A method for producing sodium fusidate

Abstract

The present invention provides a method for producing sodium fusidate, comprising the following steps: 1) salt formation reaction; 2) reflux crystallization; 3) solid-liquid separation; 4) distillation recovery. The present invention ingeniously designs the production process route of sodium fusidate, using only a single organic solvent, and the organic solvent can be recycled for production by simple distillation recovery, with less consumption, simple recovery and low cost, and has more advantages in large-scale production and production cost than other preparation processes.

Description

Technical Field

[0001] The present invention relates to the field of methods for producing antibiotic drugs, and particularly to a method for producing sodium fusidate. Background Art

[0002] In 1962, Leo Pharmaceutical in Denmark first extracted fusidic acid from Lipomyces lipofer. Fusidic acid is an antibiotic with a steroid structure. It has been widely used abroad for nearly 50 years, accumulating a large amount of clinical experience, showing little drug resistance, and having a persistent and stable anti-infective activity.

[0003] Since fusidic acid is insoluble in water, its clinical use is somewhat restricted. However, sodium fusidate is soluble in water and lower alcohols and has been widely used clinically.

[0004] Currently, there are many related studies on the clinical use of sodium fusidate, opening up new prospects for its clinical use. However, there are few studies on how to prepare sodium fusidate, especially how to improve the yield, product quality, and reduce production costs, which are problems that need to be solved by production enterprises.

[0005] The structure of sodium fusidate is as follows:

[0006]

[0007] Chinese Patent CN112979739A discloses a method for a new crystal form of sodium fusidate, its preparation method and application: dissolving fusidic acid in a lower alcohol, reacting with sodium methoxide, and crystallizing with dichloromethane to prepare sodium fusidate.

[0008] Chinese Patent CN103214540A discloses a sodium fusidate crystal and its preparation method: dissolving fusidic acid in a lower alcohol, reacting with a sodium hydroxide solution, and crystallizing with ethyl acetate to prepare sodium fusidate.

[0009] Chinese Patent CN103012536A discloses a crystallization method for sodium fusidate: dissolving fusidic acid in a mixed solution of acetone and water, reacting with a sodium hydroxide solution, and adding a large amount of acetone dropwise to crystallize to obtain sodium fusidate.

[0010] The above several patents all dissolve fusidic acid in a water-soluble solvent or a mixed solvent thereof with water, then react with an alkali solution, and then add a water-insoluble solvent for mixed organic solvent crystallization to obtain sodium fusidate.

[0011] The above preparation processes all have the following disadvantages: water-soluble organic solvents are used, and at the same time water-insoluble organic solvents are used, and a mixed organic solvent phase is formed during the crystallization process; the amount of organic solvent used is large, and separation and recovery are difficult, resulting in inability to simply produce, recycle, and reuse, and high production costs. Summary of the Invention

[0012] The present invention provides a method for producing sodium fusidate, which solves the problems existing in the existing production methods of sodium fusidate, such as large consumption of organic solvents, difficult separation and recovery, and high cost.

[0013] The technical solution of the present invention is realized as follows:

[0014] A method for producing sodium fusidate includes the following steps:

[0015] 1) Salt formation reaction: Dissolve an inorganic base in water, add fusidic acid under stirring for salt formation reaction, and filter the reacted salt solution.

[0016] 2) Reflux crystallization: Add an organic solvent that can form an azeotrope with water to the filtered salt solution under stirring, reduce the pressure under stirring for heating. The reduced pressure is used to lower the boiling point. During the heating process, collect the steam formed by the azeotrope of the organic solvent and water and condense it. Let the condensed liquid stand for stratification to form an organic solvent layer and a water layer. The organic solvent layer refluxes to continue to azeotrope with water to carry out water removal, realizing cyclic azeotropic water removal. Drain the water layer. As the water content decreases, sodium fusidate crystals gradually precipitate. When the removed water reaches 90 - 98% of the total volume of water added in the salt formation reaction, stop heating, restore the pressure to normal pressure, and then carry out cooling crystallization.

[0017] 3) Solid-liquid separation: Carry out solid-liquid separation on the crystallization porridge formed by cooling crystallization to obtain wet sodium fusidate crystals and an organic solvent mother liquor. Dry the wet sodium fusidate crystals to obtain the finished product of sodium fusidate.

[0018] 4) Distillation and recovery: Heat the separated organic solvent mother liquor, distill under reduced pressure. The reduced pressure helps to lower the boiling point. Collect the steam formed by the azeotrope of the organic solvent and water and condense it. Let the condensed liquid stand for stratification, drain the water layer, retain the organic solvent layer, and recycle and reuse the organic solvent layer. After the heating is completed, restore the pressure to normal pressure.

[0019] Further, it includes the following steps:

[0020] 1) Salt formation reaction: Add water to the upper feeding port of the salt formation reaction tank, start the stirring device in the salt formation reaction tank, introduce a liquid medium for controlling temperature into the jacket on the outer side of the salt formation reaction tank, control the reaction temperature between 20 - 40 °C, add an alkali and then fusidic acid to the upper feeding port of the salt formation reaction tank until the reaction is complete and clear. Through the transfer pump connected to the bottom of the salt formation reaction tank, filter the salt solution through a liquid filter and then transport it to the reflux crystallization tank.

[0021] 2) Recrystallization by reflux: Start the solvent delivery pump to transfer the organic solvent from the solvent collection tank to the reflux crystallization tank. Start the stirring device in the reflux crystallization tank to stir, and start the vacuum pumping device to evacuate, reducing the air pressure in the reflux crystallization tank and lowering the boiling point. The vacuum degree ≤ -0.085 Mpa. Pass the heating medium into the jacket on the outer side of the reflux crystallization tank to heat the reflux crystallization tank. The steam generated by heating the liquid in the reflux crystallization tank is condensed into a liquid by the condenser and then enters the reflux and water separator. After standing and separating layers, an organic solvent layer and a water layer are formed. The upper organic solvent layer flows back to the reflux crystallization tank through the reflux pipe connected to the upper middle part of the reflux and water separator, and continues to azeotrope with the water in the reflux crystallization tank to carry out the removal of water, realizing cyclic azeotropic dehydration. The lower water layer is drained. As the water content decreases, sodium fusidate crystals gradually precipitate. When the removed water reaches 90 - 98% of the total volume of water added in the salt-forming reaction, stop heating, introduce nitrogen to restore the air pressure in the reflux crystallization tank to normal pressure, and pass the cooling medium into the jacket on the outer side of the reflux crystallization tank to cool down, forming a crystallization porridge;

[0022] 3) Solid-liquid separation: Send the crystallization porridge to a centrifuge or a filtration device for solid-liquid separation to obtain sodium fusidate wet crystals and the liquid mother liquor respectively. The sodium fusidate wet crystals are subsequently dried to become the finished product;

[0023] 4) Distillation and recovery: Start the vacuum pumping device to evacuate the mother liquor distillation tank. Under the action of atmospheric pressure, press the mother liquor from the centrifuge or filtration device into the mother liquor distillation tank through a pipeline. Vacuum pumping is also used to lower the boiling point. The vacuum degree ≤ -0.085 Mpa. Start the stirring device in the mother liquor distillation tank to stir, and pass the heating medium into the jacket on the outer side of the mother liquor distillation tank. The steam generated by heating in the mother liquor distillation tank is condensed into a liquid by the condenser and enters the solvent collection tank. After standing and separating layers, an organic solvent layer and a water layer are formed. Drain the water layer and retain the organic solvent layer. The retained organic solvent layer is re-transported to the reflux crystallization tank through the solvent delivery pump for recycling in the next batch of production. After the heating of the mother liquor distillation tank is completed, introduce nitrogen to restore the air pressure to normal pressure.

[0024] Further, in step 1), the inorganic base is one of sodium hydroxide, sodium carbonate or sodium bicarbonate.

[0025] Further, in step 1), the concentration of fusidic acid is 20 - 36%.

[0026] Further, in step 1), the equivalent ratio of sodium ions provided by the inorganic base to fusidic acid is 1.0:0.95 - 1.05.

[0027] Further, in step 1), the added water is purified water.

[0028] Further, in step 2), the amount of the added organic solvent is 6 - 15 times the weight of the charged fusidic acid.

[0029] Further, the organic solvent is one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, toluene, xylene, cyclohexane, and heptane.

[0030] Further, in step 3), the sodium fusidate dihydrate is vacuum dried at a temperature of 50 - 65°C and a vacuum degree of ≤ -0.085 Mpa.

[0031] Further, in step 3), the solid-liquid separation method is separation by a filter or a centrifuge.

[0032] Advantages of the present invention: The present invention ingeniously designs the production process route of sodium fusidate, uses only a single organic solvent, and the organic solvent can be recycled for production by simple distillation recovery. It has less consumption, simple recovery, and low cost, and has more advantages in scale and production cost than other preparation processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0034] Figure 1 It is a process flow chart of Example 1;

[0035] Figure 2 It is a structural schematic diagram of Example 5.

[0036] In the figure: 1. Salt-forming reaction tank; 2. Jacket I; 3. Stirring device I; 4. Liquid feeding port; 5. Solid feeding port; 6. Temperature measuring device I; 7. Control valve I; 8. Pipeline I; 9. Transfer pump; 10. Liquid filter; 11. Control valve II; 12. Backflow crystallization tank; 13. Stirring device II; 14. Jacket II; 15. Control valve III; 16. Pipeline III; 17. Centrifuge; 18. Pipeline IV; 19. Control valve IV; 20. Mother liquor distillation tank; 21. Jacket III; 22. Stirring device III; 23. Waste water control valve; 24. Steam pipe I; 25. Condenser I; 26. Solvent collection tank; 27. Sight glass; 28. Drain pipe I; 29. Drain control valve I; 30. Control valve V; 31. Circulation pipe; 32. Solvent transfer pump; 33. Liquid pressure gauge; 34. Control valve VI; 35. U-shaped water seal; 36. Steam pipe II; 37. Return pipe; 38. Return water separator; 39. Drain control valve II; 40. Waste water metering tank; 41. Drain control valve III; 42. Air pressure pipe; 43. Pressure control valve II; 44. Air pressure control valve I; 45. Vacuum main pipe; 46. Vacuum control valve; 47. Back pressure pipe; 48. Back pressure control valve; 49. Condenser II. Detailed implementation mode

[0037] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0038] Embodiment 1

[0039] Refer to Figure 1 , a method for producing sodium fusidate, comprising the following steps:

[0040] 1). Salt-forming reaction: Dissolve the inorganic base in water, add fusidic acid under stirring for salt-forming reaction, and filter the reacted salt-forming liquid;

[0041] 2) Recrystallization by reflux: The filtered salt-forming solution is added with an organic solvent under stirring. This organic solvent can form an azeotrope with water. While stirring, the pressure is reduced for heating. Reducing the pressure is used to lower the boiling point. During the heating process, the vapor formed by the azeotrope of the organic solvent and water is collected and condensed. The condensed liquid is allowed to stand and separate into layers, forming an organic solvent layer and a water layer. The organic solvent layer refluxes to continue to azeotrope with water to carry out water removal, realizing cyclic azeotropic water removal. The water layer is drained. As the water content decreases, sodium fusidate crystals gradually precipitate. When the removed water reaches 90 - 98% of the total volume of water added in the salt-forming reaction, heating is stopped, and the pressure is restored to normal pressure, and then cooling crystallization is carried out;

[0042] 3) Solid-liquid separation: The crystallization porridge formed by cooling crystallization is subjected to solid-liquid separation to obtain wet sodium fusidate crystals and an organic solvent mother liquor. The wet sodium fusidate crystals are dried to obtain the finished product of sodium fusidate salt;

[0043] 4) Distillation and recovery: The separated organic solvent mother liquor is heated, and the pressure is reduced for distillation. Reducing the pressure helps to lower the boiling point. The vapor formed by the azeotrope of the organic solvent and water is collected and condensed. The condensed liquid is allowed to stand and separate into layers, the water layer is drained, and the organic solvent layer is retained. The organic solvent layer is recycled for reuse. After the heating is completed, the pressure is restored to normal pressure.

[0044] Further, in step 1), the inorganic base is one of sodium hydroxide, sodium carbonate, or sodium bicarbonate. The concentration of fusidic acid is 20 - 36%. The equivalent ratio of sodium ions provided by the inorganic base to fusidic acid is 1.0:0.95 - 1.05. The added water is purified water.

[0045] Further, the amount of the organic solvent added in step 2) is 6 - 15 times the weight of the added fusidic acid. The organic solvent is one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, toluene, xylene, cyclohexane, or heptane.

[0046] Further, in step 3), the wet sodium fusidate crystals are dried under vacuum. The vacuum drying temperature is 50 - 65°C, and the vacuum degree ≤ -0.085 Mpa.

[0047] Further, in step 3), the solid-liquid separation method uses a centrifuge for separation.

[0048] Example 2

[0049] The difference between this example and Example 1 is that in step 3), the solid-liquid separation method uses a filter for separation.

[0050] Further, the filter includes a filter membrane with a pore size of 0.5 microns to realize the separation of wet sodium fusidate crystals and the organic solvent mother liquor.

[0051] Example 3

[0052] A method for producing sodium fusidic acid comprises the following steps:

[0053] 1) Salt-forming reaction: add water to the feeding port at the upper end of the salt-forming reaction tank, start the stirring device in the salt-forming reaction tank, pass the temperature-controlled liquid medium into the jacket on the outer side of the salt-forming reaction tank, control the reaction temperature between 20-40°C, add alkali to the feeding port at the upper end of the salt-forming reaction tank, and then add fusidic acid until the reaction is complete and clear, and filter the salt-forming liquid through the liquid filter through the transfer pump connected to the bottom of the salt-forming reaction tank and then transport it to the reflux crystallization tank;

[0054] 2) Reflux crystallization: Start the solvent delivery pump to deliver the organic solvent from the solvent collection tank to the reflux crystallization tank, start the stirring device in the reflux crystallization tank for stirring, start the vacuum device for vacuuming, reduce the air pressure in the reflux crystallization tank, reduce the boiling point, the vacuum degree is ≤-0.085Mpa, and pass the heating medium into the jacket on the outer side of the reflux crystallization tank to heat the reflux crystallization tank. The steam generated by the heating of the liquid in the reflux crystallization tank is condensed into liquid through the condenser and then enters the reflux water separator, and is allowed to stand and stratify to form an organic solvent. The organic solvent layer on the upper layer is refluxed into the reflux crystallizer through the reflux pipe connected to the upper and middle part of the reflux water separator, and continues to azeotropically remove water with the water in the reflux crystallizer to achieve cyclic azeotropic water removal, and the water in the lower layer is discharged. As the water content decreases, sodium fusidate crystals are gradually formed and precipitated, until the removed water is 90-98% of the total volume of water added for the salt-forming reaction, the heating is stopped, nitrogen is introduced to restore the air pressure in the reflux crystallizer to normal pressure, and a cooling medium is introduced into the jacket on the outer side of the reflux crystallizer to cool it down to form a crystal porridge;

[0055] 3) Solid-liquid separation: the crystal porridge is sent to a centrifuge for centrifugation to separate the solid and the liquid, and the fusidic acid sodium salt tidal crystals and the liquid mother liquor are obtained respectively. The fusidic acid sodium salt tidal crystals are subsequently dried to become the finished product;

[0056] 4) Distillation recovery: Start the vacuum device to vacuum the mother liquor distillation tank, and press the mother liquor in the centrifuge into the mother liquor distillation tank through the pipeline under the action of atmospheric pressure. Vacuuming is also used to reduce the boiling point, and the vacuum degree is ≤-0.085Mpa. Start the stirring device in the mother liquor distillation tank for stirring, and pass the heating medium into the jacket on the outer side of the mother liquor distillation tank. The steam generated by the heating in the mother liquor distillation tank is condensed into liquid through the condenser and enters the solvent collection tank. Let it stand and stratify to form an organic solvent layer and a water layer. The water layer is drained and the organic solvent layer is retained. The retained organic solvent layer is re-transported to the reflux crystallization tank through the solvent delivery pump for recycling in the next batch of production. After the heating of the mother liquor distillation tank is completed, nitrogen is introduced to restore the air pressure to normal pressure.

[0057] Further, in step 1), the inorganic base is one of sodium hydroxide, sodium carbonate or sodium bicarbonate, the concentration of fusidic acid is 20-36%, the equivalent ratio of sodium ions provided by the inorganic base to fusidic acid is 1.0:0.95-1.05, and the added water is purified water.

[0058] Further, the amount of the organic solvent added in step 2) is 6-15 times the weight of the added fusidic acid, and the organic solvent is one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, toluene, xylene, cyclohexane, heptane.

[0059] Further, in step 3), the sodium fusidate tide crystal is vacuum dried, the vacuum drying temperature is 50-65 °C, and the vacuum degree ≤ -0.085 Mpa.

[0060] The present invention ingeniously designs the production process route of sodium fusidate, only uses a single organic solvent, and the organic solvent can be recycled for production only by simple distillation recovery. It has less consumption, simple recovery and low cost, and has more advantages in scale and production cost than other preparation processes.

[0061] Example 4

[0062] The difference between this example and Example 3 is that a filtration device with a 5-micron pore size filter membrane is used instead of a centrifuge to separate the sodium fusidate tide crystal and the organic solvent mother liquor. The separated organic solvent mother liquor is also pressed into the mother liquor distillation tank when the mother liquor distillation tank is evacuated.

[0063] Example 5

[0064] Refer to Figure 2, in order to implement the production method of sodium fusidate in Example 1 and Example 3, this example proposes a production device for sodium fusidate, including a salt-forming reaction tank 1, a transfer pump 9, a liquid filter 10, a reflux crystallization tank 12, a centrifuge 17, a mother liquor distillation tank 20, a solvent collection tank 26, a solvent transfer pump 32, and a reflux water separator 38; the upper part of the salt-forming reaction tank 1 includes a feeding port I, the outer peripheral side is wrapped with a jacket I 2 for introducing a medium to adjust the temperature, the bottom has a discharging port I, and the inside of the salt-forming reaction tank 1 includes a stirring device I 3; the upper part of the reflux crystallization tank 12 includes a feeding port II, a solvent circulation inlet, a vapor outlet I, and a reflux inlet, the outer peripheral side is wrapped with a jacket II 14 for introducing a medium to adjust the temperature, the bottom includes a discharging port II, and the inside of the reflux crystallization tank 12 includes a stirring device II 13; the discharging port I and the feeding port II are connected by a pipeline I 8, and a control valve I 7, a transfer pump 9, a liquid filter 10, and a control valve II 11 are sequentially connected on the pipeline I 8; the centrifuge 17 includes a feeding port III and a liquid outlet; the discharging port II and the feeding port III are connected by a pipeline III 16, and a control valve III 15 is connected on the pipeline III 16; the upper part of the mother liquor distillation tank 20 includes a feeding port IV and a vapor outlet II, the bottom includes a wastewater discharge port, the outer peripheral side is wrapped with a jacket III 21 for introducing a medium to adjust the temperature, and the inside of the mother liquor distillation tank 20 includes a stirring device III 22; the liquid outlet and the feeding port IV are connected by a pipeline IV 18, and a control valve IV 19 is connected on the pipeline IV 18, and the wastewater discharge port is connected with a wastewater control valve 23; the upper part of the solvent collection tank 26 includes a liquid inlet I, and the bottom includes a discharging port V; the upper part of the mother liquor distillation tank 20 and / or the solvent collection tank 26 includes a pressure port I, the pressure port I is connected with a pressure control valve I 44, and a pressure pipe 42 is connected to the pressure control valve I; the vapor outlet II and the liquid inlet I are connected by a steam pipe I 24, and a condenser I 25 is connected on the steam pipe I 24; the discharging port V is connected with a drain pipe I 28 and a circulation pipe 31, the drain pipe I 28 is connected with a drain control valve I 29, the other end of the circulation pipe 31 is connected with the solvent circulation inlet, and a control valve V 30, a solvent transfer pump 32, and a control valve VI 34 are sequentially connected on the circulation pipe 31; the upper part of the reflux water separator 38 includes a liquid inlet II, the bottom includes a drain port, and the middle upper part of the side has a reflux outlet; the vapor outlet I and the liquid inlet II are connected by a steam pipe II 36, the steam pipe II 36 is connected with a condenser II 49, the drain port is connected with a drain control valve II 39, and the reflux outlet is connected with the reflux inlet through a reflux pipe 37; the top of the reflux water separator 38 and / or the reflux crystallization tank 12 includes a pressure port II, the pressure port II is connected with a pressure control valve II 43, and a pressure pipe 42 is connected to the pressure control valve II; the pressure pipe 42 is connected with a vacuum main pipe 45 for vacuum pumping and a back pressure pipe 47 for intake back pressure, a vacuum control valve 46 is connected on the vacuum main pipe 45, and a back pressure control valve 48 is connected on the back pressure pipe 47.

[0065] Furthermore, a temperature measuring device I6 for measuring temperature is further included in the salt-forming reaction tank 1.

[0066] Furthermore, temperature measuring devices II for measuring temperature are included in both the reflux crystallization tank 12 and the mother liquor distillation tank 20. A gas pressure gauge is also connected to the reflux crystallization tank 12 and the mother liquor distillation tank 20, and a liquid pressure gauge 33 is connected to the circulation pipe 31.

[0067] Furthermore, the drain control valve II39 is connected to a waste water metering tank 40, and a drain control valve III41 is connected to the bottom of the waste water metering tank 40.

[0068] Furthermore, the reflux pipe 37 includes a U-shaped water seal 35.

[0069] Furthermore, sight glasses 27 for observation are included on the reflux pipe 37, between the drain outlet and the drain control valve II39, and on the drain pipe I28.

[0070] Furthermore, the feeding port I includes a liquid feeding port 4 and a solid feeding port 5.

[0071] Furthermore, the jacket I2 includes an inlet I and an outlet I, the jacket II14 includes an inlet II and an outlet II, and the jacket III21 includes an inlet III and an outlet III.

[0072] Furthermore, the stirring device I3 includes a stirring motor I, a speed reducer I, a stirring shaft I, and stirring blades I. One end of the stirring shaft I is located inside the salt-forming reaction tank 1 and stirring blades I are fixedly connected to the side surface. One end of the stirring shaft I is located outside the salt-forming reaction tank 1 and is drivingly connected to the stirring motor I through the speed reducer I; the jacket II13 includes an inlet II and an outlet II, the stirring device II includes a stirring motor II, a speed reducer II, a stirring shaft II, and stirring blades II. One end of the stirring shaft II is located inside the salt-forming reaction tank 1 and stirring blades II are fixedly connected to the side surface. One end of the stirring shaft II is located outside the salt-forming reaction tank 1 and is drivingly connected to the stirring motor II through the speed reducer II; the jacket III22 includes an inlet III and an outlet III, the stirring device III includes a stirring motor III, a speed reducer III, a stirring shaft III, and stirring blades III. One end of the stirring shaft III is located inside the salt-forming reaction tank 1 and stirring blades III are fixedly connected to the side surface. One end of the stirring shaft III is located outside the salt-forming reaction tank 1 and is drivingly connected to the stirring motor III through the speed reducer III.

[0073] Furthermore, the control valve I7, control valve II11, control valve III15, control valve IV19, control valve V30, control valve VI34, pneumatic control valve I44, pneumatic control valve II43, drain control valve I29, drain control valve II39, vacuum control valve 46, and back pressure control valve 48 are all automatic control valves.

[0074] Working principle of the present invention:

[0075] Purified water is added through the liquid feeding port 4, the stirring device I3 is started, cooling water is introduced into the inlet I of the jacket I2, alkali is added through the solid feeding port 5, and then fusidic acid is added until the reaction is complete and clear; the control valve I7 and the control valve II11 are opened, the transfer pump 9 is started, and the salt-forming solution is transported to the reflux crystallization tank 12. The control valve V30 and the control valve VI34 are opened, and the solvent delivery pump 32 is started to transport the organic solvent from the solvent collection tank 26 (the solvent collection tank has previously stored the organic solvent) to the reflux crystallization tank 12. The stirring device II13 is started for stirring. The vacuum main pipe 45 is connected to a vacuum device. The vacuum control valve 46 and the air pressure control valve II43 are opened, and the vacuum device is started to evacuate, reducing the air pressure in the reflux crystallization tank 12, lowering the boiling point, saving the energy required for heating, and saving costs. The vacuum degree is controlled ≤ -0.085 Mpa. Hot water circulation heating is introduced into the inlet II of the jacket II14 to heat the reflux crystallization tank 12. The steam generated by heating the liquid in the reflux crystallization tank 12 is condensed into a liquid by the condenser II49 and then enters the reflux water separator 38. The condensed liquid in the reflux water separator 38 includes the organic solvent and water. The organic solvent is on the upper layer and the water is on the lower layer. The organic solvent on the upper layer enters the reflux crystallization tank 12 through the reflux pipe 37, and the water on the lower layer is discharged into the waste water metering tank 40 for metering through the drain control valve II39. After the heating is completed, the back pressure control valve 48 and the air pressure control valve II43 are opened, and nitrogen is introduced through the back pressure pipe 47 to return to normal air pressure for cooling crystallization. Cold water circulation cooling is introduced into the inlet II of the jacket II14. After the cooling crystallization is completed, the control valve III15 is opened, and the crystal porridge is discharged into the centrifuge 17 for centrifugation to separate the solid and the liquid, respectively obtaining the wet crystal of sodium fusidate and the liquid mother liquor. The wet crystal of sodium fusidate is subsequently dried in vacuo to become the finished product; the air pressure control valve I44 is opened, and the vacuum device is started to evacuate. Under the action of atmospheric pressure, the mother liquor in the centrifuge 17 is pressed into the mother liquor distillation tank 20 through the pipeline IV18. And evacuating can reduce the air pressure in the mother liquor distillation tank 20, lower the boiling point, save the energy required for heating, and save costs. The vacuum degree is controlled ≤ -0.085 Mpa. The stirring device III22 is started for stirring. Hot water circulation heating is introduced into the inlet III of the jacket III21. The steam generated by heating is condensed into a liquid by the condenser I25 and enters the solvent collection tank 26. The condensed liquid includes the organic solvent and water. After standing, the organic solvent is on the upper layer and the water is on the lower layer. The waste water layer is drained by standing, and the drain control valve I29 is opened to drain the water on the lower layer through the drain pipe I28, leaving the organic solvent on the upper layer. The recovered organic solvent is re-transported to the reflux crystallization tank 12 through the solvent delivery pump 32 for recycling in the next batch of production. After the heating of the mother liquor distillation tank 20 is completed, the back pressure control valve 48 and the air pressure control valve I44 are opened, and nitrogen is introduced through the back pressure pipe 47 to return to normal air pressure.

[0076] This device can effectively recover the solvent and recycle it, without consuming the solvent, and has low cost. When the reflux crystallization tank and the mother liquor distillation tank are heating, a certain degree of vacuum pumping is carried out on the reflux crystallization tank and the mother liquor distillation tank through the main vacuum pipe, which can reduce the boiling point, save the energy required for heating, save costs. After the heating work is completed, nitrogen is filled through the back-pressure pipe to return to normal atmospheric pressure.

[0077] Example 6

[0078] To match the production methods of sodium fusidate in Example 2 and Example 4, this example proposes a production device for sodium fusidate. The difference between this example and Example 5 is that a filtering device with a 5-micron pore size filter membrane is used instead of a centrifuge to separate the sodium fusidate wet crystals and the organic solvent mother liquor. The separated organic solvent mother liquor is also pressed into the mother liquor distillation tank when the mother liquor distillation tank is under vacuum, and the other parts are the same.

[0079] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A production method of sodium fusidate, characterized in that, it comprises the following steps: 1), salt formation reaction: Dissolve an inorganic base in water, add fusidic acid under stirring for salt formation reaction, and filter the reacted salt formation solution; 2), reflux crystallization: Add an organic solvent to the filtered salt formation solution under stirring. The organic solvent can form an azeotrope with water. Heat under reduced pressure under stirring. Reducing the pressure helps to lower the boiling point. During the heating process, collect the vapor formed by the azeotrope of the organic solvent and water and condense it. Let the condensed liquid stand and separate into an organic solvent layer and an aqueous layer. The organic solvent layer refluxes to continue to azeotrope with water to carry out water removal, realizing cyclic azeotropic water removal. Drain the aqueous layer. As the water content decreases, sodium fusidate crystals gradually precipitate out. Stop heating until the removed water is 90-98% of the total volume of water added in the salt formation reaction. Restore the atmospheric pressure, and then carry out cooling crystallization; 3), solid-liquid separation: Carry out solid-liquid separation on the crystallization porridge formed by cooling crystallization to obtain wet sodium fusidate crystals and an organic solvent mother liquor. Dry the wet sodium fusidate crystals to obtain the finished product of sodium fusidate; 4), distillation recovery: Heat the separated organic solvent mother liquor, distill under reduced pressure. Reducing the pressure helps to lower the boiling point. Collect the vapor formed by the azeotrope of the organic solvent and water and condense it. Let the condensed liquid stand and separate. Drain the aqueous layer and retain the organic solvent layer. The organic solvent layer is recovered and recycled. After the heating is completed, restore the atmospheric pressure.

2. The production method of sodium fusidate according to claim 1, characterized in that, 1), salt formation reaction: Add water to the upper feeding port of the salt formation reaction tank, start the stirring device in the salt formation reaction tank, introduce a liquid medium for controlling the temperature into the jacket on the outer side of the salt formation reaction tank, control the reaction temperature between 20-40°C, add an alkali to the upper feeding port of the salt formation reaction tank, and then add fusidic acid until the reaction is complete and clear. Through the transfer pump connected to the bottom of the salt formation reaction tank, filter the salt formation solution through a liquid filter and then transport it to the reflux crystallization tank; 2) Recrystallization by reflux: Start the solvent delivery pump to transfer the organic solvent from the solvent collection tank to the reflux crystallization tank. Start the stirring device in the reflux crystallization tank to stir, and start the vacuum pumping device to evacuate, reducing the air pressure in the reflux crystallization tank and lowering the boiling point. The vacuum degree ≤ -0.085 Mpa. Pass the heating medium into the jacket on the outer side of the reflux crystallization tank to heat the reflux crystallization tank. The steam generated by heating the liquid in the reflux crystallization tank is condensed into liquid by the condenser and then enters the reflux water separator. After standing and separating, an organic solvent layer and a water layer are formed. The upper organic solvent layer returns to the reflux crystallization tank through the reflux pipe connected to the upper middle part of the reflux water separator, and continues to azeotrope with the water in the reflux crystallization tank to carry out the water removal, realizing the cyclic azeotropic water removal. The lower water layer is drained. As the water content decreases, sodium fusidate crystals gradually precipitate. When the removed water reaches 90 - 98% of the total volume of water added in the salt formation reaction, stop heating, introduce nitrogen to restore the air pressure in the reflux crystallization tank to normal pressure, and pass the cooling medium into the jacket on the outer side of the reflux crystallization tank to cool down to form a crystallization porridge; 3) Solid-liquid separation: Send the crystallization porridge to a centrifuge or a filtration device for solid-liquid separation to obtain sodium fusidate wet crystals and liquid mother liquor respectively. The sodium fusidate wet crystals are subsequently dried to become the finished product; 4) Distillation and recovery: Start the vacuum pumping device to evacuate the mother liquor distillation tank. Under the action of atmospheric pressure, the mother liquor from the centrifuge or the filtration device is pressed into the mother liquor distillation tank through a pipeline. Vacuum pumping is also used to lower the boiling point. The vacuum degree ≤ -0.085 Mpa. Start the stirring device in the mother liquor distillation tank to stir, and pass the heating medium into the jacket on the outer side of the mother liquor distillation tank. The steam generated by heating in the mother liquor distillation tank is condensed into liquid by the condenser and enters the solvent collection tank. After standing and separating, an organic solvent layer and a water layer are formed. Drain the water layer and retain the organic solvent layer. The retained organic solvent layer is re-transported to the reflux crystallization tank through the solvent delivery pump for recycling in the next batch of production. After the heating of the mother liquor distillation tank is completed, introduce nitrogen to restore the air pressure to normal pressure.

3. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, in step 1), the inorganic base is one of sodium hydroxide, sodium carbonate or sodium bicarbonate.

4. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, in step 1), the concentration of fusidic acid is 20 - 36%.

5. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, in step 1), the equivalent ratio of sodium ions provided by the inorganic base to fusidic acid is 1.0:0.95 - 1.

05.

6. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, in step 1), the added water is purified water.

7. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, in step 2), the amount of organic solvent added is 6 - 15 times the weight of the added fusidic acid.

8. The production method of sodium fusidate salt as described in claim 1 or 2, characterized in that, The organic solvent is one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, toluene, xylene, cyclohexane, and heptane.

9. The production method of sodium fusidate according to claim 1 or 2, characterized in that, in step 3), the sodium fusidate tide crystal is vacuum dried, and the vacuum drying temperature is 50-65°C, and the vacuum degree ≤ -0.085 Mpa.

10. The production method of sodium fusidate according to claim 1, characterized in that, in step 3), the solid-liquid separation method is separation by a filter or a centrifuge.

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