Purification device of N-methoxy-N-methylacetamide

Abstract

The utility model discloses a purification device of N-methoxy-N-methylacetamide, which adopts reduced pressure distillation in the whole process, a rectifying tower is internally provided with corrugated packing, the middle and the top of the rectifying tower are provided with liquid distribution plates, the rectifying tower is divided into two sections, and only the upper section is wrapped by a heat insulation sleeve; the liquid distribution plate is a device specially designed and specially used for purifying N-methoxy-N-methylacetamide; meanwhile, a fixed bracket can be used, and the joint of the fixed bracket and the liquid distribution plate is sealed by a polytetrafluoroethylene material; and the high-purity N-methoxy-N-methylacetamide is obtained from the product passing through the rectifying tower under the control of a rotor flow meter, a reflux ratio and vacuum, so that the production period is shortened, and the yield is improved.

Description

Technical Field

[0001] The utility model relates to the technical field of purification devices, in particular to a purification device for N-methoxy-N-methylacetamide. Background Art

[0002] N-methoxy-N-methylacetamide is a typical Weinreb amide with excellent biocompatibility and drug delivery properties, making it widely used in pharmaceutical formulation development. By binding it to drug molecules, it can enhance drug solubility and stability, thereby improving drug efficacy and reducing side effects. Furthermore, N-methoxy-N-methylacetamide can serve as a drug carrier, enabling targeted delivery and controlled release, enhancing therapeutic efficacy.

[0003] The synthesis of N-methoxy-N-methylacetamide consists of six main synthetic routes, depending on the starting materials used. In the prior art, after crude N-methoxy-N-methylacetamide is synthesized from hydroxylamine hydrochloride, methanol, ethyl acetate, potassium carbonate, dimethyl sulfate, sodium hydroxide, and dichloromethane, N-methoxy-N-methylacetamide is a liquid at atmospheric pressure. Therefore, it is difficult to purify using conventional purification processes such as filtration or crystallization. Rectification is used to separate various liquids, but previous studies have shown that conventional distillation processes cannot produce high-purity products and are time-consuming, making them unsuitable for large-scale production.

[0004] Therefore, there is an urgent need to design a new purification device for the purification process of N-methoxy-N-methylacetamide for large-scale production, while shortening the production cycle and improving product purity. Utility Model Content

[0005] In order to solve the above problems, the utility model provides a purification device for N-methoxy-N-methylacetamide, which adopts vacuum distillation throughout the process. Corrugated packing is arranged inside the distillation tower, and liquid distribution plates are arranged in the middle and the top. The product passing through the distillation tower is controlled by a rotor flowmeter, a reflux ratio and a vacuum to obtain high-purity N-methoxy-N-methylacetamide, and the time required for distillation can also be reduced.

[0006] On the one hand, the utility model provides a purification device for N-methoxy-N-methylacetamide, comprising a heating tank and a distillation tower, the top of the heating tank is connected to the bottom of the distillation tower, the distillation tower comprises an upper distillation tower and a lower distillation tower, the upper distillation tower and the lower distillation tower are both provided with corrugated packing, the bottom and top of the upper distillation tower are both provided with liquid distribution plates, and the liquid distribution plates are plates with evenly distributed small holes.

[0007] The liquid distribution plate is a special device specially designed for N-methoxy-N-methylacetamide. The liquid distribution plate is a plate with evenly distributed small holes. The pore size of the small holes is extremely small, so that the reflux liquid can be evenly retained on the corrugated packing.

[0008] In some embodiments, the pore size of the liquid distribution plate is 10 mm.

[0009] In some embodiments, the upper distillation column is wrapped with an insulation jacket.

[0010] Specifically, during the distillation process:

[0011] For the purpose of distinction, the liquid distribution plate at the top of the distillation tower is called the first liquid distribution plate, and the liquid distribution plate at the bottom of the distillation tower is called the second liquid distribution plate; after the organic vapor is evaporated from the heating tank, it first enters the lower distillation tower, part of the vapor is cooled or condensed and refluxed to the heating tank after heat exchange with the vapor above, and the other part of the vapor can rise to the bottom of the second liquid distribution plate. The small holes in the second liquid distribution plate allow the vapor to rise and the liquid to seep down at the same time. Under the pressure of the vapor, the liquid on the second liquid distribution plate can maintain a certain uniform liquid level height, can seep down evenly, and be evenly dispersed on the corrugated packing below. Uniform heating is beneficial to reduce the mixing of impurity vapor into the product vapor, which is beneficial to improving the purity of the product; similarly, the first liquid distribution plate can also play the role of uniform liquid and improving purity.

[0012] An insulation jacket is only installed outside the upper distillation tower. The insulation range of the insulation jacket is from the second liquid distribution plate to the first liquid distribution plate. The insulation jacket reduces heat loss and provides more precise heat exchange between steam and liquid. Therefore, with the insulation jacket, there are more impurities in the liquid above the second liquid distribution plate, while the product purity in the steam below the first liquid distribution plate is higher, thereby improving the purification effect.

[0013] In some embodiments, a fixed bracket is provided in the distillation tower, and the fixed bracket is fixed to the liquid distribution plate.

[0014] In some embodiments, a sealing component is provided at the location where the fixing bracket and the liquid distribution plate are fixed, and the sealing component includes a polytetrafluoroethylene gasket or a polytetrafluoroethylene film.

[0015] Polytetrafluoroethylene membranes can be obtained using existing spraying methods, coating methods, and electrophoretic deposition methods.

[0016] If the liquid distribution plate is directly welded to the inner wall, it will be easily damaged by the negative pressure of the vacuum pump and the rising steam from the heating tank; setting up a fixed bracket for support can prevent damage to the liquid distribution plate; further using polytetrafluoroethylene material for sealing can prevent leakage to the greatest extent, improve distillation efficiency, and significantly shorten the time required for distillation.

[0017] In some embodiments, the sealing component is a polytetrafluoroethylene film, and the thickness of the polytetrafluoroethylene film is greater than or equal to 0.5 mm.

[0018] In some embodiments, the corrugated packing is a 316 stainless steel corrugated packing, and the liquid distribution plate is made of 316 stainless steel.

[0019] In some embodiments, the heating tank and the distillation tower are made of 316 stainless steel.

[0020] In some embodiments, the purification device further includes a condenser, a rotor flowmeter, a collection tank, a buffer tank and a vacuum pump; the top of the distillation tower is connected to the condenser through a pipeline, and the condenser is connected to the rotor flowmeter through a pipeline; the rotor flowmeter is respectively connected to the distillation tower and the collection tank; the collection tank, the buffer tank and the vacuum pump are connected in sequence through pipelines.

[0021] In some embodiments, the condenser is made of 316 stainless steel, and the inner walls of the collecting tank and the buffer tank and the pipes connecting the collecting tank, the buffer tank and the vacuum pump are made of PP.

[0022] In some embodiments, the rotor flowmeter is made of glass.

[0023] Preferably, the utility model further optimizes the structure of the liquid distribution plate: the liquid distribution plate includes a top plate, a middle plate and a bottom plate, the first small hole diameter of the top plate is larger than the second small hole diameter of the middle plate, the second small hole diameter of the middle plate is larger than the third small hole diameter of the bottom plate; there are gaps between the top plate, the middle plate and the bottom plate.

[0024] The multi-layer structure and the design of different pore sizes can significantly increase the retention of liquid, and disperse it more evenly during the downward penetration process. The gap between the top plate and the middle plate is almost filled with liquid, and the gap between the middle plate and the bottom plate is almost filled with steam. The movement directions of steam and liquid are relative, so the heat exchange efficiency is significantly enhanced through convection, which can achieve higher product purity and significantly reduce the time required for distillation.

[0025] In some embodiments, the first small hole of the top plate has a diameter of 15 mm, the second small hole of the middle plate has a diameter of 10 mm, and the third small hole of the bottom plate has a diameter of 5 mm.

[0026] Preferably, the ratio of the height of the gap to the diameter of the distillation tower is 1:50.

[0027] The diameter of the distillation tower affects the liquid level of the retained liquid. The distillation effect is best when the liquid level is close to the height of the void. When the ratio of the void height to the diameter of the distillation tower is 1:50, the gap between the top plate and the middle plate is almost filled with liquid, and the gap between the middle plate and the bottom plate is almost filled with steam, which is more conducive to improving product purity and shortening distillation time.

[0028] Based on the optimized liquid distribution plate structure described above, alternative solutions using fixed brackets and PTFE seals can also be employed. For example: 1) using multiple fixed brackets with PTFE film sprayed at the junction between the brackets and each layer of liquid distribution plates; 2) using multiple fixed brackets with PTFE gaskets inserted between the brackets and each layer of liquid distribution plates. It is understood that adopting these solutions can further reduce distillation time and shorten production cycles.

[0029] The beneficial technical effects of the utility model are:

[0030] 1. The present invention provides a novel purification device for N-methoxy-N-methylacetamide. Different from the traditional purification process, the device of the present invention can obtain high-purity N-methoxy-N-methylacetamide with a purity of more than 99.8%. It can also shorten the distillation time by about 15%. Different from the existing gram-level laboratory synthesis process, the present device can also be expanded to large-scale production of kilograms and above.

[0031] 2. The liquid distribution plate is a special device specially designed for N-methoxy-N-methylacetamide. The application of liquid distribution plate and corrugated packing can improve the purity of the product; further combined with the insulation jacket that only wraps the upper distillation tower, the purity of the product can be significantly improved.

[0032] 3. Use a fixed bracket to support the liquid distribution plate, and spray polytetrafluoroethylene film at the connection between the fixed bracket and the liquid distribution plate to prevent leakage to the greatest extent and shorten the time required for distillation.

[0033] 4. The present invention further provides a more optimized liquid distribution plate structure. The multi-layer structure and the design of different pore sizes can significantly increase the retention of liquid, and the dispersion is more uniform during the downward penetration process. The gap between the top plate and the middle plate is almost filled with liquid, and the gap between the middle plate and the bottom plate is almost filled with steam. The movement directions of steam and liquid are relative, so the heat exchange efficiency is significantly enhanced through convection, higher product purity can be achieved, and the time required for distillation is significantly reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is an overall schematic diagram of the purification device for N-methoxy-N-methylacetamide of the utility model;

[0035] Figure 2 This is a schematic structural diagram of the liquid distribution plate of the present utility model;

[0036] Figure 3 This is a schematic structural diagram of a distillation tower including a fixed support according to the present invention;

[0037] Figure 4This is a schematic diagram of the partial structure of the improved liquid distribution plate of the present utility model.

[0038] Figure markings: 1-heating tank, 11-feed valve, 12-heating jacket, 13-descending stirring paddle, 14-first discharge valve, 2-distillation tower, 21-upper distillation tower, 22-lower distillation tower, 211-first liquid distribution plate, 2111-top plate, 2112-middle plate, 2113-bottom plate, 212-second liquid distribution plate, 213-insulation jacket, 2141-first fixed bracket, 2142-second fixed bracket, 3-first pipeline, 4-condenser, 41-circulating water inlet, 42-circulating water outlet, 5-rotor flowmeter, 51-second discharge valve, 52-second pipeline, 53-third pipeline, 6-collecting tank, 61-first control valve, 62-third discharge valve, 7-fourth pipeline, 8-buffer tank, 81-second control valve, 82-fourth discharge valve, 9-fifth pipeline, 10-vacuum pump. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with the accompanying drawings and embodiments. Identical components are denoted by the same reference numerals. It should be noted that the terms "front," "rear," "left," "right," "upper," and "lower" used in the following description refer to directions in the accompanying drawings, and the terms "bottom," "top," "inner," and "outer" refer to directions toward or away from the geometric center of a particular component, respectively. Example

[0040] like Figure 1 As shown, the purification device of N-methoxy-N-methylacetamide of the present invention includes a heating tank 1, a distillation tower 2, a condenser 4, a rotor flowmeter 5, a collection tank 6, a buffer tank 8, a vacuum pump 10 and pipelines connecting the above devices: a first pipeline 3 connecting the distillation tower 2 and the condenser 4, a second pipeline 52 connecting the rotor flowmeter 5 and the distillation tower 2, a third pipeline 53 connecting the rotor flowmeter 5 and the collection tank 6, a fourth pipeline 7 connecting the collection tank 6 and the buffer tank 8 and a fifth pipeline 9 connecting the buffer tank 8 and the vacuum pump 10.

[0041] First, the purification device of the present invention uses the principle of vacuum distillation. The entire equipment has good airtightness. The vacuum pump 10 can reduce the air pressure in the device and perform vacuum distillation to accelerate the purification rate.

[0042] The heating tank 1 includes a feed valve 11, a heating jacket 12, a descending stirring paddle 13 and a first discharge valve 14. The feed valve 11 is opened and controlled to feed the crude N-methoxy-N-methylacetamide solution into the heating tank 1 and control the feed rate; the heating jacket 12 heats the liquid in the heating tank 1, causing low-boiling point organic matter to evaporate, forming steam that enters the distillation tower 2; the stirring of the descending stirring paddle 13 can ensure the uniformity of the crude N-methoxy-N-methylacetamide solution, so that the various components inside it are evenly heated and evaporated; under normal circumstances, after a round of distillation is completed, the first discharge valve 14 is opened to discharge the remaining waste liquid in the heating tank 1.

[0043] The distillation tower 2 is divided into two sections, namely the upper distillation tower 21 at the top and the lower distillation tower 22 at the bottom. The heating tank 1 and the lower distillation tower 22 are connected by a flange. Both the upper distillation tower 21 and the lower distillation tower 22 are filled with 316 stainless steel corrugated packing. A first liquid distribution plate 211 is provided on the top of the upper distillation tower 21, and a second liquid distribution plate 212 is provided on the bottom of the upper distillation tower 21. The first liquid distribution plate 211 and the second liquid distribution plate 212 are respectively connected to the inner wall of the distillation tower 2 by welding. The structures of the first liquid distribution plate 211 and the second liquid distribution plate 212 are the same, as shown in FIG. Figure 2 As shown, it is a circular stainless steel plate with very small holes evenly distributed on it, the hole diameter is 10 mm, and the material is 316 stainless steel; an insulation sleeve 213 is provided on the outside of the upper distillation tower 21.

[0044] The distillation tower 2 is connected to the condenser 4 by a first pipe 3. The condenser 4 is provided with a circulating water inlet 41 and a circulating water outlet 42. The circulating water is used to condense the organic vapor, and the formed liquid flows downward to the rotor flowmeter 5. The rotor flowmeter 5 can set the reflux rate. A certain amount of liquid flows back to the distillation tower 2 through the second pipe 52. When the distillation is stable, the operator can open the second discharge valve and take samples to detect the purity. If the production requires higher purity, the reflux rate is increased and the production efficiency is reduced. On the contrary, if the required purity is higher than the product purity, the reflux rate can be reduced to speed up the production efficiency.

[0045] The collecting tank 6 includes a first control valve 61 and a third discharge valve 62. The first control valve 61 is opened by default when the device is running. Under the action of vacuum negative pressure, the product will enter the collecting tank 6 along the third pipe 53; when the collecting tank 6 is full, the first control valve 61 can be temporarily closed and the third discharge valve 62 can be opened to transfer the product inside the collecting tank 6.

[0046] Equipped with a buffer tank 8, it provides a buffering effect on the negative pressure of the vacuum pump 10, and the negative pressure is transmitted along the direction of the vacuum pump 10, the fifth pipeline 9, the buffer tank 8, the fourth pipeline 7 and the product tank 6; the buffer tank 8 includes a second control valve 81 and a fourth discharge valve 82. Similarly, when the device is running, the second control valve 81 is open by default. If the buffer tank 8 needs to be cleaned, the second control valve 81 is closed and the fourth discharge valve 82 is opened to discharge the liquid.

[0047] After the above operations were completed, the final product was sampled and tested in batches. After high performance liquid chromatography testing, the purity of N-methoxy-N-methylacetamide in all batches of products was ≥99.5%. Example

[0048] On the basis of the purification device of N-methoxy-N-methylacetamide of Example 1, as Figure 3 As shown, the interior of the distillation tower 2 is further provided with a first fixed bracket 2141 and a second fixed bracket 2142. The first fixed bracket 2141 and the second fixed bracket 2142 are both welded to the inner wall of the distillation tower 2, and are both made of 316 stainless steel; the first fixed bracket 2141 clamps the first liquid distribution plate 211 from the side, and the second fixed bracket 2142 similarly clamps the second liquid distribution plate 212 from the side, thereby playing a fixing role; the connection between the fixed bracket and the liquid distribution plate is sprayed with a polytetrafluoroethylene film with a thickness of 0.5 mm to prevent leakage.

[0049] The same steps and methods as in Example 1 were followed. After completion of the operation, the final product was sampled and tested in batches. HPLC analysis showed that the purity of N-methoxy-N-methylacetamide in all batches of products was ≥99.5%. At the same reflux ratio, the time required to fill the collection tank (i.e., collect the same volume of product) in this example was shortened by approximately 10% compared to that in Example 1, indicating that the fixed bracket and polytetrafluoroethylene seal improved the distillation efficiency by strictly preventing leakage. Example

[0050] Based on the purification device of N-methoxy-N-methylacetamide in Example 1, the structure of the first liquid distribution plate 211 is changed to the following: Figure 4 As shown, the multi-layer structure is shown. The second liquid distribution plate 212 has the same structure as the first liquid distribution plate 211. Taking the first liquid distribution plate 211 as an example, it is divided into three layers: the top plate 2111, which has evenly distributed first small holes with a diameter of 15 mm; the middle plate 2112, which has evenly distributed second small holes with a diameter of 10 mm; and the bottom plate 2113, which has evenly distributed third small holes with a diameter of 5 mm. There is a certain distance between the top plate 2111, the middle plate 2112, and the bottom plate 2113. Based on the scale of the distillation tower, the ratio of this distance to the distillation tower diameter is 1:50.

[0051] The same steps and methods as in Example 1 were followed, except that a multi-layer liquid distribution plate was used. After completion of the operation, the final product was sampled and tested in batches. High-performance liquid chromatography (HPLC) showed that the purity of N-methoxy-N-methylacetamide in all batches of product was ≥99.8%. At the same reflux ratio, the time required to fill the collection tank (i.e., collect the same volume of product) in this example was shortened by approximately 15% compared to Example 1. This indicates that the use of a liquid distribution plate with an optimized structure can improve distillation efficiency and product purity.

[0052] On this basis, if fixed brackets and polytetrafluoroethylene seals are used to strictly prevent leakage, the distillation time can be further reduced, which is conducive to shortening the production cycle.

[0053] The above description is merely a preferred embodiment of the present invention. The scope of protection of the present invention is not limited to the above embodiment. All technical solutions based on the concept of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, certain improvements and modifications that do not depart from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. A purification device for N-methoxy-N-methylacetamide, characterized in that: It includes a heating tank and a distillation tower. The top of the heating tank is connected to the bottom of the distillation tower. The distillation tower includes an upper distillation tower and a lower distillation tower. Corrugated packing is provided inside the upper distillation tower and the lower distillation tower. Liquid distribution plates are provided at the bottom and top of the upper distillation tower. The liquid distribution plates are plates with evenly distributed small holes.

2. The purification device according to claim 1, characterized in that: The upper distillation tower is wrapped with an insulation jacket.

3. The purification device according to claim 1, characterized in that: A fixed bracket is provided in the distillation tower, and the fixed bracket is fixed to the liquid distribution plate.

4. The purification device according to claim 3, characterized in that: A sealing component is provided at the fixing position of the fixing bracket and the liquid distribution plate, and the sealing component includes a polytetrafluoroethylene gasket or a polytetrafluoroethylene film.

5. The purification device according to claim 1, characterized in that: The corrugated packing is 316 stainless steel corrugated packing, and the liquid distribution plate is made of 316 stainless steel.

6. The purification device according to claim 1, characterized in that: The heating tank and distillation tower are made of 316 stainless steel.

7. The purification device according to claim 1, characterized in that: The purification device also includes a condenser, a rotor flowmeter, a collection tank, a buffer tank and a vacuum pump; the top of the distillation tower is connected to the condenser through a pipeline, and the condenser is connected to the rotor flowmeter through a pipeline; the rotor flowmeter is connected to the distillation tower and the collection tank respectively; the collection tank, the buffer tank and the vacuum pump are connected in sequence through pipelines.

8. The purification device according to claim 7, characterized in that: The condenser is made of 316 stainless steel, and the inner walls of the collecting tank and buffer tank and the pipes connecting the collecting tank, buffer tank and vacuum pump are made of PP material.

9. The purification device according to claim 7, characterized in that: The rotor flowmeter is made of glass.

10. The purification device according to claim 1, characterized in that: The liquid distribution plate includes a top plate, a middle plate and a bottom plate. The first small hole diameter of the top plate is larger than the second small hole diameter of the middle plate. The second small hole diameter of the middle plate is larger than the third small hole diameter of the bottom plate. There are gaps between the top plate, the middle plate and the bottom plate.

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