WO2023147729A1

WO2023147729A1 - Continuous synthesis system and method for metformin hydrochloride

Info

Publication number: WO2023147729A1
Application number: PCT/CN2022/123603
Authority: WO
Inventors: 洪浩; 洪亮; 陶建; 陈富荣; 王帆; 戴睿智; 张贺伟
Original assignee: 天津凯莱英医药科技发展有限公司
Priority date: 2022-02-07
Filing date: 2022-09-30
Publication date: 2023-08-10
Also published as: CN114130348A

Abstract

A continuous synthesis system for metformin hydrochloride. The continuous synthesis system for metformin hydrochloride comprises a continuous feeding unit (10) and a horizontal double-shaft reaction device (20). The horizontal double-shaft reaction device (20) comprises a first stirring shaft (22) and a second stirring shaft (23) which can rotate in opposite directions, wherein stirring blades of the first stirring shaft (22) and the second stirring shaft (23) that are located at corresponding positions engage with each other, and the first stirring shaft (22) comprises a first stirring disc (222) and first stirring blades (223), the included angle between an axis of the first stirring disc (222) and the first stirring blade (223) being an acute angle; and the second stirring shaft (23) comprises a second stirring disc (232) and second stirring blades (233), the included angle between an axis of the second stirring disc (232) and the second stirring blade (233) being an acute angle. Metformin hydrochloride is prepared by using the continuous synthesis device such that the production cost can be reduced, the period can be shortened, solvent consumption and the risk of solid material blockage can be reduced, and the safety of a whole process can also be improved and the continuous synthesis device is environmentally friendly.

Description

Metformin hydrochloride continuous synthesis system and continuous synthesis method

This application is based on the Chinese application with CN application number 202210115447.8 and the filing date is February 07, 2022, and claims its priority. The disclosure content of this CN application is incorporated into this application as a whole again.

technical field

The invention relates to the field of preparation of metformin hydrochloride, in particular to a continuous synthesis system and continuous synthesis method of metformin hydrochloride.

Background technique

Metformin hydrochloride has strong physiological activity, not only has a unique therapeutic effect on type Ⅱ diabetes, but also pharmacological studies have proved that it can also significantly lower blood pressure and reduce the concentration of glutathione in the blood and Mg ²⁺ in the liver , has the function of protecting the liver. Animal experiments have proved that metformin hydrochloride also has obvious weight loss effect. Therefore, metformin hydrochloride is a chemically synthesized substance with broad-spectrum therapeutic effects, and is clinically used as a hypoglycemic agent. The synthetic method of metformin hydrochloride mainly contains solvent method and melting method, and synthetic route is as follows:

1) Solvent method: mix dicyandiamide and dimethylamine hydrochloride in a certain ratio, and add a solvent (such as isoamyl alcohol, n-pentanol, n-hexanol and cyclohexanol, etc.) to dissolve the above-mentioned reaction raw materials. The reaction is carried out under heating conditions, and solids are continuously precipitated during the reaction process. After the reaction is completed, the solid-liquid mixture is cooled and filtered to obtain a crude product of metformin hydrochloride.

2) Melting method: mix dicyandiamide and dimethylamine hydrochloride in a certain ratio, and then heat the above-mentioned raw materials into a molten state. Solids are continuously precipitated during the reaction, and after the reaction is completed, the generated solids are cooled, dissolved, recrystallized, suction filtered and dried to obtain metformin hydrochloride in white powder form.

Although the existing continuous solvent method can solve the problems of large equipment size and many side reactions, but because the metformin hydrochloride product is easy to precipitate in the form of solid, it is easy to block the discharge channel, resulting in the problem of inability to discharge. Existing melting method, a kind of is the small test data that carries out with melting point apparatus, and a kind of generally is with twin-screw extruder. It cannot be enlarged by the method of melting point apparatus. On the one hand, using a twin-screw extruder is easy to fill the two screw pitches with materials, causing the system to lose driving force and cannot be extruded. On the other hand, it cannot solve the problem of long-term reaction solids locked in the screws and unable to discharge.

In view of the existence of the above-mentioned problems, it is necessary to provide a method for synthesizing metformin hydrochloride that can meet the needs of continuous production and low risk of solid material blocking the discharge channel.

Contents of the invention

The main purpose of the present invention is to provide a continuous synthesis system and continuous synthesis method of metformin hydrochloride, so as to solve the problem that when the existing continuous synthesis system of metformin hydrochloride is applied to a reaction system with high solid content, the solid material is prone to clogging during the long-term reaction process , the problem of not being able to produce materials.

In order to achieve the above object, the present invention provides a continuous metformin hydrochloride synthesis system on the one hand. The metformin hydrochloride continuous synthesis system includes: a continuous feeding unit and a horizontal twin-shaft reaction device. The continuous feeding unit is provided with a dicyandiamide outlet, a dimethylamine hydrochloride outlet and a liquid material outlet; the horizontal biaxial reaction device includes a first stirring shaft and a second stirring shaft that can rotate in opposite directions, and the first stirring shaft and the second stirring shaft The stirring blades at the corresponding positions of the two stirring shafts are meshed with each other. The horizontal biaxial reaction device is provided with a feed port and a discharge port. The feed port is respectively connected with the dicyandiamide outlet, the dimethylamine hydrochloride outlet and the liquid material outlet. To make the reaction material continuously enter the horizontal biaxial reaction device; the stirring blade includes a first stirring blade and a second stirring blade, and the horizontal biaxial reaction device includes: a shell, a first stirring shaft, a second stirring shaft; the first stirring The shaft includes a first stirring rod, a first stirring disc and a first stirring blade connected in sequence, the first stirring shaft is arranged inside the casing and extends along the axial direction of the casing; the second stirring shaft includes a second stirring blade connected in sequence The stirring rod, the second stirring disc and the second stirring blade, the second stirring shaft is also arranged inside the housing, and is arranged parallel to the first stirring shaft; the axis of the first stirring disc and the first stirring blade are arranged at a first acute angle , the axis of the second stirring disc and the second stirring blade are arranged at a second acute angle.

Further, the first acute angle and the second acute angle are independently selected from 1° to 15°.

Further, the housing is two hollow connected cylinders, the first stirring shaft and the second stirring shaft are correspondingly arranged at the axial positions of the two cylinders, and the first stirring blade, the second stirring blade and the housing The minimum distance between them is 3~5mm.

Further, the first stirring disc and the second stirring disc are polygonal stirring discs; the first stirring blade and the second stirring blade are correspondingly arranged at the apex positions of the first stirring disc and the second stirring disc; preferably, the first stirring blade and the second stirring blade is an E-shaped stirring blade.

Further, the metformin hydrochloride continuous synthesis system also includes a continuous discharge device, and the continuous discharge device is used to continuously discharge the reactants discharged from the discharge port; preferably, the continuous discharge device is selected from a twin-screw discharge device or a double-screw Discharge device.

Further, the continuous feeding unit includes: a dicyandiamide feeding device and a dimethylamine hydrochloride feeding device, the dicyandiamide feeding device is provided with a dicyandiamide feeding port and a dicyandiamide outlet, and the dimethylamine hydrochloride feeding device It is provided with a dimethylamine hydrochloride inlet and a dimethylamine hydrochloride outlet; an optional solvent feeding device is provided with a solvent inlet and a liquid material outlet.

Further, the metformin hydrochloride continuous synthesis system also includes a vacuum device, and the vacuum device communicates with the horizontal biaxial reaction device.

Further, the metformin hydrochloride continuous synthesis system also includes a post-processing unit, the post-processing unit is provided with an inlet for the material to be treated, and the inlet for the material to be treated is connected to the outlet of the continuous discharge device for purifying the product.

Further, the post-processing unit includes: at least one alcohol washing device, a temperature-controlled crystallization device and a filtration washing and drying device, the alcohol washing device is provided with an alcohol solvent inlet, a water inlet, a material inlet to be treated and an alcohol washing outlet; the temperature-controlled crystallization device is provided with There is an inlet to be crystallized and a crystal outlet, and the inlet to be crystallized is connected with the alcohol washing outlet through the alcohol washing product delivery pipeline; the filter washing and drying device is provided with a washing inlet, and the washing inlet and the crystal outlet are connected through the crystal delivery pipeline; preferably, the alcohol The washing device is a fully mixed flow reactor; preferably, the temperature of the alcohol washing device is 45-90°C, more preferably 60-80°C; preferably, in the alcohol washing device, the weight ratio of alcohol solvent to water is 5:5 ~9:1, more preferably 6:4~8:2; and the sum of the volumes of alcohol solvent and water is 2~12 times, preferably 3~6 times of the volume of dicyandiamide in the reaction raw materials.

Further, the alcohol washing device is also provided with an activated carbon inlet, and the post-processing unit also includes a filter device, which is arranged on the alcohol washing product delivery pipeline.

Further, along the flow direction of the material, the temperature-controlled crystallization device includes multiple temperature-controlled areas; preferably, the temperature-controlled range of the temperature-controlled crystallization device is -40-90°C, more preferably -20-80°C.

Further, the temperature difference between two adjacent temperature control areas is 5-40°C.

The second aspect of the present application also provides a continuous synthesis method of metformin hydrochloride. The device used in the continuous synthesis method of metformin hydrochloride is the above-mentioned continuous synthesis system of metformin hydrochloride.

Applying the technical scheme of the present invention, the metformin hydrochloride continuous synthesis system provided by the application adopts a horizontal biaxial reaction device as the reaction device, and the continuous feeding unit provides reaction raw materials for the horizontal biaxial reaction device. The stirring blades at the corresponding positions of the first stirring shaft and the second stirring shaft can rotate at different speeds and scrape each other, which enables the solid materials produced in the reaction system with high solid content to be discharged continuously, while the unreacted liquid materials remain Stay in the horizontal biaxial reaction device; Simultaneously the included angle of the axis of the first stirring blade and the first stirring disk, and the included angle between the axis of the second stirring blade and the second stirring disk are all set to acute angle and can improve The discharge rate of solid materials solves the problem that solid materials are easy to lock the stirring shaft during the long-term reaction process, and then blockage occurs and the problem of inability to discharge materials occurs. The preparation of metformin hydrochloride by using the above-mentioned continuous synthesis device can not only reduce the production cost, shorten the cycle, reduce the amount of solvent used and the risk of solid material clogging, but also improve the safety of the entire process and be environmentally friendly. At the same time, it also has the advantages of easy scale-up production, stable quality, high safety, simple process, and precise control.

Description of drawings

The accompanying drawings constituting a part of the present application are used to provide a further understanding of the present invention, and the schematic embodiments and descriptions of the present invention are used to explain the present invention, and do not constitute an improper limitation of the present invention. In the attached picture:

Fig. 1 is the structural representation of the metformin hydrochloride continuous synthesis system that a kind of preferred embodiment of the present application provides;

Figure 2 is a side view of a horizontal biaxial reaction device provided by a preferred embodiment of the present application;

Fig. 3 is a schematic structural diagram of an E-shaped stirring blade provided by a preferred embodiment of the present application.

Wherein, the above-mentioned accompanying drawings include the following reference signs:

10. Continuous feeding unit; 11. Dicyandiamide feeding device; 12. Dimethylamine hydrochloride feeding device; 13. Solvent feeding device; 14. First conveying device; 20. Horizontal biaxial reaction device; 21. Shell; 22, the first stirring shaft; 221, the first stirring rod; 222, the first stirring plate; 223, the first stirring blade; 224, the first inner tube; 23, the second stirring shaft; 231, the second stirring Rod; 232, the second stirring plate; 233, the second stirring blade; 234, the second inner tube; 30, vacuum device; 40, solvent storage tank; 50, continuous discharge device; 60, post-processing unit; 61, Alcohol washing device; 62. Temperature-controlled crystallization device; 621. Fifth conveying device; 63. Filtration washing and drying device; 631. Eluent washing device; 632. Eluent recovery device; 633. Product receiving device; 641. The fourth conveying device; 65. The alcohol solution supply device; 651. The second conveying device; 66. The activated carbon supply device; 661. The third conveying device.

Detailed ways

It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below in conjunction with examples.

As described in the background technology, when the existing metformin hydrochloride continuous synthesis system is applied to a high solid content reaction system, there is a problem that the solid material is easily blocked during the long-term reaction process and cannot be discharged. In order to solve the above-mentioned technical problems, the application provides a kind of metformin hydrochloride continuous synthesis system, as shown in Figure 1, this metformin hydrochloride continuous synthesis system comprises: continuous feed unit 10 and horizontal biaxial reaction device 20, continuous feed unit 10 is provided with dicyandiamide outlet, dimethylamine hydrochloride outlet and liquid material outlet; The stirring blades at the corresponding positions of the second stirring shaft 23 are meshed with each other, and the horizontal biaxial reaction device 20 is provided with a feed inlet and a feed outlet, and the feed inlet is connected to the dicyandiamide outlet, the dimethylamine hydrochloride outlet and the liquid material respectively. The outlet is communicated so that the reaction materials continuously enter the horizontal biaxial reaction device 20; the continuous discharge device 50 is used to continuously discharge the reactants discharged from the discharge port; the stirring blades include a first stirring blade 223 and a second stirring blade 233 , The horizontal double-shaft reaction device 20 includes: a housing 21, a first stirring shaft 22 and a second stirring shaft 23; wherein the first stirring shaft 22 includes a first stirring rod 221, a first stirring plate 222 and a first stirring plate connected in sequence. Stirring blades 223, the first stirring shaft 22 is arranged inside the housing 21, and extends along the axial direction of the housing 21; the second stirring shaft 23 includes a second stirring rod 231, a second stirring disc 232 and a second The stirring blade 233, the second stirring shaft 23 is also arranged in the inside of the housing 21, and is arranged parallel to the first stirring shaft 22; the axis of the first stirring disc 222 and the first stirring blade 223 are arranged at a first acute angle, and the second stirring The axis of the disk 232 and the second stirring blade 233 are arranged at a second acute angle.

In the metformin hydrochloride continuous synthesis system provided by the present application, a horizontal biaxial reaction device 20 is used as the reaction device, and the continuous feeding unit 10 provides reaction raw materials for the horizontal biaxial reaction device 20 . Utilizing the stirring blades at the corresponding positions of the first stirring shaft 22 and the second stirring shaft 23 can rotate at different speeds and scrape each other, which enables the solid material produced in the reaction system with high solid content to be continuously discharged, while the unreacted liquid Material still stays in the horizontal biaxial reaction device 20; Setting the angle as an acute angle can increase the discharge rate of the solid material, thus solving the problem that the solid material is easy to lock the agitator shaft during the long-term reaction process, and then blockage occurs and the discharge cannot be discharged. Therefore, the preparation of metformin hydrochloride by using the above-mentioned continuous synthesis device can not only reduce the production cost, shorten the cycle, reduce the amount of solvent used and the risk of solid material clogging, but also improve the safety of the entire process and be environmentally friendly. At the same time, it also has the advantages of easy scale-up production, stable quality, high safety, simple process, and precise control.

In order to further increase the discharge rate of solid materials, preferably, the first acute angle and the second acute angle are independently selected from 1° to 15°.

In a preferred embodiment, as shown in Figures 1 and 2, the housing 21 is two hollow connected cylinders, and the first stirring shaft 22 and the second stirring shaft 23 are correspondingly arranged on the sides of the two cylinders. The axis position, and the minimum distance between the first stirring blade 223 and the second stirring blade 233 and the housing 21 is 3-5 mm. Limiting the minimum distance between the first stirring blade 223 and the second stirring blade 233 and the casing 21 within the above range is beneficial to further reduce the risk of material jams due to too high solid content. On the other hand, the driving force of solid materials can be used to increase the discharge speed, thereby further reducing the risk of material jams.

The cross-section of the housing 21 is two connected circles, and the first stirring shaft 22 and the second stirring shaft 23 are correspondingly arranged at the axial positions of the two cylinders, which is beneficial to better agitate the solid materials in the housing 21 . At the same time, limiting the minimum distance between the first stirring blade 223 and the second stirring blade 233 and the housing 21 within the above range is conducive to further cleaning the solid material on the inner wall of the housing 21 , thereby further reducing the risk of solid material accumulation.

In a preferred embodiment, as shown in Figure 1, the first stirring disc 222 and the second stirring disc 232 are polygonal stirring discs; the first stirring blade 223 and the second stirring blade 233 are arranged on the first stirring disc 222 and the apex position of the second stirring plate 232. The first stirring blade 223 and the second stirring blade 233 are correspondingly arranged at the apex positions of the first stirring disk 222 and the second stirring disk 232, so that multi-rate cooperation can be realized to stir the solid material in the horizontal biaxial reaction device 20, thereby effectively It is beneficial to further improve the transfer rate of solid materials. The shapes of the first stirring blade 223 and the second stirring blade 233 can be selected from common types in the field. In order to further improve the stirring effect, preferably, the first stirring blade 223 and the second stirring blade 233 are E-shaped stirring blades ,As shown in Figure 3. There can be multiple E-shaped stirring blades, and the angles of each E-shaped stirring blade are different, so as to better improve the stirring effect.

In a preferred embodiment, as shown in Figure 1, the metformin hydrochloride continuous synthesis system also includes a continuous discharge device 50, and the continuous discharge device 50 is used to continuously discharge the reactant discharged from the discharge port . By setting the continuous discharge device 50, the solid material discharged from the discharge port can be transferred out more quickly, thereby further reducing the risk of solid material accumulation. More preferably, the above-mentioned continuous discharge device 50 includes but is not limited to a single-screw discharge device, a twin-screw discharge device, a single-screw discharge device or a double-screw discharge device. In order to ensure discharge at a specific required flow rate, the continuous discharge device 50 can select overflow discharge or direct discharge.

When adopting solvent method to synthesize metformin hydrochloride, in a kind of preferred embodiment, as shown in Figure 1, above-mentioned continuous feeding unit 10 comprises: dicyandiamide feeding device 11 and dimethylamine hydrochloride feeding device 12 and solvent Feeding device 13, dicyandiamide feeding device 11 is provided with dicyandiamide feeding port and dicyandiamide outlet, dimethylamine hydrochloride feeding device 12 is provided with dimethylamine hydrochloride inlet and dimethylamine hydrochloride outlet; The solvent feeding device 13 is provided with a solvent inlet and a liquid material outlet.

When adopting melting method to synthesize metformin hydrochloride, in another preferred embodiment, above-mentioned continuous feeding unit 10 comprises: dicyandiamide feeding device 11 and dimethylamine hydrochloride feeding device 12, dicyandiamide feeding device 11 Dicyandiamide feeding port and dicyandiamide outlet are provided, and dimethylamine hydrochloride feeding device 12 is provided with dimethylamine hydrochloride inlet and dimethylamine hydrochloride outlet, dicyandiamide outlet and dimethylamine hydrochloride The salt outlets are all communicated with the solid material outlets through solid material conveying pipelines.

Preferably, as shown in FIG. 1 , the above-mentioned metformin hydrochloride continuous synthesis system further includes a vacuum device 30 , and the vacuum device 30 communicates with the horizontal biaxial reaction device 20 . When using the solvent method to synthesize metformin hydrochloride, after the reaction, the solvent can be taken out from the reaction system by vacuuming the vacuum device 30 , and the extracted solvent is stored in the solvent storage tank 40 . When adopting the melting method to synthesize metformin hydrochloride, there is no need to set solvent feeding device 13 and solvent storage tank 40, and vacuum device 30 can be used to discharge excess gas in the reaction system before the reaction, so as to reduce its inhibitory effect on feed .

In order to better control the reaction temperature in the horizontal biaxial reaction device 20, preferably, the metformin hydrochloride continuous synthesis system further includes a temperature control device for controlling the temperature in the horizontal biaxial reaction device 20. More preferably, the above-mentioned temperature control device includes, but is not limited to, a microwave heating device, an infrared heating device, an oil bath heating device or a steam heating device. And the temperature of the reactor can be controlled in stages according to the reaction process. In order to make the temperature difference between the inside and outside of the horizontal biaxial reaction device 20 within the acceptable range of the process, further preferably, as shown in Figure 2, the first stirring rod 221 and the second stirring rod 231 of the above-mentioned horizontal biaxial reaction device 20 are Hollow shafts, and the inner sleeves of each hollow shaft are respectively provided with inner tubes (corresponding to the first inner tube 224, the second inner tube 234), an annular channel is formed between each inner tube and the inner wall of the corresponding hollow shaft, and the heat transfer medium can Circulation is carried out in the annular passage and the inner passage of the inner pipe, thereby reducing the temperature difference between the inside and outside of the horizontal biaxial reaction device 20 and reducing the generation of by-products.

In a preferred embodiment, the above-mentioned metformin hydrochloride continuous synthesis system also includes a post-processing unit 60, as shown in Figure 1, the post-processing unit 60 is provided with a material inlet to be treated, an outlet of the material inlet to be treated and the continuous discharge device 50 End connection for decontamination of product.

With the above post-processing unit 60 installed, the solid-liquid mixture discharged from the continuous discharge device 50 can be continuously and rapidly separated and purified to obtain the target product. The entire continuous process reduces batch operation steps, reduces the exposure risk of chemicals, improves the continuity and connection of each operation, greatly improves production efficiency, and reduces manual labor.

In a preferred embodiment, as shown in FIG. 1 , the post-processing unit 60 includes: at least one alcohol washing device 61 , a temperature-controlled crystallization device 62 and a filtration washing and drying device 63 . The alcohol washing device 61 is provided with an alcohol solvent inlet, a water inlet, an inlet for materials to be treated, and an alcohol washing outlet; the temperature-controlled crystallization device 62 is provided with an inlet for crystallization and a crystal outlet, and the inlet for crystallization and the outlet for alcohol washing pass through the alcohol washing product delivery pipeline Communication; the filter washing and drying device 63 is provided with a washing inlet, and the washing inlet and the crystal outlet are connected through the crystal delivery pipeline.

During the process of the alcohol washing device 61, the metformin hydrochloride hydrochloride can be dissolved and the solubility of the impurities is small, so the impurities can be removed in one step through the alcohol washing process. In the temperature-controlled crystallization device 62, the metformin hydrochloride in the solution can be precipitated from the solution through temperature control, thereby realizing another purification treatment. The crystals discharged through the crystal outlet are rinsed in the filtering, washing and drying device 63, and the impurities on the crystal surface are removed by using the solubility difference between the crystal and its surface impurities in the eluent, and then metformin hydrochloride crystals are recovered through the product receiving device 633 .

Preferably, the above-mentioned alcohol washing device 61 is a fully mixed flow reactor. During the alcohol washing process, the materials to be alcohol washed can be fully mixed in the fully mixed flow reactor, so using it as the alcohol washing device 61 is conducive to further improving the removal rate of impurities.

Preferably, the temperature of the alcohol washing device 61 is 45-90°C. The temperature of the alcohol washing process includes but is not limited to the above-mentioned range, and being limited to the above-mentioned range is conducive to further improving the solubility of metformin hydrochloride, thereby further improving the removal rate of impurities and improving the purity of metformin hydrochloride obtained subsequently. More preferably, the temperature of the alcohol washing device 61 is 60-80°C.

Preferably, in the alcohol washing process, the weight ratio of alcohol (preferably ethanol) to water is 5:5 to 9:1, preferably 6:4 to 8:2, and the sum of the volumes of the two is equal to the double volume of the reaction raw material. 2 to 12 times the volume of cyanamide, preferably 3 to 6 times.

In another preferred embodiment, the above-mentioned alcohol washing device 61 is further provided with an activated carbon inlet, and the above-mentioned post-processing unit 60 further includes a filtering device 64, which is arranged on the transportation pipeline of the alcohol washing product.

Adding activated carbon in the alcohol washing process can decolorize the reaction system in the alcohol washing process, and at the same time remove part of the suspended solids to a certain extent, and then separate the activated carbon from the alcohol washing liquid phase material through the subsequent filter device 64, thereby to recover activated carbon. Preferably, the amount of activated carbon added is 1/10 to 1/30 of the weight of dicyandiamide in the reaction raw materials.

In a preferred embodiment, along the flow direction of the material, the temperature-controlled crystallization device 62 includes a plurality of temperature-controlled regions. Setting multiple temperature control areas can achieve multiple purification purposes through multiple recrystallization processes, thereby helping to further improve the purity of the finally obtained metformin hydrochloride. Preferably, the temperature control range of the temperature-controlled crystallization device 62 is -40-90°C, more preferably -20-80°C.

In order to improve the effect of each recrystallization process and increase the yield of the target product, in a preferred embodiment, the temperature difference between two adjacent temperature control areas is 5-40°C.

Another aspect of the present application also provides a method for the continuous synthesis of metformin hydrochloride. The device used in the continuous synthesis reaction of metformin hydrochloride is the continuous synthesis system of metformin hydrochloride provided by the present application.

In the metformin hydrochloride continuous synthesis system provided by the present application, the horizontal twin-shaft reaction device 20 is used as the reaction device, and the continuous feeding unit provides reaction raw materials for the horizontal twin-shaft reaction device 20 . Utilizing the stirring blades at the corresponding positions of the first stirring shaft 22 and the second stirring shaft 23 can continuously discharge the solid material produced by the reaction, while the unreacted liquid material remains in the reaction device, so the above-mentioned metformin hydrochloride continuous synthesis reaction device is adopted The preparation of metformin hydrochloride can solve the problem that the stirring shaft is easily locked by the solid material during the long-term reaction process, and then blocked and cannot be discharged.

In a preferred embodiment, the continuous synthesis method of metformin hydrochloride includes: reacting dicyandiamide, dimethylamine hydrochloride and optional solvents in the above-mentioned horizontal biaxial reaction device 20 to obtain the desired metformin hydrochloride.

In order to further improve the yield and the purity of metformin hydrochloride, preferably, in the above-mentioned reaction process, the ratio of the feed moles of dicyandiamide and dimethylamine hydrochloride (converted to pure product) is 1:(0.9～1.5) , more preferably 1:(0.9-1.2). The reaction temperature is 125°C-175°C, preferably 130-140°C; the retention time is 1-5h, more preferably 2-3h.

The above-mentioned continuous synthesis method can be applied to ultra-low solvent method (solvent types include but not limited to solvents that can be used for reactions such as isoamyl alcohol, n-pentanol, n-hexanol and cyclohexanol, DMAC, DMF and water) and solvent-free method (including melting method and first adding a small amount of solvent and then distilling under reduced pressure). Optionally, the amount of solvent used is added according to the standard of 1 g of dicyandiamide corresponding to 0-1 mL of reaction solvent.

In a preferred embodiment, the continuous synthesis method of metformin hydrochloride further includes: a step of post-processing the reaction product system continuously discharged from the continuous discharge device 50, so as to improve the purity of metformin hydrochloride. Specifically, the post-processing step includes: washing the reaction product system continuously discharged from the continuous discharge device 50 (subsequently referred to as the material to be treated) in the alcohol washing device 61 to obtain an alcohol washing product; The product is subjected to temperature-controlled crystallization in the temperature-controlled crystallization device 62, and then is subjected to filter detergent drying treatment in the filter washing and drying device 63 to obtain crystals.

Preferably, the temperature of the alcohol washing process in the alcohol washing device 61 is 45-90°C. The temperature of the alcohol washing process includes but is not limited to the above-mentioned range, and being limited to the above-mentioned range is conducive to further improving the solubility of metformin hydrochloride, thereby further improving the removal rate of impurities and improving the purity of metformin hydrochloride obtained subsequently. More preferably, the temperature of the alcohol washing process is 60-80°C.

Preferably, the temperature control range for the temperature-controlled crystallization process in the temperature-controlled crystallization device 62 is -40-90°C, more preferably -20-80°C. In order to improve the effect of each recrystallization process and improve the yield and purity of the target product, in a preferred embodiment, the above-mentioned temperature-controlled crystallization process carries out at least two recrystallization processes, and the temperature difference in each recrystallization process is 5～40℃.

In order to further improve the effect of the alcohol washing process, preferably, in the alcohol washing process, the weight ratio of alcohol (preferably ethanol) to water is 5:5 to 9:1, more preferably 6:4 to 8:2, and two The sum of the added volumes is 2 to 12 times the volume of dicyandiamide in the reaction raw materials, more preferably 3 to 6 times.

In another preferred embodiment, the above-mentioned metformin hydrochloride continuous synthesis method also includes: during the alcohol washing process, adding activated carbon to the alcohol washing device 61, then filtering the alcohol washing product in the filter device 64, and then Temperature-controlled crystallization and filter detergent drying treatment are carried out to obtain the above-mentioned crystals. Adding activated carbon can decolorize the material to be treated, and at the same time remove part of the suspended solids to a certain extent. In order to further improve the effect of decolorization and removal of suspended solids, preferably, the amount of activated carbon added is 1/10-1/30 of the weight of dicyandiamide in the reaction raw materials.

The present application will be described in further detail below in conjunction with specific examples, and these examples should not be construed as limiting the scope of protection claimed in the present application.

The continuous synthesis method adopted in Examples 1 to 16 prepares metformin hydrochloride, and the structural representation of the continuous synthesis device it adopts is shown in Figures 1 and 2, specifically comprising the following steps:

Dicyandiamide and dimethylamine hydrochloride are continuously added to the horizontal twin-shaft reaction device 20 (comprising a shell) by the dicyandiamide feeding device 11 in the continuous feeding unit 10 and the dimethylamine hydrochloride feeding device 12 according to the process flow rate respectively. Body 21, the first stirring shaft 22 and the second stirring shaft 23. When adopting the solvent method to synthesize metformin hydrochloride, the solvent was continuously added in the horizontal biaxial reaction device 20 through the first conveying device 14 from the solvent feeding device 13; After the continuous reaction in the horizontal biaxial reaction device 20, the solvent can be selected to be taken out from the reaction system by vacuuming the vacuum device 30, and the extracted solvent is stored in the solvent storage tank 40. When adopting the melting method to synthesize hydrochloric acid During metformin, there is no need to set solvent feeding device 13 and first conveying device 14 and solvent storage tank 40, adopt vacuum device 30 to discharge the unnecessary gas in the reaction system before reaction.The solid material that reaction obtains passes through continuous discharge device 50 After being discharged, it enters the post-processing unit 60 .

The material discharged through the continuous discharge device 50 enters the alcohol washing device 61, and the alcohol solution supply device 65 adds the mixed solution of alcohol and water to the alcohol washing device 61 through the second conveying device 651, and the activated carbon supply device 66 passes through the third conveying device. The device 661 adds activated carbon into the alcohol washing device 61 to perform alcohol washing treatment. After the alcohol washing process is completed, the alcohol-washed material enters the filter device 64 through the fourth conveying device 641 for filtration, and the obtained liquid phase product enters the temperature-controlled crystallization device 62 for recrystallization treatment. After the crystals are discharged from the crystal outlet, they pass through the fifth conveying device 621 and enter the filtering, washing and drying device 63 . In the filtering, washing and drying device 63 , the crystals to be processed are first rinsed through the rinse device 631 , and then the rinsed liquid is recovered in the rinse liquid recovery device 632 , and the final product is stored in the product receiving device 633 .

Comparative example 1

The metformin hydrochloride was prepared in a reaction kettle by a batch method, and the post-treatment was carried out by a batch method at the same time.

The specific reaction conditions, product purity and yield in Examples 1 to 16 and Comparative Example 1 are shown in Tables 1 and 2.

Table 1

Table 2

In addition, "solvent equivalent (V/m)" means: the volume (unit mL) of the solvent corresponding to 1 g of reaction raw materials (dicyandiamide).

"The volume equivalent (V) of solvent" refers to: the ratio of the volume of alcohol washing solvent and dicyandiamide added in the reaction raw materials. For example, when 1 mL of dicyandiamide is added to the reaction raw materials, the volume equivalent of the solvent is 10, which means that the volume of the alcohol washing solvent required in the alcohol washing process is 10 mL.

"5V solvent 30L reactor batch" means: batch reaction is carried out in a 30L reactor, and the solvent equivalent (V/m) is 5 (that is, for every 1g of dicyandiamide added, the required solvent volume is 5mL).

It can be seen from the data in Tables 1 and 2 that, compared with the batch process, when the continuous preparation and post-treatment process provided by the present application is adopted, during the post-treatment process, the dissolution rate of the target product in the solvent is faster, and the final product crystallizes The rate of appearance is fast and the yield is also high.

Comparing Examples 3 to 8, it can be seen that limiting the ratio of alcohol solvent to water and the temperature of alcohol washing in the preferred range of the present application helps to improve the separation effect and the yield of the target product during the alcohol washing process.

Comparing Examples 9 to 11, it can be seen that limiting the amount of alcohol washing solvent in the alcohol washing process to the preferred range of the present application is conducive to improving the separation effect and increasing the yield of the target product.

Comparing Examples 6 and 12 to 16, it can be seen that limiting the temperature difference during the recrystallization process within the preferred range of the present application is conducive to improving the separation effect and increasing the yield of the target product.

It should be noted that the terms "first" and "second" in the specification and claims of the present application are used to distinguish similar objects, but not necessarily used to describe a specific order or sequence. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the application described herein are, for example, capable of operation in sequences other than those described herein.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

A metformin hydrochloride continuous synthesis system is characterized in that, the metformin hydrochloride continuous synthesis system comprises:

Continuous feeding unit (10), described continuous feeding unit (10) is provided with dicyandiamide outlet, dimethylamine hydrochloride outlet and liquid material outlet;

A horizontal biaxial reaction device (20), the horizontal biaxial reaction device (20) includes a first stirring shaft (22) and a second stirring shaft (23) that can rotate in opposite directions, and the first stirring shaft (22 ) and the stirring blades at the corresponding positions of the second stirring shaft (23) are engaged with each other, and the horizontal biaxial reaction device (20) is provided with a feed port and a discharge port, and the feed port is respectively connected to the dual The cyanamide outlet, the dimethylamine hydrochloride outlet and the liquid material outlet are in communication, so that the reaction material continuously enters the horizontal biaxial reaction device (20);

Wherein, the stirring blade comprises a first stirring blade (223) and a second stirring blade (233), and the horizontal biaxial reaction device (20) comprises:

housing (21);

The first stirring shaft (22) comprises a first stirring rod (221), a first stirring plate (222) and the first stirring blade (223) connected in sequence, and the first stirring shaft (22) is set inside the housing (21) and extending along the axial direction of the housing (21);

The second stirring shaft (23) comprises a second stirring rod (231), a second stirring plate (232) and the second stirring blade (233) connected in sequence, and the second stirring shaft (23) is also arranged inside the housing (21), and arranged parallel to the first stirring shaft (22);

The axis of the first stirring disk (222) and the first stirring blade (223) are arranged at a first acute angle, and the axis of the second stirring disk (232) and the second stirring blade (233) are arranged at a first acute angle. Two acute angles are set; the first acute angle and the second acute angle are independently selected from 1 to 15°; the first stirring plate (222) and the second stirring plate (232) are polygonal stirring plates; The first stirring blade (223) and the second stirring blade (233) are correspondingly arranged at the apex positions of the first stirring plate (222) and the second stirring plate (232); the first stirring The blade (223) and the second stirring blade (233) are E-shaped stirring blades;

The metformin hydrochloride continuous synthesis system also includes a continuous discharge device (50), and the continuous discharge device (50) is used to continuously discharge the reactant discharged from the discharge port; the continuous discharge device (50) ) is selected from a twin-screw discharge device or a twin-screw discharge device;

The metformin hydrochloride continuous synthesis system also includes an aftertreatment unit (60), the aftertreatment unit (60) is provided with a material inlet to be treated, and the material inlet to be treated is communicated with the outlet end of the continuous discharge device (50) , used to purify the product;

The post-processing unit (60) includes:

At least one alcohol washing device (61), the alcohol washing device (61) is provided with an alcohol solvent inlet and a water inlet, as well as the material to be treated inlet and alcohol washing outlet;

A temperature-controlled crystallization device (62), the temperature-controlled crystallization device (62) is provided with an inlet to be crystallized and a crystal outlet, and the inlet to be crystallized is connected to the alcohol washing outlet through an alcohol washing product delivery pipeline;

A filter washing and drying device (63), the filter washing and drying device (63) is provided with a washing inlet, and the washing inlet is communicated with the crystal outlet through a crystal delivery pipeline;

The alcohol washing device (61) is a fully mixed flow reactor;

The temperature of the alcohol washing device (61) is 45-90°C;

In the alcohol washing device (61), the weight ratio of the alcohol solvent to water is 5:5 to 9:1;

Along the flow direction of the material, the temperature-controlled crystallization device (62) includes a plurality of temperature-controlled areas; the temperature-controlled range of the temperature-controlled crystallization device (62) is -40 to 90°C; two adjacent temperature-controlled The temperature difference in the area is 5-40°C.
The metformin hydrochloride continuous synthesis system according to claim 1, is characterized in that, described casing (21) is two connected cylinders of hollow, described first stirring shaft (22) and described second stirring shaft (23) correspondingly set at the axial positions of the two cylinders, and the minimum distance between the first stirring blade (223) and the second stirring blade (233) and the housing (21) It is 3~5mm.
Metformin hydrochloride continuous synthesis system according to claim 1, is characterized in that, described continuous feeding unit (10) comprises:

Dicyandiamide feeding device (11), described dicyandiamide feeding device (11) is provided with dicyandiamide feeding port and described dicyandiamide outlet, dimethylamine hydrochloride feeding device (12), described dimethylamine The amine hydrochloride feeding device (12) is provided with an inlet of dimethylamine hydrochloride and an outlet of said dimethylamine hydrochloride.
The metformin hydrochloride continuous synthesis system according to claim 3, is characterized in that, described continuous feeding unit (10) also comprises solvent feeding device (13), and described solvent feeding device (13) is provided with solvent inlet and described Liquid material outlet.
The metformin hydrochloride continuous synthesis system according to claim 3 or 4, is characterized in that, the metformin hydrochloride continuous synthesis system also comprises a vacuum device (30), and the described vacuum device (30) is connected with the horizontal biaxial The reaction device (20) communicates.
The metformin hydrochloride continuous synthesis system according to claim 1, is characterized in that, described alcohol washing device (61) is also provided with gac inlet, and described aftertreatment unit (60) also comprises filtering device (64), and described filtering The device (64) is arranged on the transportation pipeline of the alcohol washing product.
A continuous synthesis method of metformin hydrochloride, characterized in that the device used in the continuous synthesis method of metformin hydrochloride is the continuous synthesis system of metformin hydrochloride according to any one of claims 1 to 6.