WO2023147729A1 - Système et procédé de synthèse continue de chlorhydrate de metformine - Google Patents

Système et procédé de synthèse continue de chlorhydrate de metformine Download PDF

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WO2023147729A1
WO2023147729A1 PCT/CN2022/123603 CN2022123603W WO2023147729A1 WO 2023147729 A1 WO2023147729 A1 WO 2023147729A1 CN 2022123603 W CN2022123603 W CN 2022123603W WO 2023147729 A1 WO2023147729 A1 WO 2023147729A1
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stirring
metformin hydrochloride
continuous
outlet
continuous synthesis
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PCT/CN2022/123603
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English (en)
Chinese (zh)
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洪浩
洪亮
陶建
陈富荣
王帆
戴睿智
张贺伟
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天津凯莱英医药科技发展有限公司
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Publication of WO2023147729A1 publication Critical patent/WO2023147729A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/18—Stationary reactors having moving elements inside
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B01J19/0013—Controlling the temperature of the process
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0053—Details of the reactor
    • B01J19/0066—Stirrers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines

Definitions

  • 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.
  • 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:
  • 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.
  • a solvent such as isoamyl alcohol, n-pentanol, n-hexanol and cyclohexanol, etc.
  • 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.
  • 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.
  • 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.
  • the stirring blade includes a first stirring blade and a second stirring blade
  • 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.
  • first acute angle and the second acute angle are independently selected from 1° to 15°.
  • 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.
  • 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.
  • 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.
  • 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.
  • metformin hydrochloride continuous synthesis system also includes a vacuum device, and the vacuum device communicates with the horizontal biaxial reaction device.
  • 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.
  • 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 alcohol washing device is also provided with an activated carbon inlet
  • the post-processing unit also includes a filter device, which is arranged on the alcohol washing product delivery pipeline.
  • 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.
  • 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.
  • the metformin hydrochloride continuous synthesis system 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.
  • 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.
  • 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 The third conveying device.
  • 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.
  • 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.
  • 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.
  • 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.
  • the first acute angle and the second acute angle are independently selected from 1° to 15°.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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 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.
  • the continuous discharge device 50 can select overflow discharge or direct discharge.
  • 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.
  • 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.
  • 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 .
  • 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 .
  • 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 .
  • the metformin hydrochloride continuous synthesis system further includes a temperature control device for controlling the temperature in the horizontal biaxial reaction device 20.
  • a temperature control device for controlling the temperature in the horizontal biaxial reaction device 20.
  • 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.
  • the temperature of the reactor can be controlled in stages according to the reaction process.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • the above-mentioned alcohol washing device 61 is a fully mixed flow reactor.
  • 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.
  • 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.
  • 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.
  • 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.
  • the amount of activated carbon added is 1/10 to 1/30 of the weight of dicyandiamide in the reaction raw materials.
  • 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.
  • the temperature control range of the temperature-controlled crystallization device 62 is -40-90°C, more preferably -20-80°C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • solvent-free method including melting method and first adding a small amount of solvent and then distilling under reduced pressure.
  • the amount of solvent used is added according to the standard of 1 g of dicyandiamide corresponding to 0-1 mL of reaction solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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°C.
  • 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.
  • 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.
  • the amount of activated carbon added is 1/10-1/30 of the weight of dicyandiamide in the reaction raw materials.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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 .
  • 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.
  • 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).

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Abstract

L'invention concerne un système de synthèse en continu de chlorhydrate de metformine. Le système de synthèse en continu de chlorhydrate de metformine comprend une unité d'alimentation continue (10) et un dispositif de réaction à double arbre horizontal (20). Le dispositif de réaction à double arbre horizontal (20) comprend un premier arbre d'agitation (22) et un second arbre d'agitation (23) qui peuvent tourner dans des directions opposées, des pales d'agitation du premier arbre d'agitation (22) et du second arbre d'agitation (23) qui se trouvent à des positions correspondantes venant en prise l'une avec l'autre, et le premier arbre d'agitation (22) comprenant un premier disque d'agitation (222) et des premières pales d'agitation (223), l'angle inclus entre un axe du premier disque d'agitation (222) et la première pale d'agitation (223) étant un angle aigu ; et le second arbre d'agitation (23) comprenant un second disque d'agitation (232) et des secondes pales d'agitation (233), l'angle inclus entre un axe du second disque d'agitation (232) et la seconde pale d'agitation (233) étant un angle aigu. Le chlorhydrate de metformine est préparé au moyen du dispositif de synthèse continue de sorte que le coût de production puisse être réduit, la période peut être raccourcie, la consommation de solvant et le risque de blocage de matériau solide peuvent être réduits, et la sécurité de l'ensemble d'un processus peut également être améliorée et le dispositif de synthèse continue est respectueux de l'environnement.
PCT/CN2022/123603 2022-02-07 2022-09-30 Système et procédé de synthèse continue de chlorhydrate de metformine WO2023147729A1 (fr)

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CN202210115447.8 2022-02-07
CN202210115447.8A CN114130348A (zh) 2022-02-07 2022-02-07 盐酸二甲双胍连续合成系统及连续化合成方法

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