A low-temperature synthesis method of metformin hydrochloride

Abstract

This invention discloses a low-temperature synthesis method for metformin hydrochloride, belonging to the field of pharmaceutical chemical synthesis and active pharmaceutical ingredient preparation technology. The method includes the following steps: salting an aqueous solution of dimethylamine, followed by vacuum concentration to remove some water, resulting in a water content of 10wt%–35wt% in the system; adding ethanol or a mixed solvent of N,N-dimethylformamide and ethanol to the concentrated system; cooling the system and adding dicyandiamide, then maintaining the reaction at 70℃–90℃, followed by cooling crystallization, crystal growth, separation, and drying to obtain metformin hydrochloride. This invention, at a reaction temperature significantly lower than that of traditional processes, not only does not show a decrease in yield or purity, but also simultaneously achieves higher product yield, higher HPLC purity, and effective inhibition of melamine byproducts.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis and active pharmaceutical ingredient preparation technology, specifically relating to a low-temperature synthesis method for metformin hydrochloride. Background Technology

[0002] Metformin hydrochloride is a representative biguanide hypoglycemic drug, characterized by its wide application, stable clinical demand, and large-scale industrial production. Current industrial routes typically involve the reaction of dicyandiamide with dimethylamine hydrochloride to generate the target product. Common processes include high-temperature melting or high-temperature solvent methods, where dicyandiamide and dimethylamine hydrochloride undergo a condensation reaction at 130℃–160℃ to form the biguanide skeleton, followed by cooling, crystallization, separation, and drying to obtain the metformin hydrochloride product.

[0003] While the aforementioned high-temperature process can achieve industrial-scale production, it still has the following shortcomings: First, the system needs to be maintained above 130°C for a long time, resulting in high heat consumption and low energy utilization efficiency. Second, in scale-up production, local overheating, uneven heat transfer, and adhesion to the reactor wall are prone to occur under high-temperature conditions, leading to a decrease in process safety margin. Third, dicyandiamide is more likely to undergo self-condensation, rearrangement, or deep condensation at high temperatures, increasing the probability of the formation of byproducts such as melamine, which is not conducive to purity control and post-processing. Fourth, although some published low-temperature methods attempt to reduce the reaction temperature, they often rely on expensive and complex special solvents or complex catalytic systems, resulting in limited industrial applicability.

[0004] While existing technologies disclose reactions under low-temperature conditions, for example, Chinese invention patent application number 201410334351.6 discloses a method for producing high-purity metformin hydrochloride. Specifically, the solvent is heated to 75-90°C, solid dicyandiamide is added while stirring, the solution temperature is maintained at 75-90°C, dimethylamine hydrochloride solution is added dropwise, and the reaction is carried out at this temperature, with crystals precipitating out successively. After reacting for a period of time, stirring is stopped, the temperature is cooled to 25-30°C, filtered, and the crystals are dried to obtain metformin hydrochloride product with a yield of 91%-91.6%. However, this yield is still relatively low and it is necessary to further improve it. Summary of the Invention

[0005] Based on this, this application provides a low-temperature synthesis method for metformin hydrochloride to solve the technical problem that the yield of the prior art is still low and needs to be further improved.

[0006] The technical solution to the above-mentioned technical problems in this application is as follows: A method for the low-temperature synthesis of metformin hydrochloride, comprising the following steps: S10. Obtain the acidified dimethylamine salt solution and concentrate it under reduced pressure until the water content in the system is 10wt% to 35wt%; S20. Add a moderately polar organic solvent to the system after vacuum concentration, stir until homogeneous, cool to 45°C–55°C, and then add dicyandiamide; the amount of dicyandiamide added is 62%–67% of the mass of pure dimethylamine; S30. Heat the system obtained in step S20 to 70℃~90℃ and keep it at that temperature for 1h~12h to obtain the reaction solution.

[0007] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, step S10, "obtaining an acidified dimethylamine salting solution" includes: A 20%–50% dimethylamine aqueous solution was added to the reactor, and a 31%–37% hydrochloric acid solution was added dropwise under stirring. The system temperature was controlled at 10℃–35℃, and the pH of the system was adjusted to 1.8–2.3 to obtain an acidified dimethylamine salt solution.

[0008] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, in step S10, the absolute pressure of the vacuum concentration is 0.04 MPa to 0.09 MPa, and the concentration temperature is 40°C to 70°C.

[0009] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, in step S20, the amount of the moderately polar organic solvent added is 20% to 80% of the mass of pure dimethylamine.

[0010] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, the moderately polar organic solvent is selected from at least one of ethanol, N,N-dimethylformamide and ethanol.

[0011] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, when the moderately polar organic solvent is a mixed solvent of N,N-dimethylformamide and ethanol, the mass ratio of N,N-dimethylformamide to ethanol is 1:5 to 5:1.

[0012] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, in step S30, the system obtained in step S20 is heated to 75°C to 85°C.

[0013] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, in step S30, the reaction is kept at a constant temperature for 2 to 8 hours.

[0014] Preferably, the above-mentioned low-temperature synthesis method of metformin hydrochloride further includes the following steps: S40. The reaction solution is cooled and crystallized to obtain a crystallized slurry; S50. The crystallized slurry is subjected to solid-liquid separation and dried to obtain metformin hydrochloride.

[0015] Preferably, in the above-mentioned low-temperature synthesis method of metformin hydrochloride, step S40, "cooling the reaction solution to crystallize and grow crystals" specifically means: controlling the cooling rate to be 0.5℃ / min~2.0℃ / min, and keeping the temperature at 0℃~15℃ for crystal growth for 0.5h~6h.

[0016] Compared with the prior art, this application has at least the following advantages: This invention discloses a low-temperature synthesis method for metformin hydrochloride, belonging to the field of pharmaceutical chemical synthesis and active pharmaceutical ingredient preparation technology. The method includes the following steps: adjusting the pH of an aqueous dimethylamine solution to 1.8–2.3 with acid; concentrating the resulting salinized solution under reduced pressure to remove some water, resulting in a water content of 10 wt%–35 wt% in the system; adding ethanol or a mixed solvent of N,N-dimethylformamide and ethanol to the concentrated system; cooling the system to 45°C–55°C and then adding dicyandiamide, wherein the amount of dicyandiamide added is 62%–67% of the mass of pure dimethylamine; subsequently, maintaining the reaction temperature at 70°C–90°C, cooling to crystallize, growing crystals, separating and drying to obtain metformin hydrochloride.

[0017] This invention achieves biguanide bridge construction at lower temperatures through synergistic control of pH, free water content, solvent environment, and feeding sequence. This offers advantages such as reduced energy consumption, improved industrial safety, suppression of side reactions, and increased feasibility for process scale-up. At 80°C, this invention achieves a product yield of 94.5% and HPLC purity of 99.85%, with melamine not detected (<0.01%); at 75°C, it achieves a product yield of 93.2% and HPLC purity of 99.78%, with melamine not detected (<0.01%). In comparison, the traditional process at 130°C–140°C achieves a product yield of 88.2%, an HPLC purity of 99.12%, and a melamine content of 0.08%. These comparisons demonstrate that this invention, at reaction temperatures significantly lower than traditional processes, not only avoids a decrease in yield or purity but also simultaneously achieves higher product yields, higher HPLC purity, and effective suppression of melamine byproducts.

[0018] Meanwhile, this invention does not rely on high-temperature melting conditions above 130°C, nor on complex and expensive special catalytic systems. It is applicable to conventional glass-lined or stainless steel reactors, vacuum concentration equipment, crystallization equipment, and conventional solid-liquid separation equipment, and has good prospects for industrial implementation. Attached Figure Description

[0019] Figure 1 This is a process flow diagram of the low-temperature synthesis method of metformin hydrochloride in this application. Detailed Implementation

[0020] It should be noted that, unless otherwise specified, the embodiments and features described in the embodiments of this invention can be combined with each other. The technical solutions of this invention will be further described below with reference to the embodiments and accompanying drawings. This invention is not limited to the specific embodiments described below.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in this specification is for descriptive purposes only and is not intended to limit the scope of this application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0022] Please see Figure 1 In one specific embodiment of this application, a low-temperature synthesis method for metformin hydrochloride includes the following steps: S10. Obtain the acidified dimethylamine salt solution and concentrate it under reduced pressure until the water content in the system is 10wt% to 35wt%; The "obtaining the acidified dimethylamine salt solution" includes: A dimethylamine aqueous solution with a mass concentration of 20% to 50%, preferably 30% to 45%, is added to the reactor. Under stirring conditions, a hydrochloric acid solution with a mass concentration of 31% to 37% is added dropwise. The system temperature is controlled at 10℃ to 35℃, and the pH of the system is adjusted to 1.8 to 2.3 to obtain an acidified dimethylamine salt solution.

[0023] This invention controls the system pH at 1.8–2.3, preferably 1.9–2.1, and more preferably 2.0, not simply to form dimethylamine salt, but to establish an acid-base microenvironment suitable for the target condensation reaction at low temperatures. If the acidity is too low, dimethylamine is over-protonated, reducing the activity of the effective reactants that can participate in the formation of biguanide bridges; if the acidity is insufficient, the activation and ion association state of dicyandiamide are unfavorable to the target reaction. Limiting the pH within the above-mentioned window balances reaction activity and selectivity in reaction kinetics, thus facilitating the achievement of stable conversion rates at lower temperatures.

[0024] Preferably, the absolute pressure of the vacuum concentration is 0.04 MPa to 0.09 MPa, and the concentration temperature is 40°C to 70°C; further, the absolute pressure of the vacuum concentration is 0.05 MPa to 0.08 MPa, and the concentration temperature is 45°C to 60°C.

[0025] S20. Add a moderately polar organic solvent to the system after vacuum concentration, stir until homogeneous, cool to 45°C–55°C, and then add dicyandiamide; the amount of dicyandiamide added is 62%–67% of the mass of pure dimethylamine; Preferably, the amount of the moderately polar organic solvent added is 20% to 80% of the mass of pure dimethylamine, and more preferably 30% to 40%; the moderately polar organic solvent is selected from at least one of ethanol or N,N-dimethylformamide, and when the moderately polar organic solvent is a mixed solvent of N,N-dimethylformamide and ethanol, the mass ratio of N,N-dimethylformamide to ethanol is 1:5 to 5:1; This invention employs a method of first concentrating under reduced pressure, then adding a moderately polar organic solvent, followed by the addition of dicyandiamide at 45°C–55°C. This sequence significantly improves engineering feasibility. In this scheme, dicyandiamide is added in batches or continuously over a period of 5–120 minutes, preferably 10–60 minutes. Directly adding dicyandiamide to a high-concentration salt system can easily lead to localized high viscosity, agglomeration, limited mass transfer, and difficulty in stirring. By first adding ethanol or a mixture of N,N-dimethylformamide and ethanol, a stirable slurry system can be established, significantly improving the wetting, dispersion, and heat transfer pathways of solid dicyandiamide, thereby enhancing the uniformity of feed and the stability of reaction scale-up.

[0026] At the molecular level, the N,N-dimethylformamide and ethanol dual-solvent system exhibits a synergistic effect. N,N-dimethylformamide enhances the apparent solubility and dispersion of dicyandiamide and ionic intermediates at lower temperatures, reducing the probability of side reactions caused by local supersaturation and high concentrations. Ethanol, on the other hand, regulates the overall polarity and solute activity of the system and reduces the solubility of the target product in the mother liquor in the later stages of the reaction, promoting crystallization. When both work together, a more suitable mass transfer and dissolution environment for biguanide bridge formation can be established without relying on high-temperature melting conditions, thereby improving the reaction homogeneity and subsequent crystallization controllability under low-temperature conditions. This composite solvent system is beneficial for improving the dispersion and apparent solubility of dicyandiamide at lower temperatures, keeping the system viscosity within a range suitable for stirring and heat transfer during the reaction.

[0027] S30. Heat the system obtained in step S20 to 70℃~90℃ and keep it at that temperature for 1h~12h to obtain the reaction solution; This invention limits the main reaction temperature to 70℃~90℃, significantly lower than the traditional high-temperature processes above 130℃. For industrial equipment, the lower temperature window can reduce the temperature difference between the jacket and the material inside the vessel, alleviate local overheating and the tendency of adhesion to the vessel wall, and improve heat transfer uniformity and intrinsic safety.

[0028] Preferably, the system obtained in step S20 is heated to 75℃~85℃ and kept at that temperature for 2h~8h.

[0029] S40. The reaction solution is cooled and crystallized to obtain a crystallized slurry; Specifically, the cooling rate is controlled at 0.5℃ / min to 2.0℃ / min, and the crystals are grown at 0℃ to 15℃ for 0.5h to 6h. This invention uses cooling at 0℃ to 15℃ during the crystallization stage, supplemented by controlled crystal growth, to achieve a more balanced nucleation and crystal growth process. Preferably, the cooling rate is controlled at 0.5℃ / min to 2.0℃ / min, and the crystals are grown at 0℃ to 15℃ for 0.5h to 6h, with a further crystallization temperature of 3℃ to 8℃ and a crystal growth time of 1h to 3h. These parameters help avoid the formation of a large number of fine crystals caused by instantaneous supersaturation, reduce mother liquor entrainment, and improve crystal flowability, filterability, and drying properties, thereby improving yield and the purity stability of the final product.

[0030] S50. The crystalline slurry is subjected to solid-liquid separation and dried to obtain metformin hydrochloride. Preferably, the drying temperature is 50℃~90℃.

[0031] This invention reduces the likelihood of self-condensation, deep condensation, and side reactions of dicyandiamide at high temperatures and localized high concentrations by controlling pH, free water content, feeding sequence, and solvent environment. For melamine-related byproducts, their formation is typically related to further condensation of dicyandiamide in unfavorable microenvironments. This invention operates at temperatures lower than conventional high-temperature methods and reduces the activation opportunities of side reactions by improving micro-dispersion and localized thermodynamic environment, thus contributing to lower levels of melamine and related impurities. Based on the experimental results of examples and comparative examples, this invention achieves a product yield of 94.5% and HPLC purity of 99.85% at 80°C, with melamine not detected (<0.01%). In contrast, the conventional 130°C–140°C process achieves a product yield of 88.2%, HPLC purity of 99.12%, and a melamine content of 0.08%. The above comparison shows that, at a reaction temperature significantly lower than that of traditional processes, the present invention not only did not result in a decrease in yield or purity, but also achieved higher product yield, higher HPLC purity, and effective suppression of melamine byproducts.

[0032] This invention does not rely on high-temperature melting conditions above 130°C, nor on complex and expensive special catalytic systems. It is applicable to conventional glass-lined or stainless steel reactors, vacuum concentration equipment, crystallization equipment, and conventional solid-liquid separation equipment, and has good prospects for industrial implementation.

[0033] It is worth noting that the process temperature and process time involved in the above embodiments are all temperatures or times used in the experiment. Any reasonable adjustments made by those skilled in the art based on the process temperature and process time provided by the present invention, within the error range, should be included within the protection scope of the present invention.

[0034] The technical solution and effects of the present invention will be further illustrated below through specific embodiments.

[0035] 1. Experimental Materials and Methods It should be noted that in the embodiments of this invention, all raw materials and reagents are commercially available and can be used without further purification. Unless otherwise stated, "parts" as used herein refers to parts by mass; when the ratio of dimethylamine to dicyandiamide is involved, dimethylamine is calculated based on its pure mass (100%).

[0036] The yield calculation formula for metformin hydrochloride samples is as follows: Yield (%) = Actual product mass / Theoretical product mass × 100% Wherein, actual product quality = crude product quality × purity (%) 2. Example 1 Add 250 parts of a 40% dimethylamine aqueous solution (equivalent to 100 parts of pure dimethylamine) to a reactor equipped with a stirrer, thermometer, dropping device, and pressure reducing port. Turn on the stirrer and maintain the reactor temperature at 20°C. Slowly add a 35% hydrochloric acid solution while stirring, controlling the system temperature not to exceed 30°C during the addition process, and monitor the pH in real time. Stop adding acid when the pH reaches 2.0 ± 0.1, and continue stirring for 15 minutes to obtain an acidified dimethylamine salt solution. The acidified dimethylamine salt solution was concentrated under reduced pressure at 0.06 MPa and 55°C to remove some water, bringing the water content of the system down to approximately 22 wt%. Then, 30 parts of anhydrous ethanol were added to the concentrated system and stirred for 15 minutes to form a homogeneous, flowable medium. Cool the system to 50°C, add 64 parts of dicyandiamide in batches, then heat to 80°C and keep the temperature for 4 hours. After the reaction was completed, the system was cooled to 5°C at a cooling rate of 1.0°C / min and kept at this temperature for 2 hours to promote the precipitation of metformin hydrochloride crystals. Subsequently, centrifugation was performed, the filter cake was washed with cold ethanol and dried under vacuum at 70°C to obtain the finished metformin hydrochloride product.

[0037] 3. Example 2 The dimethylamine salting and vacuum concentration steps were completed according to the method of Example 1. Then, 40 parts of a composite solvent were added to the concentration system, wherein the mass ratio of N,N-dimethylformamide to ethanol was 1:1, and the mixture was stirred for 15 minutes to form a homogeneous and flowable medium. Adjust the system temperature to 50℃, add 64 parts of dicyandiamide in batches, then raise the temperature to 75℃ and keep the reaction at that temperature for 6 hours; After the reaction was completed, the system was cooled to 5°C at a cooling rate of 1.0°C / min and kept at this temperature for 2 hours to promote the precipitation of metformin hydrochloride crystals. Subsequently, centrifugation was performed, the filter cake was washed with cold ethanol and dried under vacuum at 70°C to obtain the finished metformin hydrochloride product.

[0038] 4. Comparative Example 1 The other steps are the same as in Example 1, except that the acidified dimethylamine salt solution is not concentrated under pressure, but anhydrous ethanol is added directly to it for subsequent operations.

[0039] 5. Comparative Example 2 Using a traditional high-temperature process, dicyandiamide and dimethylamine hydrochloride were mixed and stirred with DMF in a molar ratio of 1:1.05 and 2.5 times the total solid mass of the solvent. The mixture was heated to 135°C and kept at that temperature for 7 hours. After the reaction was completed, the temperature was slowly lowered to 20°C, followed by centrifugation. The filter cake was washed with cold ethanol and dried to obtain the finished product, metformin hydrochloride.

[0040] The purity of the above metformin hydrochloride product was tested and the yield was calculated, as shown in the table below: Table 1. Test data of finished metformin hydrochloride product

[0041] Note: Unit batch heat consumption is calculated based on the total heat consumed to produce one unit mass (kg) of metformin hydrochloride product. Although Comparative Example 1 has a lower reaction temperature, its energy consumption advantage per unit output is not as significant as that of Example 1 due to its lower yield.

[0042] Please refer to the table above. In Examples 1 and 2 of the present invention, higher yields (93.2%–94.5%) and higher purity (99.78%–99.85%) can still be obtained at lower main reaction temperatures. The level of melamine byproducts can be significantly reduced (not detected). At the same time, the heat consumption per unit batch is reduced by about 35%–43% compared with the traditional process. Better reaction selectivity and impurity control are achieved at lower temperatures, thus demonstrating the advantages of low-temperature process and the engineering advantage of reducing heat consumption.

[0043] The above embodiments merely illustrate several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A low-temperature synthesis method for metformin hydrochloride, characterized in that, Includes the following steps: S10. Obtain the acidified dimethylamine salt solution and concentrate it under reduced pressure until the water content in the system is 10wt% to 35wt%; S20. Add a moderately polar organic solvent to the system after vacuum concentration, stir until homogeneous, cool to 45°C–55°C, and then add dicyandiamide; the amount of dicyandiamide added is 62%–67% of the mass of pure dimethylamine; S30. Heat the system obtained in step S20 to 70℃~90℃ and keep it at that temperature for 1h~12h to obtain the reaction solution.

2. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, In step S10, "obtaining the acidified dimethylamine salting solution" includes: A 20%–50% dimethylamine aqueous solution was added to the reactor, and a 31%–37% hydrochloric acid solution was added dropwise under stirring. The system temperature was controlled at 10℃–35℃, and the pH of the system was adjusted to 1.8–2.3 to obtain an acidified dimethylamine salt solution.

3. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, In step S10, the absolute pressure of the vacuum concentration is 0.04 MPa to 0.09 MPa, and the concentration temperature is 40°C to 70°C.

4. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, In step S20, the amount of the moderately polar organic solvent added is 20% to 80% of the mass of pure dimethylamine.

5. The low-temperature synthesis method of metformin hydrochloride as described in claim 4, characterized in that, The moderately polar organic solvent is selected from at least one of ethanol or a mixture of N,N-dimethylformamide and ethanol.

6. The low-temperature synthesis method of metformin hydrochloride as described in claim 5, characterized in that, When the moderately polar organic solvent is a mixture of N,N-dimethylformamide and ethanol, the mass ratio of N,N-dimethylformamide to ethanol is 1:5 to 5:

1.

7. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, In step S30, the system obtained in step S20 is heated to 75℃~85℃.

8. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, In step S30, the reaction is kept at a constant temperature for 2 to 8 hours.

9. The low-temperature synthesis method of metformin hydrochloride as described in claim 1, characterized in that, It also includes the following steps: S40. The reaction solution is cooled and crystallized to obtain a crystallized slurry; S50. The crystallized slurry is subjected to solid-liquid separation and dried to obtain metformin hydrochloride.

10. The low-temperature synthesis method of metformin hydrochloride as described in claim 9, characterized in that, In step S40, "cooling the reaction solution to crystallize and grow crystals" specifically means: controlling the cooling rate to be 0.5℃ / min to 2.0℃ / min, and keeping the solution at 0℃ to 15℃ for crystal growth for 0.5h to 6h.

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