A synthetic device for gadobutrol epoxy side chain

Abstract

The utility model belongs to chemical organic synthesis equipment technical field especially relates to a kind of synthesis device of gadobutrol epoxy side chain, including three-step synthesis device, first step device includes the first synthesis kettle, second distillation kettle, first condenser and first receiving kettle that are sequentially communicated, by first vacuum pump provides negative pressure;Second step device includes third synthesis kettle, second and third receiving kettle in parallel, and fourth drying kettle, filter, fifth recovery kettle, second condenser and fourth receiving kettle that are sequentially communicated, by second vacuum pump provides negative pressure;Third step device includes sixth distillation kettle, third condenser and fifth receiving kettle, by third vacuum pump provides negative pressure.The gadobutrol epoxy side chain of the present application is synthesized by three-step device, three-step device independently operates and can parallel operation, up to 3 batches of simultaneous production is realized by modular process design, the device can shorten production cycle, synthesis total time is reduced by 80% compared with conventional method, and production efficiency is improved.

Description

Technical Field

[0001] This utility model belongs to the technical field of chemical organic synthesis equipment, and specifically relates to a synthesis device for gadobutrol epoxy side chains. Background Technology

[0002] Gadobutrol Injection, marketed as Gadovist.

[0003] Gadovist is a gadolinium-based non-ionic contrast agent that can be administered intravenously and used in magnetic resonance imaging (MRI) examinations of the brain, spinal cord, and liver. In patients with central nervous system disorders, MRI provides contrast-enhanced images of the central nervous system to help detect and visualize lesions that disrupt the cell barrier, as well as abnormal blood supply and circulation within the central nervous system.

[0004] There are many existing technologies for synthesizing gadobutrol epoxy side chains. This invention relates to a synthesis apparatus for gadobutrol epoxy side chains, which uses butenediol and methoxypropane as the main raw materials to synthesize gadobutrol epoxy side chains. The synthesis apparatus is mature and stable, and the product yield and purity are high. The process is mature and suitable for industrial production. Utility Model Content

[0005] The purpose of this invention is to overcome the shortcomings of the existing technology and provide a synthesis apparatus for gadobutrol epoxy side chains. Using this synthesis apparatus, the process is advanced and reasonable, the product yield is high, the product purity is high, and the process is mature and stable.

[0006] The technical solution adopted by this utility model to solve its technical problem is: to provide a synthesis apparatus for gadobutrol epoxy side chains, comprising a three-step synthesis apparatus: the first step apparatus includes a first synthesis vessel, a second distillation vessel, a first receiving vessel, a first vacuum pump, and a first condenser; wherein:

[0007] The bottom discharge control valve of the first synthesis reactor is connected to the top feed control valve of the second distillation reactor; the top discharge control valve of the second distillation reactor is connected to the feed control valve of the first condenser; the discharge control valve of the first condenser is connected to the feed control valve of the first receiving reactor; another control valve at the top of the first receiving reactor is connected to the first vacuum pump.

[0008] The second-step apparatus includes a third synthesis vessel, a second receiving vessel, a third receiving vessel, a fourth drying vessel, a fifth recovery vessel, a fourth receiving vessel, a second vacuum pump, a second condenser, and a filter; wherein:

[0009] The bottom discharge control valve of the third synthesis reactor is connected to the second and third receiving reactors respectively; the discharge control valve of the third receiving reactor is connected to the top feed control valve of the fourth drying reactor; the bottom discharge control valve of the fourth drying reactor is connected to the filter feed control valve; the filter discharge control valve is connected to the top feed control valve of the fifth recovery reactor; the top discharge control valve of the fifth recovery reactor is connected to the second condenser feed control valve; the second condenser discharge control valve is connected to the fourth receiving reactor feed control valve; the top control valve of the fourth receiving reactor is connected to the second vacuum pump.

[0010] The third-step apparatus includes a sixth distillation vessel, a fifth receiving vessel, a third vacuum pump, and a third condenser; wherein:

[0011] The top discharge control valve of the sixth distillation vessel is connected to the feed control valve of the third condenser; the discharge control valve of the third condenser is connected to the feed control valve of the fifth receiving vessel; and the top control valve of the fifth receiving vessel is connected to the third vacuum pump.

[0012] Furthermore, the inner walls of the first synthesis vessel, the second distillation vessel, the third synthesis vessel, the fourth drying vessel, the fifth recovery vessel, and the sixth distillation vessel are all made of enamel material, and each vessel is equipped with a stirrer inside and an insulation jacket on the outside.

[0013] Furthermore, in the first step device, the first condenser is made of stainless steel; in the second step device, the second condenser is made of PP material; and in the third step device, the third condenser is made of stainless steel.

[0014] Furthermore, in the second step device, the top of the third synthesis reactor is provided with two high-level tanks, which are made of PP material.

[0015] Furthermore, in the second step device, the first receiving vessel, the second receiving vessel, the third receiving vessel, the fourth receiving vessel, and the filter are made of PP material.

[0016] Furthermore, the first receiving vessel, the fourth receiving vessel, and the fifth receiving vessel are all made of PP material.

[0017] Furthermore, in the second step device, the second condenser is made of PP material; the third condenser is made of stainless steel material.

[0018] Furthermore, in the second step device, the top of the third synthesis reactor is equipped with three control valves, two of which are connected to the first high-level tank and the second high-level tank respectively.

[0019] Furthermore, in the second step device, the bottom discharge control valve of the third synthesis reactor is connected to the second receiving reactor and the third receiving reactor respectively through a three-way valve.

[0020] Furthermore, the output pipes of the discharge control valves of the first and third condensers are equipped with rotor flow meters to control a certain reflux ratio.

[0021] This utility model has the following beneficial effects:

[0022] This invention designs the synthesis of gadobutrol epoxy side chain into three steps, thus enabling up to three batches of production to be carried out simultaneously, significantly improving production efficiency. In actual production, three batches of production can be carried out at the same time, and the total time in the gadobutrol epoxy side chain production test is reduced by 80% compared to conventional production. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the first step of the synthesis apparatus of the gadobutrol epoxy side chain synthesis apparatus of this utility model;

[0024] Figure 2 This is a schematic diagram of the second-step synthesis apparatus of the gadobutrol epoxy side chain synthesis apparatus of this utility model;

[0025] Figure 3 This is a schematic diagram of the third step of the synthesis apparatus of the gadobutrol epoxy side chain synthesis apparatus of this utility model.

[0026] The components in the attached diagram are labeled as follows:

[0027] 11. First synthesis vessel; 12. First stirrer; 13. Second distillation vessel; 14. Second stirrer; 15. First condenser; 16. First rotor flow meter; 17. First receiving vessel; 18. First vacuum pump; 20. First high-level tank; 21. Second high-level tank; 22. Third synthesis vessel; 23. Third stirrer; 24. Second receiving vessel; 25. Third receiving vessel; 26. Fourth drying vessel; 27. First stirrer; 28. Filter; 211. Fifth recovery vessel; 212. Fifth stirrer; 213. Second condenser; 214. Fourth receiving vessel; 215. Second vacuum pump; 31. Sixth distillation vessel; 33. Third condenser; 34. Second rotor flow meter; 35. Fifth receiving vessel; 36. Third vacuum pump. Detailed Implementation

[0028] The technical solutions of the present utility model will be clearly and completely described below with reference to the accompanying drawings of the embodiments. Obviously, the described embodiments are only some embodiments of the present utility model, and not all embodiments. Based on the embodiments of the present utility model, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present utility model.

[0029] This utility model patent relates to a synthesis apparatus for gadobutrol epoxy side chains. The apparatus comprises a three-step synthesis unit. The first step includes a synthesis vessel, a distillation vessel, a receiving vessel, and a vacuum pump. The bottom discharge control valve of the first reaction vessel 11 is connected to the top feed control valve of the second distillation vessel 13. The top discharge control valve of the second distillation vessel 13 is connected to the feed control valve of the first condenser 15. The discharge control valve of the first condenser 15 is connected to the feed control valve of the first receiving tank 17. Another control valve at the top of the first receiving tank 17 is connected to the first vacuum pump 18.

[0030] The second-step synthesis apparatus includes a synthesis vessel, a drying vessel, a recovery vessel, a receiving vessel, and a vacuum pump. The third synthesis vessel 22 has three control valves at its top. Two of these control valves are connected to two high-level tanks 20 and 21, respectively. The bottom discharge control valve of the third synthesis vessel 22 is connected to the second receiving vessel 24 and the third receiving vessel 25, respectively. The discharge control valve of the third receiving vessel 25 is connected to the top feed control valve of the fourth drying vessel 26. The bottom discharge control valve of the fourth drying vessel 26 is connected to the feed control valve of the filter 28. The discharge control valve of the filter 28 is connected to the top feed control valve of the fifth recovery vessel 211. The top discharge control valve of the fifth recovery vessel 211 is connected to the feed control valve of the second condenser 213. The discharge control valve of the second condenser 213 is connected to the feed control valve of the fourth receiving vessel 214. The other control valve at the top of the fourth receiving vessel 214 is connected to the second vacuum pump 215.

[0031] The third-step synthesis apparatus includes a distillation kettle, a condenser, a receiving kettle, and a vacuum pump. The top discharge control valve of the sixth distillation kettle 31 is connected to the feed control valve of the third condenser 33, the discharge control valve of the third condenser 33 is connected to the top feed control valve of the fifth receiving kettle 35, and another control valve at the top of the fifth receiving kettle 35 is connected to the third vacuum pump 36.

[0032] The synthesis process of gadobutrol epoxy side chain of this invention is as follows: First, butenediol and methoxypropane are used as main raw materials. Butenediol and methoxypropane are pumped sequentially into the first synthesis vessel 11, and stirring is started. During stirring, TSO is added to the synthesis vessel, stirring continues, and the heating system is activated to raise the internal temperature of the first synthesis vessel 11 to 120°C. The reaction is carried out for one hour, after which the reaction is complete. Then, the bottom discharge control valve of the first reaction vessel 11 is opened, allowing the reactants in the first reaction vessel 11 to enter the second distillation vessel 13 under the action of the pump. In the process, the water circulation vacuum pump is started to bring the entire distillation system to a certain vacuum level and slowly heat it, causing the material in the second distillation vessel 13 to boil and form steam. The steam is then condensed into liquid by the first condenser 15 at the top of the second distillation vessel 13. A certain reflux ratio is controlled by the rotor flow meter 16. After distillation for a period of time, a sample is taken from the discharge control valve of the first condenser 15 for testing. Once the purity of the gas phase test reaches 96% or higher, the sample is gradually separated into the first receiving vessel 17 until the crude product in the second distillation vessel 13 is completely distilled.

[0033] In the second step, a measured amount of the intermediate from the first step reaction is added to the third synthesis reactor 22. Acetonitrile and methanol are pumped sequentially into the third synthesis reactor 22. Then, an aqueous solution of disodium hydrogen phosphate is added to the third synthesis reactor 22, and stirring is started to heat the reactor to 50°C. At this point, hydrogen peroxide in high-level tank 20 and sodium hydroxide aqueous solution in high-level tank 21 are added dropwise, controlling the pH value in the third synthesis reactor 22 to be between 7 and 9.5, until the addition is complete. After the reaction is maintained at this temperature for 8 hours, heating is stopped, and the cooling system is activated to lower the temperature in the third synthesis reactor 22 to 20°C. After cooling, a saturated aqueous solution of sodium chloride and dichloromethane are added to the third synthesis reactor 22 while stirring. Stirring is stopped after 10 minutes, and the mixture separates into layers. Open the bottom control valve of the third synthesis vessel 22 and observe through the glass sight glass 29. The water layer flows into the second receiving tank 24, and the dichloromethane layer flows into the third receiving tank 25. The liquid in the third receiving tank 25 is pumped into the fourth drying vessel 26. Start stirring and add anhydrous sodium sulfate into the fourth drying vessel 26. Dry for 6 hours with stirring on. After drying, open the bottom discharge control valve of the fourth drying vessel 26 and the reaction flow in the vessel flows into the filter 28. The filtered reaction zone flows into the fifth recovery vessel 211. Start stirring, turn on the second condenser 213, and turn on the second vacuum pump 215 to start the atmospheric pressure distillation of dichloromethane. The temperature in the fifth recovery vessel 211 is controlled at 40°C until no liquid flows out.

[0034] The third step involves pumping the liquid from the fifth recovery vessel 211 into the sixth distillation vessel 31. A water-circulating vacuum pump is then activated to achieve a certain vacuum level in the entire distillation system, causing slow heating and boiling of the material in the sixth distillation vessel 31. This vapor is then condensed into liquid by the third condenser 33 at the top of the sixth distillation vessel 31. A certain reflux ratio is controlled by the second rotor flow meter 34. After distillation for a period of time, a sample is taken from the discharge control valve of the third condenser 33 for testing. Once the gas phase purity reaches 99.5% or higher, the sample is gradually transferred to the fifth receiving vessel 35 until all the product in the distillation vessels has been distilled.

[0035] The above description is merely a preferred embodiment of this utility model. The protection scope of this utility model is not limited to the above embodiments. All technical solutions falling within the scope of this utility model's concept are protected. It should be noted that for those skilled in the art, continuous updates and advancements made without departing from the principle of this utility model should also be considered within the protection scope of this utility model.

Claims

1. An apparatus for synthesizing gadobutrol epoxy side chains, characterized in that, The apparatus includes a three-step synthesis unit: the first step unit includes a first synthesis vessel (11), a second distillation vessel (13), a first receiving vessel (17), a first vacuum pump (18), and a first condenser (15); wherein: The bottom discharge control valve of the first synthesis vessel (11) is connected to the top feed control valve of the second distillation vessel (13); The top discharge control valve of the second distillation vessel (13) is connected to the feed control valve of the first condenser (15); The discharge control valve of the first condenser (15) is connected to the feed control valve of the first receiving vessel (17); The first receiving vessel (17) is connected to a first vacuum pump (18) via another control valve at its top; the second step device includes a third synthesis vessel (22), a second receiving vessel (24), a third receiving vessel (25), a fourth drying vessel (26), a fifth recovery vessel (211), a fourth receiving vessel (214), a second vacuum pump (215), a second condenser (213), and a filter (28); wherein: The bottom discharge control valve of the third synthesis reactor (22) is connected to the second receiving reactor (24) and the third receiving reactor (25) respectively. The discharge control valve of the third receiving vessel (25) is connected to the top feed control valve of the fourth drying vessel (26); The bottom discharge control valve of the fourth drying kettle (26) is connected to the feed control valve of the filter (28); The filter (28) discharge control valve is connected to the top feed control valve of the fifth recovery vessel (211); The top discharge control valve of the fifth recovery vessel (211) is connected to the feed control valve of the second condenser (213); The discharge control valve of the second condenser (213) is connected to the feed control valve of the fourth receiving vessel (214); The top control valve of the fourth receiving vessel (214) is connected to the second vacuum pump (215); the third-step device includes the sixth distillation vessel (31), the fifth receiving vessel (35), the third vacuum pump (36), and the third condenser (33); wherein: The top discharge control valve of the sixth distillation vessel (31) is connected to the feed control valve of the third condenser (33); The discharge control valve of the third condenser (33) is connected to the feed control valve of the fifth receiving vessel (35); The top control valve of the fifth receiving vessel (35) is connected to the third vacuum pump (36).

2. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: The inner walls of the first synthesis vessel (11), the second distillation vessel (13), the third synthesis vessel (22), the fourth drying vessel (26), the fifth recovery vessel (211), and the sixth distillation vessel (31) are all made of enamel material, and each vessel is equipped with a stirrer inside and a heat insulation jacket outside.

3. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the first step device, the first condenser (15) is made of stainless steel; In the second step device, the second condenser (213) is made of PP material. In the third step device, the third condenser (33) is made of stainless steel.

4. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the second step device, the top of the third synthesis reactor (22) is provided with two high-level tanks, which are made of PP material.

5. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the second step device, the first receiving vessel (17), the second receiving vessel (24), the third receiving vessel (25), the fourth receiving vessel (214) and the filter (28) are made of PP material.

6. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: The first receiving vessel (17), the fourth receiving vessel (214), and the fifth receiving vessel (35) are all made of PP material.

7. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the second step device, the second condenser (213) is made of PP material; the third condenser (33) is made of stainless steel.

8. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the second step device, the top of the third synthesis vessel (22) is equipped with three control valves, two of which are connected to the first high-level tank (20) and the second high-level tank (21) respectively.

9. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: In the second step device, the bottom discharge control valve of the third synthesis vessel (22) is connected to the second receiving vessel (24) and the third receiving vessel (25) respectively through a three-way valve.

10. The apparatus for synthesizing gadobutrol epoxy side chains according to claim 1, characterized in that: The discharge control valves of the first condenser (15) and the third condenser (33) are equipped with rotor flow meters to control a certain reflux ratio.

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