; the reaction section is provided with a hydrogen chloride feeding port close to the side of the contact section; the reaction section is further provided with a heating device for heating the material in the contact section; the cooling section is provided with a discharging port away from the side of the contact section; and the cooling section is provided with a cooling device for cooling the material in the cooling section.

[0020] The rotating part is arranged in the body and penetrates through the body along the flow direction of the material, and comprises a rotating shaft and helical blades arranged along the length direction of the rotating shaft.

[0021] Preferably, the synthesis device of metformin hydrochloride is further connected with a hydrophobic filter between the reaction section and the cooling section, the outlet of the hydrophobic filter is connected with a vacuum pump, and the outlet of the vacuum pump is connected with the hydrogen chloride feeding port.

[0022] The technical scheme of the present application has at least the following beneficial effects:

[0023] The present application provides a synthesis method of metformin hydrochloride, which uses dimethylamine aqueous solution and dicyandiamide as reaction raw materials, a small amount of water as a solvent, firstly mixes the dimethylamine aqueous solution, dicyandiamide and water sufficiently, then passes excess hydrogen chloride solution or hydrogen chloride gas, especially when hydrogen chloride gas is passed, a gas-liquid mixed reaction system is formed, and the reaction is carried out at 150-250 DEG C, so that the reaction is more sufficient, the reaction efficiency is higher, the reaction time is shortened, and the ideal metformin hydrochloride yield is obtained. Experiments show that the yield of metformin hydrochloride can be increased to more than 90%, and the reaction time can be shortened to less than 60 minutes.

[0024] The present application also provides a synthesis device of metformin hydrochloride, which is a continuous reaction device and mainly comprises a contact section, a reaction section, a cooling section, a rotating part and a hydrophobic filter. The device has compact structure and is suitable for the above-mentioned synthesis method. The use of the synthesis device is beneficial to shorten the reaction time and improve the reaction efficiency. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 It is a liquid chromatogram of Example 9 of the present application.

[0026] Figure 2 It is a synthesis device schematic diagram of metformin hydrochloride of the present application.

[0027] In the figure: the body 100, the contact section 110, the dimethylamine aqueous solution feed port 111, the dicyandiamide feed port 112, the water inlet 113, the reaction section 120, the hydrogen chloride feed port 121, the heating device 122, the cooling section 130, the discharge port 131, the cooling device 132, the rotating part 200, the rotating shaft 210, the spiral blade 220, the hydrophobic filter 300, and the vacuum pump 400. DETAILED DESCRIPTION

[0028] It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. The technical solutions of the present application will be further described below in combination with the embodiments of the present application. The present application is not limited to the following specific embodiments.

[0029] In one specific embodiment of the present application, a synthesis method of metformin hydrochloride comprises the following steps:

[0030] S10. The dimethylamine aqueous solution, dicyandiamide, and water are added into the reactor respectively, and heated to a first temperature for mixing to obtain a first mixture.

[0031] In the present solution, the dimethylamine aqueous solution is selected from dimethylamine aqueous solutions with a concentration of 30% to 50%, and preferably a dimethylamine aqueous solution with a concentration of 40%. The amount of water added is such that the water content in the mixing system is 30% to 50%. Only a small amount of water is used as a solvent, which is lower in cost, less toxic, less waste liquid discharge, and more environmentally friendly compared to traditional processes. It should be noted that since the dimethylamine aqueous solution contains a certain amount of water, the amount of water added is adjusted according to the concentration of the dimethylamine aqueous solution, and the overall water content in the mixing system is 30% to 50%. For example, if the reaction raw material is a dimethylamine aqueous solution with a concentration of 40%, and the molar ratio of dimethylamine to dicyandiamide is 1:1, 112.7 g of dimethylamine aqueous solution with a concentration of 40% and 84.08 g of dicyandiamide are added. If the process requires the water content in the mixing system to be less than or equal to 34.3%, no additional water is needed. If the process requires the water content in the mixing system to be greater than 34.3%, water needs to be added. The amount of water added is calculated according to the process requirement for the water content in the mixing system.

[0032] This step is mainly to make the materials fully contact first. The dimethylamine aqueous solution, dicyandiamide, and water are fully mixed at a first temperature. Further, the first temperature is 80°C to 100°C, which can make the heat transfer between the dimethylamine aqueous solution and the dicyandiamide powder more uniform, so that the subsequent reaction is more complete.

[0033] S20. Hydrogen chloride is introduced into the first mixture, heated to a second temperature for reaction, and then cooled to a third temperature to obtain crude metformin hydrochloride. In step S20, the reaction time is 20 min to 60 min.

[0034] Specifically, the molar ratio of dimethylamine, dicyandiamide and hydrogen chloride is 1: (0.95 to 1.05): (1 to 1.5), and further 1:1.05:1.2. Hydrogen chloride is added, and the reaction is carried out by heating to 150°C to 250°C. As preferred, the first temperature is 200°C to 250°C, and the reaction pressure is 0.1 to 1.0 MPa. After the reaction is sufficiently completed, the reaction system is cooled to a second temperature, and as preferred, the second temperature is 30°C to 50°C. Further, the pH of the reaction system is 6 to 8. In the present application, the reactor is preferably a continuous reactor, and the above mixing, reaction and cooling steps are continuously carried out. According to the actual working conditions, a suitable reactor and material addition rate are selected, and under the condition of ensuring the purity and yield of metformin hydrochloride, the reaction time in step S20 is 20 min to 60 min.

[0035] S30. Crystallizing and separating the crude metformin hydrochloride to obtain crystalline metformin hydrochloride.

[0036] In another specific embodiment of the present application, a metformin hydrochloride synthesis device is applied to the above-mentioned metformin hydrochloride synthesis method, and the synthesis device comprises:

[0037] The body 100 is sequentially provided with a contact section 110, a reaction section 120 and a cooling end in the flow direction of the material. The contact section 110 is provided with a dimethylamine aqueous solution feeding port 111, a dicyandiamide feeding port 112 and a water feeding port 113. The reaction section 120 is provided with a hydrogen chloride feeding port 121 close to the side of the contact section 110. The reaction section 120 is further provided with a heating device 122 for heating the material in the contact section 110. The cooling section 130 is provided with a discharging port 131 away from the side of the contact section 110. The cooling section 130 is provided with a cooling device 132 for cooling the material in the cooling section 130.

[0038] The rotating part 200 is arranged in the body 100 and penetrates the body 100 in the flow direction of the material.

[0039] The synthesis device of metformin hydrochloride in the application is a continuous reactor. According to the reaction sequence, that is, the flow direction of the material, firstly, the contact section 110, the reaction raw materials, aqueous dimethylamine solution, dicyandiamide and water are respectively added into the contact section 110 from the aqueous dimethylamine solution feeding port 111, the dicyandiamide feeding port 112 and the water feeding port 113. In the contact section 110, the raw materials are fully mixed. The rotating part 200 transports the contact-mixed material to the reaction section 120. In the reaction section 120, the hydrogen chloride feeding port 121 passes in hydrogen chloride gas, and at the same time, the heating device 122 heats the material in the reaction section 120, so that the material reacts in the reaction section 120. The heating device 122 can be an electric heating device, a heating jacket, a heating coil, a microwave heating device, etc. The specific form is preferably selected according to the needs of the use site. The material after reaction in the reaction section 120 is transported by the rotating part 200 to the cooling section 130. The cooling device 132 of the cooling section 130 cools the material to the required temperature, thereby cooling and crystallizing the material. The cooling device 132 can be a coil heat exchanger, a cooling jacket, etc. The reactor can use a multi-stage parallel reactor, for example, a reactor of (1m long, 20cm in diameter) * n, where n is the number of stages of the reactor. In actual production, the specific specifications and number of stages of the reactor are reasonably selected according to the actual production capacity and other production conditions.

[0040] The rotating part 200 not only plays a transmission role, but also plays a stirring role on the material, so that the material is more fully mixed and the reaction is more efficient. Therefore, as a preferred embodiment, the rotating part 200 comprises a rotating shaft 210 and a spiral blade 220 arranged along the length direction of the rotating shaft 210. When the rotating part 200 rotates, the spiral blade 220 rotates with it, conveying the material from the contact section 110 to the cooling section 130, and at the same time, the blade also stirs and mixes the material, so that it fully reacts.

[0041] In a preferred embodiment, a hydrophobic filter 300 is further connected between the reaction section 120 and the cooling end, and a vacuum pump 400 is connected to the outlet of the hydrophobic filter 300, and the outlet of the vacuum pump 400 is connected to the hydrogen chloride inlet 121. The filter membrane of the hydrophobic filter 300 is made of a "hydrophobic porous material" (such as polytetrafluoroethylene PTFE, hydrophobic ceramic), and the membrane hole diameter is only 0.1-1 microns, and the surface is hydrophobic, so that liquid droplets cannot infiltrate the membrane holes and are intercepted on the membrane surface, while the gas can pass through smoothly. Since there may be unreacted hydrogen chloride gas in the reactor, in order to facilitate subsequent separation and avoid waste, a hydrophobic filter 300 is connected between the reaction section 120 and the cooling end, that is, the end of the reaction section 120 is connected with the hydrophobic filter 300. Since the reactor is under pressure, and the vacuum pump 400 extracts the gas in the reactor, the unreacted hydrogen chloride gas can pass through the hydrophobic filter 300, while the liquid in the reactor cannot pass through. The hydrogen chloride gas passing through the hydrophobic filter 300 can be transported to the hydrogen chloride inlet 121 of the reaction section 120 for recycling and reuse, which is beneficial to save raw materials and reduce costs.

[0042] It should be noted that in the above embodiments, the process temperature and process time are a temperature or time used in the experiment. Those skilled in the art can make reasonable adjustments within the error range on the basis of the process temperature and process time provided by the present application, which should be included in the protection scope of the present application.

[0043] The technical solutions and technical effects of the present application are further illustrated by specific experimental examples.

[0044] It should be noted that all raw materials and reagents in the embodiments of the present application are commercially available and can be used without further purification.

[0045] The yield (calculated as dicyandiamide) of the metformin hydrochloride sample is calculated according to the following formula:

[0046] Yield (%) = actual product mass / theoretical product mass x 100%.

[0047] 1. Comparative Example 1

[0048] In this experiment, the reactor has the following specifications: a reactor with a length of 1 m and a diameter of 20 cm.

[0049] In the reactor contact section, 154.56 g of dimethylammonium chloride, 88.28 g of dicyandiamide powder, and 24.35 g of water were added, and the contact section was heated to 90°C; the reaction section was heated to 200°C, and the pressure in the reactor was 0.6 MPa; the temperature of the cooling section was reduced to 40°C. The residence time of the reaction was controlled to be 60 min throughout the process. The crude metformin hydrochloride at the outlet of the reactor was sent to a crystallization reactor, cooled to room temperature, and allowed to crystallize. After centrifugal separation and vacuum drying, metformin hydrochloride crystals were obtained.

[0050] 2. Comparative Example 2

[0051] In the reactor contact section, 112.7 g of 40% dimethylamine aqueous solution, 88.28 g of dicyandiamide powder, and 21.28 g of water were added, so that the water content in the mixing system was 40%, and the contact section was heated to 90°C for mixing; in the reaction section, 145.83 g of 30% hydrogen chloride solution was slowly introduced to maintain the pH of the reaction system at 7, and the reaction section was heated to 200°C, and the pressure in the reactor was 0.6 MPa; the temperature of the cooling section was reduced to 40°C. The residence time of the reaction was controlled to be 60 min throughout the process. The crude metformin hydrochloride at the outlet of the reactor was sent to a crystallization reactor, cooled to room temperature, and allowed to crystallize. After centrifugal separation and vacuum drying, metformin hydrochloride crystals were obtained.

[0052] 3. Experimental Example 1

[0053] In the reactor contact section, 112.7 g of 40% dimethylamine aqueous solution, 88.28 g of dicyandiamide powder, and 21.28 g of water were added, so that the water content in the mixing system was 40%, and the contact section was heated to 90°C for mixing; in the reaction section, 145.83 g of 30% hydrogen chloride solution was slowly introduced to maintain the pH of the reaction system at 7, and the reaction section was heated to 200°C, and the pressure in the reactor was 0.6 MPa; the temperature of the cooling section was reduced to 40°C. The residence time of the reaction was controlled to be 60 min throughout the process. The crude metformin hydrochloride at the outlet of the reactor was sent to a crystallization reactor, cooled to room temperature, and allowed to crystallize. After centrifugal separation and vacuum drying, metformin hydrochloride crystals were obtained.

[0054] 4. Experimental Example 2

[0055] The other conditions were the same as in Experimental Example 1, except that the residence time of the reaction was controlled to be 50 min throughout the process.

[0056] 5. Experimental Example 3

[0057] The other conditions were the same as in Experimental Example 1, except that the residence time of the reaction was controlled to be 40 min throughout the process.

[0058] 6. Experimental Example 4

[0059] Other conditions are the same as experimental example 1, except that the reaction residence time is controlled at 30 min.

[0060] 7. Experimental example 5

[0061] Other conditions are the same as experimental example 1, except that the reaction residence time is controlled at 20 min.

[0062] The mass and yield of the above metformin hydrochloride sample are calculated, the purity of the sample is detected by high performance liquid chromatography, and the yield of metformin hydrochloride is calculated, and the results are as follows:

[0063] Table 1 Summary of experimental results

[0064] Item Total reaction time (min) Metformin hydrochloride mass (g) Metformin hydrochloride yield (%) Metformin hydrochloride purity (%) Comparative Example 1 60 111.25 63.97 89 Comparative Example 2 60 148.31 85.28 93.1 Experimental Example 1 60 161.12 92.65 98.4 Experimental Example 2 50 160.79 92.46 98.4 Experimental Example 3 40 159.32 91.61 98.4 Experimental Example 4 30 156.92 90.23 98.4 Experimental Example 5 20 151.33 87.02 98.4

[0065] As can be seen from the above table, under the condition of the same reaction residence time (60 min), the yield and purity of metformin hydrochloride synthesized by Comparative Example 1 using the same reaction raw materials as the prior art are lower; in Comparative Example 2, 40% dimethylamine aqueous solution and dicyandiamide and a small amount of water are used as reaction materials, and 30% hydrogen chloride solution is added in the reaction section; from the experimental data, it can be seen that the final yield of metformin hydrochloride has been improved to 85.28%; in Experimental Example 1, hydrogen chloride gas is introduced in the reaction section, and the yield and purity of metformin hydrochloride synthesized are significantly improved, with a yield of 92.65% and a purity of 98.4%, and the effect is excellent. Experimental Examples 2 to 5 maintain the same process conditions as Experimental Example 1, and control different reaction times to obtain results, which can be seen that when the reaction time is controlled to be more than 20 min, the yield of metformin hydrochloride can be maintained at more than 90%, which is better than Comparative Example 1.

[0066] In summary, the synthesis method of metformin hydrochloride of the present application uses dimethylamine aqueous solution and dicyandiamide as reaction raw materials, and a small amount of water as solvent, first mixes the dimethylamine aqueous solution, dicyandiamide and water, and then introduces excess hydrogen chloride solution or hydrogen chloride gas, especially when hydrogen chloride gas is introduced, a gas-liquid mixed reaction system is formed, and the reaction is carried out at 150℃ to 250℃, so that the reaction is more complete and the reaction efficiency is higher, not only the reaction time is shortened, but also the ideal yield of metformin hydrochloride is obtained.

[0067] Obviously, the above embodiments of the present application are only examples for clearly illustrating the present application, and are not intended to limit the implementation modes of the present application. Based on the above description, any modifications, equivalent replacements and improvements made by those skilled in the art within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A process for the synthesis of metformin hydrochloride, characterized in that, The method comprises the following steps: S10. Adding dimethylamine aqueous solution, dicyandiamide and water into a reactor respectively, heating to a first temperature for mixing to obtain a first mixture; S20. Passing hydrogen chloride into the first mixture, heating to a second temperature for reaction, and cooling to a third temperature after reaction to obtain crude metformin hydrochloride; wherein, in step S20, the reaction time is 20 min to 60 min; S30. Crystallizing and separating the crude metformin hydrochloride, and drying to obtain crystalline metformin hydrochloride.

2. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, The molar ratio of dimethylamine, dicyandiamide and hydrogen chloride is 1:(0.95 to 1.05):(1 to 1.5).

3. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, The amount of water added is such that the water content in the mixing system is 30% to 50%.

4. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, In step S10, the first temperature is 80°C to 100°C.

5. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, In step S20, the second temperature is 150°C to 250°C.

6. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, In step S20, the third temperature is 30°C to 50°C.

7. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, In step S20, the hydrogen chloride includes any one of hydrogen chloride solution and hydrogen chloride gas.

8. The process for the synthesis of metformin hydrochloride as claimed in claim 1 wherein, In step S20, the pH of the reaction system is 6 to 8.

9. A device for the synthesis of metformin hydrochloride, characterized by, The method comprises: A body, which is sequentially provided with a contact section, a reaction section and a cooling section in the flow direction of the material; the contact section is provided with a dimethylamine aqueous solution inlet, a dicyandiamide inlet and a water inlet; the reaction section is provided with a hydrogen chloride inlet close to one side of the contact section; the reaction section is further provided with a heating device for heating the material in the contact section; the cooling section is provided with a discharge outlet away from one side of the contact section; and the cooling section is provided with a cooling device for cooling the material in the cooling section. A rotating component, which is provided in the body along the flow direction of the material and penetrates through the body, and comprises a rotating shaft and helical blades arranged along the length direction of the rotating shaft.

10. The apparatus for synthesis of metformin hydrochloride as claimed in claim 9 wherein, The reaction section and the cooling end are further connected with a hydrophobic filter, the outlet of the hydrophobic filter is connected with a vacuum pump, and the outlet of the vacuum pump is connected with the hydrogen chloride inlet.

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