Preparation method of metformin hydrochloride

Abstract

The preparation method of metformin hydrochloride comprises the following steps: adding dimethylamine hydrochloride and dicyandiamide powder into a preheating system, mixing, preheating, adding into a reactor, adding dimethylformamide at the same time, carrying out a heating reaction for 4-7 h, adding water according to a molar ratio of dimethylamine hydrochloride to dimethylformamide to water of 1: (0.3-0.7): (0.2-0.5), carrying out a reaction for 1.5-3 h, filtering, washing, and drying to obtain the metformin hydrochloride. Cooling after heat preservation to obtain a primary reaction product, filtering, leaching and drying the primary reaction product, and refining with methanol to obtain refined metformin hydrochloride. According to the scheme, no catalyst is added in the reaction, the reaction materials can fully react only by using a small amount of dimethylformamide and water as solvents, and the product yield is 90-92%. The solvent consumption is small, the separation difficulty is reduced, the workload is reduced, the energy consumption is reduced by separating a small amount of solvent, and the production cost is further reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing metformin hydrochloride. Background Art

[0002] Metformin Hydrochloride is a commonly used hypoglycemic drug for non-insulin-dependent diabetes mellitus. It improves the blood glucose tolerance of patients with type 2 diabetes and reduces basal blood glucose and postprandial blood glucose. The mechanism of action of metformin hydrochloride is different from that of other types of oral hypoglycemic drugs. It can reduce the production of glycogen, reduce the absorption of glucose by the small intestine, and increase the sensitivity of insulin by increasing the uptake and utilization of glucose by peripheral tissues. Unlike sulfonylurea drugs, metformin hydrochloride will not cause hypoglycemia in patients with type 2 diabetes or patients with normal blood sugar. After treatment with metformin hydrochloride, insulin secretion remains unchanged, while fasting insulin levels and daily plasma insulin levels are reduced. Therefore, it is widely used by most physicians to treat type 2 diabetes.

[0003] At present, the synthesis methods of metformin hydrochloride mainly include dry method and wet method. The dry method is the melting method, which is widely used. However, the melting method uses solid materials in the early and late stages of the reaction, which requires high equipment performance. In addition, the reaction process is highly exothermic and there are safety hazards. The wet method mostly uses alcohols with a boiling point of 120 to 180°C, such as cyclohexanol, n-hexanol, n-pentanol, and isopentanol, as solvents. However, such solvents have strong viscosity at low temperatures, making it difficult to separate the product from the solvent, and the price is relatively high.

[0004] To this end, the Chinese invention patent application number CN201310375165.2 discloses a method for preparing metformin hydrochloride, using dicyandiamide and dimethylamine hydrochloride as raw materials, feeding according to a molar ratio of dicyandiamide to dimethylamine hydrochloride of 1:1 to 1:1.2, using 2 to 4 times the weight of dicyandiamide as solvent, N,N-dimethylacetamide or dimethyl sulfoxide as solvent, reacting at 140±5℃ for 4 to 8h, preparing crude metformin hydrochloride; the crude product is recrystallized with ethanol, the pH value is adjusted to 5 to 6, decolorized, stirred and cooled to -10 to 0℃ for crystallization, filtered (centrifugal drying), dried to obtain fine metformin hydrochloride, and the filtrate is used to recover the solvent, and the yield of qualified products of the present invention is 80% to 85%. The amount of solvent used in this application is relatively large (2 to 4 times the weight of dicyandiamide), which will increase the production cost, and the concentration of metformin hydrochloride in the prepared crude metformin hydrochloride is low, and crystallization separation is difficult and the workload is large. Summary of the invention

[0005] Based on this, the present application provides a method for preparing metformin hydrochloride to solve the technical problems in the prior art that excessive amount of solvent is used, the metformin hydrochloride concentration in the prepared crude metformin hydrochloride is low, the crystallization separation is difficult and the workload is large, and the production cost is increased.

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

[0007] A method for preparing metformin hydrochloride comprises the following steps:

[0008] S10. Add dimethylamine hydrochloride and dicyandiamide powder to the preheating system and preheat to a first specified temperature;

[0009] S20. Add the preheated dimethylamine hydrochloride and dicyandiamide powder into the reactor, add dimethylformamide at the same time, heat to the second specified temperature, react for 4h to 7h, then add water, react for another 1.5h to 3h, keep warm and cool to 30℃ to 40℃ to obtain the initial reaction product; wherein the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:(0.3 to 0.7):(0.2 to 0.5).

[0010] S30. The initial reaction product is filtered, then rinsed with a washing liquid and dried to obtain a crude product of metformin hydrochloride.

[0011] S40. Refining the crude metformin hydrochloride with methanol to obtain refined metformin hydrochloride.

[0012] Preferably, in the above-mentioned method for preparing metformin hydrochloride, in step S10, the dimethylamine hydrochloride and dicyandiamide powder are in a molar ratio of (1 to 1.15):1.

[0013] Preferably, in the above method for preparing metformin hydrochloride, in step S10, the first designated temperature is 70°C to 120°C.

[0014] Preferably, in the above method for preparing metformin hydrochloride, in step S10, the first designated temperature is 80°C to 90°C.

[0015] Preferably, in the above-mentioned method for preparing metformin hydrochloride, in step S20, the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:0.5:0.3.

[0016] Preferably, in the above method for preparing metformin hydrochloride, in step S20, the second designated temperature is 120°C to 150°C.

[0017] Preferably, in the above method for preparing metformin hydrochloride, in step S20, the second designated temperature is 135° C. to 140° C.

[0018] Preferably, in the above-mentioned method for preparing metformin hydrochloride, in step S20, the eluent is dimethylformamide.

[0019] Preferably, in the above-mentioned preparation method of metformin hydrochloride, in step S30, "refining the crude metformin hydrochloride with methanol" is specifically as follows: 90% methanol is added into a reaction tank, the crude metformin hydrochloride is added with stirring, and after heating and refluxing for 20 to 40 minutes, the mixed solution is filtered and pumped into a crystallization reactor, cooled to allow crystals to precipitate, and then centrifuged and dried to obtain metformin hydrochloride.

[0020] The present invention adopts the above technical solution, which has at least the following beneficial effects:

[0021] The preparation method of metformin hydrochloride of the present application, the step is to add dimethylamine hydrochloride and dicyandiamide powder to the preheating system and mix and preheat and then add the reactor, add dimethylformamide at the same time, heat the reaction for 4h to 7h, then add water, wherein the amount of dimethylamine hydrochloride, dimethylformamide and water is 1: (0.3 to 0.7): (0.2 to 0.5), then react for 1.5h to 3h, cool down after insulation to obtain the initial product of the reaction, then filter the initial product of the reaction, separate solid and liquid, rinse, and refine with methanol after drying to obtain refined metformin hydrochloride. Preheating is first carried out in the reaction process of this scheme, and preheating can make the heat transfer of dimethylamine hydrochloride and dicyandiamide powder more uniform, so that subsequent reactions are more sufficient; No catalyst is added in the reaction, and only a small amount of dimethylformamide and water are used as solvents to enable the reaction materials to fully react, and the product yield is 90% to 92%. The amount of solvent used is small, which saves the cost of raw materials on the one hand; on the other hand, the obtained initial reaction product is in the form of a solid (metformin hydrochloride) liquid (solvent) mixture, and only a small amount of liquid (solvent) exists, that is, the concentration of metformin hydrochloride in the obtained initial reaction product is very high, and most of it already exists in the form of a solid, and only a simple solid-liquid separation is required, that is, a simple filtration method, such as filter press or suction filtration, can be used for easy separation, which solves the problem of low metformin hydrochloride concentration in the crude metformin hydrochloride prepared in the prior art, resulting in difficult crystallization separation and large workload. In the present application, for separating metformin hydrochloride from the initial reaction product, not only is the separation method simple, but also separating a small amount of solvent is also conducive to reducing energy consumption, further reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the gas chromatogram of sample 1 in Example 1 of the present application. DETAILED DESCRIPTION

[0023] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present invention can be combined with each other. The technical solution of the present invention will be further described below in conjunction with the drawings of the embodiments of the present invention, and the present invention is not limited to the following specific implementation methods.

[0024] In a specific embodiment of the present application, a method for preparing metformin hydrochloride comprises the following steps:

[0025] S10. The dimethylamine hydrochloride and dicyandiamide powder are added to the preheating system and mixed and preheated to a first specified temperature;

[0026] Specifically, dimethylamine hydrochloride and dicyandiamide powder are added to a preheating system according to a molar ratio of (1 to 1.15):1 for preheating, and the preheating temperature is 70° C. to 120° C., preferably 80° C. to 90° C. Preheating can make the heat transfer of dimethylamine hydrochloride and dicyandiamide powder more uniform, so that the subsequent reaction can be more sufficient.

[0027] S20. Add the preheated dimethylamine hydrochloride and dicyandiamide powder to the reactor, add dimethylformamide at the same time, heat to the second specified temperature, react for 4h to 7h, then add water, react for 1.5h to 3h, keep warm and cool to 30°C to 40°C to obtain a reaction product; wherein the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:(0.3 to 0.7):(0.2 to 0.5);

[0028] Specifically, preheated dimethylamine hydrochloride and dicyandiamide powder are added to the reactor for reaction, and dimethylformamide is added at the same time, and the temperature is raised to 120°C to 150°C, preferably 135°C to 140°C, and the reaction is carried out for 4h to 7h, and then water is added, and the reaction is carried out for 1.5h to 3h, and the temperature is lowered to 30°C to 40°C after keeping the temperature for 1h to obtain the initial reaction product; in a preferred embodiment, the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:0.5:0.3. No catalyst is added in this step of the reaction, and dimethylformamide and water are used as solvents.

[0029] Wherein dimethylformamide (DMF) is a transparent liquid, molecular formula C3H7NO, CAS No. 68-12-2 molecular weight 73.10, relative density 0.9445 (25 ℃), can be miscible with water and most organic solvents, it is a common solvent for chemical reactions. In this scheme, the addition amount of DMF and water is very small, DMF is only 0.3 to 0.7 of the amount of substance of dimethylamine hydrochloride, preferably 0.5, and the addition amount of water is only 0.2 to 0.5 of the amount of substance of dimethylamine hydrochloride, preferably 0.3, a small amount of solvent can save the cost of raw materials, the obtained reaction initial product is in the form of a solid (metformin hydrochloride) liquid (solvent) mixture, and only a small amount of liquid (solvent) exists, that is, the concentration of metformin hydrochloride in the obtained reaction initial product is very high, and most of it already exists in the form of a solid, only simple solid-liquid separation is required, that is, a simple filtration method, such as filter press or suction filtration, can be easily separated, reduce the difficulty of separation and reduce the workload.

[0030] In this application, the reactor preferably adopts a continuous high-efficiency turbulent reactor because it is a reactor that can realize a continuous production mode. Compared with the traditional kettle reactor, it is light in weight and high in efficiency. The reactor has two material feed ports, each of which can be connected to a feeding device. By adjusting the feed amount, the proportion of the reaction materials can be accurately controlled, and there are multiple temperature detectors evenly distributed on the reactor body, which can monitor the temperature in the reaction chamber in real time. When the material continuously enters the equipment, it is forced to stir and mix through the internal mandrel, and can be directly discharged from the material port after sufficient reaction, so as to achieve continuous production and make the reaction more sufficient.

[0031] S30. The initial reaction product is filtered, then washed with a washing liquid and dried to obtain a crude product of metformin hydrochloride; the washing liquid is dimethylformamide; the filtration can be performed by pressure filtration or suction filtration according to actual production conditions.

[0032] S40. Refining the crude metformin hydrochloride with methanol to obtain refined metformin hydrochloride.

[0033] Preferably, the above steps are specifically as follows: adding 90% methanol into a reaction tank, adding the crude metformin hydrochloride with stirring, heating and reflux reaction for 20 to 40 minutes, filtering the mixed solution and pumping it into a crystallization reactor, cooling to allow crystals to precipitate, centrifuging and drying to obtain the finished metformin hydrochloride, with a yield of 90% to 92%.

[0034] For example, the preparation method of metformin hydrochloride comprises the following steps:

[0035] Dimethylamine hydrochloride and dicyandiamide powder are added to a preheating system according to a molar ratio of (1 to 1.15):1, preheated to 80°C to 90°C, added to a continuous high-efficiency turbulent reactor for reaction, and dimethylformamide is added at the same time. The temperature is raised to 135°C to 140°C, reacted for 4h to 7h, and then water is added. The reaction is continued for 1.5h to 3h, and the temperature is lowered to 30°C to 40°C after insulation for 1h to obtain a reaction initial product; wherein the mass ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:0.5:0.3; then the reaction initial product is filtered, solid-liquid separation is performed, and then the dimethylformamide is used for elution and drying to obtain a crude product of metformin hydrochloride; 90% methanol is added to a reaction tank, the crude product of metformin hydrochloride is added with stirring, and the mixture is heated under reflux for reaction for 20 to 40min, and then the mixed solution is filtered and pumped into a crystallization reactor, cooled to room temperature to precipitate crystals, centrifuged and vacuum dried to obtain a finished product of metformin hydrochloride.

[0036] The preparation method of metformin hydrochloride of the present application, the step is to add dimethylamine hydrochloride and dicyandiamide powder to the preheating system and mix and preheat and then add the reactor, add dimethylformamide at the same time, heat the reaction for 4h to 7h, then add water, wherein the amount of dimethylamine hydrochloride, dimethylformamide and water is 1: (0.3 to 0.7): (0.2 to 0.5), then react for 1.5h to 3h, cool down after insulation to obtain the initial product of the reaction, then filter the initial product of the reaction, separate solid and liquid, rinse, and refine with methanol after drying to obtain refined metformin hydrochloride. Preheating is first carried out in the reaction process of this scheme, and preheating can make the heat transfer of dimethylamine hydrochloride and dicyandiamide powder more uniform, so that subsequent reactions are more sufficient; No catalyst is added in the reaction, and only a small amount of dimethylformamide and water are used as solvents to enable the reaction materials to fully react, and the product yield is 90% to 92%. The use amount of solvent is small, which saves the cost of raw materials on the one hand; on the other hand, the obtained initial reaction product is in the form of a solid (metformin hydrochloride) liquid (solvent) mixture, and only a small amount of liquid (solvent) exists, that is, the concentration of metformin hydrochloride in the obtained initial reaction product is very high, and most of it already exists in the form of a solid, and only simple solid-liquid separation is required, that is, a simple filtration method such as filter press or suction filtration can be used to easily separate, thereby reducing the difficulty of separation and reducing the workload.

[0037] It is worth noting that the process temperature and process time involved in the above-mentioned embodiments are all temperatures or times used in the experimental process. Those skilled in the art can make reasonable adjustments within the error range based on the process temperature and process time provided by the present invention, which should be included in the protection scope of the present invention.

[0038] The technical solution and technical effects of the present invention are further illustrated below through specific experimental examples.

[0039] It should be noted that in the examples of the present invention, all raw materials and reagents are commercially available and can be used without further purification.

[0040] The yield calculation formula for metformin hydrochloride sample is as follows:

[0041] Yield (%) = actual product mass / theoretical product mass × 100%

[0042] Among them, actual product mass = crude product mass × purity (%)

[0043] 1. Experimental Example 1

[0044] Weigh 8.56 g of dimethylamine hydrochloride and 8.41 g of dicyandiamide powder, add them to a preheating system and preheat to 85±5° C., then add them to a continuous high-efficiency turbulent reactor, add DMF (the amount added is shown in Table 1), heat to 137±2° C., react for 7±1 h, keep warm for 1 h, cool to 35±2° C., and obtain a preliminary reaction product; then filter the preliminary reaction product, rinse with DMF, and dry to obtain a crude metformin hydrochloride; add 90% methanol into a reaction tank, stir and add the crude metformin hydrochloride, heat and reflux for reaction for 30±5 min, filter the mixed solution, pump it into a crystallization reactor, cool it to room temperature, allow crystals to precipitate, centrifuge and vacuum dry to obtain a finished product of metformin hydrochloride.

[0045] Table 1 Amount of raw materials used in Experimental Example 1

[0046] sample Dicyandiamide(g) Dimethylamine hydrochloride(g) DMF(g) Sample 1 8.41 8.56 0.77 Sample 2 8.41 8.56 2.30 Sample 3 8.41 8.56 3.84 Sample 4 8.41 8.56 5.37 Sample 5 8.41 8.56 6.91

[0047] The mass and yield of the above metformin hydrochloride sample were calculated, and the purity of the sample was tested by high performance liquid chromatography. The results are shown in the following table:

[0048] Table 2 Yield and purity of each sample in Experimental Example 1

[0049]

[0050]

[0051] As can be seen from the table above, each sample in Experimental Example 1 uses only DMF as a solvent, and the molar ratios of dimethylamine hydrochloride and DMF in samples 1 to 5 are 1:0.1, 1:0.3, 1:0.5, 1:0.7 and 1:0.9, respectively. The synthesized metformin hydrochloride has a low yield when the purity reaches 95%. Among them, only sample 3 has a yield of more than 80%, that is, when the molar ratio of dimethylamine hydrochloride and DMF is 1:0.5, the yield of the synthesized metformin hydrochloride is the highest, but it still needs to be further improved.

[0052] 2. Experimental Example 2

[0053] Weigh 8.56 g of dimethylamine hydrochloride and 8.41 g of dicyandiamide powder, add them to a preheating system and preheat to 85±5° C., then add them to a continuous high-efficiency turbulent reactor, add 3.65 g of DMF, heat to 137±2° C., react for 7±1 h, keep warm for 1 h, then add water (the amount added is shown in Table 3), react for another 2 h, cool to 35±2° C., and obtain a preliminary reaction product; then filter the preliminary reaction product, rinse with DMF, and dry to obtain a crude metformin hydrochloride; add 90% methanol into a reaction tank, stir and add the crude metformin hydrochloride, heat under reflux for 30±5 min, filter the mixed solution, pump it into a crystallization reactor, cool to room temperature to allow crystals to precipitate, centrifuge and vacuum dry to obtain a finished metformin hydrochloride.

[0054] Table 3 Amounts of raw materials used in Experimental Example 2

[0055] sample Dicyandiamide(g) Dimethylamine hydrochloride(g) DMF(g) Water(g) Sample 6 8.41 8.56 3.84 0.19 Sample 7 8.41 8.56 3.84 0.39 Sample 8 8.41 8.56 3.84 0.57 Sample 9 8.41 8.56 3.84 0.76 Sample 10 8.41 8.56 3.84 0.95 Sample 11 8.41 8.56 3.84 1.13 Sample 12 8.41 8.56 3.84 1.32

[0056] The mass and yield of the above metformin hydrochloride sample were calculated, and the purity of the sample was tested by high performance liquid chromatography. The results are shown in the following table:

[0057] Table 4 Yield and purity of each sample in Experimental Example 2

[0058]

[0059]

[0060] As shown in Table 3, samples 6 to 12 are when the addition of dicyandiamide and dimethylamine hydrochloride in the raw material is unchanged, and the addition of DMF is 0.5 of the amount of substance of dimethylamine hydrochloride, and the addition of water is calculated according to the amount of substance ratio of dimethylamine hydrochloride and water 1: (0.1 to 0.7). As can be seen from the above table, samples 6 to 8, that is, when the amount of substance ratio of dimethylamine hydrochloride and water is from 1: 0.1 to 1: 0.3, increase sharply from 81.3% to 92.0%, when the addition of water continues to increase, the yield of the sample metformin hydrochloride decreases slightly (sample 9, sample 10), when the addition of water increases to 0.6 to 0.7 of the amount of substance of dimethylamine hydrochloride, that is, sample 11, sample 12, the yield of metformin hydrochloride tends to be stable and maintains about 88%. Therefore, when other conditions remain unchanged and the molar ratio of dimethylamine hydrochloride to water is 1:(0.2 to 0.5), the yield of metformin hydrochloride is higher than 90%, and when the added amount of water is 1:0.3 according to the molar ratio of dimethylamine hydrochloride to water, the yield of metformin hydrochloride can reach 92%.

[0061] Combining the above two experimental examples, it can be seen that sample 3 uses only DMF as a solvent, and the amount of DMF added is 0.5 of the amount of dimethylamine hydrochloride, and the yield is 81.2%. Sample 8 is based on the preparation method of sample 3, and a small amount of water is added, and the amount of water added is 0.3 of the amount of dimethylamine hydrochloride. The yield of metformin hydrochloride prepared is 92%, which is 10.8% higher than that of sample 3, and the improvement rate is 13.3%.

[0062] In summary, the preparation method of metformin hydrochloride of the present application does not add a catalyst in the reaction, and only uses a small amount of dimethylformamide and water as solvents to enable the reaction materials to fully react. When the amount ratio of dimethylamine hydrochloride, dimethylformamide and water is 1: (0.3 to 0.7): (0.2 to 0.5), the product yield can reach 90% to 92%. The use of solvent is small, on the one hand, saving the cost of raw materials; on the other hand, the obtained initial reaction product is in the form of a solid (metformin hydrochloride) liquid (solvent) mixture, and only a small amount of liquid (solvent) exists, that is, the concentration of metformin hydrochloride in the initial reaction product is very high, and most of it already exists in the form of a solid state, and only a simple solid-liquid separation is required, that is, a simple filtration method, such as filter press or suction filtration, can be easily separated, reducing the difficulty of separation and reducing the workload, and separating a small amount of solvent is also conducive to reducing energy consumption, further reducing production costs.

[0063] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing metformin hydrochloride, characterized in that: The following steps are involved: S10. The dimethylamine hydrochloride and dicyandiamide powder are added to the preheating system and mixed and preheated to a first specified temperature; S20. Add the preheated dimethylamine hydrochloride and dicyandiamide powder into the reactor, add dimethylformamide at the same time, heat to the second specified temperature, react for 4h to 7h, then add water, react for 1.5h to 3h, keep warm and cool to 30°C to 40°C to obtain a reaction product; wherein the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:(0.3 to 0.7):(0.2 to 0.5); S30. The initial reaction product is filtered, then washed with an eluent and dried to obtain a crude product of metformin hydrochloride; S40. Refining the crude metformin hydrochloride with methanol to obtain refined metformin hydrochloride.

2. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S10, the dimethylamine hydrochloride and dicyandiamide powder are mixed in a molar ratio of (1 to 1.15):

1.

3. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S10, the first designated temperature is 70°C to 120°C.

4. The method for preparing metformin hydrochloride according to claim 3, characterized in that: In step S10, the first designated temperature is 80°C to 90°C.

5. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S20, the molar ratio of dimethylamine hydrochloride, dimethylformamide and water is 1:0.5:0.

3.

6. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S20, the second designated temperature is 120°C to 150°C.

7. The method for preparing metformin hydrochloride according to claim 6, characterized in that: In step S20, the second designated temperature is 135°C to 140°C.

8. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S20, the eluent is dimethylformamide.

9. The method for preparing metformin hydrochloride according to claim 1, characterized in that: In step S40, “Refining the crude metformin hydrochloride with methanol” specifically means: 90% methanol is added into the reaction tank, and the crude metformin hydrochloride is added thereto with stirring. After heating under reflux for 20 to 40 minutes, the mixed solution is filtered and pumped into a crystallization reactor, cooled to precipitate crystals, and then centrifuged and dried to obtain metformin hydrochloride.

Images